Intraoperative Fluoroscopy Versus Navigation to Determine Cup Anteversion in Direct Anterior Total Hip Replacement: A Technical Trick for Obtaining "True" Anteversion.

During acetabular cup positioning, intraoperative measurements of cup anteversion were taken using both fluoroscopy and navigation system. With the C-arm introduced at 40°, an anteroposterior view of the pelvis is taken. The C-arm is then centered over the hip, showing an anteverted cup with an approximate inclination of 40°. The axial C-arm is tilted away until the cup opening is visualized as a straight line, indicating that the beam of the fluoroscopy is aligned with the cup's anteversion. The tilt angle on the C-arm and anteversion reading on the navigation workstation were recorded. The high degree of agreement between fluoroscopic and navigation measurement of acetabular cup anteversion supports the use of fluoroscopy in settings with limited access to navigation systems in direct anterior total hip arthroplasty.

Effect of cross-platform gene-expression, computational methods on breast cancer subtyping in PALOMA-2 and PALLET studies.

Intrinsic breast cancer molecular subtyping (IBCMS) provides significant prognostic information for patients with breast cancer and helps determine treatment. This study compared IBCMS methods on various gene-expression platforms in PALOMA-2 and PALLET trials. PALOMA-2 tumor samples were profiled using EdgeSeq and nanostring and subtyped with AIMS, PAM50, and research-use-only (ruo)Prosigna. PALLET tumor biopsies were profiled using mRNA sequencing and subtyped with AIMS and PAM50. In PALOMA-2 (n = 222), a 54% agreement was observed between results from AIMS and gold-standard ruoProsigna, with AIMS assigning 67% basal-like to HER2-enriched. In PALLET (n = 224), a 69% agreement was observed between results from PAM50 and AIMS. Different IBCMS methods may lead to different results and could misguide treatment selection; hence, a standardized clinical PAM50 assay and computational approach should be used.Trial number: NCT01740427.

Efficient High-Order Space-Angle-Energy Polytopic Discontinuous Galerkin Finite Element Methods for Linear Boltzmann Transport.

We introduce an hp-version discontinuous Galerkin finite element method (DGFEM) for the linear Boltzmann transport problem. A key feature of this new method is that, while offering arbitrary order convergence rates, it may be implemented in an almost identical form to standard multigroup discrete ordinates methods, meaning that solutions can be computed efficiently with high accuracy and in parallel within existing software. This method provides a unified discretisation of the space, angle, and energy domains of the underlying integro-differential equation and naturally incorporates both local mesh and local polynomial degree variation within each of these computational domains. Moreover, general polytopic elements can be handled by the method, enabling efficient discretisations of problems posed on complicated spatial geometries. We study the stability and hp-version a priori error analysis of the proposed method, by deriving suitable hp-approximation estimates together with a novel inf-sup bound. Numerical experiments highlighting the performance of the method for both polyenergetic and monoenergetic problems are presented.

High-dimensional mapping of human CEACAM1 expression on immune cells and association with melanoma drug resistance.

BACKGROUND: Human carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1) is an inhibitory cell surface protein that functions through homophilic and heterophilic ligand binding. Its expression on immune cells in human tumors is poorly understood. METHODS: An antibody that distinguishes human CEACAM1 from other highly related CEACAM family members was labeled with 159Tb and inserted into a panel of antibodies that included specificity for programmed cell death protein 1 (PD1) and PD-L1, which are targets of immunotherapy, to gain a data-driven immune cell atlas using cytometry by time-of-flight (CyTOF). A detailed inventory of CEACAM1, PD1, and PD-L1 expression on immune cells in metastatic lesions to lymph node or soft tissues and peripheral blood samples from patients with treatment-naive and -resistant melanoma as well as peripheral blood samples from healthy controls was performed. RESULTS: CEACAM1 is absent or at low levels on healthy circulating immune cells but is increased on immune cells in peripheral blood and tumors of melanoma patients. The majority of circulating PD1-positive NK cells, innate T cells, B cells, monocytic cells, dendritic cells, and CD4+ T cells in the peripheral circulation of treatment-resistant disease co-express CEACAM1 and are demonstrable as discrete populations. CEACAM1 is present on distinct types of cells that are unique to the tumor microenvironment and exhibit expression levels that are highest in treatment resistance; this includes tumor-infiltrating CD8+ T cells. CONCLUSIONS: To the best of our knowledge, this work represents the first comprehensive atlas of CEACAM1 expression on immune cells in a human tumor and reveals an important correlation with treatment-resistant disease. These studies suggest that agents targeting CEACAM1 may represent appropriate partners for PD1-related pathway therapies.

