US drinking water quality: exposure risk profiles for seven legacy and emerging contaminants.

BACKGROUND: Advances in drinking water infrastructure and treatment throughout the 20th and early 21st century dramatically improved water reliability and quality in the United States (US) and other parts of the world. However, numerous chemical contaminants from a range of anthropogenic and natural sources continue to pose chronic health concerns, even in countries with established drinking water regulations, such as the US. OBJECTIVE/METHODS: In this review, we summarize exposure risk profiles and health effects for seven legacy and emerging drinking water contaminants or contaminant groups: arsenic, disinfection by-products, fracking-related substances, lead, nitrate, per- and polyfluorinated alkyl substances (PFAS) and uranium. We begin with an overview of US public water systems, and US and global drinking water regulation. We end with a summary of cross-cutting challenges that burden US drinking water systems: aging and deteriorated water infrastructure, vulnerabilities for children in school and childcare facilities, climate change, disparities in access to safe and reliable drinking water, uneven enforcement of drinking water standards, inadequate health assessments, large numbers of chemicals within a class, a preponderance of small water systems, and issues facing US Indigenous communities. RESULTS: Research and data on US drinking water contamination show that exposure profiles, health risks, and water quality reliability issues vary widely across populations, geographically and by contaminant. Factors include water source, local and regional features, aging water infrastructure, industrial or commercial activities, and social determinants. Understanding the risk profiles of different drinking water contaminants is necessary for anticipating local and general problems, ascertaining the state of drinking water resources, and developing mitigation strategies. IMPACT STATEMENT: Drinking water contamination is widespread, even in the US. Exposure risk profiles vary by contaminant. Understanding the risk profiles of different drinking water contaminants is necessary for anticipating local and general public health problems, ascertaining the state of drinking water resources, and developing mitigation strategies.

ResearchMatch on FHIR: Development and evaluation of a recruitment registry and electronic health record system interface for volunteer profile completion.

Background: Obtaining complete and accurate information in recruitment registries is essential for matching potential participants to research studies for which they qualify. Since electronic health record (EHR) systems are required to make patient data available to external systems, an interface between EHRs and recruitment registries may improve accuracy and completeness of volunteers' profiles. We tested this hypothesis on ResearchMatch (RM), a disease- and institution-neutral recruitment registry with 1357 studies across 255 institutions. Methods: We developed an interface where volunteers signing up for RM can authorize transfer of demographic data, medical conditions, and medications from the EHR into a registration form. We obtained feedback from a panel of community members to determine acceptability of the planned integration. We then developed the EHR interface and performed an evaluation study of 100 patients to determine whether RM profiles generated with EHR-assisted adjudication included more conditions and medications than those without the EHR connection. Results: Community member feedback revealed that members of the public were willing to authenticate into the EHR from RM with proper messaging about choice and privacy. The evaluation study showed that out of 100 participants, 75 included more conditions and 69 included more medications in RM profiles completed with the EHR connection than those without. Participants also completed the EHR-connected profiles in 16 fewer seconds than non-EHR-connected profiles. Conclusions: The EHR to RM integration could lead to more complete profiles, less participant burden, and better study matches for many of the over 148,000 volunteers who participate in ResearchMatch.

Species-specific responses to white-nose syndrome in the Great Lakes region.

