First-trimester exposure to newer antiretroviral agents and congenital anomalies in a U.S. cohort.

OBJECTIVE: To characterize associations of exposure to newer antiretroviral medications in the first trimester with congenital anomalies among infants born to persons with HIV in the United States. DESIGN: Longitudinal cohort of infants born 2012-2022 to pregnant persons with HIV enrolled in the Surveillance Monitoring for ART Toxicities (SMARTT) study. METHODS: First-trimester exposures to newer ARVs were abstracted from maternal medical records. Trained site staff conducted physical exams and abstracted congenital anomalies from infant medical records. Investigators classified anomalies using the Metropolitan Atlanta Congenital Defects Program classification system. The prevalence of major congenital anomalies identified by age one year was estimated for infants exposed and unexposed to each ARV. Generalized estimating equation models were used to estimate the odds ratio (OR) of major congenital anomalies for each ARV exposure, adjusting for potential confounders. RESULTS: Of 2034 infants, major congenital anomalies were identified in 135 (6.6%; 95% CI: 5.6%-7.8%). Cardiovascular (n = 43) and musculoskeletal (n = 37) anomalies were the most common. Adjusted ORs (95% CI) of congenital anomalies were 1.03 (0.62-1.72) for darunavir, 0.91 (0.46-1.81) for raltegravir, 1.04 (0.58-1.85) for rilpivirine, 1.31 (0.71-2.41) for elvitegravir, 0.76 (0.37-1.57) for dolutegravir, and 0.34 (0.05-2.51) for bictegravir, compared to those unexposed to each specific ARV. Findings were similar after adjustment for nucleoside/nucleotide backbones. CONCLUSIONS: The odds of congenital anomalies among infants with first-trimester exposure to newer ARVs did not differ substantially from those unexposed to these specific ARVs, which is reassuring. Continued evaluation of these ARVs with larger studies will be needed to confirm these findings.

Radical hope in parents of transgender and gender diverse youth in the United States.

Parental support is crucial in the well-being of transgender and gender diverse (TGD) youth. Research shows that parents of TGD youth often experience stigma and negative mental health outcomes as a result of being exposed to cissexist settings as they advocate and seek services for their child. Yet, there is a lack of research on the experiences of parents of TGD youth in the United States. This study explores the reported hopes of 990 parents (Mage = 48.6 years; SD = 6.7; 88.1% White; 67.3% heterosexual; 89.4% cisgender women) of TGD youth for their children (youth ages 3-18 years) in the United States. Radical hope framework is applied to unpack narratives of hopes by parents of TGD youth as a critical component of resistance and motivation toward healing from oppression. For this study, the following open-ended question was analyzed using thematic analysis: What is your greatest hope for your child? Four main themes and 11 subthemes of parental hopes emerged: (1) living authentically (freely expressing themselves, developing self-love, living a happy and normal life), (2) interpersonal connections (finding community, building social networks and friendships, developing romantic relationships, building their own family, and loved by others), (3) meeting life milestones (career and employment, achieving goals and dreams, and becoming an advocate), and (4) acceptance by society. We provide clinical recommendations grounded on the tenets of radical hope such as collective ways in which parents of TGD youth can engage in both resisting systemic oppression and building strong loving relationships with their child. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Design principles and therapeutic applications of novel synthetic WNT signaling agonists.

Wingless-related integration site or Wingless and Int-1 or Wingless-Int (WNT) signaling is crucial for embryonic development, and adult tissue homeostasis and regeneration, through its essential roles in cell fate, patterning, and stem cell regulation. The biophysical characteristics of WNT ligands have hindered efforts to interrogate ligand activity in vivo and prevented their development as therapeutics. Recent breakthroughs have enabled the generation of synthetic WNT signaling molecules that possess characteristics of natural ligands and potently activate the pathway, while also providing distinct advantages for therapeutic development and manufacturing. This review provides a detailed discussion of the protein engineering of these molecular platforms for WNT signaling agonism. We discuss the importance of WNT signaling in several organs and share insights from the initial application of these new classes of molecules in vitro and in vivo. These molecules offer a unique opportunity to enhance our understanding of how WNT signaling agonism promotes tissue repair, enabling targeted development of tailored therapeutics.

