Publications by authors named "Jochem König"

103 Publications

Risk factors, physical and mental health burden of male and female pathological gamblers in the German general population aged 40-80.

BMC Psychiatry 2021 Mar 4;21(1):123. Epub 2021 Mar 4.

Department of Psychosomatic Medicine and Psychotherapy, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.

Background: Gambling Disorder (GD) has been associated with considerable mental and physical health risks in clinical samples. The paper determines risk factors, mental and physical health burden of probable GD for both men and women in the general population.

Methods: In the Gutenberg Health Study, a population-based sample of N = 11,875 aged 40-80 years was analyzed regarding lifetime probable GD prevalence (measured with the Lie/ Bet Questionnaire) and a wide array of health variables including standardized measures of depression, anxiety, and somatic symptoms.

Results: Probable GD lifetime prevalence was 2.1%, with higher rates among 1st generation migrants (5.5%; vs. non-migrants 1.6%), men (3.0%; vs. women 1.2%), and the sample's youngest age decade (40-49 y., 3.1%). Lifetime probable GD was associated with current work-related, family and financial stressors as well as unhealthy behavior (smoking, extended screen time), and lifetime legal offenses. In men, but not in women, increased rates of imprisonment, mental and somatic symptoms were found.

Conclusions: GD is a major public health problem with serious social, mental and physical health burden. Epidemiological findings underscore the preponderance of GD among 1st generation migrants and men. Findings are consistent with a vicious cycle of family, work related and financial stress factors, and mental and physical burden, particularly in men. Demographic risk factors may help to target specific prevention and treatment efforts.
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http://dx.doi.org/10.1186/s12888-021-03110-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7931586PMC
March 2021

Systematic Analysis of Combined Thrombolysis Using Ultrasound and Different Fibrinolytic Drugs in an in Vitro Clot Model of Intracerebral Hemorrhage.

Ultrasound Med Biol 2021 May 3;47(5):1334-1342. Epub 2021 Feb 3.

Department of Neurosurgery, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.

Adequate removal of blood clots by minimally invasive surgery seems to correlate with a better clinical outcome in patients with intracerebral hemorrhages (ICHs). Moreover, neurotoxic effects of recombinant tissue plasminogen activator have been reported. The aim of this study was to improve fibrinolysis using an intra-clot ultrasound application with tenecteplase and urokinase in our established ICH clot model. One hundred thirty clots were produced from 25 or 50 mL of human blood, incubated for different periods and equipped with drainage, through which an ultrasound catheter was placed in 65 treatment clots for 1 h, randomly allocated into three groups: administration of ultrasound, administration of 60 IU of tenecteplase or administration of 30,000 IU urokinase. Relative end weights were compared. This study found a significant increase in thrombolysis caused by a combination of ultrasound and fibrinolytic drugs, whereas ultrasound and tenecteplase are significantly more effective in the treatment of larger and aged clots.
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http://dx.doi.org/10.1016/j.ultrasmedbio.2021.01.005DOI Listing
May 2021

Inflammation predicts new onset of depression in men, but not in women within a prospective, representative community cohort.

Sci Rep 2021 Jan 26;11(1):2271. Epub 2021 Jan 26.

Department of Psychosomatic Medicine and Psychotherapy, University Medical Center of the Johannes Gutenberg-University Mainz, Untere Zahlbacher Str. 8, 55131, Mainz, Germany.

Depression has been associated with increased inflammation. However, only few large-scale, prospective studies have evaluated whether inflammation leads to new cases of depression and whether this association can be found in men and women. Longitudinal data of N = 10,357 adult participants with no evidence of depression at baseline (based on Patient Health Questionnaire (PHQ-9), lifetime diagnoses, and current antidepressant medication) were evaluated for depression 5 years later. Multivariate logistic regression models were used to predict the onset of depression based on C-reactive protein (CRP) and white blood cell count (WBC). We used interaction terms and separate analyses in men and women to investigate gender-dependent associations. Based on both markers, inflammation was predictive of new cases of depression 5 years later, even when adjusting for sociodemographic, physical health, health behavior variables, and baseline depression symptoms. As established by interaction terms and separate analyses, inflammatory markers were predictive of depression in men, but not in women. Additional predictors of new onset of depression were younger age, loneliness, smoking (only in men), cancer and less alcohol consumption (only in women). The study indicates gender differences in the etiology of depressive disorders within the community, with a greater role of physical factors in men.
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http://dx.doi.org/10.1038/s41598-021-81927-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7838404PMC
January 2021

[Psychosomatic medicine in the Gutenberg Health Study (GHS) - research questions, measurement instruments, selected results].

Z Psychosom Med Psychother 2020 Dec;66(4):355-375

Klinik und Poliklinik für Psychosomatische Medizin und Psychotherapie Universitätsmedizin Mainz Johannes Gutenberg-Universität Mainz Deutschland.

Main questions from the Gutenberg Health Study (GHS) related to psychosomatic medicine are presented: (1) Prevalence and incidence of mental illnesses, (2) Sex-specific risk- and protective factors for mental health, (3) Interplay between psychological and somatic diseases and (4) methodical-psychometric developments. The GHS is an ongoing, prospective and interdisciplinary cohort study in Mainz. The comprehensive examinations include psychological characteristics and clinical and laboratory tests. 15010 respondents were selected in the baseline study from 2007 until 2012 and re-examined after 2.5 years and 5 years. Of the first 5000 respondents in the baseline study 413 women (8.7 %) and 276 men (5.8 %) indicated depressive symptoms (PHQ-9 > = 10). After five years, half of the participants with depressive symptoms at baseline also indicated depressive symptoms five years later. Risk factors for men were a lack of social support, for women smoking and Type D personality. The proportion of new cases of depression at follow-up was 4.4 %. Risk factors were symptoms of anxiety, Type D, smoking and comorbid cancer. Protective were age and social support. Findings on the association of physical and mental disorders and their behavioral and biological links (atherosclerosis, inflammation) are presented. Prospective assessment of biological, psychological and social parameters offers the possibility to study their interplay in the development of mental and somatic illnesses.
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http://dx.doi.org/10.13109/zptm.2020.66.4.355DOI Listing
December 2020

Efficacy and Toxicity of Different Chemotherapy Protocols for Concurrent Chemoradiation in Non-Small Cell Lung Cancer-A Secondary Analysis of the PET Plan Trial.

Cancers (Basel) 2020 Nov 13;12(11). Epub 2020 Nov 13.

Department of Radiation Oncology, Medical Center-University of Freiburg, Robert-Koch-Str. 3, 79106 Freiburg, Germany.

(1) Background: The optimal chemotherapy (CHT) regimen for concurrent chemoradiation (cCRT) is not well defined. In this secondary analysis of the international randomized PET-Plan trial, we evaluate the efficacy of different CHT. (2) Methods: Patients with inoperable NSCLC were randomized at a 1:1 ratio regarding the target volume definition and received isotoxically dose-escalated cCRT using cisplatin 80 mg/m (day 1, 22) and vinorelbin 15 mg/m (day 1, 8, 22, 29) (P1) or cisplatin 20 mg/m (day 1-5, 29-33) and vinorelbin 12.5 mg/m (day 1, 8, 15, 29, 36, 43) (P2) or carboplatin AUC1 (day 1-5, 29-33) and vinorelbin 12.5 mg/m (day 1, 8, 15, 29, 36, 43) (P3) or other CHT at the treating physician's discretion. (3) Results: Between 05/2009 and 11/2016, 205 patients were randomized and 172 included in the per-protocol analysis. Patients treated in P1 or P2 had a better overall survival (OS) compared to P3 ( = 0.015, = 0.01, respectively). Patients treated with carboplatin had a worse OS compared to cisplatin (HR 1.78, = 0.03), but the difference did not remain significant after adjusting for age, ECOG, cardiac function creatinine and completeness of CHT. (4) Conclusions: Carboplatin doublets show no significant difference compared to cisplatin, after adjusting for possibly relevant factors, probably due to existing selection bias.
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http://dx.doi.org/10.3390/cancers12113359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7697287PMC
November 2020

Recalled parental rearing behavior in adult women and men with depressive and anxiety symptoms: Findings from a community study.