White-nose syndrome is a fungal disease that is threatening bat populations across North America. The disease primarily affects cave-hibernating bats by depleting fat reserves during hibernation and causing a range of other physiological consequences when immune responses are suppressed. Since it was first detected in 2006, the disease has killed millions of bats and is responsible for extensive local extinctions. To better understand the effects of white-nose syndrome on various bat species, we analyzed summer acoustic survey data collected from 2016 to 2020 at nine US National Parks within the Great Lakes region. We examined the effect that white-nose syndrome, time of the year relative to pup volancy, habitat type, and regional variation (i.e., park) have on the acoustic abundance (i.e., mean call abundance) of six bat species. As expected, little brown bat (Myotis lucifugus) and northern long-eared bat (Myotis septentrionalis), both hibernating species, experienced a significant decline in acoustic abundance following white-nose syndrome detection. We observed a significant increase in acoustic abundance as white-nose syndrome progressed for hoary bats (Lasiurus cinereus) and silver-haired bats (Lasionycteris noctivagans), both migratory species that are not impacted by the disease. Contrary to our predictions, we observed an increase in big brown bat (Eptesicus fuscus; hibernating) acoustic abundance and a decrease in eastern red bat (Lasiurus borealis; migratory) acoustic abundance following the detection of white-nose syndrome. We did not observe any significant changes after the onset of white-nose syndrome in the seasonal patterns of acoustic activity related to pup volancy, suggesting that production or recruitment of young may not be affected by the disease. Our results suggest that white-nose syndrome is affecting the acoustic abundance of certain species; however, these changes may not be a result of reduced reproductive success caused by the disease. In addition, species population dynamics may be indirectly affected by white-nose syndrome as a result of reduced competition or a foraging niche release. We also found that for parks located at higher latitudes, little brown bat and northern long-eared bat were more likely to experience greater declines in acoustic abundance as a result of white-nose syndrome. Our work provides insight into species-specific responses to white-nose syndrome at a regional scale and examines factors that may facilitate resistance or resiliency to the disease.

Takotsubo Syndrome and Complete Heart Block: A Diagnostic and Management Conundrum.

There is increasing evidence that Takotsubo cardiomyopathy behaves more like a highly variable and dangerous syndrome than an isolated cardiomyopathy. In this case report, we describe a case of Takotsubo cardiomyopathy complicated by complete heart block. We discuss the potential mechanisms for its etiology and examine the need for pacemaker placement.

Unveiling the Hazards: A Case Report on Kayexalate-induced Colonic Necrosis.

Sodium polystyrene sulphonate (SPS), employed in the management of severe hyperkalemia, is typically combined with sodium sorbitol to avert potential intestinal obstruction. Nonetheless, the administration of Kayexalate, even in the presence of minimal sorbitol, can lead to the grave complication of colonic necrosis. We present a case of Kayexalate-mediated colonic necrosis, highlighting the vital necessity of acknowledging the inherent risks associated with its usage in spite of its efficacy in potassium reduction. In light of these potential risks, it is incumbent upon physicians to exercise caution, and contemplate the use of alternative pharmacological agents that effectively eliminate excess potassium, whilst minimizing associated adverse effects.

A Unique Presentation of Extrapulmonary Legionella: Rhabdomyolysis-Induced Acute Renal Failure and Cerebellar Dysfunction.

Legionella is most known for causing pneumonia. However, it is a systemic disease that can directly cause severe multi-organ injury in what is sometimes referred to as "extrapulmonary Legionella." In this case report, a reasonably healthy 80-year-old man is found to have Legionella pneumonia complicated by rhabdomyolysis with acute, severe, non-oliguric acute kidney injury, uremic encephalopathy, transaminitis, and cerebellar dysfunction. With a 14-day course of azithromycin and prompt initiation of dialysis, the patient's pneumonia and systemic sequelae improved. This case demonstrates the importance of considering Legionella in the differential diagnosis of patients who present with community-acquired pneumonia and multi-organ dysfunction. Prompt diagnosis and management may decrease mortality associated with this disease sequela.

Mixed reality surgical mentoring of combat casualty care related procedures in a perfused cadaver model: Initial results of a randomized feasibility study.

BACKGROUND: Most telemedicine modalities have limited ability to enhance procedural and operative care. We developed a novel system to provide synchronous bidirectional expert mixed reality-enabled virtual procedural mentoring. In this feasibility study, we evaluated mixed reality mentoring of combat casualty care related procedures in a re-perfused cadaver model. METHODS: Novices received real-time holographic mentoring from experts using augmented reality via Hololens (Microsoft Inc, Redmond, WA). The experts maintained real-time awareness of the novice's operative environment using virtual reality via HTC-Vive (HTC Corp, Xindian District, Taiwan). Additional cameras (both environments) and novel software created the immersive, shared, 3-dimensional mixed reality environment in which the novice and expert collaborated. The novices were prospectively randomized to either mixed reality or audio-only mentoring. Blinded experts independently evaluated novice procedural videos using a 5-point Likert scale-based questionnaire. Nonparametric variables were evaluated using the Wilcoxon rank-sum test and comparisons using the χ2 analysis; significance was defined at P < .05. RESULTS: Surgeon and nonsurgeon novices (14) performed 69 combat casualty care-related procedures (38 mixed reality, 31 audio), including various vascular exposures, 4-compartment lower leg fasciotomy, and emergency neurosurgical procedures; 85% were performed correctly with no difference in either group. Upon video review, mixed reality-mentored novices showed no difference in procedural flow and forward planning (3.67 vs 3.28, P = .21) or the likelihood of performing individual procedural steps correctly (4.12 vs 3.59, P = .06). CONCLUSION: In this initial feasibility study, our novel mixed reality-based mentoring system successfully facilitated the performance of a wide variety of combat casualty care relevant procedures using a high fidelity re-perfused cadaver model. The small sample size and limited variety of novice types likely impacted the ability of holographically mentored novices to demonstrate improvement over the audio-only control group. Despite this, using virtual, augmented, and mixed reality technologies for procedural mentoring demonstrated promise, and further study is needed.

