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Abstract Background Falls are a significant public health issue. There is strong evidence that exercise can prevent falls and the most effective programs are those that primarily involve balance and functional exercises, however uptake of such programs is low. Exercise prescribed during home visits by health professionals can prevent falls however this strategy would be costly to deliver at scale. We developed a new approach to teach home exercise through group-based workshops delivered by physiotherapists. The primary aim was to determine the effect of this approach on the rate of falls among older community-dwelling people over 12 months. Secondary outcomes included the proportion of people falling, fear of falling, physical activity, lower limb strength, balance and quality of life. Methods A randomised controlled trial was conducted among community-dwelling people aged ≥65 in New South Wales, Australia. Participants were randomised to either the intervention group (exercise targeting balance and lower limb strength) or control group (exercise targeting upper limb strength). Results A total of 617 participants (mean age 73 years, +SD 6, 64% female) were randomly assigned to the intervention group (n = 307) or control group (n = 310). There was no significant between-group difference in the rate of falls (IRR 0.91, 95% CI 0.64 to 1.29, n = 579, p = 0.604) or the number of participants reporting one or more falls (IRR 0.99, 95% CI 0.76 to 1.29, n = 579, p = 0.946) during 12 month follow-up. A significant improvement in the intervention group compared to control group was found for fear of falling at 3, 6 and 12 months (mean difference 0.50, 95% CI 0.2 to 0.8, p = 0.004; 0.39, 95% CI 0.001 to 0.8, p = 0.049; 0.46, 95% CI 0.006 to 0.9, p = 0.047, respectively), and gait speed at 3 months (mean difference 0.09 s, 95% CI 0.003 to 0.19, p = 0.043). No statistically significant between-group differences were detected for the other secondary outcomes. Conclusions There was no significant intervention impact on the rate of falls, but the program significantly reduced fear of falling and improved gait speed. Other exercise delivery approaches are needed to ensure an adequate intensity of balance and strength challenge and dose of exercise to prevent falls.

In contrast to the way economic history is often presented, our aim is to provide a concise coverage of economic growth in the UK in four short essays that are written for a general audience of non-economists. In this first essay, we explore the drastic change Britain underwent in the mid-18th century, as agriculture and traditional production methods began to mechanise, increasing productivity to exceed the limits of the land and human strength. For the first time, people witnessed increases in the standard of living within a generation as national wealth soared. It ended centuries of subsistence living in which growth was negligible. As the 19th century dawned, Britain welcomed the steam era, an ignition of modernity, transforming travel, trade and production. We shed light on the wider repercussions of Britain’s economic dominance, highlighting the consequences of rapid urbanisation and assessing the implications of the era of Imperial strength.

Abstract Background Primary photosensitization rarely occurs in horses and can easily be misinterpreted. Descriptions of the disease in horses after ingestion of parsnip are lacking. The aim of this case series was to describe the dermatological and ocular changes due to photosensitization and to raise awareness of parsnip being a possible aetiologic agent. Case presentation Nine horses from three different stables in Berlin and Brandenburg, Germany, presented variable degrees of erythema, scaling, crusting and necrosis of unpigmented skin at the head and prepuce. Horses were of different breeds with a median age of 15 ± 5.9 years. A mild leukocytosis was diagnosed in 1/9 horses at admission. Analyzed liver enzymes were within the reference ranges in all horses. Ocular changes were diagnosed as follows: blepharitis (3/9), conjunctivitis (7/9), corneal edema without additional signs of keratitis and/or uveitis (2/9), corneal edema with signs of uveitis (1/9) and photophobia (4/9). One horse developed a fluorescein positive corneal erosion. Skin biopsy (1/9) revealed a moderate to severe acute, eosinophilic and lymphocytic dermatitis with dermal edema and vasculitis. All stables housing these patients fed hay from the same distributer. Analyzed hay samples showed high contents of wild parsnip (plants, seeds, roots). Wild parsnip is widespread in Europe and contains furocoumarins, a family of photodynamic pigments, which may cause primary photodermatitis, keratoconjunctivitis and uveitis. Horses were treated according to severity of clinical symptoms systemically with flunixine meglumine (1.1 mg/kg BW 1-2x/day) or prednisolone (1 mg/kg BW 1x/day). Topically, either gentamicin (3x/day), dexamethasone (2-3x/day) and/or atropine (1x/day) were used. Skin care was provided with almond oil or dexpanthenol (2x/day). All horses were kept in a dark environment or were treated with sunscreen and facemasks. Duration of treatment varied from 6–30 days (median 11.3 days). Conclusion Ingestion of wild parsnip (Pastinaca sativa) can induce primary photosensitization with dermatitis and ocular injury in horses. In times of extreme weather, hay may alter in botanical composition, resulting in high amounts of uncharacteristic plants causing novel problems.

