MYC Controls the Epstein-Barr Virus Lytic Switch.

Epstein-Barr virus (EBV) is associated with multiple human malignancies. To evade immune detection, EBV switches between latent and lytic programs. How viral latency is maintained in tumors or in memory B cells, the reservoir for lifelong EBV infection, remains incompletely understood. To gain insights, we performed a human genome-wide CRISPR/Cas9 screen in Burkitt lymphoma B cells. Our analyses identified a network of host factors that repress lytic reactivation, centered on the transcription factor MYC, including cohesins, FACT, STAGA, and Mediator. Depletion of MYC or factors important for MYC expression reactivated the lytic cycle, including in Burkitt xenografts. MYC bound the EBV genome origin of lytic replication and suppressed its looping to the lytic cycle initiator BZLF1 promoter. Notably, MYC abundance decreases with plasma cell differentiation, a key lytic reactivation trigger. Our results suggest that EBV senses MYC abundance as a readout of B cell state and highlights Burkitt latency reversal therapeutic targets.

Phosphorylation of EZH2 by AMPK Suppresses PRC2 Methyltransferase Activity and Oncogenic Function.

Sustained energy starvation leads to activation of AMP-activated protein kinase (AMPK), which coordinates energy status with numerous cellular processes including metabolism, protein synthesis, and autophagy. Here, we report that AMPK phosphorylates the histone methyltransferase EZH2 at T311 to disrupt the interaction between EZH2 and SUZ12, another core component of the polycomb repressive complex 2 (PRC2), leading to attenuated PRC2-dependent methylation of histone H3 at Lys27. As such, PRC2 target genes, many of which are known tumor suppressors, were upregulated upon T311-EZH2 phosphorylation, which suppressed tumor cell growth both in cell culture and mouse xenografts. Pathologically, immunohistochemical analyses uncovered a positive correlation between AMPK activity and pT311-EZH2, and higher pT311-EZH2 correlates with better survival in both ovarian and breast cancer patients. Our finding suggests that AMPK agonists might be promising sensitizers for EZH2-targeting cancer therapies.

Urinary incontinence indicates mortality, disability, and infections in hospitalised stroke patients.

OBJECTIVES: To assess the impact of urinary incontinence (UI) on health outcomes over the entire spectrum of acute stroke severity (National Institutes of Health Stroke Scale [NIHSS] scores: 0-42), due to a paucity of data on patients with milder strokes. PATIENTS AND METHODS: Data were prospectively collected (2014-2016) from the Sentinel Stroke National Audit Programme (1593 men, 1591 women; mean [SD] age 76.8 [13.3] years) admitted to four UK hyperacute stroke units (HASUs). Relationships between variables were assessed by multivariable logistic regression. Data were adjusted for age, sex, comorbidities, pre-stroke disability and intra-cranial haemorrhage, and presented as odds ratios with 95% confidence intervals. RESULTS: Amongst patients with no symptoms or a minor stroke (NIHSS scores of 0-4), compared to patients without UI, patients with UI had significantly greater risks of poor outcomes including: in-hospital mortality; disability at discharge; in-hospital pneumonia; urinary tract infection within 7 days of admission; prolonged length of stay on the HASU; palliative care by discharge; activity of daily living (ADL) support, and new discharge to care home. In patients with more moderate stroke (NIHSS score of 5-15) the same outcomes were identified; being at greater risk for patients with UI, except for palliative care by discharge and ADL support. With the highest stroke severity group (NIHSS score of 16-48) all outcomes were identified except in-patient mortality, pneumonia, and ADL support. However, odds ratios diminished as NIHSS scores increased. CONCLUSIONS: Urinary incontinence is a useful indicator of poor short-term outcomes in older patients with an acute stroke, but irrespective of stroke severity. This provides valuable information to healthcare professionals to identify at-risk individuals.

Sex-specific independent risk factors of urinary incontinence in acute stroke patients: A multicentre registry-based cohort study.

