Acute rapamycin treatment reveals novel mechanisms of behavioral, physiological, and functional dysfunction in a maternal inflammation mouse model of autism and sensory over-responsivity.

Maternal inflammatory response (MIR) during early gestation in mice induces a cascade of physiological and behavioral changes that have been associated with autism spectrum disorder (ASD). In a prior study and the current one, we find that mild MIR results in chronic systemic and neuro-inflammation, mTOR pathway activation, mild brain overgrowth followed by regionally specific volumetric changes, sensory processing dysregulation, and social and repetitive behavior abnormalities. Prior studies of rapamycin treatment in autism models have focused on chronic treatments that might be expected to alter or prevent physical brain changes. Here, we have focused on the acute effects of rapamycin to uncover novel mechanisms of dysfunction and related to mTOR pathway signaling. We find that within 2 hours, rapamycin treatment could rapidly rescue neuronal hyper-excitability, seizure susceptibility, functional network connectivity and brain community structure, and repetitive behaviors and sensory over-responsivity in adult offspring with persistent brain overgrowth. These CNS-mediated effects are also associated with alteration of the expression of several ASD-,ion channel-, and epilepsy-associated genes, in the same time frame. Our findings suggest that mTOR dysregulation in MIR offspring is a key contributor to various levels of brain dysfunction, including neuronal excitability, altered gene expression in multiple cell types, sensory functional network connectivity, and modulation of information flow. However, we demonstrate that the adult MIR brain is also amenable to rapid normalization of these functional changes which results in the rescue of both core and comorbid ASD behaviors in adult animals without requiring long-term physical alterations to the brain. Thus, restoring excitatory/inhibitory imbalance and sensory functional network modularity may be important targets for therapeutically addressing both primary sensory and social behavior phenotypes, and compensatory repetitive behavior phenotypes.

Feasibility of Delivering a 5-Day Normobaric Hypoxia Breathing in Healthy Volunteers in a Hospital Setting.

BACKGROUND: Beneficial effects of breathing at FIO2 < 0.21 on disease outcomes have been reported in previous preclinical and clinical studies. However, the safety and intra-hospital feasibility of breathing hypoxic gas for 5 d have not been established. In this study, we examined the physiologic effects of breathing a gas mixture with FIO2 as low as 0.11 in 5 healthy volunteers. METHODS: All 5 subjects completed the study, spending 5 consecutive days in a hypoxic tent, where the ambient oxygen level was lowered in a stepwise manner over 5 d, from FIO2 of 0.16 on the first day to FIO2 of 0.11 on the fifth day of the study. All the subjects returned to an environment at room air on the sixth day. The subjects' SpO2 , heart rate, and breathing frequency were continuously recorded, along with daily blood sampling, neurologic evaluations, transthoracic echocardiography, and mental status assessments. RESULTS: Breathing hypoxia concentration dependently caused profound physiologic changes, including decreased SpO2 and increased heart rate. At FIO2 of 0.14, the mean SpO2 was 92%; at FIO2 of 0.13, the mean SpO2 was 93%; at FIO2 of 0.12, the mean SpO2 was 88%; at FIO2 of 0.11, the mean SpO2 was 85%; and, finally, at an FIO2 of 0.21, the mean SpO2 was 98%. These changes were accompanied by increased erythropoietin levels and reticulocyte counts in blood. All 5 subjects concluded the study with no adverse events. No subjects exhibited signs of mental status changes or pulmonary hypertension. CONCLUSIONS: Results of the current physiologic study suggests that, within a hospital setting, delivering FIO2 as low as 0.11 is feasible and safe in healthy subjects, and provides the foundation for future studies in which therapeutic effects of hypoxia breathing are tested.

Temporal drivers of tryptophan-like fluorescent dissolved organic matter along a river continuum.