Purpose: Use administrative discharge data from 2018 to 2020 to determine if there are differences in the prevalence of hypertensive disorders of pregnancy (HDP) and gestational diabetes mellitus (GDM) by race and ethnicity in Illinois. Study Design and Methods: This retrospective cross-sectional study used administrative discharge records from all patients who had live births in Illinois over a 3-year period; 2018, 2019, 2020. Multivariate analyses were performed to control for covariates and determine if associations vary by race and ethnicity for HDP and GDM. Results: A total of 287,250 discharge records were included. Multivariate analyses showed that after adjusting for covariates, non-Hispanic Black women had 1.60 increased odds of HDP compared to non-Hispanic White women (OR, 1.60; 95% CI, 1.55-1.65). Hispanic women (OR, 1.45; 95% CI, 1.40-1.50), Asian/Pacific Islander women (OR, 2.07; 95% CI, 1.97-2.17), and American Indian/Alaska Native women (OR, 1.43; 95% CI, 1.17-1.74) had an increased odds of GDM compared to non-Hispanic White women. Clinical Implications: Women of color were at Increased odds for HDP and GDM In Illinois. To eliminate poor maternal outcomes in women of color at risk for HDP and GDM, more culturally congruent health equity practices, policies, and comprehensive care interventions must be adopted. [ABSTRACT FROM AUTHOR]

Biological variation (BV) describes the physiological random fluctuation around a homeostatic set point, which is a characteristic of all blood measurands (analytes). That variation may impact the clinical relevance of the changes that are observed in the serial results for an individual. Biological variation is represented mathematically by the coefficient of variation (CV) and occurs within each individual (CVI) and between individuals in a population (CVG). Biological variation data can be used to assess whether population-based reference or subject-based reference intervals should be used for the interpretation of laboratory results through the calculation of the index of individuality (IoI). This study aimed to determine the biological variations, calculate the IoI and reference change values (RCV) of clinical chemistry analytes in an outbred strain colony of Hartley guinea pigs (GPs), and set the quality specifications for clinical chemistry analytes. Blood was collected from 16 healthy adult laboratory colony GPs via jugular venipuncture at weekly intervals over six weeks. All the samples were frozen and analyzed in a single run. Analytical, CVI, and CVG biological variations, together with the IoI and RCV, were calculated for each measurand. Based on the estimated BV, the calculated IoI was low for glucose, so individual reference intervals (RCV) should be used. The majority of the measurands should be interpreted using both population-based and subject-based reference intervals as the IoIs were intermediate.

Fatigue-related subchondral bone injuries of the third metacarpal/metatarsal (McIII/MtIII) bones are common causes of wastage, and they are welfare concerns in racehorses. A better understanding of bone health and strength would improve animal welfare and be of benefit for the racing industry. The porosity index (PI) is an indirect measure of osseous pore size and number in bones, and it is therefore an interesting indicator of bone strength. MRI of compact bone using traditional methods, even with short echo times, fail to generate enough signal to assess bone architecture as water protons are tightly bound. Ultra-short echo time (UTE) sequences aim to increase the amount of signal detected in equine McIII/MtIII condyles. Cadaver specimens were imaged using a novel dual-echo UTE MRI technique, and PI was calculated and validated against quantitative CT-derived bone mineral density (BMD) measures. BMD and PI are inversely correlated in equine distal Mc/MtIII bone, with a weak mean r value of −0.29. There is a statistically significant difference in r values between the forelimbs and hindlimbs. Further work is needed to assess how correlation patterns behave in different areas of bone and to evaluate PI in horses with and without clinically relevant stress injuries.

Abstract Background Geographic heterogeneity in COVID-19 outcomes in the United States is well-documented and has been linked with factors at the county level, including sociodemographic and health factors. Whether an integrated measure of place-based risk can classify counties at high risk for COVID-19 outcomes is not known. Methods We conducted an ecological nationwide analysis of 2,701 US counties from 1/21/20 to 2/17/21. County-level characteristics across multiple domains, including demographic, socioeconomic, healthcare access, physical environment, and health factor prevalence were harmonized and linked from a variety of sources. We performed latent class analysis to identify distinct groups of counties based on multiple sociodemographic, health, and environmental domains and examined the association with COVID-19 cases and deaths per 100,000 population. Results Analysis of 25.9 million COVID-19 cases and 481,238 COVID-19 deaths revealed large between-county differences with widespread geographic dispersion, with the gap in cumulative cases and death rates between counties in the 90th and 10th percentile of 6,581 and 291 per 100,000, respectively. Counties from rural areas tended to cluster together compared with urban areas and were further stratified by social determinants of health factors that reflected high and low social vulnerability. Highest rates of cumulative COVID-19 cases (9,557 [2,520]) and deaths (210 [97]) per 100,000 occurred in the cluster comprised of rural disadvantaged counties. Conclusions County-level COVID-19 cases and deaths had substantial disparities with heterogeneous geographic spread across the US. The approach to county-level risk characterization used in this study has the potential to provide novel insights into communicable disease patterns and disparities at the local level.

