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Introduction There are no established methods to identify children with atypical diabetes for further study. We aimed to develop strategies to systematically ascertain cases of atypical pediatric diabetes using electronic medical records (EMR).Research design and methods We tested two strategies in a large pediatric hospital in the USA. Strategy 1: we designed a questionnaire to rule out typical diabetes and applied it to the EMR of 100 youth with diabetes. Strategy 2: we built three electronic queries to generate reports of three atypical pediatric diabetes phenotypes: unknown type, type 2 diabetes (T2D) diagnosed

Abstract Introduction Recurrent Clostridioides difficile infection (rCDI) often occurs after standard-of-care antibiotics. VOWST oral spores (VOS, previously SER-109), an FDA-approved orally administered microbiome therapeutic, is indicated to prevent rCDI following antibiotics for rCDI. Objective, Design, and Patients To evaluate safety and efficacy of VOS from two phase 3 trials, (randomized, placebo-controlled [ECOSPOR III: NCT03183128] and open-label, single arm [ECOSPOR IV: NCT03183141]) of 349 adults with rCDI and prevalent comorbidities. Methods VOS or placebo [ECOSPOR III only] (4 capsules once daily for 3 days). Integrated analysis of treatment-emergent adverse events (TEAEs) collected through week 8; serious TEAEs and TEAEs of special interest collected through week 24; and rates of rCDI (toxin-positive diarrhea requiring treatment) evaluated through weeks 8 and 24. Results TEAEs were mostly mild or moderate and gastrointestinal. Most common treatment-related TEAEs were flatulence, abdominal pain and distension, fatigue, and diarrhea. There were 11 deaths (3.2%) and 48 patients (13.8%) with serious TEAEs, none treatment-related. The rCDI rate through week 8 was 9.5% (95% CI 6.6–13.0) and remained low through 24 weeks (15.2%; 95% CI 11.6–19.4). Safety and rCDI rates were consistent across subgroups including age, renal impairment/failure, diabetes, and immunocompromise/immunosuppression. Conclusions VOS was well tolerated and rates of rCDI remained low through week 24 including in those with comorbidities. These data support the potential benefit of VOS following antibiotics to prevent recurrence in high-risk patients. Trial Registration ClinicalTrials.gov identifier, NCT03183128 and NCT03183141.

BackgroundDue to recent advances in artificial intelligence, large language models (LLMs) have emerged as a powerful tool for a variety of language-related tasks, including sentiment analysis, and summarization of provider-patient interactions. However, there is limited research on these models in the area of crisis prediction. ObjectiveThis study aimed to evaluate the performance of LLMs, specifically OpenAI’s generative pretrained transformer 4 (GPT-4), in predicting current and future mental health crisis episodes using patient-provided information at intake among users of a national telemental health platform. MethodsDeidentified patient-provided data were pulled from specific intake questions of the Brightside telehealth platform, including the chief complaint, for 140 patients who indicated suicidal ideation (SI), and another 120 patients who later indicated SI with a plan during the course of treatment. Similar data were pulled for 200 randomly selected patients, treated during the same time period, who never endorsed SI. In total, 6 senior Brightside clinicians (3 psychologists and 3 psychiatrists) were shown patients’ self-reported chief complaint and self-reported suicide attempt history but were blinded to the future course of treatment and other reported symptoms, including SI. They were asked a simple yes or no question regarding their prediction of endorsement of SI with plan, along with their confidence level about the prediction. GPT-4 was provided with similar information and asked to answer the same questions, enabling us to directly compare the performance of artificial intelligence and clinicians. ResultsOverall, the clinicians’ average precision (0.7) was higher than that of GPT-4 (0.6) in identifying the SI with plan at intake (n=140) versus no SI (n=200) when using the chief complaint alone, while sensitivity was higher for the GPT-4 (0.62) than the clinicians’ average (0.53). The addition of suicide attempt history increased the clinicians’ average sensitivity (0.59) and precision (0.77) while increasing the GPT-4 sensitivity (0.59) but decreasing the GPT-4 precision (0.54). Performance decreased comparatively when predicting future SI with plan (n=120) versus no SI (n=200) with a chief complaint only for the clinicians (average sensitivity=0.4; average precision=0.59) and the GPT-4 (sensitivity=0.46; precision=0.48). The addition of suicide attempt history increased performance comparatively for the clinicians (average sensitivity=0.46; average precision=0.69) and the GPT-4 (sensitivity=0.74; precision=0.48). ConclusionsGPT-4, with a simple prompt design, produced results on some metrics that approached those of a trained clinician. Additional work must be done before such a model can be piloted in a clinical setting. The model should undergo safety checks for bias, given evidence that LLMs can perpetuate the biases of the underlying data on which they are trained. We believe that LLMs hold promise for augmenting the identification of higher-risk patients at intake and potentially delivering more timely care to patients.

This paper explores the phenomenon of lapsing among young Japanese Catholics, highlighting how both local and translocal experiences of Roman Catholicism shape the ebbs and flows of faith for our interlocutors. While global Catholic events such as World Youth Day can reignite faith by fostering a sense of belonging to a larger, global Church, the contrast with the small and socially isolated Catholic community in Japan often precipitates lapsing. This study examines the influence of the New Evangelisation, which promotes active belief and translocal unity, and argues that this movement can both strengthen global Catholic identity and exacerbate feelings of alienation in local, non-Catholic societies. Ultimately, we stress, in the context of Roman Catholicism, that lapsing should not be seen as simply a rupture in faith but as part of a continuous, if turbulent, Catholic identity, mediated by translocal flows of belief and institutional authority.

IntroductionWomen living with human immunodeficiency virus (WLHIV) face elevated risks of human papillomavirus (HPV) acquisition and cervical cancer (CC). Coverage of CC screening and treatment remains low in low-and-middle-income settings, reflecting resource challenges and loss to follow-up with current strategies. We estimated the health and economic impact of alternative scalable CC screening strategies in KwaZulu-Natal, South Africa, a region with high burden of CC and HIV.MethodsWe parameterized a dynamic compartmental model of HPV and HIV transmission and CC natural history to KwaZulu-Natal. Over 100 years, we simulated the status quo of a multi-visit screening and treatment strategy with cytology and colposcopy triage (South African standard of care) and six single-visit comparator scenarios with varying: 1) screening strategy (HPV DNA testing alone, with genotyping, or with automated visual evaluation triage, a new high-performance technology), 2) screening frequency (once-per-lifetime for all women, or repeated every 5 years for WLHIV and twice for women without HIV), and 3) loss to follow-up for treatment. Using the Ministry of Health perspective, we estimated costs associated with HPV vaccination, screening, and pre-cancer, CC, and HIV treatment. We quantified CC cases, deaths, and disability-adjusted life-years (DALYs) averted for each scenario. We discounted costs (2022 US dollars) and outcomes at 3% annually and calculated incremental cost-effectiveness ratios (ICERs).ResultsWe projected 69,294 new CC cases and 43,950 CC-related deaths in the status quo scenario. HPV DNA testing achieved the greatest improvement in health outcomes, averting 9.4% of cases and 9.0% of deaths with one-time screening and 37.1% and 35.1%, respectively, with repeat screening. Compared to the cost of the status quo ($12.79 billion), repeat screening using HPV DNA genotyping had the greatest increase in costs. Repeat screening with HPV DNA testing was the most effective strategy below the willingness to pay threshold (ICER: $3,194/DALY averted). One-time screening with HPV DNA testing was also an efficient strategy (ICER: $1,398/DALY averted).ConclusionsRepeat single-visit screening with HPV DNA testing was the optimal strategy simulated. Single-visit strategies with increased frequency for WLHIV may be cost-effective in KwaZulu-Natal and similar settings with high HIV and HPV prevalence.

