1,25-dihydroxyvitamin D3 augments low-dose PMA-based monocyte-to-macrophage differentiation in THP-1 cells.

The human monocytic THP-1 cell line is the most routinely employed in vitro model for studying monocyte-to-macrophage differentiation. Despite the wide use of this model, differentiation protocols using phorbol 12-myristate-13-acetate (PMA) or 1,25-dihydroxyvitamin D3 (1,25D3) vary drastically between studies. Given that differences in differentiation protocols have the potential to impact the characteristics of the macrophages produced, we aimed to assess the efficacy of three different THP-1 differentiation protocols by assessing changes in morphology and gene- and cell surface macrophage marker expression. THP-1 cells were differentiated with either 5 nM PMA, 10 nM 1,25D3, or a combination thereof, followed by a rest period. The results indicated that all three protocols significantly increased the expression of the macrophage markers, CD11b (p < 0.001) and CD14 (p < 0.010). Despite this, THP-1 cells exposed to 1,25D3 alone did not adopt the morphological and expression characteristics associated with macrophages. PMA was required to produce these characteristics, which were found to be more pronounced in the presence of 1,25D3. Both PMA- and PMA with 1,25D3-differentiated THP-1 cells were capable of M1 and M2 macrophage polarization, though the gene expression of polarization-associated markers was most pronounced in PMA with 1,25D3-differentiated THP-1 cells. Moreover, the combination of PMA with 1,25D3 appeared to support the process of commitment to a particular polarization state.

Microarray analysis demonstrates up-regulation of the endothelin-1 gene with compensatory down-regulation of the ETA receptor gene in human portal vein.

High blood pressure in the portal vein, portal hypertension (PH), is the final common pathway in liver cirrhosis regardless of aetiology. Complications from PH are the major cause of morbidity and mortality in these patients. Current drug therapy to reduce portal pressure is mainly limited to ß-adrenergic receptor blockade but approximately 40% of patients do not respond. Our aim was to use microarray to measure the expression of ∼20,800 genes in portal vein from patients with PH undergoing transplantation for liver cirrhosis (PH, n=12) versus healthy vessels (control, n=9) to identify potential drug targets to improve therapy. Expression of 9,964 genes above background was detected in portal vein samples. Comparing PH veins versus control (adjusted P-value < 0.05, fold change > 1.5) identified 548 up-regulated genes and 1,996 down-regulated genes. The 2,544 differentially expressed genes were subjected to pathway analysis. We identified 49 significantly enriched pathways. The endothelin pathway was ranked the tenth most significant, the only vasoconstrictive pathway to be identified. ET-1 gene (EDN1) was significantly up-regulated, consistent with elevated levels of ET-1 peptide previously measured in PH and cirrhosis. ETA receptor gene (EDNRA) was significantly down-regulated, consistent with an adaptive response to increased peptide levels in the portal vein but there was no change in the ETB gene (EDNRB). The results provide further support for evaluating the efficacy of ETA receptor antagonists as a potential therapy in addition to ß-blockers in patients with PH and cirrhosis.

Mucocutaneous Ulcers Unmasking Severe Systemic Methotrexate Toxicity - A Case-Series and Review of Literature.

Background: Methotrexate is a widely used immunosuppressant with good efficacy and cost-effectiveness. However, one of the drawbacks of methotrexate has been toxicity due to accidental overdose. During the COVID pandemic, there was an alarming increase in the number of patients with methotrexate toxicity which prompted us to do this study. Objective: To evaluate the clinical features and contributing factors in patients presenting with methotrexate toxicity. Materials and Methods: A detailed evaluation of the clinical features, laboratory indices, contributing factors, and outcomes of the patients presenting with methotrexate toxicity was analyzed. Results: A total of 19 cases were seen during the study period. All of the patients had oral mucositis and several developed cutaneous ulcerations. Laboratory abnormalities included cytopenia, transaminitis, and renal impairment. While sixteen patients recovered successfully, three people died as a result of delays in medical assistance. In addition to comorbidities, pandemic-induced restrictions played a major role in patients accidentally overdosing with methotrexate. Conclusion: This study highlights the fact that even low-dose methotrexate taken incorrectly can result in a lethal outcome, which is preventable.

