Exposure to statin therapy decreases the incidence of venous thromboembolism after trauma.

INTRODUCTION: Venous thromboembolism (VTE) is a leading cause of morbidity and mortality in trauma patients, despite chemoprophylaxis. Statins have been shown capable of acting upon the endothelium. We hypothesized that statin therapy in the pre- or in-hospital settings leads to a decreased incidence of VTE. METHODS: We conducted a retrospective cohort study of injured patients who received statin therapy pre- or in-hospital. Adult, highest-level trauma activation patients admitted from January 2018 to June 2022 were included. Patients on prehospital anticoagulants, had history of inherited bleeding disorder, and who died within the first 24 hours were excluded. Statin users were matched to nonusers by statin use indications including age, current heart and cardiovascular conditions and history, hyperlipidemia, injury severity, and body mass index. Time to in-hospital statin initiation and occurrence of VTE and other complications within 60 days were collected. Differences between groups were determined by univariate, multivariable logistic regression, and Cox proportional hazard analyses. RESULTS: Of 3,062 eligible patients, 79 were statin users, who were matched to 79 nonusers. There were no differences in admission demographics, vital signs, injury pattern, transfusion volumes, lengths of stay, or mortality between groups. The overall VTE incidence was 10.8% (17 of 158). Incidence of VTE in statin users was significantly lower (3%) than nonusers (19%; p = 0.003). Differences between statin users and nonusers were observed for rates of deep vein thrombosis (0% vs. 9%), pulmonary embolism (3% vs. 15%), and sepsis (0% vs. 5%). Exposure to statins was associated with an 82% decreased risk of developing VTE (hazard ratio, 0.18; 95% confidence interval, 0.04-0.86; p = 0.033). CONCLUSION: Statin exposure was associated with decline in VTE and lower individual rates of deep vein thrombosis, pulmonary embolism, and sepsis. Our findings indicate that statins should be evaluated further as a possible adjunctive therapy for VTE chemoprophylaxis after traumatic injury. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level IV.

Telerehabilitation in Physical Therapist Practice: A Clinical Practice Guideline From the American Physical Therapy Association.

A clinical practice guideline on telerehabilitation was developed by an American Physical Therapy Association volunteer guideline development group consisting of international physical therapists and physiotherapists, a physician, and a consumer. The guideline was based on systematic reviews of current scientific literature, clinical information, and accepted approaches to telerehabilitation in physical therapist practice. Seven recommendations address the impact of, preparation for, and implementation of telerehabilitation in physical therapist practice. Research recommendations identify current gaps in knowledge. Overall, with shared decision-making between clinicians and patients to inform patients of service delivery options, direct and indirect costs, barriers, and facilitators of telerehabilitation, the evidence supports the use of telerehabilitation by physical therapists for both examination and intervention. The Spanish and Chinese versions of this clinical practice guideline, as well as the French version of the recommendations, are available as supplementary material (Suppl. Materials).

Structure of the two-component S-layer of the archaeon Sulfolobus acidocaldarius.

Surface layers (S-layers) are resilient two-dimensional protein lattices that encapsulate many bacteria and most archaea. In archaea, S-layers usually form the only structural component of the cell wall and thus act as the final frontier between the cell and its environment. Therefore, S-layers are crucial for supporting microbial life. Notwithstanding their importance, little is known about archaeal S-layers at the atomic level. Here, we combined single-particle cryo electron microscopy, cryo electron tomography, and Alphafold2 predictions to generate an atomic model of the two-component S-layer of Sulfolobus acidocaldarius. The outer component of this S-layer (SlaA) is a flexible, highly glycosylated, and stable protein. Together with the inner and membrane-bound component (SlaB), they assemble into a porous and interwoven lattice. We hypothesise that jackknife-like conformational changes in SlaA play important roles in S-layer assembly.

TIME-DEPENDENT CHANGES IN PROINFLAMMATORY MEDIATORS ARE ASSOCIATED WITH TRAUMA-RELATED VENOUS THROMBOEMBOLISM.