Health equity is defined as ?the state in which everyone has a fair and just opportunity to attain their highest level of health.?1 While national efforts around health equity have intensified due to significant health disparities highlighted by the COVID-19 pandemic, more work remains to address health disparities and advance health equity for all. As a part of these efforts, in 2019 Food and Drug Administration (FDA)'s Office of Minority Health was renamed as the Office of Minority Health and Health Equity (OMHHE) to highlight the scope of the work the office has historically performed2 and that we will continue to advance. Since its inception in 2010, the office has provided leadership and policy direction for the Agency on issues related to the health of racial and ethnic minority populations. These efforts include advancing diverse participation in clinical trials through education, developing an online catalogue of resources (such as brochures, infographics, videos, and fact sheets) in multiple languages about various diseases and conditions to strengthen consumer decision-making regarding FDA regulated products, and fostering collaborations internally across the FDA, as well as externally with academia, nonprofit organizations, regulated industry, and patients. OMHHE's longstanding and continuous work on these issues is a priority and is intrinsic to the work we do across the Agency. A crucial element of a forward-facing health equity approach is one that focuses on increasing public trust, engagement, collaboration, and transparency to address the gaps and needs of diverse communities and amplifying diverse voices and perspectives. This article describes the most recent efforts of the FDA's OMHHE in specific areas pertinent to our dedicated mission of promoting and protecting the health of diverse populations through research and communication of science that addresses health disparities and advances health equity. OMHHE's Research Program is designed to enhance the knowledge needed to advance health equity by supporting intramural and extramural research aimed at understanding and reducing health disparities. Over the past few years, we have worked to create several new research initiatives focused on health equity. For example, in 2021, we developed the Enhance Equity Initiative,3 which aims to advance equity in clinical trials, equitable data efforts, and equity of voices to address the increasing complexity of health disparities and the need to protect those most at risk, including across racial, ethnic, and rural/urban lines. Through this initiative, we were able to provide multiple funding opportunities that have allowed us to engage with diverse researchers and scientists across various organizations and academic institutions. The Initiative has three key aims, enhancing: Equity in clinical trials by continuing our efforts to advance diversity in clinical trials, Equitable data efforts by funding research that helps us increase data available on diverse populations, and finally Equity of voices which focuses on continuing to understand diverse patient perspectives, preferences and unmet needs, and support expansion of culturally and linguistically tailored health education. Through the Enhance Equity Initiative, we awarded more than $20 million in funding to support over 40 research projects to advance health equity. These projects include, among others, topics ranging from tailoring clinical trial communication strategies for diverse populations to leveraging real world data to increase data available on diverse populations (e.g., epidemiological studies). The OMHHE Research Hub,4 launched in 2023, enables the public to search OMHHE-funded research by study population or by the Enhance Equity Initiative aim (e.g., equity in clinical trials, equitable data efforts, and equity of voices). We also have continued to develop national education campaigns to raise awareness on important issues impacting diverse communities. In support of FDA's efforts in educating the public on the potential risks of certain products, in 2022, we launched Skin Facts!5?a public health education campaign to warn consumers about the potential dangers of using over-the-counter skin lightening products that contain hydroquinone or mercury and are often marketed to racial and ethnic minority communities. Effective coordination of collaborative relationships is vital to advancing health equity. In 2023, OMHHE launched its newest initiative, the Racial and Ethnic Minority Acceleration Consortium for Health Equity.6 REACH is a research consortium of organizations and institutions serving racial and ethnic minority, tribal, and rural populations, which aim to timely and efficiently help respond to OMHHE's health equity-focused research needs. As we continue to look forward and find new ways to advance health equity, we have also embraced our responsibility to expand the pipeline for future scientists and researchers and to help train the next generation of public health professionals and scientists to make sure they are equipped with the knowledge and tools needed to answer critical health equity questions through internships and fellowships. For example, in 2020, we offered a joint postdoctoral fellowship in genomic science and health equity in partnership with the National Human Genome Research Institute at NIH. This 3-year fellowship program is designed to prepare fellows to use genetic, genomic, and pharmacogenomic approaches to advance minority health and health equity.7 The current Genomic Science and Health Equity Postdoctoral Fellow is conducting research on sickle cell disease, a condition that primarily impacts Black and African American populations. The increased visibility, attention, and momentum toward advancing health equity should also be a reminder of the work that needs to be done, particularly in developing long-term sustainable solutions to solve the issues. Stakeholders and partners in the national health ecosystem can leverage the models, communication, and educational materials developed by OMHHE in their own pursuit of achieving this important goal. We all have a role in improving the nation's health, and FDA's OMHHE will continue our work to advance health equity for all.

Objective: We aimed to evaluate the safety and efficacy of delaying lung transplantation until morning for donors with cross-clamp times occurring after 1:30 am. Methods: All consented adult lung transplant recipients between March 2018 and May 2022 with donor cross-clamp times between 1:30 am and 5 am were enrolled prospectively in this study. Skin incision for enrolled recipients was delayed until 6:30 am (Night group). The control group was identified using a 1:2 logistic propensity score method and included recipients of donors with cross-clamp times occurring at any other time of day (Day group). Short- and medium-term outcomes were examined between groups. The primary endpoint was early mortality (30-day and in-hospital). Results: Thirty-four patients were enrolled in the Night group, along with 68 well-matched patients in the Day group. As expected, donors in the Night group had longer cold ischemia times compared to the Day group (344 minutes vs 285 minutes; P

Abstract Mustn1, a gene expressed exclusively in the musculoskeletal system, was shown in previous in vitro studies to be a key regulator of myogenic differentiation and myofusion. Other studies also showed Mustn1 expression associated with skeletal muscle development and hypertrophy. However, its specific role in skeletal muscle function remains unclear. This study sought to investigate the effects of Mustn1 in a conditional knockout (KO) mouse model in Pax7 positive skeletal muscle satellite cells. Specifically, we investigated the potential effects of Mustn1 on myogenic gene expression, grip strength, alterations in gait, ex vivo investigations of isolated skeletal muscle isometric contractions, and potential changes in the composition of muscle fiber types. Results indicate that Mustn1 KO mice did not present any substantial phenotypic changes or significant variations in genes related to myogenic differentiation and fusion. However, an approximately 10% decrease in overall grip strength was observed in the 2‐month‐old KO mice in comparison to the control wild type (WT), but this decrease was not significant when normalized by weight. KO mice also generated approximately 8% higher vertical force than WT at 4 months in the hindlimb. Ex vivo experiments revealed decreases in about 20 to 50% in skeletal muscle contractions and about 10%–20% fatigue in soleus of both 2‐ and 4‐month‐old KO mice, respectively. Lastly, immunofluorescent analyses showed a persistent increase of Type IIb fibers up to 15‐fold in the KO mice while Type I fibers decreased about 20% and 30% at both 2 and 4 months, respectively. These findings suggest a potential adaptive or compensatory mechanism following Mustn1 loss, as well as hinting at an association between Mustn1 and muscle fiber typing. Collectively, Mustn1's complex roles in skeletal muscle physiology requires further research, particularly in terms of understanding the potential role of Mustn1 in muscle repair and regeneration, as well as with influence of exercise. Collectively, these will offer valuable insights into Mustn1's key biological functions and regulatory pathways.

Abstract Drug development teams must evaluate the risk/benefit profile of new drug candidates that perpetrate drug–drug interactions (DDIs). Real‐world data (RWD) can inform this decision. The purpose of this study was to develop a predicted impact score for DDIs perpetrated by three hypothetical drug candidates via CYP3A, CYP2D6, or CYP2C9 in type 2 diabetes mellitus (T2DM), obesity, or migraine. Optum Market Clarity was analyzed to estimate use of CYP3A, CYP2D6, or CYP2C9 substrates classified in the University of Washington Drug Interaction Database as moderate sensitive, sensitive, narrow therapeutic index, or QT prolongation. Scoring was based on prevalence of exposure to victim substrates and characteristics (age, polypharmacy, duration of exposure, and number of prescribers) of those exposed. The study population of 14,163,271 adults included 1,579,054 with T2DM, 3,117,753 with obesity, and 410,436 with migraine. For T2DM, 71.3% used CYP3A substrates, 44.3% used CYP2D6 substrates, and 44.3% used CYP2C9 substrates. For obesity, 57.1% used CYP3A substrates, 34.6% used CYP2D6 substrates, and 31.0% used CYP2C9 substrates. For migraine, 64.1% used CYP3A substrates, 44.0% used CYP2D6 substrates, and 28.9% used CYP2C9 substrates. In our analyses, the predicted DDI impact scores were highest for DDIs involving CYP3A, followed by CYP2D6, and CYP2C9 substrates, and highest for T2DM, followed by migraine, and obesity. Insights from RWD can be used to estimate a predicted DDI impact score for pharmacokinetic DDIs perpetrated by new drug candidates currently in development. This score can inform the risk/benefit profile of new drug candidates in a target patient population.

