Examining effects of a novel estrogenic perfluoro-alcohol, 1H,1H,8H,8H-Perfluorooctane-1,8-diol (FC8-diol), using the fathead minnow EcoToxChip.

In a previous in vivo study, adult male fathead minnows (Pimephales promelas) were exposed via water for 4 days to 1H,1H,8H,8H-perfluorooctane-1,8-diol (FC8-diol). The present study expands on the evaluation of molecular responses to this perfluoro-alcohol by analyzing 26 male fathead minnow liver RNA samples from that study (five from each test concentration: 0, 0.018, 0.051, 0.171, and 0.463 mg FC8-diol/L) using fathead minnow EcoToxChips Ver. 1.0. EcoToxChips are a quantitative polymerase chain reaction array that allows for simultaneous measurement of >375 species-specific genes of toxicological interest. Data were analyzed with the online tool EcoToxXplorer. Among the genes analyzed, 62 and 96 were significantly up- and downregulated, respectively, by one or more FC8-diol treatments. Gene expression results from the previous study were validated, showing an upregulation of vitellogenin mRNA (vtg) and downregulation of insulin-like growth factor 1 mRNA (igf1). Additional genes related to estrogen receptor activation including esr2a (estrogen receptor 2a) and esrrb (estrogen related receptor beta) were also affected, providing further confirmation of the estrogenic nature of FC8-diol. Furthermore, genes involved in biological pathways related to lipid and carbohydrate metabolism, innate immune response, endocrine reproduction, and endocrine thyroid were significantly affected. These results both add confidence in the use of the EcoToxChip tool for inferring chemical mode(s) of action and provide further insights into the possible biological effects of FC8-diol. Environ Toxicol Chem 2024;00:1-9. © 2024 SETAC. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

Potential Hazards of Polycyclic Aromatic Hydrocarbons in Great Lakes Tributaries Using Water Column and Porewater Passive Samplers and Sediment Equilibrium Partitioning.

The potential for polycyclic aromatic hydrocarbon (PAH)-related effects in benthic organisms is commonly estimated from organic carbon-normalized sediment concentrations based on equilibrium partitioning (EqP). Although this approach is useful for screening purposes, it may overestimate PAH bioavailability by orders of magnitude in some sediments, leading to inflated exposure estimates and potentially unnecessary remediation costs. Recently, passive samplers have been shown to provide an accurate assessment of the freely dissolved concentrations of PAHs, and thus their bioavailability and possible biological effects, in sediment porewater and overlying surface water. We used polyethylene passive sampling devices (PEDs) to measure freely dissolved porewater and water column PAH concentrations at 55 Great Lakes (USA/Canada) tributary locations. The potential for PAH-related biological effects using PED concentrations were estimated with multiple approaches by applying EqP, water quality guidelines, and pathway-based biological activity based on in vitro bioassay results from ToxCast. Results based on the PED-based exposure estimates were compared with EqP-derived exposure estimates for concurrently collected sediment samples. The results indicate a potential overestimation of bioavailable PAH concentrations by up to 960-fold using the EqP-based method compared with measurements using PEDs. Even so, PED-based exposure estimates indicate a high potential for PAH-related biological effects at 14 locations. Our findings provide an updated, weight-of-evidence-based site prioritization to help guide possible future monitoring and mitigation efforts. Environ Toxicol Chem 2024;43:1509-1523. © 2024 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

Innovative approaches to cardiovascular safety pharmacology assessment.

This editorial prefaces the annual themed issue on safety pharmacology (SP) methods which has been published since 2004 in the Journal of Pharmacological and Toxicological Methods (JPTM). Here we highlight content derived from the 2023 Safety Pharmacology Society (SPS) meeting held in Brussels, Belgium. The meeting generated 138 abstracts, reproduced in the current volume of JPTM. As in prior years, the manuscripts reflect various areas of innovation in SP including in silico modeling of stroke volume, cardiac output and systemic vascular resistance, computational approaches that compare drug-induced proarrhythmic sensitivity of human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), an evaluation of the utility of the corrected J-Tpeak and Tpeak-to-Tend parameters from the ECG as potential proarrhythmia biomarkers, and the applicability of nonclinical concentration-QTc (C-QTc) modeling of data derived from the conduct of the in vivo QTc study as a component of the core battery of safety pharmacology studies.

