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Results of the Wellcome Trust funded trial of the experimental anti-Ebola drug TKM-130803 have been published today in PLOS Medicine. Using a novel approach designed to get rapid indications of a drug's effectiveness, the trial showed that at the dose given the drug did not improve survival compared to historic controls.
Knowledge and practice of healthy behaviors for dementia and stroke prevention in a United States cohort
Abstract At least 45% of dementia and 60% of stroke cases are due to modifiable risk factors and could in part be prevented through healthy behavior. This cross-sectional study clustered and characterized a U.S. cohort’s knowledge and practice of healthy behavior associated with dementia and stroke. A total of 1,478 participants (mean age: 45.5 years, 51.8% female) were included. A hierarchical cluster analysis was performed to identify clusters based on the level of knowledge and practice of healthy behavior. We defined knowledge as recognizing eight modifiable risk factors (alcohol, diet, smoking, physical activity, sleep, stress, social relationships, and purpose in life) as important. We defined practice as complying with validated recommendations for each healthy behavior. Three clusters emerged: (I) high knowledge and poor practice (II) high knowledge and good practice, and (III) lower knowledge and poor practice. Participants in the high knowledge and good practice cluster were statistically significantly older, more educated, perceived fewer barriers (financial and time limitations), and more facilitators (motivation or knowing someone with dementia or stroke) compared to the other clusters. Our findings could assist in tailoring preventative strategies to enhance knowledge, translating knowledge into practice, and addressing particular facilitators and barriers per identified cluster.
How, why and when are delayed (back-up) antibiotic prescriptions used in primary care? A realist review integrating concepts of uncertainty in healthcare
Abstract Background Antimicrobial resistance is a global patient safety priority and inappropriate antimicrobial use is a key contributing factor. Evidence have shown that delayed (back-up) antibiotic prescriptions (DP) are an effective and safe strategy for reducing unnecessary antibiotic consumption but its use is controversial. Methods We conducted a realist review to ask why, how, and in what contexts general practitioners (GPs) use DP. We searched five electronic databases for relevant articles and included DP-related data from interviews with healthcare professionals in a related study. Data were analysed using a realist theory-driven approach – theorising which context(s) influenced (mechanisms) resultant outcome(s) (context-mechanism-outcome-configurations: CMOCs). Results Data were included from 76 articles and 41 interviews to develop a program theory comprising nine key and 56 related CMOCs. These explain the reasons for GPs’ tolerance of risk to different uncertainties and how these may interact with GPs’ work environment, self-efficacy and perceived patient concordance to make using DP as a safety-net or social tool more or less likely, at a given time-point. For example, when a GP uses clinical scores or diagnostic tests: a clearly high or low score/test result may mitigate scientific uncertainty and lead to an immediate or no antibiotic decision; an intermediary result may provoke hermeneutic (interpretation-related) uncertainty and lead to DP becoming preferred and used as a safety net. Our program theory explains how DP can be used to mitigate some uncertainties but also provoke or exacerbate others. Conclusion This review explains how, why and in what contexts GPs are more or less likely to use DP, as well as various uncertainties GPs face which DP may mitigate or provoke. We recommend that efforts to plan and implement interventions to optimise antibiotic prescribing in primary care consider these uncertainties and the contexts when DP may be (dis)preferred over other interventions to reduce antibiotic prescribing. We also recommend the following and have included example activities for: (i) reducing demand for immediate antibiotics; (ii) framing DP as an ‘active’ prescribing option; (iii) documenting the decision-making process around DP; and (iv) facilitating social and system support.
A common form of dominant human IFNAR1 deficiency impairs IFN-α and -ω but not IFN-β-dependent immunity.
Autosomal recessive deficiency of the IFNAR1 or IFNAR2 chain of the human type I IFN receptor abolishes cellular responses to IFN-α, -β, and -ω, underlies severe viral diseases, and is globally very rare, except for IFNAR1 and IFNAR2 deficiency in Western Polynesia and the Arctic, respectively. We report 11 human IFNAR1 alleles, the products of which impair but do not abolish responses to IFN-α and -ω without affecting responses to IFN-β. Ten of these alleles are rare in all populations studied, but the remaining allele (P335del) is common in Southern China (minor allele frequency ≈2%). Cells heterozygous for these variants display a dominant phenotype in vitro with impaired responses to IFN-α and -ω, but not -β, and viral susceptibility. Negative dominance, rather than haploinsufficiency, accounts for this dominance. Patients heterozygous for these variants are prone to viral diseases, attesting to both the dominance of these variants clinically and the importance of IFN-α and -ω for protective immunity against some viruses.