Co-localization of the sodium-glucose co-transporter-2 channel (SGLT-2) with endothelin ETA and ETB receptors in human cardiorenal tissue.

Endothelin (ET) receptor antagonists are being investigated in combination with sodium-glucose co-transporter-2 inhibitors (SGLT-2i). These drugs primarily inhibit the SGLT-2 transporter that, in humans, is thought to be mainly restricted to the renal proximal convoluted tubule, resulting in increased glucose excretion favouring improved glycaemic control and diuresis. This action reduces fluid retention with ET receptor antagonists. Studies have suggested SGLT-2 may also be expressed in cardiomyocytes of human heart. To understand the potential of combining the two classes of drugs, our aim was to compare the distribution of ET receptor sub-types in human kidney, with SGLT-2. Secondly, using the same experimental conditions, we determined if SGLT-2 expression could be detected in human heart and whether the transporter co-localised with ET receptors. METHODS: Immunocytochemistry localised SGLT-2, ETA and ETB receptors in sections of histologically normal kidney, left ventricle from patients undergoing heart transplantation or controls. Primary antisera were visualised using fluorescent microscopy. Image analysis was used to measure intensity compared with background in adjacent control sections. RESULTS: As expected, SGLT-2 localised to epithelial cells of the proximal convoluted tubules, and co-localised with both ET receptor sub-types. Similarly, ETA receptors predominated in cardiomyocytes; low (compared with kidney but above background) positive staining was also detected for SGLT-2. DISCUSSION: Whether low levels of SGLT-2 have a (patho)physiological role in cardiomyocytes is not known but results suggest the effect of direct blockade of sodium (and glucose) influx via SGLT-2 inhibition in cardiomyocytes should be explored, with potential for additive effects with ETA antagonists.

Expression of the apelin receptor, a novel potential therapeutic target, and its endogenous ligands in diverse stem cell populations in human glioblastoma.

Glioblastoma multiforme (GBM) is one of the most common and lethal forms of brain cancer, carrying a very poor prognosis (median survival of ~15 months post-diagnosis). Treatment typically involves invasive surgical resection of the tumour mass, followed by radiotherapy and adjuvant chemotherapy using the alkylating agent temozolomide, but over half of patients do not respond to this drug and considerable resistance is observed. Tumour heterogeneity is the main cause of therapeutic failure, where diverse progenitor glioblastoma stem cell (GSC) lineages in the microenvironment drive tumour recurrence and therapeutic resistance. The apelin receptor is a class A GPCR that binds two endogenous peptide ligands, apelin and ELA, and plays a role in the proliferation and survival of cancer cells. Here, we used quantitative whole slide immunofluorescent imaging of human GBM samples to characterise expression of the apelin receptor and both its ligands in the distinct GSC lineages, namely neural-progenitor-like cells (NPCs), oligodendrocyte-progenitor-like cells (OPCs), and mesenchymal-like cells (MES), as well as reactive astrocytic cells. The data confirm the presence of the apelin receptor as a tractable drug target that is common across the key cell populations driving tumour growth and maintenance, offering a potential novel therapeutic approach for patients with GBM.

Contemporary trends in incident ischemic stroke, intracranial hemorrhage, and mortality in individuals with atrial fibrillation.