BACKGROUND: The presence of urinary incontinence (UI) in acute stroke patients indicates poor outcomes in men and women. However, there is a paucity and inconsistency of data on UI risk factors in this group and hence we conducted a sex-specific analysis to identify risk factors. METHODS: Data were collected prospectively (2014-2016) from the Sentinel Stroke National Audit Program for patients admitted to four UK hyperacute stroke units. Relevant risk factors for UI were determined by stepwise multivariable logistic regression, presented as odds ratios (OR) and 95% confidence intervals (CI). RESULTS: The mean (±SD) age of UI onset in men (73.9 year ± 13.1; n = 1593) was significantly earlier than for women (79.8 year ± 12.9; n = 1591: p < 0.001). Older age between 70 and 79 year in men (OR = 1.61: CI = 1.24-2.10) and women (OR = 1.55: CI = 1.12-2.15), or ≥80 year in men (OR = 2.19: CI = 1.71-2.81), and women (OR = 2.07: CI = 1.57-2.74)-reference: <70 year-both predicted UI. In addition, intracranial hemorrhage (reference: acute ischemic stroke) in men (OR = 1.64: CI = 1.22-2.20) and women (OR = 1.75: CI = 1.30-2.34); and prestroke disability (mRS scores ≥ 4) in men (OR = 1.90: CI = 1.02-3.5) and women (OR = 1.62: CI = 1.05-2.49) (reference: mRS scores < 4); and stroke severity at admission: NIHSS scores = 5-15 in men (OR = 1.50: CI = 1.20-1.88) and women (OR = 1.72: CI = 1.37-2.16), and NIHSS scores = 16-42 in men (OR = 4.68: CI = 3.20-6.85) and women (OR = 3.89: CI = 2.82-5.37) (reference: NIHSS scores = 0-4) were also significant. Factors not selected were: a history of congestive heart failure, hypertension, atrial fibrillation, diabetes and previous stroke. CONCLUSIONS: We have identified similar risk factors for UI after stroke in men and women including age >70 year, intracranial hemorrhage, prestroke disability and stroke severity.

TWIST1 methylation by SETD6 selectively antagonizes LINC-PINT expression in glioma.

Gliomas are one of the most common and lethal brain tumors among adults. One process that contributes to glioma progression and recurrence is the epithelial to mesenchymal transition (EMT). EMT is regulated by a set of defined transcription factors which tightly regulate this process, among them is the basic helix-loop-helix family member, TWIST1. Here we show that TWIST1 is methylated on lysine-33 at chromatin by SETD6, a methyltransferase with expression levels correlating with poor survival in glioma patients. RNA-seq analysis in U251 glioma cells suggested that both SETD6 and TWIST1 regulate cell adhesion and migration processes. We further show that TWIST1 methylation attenuates the expression of the long-non-coding RNA, LINC-PINT, thereby promoting EMT in glioma. Mechanistically, TWIST1 methylation represses the transcription of LINC-PINT by increasing the occupancy of EZH2 and the catalysis of the repressive H3K27me3 mark at the LINC-PINT locus. Under un-methylated conditions, TWIST1 dissociates from the LINC-PINT locus, allowing the expression of LINC-PINT which leads to increased cell adhesion and decreased cell migration. Together, our findings unravel a new mechanistic dimension for selective expression of LINC-PINT mediated by TWIST1 methylation.

Muscle Fiber Cross-Sectional Area Is Associated With Quadriceps Strength and Rate of Torque Development After ACL Injury.

