Evolution of neuronal cell classes and types in the vertebrate retina.

The basic plan of the retina is conserved across vertebrates, yet species differ profoundly in their visual needs1. Retinal cell types may have evolved to accommodate these varied needs, but this has not been systematically studied. Here we generated and integrated single-cell transcriptomic atlases of the retina from 17 species: humans, two non-human primates, four rodents, three ungulates, opossum, ferret, tree shrew, a bird, a reptile, a teleost fish and a lamprey. We found high molecular conservation of the six retinal cell classes (photoreceptors, horizontal cells, bipolar cells, amacrine cells, retinal ganglion cells (RGCs) and Müller glia), with transcriptomic variation across species related to evolutionary distance. Major subclasses were also conserved, whereas variation among cell types within classes or subclasses was more pronounced. However, an integrative analysis revealed that numerous cell types are shared across species, based on conserved gene expression programmes that are likely to trace back to an early ancestral vertebrate. The degree of variation among cell types increased from the outer retina (photoreceptors) to the inner retina (RGCs), suggesting that evolution acts preferentially to shape the retinal output. Finally, we identified rodent orthologues of midget RGCs, which comprise more than 80% of RGCs in the human retina, subserve high-acuity vision, and were previously believed to be restricted to primates2. By contrast, the mouse orthologues have large receptive fields and comprise around 2% of mouse RGCs. Projections of both primate and mouse orthologous types are overrepresented in the thalamus, which supplies the primary visual cortex. We suggest that midget RGCs are not primate innovations, but are descendants of evolutionarily ancient types that decreased in size and increased in number as primates evolved, thereby facilitating high visual acuity and increased cortical processing of visual information.

A 680,000-person megastudy of nudges to encourage vaccination in pharmacies.

Encouraging vaccination is a pressing policy problem. To assess whether text-based reminders can encourage pharmacy vaccination and what kinds of messages work best, we conducted a megastudy. We randomly assigned 689,693 Walmart pharmacy patients to receive one of 22 different text reminders using a variety of different behavioral science principles to nudge flu vaccination or to a business-as-usual control condition that received no messages. We found that the reminder texts that we tested increased pharmacy vaccination rates by an average of 2.0 percentage points, or 6.8%, over a 3-mo follow-up period. The most-effective messages reminded patients that a flu shot was waiting for them and delivered reminders on multiple days. The top-performing intervention included two texts delivered 3 d apart and communicated to patients that a vaccine was "waiting for you." Neither experts nor lay people anticipated that this would be the best-performing treatment, underscoring the value of simultaneously testing many different nudges in a highly powered megastudy.

Sestrins in Physiological Stress Responses.

Sestrins are a family of proteins that respond to a variety of environmental stresses, including genotoxic, oxidative, and nutritional stresses. Sestrins affect multiple signaling pathways: AMP-activated protein kinase, mammalian target of rapamycin complexes, insulin-AKT, and redox signaling pathways. By regulating these pathways, Sestrins are thought to help adapt to stressful environments and subsequently restore cell and tissue homeostasis. In this review, we describe how Sestrins mediate physiological stress responses in the context of nutritional and chemical stresses (liver), physical movement and exercise (skeletal muscle), and chemical, physical, and inflammatory injuries (heart). These findings also support the idea that Sestrins are a molecular mediator of hormesis, a paradoxical beneficial effect of low- or moderate-level stresses in living organisms.

Broad-scale seasonal climate tracking is a consequence, not a driver, of avian migratory connectivity.

Tracking climatic conditions throughout the year is often assumed to be an adaptive behaviour underlying seasonal migration patterns in animal populations. We investigate this hypothesis using genetic markers data to map migratory connectivity for 27 genetically distinct bird populations from 7 species. We found that the variation in seasonal climate tracking across our suite of populations at a continental scale is more likely a consequence, rather than a direct driver, of migratory connectivity, which is primarily shaped by energy efficiency-i.e., optimizing the balance between accessing available resources and movement costs. However, our results also suggest that regional-scale seasonal precipitation tracking affects population migration destinations, thus revealing a potential scale dependency of ecological processes driving migration. Our results have implications for the conservation of these migratory species under climate change, as populations tracking climate seasonally are potentially at higher risk if they adapt to a narrow range of climatic conditions.

