Publications by authors named "Mohamad A Kalot"

25 Publications

  • Page 1 of 1

Gynecologic and obstetric management of women with von Willebrand disease: summary of 3 systematic reviews of the literature.

Blood Adv 2021 Oct 21. Epub 2021 Oct 21.

McMaster University, Canada.

Von Willebrand disease, (VWD) disproportionately affects women due to potential issues with heavy menstrual bleeding (HMB), delivery complications, and postpartum hemorrhage (PPH). To systematically synthesize the evidence regarding first line management of HMB, treatment of women requiring/desiring neuraxial analgesia, and management of PPH. We searched Medline and EMBASE through October 2019 for randomized trials, comparative observational studies, and case series comparing the effects of desmopressin, hormonal therapy, and tranexamic acid (TXA) on HMB, comparing different von Willebrand factor (VWF) levels in women with VWD undergoing labor and receiving neuraxial anesthesia and the effects of TXA on PPH We conducted duplicate study selection, data abstraction, and appraisal of risk of bias. Whenever possible, we conducted meta-analyses. We assessed the quality of the evidence using the GRADE approach. We included 1 randomized trial, 3 comparative observational studies and 10 case series. Moderate certainty evidence showed that desmopressin results in a smaller reduction of menstrual blood loss (difference in mean change from baseline, 41.6 [95% CI, 16.6 to 63.6] points in pictorial blood assessment chart score as compared to TXA. There was very low certainty evidence about how first line treatments compare against each other, the effects of different VWF levels in women receiving neuraxial anesthesia, and the effects of TXA administration postpartum. Most of the evidence relevant to the gynecologic and obstetric management of women with VWD addressed by most guidelines is very low quality. Future studies addressing research priorities will be key when updating such guidelines.
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http://dx.doi.org/10.1182/bloodadvances.2021005589DOI Listing
October 2021

Surgical management of patients with von Willebrand Disease: summary of 2 systematic reviews of the literature.

Blood Adv 2021 Oct 15. Epub 2021 Oct 15.

Department of Health Research Methods, Evidence and Impact, McMaster University, Canada.

Von Willebrand disease (VWD) is the most common inherited bleeding disorder. The management of patients with VWD undergoing surgeries is crucial to prevent bleeding complications. To systematically summarize the evidence on the management of patients with VWD undergoing major and minor surgeries to support the development of practice guidelines. We searched Medline and EMBASE through October 2019 for randomized clinical trials (RCTs), comparative observational studies and case series comparing maintaining factor VIII levels or VWF levels >0.50 IU/mL for at least 3 days in patients undergoing major surgery, and options for perioperative management of patients undergoing minor surgery. Two authors screened, abstracted data, and assessed the risk of bias. We conducted meta-analysis when possible. We evaluated the certainty of the evidence using the GRADE approach. We included 7 case series for major surgeries and 2 RCTs and 12 case series for minor surgeries. Very low certainty evidence showed that maintaining factor VIII levels, or VWF levels > 0.50 IU/mL for at least 3 consecutive days showed excellent hemostatic efficacy (as labeled by the researchers) after 74-100% of major surgeries. Low to very low certainty evidence showed that prescribing tranexamic acid and increasing VWF levels to 0.50 IU/mL resulted in less bleeding complications after minor procedures compared to increasing VWF levels to 0.50 IU/mL alone. Given the low-quality evidence to guide management decisions, a shared-decision model leading to individualized therapy plans will be important in patients with VWD undergoing surgical and invasive procedures.
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http://dx.doi.org/10.1182/bloodadvances.2021005666DOI Listing
October 2021

Von Willebrand Factor Levels in The Diagnosis of Von Willebrand Disease: A Systematic Review and Meta-Analysis.

Blood Adv 2021 Oct 5. Epub 2021 Oct 5.

University of Kansas Medical Center, Kansas City, Kansas, United States.

Von Willebrand Disease (VWD) is associated with significant morbidity as a result of excessive mucocutaneous bleeding symptoms. Patients with VWD can experience easy bruising, epistaxis, gastrointestinal and oral cavity bleeding, as well as heavy menstrual bleeding and bleeding after dental work, surgical procedures, and childbirth. Early diagnosis and treatment is important to prevent and treat these symptoms. We systematically reviewed the accuracy of diagnostic tests using different cut-off values of VWF:Ag and platelet-dependent VWF activity assays in the diagnosis of VWD. We searched Cochrane Central, MEDLINE, and EMBASE for eligible studies. Two investigators screened and abstracted data. Risk of bias was assessed using QUADAS-2 and certainty of evidence using the GRADE framework. We pooled estimates of sensitivity and specificity and reported patient important outcomes when relevant. This review included 21 studies that evaluated VWD diagnosis, including the approach to patients with VWF levels that have normalized with age (6 studies), VWF cut-off levels for the diagnosis of Type 1 VWD (9 studies), and platelet-dependent VWF activity/VWF:Ag ratio cut-off levels for the diagnosis of Type 2 VWD (6 studies). The results showed low certainty in the evidence for a net health benefit from reconsidering the diagnosis of VWD versus simply removing the disease in patients with VWF levels that have normalized with age. For the diagnosis of Type 1 VWD, in patients with VWF:Ag <0.30 IU/mL, VWF sequence variants were detected in 75-82% of patients in 2 studies, and for VWF:Ag between 0.30-0.50 IU/mL, VWF sequence variants were detected in 44-60% of patients in 3 studies. A sensitivity of 0.90 (95% CI: 0.83 to 0.94), and a specificity of 0.91 (95% CI: 0.76 to 0.97) were observed for a platelet-dependent VWF activity /VWF:Ag ratio of <0.7 in detecting type 2 VWD (moderate certainty in the test accuracy results). VWF antigen and platelet-dependent activity are continuous variables with an increase in bleeding risk with decreasing levels. This systematic review shows that using a VWF activity/VWF:Ag ratio of <0.7 versus lower cutoff levels in patients with an abnormal initial VWD screen is more accurate for the diagnosis of type 2 VWD.
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http://dx.doi.org/10.1182/bloodadvances.2021005430DOI Listing
October 2021

Bleeding assessment tools in the diagnosis of VWD in adults and children: a systematic review and meta-analysis of test accuracy.

