Publications by authors named "Nicole Skoetz"

88 Publications

"The system has to be health literate, too" - perspectives among healthcare professionals on health literacy in transcultural treatment settings.

BMC Health Serv Res 2021 Jul 21;21(1):716. Epub 2021 Jul 21.

Cologne Center for Ethics, Rights, Economics, and Social Sciences of Health (CERES), University of Cologne and Research Unit Ethics, Faculty of Medicine and University Hospital Cologne, 50931, Cologne, Germany.

Background: Effective communication is a central aspect of organizational health literacy. Healthcare professionals are expected to ensure an effective and satisfactory flow of information and to support their patients in accessing, understanding, appraising, and applying health information. This qualitative study aimed to examine the health literacy-related challenges, needs, and applied solutions of healthcare professionals when engaging with persons with a migrant background. Based on the integrated model of health literacy (Sørensen et al., BMC Public Health 12:80, 2012), we focused on environmental, personal, and situational factors that shape health literacy in transcultural treatment settings.

Methods: We conducted five focus group discussions with healthcare professionals (N = 31) who are in regular contact with persons with a migrant background. Discussions were transcribed verbatim and analyzed using qualitative content analysis by applying a deductive-inductive categorization procedure. Deductive categories were derived from the integrated model of health literacy.

Results: Challenges included a mismatch in the provision and use of health services. Participants regarded easily accessible services and outreach counselling as helpful solutions. Further challenges were the migrant patients' distrust in healthcare professionals and the German healthcare system, the participants' uncertainty in dealing with patients' expectations and needs, and the patients' non-compliance with appointments. Environmental factors included systemic lack of time and economic pressure. Both were reported as impeding the flow of information in all treatment settings. Participants with a migrant background themselves (n = 16) regarded this personal factor as an opportunity that increased patients' trust in them. They also reported challenges such as high levels of responsibility felt when ad hoc interpreting for colleagues.

Conclusions: Known issues observed in the delivery of healthcare for the majority population (i.e., systemic lack of time, economic pressure) appear to be intensified in the context of migration. An increasingly diverse patient clientele indicates a growing need for culture-sensitive, health-literate healthcare organizations. A corresponding diversity of the health workforce is desirable and should be strengthened by national finance and educational programs. Healthcare professionals who interpret for colleagues should be given the necessary time. Further studies are needed to develop appropriate interventions for improving health literacy at individual and organizational levels. Funding for interpreting services should be expanded.
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http://dx.doi.org/10.1186/s12913-021-06614-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8293586PMC
July 2021

Key summary of German national treatment guidance for hospitalized COVID-19 patients Key pharmacologic recommendations from a national German living guideline using an Evidence to Decision Framework (last updated 17.05.2021).

Infection 2021 Jul 6. Epub 2021 Jul 6.

Department of Intensive Care, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Purpose: This executive summary of a national living guideline aims to provide rapid evidence based recommendations on the role of drug interventions in the treatment of hospitalized patients with COVID-19.

Methods: The guideline makes use of a systematic assessment and decision process using an evidence to decision framework (GRADE) as recommended standard WHO (2021). Recommendations are consented by an interdisciplinary panel. Evidence analysis and interpretation is supported by the CEOsys project providing extensive literature searches and living (meta-) analyses. For this executive summary, selected key recommendations on drug therapy are presented including the quality of the evidence and rationale for the level of recommendation.

Results: The guideline contains 11 key recommendations for COVID-19 drug therapy, eight of which are based on systematic review and/or meta-analysis, while three recommendations represent consensus expert opinion. Based on current evidence, the panel makes strong recommendations for corticosteroids (WHO scale 5-9) and prophylactic anticoagulation (all hospitalized patients with COVID-19) as standard of care. Intensified anticoagulation may be considered for patients with additional risk factors for venous thromboembolisms (VTE) and a low bleeding risk. The IL-6 antagonist tocilizumab may be added in case of high supplemental oxygen requirement and progressive disease (WHO scale 5-6). Treatment with nMABs may be considered for selected inpatients with an early SARS-CoV-2 infection that are not hospitalized for COVID-19. Convalescent plasma, azithromycin, ivermectin or vitamin D should not be used in COVID-19 routine care.

Conclusion: For COVID-19 drug therapy, there are several options that are sufficiently supported by evidence. The living guidance will be updated as new evidence emerges.
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http://dx.doi.org/10.1007/s15010-021-01645-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8259552PMC
July 2021

Vitamin D supplementation for the treatment of COVID-19: a living systematic review.

Cochrane Database Syst Rev 2021 05 24;5:CD015043. Epub 2021 May 24.

Cochrane Haematology, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.

Background: The role of vitamin D supplementation as a treatment for COVID-19 has been a subject of considerable discussion. A thorough understanding of the current evidence regarding the effectiveness and safety of vitamin D supplementation for COVID-19 based on randomised controlled trials is required.

Objectives: To assess whether vitamin D supplementation is effective and safe for the treatment of COVID-19 in comparison to an active comparator, placebo, or standard of care alone, and to maintain the currency of the evidence, using a living systematic review approach.

Search Methods: We searched the Cochrane COVID-19 Study Register, Web of Science and the WHO COVID-19 Global literature on coronavirus disease to identify completed and ongoing studies without language restrictions to 11 March 2021.

Selection Criteria: We followed standard Cochrane methodology. We included randomised controlled trials (RCTs) evaluating vitamin D supplementation for people with COVID-19, irrespective of disease severity, age, gender or ethnicity. We excluded studies investigating preventive effects, or studies including populations with other coronavirus diseases (severe acute respiratory syndrome (SARS) or Middle East respiratory syndrome (MERS)).

Data Collection And Analysis: We followed standard Cochrane methodology. To assess bias in included studies, we used the Cochrane risk of bias tool (ROB 2) for RCTs. We rated the certainty of evidence using the GRADE approach for the following prioritised outcome categories: individuals with moderate or severe COVID-19: all-cause mortality, clinical status, quality of life, adverse events, serious adverse events, and for individuals with asymptomatic or mild disease: all-cause mortality, development of severe clinical COVID-19 symptoms, quality of life, adverse events, serious adverse events.

Main Results: We identified three RCTs with 356 participants, of whom 183 received vitamin D. In accordance with the World Health Organization (WHO) clinical progression scale, two studies investigated participants with moderate or severe disease, and one study individuals with mild or asymptomatic disease. The control groups consisted of placebo treatment or standard of care alone. Effectiveness of vitamin D supplementation for people with COVID-19 and moderate to severe disease We included two studies with 313 participants. Due to substantial clinical and methodological diversity of both studies, we were not able to pool data. Vitamin D status was unknown in one study, whereas the other study reported data for vitamin D deficient participants. One study administered multiple doses of oral calcifediol at days 1, 3 and 7,  whereas the other study gave a single high dose of oral cholecalciferol at baseline. We assessed one study with low risk of bias for effectiveness outcomes, and the other with some concerns about randomisation and selective reporting. All-cause mortality at hospital discharge (313 participants) We found two studies reporting data for this outcome. One study reported no deaths when treated with vitamin D out of 50 participants, compared to two deaths out of 26 participants in the control group (Risk ratio (RR) 0.11, 95% confidence interval (CI) 0.01 to 2.13). The other study reported nine deaths out of 119 individuals in the vitamin D group, whereas six participants out of 118 died in the placebo group (RR 1.49, 95% CI 0.55 to 4.04]. We are very uncertain whether vitamin D has an effect on all-cause mortality at hospital discharge (very low-certainty evidence). Clinical status assessed by the need for invasive mechanical ventilation (237 participants) We found one study reporting data for this outcome. Nine out of 119 participants needed invasive mechanical ventilation when treated with vitamin D, compared to 17 out of 118 participants in the placebo group (RR 0.52, 95% CI 0.24 to 1.13). Vitamin D supplementation may decrease need for invasive mechanical ventilation, but the evidence is uncertain (low-certainty evidence). Quality of life We did not find data for quality of life. Safety of vitamin D supplementation for people with COVID-19 and moderate to severe disease We did not include data from one study, because assessment of serious adverse events was not described and we are concerned that data might have been inconsistently measured. This study reported vomiting in one out of 119 participants immediately after vitamin D intake (RR 2.98, 95% CI 0.12 to 72.30). We are very uncertain whether vitamin D supplementation is associated with higher risk for adverse events (very low-certainty). Effectiveness and safety of vitamin D supplementation for people with COVID-19 and asymptomatic or mild disease We found one study including 40 individuals, which did not report our prioritised outcomes, but instead data for viral clearance, inflammatory markers, and vitamin D serum levels. The authors reported no events of hypercalcaemia, but recording and assessment of further adverse events remains unclear. Authors administered oral cholecalciferol in daily doses for at least 14 days, and continued with weekly doses if vitamin D blood levels were > 50 ng/mL.

Authors' Conclusions: There is currently insufficient evidence to determine the benefits and harms of vitamin D supplementation as a treatment of COVID-19. The evidence for the effectiveness of vitamin D supplementation for the treatment of COVID-19 is very uncertain. Moreover, we found only limited safety information, and were concerned about consistency in measurement and recording of these outcomes. There was substantial clinical and methodological heterogeneity of included studies, mainly because of different supplementation strategies, formulations, vitamin D status of participants, and reported outcomes. There is an urgent need for well-designed and adequately powered randomised controlled trials (RCTs) with an appropriate randomisation procedure, comparability of study arms and preferably double-blinding. We identified 21 ongoing and three completed studies without published results, which indicates that these needs will be addressed and that our findings are subject to change in the future. Due to the living approach of this work, we will update the review periodically.
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http://dx.doi.org/10.1002/14651858.CD015043DOI Listing
May 2021

Convalescent plasma or hyperimmune immunoglobulin for people with COVID-19: a living systematic review.

Cochrane Database Syst Rev 2021 05 20;5:CD013600. Epub 2021 May 20.

Cochrane Cancer, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.

Background: Convalescent plasma and hyperimmune immunoglobulin may reduce mortality in patients with viral respiratory diseases, and are being investigated as potential therapies for coronavirus disease 2019 (COVID-19). A thorough understanding of the current body of evidence regarding benefits and risks of these interventions is required.  OBJECTIVES: Using a living systematic review approach, to assess whether convalescent plasma or hyperimmune immunoglobulin transfusion is effective and safe in the treatment of people with COVID-19; and to maintain the currency of the evidence.

Search Methods: To identify completed and ongoing studies, we searched the World Health Organization (WHO) COVID-19 Global literature on coronavirus disease Research Database, MEDLINE, Embase, the Cochrane COVID-19 Study Register, the Epistemonikos COVID-19 L*OVE Platform, and trial registries. Searches were done on 17 March 2021.

Selection Criteria: We included randomised controlled trials (RCTs) evaluating convalescent plasma or hyperimmune immunoglobulin for COVID-19, irrespective of disease severity, age, gender or ethnicity. For safety assessments, we also included non-controlled non-randomised studies of interventions (NRSIs) if 500 or more participants were included. We excluded studies that included populations with other coronavirus diseases (severe acute respiratory syndrome (SARS) or Middle East respiratory syndrome (MERS)), as well as studies evaluating standard immunoglobulin.

Data Collection And Analysis: We followed standard Cochrane methodology. To assess bias in included studies, we used the Cochrane 'Risk of Bias 2' tool for RCTs, and for NRSIs, the assessment criteria for observational studies, provided by Cochrane Childhood Cancer. We rated the certainty of evidence, using the GRADE approach, for the following outcomes: all-cause mortality, improvement and worsening of clinical status (for individuals with moderate to severe disease), development of severe clinical COVID-19 symptoms (for individuals with asymptomatic or mild disease), quality of life (including fatigue and functional independence), grade 3 or 4 adverse events, and serious adverse events.