Z Psychosom Med Psychother 2020 Sep;66(3):243-258

Department of Psychosomatic Medicine and Psychotherapy University Medical Center of the Johannes Gutenberg University Mainz Germany.

Addressing the lack of population-based data, the purpose of this representative study was to assess sex- and age-specific associations of maternal and paternal rearing behavior with depressiveness and anxiety controlling for sociodemographic and somatic variables. 8,175 subjects participating in a population-based study completed standardized questionnaires measuring Recalled Parental Rearing Behavior and distress. Women recalled their fathers as more controlling and warmer, and their mothers as more rejecting than men. Comparisons between age groups (≤ 60 vs. > 60 years) revealed that younger participants recalled more parental control and emotional warmth. In addition to sociodemographic and somatic risk factors, paternal rejection and maternal control were associated with depressiveness and anxiety both for women and men (OR 1.58-1.96; OR 1.37-1.66). Maternal warmth was negatively related to distress (OR 0.66-0.69). Findings suggested sex- and age-specific differences in recalled maternal and paternal rearing behavior. The current results highlighted the important role of recalled parental rearing behavior besides sociodemographic factors and somatic diseases for the occurrence of depression and anxiety symptoms across the age groups.
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http://dx.doi.org/10.13109/zptm.2020.66.3.243DOI Listing
September 2020

Discrepancies from registered protocols and spin occurred frequently in randomized psychotherapy trials-A meta-epidemiologic study.

J Clin Epidemiol 2020 12 20;128:49-56. Epub 2020 Aug 20.

Department of Psychiatry and Psychotherapy, University Medical Center Mainz, Untere Zahlbacher Straße 8, 55131 Mainz, Germany; Leibniz Institute for Resilience Research, Wallstraße 7, 55122 Mainz, Germany.

Objectives: This study aimed to investigate the relationship between trial registration, trial discrepancy from registered protocol, and spin in nonpharmacological trials.

Study Design And Setting: Recent psychotherapy trials on depression (2015-2018) were analyzed regarding their registration status and its relationship to discrepancies between registered and published primary outcomes and to spin (discrepancy between the nonsignificant finding in a study and an overly beneficial interpretation of the effect of the treatment).

Results: A total of 196 trials were identified, of which 78 (40%) had been registered prospectively and 56 (29%) had been registered retrospectively. In 102 (76%) of 134 registered trials, discrepancies between trial and protocol were present. Of 72 trials with a nonsignificant difference between treatments for the primary outcome, 68 trials (94%) showed spin. Discrepancies from protocol were less frequent in prospectively than in retrospectively registered trials (odds ratio= 0.19; 95% confidence interval [CI]: 0.07-0.52), but regarding the amount of spin, there was no difference between prospectively and retrospectively registered trials (r = -0.12; 95% CI: -0.41 to 0.19) or between registered and unregistered trials (r = -0.22, 95% CI -0.49 to 0.08).

Conclusion: Protocol discrepancies and spin have a high prevalence in psychotherapy outcome research. The results show no relation between registration and spin, but prospective registration may prevent discrepancies from protocol.
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http://dx.doi.org/10.1016/j.jclinepi.2020.08.013DOI Listing
December 2020

Comparative analysis of fibrinolytic properties of Alteplase, Tenecteplase and Urokinase in an in vitro clot model of intracerebral haemorrhage.

J Stroke Cerebrovasc Dis 2020 Sep 29;29(9):105073. Epub 2020 Jun 29.

Department of Neurosurgery, University Medical Centre of the Johannes Gutenberg University of Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.

Objective: Hematoma lysis with recombinant tissue plasminogen activator (rtPA) has emerged as an alternative therapy for spontaneous intracerebral and intraventricular haemorrhage (ICH and IVH). However, the MISTIE III and CLEAR III trial failed to show significant improvement of favourable outcomes. Besides experimental and clinical trials revealed neurotoxic effects of rtPA. The demand for optimization of fibrinolytic therapy persists. Herein, we used our recently devised clot model of ICH to systematically analyse fibrinolytic properties of rtPA, tenecteplase and urokinase.

Methods: In vitro clots of human blood (size: 25 ml and 50 ml; age: 1.5 tenecteplase, 24 tenecteplase and 48 tenecteplase) were produced and equipped with a catheter into the clot core for drug delivery and drainage. Various doses of tenecteplase and urokinase with different treatment periods were examined (overall 117 clots), assessing the optimal dose and treatment time of these fibrinolytics. Clots were weighed before and at the end of treatment. These results were compared with clots treated with 1 mg rtPA or with 0.9% sodium chloride solution.

Results: The optimal treatment scheme of tenecteplase was found to be 100 IU with an incubation time of 30 min, for urokinase it was 50 000 IU with an incubation time of 20 min. The relative clot end weight of tenecteplase and urokinase (31.3±11.9%, 34.8 ±7.7%) was comparable to rtPA (36.7±10.7%). Larger clots were more effectively treated with tenecteplase compared to the control group (P=0.0013). urokinase and tenecteplase had similar lysis rates in aged clots and 90 min clots. One and two repetitive treatments with tenecteplase were as effective as two and three cycles of urokinase.

Conclusions: In our in vitro clot model we could determine optimal treatment regimens of tenecteplase (100 IU, 30 min) and urokinase (50 000 IU, 20 min). Urokinase and tenecteplase were comparable in their fibrinolytic potential compared to 1mg rtPA in small clots and showed an effective lysis in aged clots. tenecteplase was more effective in larger clots.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2020.105073DOI Listing
September 2020

Comparative analysis of fibrinolytic properties of Alteplase, Tenecteplase and Urokinase in an in vitro clot model of intracerebral haemorrhage.

J Stroke Cerebrovasc Dis 2020 Sep 29;29(9):105073. Epub 2020 Jun 29.

Department of Neurosurgery, University Medical Centre of the Johannes Gutenberg University of Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.

Objective: Hematoma lysis with recombinant tissue plasminogen activator (rtPA) has emerged as an alternative therapy for spontaneous intracerebral and intraventricular haemorrhage (ICH and IVH). However, the MISTIE III and CLEAR III trial failed to show significant improvement of favourable outcomes. Besides experimental and clinical trials revealed neurotoxic effects of rtPA. The demand for optimization of fibrinolytic therapy persists. Herein, we used our recently devised clot model of ICH to systematically analyse fibrinolytic properties of rtPA, tenecteplase and urokinase.

Methods: In vitro clots of human blood (size: 25 ml and 50 ml; age: 1.5 tenecteplase, 24 tenecteplase and 48 tenecteplase) were produced and equipped with a catheter into the clot core for drug delivery and drainage. Various doses of tenecteplase and urokinase with different treatment periods were examined (overall 117 clots), assessing the optimal dose and treatment time of these fibrinolytics. Clots were weighed before and at the end of treatment. These results were compared with clots treated with 1 mg rtPA or with 0.9% sodium chloride solution.

Results: The optimal treatment scheme of tenecteplase was found to be 100 IU with an incubation time of 30 min, for urokinase it was 50 000 IU with an incubation time of 20 min. The relative clot end weight of tenecteplase and urokinase (31.3±11.9%, 34.8 ±7.7%) was comparable to rtPA (36.7±10.7%). Larger clots were more effectively treated with tenecteplase compared to the control group (P=0.0013). urokinase and tenecteplase had similar lysis rates in aged clots and 90 min clots. One and two repetitive treatments with tenecteplase were as effective as two and three cycles of urokinase.

