Drawbacks to strengthening neural salience encoding: a link between cortisol and risky drinking.

Emotionally salient experiences are encoded and remembered more strongly, an effect that can be amplified by hormones like cortisol. Such memories can in turn profoundly influence later behavior. However, little is known about the link between amplified salience encoding and subsequent behavior. This pathway may be particularly important for risky alcohol drinking, which has been linked to sensitized salience responses, memory, and cortisol. To test this possibility, we integrated pharmacology using a double-blind cross-over design with fMRI, cognitive, and motivation assays across a range of healthy male and female social drinkers. As anticipated, cortisol enhanced memory for salient alcohol-related events; critically, this bias was in turn associated with later alcohol motivation. Increased alcohol motivation was particularly pronounced in more susceptible risky drinkers, for whom cortisol enhanced brain salience responses to alcohol. These sensitized salience responses predicted both memory biases and alcohol motivation. Together, these findings reveal maladaptive consequences of enhanced salience encoding.Significance Statement Our memories for salient experiences can strongly influence what we choose to do. Despite the importance of such memories for motivated behaviors like alcohol drinking, the mechanisms by which salient memories are strengthened and influence later behavior are unclear. In the current study, we integrated findings from human research (glucocorticoids enhance salient memory encoding) with findings from rodent models (glucocorticoids enhance alcohol motivation, especially with a history of ethanol exposure) to examine whether these processes are linked in humans. We found evidence for this pathway: hydrocortisone amplified brain signatures of salience (particularly for participants who drank more), which predicted enhanced memory. Both brain salience and enhanced memory predicted increased alcohol motivation. This translational pathway reveals downsides to amplifying salient memories.

Hippocampal Mechanisms Support Cortisol-Induced Memory Enhancements.

Stress can powerfully influence episodic memory, often enhancing memory encoding for emotionally salient information. These stress-induced memory enhancements stand at odds with demonstrations that stress and the stress-related hormone cortisol can negatively affect the hippocampus, a brain region important for episodic memory encoding. To resolve this apparent conflict and determine whether and how the hippocampus supports memory encoding under cortisol, we combined behavioral assays of associative memory, high-resolution fMRI, and pharmacological manipulation of cortisol in a within-participant, double-blinded procedure (in both sexes). Behaviorally, hydrocortisone promoted the encoding of subjectively arousing, positive associative memories. Neurally, hydrocortisone led to enhanced functional connectivity between hippocampal subregions, which predicted subsequent memory enhancements for emotional associations. Cortisol also modified the relationship between hippocampal representations and associative memory: whereas hippocampal signatures of distinctiveness predicted memory under placebo, relative integration predicted memory under cortisol. Together, these data provide novel evidence that the human hippocampus contains the necessary machinery to support emotional associative memory enhancements under cortisol.SIGNIFICANCE STATEMENT Our daily lives are filled with stressful events, which powerfully shape the way we form episodic memories. For example, stress and stress-related hormones can enhance our memory for emotional events. However, the mechanisms underlying these memory benefits are unclear. In the current study, we combined functional neuroimaging, behavioral tests of memory, and double-blind, placebo-controlled hydrocortisone administration to uncover the effects of the stress-related hormone cortisol on the function of the human hippocampus, a brain region important for episodic memory. We identified novel ways in which cortisol can enhance hippocampal function to promote emotional memories, highlighting the adaptive role of cortisol in shaping memory formation.

Lytic to temperate switching of viral communities.

Microbial viruses can control host abundances via density-dependent lytic predator-prey dynamics. Less clear is how temperate viruses, which coexist and replicate with their host, influence microbial communities. Here we show that virus-like particles are relatively less abundant at high host densities. This suggests suppressed lysis where established models predict lytic dynamics are favoured. Meta-analysis of published viral and microbial densities showed that this trend was widespread in diverse ecosystems ranging from soil to freshwater to human lungs. Experimental manipulations showed viral densities more consistent with temperate than lytic life cycles at increasing microbial abundance. An analysis of 24 coral reef viromes showed a relative increase in the abundance of hallmark genes encoded by temperate viruses with increased microbial abundance. Based on these four lines of evidence, we propose the Piggyback-the-Winner model wherein temperate dynamics become increasingly important in ecosystems with high microbial densities; thus 'more microbes, fewer viruses'.

