PurposeTo determine the opinions from a patient perspective on relevant variables in the delivery of treatment for neovascular age-related macular degeneration (nAMD).MethodsPilot interviews with ...patients and doctors were conducted to identify what variables in the provision of a nAMD service were important. This led to the generation of two sets of scenario options. Subsequently 100 patients undergoing active treatment for nAMD in the National Health Service University Hospital, United Kingdom underwent interview assessment. They were asked to rank their preferences for provision of their care with reference to these two sets of scenario options. Using conjoint analysis, percentage preferences, and utility scores for each variable in each scenario design were calculated.ResultsNinety-five patients completed the preference ranking for both scenarios. Eight patients ranked worse vision as preferable to better vision and were excluded on the basis that they had not understood the task. The results of the remaining 87 patients are presented. The most important factor to patients was having good vision, followed by a one-stop service and less frequent follow up. The least important factors were label status of the drug, cost to the health service, and grade of the injector.ConclusionPatients regard good vision and minimal visits to the hospital above the status of injector, label status of drug, or cost to the NHS.
The GluN2 subtype (2A versus 2B) determines biophysical properties and signaling of forebrain NMDA receptors (NMDARs). During development, GluN2A becomes incorporated into previously GluN2B-dominated ...NMDARs. This “switch” is proposed to be driven by distinct features of GluN2 cytoplasmic C-terminal domains (CTDs), including a unique CaMKII interaction site in GluN2B that drives removal from the synapse. However, these models remain untested in the context of endogenous NMDARs. We show that, although mutating the endogenous GluN2B CaMKII site has secondary effects on GluN2B CTD phosphorylation, the developmental changes in NMDAR composition occur normally and measures of plasticity and synaptogenesis are unaffected. Moreover, the switch proceeds normally in mice that have the GluN2A CTD replaced by that of GluN2B and commences without an observable decline in GluN2B levels but is impaired by GluN2A haploinsufficiency. Thus, GluN2A expression levels, and not GluN2 subtype-specific CTD-driven events, are the overriding factor in the developmental switch in NMDAR composition.
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•Mutating the GluN2B CaMKII site affects phosphorylation of its C-terminal domain•The developmental changes in NMDAR composition and synaptogenesis occur normally•Changes in NMDAR composition do not require distinct GluN2 C-terminal domains•Developmental changes in NMDAR composition are primarily sensitive to GluN2A levels
An important milestone in forebrain neuronal development is the switch in composition of the NMDA receptor: GluN2A becomes incorporated into previously GluN2B-dominated NMDARs. Using knockin mice, McKay et al. find that, contrary to earlier proposed models, the switch does not require GluN2A and GluN2B to possess distinct C-terminal domain sequences.
Of 1,927 Enterococcus species isolates collected across Canada from 2007 to 2013, 80 (4.2%) were identified as vancomycin-resistant enterococci (VRE). VRE infections during this time tripled in ...Canadian hospitals, from 1.8% to 6.0% (P = 0.03). All VRE were Enterococcus faecium, with 90% possessing vanA. The prevalence of vanB decreased from 37.5% in 2007 to 0% in 2013 (P < 0.05). The VRE were multidrug resistant, but 70.6%, 86.3%, and 100% were susceptible to doxycycline, linezolid, and daptomycin, respectively.
We report on a blinded analysis of low-energy electronic recoil data from the first science run of the XENONnT dark matter experiment. Novel subsystems and the increased 5.9 ton liquid xenon target ...reduced the background in the (1, 30) keV search region to (15.8±1.3) events/(ton×year×keV), the lowest ever achieved in a dark matter detector and ∼5 times lower than in XENON1T. With an exposure of 1.16 ton-years, we observe no excess above background and set stringent new limits on solar axions, an enhanced neutrino magnetic moment, and bosonic dark matter.
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Mortality-associated burden of disease estimates from the Global Burden of Disease 2010 (GBD 2010) may erroneously lead to the interpretation that premature death in people with mental, neurological ...and substance use disorders (MNSDs) is inconsequential when evidence shows that people with MNSDs experience a significant reduction in life expectancy. We explore differences between cause-specific and excess mortality of MNSDs estimated by GBD 2010.
GBD 2010 cause-specific death estimates were produced using the International Classification of Diseases death-coding system. Excess mortality (all-cause) was estimated using natural history models. Additional mortality attributed to MNSDs as underlying causes but not captured through GBD 2010 methodology is quantified in the comparative risk assessments.
In GBD 2010, MNSDs were estimated to be directly responsible for 840 000 deaths compared with more than 13 million excess deaths using natural history models.
Numbers of excess deaths and attributable deaths clearly demonstrate the high degree of mortality associated with these disorders. There is substantial evidence pointing to potential causal pathways for this premature mortality with evidence-based interventions available to address this mortality. The life expectancy gap between persons with MNSDs and the general population is high and should be a focus for health systems reform.
