Assessment of disease progression in dysferlinopathy: A 1-year cohort study

ObjectiveTo assess the ability of functional measures to detect disease progression in dysferlinopathy over 6 months and 1 year.MethodsOne hundred ninety-three patients with dysferlinopathy were recruited to the Jain Foundation's International Clinical Outcome Study for Dysferlinopathy. Baseline, 6-month, and 1-year assessments included adapted North Star Ambulatory Assessment (a-NSAA), Motor Function Measure (MFM-20), timed function tests, 6-minute walk test (6MWT), Brooke scale, Jebsen test, manual muscle testing, and hand-held dynamometry. Patients also completed the ACTIVLIM questionnaire. Change in each measure over 6 months and 1 year was calculated and compared between disease severity (ambulant [mild, moderate, or severe based on a-NSAA score] or nonambulant [unable to complete a 10-meter walk]) and clinical diagnosis.ResultsThe functional a-NSAA test was the most sensitive to deterioration for ambulant patients overall. The a-NSAA score was the most sensitive test in the mild and moderate groups, while the 6MWT was most sensitive in the severe group. The 10-meter walk test was the only test showing significant change across all ambulant severity groups. In nonambulant patients, the MFM domain 3, wrist flexion strength, and pinch grip were most sensitive. Progression rates did not differ by clinical diagnosis. Power calculations determined that 46 moderately affected patients are required to determine clinical effectiveness for a hypothetical 1-year clinical trial based on the a-NSAA as a clinical endpoint.ConclusionCertain functional outcome measures can detect changes over 6 months and 1 year in dysferlinopathy and potentially be useful in monitoring progression in clinical trials.ClinicalTrials.gov identifier:NCT01676077

Assessment of disease progression in dysferlinopathy: A 1-year cohort study

ObjectiveTo assess the ability of functional measures to detect disease progression in dysferlinopathy over 6 months and 1 year.MethodsOne hundred ninety-three patients with dysferlinopathy were recruited to the Jain Foundation's International Clinical Outcome Study for Dysferlinopathy. Baseline, 6-month, and 1-year assessments included adapted North Star Ambulatory Assessment (a-NSAA), Motor Function Measure (MFM-20), timed function tests, 6-minute walk test (6MWT), Brooke scale, Jebsen test, manual muscle testing, and hand-held dynamometry. Patients also completed the ACTIVLIM questionnaire. Change in each measure over 6 months and 1 year was calculated and compared between disease severity (ambulant [mild, moderate, or severe based on a-NSAA score] or nonambulant [unable to complete a 10-meter walk]) and clinical diagnosis.ResultsThe functional a-NSAA test was the most sensitive to deterioration for ambulant patients overall. The a-NSAA score was the most sensitive test in the mild and moderate groups, while the 6MWT was most sensitive in the severe group. The 10-meter walk test was the only test showing significant change across all ambulant severity groups. In nonambulant patients, the MFM domain 3, wrist flexion strength, and pinch grip were most sensitive. Progression rates did not differ by clinical diagnosis. Power calculations determined that 46 moderately affected patients are required to determine clinical effectiveness for a hypothetical 1-year clinical trial based on the a-NSAA as a clinical endpoint.ConclusionCertain functional outcome measures can detect changes over 6 months and 1 year in dysferlinopathy and potentially be useful in monitoring progression in clinical trials.ClinicalTrials.gov identifier:NCT01676077

Think TB! Is the diagnosis of pulmonary tuberculosis delayed by the use of antibiotics?

SETTING: Effective tuberculosis (TB) control requires prompt diagnosis of infectious cases through early suspicion of pulmonary TB in all subjects with suspected respiratory infection.OBJECTIVE: To test our hypothesis that prior antibiotic treatment for presumed bacterial infection leads to a delay in diagnosing TB in a European country with low TB incidence.DESIGN: Adults with culture-confirmed pulmonary TB at a single metropolitan centre were assessed for the impact of any previous antibiotic treatment on symptoms and the time to starting specific anti-tuberculosis treatment.RESULTS: Of 83 patients, 42 (51%) received antibiotics prior to TB diagnosis, with symptomatic improvement reported in 20 of the 42 (48%) patients. This was unrelated to specific drug class. Although the median time to diagnosis in subjects receiving antibiotics was prolonged (P = 0.001), this was not predicted by treatment response. In 94% of cases, the initial chest radiograph was suggestive of TB infection.CONCLUSION: Patients receiving antibiotics prior to TB confirmation experience a process-related delay in starting treatment. To minimise the risk of ongoing TB transmission, we propose that clinicians should include TB in their differential diagnosis and initiate simple, TB-focused investigations early on in the diagnostic process