Recombinant inbred line panels inform the genetic architecture and interactions of adaptive traits in Drosophila melanogaster.

The distribution of allelic effects on traits, along with their gene-by-gene and gene-by-environment interactions, contributes to the phenotypes available for selection and the trajectories of adaptive variants. Nonetheless, uncertainty persists regarding the effect sizes underlying adaptations and the importance of genetic interactions. Herein, we aimed to investigate the genetic architecture and the epistatic and environmental interactions involving loci that contribute to multiple adaptive traits using two new panels of Drosophila melanogaster recombinant inbred lines (RILs). To better fit our data, we re-implemented functions from R/qtl (Broman et al. 2003) using additive genetic models. We found 14 quantitative trait loci (QTL) underlying melanism, wing size, song pattern, and ethanol resistance. By combining our mapping results with population genetic statistics, we identified potential new genes related to these traits. None of the detected QTLs showed clear evidence of epistasis, and our power analysis indicated that we should have seen at least one significant interaction if sign epistasis or strong positive epistasis played a pervasive role in trait evolution. In contrast, we did find roles for gene-by-environment interactions involving pigmentation traits. Overall, our data suggest that the genetic architecture of adaptive traits often involves alleles of detectable effect, that strong epistasis does not always play a role in adaptation, and that environmental interactions can modulate the effect size of adaptive alleles.

Phosphaturia in HIV-exposed Uninfected Neonates Associated with Maternal Use of Tenofovir Disoproxil Fumarate in Late Pregnancy.

BACKGROUND: Tenofovir disoproxil fumarate (TDF) is often used in treating pregnant women living with HIV. Third trimester TDF exposure is associated with a 12% reduction in bone mineral content in HIV-exposed uninfected (HEU) neonates. Potential mechanisms underlying this observation are unknown. METHODS: The TDF study enrolled newborns of gestational age ≥36 weeks from the Surveillance Monitoring for Antiretroviral Therapy and Toxicities study based on in utero TDF exposure (TDF use ≥8 weeks in third trimester versus none). Blood and urine samples were collected cross-sectionally within 30 days of birth to assess renal function (serum creatinine, serum phosphate, eGFR, percent tubular reabsorption of phosphate [PTRP]), and bone turnover (serum parathyroid hormone, 25-OH vitamin D [25(OH)D], and urinary cross-linked N-telopeptide of type 1 collagen). For each biomarker, a LOESS plot was fit using values at age at specimen collection; regression lines over age were fit among samples collected from 4-30 days, to compare slopes by TDF exposure. RESULTS: Among 141 neonates, 77 were TDF-exposed and 64 TDF-unexposed. Between age 4 and 30 days, PTRP decreased more rapidly in the TDF-exposed compared to the unexposed group with slopes of -0.58 versus -0.08/day (difference -0.50/day [95%CI -0.88, -0.11]). Slopes for 25(OH)D were similar in both groups, but serum levels lower in TDF-exposed neonates (median [IQR]: 22 [19, 29] versus 26 [22,37] ng/mL). No differences were observed for other biomarkers. CONCLUSIONS: Third trimester in utero exposure to TDF is associated with increased urinary loss of phosphate and lower serum concentrations of 25(OH)D in HEU neonates.

On an electromagnetic calculation of ionospheric conductance that seems to override the field line integrated conductivity.

The ionospheric conductance is the major quantity that determines the interaction of the magnetosphere with the ionosphere, where the magnetosphere is the large region of space affected by Earth's geomagnetic field, and the ionosphere is its electrically conducting inner boundary, lying right on the edge of the atmosphere. Storms and substorms in space dissipate their energy through ionospheric currents, which heat the atmosphere and disrupt satellite orbits. The ionospheric conductance has, heretofore, been estimated using the staticized physics known as electrostatic theory, which finds that it can be computed by integrating the zero-frequency conductivity along the lines of Earth's geomagnetic field. In this work we test this supposition by deriving an electromagnetic solution for collisional plasma, and applying it to obtain a first-ever fully-electromagnetic calculation of ionospheric conductance. We compare the results to the field line integrated conductivity, and find significant differences on all scales investigated. We find short-wavelength, mode-mixing, and wave-admittance effects that were completely unexpected. When this theoretical result is matched with recent observational findings for the scale of the magnetosphere-ionosphere coupling-interaction, there results a situation where small- to intermediate-scale effects really may contribute to global modeling of the Sun-Earth system.

