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The assessment and regulation of chemical toxicity to protect human health and the environment are done one chemical at a time and seldom at environmentally relevant concentrations. However, chemicals are found in the environment as mixtures, and their toxicity is largely unknown. Understanding the hazard posed by chemicals within the mixture is critical to enforce protective measures. Here, we demonstrate the application of bioactivity profiling of environmental water samples using the sentinel and ecotoxicology model species Daphniato reveal the biomolecular response induced by exposure to real-world mixtures. We exposed a Daphniastrain to 30 sampled waters of the Chaobai River and measured the gene expression response profiles. Using a multiblock correlation analysis, we establish correlations between chemical mixtures identified in 30 water samples with gene expression patterns induced by these chemical mixtures. We identified 80 metabolic pathways putatively activated by mixtures of inorganic ions, heavy metals, polycyclic aromatic hydrocarbons, industrial chemicals, and a set of biocides, pesticides, and pharmacologically active substances. Our data-driven approach discovered both known bioactivity signatures with previously described modes of action and new pathways linked to undiscovered potential hazards. This study demonstrates the feasibility of reducing the complexity of real-world mixture toxicity to characterize the biomolecular effects of a defined number of chemical components based on gene expression monitoring of the sentinel species Daphnia.

Introduction: Vedolizumab is a gut‐selective anti‐lymphocyte trafficking biologic indicated for the treatment of adult patients with moderately to severely active ulcerative colitis (UC) and Crohn’s disease (CD) in Canada. Objective: The objective of this study was to evaluate the cost effectiveness of treatment sequencing for UC and CD from a public healthcare payer perspective, leveraging new real-world evidence from the literature and the EVOLVE study, a retrospective chart review. Methods: Using separate decision tree/Markov models to assess cost effectiveness for UC and CD, two sequencing approaches were estimated for adult patients (≥ 18 years) diagnosed with UC or CD who were biologic-naïve: vedolizumab as first-line biologic followed by anti-tumor necrosis factor (TNF)-α versus first-line anti-TNFα followed by vedolizumab. Treatment effectiveness (response and remission), surgery rates, dose escalation and regain of response and safety inputs were estimated from EVOLVE, a retrospective chart review of real-world data, and evidence synthesis from the literature, whereas costs and utilities were estimated from health technology assessment reports, clinical trials, and the literature. Biosimilar costs were used for anti-TNFα. Both models simulated a 5-year time horizon and discounted costs and outcomes at 1.5%. Probabilistic base-case analyses (n= 10,000) reported total costs (2023 Canadian dollars) and quality-adjusted life-years (QALYs). Several scenario analyses were conducted to explore robustness of results. Results: In UC, vedolizumab as a first-line biologic followed by anti-TNFα resulted in an incremental gain of 0.09 QALYs (2.46 vs. 2.55) and saved $7179 ($134,028 vs. $126,848), making this a dominant strategy compared with first-line anti-TNFα followed by vedolizumab. In CD, use of vedolizumab as a first-line biologic resulted in an incremental gain of 0.04 QALYs (3.35 vs. 3.39) at an incremental cost of $50,631 ($89,850 vs. $140,381) versus first-line anti-TNFα followed by vedolizumab (incremental cost-effectiveness ratio of $1,265,775 per QALY). Conclusions: Based on this analysis, sequencing vedolizumab as a first-line biologic prior to anti-TNFα in UC and CD provided additional clinical benefit to patients. In UC, vedolizumab as a first-line biologic also saved healthcare system costs compared with anti-TNFα, whereas in CD, vedolizumab provided incremental benefit at an incremental cost, which was not considered cost effective at a threshold of $50,000/QALY.