Dysregulated Amino Acid Sensing Drives Colorectal Cancer Growth and Metabolic Reprogramming Leading to Chemoresistance.

BACKGROUND & AIMS: Colorectal cancer (CRC) is a devastating disease that is highly modulated by dietary nutrients. Mechanistic target of rapamycin complex 1 (mTORC1) contributes to tumor growth and limits therapy responses. Growth factor signaling is a major mechanism of mTORC1 activation. However, compensatory pathways exist to sustain mTORC1 activity after therapies that target oncogenic growth factor signaling. Amino acids potently activate mTORC1 via amino acid-sensing GTPase activity towards Rags (GATOR). The role of amino acid-sensing pathways in CRC is unclear. METHODS: Human colon cancer cell lines, preclinical intestinal epithelial-specific GATOR1 and GATOR2 knockout mice subjected to colitis-induced or sporadic colon tumor models, small interfering RNA screening targeting regulators of mTORC1, and tissues of patients with CRC were used to assess the role of amino acid sensing in CRC. RESULTS: We identified loss-of-function mutations of the GATOR1 complex in CRC and showed that altered expression of amino acid-sensing pathways predicted poor patient outcomes. We showed that dysregulated amino acid-sensing induced mTORC1 activation drives colon tumorigenesis in multiple mouse models. We found amino acid-sensing pathways to be essential in the cellular reprogramming of chemoresistance, and chemotherapeutic-resistant patients with colon cancer exhibited de-regulated amino acid sensing. Limiting amino acids in in vitro and in vivo models (low-protein diet) reverted drug resistance, revealing a metabolic vulnerability. CONCLUSIONS: Our findings suggest a critical role for amino acid-sensing pathways in driving CRC and highlight the translational implications of dietary protein intervention in CRC.

Evolutionary history influences the microbiomes of a female symbiotic reproductive organ in cephalopods.

Many female squids and cuttlefishes have a symbiotic reproductive organ called the accessory nidamental gland (ANG) that hosts a bacterial consortium involved with egg defense against pathogens and fouling organisms. While the ANG is found in multiple cephalopod families, little is known about the global microbial diversity of these ANG bacterial symbionts. We used 16S rRNA gene community analysis to characterize the ANG microbiome from different cephalopod species and assess the relationship between host and symbiont phylogenies. The ANG microbiome of 11 species of cephalopods from four families (superorder: Decapodiformes) that span seven geographic locations was characterized. Bacteria of class Alphaproteobacteria, Gammaproteobacteria, and Flavobacteriia were found in all species, yet analysis of amplicon sequence variants by multiple distance metrics revealed a significant difference between ANG microbiomes of cephalopod families (weighted/unweighted UniFrac, Bray-Curtis, P = 0.001). Despite being collected from widely disparate geographic locations, members of the family Sepiolidae (bobtail squid) shared many bacterial taxa including (~50%) Opitutae (Verrucomicrobia) and Ruegeria (Alphaproteobacteria) species. Furthermore, we tested for phylosymbiosis and found a positive correlation between host phylogenetic distance and bacterial community dissimilarity (Mantel test r = 0.7). These data suggest that closely related sepiolids select for distinct symbionts from similar bacterial taxa. Overall, the ANGs of different cephalopod species harbor distinct microbiomes and thus offer a diverse symbiont community to explore antimicrobial activity and other functional roles in host fitness.IMPORTANCEMany aquatic organisms recruit microbial symbionts from the environment that provide a variety of functions, including defense from pathogens. Some female cephalopods (squids, bobtail squids, and cuttlefish) have a reproductive organ called the accessory nidamental gland (ANG) that contains a bacterial consortium that protects eggs from pathogens. Despite the wide distribution of these cephalopods, whether they share similar microbiomes is unknown. Here, we studied the microbial diversity of the ANG in 11 species of cephalopods distributed over a broad geographic range and representing 15-120 million years of host divergence. The ANG microbiomes shared some bacterial taxa, but each cephalopod species had unique symbiotic members. Additionally, analysis of host-symbiont phylogenies suggests that the evolutionary histories of the partners have been important in shaping the ANG microbiome. This study advances our knowledge of cephalopod-bacteria relationships and provides a foundation to explore defensive symbionts in other systems.