BACKGROUND: The prognosis for atrial fibrillation (AF) patients is based on data that is decades old. Given evolving standards of clinical practice, we sought to evaluate temporal trends in clinically important outcomes among patients with AF. METHODS: California's Department of Health Care Access and Information databases were used to identify adults aged ≥ 18 years with AF receiving hospital-based care in California. We compared 3 time-periods: 2005-2009, 2010-2014, and 2015-2019. ICD codes were used to identify chronic diseases and acute events. The outcomes were incident ischemic stroke, intracranial hemorrhage, and overall mortality. RESULTS: We included 2 009 832 patients with AF (52.7% males, 70.7% Whites, and mean age of 75.0 years), divided in 3 cohorts: 2005-2009 (n = 738 954), 2010-2014 (n = 609 447), and 2015-2019 (n = 661 431). Each outcome became substantially less common with time: compared to 2005-2009, AF patients diagnosed in 2015-2019 experienced a 34% (adjusted hazard ratio [HR] 0.66, 95% CI 0.64-0.69), 22% (HR 0.78, 0.75-0.82), and 24% (HR 0.76, 0.75-0.77) reduction in risk of incident ischemic stroke, intracranial hemorrhage, and mortality, respectively. Between 2005-2009 and 2015-2019, patients aged ≥ 65 years experienced more reductions in each outcome compared to younger patients (p < 0.001 for all), and declines in each outcome were significantly lower for Hispanics and Blacks compared to white patients. CONCLUSION: The risks of stroke, intracranial hemorrhage, and death have significantly declined among AF patients, although differences in the magnitude of improvement of these outcomes by demographic groups were observed. Commonly described estimates of the prognosis for AF patients should be updated to reflect contemporary care.

The biased apelin receptor agonist, MM07, reverses Sugen/hypoxia-induced pulmonary arterial hypertension as effectively as the endothelin antagonist macitentan.

Introduction: Pulmonary arterial hypertension (PAH) is characterised by endothelial dysfunction and pathological vascular remodelling, resulting in the occlusion of pulmonary arteries and arterioles, right ventricular hypertrophy, and eventually fatal heart failure. Targeting the apelin receptor with the novel, G protein-biased peptide agonist, MM07, is hypothesised to reverse the developed symptoms of elevated right ventricular systolic pressure and right ventricular hypertrophy. Here, the effects of MM07 were compared with the clinical standard-of-care endothelin receptor antagonist macitentan. Methods: Male Sprague-Dawley rats were randomised and treated with either normoxia/saline, or Sugen/hypoxia (SuHx) to induce an established model of PAH, before subsequent treatment with either saline, macitentan (30 mg/kg), or MM07 (10 mg/kg). Rats were then anaesthetised and catheterised for haemodynamic measurements, and tissues collected for histopathological assessment. Results: The SuHx/saline group presented with significant increases in right ventricular hypertrophy, right ventricular systolic pressure, and muscularization of pulmonary arteries compared to normoxic/saline controls. Critically, MM07 was as at least as effective as macitentan in significantly reversing detrimental structural and haemodynamic changes after 4 weeks of treatment. Discussion: These results support the development of G protein-biased apelin receptor agonists with improved pharmacokinetic profiles for use in human disease.

eHealth-Enhanced Peer Navigation for Substance Use Treatment and HIV Prevention Service Linkage for Young Adults Surveilled by the Criminal Legal System: Protocol for a Pilot Randomized Trial Study.