Conclusions: In our in vitro clot model we could determine optimal treatment regimens of tenecteplase (100 IU, 30 min) and urokinase (50 000 IU, 20 min). Urokinase and tenecteplase were comparable in their fibrinolytic potential compared to 1mg rtPA in small clots and showed an effective lysis in aged clots. tenecteplase was more effective in larger clots.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2020.105073DOI Listing
September 2020

Psychological interventions to foster resilience in healthcare students.

Cochrane Database Syst Rev 2020 07 20;7:CD013684. Epub 2020 Jul 20.

Leibniz Institute for Resilience Research (LIR), Mainz, Germany.

Background: Resilience can be defined as maintaining or regaining mental health during or after significant adversities such as a potentially traumatising event, challenging life circumstances, a critical life transition or physical illness. Healthcare students, such as medical, nursing, psychology and social work students, are exposed to various study- and work-related stressors, the latter particularly during later phases of health professional education. They are at increased risk of developing symptoms of burnout or mental disorders. This population may benefit from resilience-promoting training programmes.

Objectives: To assess the effects of interventions to foster resilience in healthcare students, that is, students in training for health professions delivering direct medical care (e.g. medical, nursing, midwifery or paramedic students), and those in training for allied health professions, as distinct from medical care (e.g. psychology, physical therapy or social work students).

Search Methods: We searched CENTRAL, MEDLINE, Embase, 11 other databases and three trial registries from 1990 to June 2019. We checked reference lists and contacted researchers in the field. We updated this search in four key databases in June 2020, but we have not yet incorporated these results.

Selection Criteria: Randomised controlled trials (RCTs) comparing any form of psychological intervention to foster resilience, hardiness or post-traumatic growth versus no intervention, waiting list, usual care, and active or attention control, in adults (18 years and older), who are healthcare students. Primary outcomes were resilience, anxiety, depression, stress or stress perception, and well-being or quality of life. Secondary outcomes were resilience factors.

Data Collection And Analysis: Two review authors independently selected studies, extracted data, assessed risks of bias, and rated the certainty of the evidence using the GRADE approach (at post-test only).

Main Results: We included 30 RCTs, of which 24 were set in high-income countries and six in (upper- to lower-) middle-income countries. Twenty-two studies focused solely on healthcare students (1315 participants; number randomised not specified for two studies), including both students in health professions delivering direct medical care and those in allied health professions, such as psychology and physical therapy. Half of the studies were conducted in a university or school setting, including nursing/midwifery students or medical students. Eight studies investigated mixed samples (1365 participants), with healthcare students and participants outside of a health professional study field. Participants mainly included women (63.3% to 67.3% in mixed samples) from young adulthood (mean age range, if reported: 19.5 to 26.83 years; 19.35 to 38.14 years in mixed samples). Seventeen of the studies investigated group interventions of high training intensity (11 studies; > 12 hours/sessions), that were delivered face-to-face (17 studies). Of the included studies, eight compared a resilience training based on mindfulness versus unspecific comparators (e.g. wait-list). The studies were funded by different sources (e.g. universities, foundations), or a combination of various sources (four studies). Seven studies did not specify a potential funder, and three studies received no funding support. Risk of bias was high or unclear, with main flaws in performance, detection, attrition and reporting bias domains. At post-intervention, very-low certainty evidence indicated that, compared to controls, healthcare students receiving resilience training may report higher levels of resilience (standardised mean difference (SMD) 0.43, 95% confidence interval (CI) 0.07 to 0.78; 9 studies, 561 participants), lower levels of anxiety (SMD -0.45, 95% CI -0.84 to -0.06; 7 studies, 362 participants), and lower levels of stress or stress perception (SMD -0.28, 95% CI -0.48 to -0.09; 7 studies, 420 participants). Effect sizes varied between small and moderate. There was little or no evidence of any effect of resilience training on depression (SMD -0.20, 95% CI -0.52 to 0.11; 6 studies, 332 participants; very-low certainty evidence) or well-being or quality of life (SMD 0.15, 95% CI -0.14 to 0.43; 4 studies, 251 participants; very-low certainty evidence). Adverse effects were measured in four studies, but data were only reported for three of them. None of the three studies reported any adverse events occurring during the study (very-low certainty of evidence).

Authors' Conclusions: For healthcare students, there is very-low certainty evidence for the effect of resilience training on resilience, anxiety, and stress or stress perception at post-intervention. The heterogeneous interventions, the paucity of short-, medium- or long-term data, and the geographical distribution restricted to high-income countries limit the generalisability of results. Conclusions should therefore be drawn cautiously. Since the findings suggest positive effects of resilience training for healthcare students with very-low certainty evidence, high-quality replications and improved study designs (e.g. a consensus on the definition of resilience, the assessment of individual stressor exposure, more attention controls, and longer follow-up periods) are clearly needed.
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http://dx.doi.org/10.1002/14651858.CD013684DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7388680PMC
July 2020

The association between recalled parental rearing behavior and depressiveness: a comparison between 1st immigrants and non-immigrants in the population-based Gutenberg Health Study.

BMC Psychiatry 2020 07 13;20(1):367. Epub 2020 Jul 13.

Department of Psychosomatic Medicine and Psychotherapy, University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstraße 1, 55131, Mainz, Germany.

Background: Studies in immigrant youth have suggested differences in parenting patterns by immigration status. Knowledge of variation in recalled parenting pattern and its distinctive impact on mental health in adult immigrants, however, is limited. Therefore, the purpose of the current study was to investigate similarities and differences in recalled maternal and paternal rearing behavior and its association with depressiveness in adult 1st generation immigrants compared to non-immigrants.

Methods: Seven hundred and forty-three 1st generation immigrants (M = 57.4, SD = 10.1 years) and 6518 non-immigrants (M = 60.3, SD = 10.7 years) participated in a population-based study. Regarding countries of origin, the largest subgroups were immigrants from Eastern-Europe, Former-SU, and Arabic-Islamic countries. All participants completed the ultra-short version of The Recalled Parental Rearing Behavior-questionnaire and the PHQ-9 assessing depressiveness. Multiple linear regressions with depressiveness as outcome variable were analyzed separately for each facet of parental rearing behavior adjusting for socio-demographic and migration-related variables.

Results: In addition to differences in depressiveness and socioeconomic status, 1st generation immigrants recalled both their mothers and fathers as more controlling and overprotecting than non-immigrants. Parental emotional warmth was negatively associated with depressiveness across all groups. The relationship between parental control, respectively parental rejection and depressiveness, however, varied in direction and severity between the groups.

Conclusion: The results support the notion that parental warmth is a universal protective factor against depressiveness, whereas the impact of parental control on mental health might be more culturally influenced. Analyses point to the importance of considering the unique contribution of fathers' rearing behavior on mental health, particularly in immigrant samples.
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http://dx.doi.org/10.1186/s12888-020-02755-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7358206PMC
July 2020

Psychological interventions to foster resilience in healthcare professionals.

Cochrane Database Syst Rev 2020 07 5;7:CD012527. Epub 2020 Jul 5.

Leibniz Institute for Resilience Research (LIR), Mainz, Germany.

Background: Resilience can be defined as the maintenance or quick recovery of mental health during or after periods of stressor exposure, which may result from a potentially traumatising event, challenging life circumstances, a critical life transition phase, or physical illness. Healthcare professionals, such as nurses, physicians, psychologists and social workers, are exposed to various work-related stressors (e.g. patient care, time pressure, administration) and are at increased risk of developing mental disorders. This population may benefit from resilience-promoting training programmes.

Objectives: To assess the effects of interventions to foster resilience in healthcare professionals, that is, healthcare staff delivering direct medical care (e.g. nurses, physicians, hospital personnel) and allied healthcare staff (e.g. social workers, psychologists).

Search Methods: We searched CENTRAL, MEDLINE, Embase, 11 other databases and three trial registries from 1990 to June 2019. We checked reference lists and contacted researchers in the field. We updated this search in four key databases in June 2020, but we have not yet incorporated these results.

