Persist Or Perish: Mechanisms of Persistence And Recovery Potential in Bats Threatened with Extinction by White-nose Syndrome.

Emerging mycoses are an increasing concern in wildlife and human health. Given the historical rarity of fungal pathogens in warm-bodied vertebrates, there is a need to better understand how to manage mycoses and facilitate recovery in affected host populations. We explore challenges to host survival and mechanisms of host recovery in three bat species (Myotis lucifugus, Perimyotis subflavus, and M. septentrionalis) threatened with extinction by the mycosis, White-nose Syndrome (WNS) as it continues to spread across North America. We present evidence from the literature that bats surviving WNS are exhibiting mechanisms of avoidance (by selecting microclimates within roosts) and tolerance (by increasing winter fat reserves), which may help avoid costs of immunopathology incurred by a maladaptive host resistance response. We discuss management actions for facilitating species recovery that take into consideration disease pressures (e.g., environmental reservoir) and mechanisms underlying persistence, and suggest strategies that alleviate costs of immunopathology and target mechanisms of avoidance (protect or create refugia) and tolerance (increase body condition). We also propose strategies that target population and species-level recovery, including increasing reproductive success and reducing other stressors (e.g., wind turbine mortality). The rarity of fungal pathogens paired with the increasing frequency of emerging mycoses in warm-bodied vertebrate systems, including humans, requires a need to challenge common conventions about how diseases operate, how hosts respond, and how these systems could be managed to increase probability of recovery in host populations.

Effect of a Comprehensive School-Based Health Center on Academic Growth in K-8th Grade Students.

OBJECTIVE: School-based health centers (SBHCs) improve health care access, but associations with educational outcomes are mixed and limited for elementary and middle school students. We investigated whether students enrolled in a comprehensive SBHC demonstrated more growth in standardized math and reading assessments over 4 school years versus nonenrolled students. We also explored changes in absenteeism. METHODS: Participants were students enrolled in 2 co-located Title I schools from 2015-19 (1 elementary, 1 middle, n = 2480). Analysis of math and reading was limited to students with baseline and postbaseline scores (math n = 1622; reading n = 1607). Longitudinal regression models accounting for within-subject clustering were used to estimate the association of SBHC enrollment with academic scores and daily absenteeism, adjusting for grade, sex, body mass index category, health conditions, baseline outcomes (scores or absenteeism), and outcome pretrends. RESULTS: More than 70% of SBHC-enrolled students had math (1194 [73.6%]) and reading 1186 [73.8%]) scores. Enrollees were more likely than nonenrollees to have asthma (39.7% vs 19.6%) and overweight/obesity (42.4% vs 33.6%). Adjusted baseline scores were significantly lower in math and reading for enrollees. Mean change from baseline for enrollees exceeded nonenrollees by 3.5 points (95% confidence interval [CI]: 2.2, 4.8) in math and 2.1 points (95% CI: 0.9, 3.3) in reading. The adjusted rate of decrease in daily absenteeism was 10.8% greater for enrollees (incident rate ratio 0.772 [95% CI: 0.623, 0.956]) than nonenrollees (incident rate ratio 0.865 [95% CI: 0.696, 1.076]). CONCLUSIONS: SBHC enrollees had greater health and educational risk but demonstrated more growth in math and reading and less absenteeism than nonenrollees.

Biomarker and pharmacodynamic activity of the transforming growth factor-beta (TGFß) inhibitor SAR439459 as monotherapy and in combination with cemiplimab in a phase I clinical study in patients with advanced solid tumors.

