Discovery of RXFP2 genetic association in resistant hypertensive men and RXFP2 antagonists for the treatment of resistant hypertension.

Hypertension remains a leading cause of cardiovascular and kidney diseases. Failure to control blood pressure with ≥ 3 medications or control requiring ≥ 4 medications is classified as resistant hypertension (rHTN) and new therapies are needed to reduce the resulting increased risk of morbidity and mortality. Here, we report genetic evidence that relaxin family peptide receptor 2 (RXFP2) is associated with rHTN in men, but not in women. This study shows that adrenal gland gene expression of RXFP2 is increased in men with hypertension and the RXFP2 natural ligand, INSL3, increases adrenal steroidogenesis and corticosteroid secretion in human adrenal cells. To address the hypothesis that RXFP2 activation is an important mechanism in rHTN, we discovered and characterized small molecule and monoclonal antibody (mAb) blockers of RXFP2. The novel chemical entities and mAbs show potent, selective inhibition of RXFP2 and reduce aldosterone and cortisol synthesis and release. The RXFP2 mAbs have suitable rat pharmacokinetic profiles to evaluate the role of RXFP2 in the development and maintenance of rHTN. Overall, we identified RXFP2 activity as a potential new mechanism in rHTN and discovered RXFP2 antagonists for the future interrogation of RXFP2 in cardiovascular and renal diseases.

HIV and Syphilis Co-Screening Rates Among Patients Tested for Gonorrhea and Chlamydia at a Large, Urban Hospital.

BACKGROUND: Current guidelines recommend concurrent screening for HIV and syphilis with gonorrhea and chlamydia testing. Despite this, many patients are still not screened. This study describes trends in demographics and encounter locations associated with missed opportunities for HIV and syphilis screening among patients tested for gonorrhea or chlamydia. METHODS: This is a retrospective review of all encounters with gonorrhea or chlamydia testing in a large, urban hospital from November 1, 2018, to July 31, 2021. Demographic information and encounter location were extracted from the medical record. Encounters were categorized as including both HIV and syphilis (complete) screening, HIV screening only, or neither. Logistic regression was used to examine associations between demographics and encounter location and likelihood of complete screening. RESULTS: There were 42,791 patient encounters, of which 40.2% had complete screening, 6.2% had concurrent HIV screening only, and 53.6% had no concurrent screening. Increasing age, female sex (aOR 0.58, 95% CI 0.55-0.61, p < 0.01), non-Hispanic Black race (aOR 0.52, 95% CI 0.49-0.55, p < 0.01), and public insurance (aOR 0.72, 95% CI 0.69-0.75, p < 0.01) were associated with lower odds of complete screening. Emergency department (ED) encounters were most likely to include complete screening (aOR 3.11, 95% CI 2.96-3.26, p < 0.01). CONCLUSIONS: This study found a large proportion of patients tested for gonorrhea and chlamydia had missed opportunities for HIV and syphilis screening. Significant demographic disparities were found. The ED was most likely to screen for both HIV and syphilis. Decreasing disparities in screening could have profound effects on the HIV and syphilis epidemics.

Assessing Patient Acceptance of an Automated Algorithm to Identify Ciswomen for HIV Pre-Exposure Prophylaxis.

The use of HIV pre-exposure prophylaxis (PrEP) in cisgender women (ciswomen) lags far behind their need. Data elements from the electronic medical record (EMR), including diagnosis of a sexually transmitted infection (STI), can be incorporated into automated algorithms for identifying clients who are most vulnerable to HIV and would benefit from PrEP. However, it is unknown how women feel about the use of such technology. In this study, we assessed women's attitudes and opinions about an automated EMR-based HIV risk algorithm and determined if their perspectives varied by level of HIV risk. Respondents were identified using best practice alerts or referral to a clinic for STI symptoms from January to December 2021 in Chicago, IL. Participants were asked about HIV risk factors, their self-perceived HIV risk, and their thoughts regarding an algorithm to identify ciswomen who could benefit from PrEP. Most of the 112 women who completed the survey (85%) thought they were at low risk for HIV, despite high rates of STI diagnoses. The majority were comfortable with the use of this algorithm, but their comfort level dropped when asked about the algorithm identifying them specifically. Ciswomen had mixed feelings about the use of an automated HIV risk algorithm, citing it as a potentially helpful and empowering tool for women, yet raising concerns about invasion of privacy and potential racial bias. Clinics must balance the benefits of using an EMR-based algorithm for ciswomen with their concerns about privacy and bias to improve PrEP uptake among particularly vulnerable women.

eFluorination of Activated Alcohols Using Collidinium Tetrafluoroborate.

