PCTAIRE1 promotes mitotic progression and resistance against antimitotic and apoptotic signals.

PCTAIRE1 (also known as CDK16) is a serine-threonine kinase implicated in physiological processes like neuronal development, vesicle trafficking, spermatogenesis and cell proliferation. However, its exact role in cell division remains unclear. In this study, using a library screening approach, we identified PCTAIRE1 among several candidates that resisted mitotic arrest and mitotic cell death induced by polyomavirus small T (PolST) expression in mammalian cells. Our study showed that PCTAIRE1 is a mitotic kinase that localizes at centrosomes during G2 and at spindle poles as the cells enter mitosis, and then at the midbody during cytokinesis. We also report that PCTAIRE1 protein levels fluctuate through the cell cycle and reach their peak at mitosis, during which there is an increase in PCTAIRE1 phosphorylation as well. Interestingly, knockdown of PCTAIRE1 resulted in aberrant mitosis by interfering with spindle assembly and chromosome segregation. Further, we found that PCTAIRE1 promotes resistance of cancer cells to antimitotic drugs, and this underscores the significance of PCTAIRE1 as a potential drug target for overcoming chemotherapeutic resistance. Taken together, these studies establish PCTAIRE1 as a critical mediator of mitotic progression and highlight its role in chemotherapeutic resistance. This article has an associated First Person interview with the first author of the paper.

SERPINA11 related novel serpinopathy - A perinatal lethal disorder.

SERPINA11 is a hitherto poorly characterised gene belonging to Clade A of the SERPIN superfamily, with unknown expression pattern and functional significance. We report a perinatal lethal phenotype in two foetuses from the same family associated with a biallelic loss of function variant in SERPINA11, and provide functional evidence to support its candidature as a Mendelian disorder. The SERPINA11 variant-associated foetal phenotype is characterised by gross and histopathological features of extracellular matrix disruption. Western blot and immunofluorescence analyses revealed SERPINA11 expression in multiple mouse tissues, with pronounced expression in the bronchiolar epithelium. We observed a significant decrease in SERPINA11 immunofluorescence in the affected foetal lung compared with a healthy gestation-matched foetus. Protein expression data from HEK293T cell lines following site-directed mutagenesis support the loss of function nature of the variant. Transcriptome analysis from the affected foetal liver indicated the possibility of reduced SERPINA11 transcript abundance. This novel serpinopathy appears to be a consequence of the loss of inhibition of serine proteases involved in extracellular matrix remodelling, revealing SERPINA11 as a protease inhibitor critical for embryonic development.

The impact of timing, type, and method of instillation of intraperitoneal local anaesthetic in laparoscopic abdominal surgery: a systematic review and network meta-analysis.

BACKGROUND: Pain is common after laparoscopic abdominal surgery. Intraperitoneal local anaesthetic (IPLA) is effective in reducing pain and opioid use after laparoscopic surgery, although the optimum type, timing, and method of administration remains uncertain. We aimed to determine the optimal approach for delivering IPLA which minimises opioid consumption and pain after laparoscopic abdominal surgery. METHODS: MEDLINE, Embase, Scopus, and Cochrane Central Register of Controlled Trials (CENTRAL) databases were systematically searched for randomised controlled trials comparing different combinations of the type (bupivacaine vs lidocaine vs levobupivacaine vs ropivacaine), timing (pre-vs post-pneumoperitoneum at the beginning or end of surgery), and method (aerosol vs liquid) of IPLA instillation in patients undergoing any laparoscopic abdominal surgery. A network meta-analysis was conducted to ascertain the optimum approach for delivering IPLA resulting in the least cumulative opioid consumption and pain (overall and localising to the shoulder) 24 h after surgery. Certainty of evidence was evaluated using Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) assessments (PROSPERO ID: CRD42022307595). RESULTS: Twenty-five RCTs were included, among which 15 different combinations of delivering IPLA were analysed across 2401 participants. Aerosolised bupivacaine instilled at the end of surgery, before deflation of the pneumoperitoneum, was associated with significantly less postoperative opioid consumption compared with all other approaches for delivering IPLA (98.7% of comparisons; moderate certainty), aside from liquid levobupivacaine instilled before surgery and during or after creation of the pneumoperitoneum (mean difference -11.6, 95% credible interval: -26.1 to 2.5 i.v. morphine equivalent doses). There were no significant differences between different IPLA approaches regarding overall pain scores and incidence of shoulder pain up to 24 h after surgery. CONCLUSIONS: There are limited studies and low-quality evidence to conclude on the optimum method of delivering IPLA in laparoscopic abdominal surgery. While aerosolised bupivacaine instilled at the end of surgery but before deflation of the pneumoperitoneum minimises postoperative opioid consumption, pain scores up to 24 h did not differ between the different modalities of delivering IPLA. The generalisability of these results is limited by the lack of utilisation of non-opioid analgesics in most trials. SYSTEMATIC REVIEW PROTOCOL REGISTRATION: PROSPERO CRD42022307595.

