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.

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.

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.

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.

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.

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.

CD36 maintains lipid homeostasis via selective uptake of monounsaturated fatty acids during matrix detachment and tumor progression.

A high-fat diet (HFD) promotes metastasis through increased uptake of saturated fatty acids (SFAs). The fatty acid transporter CD36 has been implicated in this process, but a detailed understanding of CD36 function is lacking. During matrix detachment, endoplasmic reticulum (ER) stress reduces SCD1 protein, resulting in increased lipid saturation. Subsequently, CD36 is induced in a p38- and AMPK-dependent manner to promote preferential uptake of monounsaturated fatty acids (MUFAs), thereby maintaining a balance between SFAs and MUFAs. In attached cells, CD36 palmitoylation is required for MUFA uptake and protection from palmitate-induced lipotoxicity. In breast cancer mouse models, CD36-deficiency induced ER stress while diminishing the pro-metastatic effect of HFD, and only a palmitoylation-proficient CD36 rescued this effect. Finally, AMPK-deficient tumors have reduced CD36 expression and are metastatically impaired, but ectopic CD36 expression restores their metastatic potential. Our results suggest that, rather than facilitating HFD-driven tumorigenesis, CD36 plays a supportive role by preventing SFA-induced lipotoxicity.

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.

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.

Palmitoylation and PDE6δ regulate membrane-compartment-specific substrate ubiquitylation and degradation.

Substrate degradation by the ubiquitin proteasome system (UPS) in specific membrane compartments remains elusive. Here, we show that the interplay of two lipid modifications and PDE6δ regulates compartmental substrate targeting via the SCFFBXL2. FBXL2 is palmitoylated in a prenylation-dependent manner on cysteines 417 and 419 juxtaposed to the CaaX motif. Palmitoylation/depalmitoylation regulates its subcellular trafficking for substrate engagement and degradation. To control its subcellular distribution, lipid-modified FBXL2 interacts with PDE6δ. Perturbing the equilibrium between FBXL2 and PDE6δ disrupts the delivery of FBXL2 to all membrane compartments, whereas depalmitoylated FBXL2 is enriched on the endoplasmic reticulum (ER). Depalmitoylated FBXL2(C417S/C419S) promotes the degradation of IP3R3 at the ER, inhibits IP3R3-dependent mitochondrial calcium overload, and counteracts calcium-dependent cell death upon oxidative stress. In contrast, disrupting the PDE6δ-FBXL2 equilibrium has the opposite effect. These findings describe a mechanism underlying spatially-restricted substrate degradation and suggest that inhibition of FBXL2 palmitoylation and/or binding to PDE6δ may offer therapeutic benefits.

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.

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.

Ubiquitin proteasome system in immune regulation and therapeutics.

The ubiquitin proteasome system (UPS) is a proteolytic machinery for the degradation of protein substrates that are post-translationally conjugated with ubiquitin polymers through the enzymatic action of ubiquitin ligases, in a process termed ubiquitylation. Ubiquitylation of substrates precedes their proteolysis via proteasomes, a hierarchical feature of UPS. E3-ubiquitin ligases recruit protein substrates providing specificity for ubiquitylation. Innate and adaptive immune system networks are regulated by ubiquitylation and substrate degradation via E3-ligases/UPS. Deregulation of E3-ligases/UPS components in immune cells is involved in the development of lymphomas, neurodevelopmental abnormalities, and cancers. Targeting E3-ligases for therapeutic intervention provides opportunities to mitigate the unintended broad effects of 26S proteasome inhibition. Recently, bifunctional moieties such as PROTACs and molecular glues have been developed to re-purpose E3-ligases for targeted degradation of unwanted aberrant proteins, with a potential for clinical use. Here, we summarize the involvement of E3-ligases/UPS components in immune-related diseases with perspectives.

Impact of Off-Hour Admission with Subarachnoid Hemorrhage: A Meta-Analysis.