Main Results: We included 13 studies (12 RCTs, 1 NRSI) with 48,509 participants, of whom 41,880 received convalescent plasma. We did not identify any completed studies evaluating hyperimmune immunoglobulin. We identified a further 100 ongoing studies evaluating convalescent plasma or hyperimmune immunoglobulin, and 33 studies reporting as being completed or terminated. Individuals with a confirmed diagnosis of COVID-19 and moderate to severe disease Eleven RCTs and one NRSI investigated the use of convalescent plasma for 48,349 participants with moderate to severe disease. Nine RCTs compared convalescent plasma to placebo treatment or standard care alone, and two compared convalescent plasma to standard plasma (results not included in abstract). Effectiveness of convalescent plasma We included data on nine RCTs (12,875 participants) to assess the effectiveness of convalescent plasma compared to placebo or standard care alone.  Convalescent plasma does not reduce all-cause mortality at up to day 28 (risk ratio (RR) 0.98, 95% confidence interval (CI) 0.92 to 1.05; 7 RCTs, 12,646 participants; high-certainty evidence). It has little to no impact on clinical improvement for all participants when assessed by liberation from respiratory support (RR not estimable; 8 RCTs, 12,682 participants; high-certainty evidence). It has little to no impact on the chance of being weaned or liberated from invasive mechanical ventilation for the subgroup of participants requiring invasive mechanical ventilation at baseline (RR 1.04, 95% CI 0.57 to 1.93; 2 RCTs, 630 participants; low-certainty evidence). It does not reduce the need for invasive mechanical ventilation (RR 0.98, 95% CI 0.89 to 1.08; 4 RCTs, 11,765 participants; high-certainty evidence). We did not identify any subgroup differences.  We did not identify any studies reporting quality of life, and therefore, do not know whether convalescent plasma has any impact on quality of life. One RCT assessed resolution of fatigue on day 7, but we are very uncertain about the effect (RR 1.21, 95% CI 1.02 to 1.42; 309 participants; very low-certainty evidence).  Safety of convalescent plasma We included results from eight RCTs, and one NRSI, to assess the safety of convalescent plasma. Some of the RCTs reported on safety data only for the convalescent plasma group.  We are uncertain whether convalescent plasma increases or reduces the risk of grade 3 and 4 adverse events (RR 0.90, 95% CI 0.58 to 1.41; 4 RCTs, 905 participants; low-certainty evidence), and serious adverse events (RR 1.24, 95% CI 0.81 to 1.90; 2 RCTs, 414 participants; low-certainty evidence).  A summary of reported events of the NRSI (reporting safety data for 20,000 of 35,322 transfused participants), and four RCTs reporting safety data only for transfused participants (6125 participants) are included in the full text. Individuals with a confirmed diagnosis of SARS-CoV-2 infection and asymptomatic or mild disease We identified one RCT reporting on 160 participants, comparing convalescent plasma to placebo treatment (saline).  Effectiveness of convalescent plasma We are very uncertain about the effect of convalescent plasma on all-cause mortality (RR 0.50, 95% CI 0.09 to 2.65; very low-certainty evidence). We are uncertain about the effect of convalescent plasma on developing severe clinical COVID-19 symptoms (RR not estimable; low-certainty evidence).  We identified no study reporting quality of life.  Safety of convalescent plasma We do not know whether convalescent plasma is associated with a higher risk of grade 3 or 4 adverse events (very low-certainty evidence), or serious adverse events (very low-certainty evidence). This is a living systematic review. We search weekly for new evidence and update the review when we identify relevant new evidence. Please refer to the Cochrane Database of Systematic Reviews for the current status of this review.

Authors' Conclusions: We have high certainty in the evidence that convalescent plasma for the treatment of individuals with moderate to severe disease does not reduce mortality and has little to no impact on measures of clinical improvement. We are uncertain about the adverse effects of convalescent plasma. While major efforts to conduct research on COVID-19 are being made, heterogeneous reporting of outcomes is still problematic. There are 100 ongoing studies and 33 studies reporting in a study registry as being completed or terminated. Publication of ongoing studies might resolve some of the uncertainties around hyperimmune immunoglobulin therapy for people with any disease severity, and convalescent plasma therapy for people with asymptomatic or mild disease.
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http://dx.doi.org/10.1002/14651858.CD013600.pub4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8135693PMC
May 2021

Assessment of prostate-specific antigen screening: an evidence-based report by the German Institute for Quality and Efficiency in Health Care.

BJU Int 2021 May 7. Epub 2021 May 7.

Department of Urology, University of Minnesota, Minneapolis, MN, USA.

Context: Prostate-specific antigen (PSA) testing increases prostate cancer diagnoses and reduces long-term disease-specific mortality, but also results in overdiagnoses and treatment-related harms.

Objective: To systematically assess the benefits and harms of population-based PSA screening and the potential net benefit to inform health policy decision-makers in Germany.

Evidence Acquisition: We performed a protocol-guided comprehensive literature search according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement. All steps were performed by one or two investigators; any discrepancies were resolved by consensus. To allow subgroup analyses for identifying the optimal screening parameters, the eight national trials conducted under the umbrella of the European Randomised study of Screening for Prostate Cancer (ERSPC) were included as individual trials.

Evidence Synthesis: We included a total 11 randomised controlled trials (RCTs) with a total of 416 000 study participants. For all-cause mortality, we found neither benefit nor harm. PSA screening was associated with a reduced risk of both prostate cancer mortality and the development of metastases. For the outcomes of health-related quality of life, adverse effects and the consequences of false-negative screening results there was no difference; however, this was due to the lack of eligible RCT data. Finally, PSA screening was associated with large numbers of overdiagnoses with adverse downstream consequences of unnecessary treatment (e.g. incontinence, erectile dysfunction) and large numbers of false-positive PSA tests leading to biopsies associated with a small but not negligible risk of complications. Limitations of this assessment include the clinical heterogeneity and methodological limitations of the underlying studies.

Conclusions: The benefits of PSA-based prostate cancer screening do not outweigh its harms. We failed to identify eligible screening studies of newer biomarkers, PSA derivatives or modern imaging modalities, which may alter the balance of benefit to harm.

Patient Summary: In the present study, we reviewed the evidence on the PSA blood test to screen men without symptoms for prostate cancer. We found that the small benefits experienced by some men do not outweigh the harms to many more men.
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http://dx.doi.org/10.1111/bju.15444DOI Listing
May 2021

Clinical Practice Guideline: Follicular Lymphoma—Diagnosis, Treatment, and Follow-up.

Dtsch Arztebl Int 2021 04 30;118(Forthcoming). Epub 2021 Apr 30.

Background: Follicular lymphoma (FL) occurs predominantly at advanced age, with an annual incidence of 3-5 cases per 100 000 inhabitants in Western countries. The clinical course is heterogeneous.

Methods: For this new guideline, systematic literature searches were conducted in medical databases (MEDLINE, PubMed Central) (up to November 2017) and in the Guidelines International Network (G-I-N), and recent publications were added.

Results: The results of 21 systematic reviews with meta-analyses, 75 randomized controlled trials, and 58 prospective and retrospective studies were evaluated. Lymph-node biopsy is necessary for initial diagnosis of FL. CT scanning of the neck, thorax, and abdomen should be performed to assess how far the disease has spread, together with bone marrow biopsy and, if required, PET/CT. In early FL (stages I and II; 10-15 %), potentially curative radiotherapy combined with an anti-CD 20 antibody is recommended. In advanced disease (stages III and IV), watchful waiting is indicated for patients who have no clinical symptoms and a low tumor burden. Patients with clinical symptoms and/or high tumor burden should receive chemotherapy in combination with an anti-CD 20 antibody, followed by 2 years' maintenance treatment with an anti-CD 20 antibody.

Conclusion: Given the good long-term prognosis of FL, the treatment must be chosen with care and thorough follow-up is necessary to ensure detection of late sequelae such as second malignancies or organ damage.
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http://dx.doi.org/10.3238/arztebl.m2021.0022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8295529PMC
April 2021

Bisphosphonates or RANK-ligand-inhibitors for men with prostate cancer and bone metastases: a network meta-analysis.

Cochrane Database Syst Rev 2020 12 3;12:CD013020. Epub 2020 Dec 3.

Cochrane Cancer, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.

Background: Different bone-modifying agents like bisphosphonates and receptor activator of nuclear factor-kappa B ligand (RANKL)-inhibitors are used as supportive treatment in men with prostate cancer and bone metastases to prevent skeletal-related events (SREs). SREs such as pathologic fractures, spinal cord compression, surgery and radiotherapy to the bone, and hypercalcemia lead to morbidity, a poor performance status, and impaired quality of life. Efficacy and acceptability of the bone-targeted therapy is therefore of high relevance. Until now recommendations in guidelines on which bone-modifying agents should be used are rare and inconsistent.

Objectives: To assess the effects of bisphosphonates and RANKL-inhibitors as supportive treatment for prostate cancer patients with bone metastases and to generate a clinically meaningful treatment ranking according to their safety and efficacy using network meta-analysis.

Search Methods: We identified studies by electronically searching the bibliographic databases Cochrane Controlled Register of Trials (CENTRAL), MEDLINE, and Embase until 23 March 2020. We searched the Cochrane Library and various trial registries and screened abstracts of conference proceedings and reference lists of identified trials.

Selection Criteria: We included randomized controlled trials comparing different bisphosphonates and RANKL-inihibitors with each other or against no further treatment or placebo for men with prostate cancer and bone metastases. We included men with castration-restrictive and castration-sensitive prostate cancer and conducted subgroup analyses according to this criteria.

Data Collection And Analysis: Two review authors independently extracted data and assessed the quality of trials. We defined proportion of participants with pain response and the adverse events renal impairment and osteonecrosis of the jaw (ONJ) as the primary outcomes. Secondary outcomes were SREs in total and each separately (see above), mortality, quality of life, and further adverse events such as grade 3 to 4 adverse events, hypocalcemia, fatigue, diarrhea, and nausea. We conducted network meta-analysis and generated treatment rankings for all outcomes, except quality of life due to insufficient reporting on this outcome. We compiled ranking plots to compare single outcomes of efficacy against outcomes of acceptability of the bone-modifying agents. We assessed the certainty of the evidence for the main outcomes using the GRADE approach.

Main Results: Twenty-five trials fulfilled our inclusion criteria. Twenty-one trials could be considered in the quantitative analysis, of which six bisphosphonates (zoledronic acid, risedronate, pamidronate, alendronate, etidronate, or clodronate) were compared with each other, the RANKL-inhibitor denosumab, or no treatment/placebo. By conducting network meta-analysis we were able to compare all of these reported agents directly and/or indirectly within the network for each outcome. In the abstract only the comparisons of zoledronic acid and denosumab against the main comparator (no treatment/placebo) are described for outcomes that were predefined as most relevant and that also appear in the 'Summary of findings' table. Other results, as well as results of subgroup analyses regarding castration status of participants, are displayed in the Results section of the full text. Treatment with zoledronic acid probably neither reduces nor increases the proportion of participants with pain response when compared to no treatment/placebo (risk ratio (RR) 1.46, 95% confidence interval (CI) 0.93 to 2.32; per 1000 participants 121 more (19 less to 349 more); moderate-certainty evidence; network based on 4 trials including 1013 participants). For this outcome none of the trials reported results for the comparison with denosumab. The adverse event renal impairment probably occurs more often when treated with zoledronic acid compared to treatment/placebo (RR 1.63, 95% CI 1.08 to 2.45; per 1000 participants 78 more (10 more to 180 more); moderate-certainty evidence; network based on 6 trials including 1769 participants). Results for denosumab could not be included for this outcome, since zero events cannot be considered in the network meta-analysis, therefore it does not appear in the ranking. Treatment with denosumab results in increased occurrence of the adverse event ONJ (RR 3.45, 95% CI 1.06 to 11.24; per 1000 participants 30 more (1 more to 125 more); high-certainty evidence; 4 trials, 3006 participants) compared to no treatment/placebo. When comparing zoledronic acid to no treatment/placebo, the confidence intervals include the possibility of benefit or harm, therefore treatment with zoledronic acid probably neither reduces nor increases ONJ (RR 1.88, 95% CI 0.73 to 4.87; per 1000 participants 11 more (3 less to 47 more); moderate-certainty evidence; network based on 4 trials including 3006 participants). Compared to no treatment/placebo, treatment with zoledronic acid (RR 0.84, 95% CI 0.72 to 0.97) and denosumab (RR 0.72, 95% CI 0.54 to 0.96) may result in a reduction of the total number of SREs (per 1000 participants 75 fewer (131 fewer to 14 fewer) and 131 fewer (215 fewer to 19 fewer); both low-certainty evidence; 12 trials, 5240 participants). Treatment with zoledronic acid and denosumab likely neither reduces nor increases mortality when compared to no treatment/placebo (zoledronic acid RR 0.90, 95% CI 0.80 to 1.01; per 1000 participants 48 fewer (97 fewer to 5 more); denosumab RR 0.93, 95% CI 0.77 to 1.11; per 1000 participants 34 fewer (111 fewer to 54 more); both moderate-certainty evidence; 13 trials, 5494 participants). Due to insufficient reporting, no network meta-analysis was possible for the outcome quality of life. One study with 1904 participants comparing zoledronic acid and denosumab showed that more zoledronic acid-treated participants than denosumab-treated participants experienced a greater than or equal to five-point decrease in Functional Assessment of Cancer Therapy-General total scores over a range of 18 months (average relative difference = 6.8%, range -9.4% to 14.6%) or worsening of cancer-related quality of life.

Authors' Conclusions: When considering bone-modifying agents as supportive treatment, one has to balance between efficacy and acceptability. Results suggest that Zoledronic acid likely increases both the proportion of participants with pain response, and the proportion of participants experiencing adverse events However, more trials with head-to-head comparisons including all potential agents are needed to draw the whole picture and proof the results of this analysis.
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http://dx.doi.org/10.1002/14651858.CD013020.pub2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8095056PMC
December 2020

[The "gender" variable in the research process: Requirements contained in the application guidelines of funding institutions in the health sector].

Z Evid Fortbild Qual Gesundhwes 2020 Dec 27;158-159:10-15. Epub 2020 Nov 27.

Institut für Gesundheits- und Pflegewissenschaft, Medizinische Fakultät, Martin-Luther-Universität Halle-Wittenberg, Halle (Saale), Deutschland.

