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Colorectal carcinoma (CRC) is a common cause of mortality1, but a comprehensive description of its genomic landscape is lacking2–9. Here we perform whole-genome sequencing of 2,023 CRC samples from participants in the UK 100,000 Genomes Project, thereby providing a highly detailed somatic mutational landscape of this cancer. Integrated analyses identify more than 250 putative CRC driver genes, many not previously implicated in CRC or other cancers, including several recurrent changes outside the coding genome. We extend the molecular pathways involved in CRC development, define four new common subgroups of microsatellite-stable CRC based on genomic features and show that these groups have independent prognostic associations. We also characterize several rare molecular CRC subgroups, some with potential clinical relevance, including cancers with both microsatellite and chromosomal instability. We demonstrate a spectrum of mutational profiles across the colorectum, which reflect aetiological differences. These include the role of Escherichiacolipks+colibactin in rectal cancers10and the importance of the SBS93 signature11–13, which suggests that diet or smoking is a risk factor. Immune-escape driver mutations14are near-ubiquitous in hypermutant tumours and occur in about half of microsatellite-stable CRCs, often in the form of HLA copy number changes. Many driver mutations are actionable, including those associated with rare subgroups (for example, BRCA1and IDH1), highlighting the role of whole-genome sequencing in optimizing patient care.

Devices that record data generated by an aircraft and its crew during operation are known as flight data recorders (FDRs) and cockpit voice recorders (CVRs). Data recorded by these devices enable the analysis of aircraft state and behavior from takeoff to landing. The information provided by these devices is used to conduct inspections, investigations, training, and other measures by aviation experts following hazardous events or accidents. As of today, multiple instruction manuals covering the specifications of FDRs and CVRs have been presented by various organizations, experts, and scientists within the aviation industry. However, no consolidated research document that brings all this information together for regulatory and technical purposes has been published yet. Our objective is to carry out an in-depth study of FDRs for both manned and unmanned systems. We aim to examine the requirements used in the past, current technological advancements, and future intelligent FDR approaches, intending to advance FDR technology. Starting with manned aviation systems, we provide a comprehensive overview of general FDRs and then look at new challenges and the resulting requirements for unmanned aerial vehicles (UAVs). After reviewing all relevant resources, we present a roadmap for the next generation of FDRs.

Artificial neural networks, deep-learning methods and the backpropagation algorithm1form the foundation of modern machine learning and artificial intelligence. These methods are almost always used in two phases, one in which the weights of the network are updated and one in which the weights are held constant while the network is used or evaluated. This contrasts with natural learning and many applications, which require continual learning. It has been unclear whether or not deep learning methods work in continual learning settings. Here we show that they do not—that standard deep-learning methods gradually lose plasticity in continual-learning settings until they learn no better than a shallow network. We show such loss of plasticity using the classic ImageNet dataset and reinforcement-learning problems across a wide range of variations in the network and the learning algorithm. Plasticity is maintained indefinitely only by algorithms that continually inject diversity into the network, such as our continual backpropagation algorithm, a variation of backpropagation in which a small fraction of less-used units are continually and randomly reinitialized. Our results indicate that methods based on gradient descent are not enough—that sustained deep learning requires a random, non-gradient component to maintain variability and plasticity.

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.This retrospective review of a pediatric sepsis dataset shows disparities in the delivery of antibiotics within 60 min for patients less than 1 year of age and female sex.