Tryptophan-like fluorescence (TLF) is used to indicate anthropogenic inputs of dissolved organic matter (DOM), typically from wastewater, in rivers. We hypothesised that other sources of DOM, such as groundwater and planktonic microbial biomass can also be important drivers of riverine TLF dynamics. We sampled 19 contrasting sites of the River Thames, UK, and its tributaries. Multivariate mixed linear models were developed for each site using 15 months of weekly water quality observations and with predictor variables selected according to the statistical significance of their linear relationship with TLF following a stepwise procedure. The variables considered for inclusion in the models were potassium (wastewater indicator), nitrate (groundwater indicator), chlorophyll-a (phytoplankton biomass), and Total bacterial Cells Counts (TCC) by flow cytometry. The wastewater indicator was included in the model of TLF at 89 % of sites. Groundwater was included in 53 % of models, particularly those with higher baseflow indices (0.50-0.86). At these sites, groundwater acted as a negative control on TLF, diluting other potential sources. Additionally, TCC was included positively in the models of six (32 %) sites. The models on the Thames itself using TCC were more rural sites with lower sewage inputs. Phytoplankton biomass (Chlorophyll-a) was only used in two (11 %) site models, despite the seasonal phytoplankton blooms. It is also notable that, the wastewater indicator did not always have the strongest evidence for inclusion in the models. For example, there was stronger evidence for the inclusion of groundwater and TCC than wastewater in 32 % and 5 % of catchments, respectively. Our study underscores the complex interplay of wastewater, groundwater, and planktonic microbes, driving riverine TLF dynamics, with their influence determined by site characteristics.

Adapting nitric oxide: A review of its foundation, uses in austere medical conditions, and emerging applications.

Nitric oxide was first identified as a novel and effective treatment for persistent pulmonary hypertension of the newborn (PPHN), and has since been found to be efficacious in treating acute respiratory distress syndrome (ARDS) and pulmonary hypertension. Physicians and researchers have also found it shows promise in resource-constrained settings, both within and outside of the hospital, such as in high altitude pulmonary edema (HAPE) and COVID-19. The treatment has been well tolerated in these settings, and is both efficacious and versatile when studied across a variety of clinical environments. Advancements in inhaled nitric oxide continue, and the gas is worthy of investigation as physicians contend with new respiratory and cardiovascular illnesses, as well as unforeseen logistical challenges.

Evaluating the transmission risk of SARS-CoV-2 from sewage pollution.

The presence of SARS-CoV-2 in untreated sewage has been confirmed in many countries but its incidence and infection risk in contaminated waters is poorly understood. The River Thames in the UK receives untreated sewage from 57 Combined Sewer Overflows (CSOs), with many discharging dozens of times per year. This study investigated if such discharges provide a pathway for environmental transmission of SARS-CoV-2. Samples of wastewater, surface water, and sediment collected close to six CSOs on the River Thames were assayed over eight months for SARS-CoV-2 RNA and infectious virus. Bivalves were also sampled as an indicator species of viral bioaccumulation. Sediment and water samples from the Danube and Sava rivers in Serbia, where raw sewage is also discharged in high volumes, were assayed as a positive control. No evidence of SARS-CoV-2 RNA or infectious virus was found in UK samples, in contrast to RNA positive samples from Serbia. Furthermore, this study shows that infectious SARS-CoV-2 inoculum is stable in Thames water and sediment for <3 days, while SARS-CoV-2 RNA is detectable for at least seven days. This indicates that dilution of wastewater likely limits environmental transmission, and that detection of viral RNA alone is not an indication of pathogen spillover.

A Geographical Analysis of Access to Trauma Centers from US National Parks in 2018.