OBJECTIVE: This meta-analysis assessed the impact of off-hour hospitalization (weekends, and evenings or nighttime on weekdays) on mortality and morbidity in patients with nontraumatic subarachnoid hemorrhage (SAH). METHODS: Electronic databases were systematically searched for studies comparing outcomes between patients with nontraumatic SAH hospitalized during off-hour and on-hour periods (daytime on weekdays). The primary outcome was mortality (in-hospital and at different follow-up periods after hospitalization). Secondary outcomes included delays in treatment, and complications. Sensitivity analysis including only studies in which adjusted multivariate analyses were performed for any of the outcomes, and meta-regression controlling for clinically important patient factors, were also performed. RESULTS: Sixteen studies were included. There was no significant difference in in-hospital mortality (adjusted odds ratio, 1.03; 95% confidence interval [CI], 0.97-1.09; P = 0.30) and at all follow-up periods (7/14 days and 1/3/6 months) after hospitalization between SAH patients who were admitted during off-hour compared with on-hour periods, despite adjusted multivariate meta-analysis being performed. However, patients who were admitted during off-hour periods experienced greater delays from their initial scan to treatment (mean difference, 42.7, 25.2-60.1 hours; P < 0.0001) and had higher rates of pneumonia (odds ratio, 1.65, 1.12-2.44; P = 0.011). CONCLUSIONS: This meta-analysis has not shown an increased risk of mortality in the short-term and long-term among patients with nontraumatic SAH who were hospitalized during off-hour compared with on-hour periods, despite adjusting for potentially confounding patient factors. The delays to treatment and higher observed rates of pneumonia highlight areas in which hospital services and resources should be targeted during these off-hour periods in patients presenting with nontraumatic SAH.

Trends in computed tomography aortography and acute aortic syndrome in an emergency department within Aotearoa New Zealand.

OBJECTIVE: Acute aortic syndrome (AAS) comprises a triad of life-threatening aortic conditions that are difficult to diagnose because of their non-specific clinical presentations. Contrast-enhanced computed tomography aortography (CTA) has a high sensitivity and specificity for these conditions. However, under- and over-investigation of patients with suspected AAS using CTA carries significant risk. The aim of the present study was to evaluate the diagnostic imaging practices of CTA use for patients presenting to an ED with suspected AAS. METHODS: All atraumatic thoracic CTAs performed on patients aged ≥15 years old with suspected AAS who presented to Auckland City Hospital between 2009 and 2019 were included. Outcomes of interest were the annual ED and population incidences of AAS, and the rate of CTAs performed. RESULTS: A total of 1646 CTAs were included. There were 135 (8.2%) cases of at least one AAS diagnosis and 220 (13.4%) cases where an alternative diagnosis was made. The population-adjusted number of AAS diagnoses remained relatively stable over the study period, with a mean annual AAS incidence of 19.6 (95% confidence interval 9.9-33.7) per 100 000 patients, and 3.2 (95% confidence interval 1.6-5.4) per 100 000 population. The number of ED presentations increased during the study period, along with the population-adjusted rate of CTAs performed, from approximately 150 per 100 000 patients (2009) to 350 per 100 000 patients (2019). CONCLUSIONS: Thoracic CTA use for investigating suspected AAS in our ED has recently increased. However, the annual incidence of AAS did not increase over the same period, but was higher than reported in overseas institutions.

Short- and long-term impact of sarcopenia on outcomes after emergency laparotomy: A systematic review and meta-analysis.

BACKGROUND: Sarcopenia refers to the progressive age and pathology-associated loss of skeletal muscle, which has been shown to independently predict mortality in patients undergoing major elective surgery. Emergency laparotomy is commonly performed for a range of procedures and is associated with high rates of mortality. However, the prognostic utility of sarcopenia after emergency laparotomy remains unknown. The aim of this study was to compare short and long-term survival between patients with and without sarcopenia undergoing emergency laparotomy. METHODS: MEDLINE, EMBASE, and Scopus databases were systematically searched for articles comparing survival outcomes between adults with and without radiologically defined sarcopenia after emergency gastrointestinal surgery regardless of indication and approach (open/laparoscopic). The primary outcome was postoperative mortality. Sensitivity analysis of adjusted multivariate analyses was performed. RESULTS: Twenty articles comprising 6,737 patients were included. Sarcopenia was most commonly assessed using axial abdominal computerized tomography at L3, although cut-off thresholds were heterogeneous and rarely sex-specific. Postoperative mortality was higher among patients with sarcopenia than without in the in-hospital setting, and at 30- and 90-day follow-up on univariate but not on multivariate meta-analysis. However, mortality was significantly higher among sarcopenic cohorts in the 1-year (odds ratio 2.8, 95% confidence interval: 1.5-5.6; P = .002) follow-up period, despite adjusting for confounding preoperative and patient factors. CONCLUSION: The meta-analysis has shown sarcopenia to provide useful long-term prognostic information following emergency laparotomy. This may aid with preoperative risk assessment, patient counseling, and in perioperative decision-making for patients undergoing emergency laparotomy.