Improving gender-affirming care in genetic counseling: Using educational tools that amplify transgender and/or gender non-binary community voices.

Transgender and/or gender non-binary (TGNB) individuals face significant health care disparities, including deficiencies in provider knowledge. To address this knowledge gap for genetic counselors, we developed, implemented, and analyzed an educational intervention on gender-affirming genetic counseling (GC) and care for TGNB patients. In partnership with the TGNB community, we designed a 5-module (length = 146 min ± 94 min) genetic counseling-targeted online learning program focused on gender-affirming care (Amplify). Content included elements of gender-affirming care, core components of gender-inclusive GC sessions, and cancer risk assessment/management. Video testimonials featuring TGNB individuals complemented learning within each module. Educational outcomes measured included comfort working with TGNB patients (n = 2 multiple choice questions (MCQs)), impact of education on knowledge (n = 25 MCQs), and clinical self-efficacy based on the Accreditation Council for Genetic Counseling competencies (n = 35 skills). Participants (n = 40), recruited through state and national GC organizations, completed all modules, and pre- and post-education/self-efficacy assessments. Pre-Amplify, 65% (n = 26/40) of participants endorsed feeling 'somewhat comfortable' working with TGNB patients. The average knowledge score was 77.6% (SD = 11.2%) with the lowest scores related to the gender affirmation process. After Amplify, overall knowledge improvement was statistically significant with an average 16.9% (p < 0.001) increase in score. Pre-Amplify, the average self-efficacy score was 78.4% (SD = 15.8%) with lowest scores seen in statements surrounding information gathering of family and medical histories. Post-Amplify, overall self-efficacy improvement was statistically significant with an average 13.8% (p < 0.001) increase in score. Linear regression did not identify an impact of practice specialty on participants' knowledge gains or self-efficacy. This study shows online modules are an effective form of gender-affirming care education for GCs. This intervention can positively improve the care practicing genetic counselors provide to patients and inform future decision-making about the development of gender-affirming care education for genetic counselors.

Evaluation of BCL6 and SIRT1 as Non-Invasive Diagnostic Markers of Endometriosis.

(1) Background: Endometriosis is characterized by the presence of endometrial glands and stroma outside of the uterus and is often associated with severe pelvic pain and infertility. Our study explored the utilization of B-Cell Lymphoma 6 (BCL6) and Sirtuin 1 (SIRT1) as potential biomarkers in serum, plasma, urine, and cervical mucus for a non-invasive diagnostic test for endometriosis. BCL6 was chosen based on its previously reported elevated expression in endometrial biopsies, and SIRT1 is co-expressed and upregulated in the endometrium of women with endometriosis. (2) Methods: BCL6 and SIRT1 levels were measured using enzyme-linked immunoassay (ELISA) in samples from 20 women with endometriosis (ten with stages I/II and ten with stages III/IV) and ten women without endometriosis. (3) Results: Levels of SIRT1 in sera showed a statistically significant elevation in advanced stages III/IV compared to controls and stages I/II. No significant differences were found in other bodily fluids for SIRT1 or any bodily fluids tested for BCL6. (4) Conclusions: These results suggest some potential of SIRT1 expression within serum as a predictor of advanced asymptomatic stages of endometriosis. Using immunohistochemistry (IHC) staining and H-SCORE values for the elevated BCL6 (and potentially SIRT1) levels in endometrial biopsy samples seems to have higher diagnostic potential based on the previously published studies.

Basic symptoms influence real-life functioning and symptoms in individuals at high risk for psychosis.

