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Eperua is a genus of Neotropical trees that forms a major component of tropical lowland forests in Amazonia, especially in the Guiana Shield and on white-sand forests. One species occurs in the Cerrado-Caatinga ecotone, and the genus also inhabits riverine and terra firme forests. Species in Eperua exhibit one of two drastically different floral architectures and inflorescence types, each associated with distinct pollinators. Prior phylogenetic studies of Eperua have revealed an unstructured topology concerning floral architectures and inflorescence types. In addition, no investigation has been conducted on how the evolution of these traits and habitat preferences influenced the dispersal and diversification of Eperua. Using target capture sequencing, we inferred the most comprehensive phylogeny for Eperua to date, sampling all 19 known species, five for the first time. We used coalescence, concatenation, and network methods to infer the Eperua phylogeny and investigate sources of incongruence impacting resolution and support. We reconstructed the biogeographic history and ancestral states for the flower architecture, inflorescence type, and habitat preference. Our phylogenomic analyses successfully resolved relationships within Eperua, attributing conflicts between the species tree and concatenated tree to gene tree discordance linked to reticulation events. Biogeographical analyses indicate that Eperua originated and initially diversified in the white-sand forests of the Guiana Shield. A subsequent adaptation to riverine and terra firme forests enabled Eperua to expand into new habitats and regions. Still, its historical preference for white-sand forests probably accounts for its absence in the southern and western parts of Amazonia. Ancestral geographic areas and corolla morphotype reconstructions suggest that speciation in Eperua has occurred in sympatry, likely driven by pollinator shifts mediated by drastic changes in floral architecture., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Phagocytosis is usually carried out by professional phagocytic cells in the context of pathogen response or wound healing. The transient surface proteins that regulate phagocytosis pose a challenging proteomics target; knowledge thereof could lead to new therapeutic insights. Herein, we describe a novel photocatalytic proximity labeling method: "μMap-Interface", allowing for spatiotemporal mapping of phagocytosis. Utilizing photocatalyst-conjugated IGG-opsonized beads and initiating phagocytosis in a synchronized manner, we capture phagocytic interactome "snapshots" at the interface of the phagocyte and its target. This allows profiling of the dynamic surface proteome of human macrophages during the engulfment process. We reveal previously known phagocytic mediators as well as potential novel interactors and validate their presence with super-resolution microscopy. This includes F11R, an important cancer target yet to be investigated in the context of phagocytosis. Further, we demonstrate that knocking down F11R leads to an increased degree of phagocytosis; this insight could contribute to explaining its oncogenic activity. Lastly, we show capture of orthogonal phagocytic surfaceomes across different cells, using a neutrophil-like model. We believe this method will enable new insights into phagocytic processes in a variety of contexts.

The population-level reductions in HIV incidence attributed to pre-exposure prophylaxis (PrEP) have not been fully realized among sexual, gender, and racial/ethnic minority youth. P3 (Prepared, Protected, emPowered) is a comprehensive mobile application (app) intervention developed to support PrEP adherence through gamification, medication tracking, and social engagement. A randomized controlled trial was conducted with 246 young men who have sex with men (YMSM) and young transgender women who have sex with men (YTWMSM) currently on or planning to begin PrEP. Participants were randomized in a 1:1:1 ratio to: standard of care (SOC), P3 app (P3), or P3 app plus in-app adherence coaching (P3+). Adherence was measured at 3- and 6- months post enrollment by emtricitabine-triphosphate (FTC-TP) and tenofovir-diphosphate (TFV-DP) levels in dried blood spots consistent with PrEP use > 4 days/week. The primary outcome was the difference in the proportion adherent comparing P3/P3+ to SOC. P3/P3+ was associated with a higher proportion adherent compared to SOC for both outcome measures. At 3 months, the estimated increase in the proportion adherent was 0.13 (95% CI: 0.00, 0.27, p: 0.05) and 0.12 (95% CI: -0.03, 0.26, p: 0.11) for TFV-DP and FTC-TP, respectively. Estimated adherence was higher, but not statistically different, in P3+ compared to P3, for both TFV-DP and FTC-TP. Receipt of P3 (P3 or P3+) is associated with an increase in PrEP adherence among YMSM and YTWSM at 3 months. Additional analyses to discern the role of app usage and sociodemographic and behavioral factors on intervention effects are warranted., Competing Interests: Declarations Conflict of interest The authors have no conflict of interest to declare., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The link between the oral microbiome and neurodevelopmental disorders remains a compelling hypothesis, still requiring confirmation in large-scale datasets. Leveraging over 7000 whole-genome sequenced salivary samples from 2025 US families with children diagnosed with autism spectrum disorders (ASD), our cross-sectional study shows that the oral microbiome composition can discriminate ASD subjects from neurotypical siblings (NTs, AUC = 0.66), with 108 differentiating species (q < 0.005). The relative abundance of these species is highly correlated with cognitive impairment as measured by Full-Scale Intelligence Quotient (IQ). ASD children with IQ < 70 also exhibit lower microbiome strain sharing with parents (p < 10 -6 ) with respect to NTs. A two-pronged functional enrichment analysis suggests the contribution of enzymes from the serotonin, GABA, and dopamine degradation pathways to the distinct microbial community compositions observed between ASD and NT samples. Although measures of restrictive eating diet and proxies of oral hygiene show relatively minor effects on the microbiome composition, the observed associations with ASD and IQ may still represent unaccounted-for underlying differences in lifestyle among groups. While causal relationships could not be established, our study provides substantial support to the investigation of oral microbiome biomarkers in ASD., Competing Interests: Competing interests The authors do not have any competing interests to declare., (© 2024. The Author(s).)

Understanding the maintenance and shift in reproductive strategies is a fundamental question in evolutionary research. Although many efforts have been made to compare different reproductive strategies, the association between reproductive strategies and lineage divergence is largely unknown. To explore the impact of different reproductive strategies on lineage divergence, we investigated the evolution of clonality in Saxifraga sect. Irregulares+Heterisia. By integrating several lines of evidence, we found that the loss of clonality in Irregulares+Heterisia was associated with a progressive increase in diversification rate and intraspecific morphological diversity but with a reduction in species distribution range. Our findings provide insights into the ecological and evolutionary effects of different reproductive strategies, suggesting the necessity of integrating clonality into ecological and evolutional research., (© 2024. Science China Press.)

Minipigs are valid nonrodent species infrequently utilized for pharmaceutical research and development (R&D) compared with dogs or nonhuman primates (NHPs). A 2022 IQ DruSafe survey revealed a modest increase in minipig use by pharmaceutical companies compared with a prior 2014 survey, primarily in the development of oral small molecules and parenteral protein molecules. Some companies considered using minipigs more often due to NHP shortages and regional ethical concerns with using NHPs and dogs. However, for most pharmaceutical companies, minipigs still represent ≤5% of their nonrodent animal use. Key challenges noted by companies to wider adoption of minipigs were high test article requirement, limited historical control data, and lack of relevant reagents or assays. Additionally, some companies expressed uncertainties about contract research organization (CRO) capabilities and experience, a perception not shared by respondent CROs. These latest survey results indicate persistence of many concerns previously identified in 2014. Several case studies are included to illustrate areas of expanded minipig use as well as the challenges that hinder broader adoption. Ongoing, focused, and industry-wide initiatives to address the identified or perceived challenges may lead to more frequent or routine consideration of minipigs as a test species in pharmaceutical R&D., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: This publication was developed with the support of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ, www.iqconsortium.org). IQ is a not-for-profit organization of pharmaceutical and biotechnology companies with a mission of advancing science and technology to augment the capability of member companies to develop transformational solutions that benefit patients, regulators and the broader research and development community., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Currently, there are no reliable biomarkers for predicting treatment response in chronic inflammatory diseases (CIDs)., Objective: To determine whether serum microfibrillar-associated protein 4 (MFAP4) levels can predict the treatment response to biological therapy in patients with CIDs., Methods: The BELIEVE study was originally designed as a prospective, multi-center cohort study of 233 patients with either rheumatoid arthritis, psoriatic arthritis, psoriasis, axial spondyloarthritis, Crohn's disease, or ulcerative colitis, initiating treatment with a biologic agent (or switching to another). Clinical assessment and blood sample collection were performed at baseline and 14-16 weeks after treatment initiation. The primary analyses included participants with available blood samples at baseline; missing data were handled as non-responders. The patients were stratified into the upper tertile of serum MFAP4 (High MFAP4) versus a combined category of middle and lower tertiles (Other MFAP4). The primary outcome was the proportion of patients with clinical response to biologic therapy after 14-16 weeks., Results: 211 patients were included in the primary analysis population. The mean age was 43.7 (SD: 14.8) years, and 120 (59%) were female. Positive treatment response was observed in 41 (59%) and 69 (49%) for High MFAP4 and Other MFAP4, respectively. When adjusting for pre-specified variables (CID, age, sex, smoking status, and BMI), the adjusted OR was 2.28 (95% CI: 1.07 to 4.85) for a positive treatment outcome in the High MFAP4 group., Conclusion: A high MFAP4 status before initiating biological treatment is associated with a positive clinical response, when adjusting for confounding factors., (© 2024. The Author(s).)