ABSTRACT: Graham, MC, Thompson, KL, Hawk, GS, Fry, CS, and Noehren, B. Muscle fiber cross-sectional area is associated with quadriceps strength and rate of torque development after ACL injury. J Strength Cond Res 38(6): e273-e279, 2024-The purpose of this study was to investigate the relationship between muscle fiber type-specific properties of the vastus lateralis and quadriceps muscle performance in individuals after an anterior cruciate ligament (ACL) tear. 26 subjects (22.0 ± 5.4 years) were included in this cross-sectional study, and all data were collected before ACL reconstruction. Quadriceps peak torque (QPT) and early (0-100 ms) and late (100-200 ms) rate of torque development (RTD) were obtained from maximal voluntary isometric quadriceps strength testing. Muscle fiber cross-sectional area (fCSA) and percent fiber type distribution (FT%) were evaluated through immunohistochemical analysis of a muscle biopsy. Between-limb differences in fiber characteristics were assessed using paired t-tests (with α-level 0.05). Relationships between fiber-specific properties and quadriceps muscle performance were determined using separate multiple linear regression analyses for ACL-injured and noninjured limbs. There were significant differences in fCSA between ACL-injured and noninjured limbs across all fiber types, but no differences in FT%. Type 1 fCSA, type 2a fCSA, and their interaction effect were the explanatory variables with the strongest relationship to all performance outcomes for the ACL-injured limb. The explanatory variables in the ACL-injured limb had a significant relationship to QPT and late RTD, but not early RTD. These findings suggest that QPT and late RTD are more heavily influenced by fCSA than FT% in ACL-injured limbs. This work serves as a foundation for the development of more specific rehabilitation strategies aimed at improving quadriceps muscle function before ACL reconstruction or for individuals electing nonsurgical management.

A molecular signature defining exercise adaptation with ageing and in vivo partial reprogramming in skeletal muscle.

Exercise promotes functional improvements in aged tissues, but the extent to which it simulates partial molecular reprogramming is unknown. Using transcriptome profiling from (1) a skeletal muscle-specific in vivo Oct3/4, Klf4, Sox2 and Myc (OKSM) reprogramming-factor expression murine model; (2) an in vivo inducible muscle-specific Myc induction murine model; (3) a translatable high-volume hypertrophic exercise training approach in aged mice; and (4) human exercise muscle biopsies, we collectively defined exercise-induced genes that are common to partial reprogramming. Late-life exercise training lowered murine DNA methylation age according to several contemporary muscle-specific clocks. A comparison of the murine soleus transcriptome after late-life exercise training to the soleus transcriptome after OKSM induction revealed an overlapping signature that included higher JunB and Sun1. Also, within this signature, downregulation of specific mitochondrial and muscle-enriched genes was conserved in skeletal muscle of long-term exercise-trained humans; among these was muscle-specific Abra/Stars. Myc is the OKSM factor most induced by exercise in muscle and was elevated following exercise training in aged mice. A pulse of MYC rewired the global soleus muscle methylome, and the transcriptome after a MYC pulse partially recapitulated OKSM induction. A common signature also emerged in the murine MYC-controlled and exercise adaptation transcriptomes, including lower muscle-specific Melusin and reactive oxygen species-associated Romo1. With Myc, OKSM and exercise training in mice, as well habitual exercise in humans, the complex I accessory subunit Ndufb11 was lower; low Ndufb11 is linked to longevity in rodents. Collectively, exercise shares similarities with genetic in vivo partial reprogramming. KEY POINTS: Advances in the last decade related to cellular epigenetic reprogramming (e.g. DNA methylome remodelling) toward a pluripotent state via the Yamanaka transcription factors Oct3/4, Klf4, Sox2 and Myc (OKSM) provide a window into potential mechanisms for combatting the deleterious effects of cellular ageing. Using global gene expression analysis, we compared the effects of in vivo OKSM-mediated partial reprogramming in skeletal muscle fibres of mice to the effects of late-life murine exercise training in muscle. Myc is the Yamanaka factor most induced by exercise in skeletal muscle, and so we compared the MYC-controlled transcriptome in muscle to Yamanaka factor-mediated and exercise adaptation mRNA landscapes in mice and humans. A single pulse of MYC is sufficient to remodel the muscle methylome. We identify partial reprogramming-associated genes that are innately altered by exercise training and conserved in humans, and propose that MYC contributes to some of these responses.

Postabsorptive muscle protein synthesis is higher in outpatients as compared to inpatients.