Pre-workout Dietary Nitrate Magnifies Training-induced Benefits to Physical Function in Late Postmenopausal Women: A Randomized Pilot Study.

To inform endpoints for future work, we explored the utility of pre-workout (i.e., an acute dose before training) beetroot juice (BRJ) combined with exercise (BRJ+EX) to augment indices of physical function in postmenopausal women compared to exercise only (EX). A two-arm pilot was employed to compare 24 postmenopausal women following an 8-wk, circuit-based exercise intervention. Participants were randomized to BRJ+EX (n = 12) or EX (n = 12). BRJ+EX participants consumed 140-mL of BRJ 120-180 min (only) before training for 7-wk, then discontinued during the final week to mitigate carryover effects. Physical function indices were: 6-min walk test (6MWT), estimated V̇O2peak, heart rate recovery (HRR), and maximal knee extensor power (Pmax). A treadmill task was used to measure V̇O2 on-kinetics wherein mean response time (MRT) coincided with the duration to reach 63% of steady-state V̇O2. Results showed greater changes (Δ) among BRJ+EX participants for 6MWT distance (40 ± 23 m vs. 8 ± 25 m; p = 0.003, d = 1.35), ΔV̇O2peak (1.5 ± 0.9 mLꞏkg-1ꞏmin-1 vs. 0.3 ± 1.0 mLꞏkg-1ꞏmin-1; p = 0.008, d = 1.20), and ΔHRR (-10 ± 6 bpm vs. -1 ± 9 bpm; p = 0.017, d = 1.05). Large and medium effect sizes favoring BRJ+EX were detected for ΔPmax (p = 0.07, d = 0.83) and ΔMRT (p = 0.257, d = 0.50), respectively. In postmenopausal women, BRJ+EX appears to magnify some adaptive benefits to physical function including aerobic capacity and recovery beyond that of training without BRJ. Investigation into contributing mechanisms is needed.

Describing the Heterogeneity of Clinical Utilization of Congenital Syphilis Diagnostic Modalities Among Major United States Tertiary Children's Hospitals, 2017-2022.

ABSTRACT: This retrospective cohort study drawing data from 48 major tertiary children's hospitals found heterogeneity in the diagnosis and management of congenital syphilis (CS) despite CDC guideline recommendations. The noted overall rise in the number of congenital syphilis cases mirrors the nationwide increase.

Navigating the Global Pandemic in Pediatric Overweight and Obesity: Emerging Challenges and Proposed Solutions.

BACKGROUND: Since 1990, childhood overweight and obesity have been rising on every continent and have almost doubled worldwide. The deleterious consequences include hypertension, type 2 diabetes mellitus, and dyslipidemia leading to metabolic syndrome in childhood and myocardial infarction, stroke, cancer and other disabling conditions in adulthood. PURPOSE: In Southern Europe, including Greece, Italy, and Spain, 10 to 15% of children are obese. Obesity in Eastern European countries is somewhat lower, but the rates of rise are very steep and will approach those in Southern Europe during the next few years. Worldwide, Asia accounts for nearly half of all overweight children under the age of 5, while Africa is home to one quarter of overweight children under 5. In Latin America, about 20% of children under 20 are overweight. Further, children living in poverty can suffer simultaneous overweight and obesity as well as malnutrition. In the US, the risk of being overweight in adolescence is several times higher when a younger child has a body mass index (BMI) in the 50th or greater percentile. FINDINGS: If the clinical, non-clinical and public health communities ignore these challenges, such inaction will surely portend an unprecedented future pandemic of overweight and obesity in children and adolescents leading to future premature morbidity and mortality. All clinical, non-clinical and public health professionals should exert concerted efforts concerning their individual patients, their families, communities, and policymakers. CONCLUSIONS: Such coordinated interdisciplinary efforts may curb these alarming trends and secure healthier futures for children and their families throughout the world.