A WNT mimetic with broad spectrum FZD-specificity decreases fibrosis and improves function in a pulmonary damage model.

BACKGROUND: Wnt/ß-catenin signaling is critical for lung development and AT2 stem cell maintenance in adults, but excessive pathway activation has been associated with pulmonary fibrosis, both in animal models and human diseases such as idiopathic pulmonary fibrosis (IPF). IPF is a detrimental interstitial lung disease, and although two approved drugs limit functional decline, transplantation is the only treatment that extends survival, highlighting the need for regenerative therapies. METHODS: Using our antibody-based platform of Wnt/ß-catenin modulators, we investigated the ability of a pathway antagonist and pathway activators to reduce pulmonary fibrosis in the acute bleomycin model, and we tested the ability of a WNT mimetic to affect alveolar organoid cultures. RESULTS: A WNT mimetic agonist with broad FZD-binding specificity (FZD1,2,5,7,8) potently expanded alveolar organoids. Upon therapeutic dosing, a broad FZD-binding specific Wnt mimetic decreased pulmonary inflammation and fibrosis and increased lung function in the bleomycin model, and it impacted multiple lung cell types in vivo. CONCLUSIONS: Our results highlight the unexpected capacity of a WNT mimetic to effect tissue repair after lung damage and support the continued development of Wnt/ß-catenin pathway modulation for the treatment of pulmonary fibrosis.

Patient-derived response estimates from zero-passage organoids of luminal breast cancer.

Background: Primary luminal breast cancer cells lose their identity rapidly in standard tissue culture, which is problematic for testing hormone interventions and molecular pathways specific to the luminal subtype. Breast cancer organoids are thought to retain tumor characteristics better, but long-term viability of luminal-subtype cases is a persistent challenge. Our goal was to adapt short-term organoids of luminal breast cancer for parallel testing of genetic and pharmacologic perturbations. Methods: We freshly isolated patient-derived cells from luminal tumor scrapes, miniaturized the organoid format into 5 µl replicates for increased throughput, and set an endpoint of 14 days to minimize drift. Therapeutic hormone targeting was mimicked in these "zero-passage" organoids by withdrawing ß-estradiol and adding 4-hydroxytamoxifen. We also examined sulforaphane as an electrophilic stress and commercial neutraceutical with reported anti-cancer properties. Downstream mechanisms were tested genetically by lentiviral transduction of two complementary sgRNAs and Cas9 stabilization for the first week of organoid culture. Transcriptional changes were measured by RT-qPCR or RNA sequencing, and organoid phenotypes were quantified by serial brightfield imaging, digital image segmentation, and regression modeling of cellular doubling times. Results: We achieved >50% success in initiating luminal breast cancer organoids from tumor scrapes and maintaining them to the 14-day zero-passage endpoint. Success was mostly independent of clinical parameters, supporting general applicability of the approach. Abundance of ESR1 and PGR in zero-passage organoids consistently remained within the range of patient variability at the endpoint. However, responsiveness to hormone withdrawal and blockade was highly variable among luminal breast cancer cases tested. Combining sulforaphane with knockout of NQO1 (a phase II antioxidant response gene and downstream effector of sulforaphane) also yielded a breadth of organoid growth phenotypes, including growth inhibition with sulforaphane, growth promotion with NQO1 knockout, and growth antagonism when combined. Conclusions: Zero-passage organoids are a rapid and scalable way to interrogate properties of luminal breast cancer cells from patient-derived material. This includes testing drug mechanisms of action in different clinical cohorts. A future goal is to relate inter-patient variability of zero-passage organoids to long-term outcomes.

Are Instagram Gym Advertisements Working Out? An Experimental Study of Model Body-Size and Slogan-Type.