Phosphomimetic S207D Lysyl-tRNA Synthetase Binds HIV-1 5'UTR in an Open Conformation and Increases RNA Dynamics.

Interactions between lysyl-tRNA synthetase (LysRS) and HIV-1 Gag facilitate selective packaging of the HIV-1 reverse transcription primer, tRNALys3. During HIV-1 infection, LysRS is phosphorylated at S207, released from a multi-aminoacyl-tRNA synthetase complex and packaged into progeny virions. LysRS is critical for proper targeting of tRNALys3 to the primer-binding site (PBS) by specifically binding a PBS-adjacent tRNA-like element (TLE), which promotes release of the tRNA proximal to the PBS. However, whether LysRS phosphorylation plays a role in this process remains unknown. Here, we used a combination of binding assays, RNA chemical probing, and small-angle X-ray scattering to show that both wild-type (WT) and a phosphomimetic S207D LysRS mutant bind similarly to the HIV-1 genomic RNA (gRNA) 5'UTR via direct interactions with the TLE and stem loop 1 (SL1) and have a modest preference for binding dimeric gRNA. Unlike WT, S207D LysRS bound in an open conformation and increased the dynamics of both the PBS region and SL1. A new working model is proposed wherein a dimeric phosphorylated LysRS/tRNA complex binds to a gRNA dimer to facilitate tRNA primer release and placement onto the PBS. Future anti-viral strategies that prevent this host factor-gRNA interaction are envisioned.

"Send My Information": Increasing public accessibility to clinical trials by facilitating participant expression of interest.

Introduction: The process of identifying and connecting with clinical trial study teams can be challenging and difficult for members of the public. The national volunteer community registry, ResearchMatch, and the public clinical trials search tool, Trials Today, work in tandem to bridge this connection by providing a streamlined process for potential participants to identify clinical trials which may be of interest. Methods: Building on the existing infrastructure of ResearchMatch and Trials Today, we created a mechanism by which the public can request that their basic contact information (e.g., email/phone) be securely shared with any actively recruiting clinical trial, including trials with no existing relationship with ResearchMatch. Results: Within the first 2 years of use (July 2019-July 2021), ResearchMatch Volunteers sent 12,251 requests to study teams. On average, 20% of these requests were accepted by the study teams. Conclusions: The utilization of this tool indicates that there is active interest among members of the public to independently contact study teams about trials of interest. Additionally, research teams unaffiliated with ResearchMatch are willing to at minimum accept contact information. This allows ResearchMatch to successfully serve as a medium, connecting members of the public with actively recruiting trials.

Human disturbance and shifts in vertebrate community composition in a biodiversity hotspot.

