The City of Brewer, Maine - Centennial 1889-1989

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Core data set on safety, efficacy, and durability of hemophilia gene therapy for a global registry: Communication from the SSC of the ISTH

BackgroundGene therapy for people with hemophilia (PWH) will soon become available outside current clinical trials. The World Federation of Hemophilia (WFH), in collaboration with International Society of Thrombosis and Hemostasis Scientific and Standardization Committee (ISTH SSC), the European Haemophilia Consortium (EHC), the US National Hemophilia Foundation (NHF), the American Thrombosis and Hemostasis Network (ATHN), industry gene therapy development partners and Regulatory liaisons have developed the Gene Therapy Registry (GTR), designed to collect long- term data on all PWH who receive hemophilia gene therapy.ObjectiveThe objectives of the GTR are to record the long- term safety and efficacy data post gene therapy infusion and to assess the changes in quality of life and burden of disease post- gene- therapy infusion.MethodsThe GTR is a prospective, observational, and longitudinal registry developed under the guidance of a multi- stakeholder GTR Steering Committee (GTR SC), composed of health care professionals, patient advocates, industry representatives, and regulatory agency liaisons. All PWH who receive gene therapy by clinical trial or commercial product will be invited to enrol in the registry through their hemophilia treatment centers (HTCs). The registry aims to recruit 100% of eligible post gene therapy PWH globally. Through an iterative process, and following the guidance of the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA), the GTR SC has developed a core set of data to be collected on all patients post gene therapy.ResultsThe core data set includes demographic information, vector infusion details, safety, efficacy, quality of life and burden of disease.ConclusionsThe GTR is a global effort to ensure that long term safety and efficacy outcomes are recorded and analysed and rare adverse events, in a small patient population, are identified. Many unknowns on the long- term safety and efficacy of gene therapy for hemophilia may also be addressed.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/163440/2/jth15023.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/163440/1/jth15023_am.pd

World Federation of Hemophilia Gene Therapy Registry

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/156126/2/hae14015_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/156126/1/hae14015.pd

Short-Course Therapy for Urinary Tract Infections in Children: The SCOUT Randomized Clinical Trial

IMPORTANCE: There is a paucity of pediatric-specific comparative data to guide duration of therapy recommendations in children with urinary tract infection (UTI). OBJECTIVE: To compare the efficacy of standard-course and short-course therapy for children with UTI. DESIGN, SETTING, PARTICIPANTS: The Short Course Therapy for Urinary Tract Infections (SCOUT) randomized clinical noninferiority trial took place at outpatient clinics and emergency departments at 2 children\u27s hospitals from May 2012, through, August 2019. Data were analyzed from January 2020, through, February 2023. Participants included children aged 2 months to 10 years with UTI exhibiting clinical improvement after 5 days of antimicrobials. INTERVENTION: Another 5 days of antimicrobials (standard-course therapy) or 5 days of placebo (short-course therapy). MAIN OUTCOME MEASURES: The primary outcome, treatment failure, was defined as symptomatic UTI at or before the first follow-up visit (day 11 to 14). Secondary outcomes included UTI after the first follow-up visit, asymptomatic bacteriuria, positive urine culture, and gastrointestinal colonization with resistant organisms. RESULTS: Analysis for the primary outcome included 664 randomized children (639 female [96%]; median age, 4 years). Among children evaluable for the primary outcome, 2 of 328 assigned to standard-course (0.6%) and 14 of 336 assigned to short-course (4.2%) had a treatment failure (absolute difference of 3.6% with upper bound 95% CI of 5.5.%). Children receiving short-course therapy were more likely to have asymptomatic bacteriuria or a positive urine culture at or by the first follow-up visit. There were no differences between groups in rates of UTI after the first follow-up visit, incidence of adverse events, or incidence of gastrointestinal colonization with resistant organisms. CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, children assigned to standard-course therapy had lower rates of treatment failure than children assigned to short-course therapy. However, the low failure rate of short-course therapy suggests that it could be considered as a reasonable option for children exhibiting clinical improvement after 5 days of antimicrobial treatment. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01595529

Dynamic loading of human engineered heart tissue enhances contractile function and drives a desmosome-linked disease phenotype

