A pangenomic atlas reveals eco-evolutionary dynamics that shape type VI secretion systems in plant-pathogenic Ralstonia.

Soilborne Ralstonia solanacearum species complex (RSSC) pathogens disrupt microbial communities as they invade roots and fatally wilt plants. RSSC pathogens secrete antimicrobial toxins using a type VI secretion system (T6SS). To investigate how evolution and ecology have shaped the T6SS of these bacterial pathogens, we analyzed the T6SS gene content and architecture across the RSSC and their evolutionary relatives. Our analysis reveals that two ecologically similar Burkholderiaceae taxa, xylem-pathogenic RSSC and Paracidovorax, have convergently evolved to wield large arsenals of T6SS toxins. To understand the mechanisms underlying genomic enrichment of T6SS toxins, we compiled an atlas of 1,066 auxiliary T6SS toxin clusters ("aux" clusters) across 99 high-quality RSSC genomes. We classified 25 types of aux clusters with toxins that predominantly target lipids, nucleic acids, or unknown cellular substrates. The aux clusters were located in diverse genetic neighborhoods and had complex phylogenetic distributions, suggesting frequent horizontal gene flow. Phages and other mobile genetic elements account for most of the aux cluster acquisition on the chromosome but very little on the megaplasmid. Nevertheless, RSSC genomes were more enriched in aux clusters on the megaplasmid. Although the single, ancestral T6SS was broadly conserved in the RSSC, the T6SS has been convergently lost in atypical, non-soilborne lineages. Overall, our data suggest dynamic interplay between the lifestyle of RSSC lineages and the evolution of T6SSes with robust arsenals of toxins. This pangenomic atlas poises the RSSC as an emerging, tractable model to understand the role of the T6SS in shaping pathogen populations.IMPORTANCEWe explored the eco-evolutionary dynamics that shape the inter-microbial warfare mechanisms of a globally significant plant pathogen, the Ralstonia solanacearum species complex. We discovered that most Ralstonia wilt pathogens have evolved extensive and diverse repertoires of type VI secretion system-associated antimicrobial toxins. These expansive toxin arsenals potentially enhance the ability of Ralstonia pathogens to invade plant microbiomes, enabling them to rapidly colonize and kill their host plants. We devised a classification system to categorize the Ralstonia toxins. Interestingly, many of the toxin gene clusters are encoded on mobile genetic elements, including prophages, which may be mutualistic symbionts that enhance the inter-microbial competitiveness of Ralstonia wilt pathogens. Moreover, our findings suggest that the convergent loss of this multi-gene trait contributes to genome reduction in two vector-transmitted lineages of Ralstonia pathogens. Our findings demonstrate that the interplay between microbial ecology and pathogen lifestyle shapes the evolution of a genetically complex antimicrobial weapon.

Study of Postacute Sequelae of COVID-19 Using Digital Wearables: Protocol for a Prospective Longitudinal Observational Study.

BACKGROUND: Postacute sequelae of COVID-19 (PASC) remain understudied in nonhospitalized patients. Digital wearables allow for a continuous collection of physiological parameters such as respiratory rate and oxygen saturation that have been predictive of disease trajectories in hospitalized patients. OBJECTIVE: This protocol outlines the design and procedures of a prospective, longitudinal, observational study of PASC that aims to identify wearables-collected physiological parameters that are associated with PASC in patients with a positive diagnosis. METHODS: This is a single-arm, prospective, observational study of a cohort of 550 patients, aged 18 to 65 years, male or female, who own a smartphone or a tablet that meets predetermined Bluetooth version and operating system requirements, speak English, and provide documentation of a positive COVID-19 test issued by a health care professional within 5 days before enrollment. The primary end point is long COVID-19, defined as ≥1 symptom at 3 weeks beyond the first symptom onset or positive diagnosis, whichever comes first. The secondary end point is chronic COVID-19, defined as ≥1 symptom at 12 weeks beyond the first symptom onset or positive diagnosis. Participants must be willing and able to consent to participate in the study and adhere to study procedures for 6 months. RESULTS: The first patient was enrolled in October 2021. The estimated year for publishing the study results is 2025. CONCLUSIONS: This is a fully decentralized study investigating PASC using wearable devices to collect physiological parameters and patient-reported outcomes. The study will shed light on the duration and symptom manifestation of PASC in nonhospitalized patient subgroups and is an exemplar of the use of wearables as population-level monitoring health tools for communicable diseases. TRIAL REGISTRATION: ClinicalTrials.gov NCT04927442; https://clinicaltrials.gov/study/NCT04927442. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/57382.