Several factors affect muscle protein synthesis (MPS) in the postabsorptive state. Extreme physical inactivity (e.g., bedrest) may reduce basal MPS, whereas walking may augment basal MPS. We hypothesized that outpatients would have a higher postabsorptive MPS than inpatients. To test this hypothesis, we conducted a retrospective analysis. We compared 152 outpatient participants who arrived at the research site the morning of the MPS assessment with 350 Inpatient participants who had an overnight stay in the hospital unit before the MPS assessment the following morning. We used stable isotopic methods and collected vastus lateralis biopsies ∼2 to 3 h apart to assess mixed MPS. MPS was ∼12% higher (P < 0.05) for outpatients than inpatients. Within a subset of participants, we discovered that after instruction to limit activity, outpatients (n = 13) took 800 to 900 steps in the morning to arrive at the unit, seven times more steps than inpatients (n = 12). We concluded that an overnight stay in the hospital as an inpatient is characterized by reduced morning activity and causes a slight but significant reduction in MPS compared with participants studied as outpatients. Researchers should be aware of physical activity status when designing and interpreting MPS results.NEW & NOTEWORTHY The postabsorptive muscle protein synthesis rate is lower in the morning after an overnight inpatient hospital stay compared with an outpatient visit. Although only a minimal amount of steps was conducted by outpatients (∼900), this was enough to increase postabsorptive muscle protein synthesis rate.

Association of Polypharmacy and Anticholinergic Burden with Length of Stay in Hospital Amongst Older Adults Admitted with Hip Fractures: A Retrospective Observational Study.

BACKGROUND: Age-associated multimorbidity and polypharmacy, predispose individuals to falls and consequent hip fractures. We examined the impact of polypharmacy (≥ 4 drugs daily), including anticholinergic agents, on hospital length of stay (LOS), mobility within 1-day of hip surgery and pressure ulcers in adults ≥ 60 years admitted with hip fractures. METHODS: In this retrospective observational study, information on medications at admission was obtained to calculate the total number of drugs taken, including those imposing an anticholinergic burden (ACB). Associations between variables were examined by logistic regression; adjusted for age, sex, co-morbidities, pre-fracture functional limitations and alcohol consumption. RESULTS: There were 787 women and 318 men of similar mean age (± SD): 83.1 years (± 8.6) and 82.5 years (± 9.0), respectively. Compared to patients with an ACB score = 0 and taking < 4 drugs daily, those with an ACB score ≥ 1 and taking ≥ 4 drugs daily had greater risk of prolonged LOS (≥ 2 weeks), OR 1.8 (1.2-2.7); failure to mobilise within 1-day of surgery, OR 1.9 (1.1-3.3); and pressure ulcers, OR 3.0 (95% CI 1.2-7.9). LOS was further prolonged by failure to mobilise within 1-day of surgery and/or pressure ulcers. Those with either an ACB score ≥ 1 or the use of ≥ 4 drugs daily had intermediate risks. CONCLUSIONS: Anticholinergic agents and polypharmacy in patients with hip fractures are associated with longer LOS in hospital, further accentuated by failure to mobilise within 1-day after surgery and pressure ulcers. This study provides further evidence of the impact of polypharmacy, including those with an ACB, on adverse health outcomes and lends support to reduce potentially inappropriate prescribing.

Skeletal Muscle Bioenergetics in Critical Limb Ischemia and Diabetes.

INTRODUCTION: Mitochondrial dysfunction is implicated in the metabolic myopathy accompanying peripheral artery disease (PAD) and critical limb ischemia (CLI). Type-2 diabetes mellitus (T2DM) is a major risk factor for PAD development and progression to CLI and may also independently be related to mitochondrial dysfunction. We set out to determine the effect of T2DM in the relationship between CLI and muscle mitochondrial respiratory capacity and coupling control. METHODS: We studied CLI patients undergoing revascularization procedures or amputation, and non-CLI patients with or without T2DM of similar age. Mitochondrial respiratory capacity and function were determined in lower limb permeabilized myofibers by high-resolution respirometry. RESULTS: Fourteen CLI patients (65 ± 10y) were stratified into CLI patients with (n = 8) or without (n = 6) T2DM and were compared to non-CLI patients with (n = 18; 69 ± 5y) or without (n = 19; 71 ± 6y) T2DM. Presence of CLI but not T2DM had a marked impact on all mitochondrial respiratory states in skeletal muscle, adjusted for the effects of sex. Leak respiration (State 2, P < 0.025 and State 4o, P < 0.01), phosphorylating respiration (P < 0.001), and maximal respiration in the uncoupled state (P < 0.001), were all suppressed in CLI patients, independent of T2DM. T2DM had no significant effect on mitochondrial respiratory capacity and function in adults without CLI. CONCLUSIONS: Skeletal muscle mitochondrial respiratory capacity was blunted by ∼35% in patients with CLI. T2DM was not associated with muscle oxidative capacity and did not moderate the relationship between muscle mitochondrial respiratory capacity and CLI.