Background: When addressing the variable "gender" in health research designs, a distinction is made between biological ("sex") and sociocultural or psychosocial aspects ("gender"). In health research, it is important to avoid systematic errors that may result when gender aspects are inappropriately or not sufficiently addressed (so-called gender bias). A gender bias occurs, for instance, when the presence of gender differences is assumed without empirical evidence or when research data that was generated from samples of male participants is automatically applied to women. Funding institutions can create incentives for researchers to integrate gender-sensitive analyses into their research projects and to consider the potential influence of the "gender" variable. The aim of this study was to explore which explicit requirements concerning gender aspects applicants to German funding institutions in the various health sectors need to meet in their research designs.

Methods: From March to June 2019, we researched funding institutions in the health sector at the German federal level. We examined the funding guidelines of each identified institution in light of their requirements for applicants to take gender aspects into consideration in their research. We explored this in a two-step procedure (online document search and e-mail contact).

Results: We examined 18 institutions. Information on the requirements for applicants to address gender aspects in their research projects was identified for four institutions: the German Federal Ministry of Education and Research, the German Federal Ministry of Health, the German Research Foundation, and the Volkswagen Stiftung. In particular, the consideration of gender aspects for planned research projects was used as an evaluation criterion in the institutions' application guidelines available online. If considered relevant for a planned research project, the consideration of gender aspects affects project planning, implementation and evaluation of results. Eight institutions had no such requirements. For the remaining six institutions, we were not able to find any such information, neither by document research nor through e-mail contact.

Discussion And Conclusion: Only a few funding institutions in the health sector have so far included requirements regarding the consideration of the "gender" variable in health research in their application guidelines. Furthermore, the funding institutions' requirements are somewhat heterogeneous and need standardization. Funding institutions in the health sector could identify research needs and set new research priorities in order to expand the empirical evidence on gender aspects in the various health sectors and to increase the social benefit of the scientific results obtained. In this way, applicants can be sensitized and encouraged to consider gender aspects in their research projects and, if necessary, to conduct them in a gender-differentiated manner.
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http://dx.doi.org/10.1016/j.zefq.2020.11.003DOI Listing
December 2020

A Systematic Review on Predictors of Working Memory Training Responsiveness in Healthy Older Adults: Methodological Challenges and Future Directions.

Front Aging Neurosci 2020 14;12:575804. Epub 2020 Oct 14.

Department of Medical Psychology | Neuropsychology & Gender Studies, Center for Neuropsychological Diagnostics and Intervention (CeNDI), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.

Research on predictors of working memory training responsiveness, which could help tailor cognitive interventions individually, is a timely topic in healthy aging. However, the findings are highly heterogeneous, reporting partly conflicting results following a broad spectrum of methodological approaches to answer the question "who benefits most" from working memory training. The present systematic review aimed to systematically investigate prognostic factors and models for working memory training responsiveness in healthy older adults. Four online databases were searched up to October 2019 (MEDLINE Ovid, Web of Science, CENTRAL, and PsycINFO). The inclusion criteria for full texts were publication in a peer-reviewed journal in English/German, inclusion of healthy older individuals aged ≥55 years without any neurological and/or psychiatric diseases including cognitive impairment, and the investigation of prognostic factors and/or models for training responsiveness after targeted working memory training in terms of direct training effects, near-transfer effects to verbal and visuospatial working memory as well as far-transfer effects to other cognitive domains and behavioral variables. The study design was not limited to randomized controlled trials. A total of 16 studies including = 675 healthy older individuals with a mean age of 63.0-86.8 years were included in this review. Within these studies, five prognostic model approaches and 18 factor finding approaches were reported. Risk of bias was assessed using the Quality in Prognosis Studies checklist, indicating that important information, especially regarding the domains study attrition, study confounding, and statistical analysis and reporting, was lacking throughout many of the investigated studies. Age, education, intelligence, and baseline performance in working memory or other cognitive domains were frequently investigated predictors across studies. Given the methodological shortcomings of the included studies, no clear conclusions can be drawn, and emerging patterns of prognostic effects will have to survive sound methodological replication in future attempts to promote precision medicine approaches in the context of working memory training. Methodological considerations are discussed, and our findings are embedded to the cognitive aging literature, considering, for example, the cognitive reserve framework and the compensation vs. magnification account. The need for personalized cognitive prevention and intervention methods to counteract cognitive decline in the aging population is high and the potential enormous. PROSPERO, ID CRD42019142750.
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http://dx.doi.org/10.3389/fnagi.2020.575804DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7591761PMC
October 2020

Convalescent plasma or hyperimmune immunoglobulin for people with COVID-19: a living systematic review.

Cochrane Database Syst Rev 2020 10 12;10:CD013600. Epub 2020 Oct 12.

Cochrane Cancer, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.

Background: Convalescent plasma and hyperimmune immunoglobulin may reduce mortality in patients with viral respiratory diseases, and are currently being investigated in trials as potential therapy for coronavirus disease 2019 (COVID-19). A thorough understanding of the current body of evidence regarding the benefits and risks is required.  OBJECTIVES: To continually assess, as more evidence becomes available, whether convalescent plasma or hyperimmune immunoglobulin transfusion is effective and safe in treatment of people with COVID-19.

Search Methods: We searched the World Health Organization (WHO) COVID-19 Global Research Database, MEDLINE, Embase, Cochrane COVID-19 Study Register, Centers for Disease Control and Prevention COVID-19 Research Article Database and trial registries to identify completed and ongoing studies on 19 August 2020.

Selection Criteria: We followed standard Cochrane methodology. We included studies evaluating convalescent plasma or hyperimmune immunoglobulin for people with COVID-19, irrespective of study design, disease severity, age, gender or ethnicity. We excluded studies including populations with other coronavirus diseases (severe acute respiratory syndrome (SARS) or Middle East respiratory syndrome (MERS)) and studies evaluating standard immunoglobulin.

Data Collection And Analysis: We followed standard Cochrane methodology. To assess bias in included studies, we used the Cochrane 'Risk of bias' 2.0 tool for randomised controlled trials (RCTs), the Risk of Bias in Non-randomised Studies - of Interventions (ROBINS-I) tool for controlled non-randomised studies of interventions (NRSIs), and the assessment criteria for observational studies, provided by Cochrane Childhood Cancer for non-controlled NRSIs. We rated the certainty of evidence using the GRADE approach for the following outcomes: all-cause mortality at hospital discharge, mortality (time to event), improvement of clinical symptoms (7, 15, and 30 days after transfusion), grade 3 and 4 adverse events (AEs), and serious adverse events (SAEs).

Main Results: This is the second living update of our review. We included 19 studies (2 RCTs, 8 controlled NRSIs, 9 non-controlled NRSIs) with 38,160 participants, of whom 36,081 received convalescent plasma. Two completed RCTs are awaiting assessment (published after 19 August 2020). We identified a further 138 ongoing studies evaluating convalescent plasma or hyperimmune immunoglobulin, of which 73 are randomised (3 reported in a study registry as already being completed, but without results). We did not identify any completed studies evaluating hyperimmune immunoglobulin. We did not include data from controlled NRSIs in data synthesis because of critical risk of bias. The overall certainty of evidence was low to very low, due to study limitations and results including both potential benefits and harms.  Effectiveness of convalescent plasma for people with COVID-19  We included results from two RCTs (both stopped early) with 189 participants, of whom 95 received convalescent plasma. Control groups received standard care at time of treatment without convalescent plasma. We are uncertain whether convalescent plasma decreases all-cause mortality at hospital discharge (risk ratio (RR) 0.55, 95% confidence interval (CI) 0.22 to 1.34; 1 RCT, 86 participants; low-certainty evidence).  We are uncertain whether convalescent plasma decreases mortality (time to event) (hazard ratio (HR) 0.64, 95% CI 0.33 to 1.25; 2 RCTs, 189 participants; low-certainty evidence). Convalescent plasma may result in little to no difference in improvement of clinical symptoms (i.e. need for respiratory support) at seven days (RR 0.98, 95% CI 0.30 to 3.19; 1 RCT, 103 participants; low-certainty evidence). Convalescent plasma may increase improvement of clinical symptoms at up to 15 days (RR 1.34, 95% CI 0.85 to 2.11; 2 RCTs, 189 participants; low-certainty evidence), and at up to 30 days (RR 1.13, 95% CI 0.88 to 1.43; 2 studies, 188 participants; low-certainty evidence).  No studies reported on quality of life.  Safety of convalescent plasma for people with COVID-19 We included results from two RCTs, eight controlled NRSIs and nine non-controlled NRSIs assessing safety of convalescent plasma. Reporting of safety data and duration of follow-up was variable. The controlled studies reported on AEs and SAEs only in participants receiving convalescent plasma. Some, but not all, studies included death as a SAE.  The studies did not report the grade of AEs. Fourteen studies (566 participants) reported on AEs of possible grade 3 or 4 severity. The majority of these AEs were allergic or respiratory events. We are very uncertain whether convalescent plasma therapy affects the risk of moderate to severe AEs (very low-certainty evidence).  17 studies (35,944 participants) assessed SAEs for 20,622 of its participants. The majority of participants were from one non-controlled NRSI (20,000 participants), which reported on SAEs within the first four hours and within an additional seven days after transfusion. There were 63 deaths, 12 were possibly and one was probably related to transfusion. There were 146 SAEs within four hours and 1136 SAEs within seven days post-transfusion. These were predominantly allergic or respiratory, thrombotic or thromboembolic and cardiac events. We are uncertain whether convalescent plasma therapy results in a clinically relevant increased risk of SAEs (low-certainty evidence).

Authors' Conclusions: We are uncertain whether convalescent plasma is beneficial for people admitted to hospital with COVID-19. There was limited information regarding grade 3 and 4 AEs to determine the effect of convalescent plasma therapy on clinically relevant SAEs. In the absence of a control group, we are unable to assess the relative safety of convalescent plasma therapy.  While major efforts to conduct research on COVID-19 are being made, recruiting the anticipated number of participants into these studies is problematic. The early termination of the first two RCTs investigating convalescent plasma, and the lack of data from 20 studies that have completed or were due to complete at the time of this update illustrate these challenges. Well-designed studies should be prioritised. Moreover, studies should report outcomes in the same way, and should consider the importance of maintaining comparability in terms of co-interventions administered in all study arms.  There are 138 ongoing studies evaluating convalescent plasma and hyperimmune immunoglobulin, of which 73 are RCTs (three already completed). This is the second living update of the review, and we will continue to update this review periodically. Future updates may show different results to those reported here.
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October 2020

Developing trustworthy recommendations as part of an urgent response (1-2 weeks): a GRADE concept paper.

J Clin Epidemiol 2021 Jan 30;129:1-11. Epub 2020 Sep 30.

American College of Physicians, 190 N Independence Mall West, Philadelphia, PA 19087, USA.

Objectives: The aim of this study is to propose an approach for developing trustworthy recommendations as part of urgent responses (1-2 week) in the clinical, public health, and health systems fields.

Study Design And Setting: We conducted a review of the literature, outlined a draft approach, refined the concept through iterative discussions, a workshop by the Grading of Recommendations Assessment, Development and Evaluation Rapid Guidelines project group, and obtained feedback from the larger Grading of Recommendations Assessment, Development and Evaluation working group.

Results: A request for developing recommendations within 2 week is the usual trigger for an urgent response. Although the approach builds on the general principles of trustworthy guideline development, we highlight the following steps: (1) assess the level of urgency; (2) assess feasibility; (3) set up the organizational logistics; (4) specify the question(s); (5) collect the information needed; (6) assess the adequacy of identified information; (7) develop the recommendations using one of the 4 potential approaches: adopt existing recommendations, adapt existing recommendations, develop new recommendations using existing adequate systematic review, or develop new recommendations using expert panel input; and (8) consider an updating plan.

Conclusion: An urgent response for developing recommendations requires building a cohesive, skilled, and highly motivated multidisciplinary team with the necessary clinical, scientific, and methodological expertise; adapting to shifting needs; complying with the principles of transparency; and properly managing conflicts of interest.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7526592PMC
January 2021

GRADE Guidelines: 29. Rating the certainty in time-to-event outcomes-Study limitations due to censoring of participants with missing data in intervention studies.

J Clin Epidemiol 2021 Jan 30;129:126-137. Epub 2020 Sep 30.

Department of Internal Medicine, University of Cologne, Faculty of Medicine and University Hospital Cologne, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Kerpener Str. 62, 50937, Cologne, Germany.

Objectives: To provide Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) guidance for the consideration of study limitations (risk of bias) due to missing participant outcome data for time-to-event outcomes in intervention studies.

Study Design And Setting: We developed this guidance through an iterative process that included membership consultation, feedback, presentation, and iterative discussion at meetings of the GRADE working group.

Results: The GRADE working group has published guidance on how to account for missing participant outcome data in binary and continuous outcomes. When analyzing time-to-event outcomes (e.g., overall survival and time-to-treatment failure) data of participants for whom the outcome of interest (e.g., death and relapse) has not been observed are dealt with through censoring. To do so, standard methods require that censored individuals are representative for those remaining in the study. Two types of censoring can be distinguished, end of study censoring and censoring because of missing data, commonly named loss to follow-up censoring. However, both types are not distinguishable with the usual information on censoring available to review authors. Dealing with individuals for whom data are missing during follow-up in the same way as individuals for whom full follow-up is available at the end of the study increases the risk of bias. Considerable differences in the treatment arms in the distribution of censoring over time (early versus late censoring), the overall degree of missing follow-up data, and the reasons why individuals were lost to follow-up may reduce the certainty in the study results. With often only very limited data available, review and guideline authors are required to make transparent and well-considered judgments when judging risk of bias of individual studies and then come to an overall grading decision for the entire body of evidence.

