von Willebrand disease (VWD) is the most common inherited bleeding disorder known in humans. Accurate and timely diagnosis presents numerous challenges.
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.
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.
The panel agreed on 11 recommendations.
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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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Widespread vaccination is a principal strategy to mitigate the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and lessen the global burden of coronavirus disease 2019 ...(COVID-19). Information is rapidly evolving about the impact of SARS-CoV-2 vaccines on the immune and endocrine systems. This case series heightens clinical awareness of possible thyroid effects and conveys knowledge of what to monitor, which are fundamental components of public health and pharmacovigilance. We present a case series of Graves disease following mRNA SARS-CoV-2 vaccination, with symptoms and altered thyroid function tests developing within 7 days of the first dose in 2 women aged 38 and 63 years, and 28 days after the second dose in a 30-year-old man. New-onset Graves disease occurred following administration of mRNA vaccines against SARS-CoV-2. Based on the timing of signs and symptoms relative to administration of the vaccine and the absence of other probable causes, we consider the vaccine as a potential contributor to the diagnosis. The viral spike protein, delivered indirectly through an encoded mRNA vaccine, may be capable of triggering an inflammatory cascade and immune response triggering thyroid dysfunction.
•COVID-19 has revealed many shortcomings in drug development processes and accelerated innovation, despite inflicting human suffering and death tolls.•The advent of antiviral therapeutics and ...COVID-19 vaccines yield hopes, while it is possible that pockets of virulence can remain.•Actionable processes to be adopted for this crisis include regulatory partnership and leadership, good science, patient centricity, complex innovative design, global perspective, and team effort.•We are poised to revamp the traditional drug development processes for the better, which will benefit humankinds after this health crisis.
Oncology is the frontline of drug development. The current pharmaceutical pipeline is disproportional focused on oncology, where about 1/3 of all phases of development is in this therapeutic area. The emphasis brings about substantial breakthroughs and has made positive impact on the quality of life. However, oncology remains a threat to human existence. To facilitate this process, a comprehensive list of novel/first molecularly targeted oncology drug approvals by the FDA from 2017 to 2020 is assessed. Here, we focus on molecularly targeted oncology drugs and not cytotoxic ones, although the latter remain important. To achieve this purpose, besides their sponsors, years of approval, drug classes, and cancer indications, clinical significance is included. The results show that approved molecularly targeted drugs span across diverse classes, including small molecule receptor inhibitors, and biologics such as monoclonal antibodies, antibody-drug conjugates, check-point inhibitors (i.e., PD1, PDL1, CTLA4) and CAR-T cell therapies. Although complete cure of cancer remains limited, we have made substantial inroads and more is yet to come. Moreover, many of these new knowledge can be extrapolated to other therapeutic areas, especially to those of currently unmet medical needs such as in neurology and other chronic diseases.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Medication management in children and adolescents with obesity is challenging because both developmental and pathophysiological changes may impact drug disposition and response. Evidence to date ...indicates an effect of obesity on drug disposition for certain drugs used in this population. This work identified published studies evaluating drug dosing, pharmacokinetics (PK), and effect in pediatric patients with obesity, focusing on 70 common medications used in a pediatric network of 42 US medical centers. A PubMed search revealed 33 studies providing PK and/or effectiveness data for 23% (16 of 70) of medications, 44% of which have just one study and can be considered exploratory. This work appraising 4 decades of literature shows several promising approaches: greater use of PK models applied to prospective clinical studies, dosing recommendations derived from both PK and safety, and multiyear effectiveness data on drugs for chronic conditions (e.g., asthma). Most studies make dose recommendations but are weakened by retrospective study design, small study populations, and no controls or historic controls. Dosing decisions continue to rely on extrapolating knowledge, including targeting systemic drug exposure typically achieved in adults. Optimal weight‐based dosing strategies vary by drug and warrant prospective, controlled studies incorporating PK and modeling and simulation to complement clinical assessment.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Obesity is an ongoing global health concern and has only recently been recognized as a chronic disease of energy homeostasis and fuel partitioning. Obesity afflicts 17% of U.S. children and ...adolescents. Severe obesity (≥120% of the 95th percentile of body mass index (BMI) for age, or a BMI ≥ 35 kg/m2) is the fastest‐growing subgroup and now approaches 6% of all U.S. youth. Health consequences (eg, type 2 diabetes, coronary heart disease) are related in a dose‐dependent manner to severity of obesity. Because therapeutic interventions are less effective in severe obesity, prevention is a high priority. Treatment plans involving combinations of behavioral therapy, nutrition, and exercise achieve limited success. Only one drug, orlistat, is U.S. Food and Drug Administration approved for long‐term obesity management in adolescents 12 years and older. As part of comprehensive medication management, clinicians should consider the propensity for a given drug to aggravate weight gain and to consider alternatives that minimize weight impact. Medication management must take into account developmental changes as well as the pathophysiology of obesity and comorbidities. Despite expanding insight into obesity pathophysiology, there are gaps in its translation to therapeutic application. The historical construct of obesity as simply a fat‐storage disorder is fundamentally inaccurate. The approach to adjusting doses based solely on body size and extrapolating from therapeutic knowledge of adult obesity may be based on assumptions that are not fully substantiated. Classes of drugs commonly prescribed for comorbidities associated with obesity should be prioritized for clinical research evaluations aimed at optimizing dosing regimens in pediatric obesity.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
To assess the correlation between high sensitive troponin I (HsTnI) levels and myocardial damage on cardiac magnetic resonance (CMR) represented by late gadolinium enhancement (LGE) percentage in ...patients diagnosed with myocarditis.
Retrospective analysis of consecutive patients who underwent CMR following a suspected diagnosis of acute myocarditis, comparing CMR findings viewed as LGE percentage and HsTnI levels.
Between February 2016 and December 2021, 101 patients underwent CMR for suspected myocarditis in Rambam Medical Center. Seventy-six (75.2%) patients with a documented diagnosis of acute myocarditis in the medical records based on clinical history and lab work were included in the final analysis. The median age was 30 years interquartile range (IQR) 22,42 and 62 patients (81.6%) were male. Thirty-four patients (44.7%) had a history of fever and 26 (34.2%) had upper respiratory tract symptoms. The median maximal HsTnI was 3935 ng/l (1165,10 380) and the median C-reactive protein (CRP) was 7.97 mg/l (2.35,19.28). The median LGE percentage was 4.65% (2.6,8.5) and ventricular ejection fraction 60% (56.00,64.75).Linear association was found between LGE (%) and maximal HsTnI (ng/l) value with r = 0.49 ( P < 0.001). After including only patients in whom the CMR was performed within 5 days of the maximal HsTnI the correlation improved to r = 0.67 ( P < 0.001).
HsTnI is an indicator for myocardial damage extent resulting from inflammation in patients with acute myocarditis.
Novel approaches to drug development along with incentives to reward risk undertaken during early drug development have been proposed to improve the medical product development process. The American ...College of Clinical Pharmacology held its 19th Frontiers Symposium in mid‐2007 to provide a forum to share new knowledge about disease progression models and adaptive and other novel trial designs. These topics reflect the changing paradigm of drug development and regulatory innovation as outlined in the Food and Drug Administration's Critical Path Initiative. This meeting report summarizes some of the presentations and panel discussions among academic, industrial, and regulatory participants regarding clinical trial design, including adaptive Bayesian approaches.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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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DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
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