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Background and aims: Liver donors with serological evidence of resolved hepatitis B virus (HBV) infection (HBV surface antigen (HBsAg) negative, anti-HBV core (HBc) positive) can transmit HBV infection to recipients. [...]

Purpose: Hemophilia B is an X-linked congenital bleeding disorder caused by a deficiency of coagulation factor IX (FIX) clotting activity. This study evaluated safety and efficacy of nonacog alfa, a recombinant human blood coagulation FIX replacement product, in males aged 12-65 years with hemophilia B (FIX activity ≤ 2%) with or without inhibitors in India., Methods: In this multicenter, open-label, post-approval phase 4 study, participants were treated for up to 8 weeks, with up to a 4-week screening period and a subsequent post-treatment 28-day safety observation period. Intravenous nonacog alfa 40 IU/kg (range 13-78 IU/kg) was administered at intervals of 3-4 days, in accordance with the approved local product document., Results: A total of 25 participants were enrolled and completed the study. No participants developed FIX inhibitors during the study, experienced treatment-related adverse events (AEs) or serious AEs, or developed a thrombotic event and/or hypersensitivity reaction. No participants experienced bleeding events requiring on-demand treatment with nonacog alfa. Seventeen bleeding episodes (16 spontaneous and 1 traumatic) were reported in 10 participants; all occurred post treatment, with the exception of a minor gum-bleeding event, and were managed without treatment. The mean (SD) annualized total factor consumption (TFC) per patient was 224,582 (75,527) IU; the mean (SD) annualized TFC by weight per patient was 3639 (573) IU/kg., Conclusion: Nonacog alfa was safe and effective for the prevention of hemorrhagic episodes in Indian males with congenital, severe hemophilia B. No participants developed FIX inhibitors, and no new safety signals were reported., Competing Interests: Competing InterestsNirmalkumar Choraria and Shashikant Apte have no conflicts to disclose. Savita Rangarajan has served on an advisory board for Pfizer and for Sanofi Sigilon; has served on a speakers’ bureau for Pfizer and Takeda; and has served as a consultant for Reliance Life Sciences. M. Joseph John has served as a speaker/consultant or advisory board member, and/or received research support for attendance at educational meetings from Dr Reddy’s Lab, Grifols, Janssen, Mylan, Novo Nordisk, Pfizer, Roche, and Takeda. Pritam Gupta, Shyam Parvatini, Rohit Chand, Seema Pai, G. S. H. Ramakanth, Jeremy Rupon, Chhabra Amit, Hitesh Bhaskarrao Muley, and Damien Simoneau are employees of Pfizer Inc. and may own stock/options in the company., (© The Author(s) 2022.)

Cardiac amyloidosis is a rare, debilitating, and usually fatal disease increasingly recognized in clinical practice despite patients presenting with non-specific symptoms of cardiomyopathy. The current standard of care (SoC) focuses on preventing further amyloid formation and deposition, either with anti-plasma cell dyscrasia (anti-PCD) therapies in light-chain (AL) amyloidosis or stabilizers of transthyretin (TTR) in transthyretin amyloidosis (ATTR). The SoC is supplemented by therapies to treat the complications arising from organ dysfunction; for example, heart failure, arrhythmia, and proteinuria. Advancements in treatments have improved patient survival, especially for those whose disease is detected and for whom treatment is initiated at an early stage. However, there still are many unmet medical needs, particularly for patients with severe disease for whom morbidity and mortality remain high. There currently are no approved treatments to reverse amyloid infiltration and deplete the amyloid fibrils already deposited in organs, which can continue to cause progressive dysfunction. Anti-fibril therapies aimed at removing the deposited fibrils are being investigated for safety and efficacy in improving outcomes for patients with severe disease. However, there is no clinical evidence yet that removing deposited amyloid fibrils will improve organ function, thereby improving quality of life or extending life. Nevertheless, anti-fibril therapies are actively being investigated in clinical trials to evaluate their ability to complement and synergize with current SoC., Competing Interests: CCQ, JC, DS, and MM are employed by Alexion, AstraZeneca Rare Disease. MF: consultant (Akcea, Alexion, Alnylam, Eidos, Ionis, Intellia, Pfizer, Prothena, and Sanofi); advisory board (Akcea, Alnylam, Eidos, Intellia, Pfizer, and Prothena). TD: consultant (Alnylam, GlaxoSmithKline, Pfizer, and Prothena); honoraria (Alnylam, Pfizer, and Prothena; research grants (GlaxoSmithKline and Pfizer); clinical trial support (Alnylam, Ionis, and Pfizer). PG-P: consultant (Alexion, Alnylam, AstraZeneca, Attralus, Bridgebio, Intellia, Ionis, Neurimmune, NovoNordisk, and Pfizer); speakers bureau (Alnylam, Bridgebio, Ionis, and Pfizer); grant support to his institution (Alnylam and Pfizer). MM: advisory board or DSMB (Alnylam, Eidos, Intellia, Ionis, NovoNordisk); research grants (Eidos, Janssen, Pfizer); clinical trial support (Alnylam, Attralus, Eidos, Ionis, Pfizer). GP: advisory board (Alexion, Argobio, Janssen, Protego); honoraria (Alexion, Argobio, The Binding Site Group, Janssen, Pfizer, Protego, Prothena, Sebia, and Siemens); research funding (Gate Bioscience, The Binding Site Group). The remaining author declare that the article was developed in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Quarta, Fontana, Damy, Catini, Simoneau, Mercuri, Garcia-Pavia, Maurer and Palladini.)