SAR439459, a 'second-generation' human anti-transforming growth factor-beta (TGFß) monoclonal antibody, inhibits all TGFß isoforms and improves the antitumor activity of anti-programmed cell death protein-1 therapeutics. This study reports the pharmacodynamics (PD) and biomarker results from phase I/Ib first-in-human study of SAR439459 ± cemiplimab in patients with advanced solid tumors (NCT03192345). In dose-escalation phase (Part 1), SAR439459 was administered intravenously at increasing doses either every 2 weeks (Q2W) or every 3 weeks (Q3W) with cemiplimab IV at 3 mg/kg Q2W or 350 mg Q3W, respectively, in patients with advanced solid tumors. In dose-expansion phase (Part 2), patients with melanoma received SAR439459 IV Q3W at preliminary recommended phase II dose (pRP2D) of 22.5/7.5 mg/kg or at 22.5 mg/kg with cemiplimab 350 mg IV Q3W. Tumor biopsy and peripheral blood samples were collected for exploratory biomarker analyses to assess target engagement and PD, and results were correlated with patients' clinical parameters. SAR439459 ± cemiplimab showed decreased plasma and tissue TGFß, downregulation of TGFß-pathway activation signature, modulation of peripheral natural killer (NK) and T cell expansion, proliferation, and increased secretion of CXCL10. Conversion of tumor tissue samples from 'immune-excluded' to 'immune-infiltrated' phenotype in a representative patient with melanoma SAR439459 22.5 mg/kg with cemiplimab was observed. In paired tumor and plasma, active and total TGFß1 was more consistently elevated followed by TGFß2, whereas TGFß3 was only measurable (lower limit of quantitation ≥2.68 pg/mg) in tumors. SAR439459 ± cemiplimab showed expected peripheral PD effects and TGFß alteration. However, further studies are needed to identify biomarkers of response.

The impact of COVID-19 on psychiatric clinical encounters among low-income racially-diverse children.

BACKGROUND: There is a lack of longitudinal data to examine the impact of COVID-19 on all types of clinical encounters among United States, underrepresented BIPOC (Black, Indigenous, and people of color), children. This study aims to examine the changes in all the outpatient clinical encounters during the pandemic compared to the baseline, with particular attention to psychiatric encounters and diagnoses. METHOD: This study analyzed 3-year (January 2019 to December 2021) longitudinal clinical encounter data from 3,394 children in the Boston Birth Cohort, a US urban, predominantly low-income, Black and Hispanic children. Outcomes of interest were completed outpatient clinical encounters and their modalities (telemedicine vs. in person), including psychiatric care and diagnoses, primary care, emergency department (ED), and developmental and behavioral pediatrics (DBP). RESULTS: The study children's mean (SD) age is 13.9 (4.0) years. Compared to 2019, psychiatric encounters increased by 38% in 2020, most notably for diagnoses of adjustment disorders, depression, and post-traumatic stress disorders (PTSD). In contrast, primary care encounters decreased by 33%, ED encounters decreased by 55%, and DBP care decreased by 16% in 2020. Telemedicine was utilized the most for psychiatric and DBP encounters and the least for primary care encounters in 2020. A remarkable change in 2021 was the return of primary care encounters to the 2019 level, but psychiatric encounters fluctuated with spikes in COVID-19 case numbers. CONCLUSIONS: Among this sample of US BIPOC children, compared to the 2019 baseline, psychiatric encounters increased by 38% during 2020, most notably for the new diagnoses of adjustment disorder, depression, and PTSD. The 2021 data showed a full recovery of primary care encounters to the baseline level but psychiatric encounters remained sensitive to the pandemic spikes. The long-term impact of the pandemic on children's mental health warrants further investigation.

Adjuvant Systemic Therapies for Resected Stages III and IV Melanoma: A Multi-Center Retrospective Clinical Study.

BACKGROUND: Adjuvant therapies have been approved for resected melanoma based on improved recurrence-free survival. We present early findings from a real-world study on adjuvant treatments for melanoma. METHODS: A comprehensive chart review was conducted for patients receiving adjuvant systemic therapy for resected high-risk stages III and IV melanoma. Statistical analysis was performed to assess recurrence-free survival and subgroup differences. RESULTS: A total of 149 patients (median age = 58.0 years, 61.1% men, 49.7% with BRAF V600E/K genotypes) were included, with 94.6% having resected stage III melanoma. Anti-PD-1 immunotherapy was received by 86.5% of patients, while 13.4% received BRAF-targeted therapy. At a median follow-up of 22.4 months, the recurrence rate was 31.5%, with 1-year and 2-year recurrence-free survival rates of 79% and 62%, respectively. Similar recurrence rates were observed between anti-PD-1 immunotherapy and BRAF-targeted therapy. Long-term toxicity affected 27.4% of patients, with endocrinopathies and late-emergent immune-related adverse events being common. CONCLUSIONS: Real-world adjuvant systemic therapy aligns with clinical trial practice. Recurrence rates remain high despite treatment, and long-term toxicities, including endocrinopathies and chronic inflammatory conditions, are not uncommon.

