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One in every twenty-five persons in America is a racial/ethnic minority who lives in a rural area. Our objective was to summarize how racism and, subsequently, the social determinants of health disproportionately affect rural racial/ethnic minority populations, provide a review of the cancer disparities experienced by rural racial/ethnic minority groups, and recommend policy, research, and intervention approaches to reduce these disparities. We found that rural Black and American Indian/Alaska Native populations experience greater poverty and lack of access to care, which expose them to greater risk of developing cancer and experiencing poorer cancer outcomes in treatment and ultimately survival. There is a critical need for additional research to understand the disparities experienced by all rural racial/ethnic minority populations. We propose that policies aim to increase access to care and healthcare resources for these communities. Further, that observational and interventional research should more effectively address the intersections of rurality and race/ethnicity through reduced structural and interpersonal biases in cancer care, increased data access, more research on newer cancer screening and treatment modalities, and continued intervention and implementation research to understand how evidence-based practices can most effectively reduce disparities among these populations.

Objectives. To examine rural-urban disparities in overall mortality and leading causes of death across Hispanic (any race) and non-Hispanic White, Black, American Indian/Alaska Native (AI/AN), and Asian/Pacific Islander populations. Methods. We performed a retrospective analysis of age-adjusted death rates for all-cause mortality and 5 leading causes of death (cardiovascular, cancer, unintentional injuries, chronic lower respiratory disease, and stroke) by rural versus urban county of residence in the United States and race/ethnicity for the period 2013 to 2017. Results. Rural populations, across all racial/ethnic groups, had higher all-cause mortality rates than did their urban counterparts. Comparisons within causes of death documented rural disparities for all conditions except cancer and stroke among Hispanic individuals; Hispanic rural residents had death rates similar to or lower than urban residents. Rural Black populations experienced the highest mortality for cardiovascular disease, cancer, and stroke. Unintentional injury and chronic lower respiratory disease mortality were highest in rural AI/AN and rural non-Hispanic White populations, respectively. Conclusions. Investigating rural-urban disparities without also considering race/ethnicity leaves minority health disparities unexamined and thus unaddressed. Further research is needed to clarify local factors associated with these disparities and to test appropriate interventions.

To examine the associations between adverse childhood experiences (ACEs) and children’s obesogenic behaviors (meeting recommendations for sleep duration and screen time) in a representative sample of U.S. children and adolescents. This study assessed data from the 2019–2020 National Survey of Children’s Health. Separate multinomial logistic regressions examined the likelihood of failing to meet sleep and screen time recommendations given individual and cumulative ACE scores. 15,581 children (48% female, 32% non-White) experienced one ACE, representing 32% of the analyzed sample. Parents reported financial hardship as the most prevalent ACE (48%). After adjusting for child race/ethnicity, sex of the child, highest education in the household, and child age, we found that participants with four or more ACEs were (1) age-specific sleep recommendations compared with participants with zero ACEs (OR 1.96; 95%CI = 1.64–2.35), and (2) more likely to fall short of meeting screen use recommendations compared with participants with zero ACEs (OR 1.61; 95%CI = 1.26–2.07). U.S. children and adolescents who have experienced four or more ACEs are significantly more likely to fall short of sleep and screen time recommendations compared to their counterparts who experienced zero ACEs. Given the strong associations between ACEs and health outcomes in adulthood, screening for ACEs may better inform practitioners when attempting to improve youth health outcomes.

In this randomized, double-blind trial in 1062 adults hospitalized with Covid-19, remdesivir was superior to placebo in shortening the time to recovery (10 days, vs. 15 days with placebo). The estimates of mortality by day 29 were 11.4% with remdesivir and 15.2% with placebo. The benefit of remdesivir was most apparent in patients who were receiving low-flow oxygen at baseline.