Some proteins, such as programmed cell death protein 1 (PD1), can stop the immune system from attacking cancer cells, allowing cancers to grow. Therapies targeting these proteins can be highly effective, but tumors can become resistant. It is important to identify factors involved in this resistance to develop improved cancer therapies. Human carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1) is a protein that inhibits an immune response and its levels have been associated with poor patient outcomes. We applied a method that allows for the detection of proteins on a single cell to uncover CEACAM1 patterns in melanoma. We found that increased CEACAM1 expression levels on multiple different immune cell types was associated with tumors that were resistant to therapy. These findings may help us to understand the role of CEACAM1 in cancer and to develop better cancer therapies.

The plastisphere can protect Salmonella Typhimurium from UV stress under simulated environmental conditions.

Plastic waste is found with increasing frequency in the environment, in low- and middle-income countries. Plastic pollution has increased concurrently with both economic development and rapid urbanisation, amplifying the effects of inadequate waste management. Distinct microbial communities can quickly colonise plastic surfaces in what is collectively known as the 'plastisphere'. The plastisphere can act as a reservoir for human pathogenic bacteria, including Salmonella enterica sp. (such as S. Typhimurium), which can persist for long periods, retain pathogenicity, and pose an increased public health risk. Through employing a novel mesocosm setup, we have shown here that the plastisphere provides enhanced protection against environmental pressures such as ultraviolet (UV) radiation and allows S. Typhimurium to persist at concentrations (>1 × 103 CFU/ml) capable of causing human infection, for up to 28 days. Additionally, using a Galleria Mellonella model of infection, S. Typhimurium exhibits greater pathogenicity following recovery from the UV-exposed plastisphere, suggesting that the plastisphere may select for more virulent variants. This study demonstrates the protection afforded by the plastisphere and provides further evidence of environmental plastic waste acting as a reservoir for dangerous clinical pathogens. Quantifying the role of plastic pollution in facilitating the survival, persistence, and dissemination of human pathogens is critical for a more holistic understanding of the potential public health risks associated with plastic waste.

Mechanisms of sensitivity and resistance to CDK4/CDK6 inhibitors in hormone receptor-positive breast cancer treatment.

Cell cycle dysregulation is a hallmark of cancer that promotes eccessive cell division. Cyclin-dependent kinase 4 (CDK4) and cyclin-dependent kinase 6 (CDK6) are key molecules in the G1-to-S phase cell cycle transition and are crucial for the onset, survival, and progression of breast cancer (BC). Small-molecule CDK4/CDK6 inhibitors (CDK4/6i) block phosphorylation of tumor suppressor Rb and thus restrain susceptible BC cells in G1 phase. Three CDK4/6i are approved for the first-line treatment of patients with advanced/metastatic hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) BC in combination with endocrine therapy (ET). Though this has improved the clinical outcomes for survival of BC patients, there is no established standard next-line treatment to tackle drug resistance. Recent studies suggest that CDK4/6i can modulate other distinct effects in both BC and breast stromal compartments, which may provide new insights into aspects of their clinical activity. This review describes the biochemistry of the CDK4/6-Rb-E2F pathway in HR+ BC, then discusses how CDK4/6i can trigger other effects in BC/breast stromal compartments, and finally outlines the mechanisms of CDK4/6i resistance that have emerged in recent preclinical studies and clinical cohorts, emphasizing the impact of these findings on novel therapeutic opportunities in BC.

Outcome of Patients with Locally Advanced Rectal Cancer Pursuing Non-Surgical Strategy in National Cancer Database.