Selection Criteria: Randomised controlled trials (RCTs) in adults aged 18 years and older who are employed as healthcare professionals, comparing any form of psychological intervention to foster resilience, hardiness or post-traumatic growth versus no intervention, wait-list, usual care, active or attention control. Primary outcomes were resilience, anxiety, depression, stress or stress perception and well-being or quality of life. Secondary outcomes were resilience factors.

Data Collection And Analysis: Two review authors independently selected studies, extracted data, assessed risks of bias, and rated the certainty of the evidence using the GRADE approach (at post-test only).

Main Results: We included 44 RCTs (high-income countries: 36). Thirty-nine studies solely focused on healthcare professionals (6892 participants), including both healthcare staff delivering direct medical care and allied healthcare staff. Four studies investigated mixed samples (1000 participants) with healthcare professionals and participants working outside of the healthcare sector, and one study evaluated training for emergency personnel in general population volunteers (82 participants). The included studies were mainly conducted in a hospital setting and included physicians, nurses and different hospital personnel (37/44 studies). Participants mainly included women (68%) from young to middle adulthood (mean age range: 27 to 52.4 years). Most studies investigated group interventions (30 studies) of high training intensity (18 studies; > 12 hours/sessions), that were delivered face-to-face (29 studies). Of the included studies, 19 compared a resilience training based on combined theoretical foundation (e.g. mindfulness and cognitive-behavioural therapy) versus unspecific comparators (e.g. wait-list). The studies were funded by different sources (e.g. hospitals, universities), or a combination of different sources. Fifteen studies did not specify the source of their funding, and one study received no funding support. Risk of bias was high or unclear for most studies in performance, detection, and attrition bias domains. At post-intervention, very-low certainty evidence indicated that, compared to controls, healthcare professionals receiving resilience training may report higher levels of resilience (standardised mean difference (SMD) 0.45, 95% confidence interval (CI) 0.25 to 0.65; 12 studies, 690 participants), lower levels of depression (SMD -0.29, 95% CI -0.50 to -0.09; 14 studies, 788 participants), and lower levels of stress or stress perception (SMD -0.61, 95% CI -1.07 to -0.15; 17 studies, 997 participants). There was little or no evidence of any effect of resilience training on anxiety (SMD -0.06, 95% CI -0.35 to 0.23; 5 studies, 231 participants; very-low certainty evidence) or well-being or quality of life (SMD 0.14, 95% CI -0.01 to 0.30; 13 studies, 1494 participants; very-low certainty evidence). Effect sizes were small except for resilience and stress reduction (moderate). Data on adverse effects were available for three studies, with none reporting any adverse effects occurring during the study (very-low certainty evidence).

Authors' Conclusions: For healthcare professionals, there is very-low certainty evidence that, compared to control, resilience training may result in higher levels of resilience, lower levels of depression, stress or stress perception, and higher levels of certain resilience factors at post-intervention. The paucity of medium- or long-term data, heterogeneous interventions and restricted geographical distribution limit the generalisability of our results. Conclusions should therefore be drawn cautiously. The findings suggest positive effects of resilience training for healthcare professionals, but the evidence is very uncertain. There is a clear need for high-quality replications and improved study designs.
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http://dx.doi.org/10.1002/14651858.CD012527.pub2DOI Listing
July 2020

Less is more? Imaging-based target volume reduction - Authors' reply.

Lancet Oncol 2020 06;21(6):e303

Institute of Medical Biostatistics, Epidemiology and Informatics, University Hospital Mainz, Mainz, Germany.

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http://dx.doi.org/10.1016/S1470-2045(20)30284-9DOI Listing
June 2020

Chromogranin Serves as Novel Biomarker of Endocrine and Gastric Autoimmunity.

J Clin Endocrinol Metab 2020 08;105(8)

Department of Medicine I, Johannes Gutenberg University (JGU) Medical Center, Mainz, Germany.

Context: The glycoprotein chromogranin A (CgA) is expressed by endocrine and neuroendocrine cells. High levels of serum CgA serve as markers of neuroendocrine tumors (NET), but its role in autoimmunity has not been assessed.

Objective: To investigate CgA utility as a marker of endocrine autoimmunity.

Methods: CgA serum levels were evaluated in 807 consecutive unselected participants (cross-sectional study) with the time-resolved amplified cryptate emission technology.

Results: Serum CgA concentrations were increased in 66%, 39%, 38%, and 24% of patients with NET, type 1 diabetes (T1D), autoimmune gastritis (AG) and autoimmune polyendocrinopathy (AP), respectively. Compared with healthy participant controls (C), the odds of positive CgA measurement were up to 28 times higher in the disease groups. In detail, the odds ratios (ORs) for positive CgA levels were 27.98, 15.22, 7.32 (all P < 0.0001) and 3.89 (P = 0.0073) in patients with NET, T1D, AG, and AP, respectively. In AG, CgA and serum gastrin correlated positively (r = 0.55; P < 0.0001). The area under the receiver operating characteristic curve to predict AG was higher for parietal cell antibody (PCA) positivity than for CgA (0.84 vs 0.67; P < 0.0001). However, in combination with PCA and intrinsic factor autoantibodies, CgA independently improved prediction of AG (OR 6.5; P = 0.031). An impact of age on CgA positivity and on CgA value was detected (P < 0.0001) while current smoking significantly increased CgA serum levels by 25% (P = 0.0080).

Conclusion: CgA qualifies as a novel biomarker for T1D, AP, and AG.
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http://dx.doi.org/10.1210/clinem/dgaa288DOI Listing
August 2020

Acoustic radiation force impulse point shear wave elastography of the liver and spleen in patients with Gaucher disease type 1: Correlations with clinical data and markers of disease severity.

Mol Genet Metab 2020 06 27;130(2):140-148. Epub 2020 Mar 27.

Department of Diagnostic and Interventional Radiology, Section of Pediatric Radiology, Medical Center of the Johannes Gutenberg-University, Mainz, Germany.

Purpose: To evaluate the feasibility of acoustic radiation force impulse point shear wave elastography (ARFI-pSWE) of the liver and spleen in patients with Gaucher disease type 1 (GD1), and to assess correlations between organ stiffness and clinico-radiologic data, particularly the GD1 Severity Scoring System (GD-DS3).

Materials And Methods: We retrospectively evaluated the results of ARFI-pSWE as measures of liver and spleen stiffness in 57 patients with GD1. The feasibility of the method was assessed. Correlations between elastography data and clinical data related to the metabolic syndrome, laboratory tests, and GD1-related clinico-radiologic data (bone marrow burden score, GD-DS3) were assessed.

Results: ARFI-pSWE provided reliable results (i.e. standard deviation <30% of the mean value between the measurements) in 50/57 patients. Significant liver fibrosis was present in 35/50 patients (70%). Liver stiffness significantly correlated with GD-DS3 score (p = .03), and number of fulfilled criteria of metabolic syndrome (p = .03). Spleen stiffness significantly correlated with age (p = .021), body mass index (p = .002), number of fulfilled criteria of metabolic syndrome (p = .02), and several laboratory parameters (alanine aminotransferase, gamma glutamyltranspeptidase, triglycerides, cholesterol), and nearly significantly with GD-DS3 score (p = .059).

Conclusion: ARFI-pSWE is a useful tool for a more detailed assessment of disease severity in patients with GD1, which adds relevant information to the standard clinical scores. Thus, elastography might allow for extended therapy monitoring, especially in patients with significant liver fibrosis. Spleen elastography showed promising results; thus, its role should be further investigated.
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http://dx.doi.org/10.1016/j.ymgme.2020.03.006DOI Listing
June 2020

Prevalence and new onset of depression and anxiety among participants with AMD in a European cohort.

Sci Rep 2020 03 16;10(1):4816. Epub 2020 Mar 16.

Department of Psychosomatic Medicine and Psychotherapy, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, 55131, Germany.