Blood Adv 2021 Dec;5(23):5023-5031

Department of Internal Medicine.

Von Willebrand disease (VWD) can be associated with significant morbidity. Patients with VWD can experience bruising, mucocutaneous bleeding, and bleeding after dental and surgical procedures. Early diagnosis and treatment are important to minimize the risk of these complications. Several bleeding assessment tools (BATs) have been used to quantify bleeding symptoms as a screening tool for VWD. We systematically reviewed diagnostic test accuracy results of BATs to screen patients for VWD. We searched Cochrane Central, MEDLINE, and EMBASE for eligible studies, reference lists of relevant reviews, registered trials, and relevant conference proceedings. Two investigators screened and abstracted data. Risk of bias was assessed using the revised tool for the quality assessment of diagnostic accuracy studies and certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation framework. We pooled estimates of sensitivity and specificity. The review included 7 cohort studies that evaluated the use of BATs to screen adult and pediatric patients for VWD. The pooled estimates for sensitivity and specificity were 75% (95% confidence interval, 66-83) and 54% (29-77), respectively. Certainty of evidence varied from moderate to high. This systematic review provides accuracy estimates for validated BATs as a screening modality for VWD. A BAT is a useful initial screening test to determine who needs specific blood testing. The pretest probability of VWD (often determined by the clinical setting/patient population), along with sensitivity and specificity estimates, will influence patient management.
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http://dx.doi.org/10.1182/bloodadvances.2021004368DOI Listing
December 2021

Burden of Renal Cysts Imaging: A Survey of Patients among the Greater Plains Collaborative.

Urol Int 2021 Sep 15:1-7. Epub 2021 Sep 15.

Division of Nephrology and Hypertension, Department of Medicine, University of Kansas Medical Center, Kansas City, Kansas, USA.

Purpose: Renal cysts are a frequent incidental finding on cross-sectional radiographic imaging. While most cysts are indolent, individuals with such cysts are frequently monitored for interval growth and potential malignant transformation, which is ultimately rare. In this study, we aimed to assess patients' values and preferences (believes and attitudes) about renal cysts.

Methods: We deployed a cross-sectional survey to a random sample of patients with a diagnosis of renal cysts who were identified by billing code and self-identification. We collected data about demographics, insurance status, family history and overall health, and characteristics of patients with renal cysts. We performed a binary regression analysis (adjusted for age, gender, family history of cancer and kidney disease, and treatment plan for renal cysts) to determine anxiety predictors in patients with renal cysts.

Results: We included 301 respondents in whom billing code and self-identification corresponded; of these, 138 had renal cysts and 163 did not. In an adjusted regression analysis, there was a suggestion that a clear management plan (OR = 0.49, 95% CI [0.22-1.11]) (p value 0.08) may be associated with less anxiety and a family history of renal disease may be associated with more anxiety (OR = 1.94 [0.76-4.94]) (p value 0.17). Family history of cancer also did not significantly predict anxiety (OR = 0.54 [0.24-1.19]) (p value 0.13). All these results were not statistically significant and had wide confidence intervals of the effect estimates make the results imprecise.

Conclusion: Findings of this pilot study suggest a clear management plan for the renal cyst(s) management may be associated with a lower level of anxiety, thereby by emphasizing the importance of good communication, patient engagement and evidence-based guidance. More definitive, adequately powered studies are needed to evaluate this finding further. In addition, further studies exploring differences in imaging practices, patient symptomatology and patient engagement by different provider types would be insightful. Ultimately, tools to improve shared decision-making are needed to provide more patient-centered care.
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http://dx.doi.org/10.1159/000517791DOI Listing
September 2021

Kawasaki Disease: A Systematic Review and Meta-Analysis of Benefits and Harms of Common Treatments.

ACR Open Rheumatol 2021 Oct 27;3(10):671-683. Epub 2021 Jul 27.

University of Kansas Medical Center, Kansas City, KS.

Objective: Kawasaki disease (KD) is a self-limited vasculitis affecting medium-sized vessels with a predilection for the coronary arteries. Although treatment reduces the likelihood of developing of coronary artery aneurysms, 5% of patients still develop aneurysms despite treatment, making KD the leading cause of acquired heart disease in children in the United States. Consequently, there is a great deal of interest in optimizing treatment regimens, particularly for higher-risk patients, to decrease morbidity. The aim of this systematic review is to support the development of the American College of Rheumatology/Vasculitis Foundation for the diagnosis and management of KD, focusing on the more complex scenarios in which rheumatologists may become involved, such as high-risk and refractory disease.

Methods: Eighty-nine articles were considered for full review in this systematic literature review to address 16 Population, Intervention, Comparison, and Outcome questions related to KD. Data were abstracted in hierarchical fashion. Randomized control trials (RCTs) were considered first; if none were identified or if they contained insufficient information, comparative observational studies were then viewed, followed by single-arm observational studies/single arms from comparative studies. Only observational studies with more than 10 subjects with vasculitis were included.

