Association between EMS Workforce Density and Population Health Outcomes in the U.S.

BACKGROUND: The prehospital care provided by emergency medical services (EMS) personnel is a critical component of the public health, public safety, and health care systems in the U.S.; however, the population-level value of EMS care is often overlooked. No studies have examined how the density of EMS personnel relates to population-level health outcomes. Our objectives were to examine the geographic distribution and density of EMS personnel in the U.S.; and quantify the association between EMS personnel density and population-level health outcomes. METHODS: We conducted a cross-sectional evaluation of county-level EMS personnel density using estimates from the National Registry of Emergency Medical Technicians in nine states that require continuous national certification (Alabama, Louisiana, Massachusetts, Minnesota, New Hampshire, North Dakota, South Carolina, Vermont, and Washington, D.C.). Outcomes of interest included life expectancy, all-cause mortality, and cardiac arrest mortality. We used quantile regression models to examine the association between a 10-person increase in EMS personnel density and each outcome at the 10th, 50th (median), and 90th percentiles, controlling for population characteristics and area health resources. RESULTS: There were 356 counties included, with a mean EMS density of 223 EMS personnel per 100,000 population. Density was higher in rural compared to urban counties (247 versus 186 per 100,000 population; p = 0.001). In unadjusted models, there was a significant association between increase in EMS personnel density and an increase in life expectancy at each examined percentile (e.g., 50th percentile, increase of 52.9 days; 95% CI 40.2, 65.5; p < 0.001), decrease in all-cause mortality at each examined percentile, and decrease in cardiac arrest mortality at the 50th and 90th percentiles. These associations were not statistically significant in the adjusted models. CONCLUSIONS: EMS personnel density differs between urban and rural areas, with higher density per population in rural areas. There were no statistically significant associations between EMS density and population-level health outcomes after controlling for population characteristics and other health resources. The best approach to quantifying the community-level value that EMS care may or may not provide remains unclear.

Emergency Medical Services Management of Bronchospasm in the United States: A Cross-Sectional Analysis and Nationwide Quality Assessment.

Background/Objective: Bronchospasm, caused by asthma and other related conditions, is a significant cause of morbidity and mortality commonly managed by emergency medical services (EMS). We aimed to evaluate the quality of prehospital management of bronchospasm by EMS in the US.Methods: The National EMS Information System Public Release Research dataset, a nationwide convenience sample of prehospital patient care report data from 2018 to 2019, was used to capture 9-1-1 activations where patients aged ≥2 years were treated and transported by EMS for suspected bronchospasm. First, we described the extent to which EMS care met eight quality measures identified from available statewide EMS protocols, existing quality measures, and national guidelines. Second, we quantified the extent of risk-standardized agency-level variation in administration of inhaled beta agonists and systemic corticosteroids using logistic regression models, accounting for patient characteristics, severity, and clustering by agencies. Third, we compared rates of completed prehospital interventions between pediatric (age <18 years) versus adult patients using two-sample t-tests.Results: A total of 1,336,988 EMS encounters for suspected bronchospasm met inclusion criteria. Median age of patients was 66 years, with only 4% pediatric; 55% were female. Advanced life support (ALS) units managed 94% of suspected bronchospasm. Respiratory rate (98%) and pulse oximetry (96%) were documented in nearly all cases. Supplemental oxygen was administered to hypoxic patients by 65% of basic life support (BLS) and 73% of ALS units. BLS administered inhaled beta-agonist therapy less than half the time (48%), compared to 77% by ALS. ALS administered inhaled anticholinergic therapy in 38% of cases, and systemic corticosteroids in 19% of cases. Pediatric patients were significantly less likely to receive supplemental oxygen when hypoxic, inhaled beta-agonists, inhaled anticholinergics, or systemic corticosteroids.Conclusions: We found important gaps in recent EMS practice for prehospital care of suspected bronchospasm. We highlight three targets for improvement: inhaled beta-agonist administration by BLS, systemic corticosteroid administration by ALS, and increased interventions for pediatric patients. These findings indicate important areas for research, protocol modification, and quality improvement efforts to improve EMS management of bronchospasm.

Out-of-Hospital Presentation and Management of Asthma and Chronic Obstructive Pulmonary Disease Exacerbations in the United States: A Nationwide Retrospective Cohort Study.