Let's Move with Leon-A qualitative evaluation of a UK digital intervention to improve physical activity in people with a musculoskeletal condition.

OBJECTIVE: This article presents a qualitative evaluation of a 13-week digital intervention, 'Let's Move with Leon', designed to improve physical activity in people with a musculoskeletal condition. STUDY DESIGN: A qualitative evaluation embedded within a randomised controlled trial assessing the effectiveness of the intervention at improving self-reported physical activity. METHODS: A total of 184 participants received the intervention and were asked each week for 13 weeks to provide comment on their use and the usefulness of the digital physical activity behaviour change intervention. In addition, after 13 weeks, 12 participants took part in a semistructured interview to understand their use and the usefulness of the intervention. A thematic analysis was conducted on the combined qualitative data set. RESULTS: A total of 128 of the 184 intervention participants (70.11%) provided at least one qualitative comment over the course of the evaluation (mean number of comments per participant = 5); in total, 674 comments were received. The thematic analysis identified three themes: (1) dipping in and out, (2) one size does not fit all and (3) monitoring and feedback. The qualitative data suggest that participants used the intervention sporadically, dipping in and out due to other commitments, and competing programmes, their changing physical ability, confidence and motivation. Not getting off to a good start was detrimental to use; many wanted to come back to the programme at a more appropriate time. A 'one size fits' approach catered for some but not all participants. Whilst not a predetermined intervention component the act of monitoring levels of activity as a data collection method seemed to encourage physical activity but may also result in negative social comparisons. CONCLUSION: Digital physical activity behaviour change interventions are not one-size-fits-all; personalisation is key. Monitoring of activity by a named person can create commitment. Many dip in and out. Digital physical activity behaviour change interventions could complement physiotherapy exercises for people with musculoskeletal conditions. Signposting to local activities should be considered.

Are Gait Patterns during In-Lab Running Representative of Gait Patterns during Real-World Training? An Experimental Study.

Biomechanical assessments of running typically take place inside motion capture laboratories. However, it is unclear whether data from these in-lab gait assessments are representative of gait during real-world running. This study sought to test how well real-world gait patterns are represented by in-lab gait data in two cohorts of runners equipped with consumer-grade wearable sensors measuring speed, step length, vertical oscillation, stance time, and leg stiffness. Cohort 1 (N = 49) completed an in-lab treadmill run plus five real-world runs of self-selected distances on self-selected courses. Cohort 2 (N = 19) completed a 2.4 km outdoor run on a known course plus five real-world runs of self-selected distances on self-selected courses. The degree to which in-lab gait reflected real-world gait was quantified using univariate overlap and multivariate depth overlap statistics, both for all real-world running and for real-world running on flat, straight segments only. When comparing in-lab and real-world data from the same subject, univariate overlap ranged from 65.7% (leg stiffness) to 95.2% (speed). When considering all gait metrics together, only 32.5% of real-world data were well-represented by in-lab data from the same subject. Pooling in-lab gait data across multiple subjects led to greater distributional overlap between in-lab and real-world data (depth overlap 89.3-90.3%) due to the broader variability in gait seen across (as opposed to within) subjects. Stratifying real-world running to only include flat, straight segments did not meaningfully increase the overlap between in-lab and real-world running (changes of <1%). Individual gait patterns during real-world running, as characterized by consumer-grade wearable sensors, are not well-represented by the same runner's in-lab data. Researchers and clinicians should consider "borrowing" information from a pool of many runners to predict individual gait behavior when using biomechanical data to make clinical or sports performance decisions.

A proteomics approach identifies novel resident zebrafish Balbiani body proteins Cirbpa and Cirbpb.