Results: Eight RCTs and 28 observational studies that addressed the questions were identified. Two questions were addressed by RCTs, seven questions had at least some comparative observational studies, three questions were only addressed by single-arm data, and four questions had no relevant studies.

Conclusion: This systematic review evaluates the benefits and harms of treatments for KD beyond first-line therapy.
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http://dx.doi.org/10.1002/acr2.11308DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8516108PMC
October 2021

2021 American College of Rheumatology/Vasculitis Foundation Guideline for the Management of Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.

Arthritis Rheumatol 2021 08 8;73(8):1366-1383. Epub 2021 Jul 8.

Cleveland Clinic, Cleveland, Ohio.

Objective: To provide evidence-based recommendations and expert guidance for the management of antineutrophil cytoplasmic antibody-associated vasculitis (AAV), including granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA).

Methods: Clinical questions regarding the treatment and management of AAV were developed in the population, intervention, comparator, and outcome (PICO) format (47 for GPA/MPA, 34 for EGPA). Systematic literature reviews were conducted for each PICO question. The Grading of Recommendations Assessment, Development and Evaluation methodology was used to assess the quality of evidence and formulate recommendations. Each recommendation required ≥70% consensus among the Voting Panel.

Results: We present 26 recommendations and 5 ungraded position statements for GPA/MPA, and 15 recommendations and 5 ungraded position statements for EGPA. This guideline provides recommendations for remission induction and maintenance therapy as well as adjunctive treatment strategies in GPA, MPA, and EGPA. These recommendations include the use of rituximab for remission induction and maintenance in severe GPA and MPA and the use of mepolizumab in nonsevere EGPA. All recommendations are conditional due in part to the lack of multiple randomized controlled trials and/or low-quality evidence supporting the recommendations.

Conclusion: This guideline presents the first recommendations endorsed by the American College of Rheumatology and the Vasculitis Foundation for the management of AAV and provides guidance to health care professionals on how to treat these diseases.
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http://dx.doi.org/10.1002/art.41773DOI Listing
August 2021

2021 American College of Rheumatology/Vasculitis Foundation Guideline for the Management of Giant Cell Arteritis and Takayasu Arteritis.

Arthritis Rheumatol 2021 08 8;73(8):1349-1365. Epub 2021 Jul 8.

Cleveland Clinic Foundation, Cleveland, Ohio.

Objective: To provide evidence-based recommendations and expert guidance for the management of giant cell arteritis (GCA) and Takayasu arteritis (TAK) as exemplars of large vessel vasculitis.

Methods: Clinical questions regarding diagnostic testing, treatment, and management were developed in the population, intervention, comparator, and outcome (PICO) format for GCA and TAK (27 for GCA, 27 for TAK). Systematic literature reviews were conducted for each PICO question. The Grading of Recommendations Assessment, Development and Evaluation methodology was used to rate the quality of the evidence. Recommendations were developed by the Voting Panel, comprising adult and pediatric rheumatologists and patients. Each recommendation required ≥70% consensus among the Voting Panel.

Results: We present 22 recommendations and 2 ungraded position statements for GCA, and 20 recommendations and 1 ungraded position statement for TAK. These recommendations and statements address clinical questions relating to the use of diagnostic testing, including imaging, treatments, and surgical interventions in GCA and TAK. Recommendations for GCA include support for the use of glucocorticoid-sparing immunosuppressive agents and the use of imaging to identify large vessel involvement. Recommendations for TAK include the use of nonglucocorticoid immunosuppressive agents with glucocorticoids as initial therapy. There were only 2 strong recommendations; the remaining recommendations were conditional due to the low quality of evidence available for most PICO questions.

Conclusion: These recommendations provide guidance regarding the evaluation and management of patients with GCA and TAK, including diagnostic strategies, use of pharmacologic agents, and surgical interventions.
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http://dx.doi.org/10.1002/art.41774DOI Listing
August 2021

2021 American College of Rheumatology/Vasculitis Foundation Guideline for the Management of Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.

Arthritis Care Res (Hoboken) 2021 08 8;73(8):1088-1105. Epub 2021 Jul 8.

Cleveland Clinic, Cleveland, Ohio.

Objective: To provide evidence-based recommendations and expert guidance for the management of antineutrophil cytoplasmic antibody-associated vasculitis (AAV), including granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA).

Methods: Clinical questions regarding the treatment and management of AAV were developed in the population, intervention, comparator, and outcome (PICO) format (47 for GPA/MPA, 34 for EGPA). Systematic literature reviews were conducted for each PICO question. The Grading of Recommendations Assessment, Development and Evaluation methodology was used to assess the quality of evidence and formulate recommendations. Each recommendation required ≥70% consensus among the Voting Panel.

Results: We present 26 recommendations and 5 ungraded position statements for GPA/MPA, and 15 recommendations and 5 ungraded position statements for EGPA. This guideline provides recommendations for remission induction and maintenance therapy as well as adjunctive treatment strategies in GPA, MPA, and EGPA. These recommendations include the use of rituximab for remission induction and maintenance in severe GPA and MPA and the use of mepolizumab in nonsevere EGPA. All recommendations are conditional due in part to the lack of multiple randomized controlled trials and/or low-quality evidence supporting the recommendations.

Conclusion: This guideline presents the first recommendations endorsed by the American College of Rheumatology and the Vasculitis Foundation for the management of AAV and provides guidance to health care professionals on how to treat these diseases.
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http://dx.doi.org/10.1002/acr.24634DOI Listing
August 2021

2021 American College of Rheumatology/Vasculitis Foundation Guideline for the Management of Giant Cell Arteritis and Takayasu Arteritis.