BACKGROUND: Survival data on patients with locally advanced rectal cancer (LARC) undergoing non-operative management (NOM) in a real-world setting are lacking. METHODS: We analyzed LARC patients from the National Cancer Database with the following features: treated between 2010 and 2020, age 18-65 years, Charlson comorbidity index (CCI) ≤ 1, received neoadjuvant multiagent chemotherapy plus radiation ≥ 45 Gray, and underwent surgery or NOM. Patients were stratified into two groups: (A) clinical T1-3 tumors with positive nodes (cT1-3N+) and (B) clinical T4 tumors, N+/- (cT4N+/-). We performed a comparative analysis of overall survival (OS) with NOM versus surgery by the Kaplan-Meier method and propensity score matching. Additionally, a multivariable analysis explored the association between NOM and OS. RESULTS: NOM exhibited significantly lower OS than surgery in both groups. In cT1-3N+ patients, NOM resulted in a 5-year OS of 73.9% (95% confidence interval [CI] = 69.7-77.6%) versus 84.5% (95% CI = 83.6-85.3%) with surgery (p < 0.001). In the cT4N+/- group, NOM yielded a 5-year OS of 44.5% (95% CI = 37.0-51.8%) versus 72.5% (95% CI = 69.9-74.8%) with surgery (p < 0.001). Propensity score matching and multivariable analyses revealed similar conclusions. CONCLUSION: Patients with LARC undergoing NOM versus surgery in real-world settings appear to have inferior survival.

Off-Policy Prediction Learning: An Empirical Study of Online Algorithms.

Off-policy prediction-learning the value function for one policy from data generated while following another policy-is one of the most challenging problems in reinforcement learning. This article makes two main contributions: 1) it empirically studies 11 off-policy prediction learning algorithms with emphasis on their sensitivity to parameters, learning speed, and asymptotic error and 2) based on the empirical results, it proposes two step-size adaptation methods called and that help the algorithm with the lowest error from the experimental study learn faster. Many off-policy prediction learning algorithms have been proposed in the past decade, but it remains unclear which algorithms learn faster than others. In this article, we empirically compare 11 off-policy prediction learning algorithms with linear function approximation on three small tasks: the Collision task, the task, and the task. The Collision task is a small off-policy problem analogous to that of an autonomous car trying to predict whether it will collide with an obstacle. The and tasks are designed such that learning fast in them is challenging. In the Rooms task, the product of importance sampling ratios can be as large as 214 . To control the high variance caused by the product of the importance sampling ratios, step size should be set small, which, in turn, slows down learning. The task is more extreme in that the product of the ratios can become as large as 214 × 25 . The algorithms considered are Off-policy TD, five Gradient-TD algorithms, two Emphatic-TD algorithms, Vtrace, and variants of Tree Backup and ABQ that are applicable to the prediction setting. We found that the algorithms' performance is highly affected by the variance induced by the importance sampling ratios. Tree Backup, Vtrace, and ABTDare not affected by the high variance as much as other algorithms, but they restrict the effective bootstrapping parameter in a way that is too limiting for tasks where high variance is not present. We observed that Emphatic TDtends to have lower asymptotic error than other algorithms but might learn more slowly in some cases. Based on the empirical results, we propose two step-size adaptation algorithms, which we collectively refer to as the Ratchet algorithms, with the same underlying idea: keep the step-size parameter as large as possible and ratchet it down only when necessary to avoid overshoot. We show that the Ratchet algorithms are effective by comparing them with other popular step-size adaptation algorithms, such as the Adam optimizer.

COVID-19 vaccinations and infections among individuals with systemic sclerosis: A Scleroderma Patient-centered Intervention Network (SPIN) Cohort study.

BACKGROUND/PURPOSE: We previously surveyed adults with systemic sclerosis (SSc) regarding COVID-19 vaccination in April-May 2021. The objective of the present study was to update through June-July 2022 and assess self-reported (1) COVID-19 vaccination rates, including boosters; (2) vaccine-related adverse events; (3) peri­vaccination immunosuppressive medication management; (4) vaccine hesitancy; and (5) prevalence and severity of COVID-19 infections. METHODS: In April-May 2021 and June-July 2022, SPIN Cohort participants completed surveys on COVID-19 vaccination and infection. Primary vaccine series was defined according to the standard for each COVID-19 vaccine; additional vaccine administrations were considered booster doses. Fully vaccinated was defined as having completed a primary vaccine series and at least one booster dose. RESULTS: 544 participants completed the 2021 survey only, 101 the 2022 survey only, and 388 both surveys. Among 489 participants with 2022 data, 437 (89 %) had received both primary and booster vaccines. Among all 1,033 participants, 960 (93 %) received at least one dose. At least one adverse reaction was reported by 34 % (330 of 960 participants) following first, 48 % (314 of 657 participants) following second, and 34 % (147 of 437 participants) following booster vaccine doses (primarily sore arm and fatigue); no severe adverse reactions were reported. SSc symptom worsening was reported in 6 % (53 of 960) after the first, 6 % after the second (39 of 657), and 4 % (17 of 437) after the booster dose. Of participants taking methotrexate or mycophenolate (including Cellcept or Myfortic), 34 of 266 (13 %) reported that they temporarily stopped or decreased their medication at the first dose, 32 of 215 (15 %) at the second dose, and 28 of 148 (19 %) for booster vaccination. Of 52 individuals not fully vaccinated with primary and booster doses in 2022, 29 (56 %) reported worry about vaccine related SSc flares. 172 of 489 (35 %) 2022 participants reported a history of at least one COVID-19 infection; 114 (66 %) occurred after receiving at least a primary vaccine series. Among initial COVID-19 infections, 9 (5 %) were asymptomatic, 66 (38 %) involved mild symptoms, 82 (48 %) moderate symptoms, and 15 (9 %) required hospitalization. CONCLUSION: Most people with SSc in the study were fully vaccinated, and most continued their methotrexate or mycophenolate post-primary and booster vaccinations. Over half of vaccine-hesitant participants were concerned regarding risk of SSc flare; however, few vaccinated participants reported this. These data may be useful for counselling people with SSc regarding COVID-19 vaccine safety and outcomes.

