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Background Chronic pain, regardless of its type, is a significant risk factor for suicide. However, not all individuals with chronic pain also experience suicidal thoughts and behaviors. Better characterization of clinical risk profiles and comorbidities across the medical spectrum among people with chronic pain who die by suicide is urgently needed to aid treatment and prevention strategies. Methods This case–control study leverages population-based data from the Utah Suicide Mortality Risk Study. Specifically, we identify clinical phenotypes from diagnostic data that differentiate between individuals that died by suicide with chronic pain diagnoses ( N  = 1,410) and living control individuals who also had chronic pain diagnoses ( N  = 4,664). Medical diagnostic codes were aggregated via phecodes to perform a phenotype-based phenome-wide association study. Using multivariable logistic regression analysis adjusting for covariates and multiple testing, differences in 1,727 common clinical phenotypes (phecodes) were assessed between suicide deaths and controls with chronic pain diagnoses. Models were also stratified by sex. Results Chronic pain diagnoses were nearly three times more prevalent in individuals who died by suicide compared with those who did not. Sixty-five phecodes were significantly overrepresented among suicide deaths with chronic pain diagnoses compared with controls with chronic pain diagnoses. Utah suicide deaths with chronic pain had significantly more psychiatric diagnoses (mood disorders, anxiety disorders, attention deficit hyperactivity disorder, posttraumatic stress disorder, personality disorders, schizophrenia/psychosis, substance use related traits and prior overdoses, and diagnoses related to previous suicidal thoughts and behaviors) in addition to insomnia and specific pain related diagnoses compared to Utah controls with chronic pain (odds ratios ranged from 1.40–7.10). Twenty-five phecodes were overrepresented in controls with chronic pain compared to suicides. These were related to preventative care, cancer, obesity and other conditions (odds ratios ranged from 0.16–0.73). Sex-specific analyses largely replicated the combined analyses, yet the strength of the association was stronger for women with phecodes related to prior self-harm. Conclusions Results identified multiple clinical comorbidities with chronic pain that differentiate suicide deaths from living control individuals with a history of diagnosed chronic pain. Our findings may help discern individuals with chronic pain who may be at greater risk for suicide death.

We present IPU Trusted Extensions (ITX), a set of experimental hardware extensions that enable trusted execution environments in Graphcore's AI accelerators. ITX enables the execution of AI workloads with strong confidentiality and integrity guarantees at low performance overheads. ITX isolates workloads from untrusted hosts, and ensures their data and models remain encrypted at all times except within the IPU. ITX includes a hardware root-of-trust that provides attestation capabilities and orchestrates trusted execution, and on-chip programmable cryptographic engines for authenticated encryption of code and data at PCIe bandwidth. We also present software for ITX in the form of compiler and runtime extensions that support multi-party training without requiring a CPU-based TEE. Experimental support for ITX is included in Graphcore's GC200 IPU taped out at TSMC's 7nm technology node. Its evaluation on a development board using standard DNN training workloads suggests that ITX adds less than 5% performance overhead, and delivers up to 17x better performance compared to CPU-based confidential computing systems relying on AMD SEV-SNP.

New types of machine learning hardware in development and entering the market hold the promise of revolutionizing deep learning in a manner as profound as GPUs. However, existing software frameworks and training algorithms for deep learning have yet to evolve to fully leverage the capability of the new wave of silicon. We already see the limitations of existing algorithms for models that exploit structured input via complex and instance-dependent control flow, which prohibits minibatching. We present an asynchronous model-parallel (AMP) training algorithm that is specifically motivated by training on networks of interconnected devices. Through an implementation on multi-core CPUs, we show that AMP training converges to the same accuracy as conventional synchronous training algorithms in a similar number of epochs, but utilizes the available hardware more efficiently even for small minibatch sizes, resulting in significantly shorter overall training times. Our framework opens the door for scaling up a new class of deep learning models that cannot be efficiently trained today.

From Positive News No 15 (Winter/Spring 1998). Other positive headlines from this issue include `Cancer conferences herald new hope for all', `Farmers markets here to stay', and `World on course of spiritual convergence'.

[Al Gore]'s 2000 presidential nomination acceptance speech: \"I know my own imperfections. I know that sometimes people say I'm too serious, that I talk too much substance and policy.\" Referring to soldiers as the pride of Britain echoed Colin Powell's description of soldiers as the pride of America. A former senior aide to Mr [Bill Clinton] and 2004 Democrat presidential candidate John Kerry said yesterday that Mr Brown's references to \"values\" were a favourite theme of Mr [Bob Shrum].. \"Sometimes people say I am too serious and I fight too hard and maybe that's true\" [GORDON Brown], at Monday's Labour Party conference in Bournemouth