INTRODUCTION: Millions of people visit US national parks annually to engage in recreational wilderness activities, which can occasionally result in traumatic injuries that require timely, high-level care. However, no study to date has specifically examined timely access to trauma centers from national parks. This study aimed to examine the accessibility of trauma care from national parks by calculating the travel time by ground and air from each park to its nearest trauma center. Using these calculations, the percentage of parks by census region with timely access to a trauma center was determined. METHODS: This was a cross-sectional study analyzing travel times by ground and air transport between national parks and their closest adult advanced trauma center (ATC) in 2018. A list of parks was compiled from the National Parks Service (NPS) website, and the location of trauma centers from the 2018 National Emergency Department Inventory (NEDI)-USA database. Ground and air transport times were calculated using Google Maps and ArcGIS, with medians and interquartile ranges reported by US census region. Percentage of parks by region with timely trauma center access-defined as access within 60 minutes of travel time-were determined based on these calculated travel times. RESULTS: In 2018, 83% of national parks had access to an adult ATC within 60 minutes of air travel, while only 26% had timely access by ground. Trauma center access varied by region, with median travel times highest in the West for both air and ground transport. At a national level, national parks were unequally distributed, with the West housing the most parks of all regions. CONCLUSION: While most national parks had timely access to a trauma center by air travel, significant gaps in access remain for ground, the extent of which varies greatly by region. To improve the accessibility of trauma center expertise from national parks, the study highlights the potential that increased implementation of trauma telehealth in emergency departments (EDs) may have in bridging these gaps.

Safety and practicality of high dose inhaled nitric oxide in emergency department COVID-19 patients.

BACKGROUND: Inhaled nitric oxide (iNO) is a selective pulmonary vasodilator and mild bronchodilator that has been shown to improve systemic oxygenation, but has rarely been administered in the Emergency Department (ED). In addition to its favorable pulmonary vascular effects, in-vitro studies report that NO donors can inhibit replication of viruses, including SARS Coronavirus 2 (SARS-CoV-2). This study evaluated the administration of high-dose iNO by mask in spontaneously breathing emergency department (ED) patients with respiratory symptoms attributed to Coronavirus disease 2019 (COVID-19). METHODS: We designed a randomized clinical trial to determine whether 30 min of high dose iNO (250 ppm) could be safely and practically administered by emergency physicians in the ED to spontaneously-breathing patients with respiratory symptoms attributed to COVID-19. Our secondary goal was to learn if iNO could prevent the progression of mild COVID-19 to a more severe state. FINDINGS: We enrolled 47 ED patients with acute respiratory symptoms most likely due to COVID-19: 25 of 47 (53%) were randomized to the iNO treatment group; 22 of 47 (46%) to the control group (supportive care only). All patients tolerated the administration of high-dose iNO in the ED without significant complications or symptoms. Five patients receiving iNO (16%) experienced asymptomatic methemoglobinemia (MetHb) > 5%. Thirty-four of 47 (72%) subjects tested positive for SARS-CoV-2: 19 of 34 were randomized to the iNO treatment group and 15 of 34 subjects to the control group. Seven of 19 (38%) iNO patients returned to the ED, while 4 of 15 (27%) control patients did. One patient in each study arm was hospitalized: 5% in iNO treatment and 7% in controls. One patient was intubated in the iNO group. No patients in either group died. The differences between these groups were not significant. CONCLUSION: A single dose of iNO at 250 ppm was practical and not associated with any significant adverse effects when administered in the ED by emergency physicians. Local disease control led to early study closure and prevented complete testing of COVID-19 safety and treatment outcomes measures.

The effects of high-intensity functional training on cardiometabolic risk factors and exercise enjoyment in men and women with metabolic syndrome: study protocol for a randomized, 12-week, dose-response trial.

BACKGROUND: Individuals with metabolic syndrome (MetS) are at a greater risk for developing atherosclerotic cardiovascular disease (ASCVD) than those without MetS, due to underlying endothelial dysfunction, dyslipidemia, and insulin resistance. Exercise is an effective primary and secondary prevention strategy for MetS; however, less than 25% of adults meet the minimum stated public recommendations. Barriers often identified are lack of enjoyment and lack of time. High-intensity functional training (HIFT), a time-efficient modality of exercise, has shown some potential to elicit positive affectivity and elicit increased fitness and improved glucose metabolism. However, the effects of HIFT on dyslipidemia and endothelial dysfunction have not been explored nor have the effects been explored in a population with MetS. Additionally, no studies have investigated the minimal dose of HIFT per week to see clinically meaningful changes in cardiometabolic health. The purpose of this study is to (1) determine the dose-response effect of HIFT on blood lipids, insulin resistance, and endothelial function and (2) determine the dose-response effect of HIFT on body composition, fitness, and perceived enjoyment and intention to continue the exercise. METHODS/DESIGN: In this randomized, dose-response trial, participants will undergo a 12-week HIFT intervention of either 1 day/week, 2 days/week, or 3 days/week of supervised, progressive exercise. Outcomes assessed at baseline and post-intervention will be multiple cardiometabolic markers, and fitness. Additionally, the participant's affective response will be measured after the intervention. DISCUSSION: The findings of this research will provide evidence on the minimal dose of HIFT per week to see clinically meaningful improvements in the risk factors of MetS, as well as whether this modality is likely to mitigate the barriers to exercise. If an effective dose of HIFT per week is determined and if this modality is perceived positively, it may provide exercise specialists and health care providers a tool to prevent and treat MetS. TRIAL REGISTRATION: ClinicalTrials.gov NCT05001126 . August 11, 2021.