OBJECTIVE: To investigate potential clinical differences in high-risk profiles presenting with and without basic symptoms, and additionally investigate the association between basic symptoms and clinical symptoms, functioning, and cognition. METHODS: High-risk individuals (n = 133) were stratified into individuals fulfilling ultra-high-risk (UHR) criteria (n = 59) and individuals fulfilling UHR+ basic symptoms criteria (BS) (n = 74). Group differences were assessed on clinical symptoms, real-life functioning, and cognition. Regression analyses were conducted to elucidate on the relationship between BS and clinical symptoms, functioning, neurocognition, and social cognition. RESULTS: The group fulfilling both UHR+ BS criteria had significantly more symptoms and lower real-life functioning and quality of life but not more cognitive deficits. BS influenced on attenuated psychotic, depressive, and general symptoms, but only modestly on negative symptoms. No relationship between BS and neuro- and social cognition was established except for an association with emotion recognition processing speed. BS influenced real-life functioning, and this finding was sustained when controlling for the effect of negative symptoms. CONCLUSIONS: Our findings indicate that BS contribute highly to the distress and symptom load of clinical high-risk individuals. Longitudinal findings are needed to establish the predictive validity of BS on high-risk individuals' clinical and functional prognosis.

Intranasal fentanyl and inhaled nitrous oxide for fracture reduction: The FAN observational study.

INTRODUCTION: Procedural sedation and analgesia (PSA) are frequently used for fracture reduction in pediatric emergency departments (ED). Combining intranasal (IN) fentanyl with inhalation of nitrous oxide (N2O) allow for short recovery time and obviates painful and time-consuming IV access insertions. METHODS: We performed a bicentric, prospective, observational cohort study. Patients aged 4-18years were included if they received combined PSA with IN fentanyl and N2O for the reduction of mildly/moderately displaced fracture or of dislocation. Facial Pain Scale Revised (FPS-R) and Face, Leg, Activity, Cry, Consolability (FLACC) scores were used to evaluate pain and anxiety before, during and after procedure. University of Michigan Sedation Score (UMSS), adverse events, detailed side effects and satisfaction of patients, parents and medical staff were recorded at discharge. A follow up telephone call was made after 24-72h. RESULTS: 90 patients were included. There was no difference in FPS-R during the procedure (median score 2 versus 2), but the FLACC score was significantly higher as compared to before (median score 4 versus 0, Δ 2, 95% CI 0, 2). Median UMSS was 1 (95% CI 1, 2). We recorded no serious adverse events. Rate of vomiting was 12% (11/84). Satisfaction was high among participants responding to this question 85/88 (97%) of parents, 74/83 (89%) of patients and 82/85 (96%) of physicians would want the same sedation again. CONCLUSION: PSA with IN fentanyl and N2O is effective and safe for the reduction of mildly/moderately displaced fracture or dislocation, and has a high satisfaction rate.

A Qualitative Study of Anticipated Decision Making around Type 2 Diabetes Genetic Testing: the Role of Scientifically Concordant and Discordant Expectations.

Type 2 diabetes mellitus (T2DM) genetic testing is undergoing clinical trials to measure the efficacy of genetic counseling for behavior-based risk reduction. The expectations patients bring to the testing process may play an important role in individual outcomes. We conducted a qualitative exploration of anticipated decision-making and expectations around T2DM genetic testing. Semi-structured interviews were completed with Mexican Americans (n = 34), non-Hispanic Black Americans (n = 39), and non-Hispanic White Americans (n = 39) at risk for T2DM. Transcripts were analyzed for themes. Most participants would accept T2DM genetic testing in order to motivate risk-reducing behaviors or apprise family members of their risk. Participants who would decline testing wished to avoid emotional distress or believed the test would not reveal new risk information. Non-Hispanic Whites and those with college education declined genetic testing more often than other groups. Those without college education were more likely to have testing expectations that were discordant with current science, such as conflating genetic testing with common 'blood tests.' Understanding expectations and decision-making factors around T2DM genetic testing will better prepare healthcare professionals to counsel their patients. This may lead to a higher efficacy of T2DM genetic testing and counseling.

Generation and evaluation of typical meteorological year datasets for greenhouse and external conditions on the Mediterranean coast.