Background: Using a large, geographically diverse, hospital-based database in the United States (Premier PINC AI Healthcare Database), we aimed to describe the proportion and characteristics of patients receiving phenotype-desirable antimicrobial therapy (PDAT) among those hospitalized with Enterobacterales bloodstream infections., Methods: Adult patients with an admission between January 1, 2017 and June 30, 2022 with ≥1 blood culture positive for Escherichia coli , Klebsiella oxytoca , Klebsiella pneumoniae , or Proteus mirabilis and receiving an empiric antibiotic therapy on blood culture collection (BCC) Days 0 or 1 were included. Receiving PDAT (defined as receipt of any antimicrobial categorized as "desirable" for the respective phenotype) on BCC Days 0-2 was defined as receiving early PDAT., Results: Among 35,880 eligible patients, the proportion of patients receiving PDAT increased (from 6.8% to 22.8%) from BCC Day 0-4. Patients who received PDAT (8,193, 22.8%) were more likely to visit large (500 + beds, 36% vs 31%), teaching (45% vs 39%), and urban (85% vs 82%) hospitals in the Northeast (22% vs 13%) compared to patients not receiving PDAT (all P <. 01). Among patients receiving PDAT, 61.4% (n = 5,033) received it early; they had a lower mean comorbidity score (3.2 vs 3.6), were less likely to have severe or extreme severity of illness (71% vs 79%), and were less likely to have a pathogen susceptible to narrow-spectrum β-lactams (31% vs 71%) compared to patients in the delayed PDAT group (all P < .01)., Conclusions: The proportion of patients receiving desirable therapy increased between BCC Day 0 and 4. Receipts of PDAT and early PDAT were associated with hospital, clinical, and pathogen characteristics., Competing Interests: RM, JD, and NR worked on the study as full-time employees of Premier, Inc. SHM and JBM worked on the study as full-time employees of bioMérieux, Inc. KCC worked on the study as a paid consultant to bioMérieux, Inc. Receipt of PDAT was associated with hospital characteristics and pathogen characteristics (including phenotype and pathogen type) and less with patient characteristics. Severity of illness was lower among patients receiving early PDAT compared to those receiving delayed PDAT. Most AST results took ∼ 3 days., (© The Author(s) 2024.)

Millions of United States (U.S.) troops deployed to the Middle East and Southwest Asia were exposed to toxic airborne hazards and/or open-air burn pits. Burn pit emissions contain particulate matter combined with toxic gasses and heavy metals. Ongoing research has demonstrated that exposures to the airborne hazards from military burn pits have profound and lasting health and wellness consequences. Research on the long-term health consequences of exposure to open burn pits has been limited. Work continues to understand the scope of the health impacts and the underlying pathobiology following exposures and to establish care standards. The U.S. Sergeant First Class Heath Robinson Honoring our Promise to Address Comprehensive Toxics (PACT) Act was signed into law August 2022. This act expands the benefits and services to U.S. Veterans exposed to toxicants, requires the Veterans Health Administration to provide toxic exposure screening, and supports increased research, education, and treatment due to toxic occupational exposures. This review highlights the state of the science related to military burn pit exposures research with an emphasis on pulmonary health. Clinical data demonstrate areas of reduced or delayed pulmonary ventilation and lung pathologies such as small airways scarring, diffuse collagen deposition and focal areas of ossification. Identification and characterization of foreign matter deposition in lung tissues are reported, including particulate matter, silica, titanium oxides, and polycyclic aromatic hydrocarbons. These data are consistent with toxic exposures and with the symptoms reported by post-deployment Veterans despite near-normal non-invasive pulmonary evaluations. On-going work toward new methods for non-invasive pulmonary diagnoses and disease monitoring are described. We propose various studies and databases as resources for clinical and health outcomes research. Pre-clinical research using different burn pit modeling approaches are summarized, including oropharyngeal aspiration, intranasal inhalation, and whole-body exposure chamber inhalation. These studies focus on the impacts of specific toxic substances as well as the effects of short-term and sustained insults over time on the pulmonary systems., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Ecuador has gone through a significant reduction in new cases from 2000 (106) to 2023 (12), suggesting a trend towards zero leprosy. An ecological spatiotemporal study design was used to describe the epidemiological distribution of the disease in the country during 2000-2023. Leprosy cases registered by the surveillance system of the Ecuadorian Ministry of Public Health were the data utilized for the study. From January 2000 to December 2023, 1539, incidence cases were diagnosed with leprosy in Ecuador. At the time of diagnosis, the median age was 54 years. Most of the cases were males (71.5%). The proportion of incidence cases in subjects over 50 years was 63% and 1.5% in children ≤ 15 years old. The yearly incidence rate ranged from 8.5/1,000,000 population in 2000 to 0.68/1,000,000 population in 2023, remaining within the low-endemic parameter. In total, 35 cantons reported newly detected leprosy cases in the year 2000. By the end of 2023, only eight cantons actively reported cases of leprosy. High-risk clusters for leprosy were detected in the tropical coastal region of Ecuador. The provinces with the highest number of cases during the study period were Guayas (44.8%) and Los Rios (15.7%), with zero cases being found in the Galapagos Islands. Our study is unique in that it documents a retrospective dataset over a two-decade timespan from a South American country that has effectively applied global guidelines for the control and elimination of leprosy.

Environmental enrichment (EE) consists of increased living space, complex stimuli, and social interaction that collectively confer neurobehavioral benefits in preclinical models of traumatic brain injury (TBI). The typical EE approach entails implementation immediately after surgery and continual exposure, which is not clinically applicable, as TBI patients often only receive rehabilitation after critical care, and then only for a few hours per day. We are focused on developing a clinically relevant model of neurorehabilitation by refining the timing of initiation and duration of EE exposure after TBI. The goal of this experiment is to compare the typical EE approach to paradigms where EE is delayed by 3 or 7 days after TBI and then provided for only 6 h per day, which better mimics the clinic. The hypothesis is that the delayed-and-abbreviated EE paradigms will promote neurobehavioral benefits like the typical approach of immediate-and-continuous exposure. To test the hypothesis, anesthetized adult male rats underwent a controlled cortical impact of moderate severity (2.8 mm deformation at 4 m/s) or sham injury and then were randomly assigned to post-operative EE or standard (STD) housing. Motor ability, spatial learning, and memory retention were assessed. The hypothesis was confirmed as all EE-treated groups performed better than the STD group in all behavioral assessments (p < 0.05) and did not differ from one another (p > 0.05). The ability of EE to provide significant behavioral benefits even when delayed and delivered in moderation affords further support for EE as a preclinical model of neurorehabilitation and offers greater insight into the length of the therapeutic window., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Theta emitters are useful for generating microdroplets for rapid-mixing reactions. Theta emitters are glass tips containing an internal septum that separates two channels. When used for mixing, the solutions from each channel are sprayed with mixing occurring during electrospray ionization (ESI) with reaction times on the order of microseconds to milliseconds. Theta emitters of increasing size cause the formation of ESI droplets of increasing size, which require longer times for desolvation and increase droplet lifetimes. Droplets with longer lifetimes provide more time for mixing and allow for increased reaction times prior to desolvation. Because theta emitters are typically produced in-house, there is a need to consistently pull tips with a variety of sizes. Herein, we characterize the effect of pull parameters on the generation of distinct-sized theta emitters using a P-1000 tip puller. Of the examined parameters, the velocity value had the largest impact on the channel diameter. This work also compares the effect of pulling parameters between single-channel and theta capillaries to examine how the internal septum in theta capillaries affects tip pulling. We demonstrate the utility of using theta emitters with different sizes for establishing distinct reaction times. Finally, we offer suggestions on producing theta emitters of various sizes while maintaining high repeatability. Through this work, we provide resources to establish a versatile and inexpensive rapid-mixing system for probing biologically relevant systems and performing rapid derivatizations.

