Chronic Activation of γ2 AMPK Induces Obesity and Reduces β Cell Function.

Despite significant advances in our understanding of the biology determining systemic energy homeostasis, the treatment of obesity remains a medical challenge. Activation of AMP-activated protein kinase (AMPK) has been proposed as an attractive strategy for the treatment of obesity and its complications. AMPK is a conserved, ubiquitously expressed, heterotrimeric serine/threonine kinase whose short-term activation has multiple beneficial metabolic effects. Whether these translate into long-term benefits for obesity and its complications is unknown. Here, we observe that mice with chronic AMPK activation, resulting from mutation of the AMPK γ2 subunit, exhibit ghrelin signaling-dependent hyperphagia, obesity, and impaired pancreatic islet insulin secretion. Humans bearing the homologous mutation manifest a congruent phenotype. Our studies highlight that long-term AMPK activation throughout all tissues can have adverse metabolic consequences, with implications for pharmacological strategies seeking to chronically activate AMPK systemically to treat metabolic disease

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

Increasing frailty is associated with higher prevalence and reduced recognition of delirium in older hospitalised inpatients: results of a multi-centre study

Purpose: Delirium is a neuropsychiatric disorder delineated by an acute change in cognition, attention, and consciousness. It is common, particularly in older adults, but poorly recognised. Frailty is the accumulation of deficits conferring an increased risk of adverse outcomes. We set out to determine how severity of frailty, as measured using the CFS, affected delirium rates, and recognition in hospitalised older people in the United Kingdom. Methods: Adults over 65 years were included in an observational multi-centre audit across UK hospitals, two prospective rounds, and one retrospective note review. Clinical Frailty Scale (CFS), delirium status, and 30-day outcomes were recorded. Results: The overall prevalence of delirium was 16.3% (483). Patients with delirium were more frail than patients without delirium (median CFS 6 vs 4). The risk of delirium was greater with increasing frailty [OR 2.9 (1.8–4.6) in CFS 4 vs 1–3; OR 12.4 (6.2–24.5) in CFS 8 vs 1–3]. Higher CFS was associated with reduced recognition of delirium (OR of 0.7 (0.3–1.9) in CFS 4 compared to 0.2 (0.1–0.7) in CFS 8). These risks were both independent of age and dementia. Conclusion: We have demonstrated an incremental increase in risk of delirium with increasing frailty. This has important clinical implications, suggesting that frailty may provide a more nuanced measure of vulnerability to delirium and poor outcomes. However, the most frail patients are least likely to have their delirium diagnosed and there is a significant lack of research into the underlying pathophysiology of both of these common geriatric syndromes

Patients aged 90 years and above with Acute Coronary Syndrome in the Cardiac Intensive Care Unit: Management and Outcomes.

Limited data exist regarding outcomes after coronary angiography (CAG) and percutaneous coronary intervention (PCI) in patients aged ≥90 years admitted to the cardiac intensive care unit (CICU) with acute coronary syndrome (ACS). We studied sequential CICU patients ≥90 years admitted with ACS from 2007-2018. Three therapeutic approaches were defined: 1) No CAG; 2) CAG without PCI (CAG/No PCI); and 3) CAG with PCI (CAG/PCI). In-hospital mortality was evaluated using multivariable logistic regression. All-cause 1-year mortality was evaluated using Kaplan-Meier and multivariable Cox proportional-hazards analysis. The study included 239 patients with a median age of 92 (range 90-100) years (57% females; 45% STEMI; 8% cardiac arrest; 16% shock). The No CAG group had higher Day 1 Sequential Organ Failure Assessment score, more comorbidities, worse kidney function, and fewer STEMI. In-hospital mortality was 20.8% overall and did not differ between the No CAG (n = 103; 21.4%), CAG/No PCI (n = 47; 21.3%) and CAG/PCI (n = 90; 20.0%) groups, before or after adjustment. Overall 1-year mortality was 52.5% and did not differ between groups before or after adjustment. Median survival was 6.9 months overall and 41.2% of hospital survivors died within 1 year of CICU admission. CICU patients aged ≥90 with ACS have a substantial burden of illness with high in-hospital and 1-year mortality that was not lower in those who underwent CAG or PCI. These results suggest that careful patient selection for invasive coronary procedures is essential in this vulnerable population

Rbf/E2F1 control growth and endoreplication via steroid-independent Ecdysone Receptor signalling in Drosophila prostate-like secondary cells.