Abstract Background A disproportionate number of people who are killed by police each year are Black. While much attention rightly remains on victims of police brutality, there is a sparse literature on police brutality and perinatal health outcomes. We aimed to explore how Black pregnant women perceive police brutality affects them during pregnancy and might affect their children. Methods This qualitative study involved semi-structured interviews among 24 Black pregnant women in New Haven, Connecticut (January 2017 to August 2018). Interview questions explored neighborhood factors, safety, stressors during pregnancy, and anticipated stressors while parenting. Grounded theory informed the analysis. Results Participants, regardless of socioeconomic status, shared experiences with police and beliefs about anticipated police brutality, as summarized in the following themes: (1) experiences that lead to police distrust – “If this is the way that mommy’s treated [by police]”; (2) anticipating police brutality – “I’m always expecting that phone call”; (3) stress and fear during pregnancy – “It’s a boy, [I feel] absolutely petrified”; and (4) ‘the talk’ about avoiding police brutality – “How do you get prepared?” Even participants who reported positive experiences with police anticipated brutality towards their children. Conclusions Interactions between Black people and police on a personal, familial, community, and societal level influenced how Black pregnant women understand the potential for police brutality towards their children. Anticipated police brutality is a source of stress during pregnancy, which may adversely influence maternal and infant health outcomes. Police brutality must be addressed in all communities to prevent harming the health of birthing people and their children.

Quadratic mean diameter is the most frequently reported descriptor of the diameter distribution of forests. As such, it is often used as an indicator of forest stand structure, developmental stage, and ecological and economic potential. However, quadratic mean diameter can be heavily influenced by the presence or absence of large numbers of small stems in lower canopy strata, and it is also sensitive to left-truncation of the diameter distribution, making its interpretation across inventories with different protocols challenging. Here, we examine three alternative expressions of stand diameter: the arithmetic and quadratic mean diameter of the thickest 100 trees per hectare, and the basal area-weighted mean diameter. Using data from the United States Forest Inventory and Analysis program for New York and New England, these alternative expressions showed closer correlation with multiple stand structural variables than did quadratic mean diameter, including merchantable cubic and board foot volume per hectare, aboveground live tree carbon per hectare, and total number of live and dead standing trees greater than 40 ​cm diameter at breast height per hectare (previously proposed as an index of old-growth structure). Arithmetic and quadratic mean diameter of the thickest 100 trees per hectare showed nearly identical performance, and the strongest correlations across the board. We develop closed-form expressions for these variables when the diameter distribution is a Weibull, and illustrate their behavior relative to quadratic mean diameter for that situation. While the reasons for prevalence of quadratic mean diameter as an indicator remain valid, we suggest that these alternative measures should be more widely reported and analyzed to give a more informative depiction of stand structure and development in complex forests.

Employees with mental health problems often struggle to remain in employment. During the COVID-19 pandemic, these employees face multiple additional stressors, which are likely to worsen their mental health and work productivity. Currently, it is unclear how to best support employees with mental health problems (and their managers) to improve wellbeing and productivity. We aim to develop a new intervention (MENTOR) that will jointly involve employees, managers, and a new professional (mental health employment liaison worker, MHELW), to help employees who are still at work with a mental health condition and currently receiving professional support for their mental health. A feasibility pilot study will then be undertaken to examine the feasibility and acceptability of the intervention from the perspective of employees and line managers. The study involves a feasibility randomised controlled study comparing outcomes of participants randomised to receive the intervention (MENTOR) with wait-list controls. Participants allocated to the waitlist control group will receive the intervention after three months. We aim to randomise 56 employee-manager pairs recruited from multiple organisations in the Midlands region of England. An intervention including 10 sessions for employees and managers (3 individual sessions and 4 joint sessions) will be delivered over 12 weeks by trained MHELWs. Primary outcomes include measures of feasibility and acceptability of the intervention and work productivity. Secondary outcomes include mental health outcomes. Qualitative interviews will be undertaken with a purposively selected sub-sample of employees and line managers at three-month post-intervention assessment. To our knowledge, this will be the first trial with a joint employee-manager intervention delivered by MHELWs. Anticipated challenges are dual-level consent (employees and managers), participants' attrition, and recruitment strategies. If the intervention and trial processes are shown to be feasible and acceptable, the outcomes from this study will inform future randomised controlled trials. Trial registration: This trial is pre-registered with the ISRCTN registry, registration number: ISRCTN79256498. Protocol version: 3.0_March_2023. https://www.isrctn.com/ISRCTN79256498.