Revision Hip Arthroplasty Performed by Fellowship-Trained Versus Non-Fellowship-Trained Surgeons: A Comparison of Perioperative Management and Complications.

INTRODUCTION: Successful revision hip arthroplasty (rTHA) requires major resource allocation and a surgical team adept at managing these complex cases. The purpose of this study was to compare the results of rTHA performed by fellowship-trained and non-fellowship-trained surgeons. METHODS: A national administrative database was utilized to identify 5,880 patients who underwent aseptic rTHA and 1,622 patients who underwent head-liner exchange for infection by fellowship- and non-fellowship-trained surgeons from 2010 to 2020 with a 5-year follow-up. Postoperative opioid and anticoagulant prescriptions were compared among surgeons. Patients treated by fellowship- and non-fellowship-trained surgeons had propensity scores matched based on age, sex, comorbidity index, and diagnosis. The five-year surgical complications were compared using descriptive statistics. Multivariable analysis was performed to determine the odds of failure following head-liner exchange when performed by a fellowship-trained versus non-fellowship-trained surgeon. RESULTS: Aseptic rTHA patients treated by fellowship-trained surgeons received fewer opioids (132 versus 165 milligram morphine equivalents per patient) and non-aspirin anticoagulants (21.4 versus 32.0%, P < 0.001). Fellowship-training was associated with lower dislocation rates (9.9 versus 14.2%, P = 0.011), fewer postoperative infections, and fewer periprosthetic fractures and re-revisions (15.2 versus 21.3%, P < 0.001). Head-liner exchange for infection performed by fellowship-trained surgeons was associated with lower odds of failure (31.2 versus 45.7%, odds ratio (OR) 0.76, 95% confidence interval (CI) 0.62 to 0.91, P < 0.001). CONCLUSIONS: Revision THA performed by adult reconstruction fellowship-trained surgeons results in fewer re-revisions in aseptic cases and head-liner exchanges. Variations in resources, volumes, and perioperative protocols may account for some of the differences.

The Society of Thoracic Surgeons Clinical Practice Guidelines on the Management of Neonates and Infants with Coarctation.

BACKGROUND: Although coarctation of the aorta without concomitant intracardiac pathology is relatively common, there is lack of guidance regarding aspects of its management in neonates and infants. METHODS: A panel of experienced congenital cardiac surgeons, cardiologists, and intensivists was created, and key questions related to the management of isolated coarctation in neonates and infants were formed using the PICO (Patients/Population, Intervention, Comparison/Control, Outcome) Framework. A literature search was then performed for each question. Practice guidelines were developed with classification of recommendation and level of evidence using a modified Delphi method. RESULTS: For neonates and infants with isolated coarctation, surgery is indicated in the absence of obvious surgical contraindications. For patients with risk factors for surgery, medical management before intervention is reasonable. For those stable off prostaglandin E1, the threshold for intervention remains unclear. Thoracotomy is indicated when arch hypoplasia is not present. Sternotomy is preferable when arch hypoplasia is present that cannot be adequately addressed through a thoracotomy. Sternotomy may also be considered in the presence of a bovine aortic arch. Antegrade cerebral perfusion may be reasonable when the repair is performed through a sternotomy. Extended end-to-end, arch advancement, and patch augmentation are all reasonable techniques. CONCLUSIONS: Surgery remains the standard of care for the management of isolated coarctation in neonates and infants. Depending on degree and location, arch hypoplasia may require a sternotomy approach as opposed to a thoracotomy approach. Significant opportunities remain to better delineate management in these patients.