Benign prostatic hyperplasia/obstruction ameliorated using a soluble guanylate cyclase activator.

Benign prostatic hyperplasia (BPH) is a feature of ageing males. Up to half demonstrate bladder outlet obstruction (BOO) with associated lower urinary tract symptoms (LUTS) including bladder overactivity. Current therapies to reduce obstruction, such as α1-adrenoceptor antagonists and 5α-reductase inhibitors, are not effective in all patients. The phosphodiesterase-5 inhibitor (PDE5I) tadalafil is also approved to treat BPH and LUTS, suggesting a role for nitric oxide (NO• ), soluble guanylate cyclase (sGC), and cGMP signalling pathways. However, PDE5I refractoriness can develop for reasons including nitrergic nerve damage and decreased NO• production, or inflammation-related oxidation of the sGC haem group, normally maintained in a reduced state by the cofactor cytochrome-b5-reductase 3 (CYB5R3). sGC activators, such as cinaciguat (BAY 58-2667), have been developed to enhance sGC activity in the absence of NO• or when sGC is oxidised. Accordingly, their effects on the prostate and LUT function of aged mice were evaluated. Aged mice (≥24 months) demonstrated a functional BPH/BOO phenotype, compared with adult animals (2-12 months), with low, delayed voiding responses and elevated intravesical pressures as measured by telemetric cystometry. This was consistent with outflow tract histological and molecular data that showed urethral constriction, increased prostate weight, greater collagen deposition, and cellular hyperplasia. All changes in aged animals were attenuated by daily oral treatment with cinaciguat for 2 weeks, without effect on serum testosterone levels. Cinaciguat had only transient (1 h) cardiovascular effects with oral gavage, suggesting a positive safety profile. The benefit of cinaciguat was suggested by its reversal of an overactive cystometric profile in CYB5R3 smooth muscle knockout mice that mirrors a profile of oxidative dysfunction where PDE5I may not be effective. Thus, the aged male mouse is a suitable model for BPH-induced BOO and cinaciguat has a demonstrated ability to reduce prostate-induced obstruction and consequent effects on bladder function. © 2021 The Pathological Society of Great Britain and Ireland.

The Lower Urinary Tract Science Group-ICI-RS. 7th June 2023 record of a meeting at Bristol University, UK.

AIMS: The aim of a preliminary session of the International Continence on Incontinence-Research Society (ICI-RS) was to provide a forum for an international group of experimental scientists, who are members of ICI-RS, to explain their on-going work to fellow laboratory scientists, to obtain feedback about future directions and discuss potential future collaborations. METHODS: Fourteen Individual abstracts are presented as submitted by the attendees. RESULTS AND CONCLUSIONS: The presentations and attendant abstracts reflect a wide variety of fundamental research currently underway that is designed to have translational outputs with respect to the management and treatment of lower urinary tract pathologies.

Nitric oxide signaling pathways in the normal and pathological bladder: Do they provide new pharmacological pathways?-ICI-RS 2023.

AIMS: The nitric oxide (NO•)/soluble guanylate cyclase/cyclic-GMP (cGMP) signaling pathway is ubiquitous and regulates several functions in physiological systems as diverse as the vascular, nervous, and renal systems. However, its roles in determining normal and abnormal lower urinary tract functions are unclear. The aim was to identify potential therapeutic targets associated with this pathway to manage lower urinary tract functional disorders. METHODS: This review summarizes a workshop held under the auspices of ICI-RS with a view to address these questions. RESULTS: Four areas were addressed: NO• signaling to regulate neurotransmitter release to detrusor smooth muscle; its potential dual roles in alleviating and exacerbating inflammatory pathways; its ability to act as an antifibrotic mediator; and the control by nitrergic nerves of lower urinary tract vascular dynamics and the contractile performance of muscular regions of the bladder wall. Central to much of the discussion was the role of the NO• receptor, soluble guanylate cyclase (sGC) in regulating the generation of the enzyme product, the second messenger cGMP. The redox state of sGC is crucial in determining its enzymic activity and the role of a class of novel agents, sGC activators, to optimize activity and to potentially alleviate the consequences of lower urinary tract disorders was highlighted. In addition, the consequences of a functional relationship between nitrergic and sympathetic nerves to regulate vascular dynamics was discussed. CONCLUSIONS: Several potential NO•-dependent drug targets in the lower urinary tract were identified that provide the basis for future research and translation to clinical trials.