BACKGROUND: In the United States, the proportion of criminal legal-involved (CLI) adults with a substance use disorder reaches 72%, and ~150,000 persons with HIV pass through a carceral setting annually, which represents 16% of the HIV-infected population nationally. Despite the high need for substance use treatment and HIV prevention services, few carceral settings successfully link CLI individuals to treatment upon release. Young adults represent 41.9% of the adults incarcerated in the United States and have the highest HIV incidence rates nationally. Peer patient navigation has successfully increased community-based care linkage for people living with HIV leaving jail; yet, peer-led navigation for HIV prevention among HIV-negative CLI populations is undeveloped and untested. eHealth approaches to substance use and HIV prevention services hold promise because they improve access to effective intervention services, particularly for younger people. OBJECTIVE: This paper describes a protocol for a pilot randomized controlled trial that aims to improve linkage to substance use treatment and HIV prevention services using peer navigation and a codeveloped eHealth technology adjunct. METHODS: The three aims of this study are to (1) adapt an existing evidence-based navigator model and incorporate codeveloped eHealth technology to refer and link young adults (18 to 29 years) surveilled by the criminal legal system to substance use and pre-exposure prophylaxis (PrEP) services; (2) refine and test the intervention with criminal legal-involved young adults (CLI-YAs); and (3) assess the feasibility, acceptability, and impact of the intervention. Data to inform the intervention will be collected via system partner interviews (n=4) and focus groups with CLI-YAs (n=24). Next, an open trial (n=10) will be conducted. The intervention will be refined via interviews with participants and facilitators, and a randomized pilot trial (n=75) will be conducted to assess the feasibility, acceptability, and preliminary impact of the eHealth-enhanced navigation on substance use and PrEP services linkage. Exit interviews conducted with a subsample of intervention participants (n=10), the navigator (n=1), and system partners (n=4) will assess intervention acceptability and suggestions for improvement. A community of practice, a group of system partners with an interest in working toward solutions to common problems, will inform each phase of the study. RESULTS: The project is currently ongoing. The project was funded in September 2022. Internal review board approval was received on March 21, 2022. The first results from early study aims are expected to be published in 2025. CONCLUSIONS: This study provides an opportunity to reduce HIV acquisition and improve access to substance use treatment in a systemically marginalized group: young CLI-YAs. The results will contribute to the development and testing of a future multilevel randomized controlled trial. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/54815.

Systemic infarcts among patients with atrial fibrillation.

BACKGROUND: The epidemiology of atrial fibrillation (AF)-associated thromboembolic complications outside of ischemic strokes has not been thoroughly elucidated. OBJECTIVE: The aim of this study was to describe the epidemiology of AF-associated systemic infarcts and relevant interactions by sex and race/ethnicity. METHODS: Using the Office of Statewide Health Planning and Development, we performed a longitudinal analysis of patients aged ≥18 years who received ambulatory surgery, emergency, or inpatient medical care in California between 2005 and 2015. We determined the distribution of infarct locations and risks of systemic infarcts for patients with AF. Interaction analyses by sex and race/ethnicity were conducted. RESULTS: Of 1,321,694 patients with AF, the average annual rate of systemic infarct was 2.1% ± 0.18% compared with 0.56% ± 0.06% in the 22,944,488 patients without AF. The increased frequency of these infarcts was observed for every body area investigated. After adjustment for potential confounders and mediators, patients with AF experienced a 45% increased risk of a systemic infarct (hazard ratio, 1.45; 95% confidence interval, 1.44-1.47; P < .001). Women, Asians, Blacks, and Hispanics each exhibited a statistically significant heightened relative risk of systemic infarcts in the presence of AF. CONCLUSION: AF increases the risk of infarcts throughout the body. Susceptibility to these systemic infarcts varies by sex and race/ethnicity in patterns similar to differential risks for stroke. The presence of a systemic infarct in the absence of a clear cause should raise suspicion for AF, and the potential benefits of AF prevention and anticoagulation should be considered beyond only infarcts to the brain.

Electronic Case Reporting Development, Implementation, and Expansion in the United States.