Understanding how human modification of the landscape shapes vertebrate community composition is vital to understanding the current status and future trajectory of wildlife. Using a participatory approach, we deployed the largest camera-trap network in Mesoamerica to date to investigate how anthropogenic disturbance shapes the occupancy and co-occurrence of terrestrial vertebrate species in a tropical biodiversity hotspot: the Osa Peninsula, Costa Rica. We estimated species richness in different categories of land protection with rarefaction analysis and estimated the expected occupancy with a joint species distribution model that included covariates for anthropogenic disturbance, land protection, habitat quality, and habitat availability. Areas with the most stringent land-use protections (e.g., Corcovado National Park, 24 species [95% CI 23-25]) harbored significantly more species than unprotected areas (20 species [19.7-20.3]), mainly due to a reduced presence of large-bodied species of conservation concern in unprotected areas (e.g., jaguar Panthera onca and white-lipped peccary Tayassu pecari). Small-bodied generalist species, such as opossums (Didelphidae) and armadillos (Dasypus novemcinctus), in contrast, were more common at disturbed sites, resulting in a significant difference in vertebrate community composition between sites with low and high disturbance. Co-occurrence of species was also mainly associated with response to disturbance. Similar responses to disturbance create two groups of species, those whose site-level occupancy usually increased as anthropogenic disturbance increased and those whose estimated occupancy decreased. The absence of large-bodied species entails an important loss of ecological function in disturbed areas and can hinder forest development and maintenance. Efforts to protect and restore forested landscapes are likely having a positive effect on the abundance of some threatened species. These efforts, however, must be sustained and expanded to increase connectivity and ensure the long-term viability of the wildlife community.

Perturbaciones Humanas y Cambios en la Composición de la Comunidad de Vertebrados en un Punto Caliente de Biodiversidad Resumen El entendimiento de cómo las modificaciones humanas del paisaje conforman la composición de las comunidades de vertebrados es vital para entender el estado actual y la trayectoria futura de la fauna. Mediante una estrategia participativa, desplegamos la mayor red de cámaras trampa en Mesoamérica hasta la fecha para investigar cómo la perturbación antropogénica determina la ocupación y coocurrencia de las especies terrestres de vertebrados en un punto caliente de biodiversidad tropical: la Península de Osa, Costa Rica. Estimamos la riqueza de especies en diferentes categorías de protección de suelo con un análisis de rarefacción y estimamos la ocupación esperada con un modelo de distribución conjunta de especies que incluyó covariables para la perturbación antropogénica, la protección del suelo, la calidad del hábitat y la disponibilidad del hábitat. Las áreas con la protección más estricta de uso de suelo (p. ej.: Parque Nacional Corcovado, 24 especies [95% CI 23-25]) albergaron significativamente a más especies que las áreas desprotegidas (20 especies [19.7-20.3]), principalmente debido a la presencia reducida de especies de talla grande de interés para la conservación en las áreas desprotegidas (p. ej.: el jaguar Panthera onca, el pecarí de labios blancos, Tayassu pecari). Al contrario, las especies generalistas de talla pequeña, como las zarigüeyas (Didelphidae) y el armadillo (Dasypus novemcinctus) fueron más comunes en los sitios perturbados, lo que resulta en una diferencia significativa en la composición de las comunidades de vertebrados entre los sitios con una perturbación baja y alta. La coocurrencia de especies también estuvo asociada principalmente con la respuesta a la perturbación. Las respuestas similares a la perturbación crean dos grupos de especies: aquellas cuya ocupación a nivel de sitio generalmente incrementó conforme incrementó la perturbación antropogénica y aquellas cuya ocupación estimada disminuyó. La ausencia de especies de talla grande conlleva una pérdida importante de la función ecológica en las áreas perturbadas y puede dificultar el desarrollo y mantenimiento del bosque. Los esfuerzos para proteger y restaurar los paisajes forestales probablemente estén teniendo un efecto positivo sobre la abundancia de algunas especies amenazadas. Estos esfuerzos, sin embargo, deben ser sostenidos y expandidos para incrementar la conectividad y asegurar la viabilidad a largo plazo de la comunidad faunística.

A Rare Case of Serrated Polyposis Syndrome with the MSH6 and SMARCA4 variants.

Serrated polyposis syndrome (SPS) is the most common form of polyposis syndrome and has been shown to increase the risk of colorectal cancer (CRC). The genetic pathway of CRC in SPS is different from the classic adenomatous polyposis coli (APC) pathway, which accounts for 70-80% of cases of CRC. Most commonly, SPS mutations include BRAF and KRAS, with activation of the RAS-RAF-MAP kinase pathway involved in the pathogenesis of serrated lesions. We present a rare case of SPS in a 32-year-old woman with MSH6 and SMARCA4 variants, which have not previously been reported in the literature. LEARNING POINTS: Patients with serrated polyposis syndrome should receive frequent colon cancer screening.Patients and their relatives should undergo surveillance.

A recovery network leads to the natural recolonization of an archipelago and a potential trailing edge refuge.