STUDY OBJECTIVE: To describe the demographic, clinical, and emergency medical service (EMS) response characteristics associated with EMS activations for asthma and chronic obstructive pulmonary disease (COPD) exacerbations in the US. METHODS: Using a nationwide set of out-of-hospital patient care report data from 2018 to 2019, we analyzed 9-1-1 EMS activations where asthma/COPD exacerbation was indicated by symptom, impression, or treatment provided. We excluded patients with ages less than 2 years or unknown, nonemergency transports, and encounters with any indication of anaphylaxis. Demographic, clinical, and EMS response characteristics were described for pediatric and adult patients with asthma/COPD exacerbations. RESULTS: A total of 1,336,988 asthma/COPD exacerbations were included, comprising 5% of qualifying 9-1-1 scene activations from 2018 to 2019. Most patients were adults (96%). Most adult patients were female (55%), whereas most pediatric patients were male (58%). Most activations occurred in urban settings (82%), particularly in pediatric patients (90%). Most asthma/COPD exacerbations were managed by advanced life support units (94%). Inhaled bronchodilators and systemic corticosteroid therapy were administered to 75% and 14% of all patients, respectively. Adults more often had oxygen saturation <92% (43% vs 20% of pediatric patients) and were more often treated with assisted ventilation (9% vs 1%). CONCLUSION: In this large nationwide sample of 9-1-1 activations treated and transported by EMS, 5% were for asthma/COPD exacerbation. Future work should focus on evidence-based standardization of EMS protocols and practice for asthma/COPD exacerbations to improve the quality of EMS care.

Twenty Years After the EMS Research Agenda: Trends in Emergency Medical Services Publications and Research Funding.

STUDY OBJECTIVE: Since its publication in 2001, the National EMS Research Agenda has brought attention to a relative paucity of emergency medical services (EMS)-specific research and has called for an increase in funding and infrastructure to support EMS research. We investigated the trends in EMS-specific publications and National Institutes of Health (NIH)-funded research grants in the 20 years since this landmark publication. METHODS: We performed a structured PubMed search of English-language citations from 2001 to 2020 to identify publications with populations, settings, or topics related to EMS care, education, or operations. Publications in trade journals and studies not involving humans were excluded. We also queried NIH Research Portfolio Online Reporting Tools Expenditures and Results (RePORTER) using a similar structured search. Titles, keywords, and abstracts were reviewed. Descriptive statistics were calculated, and nonlinear trends were described using segmented regression models. RESULTS: A total of 183,307 references met the search criteria in PubMed, and 4,281 grants were identified in NIH RePORTER. After removing duplicates, 152,408 titles were screened, with 17,314 (11.5%) included. EMS-related publications increased from 419 in 2001 to 1,788 in 2020, a 327% increase, compared with a 197% increase in total PubMed publications. There was a statistically significant nonlinear (J-shaped) increase in EMS publications after 2007. There were 1,166 funded EMS-related NIH grants, with a 469% increase from 2001 to 2020 compared with an 18% increase in overall NIH awards. CONCLUSION: Although total publications have doubled in the United States over the past 20 years, EMS-specific research has more than tripled and the number of funded EMS research grants has increased nearly 5-fold. Future evaluation should examine the quality of this research and its application to clinical practice.

Differences in Out-of-Hospital Cardiac Arrest Management and Outcomes across Urban, Suburban, and Rural Settings.