Purpose: Hemophilia A is an X-linked congenital disorder, characterized by factor VIII (FVIII) deficiency. Globally, India has the highest population of patients with hemophilia, and there is a clear unmet need for appropriate and effective treatment for this patient population. This multicenter, open-label, post-approval study evaluated the safety and efficacy of moroctocog alfa in patients with moderate or severe congenital hemophilia A in India., Methods: Intravenous moroctocog alfa was administered 30 ± 5 IU/kg 3 times weekly for bleeding prophylaxis, according to the local product document. Participants were treated for up to 8 weeks, with an up to 4-week screening period and a subsequent post-treatment, 28-day safety observation period. Patients continued in the study until at least 24 exposure days or a period of up to 8 weeks on moroctocog alfa., Results: A total of 50 participants were enrolled, and 48 (85.7%) completed the study. No participants developed FVIII inhibitors during the study. The mean (SD) annualized bleeding rate during moroctocog alfa prophylaxis was 0.79 (2.0) with a median (range) of 0.00 (0.0, 6.8). The mean (SD) annualized total factor consumption (TFC) per participant was 287,432 (93,866) IU; the mean (SD) annualized TFC by weight per participant was 4176 (858) IU/kg. Moroctocog alfa was well tolerated with no reported treatment-emergent adverse event-related dose reductions, discontinuations, or serious adverse events., Conclusion: Moroctocog alfa was safe, effective, and well tolerated in Indian participants with congenital moderate to severe hemophilia A. No participant developed FVIII inhibitors during the study., Competing Interests: Competing InterestsNirmalkumar Choraria and Shashikant Apte have no conflicts to disclose. Savita Rangarajan has served on advisory boards for Pfizer and Sanofi Sigilon; on speakers’ bureaus for Pfizer and Takeda; and as a consultant for Reliance Life Sciences. M. Joseph John has received honoraria as a speaker/consultant and/or advisory board member, and has received research grants for attendance at educational meetings from Dr Reddy’s Lab, Grifols, Janssen, Mylan, Novo Nordisk, Pfizer, Roche, and Takeda. Pritam Gupta, Shyam Parvatini, Rohit Chand, Seema Pai, G. S. H. Ramakanth, Jeremy Rupon, Chhabra Amit, Hitesh Bhaskarrao Muley, and Damien Simoneau are employees of Pfizer Inc. and may own stock/options in the company., (© The Author(s) 2022.)

Acromegaly is a rare condition typically caused by benign pituitary adenomas, resulting in excessive production of growth hormone. Clinical manifestations of acromegaly are diverse, varying from the overgrowth of body tissue to cardiovascular, metabolic, and osteoarticular disorders. Symptoms may emerge slowly, overlapping with other diseases and often involve many different healthcare specialists. In the last decade, efforts to provide an accurate and timely diagnosis of acromegaly have improved disease management and clinical experience. Despite this progress, marked differences in the diagnosis, treatment, and management of acromegaly exist from country-to-country. To address these inconsistencies in the region comprising Central and Eastern Europe, Israel, and Kazakhstan, a panel of acromegaly experts from 13 of these countries was convened. Acromegaly experts from each country provided available information on the approaches from their country, including regional treatment centers and multidisciplinary teams, treatment access, reimbursement and availability, and physician education, disease awareness, and patient advocacy. Across several areas of acromegaly management, divergent approaches were identified and discussed, including the provision of multidisciplinary care, approved and available treatments, and disease awareness programs. These were recognized as areas of potential improvement in the management of acromegaly, in addition to participation in national and regional acromegaly registries. Further experience exchange will facilitate the identification of specific strategies that can be adapted in each country, and widespread participation in acromegaly registries will enable their evaluation. It is anticipated that this approach will support the optimization of acromegaly patient care across this region., Competing Interests: The authors declare competing interests as follows: MB reports personal fees and non-financial support from Novartis; grants, personal fees and non-financial support from Ipsen; personal fees, non-financial support and other from Pfizer; and personal fees from Recordati outside the submitted work. MD reports personal fees from Pfizer and personal fees from Novartis outside the submitted work. MG reports personal fees from Pfizer and personal fees from Novartis outside the submitted work. VH reports personal fees and non-financial support from Pfizer and Ipsen outside the submitted work. II reports lectures’ fees from Pfizer and Ipsen outside the submitted work. DK reports personal fees from Pfizer outside the submitted work. TK reports personal fees from Pfizer and personal fees from Novartis outside the submitted work. MK reports personal fees from Pfizer outside the submitted work. CP reports personal fees from Pfizer, Novartis and Ipsen outside the submitted work. SV reports personal fees from Pfizer outside the submitted work. RG reports employment with Pfizer. SP reports employment with Pfizer. DS reports employment with Pfizer. IS reports personal fees and other from Pfizer; personal fees and other from Medison Pharma; and grants, personal fees and other from Novartis outside the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. This project received funding from Pfizer. The funder had the following involvement with the study: supported the face-to-face advisory board meeting and funded medical writing and editorial assistance., (Copyright © 2022 Bolanowski, Adnan, Doknic, Guk, Hána, Ilovayskaya, Kastelan, Kocjan, Kužma, Nurbekova, Poiana, Szücs, Vandeva, Gomez, Paidac, Simoneau and Shimon.)