Key Clinical Message Gastric outlet obstruction can be a dangerous complication of intragastric balloons, as it can result in severe metabolic alkalosis. As weight loss procedures and medical tourism become more popular, physicians should have a high index of suspicion for complications of invasive procedures, particularly in returning travelers. Abstract Intragastric balloons for weight loss have decreased in frequency in the United States. However, they are still frequent in low‐ and middle‐income countries. Severe complications occur in less than 3% of patients who undergo this procedure. Herein, we present a case of gastric outlet obstruction, severe metabolic alkalosis, and refeeding syndrome in a patient returning from the Dominican Republic. She presented with 2 weeks of emesis and obstipation, followed by a pre‐syncope and altered mental status. An intragastric mass was observed on computerized tomography, which was characterized as an intragastric balloon and retrieved endoscopically. All metabolic derangements were corrected, and the patient improved without sequelae. As weight loss procedures and medical tourism become more popular, physicians should have a high index of suspicion for complications of invasive procedures, particularly in returning travelers.

Idiopathic granulomatous mastitis (IGM) is a rare, benign inflammatory disorder of the breast that is often underrecognized. The exact etiology and pathophysiology are unknown, but milk stasis is felt to play a role. Classically, this condition is noninfectious, but many cases are noted to be associated with Corynebacterium species. Most patients affected are parous women with a mean age of 35, and many have breastfed within five years of diagnosis. Patients typically present with a painful mass and symptoms of inflammation, and these features can sometimes mimic breast cancer. Biopsy is needed to make a definitive diagnosis, and noncaseating granulomas are found on core biopsy. Many patients have a waxing and waning course over a period of six months to two years. Goal of treatment is to avoid surgery given poor wound healing, high risk of recurrence, and poor cosmetic outcomes. Medical treatment is preferred and includes observation, antibiotics, steroids, and immune modulators such as methotrexate. In more recent years, topical and intralesional steroids have become the treatment of choice, with similar outcomes to oral steroids.

Abstract Introduction Effective treatments for recurrent Clostridioides difficile infection (rCDI) are urgently needed. RBX2660 is an investigational microbiota-based live biotherapeutic to reduce CDI recurrence following standard-of-care antibiotic treatment in individuals with rCDI. Here we report the final safety data through 24 months of follow-up as well as final efficacy data, reflecting alignment of the pre-specified statistical analysis plan definitions with the data presented. Methods The PUNCH CD2 clinical trial was a prospective, multicenter, randomized, double-blinded, placebo-controlled, three-arm phase 2b study conducted to evaluate the efficacy and safety of RBX2660 for the reduction of rCDI compared to placebo. Eligible patients were at least 18 years of age and had at least three episodes of CDI and at least two rounds of standard antibiotic treatment or had at least two episodes of severe CDI resulting in hospitalization. Patients were randomized 1:1:1 to group A, two doses of RBX2660; group B, two doses of placebo; or group C, one dose of RBX2660 and one dose of placebo; all administered 7 ± 2 days apart. Treatment success was prevention of recurrence, defined as absence of diarrhea and no re-treatment for CDI any time after the first dose until 8 weeks after the second dose of the study treatment. Safety was assessed by reports of adverse events and symptoms. The final efficacy and safety are reported for data available through 24 months. Results For the primary endpoint, treatment success at 8 weeks, 56.8% (25/45) of participants who received one dose of RBX2660 + one dose of placebo, 55.6% (25/45) of participants who received two doses of RBX2660, and 43.2% (19/44) of participants who received two doses of placebo in the final intention-to-treat (ITT) population were responders (both p = 0.2 vs placebo). In the per-protocol population, 87.5% (21/24) of participants who received one dose of RBX2660 + one dose of placebo and 58.1% (18/31) of those who received two doses of placebo had treatment success (p = 0.017; treatment difference, 29.4 [95% CI 7.6, 51.3]); 75.0% (21/28) of participants in the PP population who received two doses of RBX2660 were responders (p = 0.17 vs placebo). The safety profile of RBX2660, whether delivered as one or two doses, was similar to the placebo group. Conclusion While the phase 2b PUNCH CD2 clinical trial did not meet its pre-defined primary endpoint of treatment success at 8 weeks after two doses of RBX2660 vs two doses of placebo, clinically meaningful data were obtained to justify proceeding with the single dose regimen in the phase 3 clinical trial, PUNCH CD3, now complete. To date, the cumulative data for RBX2660 demonstrate consistent efficacy and safety outcomes for reduction of CDI recurrence in adults. Clinical Trial Registration ClinicalTrials.gov: NCT02299570. Infographic Digital Features This article includes an infographic. To view digital features for this article go to https://doi.org/10.6084/m9.figshare.22100540 .

Abstract Basal‐like breast cancer (BLBC) has a greater overlap in molecular features with high‐grade serous ovarian cancer (HGSOC) than with other breast cancer subtypes. Similarities include BRCA1 mutation, high frequency of TP53 mutation, and amplification of CCNE1 (encoding the cyclin E1 protein) in 6–34% of cases, and these features can be used to group patients for targeted therapies in clinical trials. In HGSOC, we previously reported two subsets with high levels of cyclin E1: those in which CCNE1 is amplified, have intact homologous recombination (HR), and very poor prognosis; and a CCNE1 non‐amplified subset, with more prevalent HR defects. Here, we investigate whether similar subsets are identifiable in BLBC that may allow alignment of patient grouping in clinical trials of agents targeting cyclin E1 overexpression. We examined cyclin E1 protein and CCNE1 amplification in a cohort of 76 BLBCs and validated the findings in additional breast cancer datasets. Compared to HGSOC, CCNE1 amplified BLBC had a lower level of amplification (3.5 versus 5.2 copies) and lower relative cyclin E1 protein, a lack of correlation of amplification with expression, and no association with polyploidy. BLBC with elevated cyclin E1 protein also had prevalent HR defects, and high‐level expression of the cyclin E1 deubiquitinase ubiquitin‐specific protease 28 (USP28). Using a meta‐analysis across multiple studies, we determined that cyclin E1 protein overexpression but not amplification is prognostic in BLBC, while both cyclin E1 overexpression and amplification are prognostic in HGSOC. Overall CCNE1 gene amplification is not equivalent between BLBC and HGSOC. However, high cyclin E1 protein expression can co‐occur with HR defects in both BLBC and HGSOC, and is associated with poor prognosis in BLBC.

Background: Antibiotics alone are often insufficient to treat recurrent C. difficile infection (rCDI) because they have no activity against C. difficile spores that germinate within a disrupted microbiome. SER-109, an investigational, oral, microbiome therapeutic comprised of purified Firmicutes spores, was designed to reduce rCDI through microbiome repair. We report an integrated efficacy analysis through week 24 for SER-109 from phase 3 studies, ECOSPOR III and ECOSPOR IV. Methods: ECOSPOR III was a randomized, placebo-controlled phase 3 trial conducted at 56 US or Canadian sites that included 182 participants with ≥2 CDI recurrences, confirmed via toxin EIA testing. Participants were stratified by age (

Key Clinical Message Cat‐scratch disease (CSD) is caused by Bartonella henselae and usually presents with regional lymphadenopathy. Skull base osteomyelitis and cerebral venous sinus thrombosis are rarely reported, particularly in immunocompetent children. CSD should be considered in the differential diagnosis of any patient with persistent headaches in the setting of cat exposure.

Background: Microbiota-based treatments reduce the incidence of recurrent Clostridioides difficile infections (rCDIs), but prospectively collected safety data needed to broaden patient access and protect public health have been limited. Objectives: We provide cumulative safety data from five prospective clinical trials evaluating fecal microbiota, live-jslm (RBL) – the first microbiota-based live biotherapeutic product approved by the US Food and Drug Administration – for preventing rCDI in adults. Design: Integrated safety analysis includes three phase II trials (PUNCH CD, PUNCH CD2, PUNCH Open-Label) and two phase III trials (PUNCH CD3, PUNCH CD3-OLS) of RBL. Methods: Trial participants were at least 18 years of age with documented rCDI who completed standard-of-care antibiotic therapy before treatment with RBL. Assigned study treatment regimen was one or two doses of RBL (or placebo) administered rectally, depending on the trial design. In four of the five trials, participants with CDI recurrence within 8 weeks after RBL or placebo administration were eligible for treatment with open-label RBL. Treatment-emergent adverse events (TEAEs) were recorded for at least 6 months following last study treatment; in PUNCH CD2 and PUNCH Open-Label trials, TEAEs and serious TEAEs were collected through 12 and 24 months, respectively. Results: Among the five trials, 978 participants received at least one dose of RBL (assigned treatment or after recurrence) and 83 participants received placebo only. TEAEs were reported in 60.2% of Placebo Only participants and 66.4% of RBL Only participants. Only abdominal pain, nausea, and flatulence were significantly higher in the RBL Only group compared with the Placebo Only group. Most TEAEs were mild or moderate in severity and were most frequently related to preexisting conditions. There were no reported infections for which the causative pathogen was traced to RBL. Potentially life-threatening TEAEs were infrequent (3.0% of participants). Conclusion: Across five clinical trials, RBL was well tolerated in adults with rCDI. In aggregate, these data consistently demonstrated the safety of RBL.