The Balbiani body (Bb) is the first marker of polarity in vertebrate oocytes. The Bb is a conserved structure found in diverse animals including insects, fish, amphibians, and mammals. During early zebrafish oogenesis, the Bb assembles as a transient aggregate of mRNA, proteins, and membrane-bound organelles at the presumptive vegetal side of the oocyte. As the early oocyte develops, the Bb appears to grow slowly, until at the end of stage I of oogenesis it disassembles and deposits its cargo of localized mRNAs and proteins. In fish and frogs, this cargo includes the germ plasm as well as gene products required to specify dorsal tissues of the future embryo. We demonstrate that the Bb is a stable, solid structure that forms a size exclusion barrier similar to other biological hydrogels. Despite its central role in oocyte polarity, little is known about the mechanism behind the Bb's action. Analysis of the few known protein components of the Bb is insufficient to explain how the Bb assembles, translocates, and disassembles. We isolated Bbs from zebrafish oocytes and performed mass spectrometry to define the Bb proteome. We successfully identified 77 proteins associated with the Bb sample, including known Bb proteins and novel RNA-binding proteins. In particular, we identified Cirbpa and Cirbpb, which have both an RNA-binding domain and a predicted self-aggregation domain. In stage I oocytes, Cirbpa and Cirbpb localize to the Bb rather than the nucleus (as in somatic cells), indicating that they may have a specialized function in the germ line. Both the RNA-binding domain and the self-aggregation domain are sufficient to localize to the Bb, suggesting that Cirbpa and Cirbpb interact with more than just their mRNA targets within the Bb. We propose that Cirbp proteins crosslink mRNA cargo and proteinaceous components of the Bb as it grows. Beyond Cirbpa and Cirbpb, our proteomics dataset presents many candidates for further study, making it a valuable resource for building a comprehensive mechanism for Bb function at a protein level.

Genetic mutations in smoking-associated prostate cancer.

OBJECTIVES: Tobacco smoking is known to cause cancers potentially predisposed by genetic risks. We compared the frequency of gene mutations using a next generation sequencing database of smokers and nonsmokers with prostate cancer (PCa) to identify subsets of patients with potential genetic risks. MATERIALS AND METHODS: Data from the American Association for Cancer Research Project Genomics Evidence Neoplasia Information Exchange (GENIE) registry was analyzed. The GENIE registry contains clinically annotated sequenced tumor samples. We included 1832 men with PCa in our cohort, categorized as smokers and nonsmokers, and compared the frequency of mutations (point mutations, copy number variations, and structural variants) of 47 genes with more than 5% mutation rate between the two categories and correlated with overall survival using logistic regression analysis. RESULTS: Overall, 1007 (55%) patients were nonsmokers, and 825 (45%) were smokers. The mutation frequency was significantly higher in smokers compared to nonsmokers, 47.6% and 41.3%, respectively (p = 0.02). The median tumor mutational burden was also significantly higher in the samples from smokers (3.59 mut/MB) compared to nonsmokers (1.87 mut/MB) (p < 0.001). Patients with a smoking history had a significantly higher frequency of PREX2, PTEN, AGO2, KMT2C, and a lower frequency of adenomatous polyposis coli (APC) and KMT2A mutations than compared to nonsmokers. The overall mortality rate (28.5% vs. 22.8%) was significantly higher among smokers (p = 0.006). On a multivariate logistic regression analysis, the presence of metastatic disease at the time of diagnosis (OR: 2.26, 95% CI: 1.78-2.89, p < 0.001), smoking history (OR: 1.32, 95% CI: 1.05-1.65, p = 0.02), and higher frequency of PTEN somatic gene mutation (OR: 1.89, 95% CI: 1.46-2.45, p < 0.001) were independent predictors of increased overall mortality among patients with PCa. Patients with PTEN mutation had poorer overall survival compared to men without PTEN mutations: 96.00 (95% CI: 65.36-113.98) and 120.00 (95% CI: 115.05-160.00) months, respectively (p < 0.001) irrespective of smoking history although the G129R PTEN mutation was characteristically detected in smokers. CONCLUSIONS: PCa patients with a tobacco smoking history demonstrated a significantly higher frequency of somatic genetic mutations. Whereas mutations of PREX2, KMT2C, AGO2, and PTEN genes were higher in smokers, the APC and KMT2A mutations were higher in nonsmokers. The PTEN somatic gene mutation was associated with increased overall mortality among patients with PCa irrespective of smoking history. We found that G129R PTEN mutation known to reduce the PTEN phosphatase activity and K267Rfs*9 a frameshift deletion mutation in the C2 domain of PTEN associated with membrane binding exclusively detected in smokers and nonsmokers, respectively. These findings may be used to further our understanding of PCa associated with smoking.

