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Abstract A regulated stress response is essential for healthy child growth and development trajectories. We conducted a cluster-randomized trial in rural Bangladesh (funded by the Bill & Melinda Gates Foundation, ClinicalTrials.gov NCT01590095) to assess the effects of an integrated nutritional, water, sanitation, and handwashing intervention on child health. We previously reported on the primary outcomes of the trial, linear growth and caregiver-reported diarrhea. Here, we assessed additional prespecified outcomes: physiological stress response, oxidative stress, and DNA methylation (N = 759, ages 1–2 years). Eight neighboring pregnant women were grouped into a study cluster. Eight geographically adjacent clusters were block-randomized into the control or the combined nutrition, water, sanitation, and handwashing (N + WSH) intervention group (receiving nutritional counseling and lipid-based nutrient supplements, chlorinated drinking water, upgraded sanitation, and handwashing with soap). Participants and data collectors were not masked, but analyses were masked. There were 358 children (68 clusters) in the control group and 401 children (63 clusters) in the intervention group. We measured four F2-isoprostanes isomers (iPF(2α)-III; 2,3-dinor-iPF(2α)-III; iPF(2α)-VI; 8,12-iso-iPF(2α)-VI), salivary alpha-amylase and cortisol, and methylation of the glucocorticoid receptor (NR3C1) exon 1F promoter including the NGFI-A binding site. Compared with control, the N + WSH group had lower concentrations of F2-isoprostanes isomers (differences ranging from −0.16 to −0.19 log ng/mg of creatinine, P

Summary: Treatment of rare/ultra-rare tumors is an unmet need due to a lack of standardized therapies and clinical trials. We developed the Molecular Tumor Board (MTB), a multidisciplinary team that integrates molecular profiling to generate personalized, N-of-One treatments for advanced cancers. This study evaluates 112 patients with rare/ultra-rare tumors who presented to the MTB and were evaluable for clinical therapeutic outcome. Overall, 46/112 patients (41%) received a treatment regimen with a high degree of matching between tumor molecular alterations and drugs given (reflected by a high Matching Score (≥50%)). Patients with a high versus low Matching Score experienced significantly longer progression-free survival (p = 0.005) and overall survival (p = 0.047), and higher rates of clinical benefit (stable disease ≥6 months, partial response, or complete response) (54% vs. 32% p = 0.027). The MTB facilitated personalized N-of-One matching of drugs to tumor molecular alterations, which was associated with improved clinical outcomes in patients with rare/ultra-rare cancers.

Introduction Given the increasing prevalence of both obesity and pre-diabetes in pregnant adults, there is growing interest in identifying hyperglycaemia in early pregnancy to optimise maternal and perinatal outcomes. Multiple organisations recommend first-trimester diabetes screening for individuals with risk factors; however, the benefits and drawbacks of detecting glucose abnormalities more mild than overt diabetes in early gestation and the best screening method to detect such abnormalities remain unclear.Methods and analysis The goal of the Glycemic Observation and Metabolic Outcomes in Mothers and Offspring study (GO MOMs) is to evaluate how early pregnancy glycaemia, measured using continuous glucose monitoring and oral glucose tolerance testing, relates to the diagnosis of gestational diabetes (GDM) at 24–28 weeks’ gestation (maternal primary outcome) and large-for-gestational-age birth weight (newborn primary outcome). Secondary objectives include relating early pregnancy glycaemia to other adverse pregnancy outcomes and comprehensively detailing longitudinal changes in glucose over the course of pregnancy. GO MOMs enrolment began in April 2021 and will continue for 3.5 years with a target sample size of 2150 participants.Ethics and dissemination GO MOMs is centrally overseen by Vanderbilt University’s Institutional Review Board and an Observational Study Monitoring Board appointed by National Institute of Diabetes and Digestive and Kidney Diseases. GO MOMs has potential to yield data that will improve understanding of hyperglycaemia in pregnancy, elucidate better approaches for early pregnancy GDM screening, and inform future clinical trials of early GDM treatment.Trial registration number NCT04860336.