BackgroundPatient perspectives are central to the US Food and Drug Administration’s benefit-risk decision-making process in the evaluation of medical products. Traditional channels of communication may not be feasible for all patients and consumers. Social media websites have increasingly been recognized by researchers as a means to gain insights into patients’ views about treatment and diagnostic options, the health care system, and their experiences living with their conditions. Consideration of multiple patient perspective data sources offers the Food and Drug Administration the opportunity to capture diverse patient voices and experiences with chronic pain. ObjectiveThis pilot study explores posts from a web-based patient platform to gain insights into the key challenges and barriers to treatment faced by patients with chronic pain and their caregivers. MethodsThis research compiles and analyzes unstructured patient data to draw out the key themes. To extract relevant posts for this study, predefined keywords were identified. Harvested posts were published between January 1, 2017, and October 22, 2019, and had to include #ChronicPain and at least one other relevant disease tag, a relevant chronic pain management tag, or a chronic pain management tag for a treatment or activity specific to chronic pain. ResultsThe most common topics discussed among persons living with chronic pain were related to disease burden, the need for support, advocacy, and proper diagnosis. Patients’ discussions focused on the negative impact chronic pain had on their emotions, playing sports, or exercising, work and school, sleep, social life, and other activities of daily life. The 2 most frequently discussed treatments were opioids or narcotics and devices such as transcutaneous electrical nerve stimulation machines and spinal cord stimulators. ConclusionsSocial listening data may provide valuable insights into patients’ and caregivers’ perspectives, preferences, and unmet needs, especially when conditions may be highly stigmatized.

Abstract Glucose homeostasis is closely regulated to maintain energy requirements of vital organs and skeletal muscle plays a crucial role in this process. Mustn1 is expressed during embryonic and postnatal skeletal muscle development and its function has been implicated in myogenic differentiation and myofusion. Whether Mustn1 plays a role in glucose homeostasis in anyway remains largely unknown. As such, we deleted Mustn1 in skeletal muscle using a conditional knockout (KO) mouse approach. KO mice did not reveal any specific gross phenotypic alterations in skeletal muscle. However, intraperitoneal glucose tolerance testing (IPGTT) revealed that 2‐month‐old male KO mice had significantly lower glycemia than their littermate wild type (WT) controls. These findings coincided with mRNA changes in genes known to be involved in glucose metabolism, tolerance, and insulin sensitivity; 2‐month‐old male KO mice had significantly higher expression of GLUT1 and GLUT10 transporters, MUP‐1 while OSTN expression was lower. These differences in glycemia and gene expression were statistically insignificant after 4 months. Identical experiments in female KO and WT control mice did not indicate any differences at any age. Our results suggest a link between Mustn1 expression and glucose homeostasis during a restricted period of skeletal muscle development/maturation. While this is an observational study, Mustn1's relationship to glucose homeostasis appears to be more complex with a possible connection to other key proteins such as GLUTs, MUP‐1, and OSTN. Additionally, our data indicate temporal and sex differences. Lastly, our findings strengthen the notion that Mustn1 plays a role in the metabolic capacity of skeletal muscle.

Self-efficacy is an essential component of students’ motivation and success in writing. There have been great advancements in our theoretical understanding of writing self-efficacy over the past 40 years; however, there is a gap in how we empirically model the multidimensionality of writing self-efficacy. The purpose of the present study was to examine the multidimensionality of writing self-efficacy, and present validity evidence for the adapted Self-Efficacy for Writing Scale (SEWS) through a series of measurement model comparisons and person-centered approaches. Using a sample of 1,466 8th–10th graders, results showed that a bifactor exploratory structural equation model best represented the data, demonstrating that the SEWS exhibits both construct-relevant multidimensionality and the presence of a global theme. Using factor scores derived from this model, we conducted latent profile analysis to further establish validity of the measurement model and examine how students disaggregate into groups based on their response trends of the SEWS. Three profiles emerged, differentiated by global writing self-efficacy, with substantively varying factor differences among the profiles. Concurrent, divergent, and discriminant validity evidence was established through a series of analyses that assessed predictors and outcomes of the profiles (e.g., demographics, standardized writing assessments, and grades). Theoretical and practical implications and avenues for future research are discussed.

University settings have demonstrated potential for coronavirus disease (COVID-19) outbreaks; they combine congregate living, substantial social activity, and a young population predisposed to mild illness. Using genomic and epidemiologic data, we describe a COVID-19 outbreak at the University of Wisconsin–Madison, Madison, Wisconsin, USA. During August–October 2020, a total of 3,485 students, including 856/6,162 students living in dormitories, tested positive. Case counts began rising during move-in week, August 25–31, 2020, then rose rapidly during September 1–11, 2020. The university initiated multiple prevention efforts, including quarantining 2 dormitories; a subsequent decline in cases was observed. Genomic surveillance of cases from Dane County, in which the university is located, did not find evidence of transmission from a large cluster of cases in the 2 quarantined dorms during the outbreak. Coordinated implementation of prevention measures can reduce COVID-19 spread in university settings and may limit spillover to the surrounding community.

Coral reefs are highly diverse ecosystems that provide many goods and ecosystem services globally. Coral reef ecosystems are also threatened by environmental stressors from anthropogenic sources and shifting climates. The United Nations Sustainable Development Goal 14 (“Life Below Water”) addresses the need to conserve and sustainably use the ocean, seas, and marine ecosystems, including reef systems. Belize’s coral reef system is the second largest in the world, providing sources of income to Belizeans through tourism and fisheries as well as coastline protection. In order to conserve their marine ecosystems, Belize has a network of Marine Protected Areas (MPAs) throughout their coastal waters. Using Aqua MODIS satellite imagery from 2002 to 2022, Google Earth Engine, and RStudio, we present a workflow to calculate stress days on MPAs and a coral vulnerability index based on sea surface temperature (SST) and Kd (490), a proxy of water clarity. The Corozal Bay, Swallow Caye, Port Honduras, and South Water Caye MPAs had the highest percentages of stress days and coral vulnerability stress index score based on these two parameters among the 24 MPAs analyzed. Additionally, SST in the warmest month of the year in Belize were seen to increase across all MPAs from 2002 to 2022 (p < 0.01). This GEE toolkit provides a straightforward and accessible tool to help governments monitor both water quality and risks to coral reefs in accordance with SDG 14.

Abstract Basal-like breast cancers (BLBC) are aggressive breast cancers that respond poorly to targeted therapies and chemotherapies. In order to define therapeutically targetable subsets of BLBC we examined two markers: cyclin E1 and BRCA1 loss. In high grade serous ovarian cancer (HGSOC) these markers are mutually exclusive, and define therapeutic subsets. We tested the same hypothesis for BLBC. Using a BLBC cohort enriched for BRCA1 loss, we identified convergence between BRCA1 loss and high cyclin E1 protein expression, in contrast to HGSOC in which CCNE1 amplification drives increased cyclin E1. In cell lines, BRCA1 loss was associated with stabilized cyclin E1 during the cell cycle, and BRCA1 siRNA led to increased cyclin E1 in association with reduced phospho-cyclin E1 T62. Mutation of cyclin E1 T62 to alanine increased cyclin E1 stability. We showed that tumors with high cyclin E1/BRCA1 mutation in the BLBC cohort also had decreased phospho-T62, supporting this hypothesis. Since cyclin E1/CDK2 protects cells from DNA damage and cyclin E1 is elevated in BRCA1 mutant cancers, we hypothesized that CDK2 inhibition would sensitize these cancers to PARP inhibition. CDK2 inhibition induced DNA damage and synergized with PARP inhibitors to reduce cell viability in cell lines with homologous recombination deficiency, including BRCA1 mutated cell lines. Treatment of BRCA1 mutant BLBC patient-derived xenograft models with combination PARP and CDK2 inhibition led to tumor regression and increased survival. We conclude that BRCA1 status and high cyclin E1 have potential as predictive biomarkers to dictate the therapeutic use of combination CDK inhibitors/PARP inhibitors in BLBC.