In prostate cancer, loss of the tumour suppressor gene, Retinoblastoma (Rb), and consequent activation of transcription factor E2F1 typically occurs at a late-stage of tumour progression. It appears to regulate a switch to an androgen-independent form of cancer, castration-resistant prostate cancer (CRPC), which frequently still requires androgen receptor (AR) signalling. We have previously shown that upon mating, binucleate secondary cells (SCs) of the Drosophila melanogaster male accessory gland (AG), which share some similarities with prostate epithelial cells, switch their growth regulation from a steroid-dependent to a steroid-independent form of Ecdysone Receptor (EcR) control. This physiological change induces genome endoreplication and allows SCs to rapidly replenish their secretory compartments, even when ecdysone levels are low because the male has not previously been exposed to females. Here, we test whether the Drosophila Rb homologue, Rbf, and E2F1 regulate this switch. Surprisingly, we find that excess Rbf activity reversibly suppresses binucleation in adult SCs. We also demonstrate that Rbf, E2F1 and the cell cycle regulators, Cyclin D (CycD) and Cyclin E (CycE), are key regulators of mating-dependent SC endoreplication, as well as SC growth in both virgin and mated males. Importantly, we show that the CycD/Rbf/E2F1 axis requires the EcR, but not ecdysone, to trigger CycE-dependent endoreplication and endoreplication-associated growth in SCs, mirroring changes seen in CRPC. Furthermore, Bone Morphogenetic Protein (BMP) signalling, mediated by the BMP ligand Decapentaplegic (Dpp), intersects with CycD/Rbf/E2F1 signalling to drive endoreplication in these fly cells. Overall, our work reveals a signalling switch, which permits rapid growth of SCs and increased secretion after mating, independently of previous exposure to females. The changes observed share mechanistic parallels with the pathological switch to hormone-independent AR signalling seen in CRPC, suggesting that the latter may reflect the dysregulation of a currently unidentified physiological process

Retrospective delirium ascertainment from case notes: a retrospective cohort study

Objectives This study sets out to ascertain if recognition of delirium impacts on patient outcomes. Design Retrospective cohort study. Setting Unscheduled admissions to acute care trust/secondary care UK hospitals. Participants Six hundred and fifty-six older adults aged ≥65 years admitted on 14 September 2018. Measurements Delirium was ascertained retrospectively from case notes using medical notes. Documented delirium was classified as recognised delirium and retrospectively ascertained delirium was classified as unrecognised delirium. Primary and secondary outcome measures Primary outcome measure: inpatient mortality. Secondary outcome measures: length of stay, discharge destination. Results Delirium was present in 21.1% (132/626) of patients at any point during admission. The presence of delirium was associated with increased mortality (HR 2.65, CI 1.40 to 5.01). Recognition of delirium did not significantly impact on outcomes. Conclusions Delirium is associated with adverse outcomes in hospitalised older adults. However, there is insufficient evidence that recognition of delirium affects outcomes. However, delirium recognition presents an opportunity to discuss a person’s overall prognosis and discuss this with the patient and their family. Further research is needed to assess the pathophysiology of delirium to enable development of targeted interventions towards improved outcomes in patients with delirium

Pseudorapidity densities of charged particles with transverse momentum thresholds in pp collisions at √ s = 5.02 and 13 TeV

The pseudorapidity density of charged particles with minimum transverse momentum (pT) thresholds of 0.15, 0.5, 1, and 2 GeV/c is measured in pp collisions at the center of mass energies of √s=5.02 and 13 TeV with the ALICE detector. The study is carried out for inelastic collisions with at least one primary charged particle having a pseudorapidity (η) within 0.8pT larger than the corresponding threshold. In addition, measurements without pT-thresholds are performed for inelastic and nonsingle-diffractive events as well as for inelastic events with at least one charged particle having |η|2GeV/c), highlighting the importance of such measurements for tuning event generators. The new measurements agree within uncertainties with results from the ATLAS and CMS experiments obtained at √s=13TeV.

Measurement of inclusive J/ψ\psi pair production cross section in pp collisions at s=13\sqrt{s} = 13 TeV

International audienceThe production cross section of inclusive J/$\psi$ pairs in pp collisions at a centre-of-mass energy $\sqrt{s} = 13$ TeV is measured with ALICE. The measurement is performed for J/$\psi$ in the rapidity interval $2.5 0$. The production cross section of inclusive J/$\psi$ pairs is reported to be $10.3 \pm 2.3 {\rm (stat.)} \pm 1.3 {\rm (syst.)}$ nb in this kinematic interval. The contribution from non-prompt J/$\psi$ (i.e. originated from beauty-hadron decays) to the inclusive sample is evaluated. The results are discussed and compared with data