Impact of Social Determinants of Health on Predictive Models for Outcomes After Congenital Heart Surgery.

BACKGROUND: Despite documented associations between social determinants of health and outcomes post-congenital heart surgery, clinical risk models typically exclude these factors. OBJECTIVES: The study sought to characterize associations between social determinants and operative and longitudinal mortality as well as assess impacts on risk model performance. METHODS: Demographic and clinical data were obtained for all congenital heart surgeries (2006-2021) from locally held Congenital Heart Surgery Collaborative for Longitudinal Outcomes and Utilization of Resources Society of Thoracic Surgeons Congenital Heart Surgery Database data. Neighborhood-level American Community Survey and composite sociodemographic measures were linked by zip code. Model prediction, discrimination, and impact on quality assessment were assessed before and after inclusion of social determinants in models based on the 2020 Society of Thoracic Surgeons Congenital Heart Surgery Database Mortality Risk Model. RESULTS: Of 14,173 total index operations across New York State, 12,321 cases, representing 10,271 patients at 8 centers, had zip codes for linkage. A total of 327 (2.7%) patients died in the hospital or before 30 days, and 314 children died by December 31, 2021 (total n = 641; 6.2%). Multiple measures of social determinants of health explained as much or more variability in operative and longitudinal mortality than clinical comorbidities or prior cardiac surgery. Inclusion of social determinants minimally improved models' predictive performance (operative: 0.834-0.844; longitudinal 0.808-0.811), but significantly improved model discrimination; 10.0% more survivors and 4.8% more mortalities were appropriately risk classified with inclusion. Wide variation in reclassification was observed by site, resulting in changes in the center performance classification category for 2 of 8 centers. CONCLUSIONS: Although indiscriminate inclusion of social determinants in clinical risk modeling can conceal inequities, thoughtful consideration can help centers understand their performance across populations and guide efforts to improve health equity.

Optimizing Professional Development for New York State Public Health Association Members: Findings From a Mixed Methods Assessment of Public Health Professionals.

The COVID-19 pandemic placed significant burden on public health professionals, with many experiencing burnout and leaving the profession. The New York State Public Health Association (NYSPHA) recognized the impact of the pandemic on the state's public health workforce and sought professional development opportunities to support current and future generations of public health professionals. To achieve this goal, NYSPHA solicited input from its members and potential members via survey and focus groups as part of its New Directions Initiative. Seventy individuals participated in listening sessions, and 850 responded to the survey. While more than half felt that NYSPHA is invested in the health and wellness of New Yorkers, fewer considered NYSPHA a leader in public health or a go-to source for public health information. Only about one-third felt connected to NYSPHA as a public health professional. Participants identified multiple professional development opportunities that would encourage them to join or renew their membership including sections or special interest groups (57.4%), opportunities to gain leadership experience (56.7%), volunteering (58.1%), a new committee that addresses public health in the community (55.9%), and mentorship (48.4%). NYSPHA used the results of the survey and focus groups to provide several professional development opportunities including a mentorship program, a new Public Health in Action Committee, and special interest groups in mental health and climate change that have already made a difference in local New York State communities. Similar organizations may use NYSPHA's experience as an example for supporting their workforce to maximize impact on the communities they serve.

Differential cholinergic innervation of lemniscal versus non-lemniscal regions of the inferior colliculus.