Previous health communication research has demonstrated the negative psychological and health effects of depicting thin-sized models in mass media advertisements including on social media sites such as Instagram. However, gym advertisements are one common source for the presentation of lean and thin-sized models on Instagram. Therefore, the current study guided by social comparison theory and signaling theory aimed to experimentally examine the effect of thin-sized models relative to plus-sized models as well as slogan-type (health and wellness versus physique-based) on women's appearance comparison, body satisfaction, perceived gym fit, and intentions to join the gym. A sample of 217 undergraduate students who identified as women were randomly assigned to one of four Instagram gym advertisement conditions varying in model body-size and slogan-type. Appearance comparisons, perceived gym fit, and intentions to join the gym were measured post advertisement exposure and body satisfaction was measured pre-and-post advertisement exposure. As expected, exposure to Instagram gym advertisements featuring thin-sized models resulted in greater appearance comparisons and lower body satisfaction than exposure to Instagram gym advertisements featuring plus-sized models. Moreover, the combination of plus-sized models with health and wellness slogans in Instagram gym advertisements resulted in greater gym fit perceptions although there was no effect of model body-size and slogan-type on intentions to join the gym. This study supports social comparison theory, signaling theory, and practically the findings indicate that Instagram gym advertisements that depict plus-sized models (versus thin) with health-and-wellness slogans (versus physique) generate fewer body image concerns and lead to greater gym fit perceptions.

Climate change drives migratory range shift via individual plasticity in shearwaters.

How individual animals respond to climate change is key to whether populations will persist or go extinct. Yet, few studies investigate how changes in individual behavior underpin these population-level phenomena. Shifts in the distributions of migratory animals can occur through adaptation in migratory behaviors, but there is little understanding of how selection and plasticity contribute to population range shift. Here, we use long-term geolocator tracking of Balearic shearwaters (Puffinus mauretanicus) to investigate how year-to-year changes in individual birds' migrations underpin a range shift in the post-breeding migration. We demonstrate a northward shift in the post-breeding range and show that this is brought about by individual plasticity in migratory destination, with individuals migrating further north in response to changes in sea-surface temperature. Furthermore, we find that when individuals migrate further, they return faster, perhaps minimizing delays in return to the breeding area. Birds apparently judge the increased distance that they will need to migrate via memory of the migration route, suggesting that spatial cognitive mechanisms may contribute to this plasticity and the resulting range shift. Our study exemplifies the role that individual behavior plays in populations' responses to environmental change and highlights some of the behavioral mechanisms that might be key to understanding and predicting species persistence in response to climate change.

Impact of a pharmacist-driven COPD clinic on outcomes related to COPD in a federally qualified health center.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) affects many patients across the United States. Morbidity related to COPD can lead to increased financial strain to health care system. The United States is also shifting toward value-based payments, which rely on satisfying quality measures. Pharmacists are equipped with knowledge in adjusting medications based on symptom burden and guideline recommendations in COPD and are equipped with the proper knowledge to address quality measures. OBJECTIVE: This project aimed to determine the impact of a clinical pharmacy service centered around inhaler education and optimization on COPD morbidity and Uniform Data System (UDS) quality measure satisfaction in a federally qualified health center. METHODS: This quality improvement project consisted of patient referrals by and reports from a population health software for the pharmacy service from November 2022 to March 2023. The outcomes in this study included symptom change measured by follow-up modified Medical Research Council (mMRC) Dyspnea Scale in addition to changes in compliance with UDS quality measures. At follow-up, patients were administered another mMRC to evaluate treatment effect and determine quality measure satisfaction. RESULTS: Thirteen patient visits were conducted. Most patients were female (84.6%) with an exacerbation in the previous year (46.1%). All patients received an adjustment in their pharmacotherapy along with inhaler education. The average baseline mMRC score decreased from 2.1 to 0.6, indicating a decrease in overall COPD symptoms. Five quality measures of 13 were satisfied during the follow-up period. CONCLUSION: The COPD clinical pharmacy service led to an increase in guideline-driven pharmacotherapy regimens for patients with COPD while having an overall decrease in morbidity. Quality measures were also addressed and satisfied after the appointment. Continuation of this quality improvement service will ensure proper assessment of COPD along with addressing UDS quality measures.