A growing body of research suggests that obesity can be understood as a complex and biobehavioral condition influenced by social relationships ─social networks. Social network analysis allows us to examine how an individual's network characteristics (e.g., popularity) are associated with obesity and obesity-related behaviors. The objectives of the study were to (a) examine whether network members in African American churches are similar in body mass index (BMI) and obesity-related behaviors (physical activity, eating, alcohol consumption) and (b) examine whether an individual's network characteristics, such as popularity (i.e., receiving nominations from peers) and expansiveness (i.e., sending nominations to peers) are associated with BMI and obesity-related behaviors. We used a cross-sectional study design and conducted social network analysis using Exponential random graph models with three African American church-based social networks (network A, B, and C, n = 281). There were no significant network members' similarities on BMI in the three church-based networks. One out of three networks showed similarities in fruit and vegetable consumption (network B), fast food consumption (network C), physical activity, sedentary behaviors, and alcohol consumption (network A). African Americans with a high BMI were more popular, as were individuals with greater fat intake and alcohol consumption. Our findings support the perspective that we need to improve obesity-related behaviors by targeting influential individuals and existing ties and to develop obesity interventions using social networks. The degree to which our findings varied across churches also suggests that the relationship among an individual's obesity-related behaviors and network characteristics should be understood in the unique social context.

Tree mortality plays a fundamental role in the dynamics of forest ecosystems, yet it is one of the most difficult phenomena to accurately predict. Various modeling strategies have been developed to improve individual tree mortality predictions. One less explored strategy is the use of a multistage modeling approach. Potential improvements from this approach have remained largely unknown. In this study, we developed a novel multistage approach and compared its performance in individual tree mortality predictions with a more conventional approach using an identical individual tree mortality model formulation. Extensive permanent plot data (n ​= ​9442) covering the Acadian Region of North America and over multiple decades (1965–2014) were used in this study. Our results indicated that the model behavior with the multistage approach better depicted the observed mortality and showed a notable improvement over the conventional approach. The difference between the observed and predicted numbers of dead trees using the multistage approach was much smaller when compared with the conventional approach. In addition, tree survival probabilities predicted by the multistage approach generally were not significantly different from the observations, whereas the conventional approach consistently underestimated mortality across species and overestimated tree survival probabilities over the large range of DBH in the data. The new multistage approach also predictions of zero mortality in individual plots, a result not possible in conventional models. Finally, the new approach was more tolerant of modeling errors because it based estimates on ranked tree mortality rather than error-prone predicted values. Overall, this new multistage approach deserves to be considered and tested in future studies.

IntroductionAs the movement of water in the brain is known to be involved in neural activity and various brain pathologies, the ability to assess water dynamics in the brain will be important for the understanding of brain function and the diagnosis and treatment of brain diseases. Aquaporin-4 (AQP4) is a membrane channel protein that is highly expressed in brain astrocytes and is important for the movement of water molecules in the brain.MethodsIn this study, we investigated the contribution of AQP4 to brain water dynamics by administering deuterium-labeled water (D2O) intraperitoneally to wild-type and AQP4 knockout (AQP4-ko) mice that had undergone surgical occlusion of the middle cerebral artery (MCA). Water dynamics in the infarct region and on either side of the anterior cerebral artery (ACA) was monitored with proton-density-weighted imaging (PDWI) performed on a 7T animal MRI.ResultsD2O caused a negative signal change quickly after administration. The AQP4-ko mice showed a delay of the time-to-minimum in both the contralateral and ipsilateral ACA regions compared to wild-type mice. Also, only the AQP4- ko mice showed a delay of the time-to-minimum in the ipsilateral ACA region compared to the contralateral side. In only the wild-type mice, the signal minimum in the ipsilateral ACA region was higher than that in the contralateral ACA region. In the infarct region, the signal attenuation was slower for the AQP4-ko mice in comparison to the wild-type mice.DiscussionThese results suggest that AQP4 loss affects water dynamics in the ACA region not only in the infarct region. Dynamic PDWI after D2O administration may be a useful tool for showing the effects of AQP4 in vivo.

Summary: Current understanding of lipid genetics has come mainly from studies in European-ancestry populations; limited effort has focused on Polynesian populations, whose unique population history and high prevalence of dyslipidemia may provide insight into the biological foundations of variation in lipid levels. Here, we performed an association study to fine map a suggestive association on 5q35 with high-density lipoprotein cholesterol (HDL-C) seen in Micronesian and Polynesian populations. Fine-mapping analyses in a cohort of 2,851 Samoan adults highlighted an association between a stop-gain variant (rs200884524; c.652C>T, p.R218∗; posterior probability = 0.9987) in BTNL9 and both lower HDL-C and greater triglycerides (TGs). Meta-analysis across this and several other cohorts of Polynesian ancestry from Samoa, American Samoa, and Aotearoa New Zealand confirmed the presence of this association (βHDL-C = −1.60 mg/dL, pHDL-C = 7.63 × 10−10; βTG = 12.00 mg/dL, pTG = 3.82 × 10−7). While this variant appears to be Polynesian specific, there is also evidence of association from other multiancestry analyses in this region. This work provides evidence of a previously unexplored contributor to the genetic architecture of lipid levels and underscores the importance of genetic analyses in understudied populations.