The inferior colliculus (IC), a midbrain hub for integration of auditory information, receives dense cholinergic input that could modulate nearly all aspects of hearing. A key step in understanding cholinergic modulation is to identify the source(s) and termination patterns of cholinergic input. These issues have not been addressed for the IC in mice, an increasingly important model for study of hearing. We examined cholinergic inputs to the IC in adult male and female mice. We used retrograde tracing and immunochemistry to identify three sources of cholinergic innervation of the mouse IC: the pedunculopontine tegmental nucleus (PPT), the laterodorsal tegmental nucleus (LDT) and the lateral paragigantocellular nucleus (LPGi). We then used Cre-dependent labeling of cholinergic neurons in normal-hearing ChAT-Cre mice to selectively label the cholinergic projections to the IC from each of the cholinergic sources. Labeling of cholinergic projections from the PPT and LDT revealed cholinergic axons and boutons terminating throughout the IC, with the ipsilateral projection being denser. Electron microscopic examination showed that these cholinergic axons can form traditional synaptic junctions with IC neurons. In separate experiments, selective labeling of cholinergic projections from the LPGi revealed bilateral projections to the IC. The LPGi axons exhibited relatively equal densities on ipsilateral and contralateral sides, but on both sides the terminations were largely restricted to the non-lemniscal regions of the IC (i.e., the dorsal cortex, lateral cortex and intercollicular tegmentum). We conclude first that cholinergic axons can form traditional synapses in the IC. In addition, lemniscal and non-lemniscal regions of the IC receive different patterns of cholinergic innervation. The lemniscal IC (IC central nucleus) is innervated by cholinergic neurons in the PPT and the LDT whereas the non-lemniscal "shell" areas of the IC are innervated by the PPT and LDT and by cholinergic neurons in the LPGi. DATA AVAILABILITY: Data will be made available on request.

Outbreeding reduces survival during metamorphosis in a headwater stream salamander.

Assessing direct fitness effects of individual genetic diversity is challenging due to the intensive and long-term data needed to quantify survival and reproduction in the wild. But resolving these effects is necessary to determine how inbreeding and outbreeding influence eco-evolutionary processes. We used 8 years of capture-recapture data and single nucleotide polymorphism genotypes for 1906 individuals to test for effects of individual heterozygosity on stage-specific survival probabilities in the salamander Gyrinophilus porphyriticus. The life cycle of G. porphyriticus includes an aquatic larval stage followed by metamorphosis into a semi-aquatic adult stage. In our study populations, the larval stage lasts 6-10 years, metamorphosis takes several months, and lifespan can reach 20 years. Previous studies showed that metamorphosis is a sensitive life stage, leading us to predict that fitness effects of individual heterozygosity would occur during metamorphosis. Consistent with this prediction, monthly probability of survival during metamorphosis declined with multi-locus heterozygosity (MLH), from 0.38 at the lowest MLH (0.10) to 0.06 at the highest MLH (0.38), a reduction of 84%. Body condition of larvae also declined significantly with increasing MLH. These relationships were consistent in the three study streams. With evidence of localised inbreeding within streams, these results suggest that outbreeding disrupts adaptations in pre-metamorphic and metamorphic individuals to environmental gradients along streams, adding to evidence that headwater streams are hotspots of microgeographic adaptation. Our results also underscore the importance of incorporating life history in analyses of the fitness effects of individual genetic diversity and suggest that metamorphosis and similar discrete life stage transitions may be critical periods of viability selection.

Researching COVID to enhance recovery (RECOVER) pediatric study protocol: Rationale, objectives and design.