A typical meteorological year (TMY) represents the typical meteorological conditions over many years but still contains the short term fluctuations which are absent from long-term averaged data. Meteorological data were measured at the Experimental Station of Cajamar 'Las Palmerillas' (Cajamar Foundation) in Almeria, Spain, over 19 years at the meteorological station and in a reference greenhouse which is typical of those used in the region. The two sets of measurements were subjected to quality control analysis and then used to create TMY datasets using three different methodologies proposed in the literature. Three TMY datasets were generated for the external conditions and two for the greenhouse. They were assessed by using each as input to seven horticultural models and comparing the model results with those obtained by experiment in practical trials. In addition, the models were used with the meteorological data recorded during the trials. A scoring system was used to identify the best performing TMY in each application and then rank them in overall performance. The best methodology was that of Argiriou for both greenhouse and external conditions. The average relative errors between the seasonal values estimated using the 19-year dataset and those using the Argiriou greenhouse TMY were 2.2 % (reference evapotranspiration), -0.45 % (pepper crop transpiration), 3.4 % (pepper crop nitrogen uptake) and 0.8 % (green bean yield). The values obtained using the Argiriou external TMY were 1.8 % (greenhouse reference evapotranspiration), 0.6 % (external reference evapotranspiration), 4.7 % (greenhouse heat requirement) and 0.9 % (loquat harvest date). Using the models with the 19 individual years in the historical dataset showed that the year to year weather variability gave results which differed from the average values by ± 15 %. By comparison with results from other greenhouses it was shown that the greenhouse TMY is applicable to greenhouses which have a solar radiation transmission of approximately 65 % and rely on manual control of ventilation which constitute the majority in the south-east of Spain and in most Mediterranean greenhouse areas.

Effect of resistance training on body composition, self-efficacy, depression, and activity in postpartum women.

This study assessed the effect of resistance training (RT) in 60 healthy postpartum women. Participants were randomized to 18 weeks of RT or an active comparison group (flexibility training). RT and flexibility training (FT) exercises were completed twice-weekly based on the American College of Sports Medicine recommendations. Study outcomes included muscular strength, body composition (dual-energy x-ray absorptiometry), exercise self-efficacy, depressive symptoms [Center for Epidemiological Studies Depression Scale (CES-D)], and physical activity (accelerometery). For completers (n = 44), the RT group showed greater strength gains than the FT group, respectively (bench press: +36% vs +8%, P < 0.001; leg press: +31% vs +7%, P < 0.01; abdominal curl-ups: +228% vs +43%, P < 0.01); however, body composition changes were not different. There was a significant group × time interaction for exercise self-efficacy (F = 5.33, P = 0.026). For CES-D score, the RT group decreased (F = 4.61, P = 0.016), while the FT group did not; however, the group × time interaction in CES-D score was not significant (F = 1.33, P = 0.255). Sedentary time decreased (F = 5.27, P = 0.027) and light-intensity activity time increased (F = 5.55, P = 0.023) more in the RT than FT group. Intent-to-treat analyses did not alter the results. Twice-weekly RT increases strength and may be associated with better exercise self-efficacy and improved physical activity outcomes compared with FT in postpartum women.

Clinical pharmacist intervention to ensure safe stimulant prescribing practices at a Veterans Affairs facility.

Introduction: The Psychotropic Drug Safety Initiative (PDSI) is a national Veterans Affairs program that recommends obtaining cardiovascular vital signs semiannually and urine toxicology screening annually for veterans prescribed stimulants. The PDSI also recommends a risk review of concurrent central nervous system (CNS) depressants to ensure the benefits of coadministration with stimulants outweigh the risks. This project's purpose was to evaluate the occurrence of coprescriptions for CNS depressants and stimulants and encourage compliance with the PDSI recommendations to increase safe and appropriate management of veterans prescribed the combination. This study aimed to evaluate the occurrence of coprescriptions for CNS depressants and stimulants, evaluate compliance with stimulant monitoring recommendations, and measure the proportion of pharmacist recommendations implemented by the prescriber. Methods: This quality improvement project identified veterans with an outpatient prescription for a stimulant and any coprescription(s) for benzodiazepines, sedative-hypnotics, and/or opioids. A pharmacy intervention note was generated to request a risk review, provide recommendations for de-escalation, and notify the stimulant prescriber of overdue monitoring parameters. Impact was measured 60 days after intervention. Descriptive statistics and a McNemar test were used to compare preintervention and postintervention data. Results: From the 61 patients included, there were 67 unique prescriptions for benzodiazepines (49.3%), sedative-hypnotics (34.3%), and opioids (16.4%) in combination with a stimulant. Pharmacist intervention resulted in de-escalation of coprescribing for 9 patients (16.1%) and was associated with statistically significant improvement in compliance to stimulant monitoring recommendations. Discussion: Clinical pharmacists can assist in ensuring safe and appropriate monitoring and management of veterans prescribed stimulants.