INTRODUCTION: The COVID-19 pandemic highlighted the need for a nationwide health information technology solution that could improve upon manual case reporting and decrease the clinical and administrative burden on the US health care system. We describe the development, implementation, and nationwide expansion of electronic case reporting (eCR), including its effect on public health surveillance and pandemic readiness. METHODS: Multidisciplinary teams developed and implemented a standards-based, shared, scalable, and interoperable eCR infrastructure during 2014-2020. From January 27, 2020, to January 7, 2023, the team conducted a nationwide scale-up effort and determined the number of eCR-capable electronic health record (EHR) products, the number of reportable conditions available within the infrastructure, and technical connections of health care organizations (HCOs) and jurisdictional public health agencies (PHAs) to the eCR infrastructure. The team also conducted data quality studies to determine whether HCOs were discontinuing manual case reporting and early results of eCR timeliness. RESULTS: During the study period, the number of eCR-capable EHR products developed or in development increased 11-fold (from 3 to 33), the number of reportable conditions available increased 28-fold (from 6 to 173), the number of HCOs connected to the eCR infrastructure increased 143-fold (from 153 to 22 000), and the number of jurisdictional PHAs connected to the eCR infrastructure increased 2.75-fold (from 24 to 66). Data quality reviews with PHAs resulted in select HCOs discontinuing manual case reporting and using eCR-exclusive case reporting in 13 PHA jurisdictions. The timeliness of eCR was <1 minute. PRACTICE IMPLICATIONS: The growth of eCR can revolutionize public health case surveillance by producing data that are more timely and complete than manual case reporting while reducing reporting burden.

Iron Sequestration by Murine Calprotectin Induces Starvation Responses in Pseudomonas aeruginosa.

Pathogen sensing by the mammalian host induces a pro-inflammatory response that involves release of the antimicrobial metal-sequestering protein calprotectin (CP, S100A8/S100A9 heterooligomer, MRP8/MRP14 heterooligomer) from neutrophils. Biochemical investigations on human CP (hCP) have informed the molecular basis of how this protein sequesters metal ions. Murine models of infection have provided invaluable insights into the ability of murine CP (mCP) to compete with bacterial pathogens for essential metal nutrients. Despite this extensive work, our knowledge of how mCP sequesters metals from bacterial pathogens and its impacts on bacterial physiology is limited. Moreover, whether mCP sequesters iron and induces iron-starvation responses in bacterial pathogens has not been evaluated. Here, we examine the ability of mCP to withhold iron from Pseudomonas aeruginosa, a Gram-negative opportunistic pathogen that causes severe infections in immunocompromised individuals and cystic fibrosis patients. We demonstrate that mCP prevents iron uptake and induces iron-starvation responses in P. aeruginosa laboratory strains PA14 and PAO1 and the JSRI-1 clinical isolate from a cystic fibrosis patient. We also show that mCP prevents iron uptake and induces an iron-starvation response in the Gram-positive bacterial pathogen Staphylococcus aureus. The His6 site of mCP is the iron-sequestering site; it exhibits Ca(II)-dependent Fe(II) affinity and binds Fe(II) with subpicomolar affinity in the presence of excess Ca(II) ions. This work is important for understanding the structure, function, and physiological consequences of mCP and how the mammalian host and bacterial pathogens compete for essential metal nutrients.

Susceptibility of northern corn rootworm (Diabrotica barberi) populations to Cry3Bb1 and Gpp34/Tpp35Ab1 proteins in seedling and diet overlay toxicity assays.

The northern corn rootworm, Diabrotica barberi Smith & Lawrence (Coleoptera: Chrysomelidae) is a major pest of maize in the United States Corn Belt. Recently, resistance to Bacillus thuringiensis (Bt) maize was reported in North Dakota and increased use of Bt maize hybrids could facilitate resistance evolution in other maize-producing states. In this study, susceptibility to Bt proteins was evaluated in wild D. barberi populations from 8 fields collected in 5 different states (Minnesota, Missouri, Nebraska, Iowa, and North Dakota). Field populations were compared to a susceptible D. barberi colony in seedling and diet toxicity assays conducted with 3 concentrations of Cry3Bb1 (0.4, 4.0, and 40.0 µg/cm2) and Gpp34/Tpp35Ab1 (previously called Cry34/35Ab1; 1.4, 14.0, and 140.0 µg/cm2). The 2019 population from Meeker Co., Minnesota (MN-2019), exhibited the lowest mortality to Cry3Bb1 and also had nominally lowest mortality to Gpp34/Tpp35Ab1 at the highest concentrations tested in diet toxicity assays. Percent second instar was also highest for larvae of the Minnesota population surviving Cry3Bb1. In seedling assays, MN and IA-2018 populations exhibited the highest proportion survival and dry weight to both proteins expressed in corn. No significant differences in mortality, percent second instar, and dry weight were observed at the highest concentration for both proteins among the populations collected in in 2020. Most D. barberi populations were still highly susceptible to Cry3Bb1 and Gpp34/Tpp35Ab1 proteins based on diet and seedling assays, but resistance appears to be developing in some D. barberi populations. Now that methods are available, resistance monitoring may also be needed for D. barberi in some regions.