New therapeutic targets to prevent benign prostatic enlargement and symptomatic progression to benign prostatic obstruction-ICI-RS 2023.

AIMS: Benign prostatic enlargement (BPE) can impact lower urinary tract function due to its potential progression to benign prostatic obstruction (BPO). Treatment options include removal of the obstruction by surgery or through use of therapeutics designed to slow growth or reduce tissue stress imposed by muscular stromal components. Inflammation and development of fibrosis can also raise intrinsic tissue stress within the gland, further impacting obstruction. Outflow tract obstruction can also impact emission and ejaculation if the obstruction persists. METHODS: This review summarizes an ICI-RS think tank considering novel drug treatments that might address BPO caused by progressive development of BPE, as well as manage decompensation changes to bladder function. RESULTS: Topics included recent advances in our understanding of pathological changes occurring to the prostate and other lower urinary tract tissues during progressive development of BPE, and how prevention or reversal might benefit from the identification of novel drug targets. These included contractile properties of prostatic tissues, the impact of BPE and its effects on bladder function, the deposition of intramural fibrotic tissue with protracted BPO, the role of inflammation in the development of BPE and its progression to BPO. In particular, we discussed current therapeutic options for treating BPE/BPO, and new therapeutic targets, what they treat and their advantage over current medications. CONCLUSION: Several new drug targets were identified, including soluble guanylate cyclase (sGC), the receptor for nitric oxide (NO•), and sGC activators that promotes sGC-mediated cGMP production when sGC is inactivated and unresponsive to NO•.

How does the lower urinary tract contribute to bladder sensation? ICI-RS 2023.

AIM: Bladder sensation is critical for coordinating voluntary micturition to maintain healthy bladder function. Sensations are initiated by the activation of sensory afferents that innervate throughout the bladder wall. However, the physiological complexity that underlies the initiation of bladder sensory signaling in health and disease remains poorly understood. This review summarises the latest knowledge of the mechanisms underlying the generation of bladder sensation and identifies key areas for future research. METHODS: Experts in bladder sensory signaling reviewed the literature on how the lower urinary tract contributes to bladder sensation and identified key research areas for discussion at the 10th International Consultation on Incontinence-Research Society. RESULTS: The importance of bladder sensory signals in maintaining healthy bladder function is well established. However, better therapeutic management of bladder disorders with exaggerated bladder sensation, including overactive bladder syndrome (OAB) and interstitial cystitis/bladder pain syndrome (IC/BPS) is limited by a lack of knowledge in a number of key research areas including; the contribution of different nerves (pudendal, pelvic, hypogastric) to filling sensations in health and disease; the relative contribution of stretch sensitive (muscular) and stretch-insensitive (mucosal) afferents to bladder sensation in health and disease; the direct and indirect contributions of the muscularis mucosae to bladder contraction and sensation; and the impact of manipulating urothelial release factors on bladder sensation. CONCLUSION: Disturbances in bladder sensory signaling can have severe consequences for bladder sensation and function including the development of OAB and IC/BPS. Advancing therapeutic treatments for OAB and IC/BPS requires a deeper understanding of the mechanisms underlying the generation of bladder sensation, and key areas for future research have been identified.

Adverse stroke outcomes amongst UK ethnic minorities: a multi-centre registry-based cohort study of acute stroke.