Qualitative Insights Into Patients' and Family Members' Experiences of In-Hospital Medication Management After a Critical Care Episode.

Background: Patient recovery after a critical illness can be protracted, requiring a care continuum that extends along a patient pathway from the critical care unit, hospital ward, and into the community care setting. High-quality care on patient transfer from critical care, including medication safety, is facilitated by education for patients and families, family engagement, support systems, and health care professional (HCP)-patient communication. Currently, uncertainty exists regarding how HCPs can and should engage with critical care patients and family members about their medication. Research Question: What are the views and experiences of critical care patients and family members about their involvement in, communication about, understanding of, and decision-making related to their medication after transfer from critical care to the hospital ward? Study Design and Methods: This qualitative study used semistructured interviews, conducted with critical care patients and family members after transfer from critical care to a hospital ward in a large National Health Service hospital trust. Anonymized transcripts of interviews were analyzed thematically using a coding framework developed from understandings of patient and family engagement in medication administration. Results: Twenty-seven participants (15 patients and 12 family members of patients) completed the interviews. We identified five themes and 15 subthemes, providing an overview of patients' and family members' views on medication management during acute illness and ongoing recovery. Themes identified were: impact of acute illness and treatment burden on preexisting illness, preexisting knowledge and capability, beliefs about persons roles and expectations, care continuity and individualized information exchange, and engagement in practice. Interpretation: This study demonstrated that critical care patients and family members want to engage with HCPs about medication administration. HCPs must take an individualized approach to communication and timing, acknowledging the dynamic interplay between patients and family members, using multimodal forms of communication.

Bariatric surgery and the diseased kidney: a 5-year assessment of safety and postoperative renal outcomes.

BACKGROUND: Obesity and its related medical conditions are well-established contributors to the development of chronic kidney disease (CKD). Metabolic and bariatric surgery (MBS), including procedures such as sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB), is a potential intervention for these individuals. However, the heightened risk of postoperative complications casts doubts on the suitability of MBS in this population. Our aim is to evaluate the long-term safety, anthropometric and renal outcomes of MBS in patients with CKD. METHODS: A retrospective review of patients who underwent primary laparoscopic MBS with a BMI ≥ 35 kg/m2 and a preoperative diagnosis of stage 2 to 5 CKD. Criteria for CKD diagnosis and staging were based on estimated glomerular filtration rate measurements in accordance with established guidelines. Anthropometric and renal outcomes were measured at 3-, 6-, 12-, 24- and 60-months postoperatively. RESULTS: A total of 302 patients (177 SG, 125 RYGB) were included. RYGB was preferred for patients with stage 3 CKD, while SG was more common in stages 4 and 5. At 5-year follow-up, percentage of total weight loss was higher in the RYGB cohort compared to SG (25.1% vs. 18.6%, p = 0.036). Despite SG patients having more advanced CKD, the incidence of late complications was significantly higher following RYGB, with 11 incidents (8.8%), compared to the SG cohort with only 4 cases (2.3%) (p = 0.014). In those with preoperative CKD stage 3, 76 patients (43.2%) improved to stage 2, with another 9 patients (5.1%) improving further to stage 1. Of all patients, 63 (20.8%) eventually received a successful renal transplant. CONCLUSIONS: MBS is an effective strategy for sustained weight loss in patients with CKD with acceptable complications rates. RYGB leads to a higher percentage of overall weight loss, albeit with an elevated likelihood of late surgical complications. Future studies are needed to determine the safety of MBS in this demographic.