Ancient whole-genome duplications are believed to facilitate novelty and adaptation by providing the raw fuel for new genes. However, it is unclear how recent whole-genome duplications may contribute to evolvability within recent polyploids. Hybridization accompanying some whole-genome duplications may combine divergent gene content among diploid species. Some theory and evidence suggest that polyploids have a greater accumulation and tolerance of gene presence–absence and genomic structural variation, but it is unclear to what extent either is true. To test how recent polyploidy may influence pangenomic variation, we sequenced, assembled, and annotated 12 complete, chromosome-scale genomes of Camelina sativa, an allohexaploid biofuel crop with 3 distinct subgenomes. Using pangenomic comparative analyses, we characterized gene presence–absence and genomic structural variation both within and between the subgenomes. We found over 75% of ortholog gene clusters are core in C. sativaand <10% of sequence space was affected by genomic structural rearrangements. In contrast, 19% of gene clusters were unique to one subgenome, and the majority of these were Camelina specific (no ortholog in Arabidopsis). We identified an inversion that may contribute to vernalization requirements in winter-type Camelina and an enrichment of Camelina-specific genes with enzymatic processes related to seed oil quality and Camelina's unique glucosinolate profile. Genes related to these traits exhibited little presence–absence variation. Our results reveal minimal pangenomic variation in this species and instead show how hybridization accompanied by whole-genome duplication may benefit polyploids by merging diverged gene content of different species.

Study Design Observational Study.Objectives This study aimed to investigate the most searched types of questions and online resources implicated in the operative and nonoperative management of scoliosis.Methods Six terms related to operative and nonoperative scoliosis treatment were searched on Google’s People Also Ask section on October 12, 2023. The Rothwell classification was used to sort questions into fact, policy, or value categories, and associated websites were classified by type. Fischer’s exact tests compared question type and websites encountered between operative and nonoperative questions. Statistical significance was set at the .05 level.Results The most common questions concerning operative and nonoperative management were fact (53.4%) and value (35.5%) questions, respectively. The most common subcategory pertaining to operative and nonoperative questions were specific activities/restrictions (21.7%) and evaluation of treatment (33.3%), respectively. Questions on indications/management (13.2% vs 31.2%, P< .001) and evaluation of treatment (10.1% vs 33.3%, P< .001) were associated with nonoperative scoliosis management. Medical practice websites were the most common website to which questions concerning operative (31.9%) and nonoperative (51.4%) management were directed to. Operative questions were more likely to be directed to academic websites (21.7% vs 10.0%, P= .037) and less likely to be directed to medical practice websites (31.9% vs 51.4%, P= .007) than nonoperative questions.Conclusions During scoliosis consultations, spine surgeons should emphasize the postoperative recovery process and efficacy of conservative treatment modalities for the operative and nonoperative management of scoliosis, respectively. Future research should assess the impact of website encounters on patients’ decision-making.

AbstractThe selection of a project delivery method significantly impacts design documentation quality. Among various methods globally, the Conventional Project Delivery (CPD) is the most common but criticized for limitations. While previous studies criticize the CPD for causing project delays, compromised quality, and increased costs, there is a paucity of research on the specific limitations of this approach, particularly during the design phase. This study focuses on Ghana’s construction sector, aiming to identify CPD’s specific limitations particularly during design documentation. Using questionnaires and semi-structured interviews, data was collected. IBM SPSS analysed questionnaire responses, while QSR Nvivo 12 Pro dissects interview data. Findings uncover CPD’s limitations: lack of designer coordination, insufficient commitment to objectives, prioritizing individual gains, and disregarding quality standards. Exposing these issues will drive a fundamental shift in the construction industry, fostering greater efficiency, cost-effectiveness, and overall success. This will significantly impact projects execution, leading to better outcomes.

Digital health applications can help patients with inflammatory bowel disease (IBD). This study looked at whether the MyGut app improves health outcomes for patients with IBD. Patients in gastroenterology clinics were asked to install the MyGut app and were followed for 1 year. Initially, all 84 patients were willing to use the application. After 1 year, the patients had significant improvements in their quality of life and symptom control. However, less than half of the patients were willing to continue using the application after the study. Although these applications can help our patients, we need to find more ways to encourage their long-term use.