Rapid and sensitive determination of residual prion infectivity from prion-decontaminated surfaces.

Prion diseases are untreatable fatal transmissible neurodegenerative diseases that affect a wide range of mammals, including humans, and are caused by PrPSc, the infectious self-templating conformation of the host-encoded protein, PrPC. Prion diseases can be transmitted via surfaces (e.g., forceps, EEG electrodes) in laboratory and clinical settings. Here, we use a combination of surface swabbing and real-time quaking-induced conversion (RT-QuIC) to test for residual surface-associated prions following prion disinfection. We found that treatment of several prion-contaminated laboratory and clinically relevant surfaces with either water or 70% EtOH resulted in robust detection of surface-associated prions. In contrast, treatment of surfaces with sodium hypochlorite resulted in a failure to detect surface-associated prions. RT-QuIC analysis of prion-contaminated stainless steel wires paralleled the findings of the surface swab studies. Importantly, animal bioassay and RT-QuIC analysis of the same swab extracts are in agreement. We report on conditions that may interfere with the assay that need to be taken into consideration before using this technique. Overall, this method can be used to survey laboratory and clinical surfaces for prion infectivity following prion decontamination protocols.IMPORTANCEPrion diseases can be accidentally transmitted in clinical and occupational settings. While effective means of prion decontamination exist, methods for determining the effectiveness are only beginning to be described. Here, we analyze surface swab extracts using real-time quaking-induced conversion (RT-QuIC) to test for residual prions following prion disinfection of relevant clinical and laboratory surfaces. We found that this method can rapidly determine the efficacy of surface prion decontamination. Importantly, examination of surface extracts with RT-QuIC and animal bioassay produced similar findings, suggesting that this method can accurately assess the reduction in prion titer. We identified surface contaminants that interfere with the assay, which may be found in clinical and laboratory settings. Overall, this method can enhance clinical and laboratory prion safety measures.

Prior Bariatric Surgery Is Associated With Improved Total Hip Arthroplasty Outcomes in Patients Who Have Obesity: A National Cohort Study With 6 Years of Follow-Up.

BACKGROUND: Obesity is a risk factor for end-stage hip osteoarthritis. While total hip arthroplasty (THA) is commonly performed to reduce pain and improve function associated with osteoarthritis, obesity has been associated with an increased risk of complications after THA. Although bariatric surgery may also be utilized to reduce weight, the impact of bariatric surgery on THA outcomes remains inadequately understood. METHODS: This retrospective cohort analysis utilized multicenter electronic medical record data ranging from 2003 to 2023. Patients who have obesity who underwent THA were stratified based on prior bariatric surgery. The final bariatric cohort comprised 451 patients after propensity score matching. Complication rates and revision risks were compared between cohorts at 6, 24, and 72 months. Additional analysis stratified patients by interval between bariatric surgery and THA. RESULTS: At 6-month follow-up, the bariatric cohort had significantly lower risks of surgical site infection, wound dehiscence, and deep vein thrombosis (DVT). At 24 months, the bariatric cohort had a lower risk of DVT. At 72-month follow-up, the bariatric cohort had reduced rates of revision, mortality, cardiac morbidity, and Clavien-Dindo grade IV complications. CONCLUSIONS: Obese patients who underwent bariatric surgery prior to THA experienced reduced medical complications at all time points and reduced rates of revision at 72 months relative to a matched cohort who did not undergo bariatric surgery.