Patterns of Smoking Cessation Strategies and Perception of E-cigarette Harm Among Bladder Cancer Survivors.

BACKGROUND: Cigarette smoking is the leading preventable cause of bladder cancer (BC). Some proponents of e-cigarettes describe their use as a risk mitigation strategy despite potential carcinogen exposure and uncertain long-term risks. OBJECTIVE: We assessed smoking cessation strategies, including e-cigarette use, and harm perception among patients with BC. METHODS: We performed a cross-sectional study on a convenience sample of patients with BC at a single institution from August 2021 - October 2022. The survey instrument was sourced from the Cancer Patient Tobacco Use Questionnaire (C-TUQ) from the American Association for Cancer Research with standardized questions on tobacco use, cessation questions, and e-cigarette harm perceptions. RESULTS: Of the 104 surveyed BC patients (mean age: 72 years; 27% female; 55% with muscle-invasive disease), 20% were current smokers (median pack years: 40) and 51% were former smokers (median pack years: 20). A minority (9%) had quit smoking at the time of diagnosis. Pharmacotherapy for smoking cessation included nicotine patches (25%), gum (21%), lozenges (8%), e-cigarettes (8%), and Varenicline/Bupropion (4%). Notably, 43% of patients who continued to smoke expressed willingness to switch to e-cigarettes as a cessation aid. E-cigarette users (11%) more commonly perceived e-cigarettes as non-harmful compared to former (4%) and non-smokers (4%) (P = .048), though all groups regarded e-cigarettes as equally addictive as traditional cigarettes. CONCLUSIONS: Despite the prevalence of BC survivors who continue to smoke, a significant proportion perceive e-cigarettes as a viable and less harmful cessation aid. The infrequent use of FDA-approved pharmacotherapies underscores potential implementation gaps. These findings highlight the need for further research and targeted interventions in addressing smoking cessation among BC survivors.

Influence of Solvent Selection on the Crystallizability and Polymorphic Selectivity Associated with the Formation of the "Disappeared" Form I Polymorph of Ritonavir.

The comparative crystallizability and polymorphic selectivity of ritonavir, a novel protease inhibitor for the treatment of acquired immune-deficiency syndrome, as a function of solvent selection are examined through an integrated and self-consistent experimental and computational molecular modeling study. Recrystallization at high supersaturation by rapid cooling at 283.15 K is found to produce the metastable "disappeared" polymorphic form I from acetone, ethyl acetate, acetonitrile, and toluene solutions in contrast to ethanol which produces the stable form II. Concomitant crystallization of the other known solid forms is not found under these conditions. Isothermal crystallization studies using turbidometric detection based upon classical nucleation theory reveal that, for an equal induction time, the required driving force needed to initiate solution nucleation decreases with solubility in the order of ethanol, acetone, acetonitrile, ethyl acetate, and toluene consistent with the expected desolvation behavior predicted from the calculated solute solvation free energies. Molecular dynamics simulations of the molecular and intermolecular chemistry reveal the presence of conformational interplay between intramolecular and intermolecular interactions within the solution phase. These encompass the solvent-dependent formation of intramolecular O-H...O hydrogen bonding between the hydroxyl and carbamate groups coupled with differing conformations of the hydroxyl's shielding phenyl groups. These conformational preferences and their relative interaction propensities, as a function of solvent selection, may play a rate-limiting role in the crystallization behavior by not only inhibiting to different degrees the nucleation process but also restricting the assembly of the optimal intermolecular hydrogen bonding network needed for the formation of the stable form II polymorph.

Predictive Impact of Tumor Mutational Burden on Real-World Outcomes of First-Line Immune Checkpoint Inhibition in Metastatic Melanoma.