Conclusion: Concern for risk of bias resulting from censoring of participants for whom follow-up data are missing in the underlying studies of a body of evidence can be expressed in the study limitations (risk of bias) domain of the GRADE approach.
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January 2021

[DNVF Memorandum Health Services Research in Oncology].

Gesundheitswesen 2020 Sep 28;82(8-09):e108-e121. Epub 2020 Aug 28.

Nationales Zentrum für Tumorerkrankungen Heidelberg, Heidelberg.

Health services research in oncology deals with all situations which cancer patients face. It looks at the different phases of care, i. e. prevention / early detection, prehabilitation, diagnostics, therapy, rehabilitation and palliative care as well as the various actors, including those affected, the carers and self-help. It deals with healthy people (e. g. in the context of prevention / early detection), patients and cancer survivors. Due to the nature of cancer and the existing care structures, there are a number of specific contents for health services research in oncology compared to general health services research while the methods remain essentially identical. This memorandum describes the subject, illustrates the care structures and identifies areas of health services research in oncology. This memorandum has been prepared by the Oncology Section of the German Network for Health Services Research and is the result of intensive discussions.
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September 2020

Prognostic models for newly-diagnosed chronic lymphocytic leukaemia in adults: a systematic review and meta-analysis.

Cochrane Database Syst Rev 2020 07 31;7:CD012022. Epub 2020 Jul 31.

Cochrane Cancer, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.

Background: Chronic lymphocytic leukaemia (CLL) is the most common cancer of the lymphatic system in Western countries. Several clinical and biological factors for CLL have been identified. However, it remains unclear which of the available prognostic models combining those factors can be used in clinical practice to predict long-term outcome in people newly-diagnosed with CLL.

Objectives: To identify, describe and appraise all prognostic models developed to predict overall survival (OS), progression-free survival (PFS) or treatment-free survival (TFS) in newly-diagnosed (previously untreated) adults with CLL, and meta-analyse their predictive performances.

Search Methods: We searched MEDLINE (from January 1950 to June 2019 via Ovid), Embase (from 1974 to June 2019) and registries of ongoing trials (to 5 March 2020) for development and validation studies of prognostic models for untreated adults with CLL. In addition, we screened the reference lists and citation indices of included studies.

Selection Criteria: We included all prognostic models developed for CLL which predict OS, PFS, or TFS, provided they combined prognostic factors known before treatment initiation, and any studies that tested the performance of these models in individuals other than the ones included in model development (i.e. 'external model validation studies'). We included studies of adults with confirmed B-cell CLL who had not received treatment prior to the start of the study. We did not restrict the search based on study design.

Data Collection And Analysis: We developed a data extraction form to collect information based on the Checklist for Critical Appraisal and Data Extraction for Systematic Reviews of Prediction Modelling Studies (CHARMS). Independent pairs of review authors screened references, extracted data and assessed risk of bias according to the Prediction model Risk Of Bias ASsessment Tool (PROBAST). For models that were externally validated at least three times, we aimed to perform a quantitative meta-analysis of their predictive performance, notably their calibration (proportion of people predicted to experience the outcome who do so) and discrimination (ability to differentiate between people with and without the event) using a random-effects model. When a model categorised individuals into risk categories, we pooled outcome frequencies per risk group (low, intermediate, high and very high). We did not apply GRADE as guidance is not yet available for reviews of prognostic models.

Main Results: From 52 eligible studies, we identified 12 externally validated models: six were developed for OS, one for PFS and five for TFS. In general, reporting of the studies was poor, especially predictive performance measures for calibration and discrimination; but also basic information, such as eligibility criteria and the recruitment period of participants was often missing. We rated almost all studies at high or unclear risk of bias according to PROBAST. Overall, the applicability of the models and their validation studies was low or unclear; the most common reasons were inappropriate handling of missing data and serious reporting deficiencies concerning eligibility criteria, recruitment period, observation time and prediction performance measures. We report the results for three models predicting OS, which had available data from more than three external validation studies: CLL International Prognostic Index (CLL-IPI) This score includes five prognostic factors: age, clinical stage, IgHV mutational status, B2-microglobulin and TP53 status. Calibration: for the low-, intermediate- and high-risk groups, the pooled five-year survival per risk group from validation studies corresponded to the frequencies observed in the model development study. In the very high-risk group, predicted survival from CLL-IPI was lower than observed from external validation studies. Discrimination: the pooled c-statistic of seven external validation studies (3307 participants, 917 events) was 0.72 (95% confidence interval (CI) 0.67 to 0.77). The 95% prediction interval (PI) of this model for the c-statistic, which describes the expected interval for the model's discriminative ability in a new external validation study, ranged from 0.59 to 0.83. Barcelona-Brno score Aimed at simplifying the CLL-IPI, this score includes three prognostic factors: IgHV mutational status, del(17p) and del(11q). Calibration: for the low- and intermediate-risk group, the pooled survival per risk group corresponded to the frequencies observed in the model development study, although the score seems to overestimate survival for the high-risk group. Discrimination: the pooled c-statistic of four external validation studies (1755 participants, 416 events) was 0.64 (95% CI 0.60 to 0.67); 95% PI 0.59 to 0.68. MDACC 2007 index score The authors presented two versions of this model including six prognostic factors to predict OS: age, B2-microglobulin, absolute lymphocyte count, gender, clinical stage and number of nodal groups. Only one validation study was available for the more comprehensive version of the model, a formula with a nomogram, while seven studies (5127 participants, 994 events) validated the simplified version of the model, the index score. Calibration: for the low- and intermediate-risk groups, the pooled survival per risk group corresponded to the frequencies observed in the model development study, although the score seems to overestimate survival for the high-risk group. Discrimination: the pooled c-statistic of the seven external validation studies for the index score was 0.65 (95% CI 0.60 to 0.70); 95% PI 0.51 to 0.77.

Authors' Conclusions: Despite the large number of published studies of prognostic models for OS, PFS or TFS for newly-diagnosed, untreated adults with CLL, only a minority of these (N = 12) have been externally validated for their respective primary outcome. Three models have undergone sufficient external validation to enable meta-analysis of the model's ability to predict survival outcomes. Lack of reporting prevented us from summarising calibration as recommended. Of the three models, the CLL-IPI shows the best discrimination, despite overestimation. However, performance of the models may change for individuals with CLL who receive improved treatment options, as the models included in this review were tested mostly on retrospective cohorts receiving a traditional treatment regimen. In conclusion, this review shows a clear need to improve the conducting and reporting of both prognostic model development and external validation studies. For prognostic models to be used as tools in clinical practice, the development of the models (and their subsequent validation studies) should adapt to include the latest therapy options to accurately predict performance. Adaptations should be timely.
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http://dx.doi.org/10.1002/14651858.CD012022.pub2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8078230PMC
July 2020

Convalescent plasma or hyperimmune immunoglobulin for people with COVID-19: a living systematic review.

Cochrane Database Syst Rev 2020 07 10;7:CD013600. Epub 2020 Jul 10.

Cochrane Cancer, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.

Background: Convalescent plasma and hyperimmune immunoglobulin may reduce mortality in patients with viral respiratory diseases, and are currently being investigated in trials as potential therapy for coronavirus disease 2019 (COVID-19). A thorough understanding of the current body of evidence regarding the benefits and risks is required.  OBJECTIVES: To continually assess, as more evidence becomes available, whether convalescent plasma or hyperimmune immunoglobulin transfusion is effective and safe in treatment of people with COVID-19.

Search Methods: We searched the World Health Organization (WHO) COVID-19 Global Research Database, MEDLINE, Embase, Cochrane COVID-19 Study Register, Centers for Disease Control and Prevention COVID-19 Research Article Database and trial registries to identify completed and ongoing studies on 4 June 2020.

Selection Criteria: We followed standard Cochrane methodology. We included studies evaluating convalescent plasma or hyperimmune immunoglobulin for people with COVID-19, irrespective of study design, disease severity, age, gender or ethnicity. We excluded studies including populations with other coronavirus diseases (severe acute respiratory syndrome (SARS) or Middle East respiratory syndrome (MERS)) and studies evaluating standard immunoglobulin.

Data Collection And Analysis: We followed standard Cochrane methodology. To assess bias in included studies, we used the Cochrane 'Risk of bias' tool for randomised controlled trials (RCTs), the Risk of Bias in Non-randomised Studies - of Interventions (ROBINS-I) tool for controlled non-randomised studies of interventions (NRSIs), and the assessment criteria for observational studies, provided by Cochrane Childhood Cancer for non-controlled NRSIs.  MAIN RESULTS: This is the first living update of our review. We included 20 studies (1 RCT, 3 controlled NRSIs, 16 non-controlled NRSIs) with 5443 participants, of whom 5211 received convalescent plasma, and identified a further 98 ongoing studies evaluating convalescent plasma or hyperimmune immunoglobulin, of which 50 are randomised. We did not identify any completed studies evaluating hyperimmune immunoglobulin. Overall risk of bias of included studies was high, due to study design, type of participants, and other previous or concurrent treatments. Effectiveness of convalescent plasma for people with COVID-19  We included results from four controlled studies (1 RCT (stopped early) with 103 participants, of whom 52 received convalescent plasma; and 3 controlled NRSIs with 236 participants, of whom 55 received convalescent plasma) to assess effectiveness of convalescent plasma. Control groups received standard care at time of treatment without convalescent plasma. All-cause mortality at hospital discharge (1 controlled NRSI, 21 participants) We are very uncertain whether convalescent plasma has any effect on all-cause mortality at hospital discharge (risk ratio (RR) 0.89, 95% confidence interval (CI) 0.61 to 1.31; very low-certainty evidence). Time to death (1 RCT, 103 participants; 1 controlled NRSI, 195 participants) We are very uncertain whether convalescent plasma prolongs time to death (RCT: hazard ratio (HR) 0.74, 95% CI 0.30 to 1.82; controlled NRSI: HR 0.46, 95% CI 0.22 to 0.96; very low-certainty evidence). Improvement of clinical symptoms, assessed by need for respiratory support (1 RCT, 103 participants; 1 controlled NRSI, 195 participants) We are very uncertain whether convalescent plasma has any effect on improvement of clinical symptoms at seven days (RCT: RR 0.98, 95% CI 0.30 to 3.19), 14 days (RCT: RR 1.85, 95% CI 0.91 to 3.77; controlled NRSI: RR 1.08, 95% CI 0.91 to 1.29), and 28 days (RCT: RR 1.20, 95% CI 0.80 to 1.81; very low-certainty evidence). Quality of life No studies reported this outcome.  Safety of convalescent plasma for people with COVID-19 We included results from 1 RCT, 3 controlled NRSIs and 10 non-controlled NRSIs assessing safety of convalescent plasma. Reporting of adverse events and serious adverse events was variable. The controlled studies reported on adverse events and serious adverse events only in participants receiving convalescent plasma. The duration of follow-up varied. Some, but not all, studies included death as a serious adverse event.  Grade 3 or 4 adverse events (13 studies, 201 participants) The studies did not report the grade of adverse events. Thirteen studies (201 participants) reported on adverse events of possible grade 3 or 4 severity. The majority of these adverse events were allergic or respiratory events. We are very uncertain whether or not convalescent plasma therapy affects the risk of moderate to severe adverse events (very low-certainty evidence).  Serious adverse events (14 studies, 5201 participants)  Fourteen studies (5201 participants) reported on serious adverse events. The majority of participants were from one non-controlled NRSI (5000 participants), which reported only on serious adverse events limited to the first four hours after convalescent plasma transfusion. This study included death as a serious adverse event; they reported 15 deaths, four of which they classified as potentially, probably or definitely related to transfusion. Other serious adverse events reported in all studies were predominantly allergic or respiratory in nature, including anaphylaxis, transfusion-associated dyspnoea, and transfusion-related acute lung injury (TRALI). We are very uncertain whether or not convalescent plasma affects the number of serious adverse events.

Authors' Conclusions: We are very uncertain whether convalescent plasma is beneficial for people admitted to hospital with COVID-19. For safety outcomes we also included non-controlled NRSIs. There was limited information regarding adverse events. Of the controlled studies, none reported on this outcome in the control group. There is only very low-certainty evidence for safety of convalescent plasma for COVID-19.  While major efforts to conduct research on COVID-19 are being made, problems with recruiting the anticipated number of participants into these studies are conceivable. The early termination of the first RCT investigating convalescent plasma, and the multitude of studies registered in the past months illustrate this. It is therefore necessary to critically assess the design of these registered studies, and well-designed studies should be prioritised. Other considerations for these studies are the need to report outcomes for all study arms in the same way, and the importance of maintaining comparability in terms of co-interventions administered in all study arms.  There are 98 ongoing studies evaluating convalescent plasma and hyperimmune immunoglobulin, of which 50 are RCTs. This is the first living update of the review, and we will continue to update this review periodically. These updates may show different results to those reported here.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7389743PMC
July 2020

Prognostic factors for change in memory test performance after memory training in healthy older adults: a systematic review and outline of statistical challenges.