IMPORTANCE: Climate change may increase the risk of adverse cardiovascular outcomes by causing direct physiologic changes, psychological distress, and disruption of health-related infrastructure. Yet, the association between numerous climate change–related environmental stressors and the incidence of adverse cardiovascular events has not been systematically reviewed. OBJECTIVE: To review the current evidence on the association between climate change–related environmental stressors and adverse cardiovascular outcomes. EVIDENCE REVIEW: PubMed, Embase, Web of Science, and Cochrane Library were searched to identify peer-reviewed publications from January 1, 1970, through November 15, 2023, that evaluated associations between environmental exposures and cardiovascular mortality, acute cardiovascular events, and related health care utilization. Studies that examined only nonwildfire-sourced particulate air pollution were excluded. Two investigators independently screened 20 798 articles and selected 2564 for full-text review. Study quality was assessed using the Navigation Guide framework. Findings were qualitatively synthesized as substantial differences in study design precluded quantitative meta-analysis. FINDINGS: Of 492 observational studies that met inclusion criteria, 182 examined extreme temperature, 210 ground-level ozone, 45 wildfire smoke, and 63 extreme weather events, such as hurricanes, dust storms, and droughts. These studies presented findings from 30 high-income countries, 17 middle-income countries, and 1 low-income country. The strength of evidence was rated as sufficient for extreme temperature; ground-level ozone; tropical storms, hurricanes, and cyclones; and dust storms. Evidence was limited for wildfire smoke and inadequate for drought and mudslides. Exposure to extreme temperature was associated with increased cardiovascular mortality and morbidity, but the magnitude varied with temperature and duration of exposure. Ground-level ozone amplified the risk associated with higher temperatures and vice versa. Extreme weather events, such as hurricanes, were associated with increased cardiovascular risk that persisted for many months after the initial event. Some studies noted a small increase in cardiovascular mortality, out-of-hospital cardiac arrests, and hospitalizations for ischemic heart disease after exposure to wildfire smoke, while others found no association. Older adults, racial and ethnic minoritized populations, and lower-wealth communities were disproportionately affected. CONCLUSIONS AND RELEVANCE: Several environmental stressors that are predicted to increase in frequency and intensity with climate change are associated with increased cardiovascular risk, but data on outcomes in low-income countries are lacking. Urgent action is needed to mitigate climate change–associated cardiovascular risk, particularly in vulnerable populations.

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/m2and 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.

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.

Respiratory tract infections represent a significant global public health concern, disproportionately affecting vulnerable populations such as children, the elderly, and immunocompromised individuals. RNA viruses, particularly influenza viruses and coronaviruses, significantly contribute to respiratory illnesses, especially in immunosuppressed and elderly individuals. Influenza A viruses (IAVs) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continue to pose global health threats due to their capacity to cause annual epidemics, with profound implications for public health. In addition, the increase in global life expectancy is influencing the dynamics and outcomes of respiratory viral infections. Understanding the molecular mechanisms by which IAVs and SARS-CoV-2 contribute to lung disease progression is therefore crucial. The aim of this review is to comprehensively explore the impact of IAVs and SARS-CoV-2 on chronic lung diseases, with a specific focus on pulmonary fibrosis in the elderly. It also outlines potential preventive and therapeutic strategies and suggests directions for future research.

The combination of rectally administered indomethacin and placement of a prophylactic pancreatic stent is recommended to prevent pancreatitis after endoscopic retrograde cholangiopancreatography (ERCP) in high-risk patients. Preliminary evidence suggests that the use of indomethacin might eliminate or substantially reduce the need for stent placement, a technically complex, costly, and potentially harmful intervention.