Germinal matrix hemorrhage (GMH) is a devastating neurodevelopmental condition affecting preterm infants, but why blood vessels in this brain region are vulnerable to rupture remains unknown. Here we show that microglia in prenatal mouse and human brain interact with nascent vasculature in an age-dependent manner and that ablation of these cells in mice reduces angiogenesis in the ganglionic eminences, which correspond to the human germinal matrix. Consistent with these findings, single-cell transcriptomics and flow cytometry show that distinct subsets of CD45 + cells from control preterm infants employ diverse signaling mechanisms to promote vascular network formation. In contrast, CD45 + cells from infants with GMH harbor activated neutrophils and monocytes that produce proinflammatory factors, including azurocidin 1, elastase and CXCL16, to disrupt vascular integrity and cause hemorrhage in ganglionic eminences. These results underscore the brain’s innate immune cells in region-specific angiogenesis and how aberrant activation of these immune cells promotes GMH in preterm infants. Chen et al. show that subtypes of immune cells in prenatal human brain promote angiogenesis in the germinal matrix. Conversely, in preterm infants, proinflammatory immune cells disrupt angiogenesis and promote germinal matrix hemorrhage.

Background Eating disorders (EDs) are potentially severe, complex, and life-threatening illnesses. The mortality rate of EDs is significantly elevated compared to other psychiatric conditions, primarily due to medical complications and suicide. The current rapid review aimed to summarise the literature and identify gaps in knowledge relating to any psychiatric and medical comorbidities of eating disorders. Methods This paper forms part of a rapid review) series scoping the evidence base for the field of EDs, conducted to inform the Australian National Eating Disorders Research and Translation Strategy 2021–2031, funded and released by the Australian Government. ScienceDirect, PubMed and Ovid/Medline were searched for English-language studies focused on the psychiatric and medical comorbidities of EDs, published between 2009 and 2021. High-level evidence such as meta-analyses, large population studies and Randomised Control Trials were prioritised. Results A total of 202 studies were included in this review, with 58% pertaining to psychiatric comorbidities and 42% to medical comorbidities. For EDs in general, the most prevalent psychiatric comorbidities were anxiety (up to 62%), mood (up to 54%) and substance use and post-traumatic stress disorders (similar comorbidity rates up to 27%). The review also noted associations between specific EDs and non-suicidal self-injury, personality disorders, and neurodevelopmental disorders. EDs were complicated by medical comorbidities across the neuroendocrine, skeletal, nutritional, gastrointestinal, dental, and reproductive systems. Medical comorbidities can precede, occur alongside or emerge as a complication of the ED. Conclusions This review provides a thorough overview of the comorbid psychiatric and medical conditions co-occurring with EDs. High psychiatric and medical comorbidity rates were observed in people with EDs, with comorbidities contributing to increased ED symptom severity, maintenance of some ED behaviours, and poorer functioning as well as treatment outcomes. Early identification and management of psychiatric and medical comorbidities in people with an ED may improve response to treatment and overall outcomes. Plain English Summary The mortality rate of eating disorders is significantly elevated compared to other psychiatric conditions, primarily due to medical complications and suicide. Further, individuals with eating disorders often meet the diagnostic criteria of at least one comorbid psychiatric or medical disorder, that is, the individual simultaneously experiences both an ED and at least one other condition. This has significant consequences for researchers and health care providers – medical and psychiatric comorbidities impact ED symptoms and treatment effectiveness. The current review is part of a larger Rapid Review series conducted to inform the development of Australia’s National Eating Disorders Research and Translation Strategy 2021–2031. A Rapid Review is designed to comprehensively summarise a body of literature in a short timeframe, often to guide policymaking and address urgent health concerns. The Rapid Review synthesises the current evidence base and identifies gaps in eating disorder research and care. This paper gives a critical overview of the scientific literature relating to the psychiatric and medical comorbidities of eating disorders. It covers recent literature regarding psychiatric comorbidities including anxiety disorders, mood disorders, substance use disorders, trauma and personality disorders and neurodevelopmental disorders. Further, the review discusses the impact and associations between EDs and medical comorbidities, some of which precede the eating disorder, occur alongside, or as a consequence of the eating disorder.