Diagn Progn Res 2020 21;4. Epub 2020 May 21.

1Department of Medical Psychology | Neuropsychology and Gender Studies & Center for Neuropsychological Diagnostics and Intervention (CeNDI), Faculty of Medicine and University Hospital Cologne, University of Cologne, Kerpener Str. 68, 50937 Cologne, Germany.

Background: The goal is to investigate prognostic factors for change in memory test performance in healthy older adults and to report and discuss the different statistical procedures used for investigating this topic in the literature.

Methods: Prognostic factors were here understood as any measures that were investigated to estimate change in memory test performance. MEDLINE, Web of Science Core Collection, CENTRAL, and PsycInfo were searched up to November 2019. Prognostic factor and prognostic factor finding studies investigating prognostic factors on verbal and non-verbal short- and long-term memory after conducting memory training in healthy older adults were included. Risk of bias was assessed using the QUIPS tool.

Results: Our search yielded 12,974 results. We included 29 studies that address prognostic factors of change in memory test performance, including sociodemographic, (neuro-)psychological, genetic, and biological parameters. Studies showed high variation and methodological shortcomings with regard to the assessment, statistical evaluation, and reporting of the investigated prognostic factors. Included studies used different types of dependent variables (change scores vs. post-test scores) when defining change in memory test performance leading to contradictory results. Age was the only variable investigated throughout most of the studies, showing that older adults benefit more from training when using the change score as the dependent variable.

Conclusion: Overall, there is a need for adequate reporting in studies of prognostic factors for change in memory test performance. Because of inconsistencies and methodological shortcomings in the literature, conclusions regarding prognostic factors remain uncertain. As a tentative conclusion, one may say that the higher the age of the participant, the more profound the improvement in memory test performance will be after memory training.

Trial Registration: CRD42019127479.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7240921PMC
May 2020

Convalescent plasma or hyperimmune immunoglobulin for people with COVID-19: a rapid review.

Cochrane Database Syst Rev 2020 05 14;5:CD013600. Epub 2020 May 14.

Cochrane Cancer, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.

Background: Convalescent plasma and hyperimmune immunoglobulin may reduce mortality in patients with respiratory virus diseases, and are currently being investigated in trials as a potential therapy for coronavirus disease 2019 (COVID-19). A thorough understanding of the current body of evidence regarding the benefits and risks is required.  OBJECTIVES: To assess whether convalescent plasma or hyperimmune immunoglobulin transfusion is effective and safe in the treatment of people with COVID-19.

Search Methods: The protocol was pre-published with the Center for Open Science and can be accessed here: osf.io/dwf53  We searched the World Health Organization (WHO) COVID-19 Global Research Database, MEDLINE, Embase, Cochrane COVID-19 Study Register, Centers for Disease Control and Prevention COVID-19 Research Article Database and trials registries to identify ongoing studies and results of completed studies on 23 April 2020 for case-series, cohort, prospectively planned, and randomised controlled trials (RCTs).

Selection Criteria: We followed standard Cochrane methodology and performed all steps regarding study selection in duplicate by two independent review authors (in contrast to the recommendations of the Cochrane Rapid Reviews Methods Group). We included studies evaluating convalescent plasma or hyperimmune immunoglobulin for people with COVID-19, irrespective of disease severity, age, gender or ethnicity. We excluded studies including populations with other coronavirus diseases (severe acute respiratory syndrome (SARS) or Middle East respiratory syndrome (MERS)) and studies evaluating standard immunoglobulins.

Data Collection And Analysis: We followed recommendations of the Cochrane Rapid Reviews Methods Group regarding data extraction and assessment. To assess bias in included studies, we used the assessment criteria tool for observational studies, provided by Cochrane Childhood Cancer. We rated the certainty of evidence using the GRADE approach for the following outcomes: all-cause mortality at hospital discharge, improvement of clinical symptoms (7, 15, and 30 days after transfusion), grade 3 and 4 adverse events, and serious adverse events.  MAIN RESULTS: We included eight studies (seven case-series, one prospectively planned, single-arm intervention study) with 32 participants, and identified a further 48 ongoing studies evaluating convalescent plasma (47 studies) or hyperimmune immunoglobulin (one study), of which 22 are randomised. Overall risk of bias of the eight included studies was high, due to: study design; small number of participants; poor reporting within studies; and varied type of participants with different severities of disease, comorbidities, and types of previous or concurrent treatments, including antivirals, antifungals or antibiotics, corticosteroids, hydroxychloroquine and respiratory support. We rated all outcomes as very low certainty, and we were unable to summarise numerical data in any meaningful way. As we identified case-series studies only, we reported results narratively. Effectiveness of convalescent plasma for people with COVID-19 The following reported outcomes could all be related to the underlying natural history of the disease or other concomitant treatment, rather than convalescent plasma. All-cause mortality at hospital discharge All studies reported mortality. All participants were alive at the end of the reporting period, but not all participants had been discharged from hospital by the end of the study (15 participants discharged, 6 still hospitalised, 11 unclear). Follow-up ranged from 3 days to 37 days post-transfusion. We do not know whether convalescent plasma therapy affects mortality (very low-certainty evidence).  Improvement of clinical symptoms (assessed by respiratory support) Six studies, including 28 participants, reported the level of respiratory support required; most participants required respiratory support at baseline. All studies reported improvement in clinical symptoms in at least some participants. We do not know whether convalescent plasma improves clinical symptoms (very low-certainty evidence). Time to discharge from hospital Six studies reported time to discharge from hospital for at least some participants, which ranged from four to 35 days after convalescent plasma therapy.  Admission on the intensive care unit (ICU) Six studies included patients who were critically ill. At final follow-up the majority of these patients were no longer on the ICU or no longer required mechanical ventilation. Length of stay on the ICU Only one study (1 participant) reported length of stay on the ICU. The individual was discharged from the ICU 11 days after plasma transfusion. Safety of convalescent plasma for people with COVID-19 Grade 3 or 4 adverse events  The studies did not report the grade of adverse events after convalescent plasma transfusion. Two studies reported data relating to participants who had experienced adverse events, that were presumably grade 3 or 4. One case study reported a participant who had moderate fever (38.9 °C). Another study (3 participants) reported a case of severe anaphylactic shock. Four studies reported the absence of moderate or severe adverse events (19 participants). We are very uncertain whether or not convalescent plasma therapy affects the risk of moderate to severe adverse events (very low-certainty evidence). Serious adverse events One study (3 participants) reported one serious adverse event. As described above, this individual had severe anaphylactic shock after receiving convalescent plasma. Six studies reported that no serious adverse events occurred. We are very uncertain whether or not convalescent plasma therapy affects the risk of serious adverse events (very low-certainty evidence).  AUTHORS' CONCLUSIONS: We identified eight studies (seven case-series and one prospectively planned single-arm intervention study) with a total of 32 participants (range 1 to 10). Most studies assessed the risks of the intervention; reporting two adverse events (potentially grade 3 or 4), one of which was a serious adverse event. We are very uncertain whether convalescent plasma is effective for people admitted to hospital with COVID-19 as studies reported results inconsistently, making it difficult to compare results and to draw conclusions. We identified very low-certainty evidence on the effectiveness and safety of convalescent plasma therapy for people with COVID-19; all studies were at high risk of bias and reporting quality was low. No RCTs or controlled non-randomised studies evaluating benefits and harms of convalescent plasma have been completed. There are 47 ongoing studies evaluating convalescent plasma, of which 22 are RCTs, and one trial evaluating hyperimmune immunoglobulin. We will update this review as a living systematic review, based on monthly searches in the above mentioned databases and registries. These updates are likely to show different results to those reported here.
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May 2020

Prediction models for diagnosis and prognosis of covid-19: systematic review and critical appraisal

BMJ 2020 04 7;369:m1328. Epub 2020 Apr 7.

Department of Epidemiology, CAPHRI Care and Public Health Research Institute, Maastricht University, Peter Debyeplein 1, 6229 HA Maastricht, Netherlands

Objective: To review and appraise the validity and usefulness of published and preprint reports of prediction models for diagnosing coronavirus disease 2019 (covid-19) in patients with suspected infection, for prognosis of patients with covid-19, and for detecting people in the general population at increased risk of covid-19 infection or being admitted to hospital with the disease.

Design: Living systematic review and critical appraisal by the COVID-PRECISE (Precise Risk Estimation to optimise covid-19 Care for Infected or Suspected patients in diverse sEttings) group.

Data Sources: PubMed and Embase through Ovid, up to 1 July 2020, supplemented with arXiv, medRxiv, and bioRxiv up to 5 May 2020.

Study Selection: Studies that developed or validated a multivariable covid-19 related prediction model.

Data Extraction: At least two authors independently extracted data using the CHARMS (critical appraisal and data extraction for systematic reviews of prediction modelling studies) checklist; risk of bias was assessed using PROBAST (prediction model risk of bias assessment tool).

Results: 37 421 titles were screened, and 169 studies describing 232 prediction models were included. The review identified seven models for identifying people at risk in the general population; 118 diagnostic models for detecting covid-19 (75 were based on medical imaging, 10 to diagnose disease severity); and 107 prognostic models for predicting mortality risk, progression to severe disease, intensive care unit admission, ventilation, intubation, or length of hospital stay. The most frequent types of predictors included in the covid-19 prediction models are vital signs, age, comorbidities, and image features. Flu-like symptoms are frequently predictive in diagnostic models, while sex, C reactive protein, and lymphocyte counts are frequent prognostic factors. Reported C index estimates from the strongest form of validation available per model ranged from 0.71 to 0.99 in prediction models for the general population, from 0.65 to more than 0.99 in diagnostic models, and from 0.54 to 0.99 in prognostic models. All models were rated at high or unclear risk of bias, mostly because of non-representative selection of control patients, exclusion of patients who had not experienced the event of interest by the end of the study, high risk of model overfitting, and unclear reporting. Many models did not include a description of the target population (n=27, 12%) or care setting (n=75, 32%), and only 11 (5%) were externally validated by a calibration plot. The Jehi diagnostic model and the 4C mortality score were identified as promising models.

Conclusion: Prediction models for covid-19 are quickly entering the academic literature to support medical decision making at a time when they are urgently needed. This review indicates that almost all pubished prediction models are poorly reported, and at high risk of bias such that their reported predictive performance is probably optimistic. However, we have identified two (one diagnostic and one prognostic) promising models that should soon be validated in multiple cohorts, preferably through collaborative efforts and data sharing to also allow an investigation of the stability and heterogeneity in their performance across populations and settings. Details on all reviewed models are publicly available at https://www.covprecise.org/. Methodological guidance as provided in this paper should be followed because unreliable predictions could cause more harm than benefit in guiding clinical decisions. Finally, prediction model authors should adhere to the TRIPOD (transparent reporting of a multivariable prediction model for individual prognosis or diagnosis) reporting guideline.

Systematic Review Registration: Protocol https://osf.io/ehc47/, registration https://osf.io/wy245.

Readers' Note: This article is a living systematic review that will be updated to reflect emerging evidence. Updates may occur for up to two years from the date of original publication. This version is update 3 of the original article published on 7 April 2020 (BMJ 2020;369:m1328). Previous updates can be found as data supplements (https://www.bmj.com/content/369/bmj.m1328/related#datasupp). When citing this paper please consider adding the update number and date of access for clarity.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7222643PMC
April 2020

Gender-Specific Aspects of Health Literacy: Perceptions of Interactions with Migrants among Health Care Providers in Germany.

Int J Environ Res Public Health 2020 03 25;17(7). Epub 2020 Mar 25.

Medical Psychology | Neuropsychology and Gender Studies & Center for Neuropsychological Diagnostics and Intervention (CeNDI), Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany.

Health literacy can be described as a complex process shaped by individual resources and preferences and by the nature and quality of health-related information people encounter. The main objective of this study was to explore the views of health care professionals on how gender as a personal determinant of health literacy affected their interactions with migrant patients. The interrelated challenges, needs and applied solutions were analyzed from a health literacy perspective. Five focus group discussions with health care professionals working with migrants ( = 31) were conducted in Cologne, Germany, audio recorded, transcribed and analyzed by qualitative content analysis. Gender-specific aspects, such as the gender of health care providers as a factor, were portrayed above all in relation to patients from Turkey and Arab countries regarding access to and understanding of health-related information. These statements exclusively represent the possibly biased or assumptions-based perspectives of health care professionals on their migrant patients and were made against the background of a systemic lack of time and the challenge of overcoming language barriers. Especially in this context, reducing time pressure and improving communication in the treatment setting may be to the benefit of all actors within healthcare.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7177965PMC
March 2020

Interim PET-results for prognosis in adults with Hodgkin lymphoma: a systematic review and meta-analysis of prognostic factor studies.

Cochrane Database Syst Rev 2020 01 13;1:CD012643. Epub 2020 Jan 13.

Faculty of Medicine and University Hospital Cologne, University of Cologne, Cochrane Cancer, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Kerpener Str. 62, Cologne, Germany, 50937.