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.

A systematic review and network meta-analysis comparing treatments for anal fissure.

BACKGROUND: There are multiple treatments for anal fissures. These range from medical treatment to surgical procedures, such as sphincterotomy. The aim of this study was to compare the relative clinical outcomes and effectiveness of interventional treatments for anal fissure. METHODS: Randomized controlled trials were identified by means of a PRISMA-compliant systematic review using the Medline, EMBASE, and CENTRAL databases. Inclusion criteria were randomized controlled trials comparing treatments for anal fissure. A Bayesian network meta-analysis was performed using BUGSnet package in R. Outcomes of interest were healing (6-8-, 10-16-, and >16-week follow-up), symptom recurrence, pain (measured on a visual analog scale), and fecal or flatus incontinence. PROPSERO Registration: CRD42021229615. RESULTS: Sixty-nine randomized controlled trials were included in the analysis. Lateral sphincterotomy remains the treatment with the highest odds of healing compared to botulinum toxin and medical therapy at all follow-up time points. There was no significant difference in healing between botulinum toxin and medical therapy at any time point. Advancement flap showed similar effectiveness compared to lateral sphincterotomy. Medical treatment and botulinum toxin had the highest pain scores at follow-up. Sphincterotomy had the highest odds of fecal and flatus incontinence. CONCLUSION: Lateral sphincterotomy had the highest rates of healing and should be considered as the definitive treatment after failed initial therapy with botulinum toxin or medical treatment. Botulinum toxin was equally effective compared to medical treatment. Advancement flap shows similar effectiveness compared to lateral sphincterotomy, but more studies are needed to evaluate its efficacy.

Short and long-term impact of sarcopenia on outcomes from emergency laparotomy.

PURPOSE: Emergency laparotomy (EL) carries a high risk of morbidity and mortality, that is greater among older patients. Sarcopenia refers to an age- or pathology-associated muscle loss and has been demonstrated to correlate with poorer outcomes in several surgical conditions. This study assessed the impact of sarcopenia on morbidity and mortality in elderly patients undergoing EL. METHODS: Patients aged ≥ 65 years-old undergoing EL between May 2012-June 2017 with a pre-operative abdominal computerised tomography (CT) scan at Middlemore Hospital (New Zealand) were included. Psoas and Skeletal Muscle Index (PMI and SMI) were calculated from abdominal CT measurements after standardisation based on height. Validated cut-offs for sarcopenia were used. Frailty was estimated using the 11-point modified frailty index (mFI). The primary outcome was 30-day, 1-year, and 4-year post-operative mortality. Secondary outcomes included correlations between mFI and sarcopenic measures, unplanned readmissions, and post-operative complications. RESULTS: A total of 167 patients (84 sarcopenic; 83 non-sarcopenic) were included. Sarcopenic and non-sarcopenic patients had similar 30-day (14.2 vs. 12.0%; p = 0.84), 1-year (23.8 vs. 25.3%; p = 0.96), and 4-year (39.3 vs. 47.0%; p = 0.40) mortality rates following an EL. Survivors had a higher mean PMI at 1-year (p = 0.0078) and 4-year (p = 0.013) but not 30-day (p = 0.40) follow-up. Sarcopenia performed poorly in discriminating between 30-day (AUC 0.51) and 1-year (AUC 0.53) mortality. The mFI did not correlate with PMI (p = 0.85) nor SMI (p = 0.18). Rates of readmissions and post-operative complications did not differ between sarcopenic and non-sarcopenic cohorts. CONCLUSION: Sarcopenia does not provide useful short-term prognostic information in elderly EL patients.

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.