High-dose chemotherapy with autologous stem-cell transplantation for relapsed metastatic germ cell tumors The Alberta experience.

INTRODUCTION: High-dose chemotherapy with autologous stem-cell transplantation (HDC-ASCT) is standard therapy for metastatic germ cell tumors (mGCTs) in patients whose disease progresses during or after conventional chemotherapy. We conducted a retrospective review of HDC-ASCT in relapsed mGCT patients in the province of Alberta, Canada, over the past two decades. METHODS: Patients with mGCTs who received HDC-ASCT at two provincial cancer referral centers from 2000-2018 were identified from institutional databases. Baseline clinical and treatment characteristics were collected, as well as overall survival (OS ) and disease-free survival (DFS). Relevant prognostic variables were analyzed. RESULTS: Forty-three patients were identified. The median age was 28 years (range 19-56). A majority (95%) had non-seminoma histology and testis/retroperitoneal primary (84%). Twenty patients (47%) had poor-risk disease, as per The International Germ Cell Consensus Classification (IGCCC), at start of first-line chemotherapy. HDC-ASCT was used as second-line therapy in 65% of patients, and 58% of ASCT patients received tandem transplants. Median followup after ASCT was 22 months (range 2-181). At last followup, 42% of patients were alive without disease, including 3/7 (43%) of patients with primary mediastinal disease. Two-year and five-year DFS/OS ratios were 44%/65% and 38%/45%, respectively. Median OS and DFS for all patients were 30.0 months (13.3-46.6) and 8.0 months (0.9-15.1), respectively. CONCLUSIONS: We found that HDC-ASCT is an effective salvage therapy in mGCT, consistent with existing literature. Patients appeared to benefit regardless of primary site. Although limited by small sample size, we found a numerical difference in DFS and OS between second- and third-line HDC-ASCT and single vs. tandem ASCT.

Effectiveness of Immune Checkpoint Inhibitor with Anti-PD-1 Monotherapy or in Combination with Ipilimumab in Younger versus Older Adults with Advanced Melanoma.

Background: The majority of melanoma is diagnosed in individuals between 55 and 84 years old. Current data varied in reporting differences in survival outcomes amongst different age groups. Methods: A retrospective, multi-center, provincial cohort database was used to investigate the relationship between age (<65 or ≥65 years old) and overall survival. Patients must have had histologically confirmed locally advanced or metastatic melanoma and had to have received at least one cycle of immunotherapy (single agent nivolumab, pembrolizumab, or combination ipilimumab plus nivolumab). Results: From August 2013 to May 2020, we identified 497 patients (median age = 64 [range 12-96 years]; 65.2% men; 36.4% with a BRAF mutation (V600E and V600K)). Of these, 260 were < 65 years old, and 237 were ≥65 years old. A total of 39.1% of the patients in the younger cohort received combination ICI compared with 10.2% in the older cohort, and the difference was statistically significant. Median survival amongst individuals aged ≥65 years old was shorter compared to individuals <65 years old, with a median overall survival of 17.1 (95% CI 12.3-22.9 months) months and 22.2 months (95% CI 18.7-33.8 months), respectively (p = 0.04), at a median follow-up of 34.4 months (range: 1.84-81.4 months). The survival difference was present in the cutaneous melanoma cohort where median OS was 18.2 months (95% CI 12.3-30.4 months) in patients ≥65 years old and 23.8 months (95% CI 19.2-48.2 months) in patients <65 years old, p = 0.04. There were no significant differences by age in the non-cutaneous melanoma cohort. A combination of nivolumab plus ipilimumab was associated with an improved overall survival hazard ratio of 0.48 (95% CI 0.36-0.65) as compared to anti-PD-1 monotherapy alone (p < 0.001). In the cutaneous cohort treated with anti-PD-1 monotherapy (n = 306), no significant differences were seen with median OS at 16.1 months (95% CI 11.4-25.7 months) in patients ≥65 years old and 17.1 months (95% CI 12.0-22.2 months) in patients <65 years old (p = 0.84). Tumor response to anti-PD-1 was higher in the older patients compared with the response in younger patients with cutaneous melanoma. Conclusions: Older melanoma patients have similar survival compared with younger patients after receiving the same treatment with anti-PD-1 monotherapy. The superior survival observed in the younger patients is possibly related to the higher utilization of combination ICI. Tumor response to immunotherapy is superior in older patients with cutaneous melanoma; however, younger patients may improve their survival by using combination ICI.