ABSTRACT: Background: Tissue trauma and hemorrhage result in pronounced activation of the innate immune system. Given known crosstalk between inflammation and coagulation, soluble inflammatory mediators could be associated with venous thromboembolisms (VTEs) after major trauma. Objectives : This study aimed to identify plasma inflammatory mediators that are independent predictors of VTE risk in trauma patients. Methods: We performed a secondary analysis of the Pragmatic Randomized Optimal Platelets and Plasma Ratios (PROPPR) study. Plasma levels of 27 cytokines/chemokines were measured by Bio-Plex at admission and 2, 4, 6, 12, 24, 48, and 72 h later. Patients who died from exsanguination or within 24 h were excluded. Mann-Whitney tests were performed to assess no-VTE and VTE groups at each time point. Multivariable logistic regression was used to determine the adjusted effects of inflammatory mediators on VTE risk. Results: Eighty-six of the 575 patients (15%) included developed VTE. Interleukin (IL)-1ra, IL-6, IL-8, IL-10, eotaxin, granulocyte colony-stimulating factor, interferon-γ-inducible protein, monocyte chemoattractant protein 1 (MCP-1), and chemokine ligand 5 (regulated on activation, normal T cell expressed and secreted) were all significantly increased among VTE patients. Multivariable analyses demonstrated that IL-6, IL-8, interferon-γ-inducible protein, and MCP-1 were independently associated with VTE. Cox proportional hazards modeling identified IL-6, IL-8, and MCP-1 as independent predictors of accelerated VTE development. We identified significant correlations between inflammation and markers of coagulation and endothelial activation. Conclusion: Sustained systemic inflammation is a key driver of VTE risk after major trauma. Therapeutics targeting innate immune activation should be considered for development of future multimodal strategies to augment current VTE prophylaxis.

Soluble endothelial protein C receptor is an independent predictor of venous thromboembolism after severe injury: Secondary analysis of a prospective cohort study.

BACKGROUND: Venous thromboembolism is a leading cause of morbidity after trauma. Endothelial cells are essential regulators of coagulation. Although endothelial cell dysregulation is widely reported after trauma, the link between endothelial injury and venous thromboembolism has not been reported. METHODS: We conducted a secondary analysis of the Pragmatic Randomized Optimal Platelets and Plasma Ratios study. Deaths from hemorrhage or within 24 hours were excluded. Venous thromboembolism was diagnosed by duplex ultrasound or chest computed tomography. Endothelial markers soluble endothelial protein c receptor, thrombomodulin, and syndecan-1 were measured in plasma by enzyme-linked immunosorbent assay and compared over the first 72 hours from admission using the Mann-Whitney test. Multivariable logistic regression assessed the adjusted effects of endothelial markers on venous thromboembolism risk. RESULTS: Of 575 patients enrolled, 86 developed venous thromboembolism (15%). The median time to venous thromboembolism was 6 days ([Q1, Q3], [4, 13]). No differences were identified in demographics or injury severity. Soluble endothelial protein c receptor, thrombomodulin, and syndecan-1 showed significant increases over time among patients who developed venous thromboembolism compared to those who did not. Using the last available values, patients were stratified into high and low-soluble endothelial protein c receptor, thrombomodulin, and syndecan-1 groups. Multivariable analyses revealed an independent association between elevated soluble endothelial protein c receptor and venous thromboembolism risk (odds ratio 1.63; 95% confidence interval 1.01, 2.63; P = .04). Cox proportional hazards modeling demonstrated a strong yet nonsignificant trend between elevated soluble endothelial protein c receptor and time to venous thromboembolism. CONCLUSION: Plasma markers of endothelial injury, particularly soluble endothelial protein c receptor, are strongly associated with trauma-related venous thromboembolism. Therapeutics targeting endothelial function could mitigate the incidence of venous thromboembolism after trauma.

The role of extreme heat exposure on premature rupture of membranes in Southern California: A study from a large pregnancy cohort.