BACKGROUND: Rural prehospital care settings are underrepresented in the out-of-hospital cardiac arrest (OHCA) literature. This study aimed to describe treatment patterns and the odds of a favorable patient outcome (e.g., return of spontaneous circulation (ROSC) or being presumptively alive at the end of the incident) among rural OHCA patients in the U.S. METHODS: Using the 2018 National Emergency Medical Services Informational System (NEMSIS) dataset, we analyzed OHCA incidents where an emergency medical services (EMS) unit provided cardiopulmonary resuscitation (CPR) and either terminated the resuscitation or completed transport. We excluded traumatic injuries, pediatric patients, and incidents with response time >60 minutes. The primary outcome was ROSC at any time during the EMS incident. The secondary outcome was a binary end-of-event indicator previously described for use in NEMSIS to estimate longer-term outcomes. Multivariable logistic regression was performed for each outcome measure comparing rural, suburban, and urban settings while controlling for key factors. RESULTS: A total of 64,489 OHCA incidents were included, with 5,601 (8.9%) in rural settings. Among the full sample of OHCA incidents, ROSC was achieved in 20,578 (33.6%) cases, including 29.2% in rural settings and 34.1% in urban or suburban settings (p < 0.001). Advanced life support units responded to 95.3% of all calls, and a greater proportion of rural OHCA incidents were managed by basic life support units (7.4% vs. 4.2%, p < 0.001). Rural OHCA incidents had longer response times (7.5 vs. 5.9 minutes, p < 0.001), and rural patients were less likely to receive epinephrine (69.3% vs. 73.3%, p < 0.001). Further, EMS clinicians in rural areas were more likely to use mechanical CPR (29.5% vs. 27.6%, p < 0.01) and were less likely to perform advanced airway management (48.5% vs. 54.2%, p < 0.001). Rural patients had lower odds of achieving ROSC than urban patients after controlling for other factors (OR 0.81, 95% CI: 0.75-0.87). Rural patients also had lower odds of having a positive end-of-event outcome (i.e., presumptively alive) after controlling for other factors (OR 0.86, 95% CI: 0.79-0.93). CONCLUSION: In this national sample of EMS-treated OHCAs, rural patients had lower odds of a favorable outcome (e.g., ROSC or presumptively alive) compared to those in urban settings.

Prior Knowledge for Predictive Modeling: The Case of Acute Aquatic Toxicity.

Early assessment of the potential impact of chemicals on health and the environment requires toxicological properties of the molecules. Predictive modeling is often used to estimate the property values in silico from pre-existing experimental data, which is often scarce and uncertain. One of the ways to advance the predictive modeling procedure might be the use of knowledge existing in the field. Scientific publications contain a vast amount of knowledge. However, the amount of manual work required to process the enormous volumes of information gathered in scientific articles might hinder its utilization. This work explores the opportunity of semiautomated knowledge extraction from scientific papers and investigates a few potential ways of its use for predictive modeling. The knowledge extraction and predictive modeling are applied to the field of acute aquatic toxicity. Acute aquatic toxicity is an important parameter of the safety assessment of chemicals. The extensive amount of diverse information existing in the field makes acute aquatic toxicity an attractive area for investigation of knowledge use for predictive modeling. The work demonstrates that the knowledge collection and classification procedure could be useful in hybrid modeling studies concerning the model and predictor selection, addressing data gaps, and evaluation of models' performance.

An Outdoor Aging Study to Investigate the Release of Per- And Polyfluoroalkyl Substances (PFAS) from Functional Textiles.

The emission of per- and polyfluoroalkyl substances (PFAS) from functional textiles was investigated via an outdoor weathering experiment in Sydney, Australia. Polyamide (PA) textile fabrics treated with different water-repellent, side-chain fluorinated polymers (SFPs) were exposed on a rooftop to multiple natural stressors, including direct sunlight, precipitation, wind, and heat for 6-months. After weathering, additional stress was applied to the fabrics through abrasion and washing. Textile characterization using a multiplatform analytical approach revealed loss of both PFAS-containing textile fragments (e.g., microfibers) as well as formation and loss of low molecular weight PFAS, both of which occurred throughout weathering. These changes were accompanied by a loss of color and water repellency of the textile. The potential formation of perfluoroalkyl acids (PFAAs) from mobile residuals was quantified by oxidative conversion of extracts from unweathered textiles. Each SFP-textile finish emitted a distinct PFAA pattern following weathering, and in some cases the concentrations exceeded regulatory limits for textiles. In addition to transformation of residual low molecular weight PFAA-precursors, release of polymeric PFAS from degradation and loss of textile fibers/particles contributed to overall PFAS emissions during weathering.

Combining In Silico Tools with Multicriteria Analysis for Alternatives Assessment of Hazardous Chemicals: Accounting for the Transformation Products of decaBDE and Its Alternatives.