The omicron variant (B.1.1.529) of SARS-CoV-2 has demonstrated partial vaccine escape and high transmissibility, with early studies indicating lower severity of infection than that of the delta variant (B.1.617.2). We aimed to better characterise omicron severity relative to delta by assessing the relative risk of hospital attendance, hospital admission, or death in a large national cohort. Individual-level data on laboratory-confirmed COVID-19 cases resident in England between Nov 29, 2021, and Jan 9, 2022, were linked to routine datasets on vaccination status, hospital attendance and admission, and mortality. The relative risk of hospital attendance or admission within 14 days, or death within 28 days after confirmed infection, was estimated using proportional hazards regression. Analyses were stratified by test date, 10-year age band, ethnicity, residential region, and vaccination status, and were further adjusted for sex, index of multiple deprivation decile, evidence of a previous infection, and year of age within each age band. A secondary analysis estimated variant-specific and vaccine-specific vaccine effectiveness and the intrinsic relative severity of omicron infection compared with delta (ie, the relative risk in unvaccinated cases). The adjusted hazard ratio (HR) of hospital attendance (not necessarily resulting in admission) with omicron compared with delta was 0·56 (95% CI 0·54–0·58); for hospital admission and death, HR estimates were 0·41 (0·39–0·43) and 0·31 (0·26–0·37), respectively. Omicron versus delta HR estimates varied with age for all endpoints examined. The adjusted HR for hospital admission was 1·10 (0·85–1·42) in those younger than 10 years, decreasing to 0·25 (0·21–0·30) in 60–69-year-olds, and then increasing to 0·47 (0·40–0·56) in those aged at least 80 years. For both variants, past infection gave some protection against death both in vaccinated (HR 0·47 [0·32–0·68]) and unvaccinated (0·18 [0·06–0·57]) cases. In vaccinated cases, past infection offered no additional protection against hospital admission beyond that provided by vaccination (HR 0·96 [0·88–1·04]); however, for unvaccinated cases, past infection gave moderate protection (HR 0·55 [0·48–0·63]). Omicron versus delta HR estimates were lower for hospital admission (0·30 [0·28–0·32]) in unvaccinated cases than the corresponding HR estimated for all cases in the primary analysis. Booster vaccination with an mRNA vaccine was highly protective against hospitalisation and death in omicron cases (HR for hospital admission 8–11 weeks post-booster vs unvaccinated: 0·22 [0·20–0·24]), with the protection afforded after a booster not being affected by the vaccine used for doses 1 and 2. The risk of severe outcomes following SARS-CoV-2 infection is substantially lower for omicron than for delta, with higher reductions for more severe endpoints and significant variation with age. Underlying the observed risks is a larger reduction in intrinsic severity (in unvaccinated individuals) counterbalanced by a reduction in vaccine effectiveness. Documented previous SARS-CoV-2 infection offered some protection against hospitalisation and high protection against death in unvaccinated individuals, but only offered additional protection in vaccinated individuals for the death endpoint. Booster vaccination with mRNA vaccines maintains over 70% protection against hospitalisation and death in breakthrough confirmed omicron infections. Medical Research Council, UK Research and Innovation, Department of Health and Social Care, National Institute for Health Research, Community Jameel, and Engineering and Physical Sciences Research Council.

Background Serum concentrations of 25‐hydroxyvitamin D (25(OH)VD) and C‐reactive protein (CRP) and von Willebrand's factor (vWF) concentration correlate with histopathologic disease grade and stage in chronic inflammatory and fibrotic hepatopathies (CH) in humans. Objectives To evaluate serum 25(OH)VD and serum CRP concentrations and plasma vWF concentration and determine if they correlate with histopathologic and biochemical variables in dog with CH. Animals Twenty‐three client‐owned dogs with a histopathologic diagnosis of CH were prospectively enrolled. Methods Blood samples were collected before liver biopsy. Correlations between biomarkers and clinical pathological and histopathologic variables were evaluated using Pearson's or Spearman's test. Results Serum 25(OH)VD concentration (median, 213 nmol/L; range, 42‐527 nmol/L) was negatively correlated with serum aspartate aminotransferase activity (AST; rho = −0.59, P < .01), polymorphonuclear neutrophil count (PMN; r = −0.46, P < .05), and positively correlated with serum albumin concentration (r = 0.69, P < .001). Serum CRP concentration (median, 7.4 μg/L; range, 1‐44.9 μg/L) was positively correlated with overall histopathologic necroinflammatory activity (r = 0.78, P < .001) and fibrosis score (rho = 0.49, P < .05). Plasma vWF concentration (median, 73.3%; range, 15‐141%) was positively correlated with fibrosis score (r = 0.53, P < .05) and prothrombin time (rho = 0.67, P < .01), and negatively correlated with serum albumin concentration (r = −0.73, P < .001). Conclusion and Clinical Importance In dogs with CH, serum 25(OH)VD concentration was negatively correlated with disease activity, whereas serum CRP concentration and plasma vWF concentration were positively correlated with histopathologic grade and stage. Our results provide preliminary evidence that these biomarkers may be useful to assess grade and stage of CH in dogs in the absence of liver biopsy.