ABSTRACTVector-borne infections may underlie some rheumatic diseases, particularly in people with joint effusions. This study aimed to compare serum and synovial fluid antibodies to B. burgdorferi and Bartonella spp. in patients with rheumatic diseases. This observational, cross-sectional study examined paired synovial fluid and serum specimens collected from 110 patients with joint effusion between October 2017 and January 2022. Testing for antibodies to B. burgdorferi (using CDC criteria) and Bartonella spp. via two indirect fluorescent antibody (IFA) assays was performed as part of routine patient care at the Institute for Specialized Medicine (San Diego, CA, USA). There were 30 participants (27%) with positive two-tier B. burgdorferi serology and 26 participants (24%) with IFA seroreactivity (≥1:256) to B. henselae and/or B. quintana. Both B. burgdorferi IgM and IgG were detected more frequently in synovial fluid than serum: 27% of patients were either IgM or IgG positive in synovial fluid, compared to 15.5% in serum (P = 0.048). Conversely, B. henselae and B. quintana antibodies were detected more frequently in serum than synovial fluid; overall only 2% of patients had positive IFA titers in synovial fluid, compared to 24% who had positive IFA titers in serum (P < 0.001). There were no significant associations between B. burgdorferi or Bartonella spp. seroreactivity with any of the clinical rheumatological diagnoses. This study provides preliminary support for the importance of synovial fluid antibody testing for documenting exposure to B. burgdorferi but not for documenting exposure to Bartonella spp.IMPORTANCEThis study focuses on diagnostic testing for two common vector-borne diseases in an affected patient population. In it, we provide data showing that antibodies to B. burgdorferi, but not Bartonella spp., are more commonly found in synovial fluid than serum of patients with joint effusion. Since Lyme arthritis is a common—and sometimes difficult to diagnose—rheumatic disease, improving diagnostic capabilities is of utmost importance. While our findings are certainly not definitive for changes to practice, they do suggest that synovial fluid could be a useful sample for the clinical diagnosis of Lyme disease, and future prospective studies evaluating this claim are warranted.

Abstract Background Contemporary therapies improve breast cancer (BC) outcomes. Yet, many of these therapies have been increasingly linked with serious cardiotoxicity, including reports of profound hypertension. Yet, the incidence, predictors, and impacts of these events are largely unknown. Methods Leveraging two large U.S.‐based registries, the National Inpatient Sample (NIS) and the Food and Drug Administration Adverse Event Reporting System (FAERS) databases, we assessed the incidence, factors, and outcomes of hypertensive events among BC patients from 2007 to 2015. Differences in baseline characteristics, hypertension‐related discharges, and complications were examined over time. Further, we performed a disproportionality analysis using reporting‐odds‐ratios (ROR) to determine the association between individual BC drugs and hypertensive events. Utilizing an ROR cutoff of >1.0, we quantified associations by drug‐class, and individual drugs with the likelihood of excess hypertension. Results Overall, there were 5,464,401 BC‐admissions, of which 46,989 (0.8%) presented with hypertension. Hypertensive BC patients were older, and saw initially increased in‐hospital mortality, which equilibrated over time. The mean incidence of hypertension‐related admissions was 732 per 100,000 among BC patients, versus 96 per 100,000 among non‐cancer patients (RR 7.71, p

Genetic networks are surprisingly robust to perturbations caused by new mutations. This robustness is conferred in part by compensation for loss of a gene's activity by genes with overlapping functions, such as paralogs. Compensation occurs passively when the normal activity of one paralog can compensate for the loss of the other, or actively when a change in one paralog's expression, localization, or activity is required to compensate for loss of the other. The mechanisms of active compensation remain poorly understood in most cases. Here we investigate active compensation for the loss or reduction in expression of the Saccharomyces cerevisiae gene TDH3 by its paralog TDH2. TDH2 is upregulated in a dose-dependent manner in response to reductions in TDH3 by a mechanism requiring the shared transcriptional regulators Gcr1p and Rap1p. TDH1, a second and more distantly related paralog of TDH3, has diverged in its regulation and is upregulated by another mechanism. Other glycolytic genes regulated by Rap1p and Gcr1p show changes in expression similar to TDH2, suggesting that the active compensation by TDH3 paralogs is part of a broader homeostatic response mediated by shared transcriptional regulators.