Prior to the national shortage of iron dextran in early 2023, it was the most commonly administered intravenous iron infusion at our institution. After the shortage impacted the health system, alternatives such as iron sucrose and sodium ferric gluconate/sucrose were required that utilized lower doses given at more frequent patient visits. Coinciding with their more prevalent use, an increase in iron infusion reactions was observed. Our study analyzed 880 patients who received iron infusions in three Henry Ford Hospital clinics in metropolitan Detroit, Michigan, from July 2022-June 2023. The 74 reactions that occurred were most commonly associated with iron sucrose at the 500 mg dose (41/74, 55.41%, p < 0.0001). Most reactions observed across all iron formulations and doses were mild, with 83.7% being Grade 0 or 1 as defined by the United States Drug Allergy Registry (USDAR) grading scale for immediate reactions. Patients who experienced an infusion reaction were less likely to complete their infusion plans (OR 0.004 for iron dextran, OR 0.128 for iron sucrose, p < 0.0001), with infusions most commonly being completely discontinued thereafter, with a minority pursuing alternative options. More patients with lower number of doses scheduled for iron dextran completed their infusion schedules than those with more doses, but the opposite was seen for iron sucrose. We assessed the impact of the national shortage of iron dextran examining infusion reactions with various iron infusions and doses., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

In two laboratory trials, natural products, including freshly picked leaves from spearmint, rosemary, and tansy plants, a water extract from soybean plants, peels from a common cucumber, and 1% peppermint oil in hexane, were placed in a moist harborage preferred by Argentine ants, Linepithema humile (Mayr), and the number of ants entering the harborage after two and four hours was counted. None of the recommended home remedies (tansy, cucumber, or soybean extract) deterred ants from an attractive, moist harborage in either trial, even when the quantity of these treatments was increased 4- to 10-fold. Freshly picked leaves from rosemary and spearmint plants deterred ants from harboring, and the 1% peppermint oil was the most deterrent of all treatments.

Background: Obese patients experience more complications after autologous breast reconstruction. This study evaluates how bariatric surgery modulates risk of complications in the setting of microvascular breast reconstruction., Methods: Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program (MBSAQIP) databases were queried for patients with body mass index (BMI) ≥35 kg/m2 undergoing bariatric surgery from 2017-2022. Outcomes included BMI and obesity-related comorbidities before and 1 year after bariatric surgery. Paired Breast Reconstruction Risk Assessment (BRA) scores were analyzed to evaluate risk modulation before and after bariatric surgery in the setting of microvascular breast reconstruction., Results: A total of 1,026 patients were included with an average age of 47 and BMI of 44.7 kg/m2. Comorbidities included hypertension (601, 59%), type 2 diabetes (291, 28%), and cardiovascular disease (10, 1%). One-year outcomes after bariatric surgery included an average BMI of 32.7 kg/m2, with remission of type 2 diabetes in 29% of patients. Paired BRA risk analysis for microvascular breast reconstruction before and after bariatric surgery showed reduction in 30-day surgical complications (40.4% vs. 24.8%, P<0.0001), with an absolute risk reduction (ARR) of 15%, relative risk reduction (RRR) of 36%, and a number needed to treat (NNT) of 7. Each 1 kg/m2 reduction in preoperative BMI was associated with a 3.4% reduction in surgical complications (P<0.0001)., Conclusions: There is potential efficacy for metabolic bridge therapy in reducing complications for obese patients undergoing microvascular breast reconstruction., Competing Interests: Financial Disclosure Statement: The authors have no financial conflicts of interest to disclose., (Copyright © 2024 by the American Society of Plastic Surgeons.)

Seizures induce hippocampal subregion dependent enhancements in microglia/macrophage phagocytosis and cytokine release that may contribute to the development of epilepsy. As a model of hyperactive mTOR induced epilepsy, neuronal subset specific phosphatase and tensin homolog (NS-Pten) knockout (KO) mice exhibit hyperactive mTOR signaling in the hippocampus, seizures that progress with age, and enhanced hippocampal microglia/macrophage activation. However, it is unknown where microglia/macrophages are most active within the hippocampus of NS-Pten KO mice. We quantified the density of IBA1 positive microglia/macrophages in the CA1, CA2/3, and dentate gyrus of NS-Pten KO and wildtype (WT) male and female mice at 4, 10, and 15 weeks of age. NS-Pten KO mice exhibited an overall increase in the number of IBA1 positive microglia/macrophages in each subregion and in the entire hippocampus. After accounting for differences in size, the whole hippocampus of NS-Pten KO mice still exhibited an increased density of IBA1 positive microglia/macrophages. Subregion analyses showed that this increase was restricted to the dentate gyrus of both male and female NS-Pten KO mice and to the CA1 of male NS-Pten KO mice. These data suggest enhanced microglia/macrophage activity may occur in the NS-Pten KO mice in a hippocampal subregion and sex-dependent manner. Future work should seek to determine whether these region-specific increases in microgliosis play a role in the progression of epilepsy in this model., Competing Interests: Declaration of Competing Interest The authors report no conflicts of interest in relation to this work., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: To discuss the potential benefit of belzutifan therapy in a patient with von Hippel-Lindau (VHL) disease-associated endolymphatic sac tumor (ELST)., Patients: Case report., Interventions: Clinical details of a patient with residual ELST after hearing preservation surgery who initiated belzutifan therapy postoperatively for concurrent renal cell carcinoma, as well as literature review of belzutifan and ELST., Main Outcome Measures: The patient remained without radiologic evidence of growth of her residual tumor at 17 months post-initiation of belzutifan. It is unknown whether this represents therapeutic drug effect, nonviability of residual tumor, or slow tumor growth not captured radiographically within the duration of follow-up., Conclusions: Belzutifan could have direct therapeutic benefit in patients with VHL-associated ELST., Competing Interests: The authors otherwise have no relevant disclosures with regard to financial support, acknowledgement, or conflicts of interest., (Copyright © 2024, Otology & Neurotology, Inc.)