Pompe disease, a rare genetic neuromuscular disorder, is caused by a deficiency of acid alpha-glucosidase (GAA), leading to an accumulation of glycogen in lysosomes, and resulting in the progressive development of muscle weakness. The current standard treatment, enzyme replacement therapy (ERT), is not curative and has limitations such as poor penetration into skeletal muscle and both the central and peripheral nervous systems, a risk of immune responses against the recombinant enzyme, and the requirement for high doses and frequent infusions. To overcome these limitations, lentiviral vector-mediated hematopoietic stem and progenitor cell (HSPC) gene therapy has been proposed as a next-generation approach for treating Pompe disease. This study demonstrates the potential of lentiviral HSPC gene therapy to reverse the pathological effects of Pompe disease in a preclinical mouse model. It includes a comprehensive safety assessment via integration site analysis, along with single-cell RNA sequencing analysis of central nervous tissue samples to gain insights into the underlying mechanisms of phenotype correction.

The aim of this study was to describe real-world use of immune checkpoint inhibitors for women with advanced or recurrent endometrial cancer.

IMPORTANCE: With a recent surge in anti–lesbian, gay, bisexual, transgender, or queer (LGBTQ+) policies and associated news and media coverage, there is a need to study the association of LGBTQ+ focused news or media exposure and short-term changes in suicidal ideation (SI) among LGBTQ+ youth. OBJECTIVE: To examine within-person direct and indirect associations between exposure to general and LGBTQ+ negative news or media and SI intensity through expectations of rejection. DESIGN, SETTING, AND PARTICIPANTS: This intensive longitudinal cohort study used a smartphone-based ecological momentary assessment (EMA) protocol wherein participants responded to EMAs 3 times per day for 28 consecutive days. Young adults aged 18 to 24 years who self-identified as LGBTQ+, resided in Tennessee, and had past-year SI and at least mild depression (defined as a score ≥5 on the Patient Health Questionnaire-9) were eligible for inclusion. Participants were recruited through social media advertisements, LGBTQ+ community organizations, and mental and behavioral health clinics. Participants were recruited between March 30, 2023, and August 23, 2023, and data analyses were conducted from August 28, 2023, through April 20, 2024. EXPOSURES: At each EMA, participants reported on recent exposure to negative news or media. A 3-level categorical exposure variable denoted (1) no news or media exposure (reference); (2) exposure to general negative news or media; and (3) exposure to LGBTQ+ negative news or media. Each EMA also assessed expectations of rejection due to LGBTQ+ identity on a scale of 0 (not at all) through 10 (very much). MAIN OUTCOMES AND MEASURES: Three primary outcomes assessed current (ie, “right now”) intensity of active SI, passive SI, and self-harm ideation, each measured on a scale from 0 (not at all) to 10 (very strong). Multilevel modeling approaches were used to account for the hierarchical structure of EMA data, with assessments (level 1) nested within people (level 2). Linear mixed models and multilevel mediation models were used to examine within-person associations between exposure to negative news or media and the 3 primary outcomes, as well as the mediating role of expectations of rejection. RESULTS: Of 31 total participants, 22 were assigned female sex at birth (71%), and 16 (52%) self-identified as transgender or gender diverse. The median (IQR) participant age was 21 (18-22) years, and a total of 2189 EMAs were completed, with a median (range) compliance of 90.5% (41.7%-100%). At the within-person level, recent exposure to LGBTQ+ negative news or media was significantly associated with increased active SI (estimate [b], 0.14; 95% CI, 0.04-0.25; P = .009), passive SI (b, 0.23; 95% CI, 0.04-0.41; P = .02), and self-harm ideation (b, 0.13; 95% CI, 0.02-0.23; P = .02). No statistically significant associations were detected for exposure to general negative news or media. In multilevel mediation models, heightened expectations of rejection explained some of the total effect of exposure to LGBTQ+ negative news or media on active SI (23%) and passive SI (37%). CONCLUSIONS AND RELEVANCE: This intensive longitudinal cohort study found that SI intensity modestly increased in the hours immediately following exposure to LGBTQ+ negative news or media among LGBTQ+ young adults. These findings have timely implications for research and intervention, particularly within sociopolitical and geographic contexts where news or media coverage about LGBTQ+ topics is intensified.