Association between frailty, long-term mortality and functional outcomes for older adults undergoing emergency laparotomy.

BACKGROUND: An increasing number of older patients are undergoing emergency laparotomy (EL). Frailty is thought to contribute to adverse outcomes in this group. The best method to assess frailty and impacts on long-term mortality and other important functional outcomes for older EL patients have not been fully explored. METHODS: A prospective multicenter study of older EL patients was conducted across four hospital sites in New Zealand from August 2017 to September 2022. The Clinical Frailty Scale (CFS) was used to measure frailty-defined as a CFS of ≥5. Primary outcomes were 30-day and one-year mortality. Secondary outcomes were postoperative morbidity, admission for rehabilitation, and increased care level on discharge. A multivariate logistic regression analysis was conducted, adjusting for age, sex, and ethnicity. RESULTS: A total of 629 participants were included. Frailty prevalence was 14.6%. Frail participants demonstrated higher 30-day and 1-year mortality-20.7% and 39.1%. Following adjustment, frailty was directly associated with a significantly increased risk of short- and long-term mortality (30-day aRR 2.6, 95% CI 1.5, 4.3, p = <0.001, 1-year aRR 2.0, 95% CI 1.5, 2.8, p < 0.001). Frailty was correlated with a 2-fold increased risk of admission for rehabilitation and propensity of being discharged to an increased level of care, complications, and readmission within 30 days. CONCLUSION: Frailty was associated with increased risk of postoperative mortality up to 1-year and other functional outcomes for older patients undergoing EL. Identification of frailty in older EL patients aids in patient-centered decision-making, which may lead to improvement in outcomes.

Interaction of DBC1 with polyoma small T antigen promotes its degradation and negatively regulates tumorigenesis.

Deleted in Breast Cancer 1 (DBC1) is an important metabolic sensor. Previous studies have implicated DBC1 in various cellular functions, notably cell proliferation, apoptosis, histone modification, and adipogenesis. However, current reports about the role of DBC1 in tumorigenesis are controversial and designate DBC1 alternatively as a tumor suppressor or a tumor promoter. In the present study, we report that polyoma small T antigen (PyST) associates with DBC1 in mammalian cells, and this interaction leads to the posttranslational downregulation of DBC1 protein levels. When coexpressed, DBC1 overcomes PyST-induced mitotic arrest and promotes the exit of cells from mitosis. Using both transient and stable modes of PyST expression, we also show that cellular DBC1 is subjected to degradation by LKB1, a tumor suppressor and cellular energy sensor kinase, in an AMP kinase-independent manner. Moreover, LKB1 negatively regulates the phosphorylation as well as activity of the prosurvival kinase AKT1 through DBC1 and its downstream pseudokinase substrate, Tribbles 3 (TRB3). Using both transient transfection and stable cell line approaches as well as soft agar assay, we demonstrate that DBC1 has oncogenic potential. In conclusion, our study provides insight into a novel signaling axis that connects LKB1, DBC1, TRB3, and AKT1. We propose that the LKB1-DBC1-AKT1 signaling paradigm may have an important role in the regulation of cell cycle and apoptosis and consequently tumorigenesis.

Interventions to Improve Patient Care on Surgical Ward Rounds: A Systematic Review.