Arthritis Care Res (Hoboken) 2021 08 8;73(8):1071-1087. Epub 2021 Jul 8.

Cleveland Clinic Foundation, Cleveland, Ohio.

Objective: To provide evidence-based recommendations and expert guidance for the management of giant cell arteritis (GCA) and Takayasu arteritis (TAK) as exemplars of large vessel vasculitis.

Methods: Clinical questions regarding diagnostic testing, treatment, and management were developed in the population, intervention, comparator, and outcome (PICO) format for GCA and TAK (27 for GCA, 27 for TAK). Systematic literature reviews were conducted for each PICO question. The Grading of Recommendations Assessment, Development and Evaluation methodology was used to rate the quality of the evidence. Recommendations were developed by the Voting Panel, comprising adult and pediatric rheumatologists and patients. Each recommendation required ≥70% consensus among the Voting Panel.

Results: We present 22 recommendations and 2 ungraded position statements for GCA, and 20 recommendations and 1 ungraded position statement for TAK. These recommendations and statements address clinical questions relating to the use of diagnostic testing, including imaging, treatments, and surgical interventions in GCA and TAK. Recommendations for GCA include support for the use of glucocorticoid-sparing immunosuppressive agents and the use of imaging to identify large vessel involvement. Recommendations for TAK include the use of nonglucocorticoid immunosuppressive agents with glucocorticoids as initial therapy. There were only 2 strong recommendations; the remaining recommendations were conditional due to the low quality of evidence available for most PICO questions.

Conclusion: These recommendations provide guidance regarding the evaluation and management of patients with GCA and TAK, including diagnostic strategies, use of pharmacologic agents, and surgical interventions.
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http://dx.doi.org/10.1002/acr.24632DOI Listing
August 2021

Giant Cell Arteritis: A Systematic Review and Meta-Analysis of Test Accuracy and Benefits and Harms of Common Treatments.

ACR Open Rheumatol 2021 Jul 2;3(7):429-441. Epub 2021 Apr 2.

University of Kansas Medical Center, Kansas City.

This systematic review compares treatment options for patients with giant cell arteritis (GCA) and evaluates the test accuracy of studies used in diagnosing and monitoring GCA. These studies were used to inform evidence-based recommendations for the American College of Rheumatology (ACR)/Vasculitis Foundation (VF) vasculitis management guidelines. A systematic review and search of articles in English in Ovid Medline, PubMed, Embase, and the Cochrane Library was conducted. Articles were screened for suitability, and studies presenting the highest level of evidence were given preference. Three hundred ninety-nine full-text articles addressing GCA questions were reviewed to inform 27 Population, Intervention, Comparison, and Outcome questions. No benefit was found with intravenous glucocorticoids (GCs) compared with high-dose oral GCs in patients with cranial ischemic symptoms (27.4% vs 12.3%; odds ratio [OR] 2.39 [95% confidence interval (CI) 0.75-7.62], [very low certainty of evidence]). Weekly tocilizumab with a 26-week GC taper was superior to a 52-week GC taper in patients achieving remission (risk ratio 4.00 [95% CI 1.97-8.12], [low certainty of evidence]). Non-GC immunosuppressive therapies with GCs compared with GCs alone showed no statistically significant in relapse at 1 year (OR 0.87 [95% CI 0.73-1.04], [moderate certainty of evidence]) or serious adverse events (OR 0.81 [95% CI 0.54-1.20]; [moderate certainty of evidence]). Temporal artery biopsy has a sensitivity of 61% (95% CI 38%-79%) and a specificity of 98% (95% CI 95%-99%) in patients with a clinical diagnosis of suspected GCA. This comprehensive systematic review synthesizes and evaluates the benefits and harms of different treatment options and the accuracy of commonly used tests for the diagnosis and monitoring of GCA.
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http://dx.doi.org/10.1002/acr2.11226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8280815PMC
July 2021

Granulomatosis With Polyangiitis and Microscopic Polyangiitis: A Systematic Review and Meta-Analysis of Benefits and Harms of Common Treatments.

ACR Open Rheumatol 2021 Mar 16;3(3):196-205. Epub 2021 Feb 16.

University of Kansas Medical Center, Kansas City, Kansas.

Objective: The aim of this systemic review is to compare different treatments for patients with granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) to inform evidence-based recommendations for the American College of Rheumatology (ACR)/Vasculitis Foundation (VF) Vasculitis Management Guidelines.

Methods: A systemic review was conducted by searching articles in English using OVID Medline, PubMed, Embase, and the Cochrane Library. Articles were screened for suitability in addressing PICO questions, with studies presenting the highest level of evidence given preference.

Results: A total of 729 full-text articles addressing GPA and MPA PICO questions were reviewed. For remission induction, rituximab was shown to be noninferior to cyclophosphamide (CYC) (odds ratio [OR]: 1.55, moderate certainty of evidence). The addition of plasma exchange to induction therapy in severe disease did not improve the composite end point of death or end stage renal disease (hazard ratio [HR]: 0.86 [95% confidence interval CI: 0.65, 1.13], moderate certainty of evidence). In nonsevere disease, methotrexate was noninferior to CYC for induction of remission (remission at 6 months of 90% vs. 94%). For maintenance of remission, methotrexate and azathioprine showed no difference in the risk of relapse over a mean follow-up of 29 months (HR: 0.92, [95% CI: 0.52, 1.65]low certainty of evidence). As maintenance therapy, rituximab was superior to a tapering azathioprine strategy in major relapse-free survival at 28 months (HR: 6.61, [95% CI: 1.56, 27.96], moderate certainty of evidence). In two randomized trials, longer-term azathioprine maintenance therapy (>24 months) is associated with fewer relapses without an increase in adverse events.