Neoadjuvant combination treatment with checkpoint inhibitors, chemotherapy, and BRAF/MEK inhibitors for BRAFV600E glioblastoma results in sustained response: A case report.

Radiation's confounding and adverse effects on tumor microenvironment and normal brain could potentially be delayed by upfront combination treatment. We present a patient with newly diagnosed BRAF V600E-mutant, PD-L1-positive glioblastoma treated with off-label RAF/MEK inhibitors encorafenib/binimetinib after progressing on postoperative immune checkpoint blockade and temozolomide (no radiation administered: NCT03425292). Complete response occurred 6 months after adding encorafenib/binimetinib, and clinical benefit was sustained for over 20 months. Treatment was well tolerated with manageable toxicities, with quality of life and cognitive function maintained throughout treatment. Adding encorafenib/binimetinib to immunotherapy and temozolomide conferred favorable and lasting efficacy for our BRAF V600E -mutant glioblastoma patient, justifying future studies.

Decoding the Reference Letter: Strategies to Reduce Unintentional Gender Bias in Letters of Recommendation.

Introduction: There is a growing body of literature on gender bias in letters of recommendation (LORs) in academic medicine and the negative effect of bias on promotion and career advancement. Thus, increasing knowledge about gender bias and developing skills to mitigate it is important for advancing gender equity in medicine. This workshop aims to provide participants with knowledge about linguistic bias (focused on gender), how to recognize it, and strategies to apply to mitigate it when writing LORs. Methods: We developed an interactive 60-minute workshop for faculty and graduate medical education program directors consisting of didactics, reflection exercises, and group activities. We used a postworkshop survey to evaluate the effectiveness of the workshop. Descriptive statistics were used to analyze Likert-scale questions and a thematic content analysis for open-ended prompts. Results: We presented the workshop four times (two local and two national conferences) with one in-person and one virtual format for each. There were 50 participants who completed a postworkshop survey out of 74 total participants (68% response rate). Ninety-nine percent of participants felt the workshop met its educational objectives, and 100% felt it was a valuable use of their time. Major themes described for intended behavior change included utilization of the gender bias calculator, mindful use and balance of agentic versus communal traits, closer attention to letter length, and dissemination of this knowledge to colleagues. Discussion: This workshop was an effective method for helping participants recognize gender bias when writing LORs and learn strategies to mitigate it.

Co-regulation, relationship quality, and infant distress vocalizations observed during mother-infant interactions: Influences of maternal depression and different contexts.

Mother-infant interactions are co-regulated and provide the foundation for mother-infant relationship quality. The implications of maternal depression and contextual demands (i.e., reinstating the interaction following maternal unavailability and vocalized infant distress) on observationally coded co-regulation in mother-infant dyads (n = 40) at 4-months was investigated. Associations among co-regulation patterns and mother-infant relationship quality was also examined. Dyads participated in Still-Face (SF) and Separation (SP) procedures, with periods of maternal emotional and physical unavailability. Co-regulation was captured using the Revised Relational Coding System. Relationship quality was examined using the Emotional Availability Scales. Dyads in the depressed group had significantly more unilateral exchanges than the non-depressed group following the SF and SP perturbations. The depressed group also had significantly more distress vocalizations during the SP perturbation than the non-depressed group. Co-regulation in the depressed group was less disrupted by the SF perturbation. Positive relationship quality dimensions (maternal sensitivity, structuring, and infant responsiveness) were associated with more symmetrical and less unilateral co-regulation regardless of the interaction period. There were also context-specific results pertaining to patterns of co-regulation and associated maternal hostility and infant responsiveness. Results highlight co-regulatory differences in depressed mothers and their infants and how these differences are exacerbated by contextual demands.