Detection of Mycoplasma pneumoniae in hospitalized children with pneumonia in Laos
Mycoplasma pneumoniae has been described worldwide as an important cause of community-acquired pneumonia. From December 2013 to December 2014, 461 children admitted to Mahosot Hospital, Vientiane, Laos, with acute respiratory infection were investigated for upper respiratory microorganisms using probe-based real-time polymerase chain reaction (PCR) (FTD33). M. pneumoniae was detected by FTD33 in the upper respiratory tract of three patients, two girls and one boy, 5.7 and 3.9 years old and 13.6 years old, respectively. They presented with clinical features compatible with M. pneumoniae infection. They improved without M. pneumoniae directed therapy. The two girls were also positive for other potential pathogens. The boy had abnormal pulmonary auscultation, and one of the girls had significant anaemia. These results suggest that enhancement of diagnostic systems for M. pneumoniae detection is needed to improve understanding of the epidemiology of M. pneumoniae infection in Laos.
Case Report: Genetic evolution of Burkholderia pseudomallei during treatment leading to antibiotic resistance and disease relapse – a case report.
Background Melioidosis is a significant yet neglected cause of sepsis in tropical regions, particularly in southeast Asia, with poor clinical outcomes. It is a growing threat with an expanding global footprint. The causative organism, Burkholderia pseudomallei, is intrinsically resistant to most first-line empiric antibiotic regimens, but acquired resistance to recommended antibiotics for this infection is uncommon. Nonetheless, the genetic determinants of resistance in this species remain poorly elucidated. Case presentation A 60-year-old farmer presented in septic shock to a hospital in Laos, and B. pseudomallei was grown from blood cultures. Following initial antibiotic treatment with meropenem and co-trimoxazole, his infection relapsed. Several subsequent B. pseudomallei isolates from the patient were resistant to multiple antibiotics, and whole genome sequencing demonstrated that this phenotype was associated with a novel 54-kb genomic deletion. This deletion, on chromosome 1, includes the 5’ end of amrR – which encodes a regulator of an efflux pump known to be important in conferring meropenem resistance – as well as 46 other genes, some of which have not been characterised. Treatment was targeted to the new antibiogram, requiring a further prolonged intravenous course and second-line oral eradication therapy. The patient made a full recovery. Conclusions Mutations in Burkholderia pseudomallei lead to increased virulence and drug resistance. Repeat microbiological sampling of patients who do not make clinical improvement as anticipated is essential, with repeat full antimicrobial susceptibility testing on subsequent isolates. Characterisation of drug-resistant mutants is required to understand mechanisms of resistance and to predict phenotypes from whole genome sequencing.
Robotic Mouse
Gene targeting is a very powerful approach for the generation of clinically relevant mouse models to elucidate the underlying molecular basis of cerebellar disorders. However, with the etiology of the vast majority of these conditions still unknown, a complementary approach based on large-scale random mutagenesis is now being employed to identify new genes and downstream signaling pathways that control neuronal cell death and survival in the cerebellum. This chapter presents the characterization of the robotic mouse, a novel model of autosomal dominant cerebellar ataxia isolated from an N-ethyl-N-nitrosourea (ENU) mutagenesis screen, which shows general growth retardation, adult-onset regionspecific Purkinje cell (PC) loss, cataracts, and defects in early T-cell maturation. The mutated protein ALL1-fused gene from chromosome 4 (AF4), which functions as a cofactor of RNA polymerase II (Pol II) elongation and disruptor of telomeric silencing-1 (DOT1)-mediated chromatin remodeling during transcription, abnormally accumulates in PCs of the cerebellum due to a slower turnover by the ubiquitin-proteasome pathway. This results in the sustained transcriptional repression of the PC survival factor insulin-like growth factor 1 (IGF-1) and deficits in downstream signaling activation, leading to degeneration and eventually death of PCs. The identification of AF4 and DOT1 as the first transcriptional negative regulators of IGF-1 expression in the cerebellum opens new avenues of research into the manipulation of this pathway for the treatment of cerebellar ataxia. In addition, the functional conservation among the AF4-related proteins implies that deregulation of transcriptional elongation and chromatin remodeling may also underlie the pathogenesis of other disorders of the central nervous system (CNS), in particular mental retardation. The robotic mouse has revealed a critical novel function for AF4 in the cerebellum which could not have been predicted otherwise and has been instrumental in the elucidation of the relevant transcriptional regulatory mechanisms.