BACKGROUND: Ward rounds are an essential component of surgical and perioperative care. However, the relative effectiveness of different interventions to improve the quality of surgical ward rounds remains uncertain. The aim of this systematic review was to evaluate the efficacy of various ward round interventions among surgical patients. METHODS: A systematic literature search of the MEDLINE (OVID), EMBASE (OVID), Scopus, Cumulative Index of Nursing and Allied Health (CINAHL), and PsycInfo databases was performed on 7 October 2022 in accordance with PRISMA guidelines. All studies investigating surgical ward round quality improvement strategies with measurable outcomes were included. Data were analysed via narrative synthesis based on commonly reported themes. RESULTS: A total of 28 studies were included. Most were cohort studies (n = 25), followed by randomised controlled trials (n = 3). Checklists/proformas were utilised most commonly (n = 22), followed by technological (n = 3), personnel (n = 2), and well-being (n = 1) quality improvement strategies. The majority of checklist interventions (n = 21, 95%) showed significant improvements in documentation compliance, staff understanding, or patient satisfaction. Other less frequently reported ward round interventions demonstrated improvements in communication, patient safety, and reductions in patient stress levels. CONCLUSIONS: Use of checklists, technology, personnel, and well-being improvement strategies have been associated with improvements in ward round documentation, communication, as well as staff and patient satisfaction. Future studies should investigate the ease of implementation and long-term durability of these interventions, in addition to their impact on clinically relevant outcomes such as patient morbidity and mortality.

Efficacy and safety of laparoscopic Roux-en-Y gastric bypass in symptomatic patients following fundoplication failure: a meta-analysis.

Revisional surgery may be required in a subset of patients who remain symptomatic despite undergoing laparoscopic fundoplication (LF) for gastroesophageal reflux disease (GERD). While revisional LF (RLF) is feasible in these patients, laparoscopic Roux-en-Y gastric bypass (LRYGB) may serve as an alternative, although its efficacy and safety remains unknown. This study aimed to determine the outcomes of LRYGB in symptomatic patients following failed LF for GERD. MEDLINE, EMBASE, and PubMed databases were systematically searched for studies reporting LRYGB outcomes in symptomatic adults despite undergoing LF for GERD. Postoperative symptom resolution, recurrence of heartburn and dysphagia, proton pump inhibitor (PPI) use, and body mass index (BMI) reduction were assessed to determine LRYGB efficacy. Postoperative morbidity and mortality were used to evaluate LRYGB safety. Twenty-two studies with 1523 patients were included. Pooled rates of symptom resolution, recurrence of heartburn and dysphagia, PPI use, morbidity, and mortality were 71.6% (95% CI 59.4-86.4), 15.6% (8.9-27.3), 20.7% (12.5-34.3), 29.6% (18.8-46.5), 39.5% (29.9-52.3), and 2.2% (1.2-4.0), respectively, following LRYGB. Similar rates were observed after RLF. However, BMI reduction was significantly greater after LRYGB compared with RLF (mean difference 6.1 kg/m2, 4.8-7.4; p < 0.0001). LRYGB resulted in symptom relief in a majority of patients, and proved comparable to RLF regarding symptom recurrence and PPI use. Morbidity and mortality following LRYGB also did not differ from RLF. However, LRYGB was associated with considerably greater weight loss relative to RLF. Therefore, LRYGB is efficacious and an acceptable revisional procedure in symptomatic GERD patients who have previously undergone LF.

Abnormalities on Electrogastrography in Nausea and Vomiting Syndromes: A Systematic Review, Meta-Analysis, and Comparison to Other Gastric Disorders.