Land use modulates resistance of grasslands against future climate and inter-annual climate variability in a large field experiment.

Climate and land-use change are key drivers of global change. Full-factorial field experiments in which both drivers are manipulated are essential to understand and predict their potentially interactive effects on the structure and functioning of grassland ecosystems. Here, we present 8 years of data on grassland dynamics from the Global Change Experimental Facility in Central Germany. On large experimental plots, temperature and seasonal patterns of precipitation are manipulated by superimposing regional climate model projections onto background climate variability. Climate manipulation is factorially crossed with agricultural land-use scenarios, including intensively used meadows and extensively used (i.e., low-intensity) meadows and pastures. Inter-annual variation of background climate during our study years was high, including three of the driest years on record for our region. The effects of this temporal variability far exceeded the effects of the experimentally imposed climate change on plant species diversity and productivity, especially in the intensively used grasslands sown with only a few grass cultivars. These changes in productivity and diversity in response to alterations in climate were due to immigrant species replacing the target forage cultivars. This shift from forage cultivars to immigrant species may impose additional economic costs in terms of a decreasing forage value and the need for more frequent management measures. In contrast, the extensively used grasslands showed weaker responses to both experimentally manipulated future climate and inter-annual climate variability, suggesting that these diverse grasslands are more resistant to climate change than intensively used, species-poor grasslands. We therefore conclude that a lower management intensity of agricultural grasslands, associated with a higher plant diversity, can stabilize primary productivity under climate change.

Social Determinants of Health in Cardio-Oncology: Multi-Level Strategies to Overcome Disparities in Care: JACC: CardioOncology State-of-the-Art Review.

Addressing the need for more equitable cardio-oncology care requires attention to existing disparities in cardio-oncologic disease prevention and outcomes. This is particularly important among those affected by adverse social determinants of health (SDOH). The intricate relationship of SDOH, cancer diagnosis, and outcomes from cardiotoxicities associated with oncologic therapies is influenced by sociopolitical, economic, and cultural factors. Furthermore, mechanisms in cell signaling and epigenetic effects on gene expression link adverse SDOH to cancer and the CVD-related complications of oncologic therapies. To mitigate these disparities, a multifaceted strategy is needed that includes attention to health care access, policy, and community engagement for improved disease screening and management. Interdisciplinary teams must also promote cultural humility and competency and leverage new health technology to foster collaboration in addressing the impact of adverse SDOH in cardio-oncologic outcomes.

Percent Final Height Is a Novel Method That Identifies Differences Between the Rate of Development in American Children of Different Races.

INTRODUCTION: The Greulich & Pyle (G&P) Radiographic Atlas of Skeletal Development uses hand x-rays obtained between 1926 and 1942 on children of Caucasian ancestry. Our study uses modern Caucasian, Black, Hispanic, and Asian children to investigate patterns of development as a function of percent final height (PFH). METHODS: A retrospective review, at a single institution, was conducted using children who received a hand x-ray, a height measurement taken within 60 days of that x-ray, and a final height. BA and CA were compared between races. PFH was calculated by dividing height at the time of the x-ray by their final height. To further evaluate differences between races in CA or BA, PFH was then modeled as a function of CA or BA using a fifth-degree polynomial regression, and mean ages at the 85th PFH were compared. Patients were then divided into Sanders stages 1, 2-4, and 5-8 and the mean PFH, CA, and BA of the Asian, Black, and Hispanic children were compared with the White children using Student t test. P values less than 0.05 were considered significant. RESULTS: We studied 498 patients, including 53 Asian, 83 Black, 190 Hispanic, and 172 White patients. Mean BA was significantly greater than CA in Black males (1.27 y) and females (1.36 y), Hispanic males (1.12 y) and females (1.29 y), and White females (0.74 y). Hispanic and Black patients were significantly more advanced in BA than White patients (P<0.001). At the 85th PFH, White and Hispanic males were older than Black males by at least 7 months (P<0.001), and White females were significantly older than Hispanic females by 6.4 months (P<0.001). At 85th PFH for males, Hispanic and Black males had greater BA than White males by at least 5 months (P<0.001), and Asian females had a greater BA than Black females by at least 5 months (P<0.001). Compared with White children, Hispanic children were significantly younger at Sanders 2-4 than White children, and Black children were skeletally older at Sanders 5-8. CONCLUSIONS: BA was greater than CA by ≥1 year in Black and Hispanic children, and that these children had a significantly greater BA than their White counterparts. Black males and Hispanic females reached their 85th PFH at younger ages, and Hispanic males and Asian females were the most skeletally mature at their 85th PFH. Our results suggest that BA and CA may vary as a function of race, and further studies evaluating growth via the 85th PFH may be necessary. LEVEL OF EVIDENCE: Therapeutic Study - Level IV.

