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Improving adherence to self-protective behaviours is a public health priority. We aimed to assess the potential effectiveness and ease of use of an online version of the Risk Acceptance Ladder (RAL) in promoting help-seeking for cigarette smoking, excessive alcohol consumption, insufficient physical activity, or low fruit and vegetable consumption. 843 UK adults were recruited, of whom 602 engaged in at least one risky behaviour. Those with no immediate plans to change (n = 171) completed a behaviour specific RAL. Participants were randomised to one of two conditions; a short message congruent (on-target, n = 73) or incongruent (off-target, n = 98) with their RAL response. Performance of the RAL was assessed by participants' ability to select an applicable RAL item and reported ease of use of the RAL. Effectiveness was assessed by whether or not participants clicked a link to receive information about changing their target behaviour. Two thirds (68.9%, 95% CI = 61.8%-75.3%) of participants were able to select an applicable RAL item that corresponded to what they believed would need to change in order to alter their target behaviour, with 64.9% (95% CI = 57.5%-71.7%) reporting that it was easy to select one option. Compared with the off-target group, participants allocated to the on-target group had greater odds of clicking on the link to receive information (31.5% vs 19.4%; OR = 2.07, 95% CI = 1.01-4.26). The Risk Acceptance Ladder may have utility as a tool for tailoring messages to prompt initial steps to engaging in self-protective behaviours.

Amyloid-β (Aβ) toxicity in Alzheimer's disease (AD) is considered to be mediated by phosphorylated tau protein. In contrast, we found that, at least in early disease, site-specific phosphorylation of tau inhibited Aβ toxicity. This specific tau phosphorylation was mediated by the neuronal p38 mitogen-activated protein kinase p38γ and interfered with postsynaptic excitotoxic signaling complexes engaged by Aβ. Accordingly, depletion of p38γ exacerbated neuronal circuit aberrations, cognitive deficits, and premature lethality in a mouse model of AD, whereas increasing the activity of p38γ abolished these deficits. Furthermore, mimicking site-specific tau phosphorylation alleviated Aβ-induced neuronal death and offered protection from excitotoxicity. Our work provides insights into postsynaptic processes in AD pathogenesis and challenges a purely pathogenic role of tau phosphorylation in neuronal toxicity.

Amyotrophic lateral sclerosis (ALS) is characterized by the progressive degeneration of motor neurons. There is a pathological and genetic link between ALS and frontotemporal lobar degeneration (FTLD). Although FTLD is characterized by abnormal phosphorylated tau deposition, it is unknown whether tau is phosphorylated in ALS motor neurons. Therefore, this study assessed tau epitopes that are commonly phosphorylated in FTLD, including serine 396 (pS396), 214 (pS214), and 404 (pS404) in motor neurons from clinically pure sporadic ALS cases compared with controls. In ALS lower motor neurons, tau pS396 was observed in the nucleus or the nucleus and cytoplasm. In ALS upper motor neurons, tau pS396 was observed in the nucleus, cytoplasm, or both the nucleus and cytoplasm. Tau pS214 and pS404 was observed only in the cytoplasm of upper and lower motor neurons in ALS. The number of motor neurons (per mm2) positive for tau pS396 and pS214, but not pS404, was significantly increased in ALS. Furthermore, there was a significant loss of phosphorylated tau-negative motor neurons in ALS compared with controls. Together, our data identified a complex relationship between motor neurons positive for tau phosphorylated at specific residues and disease duration, suggesting that tau phosphorylation plays a role in ALS.

Alzheimer’s disease (AD) is characterized by synapse loss due to mechanisms that remain poorly understood. We show that the neural cell adhesion molecule 2 (NCAM2) is enriched in synapses in the human hippocampus. This enrichment is abolished in the hippocampus of AD patients and in brains of mice overexpressing the human amyloid-β (Aβ) precursor protein carrying the pathogenic Swedish mutation. Aβ binds to NCAM2 at the cell surface of cultured hippocampal neurons and induces removal of NCAM2 from synapses. In AD hippocampus, cleavage of the membrane proximal external region of NCAM2 is increased and soluble extracellular fragments of NCAM2 (NCAM2-ED) accumulate. Knockdown of NCAM2 expression or incubation with NCAM2-ED induces disassembly of GluR1-containing glutamatergic synapses in cultured hippocampal neurons. Aβ-dependent disassembly of GluR1-containing synapses is inhibited in neurons overexpressing a cleavage-resistant mutant of NCAM2. Our data indicate that Aβ-dependent disruption of NCAM2 functions in AD hippocampus contributes to synapse loss. Understanding how ß-amyloid contributes to synapse loss and dysfunction is a central goal of Alzheimer’s disease research. Here, Leshchyns’ka et al. identify a novel mechanism by which Aß disassembles hippocampal glutamatergic synapses via cleavage of a neural cell adhesion molecule 2 (NCAM2).