IMPORTANCE: The prevalence, pathophysiology, and long-term outcomes of COVID-19 (post-acute sequelae of SARS-CoV-2 [PASC] or "Long COVID") in children and young adults remain unknown. Studies must address the urgent need to define PASC, its mechanisms, and potential treatment targets in children and young adults. OBSERVATIONS: We describe the protocol for the Pediatric Observational Cohort Study of the NIH's REsearching COVID to Enhance Recovery (RECOVER) Initiative. RECOVER-Pediatrics is an observational meta-cohort study of caregiver-child pairs (birth through 17 years) and young adults (18 through 25 years), recruited from more than 100 sites across the US. This report focuses on two of four cohorts that comprise RECOVER-Pediatrics: 1) a de novo RECOVER prospective cohort of children and young adults with and without previous or current infection; and 2) an extant cohort derived from the Adolescent Brain Cognitive Development (ABCD) study (n = 10,000). The de novo cohort incorporates three tiers of data collection: 1) remote baseline assessments (Tier 1, n = 6000); 2) longitudinal follow-up for up to 4 years (Tier 2, n = 6000); and 3) a subset of participants, primarily the most severely affected by PASC, who will undergo deep phenotyping to explore PASC pathophysiology (Tier 3, n = 600). Youth enrolled in the ABCD study participate in Tier 1. The pediatric protocol was developed as a collaborative partnership of investigators, patients, researchers, clinicians, community partners, and federal partners, intentionally promoting inclusivity and diversity. The protocol is adaptive to facilitate responses to emerging science. CONCLUSIONS AND RELEVANCE: RECOVER-Pediatrics seeks to characterize the clinical course, underlying mechanisms, and long-term effects of PASC from birth through 25 years old. RECOVER-Pediatrics is designed to elucidate the epidemiology, four-year clinical course, and sociodemographic correlates of pediatric PASC. The data and biosamples will allow examination of mechanistic hypotheses and biomarkers, thus providing insights into potential therapeutic interventions. CLINICAL TRIALS.GOV IDENTIFIER: Clinical Trial Registration: http://www.clinicaltrials.gov. Unique identifier: NCT05172011.

Evaluating Modern Spacer Options and Outcomes in Revision Hip Arthroplasty.

BACKGROUND: A 2-stage revision continues to be the standard treatment for periprosthetic joint infection (PJI) in hip arthroplasty. The use of "functional" spacers may allow patients to return to daily living while optimizing their health for revision surgery. We aimed to evaluate the clinical outcomes of different spacer types regarding infection eradication, mechanical complications, and functional outcomes. METHODS: Patients who have complete Musculoskeletal Infection Society criteria for diagnosis of PJI that underwent one-stage or 2-stage revision were queried in an institutional surgical database between 2002 and 2022. Out of 286 patients, 210 met our inclusion criteria and were retrospectively reviewed for demographics, laboratory values, functional and patient-reported outcomes, and subsequent revisions. The study population had 54.3% women, a mean age of 61 years old, and a mean follow-up of 3.7 ± 3.2 years. There was no difference between age, body mass index, or Charlson Comorbidity Index scores between each cohort. Spacers were categorized as nonfunctional static, nonfunctional articulating, or functional articulating. Functional spacers were defined as those that allowed full weight bearing with no restrictions. Delphi criteria were used to define revision success, and failure was defined as a recurrent or persistent infection following definitive surgery. RESULTS: There was a significantly lower reoperation rate after a definitive implant in the functional articulating cohort (P = .003), with a trending higher infection eradication rate and a lower rate of spacer failure compared to the nonfunctional spacer cohort. At 5 years, functional articulating spacers had a 94.1% survivorship rate, nonfunctional articulating spacers had an 81.2% survival rate, and nonfunctional static spacers had a 71.4% survival rate. In the functional articulating spacer cohort, 14.6% had yet to get reimplanted, with an average follow-up time of 1.4 years. CONCLUSIONS: Within this large cohort of similar demographics, functional articulating spacers may result in better clinical outcomes and infection eradication during 2-stage revision arthroplasty for PJI.

Hover fly (Diptera: Syrphidae) diversity and seasonality in North Georgia apple and peach orchards.