BACKGROUND: Functional nausea and vomiting syndromes and gastroparesis, collectively grouped as nausea and vomiting syndromes (NVS), are overlapping conditions with incompletely understood pathophysiology. Gastric slow wave abnormalities are thought to contribute. AIMS: This study aimed to systematically review and meta-analyze the prevalence of slow wave abnormalities measured by electrogastrography (EGG) in patients with NVS. METHODS: MEDLINE, EMBASE, EMBASE classic, and CENTRAL databases were systematically searched for articles using EGG in adults (≥ 18 years) with NVS. EGG metrics of interest were percentage time in bradygastria, normogastria, and tachygastria as well as dominant frequency and dominant power. Outcomes were also compared with functional dyspepsia (FD), gastroesophageal reflux disease (GORD), and control cohorts. RESULTS: Seven hundred and sixty NVS patients and 308 controls were included from 24 studies. Overall, 64% of patients had EGG abnormalities. Average percent time in normogastria was low during fasting (50%; 95% CI 40-63%) and fed (53%; 95% CI 41-68%) states in patients, with substantial periods in fasting bradygastria (34.1%; 95% CI 25-47%) and postprandial tachygastria (21%; 95% CI 17-26%). Across gastric disorders, pooling of 84 studies showed a comparably high prevalence of EGG abnormalities in NVS (24 studies; n = 760) and GORD (13 studies; n = 427), compared to FD (47 studies; n = 1751) and controls (45 studies; n = 1027). CONCLUSIONS: Frequency-based gastric slow wave abnormalities are prominent in NVS. The strength and consistency of these associations across many studies suggests that gastric dysrhythmia may be an important factor in NVS, motivating the development of more reliable methods for their clinical assessment.

Polyomavirus Small T Antigen Induces Apoptosis in Mammalian Cells through the UNC5B Pathway in a PP2A-Dependent Manner.

UNC5B is a dependence receptor that promotes survival in the presence of its ligand, netrin-1, while inducing cell death in its absence. The receptor has an important role in the development of the nervous and vascular systems. It is also involved in the normal turnover of intestinal epithelium. Netrin-1 and UNC5B are deregulated in multiple cancers, including colorectal, neuroblastoma, and breast tumors. However, the detailed mechanism of UNC5B function is not fully understood. We have utilized the murine polyomavirus small T antigen (PyST) as a tool to study UNC5B-mediated apoptosis. PyST is known to induce mitotic arrest followed by extensive cell death in mammalian cells. Our results show that the expression of PyST increases mRNA levels of UNC5B by approximately 3-fold in osteosarcoma cells (U2OS) and also stabilizes UNC5B at the posttranslational level. Furthermore, UNC5B is upregulated predominantly in those cells that undergo mitotic arrest upon PyST expression. Interestingly, although its expression was previously reported to be regulated by p53, our data show that the increase in UNC5B levels by PyST is p53 independent. The posttranslational stabilization of UNC5B by PyST is regulated by the interaction of PyST with PP2A. We also show that netrin-1 expression, which is known to inhibit UNC5B apoptotic activity, promotes survival of PyST-expressing cells. Our results thus suggest an important role of UNC5B in small-T antigen-induced mitotic catastrophe that also requires PP2A.IMPORTANCE UNC5B, PP2A, and netrin-1 are deregulated in a variety of cancers. UNC5B and PP2A are regarded as tumor suppressors, as they promote apoptosis and are deleted or mutated in many cancers. In contrast, netrin-1 promotes survival by inhibiting dependence receptors, including UNC5B, and is upregulated in many cancers. Here, we show that UNC5B-mediated apoptosis can occur independently of p53 but in a PP2A-dependent manner. A substantial percentage of cancers arise due to p53 mutations and are insensitive to chemotherapeutic treatments that activate p53. Unexpectedly, treatment of cancers having functional p53 with many conventional drugs leads to the upregulation of netrin-1 through activated p53, which is counterintuitive. Therefore, understanding the p53-independent mechanisms of the netrin-UNC5B axis, such as those involving PP2A, assumes greater clinical significance. Anticancer strategies utilizing anti-netrin-1 antibody treatment are already in clinical trials.

Electrogastrography Abnormalities in Pediatric Gastroduodenal Disorders: A Systematic Review and Meta-analysis.