Supporting the Nurse Preceptor Role: Implementing the R2C2 Feedback Model.

Nurse preceptors are key to the successful transition of graduate nurses to practice and experienced nurses to a new organization. Providing ongoing preceptor development is essential to support nurses in this vital role. The evidence-based R2C2 (relationship, reaction, content, coach) feedback and coaching model was implemented to facilitate the delivery of constructive feedback from nurse preceptors to their orientees. Post-intervention survey results suggest an overall positive response to the use of the feedback model in practice.

Intraspecific variation in pollination ecology due to altitudinal environmental heterogeneity.

Plant-pollinator interactions are constrained by floral traits and available pollinators, both of which can vary across environmental gradients, with consequences for the stability of the interaction. Here, we quantified how the pollination ecology of a high-mountain hummingbird-pollinated plant changes across a progressively more stressful environmental gradient of the Venezuelan Andes. We compared pollination ecology between two populations of this plant: Piedras Blancas (PB) and Gavidia (GV), 4450 and 3600 m asl, respectively. We hypothesised that self-compatibility might be higher at the higher altitude site, however we found that flowers showed similar capacities for self-compatibility in both localities. Seed production by flowers exposed to natural pollinators was significantly higher in the lower locality, where we also found higher nectar quality, larger flowers and increased frequencies of pollinator visitations. Interestingly, the population energy offered in the nectar was the same for both localities due to the higher density and floral aggregation found in the higher altitude population. Our study demonstrates how two plant populations in different environmental conditions have different pollination ecology strategies. Pollinator visitations or their absence result in trait associations in one population that are independent in the other. These population differences are not explained by differences in pollinator assembly, but by environmental heterogeneity.

Forecasting the Economic Burden of Cardiovascular Disease and Stroke in the United States Through 2050: A Presidential Advisory From the American Heart Association.

BACKGROUND: Quantifying the economic burden of cardiovascular disease and stroke over the coming decades may inform policy, health system, and community-level interventions for prevention and treatment. METHODS: We used nationally representative health, economic, and demographic data to project health care costs attributable to key cardiovascular risk factors (hypertension, diabetes, hypercholesterolemia) and conditions (coronary heart disease, stroke, heart failure, atrial fibrillation) through 2050. The human capital approach was used to estimate productivity losses from morbidity and premature mortality due to cardiovascular conditions. RESULTS: One in 3 US adults received care for a cardiovascular risk factor or condition in 2020. Annual inflation-adjusted (2022 US dollars) health care costs of cardiovascular risk factors are projected to triple between 2020 and 2050, from $400 billion to $1344 billion. For cardiovascular conditions, annual health care costs are projected to almost quadruple, from $393 billion to $1490 billion, and productivity losses are projected to increase by 54%, from $234 billion to $361 billion. Stroke is projected to account for the largest absolute increase in costs. Large relative increases among the Asian American population (497%) and Hispanic American population (489%) reflect the projected increases in the size of these populations. CONCLUSIONS: The economic burden of cardiovascular risk factors and overt cardiovascular disease in the United States is projected to increase substantially in the coming decades. Development and deployment of cost-effective programs and policies to promote cardiovascular health are urgently needed to rein in costs and to equitably enhance population health.