Surveillance of the fleas and flea-borne pathogens infecting cats is important for both human and animal health. Multiple zoonotic Bartonella and Rickettsia species are known to infect the most common flea infesting cats and dogs worldwide: Ctenocephalides felis, the cat flea. The ability of other flea species to transmit pathogens is relatively unexplored. We aimed to determine cat host and flea factors independently associated with flea Bartonella and Rickettsia infection. We also assessed flea and cat infection by flea-host pair and location. To accomplish these aims, we performed qPCR for the detection of Bartonella, hemotropic Mycoplasma, Rickettsia, and Wolbachia DNA using paired cat and flea samples obtained from free-roaming cats presenting for spay or neuter across four locations in the United States. A logistic regression model was employed to identify the effect of cat (sex, body weight, geographic location, and Bartonella, hemotropic Mycoplasma, and Rickettsia spp., infection) and flea (clade and Rickettsia and Wolbachia infection) factors on C. felis Bartonella clarridgeiae infection. From 189 free roaming cats, we collected 84 fleas: Ctenocephalides felis (78/84), Cediopsylla simplex (4/84), Orchopeas howardi (1/84), and Nosopsyllus fasciatus (1/84). Ctenocephalides felis were phylogenetically assigned to Clades 1, 4, and 6 by cox1 gene amplification. Rickettsia asembonensis (52/84) and B. clarridgeiae (16/84) were the most common pathogenic bacteria detected in fleas. Our model identified host cat sex and weight as independently associated with B. clarridgeiae infection in fleas. Rickettsia asembonensis (52/84), Rickettsia felis (7/84) and Bartonella henselae (7/84) were detected in specific clades: R. felis was detected only in Clades 1 and 6 while B. henselae and R. asembonensis were detected only in Clade 4. Wolbachia spp., also displayed clade specificity with strains other than Wolbachia wCfeT only infecting fleas from Clade 6. There was poor flea and host agreement for Bartonella spp., infection; however, there was agreement in the Bartonella species detected in cats and fleas by geographic location. These findings reinforce the importance of considering reservoir host attributes and vector phylogenetic diversity in epidemiological studies of flea-borne pathogens. Widespread sampling is necessary to identify the factors driving flea-borne pathogen presence and transmission.

A subset of patients with differentiated thyroid carcinoma develop radioiodine refractory (RAIR) incurable disease, which typically has a poor prognosis. The multitargeted tyrosine kinase inhibitor lenvatinib has demonstrated significant improvements in progression-free survival in RAIR thyroid cancers compared to placebos. However, in the phase III SELECT trial of the drug in thyroid cancer, 5.4% of patients on lenvatinib experienced arterial thromboembolic events, with 2.7% experiencing severe grade ≥3 toxicities associated with arterial vascular events. This case study reports a patient with metastatic poorly differentiated follicular thyroid cancer who developed significant obstructive coronary artery disease following initiation of lenvatinib treatment, despite no predisposing cardiovascular risk factors apart from a remote smoking history. The possibility of developing coronary or peripheral artery disease should be considered in patients who are on targeted therapies, such as lenvatinib, even in the absence of traditional cardiovascular risk factors. In addition, baseline cardiac risk assessment and early treatment should be pursued to minimize interruptions to potentially lifesaving cancer therapy.