Synaptic vesicle release regulates pre-myelinating oligodendrocyte-axon interactions in a neuron subtype-specific manner.

Oligodendrocyte-lineage cells are central nervous system (CNS) glia that perform multiple functions including the selective myelination of some but not all axons. During myelination, synaptic vesicle release from axons promotes sheath stabilization and growth on a subset of neuron subtypes. In comparison, it is unknown if pre-myelinating oligodendrocyte process extensions selectively interact with specific neural circuits or axon subtypes, and whether the formation and stabilization of these neuron-glia interactions involves synaptic vesicle release. In this study, we used fluorescent reporters in the larval zebrafish model to track pre-myelinating oligodendrocyte process extensions interacting with spinal axons utilizing in vivo imaging. Monitoring motile oligodendrocyte processes and their interactions with individually labeled axons revealed that synaptic vesicle release regulates the behavior of subsets of process extensions. Specifically, blocking synaptic vesicle release decreased the longevity of oligodendrocyte process extensions interacting with reticulospinal axons. Furthermore, blocking synaptic vesicle release increased the frequency that new interactions formed and retracted. In contrast, tracking the movements of all process extensions of singly-labeled oligodendrocytes revealed that synaptic vesicle release does not regulate overall process motility or exploratory behavior. Blocking synaptic vesicle release influenced the density of oligodendrocyte process extensions interacting with reticulospinal and serotonergic axons, but not commissural interneuron or dopaminergic axons. Taken together, these data indicate that alterations to synaptic vesicle release cause changes to oligodendrocyte-axon interactions that are neuron subtype specific.

Carbon Adsorbent Properties Impact Hydrated Electron Activity and Perfluorocarboxylic Acid (PFCA) Destruction.

Carbon-based adsorbents used to remove recalcitrant water contaminants, including perfluoroalkyl substances (PFAS), are often regenerated using energy-intensive treatments that can form harmful byproducts. We explore mechanisms for sorbent regeneration using hydrated electrons (eaq -) from sulfite ultraviolet photolysis (UV/sulfite) in water. We studied the UV/sulfite treatment on three carbon-based sorbents with varying material properties: granular activated carbon (GAC), carbon nanotubes (CNTs), and polyethylenimine-modified lignin (lignin). Reaction rates and defluorination of dissolved and adsorbed model perfluorocarboxylic acids (PFCAs), perfluorooctanoic acid (PFOA) and perfluorobutanoic acid (PFBA), were measured. Monochloroacetic acid (MCAA) was employed to empirically quantify eaq - formation rates in heterogeneous suspensions. Results show that dissolved PFCAs react rapidly compared to adsorbed ones. Carbon particles in solution decreased aqueous reaction rates by inducing light attenuation, eaq - scavenging, and sulfite consumption. The magnitude of these effects depended on adsorbent properties and surface chemistry. GAC lowered PFOA destruction due to strong adsorption. CNT and lignin suspensions decreased eaq - formation rates by attenuating light. Lignin showed high eaq - quenching, likely due to its oxygenated functional groups. These results indicate that desorbing PFAS and separating the adsorbent before initiating PFAS degradation reactions will be the best engineering approach for adsorbent regeneration using UV/sulfite.

The impact of in utero cannabis exposure on fetal growth.