Study Design Comparative study.Objectives This study aims to compare Google and GPT-4 in terms of (1) question types, (2) response readability, (3) source quality, and (4) numerical response accuracy for the top 10 most frequently asked questions (FAQs) about anterior cervical discectomy and fusion (ACDF).Methods “Anterior cervical discectomy and fusion” was searched on Google and GPT-4 on December 18, 2023. Top 10 FAQs were classified according to the Rothwell system. Source quality was evaluated using JAMAbenchmark criteria and readability was assessed using Flesch Reading Ease and Flesch-Kincaid grade level. Differences in JAMAscores, Flesch-Kincaid grade level, Flesch Reading Ease, and word count between platforms were analyzed using Student’s t-tests. Statistical significance was set at the .05 level.Results Frequently asked questions from Google were varied, while GPT-4 focused on technical details and indications/management. GPT-4 showed a higher Flesch-Kincaid grade level (12.96 vs 9.28, P= .003), lower Flesch Reading Ease score (37.07 vs 54.85, P= .005), and higher JAMAscores for source quality (3.333 vs 1.800, P= .016). Numerically, 6 out of 10 responses varied between platforms, with GPT-4 providing broader recovery timelines for ACDF.Conclusions This study demonstrates GPT-4’s ability to elevate patient education by providing high-quality, diverse information tailored to those with advanced literacy levels. As AI technology evolves, refining these tools for accuracy and user-friendliness remains crucial, catering to patients’ varying literacy levels and information needs in spine surgery.

Idiopathic edema (IE) is a disease that occurs predominantly in women. It is characterized by increasing weight gain of >1.4 kg from morning to night, increasing edema, increasing truncal and abdominal girth with bloating when assuming an upright position and nocturia that is unrelated to menses. There is an increase in morbidity but not mortality. Increased capillary membrane leakage appears to be the underlying pathophysiologic abnormality that explains the myriad of clinical presentations. We present 2 cases of life-threatening complications of IE that resulted in seizures related to acute hyponatremia in one and extreme postural dizziness and fainting induced by postural hypotension in the other. The first patient was successfully treated with salt restriction, timely use of furosemide and limitation of water intake; the other was successfully treated by use of support hose. Treatment of these patients required a fundamental understanding of the intricate pathophysiological consequences of a leaky capillary membrane, an understanding of Starling forces and detailing the effectiveness of a low salt diet, use of diuretics and limited water intake in one and why support hose would be beneficial in the other patient. Both patients experienced significant physical and emotional benefits that substantially improved quality of life.

Objectives: Military training centers and seagoing vessels are often environments at high risk for the spread of COVID-19 and other contagious diseases, because military trainees and personnel arrive after traveling from many parts of the country and live in congregate settings. We examined whether levels of SARS-CoV-2 genetic material in wastewater correlated with SARS-CoV-2 infections among military personnel living in communal barracks and vessels at US Coast Guard training centers in the United States.Methods: The Coast Guard developed and established 3 laboratories with wastewater testing capability at Coast Guard training centers from March 2021 through August 2022. We analyzed wastewater from barracks housing trainees and from 4 Coast Guard vessels for the presence of SARS-CoV-2 genes Nand Eand quantified the results relative to levels of a fecal indicator virus, pepper mild mottle virus. We compared quantified data with the timing of medically diagnosed COVID-19 infection among (1) military personnel who had presented with symptoms or had been discovered through contact tracing and had medical tests and (2) military personnel who had been discovered through routine surveillance by positive SARS-CoV-2 antigen or polymerase chain reaction test results.Results: Levels of viral genes in wastewater at Coast Guard locations were best correlated with diagnosed COVID-19 cases when wastewater testing was performed twice weekly with passive samplers deployed for the entire week; such testing detected ≥1 COVID-19 case 69.8% of the time and ≥3 cases 88.3% of the time. Wastewater assessment in vessels did not continue because of logistical constraints.Conclusion: Wastewater testing is an effective tool for measuring the presence and patterns of SARS-CoV-2 infections among military populations. Success with wastewater testing for SARS-CoV-2 infections suggests that other diseases may be assessed with similar approaches.