Purpose: A complete description of the process of physical therapy clinical reasoning for walking assistive devices in patients with stroke and brain injury has never been undertaken. Describing the clinical reasoning process used in post-acute inpatient rehabilitation is important to shed light on the clinical activities and factors used in practice, prevent device abandonment, and, inform entry-level clinical training. The two purposes were first, to describe the clinical reasoning process used during inpatient rehabilitation for walking assistive devices in patients with stroke and brain injury, and second, to determine whether clinical reasoning differed by two facility types and by diagnosis., Methods: A mixed methods study of 67 participants in either an online survey or focus groups., Results: A consistent and comprehensive method to determine the need and justification for a walking assistive device regardless of diagnosis or facility type was found. The clinical reasoning process included five primary factors, considered throughout the rehabilitation stay (safety, balance, cognition, strength, and function). The three therapist-related factors (experience/preference, training parameters, and use of objective tools), and seven patient-related factors (experience/preference, fluctuations, fear, age, diagnosis/comorbidities, discharge environment, and payer) individualized care. Definitions of the five primary factors were derived from participants' responses., Conclusions: Results from this study revealed complexity in the clinical reasoning process used in physical therapy practice to determine the best walking assistive device for patients with stroke and brain injury during inpatient rehabilitation. Information from this study can inform post-acute physical therapy practice and education, and may reduce device abandonment. Implications for rehabilitation Clinical reasoning (CR) is a complex process in which a clinician must consider multiple factors, which requires non-linear and iterative thinking, and involves many people, making it shared among the patient, caregivers, and the healthcare team. Describing the actual CR process used by physiotherapists when prescribing a walking assistive device (WAD) will identify the factors considered, thus more accurately explain the process of care. Such a description could lead to better justification of rehabilitation for patients with stroke and brain injury, and furthermore, determine whether treatments are rendered consistently and when, if ever, divergent approaches occur. Better understanding of the CR process of WAD prescription may also reduce the possibility of device abandonment.

Transthyretin familial amyloid polyneuropathy (TTR-FAP) is a rare, progressive, life-threatening, hereditary disorder caused by mutations in the transthyretin gene and characterized by extracellular deposition of transthyretin-derived amyloid fibrils in peripheral and autonomic nerves, heart, and other organs. TTR-FAP is frequently diagnosed late because the disease is difficult to recognize due to phenotypic heterogeneity. Based on published literature and expert opinion, symptom clusters suggesting TTR-FAP are reviewed, and practical guidance to facilitate earlier diagnosis is provided. TTR-FAP should be suspected if progressive peripheral sensory-motor neuropathy is observed in combination with one or more of the following: family history of a neuropathy, autonomic dysfunction, cardiac hypertrophy, gastrointestinal problems, inexplicable weight loss, carpal tunnel syndrome, renal impairment, or ocular involvement. If TTR-FAP is suspected, transthyretin genotyping, confirmation of amyloid in tissue biopsy, large- and small-fiber assessment by nerve conduction studies and autonomic system evaluations, and cardiac testing should be performed., (© 2015 The Authors. Journal of the Peripheral Nervous System published by Wiley Periodicals, Inc. on behalf of Peripheral Nerve Society.)