Conclusion: This comprehensive systematic review synthesizes and evaluates the benefits and toxicities of different treatment options for GPA and MPA.
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http://dx.doi.org/10.1002/acr2.11230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7966881PMC
March 2021

ASH ISTH NHF WFH 2021 guidelines on the diagnosis of von Willebrand disease.

Blood Adv 2021 01;5(1):280-300

Outcomes and Implementation Research Unit, Division of Nephrology and Hypertension, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS.

Background: von Willebrand disease (VWD) is the most common inherited bleeding disorder known in humans. Accurate and timely diagnosis presents numerous challenges.

Objective: These evidence-based guidelines of the American Society of Hematology (ASH), the International Society on Thrombosis and Haemostasis (ISTH), the National Hemophilia Foundation (NHF), and the World Federation of Hemophilia (WFH) are intended to support patients, clinicians, and other health care professionals in their decisions about VWD diagnosis.

Methods: ASH, ISTH, NHF, and WFH established a multidisciplinary guideline panel that included 4 patient representatives and was balanced to minimize potential bias from conflicts of interest. The Outcomes and Implementation Research Unit at the University of Kansas Medical Center (KUMC) supported the guideline-development process, including performing or updating systematic evidence reviews up to 8 January 2020. The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The panel used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, including GRADE Evidence-to-Decision frameworks, to assess evidence and make recommendations, which were subsequently subject to public comment.

Results: The panel agreed on 11 recommendations.

Conclusions: Key recommendations of these guidelines include the role of bleeding-assessment tools in the assessment of patients suspected of VWD, diagnostic assays and laboratory cutoffs for type 1 and type 2 VWD, how to approach a type 1 VWD patient with normalized levels over time, and the role of genetic testing vs phenotypic assays for types 2B and 2N. Future critical research priorities are also identified.
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http://dx.doi.org/10.1182/bloodadvances.2020003265DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7805340PMC
January 2021

ASH ISTH NHF WFH 2021 guidelines on the management of von Willebrand disease.

Blood Adv 2021 01;5(1):301-325

Outcomes and Implementation Research Unit, Division of Nephrology and Hypertension, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS.

Background: von Willebrand disease (VWD) is a common inherited bleeding disorder. Significant variability exists in management options offered to patients.

Objective: These evidence-based guidelines from the American Society of Hematology (ASH), the International Society on Thrombosis and Haemostasis (ISTH), the National Hemophilia Foundation (NHF), and the World Federation of Hemophilia (WFH) are intended to support patients, clinicians, and health care professionals in their decisions about management of VWD.

Methods: ASH, ISTH, NHF, and WFH formed a multidisciplinary guideline panel. Three patient representatives were included. The panel was balanced to minimize potential bias from conflicts of interest. The University of Kansas Outcomes and Implementation Research Unit and the McMaster Grading of Recommendations Assessment, Development and Evaluation (GRADE) Centre supported the guideline development process, including performing and updating systematic evidence reviews (through November 2019). The panel prioritized clinical questions and outcomes according to their importance to clinicians and patients. The panel used the GRADE approach, including GRADE Evidence-to-Decision frameworks, to assess evidence and make recommendations, which were subject to public comment.

Results: The panel agreed on 12 recommendations and outlined future research priorities.

Conclusions: These guidelines make key recommendations regarding prophylaxis for frequent recurrent bleeding, desmopressin trials to determine therapy, use of antiplatelet agents and anticoagulant therapy, target VWF and factor VIII activity levels for major surgery, strategies to reduce bleeding during minor surgery or invasive procedures, management options for heavy menstrual bleeding, management of VWD in the context of neuraxial anesthesia during labor and delivery, and management in the postpartum setting.
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http://dx.doi.org/10.1182/bloodadvances.2020003264DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7805326PMC
January 2021

Eosinophilic Granulomatosis with Polyangiitis: A Systematic Review and Meta-Analysis of Test Accuracy and Benefits and Harms of Common Treatments.

ACR Open Rheumatol 2021 Feb 29;3(2):101-110. Epub 2021 Jan 29.

University of Kansas Medical Center, Kansas City.

Objective: Eosinophilic granulomatosis with polyangiitis (EGPA) is part of a group of vasculitides commonly referred to as antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), in addition to granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and renal-limited vasculitis. Patients with EGPA characteristically have asthma and marked peripheral eosinophilia with only approximately 30% to 35% of patients being myeloperoxidase (MPO)-ANCA positive, distinguishing it from other forms of AAV (1,2). The aim of this systematic review is to support the development of the American College of Rheumatology/Vasculitis Foundation guideline for the management of EGPA.

Methods: A systematic review was conducted of the literature for seven forms of primary systemic vasculitis (GPA, MPA, EGPA, polyarteritis nodosa, Kawasaki disease, giant cell arteritis, and Takayasu arteritis). The search was done for articles in English using Ovid Medline, PubMed, Embase, and the Cochrane Library. Articles were screened for suitability in addressing population/patients, intervention, comparator, and outcomes (PICO) questions, with studies presenting the highest level of evidence given preference. Two independent reviewers conducted a title/abstract screen and full-text review for each eligible study.