Background The Australian and New Zealand Audit of Surgical Mortality (ANZASM) National Report 2015 found that within the cohort of audited deaths, 85% were emergencies with acute life-threatening conditions, and by far, the most common procedures were laparotomy and colorectal procedures. Emergency laparotomy outcomes have shown improvement through audit and reporting in the UK. The purpose of this study was to determine the outcome of emergency laparotomy in the state of Victoria, Australia. Method The Dr Foster Quality Investigator (DFQI) database was interrogated for a set of Australian Classification of Health Intervention (ACHI) codes defined by the authors as representing an emergency laparotomy. The dataset included patients who underwent emergency laparotomy from July 2007 to July 2016 in all Victorian hospitals. Results There were 23,115 emergency laparotomies conducted over 9 years in 66 hospitals. Inpatient mortality was 2036/23,115 (8.8%). Mortality in the adult population increased with age and reached 18.1% in those patients that were 80 years or older. 51.3% were females, and there was no significant difference in survival between genders. Patients with no recorded comorbidities had a mortality of 4.3%, whereas those with > 5 comorbidities had 19.3% mortality. Conclusion Administrative data accessed via a tool such as DFQI can provide useful population data to guide further evidence-based improvement strategies. The mortality for emergency laparotomy within Victorian hospitals is comparable, if not better than that seen in overseas studies. There is a need to continue routine audit of mortality rates and implement systems improvement where necessary.

Metabolism plays a key role in the three antibiotic evasion strategies used by bacteria: tolerance, persistence and resistance. Modulation of purine metabolism is emerging as a common, and clinically relevant, contributor to tolerant and resistant phenotypes. However, whether high or low purine levels promote reduced antibiotic efficacy is unclear. Here, we review and explore the evidence for a relationship between cellular purine levels and antibiotic efficacy.

Transmission of human immunodeficiency virus type 1 (HIV-1) drug resistance mutations, particularly that of minority drug-resistant variants, remains poorly understood. Population-based studies suggest that drug-resistant HIV-1 is less transmissible than drug-susceptible viruses. We compared HIV-1 drug-resistant genotypes among partner-pairs in order to assess the likelihood of transmission of drug resistance mutations and investigate the role of minority variants in HIV transmission. From 1992-2010, 340 persons with primary HIV-1 infection and their partners were enrolled into observational research studies at the University of Washington Primary Infection Clinic (UWPIC). Out of 50 partner-pairs enrolled, 36 (72%) transmission relationships were confirmed by phylogenetic distance analysis of HIV-1 envelope (env) sequences, and 31 partner-pairs enrolled after 1995 met criteria for this study. Drug resistance mutations in the region of the HIV-1 polymerase gene (pol) that encodes protease and reverse transcriptase were assessed by 454-pyrosequencing. In 25 partner-pairs where the transmission direction could be determined, 12 (48%) transmitters had 1-4 drug resistance mutations (23 total) detected in their HIV-1 populations at a median frequency of 6.0% (IQR 1.5%-98.7%, range 1.0%-99.6%). Of 10 major mutations detected in five transmitters at a frequency >95%, 100% (95% CI 69.2%-100%) were detected in recipients. All of these transmitters were antiretroviral (ARV)-naïve at the time of specimen collection. Fourteen mutations (eight major mutations and six accessory mutations) were detected in nine transmitters at low frequencies (1.0%-11.8%); four of these transmitters had previously received ARV therapy. Two (14% [95% CI 1.8%-42.8%]) G73S accessory mutations were detected in both transmitter and recipient. This number is not significantly different from the number expected based on the observed frequencies of drug-resistant viruses in transmitting partners. Limitations of this study include the small sample size and uncertainties in determining the timing of virus transmission and mutation history. Drug-resistant majority variants appeared to be commonly transmitted by ARV-naïve participants in our analysis and may contribute significantly to transmitted drug resistance on a population level. When present at low frequency, no major mutation was observed to be shared between partner-pairs; identification of accessory mutations shared within a pair could be due to transmission, laboratory artifact, or apolipoprotein B mRNA-editing enzyme, catalytic polypeptides (APOBECs), and warrants further study.