BACKGROUND: Significant mortality and morbidity in pregnant women and their offspring are linked to premature rupture of membranes (PROM). Epidemiological evidence for heat-related PROM risk is extremely limited. We investigated associations between acute heatwave exposure and spontaneous PROM. METHODS: We conducted this retrospective cohort study among mothers in Kaiser Permanente Southern California who experienced membrane ruptures during the warm season (May-September) from 2008 to 2018. Twelve definitions of heatwaves with different cut-off percentiles (75th, 90th, 95th, and 98th) and durations (≥ 2, 3, and 4 consecutive days) were developed using the daily maximum heat index, which incorporates both daily maximum temperature and minimum relative humidity in the last gestational week. Cox proportional hazards models were fitted separately for spontaneous PROM, term PROM (TPROM), and preterm PROM (PPROM) with zip codes as the random effect and gestational week as the temporal unit. Effect modification by air pollution (i.e., PM2.5 and NO2), climate adaptation measures (i.e., green space and air conditioning [AC] penetration), sociodemographic factors, and smoking behavior was examined. RESULTS: In total, we included 190,767 subjects with 16,490 (8.6%) spontaneous PROMs. We identified a 9-14% increase in PROM risks associated with less intense heatwaves. Similar patterns as PROM were found for TPROM and PPROM. The heat-related PROM risks were greater among mothers exposed to a higher level of PM2.5 during pregnancy, under 25 years old, with lower education and household income level, and who smoked. Even though climate adaptation factors were not statistically significant effect modifiers, mothers living with lower green space or lower AC penetration were at consistently higher heat-related PROM risks compared to their counterparts. CONCLUSION: Using a rich and high-quality clinical database, we detected harmful heat exposure for spontaneous PROM in preterm and term deliveries. Some subgroups with specific characteristics were more susceptible to heat-related PROM risk.

Barriers to COVID-19 vaccine acceptance to improve messages for vaccine uptake in indigenous populations in the central highlands of Guatemala: a participatory qualitative study.

INTRODUCTION: As of July 2022, a little over one-third of Guatemalans were fully vaccinated. While COVID-19 vaccination rates are not officially reported nationally by racial/ethnic groups, non-governmental organisations and reporters have observed that COVID-19 vaccination rates are especially low among high-risk Indigenous populations. We conducted one of the first studies on COVID-19 vaccine acceptance in Indigenous populations in the Central Highlands of Guatemala, which aimed to better understand the barriers to COVID-19 vaccine uptake and how to improve vaccine promotional campaigns. METHODS: In November 2021, we conducted eight focus group discussions (FGDs) with 42 Indigenous men and women and 16 in-depth interviews (IDIs) with community health workers, nurses and physicians in Chimaltenango and Sololá. Using a participatory design approach, our qualitative analysis used constant comparative methods to understand the inductive and deductive themes from the FGD and IDI transcripts. RESULTS: We found three major overarching barriers to vaccination within the sampled population: (1) a lack of available easily understandable, linguistically appropriate and culturally sensitive COVID-19 vaccine information; (2) vaccine access and supply issues that prevented people from being vaccinated efficiently and quickly; and (3) widespread misinformation and disinformation that prey on people's fears of the unknown and mistrust of the medical establishment and government. CONCLUSION: When developing COVID-19 vaccine messages, content should be culturally relevant, appropriate for low-literacy populations and in the languages that people prefer to speak. Promotional materials should be in multiple modalities (print, radio and social media) and also have specific Maya cultural references (dress, food and concepts of disease) to ensure messaging connects with intended targets. This study supports the need for more robust research into best practices for communicating about COVID-19 vaccines to marginalised communities globally and suggests that policy makers should invest in targeted local solutions to increase vaccine uptake.

Evaluating the impact of a linguistically and culturally tailored social media ad campaign on COVID-19 vaccine uptake among indigenous populations in Guatemala: a pre/post design intervention study.

OBJECTIVES: To evaluate the impact of culturally and linguistically tailored informational videos delivered via social media campaigns on COVID-19 vaccine uptake in Indigenous Maya communities in Guatemala. METHODS: Our team designed a series of videos utilising community input and evaluated the impact using a pre-post intervention design. In-person preintervention surveys were collected from a sample of respondents in four rural municipalities in Guatemala in March 2022. Facebook, Instagram and browser ads were flooded with COVID-19 vaccine informational videos in Spanish, Kaqchikel and Kiche for 3 weeks. Postintervention surveys were conducted by telephone among the same participants in April 2022. Logistic regression models were used to estimate the OR of COVID-19 vaccine uptake following exposure to the intervention videos. RESULTS: Preintervention and postintervention surveys were collected from 1572 participants. The median age was 28 years; 63% (N=998) identified as women, and 36% spoke an Indigenous Mayan language. Twenty-one per cent of participants (N=327) reported watching the intervention content on social media. At baseline, 89% (N=1402) of participants reported having at least one COVID-19 vaccine, compared with 97% (N=1507) in the follow-up. Those who reported watching the videos had 1.78 times the odds (95% CI 1.14 to 2.77) of getting vaccinated after watching the videos compared with those who did not see the videos when adjusted by age, community, sex and language. CONCLUSION: Our findings suggest that culturally and linguistically tailored videos addressing COVID-19 vaccine misinformation deployed over social media can increase vaccinations in a rural, indigenous population in Guatemala, implying that social media content can influence vaccination uptake. Providing accurate, culturally sensitive information in local languages from trusted sources may help increase vaccine uptake in historically marginalised populations.