OBJECTIVE: Socioeconomic and health inequalities persist in multicultural western countries. Here, we compared outcomes following an acute stroke amongst ethnic minorities with Caucasian patients. METHODS: Data were prospectively collected (2014-2016) from the Sentinel Stroke National Audit Programme for 3309 patients who were admitted with an acute stroke in four UK hyperacute stroke units. Associations between variables were examined by chi-squared tests and multivariable logistic regression, adjusted for age, sex, prestroke functional limitations and co-morbidities, presented as odds ratios (OR) with 95% CI. RESULTS: There were 3046 Caucasian patients, 95 from ethnic minorities (mostly South Asians, Blacks, mixed race and a few in other ethnic groups) and 168 not stated. Compared with Caucasian patients, those from ethnic minorities had a proportionately higher history of diabetes (33.7% vs 15.4%, P < 0.001), but did not differ in other chronic conditions, functional limitations or sex distribution. Their age of stroke onset was younger both in women (76.8 year vs 83.2 year, P < 0.001) and in men (69.5 year vs 75.9 year, P = 0.002). They had greater risk for having a stroke before the median age of 79.5 year: OR = 2.15 (1.36-3.40) or in the first age quartile (< 69 year): OR = 2.91 (1.86-4.54), requiring palliative care within the first 72 h: OR = 3.88 (1.92-7.83), nosocomial pneumonia or urinary tract infection within the first 7 days of admission: OR = 1.86 (1.06-3.28), and in-hospital mortality: OR = 2.50 (1.41-4.44). CONCLUSIONS: Compared with Caucasian patients, those from ethnic minorities had earlier onset of an acute stroke by about 5 years and a 2- to fourfold increase in many stroke-related adverse outcomes and death.

An orthogeriatric service can reduce prolonged hospital length of stay in hospital for older adults admitted with hip fractures: a monocentric study.

BACKGROUND: The Blue Book (2005), recommended guidelines for patients care with fragility fractures. Together with introduction of a National Hip Fracture Database Audit and Best Practice Tariff model to financially incentivise hospitals by payment of a supplement for patients whose care satisfied six clinical standards), have improved hip fracture after-care. However, there is a lack of data-driven evidence to support its effectiveness. We aimed to verify the impact of an orthogeriatric service on hospital length of stay (LOS)-duration from admission to discharge. METHODS: We conducted a repeated cross-sectional study over a 10 year period of older individuals aged ≥ 60 years admitted with hip fractures to a hospital. RESULTS: Altogether 2798 patients, 741 men and 2057 women (respective mean ages; 80.5 ± 10.6 and 83.2 ± 8.9 years) were admitted from their own homes with a hip fracture and survived to discharge. Compared to 2009-2014, LOS during 2015-2019, when the orthogeriatric service was fully implemented, was shorter for all discharge destinations: 10.4 vs 17.5 days (P < 0.001). Each discharge destination showed reductions: back to own homes, 9.7 vs 17.7 days (P < 0.001); to rehabilitation units: 10.8 vs 13.1 days (P < 0.001); to residential care: 15.4 vs 26.2 days (P = 0.001); or nursing care, 24.4 vs 53.1 days (P < 0.001). During 2009-2014, the risk of staying > 3 weeks in hospital was greater by six-fold and pressure ulcers by three-fold. The number of bed days for every thousand patients per year was also shortened during 2015-2019 by: 1665 days for discharge back to own homes; 469 days with transfer to rehabilitation units; 1258 days for discharge to residential care, and 5465 days to nursing care. Estimated annual savings (2017 costs) per thousand patients after complete establishment of the service was about £2.7 m. CONCLUSIONS: Implementation of an orthogeriatric service generated significant reductions in hospital LOS for all patients, with associated cost-savings, especially for those discharged to nursing care.

Evaluation of independent risk factors associated with surgical site infections from caesarean section.

