Immune activation in irritable bowel syndrome: can neuroimmune interactions explain symptoms?

Irritable bowel syndrome (IBS) is a functional disorder of the gastrointestinal (GI) tract characterized by pain or discomfort from the lower abdominal region, which is associated with altered bowel habit. Despite its prevalence, there is currently a lack of effective treatment options for patients. IBS has long been considered as a neurological condition resulting from alterations in the brain gut axis, but immunological alterations are increasingly reported in IBS patients, consistent with the hypothesis that there is a chronic, but low-grade, immune activation. Mediators released by immune cells act to either dampen or amplify the activity of GI nerves. Release of a number of these mediators correlates with symptoms of IBS, highlighting the importance of interactions between the immune and the nervous systems. Investigation of the role of microbiota in these interactions is in its early stages, but may provide many answers regarding the mechanisms underlying activation of the immune system in IBS. Identifying what the key changes in the GI immune system are in IBS and how these changes modulate viscerosensory nervous function is essential for the development of novel therapies for the underlying disorder.Patrick A. Hughes, Heddy Zola, Irmeli A. Penttila, L. Ashley Blackshaw, Jane M. Andrews, and Doreen Krumbiege

Men's information-seeking behavior regarding cancer risk and screening: A meta-narrative systematic review

Objective: Preventive strategies are known to reduce cancer risk and incidence and improve prognosis. Men seldom seek medical information about cancer prevention and risk reduction. The aim of this meta‐narrative systematic review was to critically appraise evidence from qualitative, quantitative, and mixed‐methods studies that explored men's information‐seeking behaviors in relation to cancer prevention and risk reduction. // Methods: MEDLINE, CINAHL Plus with Full Text, PsycINFO, PsycARTICLES, Psychology and Behavioral Sciences Collection, Education Full Text, and ERIC were systematically searched for studies published in English between January 1, 2006 and May 30, 2016. A total of 4117 titles were identified; of which, 31 studies were included (21 qualitative studies, 9 quantitative studies, and 1 mixed‐methods study). The methodological quality of the studies was appraised by using different tools. // Results: Most studies focused on screening for prostate (n = 18) and colorectal cancer (n = 7). Most men were passive information‐gatherers rather than active information‐seekers. Key sources of information included the Internet for active information‐seekers and health care professionals for passive information‐gatherers. Barriers to information‐seeking included information overload, embarrassment, and fear. Low literacy and health literacy levels were addressed in 3 studies and were identified as impediments to active information‐seeking. Facilitators to information‐seeking included family support, media, celebrity endorsements, and targeted information. // Conclusions: Men's information‐seeking behavior regarding cancer risk reduction, prevention, and screening is influenced by several factors. This necessitates targeted interventions aimed at raising awareness of cancer prevention and screening, while accounting for men's informational needs, preferred learning strategies, and literacy levels

Expanding the Interdisciplinary Palliative Medicine Workforce: A Longitudinal Education and Mentoring Program for Practicing Clinicians.

Coleman Foundatio

Diabetes and the risk of cardiovascular events and all-cause mortality among older adults: an individual participant data analysis of five prospective studies.

BACKGROUND: Guidelines and studies provide conflicting information on whether type 2 diabetes (T2D) should be considered a coronary heart disease risk (CHD) equivalent in older adults. METHODS: We synthesized participant-level data on 82,723 individuals aged ≥65 years from five prospective studies in two-stage meta-analyses. We estimated multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of T2D (presence versus absence) on a primary composite outcome defined as cardiovascular events or all-cause mortality. Secondary outcomes were the components of the composite. We evaluated CHD risk equivalence by comparing outcomes between individuals with T2D but no CHD versus CHD but no T2D. RESULTS: The median age of participants was 71 years, 20% had T2D and 17% had CHD at baseline. A total of 29,474 participants (36%) experienced the composite outcome. Baseline T2D was associated with higher risk of cardiovascular events or all-cause mortality versus no T2D (HR 1.44, 95% CI [1.40-1.49]). The association was weaker in individuals aged ≥75 years versus 65-74 years (HR 1.32 [1.19-1.46] vs. 1.56 [1.50-1.62]; p-value for interaction = .032). Compared to individuals with CHD but no T2D, individuals with T2D but no CHD had a similar risk of the composite outcome (HR 0.95 [0.85-1.07]), but a lower risk of cardiovascular events (HR 0.76 [0.59-0.98]). CONCLUSIONS: T2D was associated with increased risk of cardiovascular events and all-cause mortality in older adults, but T2D without CHD conferred lower risk of cardiovascular events compared to CHD without T2D. Our results suggest that T2D should not be considered a CHD risk equivalent in older adults

Knockdown of ketohexokinase versus inhibition of its kinase activity exert divergent effects on fructose metabolism.