Simultaneous proton resonance frequency T1 - MR shear wave elastography for MR-guided focused ultrasound multiparametric treatment monitoring.

PURPOSE: To develop an efficient MRI pulse sequence to simultaneously measure multiple parameters that have been shown to correlate with tissue nonviability following thermal therapies. METHODS: A 3D segmented EPI pulse sequence was used to simultaneously measure proton resonance frequency shift (PRFS) MR thermometry (MRT), T1 relaxation time, and shear wave velocity induced by focused ultrasound (FUS) push pulses. Experiments were performed in tissue mimicking gelatin phantoms and ex vivo bovine liver. Using a carefully designed FUS triggering scheme, a heating duty cycle of approximately 65% was achieved by interleaving FUS ablation pulses with FUS push pulses to induce shear waves in the tissue. RESULTS: In phantom studies, temperature increases measured with PRFS MRT and increases in T1 correlated with decreased shear wave velocity, consistent with material softening with increasing temperature. During ablation in ex vivo liver, temperature increase measured with PRFS MRT initially correlated with increasing T1 and decreasing shear wave velocity, and after tissue coagulation with decreasing T1 and increasing shear wave velocity. This is consistent with a previously described hysteresis in T1 versus PRFS curves and increased tissue stiffness with tissue coagulation. CONCLUSION: An efficient approach for simultaneous and dynamic measurements of PRSF, T1 , and shear wave velocity during treatment is presented. This approach holds promise for providing co-registered dynamic measures of multiple parameters, which correlates to tissue nonviability during and following thermal therapies, such as FUS.

Prevalence and Cost of Care Cascades Following Low-Value Preoperative Electrocardiogram and Chest Radiograph Within the Veterans Health Administration.

BACKGROUND: Low-value care cascades, defined as the receipt of downstream health services potentially related to a low-value service, can result in harm to patients and wasteful healthcare spending, yet have not been characterized within the Veterans Health Administration (VHA). OBJECTIVE: To examine if the receipt of low-value preoperative testing is associated with greater utilization and costs of potentially related downstream health services in Veterans undergoing low or intermediate-risk surgery. DESIGN: Retrospective cohort study using VHA administrative data from fiscal years 2017-2018 comparing Veterans who underwent low-value preoperative electrocardiogram (EKG) or chest radiograph (CXR) with those who did not. PARTICIPANTS: National cohort of Veterans at low risk of cardiopulmonary disease undergoing low- or intermediate-risk surgery. MAIN MEASURES: Difference in rate of receipt and attributed cost of potential cascade services in Veterans who underwent low-value preoperative testing compared to those who did not KEY RESULTS: Among 635,824 Veterans undergoing low-risk procedures, 7.8% underwent preoperative EKG. Veterans who underwent a preoperative EKG experienced an additional 52.4 (95% CI 47.7-57.2) cascade services per 100 Veterans, resulting in $138.28 (95% CI 126.19-150.37) per Veteran in excess costs. Among 739,005 Veterans undergoing low- or intermediate-risk surgery, 3.9% underwent preoperative CXR. These Veterans experienced an additional 61.9 (95% CI 57.8-66.1) cascade services per 100 Veterans, resulting in $152.08 (95% CI $146.66-157.51) per Veteran in excess costs. For both cohorts, care cascades consisted largely of repeat tests, follow-up imaging, and follow-up visits, with low rates invasive services. CONCLUSIONS: Among a national cohort of Veterans undergoing low- or intermediate-risk surgeries, low-value care cascades following two routine low-value preoperative tests are common, resulting in greater unnecessary care and costs beyond the initial low-value service. These findings may guide de-implementation policies within VHA and other integrated healthcare systems that target those services whose downstream effects are most prevalent and costly.