Rapid environmental change is reshaping ecosystems and driving species loss globally. Carnivore populations have declined and retracted rapidly and have been the target of numerous translocation projects. Success, however, is complicated when these efforts occur in novel ecosystems. Identifying refuges, locations that are resistant to environmental change, within a translocation framework should improve population recovery and persistence. American martens (Martes americana) are the most frequently translocated carnivore in North America. As elsewhere, martens were extirpated across much of the Great Lakes region by the 1930s and, despite multiple translocations beginning in the 1950s, martens remain of regional conservation concern. Surprisingly, martens were rediscovered in 2014 on the Apostle Islands of Lake Superior after a putative absence of >40 yr. To identify the source of martens to the islands and understand connectivity of the reintroduction network, we collected genetic data on martens from the archipelago and from all regional reintroduction sites. In total, we genotyped 483 individual martens, 43 of which inhabited the Apostle Islands (densities 0.42-1.46 km-2 ). Coalescent analyses supported the contemporary recolonization of the Apostle Islands with progenitors likely originating from Michigan, which were sourced from Ontario. We also identified movements by a first-order relative between the Apostle Islands and the recovery network. We detected some regional gene flow, but in an unexpected direction: individuals moving from the islands to the mainland. Our findings suggest that the Apostle Islands were naturally recolonized by progeny of translocated individuals and now act as a source back to the reintroduction sites on the mainland. We suggest that the Apostle Islands, given its protection from disturbance, complex forest structure, and reduced carnivore competition, will act as a potential refuge for marten along their trailing range boundary and a central node for regional recovery. Our work reveals that translocations, even those occurring along southern range boundaries, can create recovery networks that function like natural metapopulations. Identifying refuges, locations that are resistant to environmental change, within these recovery networks can further improve species recovery, even within novel environments. Future translocation planning should a priori identify potential refuges and sources to improve short-term recovery and long-term persistence.

A model of feedforward, global, and lateral inhibition in the locust visual system predicts responses to looming stimuli.

Detection of looming obstacles is a vital task for both natural and artificial systems. Locusts possess a visual nervous system with an extensively studied obstacle detection pathway, culminating in the lobula giant movement detector (LGMD) neuron. While numerous models of this system exist, none to date have incorporated recent data on the anatomy and function of feedforward and global inhibitory systems in the input network of the LGMD. Moreover, the possibility that global and lateral inhibition shape the feedforward inhibitory signals to the LGMD has not been investigated. To address these points, a novel model of feedforward inhibitory neurons in the locust optic lobe was developed based on the recent literature. This model also incorporated global and lateral inhibition into the afferent network of these neurons, based on their observed behaviour in existing data and the posited role of these mechanisms in the inputs to the LGMD. Tests with the model showed that it accurately replicates the behaviour of feedforward inhibitory neurons in locusts; the model accurately coded for stimulus angular size in an overall linear fashion, with decreasing response saturation and increasing linearity as stimulus size increased or approach velocity decreased. The model also exhibited only phasic responses to the appearance of a grating, along with sustained movement by it at constant speed. By observing the effects of altering inhibition schemes on these responses, it was determined that global inhibition serves primarily to normalize growing excitation as collision approaches, and keeps coding for subtense angle linear. Lateral inhibition was determined to suppress tonic responses to wide-field stimuli translating at constant speed. Based on these features being shared with characterizations of the LGMD input network, it was hypothesized that the feedforward inhibitory neurons and the LGMD share the same excitatory afferents; this necessitates further investigation.

Vivid biofluorescence discovered in the nocturnal Springhare (Pedetidae).

Biofluorescence has been detected in several nocturnal-crepuscular organisms from invertebrates to birds and mammals. Biofluorescence in mammals has been detected across the phylogeny, including the monotreme duck-billed platypus (Ornithorhyncus anatinus), marsupial opossums (Didelphidae), and New World placental flying squirrels (Gluacomys spp.). Here, we document vivid biofluorescence of springhare (Pedetidae) in both museum specimens and captive individuals-the first documented biofluorescence of an Old World placental mammal. We explore the variation in biofluorescence across our sample and characterize its physical and chemical properties. The striking visual patterning and intensity of color shift was unique relative to biofluorescence found in other mammals. We establish that biofluorescence in springhare likely originates within the cuticle of the hair fiber and emanates, at least partially, from several fluorescent porphyrins and potentially one unassigned molecule absent from our standard porphyrin mixture. This discovery further supports the hypothesis that biofluorescence may be ecologically important for nocturnal-crepuscular mammals and suggests that it may be more broadly distributed throughout Mammalia than previously thought.