Analyzing changes to U.S. municipal heat response plans during the COVID-19 pandemic.

Extreme heat events are the deadliest weather-related event in the United States. Cities throughout the United States have worked to develop heat adaptation strategies to limit the impact of extreme heat on vulnerable populations. However, the COVID-19 pandemic presented unprecedented challenges to local governments. This paper provides a preliminary review of strategies and interventions used to manage compound COVID-19-extreme heat events in the 25 most populous cities of the United States. Heat adaptation strategies employed prior to the COVID-19 pandemic were not adequate to meet during the co-occurring compound hazard of COVID-19-EHE. Long-term climate-adaptation strategies will require leveraging physical, financial, and community resources across multiple city departments to meet the needs of compound hazards, such as COVID-19 and extreme heat.

CryoEM structure of the outer membrane secretin channel pIV from the f1 filamentous bacteriophage.

The Ff family of filamentous bacteriophages infect gram-negative bacteria, but do not cause lysis of their host cell. Instead, new virions are extruded via the phage-encoded pIV protein, which has homology with bacterial secretins. Here, we determine the structure of pIV from the f1 filamentous bacteriophage at 2.7 Å resolution by cryo-electron microscopy, the first near-atomic structure of a phage secretin. Fifteen f1 pIV subunits assemble to form a gated channel in the bacterial outer membrane, with associated soluble domains projecting into the periplasm. We model channel opening and propose a mechanism for phage egress. By single-cell microfluidics experiments, we demonstrate the potential for secretins such as pIV to be used as adjuvants to increase the uptake and efficacy of antibiotics in bacteria. Finally, we compare the f1 pIV structure to its homologues to reveal similarities and differences between phage and bacterial secretins.

COVID-19 Therapeutics for Low- and Middle-Income Countries: A Review of Candidate Agents with Potential for Near-Term Use and Impact.

Low- and middle-income countries (LMICs) face significant challenges in the control of COVID-19, given limited resources, especially for inpatient care. In a parallel effort to that for vaccines, the identification of therapeutics that have near-term potential to be available and easily administered is critical. Using the United States (US), European Union (EU), and World Health Organization (WHO) clinical trial registries, we reviewed COVID-19 therapeutic agents currently under investigation. The search was limited to oral or potentially oral agents, with at least a putative anti-SARS-CoV-2 virus mechanism and with at least five registered trials. The search yielded 1,001, 203, and 1,128 trials, in the US, EU, and WHO trial registers, respectively. These trials covered 13 oral or potentially oral repurposed agents that are currently used as antimicrobials and immunomodulatory therapeutics with established safety profiles. The available evidence regarding proposed mechanisms of action, potential limitations, and trial status is summarized. The results of the search demonstrate few published studies of high quality, a low proportion of trials completed, and the vast majority with negative results. These findings reflect limited investment in COVID-19 therapeutics development compared with vaccines. We also identified the need for better coordination of trials of accessible agents and their combinations in LMICs. To prevent COVID-19 from becoming a neglected tropical disease, there is a critical need for rapid and coordinated efforts in the evaluation and deployment of those agents found to be efficacious.

Cryo-electron microscopy reveals two distinct type IV pili assembled by the same bacterium.

Type IV pili are flexible filaments on the surface of bacteria, consisting of a helical assembly of pilin proteins. They are involved in bacterial motility (twitching), surface adhesion, biofilm formation and DNA uptake (natural transformation). Here, we use cryo-electron microscopy and mass spectrometry to show that the bacterium Thermus thermophilus produces two forms of type IV pilus ('wide' and 'narrow'), differing in structure and protein composition. Wide pili are composed of the major pilin PilA4, while narrow pili are composed of a so-far uncharacterized pilin which we name PilA5. Functional experiments indicate that PilA4 is required for natural transformation, while PilA5 is important for twitching motility.