PARP inhibitor (PARPi) therapy has transformed outcomes for patients with homologous recombination DNA repair (HRR) deficient ovarian cancers, for example those with BRCA1 or BRCA2 gene defects. Unfortunately, PARPi resistance is common. Multiple resistance mechanisms have been described, including secondary mutations that restore the HR gene reading frame. BRCA1 splice isoforms △11 and △11q can contribute to PARPi resistance by splicing out the mutation-containing exon, producing truncated, partially functional proteins. However, the clinical impacts and underlying drivers of BRCA1 exon skipping are not fully understood. We analyzed nine ovarian and breast cancer patient derived xenografts (PDX) with BRCA1 exon 11 frameshift mutations for exon skipping and therapy response, including a matched PDX pair derived from a patient pre- and post-chemotherapy/PARPi. BRCA1 exon 11 skipping was elevated in PARPi resistant PDX tumors. Two independent PDX models acquired secondary BRCA1 splice site mutations (SSMs) that drive exon skipping, confirmed using qRT-PCR, RNA sequencing, immunoblotting and minigene modelling. CRISPR/Cas9-mediated disruption of splicing functionally validated exon skipping as a mechanism of PARPi resistance. SSMs were also enriched in post-PARPi ovarian cancer patient cohorts from the ARIEL2 and ARIEL4 clinical trials. Few PARPi resistance mechanisms have been confirmed in the clinical setting. While secondary/reversion mutations typically restore a gene’s reading frame, we have identified secondary mutations in patient cohorts that hijack splice sites to enhance mutation-containing exon skipping, resulting in the overexpression of BRCA1 hypomorphs, which in turn promote PARPi resistance. Thus, BRCA1 SSMs can and should be clinically monitored, along with frame-restoring secondary mutations.

Targeting parasite's protein kinaseMalaria elimination goals are constantly eroded by the challenge of emerging drug and insecticide resistance. Alam et al. have taken established drug targets—CLK protein kinases involved in regulation of RNA splicing—and investigated how inhibition of the parasite's enzymes blocks completion of its complex life cycle. They identified an inhibitor of the parasite's CLK protein kinase that was 100-fold less active against the most closely related human protein kinase and effective at clearing rodent malaria parasites. Not only does this compound halt the development of sexual stages but it also limits transmission to the mosquito vector of the parasite, a key requirement for malaria drugs.Science, this issue p. eaau1682INTRODUCTIONDespite the positive effects of intervention strategies that include insecticide-impregnated bed nets and artemisinin-based drug therapies, malaria still kills nearly 500,000 people per year and infects more than 200 million individuals globally. This, together with the emerging resistance of the parasite to frontline antimalarials, means that there is an urgent need for novel treatments that not only offer a cure for malaria but also prevent transmission. We show that by inhibiting an essential protein kinase that is a key regulator of RNA processing, we are able to kill the parasite in the blood and liver stages as well as prevent the development of the sexual-stage gametocytes, thereby blocking transmission to the mosquito.RATIONALEOur group has previously published a list of 36 protein kinases that are essential for blood-stage survival of the most virulent form of the human malaria parasite, Plasmodium falciparum. Here, we focused on one of these protein kinases from the P. falciparum CLK (cyclin-dependent–like kinase) family, PfCLK3, and reasoned that inhibition of this protein kinase by a small drug-like molecule would be effective at killing blood-stage parasites. We further hypothesized that because PfCLK3 plays a key role in RNA splicing, inhibition of this kinase would be effective at killing the parasite at all stages of the life cycle where RNA splicing is required. This would include blood, liver, and sexual stages.RESULTSBy screening a focused library of nearly 30,000 compounds, we identified a probe molecule that selectively inhibited PfCLK3 and killed blood-stage P. falciparum. Using a combination of evolved resistance and chemogenetics, we established that our probe molecule had parasiticidal activity by inhibition of PfCLK3. We further showed that inhibition of PfCLK3 in parasites resulted in a reduction in more than 400 gene transcripts known to be essential for parasite survival. The finding that the vast majority of the genes down-regulated by PfCLK3 inhibition contained introns supported the notion that inhibition of PfCLK3 killed the malaria parasite by preventing the splicing of essential parasite genes. Because there is a high degree of homology between orthologs of CLK3 in other Plasmodium species, it might be expected that our probe molecule would both inhibit CLK3 contained in other malaria parasite species and have effective parasiticidal activity in these parasites. This was indeed found to be the case, with our molecule showing potent inhibition of CLK3 from P. vivax and P. berghei as well as killing the blood stages of P. berghei and P. knowlesi. Furthermore, we demonstrated that CLK3 inhibition also kills liver-stage P. berghei parasites and prevents P. berghei infection in mice. Finally, we showed that inhibition of PfCLK3 prevents the development of P. falciparum gametocytes, thereby blocking the infection of mosquitoes.CONCLUSIONWe found that inhibition of the essential malaria protein kinase CLK3 can kill multiple species of malaria parasites at the blood stage as well as killing liver-stage parasites and blocking transmission of the parasite to mosquitoes by preventing gametocyte development. In this way, we validate Plasmodium spp. CLK3 as a target that can offer prophylactic, curative, and transmission-blocking potential.The requirement for next-generation antimalarials to be both curative and transmission-blocking necessitates the identification of previously undiscovered druggable molecular pathways. We identified a selective inhibitor of the Plasmodium falciparum protein kinase PfCLK3, which we used in combination with chemogenetics to validate PfCLK3 as a drug target acting at multiple parasite life stages. Consistent with a role for PfCLK3 in RNA splicing, inhibition resulted in the down-regulation of more than 400 essential parasite genes. Inhibition of PfCLK3 mediated rapid killing of asexual liver- and blood-stage P. falciparum and blockade of gametocyte development, thereby preventing transmission, and also showed parasiticidal activity against P. berghei and P. knowlesi. Hence, our data establish PfCLK3 as a target for drugs, with the potential to offer a cure—to be prophylactic and transmission blocking in malaria.