Crop pollination and natural biological control provided by beneficial insects have an economic worth of hundreds of billions of dollars annually. Apple and peach production in North Georgia are economically important industries that benefit from these ecological services. Hover flies are dual ecosystem service providers that have been relatively understudied in orchard ecosystems. We investigated the diversity and seasonal activity of hover flies in apple and peach orchards at 2 sites in North Georgia from March to October 2020 and 2021. Bowl traps were used to sample hover flies in orchard edge and interior habitats. The aphidophagous species Toxomerus geminatus (Say) (Diptera: Syrphidae) and Toxomerus marginatus (Say) (Diptera: Syrphidae) comprised 86.6% of the total hover flies collected. Apple orchards yielded the greatest hover fly presence, species richness, and Toxomerus spp. abundance. Hover fly richness and diversity were greatest during postbloom, but Toxomerus spp. abundance was greatest during the bloom period. No differences in presence, richness, diversity, or Toxomerus spp. abundance were found between edge and interior habitats. Toxomerus geminatus and T. marginatus were dominant from March through August, with T. geminatus being more abundant than T. marginatus in March, early April, and August. October sampling produced the greatest hover fly richness. Our results suggest that hover flies are abundant in North Georgia orchards and exhibit substantial spatial and temporal variation in richness and diversity. Expanded studies incorporating additional sampling efforts and methods are needed to further characterize the hover fly fauna and their impact on North Georgia apple and peach orchards.

Comparing Transcriptomic Points of Departure to Apical Effect Concentrations For Larval Fathead Minnow Exposed to Chemicals with Four Different Modes Of Action.

It is postulated that below a transcriptomic-based point of departure, adverse effects are unlikely to occur, thereby providing a chemical concentration to use in screening level hazard assessment. The present study extends previous work describing a high-throughput fathead minnow assay that can provide full transcriptomic data after exposure to a test chemical. One-day post-hatch fathead minnows were exposed to ten concentrations of three representatives of four chemical modes of action: organophosphates, ecdysone receptor agonists, plant photosystem II inhibitors, and estrogen receptor agonists for 24 h. Concentration response modeling was performed on whole body gene expression data from each exposure, using measured chemical concentrations when available. Transcriptomic points of departure in larval fathead minnow were lower than apical effect concentrations across fish species but not always lower than toxic effect concentrations in other aquatic taxa like crustaceans and insects. The point of departure was highly dependent on measured chemical concentration which were often lower than the nominal concentration. Differentially expressed genes between chemicals within modes of action were compared and often showed statistically significant overlap. In addition, reproducibility between identical exposures using a positive control chemical (CuSO4) and variability associated with the transcriptomic point of departure using in silico sampling were considered. Results extend a transcriptomic-compatible fathead minnow high-throughput assay for possible use in ecological hazard screening.

Race/ethnicity and socioeconomic status affect the assessment of lipoprotein(a) levels in clinical practice.

Background and Objective: High Lp(a) levels are a risk factor for ASCVD, however Lp(a) ordering in clinical practice is low. This study examines how race/ethnicity and socioeconomic status influence Lp(a) ordering. Methods: This is a single center, retrospective study (2/1/2020-6/30/2023) using electronic medical records of adults with at least one ICD-10 diagnosis of ASCVD or resistant hyperlipidemia (LDL-C >160 mg/dL on statin therapy). We evaluated Lp(a) level differences among racial/ethnic groups and sexes. We also assessed associations between diagnosis type, diagnosis number, age at diagnosis, race, socioeconomic score (based on zip codes), public health coverage and presence of Lp(a) orders. Results: 4% of our cohort (N=56,833) had an Lp(a) order (17.3% Hispanic, 8.7% non-Hispanic Black, 47.5% non-Hispanic White and, 27% Asian/others). Non-Hispanic Black and Hispanic patients had lower rates of Lp(a) orders (0.17%, 0.28%, respectively) when compared to non-Hispanic White patients (2.35%), p<0.001, however, their median Lp(a) levels were higher. Individuals belonging to deprived socioeconomic groups or on Medicaid, were less likely to have an Lp(a) order (RR=0.39, p<0.001 and RR=0.40, p<0.001 respectively). Certain diagnoses (carotid stenosis, family history of ASCVD and FH) and multiple diagnoses (>2) resulted in more Lp(a) orders compared to those with only one diagnosis (p<0.001). Conclusions: Lp(a) ordering is low in patients with ASCVD. Non-Hispanic Black and Hispanic patients at risk are less likely to have an Lp(a) order. Individuals residing in socioeconomically deprived neighborhoods and on Medicaid are also less like have Lp(a) order. Lp(a) orders depend on the type and number of patients' diagnoses.