Transformation products ought to be an important consideration in chemical alternatives assessment. In this study, a recently established hazard ranking tool for alternatives assessment based on in silico data and multicriteria decision analysis (MCDA) methods was further developed to include chemical transformation products. Decabromodiphenyl ether (decaBDE) and five proposed alternatives were selected as case chemicals; biotic and abiotic transformation reactions were considered using five in silico tools. A workflow was developed to select transformation products with the highest occurrence potential. The most probable transformation products of the alternative chemicals were often similarly persistent but more mobile in aquatic environments, which implies an increasing exposure potential. When persistence (P), bioaccumulation (B), mobility in the aquatic environment (M), and toxicity (T) are considered (via PBT, PMT, or PBMT composite scoring), all six flame retardants have at least one transformation product that can be considered more hazardous, across diverse MCDA. Even when considering transformation products, the considered alternatives remain less hazardous than decaBDE, though the range of hazard of the five alternatives was reduced. The least hazardous of the considered alternatives were melamine and bis(2-ethylhexyl)-tetrabromophthalate. This developed tool could be integrated within holistic alternatives assessments considering use and life cycle impacts or additionally prioritizing transformation products within (bio)monitoring screening studies.

Ambulance Calls for Substance-Related Issues Before and After COVID-19.

Background: The United States is currently facing 2 epidemics: sustained morbidity and mortality from substance use and the more recent COVID-19 pandemic. We tested the hypothesis that the pandemic has disproportionately affected individuals with substance use disorder by evaluating average daily 9-1-1 ambulance calls for substance use-related issues compared with all other calls. Methods: This was a retrospective cross-sectional analysis of 9-1-1 ambulance calls before and after the start of COVID-19 in Massachusetts. We used consecutive samples of 9-1-1 ambulance calls, categorized into those which were substance-related or not. An interrupted time series analysis was performed to determine if there were changes in numbers of daily calls before a statewide declaration of emergency for COVID-19 (February 15-March 9, 2020), from the emergency declaration until a stay-at-home advisory (March 10-March 22, 2020) and following the stay-at-home advisory (March 23-May 15, 2020). Results: Compared with prior to the statewide emergency, the post-statewide emergency average of daily ambulance calls decreased from 2,453.2 to 1,969.6, a 19.7% decrease. Similarly, calls for substance-related reasons decreased by 16.4% compared with prior to the statewide emergency. However, despite an initial decrease in calls, after the stay-at-home advisory calls for substance use began increasing by 0.7 (95% confidence interval (CI) 0.4-1.1) calls/day, while calls for other reasons did not significantly change (+1.2 (95% CI -0.8 to 3.1) calls/day). Refusal of transport for substance-related calls increased from 5.0% before the statewide emergency to 7.5% after the declaration (p < 0.001). Conclusions: After an initial decline in substance-related ambulance calls following a statewide declaration of emergency, calls for substance use increased to pre-COVID-19 levels, while those for other reasons remained at a lower rate. The results suggest that COVID-19 is disproportionately affecting individuals with substance use disorder.

Emergency department visits for dental problems among adults with private dental insurance: A national observational study.

OBJECTIVE: Dental insurance may be a protective factor in reducing unnecessary emergency department (ED) use for nontraumatic dental pain. The purpose of this study was to 1) characterize patient demographics and identify risk factors associated with ED utilization for dental problems among individuals dually enrolled in medical and dental insurance and 2) investigate antibiotic and opioid prescription patterns among these patients following discharge. Further study of this unique population may provide insight into other causes of unmet dental need beyond lack of dental insurance. METHODS: Claims data from a large national managed health care plan from 2015 to 2018 were used to evaluate ED use for dental problems in patients with synchronous medical and dental insurance. National counts for ED visits, total visit costs, primary diagnoses, and outpatient treatments for antibiotics and opioids were assessed. Multivariable regression was used to assess any associated demographic and health-related variables. RESULTS: 1492 unique patients were admitted to the ED for dental pain and 429,376 unique patients presented for other symptoms. Utilization rates for nontraumatic dental pain were estimated to be 0.4% of all ED visits, with an average cost of $1487 per visit. Within three days following discharge from the ED, 58% of patients filled an opioid prescription and 38% filled an antibiotic prescription. Patients who presented for dental ED pain were more likely to be younger, live in a ZIP code with a lower median household income, have more medical comorbidities, and receive fewer preventive dental procedures within the prior year. CONCLUSION: Our findings demonstrate a low rate of ED utilization for nontraumatic dental pain among dentally insured patients and highlight the protective value of prior dental visits for reducing ED use. Given high rates of antibiotic and opioid prescription fill following discharge, comprehensive ED guidelines regarding appropriate antibiotic and opioid treatment pathways may be helpful to provide more definitive care to patients with dental insurance.