ABSTRACT: Electrogastrography (EGG) is a non-invasive method of measuring gastric electrophysiology. Abnormal gastric electrophysiology is thought to contribute to disease pathophysiology in patients with gastroduodenal symptoms but this has not been comprehensively quantified in pediatric populations. This study aimed to quantify the abnormalities in gastric electrophysiology on EGG in neonatal and pediatric patients.Databases were systematically searched for articles utilizing EGG in neonatal and pediatric patients (≤18 years). Primary outcomes were prevalence of abnormality, percentage of time in normal rhythm, and power ratio. Secondary outcomes were correlations between patient symptoms and abnormal gastric electrophysiology on EGG.A total of 33 articles (1444 participants) were included. EGG methodologies were variable. Pooled prevalence of abnormalities on EGG ranged from 61% to 86% in patients with functional dyspepsia (FD), gastro-esophageal reflux disease (GERD), and type 1 diabetes mellitus (T1DM). FD patients averaged 20.8% (P = 0.011) less preprandial and 21.6% (P = 0.031) less postprandial time in normogastria compared with controls. Electrophysiological abnormalities were inconsistent in GERD. T1DM patients averaged 46.2% (P = 0.0003) less preprandial and similar (P = 0.32) postprandial time in normogastria compared with controls, and had a lower power ratio (SMD -2.20, 95% confidence interval [CI]: -4.25 to -0.15; P = 0.036). Symptom correlations with gastric electrophysiology were inconsistently reported.Abnormalities in gastric electrophysiology were identifiable across a range of pediatric patients with gastroduodenal symptoms on meta-analysis. However, techniques have been inconsistent, and standardized and more reliable EGG methods are desirable to further define these findings and their potential utility in clinical practice.

Colonoscopy quality indicators in patients with and without prior colonic resection: A single-centre prospective comparative study.

AIM: Effective colonoscopy relies on meeting rigorous quality control thresholds. Some earlier studies evaluating colonoscopy key performance indicators (KPIs) have excluded patients who have previously undergone colonic resection (i.e., they have a nonintact colon); such patients also deserve high-quality colonoscopy. This study aimed to compare colonoscopy KPIs between patients with nonintact and intact colons. METHOD: Consecutive colonoscopies performed at Whanganui Hospital (New Zealand) between September 2016 and March 2020 were included. The primary outcome was the caecal or ileal intubation rate (CIIR). Secondary outcomes were the adenoma detection rate (ADR), polyp detection rate (PDR), colonoscope withdrawal time (CWT) and caecal or ileal intubation time (CIIT). RESULTS: In total, 3017 colonoscopies were performed: 322 in nonintact colons and 2695 in intact colons. CIIR was significantly higher in nonintact than in intact colons (98.4% vs. 95.0%; P = 0.0086). When all colonoscopies were included, the CIIR was 95.4%; this value decreased to 95.0% when nonintact colonoscopies were excluded. However, the ADR (39.9% vs. 38.8%; P = 0.77) and PDR (58.4% vs. 59.1%; P = 0.86) were similar for both nonintact and intact colons. CWT (P < 0.0001) and CIIT (P < 0.0001) were significantly shorter in participants with nonintact colons. CONCLUSION: The CIIR exceeded recommended targets and was 3.4% higher in patients with nonintact than intact colons. Patients with nonintact colons comprise a small proportion of the overall colonoscopy cohort and it is unlikely that this small difference is relevant for most endoscopists or endoscopy units. The ADR and PDR were similar among patients with nonintact and intact colons, despite nonintact colonoscopies being significantly quicker. Patients with nonintact colons deserve high-quality colonoscopy and therefore their KPIs should be included in colonoscopy performance reports.

Risk factors for readmission with dehydration after ileostomy formation: A systematic review and meta-analysis.

AIM: Ileostomy formation is a commonly performed procedure with substantial associated morbidity. Patients with an ileostomy experience high rates of unplanned hospital readmission with dehydration, and such events have a long-term health and economic impact. Reports of the significant risk factors associated with these readmissions have been inconsistent. This study aimed to identify the significant risk factors for readmission with dehydration following ileostomy formation. METHOD: A systematic search was conducted using the Medline, Embase, Cochrane and CINAHL databases. All original research articles reporting risk factors for readmission with dehydration following ileostomy formation in adults were included. The primary outcome was the pooled risk ratio of clinically relevant variables potentially associated with dehydration-related readmission following ileostomy formation. The secondary outcome was the incidence of dehydration-related readmission. RESULTS: Ten studies (27 089 patients) were included. The incidences of 30- and 60-day readmission with dehydration were 5.0% (range 2.1%-13.2%) and 10.3% (range 7.3%-14.1%), respectively. Eight variables were found to be significantly associated with dehydration-related readmission: age ≥65 years, body mass index ≥30 kg/m2 , diabetes mellitus, hypertension, renal comorbidity, regular diuretic use, ileal pouch-anal anastomosis procedure and length of stay after index admission. A preoperative diagnosis of colorectal cancer was less likely to result in readmission with dehydration. CONCLUSION: Readmission with dehydration following ileostomy formation is a significant issue with several risk factors. Awareness of these risk factors will help inform the design of future studies addressing risk prediction, allow risk stratification of ileostomates and aid in the development of personalized prevention strategies.