Background: Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis and glomerulonephritis is uncommon in children. We sought to characterize the histological and clinical features of the disease and report on risk factors for adverse outcomes in a pediatric cohort., Methods: Retrospective single-center cohort of all pediatric (< 20 years) patients diagnosed with ANCA-associated glomerulonephritis (AAGN) by kidney biopsy between 2002 and 2022 at Johns Hopkins University. Histological and clinical features were extracted from the medical record. Clinical, laboratory, and histological findings were analyzed to determine the association with kidney failure (KF) and/or death., Results: A total of 17 patients were identified (GPA n = 7, MPA = 10) with a median age of 15 years (IQR 12-17) at presentation, a slight female predominance (59%), with seven patients reaching the composite outcome of death (n = 1) or kidney failure (n = 6). There was no difference in presenting clinical symptoms or extra-renal manifestations between the two groups. Univariable Cox regression identified several factors associated with an increased hazard of endpoint including the degree of global or segmental sclerosis, interstitial fibrosis and tubular atrophy (IFTA), C3 and C1q staining, presence of subendothelial deposits, and proteinuria. Multivariable regression was not performed due to the small sample size. We saw a trend towards increased utilization of plasma exchange and a decrease in cyclophosphamide utilization in the more recent era. There was no association between treatment modality and outcome., Conclusions: Pediatric AAGN is a rare disease associated with significant morbidity. We identified glomerulosclerosis and IFTA on histology, and proteinuria on initial presentation as risk factors for KF/death., (© 2024. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Purpose: The aim of this study is to identify likely pathogenic (LP) and pathogenic (P) genetic results for autism that can be returned to participants in SPARK (SPARKforAutism.org): a large recontactable cohort of people with autism in the United States. We also describe the process to return these clinically confirmed genetic findings., Methods: We present results from microarray genotyping and exome sequencing of 21,532 individuals with autism and 17,785 of their parents. We returned LP and P (American College of Medical Genetics criteria) copy-number variants, chromosomal aneuploidies, and variants in genes with strong evidence of association with autism and intellectual disability., Results: We identified 1903 returnable LP/P variants in 1861 individuals with autism (8.6%). 89.5% of these variants were not known to participants. The diagnostic genetic result was returned to 589 participants (53% of those contacted). Features associated with a higher probability of having a returnable result include cognitive and medically complex features, being female, being White (versus non-White) and being diagnosed more than 20 years ago. We also find results among autistics across the spectrum, as well as in transmitting parents with neuropsychiatric features but no autism diagnosis., Conclusion: SPARK offers an opportunity to assess returnable results among autistic people who have not been ascertained clinically. SPARK also provides practical experience returning genetic results for a behavioral condition at a large scale., Competing Interests: Conflict of Interest Wendy K. Chung is on the Board of Directors for Prime Medicine and Rallybio. Jessica R. Wright, Irina Astrovskaya, Sarah D. Barns, Alexandra Goler, Xueya Zhou, Chang Shu, LeeAnne Green Snyder, Bing Han, Yufeng Shen, Natalia Volfovsky, Jacob B. Hall, and Pamela Feliciano declare no potential conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The provision of ART in South Africa has transformed the HIV epidemic, resulting in an increase in life expectancy by over 10 years. Despite this, nearly 2 million people living with HIV are not on treatment. The objective of this study was to develop and externally validate a practical risk assessment tool to identify people with HIV (PWH) at highest risk for attrition from care after testing. A machine learning model incorporating clinical and psychosocial factors was developed in a primary cohort of 498 PWH. LASSO regression analysis was used to optimize variable selection. Multivariable logistic regression analysis was applied to build a model using 80% of the primary cohort as a training dataset and validated using the remaining 20% of the primary cohort and data from an independent cohort of 96 participants. The risk score was developed using the Sullivan and D'Agostino point based method. Of 498 participants with mean age 35.7 years, 192 (38%) did not initiate ART after diagnosis. Controlling for site, factors associated with non-engagement in care included being < 35 years, feeling abandoned by God, maladaptive coping strategies using alcohol or other drugs, no difficulty concentrating, and having high levels of confidence in one's ability to handle personal challenges. An effective risk score can enable clinicians and implementers to focus on tailoring care for those most in need of ongoing support. Further research should focus on potential strategies to enhance the generalizability and evaluate the implementation of the proposed risk prediction model in HIV treatment programs., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Endocrine therapies (ET) with cyclin-dependent kinase 4/6 (CDK4/6) inhibition are the standard treatment for estrogen receptor-α-positive (ER+) breast cancer, however drug resistance is common. In this study, proteogenomic analyses of patient-derived xenografts (PDXs) from patients with 22 ER+ breast cancer demonstrated that protein kinase, membrane-associated tyrosine/threonine one (PKMYT1), a WEE1 homolog, is estradiol (E2) regulated in E2-dependent PDXs and constitutively expressed when growth is E2-independent. In clinical samples, high PKMYT1 mRNA levels associated with resistance to both ET and CDK4/6 inhibition. The PKMYT1 inhibitor lunresertib (RP-6306) with gemcitabine selectively and synergistically reduced the viability of ET and palbociclib-resistant ER+ breast cancer cells without functional p53. In vitro the combination increased DNA damage and apoptosis. In palbociclib-resistant, TP53 mutant PDX-derived organoids and PDXs, RP-6306 with low-dose gemcitabine induced greater tumor volume reduction compared to treatment with either single agent. Our study demonstrates the clinical potential of RP-6306 in combination with gemcitabine for ET and CDK4/6 inhibitor resistant TP53 mutant ER+ breast cancer., (©2024 The Authors; Published by the American Association for Cancer Research.)

Molnupiravir is registered or authorized in several countries as a 5-day oral COVID-19 treatment for adults. Molnupiravir is a prodrug of the antiviral ribonucleoside β-D-N4-hydroxycytidine (NHC) that distributes into cells, where it is phosphorylated to its pharmacologically active ribonucleoside triphosphate (NHC-TP) form. NHC-TP incorporates into SARS-CoV-2 RNA by the viral RNA-dependent RNA polymerase, resulting in an accumulation of errors in the viral genome, leading to inhibition of viral replication and loss of infectivity. The potential of molnupiravir to induce genomic mutations and DNA damage was comprehensively assessed in several in vitro and in vivo genotoxicity assays and a carcinogenicity study, in accordance with international guideline recommendations and expert opinion. Molnupiravir and NHC induced mutations in vitro in bacteria and mammalian cells but did not induce chromosome damage in in vitro or in vivo assays. The in vivo mutagenic and carcinogenic potential of molnupiravir was tested in a series of in vivo mutagenicity studies in somatic and germ cells (Pig-a Assay and Big Blue® TGR Mutation Assay) and in a carcinogenicity study (transgenic rasH2-Tg mouse), using durations of exposure and doses exceeding those used in clinical therapy. In vitro genotoxicity results are superseded by robustly conducted in vivo studies. Molnupiravir did not increase mutations in somatic or germ cells in the in vivo animal studies and was negative in the carcinogenicity study. The interpretation criteria for each study followed established regulatory guidelines. Taken together, these data indicate that molnupiravir use does not present a genotoxicity or carcinogenicity risk for patients., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society of Toxicology.)

The recent development of ultra-fast magic-angle spinning (MAS) (>100 kHz) provides new opportunities for structural characterization in solids. Here, we use NMR crystallography to validate the structure of verinurad, a microcrystalline active pharmaceutical ingredient. To do this, we take advantage of 1 H resolution improvement at ultra-fast MAS and use solely 1 H-detected experiments and machine learning methods to assign all the experimental proton and carbon chemical shifts. This framework provides a new tool for elucidating chemical information from crystalline samples with limited sample volume and yields remarkably faster acquisition times compared to 13 C-detected experiments, without the need to employ dynamic nuclear polarization.

We determine the complete atomic-level structure of the amorphous form of the drug atuliflapon, a 5-lipooxygenase activating protein (FLAP) inhibitor, via chemical-shift-driven NMR crystallography. The ensemble of preferred structures allows us to identify a number of specific conformations and interactions that stabilize the amorphous structure. These include preferred hydrogen-bonding motifs with water and with other drug molecules, as well as conformations of the cyclohexane and pyrazole rings that stabilize structure by indirectly allowing for optimization of hydrogen bonding.

The developmental regulation of body size is a fundamental life-history characteristic that in most animals is tied to the transition from juvenile to adult form. In holometabolous insects, this transition is ostensibly initiated at the attainment of a critical weight in the final larval instar. It has been hypothesized that the size-sensing mechanism used to determine attainment of critical weight exploits oxygen limitation as a larvae grows beyond the oxygen-delivery capacity of its fixed tracheal system; that is, developmentally induced cellular hypoxia initiates the synthesis of the molting hormone ecdysone by the prothoracic gland. We tested this hypothesis in Drosophila by assaying cellular hypoxia throughout the third larval instar at 21 and 10 kPa O2, using the activity of the HIF (hypoxia inducible factor)-signaling pathway as a measure of hypoxia. While HIF signaling was elevated at low levels of environmental O2, it did not markedly increase during development at either oxygen level, and was only suppressed by hyperoxia after feeding had ceased. Further, changes in HIF signaling in the prothoracic gland alone did not alter body size or developmental time in a way that would be expected if cellular hypoxia in the prothoracic gland was part of the critical weight mechanism. Our data do show, however, that reduced HIF signaling in the prothoracic gland decreases survival and retards development at 10 kPa O2, suggesting that prothoracic HIF signaling is a necessary part of the beneficial plasticity mechanism that controls growth and development in response to low oxygen level., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2024. Published by The Company of Biologists Ltd.)

Recognizing and responding to threat cues is essential to survival. In rats, freezing is the most common behavior measured. Previously we demonstrated a threat cue can organize diverse behaviors (Chu et al., 2024). However, the experimental design of Chu et al. (2024) was complex and the findings descriptive. Here, we gave female and male Long Evans rats simple paired or unpaired presentations of a light and foot shock (8 total) in a conditioned suppression setting, using a range of shock intensities (0.15, 0.25, 0.35 or 0.5 mA). We found that conditioned suppression was only observed at higher foot shock intensities (0.35 mA and 0.5 mA). We constructed comprehensive, temporal ethograms by scoring 22,272 frames of behavior for 12 mutually exclusive behavior categories in 200 ms intervals around cue presentation. A 0.5 mA and 0.35 mA shock-paired visual cue suppressed reward seeking, rearing and scaling, as well as light-directed rearing and light-directed scaling. The shock-paired visual paired cue further elicited locomotion and freezing. Linear discriminant analyses showed that ethogram data could accurately classify rats into paired and unpaired groups. Considering the complete ethogram data produced superior classification than considering subsets of behaviors. The results demonstrate diverse threat-elicited behaviors - in a simple Pavlovian fear conditioning design - containing sufficient information to distinguish the fear learning status of individual rats., Competing Interests: Declaration of Interests The authors declare no conflicts of interest.