Absolute Monocyte Count as Early and Safe Marker for Antibiotic Cessation in Febrile Neutropenia Without Etiology in Pediatric Oncology Patients.

BACKGROUND: There is no practice standard regarding antibiotic duration in children with cancer and unexplained febrile neutropenia (FN). We hypothesized that absolute monocyte count (AMC) and absolute phagocyte count (APC= ANC + AMC + bands) are more sensitive, earlier, and safe markers of antibiotic cessation compared with absolute neutrophil count (ANC). METHODS: A retrospective review of FN episodes (FNEs) in pediatric oncology patients was conducted between 2009 and 2016. Included patients were afebrile for 24 hours and without an identified infectious source at antibiotic cessation. Primary endpoints, including recurrent fever, readmission, bloodstream infection, microbiologically documented infection, and adverse outcomes, were assessed 10 days after antibiotic cessation and compared among different bone marrow recovery parameters (ANC, AMC, APC). Secondary endpoints included length of FN stay, antibiotic-free days, and cost. RESULTS: Three hundred ninety-one FNEs in 235 patients were included. Three groups were compared based on ANC (cells/µL) at the time of antibiotic cessation: < 200 in 102 (26%), 200 to 500 in 111 (28%), and >500 in 178 (46%). No statistically significant differences in primary endpoints were identified among the 3 ANC groups; however, a trend toward unfavorable outcomes in the ANC ≤200 cells/µL group compared with the ANC >200 cells/µL was observed. Primary endpoints based on AMC >100 cells/µL at the time of antibiotic cessation showed statistically significant favorable outcomes compared AMC ≤100 cells/µL (80%, 88%, 90%, 89%, and 93% risk reduction in recurrent fever, readmission, new bloodstream infection, new microbiologically documented infection, and adverse events, respectively). Similar favorable results were seen when APC >300 cells/µL was used as a threshold for antibiotic cessation. The median length of stay for FN if discharged when AMC >100 cells/µL was 3 days shorter and associated with fewer unfavorable outcomes, thus resulting in fewer hospital days, fewer antibiotic days, and decreased cost. CONCLUSION: Our results suggest that AMC >100 cells/µL (regardless of ANC) or APC >300 cells/µL may be safe thresholds for empiric antibiotic cessation and result in reduced unfavorable clinical outcomes within 10 days postdischarge, reduced antibiotic days of therapy and reduced health care costs. Further prospective studies are needed to validate AMC as an accurate surrogate marker for antibiotic cessation in FNEs in children with cancer.

Identifying Current Feelings of Mild and Moderate to High Depression in Young, Healthy Individuals Using Gait and Balance: An Exploratory Study.

Depressive mood states in healthy populations are prevalent but often under-reported. Biases exist in self-reporting of depression in otherwise healthy individuals. Gait and balance control can serve as objective markers for identifying those individuals, particularly in real-world settings. We utilized inertial measurement units (IMU) to measure gait and balance control. An exploratory, cross-sectional design was used to compare individuals who reported feeling depressed at the moment (n = 49) with those who did not (n = 84). The Quality Assessment Tool for Observational Cohort and Cross-sectional Studies was employed to ensure internal validity. We recruited 133 participants aged between 18-36 years from the university community. Various instruments were used to evaluate participants' present depressive symptoms, sleep, gait, and balance. Gait and balance variables were used to detect depression, and participants were categorized into three groups: not depressed, mild depression, and moderate-high depression. Participant characteristics were analyzed using ANOVA and Kruskal-Wallis tests, and no significant differences were found in age, height, weight, BMI, and prior night's sleep between the three groups. Classification models were utilized for depression detection. The most accurate model incorporated both gait and balance variables, yielding an accuracy rate of 84.91% for identifying individuals with moderate-high depression compared to non-depressed individuals.

Results from an LGBTQ+ Community Health Needs Assessment in Nassau and Suffolk Counties of New York State.