BACKGROUND: The goal of this study was to examine if in utero cannabis exposure predicted reduced birth size and if these effects were evident in specific growth parameters as early as the second trimester. METHODS: Eligible women had an initial prenatal visit between January 1, 2010, and March 31, 2020, completed an anatomy ultrasound between 18-24 weeks' gestation, and had no self-reported alcohol, tobacco, or other biochemically verified drug use. The two primary study groups were cannabis users (n = 109) identified through self-report and urine toxicology screens, and a randomly selected control group of non-substance users (n = 171). Medical records were manually reviewed for background and medical information, anatomy ultrasound results, and birth size parameters. RESULTS: After controlling for significant confounders, regression results indicated significant (p < .05) deficits in birth weight associated with cannabis exposure, with a trend for increasing weight effects beginning in the second trimester. A significant decrease in head circumference was evident as early as the second trimester, with differences remaining significant until birth. Significant overall length and specific bone length deficits were not predicted by cannabis exposure, at birth or earlier in gestation, after control for confounding. CONCLUSIONS: Cannabis exposure predicted growth deficits at birth, with some effects evident as early as the second trimester. The biggest and earliest effects were seen for cranial size, with an adjusted deficit of more than 14 percentile points by birth. Overall weight was not impacted until at or near delivery.

Evaluation of iodide chemical ionization mass spectrometry for gas and aerosol-phase per- and polyfluoroalkyl substances (PFAS) analysis.

Per- and polyfluoroalkyl substances (PFAS) are a class of ultra-persistent anthropogenic contaminants. PFAS are ubiquitous in environmental and built systems, but very few online methods exist for their characterization in atmospheric gases and aerosols. Iodide time-of-flight chemical ionization mass spectrometry (iodide-ToF-CIMS) is a promising technology for online characterization of PFAS in the atmosphere. Previous work using iodide-ToF-CIMS was successful in measuring gas-phase perfluoroalkyl carboxylic acids and fluorotelomer alcohols, but those are just two of the myriad classes of PFAS that are atmospherically relevant. Therefore, our first objective was to test other sample introduction methods coupled to iodide-TOF-CIMS to evaluate its ability to measure a wider suite of PFAS in both gas and aerosol phases. Using a variety of sample introduction techniques, we successfully measured gas-phase fluorotelomer alcohols (FTOHs), gas and aerosol-phase perfluoroalkyl carboxylic acids (PFCAs), and aerosol-phase perfluoroalkyl sulfonic acids and polyfluoroalkyl phosphoric acid diesters (PFSAs and diPAPs). We also determined iodide-ToF-CIMS response factors for these compounds by introducing known quantities using a Filter Inlet for Gases and AEROsols (FIGAERO). These response factors ranged from 400 to 6 × 104 ions per nanogram, demonstrating low limits of detection. Furthermore, PFAS are a poorly understood diverse class of molecules that exhibit unusual and often unexpected physicochemical properties due to their highly fluorinated nature. Since detection of PFAS with iodide-ToF-CIMS relies on the analyte molecule to either undergo proton transfer or adduct formation with iodide, understanding PFAS behavior during chemical ionization gives rise to a more fundamental understanding of these compounds. Through voltage scanning experiments and DFT calculations, we found that PFCAs and FTOHs readily form iodide adducts, while PFSAs and diPAPs preferentially undergo proton transfer to iodide. Generally, binding energy increased with increasing linear chain length, and PFCAs had stronger binding than FTOHs. Overall, our results suggest that iodide-ToF-CIMS can be used to measure even nonvolatile PFAS such as PFSAs and diPAPs in the aerosol phase in a semi-continuous online fashion.

Hippocampal mechanisms support cortisol-induced memory enhancements.

Stress can powerfully influence episodic memory, often enhancing memory encoding for emotionally salient information. These stress-induced memory enhancements stand at odds with demonstrations that stress and the stress-related hormone cortisol can negatively affect the hippocampus, a brain region important for episodic memory encoding. To resolve this apparent conflict and determine whether and how the hippocampus supports memory encoding under cortisol, we combined behavioral assays of associative memory, high-resolution functional magnetic resonance imaging (fMRI), and pharmacological manipulation of cortisol in a within-participant, double-blinded procedure. Hydrocortisone led to enhanced functional connectivity between hippocampal subregions, which predicted subsequent memory enhancements for emotional information. Cortisol also modified the relationship between hippocampal representations and memory: whereas hippocampal signatures of distinctiveness predicted memory under placebo, relative integration predicted memory under cortisol. Together, these data provide novel evidence that the human hippocampus contains the necessary machinery to support emotional memory enhancements under stress.