Background: Few validated brief scales are available to measure constructs that may hinder mpox-related prevention and care engagement, such as knowledge and stigma. Both are highly salient barriers to infectious disease care and disease understanding, precursors to evaluating one's risk and need to, for example, accept vaccination. To address this gap, we developed and validated the Mpox Stigma Scale (MSS) and Mpox Knowledge Scale (MKS)., Methods: As part of a full-scale clinical trial, we offered an optional mpox survey to participants who self-identified as African American or Black, were 18-29 years old, and lived in Alabama, Georgia, or North Carolina (2023, N = 330). We calculated psychometric properties through confirmatory factor analyses (CFA) and applied Comparative Fit Index (CFI), Goodness of Fit Index (GFI), and Tucker-Lewis Index (TLI) values equal to or exceeding 0.90 and Root Mean Square Error of Approximation (RMSEA) and Standardized Root Mean Square Residual (SRMR) values less than 0.08 to determine adequate model fit. We computed internal reliability using Cronbach's alpha and calculated Pearson or Spearman correlation coefficients between the MSS and MKS and related variables., Results: For the MSS, CFA results showed that the one-factor model fit the data well (χ 2 (df = 5, N = 330) = 34.962, CFI = 0.97, GFI = 0.99, TLI = 0.94, RMSEA = 0.13, SRMR = 0.03). For the MKS, the one-factor model provided a good fit to the data (χ 2 (df = 6, N = 330) = 8.44, CFI = 0.99, GFI = 0.99, TLI = 0.95, RMSEA = 0.15, SRMR = 0.02). Cronbach's alphas were MSS = 0.91 and MKS = 0.83, suggesting good to excellent reliability. The MSS was correlated with the MKS (r = .55, p < .001), stigmatizing attitudes (r = .24, p < .001), attitudes towards mpox vaccination (r=-.12, p = .030), and worry about contracting mpox (r = .44, p < .001). The MKS was correlated with worry about contracting mpox (r = .30, p < .001) and mpox disclosure (r=-.16, p = .003)., Conclusions: The MSS and MKS are reliable and valid tools for public health practice, treatment and prevention research, and behavioral science. Further validation is warranted across populations and geographic locations., Trial Registration: ClinicalTrials.gov NCT05490329., (© 2024. The Author(s).)

Despite numerous aging studies, the relationship between oxidative stress, aging, and decline in functions such as locomotion is still debated. Insects offer a promising model for analyzing the relationship between oxidative stress and aging, because they exhibit vast differences in lifespan that may be affected by the environment, social factors, levels of activity, and aging interventions. In this study, we explore the effects of aging on oxidative stress and locomotion using the pollinator, Megachile rotundata, a species that is very mobile and active in the adult stage. Across the adult lifespan of M. rotundata, we assessed changes in walking, flight, oxidative damage, and antioxidant defenses. Our results suggest that M. rotundata experience age-related declines in flight, but not walking. Additionally, we found that oxidative damage and antioxidant capacity initially increase with age and physical activity, but then levels are maintained. Overall, these data show that M. rotundata, like some other organisms, may not perfectly follow the free radical theory of aging., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Kendra Greenlee reports financial support was provided by USDA Agricultural Research Service. Kendra Greenlee reports financial support was provided by National Science Foundation. Giancarlo Lopez-Martinez reports financial support was provided by National Science Foundation. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Cardiovascular disease (CVD) and cancer are among the leading causes of morbidity and mortality globally, and these conditions are increasingly recognized to be fundamentally interconnected. In this Review, we present the current epidemiological data for each of the modifiable risk factors shared by the two diseases, including hypertension, hyperlipidaemia, diabetes mellitus, obesity, smoking, diet, physical activity and the social determinants of health. We then review the epidemiological data demonstrating the increased risk of CVD in patients with cancer, as well as the increased risk of cancer in patients with CVD. We also discuss the shared mechanisms implicated in the development of these conditions, highlighting their inherent bidirectional relationship. We conclude with a perspective on future research directions for the field of cardio-oncology to advance the care of patients with CVD and cancer., (© 2024. Springer Nature Limited.)

The genetic lesions that drive acute megakaryoblastic leukemia (AMKL) have not been fully elucidated. To search for genetic alterations in AMKL, we performed targeted deep sequencing in 34 AMKL patient samples and 8 AMKL cell lines and detected frequent genetic mutations in the NOTCH pathway in addition to previously reported alterations in GATA-1 and the JAK-STAT pathway. Pharmacological and genetic NOTCH activation, but not inhibition, significantly suppressed AMKL cell proliferation in both in vitro and in vivo assays employing a patient-derived xenograft model. These results suggest that NOTCH inactivation underlies AMKL leukemogenesis. and NOTCH activation holds the potential for therapeutic application in AMKL., Competing Interests: Conflicts of Interest Disclosure The authors have nothing to disclose., (Copyright © 2024 International Society for Experimental Hematology. Published by Elsevier Inc. All rights reserved.)

Objective: To compare cochlear implant (CI) speech perception outcomes in patients with sporadic vestibular schwannoma (VS) managed with observation, radiosurgery, or microsurgery., Study Design: Retrospective review., Setting: Eleven tertiary academic medical centers., Patients: One hundred patients with sporadic VS who received an ipsilateral CI., Interventions: Ipsilateral cochlear implantation., Main Outcome Measures: Pure-tone thresholds, monosyllabic speech perception testing scores, and rates of open-set speech acquisition., Results: Of the 100 patients studied, 54 underwent microsurgery, 26 underwent radiosurgery, 19 continued observation, and 1 underwent multimodal therapy. Among all patients, the median post-implantation pure-tone average was 31 dB (interquartile range [IQR] 25-39 dB) and the median monosyllabic speech perception score was 30% (IQR 0-60%) at a median of 12 months (IQR 5-25 months) post-implantation. Patients who were managed with microsurgery (median speech perception score 11%, IQR 0-52%) exhibited poorer implant outcomes overall compared with those managed with observation (median speech perception score 52%, IQR 40-72%) or radiosurgery (median speech perception score 30%, IQR 16-60%). Open-set speech perception was achieved in 61% of patients managed with microsurgery, 100% with observation, and 80% with radiosurgery. In a multivariable setting, those managed with observation (p = 0.02) or who underwent radiosurgery (p = 0.04) were significantly more likely to achieve open-set speech perception compared with patients who underwent microsurgery., Conclusions: Cochlear implants offer benefit in selected patients with sporadic VS. Although achieved in over half of people after microsurgery, open-set speech perception is more reliably attained in patients who are treated with observation or radiosurgery compared with microsurgical resection. These data may inform patient counseling and VS tumor management in people who may benefit from implantation., (Copyright © 2024, Otology & Neurotology, Inc.)

Purpose: Mpox disproportionately impacts Black people and young adults, yet the beliefs and knowledge of mpox among groups at elevated risk remain unclear. Therefore, we assessed mpox knowledge among Black young adults to inform public health efforts., Methods: We surveyed a sample (n = 330) of young Black adults (aged 18-29 years) in Alabama, Georgia, and North Carolina using nine true-or-false questions to assess their mpox knowledge., Results: Correct response rates varied (26%-96%). Approximately 26% were unaware of the mpox vaccine, and almost 21% incorrectly thought the chickenpox vaccine conferred protection against mpox. Females demonstrated statistically significantly higher mpox knowledge than males across 33% of indicators., Discussion: There were no statistically significant differences between states, suggesting that a regional approach may be suitable to improve knowledge. Findings underscore the importance of education and public health initiatives to address mpox knowledge gaps, particularly among Black young adults, to improve public health preparedness., (Copyright © 2024 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.)

Traumatic brain injury (TBI) is one of the foremost causes of disability and mortality globally. While the scientific and medical emphasis is to save lives and avoid disability during acute period of injury, a severe health problem can manifest years after injury. For instance, TBI increases the risk of cognitive impairment in the elderly. Remote TBI history was reported to be a cause of the accelerated clinical trajectory of Alzheimer's disease-related dementia (ADRD) resulting in earlier onset of cognitive impairment and increased AD-associated pathological markers like greater amyloid deposition and cortical thinning. It is not well understood whether a single TBI event may increase the risk of dementia. Moreover, the cellular signaling pathways remain elusive for the chronic effects of TBI on cognition. We have hypothesized that a single TBI induces sustained neuroinflammation and disrupts cellular communication in a way that results later in ADRD pathology. To test this, we induced TBI in young adult CD1 mice and assessed the behavioral outcomes after 11 months followed by pathological, histological, transcriptomic, and MRI assessment. On MRI scans, these mice showed significant loss of tissue, reduced CBF, and higher white matter injury compared to sham mice. We found these brains showed progressive atrophy, markers of ADRD, sustained astrogliosis, loss of neuronal plasticity, and growth factors even after 1-year post-TBI. Because of progressive neurodegeneration, these mice had motor deficits, showed cognitive impairments, and wandered randomly in open field. We, therefore, conclude that progressive pathology after adulthood TBI leads to neurodegenerative conditions such as ADRD and impairs neuronal functions., (© 2024. The Author(s), under exclusive licence to American Aging Association.)