White-nose syndrome restructures bat skin microbiomes.

IMPORTANCE: Inherent complexities in the composition of microbiomes can often preclude investigations of microbe-associated diseases. Instead of single organisms being associated with disease, community characteristics may be more relevant. Longitudinal microbiome studies of the same individual bats as pathogens arrive and infect a population are the ideal experiment but remain logistically challenging; therefore, investigations like our approach that are able to correlate invasive pathogens to alterations within a microbiome may be the next best alternative. The results of this study potentially suggest that microbiome-host interactions may determine the likelihood of infection. However, the contrasting relationship between Pd and the bacterial microbiomes of Myotis lucifugus and Perimyotis subflavus indicate that we are just beginning to understand how the bat microbiome interacts with a fungal invader such as Pd.

Defining longitudinal trajectory of body mass index percentile and predicting childhood obesity: methodologies and findings in the Boston Birth Cohort.

Background: Overweight or obesity (OWO) in school-age childhood tends to persist into adulthood. This study aims to address a critical need for early identification of children at high risk of developing OWO by defining and analyzing longitudinal trajectories of body mass index percentile (BMIPCT) during early developmental windows. Methods: We included 3029 children from the Boston Birth Cohort (BBC) with repeated BMI measurements from birth to age 18 years. We applied locally weighted scatterplot smoothing with a time-limit scheme and predefined rules for imputation of missing data. We then used time-series K-means cluster analysis and latent class growth analysis to define longitudinal trajectories of BMIPCT from infancy up to age 18 years. Then, we investigated early life determinants of the BMI trajectories. Finally, we compared whether using early BMIPCT trajectories performs better than BMIPCT at a given age for predicting future risk of OWO. Results: After imputation, the percentage of missing data ratio decreased from 36.0% to 10.1%. We identified four BMIPCT longitudinal trajectories: early onset OWO; late onset OWO; normal stable; and low stable. Maternal OWO, smoking, and preterm birth were identified as important determinants of the two OWO trajectories. Our predictive models showed that BMIPCT trajectories in early childhood (birth to age 1 or 2 years) were more predictive of childhood OWO (age 5-10 years) than a single BMIPCT at age 1 or 2 years. Conclusions: Using longitudinal BMIPCT data from birth to age 18 years, this study identified distinct BMIPCT trajectories, examined early life determinants of these trajectories, and demonstrated their advantages in predicting childhood risk of OWO over BMIPCT at a single time point.

A Framework for Pursuing Child Health Equity in Pediatric Practice.

This article brings together several disparate frameworks to help outline a needed shift in pediatric practice to ensure child health equity. That shift involves moving from a commitment to equal care delivery to an explicit commitment to equitable health outcomes. The frameworks describe (1) the distinct domains of child health where inequity can be expressed, (2) the shortfalls of equal care delivery in meeting that promise, (3) a coherent typology of the barriers that drive health inequity and (4) a characterization of interventions as downstream, midstream, and upstream in nature.

Clarity on Disparity: Who, What, When, Where, Why, and How.

This article offers a framework of who, what, when, where, why, and how of health disparities that can serve as a systematic approach to move from description to understanding causes and taking action to ensure health equity.

Crossing the Quality Chasm and the Ignored Pillar of Health Care Equity.

Although there has been tremendous progress toward the aspiration of delivering quality health care, among the National Academy of Medicine's (previously Institute of Medicine) six pillars of quality (health care should be safe, effective, timely, patient-centered, efficient, and equitable), the last pillar, equity, has been largely ignored. Examples of how the quality improvement (QI) process leads to improvements are numerous and must be applied to the pillar of equity related to race/ethnicity and socioeconomic status. This article describes how equity should be addressed using the QI process.