Background Hispanics are the fastest growing ethnic group in the United States, and little is known about how Hispanic ethnic population density impacts cardiovascular disease ( CVD ) mortality. Methods and Results We examined county-level deaths for Hispanics and non-Hispanic whites from 2003 to 2012 using data from the National Center for Health Statistics Multiple Cause of Death mortality files. Counties with more than 20 Hispanic deaths (n=715) were included in the analyses. CVD deaths were identified using International Classification of Diseases, Tenth Revision (ICD-10), I00 to I78, and population estimates were calculated using linear interpolation from 2000 and 2010 census data. Multivariate linear regression was used to examine the association of Hispanic ethnic density with Hispanic and non-Hispanic white age-adjusted CVD mortality rates. County-level age-adjusted CVD mortality rates were adjusted for county-level demographic, socioeconomic, and healthcare factors. There were a total of 4 769 040 deaths among Hispanics (n=382 416) and non-Hispanic whites (n=4 386 624). Overall, cardiovascular age-adjusted mortality rates were higher among non-Hispanic whites compared with Hispanics (244.8 versus 189.0 per 100 000). Hispanic density ranged from 1% to 96% in each county. Counties in the highest compared with lowest category of Hispanic density had 60% higher Hispanic mortality (215.3 versus 134.2 per 100 000 population). In linear regression models, after adjusting for county-level demographic, socioeconomic, and healthcare factors, increasing Hispanic ethnic density remained strongly associated with mortality for Hispanics but not for non-Hispanic whites. Conclusions CVD mortality is higher in counties with higher Hispanic ethnic density. County-level characteristics do not fully explain the higher CVD mortality among Hispanics in ethnically concentrated counties.

Risk factors can drive socioeconomic inequalities in cardiovascular disease (CVD) through differential exposure and differential vulnerability. In this paper, we show how econometric decomposition directly enables simultaneous, policy-oriented assessment of these 2 mechanisms. We specifically estimate contributions of neighborhood environment and proximal risk factors to socioeconomic inequality in CVD incidence via these mechanisms. We followed 5,608 participants in the Multi-Ethnic Study of Atherosclerosis (2000-2012) to their first CVD event (median length of follow-up, 12.2 years). We used a summary measure of baseline socioeconomic position (SEP). Covariates included baseline demographics, neighborhood characteristics, and psychosocial, behavioral, and biomedical risk factors. Using Poisson models, we decomposed the difference (inequality) in incidence rates between low- and high-SEP groups into contributions of 1) differences in covariate means (differential exposure) and 2) differences in CVD risk associated with covariates (differential vulnerability). Notwithstanding large uncertainty in neighborhood estimates, our analysis suggested that differential exposure to poorer neighborhood socioeconomic conditions, adverse social environment, diabetes, and hypertension accounted for most of the inequality. Psychosocial and behavioral contributions were negligible. Further, neighborhood SEP, female sex, and white race were more strongly associated with CVD among low-SEP (vs. high-SEP) participants. These differentials in vulnerability also accounted for nontrivial portions of the inequality and could have important implications for intervention.

This research was interested in examining if an existing rail industry accident investigation tool could be modified for inner harbour ferry operations. The Contributing Factors Framework (CFF) investigation tool was therefore modified for the maritime industry, specifically as both an investigation tool and a post safety occurrence coding tool. The outcome of this research was the development of a new practical human factors centred investigation tool. It provides a framework for the identification of complex sociotechnical system failures and contributing factors specific to inner harbour ferry operations. The new Contributing Factors Framework-Maritime Safety (CFF-MS) tool fills an existing gap in the need to be able to identify specific inter-relationships between people, technology, and the wider transport system when conducting maritime industry safety investigations.

Abstract Suppressor of cytokine signaling (SOCS)2 protein is a key negative regulator of the growth hormone (GH) and Janus kinase (JAK)-Signal Transducers and Activators of Transcription (STAT) signaling cascade. The central SOCS2-Src homology 2 (SH2) domain is characteristic of the SOCS family proteins and is an important module that facilitates recognition of targets bearing phosphorylated tyrosine (pTyr) residues. Here we identify an exosite on the SOCS2-SH2 domain which, when bound to a non-phosphorylated peptide (F3), enhances SH2 affinity for canonical phosphorylated ligands. Solution of the SOCS2/F3 crystal structure reveals F3 as an α-helix which binds on the opposite side of the SH2 domain to the phosphopeptide binding site. F3:exosite binding appears to stabilise the SOCS2-SH2 domain, resulting in slower dissociation of phosphorylated ligands and consequently, enhances binding affinity. This biophysical enhancement of SH2:pTyr binding affinity translates to increase SOCS2 inhibition of GH signaling.