Dental fluorosis is a common disorder caused by excessive fluoride intake during tooth development. The esthetic consequences of dental fluorosis can negatively affect oral health-related quality of life and have lasting psychosocial effects. In severe cases, where the fluorosed enamel is prone to chipping, flaking, and developing caries, minimally invasive procedures are ineffectual and a more substantial restorative approach is required to restore optimal function and esthetics. However, no definitive guidelines exist for the management and treatment of severe dental fluorosis due to the limited evidence available in the literature. This case report describes the full-mouth rehabilitation of a patient with severe dental fluorosis utilizing adhesively bonded all-ceramic crowns, veneers, and overlays. The successful follow-up on this case indicates that adhesively bonded restorations may provide a viable option in the functional and esthetic management of severely fluorosed dentition.

BackgroundSuicide is a leading cause of death in the United States, and suicidal ideation (SI) is a significant precursor and risk factor for suicide. ObjectiveThis study aimed to examine the impact of a telepsychiatric care platform on changes in SI over time and remission, as well as to investigate the relationship between various demographic and medical factors on SI and SI remission. MethodsParticipants included 8581 US-based adults (8366 in the treatment group and 215 in the control group) seeking treatment for depression, anxiety, or both. The treatment group included patients who had completed at least 12 weeks of treatment and had received a prescription for at least one psychiatric medication during the study period. Providers prescribed psychiatric medications for each patient during their first session and received regular data on participants. They also received decision support at treatment onset via the digital platform, which leveraged an empirically derived proprietary precision-prescribing algorithm to give providers real-time care guidelines. Participants in the control group consisted of individuals who completed the initial enrollment data and completed surveys at baseline and 12 weeks but did not receive care. ResultsGreater feelings of hopelessness, anhedonia, and feeling bad about oneself were most significantly correlated (r=0.24-0.37) with SI at baseline. Sleep issues and feeling tired or having low energy, although significant, had lower correlations with SI (r=0.13-0.14). In terms of demographic variables, advancing age and education were associated with less SI at baseline (r=−0.16) and 12 weeks (r=−0.10) but less improvement over time (r=−0.12 and −0.11, respectively). Although not different at baseline, the SI expression was evident in 34.4% (74/215) of the participants in the control group and 12.32% (1031/8366) of the participants in the treatment group at 12 weeks. Although the participants in the treatment group improved over time regardless of various demographic variables, participants in the control group with less education worsened over time, after controlling for age and depression severity. A model incorporating the treatment group, age, sex, and 8-item Patient Health Questionnaire scores was 77% accurate in its classification of complete remission. Those in the treatment group were 4.3 times more likely (odds ratio 4.31, 95% CI 2.88-6.44) to have complete SI remission than those in the control group. Female participants and those with advanced education beyond high school were approximately 1.4 times more likely (odds ratio 1.38, 95% CI 1.18-1.62) to remit than their counterparts. ConclusionsThe results highlight the efficacy of an antidepressant intervention in reducing SI, in this case administered via a telehealth platform and with decision support, as well as the importance of considering covariates, or subpopulations, when considering SI. Further research and refinement, ideally via randomized controlled trials, are needed.

Introduction Opioid analgesics are often used to treat moderate-to-severe acute non-cancer pain; however, there is little high-quality evidence to guide clinician prescribing. An essential element to developing evidence-based guidelines is a better understanding of pain management and pain control among individuals experiencing acute pain for various common diagnoses.Methods and analysis This multicentre prospective observational study will recruit 1550 opioid-naïve participants with acute pain seen in diverse clinical settings including primary/urgent care, emergency departments and dental clinics. Participants will be followed for 6 months with the aid of a patient-centred health data aggregating platform that consolidates data from study questionnaires, electronic health record data on healthcare services received, prescription fill data from pharmacies, and activity and sleep data from a Fitbit activity tracker. Participants will be enrolled to represent diverse races and ethnicities and pain conditions, as well as geographical diversity. Data analysis will focus on assessing patients’ patterns of pain and opioid analgesic use, along with other pain treatments; associations between patient and condition characteristics and patient-centred outcomes including resolution of pain, satisfaction with care and long-term use of opioid analgesics; and descriptive analyses of patient management of leftover opioids.Ethics and dissemination This study has received approval from IRBs at each site. Results will be made available to participants, funders, the research community and the public.Trial registration number NCT04509115.

Abstract In inquiry-based science lessons teachers face the challenge of adhering to curricular goals while simultaneously following students’ intuitive understandings. Improvisation (improv) provides a useful frame for understanding teaching in these inquiry-based contexts. This paper builds from prior work that uses improv as a metaphor for teaching to present a translated model for analysis of teaching in an inquiry-based, elementary school science lesson context. We call our model instructional improv, which shows how a teacher spontaneously synthesizes rules of improv with teaching practices to support student learning, engagement, and agency. We illustrate instructional improv through case study analysis of video recorded classroom interactions with one teacher and 26 first and second grade students learning about the complex system of honey bee pollination in a mixed reality environment. Our model includes the following defining features to describe how teaching happens in this context: the teacher 1) tells a story; 2) reframes mistakes as opportunities; 3) agrees; 4) yes ands; 5) makes statements (or asks questions that elicit statements); and 6) puts the needs of the classroom ensemble over individuals. Overall, we show how instructional improv helps explain how teachers can support science discourse and collective storytelling as a teacher (a) shifts power and agency to students; (b) balances learning and agency; and (c) makes purposeful instructional decisions. Findings have immediate implications for researchers analyzing interactions in inquiry-based learning environments and potential future implications for teachers to support inquiry learning.

Christian, especially Protestant, identity is often framed through the lens of belief, particularly belief understood as an interior orientation. Through an examination of the non-denominational Protestant group, the ‘Little Flock’, founded by Watchman Nee in the early 20th century, we trace enduring aspects of Little Flock theology in contemporary Chinese Protestant practice. In particular, we attend to conceptions of and debates surrounding belief and how to determine the quality of one’s faith—whether or not one might be considered not just a Christian, but a ‘good’ one.

The interaction between methadone and central nervous system depressants can cause serious adverse effects, including profound sedation, respiratory depression, coma, and death. This poses a challenge in the treatment of patients with concurrent psychiatric and substance use disorders as the combined use is often unavoidable. We report a case of a patient with opioid use disorder, mood disorder unspecified, chronic pain, and chronic obstructive pulmonary disease who experienced 2 serious episodes of CNS and respiratory depression due to polypharmacy-induced opioid toxicity. Careful consideration of pharmacokinetics, pharmacodynamics, and patient-specific factors was imperative to identify the suspected contributing medications: methadone, lorazepam, divalproex, gabapentin, and cyclobenzaprine. Cognitive and system factors that contributed to these adverse events and strategies to mitigate risk of recurrence were also identified.

BackgroundAmong racial and ethnic minority groups, the risk of HIV infection is an ongoing public health challenge. Pre-exposure prophylaxis (PrEP) is highly effective for preventing HIV when taken as prescribed. However, there is a need to understand the experiences, attitudes, and barriers of PrEP for racial and ethnic minority populations and sexual minority groups. ObjectiveThis infodemiology study aimed to leverage big data and unsupervised machine learning to identify, characterize, and elucidate experiences and attitudes regarding perceived barriers associated with the uptake and adherence to PrEP therapy. This study also specifically examined shared experiences from racial or ethnic populations and sexual minority groups. MethodsThe study used data mining approaches to collect posts from popular social media platforms such as Twitter, YouTube, Tumblr, Instagram, and Reddit. Posts were selected by filtering for keywords associated with PrEP, HIV, and approved PrEP therapies. We analyzed data using unsupervised machine learning, followed by manual annotation using a deductive coding approach to characterize PrEP and other HIV prevention–related themes discussed by users. ResultsWe collected 522,430 posts over a 60-day period, including 408,637 (78.22%) tweets, 13,768 (2.63%) YouTube comments, 8728 (1.67%) Tumblr posts, 88,177 (16.88%) Instagram posts, and 3120 (0.6%) Reddit posts. After applying unsupervised machine learning and content analysis, 785 posts were identified that specifically related to barriers to PrEP, and they were grouped into three major thematic domains: provider level (13/785, 1.7%), patient level (570/785, 72.6%), and community level (166/785, 21.1%). The main barriers identified in these categories included those associated with knowledge (lack of knowledge about PrEP), access issues (lack of insurance coverage, no prescription, and impact of COVID-19 pandemic), and adherence (subjective reasons for why users terminated PrEP or decided not to start PrEP, such as side effects, alternative HIV prevention measures, and social stigma). Among the 785 PrEP posts, we identified 320 (40.8%) posts where users self-identified as racial or ethnic minority or as a sexual minority group with their specific PrEP barriers and concerns. ConclusionsBoth objective and subjective reasons were identified as barriers reported by social media users when initiating, accessing, and adhering to PrEP. Though ample evidence supports PrEP as an effective HIV prevention strategy, user-generated posts nevertheless provide insights into what barriers are preventing people from broader adoption of PrEP, including topics that are specific to 2 different groups of sexual minority groups and racial and ethnic minority populations. Results have the potential to inform future health promotion and regulatory science approaches that can reach these HIV and AIDS communities that may benefit from PrEP.