Demographic and medical school characteristics associated with urban versus rural dermatology practice: A national cross-sectional study.

There are significant disparities in access to dermatologists in rural areas relative to urban areas. We examined the associations between demographic and medical school characteristics and entry into dermatology practice in urban versus rural counties. All dermatologists who graduated from U.S. allopathic or osteopathic medical schools in the 2020 Centers for Medicare & Medicaid Services Physician Compare Database were assessed. Dermatology practice locations were coded as metropolitan or non-metropolitan according to the Rural-Urban Continuum Codes. Of 10,076 dermatologists, 543 (5.4%) practiced in non-metropolitan counties. Male gender (odds ratio [OR] 1.48, 95% CI 1.23-1.77), public medical school attendance (OR 1.94, 95% CI 1.61-2.34), DO degree (OR 1.84, 95% CI 1.32-2.51), medical school location in a non-metropolitan county (OR 5.41, 95% CI 3.66-7.84), and medical school rural track program (OR 1.57, 95% CI 1.07-2.26) were associated with higher odds of non-metropolitan dermatology practice. Our findings highlight that male gender, graduation from a non-metropolitan or public medical school, DO degree, and rural tracks are associated with higher likelihood of non-metropolitan dermatology practice. These results can inform efforts within the field of dermatology to strengthen the rural dermatologist workforce and suggest that rural educational experiences during medical school may increase recruitment of rural dermatologists.

Superovulation with human chorionic gonadotropin (hCG) trigger and gonadotropin releasing hormone agonist (GnRHa) trigger differentially alter essential angiogenic factors in the endometrium in a mouse ART model†.

Gonadotropin-releasing hormone agonists (GnRHa) are used as an alternative to human chorionic gonadotropin (hCG) to trigger ovulation and decrease the risk of ovarian hyperstimulation syndrome. GnRHa is less potent at inducing ovarian vascular endothelial growth factor (VEGF), but may also affect endometrial angiogenesis and early placental development. In this study, we explore the effect of superovulation on endometrial angiogenesis during critical periods of gestation in a mouse model. We assigned female mice to three groups: natural mating or mating following injection with equine chorionic gonadotropin and trigger with GnRHa or hCG trigger. Females were killed prior to implantation (E3.5), post-implantation (E7.5), and at midgestation (E10.5), and maternal serum, uterus, and ovaries were collected. During peri-implantation, endometrial Vegfr1 and Vegfr2 mRNA were significantly increased in the GnRHa trigger group (P < 0.02) relative to the hCG group. Vegfr1 is highly expressed in the endometrial lining and secretory glands immediately prior to implantation. At E7.5, the ectoplacental cone expression of Vegfa and its receptor, Vegfr2, was significantly higher in the hCG trigger group compared to the GnRHa group (P < 0.05). Soluble VEGFR1 and free VEGFA were much higher in the serum of mice exposed to the hCG trigger compared to GnRHa group. At midgestation, there was significantly more local Vegfa expression in the placenta of mice triggered with hCG. GnRHa and hCG triggers differentially disrupt the endometrial expression of key angiogenic factors during critical periods of mouse gestation. These results may have significant implications for placental development and neonatal outcomes following human in vitro fertilization.

An (Eco)Toxicity Life Cycle Impact Assessment Framework for Per- And Polyfluoroalkyl Substances.

A framework for characterizing per- and polyfluoroalkyl substances (PFASs) in life cycle impact assessment (LCIA) is proposed. Thousands of PFASs are used worldwide, with special properties imparted by the fluorinated alkyl chain. Our framework makes it possible to characterize a large part of the family of PFASs by introducing transformation fractions that translate emissions of primary emitted PFASs into the highly persistent terminal degradation products: the perfluoroalkyl acids (PFAAs). Using a PFAA-adapted characterization model, human toxicity as well as marine and freshwater aquatic ecotoxicity characterization factors are calculated for three PFAAs, namely perfluorooctanoic acid (PFOA) perfluorohexanoic acid (PFHxA) and perfluorobutanesulfonic acid (PFBS). The model is evaluated to adequately capture long-term fate, where PFAAs are predicted to accumulate in open oceans. The characterization factors of the three PFAAs are ranked among the top 5% for marine ecotoxicity, when compared to 3104 chemicals in the existing USEtox results databases. Uncertainty analysis indicates potential for equally high ranks for human health impacts. Data availability constitutes an important limitation creating uncertainties. Even so, a life cycle assessment (LCA) case study illustrates practical application of our proposed framework, demonstrating that even low emissions of PFASs can have large effects on LCA results.