PURPOSE: The choice of threshold and reliability of high tumor mutational burden (TMB) to predict outcomes and guide treatment choice for patients with metastatic melanoma receiving first-line immune checkpoint inhibitor (ICI) therapy in the real world is not well known. METHODS: Using a deidentified nationwide (US-based) melanoma clinicogenomic database, we identified a real-world cohort of patients with metastatic melanoma (N = 497) who received first-line monotherapy anti-PD-1 (n = 240) or dual anti-PD-1 and anti-CTLA-4 ICI (n = 257) and had a tissue-based comprehensive genomic profiling test TMB score. RESULTS: TMB-high (TMB-H; ≥10 mutations per megabase [muts/Mb], n = 352, 71%) was independently predictive of superior real-world progression-free survival and overall survival versus TMB-low (<10 mut/Mb, n = 145, 29%) in both mono ICI (hazard ratio [HR], 0.45 [95% CI, 0.32 to 0.63]; P < .001; HR, 0.61 [95% CI, 0.41 to 0.90]; P = .01, respectively) and dual ICI (HR, 0.67 [95% CI, 0.49 to 0.90]; P = .009; HR, 0.61 [95% CI, 0.42 to 0.88]; P = .007, respectively) patients. Dual ICI offered no significant advantage in BRAFwt patients and unexpectedly demonstrated greatest benefit in the TMB 10-19 mut/Mb group, identifying a TMB-very high (≥20 mut/Mb, n = 247, 50%) BRAFmut patient subgroup for whom mono ICI may be preferable. CONCLUSION: TMB-H predicts superior outcomes on ICI while coassessment of BRAF status and TMB may inform first-line regimen choice.

Simulating implications of fish behavioral response for managing hypoxia in estuaries with spatial dissolved oxygen variability.

Hypoxia, or low dissolved oxygen (DO), is a widespread water quality problem affecting estuaries and coastal waters around the world. Water quality criteria for DO have been established for every estuary in the US and are an important part of the regulatory response to nutrient pollution and associated anthropogenic eutrophication. Experimental studies examining effects of low DO exposure have been to quantify outcomes based on hypoxia effects observed in individuals, such as increased mortality or growth impairment. Although laboratory exposure tests provide useful benchmarks for policy development, most of those considered in policy development did not consider behavioral responses to low DO. However, experimental research has shown that behavioral responses occur, and that behavior modifies exposure to low DO conditions. Here we begin development of a spatially explicit individual based model (SEIBM) intended to project behavioral outcomes of exposure to spatially variable hypoxia in estuaries. Our goal is to consider the responsiveness of an SEIBM to both different behavioral hypotheses, as well as realistic spatial patterns in hypoxia. A sensitivity analysis was used to explore responsiveness based on two movement strategies: avoidance and behavioral switching. We tested the sensitivity of a suite of movement parameters to changes in spatial patterns representative of an index estuary. The sensitivity analysis demonstrated that model responses to changes in movement strategies include biologically meaningful changes in site occupancy and movement distance centered on individual behavior near a normoxic-hypoxic boundary. Further, the model demonstrated important sensitivity to realistic changes in movement parameters, including the size and shape of the individual neighborhood describing knowledge useful for movement decisions. These results support the utility of the developed SEIBM for exploring behavioral responses of fish to hypoxia in estuaries. The sensitivity analysis also demonstrates parameter values that must be set based on empirical data and are sensitive to data quality. These results will be used to further develop the model and to plan field and laboratory studies to support model parametrization. The end goal is a model framework that can inform policy decisions regarding hypoxia resulting from anthropogenic nutrient loading in estuaries.

A mechanical transition from tension to buckling underlies the jigsaw puzzle shape morphogenesis of histoblasts in the Drosophila epidermis.

The polygonal shape of cells in proliferating epithelia is a result of the tensile forces of the cytoskeletal cortex and packing geometry set by the cell cycle. In the larval Drosophila epidermis, two cell populations, histoblasts and larval epithelial cells, compete for space as they grow on a limited body surface. They do so in the absence of cell divisions. We report a striking morphological transition of histoblasts during larval development, where they change from a tensed network configuration with straight cell outlines at the level of adherens junctions to a highly folded morphology. The apical surface of histoblasts shrinks while their growing adherens junctions fold, forming deep lobules. Volume increase of growing histoblasts is accommodated basally, compensating for the shrinking apical area. The folded geometry of apical junctions resembles elastic buckling, and we show that the imbalance between the shrinkage of the apical domain of histoblasts and the continuous growth of junctions triggers buckling. Our model is supported by laser dissections and optical tweezer experiments together with computer simulations. Our analysis pinpoints the ability of histoblasts to store mechanical energy to a much greater extent than most other epithelial cell types investigated so far, while retaining the ability to dissipate stress on the hours time scale. Finally, we propose a possible mechanism for size regulation of histoblast apical size through the lateral pressure of the epidermis, driven by the growth of cells on a limited surface. Buckling effectively compacts histoblasts at their apical plane and may serve to avoid physical harm to these adult epidermis precursors during larval life. Our work indicates that in growing nondividing cells, compressive forces, instead of tension, may drive cell morphology.