Adaptive stress response pathways (SRPs) restore cellular homeostasis following perturbation but may activate terminal outcomes like apoptosis, autophagy, or cellular senescence if disruption exceeds critical thresholds. Because SRPs hold the key to vital cellular tipping points, they are targeted for therapeutic interventions and assessed as biomarkers of toxicity. Hence, we are developing a public database of chemicals that perturb SRPs to enable new data-driven tools to improve public health. Here, we report on the automated text-mining pipeline we used to build and curate the first version of this database. We started with 100 reference SRP chemicals gathered from published biomarker studies to bootstrap the database. Second, we used information retrieval to find co-occurrences of reference chemicals with SRP terms in PubMed abstracts and determined pairwise mutual information thresholds to filter biologically relevant relationships. Third, we applied these thresholds to find 1206 putative SRP perturbagens within thousands of substances in the Library of Integrated Network-Based Cellular Signatures (LINCS). To assign SRP activity to LINCS chemicals, domain experts had to manually review at least three publications for each of 1206 chemicals out of 181,805 total abstracts. To accomplish this efficiently, we implemented a machine learning approach to predict SRP classifications from texts to prioritize abstracts. In 5-fold cross-validation testing with a corpus derived from the 100 reference chemicals, artificial neural networks performed the best (F1-macro = 0.678) and prioritized 2479/181,805 abstracts for expert review, which resulted in 457 chemicals annotated with SRP activities. An independent analysis of enriched mechanisms of action and chemical use class supported the text-mined chemical associations (p< 0.05): heat shock inducers were linked with HSP90 and DNA damage inducers to topoisomerase inhibition. This database will enable novel applications of LINCS data to evaluate SRP activities and to further develop tools for biomedical information extraction from the literature.

Background: Many people survive critical illness with the burden of new or worsened mental health issues and sleep disturbances. We examined the frequency of psychotropic prescribing after critical illness, comparing critical care to non-critical care hospitalised survivors, and whether this varied in important subgroups.Methods: This retrospective cohort study included 23,340 critical care and 367,185 non-critical care hospitalised adults from 2012 through 2019 in Lothian, Scotland, who survived to discharge.Results: One-third of critical care survivors (32%; 7527/23,340) received a psychotropic prescription within 90 days after hospital discharge (25% antidepressants; 14% anxiolytics/hypnotics; 4% antipsychotics/mania medicines). In contrast, 15% (54,589/367,185) of non-critical care survivors received a psychotropic prescription (12% antidepressants; 5% anxiolytics/hypnotics; 2% antipsychotics/mania medicines). Among patients without psychotropic prescriptions within 180 days prior to hospitalisation, after hospital discharge, the critical care group had a higher incidence of psychotropic prescription (10.3%; 1610/15,609) compared with the non-critical care group (3.2%; 9743/307,429); unadjusted hazard ratio (HR) 3.39, 95% CI: 3.22–3.57. After adjustment for potential confounders, the risk remained elevated (adjusted HR 2.03, 95% CI: 1.91–2.16), persisted later in follow-up (90–365 days; adjusted HR 1.38, 95% CI: 1.30–1.46), and was more pronounced in those without recorded comorbidities (adjusted HR 3.49, 95% CI: 3.22–3.78).Conclusions: Critical care survivors have a higher risk of receiving psychotropic prescriptions than hospitalised patients, with a significant proportion receiving benzodiazepines and other hypnotics. Future research should focus on the requirement for and safety of psychotropic medicines in survivors of critical illness, to help guide policy for clinical practice.

Spinal muscular atrophy (SMA) is a neuromuscular disorder characterised by progressive motor function decline. Motor function is assessed using several functional outcome measures including the Revised Hammersmith Scale (RHS). In this study, we present longitudinal trajectories for the RHS in an international cohort of 149 untreated paediatric SMA 2 and 3 patients (across 531 assessments collected between March 2015 and July 2019). We contextualise these trajectories using both the Hammersmith Functional Motor Scale Expanded (HFMSE) and Revised Upper Limb Module (RULM). At baseline, this cohort included 50% females and 15% of patients had undergone spinal fusion surgery. Patient trajectories were modelled using a natural cubic spline with age, sex, and random effects for each patient. RHS and HFMSE scores show similar trends over time in this cohort not receiving disease modifying therapies. The results confirm the strong correlation between the RHS and RULM previously observed in SMA types 2 and 3a. Scoliosis surgery is associated with a reduction of 3 points in the RHS, 4.5 points in the HFMSE for the SMA 2 population, and a reduction of 11.8 points in the RHS, and 13.4 points in the HFMSE for the SMA 3a populations. When comparing the RHS and RULM, there is a lower correlation in the type 3a’s than the type 2 patients. In the SMA 2 population, there is no significant difference between the sexes in either the RHS or HFMSE trajectories. There is no significant difference in the RULM trajectory in the SMA 2 or 3a participants by sex. This study demonstrates that the RHS could be used in conjunction with other functional measures such as the RULM to holistically detect SMA disease progression. This will assist with fully understanding changes that occur with treatments, further defining trajectories and therapy outcomes.