Excessive fructose intake is a risk factor for the development of obesity and its complications. Targeting ketohexokinase (KHK), the first enzyme of fructose metabolism, has been investigated for the management of metabolic dysfunction-associated steatotic liver disease (MASLD). We compared the effects of systemic, small molecule inhibitor of KHK enzymatic activity with hepatocyte-specific, N-acetylgalactosamine siRNA-mediated knockdown of KHK in mice on an HFD. We measured KHK enzymatic activity, extensively quantified glycogen accumulation, performed RNA-Seq analysis, and enumerated hepatic metabolites using mass spectrometry. Both KHK siRNA and KHK inhibitor led to an improvement in liver steatosis; however, via substantially different mechanisms, KHK knockdown decreased the de novo lipogenesis pathway, whereas the inhibitor increased the fatty acid oxidation pathway. Moreover, KHK knockdown completely prevented hepatic fructolysis and improved glucose tolerance. Conversely, the KHK inhibitor only partially reduced fructolysis, but it also targeted triokinase, mediating the third step of fructolysis. This led to the accumulation of fructose-1 phosphate, resulting in glycogen accumulation, hepatomegaly, and impaired glucose tolerance. Overexpression of wild-type, but not kinase-dead, KHK in cultured hepatocytes increased hepatocyte injury and glycogen accumulation after treatment with fructose. The differences between KHK inhibition and knockdown are, in part, explained by the kinase-dependent and -independent effects of KHK on hepatic metabolism

Intravenous aviptadil and remdesivir for treatment of COVID-19-associated hypoxaemic respiratory failure in the USA (TESICO): a randomised, placebo-controlled trial.

BACKGROUND: There is a clinical need for therapeutics for COVID-19 patients with acute hypoxemic respiratory failure whose 60-day mortality remains at 30-50%. Aviptadil, a lung-protective neuropeptide, and remdesivir, a nucleotide prodrug of an adenosine analog, were compared with placebo among patients with COVID-19 acute hypoxaemic respiratory failure. METHODS: TESICO was a randomised trial of aviptadil and remdesivir versus placebo at 28 sites in the USA. Hospitalised adult patients were eligible for the study if they had acute hypoxaemic respiratory failure due to confirmed SARS-CoV-2 infection and were within 4 days of the onset of respiratory failure. Participants could be randomly assigned to both study treatments in a 2 × 2 factorial design or to just one of the agents. Participants were randomly assigned with a web-based application. For each site, randomisation was stratified by disease severity (high-flow nasal oxygen or non-invasive ventilation vs invasive mechanical ventilation or extracorporeal membrane oxygenation [ECMO]), and four strata were defined by remdesivir and aviptadil eligibility, as follows: (1) eligible for randomisation to aviptadil and remdesivir in the 2 × 2 factorial design; participants were equally randomly assigned (1:1:1:1) to intravenous aviptadil plus remdesivir, aviptadil plus remdesivir matched placebo, aviptadil matched placebo plus remdesvir, or aviptadil placebo plus remdesivir placebo; (2) eligible for randomisation to aviptadil only because remdesivir was started before randomisation; (3) eligible for randomisation to aviptadil only because remdesivir was contraindicated; and (4) eligible for randomisation to remdesivir only because aviptadil was contraindicated. For participants in strata 2-4, randomisation was 1:1 to the active agent or matched placebo. Aviptadil was administered as a daily 12-h infusion for 3 days, targeting 600 pmol/kg on infusion day 1, 1200 pmol/kg on day 2, and 1800 pmol/kg on day 3. Remdesivir was administered as a 200 mg loading dose, followed by 100 mg daily maintenance doses for up to a 10-day total course. For participants assigned to placebo for either agent, matched saline placebo was administered in identical volumes. For both treatment comparisons, the primary outcome, assessed at day 90, was a six-category ordinal outcome: (1) at home (defined as the type of residence before hospitalisation) and off oxygen (recovered) for at least 77 days, (2) at home and off oxygen for 49-76 days, (3) at home and off oxygen for 1-48 days, (4) not hospitalised but either on supplemental oxygen or not at home, (5) hospitalised or in hospice care, or (6) dead. Mortality up to day 90 was a key secondary outcome. The independent data and safety monitoring board recommended stopping the aviptadil trial on May 25, 2022, for futility. On June 9, 2022, the sponsor stopped the trial of remdesivir due to slow enrolment. The trial is registered with ClinicalTrials.gov, NCT04843761. FINDINGS: Between April 21, 2021, and May 24, 2022, we enrolled 473 participants in the study. For the aviptadil comparison, 471 participants were randomly assigned to aviptadil or matched placebo. The modified intention-to-treat population comprised 461 participants who received at least a partial infusion of aviptadil (231 participants) or aviptadil matched placebo (230 participants). For the remdesivir comparison, 87 participants were randomly assigned to remdesivir or matched placebo and all received some infusion of remdesivir (44 participants) or remdesivir matched placebo (43 participants). 85 participants were included in the modified intention-to-treat analyses for both agents (ie, those enrolled in the 2 x 2 factorial). For the aviptadil versus placebo comparison, the median age was 57 years (IQR 46-66), 178 (39%) of 461 participants were female, and 246 (53%) were Black, Hispanic, Asian or other (vs 215 [47%] White participants). 431 (94%) of 461 participants were in an intensive care unit at baseline, with 271 (59%) receiving high-flow nasal oxygen or non-invasive ventiliation, 185 (40%) receiving invasive mechanical ventilation, and five (1%) receiving ECMO. The odds ratio (OR) for being in a better category of the primary efficacy endpoint for aviptadil versus placebo at day 90, from a model stratified by baseline disease severity, was 1·11 (95% CI 0·80-1·55; p=0·54). Up to day 90, 86 participants in the aviptadil group and 83 in the placebo group died. The cumulative percentage who died up to day 90 was 38% in the aviptadil group and 36% in the placebo group (hazard ratio 1·04, 95% CI 0·77-1·41; p=0·78). The primary safety outcome of death, serious adverse events, organ failure, serious infection, or grade 3 or 4 adverse events up to day 5 occurred in 146 (63%) of 231 patients in the aviptadil group compared with 129 (56%) of 230 participants in the placebo group (OR 1·40, 95% CI 0·94-2·08; p=0·10). INTERPRETATION: Among patients with COVID-19-associated acute hypoxaemic respiratory failure, aviptadil did not significantly improve clinical outcomes up to day 90 when compared with placebo. The smaller than planned sample size for the remdesivir trial did not permit definitive conclusions regarding safety or efficacy. FUNDING: National Institutes of Health