Racing Performance and Sale Result in 145 Thoroughbreds after Arthroscopic Removal of Osteochondral Fragments from the Lateral Femoral Trochlear Ridge as a Yearling (2012-2015).

OBJECTIVES: The lateral trochlear ridge (LTR) of the femur is the most common predilection site for osteochondritis dissecans (OCD) in the equine stifle. The objective was to investigate the relationship between lesion size, racing performance, and sale result of Thoroughbreds with LTR OCD following arthroscopic removal as a yearling. METHODS: In this retrospective study, medical records of 145 Thoroughbreds from one equine hospital that underwent surgery for LTR OCD were reviewed; the length and depth of the lesions were measured on preoperative radiographs. Horses were allocated to group S if they were presented to a public yearling sale post-surgery, and horses in group NS were not. Each horse from group S was matched with two control horses from the same sale (group C). Influence of lesion size on racing performance and sale result was analyzed. Racing performance and sale results were compared between different categories of OCD lesion sizes and between the groups. RESULTS: Lesion length and depth did not affect racing performance and did not differ between group S and group NS. However, group S did perform significantly better than group NS. When comparing groups S and C, there were no significant differences in racing performance and sale result. CONCLUSION: Thoroughbreds that had arthroscopic surgery for LTR OCD as a yearling and were presented on a public yearling sale performed comparable to Thoroughbreds that showed similar potential as a yearling. Sale result is not significantly affected in our study.

Sexual Orientation-Based Victimization and Internalized Homonegativity Among Latinx Sexual Minority Youth: The Moderating Effects of Social Support and School Level.

Latinx sexual minority adolescents and young adults experience sexual orientation-based victimization at school and may internalize these heterosexist experiences. However, social support may buffer the deleterious contributions of sexual orientation-based victimization. The current study explored associations between sexual orientation-based victimization and internalized homonegativity in different social contexts (family, peer, school adult) and across development (high school versus college) among 238 Latinx sexual minority adolescents and young adults (M = 19.03, SD = 2.28). Results indicated that sexual orientation-based victimization was positively associated with internalized homonegativity among Latinx sexual minority adolescents and young adults. Such associations were moderated by family support and the school level in the family context, such that in high school, family support exacerbated the association between sexual orientation-based victimization and internalized homonegativity. Yet, in college, family support mitigated that association. Findings also indicated that peer support exacerbated the association between sexual orientation-based victimization and internalized homonegativity in high school and college. No moderation of school adult support emerged in the context of school adults. Findings support the application of the minority stress model in Latinx sexual minority adolescents and young adults and highlight the complex moderating effect of social support across social contexts and development.

ACR Appropriateness Criteria® Staging and Post-Therapy Assessment of Head and Neck Cancer.

Imaging of head and neck cancer at initial staging and as part of post-treatment surveillance is a key component of patient care as it guides treatment strategy and aids determination of prognosis. Head and neck cancer includes a heterogenous group of malignancies encompassing several anatomic sites and histologies, with squamous cell carcinoma the most common. Together this comprises the seventh most common cancer worldwide. At initial staging comprehensive imaging delineating the anatomic extent of the primary site, while also assessing the nodal involvement of the neck is necessary. The treatment of head and neck cancer often includes a combination of surgery, radiation, and chemotherapy. Post-treatment imaging is tailored for the evaluation of treatment response and early detection of local, locoregional, and distant recurrent tumor. Cross-sectional imaging with CT or MRI is recommended for the detailed anatomic delineation of the primary site. PET/CT provides complementary metabolic information and can map systemic involvement. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.

Implementation of California COVIDNet - a multi-sector collaboration for statewide SARS-CoV-2 genomic surveillance.