Results: The initial search, conducted in August 2019, included 13 800 articles, of which 2596 full-text articles were reviewed. There were 190 articles (addressing 34 PICO questions) reporting on the diagnosis and management of EGPA.

Conclusion: This comprehensive systematic review synthesizes and evaluates the accuracy of commonly used tests for EGPA as well as benefits and toxicities of different treatment options.
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http://dx.doi.org/10.1002/acr2.11194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7882521PMC
February 2021

Takayasu Arteritis: a Systematic Review and Meta-Analysis of Test Accuracy and Benefits and Harms of Common Treatments.

ACR Open Rheumatol 2021 Feb 29;3(2):80-90. Epub 2021 Jan 29.

University of Kansas Medical Center, Kansas City.

Objective: Takayasu's arteritis (TAK) is a granulomatous large-vessel vasculitis primarily affecting the aorta and its proximal branches. TAK can be a difficult disease to diagnose and manage given the rarity of the disease as well as current limitations in biomarkers, imperfect imaging modalities, and few randomized controlled trials.

Methods: In developing the American College of Rheumatology/Vasculitis Foundation guideline for the management of TAK, we performed an extensive systematic literature review to guide our recommendations. We included RCTs first. When RCTs were not available, we included observational studies that reported on patient-important outcomes for the intervention and comparison. When studies with comparative data were not available, we included case series that present patient-important outcomes for either the intervention or the comparison.

Results: Three hundred forty-seven articles were included for full review to answer 27 population, intervention, comparison, and outcome questions related to TAK. Ten studies were evaluated that addressed the use of glucocorticoids (GCs), non-GC nonbiologic therapies, as well as biologics in treating TAK. A total of 33 studies, including 8 comparative studies, were included to determine the test accuracy of commonly available diagnostic tests for TAK.

Conclusion: This comprehensive systematic review synthesizes and evaluates the benefits and harms of different treatment options and the accuracy of commonly used tests for the management of TAK.
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http://dx.doi.org/10.1002/acr2.11186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7882531PMC
February 2021

Polyarteritis Nodosa: A Systematic Review of Test Accuracy and Benefits and Harms of Common Treatments.

ACR Open Rheumatol 2021 Feb 29;3(2):91-100. Epub 2021 Jan 29.

University of Kansas Medical Center, Kansas City, United States.

Objective: The object of this study was to analyze the benefits and harms of different treatment options and to analyze test accuracy used in the evaluation of patients with primary systemic polyarteritis nodosa (PAN).

Methods: A systematic search of published English-language literature was performed in Ovid Medline, PubMed, Embase, and the Cochrane Library from the inception of each database through August 2019. Articles were screened for suitability in addressing patient, intervention, comparison, and outcome questions, with studies presenting the highest level of evidence given preference.

Results: Of 137 articles selected for data abstraction, we analyzed 21 observational studies and seven randomized controlled trials (RCTs). The results showed indirect evidence that a deep skin biopsy provides good diagnostic accuracy. A combined nerve and muscle biopsy should be obtained for patients with PAN with peripheral neuropathy. Cyclophosphamide with high-dose glucocorticoids (GCs) is effective as an induction treatment for newly diagnosed active and severe PAN. GC monotherapy is adequate in the majority of patients with nonsevere PAN, although it has a high relapse rate with GC taper. There was insufficient data in determining the optimal duration of non-GC and GC maintenance therapy. Tumor necrosis factor inhibitors are effective treatment for patients with deficiency of adenosine deaminase 2 (DADA2) with stroke and vasculitis manifestations.

Conclusion: This comprehensive systematic review synthesizes and evaluates the harms and benefits of different treatment options and the accuracy of commonly used tests for the diagnosis of systemic PAN. Data for diagnosis and management of PAN and DADA2 are mostly limited to observational studies. More high-quality RCTs are needed.
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http://dx.doi.org/10.1002/acr2.11189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7882539PMC
February 2021

Reporting and Handling of Missing Participant Data in Systematic Reviews of Kidney Transplant Studies.

Transplantation 2021 08;105(8):1708-1717

Department of Nephrology, University of Kansas Medical Center, Kansas City, KS.

Background: Participant withdrawal from clinical trials occurs for various reasons, predominantly adverse effects or intervention inefficacy. Because these missing participant data can have implications for the validity, reproducibility, and generalizability of study results, when conducting a systematic review, it is important to collect and appropriately analyze missing data information to assess its effects on the robustness of the study results.

Methods: In this methodologic survey of missing participant data reporting and handling in systematic reviews, we included meta-analyses that provided pooled estimates of at least 1 dichotomous intervention outcome of a randomized controlled trial performed in adult kidney transplant subjects.

Results: Eighty-three systematic reviews (17 Cochrane and 66 non-Cochrane reviews) met the inclusion criteria. The most common intervention was drugs (80%), with the majority involving immunosuppressant drugs 55% (n = 46), followed by surgery in 14% (n = 12). The median follow-up duration was 12 months (maximum, 240 mo). Intention-to-treat or modified intention-to-treat analysis was reported in 24% (n = 20) of the reviews (76% of Cochrane and 10% of non-Cochrane). Overall, the majority of systematic reviews did not quantify (90% [n = 60] non-Cochrane and 29% [n = 5] Cochrane) or include the reasons for missing participant data (88% [n = 58] non-Cochrane and 24% [n = 4] Cochrane). Eleven percent (n = 9) handled missing participant data, 5% (n = 4) justified the analytical method(s) used to handle it, and 2% (n = 2) performed a sensitivity analysis for it.