To investigate the prevalence and new onset of depression and anxiety among subjects with age-related macular degeneration (AMD) and its association with AMD in a large European cohort with relatively good visual acuity. 11,834 participants enrolled in the German population-based Gutenberg Health Study were studied. AMD was diagnosed by grading of fundus photographs. Depression and anxiety were assessed with the Patient Health Questionnaire and the Generalized Anxiety Disorder-2 Scale, respectively. Logistic regression analyses were performed and adjusted for several parameters. 1,089 (9.2%) participants were diagnosed having AMD. Prevalence of depression in AMD and non-AMD participants was 7.2% and 8.0%, respectively and prevalence of anxiety was 4.2% and 7.0%, respectively. New onset of depression and anxiety at 5-year follow-up in AMD subjects was 2.6% and 3.6%, respectively. AMD was not associated with depression (OR 0.93; CI 95% 0.70-1.20; p = 0.62). AMD was associated with less anxiety (OR 0.67; CI 95% 0.47-0.93; p = 0.02). This is the first study analyzing both prevalence and new onset of depression and anxiety in AMD subjects. AMD- and non-AMD participants had a similar prevalence and new onset of depression in our population-based sample. Participants without AMD had a higher prevalence of anxiety. AMD was not associated with depression.
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http://dx.doi.org/10.1038/s41598-020-61706-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7075932PMC
March 2020

Imaging-based target volume reduction in chemoradiotherapy for locally advanced non-small-cell lung cancer (PET-Plan): a multicentre, open-label, randomised, controlled trial.

Lancet Oncol 2020 04 12;21(4):581-592. Epub 2020 Mar 12.

Department of Radiation Oncology, Faculty of Medicine, Medical Center, University of Freiburg, Freiburg, Germany; German Cancer Consortium Partner Site Freiburg and German Cancer Research Center, Heidelberg, Germany.

Background: With increasingly precise radiotherapy and advanced medical imaging, the concept of radiotherapy target volume planning might be redefined with the aim of improving outcomes. We aimed to investigate whether target volume reduction is feasible and effective compared with conventional planning in the context of radical chemoradiotherapy for patients with locally advanced non-small-cell lung cancer.

Methods: We did a multicentre, open-label, randomised, controlled trial (PET-Plan; ARO-2009-09) in 24 centres in Austria, Germany, and Switzerland. Previously untreated patients (aged older than 18 years) with inoperable locally advanced non-small-cell lung cancer suitable for chemoradiotherapy and an Eastern Cooperative Oncology Group performance status of less than 3 were included. Undergoing F-fluorodeoxyglucose (F-FDG) PET and CT for treatment planning, patients were randomly assigned (1:1) using a random number generator and block sizes between four and six to target volume delineation informed by F-FDG PET and CT plus elective nodal irradiation (conventional target group) or target volumes informed by PET alone (F-FDG PET-based target group). Randomisation was stratified by centre and Union for International Cancer Control stage. In both groups, dose-escalated radiotherapy (60-74 Gy, 2 Gy per fraction) was planned to the respective target volumes and applied with concurrent platinum-based chemotherapy. The primary endpoint was time to locoregional progression from randomisation with the objective to test non-inferiority of F-FDG PET-based planning with a prespecified hazard ratio (HR) margin of 1·25. The per-protocol set was included in the primary analysis. The safety set included all patients receiving any study-specific treatment. Patients and study staff were not masked to treatment assignment. This study is registered with ClinicalTrials.gov, NCT00697333.

Findings: From May 13, 2009, to Dec 5, 2016, 205 of 311 recruited patients were randomly assigned to the conventional target group (n=99) or the F-FDG PET-based target group (n=106; the intention-to-treat set), and 172 patients were treated per protocol (84 patients in the conventional target group and 88 in the F-FDG PET-based target group). At a median follow-up of 29 months (IQR 9-54), the risk of locoregional progression in the F-FDG PET-based target group was non-inferior to, and in fact lower than, that in the conventional target group in the per-protocol set (14% [95% CI 5-21] vs 29% [17-38] at 1 year; HR 0·57 [95% CI 0·30-1·06]). The risk of locoregional progression in the F-FDG PET-based target group was also non-inferior to that in the conventional target group in the intention-to-treat set (17% [95% CI 9-24] vs 30% [20-39] at 1 year; HR 0·64 [95% CI 0·37-1·10]). The most common acute grade 3 or worse toxicity was oesophagitis or dysphagia (16 [16%] of 99 patients in the conventional target group vs 17 [16%] of 105 patients in the F-FDG PET-based target group); the most common late toxicities were lung-related (12 [12%] vs 11 [10%]). 20 deaths potentially related to study treatment were reported (seven vs 13).

Interpretation: F-FDG PET-based planning could potentially improve local control and does not seem to increase toxicity in patients with chemoradiotherapy-treated locally advanced non-small-cell lung cancer. Imaging-based target volume reduction in this setting is, therefore, feasible, and could potentially be considered standard of care. The procedures established might also support imaging-based target volume reduction concepts for other tumours.

Funding: German Cancer Aid (Deutsche Krebshilfe).
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http://dx.doi.org/10.1016/S1470-2045(20)30013-9DOI Listing
April 2020

[Evaluation of the Language-related Domain of the Pediatric Developmental Screening Instrument for Preschool Health Examinations (SOPESS): Results from the Prospective Child Health Survey ikidS].

Gesundheitswesen 2021 Mar 27;83(3):215-221. Epub 2020 Feb 27.

Abteilung für Pädiatrische Epidemiologie, Institut für Medizinische Biometrie, Epidemiologie und Informatik, Universitätsmedizin der Johannes Gutenberg-Universität Mainz.

Purpose Of The Study: Developmental delays at school enrollment can affect early educational achievement. Thus, diagnosis and treatment prior to school entry are important. In Germany, SOPESS - a pediatric developmental screening instrument for preschool health examinations (PHE) - was introduced in several federal states. We investigated the relationships between the results of the language-related domain of the SOPESS and later academic language competencies at the end of first grade.

Procedures: Data of the population-based cohort study ikidS (Rhineland Palatinate; Germany) and the PHE provided by public health authorities were linked at individual level. The relationship between the SOPESS-language risk score (range: 0 to 6, higher values indicate more developmental delay) and class teacher-based ratings of academic language competencies (range: -4 to+4, higher values indicate better competencies) was investigated with linear regression models and adjusted for several socio-economic and medical language predictors (e. g. age at school entry, gender, parental education, migration background, hearing disorder). The additional benefits of the SOPESS-language risk score was analyzed using analysis of variance.

Results: In total, 1357 children (48% girls, age at PHE 4.9-7.2 years) were included. A clear negative relationship between the SOPESS-language risk score and competencies in spoken and written language was found. Mean academic language competencies decreased with increasing SOPESS-language risk level from 0.8 (SD=1.7) at a risk score of 0 to-3.2 (SD=0.9) at a risk score of 6. The relationship persisted after adjusting for other language predictors. Analysis of variance showed significant benefits of the SOPESS-language risk score, even when further language predictors were considered.

Conclusions: There was a clear relationship between results of the SOPESS-language screening and later academic language competencies. Hence, the language-related domain of the SOPESS may be useful for further recommendations of tailored special educational and medical support services, especially if additional socio-economic and medical factors are considered.
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http://dx.doi.org/10.1055/a-1075-2176DOI Listing
March 2021

Noise annoyance predicts symptoms of depression, anxiety and sleep disturbance 5 years later. Findings from the Gutenberg Health Study.

Eur J Public Health 2020 06;30(3):516-521

Department of Psychosomatic Medicine and Psychotherapy, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.

Background: Cross-sectional studies have shown that noise annoyance is strongly associated with mental distress, however, its long-term effects on mental health is unknown. We therefore investigated whether noise annoyance predicts depression, anxiety and sleep disturbance in a large, representative sample 5 years later.