End stage renal disease (ESRD) is associated with platelet dysfunction but also thromboembolic complications. The specific role of increased blood urea nitrogen (BUN) on coagulation is unclear. We aimed to characterize thromboelastography (TEG) parameters from males and females with ESRD and normal kidney function and evaluate if exogenous urea in vitro reproduced those TEG differences. We collected blood samples from 20 living kidney donors and 20 kidney recipients. TEG was performed without and with two increasing urea concentrations in vitro. TEG parameters were compared between recipients and donors. Blood from kidney recipients showed baseline increased maximum amplitude (MA) and shortened time to maximum amplitude (TMA) compared to donors. These differences were not confirmed in females. In all patients, BUN was inversely correlated with TMA (r = −0.342; p = 0.031). In males, BUN and creatinine concentrations showed a direct correlation with MA (0.583; p = 0.007) and an inverse correlation with TMA (r = −0.520; p = 0.019). Urea in vitro decreased R-time (p = 0.005) and increased LY30 (p = 0.009) in donors but not recipients. ESRD is associated with increased MA and decreased TMA on TEG. No change in MA was observed with increasing urea concentrations in vitro. Gender-specific variability in TEG parameters were observed. •No change in MA was observed with increasing urea concentrations in both donors and recipients•In all patients, BUN was inversely correlated with TMA•In males, BUN and creatinine concentrations showed a direct correlation with MA•Urea in vitro decreased R-time and increase LY30 in healthy kidney transplant donors but not recipients.

One in four liver transplants (LT) require return to the operating room(R-OR) within 48 h of surgery. We hypothesize that donor, recipient, and intraoperative factors will predict R-OR. LT recipients were enrolled in an observational study to measure coagulation with thrombelastography (TEG) were assessed with transplant recipient and donor variables for risk of R-OR. 160 recipients with a median age of 55 years and a MELD-Na of 22 were analyzed. R-OR occurred in 22%. Recipient BMI (p = 0.006), donor heavy alcohol use (p = 0.017), TEG MA (p = 0.013) during the anhepatic phase of surgery, TEG MA at anhepatic and 30-min after reperfusion (p < 0.05), and red blood cell transfusions (p < 0.001) were associated with R-OR. The vexing triad of recipient obesity, heavy donor alcohol use, and low TEG MA were associated with a high rate of R-OR. Strategies to reduce this sub-optimal combination of risk factors could reduce the frequency of unplanned re-operations. •Liver transplant recipient BMI greater than 30 and donor history of heavy alcohol use is associated with an 80% return rate to the operating room.•During liver transplantation, clot strength less than 45 mm during the anheptic and early reperfusion is associated with greater than 20 units of intraoperative blood loss and 80% return rate to the operating room.•The combination of coagulopathy, obesity, and donor alcohol heavy use is associated with an 100% rate of return to the operating room.