Abstract Background Malaria remains the top infectious disease threat facing the U.S. military in many forward operating environments. Compliance with malaria chemoprophylaxis remains a critical component in preventing malaria in the deployed Service Member. Studies of previous military operations show that compliance is consistently higher with weekly versus daily dosing regimens. Current FDA approved weekly chemoprophylaxis options have contraindications that can limit prescribing. The combination of chloroquine (CQ) with azithromycin (AZ) has previously been shown to be an efficacious treatment option for malaria, has pharmacokinetics compatible with weekly dosing, and has shown synergy when combined in vitro. Methods In this open label study, 18 healthy volunteers, aged 18–50 years (inclusive), were randomly assigned to receive either 300 mg CQ or 300 mg CQ and 2 gm azithromycin (CQAZ) of directly observed therapy, weekly for 3 weeks prior to undergoing mosquito bite challenge with chloroquine-resistant Plasmodium falciparum. Volunteers that remained asymptomatic and had no evidence of parasitaemia continued to receive weekly post-exposure chemoprophylaxis for 3 weeks following malaria challenge. The primary endpoint was the number of volunteers that remained asymptomatic and had no evidence of parasitaemia 28 days after the malaria challenge. Results All 6 (100%) volunteers randomized to the CQ control group became symptomatic with parasitaemia during the 28-day post-challenge period. Only 1/12 (8.3%) of volunteers in the CQAZ group developed symptoms and parasitaemia during the 28-day post-challenge period. However, after chemoprophylaxis was discontinued an additional 6 volunteers developed parasitaemia between days 28–41 after challenge, with 4 of 6 experiencing symptoms. 80% of subjects in the CQAZ group experienced treatment related gastrointestinal adverse events (including 13% that experienced severe nausea) compared to 38% in the CQ group. A comparison of the pharmacokinetics in the CQAZ group demonstrated higher azithromycin Cmax (p = 0.03) and AUC (p = 0.044) levels in those volunteers who never became parasitaemic compared to those who did. Conclusion Given the high rate of side effects and poor efficacy when administered for 3 weeks before and after challenge, the combination of weekly chloroquine and azithromycin is a suboptimal regimen combination for weekly malaria chemoprophylaxis. Trial registration ClinicalTrials.gov NCT03278808

Background Previous studies of secular change in cranial size among black South Africans have produced conflicting results. Aim We re-examined cranial size change in this population during the 19th and 20th century by evaluating its relationship with individual year-of-birth, and the significance of trends among eight decennial cohorts. Subjects and methods This study is based on 102 male and 89 female adults born between 1865 and 1959. Linear regressions were employed to evaluate possible relationships between year-of-birth and cranial dimensions; ANOVAs were used to evaluate the significance of long-term trends among decennial cohorts. Results No analysis revealed a secular change in cranial length in either sex; however, the ANOVA for cranial length in the combined sex sample was significant. There is no secular trend in female cranial breadth, but males display a negative trend in this dimension. This results in a secular trend for increased male dolichocephaly. Conclusions The factors that underlie the negative secular trend in male cranial breadth and the absence of a secular trend in overall cranial size in this population are unclear. Nevertheless, these observations accord with findings related to stature and long bone strength in this population and are consistent with observations for other sub-Saharan African populations.

Abstract During the perioperative period patients often suffer complications, including acute kidney injury (AKI), reintubation, and mortality. In order to effectively prevent these complications, high-risk patients must be readily identified. However, most current risk scores are designed to predict a single postoperative complication and often lack specificity on the patient level. In other fields, machine learning (ML) has been shown to successfully create models to predict multiple end points using a single input feature set. We hypothesized that ML can be used to create models to predict postoperative mortality, AKI, reintubation, and a combined outcome using a single set of features available at the end of surgery. A set of 46 features available at the end of surgery, including drug dosing, blood loss, vital signs, and others were extracted. Additionally, six additional features accounting for total intraoperative hypotension were extracted and trialed for different models. A total of 59,981 surgical procedures met inclusion criteria and the deep neural networks (DNN) were trained on 80% of the data, with 20% reserved for testing. The network performances were then compared to ASA Physical Status. In addition to creating separate models for each outcome, a multitask learning model was trialed that used information on all outcomes to predict the likelihood of each outcome individually. The overall rate of the examined complications in this data set was 0.79% for mortality, 22.3% (of 21,676 patients with creatinine values) for AKI, and 1.1% for reintubation. Overall, there was significant overlap between the various model types for each outcome, with no one modeling technique consistently performing the best. However, the best DNN models did beat the ASA score for all outcomes other than mortality. The highest area under the receiver operating characteristic curve (AUC) models were 0.792 (0.775–0.808) for AKI, 0.879 (0.851–0.905) for reintubation, 0.907 (0.872–0.938) for mortality, and 0.874 (0.864–0.866) for any outcome. The ASA score alone achieved AUCs of 0.652 (0.636–0.669) for AKI, 0.787 (0.757–0.818) for reintubation, 0.839 (0.804–0.875) for mortality, and 0.76 (0.748–0.773) for any outcome. Overall, the DNN architecture was able to create models that outperformed the ASA physical status to predict all outcomes based on a single feature set, consisting of objective data available at the end of surgery. No one model architecture consistently performed the best.

Abstract Background In order to combat rising rates of antimicrobial resistant infections, it is vital that antimicrobial stewardship become embedded in primary health care (PHC). Despite the high use of antimicrobials in PHC settings, there is a lack of data regarding the integration of antimicrobial stewardship programs (ASP) in non-hospital settings. Our research aimed to determine which antimicrobial stewardship interventions are optimal to introduce into PHC clinics beginning to engage with an ASP, as well as how to optimize those interventions. This work became focused specifically around management of viral upper respiratory tract infections (URTIs), as these infections are one of the main sources of inappropriate antibiotic use. Methods This mixed methods study of sequential explanatory design was developed through three research projects over 3 years in Regina, Saskatchewan, Canada. First, a survey of PHC providers was performed to determine their perceived needs from a PHC-based ASP. From this work, a “viral prescription pad” was developed to provide a tool to help PHC providers engage in patient education regarding appropriate antimicrobial use, specifically for URTIs. Next, interviews were performed with family physicians to discuss their perceived utility of this tool. Finally, we performed a public survey to determine preferences for the medium by which information is received regarding symptom management for viral URTIs. Results The majority of PHC providers responding to the initial survey indicated they were improperly equipped with tools to aid in promoting conversations with patients and providing education about the appropriate use of antimicrobials. Following dissemination of the viral prescription pad and semi-structured interviews with family physicians, the viral prescription pad was deemed to be a useful educational tool. However, about half of the physicians interviewed indicated they did not actually provide a viral prescription to patients when providing advice on symptom management for viral URTIs. When asked about their preferences, 76% of respondents to the public survey indicated they would prefer to receive written or a combination of verbal and written information in this circumstance. Conclusions PHC providers indicated a need for educational tools to promote conversations with patients and provide education about the appropriate use of antimicrobials. Viral prescription pads were regarded by family physicians and patients as useful tools in facilitating discussion on the appropriate use of antimicrobials. PHC providers should exercise caution in opting out of providing written forms of information, as many respondents to the general public survey indicated their preference in receiving both verbal and written information.