The role that mechanical forces play in shaping the structure and function of the heart is critical to understanding heart formation and the etiology of disease but is challenging to study in patients. Engineered heart tissues (EHTs) incorporating human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes have the potential to provide insight into these adaptive and maladaptive changes. However, most EHT systems cannot model both preload (stretch during chamber filling) and afterload (pressure the heart must work against to eject blood). Here, we have developed a new dynamic EHT (dyn-EHT) model that enables us to tune preload and have unconstrained contractile shortening of >10%. To do this, three-dimensional (3D) EHTs were integrated with an elastic polydimethylsiloxane strip providing mechanical preload and afterload in addition to enabling contractile force measurements based on strip bending. Our results demonstrated that dynamic loading improves the function of wild-type EHTs on the basis of the magnitude of the applied force, leading to improved alignment, conduction velocity, and contractility. For disease modeling, we used hiPSC-derived cardiomyocytes from a patient with arrhythmogenic cardiomyopathy due to mutations in the desmoplakin gene. We demonstrated that manifestation of this desmosome-linked disease state required dyn-EHT conditioning and that it could not be induced using 2D or standard 3D EHT approaches. Thus, a dynamic loading strategy is necessary to provoke the disease phenotype of diastolic lengthening, reduction of desmosome counts, and reduced contractility, which are related to primary end points of clinical disease, such as chamber thinning and reduced cardiac output

Quantitative Deep Sequencing Reveals Dynamic HIV-1 Escape and Large Population Shifts during CCR5 Antagonist Therapy In Vivo

High-throughput sequencing platforms provide an approach for detecting rare HIV-1 variants and documenting more fully quasispecies diversity. We applied this technology to the V3 loop-coding region of env in samples collected from 4 chronically HIV-infected subjects in whom CCR5 antagonist (vicriviroc [VVC]) therapy failed. Between 25,000–140,000 amplified sequences were obtained per sample. Profound baseline V3 loop sequence heterogeneity existed; predicted CXCR4-using populations were identified in a largely CCR5-using population. The V3 loop forms associated with subsequent virologic failure, either through CXCR4 use or the emergence of high-level VVC resistance, were present as minor variants at 0.8–2.8% of baseline samples. Extreme, rapid shifts in population frequencies toward these forms occurred, and deep sequencing provided a detailed view of the rapid evolutionary impact of VVC selection. Greater V3 diversity was observed post-selection. This previously unreported degree of V3 loop sequence diversity has implications for viral pathogenesis, vaccine design, and the optimal use of HIV-1 CCR5 antagonists

Patient‐relevant health outcomes for hemophilia care: Development of an international standard outcomes set

From Wiley via Jisc Publications RouterHistory: received 2020-09-04, rev-recd 2020-12-05, accepted 2020-12-29, pub-electronic 2021-03-06, pub-print 2021-05Article version: VoRPublication status: PublishedFunder: Ministry of Health, Welfare and Sports, The NetherlandsAbstract: Background: Patient‐relevant health outcomes for persons with hemophilia should be identified and prioritized to optimize and individualize care for persons with hemophilia. Therefore, an international group of persons with hemophilia and multidisciplinary health care providers set out to identify a globally applicable standard set of health outcomes relevant to all individuals with hemophilia. Methods: A systematic literature search was performed to identify possible health outcomes and risk adjustment variables. Persons with hemophilia and multidisciplinary health care providers were involved in an iterative nominal consensus process to select the most important health outcomes and risk adjustment variables for persons with hemophilia. Recommendations were made for outcome measurement instruments. Results: Persons with hemophilia were defined as all men and women with an X‐linked inherited bleeding disorder caused by a deficiency of coagulation factor VIII or IX with plasma activity levels <40 IU/dL. We recommend collecting the following 10 health outcomes at least annually, if applicable: (i) cure, (ii) impact of disease on life expectancy, (iii) ability to engage in normal daily activities, (iv) severe bleeding episodes, (v) number of days lost from school or work, (vi) chronic pain, (vii) disease and treatment complications, (viii) sustainability of physical functioning, (ix) social functioning, and (x) mental health. Validated clinical as well as patient‐reported outcome measurement instruments were endorsed. Demographic factors, baseline clinical factors, and treatment factors were identified as risk‐adjustment variables. Conclusion: A consensus‐based international set of health outcomes relevant to all persons with hemophilia, and corresponding measurement instruments, was identified for use in clinical care to facilitate harmonized longitudinal monitoring and comparison of outcomes