Prolonged postoperative ileus following right- versus left-sided colectomy: A systematic review and meta-analysis.

AIM: Prolonged postoperative ileus (PPOI) is a common complication following colonic surgery, and is associated with longer hospital stay, greater risk of complications and substantial cost for patients and hospitals. Some reports have recently suggested that gastrointestinal (GI) recovery varies based on the side of resection (i.e., right-sided vs. left-sided colectomy). This systematic review and meta-analysis aimed to compare GI recovery by resection side. METHODS: The MEDLINE, Embase, Cochrane Library and CENTRAL databases were systematically searched for articles reporting GI recovery outcomes in adults undergoing elective right- versus left-sided colectomy (excluding with ileostomy) of any surgical approach. The primary outcome was PPOI, and secondary outcomes included time to first passage of flatus, stool and tolerance of solid diet, and postoperative complications. Subgroup analyses of laparoscopic procedures and cohorts without inflammatory bowel disease and sensitivity analysis of adjusted multivariate results were also performed. RESULTS: Nine studies were identified, of which seven were included in the meta-analysis, comprising 29 068 colectomies (14 581 right-sided; 14 487 left-sided). PPOI was heterogeneously defined and was significantly more likely following right-sided compared to left-sided colectomy regardless of the surgical approach (OR 1.78, 95% CI 1.32-2.39; P < 0.01; I2  = 51%), as well as on subgroup analyses and adjusted multivariate meta-analysis. Secondary outcomes were reported in only a few small studies; hence meta-analysis did not produce reliable results. CONCLUSION: Based on heterogeneous definitions, consistently higher rates of PPOI were observed following right- versus left-sided colectomy. These differences are currently unexplained and highlight the need for further research into the pathophysiology of ileus.

Gastric dysrhythmia in gastroesophageal reflux disease: a systematic review and meta-analysis.

BACKGROUND: Gastroesophageal reflux disease (GERD) is a commonly diagnosed gastrointestinal disorder, with a substantial impact on the quality of life. The underlying pathophysiology of GERD is multifactorial and incompletely understood. Abnormal gastric electrical activity, measured using electrogastrography (EGG), may contribute. This study aimed to systematically review and meta-analyse the existing literature in which EGG was used in patients with GERD. METHODS: Databases were systematically searched for studies using EGG in adults with GERD. The primary outcome was the percentage of recording time in the normogastric frequency range. Secondary outcomes were dominant frequency, dominant power, power ratio and prevalence of any EGG abnormality. RESULTS: In total, 591 participants (427 patients with GERD; 164 healthy controls) from 13 studies were included. GERD patients spent 17.3% (SMD - 1.18, 95%CI: - 1.84, - 0.52) and 18.7% (SMD - 1.11, 95%CI: - 1.55, - 0.68) less of the preprandial and postprandial recording time in normogastric frequency ranges, respectively, compared to healthy controls. The dominant frequency, dominant power and power ratio were not significantly different to healthy controls in the preprandial and postprandial periods. The pooled prevalence of any EGG abnormality was significantly greater in patients with GERD than in healthy controls [46% (95%CI: 39-64%) vs. 10% (95%CI: 4-23%); p < 0.0001]. Correlations between GERD symptoms and EGG recordings were inconsistently studied. EGG techniques were heterogeneous. CONCLUSIONS: Consistent abnormalities in gastric slow-wave activity, as measured by EGG, were identified in adults with GERD. Further investigation into these abnormalities using novel emerging electrophysiology techniques is desirable, to better define their contribution toward GERD pathophysiology.

Acoustic Energy Harvesting and Sensing via Electrospun PVDF Nanofiber Membrane.