A modeling framework to evaluate blending of seawater and treated wastewater streams for synergistic desalination and potable reuse.

A modeling framework was developed to evaluate synergistic blending of the waste streams from seawater reverse osmosis (RO) desalination and wastewater treatment facilities that are co-located or in close proximity. Four scenarios were considered, two of which involved blending treated wastewater with the brine resulting from the seawater RO desalination process, effectively diluting RO brine prior to discharge. One of these scenarios considers the capture of salinity-gradient energy. The other two scenarios involved blending treated wastewater with the intake seawater to dilute the influent to the RO process. One of these scenarios incorporates a low-energy osmotic dilution process to provide high-quality pre-treatment for the wastewater. The model framework evaluates required seawater and treated wastewater flowrates, discharge flowrates and components, boron removal, and system energy requirements. Using data from an existing desalination facility in close proximity to a wastewater treatment facility, results showed that the influent blending scenarios (Scenarios 3 and 4) had several advantages over the brine blending scenarios (Scenarios 1 and 2), including: (1) reduced seawater intake and brine discharge flowrates, (2) no need for second-pass RO for boron control, and (3) reduced energy consumption. It should be noted that the framework was developed for use with co-located seawater desalination and coastal wastewater reclamation facilities but could be extended for use with desalination and wastewater reclamation facilities in in-land locations where disposal of RO concentrate is a serious concern.

Architecture and modular assembly of Sulfolobus S-layers revealed by electron cryotomography.

Surface protein layers (S-layers) often form the only structural component of the archaeal cell wall and are therefore important for cell survival. S-layers have a plethora of cellular functions including maintenance of cell shape, osmotic, and mechanical stability, the formation of a semipermeable protective barrier around the cell, and cell-cell interaction, as well as surface adhesion. Despite the central importance of S-layers for archaeal life, their 3-dimensional (3D) architecture is still poorly understood. Here we present detailed 3D electron cryomicroscopy maps of archaeal S-layers from 3 different Sulfolobus strains. We were able to pinpoint the positions and determine the structure of the 2 subunits SlaA and SlaB. We also present a model describing the assembly of the mature S-layer.

Costs and cost-effectiveness of malaria reactive case detection using loop-mediated isothermal amplification compared to microscopy in the low transmission setting of Aceh Province, Indonesia.

BACKGROUND: Reactive case detection (RACD) is an active case finding strategy where households and neighbours of a passively identified case (index case) are screened to identify and treat additional malaria infections with the goal of gathering surveillance information and potentially reducing further transmission. Although it is widely considered a key strategy in low burden settings, little is known about the costs and the cost-effectiveness of different diagnostic methods used for RACD. The aims of this study were to measure the cost of conducting RACD and compare the cost-effectiveness of microscopy to the more sensitive diagnostic method loop-mediated isothermal amplification (LAMP). METHODS: The study was conducted in RACD surveillance sites in five sub-districts in Aceh Besar, Indonesia. The cost inputs and yield of implementing RACD with microscopy and/or LAMP were collected prospectively over a 20 months study period between May 2014 and December 2015. Costs and cost-effectiveness (USD) of the different strategies were examined. The main cost measures were cost per RACD event, per person screened, per population at risk (PAR); defined as total population in each sub-district, and per infection found. The main cost-effectiveness measure was incremental cost-effectiveness ratio (ICER), expressed as cost per malaria infection detected by LAMP versus microscopy. The effects of varying test positivity rate or diagnostic yield on cost per infection identified and ICER were also assessed. RESULTS: Among 1495 household members and neighbours screened in 36 RACD events, two infections were detected by microscopy and confirmed by LAMP, and four infections were missed by microscopy but detected by LAMP. The average total cost of conducting RACD using microscopy and LAMP was $1178 per event with LAMP-specific consumables and personnel being the main cost drivers. The average cost of screening one individual during RACD was $11, with an additional cost of diagnostics at $0.62 and $16 per person for microscopy and LAMP, respectively. As a public health intervention, RACD using both diagnostics cost an average of $0.42 per PAR per year. Comparing RACD using microscopy only versus RACD using LAMP only, the cost per infection found was $8930 and $6915, respectively. To add LAMP as an additional intervention accompanying RACD would cost $9 per individual screened annually in this setting. The ICER was estimated to be $5907 per additional malaria infection detected by LAMP versus microscopy. Cost per infection identified and ICER declined with increasing test positivity rate and increasing diagnostic yield. CONCLUSIONS: This study provides the first estimates on the cost and cost-effectiveness of RACD from a low transmission setting. Costs per individual screened were high, though costs per PAR were low. Compared to microscopy, the use of LAMP in RACD was more costly but more cost-effective for the detection of infections, with diminishing returns observed when findings were extrapolated to scenarios with higher prevalence of infection using more sensitive diagnostics. As malaria programmes consider active case detection and the integration of more sensitive diagnostics, these findings may inform strategic and budgetary planning.