Background: Hodgkin lymphoma (HL) is one of the most common haematological malignancies in young adults and, with cure rates of 90%, has become curable for the majority of individuals. Positron emission tomography (PET) is an imaging tool used to monitor a tumour's metabolic activity, stage and progression. Interim PET during chemotherapy has been posited as a prognostic factor in individuals with HL to distinguish between those with a poor prognosis and those with a better prognosis. This distinction is important to inform decision-making on the clinical pathway of individuals with HL.

Objectives: To determine whether in previously untreated adults with HL receiving first-line therapy, interim PET scan results can distinguish between those with a poor prognosis and those with a better prognosis, and thereby predict survival outcomes in each group.

Search Methods: We searched MEDLINE, Embase, CENTRAL and conference proceedings up until April 2019. We also searched one trial registry (ClinicalTrials.gov).

Selection Criteria: We included retrospective and prospective studies evaluating interim PET scans in a minimum of 10 individuals with HL (all stages) undergoing first-line therapy. Interim PET was defined as conducted during therapy (after one, two, three or four treatment cycles). The minimum follow-up period was at least 12 months. We excluded studies if the trial design allowed treatment modification based on the interim PET scan results.

Data Collection And Analysis: We developed a data extraction form according to the Checklist for Critical Appraisal and Data Extraction for Systematic Reviews of Prediction Modelling Studies (CHARMS). Two teams of two review authors independently screened the studies, extracted data on overall survival (OS), progression-free survival (PFS) and PET-associated adverse events (AEs), assessed risk of bias (per outcome) according to the Quality in Prognosis Studies (QUIPS) tool, and assessed the certainty of the evidence (GRADE). We contacted investigators to obtain missing information and data.

Main Results: Our literature search yielded 11,277 results. In total, we included 23 studies (99 references) with 7335 newly-diagnosed individuals with classic HL (all stages). Participants in 16 studies underwent (interim) PET combined with computed tomography (PET-CT), compared to PET only in the remaining seven studies. The standard chemotherapy regimen included ABVD (16) studies, compared to BEACOPP or other regimens (seven studies). Most studies (N = 21) conducted interim PET scans after two cycles (PET2) of chemotherapy, although PET1, PET3 and PET4 were also reported in some studies. In the meta-analyses, we used PET2 data if available as we wanted to ensure homogeneity between studies. In most studies interim PET scan results were evaluated according to the Deauville 5-point scale (N = 12). Eight studies were not included in meta-analyses due to missing information and/or data; results were reported narratively. For the remaining studies, we pooled the unadjusted hazard ratio (HR). The timing of the outcome measurement was after two or three years (the median follow-up time ranged from 22 to 65 months) in the pooled studies. Eight studies explored the independent prognostic ability of interim PET by adjusting for other established prognostic factors (e.g. disease stage, B symptoms). We did not pool the results because the multivariable analyses adjusted for a different set of factors in each study. Overall survival Twelve (out of 23) studies reported OS. Six of these were assessed as low risk of bias in all of the first four domains of QUIPS (study participation, study attrition, prognostic factor measurement and outcome measurement). The other six studies were assessed as unclear, moderate or high risk of bias in at least one of these four domains. Four studies were assessed as low risk, and eight studies as high risk of bias for the domain other prognostic factors (covariates). Nine studies were assessed as low risk, and three studies as high risk of bias for the domain 'statistical analysis and reporting'. We pooled nine studies with 1802 participants. Participants with HL who have a negative interim PET scan result probably have a large advantage in OS compared to those with a positive interim PET scan result (unadjusted HR 5.09, 95% confidence interval (CI) 2.64 to 9.81, I² = 44%, moderate-certainty evidence). In absolute values, this means that 900 out of 1000 participants with a negative interim PET scan result will probably survive longer than three years compared to 585 (95% CI 356 to 757) out of 1000 participants with a positive result. Adjusted results from two studies also indicate an independent prognostic value of interim PET scan results (moderate-certainty evidence). Progression-free survival Twenty-one studies reported PFS. Eleven out of 21 were assessed as low risk of bias in the first four domains. The remaining were assessed as unclear, moderate or high risk of bias in at least one of the four domains. Eleven studies were assessed as low risk, and ten studies as high risk of bias for the domain other prognostic factors (covariates). Eight studies were assessed as high risk, thirteen as low risk of bias for statistical analysis and reporting. We pooled 14 studies with 2079 participants. Participants who have a negative interim PET scan result may have an advantage in PFS compared to those with a positive interim PET scan result, but the evidence is very uncertain (unadjusted HR 4.90, 95% CI 3.47 to 6.90, I² = 45%, very low-certainty evidence). This means that 850 out of 1000 participants with a negative interim PET scan result may be progression-free longer than three years compared to 451 (95% CI 326 to 569) out of 1000 participants with a positive result. Adjusted results (not pooled) from eight studies also indicate that there may be an independent prognostic value of interim PET scan results (low-certainty evidence). PET-associated adverse events No study measured PET-associated AEs.

Authors' Conclusions: This review provides moderate-certainty evidence that interim PET scan results predict OS, and very low-certainty evidence that interim PET scan results predict progression-free survival in treated individuals with HL. This evidence is primarily based on unadjusted data. More studies are needed to test the adjusted prognostic ability of interim PET against established prognostic factors.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6984446PMC
January 2020

Multiple drug combinations of bortezomib, lenalidomide, and thalidomide for first-line treatment in adults with transplant-ineligible multiple myeloma: a network meta-analysis.

Cochrane Database Syst Rev 2019 11 25;2019(11). Epub 2019 Nov 25.

Faculty of Medicine and University Hospital Cologne, University of Cologne, Cochrane Cancer, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Kerpener Str. 62, Cologne, Germany, 50937.

Background: Multiple myeloma is a bone marrow-based hematological malignancy accounting for approximately two per cent of cancers. First-line treatment for transplant-ineligible individuals consists of multiple drug combinations of bortezomib (V), lenalidomide (R), or thalidomide (T). However, access to these medicines is restricted in many countries worldwide.

Objectives: To assess and compare the effectiveness and safety of multiple drug combinations of V, R, and T for adults with newly diagnosed transplant-ineligible multiple myeloma and to inform an application for the inclusion of these medicines into the World Health Organization's (WHO) list of essential medicines.

Search Methods: We searched CENTRAL and MEDLINE, conference proceedings and study registries on 14 February 2019 for randomised controlled trials (RCTs) comparing multiple drug combinations of V, R and T for adults with newly diagnosed transplant-ineligible multiple myeloma.

Selection Criteria: We included RCTs comparing combination therapies of V, R, and T, plus melphalan and prednisone (MP) or dexamethasone (D) for first-line treatment of adults with transplant-ineligible multiple myeloma. We excluded trials including adults with relapsed or refractory disease, trials comparing drug therapies to other types of therapy and trials including second-generation novel agents.

Data Collection And Analysis: Two review authors independently extracted data and assessed risk of bias of included trials. As effect measures we used hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS) and risk ratios (RRs) for adverse events. An HR or RR < 1 indicates an advantage for the intervention compared to the main comparator MP. Where available, we extracted quality of life (QoL) data (scores of standardised questionnaires). Results quoted are from network meta-analysis (NMA) unless stated.

Main Results: We included 25 studies (148 references) comprising 11,403 participants and 21 treatment regimens. Treatments were differentiated between restricted treatment duration (treatment with a pre-specified amount of cycles) and continuous therapy (treatment administered until disease progression, the person becomes intolerant to the drug, or treatment given for a prolonged period). Continuous therapies are indicated with a "c". Risk of bias was generally high across studies due to the open-label study design. Overall survival (OS) Evidence suggests that treatment with RD (HR 0.63 (95% confidence interval (CI) 0.40 to 0.99), median OS 55.2 months (35.2 to 87.0)); TMP (HR 0.75 (95% CI 0.58 to 0.97), median OS: 46.4 months (35.9 to 60.0)); and VRDc (HR 0.49 (95% CI 0.26 to 0.92), median OS 71.0 months (37.8 to 133.8)) probably increases survival compared to median reported OS of 34.8 months with MP (moderate certainty). Treatment with VMP may result in a large increase in OS, compared to MP (HR 0.70 (95% CI 0.45 to 1.07), median OS 49.7 months (32.5 to 77.3)), low certainty). Progression-free survival (PFS) Treatment withRD (HR 0.65 (95% CI0.44 to 0.96), median PFS: 24.9 months (16.9 to 36.8)); TMP (HR 0.63 (95% CI 0.50 to 0.78), median PFS:25.7 months (20.8 to 32.4)); VMP (HR 0.56 (95% CI 0.35 to 0.90), median PFS: 28.9 months (18.0 to 46.3)); and VRDc (HR 0.34 (95% CI 0.20 to 0.58), median PFS: 47.6 months (27.9 to 81.0)) may result in a large increase in PFS (low certainty) compared to MP (median reported PFS: 16.2 months). Adverse events The risk of polyneuropathies may be lower with RD compared to treatment with MP (RR 0.57 (95% CI 0.16 to 1.99), risk for RD: 0.5% (0.1 to 1.8), mean reported risk for MP: 0.9% (10 of 1074 patients affected), low certainty). However, the CIs are also compatible with no difference or an increase in neuropathies. Treatment with TMP (RR 4.44 (95% CI1.77 to 11.11), risk: 4.0% (1.6 to 10.0)) and VMP (RR 88.22 (95% CI 5.36 to 1451.11), risk: 79.4% (4.8 to 1306.0)) probably results in a large increase in polyneuropathies compared to MP (moderate certainty). No study reported the amount of participants with grade ≥ 3 polyneuropathies for treatment with VRDc. VMP probably increases the proportion of participants with serious adverse events (SAEs) compared to MP (RR 1.28 (95% CI 1.06 to 1.54), risk for VMP: 46.2% (38.3 to 55.6), mean risk for MP: 36.1% (177 of 490 patients affected), moderate certainty). RD, TMP, and VRDc were not connected to MP in the network and the risk of SAEs could not be compared. Treatment with RD (RR 4.18 (95% CI 2.13 to 8.20), NMA-risk: 38.5% (19.6 to 75.4)); and TMP (RR 4.10 (95% CI 2.40 to 7.01), risk: 37.7% (22.1 to 64.5)) results in a large increase of withdrawals from the trial due to adverse events (high certainty) compared to MP (mean reported risk: 9.2% (77 of 837 patients withdrew)). The risk is probably slightly increased with VMP (RR 1.06 (95% CI 0.63 to 1.81), risk: 9.75% (5.8 to 16.7), moderate certainty), while it is much increased with VRDc (RR 8.92 (95% CI 3.82 to 20.84), risk: 82.1% (35.1 to 191.7), high certainty) compared to MP. Quality of life QoL was reported in four studies for seven different treatment regimens (MP, MPc, RD, RMP, RMPc, TMP, TMPc) and was measured with four different tools. Assessment and reporting differed between studies and could not be meta-analysed. However, all studies reported an improvement of QoL after initiation of anti-myeloma treatment for all assessed treatment regimens.

Authors' Conclusions: Based on our four pre-selected comparisons of interest, continuous treatment with VRD had the largest survival benefit compared with MP, while RD and TMP also probably considerably increase survival. However, treatment combinations of V, R, and T also substantially increase the incidence of AEs, and lead to a higher risk of treatment discontinuation. Their effectiveness and safety profiles may best be analysed in further randomised head-to-head trials. Further trials should focus on consistent reporting of safety outcomes and should use a standardised instrument to evaluate QoL to ensure comparability of treatment-combinations.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6876545PMC
November 2019

GRADE guidelines 26: informative statements to communicate the findings of systematic reviews of interventions.

J Clin Epidemiol 2020 03 9;119:126-135. Epub 2019 Nov 9.

Department of Health Research Methods, Evidence and Impact, Cochrane Canada, MacGRADE Centre and Michael G. DeGroote Cochrane Canada Centre, McMaster University, 1280 Main St East, Hamilton, L8S 4L8, Canada; Department of Medicine, McMaster University, 1280, Main St East, L8S 4L8, Hamilton, Canada.

Objectives: Clear communication of systematic review findings will help readers and decision makers. We built on previous work to develop an approach that improves the clarity of statements to convey findings and that draws on Grading of Recommendations Assessment, Development and Evaluation (GRADE).

Study Design And Setting: We conducted workshops including 80 attendants and a survey of 110 producers and users of systematic reviews. We calculated acceptability of statements and revised the wording of those that were unacceptable to ≥40% of participants.

Results: Most participants agreed statements should be based on size of effect and certainty of evidence. Statements for low, moderate and high certainty evidence were acceptable to >60%. Key guidance, for example, includes statements for high, moderate and low certainty for a large effect on intervention x as: x results in a large reduction…; x likely results in a large reduction…; x may result in a large reduction…, respectively.

Conclusions: Producers and users of systematic reviews found statements to communicate findings combining size and certainty of an effect acceptable. This article provides GRADE guidance and a wording template to formulate statements in systematic reviews and other decision tools.
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March 2020

GRADE guidelines 27: how to calculate absolute effects for time-to-event outcomes in summary of findings tables and Evidence Profiles.

J Clin Epidemiol 2020 02 9;118:124-131. Epub 2019 Nov 9.