Abstract: The variant single nucleotide polymorphism rs8104571 has been associated with poor outcomes following traumatic brain injury (TBI) and is most prevalent in those of African ancestry. This single nucleotide polymorphism (SNP) resides within a gene coding for the TRPM4 protein, which complexes with SUR1 protein to create a transmembrane ion channel and is believed to contribute to cellular swelling and cell death in neurological tissue. Our study evaluates the relationship between circulating TRPM4 and SUR1, rs8104571 genotype, and clinical outcome in TBI patients. Trauma patients with moderate to severe TBI were included in this retrospective study. rs8104571 genotyping and admission plasma TRPM4 and SUR1 quantification was performed with real-time PCR and enzyme-linked immunosorbent assay (ELISA), respectively. Adequate plasma for TRPM4 and SUR1 ELISA quantification was available for 289 patients, 54 of whom were African American (AA). Plasma TRPM4 concentration was increased in those with a variant rs8104571 allele compared to wild type when controlling for demographics and injury characteristics in the overall cohort (P = 0.04) and within the AA subgroup (P = 0.01). There was no significant association between plasma TRPM4 or SUR1 and clinical outcome (each P > 0.05). Plasma TRPM4 abundance increased with acute kidney injury severity (P = 0.02). The association between increased plasma TRPM4 and variant rs810457 supports an underlying mechanism involving increased neuroinflammation with a subsequent increase in the leakage of TRPM4 from the central nervous system into circulation. Alternative sources of plasma TRPM4 including the kidney cannot be excluded and may play a significant role in the pathophysiology of trauma as well., Competing Interests: Funding and Conflicts of Interest: This research was supported by the National Institute of General Medical Sciences of the National Institutes of Health (T32GM008792). Additional funding was provided by the William Stamps Farish Fund, the Howell Family Foundation, and the James H. "Red" Duke Professorship. Dr. Cox reports additional support from the National Institutes of Health; Department of Defense-Medical Technology Enterprise Consortium; State of Texas Emerging Technology Fund; Generate Life Sciences, Inc.; Athersys, Inc.; Celgene Cellular Therapeutics; Cellvation, Inc.; Cellularity, Inc.; Hope Biosciences, Inc.; The Bentsen Foundation; Mission Connect; Let's Cure CP; Ladybug Foundation; Evelyn Griffin Foundation; Glassell Family Foundation; The George and Cynthia Mitchell Foundation; Grace R. Walls Endowment; Brown Foundation; Cellvation, Inc.; Coagulex, Inc.; EMIT Corporation. No other authors report funding or conflicts of interest., (Copyright © 2024 by the Shock Society.)

Understanding phenology, its genetics and agronomic consequences, is critical for crop adaptation. Here we aim to (i) characterize lentil response to photoperiod with a focus on five loci: the lentil ELF3 orthologue Sn, two loci linked to clusters of lentil FT orthologues, and two loci without candidates in chromosomes 2 and 5 (Experiment 1: 36 lines, short and long days in a phytotron), and (ii) establish the phenology-yield relationship (Experiment 2: 25 lines, 11 field environments). A vintage perspective, where we quantify time trends in phenotype over three decades of breeding, links both experiments. Yield increased linearly from older to newer varieties at 29 kg ha-1 year-1 or 1.5% year-1, correlated negatively with flowering time in both winter- and summer-rainfall regimes, and decoupled from biomass in favourable environments. Time to flowering shortened from older to newer varieties at -0.56% year-1 in the field, and -0.42% year-1 (short days) and -0.99% year-1 (long days) in the phytotron. Early-flowering lines of diverse origin carried multiple early alleles for the five loci, indicating that at least some of these loci affect phenology additively. Current germplasm primarily features the early-flowering haplotype for an FTb cluster region, hence the potential to increase phenological diversity with yield implications., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Pulmonary arteriovenous malformations create continuous shunting of unoxygenated blood through the lungs into the systemic circulation. These malformations are asymptomatic if small, but cause serious symptoms as they grow in size. Treatment primarily consists of endovascular embolization; lobectomy is preserved for recurring or endovascularly untreatable cases. We describe a case of a 24-year-old man who was first treated with coil embolization 10 years previously, with complete symptom resolution. However, more recently he noted recurrent exercise intolerance, with shortness of breath and hypoxemia. After repeat re-embolization, a computed tomography scan noted some persistent flow. Given the patient's young age, we considered resection as a definite therapy. The patient underwent an uncomplicated robot-assisted right lower lobectomy. Afterward, his symptoms resolved completely. In selected cases, robotic lobectomy for pulmonary arteriovenous malformation is feasible and safe., Competing Interests: M.P.K. consults for Intuitive Surgical, Medtronic, Olympus, and AstraZeneca. A.B.L. receives research support from 10.13039/100020453W. L. Gore & Associates; consults with Boston Scientific, W. L. Gore & Associates, and Siemens; and is a shareholder in Hatch Medical., (© 2024 The Author(s).)

Next-generation energy-efficient photonic integrated systems, such as neuromorphic computational chips require efficient heterogeneous integration of ultracompact light sources and photodetectors through highly dense waveguide circuits. However, interconnecting these devices in emitter-receiver communication circuits remains a challenge and an obstacle towards upscaling heterogeneous photonic chips. Here we report on versatile air-cladded free-standing 3D polymer waveguides (OrmoCore, n≈1.5) spanning up to 900 µm in length without intermediate mechanical support structures, microprinted via two-photon polymerization. The presented waveguides are suitable for on-chip out-of-plane light coupling as well as non-connected 3D crossings, needed for high density optical circuits. The waveguides show optical transmission losses of 1.93 dB mm -1 at λ = 635 nm, and of 3.71 dB mm -1 at λ = 830 nm in the wavelength range of GaAs-based microLEDs spectral emission. On-chip imaging for high-precision alignment and TPP microfabrication are performed seamlessly by utilizing the same laser source for both steps, allowing accurate 3D printing on microstructured substrates. As proof of concept, we interconnect two GaAs-based microLEDs via an on-chip microprinted 3D waveguide. Such combined systems can serve as building blocks of future complex integrated heterogeneous photonic networks., (© 2024. The Author(s).)

Niemann-Pick disease type C (NPC) is a rare and fatal neurological disorder caused by mutations in Npc1 or Npc2 , with Npc1 accounting for 95% of cases. These mutations result in the functional loss of their respective proteins, causing cellular abnormalities characterized by disrupted lipid dysregulation, calcium dysfunction, elevated damage associated molecular patterns (DAMPs), and a pro-inflammatory environment. This cellular pathology ultimately triggers neurodegeneration, with the cerebellum being the earliest and most affected region. We have recently shown atypical activation of interferon signaling in the presymptomatic Npc1 -/- mouse cerebellum and, to a lesser extent, in the cerebral cortex. In addition, we reported that the Amyloid Precursor Protein (APP) is an NPC disease modifier. Loss of APP function leads to widespread neurodegeneration in the NPC brain, including exacerbated interferon signaling in the cerebellum. To better understand the role of APP as a disease modifier throughout the NPC brain, here we carried out a transcriptomic analysis of the cerebral cortex and cerebellum from 3-week-old Npc1 -/- mice as well as age-matched controls in the presence and absence of APP. We report differential effects of APP loss of function in the cerebral cortex and cerebellum, including cholesterol and tau dysregulation, in both brain regions. Our findings demonstrate a novel link between APP loss and early pathogenic mechanisms in NPC.