Impacts of lake breeze meteorology on ozone gradient observations along Lake Michigan Shorelines in Wisconsin.

Daytime onshore lake breezes are a critical factor controlling ozone abundance at coastal sites around Lake Michigan. Coastal counties along the western shore of Lake Michigan have historically observed high ozone episodes dating to the 1970s. We classified ozone episode days based on the extent or absence of the lake breeze (i.e., "inland", "near-shore" or "no" lake breeze) to establish a climatology of these events. This work demonstrated variable gradients in ozone abundances based on these different types of meteorology, with the sharpest ozone concentration gradients on days with a near-shore lake breeze. On 76-82% of days in which ozone reached 70 ppb for at least 1 hour, a lake breeze was present. Evidence of ozone gradients from multiple observation platforms during the 2017 Lake Michigan Ozone Study (LMOS 2017) are shown for two days with different depths of lake breezes.

Preexisting Conditions That Kill Us.

To protect human life, science and public health need to guide public policy. We call for an end to the anti-science, anti-prevention, and anti-regulatory policies that have resulted in countless preexisting conditions and deaths. Reactive responses are not a substitute for primary prevention; we must invest in environmental and public health protections.

HIV-1 Gag protein with or without p6 specifically dimerizes on the viral RNA packaging signal.

The HIV-1 Gag protein is responsible for genomic RNA (gRNA) packaging and immature viral particle assembly. Although the presence of gRNA in virions is required for viral infectivity, in its absence, Gag can assemble around cellular RNAs and form particles resembling gRNA-containing particles. When gRNA is expressed, it is selectively packaged despite the presence of excess host RNA, but how it is selectively packaged is not understood. Specific recognition of a gRNA packaging signal (Psi) has been proposed to stimulate the efficient nucleation of viral assembly. However, the heterogeneity of Gag-RNA interactions renders capturing this transient nucleation complex using traditional structural biology approaches challenging. Here, we used native MS to investigate RNA binding of wild-type (WT) Gag and Gag lacking the p6 domain (GagΔp6). Both proteins bind to Psi RNA primarily as dimers, but to a control RNA primarily as monomers. The dimeric complexes on Psi RNA require an intact dimer interface within Gag. GagΔp6 binds to Psi RNA with high specificity in vitro and also selectively packages gRNA in particles produced in mammalian cells. These studies provide direct support for the idea that Gag binding to Psi specifically promotes nucleation of Gag-Gag interactions at the early stages of immature viral particle assembly in a p6-independent manner.

Universal background checks for handgun purchases can reduce homicide rates of African Americans.

BACKGROUND: Federal law requires background checks for firearms purchased from licensed dealers, but states can extend requirements to private sales of handguns and purchases at gun shows (universal background checks for handguns [UBC-HG]). Although firearm homicide disproportionately affects African Americans, little is known about how UBG-HG impacts African Americans. We hypothesized that implementation of UBC-HG would reduce rates of firearm homicide of African Americans. METHODS: We collected Centers for Disease Control firearm homicide counts for African American and white populations in the 50 states, 1999 to 2017. Laws were drawn from the State Firearm Laws Database. The exposure and outcome of interest were UBC-HG adoption and firearm homicide. We included non-Hispanic African American and non-Hispanic white populations. We used Poisson regression to perform a differences-in-differences analysis. A categorical variable for state accounted for time-stable state characteristics. We controlled for year to account for trends over time unrelated to policy. We controlled for state-specific, time-variable factors, including median household income, population younger than 25 years or 65 years or older, alcohol consumption, and count of firearm laws (UBC-HG excluded). Standard errors were adjusted for clustering at the state level. RESULTS: The firearm homicide rate among whites was 1.8 per 100,000 (interquartile range, 1.2-2.7) ranging from 1.4 in 2011 to 1.8 in 2016. The firearm homicide rate was 15.6 per 100,000 (interquartile range, 11.6-21.0) among African Americans, ranging from 14.0 in 2009 to 19.6 in 2017. While no significant difference in firearm homicides among whites (incidence rate ratio, 0.93; 95% confidence interval, 0.73-1.20) was appreciated, the passage of UBC-HG was associated with an 19% decrease in African Americans firearm homicides (incidence rate ratio, 0.81; 95% confidence interval, 0.70-0.94; p = 0.006). CONCLUSION: Implementing UBC-HG was associated with decreased firearm homicides among African Americans-the population most at risk. Expanding UBC-HG may be an effective approach to reducing racial disparities in firearm homicides. LEVEL OF EVIDENCE: Epidemiological, level III.