Preceding Night Sleep Quality and Atrial Fibrillation Episodes in the I-STOP-AFIB Randomized Trial.

BACKGROUND: Chronic sleep disruption is associated with incident atrial fibrillation (AF), but it is unclear whether poor sleep quality acutely triggers AF. OBJECTIVES: The aim of this study was to characterize the relationship between a given night's sleep quality and the risk of a discrete AF episode. METHODS: Patients with symptomatic paroxysmal AF in the I-STOP-AFIB (Individualized Studies of Triggers of Paroxysmal Atrial Fibrillation) trial reported sleep quality on a daily basis. Participants were also queried daily regarding AF episodes and were provided smartphone-based mobile electrocardiograms (ECGs) (KardiaMobile, AliveCor). RESULTS: Using 15,755 days of data from 419 patients, worse sleep quality on any given night was associated with a 15% greater odds of a self-reported AF episode the next day (OR: 1.15; 95% CI: 1.10-1.20; P < 0.0001) after adjustment for the day of the week. No statistically significant associations between worsening sleep quality and mobile ECG-confirmed AF events were observed (OR: 1.04; 95% CI: 0.95-1.13; P = 0.43), although substantially fewer of these mobile ECG-confirmed events may have limited statistical power. Poor sleep was also associated with longer self-reported AF episodes, with each progressive category of worsening sleep associated with 16 (95% CI: 12-21; P < 0.001) more minutes of AF the next day. CONCLUSIONS: Poor sleep was associated with an immediately heightened risk for self-reported AF episodes, and a dose-response relationship existed such that progressively worse sleep was associated with longer episodes of AF the next day. These data suggest that sleep quality may be a potentially modifiable trigger relevant to the near-term risk of a discrete AF episode.

Cannabis use and incident atrial fibrillation in a longitudinal cohort.

BACKGROUND: Cannabis use is increasing worldwide. While prior studies have reported an association between cannabis use and a higher risk of atrial fibrillation (AF), most were cross-sectional and generally relied on diagnostic coding to identify cannabis users, which may not be representative of the typical recreational cannabis user. OBJECTIVE: The purpose of this study was to examine the association between recreational cannabis use and lifetime AF risk. METHODS: We evaluated the AF risk of participants of the UK Biobank cohort who completed the cannabis use lifestyle questionnaire. Cannabis exposure was categorized as "Occasional Use" for less than 100 times used, "Frequent Use" for more than 100 times used, and "Never" users. AF events were identified using International Classification of Diseases codes. Cox models were used to estimate the hazard ratios (HRs) between cannabis use and incident AF and were subsequently adjusted for age, sex, race, alcohol, coffee, smoking, education, and baseline cardiovascular comorbidities. RESULTS: A total of 150,554 participants (mean age 63.4 ± 7.7 years; 86,487 (57.4%) female; and 33,442 (22.2%) using cannabis at least once) were followed for a mean period of 6.1 ± 0.6 years. After multivariable adjustment, there were no statistically significant differences in incident AF among occasional users (HR 0.98; 95% confidence interval 0.89-1.08) nor frequent users (HR 1.03; 95% confidence interval 0.81-1.32) as compared with never users. CONCLUSION: In a large prospective cohort study, there was no evidence that cannabis use was associated with a higher risk of incident AF. An evaluation of cannabis ingestion methods and quantification was not possible using the current data set.

Carbonate Chemistry and the Potential for Acidification in Georgia Coastal Marshes and the South Atlantic Bight, USA.