Department of Medical Biometry, Institute for Quality and Efficiency in Health Care, Im Mediapark 8, D-50670 Cologne, Germany.

Objectives: To provide GRADE guidance on how to prepare Summary of Findings tables and Evidence Profiles for time-to-event outcomes with a focus on the calculation of the corresponding absolute effect estimates.

Study Design And Setting: This guidance was justified by a research project identifying frequent errors and limitations in the presentation of time-to-event outcomes in the Summary of Findings tables. We developed this guidance through an iterative process that included membership consultation, feedback, presentation, and discussion at meetings of the GRADE Working Group.

Results: Review authors need to carefully consider the definition of the outcome of interest; although often the event is used as label for the outcome of interest (e.g., death or mortality), the event-free survival (e.g., overall survival) is reported throughout individual studies. Review authors should calculate the absolute effect correctly, either for the event or absence of the event. We also provide examples on how to calculate the absolute effects for events and the absence of events for various baseline or control group risks and time points.

Conclusions: This article aids in the development of Summary of Findings tables and Evidence Profiles, including time-to-event outcomes, and addresses the most common scenarios when calculating absolute effects in order to provide an accurate interpretation.
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February 2020

Interim PET-results for prognosis in adults with Hodgkin lymphoma: a systematic review and meta-analysis of prognostic factor studies.

Cochrane Database Syst Rev 2019 09 16;9:CD012643. Epub 2019 Sep 16.

University of Cologne, Faculty of Medicine and University Hospital Cologne, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Cochrane Haematological Malignancies, Kerpener Str. 62, Cologne, Germany, 50937.

Background: Hodgkin lymphoma (HL) is one of the most common haematological malignancies in young adults and, with cure rates of 90%, has become curable for the majority of individuals. Positron emission tomography (PET) is an imaging tool used to monitor a tumour's metabolic activity, stage and progression. Interim PET during chemotherapy has been posited as a prognostic factor in individuals with HL to distinguish between those with a poor prognosis and those with a better prognosis. This distinction is important to inform decision-making on the clinical pathway of individuals with HL.

Objectives: To determine whether in previously untreated adults with HL receiving first-line therapy, interim PET scan results can distinguish between those with a poor prognosis and those with a better prognosis, and thereby predict survival outcomes in each group.

Search Methods: We searched MEDLINE, Embase, CENTRAL and conference proceedings up until April 2019. We also searched one trial registry (ClinicalTrials.gov).

Selection Criteria: We included retrospective and prospective studies evaluating interim PET scans in a minimum of 10 individuals with HL (all stages) undergoing first-line therapy. Interim PET was defined as conducted during therapy (after one, two, three or four treatment cycles). The minimum follow-up period was at least 12 months. We excluded studies if the trial design allowed treatment modification based on the interim PET scan results.

Data Collection And Analysis: We developed a data extraction form according to the Checklist for Critical Appraisal and Data Extraction for Systematic Reviews of Prediction Modelling Studies (CHARMS). Two teams of two review authors independently screened the studies, extracted data on overall survival (OS), progression-free survival (PFS) and PET-associated adverse events (AEs), assessed risk of bias (per outcome) according to the Quality in Prognosis Studies (QUIPS) tool, and assessed the certainty of the evidence (GRADE). We contacted investigators to obtain missing information and data.

Main Results: Our literature search yielded 11,277 results. In total, we included 23 studies (99 references) with 7335 newly-diagnosed individuals with classic HL (all stages).Participants in 16 studies underwent (interim) PET combined with computed tomography (PET-CT), compared to PET only in the remaining seven studies. The standard chemotherapy regimen included ABVD (16) studies, compared to BEACOPP or other regimens (seven studies). Most studies (N = 21) conducted interim PET scans after two cycles (PET2) of chemotherapy, although PET1, PET3 and PET4 were also reported in some studies. In the meta-analyses, we used PET2 data if available as we wanted to ensure homogeneity between studies. In most studies interim PET scan results were evaluated according to the Deauville 5-point scale (N = 12).Eight studies were not included in meta-analyses due to missing information and/or data; results were reported narratively. For the remaining studies, we pooled the unadjusted hazard ratio (HR). The timing of the outcome measurement was after two or three years (the median follow-up time ranged from 22 to 65 months) in the pooled studies.Eight studies explored the independent prognostic ability of interim PET by adjusting for other established prognostic factors (e.g. disease stage, B symptoms). We did not pool the results because the multivariable analyses adjusted for a different set of factors in each study.Overall survivalTwelve (out of 23) studies reported OS. Six of these were assessed as low risk of bias in all of the first four domains of QUIPS (study participation, study attrition, prognostic factor measurement and outcome measurement). The other six studies were assessed as unclear, moderate or high risk of bias in at least one of these four domains. Nine studies were assessed as high risk, and three studies as moderate risk of bias for the domain study confounding. Eight studies were assessed as low risk, and four studies as high risk of bias for the domain statistical analysis and reporting.We pooled nine studies with 1802 participants. Participants with HL who have a negative interim PET scan result probably have a large advantage in OS compared to those with a positive interim PET scan result (unadjusted HR 5.09, 95% confidence interval (CI) 2.64 to 9.81, I² = 44%, moderate-certainty evidence). In absolute values, this means that 900 out of 1000 participants with a negative interim PET scan result will probably survive longer than three years compared to 585 (95% CI 356 to 757) out of 1000 participants with a positive result.Adjusted results from two studies also indicate an independent prognostic value of interim PET scan results (moderate-certainty evidence).Progression-free survival Twenty-one studies reported PFS. Eleven out of 21 were assessed as low risk of bias in the first four domains. The remaining were assessed as unclear, moderate or high risk of bias in at least one of the four domains. Eleven studies were assessed as high risk, nine studies as moderate risk and one study as low risk of bias for study confounding. Eight studies were assessed as high risk, three as moderate risk and nine as low risk of bias for statistical analysis and reporting.We pooled 14 studies with 2079 participants. Participants who have a negative interim PET scan result may have an advantage in PFS compared to those with a positive interim PET scan result, but the evidence is very uncertain (unadjusted HR 4.90, 95% CI 3.47 to 6.90, I² = 45%, very low-certainty evidence). This means that 850 out of 1000 participants with a negative interim PET scan result may be progression-free longer than three years compared to 451 (95% CI 326 to 569) out of 1000 participants with a positive result.Adjusted results (not pooled) from eight studies also indicate that there may be an independent prognostic value of interim PET scan results (low-certainty evidence).PET-associated adverse eventsNo study measured PET-associated AEs.

Authors' Conclusions: This review provides moderate-certainty evidence that interim PET scan results predict OS, and very low-certainty evidence that interim PET scan results predict progression-free survival in treated individuals with HL. This evidence is primarily based on unadjusted data. More studies are needed to test the adjusted prognostic ability of interim PET against established prognostic factors.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6746624PMC
September 2019

Mindfulness-based stress reduction for women diagnosed with breast cancer.

Cochrane Database Syst Rev 2019 03 27;3:CD011518. Epub 2019 Mar 27.

Cochrane Haematological Malignancies, Department I of Internal Medicine, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany.

Background: Breast cancer is the most common cancer in women. Diagnosis and treatment may drastically affect quality of life, causing symptoms such as sleep disorders, depression and anxiety. Mindfulness-based stress reduction (MBSR) is a programme that aims to reduce stress by developing mindfulness, meaning a non-judgmental, accepting moment-by-moment awareness. MBSR seems to benefit patients with mood disorders and chronic pain, and it may also benefit women with breast cancer.

Objectives: To assess the effects of mindfulness-based stress reduction (MBSR) in women diagnosed with breast cancer.

Search Methods: In April 2018, we conducted a comprehensive electronic search for studies of MBSR in women with breast cancer, in the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, and two trial registries (World Health Organization's International Clinical Trials Registry Platform (WHO ICTRP) and ClinicalTrials.gov). We also handsearched relevant conference proceedings.

Selection Criteria: Randomised clinical trials (RCTs) comparing MBSR versus no intervention in women with breast cancer.

Data Collection And Analysis: We used standard methodological procedures expected by Cochrane. Using a standardised data form, the review authors extracted data in duplicate on methodological quality, participants, interventions and outcomes of interest (quality of life, fatigue, depression, anxiety, quality of sleep, overall survival and adverse events). For outcomes assessed with the same instrument, we used the mean difference (MD) as a summary statistic for meta-analysis; for those assessed with different instruments, we used the standardised mean difference (SMD). The effect of MBSR was assessed in the short term (end of intervention), medium term (up to 6 months after intervention) and long term (up to 24 months after intervention).

Main Results: Fourteen RCTs fulfilled our inclusion criteria, with most studies reporting that they included women with early breast cancer. Ten RCTs involving 1571 participants were eligible for meta-analysis, while four studies involving 185 participants did not report usable results. Queries to the authors of these four studies were unsuccessful. All studies were at high risk of performance and detection bias since participants could not be blinded, and only 3 of 14 studies were at low risk of selection bias. Eight of 10 studies included in the meta-analysis recruited participants with early breast cancer (the remaining 2 trials did not restrict inclusion to a certain cancer type). Most trials considered only women who had completed cancer treatment.MBSR may improve quality of life slightly at the end of the intervention (based on low-certainty evidence from three studies with a total of 339 participants) but may result in little to no difference up to 6 months (based on low-certainty evidence from three studies involving 428 participants). Long-term data on quality of life (up to two years after completing MBSR) were available for one study in 97 participants (MD 0.00 on questionnaire FACT-B, 95% CI -5.82 to 5.82; low-certainty evidence).In the short term, MBSR probably reduces fatigue (SMD -0.50, 95% CI -0.86 to -0.14; moderate-certainty evidence; 5 studies; 693 participants). It also probably slightly reduces anxiety (SMD -0.29, 95% CI -0.50 to -0.08; moderate-certainty evidence; 6 studies; 749 participants), and it reduces depression (SMD -0.54, 95% CI -0.86 to -0.22; high-certainty evidence; 6 studies; 745 participants). It probably slightly improves quality of sleep (SMD -0.38, 95% CI -0.79 to 0.04; moderate-certainty evidence; 4 studies; 475 participants). However, these confidence intervals (except for short-term depression) are compatible with both an improvement and little to no difference.In the medium term, MBSR probably results in little to no difference in medium-term fatigue (SMD -0.31, 95% CI -0.84 to 0.23; moderate-certainty evidence; 4 studies; 607 participants). The intervention probably slightly reduces anxiety (SMD -0.28, 95% CI -0.49 to -0.07; moderate-certainty evidence; 7 studies; 1094 participants), depression (SMD -0.32, 95% CI -0.58 to -0.06; moderate-certainty evidence; 7 studies; 1097 participants) and slightly improves quality of sleep (SMD -0.27, 95% CI -0.63 to 0.08; moderate-certainty evidence; 4 studies; 654 participants). However, these confidence intervals are compatible with both an improvement and little to no difference.In the long term, moderate-certainty evidence shows that MBSR probably results in little to no difference in anxiety (SMD -0.09, 95% CI -0.35 to 0.16; 2 studies; 360 participants) or depression (SMD -0.17, 95% CI -0.40 to 0.05; 2 studies; 352 participants). No long-term data were available for fatigue or quality of sleep.No study reported data on survival or adverse events.

Authors' Conclusions: MBSR may improve quality of life slightly at the end of the intervention but may result in little to no difference later on. MBSR probably slightly reduces anxiety, depression and slightly improves quality of sleep at both the end of the intervention and up to six months later. A beneficial effect on fatigue was apparent at the end of the intervention but not up to six months later. Up to two years after the intervention, MBSR probably results in little to no difference in anxiety and depression; there were no data available for fatigue or quality of sleep.
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http://dx.doi.org/10.1002/14651858.CD011518.pub2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6436161PMC
March 2019

["Transferability": Is GRADE the solution?]

Z Evid Fortbild Qual Gesundhwes 2019 Mar 27;140:52-57. Epub 2019 Feb 27.

Universität zu Köln, Medizinische Fakultät und Uniklinik Köln, Klinik I für Innere Medizin, Evidence-based Oncology.

Biological and social factors, such as age, comorbidities and the care system, may - as well-established effect-modifiers - limit the transferability of study results to populations with dissimilar characteristics. In order to enable transparent and evidence-based decisions in systematic reviews and guidelines targeting subpopulations that are little or not represented in the study landscape, the GRADE approach is a valid tool to assess the certainty of the evidence. GRADE provides a structured methodology that covers all steps, from developing a precise question, prioritizing patient-relevant outcomes and assessing the available evidence to derive recommendations for practice, among other things. Evaluating confidence in a body of evidence comprises judgments on risk of bias, study heterogeneity, directness, including comparability between study population and target population, precision of effect estimates and publication bias. Because GRADE demands transparent decisions about the applicability of study results from the study population to the target population, gaps in the evidence landscape can be uncovered. Overall, the approach cannot solve the problem of the transferability of study results. It does, however, support the explicit handling of applicability and can give impetus to targeted research gaps.
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http://dx.doi.org/10.1016/j.zefq.2019.02.001DOI Listing
March 2019

Yoga for treating urinary incontinence in women.