Integrative structural biology studies of HIV-1 reverse transcriptase binding to a high-affinity DNA aptamer.

The high-resolution crystal structure of HIV-1 reverse transcriptase (RT) bound to a 38-mer DNA hairpin aptamer with low pM affinity was previously described. The high-affinity binding aptamer contained 2'-O-methyl modifications and a seven base-pair GC-rich tract and the structure of the RT-aptamer complex revealed specific contacts between RT and the template strand of the aptamer. Similar to all crystal structures of RT bound to nucleic acid template-primers, the aptamer bound RT with a bend in the duplex DNA. To understand the structural basis for the ultra-high-affinity aptamer binding, an integrative structural biology approach was used. Hydrogen-deuterium exchange coupled to liquid chromatography-mass spectrometry (HDX-MS) was used to examine the structural dynamics of RT alone and in the presence of the DNA aptamer. RT was selectively labeled with 15N to unambiguously identify peptides from each subunit. HDX of unliganded RT shows a mostly stable core. The p66 fingers and thumb subdomains, and the RNase H domain are relatively dynamic. HDX indicates that both the aptamer and a scrambled version significantly stabilize regions of RT that are dynamic in the absence of DNA. No substantial differences in RT dynamics are observed between aptamer and scrambled aptamer binding, despite a large difference in binding affinity. Small-angle X-ray scattering and circular dichroism spectroscopy were used to investigate the aptamer conformation in solution and revealed a pre-bent DNA that possesses both A- and B-form helical character. Both the 2'-O-methyl modifications and the GC tract appear to contribute to an energetically favorable conformation for binding to RT that contributes to the aptamer's ultra-high affinity for RT. The X-ray structure of RT with an RNA/DNA version of the aptamer at 2.8 Å resolution revealed a potential role of the hairpin positioning in affinity. Together, the data suggest that both the 2'-O-methyl modifications and the GC tract contribute to an energetically favorable conformation for high-affinity binding to RT.

Outcomes in patients with gunshot wounds to the brain.

INTRODUCTION: Gunshot wounds to the brain (GSWB) confer high lethality and uncertain recovery. It is unclear which patients benefit from aggressive resuscitation, and furthermore whether patients with GSWB undergoing cardiopulmonary resuscitation (CPR) have potential for survival or organ donation. Therefore, we sought to determine the rates of survival and organ donation, as well as identify factors associated with both outcomes in patients with GSWB undergoing CPR. METHODS: We performed a retrospective, multicenter study at 25 US trauma centers including dates between June 1, 2011 and December 31, 2017. Patients were included if they suffered isolated GSWB and required CPR at a referring hospital, in the field, or in the trauma resuscitation room. Patients were excluded for significant torso or extremity injuries, or if pregnant. Binomial regression models were used to determine predictors of survival/organ donation. RESULTS: 825 patients met study criteria; the majority were male (87.6%) with a mean age of 36.5 years. Most (67%) underwent CPR in the field and 2.1% (n=17) survived to discharge. Of the non-survivors, 17.5% (n=141) were considered eligible donors, with a donation rate of 58.9% (n=83) in this group. Regression models found several predictors of survival. Hormone replacement was predictive of both survival and organ donation. CONCLUSION: We found that GSWB requiring CPR during trauma resuscitation was associated with a 2.1% survival rate and overall organ donation rate of 10.3%. Several factors appear to be favorably associated with survival, although predictions are uncertain due to the low number of survivors in this patient population. Hormone replacement was predictive of both survival and organ donation. These results are a starting point for determining appropriate treatment algorithms for this devastating clinical condition. LEVEL OF EVIDENCE: Level II.