PEGylated-l-asparaginase (PEG-ASNase) is a chemotherapeutic agent used to treat pediatric acute lymphoblastic leukemia (ALL). Its use is avoided in adults due to its high risk of liver injury including hepatic steatosis, with obesity and older age considered risk factors of the injury. Our study aims to elucidate the mechanism of PEG-ASNase-induced liver injury. Mice received 1500 U/kg of PEG-ASNase and were sacrificed 1, 3, 5, and 7 days after drug administration. Liver triglycerides were quantified, and plasma bilirubin, ALT, AST, and non-esterified fatty acids (NEFA) were measured. The mRNA and protein levels of genes involved in hepatic fatty acid synthesis, β-oxidation, very low-density lipoprotein (VLDL) secretion, and white adipose tissue (WAT) lipolysis were determined. Mice developed hepatic steatosis after PEG-ASNase, which associated with increases in bilirubin, ALT, and AST. The hepatic genes Ppara, Lcad/Mcad, Hadhb, Apob100, and Mttp were upregulated, and Srebp-1c and Fas were downregulated after PEG-ASNase. Increased plasma NEFA, WAT loss, and adipose tissue lipolysis were also observed after PEG-ASNase. Furthermore, we found that PEG-ASNase-induced liver injury was exacerbated in obese and aged mice, consistent with clinical studies of ASNase-induced liver injury. Our data suggest that PEG-ASNase-induced liver injury is due to drug-induced lipolysis and lipid redistribution to the liver.

Background: Hospitalizations for serious infections requiring long-term intravenous (IV) antimicrobials related to injection drug use have risen sharply over the last decade. At our rural tertiary care center, opportunities for treatment of underlying substance use disorders were often missed during these hospital admissions. Once medically stable, home IV antimicrobial therapy has not traditionally been offered to this patient population due to theoretical concerns about misuse of long-term IV catheters, leading to discharges with suboptimal treatment regimens, lengthy hospital stays, or care that is incongruent with patient goals and preferences. Methods: A multidisciplinary group of clinicians and patients set out to redesign and improve care for this patient population through a health care innovation process, with a focus on increasing the proportion of patients who may be discharged on home IV therapy. Baseline assessment of current experience was established through retrospective chart review and extensive stakeholder analysis. The innovation process was based in design thinking and facilitated by a health care delivery improvement incubator. Results: The components of the resulting intervention included early identification of hospitalized people who inject drugs with serious infections, a proactive psychiatry consultation service for addiction management for all patients, a multidisciplinary care conference to support decision making around treatment options for infection and substance use, and care coordination/navigation in the outpatient setting with a substance use peer recovery coach and infectious disease nurse for patients discharged on home IV antimicrobials. Patients discharged on home IV therapy followed routine outpatient parenteral antimicrobial therapy (OPAT) protocols and treatment protocols for addiction with their chosen provider. Conclusion: An intervention developed through a design-thinking-based health care redesign process improved patient-centered care for people with serious infections who inject drugs.

IκB proteins regulate the inhibition and activation of NF-κB transcription factor complexes. While classical IκB proteins keep NF-κB complexes inactive in the cytoplasm, atypical IκB proteins act on activated NF-κB complexes located in the nucleus. Most of the knowledge regarding the function of IκB proteins has been collected in vitro, while far less is known regarding their impact on activation and regulation of immune responses during in vivo infections. Combining in vivo Listeria monocytogenes (Lm) infection with comparative ex vivo transcriptional profiling of the hepatic response to the pathogen we observed that in contrast to wild type mice that mounted a robust inflammatory response, IκBNS-deficiency was generally associated with a transcriptional repression of innate immune responses. Whole tissue transcriptomics revealed a pronounced IκBNS-dependent reduction of myeloid cell-associated transcripts in the liver together with an exceptionally high Nfkbid promoter activity uncovered in Ly6Chigh inflammatory monocytes prompted us to further characterize the specific contribution of IκBNS in the inflammatory response of monocytes to the infectious agent. Indeed, Ly6Chigh monocytes primed during Lm infection in the absence of IκBNS displayed a blunted response compared to wild type-derived Ly6Chigh monocytes as evidenced by the reduced early expression of hallmark transcripts of monocyte-driven inflammation such as Il6, Nos2 and Il1β. Strikingly, altered monocyte activation in IκBNS-deficient mice was associated with an exceptional resistance against Lm infection and protection was associated with a strong reduction in immunopathology in Lm target organs. Of note, mice lacking IκBNS exclusively in myeloid cells failed to resist Lm infection, indicating that the observed effect was not monocyte intrinsic but monocyte extrinsic. While serum cytokine-profiling did not discover obvious differences between wild type and IκBNS-/- mice for most of the analyzed mediators, IL-10 was virtually undetectable in IκBNS-deficient mice, both in the steady state and following Lm infection. Together, we show here a crucial role for IκBNS during Lm infection with IκBNS-deficient mice showing an overall blunted pro-inflammatory immune response attributed to a reduced pro-inflammatory signature in Ly6Chigh monocytes. Reduced immunopathology and complete protection of mice against an otherwise fatal Lm infection identified IκBNS as molecular driver of inflammation in listeriosis.