Diffusion MR imaging acquisition and analytics for microstructural delineation in pre-clinical models of TBI.

Significant progress has been made toward improving both the acquisition of clinical diffusion-weighted imaging (DWI) data and its analysis in the uninjured brain, through various techniques including a large number of model-based solutions that have been proposed to fit for multiple tissue compartments, and multiple fibers per voxel. While some of these techniques have been applied to clinical traumatic brain injury (TBI) research, the majority of these technological enhancements have yet to be fully implemented in the preclinical arena of TBI animal model-based research. In this review, we describe the requirement for preclinical, MRI-based efforts to provide systematic confirmation of the applicability of some of these models as indicators of tissue pathology within the injured brain. We review how current DWI techniques are currently being used in animal TBI models, and describe how both acquisition and analytic techniques could be extended to leverage the progress made in clinical work. Finally, we highlight remaining gaps in the preclinical pipeline from data acquisition to final analysis that currently have no real, preclinical-based correlate.

Siamit: A Novel Academic-Tribal Health Partnership in Northwest Alaska.

PROBLEM: American Indians and Alaska Natives hold a state-conferred right to health, yet significant health and health care disparities persist. Academic medical centers are resource-rich institutions committed to public service, yet few are engaged in responsive, equitable, and lasting tribal health partnerships to address these challenges. APPROACH: Maniilaq Association, a rural and remote tribal health organization in Northwest Alaska, partnered with Massachusetts General Hospital and Harvard Medical School to address health care needs through physician staffing, training, and quality improvement initiatives. This partnership, called Siamit, falls under tribal governance, focuses on supporting community health leaders, addresses challenges shaped by extreme geographic remoteness, and advances the mission of academic medicine in the context of tribal health priorities. OUTCOMES: Throughout the 2019-2020 academic year, Siamit augmented local physician staffing, mentored health professions trainees, provided continuing medical education courses, implemented quality improvement initiatives, and provided clinical care and operational support during the COVID-19 pandemic. Siamit began with a small budget and limited human resources, demonstrating that relatively small investments in academic-tribal health partnerships can support meaningful and positive outcomes. NEXT STEPS: During the 2020-2021 academic year, the authors plan to expand Siamit's efforts with a broader social medicine curriculum, additional attending staff, more frequent trainee rotations, an increasingly robust mentorship network for Indigenous health professions trainees, and further study of the impact of these efforts. Such partnerships may be replicable in other settings and represent a significant opportunity to advance community health priorities, strengthen tribal health systems, support the next generation of Indigenous health leaders, and carry out the academic medicine mission of teaching, research, and service.

Experimental quantum speed-up in reinforcement learning agents.

As the field of artificial intelligence advances, the demand for algorithms that can learn quickly and efficiently increases. An important paradigm within artificial intelligence is reinforcement learning1, where decision-making entities called agents interact with environments and learn by updating their behaviour on the basis of the obtained feedback. The crucial question for practical applications is how fast agents learn2. Although various studies have made use of quantum mechanics to speed up the agent's decision-making process3,4, a reduction in learning time has not yet been demonstrated. Here we present a reinforcement learning experiment in which the learning process of an agent is sped up by using a quantum communication channel with the environment. We further show that combining this scenario with classical communication enables the evaluation of this improvement and allows optimal control of the learning progress. We implement this learning protocol on a compact and fully tunable integrated nanophotonic processor. The device interfaces with telecommunication-wavelength photons and features a fast active-feedback mechanism, demonstrating the agent's systematic quantum advantage in a setup that could readily be integrated within future large-scale quantum communication networks.