Methods: We investigated longitudinal data of N = 11 905 participants of the Gutenberg Health Study, a population-based, prospective, single-centre cohort study in mid-Germany (age at baseline 35-74 years). Noise annoyance was assessed at baseline and 5-year follow-up (sources: road traffic, aircraft, railways, industrial, neighbourhood indoor and outdoor noise; and day vs. nighttime). Depression, anxiety and sleep disturbance were assessed using the Patient Health Questionnaire-9 and Generalized Anxiety Disorder-2. Participants suffering from depression, anxiety or sleep disturbance at baseline were excluded from the respective multivariate analyses of new onset at follow-up.

Results: General noise annoyance remained stable. Daytime noise annoyance predicted new onset of depressive, anxiety symptoms (also nighttime annoyance) and sleep disturbance (beyond respective baseline scores). Additional predictors were female sex, lower age and low socioeconomic status (SES). Regarding specific sources, daytime baseline aircraft annoyance predicted depression and anxiety. Sleep disturbance was most consistently predicted by neighbourhood annoyance (baseline and follow-up) and follow-up annoyance by aircraft (night) and road traffic (day and night).

Conclusions: We identified current and past noise annoyances as risk factors for mental distress and sleep disturbance. Furthermore, women, younger adults and those with lower SES are particularly susceptible to noise annoyance. Our results indicate the need to provide regulatory measures in affected areas to prevent mental health problems.
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http://dx.doi.org/10.1093/eurpub/ckaa015DOI Listing
June 2020

Amino Acid Polymorphisms in Hla Class II Differentiate Between Thyroid and Polyglandular Autoimmunity.

J Clin Endocrinol Metab 2020 06;105(6)

Molecular Thyroid Research Laboratory, Department of medicine I, Johannes Gutenberg University (JGU) Medical Center, Mainz, Germany.

Context: The structure of the human leucocyte antigen (HLA) peptide-binding clefts strongly contributes to monoglandular and polyglandular autoimmunity (AP).

Objective: To investigate the impact of amino acid polymorphisms on the peptide-binding interactions within HLA class II and its association with AP.

Design: Immunogenetic study.

Setting: Tertiary referral center for autoimmune endocrine diseases.

Subjects: 587 subjects with AP, autoimmune thyroid disease (AITD), type 1 diabetes (T1D), and healthy unrelated controls were typed for HLA class II.

Methods: Amino acids within the peptide binding cleft that are encoded by HLA class II exon 2 were listed for all codon positions in all subjects. Overall comparisons between disease and control groups with respect to allele distribution at a given locus were performed by assembling rare alleles applying an exact Freeman Halton contingency table test with Monte-Carlo P values based on 150 000 samples.

Results: The Monte Carlo exact Fisher test demonstrated marked differences in all 3 loci, DQA1, DQB1, and DRB1 (P < .0001) between AP and both AITD and controls, as well as between AP type II (Addison's disease as a major endocrine component) and AP type III (T1D + AITD). Differences were also noted between AP and T1D pertaining to the DRB1 allele (P < .041). Seven amino acid positions, DRB1-13, DRB1-26, DRB1-71, DRB1-74, DQA1-47, DQA1-56, and DQB1-57, significantly contributed to AP. Five positions in DQA1 (11, 47, 50, 56, and 69) completely correlated (P < .0001).

Conclusion: Amino acid polymorphisms within HLA class II exon 2 mediate the AP risk and differentiate between thyroid and polyglandular autoimmunity.
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http://dx.doi.org/10.1210/clinem/dgz164DOI Listing
June 2020

Effects of closed-loop automatic control of the inspiratory fraction of oxygen (FiO-C) on outcome of extremely preterm infants - study protocol of a randomized controlled parallel group multicenter trial for safety and efficacy.

BMC Pediatr 2019 10 21;19(1):363. Epub 2019 Oct 21.

Department of Neonatology, University Children's Hospital Tübingen, Calwerstr. 7, 72076, Tübingen, Germany.

Background: Most extremely low gestational age neonates (ELGANS, postmenstrual age at birth (PMA) < 28 completed weeks) require supplemental oxygen and experience frequent intermittent hypoxemic and hyperoxemic episodes. Hypoxemic episodes and exposure to inadequately high concentrations of oxygen are associated with an increased risk of retinopathy of prematurity (ROP), chronic lung disease of prematurity (BPD), necrotizing enterocolitis (NEC), neurodevelopmental impairment (NDI), and death beyond 36 weeks PMA. Closed-loop automated control of the inspiratory fraction of oxygen (FiO-C) reduces time outside the hemoglobin oxygen saturation (SpO) target range, number and duration of hypo- and hyperoxemic episodes and caregivers' workload. Effects on clinically important outcomes in ELGANs such as ROP, BPD, NEC, NDI and mortality have not yet been studied.

Methods: An outcome-assessor-blinded, randomized controlled, parallel-group trial was designed and powered to study the effect of FiO-C (in addition to routine manual control (RMC) of FiO), compared to RMC only, on death and severe complications related to hypoxemia and/or hyperoxemia. 2340 ELGANS with a GA of 23 + 0/7 to 27 + 6/7 weeks will be recruited in approximately 75 European tertiary care neonatal centers. Study participants are randomly assigned to RMC (control-group) or FiO-C in addition to RMC (intervention-group). Central randomization is stratified for center, gender and PMA at birth (< 26 weeks and ≥ 26 weeks). FiO-C is provided by commercially available and CE-marked ventilators with an FiO-C algorithm intended for use in newborn infants. The primary outcome variable (composite of death, severe ROP, BPD or NEC) is assessed at 36 weeks PMA (or, in case of ROP, until complete vascularization of the retina, respectively). The co-primary outcome variable (composite outcome of death, language/cognitive delay, motor impairment, severe visual impairment or hearing impairment) is assessed at 24 months corrected age.

Discussion: Short-term studies on FiO-C showed improved time ELGANs spent within their assigned SpO target range, but effects of FiO-C on clinical outcomes are yet unknown and will be addressed in the FiO-C trial. This will ensure an appropriate assessment of safety and efficacy before FiO-C may be implemented as standard therapy.

Trial Registration: The study is registered at www.ClinicalTrials.gov: NCT03168516 , May 30, 2017.
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http://dx.doi.org/10.1186/s12887-019-1735-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6802113PMC
October 2019

Is faster better? A randomised crossover study comparing algorithms for closed-loop automatic oxygen control.

Arch Dis Child Fetal Neonatal Ed 2020 Jul 16;105(4):369-374. Epub 2019 Sep 16.

Division of Paediatric Epidemiology, Institute of Medical Biostatistics, Epidemiology and Informatics, University Medical Center Mainz, Mainz, Germany.

Objective: Closed-loop automatic control (CLAC) of the fractional inspired oxygen (FiO) improved oxygen administration to preterm infants on respiratory support. We investigated whether a revised CLAC algorithm (CLAC, ≤2 FiO adjustments/min), compared with routine manual control (RMC), increased the proportion of time with arterial haemoglobin oxygen saturation measured by pulse oximetry within prespecified target ranges (Target%) while not being inferior to the original algorithm (CLAC: ≤0.3 FiO adjustments/min).

Design: Unblinded randomised controlled crossover study comparing three modes of FiO control in random order for 8 hours each: RMC supported by CLAC was compared with RMC and RMC supported by CLAC. A computer-generated list of random numbers using a block size of six was used for the allocation sequence.

Setting: Two German tertiary university neonatal intensive care units.

Patients: Of 23 randomised patients, 19 were analysed (mean±SD gestational age 27±2 weeks; age at randomisation 24±10 days) on non-invasive (n=18) or invasive (n=1) respiratory support at FiO >0.21.

Main Outcome Measure: Target%.