Background: Patient-related (demographic/disease) and treatment-related (drug/clinician/hospital) characteristics were evaluated as potential predictors of healthcare resource use and opportunities for early switch (ES) from intravenous (IV)-to-oral methicillin-resistant Staphylococcus aureus (MRSA)-active antibiotic therapy and early hospital discharge (ED)., Methods: This retrospective observational medical chart study analyzed patients (across 12 European countries) with microbiologically confirmed MRSA complicated skin and soft tissue infections (cSSTI), ≥3 days of IV anti-MRSA antibiotics during hospitalization (July 1, 2010-June 30, 2011), and discharged alive by July 31, 2011. Logistic/linear regression models evaluated characteristics potentially associated with actual resource use (length of IV therapy, length of hospital stay [LOS], IV-to-oral antibiotic switch), and ES and ED (using literature-based and expert-verified criteria) outcomes., Results: 1542 patients (mean ± SD age 60.8 ± 16.5 years; 61.5% males) were assessed with 81.0% hospitalized for MRSA cSSTI as the primary reason. Several patient demographic, infection, complication, treatment, and hospital characteristics were predictive of length of IV therapy, LOS, IV-to-oral antibiotic switch, or ES and ED opportunities. Outcomes and ES and ED opportunities varied across countries. Length of IV therapy and LOS (r = 0.66, p < 0.0001) and eligibilities for ES and ED (r = 0.44, p < 0.0001) showed relatively strong correlations. IV-to-oral antibiotic switch patients had significantly shorter length of IV therapy (-5.19 days, p < 0.001) and non-significantly shorter LOS (-1.86 days, p > 0.05). Certain patient and treatment characteristics were associated with increased odds of ES (healthcare-associated/ hospital-acquired infection) and ED (patient living arrangements, healthcare-associated/ hospital-acquired infection, initiating MRSA-active treatment 1-2 days post cSSTI index date, existing ED protocol), while other factors decreased the odds of ES (no documented MRSA culture, ≥4 days from admission to cSSTI index date, IV-to-oral switch, IV line infection) and ED (dementia, no documented MRSA culture, initiating MRSA-active treatment ≥3 days post cSSTI index date, existing ES protocol)., Conclusions: Practice patterns and opportunity for further ES and ED were affected by several infection, treatment, hospital, and geographical characteristics, which should be considered in identifying ES and ED opportunities and designing interventions for MRSA cSSTI to reduce IV days and LOS while maintaining the quality of care.

This retrospective observational medical chart review aimed to describe country-specific variations across Europe in real-world meticillin-resistant Staphylococcus aureus (MRSA) complicated skin and soft-tissue infection (cSSTI) treatment patterns, antibiotic stewardship activity, and potential opportunities for early switch (ES) from intravenous (i.v.) to oral formulations and early discharge (ED) from hospital using standardised data collection and criteria and economic implications of these opportunities. Patients were randomly sampled from 12 countries (Austria, Czech Republic, France, Germany, Greece, Ireland, Italy, Poland, Portugal, Slovakia, Spain and the UK), aged ≥18 years, with documented MRSA cSSTI, hospitalised between 1 July 2010 and 30 June 2011, discharged alive by 31 July 2011. Of 1502 patients, 1468 received MRSA-targeted therapy. Intravenous-to-oral switch rates ranged from 2.0% to 20.2%, i.v. length of therapy from 10.1 to 18.6 days and hospital length of stay (LoS) from 15.2 to 25.0 days across Europe. Of 341 sites, 82.9% had antibiotic steering committees, 23.7% had i.v.-to-oral switch antibiotic protocols and 12.9% had ED protocols for MRSA cSSTI. ES and ED eligibility ranged from 12.0% (Slovakia) to 56.3% (Greece) and from 10% (Slovakia) to 48.2% (Portugal), respectively. Potential cost savings per ED-eligible patient ranged from €414 (Slovakia) to €2703 (France). MRSA cSSTI treatment patterns varied widely across countries, but further reductions in i.v. therapy, hospital LoS and associated costs could be realised. These data provide insight into clinical practice patterns across diverse European healthcare systems and identify potential opportunities for local clinicians and policy-makers to improve clinical care and cost-effectiveness of this therapeutic area., (Copyright © 2014 The Authors. Published by Elsevier B.V. All rights reserved.)

To study the effects of reduced CD4 T cell activity on hepatitis C virus (HCV) genetic heterogeneity, HCV quasi-species complexity and diversification over time were analyzed for 56 human immunodeficiency virus-coinfected patients. Patients were selected retrospectively from the French Seroconverter Cohort (SEROCO) and the French Hemophilia Cohort (HEMOCO) for having stable CD4 cell counts for 3 years. HCV complexity was assessed by single-strand conformation polymorphism analysis of the envelope-coding region (HVR) and the core region at 2 time points 3 years apart. Increased HVR complexity was associated with higher CD4 cell count and HCV genotype 1 infection. Qualitative variation of HVR and core region was not related to CD4 cell count and depended on the initial complexity. Complexity of both regions remained unchanged over 3 years. Among these HCV-HIV-coinfected patients with stable CD4 cell counts, viral genotype and CD4 cell count may have influenced HVR complexity before their inclusion in the study but were not involved in HVR diversification during the 3-year follow-up period.