Effects of fluoxetine on functional outcomes after acute stroke (FOCUS): a pragmatic, double-blind, randomised, controlled trial

Background Results of small trials indicate that fluoxetine might improve functional outcomes after stroke. The FOCUS trial aimed to provide a precise estimate of these effects. Methods FOCUS was a pragmatic, multicentre, parallel group, double-blind, randomised, placebo-controlled trial done at 103 hospitals in the UK. Patients were eligible if they were aged 18 years or older, had a clinical stroke diagnosis, were enrolled and randomly assigned between 2 days and 15 days after onset, and had focal neurological deficits. Patients were randomly allocated fluoxetine 20 mg or matching placebo orally once daily for 6 months via a web-based system by use of a minimisation algorithm. The primary outcome was functional status, measured with the modified Rankin Scale (mRS), at 6 months. Patients, carers, health-care staff, and the trial team were masked to treatment allocation. Functional status was assessed at 6 months and 12 months after randomisation. Patients were analysed according to their treatment allocation. This trial is registered with the ISRCTN registry, number ISRCTN83290762. Findings Between Sept 10, 2012, and March 31, 2017, 3127 patients were recruited. 1564 patients were allocated fluoxetine and 1563 allocated placebo. mRS data at 6 months were available for 1553 (99·3%) patients in each treatment group. The distribution across mRS categories at 6 months was similar in the fluoxetine and placebo groups (common odds ratio adjusted for minimisation variables 0·951 [95% CI 0·839–1·079]; p=0·439). Patients allocated fluoxetine were less likely than those allocated placebo to develop new depression by 6 months (210 [13·43%] patients vs 269 [17·21%]; difference 3·78% [95% CI 1·26–6·30]; p=0·0033), but they had more bone fractures (45 [2·88%] vs 23 [1·47%]; difference 1·41% [95% CI 0·38–2·43]; p=0·0070). There were no significant differences in any other event at 6 or 12 months. Interpretation Fluoxetine 20 mg given daily for 6 months after acute stroke does not seem to improve functional outcomes. Although the treatment reduced the occurrence of depression, it increased the frequency of bone fractures. These results do not support the routine use of fluoxetine either for the prevention of post-stroke depression or to promote recovery of function. Funding UK Stroke Association and NIHR Health Technology Assessment Programme

Characterization of the Si( 111 )-Ga interface using optical second-harmonic generation

Contains fulltext : 92696.pdf (publisher's version ) (Open Access

Study of surface electronic structure of Si(lll)-Ga by resonant optical second harmonic generation

Contains fulltext : 92694.pdf (publisher's version ) (Open Access

Optical second harmonic generation from the Si( 111)-Ga interface

Contains fulltext : 92692.pdf (postprint version ) (Open Access