•Deletion of the α-globin genes induces a lethal phenotype associated with high levels of red blood cells in circulation.•Transduction with a lentiviral vector expressing the human α-globin gene prevents mice from developing the lethal phenotype.

Autophagy is an essential self-degradative and recycling mechanism that maintains cellular homeostasis. Estrogen receptor-related orphan receptors (ERRs) are fundamental in regulating cardiac metabolism and function. Previously, we showed that ERR agonists improve cardiac function in models of heart failure and induce autophagy. Here, we characterized a mechanism by which ERRs induce the autophagy pathway in cardiomyocytes. Transcription factor EB (TFEB) is a master regulator of the autophagy-lysosome pathway and has been shown to be crucial regulator of genes that control autophagy. We discovered that TFEB is a direct ERR target gene whose expression is induced by ERR agonists. Activation of ERR results in increased TFEB expression in both neonatal rat ventricular myocytes and C2C12myoblasts. An ERR-dependent increase in TFEB expression results in increased expression of an array of TFEB target genes, which are critical for the stimulation of autophagy. Pharmacologically targeting ERR is a promising potential method for the treatment of many diseases where stimulation of autophagy may be therapeutic, including heart failure.

Delivery of bicarbonate during hemodialysis (HD) is aimed at correcting metabolic acidosis in end-stage renal disease patients. We tested modified prescriptions of bicarbonate concentration in dialysis fluid (CD,bic), aimed to achieve an optimal pre-dialytic bicarbonate plasma concentration (CP,bic).

ABSTRACTThis essay draws on Henry (Hank) Greenspan’s insights about recountingand retellingin the ways that Holocaust survivors testify and bear witness in narrating their experiences. Sometimes taking place from afar and in silence, my interaction with friends such as Hank Greenspan and with the voices of survivors such as Primo Levi and Elie Wiesel compels me to recount and retell that absent the overriding of moral sensibilities, if not the collapse or collaboration of ethical traditions, the Holocaust, genocide, and other mass atrocities could not take place.

Introduction: The hydrogen ion (H+) mobilization model has been previously shown to provide a quantitative description of intradialytic changes in blood bicarbonate (HCO3) concentration during hemodialysis (HD). The current study evaluated the accuracy of different methods for estimating the H+mobilization parameter (Hm) from this model.Methods: The study compared estimates of the H+mobilization parameter using predialysis, hourly during the HD treatment, and postdialysis blood HCO3concentrations (Hm-full2) with those determined using only predialysis and postdialysis blood HCO3concentrations assuming steady state conditions (Hm-SS2) during the midweek treatment in 24 chronic HD patients treated thrice weekly.Results: Estimated Hm-full2 values (0.163 ± 0.079 L/min [mean ± standard deviation]) were higher than, but not statistically different (p= 0.067) from, those of Hm-SS2 (0.152 ± 0.065 L/min); the values of Hm-full2 and Hm-SS2 were highly correlated with a correlation coefficient of 0.948 and a mean difference that was small (0.011 L/min). Further, the H+mobilization parameter values calculated using only predialysis and postdialysis blood HCO3concentrations during the first and third HD treatments of the week were not different from those calculated during the midweek treatment.Conclusions: The H+mobilization model can be used to provide estimates of the H+mobilization parameter without the need to measure hourly intradialytic blood HCO3concentrations.