Nontarget analysis and fluorine atom balances of transformation products from UV/sulfite degradation of perfluoroalkyl contaminants.

Per- and polyfluoroalkyl substances (PFAS) are a class of thousands of highly fluorinated, anthropogenic compounds that are used in a wide variety of consumer applications. Due to their widespread use and high persistence, PFAS are ubiquitous in drinking water, which is of concern due to the threats these compounds pose to human health. Reduction via the hydrated electron is a promising technology for PFAS remediation and has been well-studied. However, since previous work rarely reports fluorine atom balances and often relies on suspect screening, some transformation products are likely unaccounted for. Therefore, we performed non-target analysis using high-resolution mass spectrometry on solutions of perfluorooctanesulfonate (PFOS), perfluorobutanesulfonate (PFBS), perfluorooctanoate (PFOA), and 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)propanoate (GenX) that had been treated with UV/sulfite to produce hydrated electrons. We determined fluorine atom balances for all compounds studied, finding high fluorine atom balances for PFOS and PFBS. PFOA and GenX had lower overall fluorine atom balances, likely due to the production of volatile or very polar transformation products that were not measured by our methods. Transformation products identified by our analysis were consistent with literature, with a few exceptions. Namely, shorter-chain perfluorosulfonates (PFSA) and their H/F substituted counterparts were also detected from PFOS. This is an unexpected result based on literature, as no documented pathway exists for the formation of shorter-chain PFSA during UV/sulfite treatment. Furthermore, the nontarget approach we employed allowed for identification of novel, unsaturated products from the hydrated electron treatment of perfluorooctanesulfonate (PFOS) that warrant further investigation.

Antibody-directed evolution reveals a mechanism for enhanced neutralization at the HIV-1 fusion peptide site.

The HIV-1 fusion peptide (FP) represents a promising vaccine target, but global FP sequence diversity among circulating strains has limited anti-FP antibodies to ~60% neutralization breadth. Here we evolve the FP-targeting antibody VRC34.01 in vitro to enhance FP-neutralization using site saturation mutagenesis and yeast display. Successive rounds of directed evolution by iterative selection of antibodies for binding to resistant HIV-1 strains establish a variant, VRC34.01_mm28, as a best-in-class antibody with 10-fold enhanced potency compared to the template antibody and ~80% breadth on a cross-clade 208-strain neutralization panel. Structural analyses demonstrate that the improved paratope expands the FP binding groove to accommodate diverse FP sequences of different lengths while also recognizing the HIV-1 Env backbone. These data reveal critical antibody features for enhanced neutralization breadth and potency against the FP site of vulnerability and accelerate clinical development of broad HIV-1 FP-targeting vaccines and therapeutics.

Healthcare costs of methicillin resistant Staphylococcus aureus and Pseudomonas aeruginosa infections in veterans: role of vitamin D deficiency.

Methicillin resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa (P. aeruginosa) infections are frequently associated with hospitalization and increased healthcare costs. Vitamin D deficiency may contribute to increased costs for patients with these infections and there is evidence that vitamin D may have an antimicrobial role. To evaluate the role of vitamin D deficiency in the costs incurred with these infections, we studied the relationship of serum 25(OH)D levels to healthcare costs in veterans in the southeastern United States. Patients with both infections were vitamin D deficient to a similar extent and so were combined for further analysis. Vitamin D deficient patients had higher costs and service utilization than those who were not vitamin D deficient. Those with vitamin D deficiency had higher inpatient costs compared to the non-deficient group, and this difference was across most categories except for the number of inpatient hospitalizations or total number of days as an inpatient. Vitamin D deficiency was not significantly related to outpatient cost or service utilization parameters. We conclude that vitamin D deficiency is intimately linked to adverse healthcare costs in veterans with MRSA and P. aeruginosa infections. Vitamin D status should be assayed in patients with these infections.