Bringing traits back into the equation: A roadmap to understand species redistribution.

Ecological and evolutionary theories have proposed that species traits should be important in mediating species responses to contemporary climate change; yet, empirical evidence has so far provided mixed evidence for the role of behavioral, life history, or ecological characteristics in facilitating or hindering species range shifts. As such, the utility of trait-based approaches to predict species redistribution under climate change has been called into question. We develop the perspective, supported by evidence, that trait variation, if used carefully can have high potential utility, but that past analyses have in many cases failed to identify an explanatory value for traits by not fully embracing the complexity of species range shifts. First, we discuss the relevant theory linking species traits to range shift processes at the leading (expansion) and trailing (contraction) edges of species distributions and highlight the need to clarify the mechanistic basis of trait-based approaches. Second, we provide a brief overview of range shift-trait studies and identify new opportunities for trait integration that consider range-specific processes and intraspecific variability. Third, we explore the circumstances under which environmental and biotic context dependencies are likely to affect our ability to identify the contribution of species traits to range shift processes. Finally, we propose that revealing the role of traits in shaping species redistribution may likely require accounting for methodological variation arising from the range shift estimation process as well as addressing existing functional, geographical, and phylogenetic biases. We provide a series of considerations for more effectively integrating traits as well as extrinsic and methodological factors into species redistribution research. Together, these analytical approaches promise stronger mechanistic and predictive understanding that can help society mitigate and adapt to the effects of climate change on biodiversity.

Identifying biochemical constituents involved in the mycosynthesis of zinc oxide nanoparticles.

Filamentous fungi are known to secrete biochemicals that drive the synthesis of nanoparticles (NPs) that vary in composition, size, and shape; a process deemed mycosynthesis. Following the introduction of precursor salts directly to the fungal mycelia or their exudates, mycosynthesis proceeds at ambient temperature and pressure, and near neutral pH, presenting significant energy and cost savings over traditional chemical or physical approaches. The mycosynthesis of zinc oxide (ZnO) NPs by various fungi exhibited a species dependent morphological preference for the resulting NPs, suggesting that key differences in the biochemical makeup of their individual exudates may regulate the controlled nucleation and growth of these different morphologies. Metabolomics and proteomics of the various fungal exudates suggest that metal chelators, such as hexamethylenetetramine, present in high concentrations in exudates of Aspergillus versicolor are critical for the production dense, well-formed, spheroid nanoparticles. The results also corroborate that the proteinaceous material in the production of ZnO NPs serves as a surface modifier, or protein corona, preventing excessive coagulation of the NPs. Collectively, these findings suggest that NP morphology is regulated by the small molecule metabolites, and not proteins, present in fungal exudates, establishing a deeper understanding of the factors and mechanism underlying mycosynthesis of NPs.

Mitochondria inside acute myeloid leukemia cells hydrolyze ATP to resist chemotherapy.

Despite early optimism, therapeutics targeting oxidative phosphorylation (OxPhos) have faced clinical setbacks, stemming from their inability to distinguish healthy from cancerous mitochondria. Herein, we describe an actionable bioenergetic mechanism unique to cancerous mitochondria inside acute myeloid leukemia (AML) cells. Unlike healthy cells which couple respiration to the synthesis of ATP, AML mitochondria were discovered to support inner membrane polarization by consuming ATP. Because matrix ATP consumption allows cells to survive bioenergetic stress, we hypothesized that AML cells may resist cell death induced by OxPhos damaging chemotherapy by reversing the ATP synthase reaction. In support of this, targeted inhibition of BCL-2 with venetoclax abolished OxPhos flux without impacting mitochondrial membrane potential. In surviving AML cells, sustained polarization of the mitochondrial inner membrane was dependent on matrix ATP consumption. Mitochondrial ATP consumption was further enhanced in AML cells made refractory to venetoclax, consequential to downregulations in both the proton-pumping respiratory complexes, as well as the endogenous F1-ATPase inhibitor ATP5IF1. In treatment-naive AML, ATP5IF1 knockdown was sufficient to drive venetoclax resistance, while ATP5IF1 overexpression impaired F1-ATPase activity and heightened sensitivity to venetoclax. Collectively, our data identify matrix ATP consumption as a cancer-cell intrinsic bioenergetic vulnerability actionable in the context of mitochondrial damaging chemotherapy.