Pedometer-measured physical activity among emergency physicians during shifts.

OBJECTIVE: Tools to measure physical activity, such as pedometers, have become more prevalent and attracted popular interest in recent years. Despite this trend, research has not yet quantified pedometer-measured physical activity among Emergency Physicians. This study aims to provide the first characterization of physical activity among on-duty Emergency Physicians in terms of step count. METHODS: Emergency Physicians wore Empatica E4 research-grade accelerometers while performing routine clinical care in the Emergency Department. A publicly available algorithm was used to estimate the number of steps taken. RESULTS: Fifty-one Emergency Physicians, including thirty-four residents and seventeen attending physicians, contributed over 1500 h of accelerometer data. On average, this cohort took 577 steps per hour (SD: 72.6), totaling 4950 steps per recorded shift (SD: 737.8), which is approximately 2.6 miles (SD: 0.31). Residents walked more than attending physicians (595.9 steps per hour (SD: 99.7) vs 563.0 steps per hour (SD: 89.0), respectively; p = 0.02). CONCLUSION: The average emergency physician in this cohort walked roughly half the daily recommended number of steps during their recorded shift. Residents walk significantly more than attending physicians.

The geographic distribution of the US pediatric dermatologist workforce: A national cross-sectional study.

BACKGROUND /OBJECTIVES: Although 82% of pediatricians report that their patients have difficulty accessing pediatric dermatologists, the regions with greatest need for the specialty are not well-defined. We aimed to determine the geographic distribution of pediatric dermatologists relative to the number of children and pediatric generalists. METHODS: We performed a cross-sectional study of all US board-certified pediatric dermatologists, generalists (defined as pediatricians and family medicine physicians), and children in 2020. Data were obtained from the Society for Pediatric Dermatology, American Board of Pediatrics, Centers for Medicare and Medicaid, and US Census Bureau. Number of children, pediatric dermatologists, and pediatric generalists were tabulated in each county and state, and the distributions of pediatric dermatologists and generalists relative to the population of children were quantified with the Gini coefficient. RESULTS: Of 317 pediatric dermatologists, 243 (76.7%) were women and 311 (98.1%) worked in a metropolitan county. A pediatric dermatologist was present in 41/50 (82%) states and 142/3228 (4.4%) counties. Not a single pediatric dermatologist was found in 54/92 (58.7%) counties with 100 000-199 999 children, 15/53 (28.3%) counties with 200 000-499 999 children, and 4/13 (30.8%) counties with ≥500 000 children. The Gini coefficient for the state-level distribution of pediatric dermatologists relative to population of children was 0.488 compared to 0.132 for that of pediatric generalists. CONCLUSION: There is a maldistribution of pediatric dermatologists, resulting in children with unmet dermatologic needs in nine states and 96 heavily populated counties. These results can inform initiatives to recruit pediatric dermatologists and to expand telehealth access to specific high-density areas.

Combining in Silico Tools with Multicriteria Analysis for Alternatives Assessment of Hazardous Chemicals: A Case Study of Decabromodiphenyl Ether Alternatives.

Alternatives assessment is applied for minimizing the risk of unintentionally replacing a hazardous chemical with another hazardous chemical. Central challenges are the diversity of properties to consider and the lack of high-quality experimental data. To address this, a novel alternatives assessment procedure was developed based on in silico data and multicriteria decision analysis (MCDA) methods. As a case study, 16 alternatives to the flame retardant decabromodiphenyl ether were considered. The hazard properties included persistence (P), bioaccumulation potential (B), toxicities (T), and mobility in water (M). Databases were consulted and 2866 experimental data points were collected for the target chemicals; however, these were mostly replicate data points for some hazard criteria for a subset of alternatives. Therefore, in silico data and three MCDA strategies were tested including heat mapping, multiattribute utility theory (MAUT), and Elimination Et Choix Traduisant la REalité (ELECTRE III). The heat map clearly showed that none of the target chemicals are hazard-free, whereas MAUT and ELECTRE III agreed on ranking the "least worst" choices. This study identified several challenges and the complexity in the alternatives assessment processes motivating more case studies combining in silico and MCDA approaches.