This paper foregrounds the Turnerian experiences of pilgrims themselves, for whom pilgrimage is perhaps first and foremost the process of experiencing faith with their whole body and mind. At the Chinese Catholic pilgrimage site of Sheshan, located in western Shanghai, multiple meanings and possibilities are written onto the body of the pilgrim as it interacts with sacred materialities. In the process, the pilgrim materially orients themselves towards the transcendent other and to people and events throughout time. The boundary between subject and object is increasingly blurred in the pilgrim’s imagination, and pilgrimage becomes a ‘porous’ mind-body experience for them. In the process, as pilgrims repeatedly physically enact doctrine and doctrinal texts in the course of pilgrimage—while simultaneously rooting them in their own personal lives—Sheshan is, through the concrete actions of worshippers layered up over time, continually being re-made as sacred.

Microcystins are toxic chemicals generated by certain freshwater cyanobacteria. These chemicals can accumulate to dangerous levels during harmful algal blooms. When exposed to microcystins, humans are at risk of hepatic injury, including liver failure. Here, we describe a method to detect microcystins in human plasma by using immunocapture followed by a protein phosphatase inhibition assay. At least 279 microcystins have been identified, and most of these compounds share a common amino acid, the Adda side chain. We targeted this Adda side chain using a commercial antibody and extracted microcystins from human samples for screening and analysis. To quantitate the extracted microcystins, we fortified plasma with microcystin-LR, one of the most well-studied, commonly detected, and toxic microcystin congeners. The quantitation range for the detection of microcystin in human plasma using this method is 0.030–0.50 ng/mL microcystin-LR equivalents. This method detects unconjugated and conjugated forms (cysteine and glutathione) of microcystins. Quality control sample accuracies varied between 98.9% and 114%, with a precision of 7.18–15.8%. Finally, we evaluated plasma samples from a community health surveillance project of Florida residents living or working near harmful algae blooms.

For the first time within living memory, the rural Roman Catholic parish of Talavera in the south-central Peruvian Andes features only native clergy. By placing the Talaveran Catholic priests in theological and historical context, this article shows how this current generation of Catholic priests in Talavera must be understood within the context of the post–Vatican II Catholic Church in Latin America, which explicitly encouraged the training of native clergy and recast the relationship between the sacramental and the human as mutually compatible and constitutive. Although such initiatives are generally associated with liberal parishes unlike Talavera, the nouvelle theology that shaped Vatican II nevertheless meant that the dual nature of the Roman Catholic priesthood—as concretely human but also ineffably sacramental—fundamentally shapes the lay relationship with the Catholic priests in Talavera, too. The resulting tension between the priest as a sacramental mediator to the divine and the priest as a human man is continually renegotiated by laity and clergy alike, and is essential to understanding Catholic priests in Latin America and how lay parishioners experience the Catholic priesthood. Resumen Por la primera vez que se recuerde, la parroquia rural de Talavera en los Andes del centro-sur de Peru se presenta con un clero nativo. En este artículo, se pone los sacerdotes católicos de Talavera en un contexto histórico y teológico, y así muestra cómo entender esta generación de curas a la luz del Concilio Vaticano II y los cambios que efectuó en la Iglesia Católica en América Latina. Dichos cambios animaron a la Iglesia que se forme un clero nativo y reestructuraron la relación entre lo humano y lo sacramental como mutuamente constituidos. Tales iniciativas se asocian normalmente con parroquias liberales y Talavera es una parroquia conservadora, pero la nouvelle teología que dio forma al Concilio significa que la naturaleza dual del sacerdocio como concretamente humano y también inefablemente sacramental todavía moldea la relación entre los laicos y los padres en Talavera. Esta tensión resultante entre el sacerdote como un mediador sacramental y el sacerdote como un hombre humano es continuamente renegociado por los laicos tanto como los curas, y es esencial para entender los sacerdotes católicos en Latino América y la experiencia de los feligreses del sacerdocio católico.

ObjectiveThis study aimed to: (a) adapt the previously validated Valuation of Lost Productivity (VOLP) questionnaire for people with health problems, to a caregiver version to measure productivity losses associated with caregiving responsibilities, and (b) evaluate measurement feasibility and validity of an online version of the caregiver VOLP questionnaire.MethodsA mixed methods design was utilized. Qualitative methods, such as reviewing existing questionnaires that measured caregiver work productivity losses and performing one-on-one interviews with caregivers, were used for VOLP adaptation and online conversion. Quantitative methods were used to evaluate feasibility and validity of the online VOLP. The Work Productivity and Activity Impairment (WPAI) questionnaire for caregivers was included to compare its absenteeism and presenteeism outcomes and their correlations with VOLP outcomes.ResultsWhen adapting the VOLP for caregivers, our qualitative analysis showed the importance of adding three major components: caregiving time, work productivity loss related to volunteer activities and caregivers’ lost job opportunities. A total of 383 caregivers who completed online survey were included in our final quantitative analysis. We found small Spearman rank correlations between VOLP and WPAI, observing a larger correlation between their absenteeism [r = 0.49 (95% confidence interval: 0.37–0.60)] than their presenteeism [r = 0.36 (0.24–0.47)]. Correlations between VOLP outcomes and total caregiving hours were larger for absenteeism [r = 0.38 (0.27–0.47)] than presenteeism [r = 0.22 (0.10–0.34)]. Correlations between WPAI outcomes and total caregiving hours were smaller for absenteeism [r = 0.27 (0.15–0.38)] than presenteeism [r = 0.35 (0.23–0.46)].ConclusionThe study provides evidence of the feasibility and preliminary validity evidence of the adapted VOLP caregiver questionnaire in measuring productivity losses due to caregiving responsibilities, when compared with the results for WPAI and the results from the previous patient-VOLP validation study.

Abstract Background Clostridium difficile infection (CDI) is an important cause of diarrhea and continues to be a major burden within healthcare institutions and in the community. For a small subset of patients with frequently relapsing CDI who do not have access to fecal microbiota transplantation (FMT), or fail FMT, there are no clear treatment recommendations. We review our experience with prolonged oral vancomycin for secondary prophylaxis of relapsing CDI. Methods We performed a retrospective chart review of cases from the C. difficile consultation service at our institution since 2013. The service had three primary physicians providing consultations and performing over 1000 FMTs over the five-year period. Patients with relapsing CDI who were not candidates for FMT, refused, or relapsed after FMT were treated with vancomycin, followed by long-term oral vancomycin at a dose of 125 mg once daily. Results Twenty patients received at least 8 weeks of once-daily oral vancomycin for prophylaxis of relapsing CDI. Patients had a median age of 80 years, and experienced a median of four episodes of CDI prior to long-term vancomycin. Most were female and 75% had received FMT. Only a single case of C. difficile relapse occurred while on long-term vancomycin during 200 patient-months of follow-up. Amongst those who stopped long-term vancomycin, 31% relapsed within 6 weeks. No adverse events were observed. Conclusions For elderly patients with frequently relapsing C. difficile, prolonged vancomycin once daily at a dose of 125 mg orally was effective in preventing further relapse. Vancomycin secondary prophylaxis may be considered in patients who have failed FMT, or in cases where FMT is not available.

Architected cellular materials encompass a wide range of design and performance possibilities. While there has been significant interest in periodic cellular materials, recent emphasis has included consideration of aperiodicity, most commonly in studies of stochastic and graded cellular materials. This study proposes a classification scheme for aperiodic cellular materials, by first dividing the design domain into three main types: gradation, perturbation, and hybridization. For each of these types, two design decisions are identified: (i) the feature that is to be modified and (ii) the method of its modification. Considerations such as combining different types of aperiodic design methods, and modulating the degree of aperiodicity are also discussed, along with a review of the literature that places each aperiodic design within the classification developed here, as well as summarizing the performance benefits attributed to aperiodic cellular materials over their periodic counterparts.