Intestinal eosinophils: multifaceted roles in tissue homeostasis and disease.

Intestinal eosinophils are largely considered to be one of the central immune effector cells during helminth infection and disorders such as eosinophilic oesophagitis and food allergies. Given the abundance of these cells present in the gastrointestinal tract at homeostasis, emerging studies now reveal novel roles for eosinophils in the development and regulation of immunity, and during tissue repair. In addition, the identification of distinct eosinophil subsets indicates that we must consider the heterogeneity of these cells and how they differentially participate in mucosal immunity at steady state and during disease. Here, we summarise the literature on intestinal eosinophils, and how they contribute to mucosal homeostasis through immune regulation and interactions with the microbiome. We then explore the divergent roles of eosinophils in the context of eosinophilic gastrointestinal disorders and during helminth infection, whereby we discuss key observations and differences that have emerged from animal models and human studies. Lastly, we consider the possible interactions of eosinophils with the enteric nervous system, and how this represents an exciting area for future research which may inform future therapeutic targets.

The experience of using prompting technology from the perspective of people with Dementia and their primary carers.

OBJECTIVES: People who are living with dementia typically experience difficulties in completing multi-step, everyday tasks. However, digital technology such as touchscreen tablets provide a means of delivering concise personalised prompts that combine audio, text and pictures. This study was one component of a broader, mixed methods study that tested how an application (app) -based prompter running on a touchscreen tablet computer could support everyday activities in individuals with mild to moderate dementia. In this study we set out to understand the experiences of people living with dementia and their primary carer in using the prompter over a four-week period. METHOD: We collected qualitative data using semi-structured interviews from 26 dyads, composed of a person living with dementia and their carer. Dyads were interviewed at the start and end of this period. Transcripts were then analysed using thematic analysis. RESULTS: The study identified three overarching themes related to: participants' attitudes towards the technology; their judgements about how useful the prompter would be; and the emotional impact of using it. CONCLUSION: Consistent with the Technology Acceptance Model, carers and participants were influenced by their approaches to technology and determined the usefulness of the prompter according to whether it worked for them and fitted into their routines. In addition, participants' decisions about using the prompter were also determined by the extent to which doing so would impact on their self-identity.

Prevalence of antibiotic resistance and virulence genes in the biofilms from an aquifer recharged with stormwater.

An improved understanding of the diversity and composition of microbial communities carrying antibiotic resistance genes (ARGs) and virulence genes (VGs) in aquifers recharged with stormwater is essential to comprehend potential human health risks from water reuse. A high-throughput functional gene array was used to study the prevalence of ARGs and VGs in aquifer biofilms (n = 27) taken from three boreholes over three months. Bacterial genera annotated as opportunistic pathogens such as Aeromonas, Burkholderia, Pseudomonas, Shewanella, and Vibrio were ubiquitous and abundant in all biofilms. Bacteria from clinically relevant genera, Campylobacter, Enterobacter, Klebsiella, Mycobacterium, Mycoplasma, and Salmonella were detected in biofilms. The mean travel time of stormwater from the injection well to P1 and P3 boreholes was 260 and 360 days respectively. The presence of ARGs and VGs in the biofilms from these boreholes suggest a high spatial movement of ARGs and VGs in the aquifer. The ARGs with the highest abundance were small multidrug resistance efflux pumps (SMR) and multidrug efflux (Mex) followed by ß-lactamase C genes. ß- lactamase C encoding genes were primarily detected in Enterobacteriaceae, Pseudomonadaceae, Bacillaceae, and Rhodobacteraceae families. The VGs encoding siderophores, including aerobactin (iro and iuc genes), followed by pilin, hemolysin, and type III secretion were ubiquitous. Canonical correspondence analysis suggested that Total Organic Carbon (TOC), Dissolved Organic Carbon (DOC), turbidity, and Fe concentration has a significant impact on the microbial community structure of bacteria carrying ARGs and VGs. Post abstraction treatment of groundwater may be prudent to improve water security and reduce potential health risks.