Cochrane Database Syst Rev 2019 02 28;2:CD012668. Epub 2019 Feb 28.

Center for Integrative Medicine, University of Maryland School of Medicine, 520 W. Lombard Street, Baltimore, Maryland, USA, 21201.

Background: Urinary incontinence in women is associated with poor quality of life and difficulties in social, psychological and sexual functioning. The condition may affect up to 15% of middle-aged or older women in the general population. Conservative treatments such as lifestyle interventions, bladder training and pelvic floor muscle training (used either alone or in combination with other interventions) are the initial approaches to the management of urinary incontinence. Many women are interested in additional treatments such as yoga, a system of philosophy, lifestyle and physical practice that originated in ancient India.

Objectives: To assess the effects of yoga for treating urinary incontinence in women.

Search Methods: We searched the Cochrane Incontinence and Cochrane Complementary Medicine Specialised Registers. We searched the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) and ClinicalTrials.gov to identify any ongoing or unpublished studies. We handsearched Proceedings of the International Congress on Complementary Medicine Research and the European Congress for Integrative Medicine. We searched the NHS Economic Evaluation Database for economic studies, and supplemented this search with searches for economics studies in MEDLINE and Embase from 2015 onwards. Database searches are up-to-date as of 21 June 2018.

Selection Criteria: Randomised controlled trials in women diagnosed with urinary incontinence in which one group was allocated to treatment with yoga.

Data Collection And Analysis: Two review authors independently screened titles and abstracts of all retrieved articles, selected studies for inclusion, extracted data, assessed risk of bias and evaluated the certainty of the evidence for each reported outcome. Any disagreements were resolved by consensus. We planned to combine clinically comparable studies in Review Manager 5 using random-effects meta-analysis and to carry out sensitivity and subgroup analyses. We planned to create a table listing economic studies on yoga for incontinence but not carry out any analyses on these studies.

Main Results: We included two studies (involving a total of 49 women). Each study compared yoga to a different comparator, therefore we were unable to combine the data in a meta-analysis. A third study that has been completed but not yet fully reported is awaiting assessment.One included study was a six-week study comparing yoga to a waiting list in 19 women with either urgency urinary incontinence or stress urinary incontinence. We judged the certainty of the evidence for all reported outcomes as very low due to performance bias, detection bias, and imprecision. The number of women reporting cure was not reported. We are uncertain whether yoga results in satisfaction with cure or improvement of incontinence (risk ratio (RR) 6.33, 95% confidence interval (CI) 1.44 to 27.88; an increase of 592 from 111 per 1000, 95% CI 160 to 1000). We are uncertain whether there is a difference between yoga and waiting list in condition-specific quality of life as measured on the Incontinence Impact Questionnaire Short Form (mean difference (MD) 1.74, 95% CI -33.02 to 36.50); the number of micturitions (MD -0.77, 95% CI -2.13 to 0.59); the number of incontinence episodes (MD -1.57, 95% CI -2.83 to -0.31); or the bothersomeness of incontinence as measured on the Urogenital Distress Inventory 6 (MD -0.90, 95% CI -1.46 to -0.34). There was no evidence of a difference in the number of women who experienced at least one adverse event (risk difference 0%, 95% CI -38% to 38%; no difference from 222 per 1000, 95% CI 380 fewer to 380 more).The second included study was an eight-week study in 30 women with urgency urinary incontinence that compared mindfulness-based stress reduction (MBSR) to an active control intervention of yoga classes. The study was unblinded, and there was high attrition from both study arms for all outcome assessments. We judged the certainty of the evidence for all reported outcomes as very low due to performance bias, attrition bias, imprecision and indirectness. The number of women reporting cure was not reported. We are uncertain whether women in the yoga group were less likely to report improvement in incontinence at eight weeks compared to women in the MBSR group (RR 0.09, 95% CI 0.01 to 1.43; a decrease of 419 from 461 per 1000, 95% CI 5 to 660). We are uncertain about the effect of MBSR compared to yoga on reports of cure or improvement in incontinence, improvement in condition-specific quality of life measured on the Overactive Bladder Health-Related Quality of Life Scale, reduction in incontinence episodes or reduction in bothersomeness of incontinence as measured on the Overactive Bladder Symptom and Quality of Life-Short Form at eight weeks. The study did not report on adverse effects.

Authors' Conclusions: We identified few trials on yoga for incontinence, and the existing trials were small and at high risk of bias. In addition, we did not find any studies of economic outcomes related to yoga for urinary incontinence. Due to the lack of evidence to answer the review question, we are uncertain whether yoga is useful for women with urinary incontinence. Additional, well-conducted trials with larger sample sizes are needed.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6394377PMC
February 2019

Aerobic physical exercise for adult patients with haematological malignancies.

Cochrane Database Syst Rev 2019 01 31;1:CD009075. Epub 2019 Jan 31.

Cochrane Haematological Malignancies Group, Department I of Internal Medicine, University Hospital of Cologne, Kerpener Str. 62, Cologne, Germany.

Background: Although people with haematological malignancies have to endure long phases of therapy and immobility, which is known to diminish their physical performance level, the advice to rest and avoid intensive exercises is still common practice. This recommendation is partly due to the severe anaemia and thrombocytopenia from which many patients suffer. The inability to perform activities of daily living restricts them, diminishes their quality of life and can influence medical therapy.

Objectives: In this update of the original review (published in 2014) our main objective was to re-evaluate the efficacy, safety and feasibility of aerobic physical exercise for adults suffering from haematological malignancies considering the current state of knowledge.

Search Methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library, 2018, Issue 7) and MEDLINE (1950 to July 2018) trials registries (ISRCTN, EU clinical trials register and clinicaltrials.gov) and conference proceedings. We did not apply any language restrictions. Two review authors independently screened search results, disagreements were solved by discussion.

Selection Criteria: We included randomised controlled trials (RCTs) comparing an aerobic physical exercise intervention, intending to improve the oxygen system, in addition to standard care with standard care only for adults suffering from haematological malignancies. We also included studies that evaluated aerobic exercise in addition to strength training. We excluded studies that investigated the effect of training programmes that were composed of yoga, tai chi chuan, qigong or similar types of exercise. We also excluded studies exploring the influence of strength training without additive aerobic exercise as well as studies assessing outcomes without any clinical impact.

Data Collection And Analysis: Two review authors independently screened search results, extracted data and assessed the quality of trials. We used risk ratios (RRs) for adverse events, mortality and 100-day survival, standardised mean differences (SMD) for quality of life (QoL), fatigue, and physical performance, and mean differences (MD) for anthropometric measurements.

Main Results: In this update, nine trials could be added to the nine trials of the first version of the review, thus we included eighteen RCTs involving 1892 participants. Two of these studies (65 participants) did not provide data for our key outcomes (they analysed laboratory values only) and one study (40 patients) could not be included in the meta-analyses, as results were presented as changes scores only and not as endpoint scores. One trial (17 patients) did not report standard errors and could also not be included in meta-analyses. The overall potential risk of bias in the included trials is unclear, due to poor reporting.The majority of participants suffered from acute lymphoblastic leukaemia (ALL), acute myeloid leukaemia (AML), malignant lymphoma and multiple myeloma, and eight trials randomised people receiving stem cell transplantation. Mostly, the exercise intervention consisted of various walking intervention programmes with different duration and intensity levels.Our primary endpoint overall survival (OS) was only reported in one of these studies. The study authors found no evidence for a difference between both arms (RR = 0.67; P = 0.112). Six trials (one trial with four arms, analysed as two sub-studies) reported numbers of deceased participants during the course of the study or during the first 100 to 180 days. For the outcome mortality, there is no evidence for a difference between participants exercising and those in the control group (RR 1.10; 95% CI 0.79 to 1.52; P = 0.59; 1172 participants, low-certainty evidence).For the following outcomes, higher numbers indicate better outcomes, with 1 being the best result for the standardised mean differences. Eight studies analysed the influence of exercise intervention on QoL. It remains unclear, whether physical exercise improves QoL (SMD 0.11; 95% CI -0.03 to 0.24; 1259 participants, low-certainty evidence). There is also no evidence for a difference for the subscales physical functioning (SMD 0.15; 95% CI -0.01 to 0.32; 8 trials, 1329 participants, low-certainty evidence) and anxiety (SMD 0.03; 95% CI -0.30 to 0.36; 6 trials, 445 participants, very low-certainty evidence). Depression might slightly be improved by exercising (SMD 0.19; 95% CI 0.0 to 0.38; 6 trials, 445 participants, low-certainty evidence). There is moderate-certainty evidence that exercise probably improves fatigue (SMD 0.31; 95% CI 0.13 to 0.48; 9 trials, 826 patients).Six trials (435 participants) investigated serious adverse events. We are very uncertain, whether additional exercise leads to more serious adverse events (RR 1.39; 95% CI 0.94 to 2.06), based on very low-certainty evidence.In addition, we are aware of four ongoing trials. However, none of these trials stated, how many patients they will recruit and when the studies will be completed, thus, potential influence of these trials for the current analyses remains unclear.

Authors' Conclusions: Eighteen, mostly small RCTs did not identify evidence for a difference in terms of mortality. Physical exercise added to standard care might improve fatigue and depression. Currently, there is inconclusive evidence regarding QoL, physical functioning, anxiety and SAEs .We need further trials with more participants and longer follow-up periods to evaluate the effects of exercise intervention for people suffering from haematological malignancies. To enhance comparability of study data, development and implementation of core sets of measuring devices would be helpful.
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http://dx.doi.org/10.1002/14651858.CD009075.pub3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6354325PMC
January 2019

Methodological review showed correct absolute effect size estimates for time-to-event outcomes in less than one-third of cancer-related systematic reviews.

J Clin Epidemiol 2019 04 10;108:1-9. Epub 2018 Dec 10.

Department of Pediatric Oncology, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, PO Box 22660, Amsterdam 1100 DD, the Netherlands.

Objectives: To evaluate in how many cancer-related Cochrane reviews hazard ratio (HR)-based absolute effects in summary of findings (SoF) tables have been correctly calculated and reported.

Study Design And Setting: We identified all Cochrane cancer intervention reviews that reported an HR for at least one outcome and provided a SoF table, published between January 2011 and December 2017 in the Cochrane Database of Systematic Reviews.

Results: In 28 reviews (29%) of 96 included Cochrane reviews, absolute effects in the SoF tables were calculated in a correct manner. In 23 reviews (24%), absolute effects had been correctly calculated, but there was no explanation given why authors calculated event-free survival (e.g., overall survival) throughout the review but reported number of events in SoF tables (e.g., death). Twelve reviews (13%) provided incorrect absolute effects. For seven reviews (7%), it was unclear if absolute effects were correctly calculated. In 26 (27%) reviews, no absolute effects based on the given HR were calculated.

Conclusions: In less than one-third of cancer-related Cochrane reviews, absolute effect size estimates were correctly calculated and reported. There is a need for guidance on how to calculate and report absolute effect estimates based on HR data.
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http://dx.doi.org/10.1016/j.jclinepi.2018.12.006DOI Listing
April 2019

Hodgkin Lymphoma in Adults.

Dtsch Arztebl Int 2018 08;115(31-32):535-540

Joint first authors; Department I of Internal Medicine, University Hospital Cologne; German Hodgkin Study Group (GHSG), University Hospital Cologne; Evidence-based Oncology, University Hospital Cologne; German Guideline Program in Oncology of the German Cancer Society, Berlin.

Background: Hodgkin lymphoma is the most common neoplasm in young adults, with an incidence of 2 to 3 cases per 100 000 persons per year. Risk-adapted chemotherapy and radiotherapy usually lead to cure. Finding ways to lessen the treatment- associated morbidity and mortality is a major goal of current research.

Methods: For the creation of an updated guideline (DKH grant number 111778), a systematic literature search was carried out in medical databases (MEDLINE, CENTRAL) and guideline databases (GIN) (search dates: January 2012 to June 2017).

Results: Results from 10 meta-analyses, 89 randomized and controlled trials, and 81 prospective or retrospective trials were evaluated. The use of positron emission tomography (PET) is strongly recommended in the initial diagnostic evaluation, as well as for the guidance of treatment in advanced stages. In early stages, two cycles of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) and involved-site radiotherapy (IS-RT) at a dose of 20 Gy are recommended. For the treatment of intermedi- ate stages, two cycles of escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) + two cycles of ABVD and 30 Gy IS-RT are recommended. In advanced stages, two cycles of escalated BEACOPP are administered, and then PET is performed for the guidance of further treatment: two further cycles of escalated BEACOPP are recommended if the PET is negative and four further cycles if it is positive, followed by radiotherapy of PET- positive residual tumor tissue. The five-year survival of patients with Hodgkin lymphoma is 95%. In case of disease recurrence, high-dose chemotherapy followed by autologous stem-cell transplantation is performed, and targeted drugs including brentuxi- mab vedotin, nivolumab, and pembrolizuab are used.

Conclusion: The highly favorable long-term prognosis of HL necessitates careful consideration of the intensity of treatment as well as thorough follow-up to enable the detection of late sequelae, such as second tumors or organ damage.
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http://dx.doi.org/10.3238/arztebl.2018.0535DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6131364PMC
August 2018
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