Background: Microsatellite Instability (MSI) and Tumor Mutational Burden (TMB) are associated with immune checkpoint inhibitor (ICI) efficacy. We examined the association between TMB and MSI status with survival in patients with urothelial carcinoma (UC) treated with ICI., Methods: Patients from 15 institutions were treated with ICI monotherapy. Primary endpoint was overall survival and secondary endpoints included observed response rate (ORR), and progression-free (PFS) calculated from ICI initiation. TMB was analyzed as dichotomous (≥10 vs. <10 mut/Mb) and continuous variable., Results: We identified 411 patients: 203 were treated with ICI 1L/upfront; 104 with 2 + L. For the 1L/upfront: median [m] OS was numerically longer in patients with TMB ≥10 versus TMB <10: mOS 35 versus 26 months (HR = 0.6) and with MSI-H and MSI-S (mOS NR vs. 22 months), though neither association was statistically significant. A statistically significant association was found between TMB (continuous variable) and OS (HR = 0.96, P = .01). For 2 + L: mOS was numerically longer in patients with TMB ≥10 versus TMB <10: (20 vs. 12 months; HR = 0.9); mOS was 12 and 17 months for patients with MSI-H and MSI-S, respectively. Eighty-nine patients received maintenance avelumab (mAV): mOS was longer in patients with TMB ≥10 versus TMB <10: 61 versus 17 months; (HR = 0.2, P = .02) and with MSI-H and MSI-S (NR vs. 24 months)., Conclusions: Although not reaching statistical significance in several subsets, patients with high TMB and MSI-H had numerically longer OS with ICI, especially with mAV. Further validation is needed., (Copyright © 2024 Elsevier Inc. All rights reserved.)

We address challenges in characterizing changes in permittivity and refractive index beyond standard perturbative methods with special attention given to transparent conductive oxides (TCOs). We unveil a realistic limit to permittivity changes under high optical power densities. Our study covers both slow and ultrafast nonlinearities, demonstrating that all nonlinearities induce refractive index changes accurately described by a simple curve with saturation electric field (or irradiance) and maximum change of permittivity at saturation. Our model, grounded in material properties, like oscillator strength and characteristic times, offers a robust framework for understanding and predicting nonlinear optical phenomena in TCOs and other materials. We differentiate between the significance of higher-order nonlinear susceptibilities in ultrafast and slow nonlinear scenarios. We aim to provide valuable insights for researchers exploring strong light-matter interaction., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Purpose: Modular cementless knee arthroplasty systems are capable of precise reconstruction of the mechanical axis. However, they are considered more susceptible to complications. In contrast, non-modular cemented systems are said to be more forgiving and show good long-term results. The aim of this study was to investigate the resulting leg axis after implantation of a non-modular cemented rotating hinged knee prosthesis. Furthermore, potential risk factors for the occurrence of malalignment and complications should be identified., Methods: Between 2005 and 2015, 115 patients could be included in this monocentric retrospective cohort study. All patients underwent primary hinged non-modular cemented total knee arthroplasty. Preoperative and postoperative standardized long radiographs were analysed to determine resulting leg axis. Furthermore, epidemiological and intraoperative data as well as perioperative complications were surveyed., Results: Average leg axis was 5.8° varus preoperatively and 0.6° valgus postoperatively. Considering an axis deviation of 3° as the target corridor, 27% of all cases examined were outside the desired range. 21% cases showed a femoral deviation from the target corridor and 15% showed a tibial deviation. There was a significant relationship between the preoperative mLDFA and the mechanical alignment of the femoral component (R = 0.396, p < 0.001) as well as between the preoperative mMPTA and the mechanical alignment of the tibial component (R = 0.187, p = 0.045). The mean operative duration was 96 min. No periprosthetic fractures were observed within the study cohort., Conclusion: The main result of the present work is that a non-modular cemented rotating hinged knee arthroplasty system can reconstruct the mechanical leg axis precisely and comparable to modular cementless and unconstrained total knee prostheses. Component malalignment is primarily dependent upon extraarticular deformity preoperatively. Periprosthetic fracture rates and duration of surgery were lower compared with current literature., Level of Evidence: Level III: Retrospective cohort study., (© 2024. The Author(s).)

Background: U.S. nationwide estimates of the proportion of patients newly diagnosed with heart failure with reduced ejection fraction (HFrEF) eligible for quadruple medical therapy, and the associated benefits of rapid implementation, are not well characterized., Objectives: This study sought to characterize the degree to which patients newly diagnosed with HFrEF are eligible for quadruple medical therapy, and the projected benefits of in-hospital initiation., Methods: Among patients hospitalized for newly diagnosed HFrEF in the Get With The Guidelines-Heart Failure registry from 2016 to 2023, eligibility criteria based on regulatory labeling, guidelines, and expert consensus documents were applied for angiotensin receptor-neprilysin inhibitor, beta-blocker, mineralocorticoid receptor antagonist, and sodium-glucose cotransporter 2 inhibitor therapies. Of those eligible, the projected effect of quadruple therapy on 12-month mortality was modeled using treatment effects from pivotal clinical trials utilized by the AHA/ACC/HFSA Guideline for the Management of Heart Failure, and compared with observed outcomes among patients treated with angiotensin-converting enzyme inhibitor/angiotensin receptor blocker and beta-blockers., Results: Of 33,036 patients newly diagnosed with HFrEF, 27,158 (82%) were eligible for quadruple therapy, and 30,613 (93%) were eligible for ≥3 components. From 2021 to 2023, of patients eligible for quadruple therapy, 15.3% were prescribed quadruple therapy and 41.5% were prescribed triple therapy. Among Medicare beneficiaries eligible for quadruple therapy, 12-month incidence of mortality was 24.7% and HF hospitalization was 22.2%. Applying the relative risk reductions in clinical trials, complete implementation of quadruple therapy by time of discharge was projected to yield absolute risk reductions in 12-month mortality of 10.4% (number needed to treat = 10) compared with angiotensin-converting enzyme inhibitor/angiotensin receptor blocker and beta-blocker, and 24.8% (number needed to treat = 4) compared with no GDMT., Conclusions: In this nationwide U.S. cohort of patients hospitalized for newly diagnosed HFrEF, >4 of 5 patients were projected as eligible for quadruple therapy at discharge; yet, <1 in 6 were prescribed it. If clinical trial benefits can be fully realized, in-hospital initiation of quadruple medical therapy for newly diagnosed HFrEF would yield large absolute reductions in mortality., Competing Interests: Funding Support and Author Disclosures The Get With The Guidelines–Heart Failure (GWTG-HF) program is provided by the American Heart Association and sponsored, in part, by Novartis, Boehringer Ingelheim, and Eli Lilly Diabetes Alliance, Novo Nordisk, Sanofi, AstraZeneca, and Bayer. Dr Greene has received research support from the Duke University Department of Medicine Chair’s Research Award, American Heart Association, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Cytokinetics, Merck, Novartis, Pfizer, and Sanofi; has served on advisory boards or as consultant for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Corteria Pharmaceuticals, CSL Vifor, Cytokinetics, Eli Lilly, Lexicon, Merck, Roche Diagnostics, Sanofi, scPharmaceuticals, Tricog Health, and Urovant Pharmaceuticals; and has received speaker fees from Bayer, Boehringer Ingelheim, Cytokinetics, Lexicon, and Roche Diagnostics. Dr Fonarow has consulted for Abbott, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Eli Lilly, Johnson and Johnson, Medtronic, Merck, Novartis, and Pfizer. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Chronic multisymptom illnesses (CMI) such as Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, Long-COVID, and Gulf War Illness (GWI) are associated with an elevated risk of post-exertional malaise (PEM), an acute exacerbation of symptoms and other related outcomes following exercise. These individuals may benefit from personalized exercise prescriptions which prioritize risk minimization, necessitating a better understanding of dose-response effects of exercise intensity on PEM., Methods: Veterans with GWI (n = 40) completed a randomized controlled crossover experiment comparing 20 min of seated rest to light-, moderate-, and vigorous-intensity cycling conditions over four separate study visits. Symptoms, pain sensitivity, cognitive performance, inflammatory markers (C-reactive protein and plasma cytokines) were measured before and within 1 h after exercise and seated rest. Physical activity behavior was measured ≥ 7 days following each study visit via actigraphy. Linear mixed effects regression models tested the central hypothesis that higher intensity exercise would elicit greater exacerbation of negative outcomes, as indicated by a significant condition-by-time interaction for symptom, pain sensitivity, cognitive performance, and inflammatory marker models and a significant main effect of condition for physical activity models., Results: Significant condition-by-time interactions were not observed for primary or secondary measures of symptoms, pain sensitivity, cognitive performance, and a majority of inflammatory markers. Similarly, a significant effect of condition was not observed for primary or secondary measures of physical activity., Conclusions: Undesirable effects such as symptom exacerbation were observed for some participants, but the group-level risk of PEM following light-, moderate-, or vigorous-intensity exercise was no greater than seated rest. These findings challenge several prior views about PEM and lend support to a broader body of literature showing that the benefits of exercise outweigh the risks., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Inc.)