Abstract Background Gilteritinib is a novel FMS-like tyrosine kinase 3 inhibitor recently approved by the United States Food and Drug Administration in 2018 for relapsed or refractory acute myeloid leukemia. However, gilteritinib may be associated with underrecognized cardiotoxicities. Case presentation This case describes a patient with a history significant for hyperlipidemia who was diagnosed with relapsed acute myeloid leukemia. After four doses of gilteritinib monotherapy, she abruptly developed acute systolic heart failure with global hypokinesis and septal wall motion abnormalities. Two days after discontinuation, cardiac magnetic resonance imaging showed partial recovery of her left ventricular ejection fraction as well as myocardial edema and non-ischemic fibrosis suggestive of inflammatory cardiomyopathy. She underwent intravenous diuresis and eventually started guideline-directed heart failure therapy. Follow-up cardiac magnetic resonance imaging five months later showed improved ejection fraction with mild non-ischemic fibrosis and resolution of myocardial edema and inflammation. She later received an allogeneic stem cell transplant from a matched unrelated donor. Conclusions Gilteritinib may be associated with early cardiotoxicities, including non-ischemic cardiomyopathy and myocarditis. Cardiac magnetic resonance imaging can be an important modality to help differentiate or diagnose early cardiotoxicities associated with novel targeted therapies.

Major immunotherapy challenges include a limited number of predictive biomarkers and the unusual imaging features post-therapy, such as pseudo-progression, which denote immune infiltrate-mediated tumor enlargement. Such phenomena confound clinical decision-making, since the cancer may eventually regress, and the patient should stay on treatment. We prospectively evaluated serial, blood-derived cell-free DNA (cfDNA) (baseline and 2–3 weeks post-immune checkpoint inhibitors [ICIs]) for variant allele frequency (VAF) and blood tumor mutation burden (bTMB) changes (next-generation sequencing) (N = 84 evaluable patients, diverse cancers). Low vs. high cfDNA-derived average adjusted ΔVAF (calculated by a machine-learning model) was an independent predictor of higher clinical benefit rate (stable disease ≥6 months/complete/partial response) (69.2% vs. 22.5%), and longer median progression-free (10.1 vs. 2.25 months) and overall survival (not reached vs. 6.1 months) (all P

Eosinophilic myocarditis (EM) is a rare cause of acute heart failure. It can occur secondary to drug hypersensitivity, autoimmune diseases such as vasculitis, idiopathic hypereosinophilic syndrome (HES) or malignancy, but is often under-recognized and underdiagnosed, being confused with other causes of heart failure. While EM is associated with various clinical symptoms, it is rarely associated with cardiac tamponade that requires urgent pericardiocentesis. Here we describe a patient with EM who presented with cardiac tamponade and decompensated heart failure likely secondary to autoimmune disease.

Objective: Person-centered contraceptive care is associated with positive reproductive health outcomes. Our objective was to analyze patients’ ratings on the newly developed Person-Centered Contraceptive Counseling scale (PCCC) to provide distributions for a nationally representative population and to assess differences by sociodemographic characteristics. Study design: Using data from 2017 to 2019 National Survey of Family Growth (NSFG), we analyzed ratings across the four PCCC items among 2242 women who received contraceptive counseling in the past year. Items measured patients’ reports of how providers respected them, let them describe their contraceptive preferences, took their preferences seriously, and adequately informed them about their options. We studied each PCCC item individually as well as the combined scale, distinguishing between ratings of “excellent” versus lower ratings. Bivariate and multivariate logistic regression models assessed how patients’ characteristics (age, race/ethnicity and English proficiency, sexual orientation, income, and parity) and provider type were associated with the likelihood of experiencing person-centered care. Results: The majority of women (59%–69%) reported that their family planning provider was “excellent” across the four PCCC items and just over half (51%) reported “excellent” on all items. In multivariate analyses, having a lower income, Black race, non-heterosexual identity, and Hispanic ethnicity combined with low English proficiency were associated with lower PCCC ratings. Conclusions: In a nationally representative sample, the PCCC captured variation in women's experiences with person-centered family planning care by sociodemographic characteristics. Findings highlight the need for contraceptive counseling that centers on clients’ preferences and experiences, particularly for patients who belong to groups experiencing health inequities. Implications: Person-centered care is a key component of high-quality family planning services. This analysis highlights sociodemographic disparities in person-centered care by analyzing PCCC ratings. Findings show the value of this new health care performance measure and affirm the need for family planning care that centers individuals' preferences and lived experiences.