Ethnicity and the Prevalence of Polycystic Ovary Syndrome: The Eastern Siberia PCOS Epidemiology and Phenotype Study.

CONTEXT: Previous studies have shown that the prevalence of polycystic ovary syndrome (PCOS) may vary according to race/ethnicity, although few studies have assessed women of different ethnicities who live in similar geographic and socio-economic conditions. OBJECTIVE: To determine the prevalence of PCOS in an unselected multiethnic population of premenopausal women. DESIGN: A multicenter prospective cross-sectional study. SETTINGS: The main regional employers of Irkutsk Region and the Buryat Republic, Russia. PARTICIPANTS: During 2016-19, 1398 premenopausal women underwent a history and physical exam, pelvic ultrasound, and testing during a mandatory annual employment-related health assessment. MAIN OUTCOME MEASURES: PCOS prevalence, overall and by ethnicity in a large medically unbiased population, including Caucasian (White), Mongolic or Asian (Buryat), and mixed ethnicity individuals, living in similar geographic and socio-economic conditions for centuries. RESULTS: PCOS was diagnosed in 165/1134 (14.5%) women who had a complete evaluation for PCOS. Based on the probabilities for PCOS by clinical presentation observed in the cohort of women who had a complete evaluation we also estimated the weight-adjusted prevalence of PCOS in 264 women with an incomplete evaluation: 46.2 or 17.5%. Consequently, the total prevalence of PCOS in the population was 15.1%, higher among Caucasians and women of Mixed ethnicity compared to Asians (16.0% and 21.8% vs. 10.8%, pz <0.05). CONCLUSIONS: We observed a 15.1% prevalence of PCOS in our medically unbiased population of premenopausal women. In this population of Siberian premenopausal women of Caucasian, Asian and Mixed ethnicity living in similar geographic and socio-economic conditions, the prevalence was higher in Caucasian or Mixed than Asian women. These data highlight the need to assess carefully ethnic-dependent differences in the frequency and clinical manifestation of PCOS.

Younger Age and Female Gender Are Associated with Delayed Antibiotics in Pediatric Sepsis.

Sepsis is a leading cause of pediatric mortality and timely antibiotic administration has been shown to improve outcomes. In this retrospective review of a single center sepsis dataset, we identified younger age and female sex as more likely to have delays in antibiotics.

An Age-Stratified Analysis of Early Postoperative Mortality Among Medicare-Eligible Patients With Common Gastrointestinal and Hepato-pancreato-biliary Malignancies.

Background: The frequency of major cancer surgery in the elderly (≥80 years) has increased concomitantly with the rise in average age of the population. We assessed early postoperative mortality following hepato-pancreato-biliary (HPB) and gastrointestinal (GI) procedures for common malignancies stratified by age. Methods: The National Cancer Database (2004-2017) was queried for patients who underwent resection for GI (gastroesophageal and colorectal) or HPB (pancreatic adenocarcinoma, biliary tract, and primary liver) cancers. We compared early postoperative mortality (30 d and 90 d) stratified by age (65-79 vs ≥80 years) and procedure, and compared survival outcomes by age and operative vs nonoperative management. Results: A total of 709,358 patients were included. The 30-day mortality ranged from 1.8% to 5.8% among patients 65-79 years and from 3.2% to 12.4% among patients ≥80 years depending on procedure. The 90-day mortality ranged from 3.6% to 10.6% in patients 65-79 years compared to 8.4%-21.0% among patients ≥80 years. The overall 90-day mortality was 5.2% for patients 65-79 years and 12.0% for patients ≥80 years (P < .001). Age ≥80 was associated with worse survival among operatively managed patients with each upper GI, HPB, and lower GI malignancy relative to younger patients on multivariable analysis. However, operative management of patients ≥80 years was associated with improved survival relative to nonoperative management. Discussion: Elderly patients suffer higher postoperative mortality after major GI and HPB cancer surgery, but operative management is associated with improved survival among patients ≥80 years as compared to nonoperative management. These data are important to contextualize when counseling elderly patients on their treatment options for localized GI and HPB cancers.