Autonomous data collection is rapidly becoming an integral part of water quality monitoring, particularly for agencies looking to manage and protect aquatic ecosystems. While beneficial, it is unclear how the collection of these data can be applied in spatially complex large lakes (e.g., Laurentian Great Lakes) given the spatial heterogeneity of the ecosystem. To address this potential shortcoming in large lakes, we assessed the synchrony of sensor variables between 10 pairs of static buoys in the western basin of Lake Erie (western basin surface area = 3,282 km 2 ). Within western Lake Erie, water temperature was highly synchronous whereas dissolved oxygen, turbidity, chlorophyll and phycocyanin were asynchronous. The extent of this asynchrony was higher with increasing spatial distance between buoys. We found that between pairs of static buoys, temperature, dissolved oxygen, and turbidity all experienced decreasing correlations with increasing distance. Our results show that if researchers intend to leverage these data to answer important questions and provide real-time applications related to environmental issues like harmful algal/cyanobacterial blooms, monitoring networks need to be designed carefully with spatial complexity in mind. While autonomous data collection has many benefits, the reliance on a single or limited network of anchored monitoring buoys in large lake ecosystems has a high probability of missing important spatial features of these systems.

A successful HIV vaccine will likely induce both humoral and cell-mediated immunity, however, the enormous diversity of HIV has hampered the development of a vaccine that effectively elicits both arms of the adaptive immune response. To tackle the problem of viral diversity, T cell-based vaccine approaches have focused on two main strategies (i) increasing the breadth of vaccine-induced responses or (ii) increasing vaccine-induced responses targeting only conserved regions of the virus. The relative extent to which set-point viremia is impacted by epitope-conservation of CD8(+) T cell responses elicited during early HIV-infection is unknown but has important implications for vaccine design. To address this question, we comprehensively mapped HIV-1 CD8(+) T cell epitope-specificities in 23 ART-naïve individuals during early infection and computed their conservation score (CS) by three different methods (prevalence, entropy and conseq) on clade-B and group-M sequence alignments. The majority of CD8(+) T cell responses were directed against variable epitopes (p<0.01). Interestingly, increasing breadth of CD8(+) T cell responses specifically recognizing conserved epitopes was associated with lower set-point viremia (r = - 0.65, p = 0.009). Moreover, subjects possessing CD8(+) T cells recognizing at least one conserved epitope had 1.4 log10 lower set-point viremia compared to those recognizing only variable epitopes (p = 0.021). The association between viral control and the breadth of conserved CD8(+) T cell responses may be influenced by the method of CS definition and sequences used to determine conservation levels. Strikingly, targeting variable versus conserved epitopes was independent of HLA type (p = 0.215). The associations with viral control were independent of functional avidity of CD8(+) T cell responses elicited during early infection. Taken together, these data suggest that the next-generation of T-cell based HIV-1 vaccines should focus on strategies that can elicit CD8(+) T cell responses to multiple conserved epitopes of HIV-1.

The nuclear transactive response DNA-binding protein 43 (TDP-43) undergoes relocalization to the cytoplasm with formation of cytoplasmic deposits in neurons in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Pathogenic mutations in the TDP-43-encoding TARDBP gene in familial ALS as well as non-mutant human TDP-43 have been utilized to model FTD/ALS in cell culture and animals, including mice. Here, we report novel A315T mutant TDP-43 transgenic mice, iTDP-43 A315T , with controlled neuronal over-expression. Constitutive expression of human TDP-43 A315T resulted in pronounced early-onset and progressive neurodegeneration, which was associated with compromised motor performance, spatial memory and disinhibition. Muscle atrophy resulted in reduced grip strength. Cortical degeneration presented with pronounced astrocyte activation. Using differential protein extraction from iTDP-43 A315T brains, we found cytoplasmic localization, fragmentation, phosphorylation and ubiquitination and insolubility of TDP-43. Surprisingly, suppression of human TDP-43 A315T expression in mice with overt neurodegeneration for only 1 week was sufficient to significantly improve motor and behavioral deficits, and reduce astrogliosis. Our data suggest that functional deficits in iTDP-43 A315T mice are at least in part a direct and transient effect of the presence of TDP-43 A315T . Furthermore, it illustrates the compensatory capacity of compromised neurons once transgenic TDP-43 is removed, with implications for future treatments.