The Patch-seq approach is a powerful variation of the patch-clamp technique that allows for the combined electrophysiological, morphological, and transcriptomic characterization of individual neurons. To generate Patch-seq datasets at scale, we identified and refined key factors that contribute to the efficient collection of high-quality data. We developed patch-clamp electrophysiology software with analysis functions specifically designed to automate acquisition with online quality control. We recognized the importance of extracting the nucleus for transcriptomic success and maximizing membrane integrity during nucleus extraction for morphology success. The protocol is generalizable to different species and brain regions, as demonstrated by capturing multimodal data from human and macaque brain slices. The protocol, analysis and acquisition software are compiled at https://githubcom/AllenInstitute/patchseqtools. This resource can be used by individual labs to generate data across diverse mammalian species and that is compatible with large publicly available Patch-seq datasets.

Abstract Background It is important to be able to reliably and feasibly measure infant and toddler physical activity in order to determine adherence to current physical activity guidelines and effects on early life development, growth and health. This study aimed to describe the development of an infant wearable wrist-worn band for the measurement of physical activity; to determine the feasibility of the device data for observational measurement of physical activity and to determine the caregiver reported acceptability of the infant wearable wrist band. Methods After various iterations of prototypes and piloting thereof, a final wearable band was designed to fit an Axivity AX3 monitor. Mother and infant/toddler (aged 3–24 months) pairs (n = 152) were recruited, and mothers were asked for their child to wear the band with enclosed monitor at all times for 1 week (minimum 3 days). Feasibility was assessed by determining technical reliability of the data, as well as wear time and compliance according to requirements for observational measurement. Acceptability was assessed via questionnaire. Results Technical reliability of the Axivity AX3 monitors in this age group was good. After excluding days that did not have at least 15 h of wear time, only 2% of participants had less than three valid days of data remaining, and 4% of participants had no data (due to device loss or data loss). Therefore, 94% of participants were compliant, having three or more days of wear with at least 15 h of wear per day, thus providing enough valid data for observational measurement. The majority (60%) of mothers reported being “very happy” with the safety of the device, while only 8% were “a little worried”. A large majority (86%) of mothers stated that the band attracted attention from others, although this was mostly attributed to curiosity about the function of the band. Most (80%) of participants rated the comfort of the band as “comfortable”, and 10% rated it as “very comfortable”. Conclusions The infant wearable band proved to be feasible and acceptable according to the criteria tested, and compliance wearing the band was good. We have therefore provided a replicable, comfortable and acceptable wearable band for the measurement of infant and toddler physical activity.

The purpose of this article is to report on thedevelopment of a proof-of-concept situational judgment test (SJT) to assist inthe selection of candidates for primary teacher education (ITE) programs. Ninedevelopment steps involving practising teachers, teacher educators, andapplicants to ITE programs were carried out to establish target attributes andto develop content for the test. The results from administering the test to 124primary ITE candidates showed a near-normal distribution, high levels ofreliability, and significant positive correlations with a range of concurrentlyadministered interview scores. We conclude with a description of the necessarynext steps needed to implement evidence-supported teacher education selectionprocesses in a range of international settings.