Antihypertensive prescription is associated with improved 30-day outcomes for discharged hypertensive emergency department patients.

Background: Hypertension (HTN) is common in discharged emergency department (ED) patients, yet the short-term outcomes of treating HTN at ED discharge are unclear. This study aimed to investigate whether emergency physician (EP) prescription of oral antihypertensive therapy at ED discharge for hypertensive patients is associated with a decreased 30-day risk of the severe adverse events (AEs), death, and revisits to the ED. Methods: We conducted an observational cohort study assessing the 30-day outcomes of discharged ED patients with HTN, comparing outcomes based on whether antihypertensive therapy was prescribed. All discharged adult ED patients from an eight-hospital system with a diagnosis of HTN from January 2016 to February 2020 were screened, and consisted of a mix of suburban and urban patients with broad ethnic and socioeconomic backgrounds. Patients were categorized into the treatment group if they received a prescription for antihypertensive medication at ED discharge. The primary outcome was severe composite AEs from HTN (aortic catastrophe, heart failure, myocardial infarction, hemorrhagic and ischemic stroke, or hypertensive encephalopathy) within 30 days of ED discharge. The secondary outcomes were death or ED revisit over the same period. Results: The study sample consisted of 93,512 ED visits; 57.5% were female, and mean age was 59.3 years. 4.7% of patients were prescribed antihypertensive treatment at ED discharge. Within 30 days, 0.7% of patients experienced an AE, 0.1% died, and 15.2% had an ED revisit. The treatment group had significantly lower odds of AE (adjusted odds ratio [aOR]: 0.224, 95%CI 0.106-0.416, p < 0.001), and ED revisits (aOR: 0.610, 95%CI 0.547-0.678, p < 0.001), adjusting for age, race, degree of HTN, ED treatment for elevated HTN, Elixhauser comorbidity index, and heart failure history. There was no difference in odds of death 30 days after discharge. Conclusion and relevance: Prescription antihypertensive therapy for discharged ED patients is associated with a 30-day decrease in severe adverse events and ED revisit rate.

Stage-Specific Demographic Effects of Hydrologic Variation in a Stream Salamander.

AbstractWe lack a strong understanding of how organisms with complex life histories respond to climate variation. Many stream-associated species have multistage life histories that are likely to influence the demographic consequences of floods and droughts. However, tracking stage-specific demographic responses requires high-resolution, long-term data that are rare. We used 8 years of capture-recapture data for the headwater stream salamander Gyrinophilus porphyriticus to quantify the effects of flooding and drying magnitude on stage-specific vital rates and population growth. Drying reduced larval recruitment but increased the probability of metamorphosis (i.e., adult recruitment). Flooding reduced adult recruitment but had no effect on larval recruitment. Larval and adult survival declined with flooding but were unaffected by drying. Annual population growth rates (λ) declined with flooding and drying. Lambda also declined over the study period (2012-2021), although mean λ was 1.0 over this period. Our results indicate that G. porphyriticus populations are resilient to hydrologic variation because of compensatory effects on recruitment of larvae versus adults (i.e., reproduction vs. metamorphosis). Complex life cycles may enable this resilience to climate variation by creating opportunities for compensatory demographic responses across stages. However, more frequent and intense hydrologic variation in the latter half of this study contributed to a decline in λ over time, suggesting that increasing environmental variability poses a threat even when demographic compensation occurs.