Purpose: Rising rates of early-onset colon cancer (EOCC) present challenges in deciding how to optimally treat patients. Although standard of care for stage II CC is surgical resection, adding chemotherapy for high-risk disease, evidence suggests treatment selection may differ by age. We investigated whether adjuvant chemotherapy (AC) administration rates differ between patients with early- and later-onset stage II CC., Methods: Data originated from the nationwide Flatiron Health electronic health record (EHR)-derived deidentified database spanning January 1, 2003, to August 1, 2021. Adults with stage II CC were grouped as age 18-49 years (EOCC) and those age 50 years or older (later-onset colon cancer [LOCC]). Demographics, Eastern Cooperative Oncology Group score, tumor stage and site, and chemotherapy were included. Primary outcomes included rates of AC administration by age and ethnicity; secondary outcomes included overall survival (OS) and time to metastatic disease (TTMD). Univariate and multivariable logistic regression models evaluated relationships between chemotherapy administration, age, and ethnicity, adjusting for significant covariates., Results: One thousand sixty-five patients were included. Median age of patients with EOCC was 45.0 years versus 69.0 years for patients with LOCC. Adjusted multivariate analysis showed patients with EOCC received AC significantly more often than patients with LOCC. Non-Hispanic patients received AC at significantly lower rates than Hispanic patients in both cohorts. Subanalysis of stage IIA patients showed that patients with EOCC were more likely to receive AC than patients with LOCC. No significant differences in OS or TTMD were observed by age regardless of AC administration in stage II overall; however, patients with stage IIA EOCC receiving AC had significantly longer TTMD than those not receiving AC., Conclusion: AC was given preferentially in stage II EOCC, even in stage IIA, despite deviation from guidelines. This may expose low-risk patients to unnecessary toxicities and suggests bias toward treating younger patients more aggressively, despite unclear evidence for better outcomes.

Obesity impairs tissue insulin sensitivity and signaling, promoting type-2 diabetes. Although improving insulin signaling is key to reversing diabetes, the multi-organ mechanisms regulating this process are poorly defined. Here, we screen the secretome and receptome in Drosophila to identify the hormonal crosstalk affecting diet-induced insulin resistance and obesity. We discover a complex interplay between muscle, neuronal, and adipose tissues, mediated by Bone Morphogenetic Protein (BMP) signaling and the hormone Bursicon, that enhances insulin signaling and sugar tolerance. Muscle-derived BMP signaling, induced by sugar, governs neuronal Bursicon signaling. Bursicon, through its receptor Rickets, a Leucine-rich-repeat-containing G-protein coupled receptor (LGR), improves insulin secretion and insulin sensitivity in adipose tissue, mitigating hyperglycemia. In mouse adipocytes, loss of the Rickets ortholog LGR4 blunts insulin responses, showing an essential role of LGR4 in adipocyte insulin sensitivity. Our findings reveal a muscle-neuronal-fat-tissue axis driving metabolic adaptation to high-sugar conditions, identifying LGR4 as a critical mediator in this regulatory network., (© 2024. The Author(s).)

Premise: Traditional methods of ploidal-level estimation are tedious; using DNA sequence data for cytotype estimation is an ideal alternative. Multiple statistical approaches to leverage sequence data for ploidy inference based on site-based heterozygosity have been developed. However, these approaches may require high-coverage sequence data, use inappropriate probability distributions, or have additional statistical shortcomings that limit inference abilities. We introduce nQuack, an open-source R package that addresses the main shortcomings of current methods., Methods and Results: nQuack performs model selection for improved ploidy predictions. Here, we implement expectation maximization algorithms with normal, beta, and beta-binomial distributions. Using extensive computer simulations that account for variability in sequencing depth, as well as real data sets, we demonstrate the utility and limitations of nQuack., Conclusions: Inferring ploidy based on site-based heterozygosity alone is difficult. Even though nQuack is more accurate than similar methods, we suggest caution when relying on any site-based heterozygosity method to infer ploidy., (© 2024 The Author(s). Applications in Plant Sciences published by Wiley Periodicals LLC on behalf of Botanical Society of America.)

Direct observation is central to our understanding of adaptation, but evolution is rarely documented in a large, multicellular organism for more than a few generations. In this study, we observed evolution across a century-scale competition experiment, barley composite cross II (CCII). CCII was founded in 1929 in Davis, California, with thousands of genotypes, but we found that natural selection has massively reduced genetic diversity, leading to a single lineage constituting most of the population by generation 50. Selection favored alleles originating from climates similar to that of Davis and targeted loci contributing to reproductive development, including the barley diversification loci Vrs1 , HvCEN , Ppd-H1 , and Vrn-H2 . Our findings point to selection as the predominant force shaping genomic variation in one of the world's oldest biological experiments.

The Yamuna River in India and the Mississippi River in the United States hold significant commercial, cultural, and ecological importance. This preliminary survey compares the bacterial communities sampled in surface waters at 11 sites (Yamuna headwaters, Mississippi headwaters, Yamuna River Yamunotri Town, Mississippi River at Winona, Tons River, Yamuna River at Paonta Sahib, Yamuna River Delhi-1, Yamuna River Delhi-2, Yamuna River before Sangam, Sangam, Ganga River before Sangam). Bacterial 16S rDNA analyses demonstrate dominance of Proteobacteria and Bacteroidetes phyla. Actinobacteria were also dominant at sites near Sangam in India and sites in Minnesota. A dominance of Epsilonbacteraeota were found in Delhi, India. Principal component analysis (PCA) using unique operational taxonomic units (OTUs) resulted in the identification of 3 groups that included the Yamuna River locations in Delhi (Delhi locations), Yamuna headwaters and Yamuna River at Yamunotri (Yamuna River locations below the Glacier) and Mississippi, Ganga, Tons, and other Yamuna River locations. Diversity indices were significantly higher at the Yamuna River locations below the Glacier (Simpson D = 0.986 and Shannon H = 5.06) as compared (p value <0.001) to the Delhi locations (D = 0.951 and H = 4.23) and as compared (p value < 0.001) to Mississippi, Ganga, Tons, and other Yamuna River locations (D = 0.943 and H = 3.96). To our knowledge, this is the first survey to compare Mississippi and Yamuna River bacterial communities. We demonstrate higher diversity in the bacterial communities below the Yamunotri glacier in India., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Martinez et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Large-bore aspiration thrombectomy is emerging as a promising alternative for thrombus removal in acute pulmonary embolism (PE). In this article, we report a successful case with the newly approved AlphaVac F18 85 device in a 76-year-old patient presenting with an intermediate- to high-risk acute PE. Preoperative imaging demonstrated bilateral PE with a modified miller index of 30 and an right ventricle-to-left ventricle ratio of 2.1. Mechanical thrombectomy was performed under local anesthesia with mild sedation. The pulmonary artery pressures decreased from 85/27 to 46/13 immediately after thrombectomy. The postoperative course was notable for marked symptom improvement and repeat imaging showed a 63% decrease in clot burden with a decrease in right ventricle-to-left ventricle ratio to 1.3., Competing Interests: E.K.P. is a consultant for Voyager Medical, Venostent and Humacyte Inc. All fees are retained by Houston Methodist., (© 2024 The Authors.)

Night work is frequently associated with sleep deprivation and is associated with greater surgical and medical complications. Lung transplantation (LT) is carried out both at night and during the day and involves many medical healthcare workers. The goal of the study was to compare morbidity and mortality between LT recipients according to LT operative time. We performed a retrospective, observational, single-center study. When the procedure started between 6 AM and 6 PM, the patient was allocated to the Daytime group. If the procedure started between 6 PM and 6 AM, the patient was allocated to the Nighttime group. Between January 2015 and December 2020, 253 patients were included. A total of 168 (66%) patients were classified into the Day group, and 85 (34%) patients were classified into the Night group. Lung Donors' general characteristics were similar between the groups. The 90-day and one-year mortality rates were similar between the groups (90-days: n = 13 (15%) vs. n = 26 (15%), p = 0.970; 1 year: n = 18 (21%) vs. n = 42 (25%), p = 0.499). Daytime LT was associated with more one-year airway dehiscence (n = 36 (21%) vs. n = 6 (7.1%), p = 0.004). In conclusion, among patients who underwent LT, there was no significant association between operative time and survival., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Tanaka, De Tymowski, Dupuis, Tran-Dinh, Lortat-Jacob, Harpan, Jean-Baptiste, Boudinet, Tahri, Salpin, Castier, Mordant, Mal, Girault, Atchade, Montravers and the Bichat Lung Transplant Group.)