AbstractWe describe best practices in reporting reliability estimates in counseling research with consideration to precision, generalization, and diverse populations. We provide a historical context to reporting reliability estimates, the limitations of past practices, and new methods to address reliability generalization. We highlight best practices including consideration of reliability estimates as function of scores, not scale, diverse sample, hierarchy of reporting reliability estimates, and methods of reliability generalization.

Prescription stimulant misuse (PSM) has been studied extensively in college populations, but few studies have examined how PSM changes after graduation. We used a longitudinal design to follow individuals at risk for PSM 2 years after college graduation to document PSM prevalence, motives, and predictors of PSM persistence. Participants from two small, private colleges completed online surveys focused on intrapersonal, interpersonal, and sociocultural predictors of PSM. Overall, PSM declined over time. Lack of premeditation, perceived peer norms, positive expectancies, media exposure, and other substance use were associated with continued PSM; however, only lack of premeditation, descriptive norms, and other substance use predicted PSM in a multivariate model. This preliminary study suggests dispositional and behavioral risk factors may help to explain why PSM persists after college. Interventions that enhance decision-making skills, correct misperceptions about peers’ PSM, and reduce polysubstance use may be effective in curbing PSM in college graduates.

Long-term, real-world effectiveness and safety data of disease-modifying treatments for spinal muscular atrophy (SMA) are important for assessing outcomes and providing information for a larger number and broader range of SMA patients than included in clinical trials. We sought to describe patients with SMA treated with onasemnogene abeparvovec monotherapy in the real-world setting. RESTORE is a prospective, multicenter, multinational, observational registry that captures data from a variety of sources. Recruitment started in September 2018. As of May 23, 2022, data were available for 168 patients treated with onasemnogene abeparvovec monotherapy. Median (IQR) age at initial SMA diagnosis was 1 (0–6) month and at onasemnogene abeparvovec infusion was 3 (1–10) months. Eighty patients (47.6%) had two and 70 (41.7%) had three copies of SMN2, and 98 (58.3%) were identified by newborn screening. Infants identified by newborn screening had a lower age at final assessment (mean age 11.5 months) and greater mean final (SD) CHOP INTEND score (57.0 [10.0] points) compared with clinically diagnosed patients (23.1 months; 52.1 [8.0] points). All patients maintained/achieved motor milestones. 48.5% (n = 81/167) experienced at least one treatment-emergent adverse event (AE), and 31/167 patients (18.6%) experienced at least one serious AE, of which 8/31 were considered treatment-related. These real-world outcomes support findings from the interventional trial program and demonstrate effectiveness of onasemnogene abeparvovec over a large patient population, which was consistent with initial clinical data and published 5-year follow-up data. Observed AEs were consistent with the established safety profile of onasemnogene abeparvovec.

Duchenne muscular dystrophy (DMD) and related dystrophinopathies are neuromuscular conditions with great unmet medical needs that require the development of effective medical treatments. To aid sponsors in clinical development of drugs and therapeutic biological products for treating DMD across the disease spectrum by integrating advancements, patient registries, natural history studies, and more into a comprehensive guidance. This guidance emerged from collaboration between the FDA, the Duchenne community, and industry stakeholders. It entailed a structured approach, involving multiple committees and boards. From its inception in 2014, the guidance underwent revisions incorporating insights from gene therapy studies, cardiac function research, and innovative clinical trial designs. The guidance provides a deeper understanding of DMD and its variants, focusing on patient engagement, diagnostic criteria, natural history, biomarkers, and clinical trials. It underscores patient-focused drug development, the significance of dystrophin as a biomarker, and the pivotal role of magnetic resonance imaging in assessing disease progression. Additionally, the guidance addresses cardiomyopathy’s prominence in DMD and the burgeoning field of gene therapy. The updated guidance offers a comprehensive understanding of DMD, emphasizing patient-centric approaches, innovative trial designs, and the importance of biomarkers. The focus on cardiomyopathy and gene therapy signifies the evolving realm of DMD research. It acts as a crucial roadmap for sponsors, potentially leading to improved treatments for DMD.