Conclusions: Systematic reviews of kidney transplantation provide inadequate information on missing participant data and usually do not handle or discuss the associated risk of bias with it.
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http://dx.doi.org/10.1097/TP.0000000000003503DOI Listing
August 2021

Systematic review and meta-analysis of test accuracy for the diagnosis of suspected pulmonary embolism.

Blood Adv 2020 09;4(18):4296-4311

Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, ON, Canada.

Pulmonary embolism (PE) is a common, potentially life-threatening yet treatable condition. Prompt diagnosis and expeditious therapeutic intervention is of paramount importance for optimal patient management. Our objective was to systematically review the accuracy of D-dimer assay, compression ultrasonography (CUS), computed tomography pulmonary angiography (CTPA), and ventilation-perfusion (V/Q) scanning for the diagnosis of suspected first and recurrent PE. We searched Cochrane Central, MEDLINE, and EMBASE for eligible studies, reference lists of relevant reviews, registered trials, and relevant conference proceedings. 2 investigators screened and abstracted data. Risk of bias was assessed using Quality Assessment of Diagnostic Accuracy Studies-2 and certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation framework. We pooled estimates of sensitivity and specificity. The review included 61 studies. The pooled estimates for D-dimer sensitivity and specificity were 0.97 (95% confidence interval [CI], 0.96-0.98) and 0.41 (95% CI, 0.36-0.46) respectively, whereas CTPA sensitivity and specificity were 0.94 (95% CI, 0.89-0.97) and 0.98 (95% CI, 0.97-0.99), respectively, and CUS sensitivity and specificity were 0.49 (95% CI, 0.31-0.66) and 0.96 (95% CI, 0.95-0.98), respectively. Three variations of pooled estimates for sensitivity and specificity of V/Q scan were carried out, based on interpretation of test results. D-dimer had the highest sensitivity when compared with imaging. CTPA and V/Q scans (high probability scan as a positive and low/non-diagnostic/normal scan as negative) both had the highest specificity. This systematic review was registered on PROSPERO as CRD42018084669.
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http://dx.doi.org/10.1182/bloodadvances.2019001052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7509887PMC
September 2020

Infectious Diseases Society of America Guidelines on the Diagnosis of COVID-19.

Clin Infect Dis 2020 Jun 16. Epub 2020 Jun 16.

Division of Nephrology and Hypertension, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas.

Background: Accurate molecular diagnostic tests are necessary for confirming a diagnosis of coronavirus disease 2019 (COVID-19). Direct detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleic acids in respiratory tract specimens informs patient, healthcare institution and public health level decision-making. The numbers of available SARS-CoV-2 nucleic acid detection tests are rapidly increasing, as is the COVID-19 diagnostic literature. Thus, the Infectious Diseases Society of America (IDSA) recognized a significant need for frequently updated systematic reviews of the literature to inform evidence-based best practice guidance.

Objective: The IDSA's goal was to develop an evidence-based diagnostic guideline to assists clinicians, clinical laboratorians, patients and policymakers in decisions related to the optimal use of SARS-CoV-2 nucleic acid amplification tests. In addition, we provide a conceptual framework for understanding molecular diagnostic test performance, discuss the nuance of test result interpretation in a variety of practice settings, and highlight important unmet research needs in the COVID-19 diagnostic testing space.

Methods: IDSA convened a multidisciplinary panel of infectious diseases clinicians, clinical microbiologists, and experts in systematic literature review to identify and prioritize clinical questions and outcomes related to the use of SARS-CoV-2 molecular diagnostics. Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was used to assess the certainty of evidence and make testing recommendations.

Results: The panel agreed on 15 diagnostic recommendations.

Conclusions: Universal access to accurate SARS-CoV-2 nucleic acid testing is critical for patient care, hospital infection prevention and the public response to the COVID-19 pandemic. Information on the clinical performance of available tests is rapidly emerging, but the quality of evidence of the current literature is considered low to very low. Recognizing these limitations, the IDSA panel weighed available diagnostic evidence and recommends nucleic acid testing for all symptomatic individuals suspected of having COVID-19. In addition, testing is recommended for asymptomatic individuals with known or suspected contact with a COVID-19 case. Testing asymptomatic individuals without known exposure is suggested when the results will impact isolation/quarantine/personal protective equipment (PPE) usage decisions, dictate eligibility for surgery, or inform administration of immunosuppressive therapy. Ultimately, prioritization of testing will depend on institutional-specific resources and the needs of different patient populations.
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http://dx.doi.org/10.1093/cid/ciaa760DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7337674PMC
June 2020

Diagnosis of deep vein thrombosis of the upper extremity: a systematic review and meta-analysis of test accuracy.

Blood Adv 2020 06;4(11):2516-2522

Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON, Canada.

Upper extremity deep vein thrombosis (UEDVT) accounts for ≤10% of DVT and can be associated with morbidity and mortality. Accurate diagnosis and treatment are necessary for safe and effective patient management. We systematically reviewed the accuracy of D-dimer and duplex ultrasonography (US) for the evaluation of suspected first-episode UEDVT. We searched the Cochrane Central Register, OVID MEDLINE, EMBASE, and PubMed for eligible studies, reference lists of relevant reviews, registered trials, and relevant conference proceedings. We included prospective cross-sectional and cohort studies that evaluated test accuracy. Two investigators independently screened and collected data. The risk of bias was assessed using Quality Assessment of Diagnostic Accuracy Studies 2 and certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation framework. We pooled estimates of sensitivity and specificity. The review included 9 studies. The pooled estimates for D-dimer sensitivity and specificity were 0.96 (95% confidence interval [CI], 0.87-0.99) and 0.47 (95% CI, 0.43-0.52), respectively. The pooled estimates for duplex US sensitivity and specificity were 0.87 (95% CI, 0.73-0.94) and 0.85 (95% CI, 0.72-0.93), respectively. Certainty of evidence was moderate. In this review, we summarized the test accuracy (sensitivity and specificity) of D-dimer and duplex US for this indication. The sensitivity and specificity of the tests found in the present review should be considered in the context of whether they are used alone or in combination, which is dependent on the prevalence of disease in the population, the clinical setting in which the patient is being evaluated, cost, potential harms, and patient outcomes. This study was registered at PROSPERO as Systematic Review Registration Number CRD42018098488.
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http://dx.doi.org/10.1182/bloodadvances.2019001409DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7284086PMC
June 2020