A systematic review and meta-analysis of pediatric integrated primary care for the prevention and treatment of physical and behavioral health conditions.

OBJECTIVE: To evaluate the effects of behavioral health interventions delivered within pediatric integrated primary care models on clinical outcomes. METHODS: We searched Medline, EMBASE, CENTRAL, PsycINFO, and SCOPUS for studies published from January 1, 1998, to September 20, 2023. We included studies that evaluated onsite behavioral health integration in pediatric primary care using a comparator condition (usual, enhanced usual care, or waitlist). Outcome data on symptom change, impairment/quality of life, health indicator, and behavior change were extracted using Covidence software. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guideline was followed Risk of bias analysis was conducted using the Cochrane Risk of Bias tool. We used multilevel meta-analysis to synthesize multiple outcomes nested within studies. Open Science Foundation pre-registration: #10.17605/OSF.IO/WV7XP. RESULTS: In total, 33 papers representing 27 studies involving 6,879 children and caregivers were included. Twenty-four studies were randomized controlled trials and three were quasi-experimental designs. Seventeen papers reported on treatment trials and 16 reported on prevention trials. We found a small overall effect size (SMD = 0.19, 95% confidence interval [0.11, 0.27]) supporting the superiority of integrated primary care to usual or enhanced usual care. Moderator analyses suggested similar effectiveness between co-located and integrated models and no statistically significant differences were found between treatment and prevention trials. CONCLUSIONS: Results suggest that integrated primary care is superior to usual and enhanced usual care at improving behavior, quality of life, and symptoms. Integrated primary care research needs improved standards for reporting to promote better synthesis and understanding of the literature.

Racial and ethnic diversity in academic nursing leadership: A cross-sectional analysis.

BACKGROUND/PURPOSE: To characterize the representation of racial and ethnic minoritized faculty in leadership positions at the top 50 National Institutes of Health-ranked academic nursing institutions. METHODS: We conducted a cross-sectional observational study to characterize the racial/ethnic composition of academic leaders, including those in diversity, equity, and inclusion (DEI) positions from September 2020 to December 2020. DISCUSSION: Among the 409 leaders, the sample was predominantly composed of females (86.6%), White leaders (80.9%), affiliated with public institutions (75.1%), and in the southern region (42.1%). Exactly 13.6% were from minoritized groups. Minoritized leaders were less likely to hold dean and higher executive positions than their nonminoritized counterparts (p < .002). DEI leadership positions were mostly concentrated in lower executive positions (e.g., director) and primarily consisted of minoritized leaders (>60%). CONCLUSION: Underrepresentation of racial and ethnic minoritized individuals in academic nursing leadership persists, necessitating structural interventions within nursing academia to promote inclusivity. Achieving this goal requires a concerted investment in diversifying academic nursing leadership and ensuring positions that minoritized leaders are in, hold weight.

Pediatric Trauma Center Access, Regional Injury Burden, and Socioeconomic Disadvantage.

This cross-sectional study assesses whether populations in socioeconomically disadvantaged regions in the US lack timely access to pediatric trauma centers.

Multi-modal mechanisms of the metastasis suppressor, NDRG1: Inhibition of WNT/ß-catenin signaling by stabilization of protein kinase Cα.