IMPORTANCE: The combination of immune checkpoint inhibitors with antiangiogenic agents has revolutionized the treatment landscape of advanced hepatocellular carcinoma (HCC). However, due to rapid publication of new studies that attained their predefined primary end points, a lack of robust cross-trial comparison of first-line therapies, and diverging clinical guidelines, no clear-cut treatment flowchart and sequence of therapies are available. This critical analysis of the recommendations for the management of advanced HCC from the main scientific societies in the US and Europe adopted an integrated approach to provide information on the clinical benefit (overall survival and progression-free survival) and safety profile of these therapies using the European Society for Medical Oncology (ESMO)–Magnitude of Clinical Benefit Scale (MCBS) score and an ad hoc network meta-analysis. OBSERVATIONS: There is a major consensus among guidelines that atezolizumab plus bevacizumab has a primacy as the recommended first-line treatment of choice in advanced HCC. On progression after immunotherapy-containing regimens and for patients with contraindications for immunotherapies, most guidelines maintain the established treatment hierarchy, recommending lenvatinib or sorafenib as the preferred options, followed by either regorafenib, cabozantinib, or ramucirumab. Thus far, the first-line immune-based regimen of tremelimumab plus durvalumab has been integrated only in the American Association for the Study of Liver Diseases guidance document and the latest National Comprehensive Cancer Network guidelines and has particular utility for patients with a high risk of gastrointestinal bleeding. Overall, in the first-line setting, both atezolizumab plus bevacizumab and sintilimab plus IBI305 (a bevacizumab biosimilar) and durvalumab plus tremelimumab received the highest ESMO-MCBS score of 5, indicating a substantial magnitude of clinical benefit. In a network meta-analysis, no significant differences in overall survival were found among the various combination regimens. However, the newly reported combination of camrelizumab plus rivoceranib was associated with a significantly higher risk of treatment-related adverse events compared with atezolizumab plus bevacizumab (relative risk, 1.59; 95% CI, 1.25-2.03; P &lt; .001). CONCLUSIONS AND RELEVANCE: This narrative review found that atezolizumab plus bevacizumab is regarded as the primary standard of care for advanced HCC in the first-line setting. These findings from integrating the recommendations from scientific societies’ guidelines for managing advanced HCC along with new data from cross-trial comparisons may aid clinicians in decision-making and guide them through a rapidly evolving and complex treatment landscape.

Neutron stars and stellar-mass black holes are the remnants of massive star explosions1. Most massive stars reside in close binary systems2, and the interplay between the companion star and the newly formed compact object has been theoretically explored3, but signatures for binarity or evidence for the formation of a compact object during a supernova explosion are still lacking. Here we report a stripped-envelope supernova, SN 2022jli, which shows 12.4-day periodic undulations during the declining light curve. Narrow Hα emission is detected in late-time spectra with concordant periodic velocity shifts, probably arising from hydrogen gas stripped from a companion and accreted onto the compact remnant. A new Fermi-LAT γ-ray source is temporally and positionally consistent with SN 2022jli. The observed properties of SN 2022jli, including periodic undulations in the optical light curve, coherent Hα emission shifting and evidence for association with a γ-ray source, point to the explosion of a massive star in a binary system leaving behind a bound compact remnant. Mass accretion from the companion star onto the compact object powers the light curve of the supernova and generates the γ-ray emission.