Intimate partner violence (IPV) can impact the mental health of survivors; however, little is known about the role of state-level restorative justice policies. Restorative justice policies are survivor-centered justice approaches focused on repairing harm between the survivor and perpetrator, which may buffer mental health outcomes among IPV survivors. Furthermore, the impact of restorative justice policies on mental health may be influenced by the degree of state-level support for policy implementation. This study examined the relationship between (1) IPV exposure and mental health and whether restorative justice policies moderate the relationship; and (2) whether restorative justice policy implementation support moderates the relationship between IPV and mental health among women. Data on state restorative justice policies were drawn from a U.S. restorative justice legislation database. Individual-level data on 5104 adult women were collected from the 2010 National Intimate Partner and Sexual Violence Survey (NISVS), a nationally representative study of noninstitutionalized adult women and men. Generalized estimating equation (GEE) models were conducted to examine associations between IPV, state-level restorative justice policies, restorative justice policy implementation support, and perceived mental health (N ​= ​5104). Women who experienced IPV had worse perceived mental health compared to women without IPV (b [95% CI] ​= ​−0.13 [−0.15, −0.11], p ​

Abstract Background Aquaporin-4 is a membrane channel protein that is highly expressed in brain astrocytes and facilitates the transport of water molecules. It has been suggested that suppression of aquaporin-4 function may be an effective treatment for reducing cellular edema after cerebral infarction. It is therefore important to develop clinically applicable measurement systems to evaluate and better understand the effects of aquaporin-4 suppression on the living body. Methods Animal models of focal cerebral ischemia were created by surgically occluding the middle cerebral artery of wild-type and aquaporin-4 knockout mice, after which multi-b-value multi-diffusion-time diffusion-weighted imaging measurements were performed. Data were analyzed with both the apparent diffusion coefficient (ADC) model and a compartmental water-exchange model. Results ADCs were estimated for five different b value ranges. The ADC of aquaporin-4 knockout mice in the contralateral region was significantly higher than that of wild-type mice for each range. In contrast, aquaporin-4 knockout mice had significantly lower ADC than wild-type mice in ischemic tissue for each b-value range. Genotype-dependent differences in the ADC were particularly significant for the lowest ranges in normal tissue and for the highest ranges in ischemic tissue. The ADCs measured at different diffusion times were significantly different for both genotypes. Fitting of the water-exchange model to the ischemic region data found that the water-exchange time in aquaporin-4 knockout mice was approximately 2.5 times longer than that in wild-type mice. Conclusions Multi-b-value multi-diffusion-time diffusion-weighted imaging may be useful for in vivo research and clinical diagnosis of aquaporin-4-related diseases.

LNK is a potent negative regulator of cytokine signaling implicated in blood cells proliferation. Here the authors present structures of the substrate recognition (SH2) domain of LNK in complex with phosphorylated motifs from JAK2 and EPOR; providing insight into its binding specificity and mode of action.

Abstract Background Pre-exposure prophylaxis (PrEP) has the potential to reduce transmission of HIV among Black cisgender women in the Southern United States (U.S.); however, national data suggests that PrEP initiation is lowest in the South and among Black women compared to other U.S. regions and white women. This study applied intersectionality and PrEP multilevel resilience frameworks to assess how socio-structural and clinical contexts shaped PrEP persistence among Black cisgender women in Mississippi. Methods Semi-structured interviews were conducted with eight Black cisgender women in Jackson, Mississippi. This sample was purposively recruited to include PrEP-initiated Black cisgender women. Results Six themes identified that shaped PrEP care among Black cisgender women: (1) internal assets, (2) sole responsibility to HIV prevention, (3) added protection in HIV serodifferent relationships, (4) financial issues, (5) trust and distrust in the medical system, and (6) side effects. Black cisgender women reported that PrEP persistence increased control over their sexual health, reduced anxiety about HIV, and promoted self-care. Black cisgender women also indicated that medication assistance programs increased PrEP affordability resulting in continued persistence. Conclusions In addition to preventing HIV, PrEP may yield secondary positive impacts on the health and relationships of Black cisgender women. However, very few Black cisgender women in the South are using PrEP given intersectional barriers and thus necessitates adaptive strategies to support PrEP initiation and persistence. Efforts aimed at increasing the coverage of PrEP among Black cisgender women should consider implementation strategies responsive to lived realities of Black women.