Alphaviruses are small enveloped viruses with positive-sense RNA genomes. During infection, the alphavirus capsid protein (Cp) selectively packages and assembles with the viral genomic RNA to form the nucleocapsid core, a process critical to the production of infectious virus. Prior studies of the alphavirus Semliki Forest virus (SFV) showed that packaging and assembly are promoted by Cp binding to multiple high affinity sites on the genomic RNA. Here, we developed an in vitro Cp binding assay based on fluorescently labeled RNA oligos. We used this assay to explore the RNA sequence and structure requirements for Cp binding to site #1, the top binding site identified on the genomic RNA during all stages of virus assembly. Our results identify a stem-loop structure that promotes specific binding of the SFV Cp to site #1 RNA. This structure is also recognized by the Cps of the related alphaviruses chikungunya virus and Ross River virus.

Rising levels of obesity in South Africa require innovation in community-level lifestyle change programmes. Our aim was to co-develop Impilo neZenkolo ('Health through Faith'), a healthy lifestyle programme for low-income, black South Africans delivered through churches, and evaluate its feasibility, acceptability and potential effectiveness. In the first phase we developed programme materials with church members. In the second phase we trained lay leaders to deliver the programme and assessed feasibility, acceptability (observation, focus groups and interviews) and potential effectiveness (pre and post measurement of weight, hip and waist circumferences, blood pressure, self-reported physical activity, dietary habits, health status, self-esteem, psychological distress). The study was conducted in four churches in urban and rural South Africa. The development workshops led to increased focus on positive benefits of participation, widening inclusion criteria to all adults and greater emphasis on Christian ethos. Challenges to feasibility included: recruitment of churches; scheduling of programme sessions (leading to one church not delivering the programme); attendance at the programme (63% attended more than half of the 12 weekly sessions); and poor programme fidelity (in particular in teaching behaviour change techniques). Aspects of the programme were acceptable, particularly the way in which the programme was aligned with a Christian ethos. There was some indication that amongst the 42/68 (62%) for whom we were obtained pre- and post-programme measurements the programme has potential to support weight loss. We conclude that a healthy lifestyle programme for low-income, black South Africans, delivered through churches, may be viable with extensive re-development of delivery strategies. These include finding external funding for the programme, endorsement from national level denominational organisations and the professionalization of programme leadership, including paid rather than volunteer leaders to ensure sufficient time can be spent in training.

BackgroundApheresis is an important treatment for reducing low‐density lipoprotein cholesterol (LDL‐C) in patients with familial hypercholesterolemia (FH). We systematically reviewed the current literature surrounding LDL‐C apheresis for FH. Methods and ResultsElectronic databases were searched for publications of LDL‐C apheresis in patients with FH. Inclusion criteria include articles in English published in 2000–2013 that provide descriptions of practice patterns, efficacy/effectiveness, and costs related to LDL‐C apheresis in patients with FH. Data were stratified by country and FH genotype where possible. Thirty‐eight studies met the inclusion criteria: 8 open‐label clinical trials, 11 observational studies, 17 reviews/guidelines, and 2 health technology assessments. The prevalence of FH was not well characterized by country, and underdiagnosis was a barrier to FH treatment. Treatment guidelines varied by country, with some guidelines recommending LDL‐C apheresis as first‐line treatment in patients with homozygous FH and after drug therapy failure in patients with heterozygous FH. Additionally, guidelines typically recommended weekly or biweekly LDL‐C apheresis treatments conducted at apheresis centers that may last 2 to >3 hours per session. Studies reported a range for mean LDL‐C reduction after apheresis: 57–75% for patients with homozygous FH and 58–63% for patients with heterozygous FH. Calculated annual costs (in US$2015) may reach US$66 374 to US$228 956 per patient for weekly treatment. ConclusionsLDL‐C apheresis treatment may be necessary for patients with FH when drug therapy is inadequate in reducing LDL‐C to target levels. While apheresis reduces LDL‐C, high per‐session costs and the frequency of guideline‐recommended treatment result in substantial annual costs, which are barriers to the optimal treatment of FH.