The metastasis suppressor, N-myc downstream regulated gene-1 (NDRG1), inhibits pro-oncogenic signaling in pancreatic cancer (PC). This investigation dissected a novel mechanism induced by NDRG1 on WNT/ß-catenin signaling in multiple PC cell types. NDRG1 overexpression decreased ß-catenin and downregulated glycogen synthase kinase-3ß (GSK-3ß) protein levels and its activation. However, ß-catenin phosphorylation at Ser33, Ser37, and Thr41 are classically induced by GSK-3ß was significantly increased after NDRG1 overexpression, suggesting a GSK-3ß-independent mechanism. Intriguingly, NDRG1 overexpression upregulated protein kinase Cα (PKCα), with PKCα silencing preventing ß-catenin phosphorylation at Ser33, Ser37, and Thr41, and decreasing ß-catenin expression. Further, NDRG1 and PKCα were demonstrated to associate, with PKCα stabilization occurring after NDRG1 overexpression. PKCα half-life increased from 1.5 ± 0.8 h (3) in control cells to 11.0 ± 2.5 h (3) after NDRG1 overexpression. Thus, NDRG1 overexpression leads to the association of NDRG1 with PKCα and PKCα stabilization, resulting in ß-catenin phosphorylation at Ser33, Ser37, and Thr41. The association between PKCα, NDRG1, and ß-catenin was identified, with the formation of a potential metabolon that promotes the latter ß-catenin phosphorylation. This anti-oncogenic activity of NDRG1 was multi-modal, with the above mechanism accompanied by the downregulation of the nucleo-cytoplasmic shuttling protein, p21-activated kinase 4 (PAK4), which is involved in ß-catenin nuclear translocation, inhibition of AKT phosphorylation (Ser473), and decreased ß-catenin phosphorylation at Ser552 that suppresses its transcriptional activity. These mechanisms of NDRG1 activity are important to dissect to understand the marked anti-cancer efficacy of NDRG1-inducing thiosemicarbazones that upregulate PKCα and inhibit WNT signaling.

An ethologically relevant paradigm to assess defensive response to looming visual contrast stimuli.

In the animal kingdom, threat information is perceived mainly through vision. The subcortical visual pathway plays a critical role in the rapid processing of visual information-induced fear, and triggers a response. Looming-evoked behavior in rodents, mimicking response to aerial predators, allowed identify the neural circuitry underlying instinctive defensive behaviors; however, the influence of disk/background contrast on the looming-induced behavioral response has not been examined, either in rats or mice. We studied the influence of the dark disk/gray background contrast in the type of rat and mouse defensive behavior in the looming arena, and we showed that rat and mouse response as a function of disk/background contrast adjusted to a sigmoid-like relationship. Both sex and age biased the contrast-dependent response, which was dampened in rats submitted to retinal unilateral or bilateral ischemia. Moreover, using genetically manipulated mice, we showed that the three type of photoresponsive retinal cells (i.e., cones, rods, and intrinsically photoresponsive retinal ganglion cells (ipRGCs)), participate in the contrast-dependent response, following this hierarchy: cones > > rods > > > ipRGCs. The cone and rod involvement was confirmed using a mouse model of unilateral non-exudative age-related macular degeneration, which only damages canonical photoreceptors and significantly decreased the contrast sensitivity in the looming arena.

Demographic trends of cardiorenal and heart failure deaths in the United States, 2011-2020.