A Comparative Evaluation of Offences: Criminalising Abusive Behaviour in England, Wales, Scotland, Ireland and Tasmania

This chapter analyses the new offences introduced in England and Wales in 2015, Scotland in 2018, Ireland in 2018 and the less recent offences in Tasmania in 2004 addressing the use of coercive control in domestic relationships. Each legislature has chosen different approaches to a shared problem and, as other jurisdictions are considering whether or how to criminalise non-physical abuse at this time, it is timely to consider which model has the greatest potential to achieve the stated objectives of these offences. I argue that the Scottish model is most promising and that rollout to other nations should be a serious consideration. This is based on Scotland having developed an offence that aligns as far as could be expected with its existing policy approaches to domestic abuse. The legislation has a focus on current or ex-partners, no requirement to show that the victim actually suffered harm, an ability to reflect the wide range of behaviours and impact that abusive behaviour can cause, and a sentencing range that adequately reflects the broad range of offending covered by these offences. In comparison, other models have shortcomings, such as greater evidential barriers for prosecution, limitation periods, or a failure to take into account the different levels of severity of consequences caused by the prohibited behaviour

Alternative Constructions of a Family Violence Offence

The crime of torture was introduced into the Queensland Criminal Code in 1997. While initially this crime was introduced to respond to a gap in the criminal justice response to child abuse, it has since been used on many occasions in response to cases involving domestic and family violence. This chapter tracks the introduction of the crime of torture into Queensland law and reviews case law and sentencing data to show how it has been applied in the context of domestic and family violence. In the context of increased recognition of the serious impact of non-physical forms of family violence, it shows how the crime of torture can be applied to cases of domestic and family violence that do not involve physical abuse. Drawing on case studies, the chapter also identifies shortcomings of the offence and explores the possibility of the introduction of a less serious version of the offence

Safety and immunogenicity of a candidate tuberculosis vaccine MVA85A delivered by aerosol in BCG-vaccinated healthy adults: a phase 1, double-blind, randomised controlled trial.

BACKGROUND: Intradermal MVA85A, a candidate vaccine against tuberculosis, induces high amounts of Ag85A-specific CD4 T cells in adults who have already received the BCG vaccine, but aerosol delivery of this vaccine might offer immunological and logistical advantages. We did a phase 1 double-blind trial to compare the safety and immunogenicity of aerosol-administered and intradermally administered MVA85A METHODS: In this phase 1, double-blind, proof-of-concept trial, 24 eligible BCG-vaccinated healthy UK adults were randomly allocated (1:1) by sequentially numbered, sealed, opaque envelopes into two groups: aerosol MVA85A and intradermal saline placebo or intradermal MVA85A and aerosol saline placebo. Participants, the bronchoscopist, and immunologists were masked to treatment assignment. The primary outcome was safety, assessed by the frequency and severity of vaccine-related local and systemic adverse events. The secondary outcome was immunogenicity assessed with laboratory markers of cell-mediated immunity in blood and bronchoalveolar lavage samples. Safety and immunogenicity were assessed for 24 weeks after vaccination. Immunogenicity to both insert Ag85A and vector modified vaccinia virus Ankara (MVA) was assessed by ex-vivo interferon-γ ELISpot and serum ELISAs. Since all participants were randomised and vaccinated according to protocol, our analyses were per protocol. This trial is registered with ClinicalTrials.gov, number NCT01497769. FINDINGS: Both administration routes were well tolerated and immunogenic. Respiratory adverse events were rare and mild. Intradermal MVA85A was associated with expected mild local injection-site reactions. Systemic adverse events did not differ significantly between the two groups. Three participants in each group had no vaccine-related systemic adverse events; fatigue (11/24 [46%]) and headache (10/24 [42%]) were the most frequently reported symptoms. Ag85A-specific systemic responses were similar across groups. Ag85A-specific CD4 T cells were detected in bronchoalveolar lavage cells from both groups and responses were higher in the aerosol group than in the intradermal group. MVA-specific cellular responses were detected in both groups, whereas serum antibodies to MVA were only detectable after intradermal administration of the vaccine. INTERPRETATION: Further clinical trials assessing the aerosol route of vaccine delivery are merited for tuberculosis and other respiratory pathogens. FUNDING: The Wellcome Trust and Oxford Radcliffe Hospitals Biomedical Research Centre