Deviant and criminal behavior in sport remains a significant problem because it threatens the rules, norms and culture that value fairness. The use of performance-enhancing substances (PED), also known as “doping”, is generally prohibited in sanctioned sports because they violate this philosophy. While previous research has documented the crucial role that coaches occupy in player’s deviancy, there is a lack of theoretical perspectives used to assess the relationship between coaches and athletes in decisions to engage in doping. The present study examines a sample of Iranian sports coaches (n= 374) using situational action theory and regression models. The results indicate that deviant coaching is a form of moral action that involves an interaction between characteristics of the coach.

Background The World Database for Pediatric and Congenital Heart Surgery (WDPCHS), sponsored by the World Society for Pediatric and Congenital Heart Surgery (WSPCHS), provides complex congenital heart surgery outcomes analyses for member programs. This report represents the seven-year descriptive analysis of outcomes from active members of the WDPCHS.Methods Individual institutions submit data based on the specific procedure via a password protected platform. The data are collected, stored, and analyzed at Kirklin Solutions Inc., based in Birmingham, Alabama. This report presents a descriptive analysis of these procedures submitted from January 1, 2017, to December 31, 2023.Results A total of 50,174 procedures were submitted with an overall mortality of 4.6%. The majority of submissions were from Asian countries. The majority of cases submitted from these countries were of STAT mortality category I and II. Repair of a ventricular septal defect (with a mortality of 0.8%) and correction of tetralogy of Fallot (2.0% mortality) were the most common procedures submitted to the database.Conclusions The WSPCHS accomplished one of its missions in 2017 when the WDPCHS began accepting data from pediatric and congenital heart surgery programs across the globe. In doing so, it became one of the first organizations to create a platform for the exchange of knowledge and experience, regardless of the socioeconomic status of the particular program or country.

Background Enhanced Recovery After Surgery (ERAS) programs have spread after initial success in colorectal surgery decreasing length of stay (LOS) and decreasing opioid consumption. Adoption of ERAS specifically for ventral hernia patients remains in evolution. This study presents the development and implementation of an ERAS pathway for ventral hernia.Methods A multidisciplinary team met weekly over 6 months to develop an ERAS pathway specific to ventral hernia patients. 75 process components and outcome measures were included, spanning multiple phases of care: Preoperative-Clinic, Preoperative Day of Surgery (DOS), Intraoperative, and Postoperative. Preoperative components included education and physiologic optimization. Pain control across phases of care focuses on nonopioid, multimodal analgesia. Postoperatively, the pathway emphasizes early diet advancement, early mobilization, and minimization of IV fluids. We compared compliance and outcome measures between a Pre Go-Live (PGL) period (9/1/2020-8/30/2021) and After Go-live (AGL) period (5/12/2022-5/19/2023).Results There were 125 patients in the PGL group and 169 patients in the AGL group. Overall, ERAS compliance increased from 73.9% to 82.9% after implementation. Length of stay decreased from an average of 2.27 days PGL to 1.92 days AGL. Finally, the average daily postoperative opioid usage decreased from 25.4 to 13.5 MME after the implementation.Discussion Enhanced Recovery After Surgery can be successfully applied to the care of hernia patients with improvements in LOS and decreased opioid consumption. Institutional support and multidisciplinary cooperation were key for the development of such a program.

Vedolizumab is a treatment for two kinds of digestive problems: Crohn’s disease and ulcerative colitis. Scientists wanted to know if the amount of vedolizumab in people’s blood was linked to proteins found in people’s blood and stool. Reduced amounts of these proteins can show if the treatment is working.They studied 436 people who were taking vedolizumab between 2018 and 2020. For people with Crohn’s disease, researchers saw that more vedolizumab in the blood after 6 weeks and 14 weeks of treatment, was linked to lower amounts of one type of protein. They used a lab test to figure this out. However, when they tested a different protein, having more vedolizumab in the blood wasn’t linked to lower amounts. The same kind of results were found for people with ulcerative colitis.The study tells us that the amount of vedolizumab in the blood might not always be linked to proteins that can tell us if treatment is working. This means that it might not be helpful for doctors to do these tests regularly when treating people with digestive problems using vedolizumab.