BACKGROUND: Heart failure (HF) and kidney disease frequently co-occur, increasing mortality risk. The cardiorenal syndrome results from damage to either the heart or kidney impacting the other organ. The epidemiology of cardiorenal syndrome among the general population is incompletely characterized and despite shared risk factors with HF, differences in mortality risk across key demographics have not been well described. Thus, the primary goal of this study was to analyze annual trends in cardiorenal-related mortality, evaluate if these trends differed by age, sex, and race or ethnicity, and describe these trends against a backdrop of HF mortality. METHODS AND FINDINGS: The Centers for Disease Control and Prevention Wide-ranging ONline Data for Epidemiologic Research database was used to examine cardiorenal- and HF-related mortality in the US between 2011and 2020. International Classification of Diseases, 10 Revision codes were used to classify cardiorenal-related deaths (I13.x) and HF-related deaths (I11.0, I13.0, I13.2, and I50.x), among decedents aged 15 years or older. Decedents were further stratified by age group, sex, race, or ethnicity. Crude and age-adjusted mortality rates (AAMR) per 100,000 persons were calculated. A total of 97,135 cardiorenal-related deaths and 3,453,655 HF-related deaths occurred. Cardiorenal-related mortality (AAMR, 3.26; 95% CI: 3.23-3.28) was significantly lower than HF-related mortality (AAMR, 115.7; 95% CI: 115.6-115.8). The annual percent change (APC) was greater and increased over time for cardiorenal-related mortality (2011-2015: APC, 7.1%; 95% CI: 0.7-13.9%; 2015-2020: APC, 19.7%, 95% CI: 16.3-23.2%), whereas HF-related mortality also increased over that time period, but at a consistently lower rate (2011-2020: APC, 2.4%; 95% CI: 1.7-3.1%). Mortality was highest among older and male decedents for both causes. Cardiorenal-related deaths were more common in non-Hispanic or Latino Blacks compared to Whites, but similar rates were observed for HF-related mortality. A larger proportion of cardiorenal-related deaths, compared to HF-related deaths, listed cardiorenal syndrome as the underlying cause of death (67.0% vs. 1.2%). CONCLUSIONS: HF-related deaths substantially outnumber cardiorenal-related deaths; however, cardiorenal-related deaths are increasing at an alarming rate with the highest burden among non-Hispanic or Latino Blacks. Continued surveillance of cardiorenal-related mortality trends is critical and future studies that contain detailed biomarker and social determinants of health information are needed to identify mechanisms underlying differences in mortality trends.

Prehospital Care for Persons Experiencing Homelessness: A Cross-Sectional Survey of the Challenges, Experiences, and Perspectives of Operational EMS Agency Medical Directors.

OBJECTIVE: Persons experiencing homelessness (PEH) are among the most vulnerable populations and experience significant health disparities. Nationally, PEH utilize Emergency Medical Services (EMS) at disproportionately higher rates than their housed peers. Developing optimal strategies to care for PEH has become critically important. However, limited data exists on best practices, challenges, and experiences of providing care to PEH. The objective of this study was to describe the experiences, challenges and perspectives of operational EMS agency medical directors in Los Angeles (LA) County as they confront the homelessness crisis. METHODS: We performed a cross-sectional survey of 9-1-1 operational EMS agency medical directors in LA County, which has one of the largest populations of PEH nationally. Twenty-nine 9-1-1 operational EMS agencies operate in LA County. The link to an anonymous, web-based survey examining documentation, training, resources, operational impact, and care challenges was emailed to medical directors with three reminders during the study period (4/19/2023-9/15/2023). RESULTS: Three quarters (75.9%; 22/29) of operational EMS agencies responded to the survey, with all questions answered in 69% (20/29) of surveys. Of these, 68.2% (15/22) of agencies document housing status and 75% (15/20) agreed or strongly agreed that homelessness presents operational challenges. No operational EMS agency reported adequate EMS clinician training on homelessness. Operational EMS agencies most commonly utilized domestic violence resources (43%, 9/21), social services (38%, 8/21), and law enforcement (38%, 8/21) services to assist PEH. Referrals were limited by accessibility (86%, 18/21), time (52%, 11/21), lack of awareness (52% 11/21) and lack of mandates (52%, 11/21). All operational EMS agencies agreed or strongly agreed that mental health and substance use disorders are major issues for PEH. The most common daily challenges reported were mental health (55%, 11/20), substance use (55%, 11/20), and patient resistance (35%, 7/20). CONCLUSION: In LA County, EMS agencies experience important operational and clinical challenges in caring for PEH, with limited resources, minimal training, and high rates of substance use disorders and mental health comorbidities. Further prehospital research is essential to standardize documentation of housing status, to identify areas for intervention, increase linkage to services, and define best practices.