Introduction: The SARS-CoV-2 pandemic represented a formidable scientific and technological challenge to public health due to its rapid spread and evolution. To meet these challenges and to characterize the virus over time, the State of California established the California SARS-CoV-2 Whole Genome Sequencing (WGS) Initiative, or "California COVIDNet". This initiative constituted an unprecedented multi-sector collaborative effort to achieve large-scale genomic surveillance of SARS-CoV-2 across California to monitor the spread of variants within the state, to detect new and emerging variants, and to characterize outbreaks in congregate, workplace, and other settings. Methods: California COVIDNet consists of 50 laboratory partners that include public health laboratories, private clinical diagnostic laboratories, and academic sequencing facilities as well as expert advisors, scientists, consultants, and contractors. Data management, sample sourcing and processing, and computational infrastructure were major challenges that had to be resolved in the midst of the pandemic chaos in order to conduct SARS-CoV-2 genomic surveillance. Data management, storage, and analytics needs were addressed with both conventional database applications and newer cloud-based data solutions, which also fulfilled computational requirements. Results: Representative and randomly selected samples were sourced from state-sponsored community testing sites. Since March of 2021, California COVIDNet partners have contributed more than 450,000 SARS-CoV-2 genomes sequenced from remnant samples from both molecular and antigen tests. Combined with genomes from CDC-contracted WGS labs, there are currently nearly 800,000 genomes from all 61 local health jurisdictions (LHJs) in California in the COVIDNet sequence database. More than 5% of all reported positive tests in the state have been sequenced, with similar rates of sequencing across 5 major geographic regions in the state. Discussion: Implementation of California COVIDNet revealed challenges and limitations in the public health system. These were overcome by engaging in novel partnerships that established a successful genomic surveillance program which provided valuable data to inform the COVID-19 public health response in California. Significantly, California COVIDNet has provided a foundational data framework and computational infrastructure needed to respond to future public health crises.

Determination of the Terbium-152 half-life from mass-separated samples from CERN-ISOLDE and assessment of the radionuclide purity.

Terbium-152 is one of four terbium radioisotopes that together form a potential theranostic toolbox for the personalised treatment of tumours. As 152 Tb decay by positron emission it can be utilised for diagnostics by positron emission tomography. For use in radiopharmaceuticals and for activity measurements by an activity calibrator a high radionuclide purity of the material and an accurate and precise knowledge of the half-life is required. Mass-separation and radiochemical purification provide a production route of high purity 152Tb. In the current work, two mass-separated samples from the CERN-ISOLDE facility have been assayed at the National Physical Laboratory to investigate the radionuclide purity. These samples have been used to perform four measurements of the half-life by three independent techniques: high-purity germanium gamma-ray spectrometry, ionisation chamber measurements and liquid scintillation counting. From the four measurement campaigns a half-life of 17.8784(95) h has been determined. The reported half-life shows a significant difference to the currently evaluated half-life (ζ-score = 3.77), with a relative difference of 2.2 % and an order of magnitude improvement in the precision. This work also shows that under controlled conditions the combination of mass-separation and radiochemical separation can provide high-purity 152Tb.

A comparison of different approaches for the analysis of 36Cl in graphite samples.

This study compares different approaches for the quantification of the massic activity of 36Cl in graphite samples. All approaches consisted of a combustion step in combination with a trapping solution to collect the volatile elements. Two different resins were used to separate 36Cl from the matrix (CL resin and PS resin). Liquid scintillation counting (LSC), scintillation counting (SC) and tandem inductively coupled plasma mass spectrometry (ICP-MS/MS) were used to quantify 36Cl activity. The chemical yield in all approaches was determined by means of ion chromatography (IC). In addition, the methods were applied to a real activated graphite sample.

A hybridization target enrichment approach for pathogen genomics.

IMPORTANCE: Emerging infectious diseases require continuous pathogen monitoring. Rapid clinical diagnosis by nucleic acid amplification is limited to a small number of targets and may miss target detection due to new mutations in clinical isolates. Whole-genome sequencing (WGS) identifies genome-wide variations that may be used to determine a pathogen's drug resistance patterns and phylogenetically characterize isolates to track disease origin and transmission. WGS is typically performed using DNA isolated from cultured clinical isolates. Culturing clinical specimens increases turn-around time and may not be possible for fastidious bacteria. To overcome some of these limitations, direct sequencing of clinical specimens has been attempted using expensive capture probes to enrich the entire genomes of target pathogens. We present a method to produce a cost-effective, time-efficient, and large-scale synthesis of probes for whole-genome enrichment. We envision that our method can be used for direct clinical sequencing of a wide range of microbial pathogens for genomic epidemiology.