BACKGROUND: The present study assessed factors associated with the risk of surgical site infections (SSI) after a caesarean section (C-section). METHODS: Data were collected in 1682 women undergoing elective (53.9%) and emergency (46.1%) C-sections between 1st August 2020, and 30th December 2021, at a National Health Service hospital (Surrey, UK). RESULTS: At the time of C-section, the mean age was 33.1 yr (SD ± 5.2). Compared to women with BMI < 30 kg/m2, those with a BMI ≥ 35 kg/m2 had a greater risk of SSI, OR 4.07 (95%CI 2.48-6.69). Women with a history of smoking had a greater risk of SSI than those who had never smoked, OR 1.69 (95%CI 1.05-2.27). Women with a BMI ≥ 30 kg/m2 and had a smoking history or emergency C-section had 3- to tenfold increases for these adverse outcomes. Ethnic minority, diabetes or previous C-section did not associate with any of the outcomes. CONCLUSIONS: High BMI, smoking, and emergency C-section are independent risk factors for SSI from C-section. Women planning conception should avoid excess body weight and smoking. Women with diabetes and from ethnic minority backgrounds did not have increased risks of SSI, indicating a consistent standard of care for all patients.

Determination of independent risk factors for early healthcare-associated infections acquired after acute stroke admission: A multi-centre registry-based cohort study.

OBJECTIVE: Healthcare-associated infections (HCAIs) in patients admitted with acute conditions pose a serious risk to patients and a major challenge to healthcare services. However, there is a lack of consistency in reporting aetiological risk factors, particularly in acute stroke patients. Here, we determined independent risk factors of two common HCAIs (urinary tract infection and pneumonia) acquired within 7-days of admission after an acute stroke. METHODS: Data were prospectively collected (2014-2016) from the Sentinel Stroke National Audit Programme for 3,309 patients (mean age=76.2yr, SD=13.5) admitted to four UK hyperacute stroke units. Associations between variables were assessed by forward stepwise multivariable logistic regression (odds ratios, 95 % confidence intervals). RESULTS: The rate of urinary tract infection and/or pneumonia occurring within 7-days of admission was 15.0 %. The risk of urinary tract infection and/or pneumonia was increased amongst women: OR = 1.35 (1.08-1.68); patients from ethnic minority backgrounds: OR = 1.77 (1.01-3.10); patients aged 70-79 years: OR = 2.08 (1.42-3.06), and ≥80 years: OR = 3.20 (2.26-4.55); history of hypertension: OR = 1.59 (1.27-1.98); history of atrial fibrillation: OR = 1.67 (1.32-2.12); pre-stroke disability: OR = 2.08 (1.44-3.00); intracranial haemorrhage: OR = 1.41 (1.07-1.86); severe stroke: OR = 3.21 (2.32-4.45); swallow screening within 4-72 h: OR = 1.42 (1.08-1.86); swallow screening beyond 72 h: OR = 1.70 (1.08-2.70). History of congestive heart failure, diabetes and previous stroke did not significantly associate with HCAIs. CONCLUSIONS: A profile of independent risk factors for two common HCAIs in acute stroke was identified. These findings provide valuable information for timely intervention to reduce HCAIs, and the ability to minimise subsequent adverse outcomes.

A glitch in the matrix: the pivotal role for extracellular matrix remodeling during muscle hypertrophy.

Multinuclear muscle fibers are the most voluminous cells in skeletal muscle and the primary drivers of growth in response to loading. Outside the muscle fiber, however, is a diversity of mononuclear cell types that reside in the extracellular matrix (ECM). These muscle-resident cells are exercise-responsive and produce the scaffolding for successful myofibrillar growth. Without proper remodeling and maintenance of this ECM scaffolding, the ability to mount an appropriate response to resistance training in adult muscles is severely hindered. Complex cellular choreography takes place in muscles following a loading stimulus. These interactions have been recently revealed by single-cell explorations into muscle adaptation with loading. The intricate ballet of ECM remodeling involves collagen production from fibrogenic cells and ECM modifying signals initiated by satellite cells, immune cells, and the muscle fibers themselves. The acellular collagen-rich ECM is also a mechanical signal-transducer and rich repository of growth factors that may directly influence muscle fiber hypertrophy once liberated. Collectively, high levels of collagen expression, deposition, and turnover characterize a well-trained muscle phenotype. The purpose of this review is to highlight the most recent evidence for how the ECM and its cellular components affect loading-induced muscle hypertrophy. We also address how the muscle fiber may directly take part in ECM remodeling, and whether ECM dynamics are rate limiting for muscle fiber growth.