Incidence of Mild Cognitive Impairment with Ascending Altitude.

Background: This study aimed to longitudinally quantify the prevalence of mild cognitive impairment (MCI) in individual trekkers at three different ascending altitudes (Site 1: ∼3500 m, Site 2: ∼4400 m, and Site 3: ∼5100 m). We correlated these findings with the presence of acute mountain sickness (AMS). Materials and Methods: We performed serial assays using the environmental quick mild cognitive impairment (eQMCI) score on 103 English-speaking 18- to 65-year-old volunteers trekking to Everest Base Camp in Nepal during spring 2016. We defined MCI as a score less than 67 (lower scores indicating more cognitive impairment). Additional data collected included the Lake Louise Score, demographics, and other possible confounders. Results: eQMCI scores significantly decreased with ascent from Site 1 to 2 (a score of 78.95 [SD = 7.96] to 74.67 [SD = 8.8] [Site 1-2 p = 0.04]), but then increased on ascent to Site 3 to 83.68 (SD = 8.67) (Site 1-3 p = <0.0001, Site 2-3 p = <0.0001). However, subjects who fulfilled eQMCI criteria for MCI increased despite the overall improvement in score: 6.8% (N = 7) at Site 1, 18.7% (N = 14) at Site 2, and 3.3% (N = 2) at Site 3. Incidence of AMS at Sites 1, 2, and 3 was 22.3% (N = 23), 21.3% (N = 16), and 48.3% (N = 29), respectively. Of those with MCI, 1.94% met criteria for AMS at Site 1 (p = 0.0017), 2.67% at Site 2 (p = 0.6949), and 3.33% at Site 3 (p = <0.0001). Conclusions: There is a significant incidence of MCI at high altitude, even in those without subjective findings of AMS. Interestingly, subjects with a decline in cognitive function show an increasing trend for developing AMS at higher altitude. Future research on the clinical impact of MCI on a subject's health, judgment, and performance remains to be elucidated.

Prospective Double-Blinded Randomized Field-Based Clinical Trial of Metoclopramide and Ibuprofen for the Treatment of High Altitude Headache and Acute Mountain Sickness.

INTRODUCTION: High altitude headache (HAH) and acute mountain sickness (AMS) are common pathologies at high altitudes. There are similarities between AMS and migraine headaches, with nausea being a common symptom. Several studies have shown ibuprofen can be effective for AMS prophylaxis, but few have addressed treatment. Metoclopramide is commonly administered for migraine headaches but has not been evaluated for HAH or AMS. We aimed to evaluate metoclopramide and ibuprofen for treatment of HAH and AMS. METHODS: We performed a prospective, double-blinded, randomized, field-based clinical trial of metoclopramide and ibuprofen for the treatment of HAH and AMS in 47 adult subjects in the Mount Everest region of Nepal. Subjects received either 400 mg ibuprofen or 10 mg metoclopramide in a 1-time dose. Lake Louise Score (LLS) and visual analog scale of symptoms were measured before and at 30, 60, and 120 min after treatment. RESULTS: Subjects in both the metoclopramide and ibuprofen arms reported reduced headache severity and nausea compared to pretreatment values at 120 min. The ibuprofen group reported 22 mm reduction in headache and 6 mm reduction in nausea on a 100 mm visual analog scale at 120 min. The metoclopramide group reported 23 mm reduction in headache and 14 mm reduction in nausea. The ibuprofen group reported an average 3.5-point decrease on LLS, whereas the metoclopramide group reported an average 2.0-point decrease on LLS at 120 min. CONCLUSIONS: Metoclopramide and ibuprofen may be effective alternative treatment options in HAH and AMS, especially for those patients who additionally report nausea.