This paper introduces a new usage of piezoelectric poly (vinylidene fluoride) (PVDF) electrospun nanofiber (NF) membrane as a sensing unit for acoustic signals. In this work, an NF mat has been used as a transducer to convert acoustic signals into electric voltage outcomes. The detected voltage has been analyzed as a function of both frequency and amplitude of the excitation acoustic signal. Additionally, the detected AC signal can be retraced as a function of both frequency and amplitude with some wave distortion at relatively higher amplitudes and within a certain acoustic spectrum region. Meanwhile, the NFs have been characterized through piezoelectric responses, beta sheet calculations and surface morphology. This work is promising as a low-cost and innovative solution to harvest acoustic signals coming from wide resources of sound and noise.

Variation in the definition of 'failure to rescue' from postoperative complications: a systematic review and recommendations for outcome reporting.

BACKGROUND: Failure to rescue is the rate of death amongst patients with postoperative complications and has been proposed as a perioperative quality indicator. However, variation in its definition has limited comparisons between studies. We systematically reviewed all surgical literature reporting failure to rescue rates and examined variations in the definition of the 'numerator,' 'denominator,' and timing of failure to rescue measurement. METHODS: Databases were searched from inception to 31 December 2022. All studies reporting postoperative failure to rescue rates as a primary or secondary outcome were included. We examined the complications included in the failure to rescue denominator, the percentage of deaths captured by the failure to rescue numerator, and the timing of measurement for complications and mortality. RESULTS: A total of 359 studies, including 212,048,069 patients, were analyzed. The complications included in the failure to rescue denominator were reported in 295 studies (82%), with 131 different complications used. The median number of included complications per study was 10 (interquartile range 8-15). Studies that included a higher number of complications in the failure-to-rescue denominator reported lower failure-to-rescue rates. Death was included as a complication in the failure to rescue the denominator in 65 studies (18%). The median percentage of deaths captured by the failure to rescue calculation when deaths were not included in the denominator was 79%. Complications (52%) and mortality (40%) were mostly measured in-hospital, followed by 30-days after surgery. CONCLUSION: Failure to rescue is an important concept in the study of postoperative outcomes, although its definition is highly variable and poorly reported. Researchers should be aware of the advantages and disadvantages of different approaches to defining failure to rescue.

Geranylgeranylated-SCFFBXO10 Regulates Selective Outer Mitochondrial Membrane Proteostasis and Function.

E3-ubiquitin ligases (E3s) are main components of the ubiquitin-proteasome system (UPS), as they determine substrate specificity in response to internal and external cues to regulate protein homeostasis. However, the regulation of membrane protein ubiquitination by E3s within distinct cell membrane compartments or organelles is not well understood. We show that FBXO10, the interchangeable component of the SKP1/CUL1/F-box ubiquitin ligase complex (SCF-E3), undergoes lipid-modification with geranylgeranyl isoprenoid at Cysteine953 (C953), facilitating its dynamic trafficking to the outer mitochondrial membrane (OMM). FBXO10 polypeptide does not contain a canonical mitochondrial targeting sequence (MTS); instead, its geranylgeranylation at C953 and the interaction with two cytosolic factors, PDE6δ (a prenyl group-binding protein), and HSP90 (a mitochondrial chaperone) orchestrate specific OMM targeting of prenyl-FBXO10 across diverse membrane compartments. The geranylgeranylation-deficient FBXO10(C953S) mutant redistributes away from the OMM, leading to impaired mitochondrial ATP production, decreased mitochondrial membrane potential, and increased mitochondrial fragmentation. Phosphoglycerate mutase 5 (PGAM5) was identified as a potential substrate of FBXO10 at the OMM using comparative quantitative mass spectrometry analyses of enriched mitochondria (LFQ-MS/MS), leveraging the redistribution of FBXO10(C953S). FBXO10, but not FBXO10(C953S), promoted polyubiquitylation and degradation of PGAM5. Examination of the role of this pathway in a physiological context revealed that the loss of FBXO10 or expression of prenylation-deficient-FBXO10(C953S) inhibited PGAM5 degradation, disrupted mitochondrial homeostasis, and impaired myogenic differentiation of human iPSCs and murine myoblasts. Our studies identify a mechanism for selective E3-ligase mediated regulation of mitochondrial membrane proteostasis and metabolic health, potentially amenable to therapeutic intervention.