Results: Mean±SD [95% CI] Target% was 68%±11% [65% to 71%] for CLAC versus 65%±11% [61% to 68%] for CLAC versus 58%±11% [55% to 62%] for RMC. Prespecified hypothesis tests of: (A) superiority of CLAC versus RMC and (B) non-inferiority of CLAC versus CLAC with margin of 5% yielded one-sided p values of <0.001 for both comparisons.

Conclusions: This revised and faster CLAC algorithm was still superior to routine care in infants on respiratory support and not inferior to a previously tested slower algorithm.

Trial Registration Number: NCT03163108.
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http://dx.doi.org/10.1136/archdischild-2019-317029DOI Listing
July 2020

Linking cancer and mental health in men and women in a representative community sample.

J Psychosom Res 2019 09 2;124:109760. Epub 2019 Jul 2.

Department of Psychosomatic Medicine and Psychotherapy, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.

Objective: In aging populations, a growing number of individuals are affected by cancer. However, the relevance of the disease for mental health is still controversial, especially after treatment. We drew from a representative community sample to explore the link of cancer with mental health assessing different dimensions and different periods of time.

Methods: A cohort of 14,375 men and women (35-74 years) underwent medical assessments and was queried about cancer history, previous diagnoses of mental disorders, current mental distress symptoms, and current subjective health appraisal.

Results: 1066 participants (7.4%) reported a diagnosis of cancer (survival time M = 9.79 (SD = 9.07) years). Most common were breast (24.3%), skin (20.9%), gynecological (13.8%), and prostate cancer (12.9%). Based on cut-off-scores of standardized self-report scales (PHQ-9, GAD-2), rates of depression (8.4%; 95%CI 6.90-10.30) and anxiety symptoms (7.8%; 95%CI 6.30-9.60) corresponded to those of participants without cancer. In men, cancer was related to a lifetime diagnosis of depression (OR = 2.15; 95%CI 1.25-3.64). At the time of assessment, cancer was associated with reduced subjective health in both sexes and with anxiety symptoms in men (OR = 2.43; 95%CI 1.13-4.98).

Conclusion: Findings indicate different relations of cancer in men and in women with different operationalizations of mental health. They underscore that a history of cancer is not universally linked to distress in the general population. The study points out that different ascertainments of the association of cancer and mental health might be traced back to different assessment strategies. It also notes potential targets for interventions to alleviate distress, e.g. by physical activity.
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http://dx.doi.org/10.1016/j.jpsychores.2019.109760DOI Listing
September 2019

Planning and Analysis of Trials Using a Stepped Wedge Design.

Dtsch Arztebl Int 2019 Jun;116(26):453-458

Institute for Medical Biostatistics, Epidemiology and Informatics (IMBEI), Faculty of Medicine, Johannes Gutenberg University of Mainz; Institute for Medical Biostatistics, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany; Department of General Practice/Family Medicine, University of Marburg; Institute for Medical Biostatistics, Epidemiology and Informatics (IMBEI), Faculty of Medicine, Johannes Gutenberg University of Mainz; Institute for Medical Biostatistics, Epidemiology and Informatics (IMBEI), Faculty of Medicine, Johannes Gutenberg University of Mainz; Institute for Medical Biostatistics, Epidemiology and Informatics (IMBEI), Faculty of Medicine, Johannes Gutenberg University of Mainz.

Background: The stepped-wedge design (SWD) of clinical trials has become very popular in recent years, particularly in health services research. Typically, study participants are randomly allotted in clusters to the different treatment options.

Methods: The basic principles of the stepped wedge design and related statistical techniques are described here on the basis of pertinent publications retrieved by a selective search in PubMed and in the CIS statistical literature database.

Results: In a typical SWD trial, the intervention is begun at a time point that varies from cluster to cluster. Until this time point is reached, all participants in the cluster belong to the control arm of the trial. Once the intervention is begun, it is continued with- out change until the end of the trial period. The starting time for the intervention in each cluster is determined by randomization. At the first time point of measurement, no intervention has yet begun in any cluster; at the last one, the intervention is in prog- ress in all clusters. The treatment effect can be optimally assessed under the assumption of an identical correlation at all time points. A method is available to calculate the power and the number of clusters that would be necessary in order to achieve statistical significance by the appropriate type of significance test. All of the statistical techniques presented here are based on the assumptions of a normal distribution of cluster means and of a constant intervention effect across all time points of measure- ment.

Conclusion: The necessary statistical tools for the planning and evaluation of SWD trials now stand at our disposal. Such trials nevertheless are subject to major risks, as valid results can be obtained only if the far-reaching assumptions of the model are, in fact, justified.
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http://dx.doi.org/10.3238/arztebl.2019.0453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6712902PMC
June 2019

Depression in the nursing home: a cluster-randomized stepped-wedge study to probe the effectiveness of a novel case management approach to improve treatment (the DAVOS project).

Trials 2019 Jul 11;20(1):424. Epub 2019 Jul 11.

Department of Geriatric Medicine, Institute of General Practice, Goethe University Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany.

Background: Depression is the second most common psychiatric illness in old people. Up to 30% of nursing home residents have minor or major depression. Although depressive disorders in old age can be improved and even cured with adequate therapy, they often go unnoticed in nursing home residents and remain untreated. This highlights a striking deficit in health care and might result not only in lower quality of life among those concerned but also in poor physical functioning, premature mortality, and increased hospitalization rates.

Methods: The aims of the interdisciplinary research project DAVOS are to implement an innovative and stepped structural case management program to improve depression treatment for nursing home residents by a modularized intervention and to assess it in terms of its effectiveness. Intervention modules are in line with recommendations given by the German national treatment guidelines for depression (S3 guidelines). Ten nursing homes in Frankfurt, Germany, will participate in the project, which aims to recruit a study population of 380. The recruitment will continue throughout the trial (open cohort). Persons (>60 years) who live in a nursing home, have no medical diagnosis of dementia, and can provide their informed consent to participate are eligible for inclusion in the study. Residents with a clinical diagnosis of dementia, alcohol or substance-related disorders, or other serious psychiatric illnesses will be excluded. DAVOS is a controlled cluster-randomized study that employs a stepped-wedge design.

Discussion: Our main hypothesis is that the implementation of the intervention will lead to a decline in the prevalence of depression and a reduction in depression symptoms among the home residents. In addition, we expect the intervention to have a positive impact on secondary outcomes such as level of functioning, quality of life, and social participation. The project's results can make an important contribution toward improving the health care of nursing home residents who have late-life depression.

Trial Registration: DRKS, DRKS00015686 , Oct. 10, 2018.
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http://dx.doi.org/10.1186/s13063-019-3534-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6625077PMC
July 2019

Multiphoton microscopy in the diagnostic assessment of pediatric solid tissue in comparison to conventional histopathology: results of the first international online interobserver trial.

Cancer Manag Res 2019 29;11:3655-3667. Epub 2019 Apr 29.

Department of Pediatric Surgery, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany.

Clear resection margins are paramount for good outcome in children undergoing solid tumor resections. Multiphoton microscopy (MPM) can provide high-resolution, real-time, intraoperative microscopic images of tumor tissue. This prospective international multicenter study evaluates the diagnostic accuracy, feasibility, and interobserver congruence of MPM in diagnosing solid pediatric tissue and tumors for the first time. Representative fresh sections from six different neonatal solid tissues (liver, lung, kidney, adrenal gland, heart muscle, testicle) and two types of typical pediatric solid tumors (neuroblastoma, rhabdomyosarcoma) with adjacent nonneoplastic tissue were imaged with MPM and then presented online with corresponding H&E stained slides of the exact same tissue region. Both image sets of each tissue type were interpreted by 38 randomly selected international attending pediatric pathologists via an online evaluation software. The quality of MPM was sufficient to make the diagnosis of all normal tissue types except cardiac muscle in >94% of assessors with high interobserver congruence and 95% sensitivity. Heart muscle was interpreted as skeletal muscle in 55% of cases. Based on MPM imaging, participating pathologists diagnosed the presented pediatric neoplasms with 100% specificity, although the sensitivity reached only about 50%. Even without prior training, pathologists are able to diagnose normal pediatric tissues with valuable accuracy using MPM. While current MPM imaging protocols are not yet sensitive enough to reliably rule out neuroblastoma or rhabdomyosarcoma, they seem to be specific and therefore useful to confirm a diagnosis intraoperatively. We are confident that improved algorithms, specific training, and more experience with the method will make MPM a valuable future alternative to frozen section analysis. The trial was registered at www.researchregistry.com, registration number 2967.
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http://dx.doi.org/10.2147/CMAR.S195470DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6503203PMC
April 2019

Somatic symptom load in men and women from middle to high age in the Gutenberg Health Study - association with psychosocial and somatic factors.