LGBTQ+ individuals experience health care disparities and difficulty accessing affirming care. Little is known regarding the health and experiences among subpopulations of specific sexual orientations and gender identities (SOGI). We implemented the first LGBTQ + health needs assessment survey in Nassau and Suffolk Counties, New York, to assess individuals' health care experiences, behaviors, access to care, and health care needs. The sample (N = 1150) consisted of many SOGI subgroups. Greater than 60% of respondents reported symptoms of chronic depression; over one third reported disrespectful health care experiences; and two thirds experienced verbal harassment. Bisexual/bicurious, pansexual, queer, gender nonconforming and transgender individuals experienced highest rates of mental health concerns and difficulty accessing care. Behavioral health concerns were also high among Black, multiracial, Hispanic, Asian, young adult, and lower-income respondents. Gaining an understanding of unique differences among LGBTQ+ subgroups can guide implementation of services targeting specific subpopulations to improve access to care and reduce disparities.

Developing a stochastic hydrological model for informing lake water level drawdown management.

Winter drawdown (WD) is a common lake management tool for multiple purposes such as flood control, aquatic vegetation reduction, and lake infrastructure maintenance. To minimize adverse impacts to a lake's ecosystem, regulatory agencies may provide managers with general guidelines for drawdown and refill timing, drawdown magnitude, and outflow limitations. However, there is significant uncertainty associated with the potential to meet management targets due to variability in lake characteristics and hydrometeorology of each lake's basin, making the use of modeling tools a necessity. In this context, we developed a hydrological modeling framework for lake water level drawdown management (HMF-Lake) and evaluated it at 15 Massachusetts lakes where WDs have been applied over multiple years for vegetation control. HMF-Lake is based on the daily lake water balance, with inflows simulated by a lumped rainfall-runoff model (Cemaneige-GR4J) and outflow rate calculated by a modified Target Storage and Release Based Method (TSRB). The model showed a satisfactory performance of simulating historical water levels (0.53 ≤ NSE ≤ 0.86), however, uncertainties from meteorological inputs and TSRB determined lake outflow rate affected the result accuracy. To account for these uncertainties, the model was executed stochastically to assess the ability of study lakes to follow the Massachusetts' general WD guidelines: drawdown by Dec 1 and fully refilled by Apr 1. By using the stochastic HMF-Lake, the probabilities of each lake to reach the drawdown level by Dec 1 were calculated for different drawdown magnitudes (1-6 ft). The probability results suggest it was generally less possible for most of study lakes to achieve a drawdown of 3 ft or more by Dec 1. Moreover, we employed the stochastic model to derive the annual latest refill starting dates that ensure a 95 % probability of reaching the normal water level by Apr 1. We found starting a refill in March for drawdowns up to 6 ft was feasible for most of study lakes. These results provide lake managers with a quantitative understanding of the lake's ability to follow the state guidelines. The model may be used to systematically evaluate current WD management strategies at state or regional scales and support adaptive WD management under changing climates.

Ductal Carcinoma in Situ: State-of-the-Art Review.

Ductal carcinoma in situ (DCIS) is a nonobligate precursor of invasive cancer, and its detection, diagnosis, and management are controversial. DCIS incidence grew with the expansion of screening mammography programs in the 1980s and 1990s, and DCIS is viewed as a major driver of overdiagnosis and overtreatment. For pathologists, the diagnosis and classification of DCIS is challenging due to undersampling and interobserver variability. Understanding the progression from normal breast tissue to DCIS and, ultimately, to invasive cancer is limited by a paucity of natural history data with multiple proposed evolutionary models of DCIS initiation and progression. Although radiologists are familiar with the classic presentation of DCIS as asymptomatic calcifications at mammography, the expanded pool of modalities, advanced imaging techniques, and image analytics have identified multiple potential biomarkers of histopathologic characteristics and prognosis. Finally, there is growing interest in the nonsurgical management of DCIS, including active surveillance, to reduce overtreatment and provide patients with more personalized management options. However, current biomarkers are not adept at enabling identification of occult invasive disease at biopsy or accurately predicting the risk of progression to invasive disease. Several active surveillance trials are ongoing and are expected to better identify women with low-risk DCIS who may avoid surgery.