In coastal regions and marginal bodies of water, the increase in partial pressure of carbon dioxide (pCO2) in many instances is greater than that of the open ocean due to terrestrial (river, estuarine, and wetland) influences, decreasing buffering capacity and/or increasing water temperatures. Coastal oceans receive freshwater from rivers and groundwater as well as terrestrial-derived organic matter, both of which have a direct influence on coastal carbonate chemistry. The objective of this research is to determine if coastal marshes in Georgia, USA, may be "hot-spots" for acidification due to enhanced inorganic carbon sources and if there is terrestrial influence on offshore acidification in the South Atlantic Bight (SAB). The results of this study show that dissolved inorganic carbon (DIC) and total alkalinity (TA) are elevated in the marshes compared to predictions from conservative mixing of the freshwater and oceanic end-members, with accompanying pH around 7.2 to 7.6 within the marshes and aragonite saturation states (ΩAr) <1. In the marshes, there is a strong relationship between the terrestrial/estuarine-derived organic and inorganic carbon and acidification. Comparisons of pH, TA, and DIC to terrestrial organic material markers, however, show that there is little influence of terrestrial-derived organic matter on shelf acidification during this period in 2014. In addition, ΩAr increases rapidly offshore, especially in drier months (July). River stream flow during 2014 was anomalously low compared to climatological means; therefore, offshore influences from terrestrial carbon could also be decreased. The SAB shelf may not be strongly influenced by terrestrial inputs to acidification during drier than normal periods; conversely, shelf waters that are well-buffered against acidification may not play a significant role in mitigating acidification within the Georgia marshes. Supplementary Information: The online version contains supplementary material available at 10.1007/s12237-023-01261-3.

Impact of San Francisco's New Street crisis response Team on Service use among people experiencing homelessness with mental and substance use disorders: A mixed methods study protocol.

Mobile crisis services for people experiencing distress related to mental health or substance use are expanding rapidly across the US, yet there is little evidence to support these specific models of care. These new programs present a unique opportunity to expand the literature by utilizing implementation science methods to inform the future design of crisis systems. This mixed methods study will examine the effectiveness and acceptability of the Street Crisis Response Team (SCRT), a new 911-dispatched multidisciplinary mobile crisis intervention piloted in San Francisco, California. First, using quantitative data from electronic health records, we will conduct an interrupted time series analysis to quantitatively examine the impacts of the SCRT on people experiencing homelessness who utilized public behavioral health crisis services in San Francisco between November 2019 and August 2022, across four main outcomes within 30 days of the crisis episode: routine care utilization, crisis care reutilization, assessment for housing services, and jail entry. Second, to understand its impact on health equity, we will analyze racial and ethnic disparities in these outcomes prior to and after implementation of the SCRT. For the qualitative component, we will conduct semi-structured interviews with recipients of the SCRT's services to understand their experiences of the intervention and to identify how the SCRT influenced their health-related trajectories after the crisis encounter. Once complete, the quantitative and qualitative findings will be further analyzed in tandem to assist with more nuanced understanding of the effectiveness of the SCRT program. This evaluation of a novel mobile crisis response program will advance the field, while also providing a model for how real-world program implementation can be achieved in crisis service settings.

Targeting the apelin system for the treatment of cardiovascular diseases.

Cardiovascular disease is the leading cause of death worldwide. Its prevalence is rising due to ageing populations and the increasing incidence of diseases such as chronic kidney disease, obesity, and diabetes that are associated with elevated cardiovascular risk. Despite currently available treatments, there remains a huge burden of cardiovascular disease-associated morbidity for patients and healthcare systems, and newer treatments are needed. The apelin system, comprising the apelin receptor and its two endogenous ligands apelin and elabela, is a broad regulator of physiology that opposes the actions of the renin-angiotensin and vasopressin systems. Activation of the apelin receptor promotes endothelium-dependent vasodilatation and inotropy, lowers blood pressure, and promotes angiogenesis. The apelin system appears to protect against arrhythmias, inhibits thrombosis, and has broad anti-inflammatory and anti-fibrotic actions. It also promotes aqueous diuresis through direct and indirect (central) effects in the kidney. Thus, the apelin system offers therapeutic promise for a range of cardiovascular, kidney, and metabolic diseases. This review will discuss current cardiovascular disease targets of the apelin system and future clinical utility of apelin receptor agonism.