Sci Rep 2019 03 14;9(1):4610. Epub 2019 Mar 14.

Department of Psychosomatic Medicine and Psychotherapy, University Medical Center, Johannes Gutenberg-University, Mainz, Germany.

The purpose of the study was (1) to determine the prevalence of somatic symptoms in men and women in the general population and (2) to identify the contributions of psychosocial factors and somatic disease on symptom reporting. A total of 7,925 participants aged 40 to 80 years underwent medical and psychological assessments, based on the PHQ-15 (Patient Health Questionnaire). We excluded 3 items in order to avoid confounding findings: 2 items overlapping with the depression measure (PHQ-9) and the menstruation complaints item which biases sex comparisons. Pain complaints (arms, legs, joints, back pain) affected the majority of men and women, and somatic symptom reporting increased with age. When confounding has been reduced, psychosocial factors (lack of social support, adverse life events, loneliness, depression, generalized anxiety, panic, social phobia) have remained the strongest predictors of somatic symptoms. As shown by the interaction between sex and depression, depression plays a smaller role for somatic symptom reporting in women vs. men. Findings highlight the complex psychosocial and somatic contributions to somatic symptom reporting.
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http://dx.doi.org/10.1038/s41598-019-40709-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6418216PMC
March 2019

Mental health problems and school performance in first graders: results of the prospective cohort study ikidS.

Eur Child Adolesc Psychiatry 2019 Oct 26;28(10):1341-1352. Epub 2019 Feb 26.

Division of Paediatric Epidemiology, Institute of Medical Biostatistics, Epidemiology, and Informatics, University Medical Centre of the Johannes Gutenberg-University, Obere Zahlbacher Str. 69, 55131, Mainz, Germany.

We aimed to estimate unbiased effects of mental health problems (MHPs) on school performance in first graders, with an emphasis on rigorous adjustment for potential confounders. A population-based prospective cohort study was performed in the area of Mainz-Bingen (Germany). In 2015, all preschoolers were approached, and the presence and type of MHP (externalising/internalising) and other physical chronic health conditions were identified by the preschool health examination and study-specific questionnaires. At the end of the first grade, school performance (reading, writing, numeracy, and science) was assessed by the class teacher and rated on a four-item scale ranging from - 8 to + 8. Of 3683 children approached, 2003 (54%) were enrolled. School performance was available for 1462 children (51% boys, mean age 7.3 years). Of these, 41% had signs of at least one MHP. Compared to children without indications of mental and physical chronic health conditions, children with MHPs had lower school performance scores [adjusted mean difference - 0.98, 95% CI (- 1.35; - 0.61); P < 0.001]. Regarding the type of MHP, externalising MHPs were associated with poor school performance [adjusted mean difference - 1.44, 95% CI (- 1.83; - 1.05); P < 0.001], while internalising MHPs were not. Children with hyperactivity inattention problems were most affected [adjusted mean difference - 1.96, 95% CI (- 2.36; - 1.56); P < 0.001]. Externalising MHPs and in particular hyperactivity inattention problems may already affect school performance in early primary school. Identification of children with externalising MHPs prior to school entry may help to prevent impaired academic achievement in affected children.
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http://dx.doi.org/10.1007/s00787-019-01296-7DOI Listing
October 2019

Doppler sonography enhances rtPA-induced fibrinolysis in an in vitro clot model of spontaneous intracerebral hemorrhages.

PLoS One 2019 17;14(1):e0210810. Epub 2019 Jan 17.

Department of Neurosurgery, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.

Background: Transcranial Doppler (TCD) was shown to enhance intravascular fibrinolysis by rtPA in ischemic stroke. Studies revealed that catheter-based administration of rtPA induces lysis of intracerebral hemorrhages (ICH). However, it is unknown whether TCD would be suitable to enhance rtPA-induced fibrinolysis in patients with ICH. The aim of this study was to assess the potential of TCD to enhance rtPA-induced fibrinolysis in an in vitro clot system.

Methods: Reproducible human blood clots of 25 ml were incubated in a water bath at 37°C during treatments. They were weighed before and after 6 different treatments: (I) control (incubation only), (II) rtPA only, (III) one Doppler probe, (IV) two Doppler probes placed vis-à-vis, (V) one probe and rtPA and (VI) two probes and rtPA. To quantify lysis of the blood clots and attenuation of the Doppler through a temporal squama acoustic peak rarefaction pressure (APRP) was measured in the field of the probes. Temperature was assessed to evaluate possible side effects.

Results: Clot weight was reduced in all groups. The control group had the highest relative end weight of 70.2%±7.2% compared to all other groups (p<0,0001). Most efficient lysis was achieved using (VI) 2 probes and rtPA 36.3%±4.4% compared to (II, III, IV) (p<0.0001; p = 0.0002; p = 0.048). APRP was above lysis threshold (535.5±7.2 kPa) using 2 probes even through the temporal squama (731.6±32.5 kPa) (p = 0.0043). There was a maximal temperature elevation of 0.17±0.07°C using both probes.

Conclusions: TCD significantly enhances rtPA-induced lysis of blood clots, and the effect is amplified by using multiple probes. Our results indicate that bitemporal TCD insonation of hematomas could be a new and safe approach to enhance fibrinolysis of ICH´s treated with intralesional catheter and rtPA.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0210810PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6336417PMC
October 2019

Investigation of intraocular pressure fluctuation as a risk factor of glaucoma progression.

Clin Ophthalmol 2019 18;13:9-16. Epub 2018 Dec 18.

Department of Ophthalmology, University Medical Center Mainz, Mainz, Germany,

Purpose: Since the role of short- and long-term intraocular pressure (IOP) fluctuation as a predictor of glaucoma progression is still controversial, the purpose of this study was to investigate the role of IOP fluctuation in a non-selected patient cohort.

Materials And Methods: Two-hundred and forty eyes of 120 glaucoma patients (51% female) with a mean age of 64.5 years were included. Inclusion criteria were at least a visual field (VF) and a 48-hour diurnal phasing of IOP including nocturnal measurement. Glaucoma progression was defined as - if available - confirmed progression of reproducible VF defects in at least three VF examinations or increase of cup area on optic nerve imaging (Heidelberg Retina Tomograph [HRT]) with at least two images after baseline. If results were stable or less than previously mentioned VF or HRT examinations were available, it was classified as "no progression".

Results: Glaucoma progression was seen in seven of 240 eyes in the VF analysis and ten of 240 eyes on HRT. Of all 240 eyes, 92 and 41 eyes fulfilled the criteria to be included for progression evaluation on VF and HRT analysis, respectively. Mean time to progression ± standard error was 3.6±0.2 years on VF and 4.5±0.3 years on HRT. Univariate and multivariate Cox regression analyses revealed short-term IOP fluctuation (<0.0001) and maximum IOP (<0.001) as risk factors for glaucoma progression on VF. There was no significant influence of demographic characteristics, ocular or general health on glaucoma progression.

Conclusion: Short-term IOP fluctuation was associated with the progression of glaucoma in this non-selected cohort of glaucoma patients receiving phasing of IOP.
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http://dx.doi.org/10.2147/OPTH.S186526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6302802PMC
December 2018