Genome-wide association studies of colorectal cancer (CRC) have identified 170 autosomal risk loci. However, for most of these, the functional variants and their target genes are unknown. Here, we perform statistical fine-mapping incorporating tissue-specific epigenetic annotations and massively parallel reporter assays to systematically prioritize functional variants for each CRC risk locus. We identify plausible causal variants for the 170 risk loci, with a single variant for 40. We link these variants to 208 target genes by analyzing colon-specific quantitative trait loci and implementing the activity-by-contact model, which integrates epigenomic features and Micro-C data, to predict enhancer–gene connections. By deciphering CRC risk loci, we identify direct links between risk variants and target genes, providing further insight into the molecular basis of CRC susceptibility and highlighting potential pharmaceutical targets for prevention and treatment.

Bipolar disorder is a chronic and complex polygenic disease with high rates of comorbidity. However, the independent contribution of either diagnosis or genetic risk of bipolar disorder to the medical comorbidity profile of individuals with the disease remains unresolved. Here, we conducted a multi-step phenome-wide association study (PheWAS) of bipolar disorder using phenomes derived from the electronic health records of participants enrolled in the Mayo Clinic Biobank and the Mayo Clinic Bipolar Disorder Biobank. First, we explored the conditions associated with a diagnosis of bipolar disorder by conducting a phenotype-based PheWAS followed by LASSO-penalized regression to account for correlations within the phenome. Then, we explored the conditions associated with bipolar disorder polygenic risk score (BD-PRS) using a PRS-based PheWAS with a sequential exclusion approach to account for the possibility that diagnosis, instead of genetic risk, may drive such associations. 53,386 participants (58.7% women) with a mean age at analysis of 67.8 years (SD = 15.6) were included. A bipolar disorder diagnosis (n= 1479) was associated with higher rates of psychiatric conditions, injuries and poisonings, endocrine/metabolic and neurological conditions, viral hepatitis C, and asthma. BD-PRS was associated with psychiatric comorbidities but, in contrast, had no positive associations with general medical conditions. While our findings warrant confirmation with longitudinal-prospective studies, the limited associations between bipolar disorder genetics and medical conditions suggest that shared environmental effects or environmental consequences of diagnosis may have a greater impact on the general medical comorbidity profile of individuals with bipolar disorder than its genetic risk.

The second eigenvalue of the Robin Laplacian is shown to be maximal for a spherical cap among simply connected Jordan domains on the 2-sphere, for substantial intervals of positive and negative Robin parameters and areas. Geodesic disks in the hyperbolic plane similarly maximize the eigenvalue on a natural interval of negative Robin parameters. These theorems extend work of Freitas and Laugesen from the Euclidean case (zero curvature) and the authors’ hyperbolic and spherical results for Neumann eigenvalues (zero Robin parameter). Complicating the picture is the numerically observed fact that the second Robin eigenfunction on a large spherical cap is purely radial, with no angular dependence, when the Robin parameter lies in a certain negative interval depending on the cap aperture.

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. We assessed smoking cessation strategies, including e-cigarette use, and harm perception among patients with BC. 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. 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. 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.

In most plant species, sepals—the outermost floral organs—provide a protective shield for reproductive organs. How the floral bud becomes sealed is unknown. In Arabidopsis, we identified a small region at the sepal tip that is markedly curved inward early on and remains curved even after anthesis. Through modelling and quantitative growth analysis, we find that this hook emerges from growth arrest at the tip at a stage when cortical microtubules align with growth-derived tensile stress. Depolymerizing microtubules specifically at young sepal tips hindered hook formation and resulted in open floral buds. Mutants with defective growth pattern at the tip failed to curve inwards, whereas mutants with enhanced alignment of cortical microtubules at the tip exhibited a stronger hook. We propose that floral buds are locked due to a stress-derived growth arrest event curving the sepal tip and forming a rigid hook early on during flower development.