Among patients with occlusion of a large intracerebral vessel who had a clinical deficit that was disproportionately severe relative to the infarct volume, 90-day outcomes for disability were better ...with late thrombectomy plus standard care than with standard care alone.
Forebrain neurons have weak intrinsic antioxidant defences compared with astrocytes, but the molecular basis and purpose of this is poorly understood. We show that early in mouse cortical neuronal ...development in vitro and in vivo, expression of the master-regulator of antioxidant genes, transcription factor NF-E2-related-factor-2 (Nrf2), is repressed by epigenetic inactivation of its promoter. Consequently, in contrast to astrocytes or young neurons, maturing neurons possess negligible Nrf2-dependent antioxidant defences, and exhibit no transcriptional responses to Nrf2 activators, or to ablation of Nrf2's inhibitor Keap1. Neuronal Nrf2 inactivation seems to be required for proper development: in maturing neurons, ectopic Nrf2 expression inhibits neurite outgrowth and aborization, and electrophysiological maturation, including synaptogenesis. These defects arise because Nrf2 activity buffers neuronal redox status, inhibiting maturation processes dependent on redox-sensitive JNK and Wnt pathways. Thus, developmental epigenetic Nrf2 repression weakens neuronal antioxidant defences but is necessary to create an environment that supports neuronal development.
The prevalence of MDR Neisseria gonorrhoeae is increasing globally and represents a public health emergency. Development and approval of new anti-gonococcal agents may take years. As a concurrent ...approach to developing new antimicrobials, the laboratory and clinical evaluation of currently licensed antimicrobials not widely used for the treatment of gonorrhoea may provide new options for the treatment of gonococcal infections.
To determine the in vitro activity of nine alternative, currently licensed and late-development antimicrobials with the potential to treat gonococcal infections against 112 clinical isolates of N. gonorrhoeae resistant to one or multiple antimicrobials.
The MICs of conventional anti-gonococcal antimicrobials (penicillin, ceftriaxone, cefixime, azithromycin, ciprofloxacin, tetracycline and spectinomycin) and alternative antimicrobials (ertapenem, gentamicin, netilmicin, tigecycline, eravacycline, fosfomycin, linezolid, ceftazidime/avibactam and ceftaroline) were determined by agar dilution.
Ertapenem and the novel cephalosporins demonstrated similar MIC values to the third-generation cephalosporins, but increased MICs were observed for isolates with increased cefixime and ceftriaxone MICs. Tigecycline and eravacycline had MIC values below expected serum concentrations for all isolates tested. The aminoglycosides gentamicin and netilmicin were generally more potent than spectinomycin, with netilmicin demonstrating the greatest potency. Fosfomycin MICs were elevated compared with other agents, but remained within the MIC range for susceptible organisms, while linezolid MICs were generally higher than those for organisms considered resistant.
Among potentially therapeutically useful alternative agents, the aminoglycosides, eravacycline, tigecycline and fosfomycin had good in vitro activity. The novel cephalosporins and ertapenem had comparable activity to cefixime and ceftriaxone.
BackgroundAccess to housing is an important determinant of health, with homeless people having substantially increased morbidity and mortality compared to the housed population. Conventional ...‘Treatment First’ (TF) models for tackling homelessness provide temporary accommodation conditional on adherence to services to address health needs, particularly substance use. A new policy approach aiming to end homelessness across Europe and North America, the ‘Housing First’ (HF) model, provides rapid housing, not conditional on abstinence from substance use. This has been noted by other reviewers as improving housing stability, but at the potential cost of removing incentives to use health services and abstain from harmful substances. Conversely, increased housing stability may lead to health improvements. We aimed to systematically review the evidence from randomised controlled trials to evaluate the effects of HF on health and well-being.MethodWe searched seven databases for randomised controlled trials of interventions providing rapid access to non-abstinence-contingent, permanent housing. We extracted data for the following primary outcomes: mental health; self-reported health and quality of life; substance use; non-routine use of healthcare services. Data recording housing stability was extracted as a secondary outcome. We assessed risk of bias and calculated standardised effect sizes.ResultsWe included four studies, all with ‘high’ risk of bias. The impact of HF on most short-term health outcomes was imprecisely estimated, with varying effect directions. No clear difference in substance use was seen. Intervention groups experienced fewer emergency department visits (incidence rate ratio (IRR)=0.63; 95% CI 0.48 to 0.82), fewer hospitalisations (IRR=0.76; 95% CI 0.70 to 0.83) and less time spent hospitalised (standardised mean difference (SMD)=−0.14; 95% CI −0.41 to 0.14) than control groups. In all studies intervention participants spent more days housed (SMD=1.24; 95% CI 0.86 to 1.62) and were more likely to be housed at 18–24 months (risk ratio=2.46; 95% CI 1.58 to 3.84).ConclusionHF approaches successfully improve housing stability and may improve some aspects of health. Implementation of HF would likely reduce homelessness and non-routine health service use without an increase in problematic substance use. Impacts on long-term health outcomes require further investigation.
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