Water Use in the United States Energy System: A National Assessment and Unit Process Inventory of Water Consumption and Withdrawals.

The United States (US) energy system is a large water user, but the nature of that use is poorly understood. To support resource comanagement and fill this noted gap in the literature, this work presents detailed estimates for US-based water consumption and withdrawals for the US energy system as of 2014, including both intensity values and the first known estimate of total water consumption and withdrawal by the US energy system. We address 126 unit processes, many of which are new additions to the literature, differentiated among 17 fuel cycles, five life cycle stages, three water source categories, and four levels of water quality. Overall coverage is about 99% of commercially traded US primary energy consumption with detailed energy flows by unit process. Energy-related water consumption, or water removed from its source and not directly returned, accounts for about 10% of both total and freshwater US water consumption. Major consumers include biofuels (via irrigation), oil (via deep well injection, usually of nonfreshwater), and hydropower (via evaporation and seepage). The US energy system also accounts for about 40% of both total and freshwater US water withdrawals, i.e., water removed from its source regardless of fate. About 70% of withdrawals are associated with the once-through cooling systems of approximately 300 steam cycle power plants that produce about 25% of US electricity.

The structure and function of an RNA polymerase interaction domain in the PcrA/UvrD helicase.

The PcrA/UvrD helicase functions in multiple pathways that promote bacterial genome stability including the suppression of conflicts between replication and transcription and facilitating the repair of transcribed DNA. The reported ability of PcrA/UvrD to bind and backtrack RNA polymerase (1,2) might be relevant to these functions, but the structural basis for this activity is poorly understood. In this work, we define a minimal RNA polymerase interaction domain in PcrA, and report its crystal structure at 1.5 Å resolution. The domain adopts a Tudor-like fold that is similar to other RNA polymerase interaction domains, including that of the prototype transcription-repair coupling factor Mfd. Removal or mutation of the interaction domain reduces the ability of PcrA/UvrD to interact with and to remodel RNA polymerase complexes in vitro. The implications of this work for our understanding of the role of PcrA/UvrD at the interface of DNA replication, transcription and repair are discussed.

Spatially and Temporally Resolved Analysis of Environmental Trade-Offs in Electricity Generation.

The US power sector is a leading contributor of emissions that affect air quality and climate. It also requires a lot of water for cooling thermoelectric power plants. Although these impacts affect ecosystems and human health unevenly in space and time, there has been very little quantification of these environmental trade-offs on decision-relevant scales. This work quantifies hourly water consumption, emissions (i.e., carbon dioxide, nitrogen oxides, and sulfur oxides), and marginal heat rates for 252 electricity generating units (EGUs) in the Electric Reliability Council of Texas (ERCOT) region in 2011 using a unit commitment and dispatch model (UC&D). Annual, seasonal, and daily variations, as well as spatial variability are assessed. When normalized over the grid, hourly average emissions and water consumption intensities (i.e., output per MWh) are found to be highest when electricity demand is the lowest, as baseload EGUs tend to be the most water and emissions intensive. Results suggest that a large fraction of emissions and water consumption are caused by a small number of power plants, mainly baseload coal-fired generators. Replacing 8-10 existing power plants with modern natural gas combined cycle units would result in reductions of 19-29%, 51-55%, 60-62%, and 13-27% in CO2 emissions, NOx emissions, SOx emissions, and water consumption, respectively, across the ERCOT region for two different conversion scenarios.