Detection of membrane-anchoring lipid modifications of proteins in cells by radioactive metabolic labeling.

Prenylation and palmitoylation are two major lipid modifications of cellular proteins that anchor proteins to cell membranes. Here, we present a protocol for detecting these modifications in cellular proteins by radioactive metabolic labeling. We describe steps for metabolic labeling of cells, cell harvesting for carrying out immunoprecipitations, subjecting immunocomplexes to SDS-PAGE, and transferring them to polyvinylidine flouride (PVDF) membranes. We then detail detection of labeled target proteins by exposing PVDF membranes to phosphor screens and using a phosphor imager machine. For complete details of this protocol, please refer to Liang et al.1.

Consensus-defined sarcopenia predicts adverse outcomes after elective abdominal surgery: meta-analysis.

BACKGROUND: Sarcopenia refers to the progressive age- or pathology-associated loss of skeletal muscle. When measured radiologically as reduced muscle mass, sarcopenia has been shown to independently predict morbidity and mortality after elective abdominal surgery. However, the European Working Group on Sarcopenia in Older People (EWGSOP) recently updated their sarcopenia definition, emphasizing both low muscle 'strength' and 'mass'. The aim of this systematic review and meta-analysis was to determine the prognostic impact of this updated consensus definition of sarcopenia after elective abdominal surgery. METHODS: MEDLINE, Embase, Scopus, and Cochrane Central Register of Controlled Trials (CENTRAL) databases were systematically searched for studies comparing prognostic outcomes between sarcopenic versus non-sarcopenic adults after elective abdominal surgery from inception to 15 June 2022. The primary outcomes were postoperative morbidity and mortality. Sensitivity analyses adjusting for confounding patient factors were also performed. Methodological quality assessment of studies was performed independently by two authors using the QUality in Prognosis Studies (QUIPS) tool. RESULTS: Twenty articles with 5421 patients (1059 sarcopenic and 4362 non-sarcopenic) were included. Sarcopenic patients were at significantly greater risk of incurring postoperative complications, despite adjusted multivariate analysis (adjusted OR 1.56, 95 per cent c.i. 1.39 to 1.76). Sarcopenic patients also had significantly higher rates of in-hospital (OR 7.62, 95 per cent c.i. 2.86 to 20.34), 30-day (OR 3.84, 95 per cent c.i. 1.27 to 11.64), and 90-day (OR 3.73, 95 per cent c.i. 1.19 to 11.70) mortality. Sarcopenia was an independent risk factor for poorer overall survival in multivariate Cox regression analysis (adjusted HR 1.28, 95 per cent c.i. 1.13 to 1.44). CONCLUSION: Consensus-defined sarcopenia provides important prognostic information after elective abdominal surgery and can be appropriately measured in the preoperative setting. Development of targeted exercise-based interventions that minimize sarcopenia may improve outcomes for patients who are undergoing elective abdominal surgery.

Lipin-1 stability and its adipogenesis functions are regulated in contrasting ways by AKT1 and LKB1.

Lipin-1 is a protein that plays a critical role in many cellular functions. At molecular level, it acts as a phosphatidic acid phosphohydrolase and a transcriptional coactivator. The functions of lipin-1 are largely dependent upon its subcellular localization, post-translational modifications like phosphorylation and acetylation, and also on its interaction with other proteins such as 14-3-3. However, the kinases and phosphatases that are responsible for these post translational modifications are not entirely known. Using bioinformatics and other biochemical approaches, we demonstrate lipin-1 as a novel target for AKT1 and LKB1. While AKT1 stabilizes lipin-1, LKB1 causes its degradation. Interestingly, our findings further show that lipin-1 enhances AKT1 activity as can be seen by increased phosphorylation of the substrates of AKT1. Taken together, our results suggest that lipin-1 plays an important role in the regulation of PI3K-AKT-mTOR pathway, which is dysregulated in majority of cancers. Therefore, understating the role of lipin-1 may provide new and important insights into the regulation and functions of the PI3K-mTOR pathway, which is one of the major targets for anti-cancer drug development strategies.