AbstractAmalgamation of the Yangtze and Cathaysia blocks in the context of Gondwana assembly in the early Paleozoic has been addressed for decades, but the far-field effects on the Yangtze Block during the amalgamation remain unclear. In this study, we outline the sequence stratigraphic framework of the Ordovician succession in the central-upper Yangtze Block and analyze provenance records in sandstone compositions, distributions, and detritus zircon U-Pb dating. The Ordovician succession in the central-upper Yangtze Block is subdivided into six third-order sequences, which were deposited mainly in a carbonate platform with restricted sediments in Tremadocian to early Floian stages, mixed terrigenous-carbonate deposits in mid- to late Floian stages, and open circulation sediments in Dapingian to middle Katian stages. These sequences show the central-upper Yangtze Block experienced syn-tectonic deformation with northeast-trending long-wavelength uplift and depression alternatively and the depocenter shifting from the east during Tremadocian to mid-Floian stages to the southwest in late Floian to early Hirnantian stages. Provenance data indicate that detritus in the Ordovician succession was mainly from the northern India and Kangdian paleohighland to the southwest of South China Block. Incorporating the depositional and deformation variations, we propose a retroarc foreland basin that was developed on the South China Block in response to final suturing between the South China Block and East Gondwana at Sanya suture zone. The South China Block was thus involved in the global tectonics of the Gondwana supercontinental cycle during the Ordovician.

Background: Patients with injection drug use (IDU)-associated infections traditionally experience prolonged hospitalizations, which often result in negative experiences and bad outcomes. Harm reduction approaches that value patient autonomy and shared decision-making regarding outpatient treatment options may improve outcomes. We sought to identify health care professionals (HCPs) perspectives on the barriers to offering four different options to hospitalized people who use drugs (PWUD): long-term hospitalization, oral antibiotics, long-acting antibiotics at an infusion center, and outpatient parenteral antibiotics. Methods: We recruited HCPs ( n = 19) from a single tertiary care center in Portland, Maine. We interviewed HCPs involved with discharge decision-making and other HCPs involved in the specialized care of PWUD. Semi-structured interviews elicited lead HCP values, preferences, and concerns about presenting outpatient antimicrobial treatment options to PWUD, while support HCPs provided contextual information. We used the iterative categorization approach to code and thematically analyze transcripts. Results: HCPs were willing to present outpatient treatment options for patients with IDU-associated infections, yet several factors contributed to reluctance. First, insufficient resources, such as transportation, may make these options impractical. However, HCPs may be unaware of existing community resources or viable treatment options. They also may believe the hospital protects patients, and that discharging patients into the community exposes them to structural harms. Some HCPs are concerned that patients with substance use disorder will not make ‘good’ decisions regarding outpatient antimicrobial options. Finally, there is uncertainty about how responsibility for offering outpatient treatment is shared across changing care teams. Conclusion: HCPs perceive many barriers to offering outpatient care for people with IDU-associated infections, but with appropriate interventions to address their concerns, may be open to considering more options. This study provides important insights and contextual information that can help inform specific harm reduction interventions aimed at improving care of people with IDU-associated infections.

Objectives To assess the feasibility and effectiveness of text messaging to increase outpatient care engagement and medication adherence in an urban homeless population in Boston. Methods Between July 2017 and April 2018, 62 patients from a clinic serving a homeless population were sent automated text messages for four months. Messages were either appointment reminders and medication adherence suggestions (intervention group) or general health promotion messages (control group). Medical records were reviewed to evaluate appointment keeping, emergency room (ER) use, and hospitalizations. Pre- and post-surveys were administered to measure self-reported medication adherence. Results No significant differences were found in inpatient or outpatient care between the intervention and control groups, though differences in no-show rates and medication adherence approached significance. Appointment no-show rates were 21.0% vs. 30.6% ( p = 0.08) for intervention and control, respectively, and rates of completed appointments were 65.8% vs. 56.7% ( p = 0.12). Mean ER visits were 3.86 vs 2.33 ( p = 0.16) for intervention and control groups, and mean inpatient admissions were 0.6 versus 1.24 ( p = 0.42). Self-reported medication adherence increased from 8.27 to 9.84 in intervention participants, compared to an increase from 8.27 to 8.68 in control participants ( p = 0.07), on a 1–11 scale. Conclusions Text messaging showed the potential to improve patient engagement in care and medication adherence in an urban homeless population (findings approaching but not achieving statistical significance). Work is needed to enhance the effectiveness of text-messaging interventions, which may involve increasing ease of use for mobile phones and texting apps, and addressing high rates of phone theft and loss.