Most marine organisms present an indirect lifecycle where a planktonic larval stage reaches competency before settling to the substrate and metamorphosing. Despite the critical importance of these early life history stages, little is known about how global change-related stressors, in particular ocean acidification (OA), affect marine larval settlement and metamorphosis. To date, 48 studies have investigated the effects of OA on larval settlement, focussing mostly on tropical corals (16), echinoderms (11) and fish (8). Most studies show negative effects of OA during settlement and post-settlement processes. For instance, reduced settlement is typically seen along natural pH gradients and in experimentally lowered pH treatments. This generally results in reduced settlement selectivity and metamorphosis and poorer post-settlement fitness. Carryover effects of OA exposure can also occur, with larval environmental history influencing early post-settlement performance. We conclude that OA may (1) alter larval supply for settlement by altering horizontal swimming behaviour or vertical migration; (2) directly influence settlement success through changes in the nature and distribution of suitable settlement substrates (e.g. biofilm, crustose coralline algae); and (3) mediate carryover effects at settlement by altering larval development or larval energy budgets. In contrast to fish larvae, there is little evidence for most invertebrate larvae that their perception of settlement cues is directly influenced by reduced pH. A summation of how OA affects the settlement and metamorphosis of marine invertebrates is timely, since altered settlement rates will influence the future distributions, abundances and ecology of marine benthic communities.

Novel antimalarials are needed to address emerging resistance to artemisinin and partner drugs. We did two trials to evaluate safety, tolerability, pharmacokinetics, and activity against blood stage Plasmodium falciparum for the drug candidate MMV533. A phase 1a first-in-human (FIH) trial was conducted at Nucleus Network (Melbourne, VIC, Australia). Part 1 was a double-blind, randomised, placebo-controlled, sequential ascending dose study and part 2 was an open-label, randomised, two-period crossover, pilot food effect study. A phase 1b, open-label, volunteer infection study (VIS) was conducted at Nucleus Network (Herston, QLD, Australia). Eligible participants were adults aged 18–55 years, with a bodyweight of at least 50 kg and BMI of 18–32 kg/m2 and participants in the VIS were malaria-naive. In part 1 of the FIH study, six cohorts of up to eight participants were randomly assigned (3:1) to a single oral MMV533 dose (5, 10, 20, 50, 100, and 160 mg) or placebo using an automated system, with study staff and participants masked to treatment allocation, and follow-up until day 28. In part 2, MMV533 30 mg was administered open-label to one cohort of nine participants assigned by simple randomisation (1:1) to the fasted–fed (n=4) or fed–fasted (n=5) groups. After a 21-day washout period, fed and fasted groups crossed over with follow-up until day 42. In the VIS, seven participants were assigned using simple randomisation (1:1:1) to three dosing groups of 20 mg (n=3), 35 mg (n=2), or 100 mg (n=2) after parasitaemia was detected, with follow-up until day 28. The primary outcomes were treatment emergent adverse events and relationship to MMV533 for the FIH study assessed in the safety population, and in the VIS primary outcomes were parasite reduction ratio over 48 h (log10PRR48), parasite clearance half-life (PCT1/2), and lag phase assessed in the pharmacodynamic population. MMV533 pharmacokinetics was a secondary outcome for both studies, evaluated in the pharmacokinetic population. The studies are registered with ClinicalTrials.gov, NCT04323306 and NCT05205941 (completed). The FIH study was conducted between July 31, 2020, and Sept 27, 2022, and the VIS between March 31 and Aug 9, 2022. 335 adults were assessed for eligibility, 71 enrolled, and 69 randomly assigned (53 in part 1 and nine in part 2 of the FIH study, and seven in the VIS). 32 (45%) of 71 participants were female and 39 (55%) were male. In part 1, 24 (63%) of 38 participants had an adverse event after MMV533 administration with no apparent relationship to dose versus six (50%) of 12 after placebo. Treatment-related adverse events were reported for four (11%) participants receiving MMV533 and one (8%) receiving placebo, with no relationship to dose. In part 2, adverse events were reported for three (38%) of eight participants when fasted and four (44%) of nine when fed, with no apparent influence of food. Time to maximum plasma concentration was 4·0–6·0 h, and apparent half-life was 103·8–127·2 h. After a high-fat meal, the geometric mean ratio (fed:fasted) of MMV533 AUC0-last was 112·0 (90% CI 89·6–140·0). In the VIS for MMV533 100 mg, log10PRR48 was 2·27 (1·99–2·56), PCT1/2 was 6·36 h (5·64–7·28), and lag phase was 2 h. An acceptable safety and tolerability profile, confirmed parasiticidal activity, and a long half-life support progression of MMV533 into clinical trials in patients with malaria as a component of new antimalarial combination therapies. MMV Medicines for Malaria Venture and Bill & Melinda Gates Foundation.