The U.S. encompasses a heterogenous mix of people and health disparities exist for various subpopulations, such as minorities, women, people with limited English proficiency, those with low socioeconomic status, and other underserved groups. Differences in health outcomes arise in part due to inequalities and injustices rooted in biological, social, and structural factors. Because the origins of health disparities are multifactorial, the approaches to reduce, or even eliminate them, must be multifactorial as well. The social and behavioral sciences are well poised to address the myriad and complex factors that affect health outcomes, including those at the individual level (eg, individuals’ behaviors, attitudes, and beliefs), the neighborhood level (eg, housing), the community level (eg, cultural values and norms), and the policy level (eg, public policies that influence healthcare funding and access to healthcare resources and educational materials). In addition, the social and behavioral sciences (1) help equip government agencies with the perspectives and tools needed to promote health equity and (2) contribute to rigorous, evidence-based solutions for public health issues, such as disparities found in childhood vaccination rates, childhood obesity, tobacco use, and access to health information technology. The FDA, in particular, actively conducts social and behavioral sciences research to guide the Agency’s efforts to advance and support health equity.

Urban runoff represents the primary cause of marine pollution in the Southern California coastal oceans. This study focuses on water quality issues originating from the Tijuana River watershed, which spans the southwest border of the United States and Mexico. Frequent discharge events into the coastal ocean at this boundary include stormwater and wastewater. This study focuses on differences in spectral features, as assessed by RapidEye, Sentinel-2 A/B, and Landsat-8 satellite data, along with physical and biological in situ data, to characterize and classify plumes into four key categories: stormwater, wastewater, open ocean/no plume, and mixed (when both types of plumes are present). Key spectral differences in the visible to NIR bands showed that stormwater had elevated reflectance (0.02 to 0.09), followed by mixed (0 to 0.08), wastewater (0 to 0.05), and open ocean/no plume (0 to 0.03) events. We also examined biophysical parameters and found that stormwater events had the highest values in remote sensing based estimates of colored dissolved organic matter (CDOM) (0.98 to 2.1 m–1) and turbidity (12.4 to 45.7 FNU) and also had a large range for in situ variables of enterococcus bacteria and flow rates. This study also finds that the use of spectral features in a hierarchical cluster analysis can correctly classify stormwater from wastewater plumes when there is a dominant type. These results of this study will enable improved determination of the transport of both types of plumes and transboundary monitoring of coastal water quality across the Southern California/Baja California region.

Introduction Sex hormone binding globulin (SHBG) levels are reported to be inversely associated with diabetes risk. It is unknown whether diabetes prevention interventions increase SHBG and whether resultant changes in SHBG affect diabetes risk. The purpose of this analysis was to determine whether intensive lifestyle intervention (ILS) or metformin changed circulating SHBG and if resultant changes influenced diabetes risk in the Diabetes Prevention Program (DPP).Research design and methods This is a secondary analysis from the DPP (1996–2001), a randomized trial of ILS or metformin versus placebo on diabetes risk over a mean follow-up of 3.2 years. The DPP was conducted across 27 academic study centers in the USA. Men, premenopausal and postmenopausal women without hormone use in the DPP were evaluated. The DPP included overweight/obese persons with elevated fasting glucose and impaired glucose tolerance. Main outcomes measures were changes in SHBG levels at 1 year and risk of diabetes over 3 years.Results ILS resulted in significantly higher increases (postmenopausal women: p

In the colonial era, many Spanish missionaries in the Andes sought a total temporal and cultural break between the pagan past and desired a Christian future of indigenous Andeans. Discussions of Christian conversion in the modern-day Andes have often echoed this line of thinking, portraying conversion—whether to Protestantism or to Roman Catholicism—as an event of radical discontinuity, and mapping the rupture of conversion onto the rupture of the Spanish invasion and subsequent evangelisation of the Americas. In doing so, however, scholars have often portrayed Catholicism as a veneer over the ‘authentic’ Andes—which was assumed to not be Catholic, and indeed could never be. Recently, however, in the south-central Peruvian Andean parish of Talavera—under the guidance of a first generation of an indigenous Catholic priesthood, made up entirely of men born and raised in the local area—discourses surrounding conversion portray the past as a source of continuity rather than discontinuity with Catholicism. Drawing from historical and ethnographic sources, this article demonstrates that although conversion has been and continues to be an important point of reference in contemporary Roman Catholicism in the Andes, the question of what people convert from has shifted. Today, the Andes are spoken of as already inherently and profoundly Catholic; conversion, in the sense of the need to make the Andes ‘really’ Catholic, is considered long accomplished. As the article discusses, in a national context where Catholicism is dominant and ubiquitous to the point of hegemony, this is an inherently political stance which runs counter to longstanding harmful stereotypes of indigenous Andeans as not ‘real’ Catholics and thus unable to be ‘real’ Peruvians.

Abstract Background Obesity, metabolic syndrome (MetS), and diabetes are frequent in surgical populations and can enhance susceptibility to postoperative surgical site infections. Reduced neutrophil function has been linked with diabetes and risk of Staphylococcus aureus infection. Therefore, neutrophil function in diabetic and obese subjects (± MetS) was assessed in this prospective serological and cellular surveillance study to determine whether vaccines administered to protect against infections after surgery could be effective in these populations. Methods Neutrophil function (chemotaxis, phagocytosis, and opsonophagocytic killing of S. aureus) was assessed in subjects classified according to diabetes status, body mass index, and presence/absence of MetS. Neutrophils were characterized within functional subsets by flow cytometry. A serologic assay was used to measure baseline antibody presence to each antigen in SA4Ag: capsular polysaccharide (CP) type 5, CP8, recombinant mutant Clumping factor A (rmClfA), and recombinant Manganese transport protein C (rMntC). Results Neutrophil function was similar for comorbid and healthy cohorts, with no significant between-group differences in cell counts, migration, phagocytosis ability, neutrophil subset proportions, and S. aureus killing ability when neutrophils were isolated 3–6 months apart (Visit 1 [n = 90] and Visit 2 [n = 70]) and assessed. Median pre-existing antibody titers to CP5, CP8, and rmClfA were comparable for all cohorts (insufficient subjects with rMntC titers for determination). Conclusions MetS, diabetes, and obesity do not impact in vitro neutrophil function with regard to S. aureus killing, suggesting that if an effective S. aureus vaccine is developed it may be effective in individuals with these comorbidities.

Introduction About 42 million surgeries are performed annually in the USA. While the postoperative mortality is less than 2%, 12% of all patients in the high-risk surgery group account for 80% of postoperative deaths. New onset of haemodynamic instability is common in surgical patients and its delayed treatment leads to increased morbidity and mortality. The goal of this proposal is to develop, validate and test real-time intraoperative risk prediction tools based on clinical data and high-fidelity physiological waveforms to predict haemodynamic instability during surgery.Methods and analysis We will initiate our work using an existing annotated intraoperative database from the University of California Irvine, including clinical and high-fidelity waveform data. These data will be used for the training and development of the machine learning model (Carnegie Mellon University) that will then be tested on prospectively collected database (University of California Los Angeles). Simultaneously, we will use existing knowledge of haemodynamic instability patterns derived from our intensive care unit cohorts, medical information mart for intensive care II data, University of California Irvine data and animal studies to create smart alarms and graphical user interface for a clinical decision support. Using machine learning, we will extract a core dataset, which characterises the signatures of normal intraoperative variability, various haemodynamic instability aetiologies and variable responses to resuscitation. We will then employ clinician-driven iterative design to create a clinical decision support user interface, and evaluate its effect in simulated high-risk surgeries.Ethics and dissemination We will publish the results in a peer-reviewed publication and will present this work at professional conferences for the anaesthesiology and computer science communities. Patient-level data will be made available within 6 months after publication of the primary manuscript. The study has been approved by University of California, Los Angeles Institutional review board. (IRB #19–0 00 354).

In the years directly following the Second Vatican Council under the guidance of its second bishop Mons. Enrique Pelach i Feliu, the Andean diocese of Abancay—founded in 1959 in one of the most rural and most indigenous areas of Peru—experienced the founding of a new seminary intended to train a new generation of native clergy, and a concerted clerical effort to revive and promote the Marian pilgrimage of the Virgin of Cocharcas. The former meant the advent of a generation of native clergy made up of men born and raised in rural farming families in Abancay and native speakers of Quechua, the local indigenous language, which transformed the relationship between the institutional Church and indigenous Catholics from one rooted in antipathy and hostility to one based in a shared cultural background and language. The latter meant the elevation of the indigenous figure of Sebastian Quimichu as exemplar of both Andean Catholic faith and practice for his role in founding the Marian shrine of Cocharcas, and the legitimisation of popular Andean Catholic practices that had previously been stigmatised. This article provides a dual historical and ethnographic account of these events, and in doing so demonstrates the profound transformation of rural Andean lived religion and practice in the years following Vatican II.