Diagnosis of deep vein thrombosis of the lower extremity: a systematic review and meta-analysis of test accuracy.

Blood Adv 2020 04;4(7):1250-1264

Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON, Canada.

Deep vein thrombosis (DVT) of the lower extremities can be associated with significant morbidity and may progress to pulmonary embolism and postthrombotic syndrome. Early diagnosis and treatment are important to minimize the risk of these complications. We systematically reviewed the accuracy of diagnostic tests for first-episode and recurrent DVT of the lower extremities, including proximal compression ultrasonography (US), whole leg US, serial US, and high-sensitivity quantitative D-dimer assays. We searched Cochrane Central, MEDLINE, and EMBASE for eligible studies, reference lists of relevant reviews, registered trials, and relevant conference proceedings. Two investigators screened and abstracted data. Risk of bias was assessed using Quality Assessment of Diagnostic Accuracy Studies-2 and certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation framework. We pooled estimates of sensitivity and specificity. The review included 43 studies. For any suspected DVT, the pooled estimates for sensitivity and specificity of proximal compression US were 90.1% (95% confidence interval [CI], 86.5-92.8) and 98.5% (95% CI, 97.6-99.1), respectively. For whole-leg US, pooled estimates were 94.0% (95% CI, 91.3-95.9) and 97.3% (95% CI, 94.8-98.6); for serial US pooled estimates were 97.9% (95% CI, 96.0-98.9) and 99.8% (95% CI, 99.3-99.9). For D-dimer, pooled estimates were 96.1% (95% CI, 92.6-98.0) and 35.7% (95% CI, 29.5-42.4). Recurrent DVT studies were not pooled. Certainty of evidence varied from low to high. This systematic review of current diagnostic tests for DVT of the lower extremities provides accuracy estimates. The tests are evaluated when performed in a stand-alone fashion, and in a diagnostic pathway. The pretest probability of DVT often assessed by a clinical decision rule will influence how, together with sensitivity and specificity estimates, patients will be managed.
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http://dx.doi.org/10.1182/bloodadvances.2019000960DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7160276PMC
April 2020

An international survey to inform priorities for new guidelines on von Willebrand disease.

Haemophilia 2020 Jan 26;26(1):106-116. Epub 2019 Nov 26.

Outcomes and Implementation Research Unit, Department of Nephrology and Hypertension, University of Kansas Medical Center, Kansas City, KS, USA.

Introduction: von Willebrand disease (VWD) is an inherited bleeding disorder caused by a quantitative or qualitative dysfunction of von Willebrand factor. Clinicians, patients and other stakeholders have many questions about the diagnosis and management of the disease.

Aim: To identify topics of highest importance to stakeholders that could be addressed by guidelines to be developed by the American Society of Hematology (ASH), the International Society on Thrombosis and Haemostasis (ISTH), the National Hemophilia Foundation (NHF) and the World Federation of Hemophilia (WFH).

Methods: A survey to determine and prioritize topics to be addressed in the collaborative development of guidelines for VWD was distributed to international stakeholders including patients, caregivers and healthcare providers (HCPs). Representatives of the four organizations coordinated the distribution strategy. The survey focused on both diagnosis and management of VWD, soliciting 7-point Likert-scale responses and open-ended comments, in English, French and Spanish. We conducted descriptive analysis with comparison of results by stakeholder type, gender and countries' income classification for the rating questions and qualitative conventional content data analysis for the open-ended responses.

Results: A total of 601 participants responded to the survey (49% patients/caregivers and 51% healthcare providers). The highest priority topics identified were diagnostic criteria/classification, bleeding assessment tools and treatment options for women and surgical patients. In contrast, screening for anaemia and differentiating plasma-derived therapy versus recombinant therapies received lower ratings.

Conclusion: This survey highlighted areas of importance to a diverse representation of stakeholders in the diagnosis and management of VWD, providing a framework for future guideline development and implementation.
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http://dx.doi.org/10.1111/hae.13881DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7041556PMC
January 2020

Evolution of Omega-3 Fatty Acid Therapy and Current and Future Role in the Management of Dyslipidemia.

Cardiol Clin 2018 May 21;36(2):277-285. Epub 2018 Feb 21.

Section of Cardiology, The University of Chicago Medicine, 5841 South Maryland Avenue, MC 6080, Chicago, IL 60637, USA. Electronic address:

Omega-3 fatty acids have shown modest benefit in certain subgroups at higher cardiovascular risk. Ongoing trials are investigating cardiovascular event rate reduction with newer, more efficacious formulations with a focus on these higher risk patients. This article focuses on the previously demonstrated benefits of omega-3 fatty acid therapies, currently available formulations, and their current and future role in reducing cardiovascular risk.
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http://dx.doi.org/10.1016/j.ccl.2017.12.009DOI Listing
May 2018
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