Bacterial contact induces polar plug disintegration to mediate whipworm egg hatching.

The bacterial microbiota promotes the life cycle of the intestine-dwelling whipworm Trichuris by mediating hatching of parasite eggs ingested by the mammalian host. Despite the enormous disease burden associated with Trichuris colonization, the mechanisms underlying this transkingdom interaction have been obscure. Here, we used a multiscale microscopy approach to define the structural events associated with bacteria-mediated hatching of eggs for the murine model parasite Trichuris muris. Through the combination of scanning electron microscopy (SEM) and serial block face SEM (SBFSEM), we visualized the outer surface morphology of the shell and generated 3D structures of the egg and larva during the hatching process. These images revealed that exposure to hatching-inducing bacteria catalyzed asymmetric degradation of the polar plugs prior to exit by the larva. Unrelated bacteria induced similar loss of electron density and dissolution of the structural integrity of the plugs. Egg hatching was most efficient when high densities of bacteria were bound to the poles. Consistent with the ability of taxonomically distant bacteria to induce hatching, additional results suggest chitinase released from larva within the eggs degrade the plugs from the inside instead of enzymes produced by bacteria in the external environment. These findings define at ultrastructure resolution the evolutionary adaptation of a parasite for the microbe-rich environment of the mammalian gut.

"It Comes in Steps and Stages": Experiences of People Living with HIV in Achieving Employment.

People living with HIV who are seeking jobs experience unique barriers to obtaining employment at the individual, group, and community levels. Traditional employment assistance programs can provide support but may not be tailored to some people living with HIV who often experience barriers to work related to their social needs (such as housing instability) or their lack of consistent engagement in the workforce. To understand how people living with HIV return to work, in-depth interviews were conducted with 43 participants enrolled in interventions coordinating HIV care with housing and employment services at eight sites across the US. Four themes emerged on strategies to increase employment: (1) assessing and responding to employment needs that align with their socio-economic environment; (2) using social networks among family and friends for referrals and support; (3) engaging with navigators who are able to connect clients to skills building opportunities and job resources; and (4) addressing the system barriers such as helping with unmet basic needs (e.g. transportation), finding employers who can accommodate workers with income limits associated with public benefits, and helping immigrants, transgender individuals, and people experiencing homelessness secure legal documentsthat facilitate entry into employment by reducing stigmatized identities.

Rapid start antiretroviral therapies for improved engagement in HIV care: implementation science evaluation protocol.

BACKGROUND: In 2020, the Health Resources and Services Administration's HIV/AIDS Bureau funded an initiative to promote implementation of rapid antiretroviral therapy initiation in 14 HIV treatment settings across the U.S. The goal of this initiative is to accelerate uptake of this evidence-based strategy and provide an implementation blueprint for other HIV care settings to reduce the time from HIV diagnosis to entry into care, for re-engagement in care for those out of care, initiation of treatment, and viral suppression. As part of the effort, an evaluation and technical assistance provider (ETAP) was funded to study implementation of the model in the 14 implementation sites. METHOD: The ETAP has used implementation science methods framed by the Dynamic Capabilities Model integrated with the Conceptual Model of Implementation Research to develop a Hybrid Type II, multi-site mixed-methods evaluation, described in this paper. The results of the evaluation will describe strategies associated with uptake, implementation outcomes, and HIV-related health outcomes for patients. DISCUSSION: This approach will allow us to understand in detail the processes that sites to implement and integrate rapid initiation of antiretroviral therapy as standard of care as a means of achieving equity in HIV care.