Nemaline myopathy and distal arthrogryposis associated with an autosomal recessive TNNT3 splice variant.

A male neonate presented with severe weakness, hypotonia, contractures and congenital scoliosis. Skeletal muscle specimens showed marked atrophy and degeneration of fast fibers with striking nemaline rods and hypertrophy of slow fibers that were ultrastructurally normal. A neuromuscular gene panel identified a homozygous essential splice variant in TNNT3 (chr11:1956150G > A, NM_006757.3:c.681+1G > A). TNNT3 encodes skeletal troponin-Tfast and is associated with autosomal dominant distal arthrogryposis. TNNT3 has not previously been associated with nemaline myopathy (NM), a rare congenital myopathy linked to defects in proteins associated with thin filament structure and regulation. cDNA studies confirmed pathogenic consequences of the splice variant, eliciting exon-skipping and intron retention events leading to a frameshift. Western blot showed deficiency of troponin-Tfast protein with secondary loss of troponin-Ifast . We establish a homozygous splice variant in TNNT3 as the likely cause of severe congenital NM with distal arthrogryposis, characterized by specific involvement of Type-2 fibers and deficiency of troponin-Tfast .

Subdiffusive motion of bacteriophage in mucosal surfaces increases the frequency of bacterial encounters.

Bacteriophages (phages) defend mucosal surfaces against bacterial infections. However, their complex interactions with their bacterial hosts and with the mucus-covered epithelium remain mostly unexplored. Our previous work demonstrated that T4 phage with Hoc proteins exposed on their capsid adhered to mucin glycoproteins and protected mucus-producing tissue culture cells in vitro. On this basis, we proposed our bacteriophage adherence to mucus (BAM) model of immunity. Here, to test this model, we developed a microfluidic device (chip) that emulates a mucosal surface experiencing constant fluid flow and mucin secretion dynamics. Using mucus-producing human cells and Escherichia coli in the chip, we observed similar accumulation and persistence of mucus-adherent T4 phage and nonadherent T4∆hoc phage in the mucus. Nevertheless, T4 phage reduced bacterial colonization of the epithelium >4,000-fold compared with T4∆hoc phage. This suggests that phage adherence to mucus increases encounters with bacterial hosts by some other mechanism. Phages are traditionally thought to be completely dependent on normal diffusion, driven by random Brownian motion, for host contact. We demonstrated that T4 phage particles displayed subdiffusive motion in mucus, whereas T4∆hoc particles displayed normal diffusion. Experiments and modeling indicate that subdiffusive motion increases phage-host encounters when bacterial concentration is low. By concentrating phages in an optimal mucus zone, subdiffusion increases their host encounters and antimicrobial action. Our revised BAM model proposes that the fundamental mechanism of mucosal immunity is subdiffusion resulting from adherence to mucus. These findings suggest intriguing possibilities for engineering phages to manipulate and personalize the mucosal microbiome.

Small noncoding differentially methylated copy-number variants, including lncRNA genes, cause a lethal lung developmental disorder.

An unanticipated and tremendous amount of the noncoding sequence of the human genome is transcribed. Long noncoding RNAs (lncRNAs) constitute a significant fraction of non-protein-coding transcripts; however, their functions remain enigmatic. We demonstrate that deletions of a small noncoding differentially methylated region at 16q24.1, including lncRNA genes, cause a lethal lung developmental disorder, alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV), with parent-of-origin effects. We identify overlapping deletions 250 kb upstream of FOXF1 in nine patients with ACD/MPV that arose de novo specifically on the maternally inherited chromosome and delete lung-specific lncRNA genes. These deletions define a distant cis-regulatory region that harbors, besides lncRNA genes, also a differentially methylated CpG island, binds GLI2 depending on the methylation status of this CpG island, and physically interacts with and up-regulates the FOXF1 promoter. We suggest that lung-transcribed 16q24.1 lncRNAs may contribute to long-range regulation of FOXF1 by GLI2 and other transcription factors. Perturbation of lncRNA-mediated chromatin interactions may, in general, be responsible for position effect phenomena and potentially cause many disorders of human development.