Tertiary C-F bonds are important structural designs; however, they suffer from challenging synthesis. Current methodologies use corrosive amine-HF salts or expensive and hazardous catalysts and reagents. Our group recently introduced collidinium tetrafluoroborate as an efficient fluorinating agent for anodic decarboxyfluorination reactions. Nevertheless, tertiary carboxylic acids are less readily available and more challenging to prepare than their alcohol analogues. Herein we report a practical, mild, and cheap electrochemical method to achieve deoxyfluorination of hindered carbon centers.

Copper-Mediated N-Trifluoromethylation of O-Benzoylhydroxylamines.

The use of trifluoromethyl containing compounds is well established within medicinal chemistry, with a range of approved drugs containing C-CF3 and O-CF3 moieties. However, the utilisation of the N-CF3 functional group remains relatively unexplored. This may be attributed to the challenging synthesis of this unit, with many current methods employing harsh conditions or less accessible reagents. A robust methodology for the N-trifluoromethylation of secondary amines has been developed, which employs an umpolung strategy in the form of a copper-catalysed electrophilic amination. The method is operationally simple, uses mild, inexpensive reagents, and has been used to synthesise a range of novel, structurally complex N-CF3 containing compounds.

Avacopan, a Novel Competitive C5a Receptor Antagonist, for Severe Antineutrophil Cytoplasmic Autoantibody-Associated Vasculitis.

Avacopan is a relatively novel drug with complement antagonizing properties, and it has demonstrated promising outcomes in treating antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis. This review article seeks to investigate the current standard of care for ANCA vasculitis with the combination of avacopan. The current standard therapy involves the usage of daily corticosteroids in addition to either cyclophosphamide or rituximab; however, prolonged use of corticosteroids is known to be associated with various adverse effects. Avacopan was introduced as a possible substitution to alleviate high-corticosteroid dosages. It functions through competitive inhibition of the C5a receptor in the complement system and results in the reduction of neutrophil activation and migration to sites of inflammation. Clinical trials have observed the efficacy of avacopan both in conjunction with standard therapy with corticosteroids and without corticosteroids. The use of avacopan was able to achieve disease remission and improve renal function in patients with ANCA-associated vasculitis. Additionally, the novel treatment did not increase the risk of adverse events during treatment, while also lowering the toxic effects associated with corticosteroid usage. In summary, current evidence supports the success and safety of administering avacopan to treat patients with ANCA-associated vasculitis. Additional clinical trials are warranted to identify optimal dosage and method in using avacopan in the clinical setting.

eHydrogenation: Hydrogen-free Electrochemical Hydrogenation.

Hydrogenation reactions are staple transformations commonly used across scientific fields to synthesise pharmaceuticals, natural products, and various functional materials. However, the vast majority of these reactions require the use of a toxic and costly catalyst leading to unpractical, hazardous and often functionally limited conditions. Herein, we report a new, general, practical, efficient, mild and high-yielding hydrogen-free electrochemical method for the reduction of alkene, alkyne, nitro and azido groups. Finally, this method has been applied to deuterium labelling.

PrEP Persistence Support and Monitoring in Areas of High HIV Burden in the Midwestern United States.

Monitoring pre-exposure prophylaxis (PrEP) metrics can guide service delivery yet does not occur routinely. We developed a survey to understand current practices for monitoring PrEP at PrEP-providing organizations in Illinois and Missouri. The survey was distributed from September through November 2020; 26 organizations participated. Most respondents indicated ongoing efforts to screen for PrEP eligibility (66.7%), link to care (87.5%), and retain clients in care (70.8%); 70.8% reported collecting data on PrEP initiation, 41.7% on retention in care, and 37.5% on missed visits. Barriers to monitoring PrEP metrics included lack of IT support (69.6%), manual processes (69.6%), and lack of staff resources (65.2%). Most respondents offered clients support for PrEP retention and adherence and wanted to expand interventions for PrEP persistence, yet fewer monitored corresponding metrics. To enhance PrEP implementation, organizations should improve monitoring and evaluation of PrEP metrics along the entire continuum and respond with appropriate services to support clients.

Development of a predictive model for identifying women vulnerable to HIV in Chicago.

INTRODUCTION: Researchers in the United States have created several models to predict persons most at risk for HIV. Many of these predictive models use data from all persons newly diagnosed with HIV, the majority of whom are men, and specifically men who have sex with men (MSM). Consequently, risk factors identified by these models are biased toward features that apply only to men or capture sexual behaviours of MSM. We sought to create a predictive model for women using cohort data from two major hospitals in Chicago with large opt-out HIV screening programs. METHODS: We matched 48 newly diagnosed women to 192 HIV-negative women based on number of previous encounters at University of Chicago or Rush University hospitals. We examined data for each woman for the two years prior to either their HIV diagnosis or their last encounter. We assessed risk factors including demographic characteristics and clinical diagnoses taken from patient electronic medical records (EMR) using odds ratios and 95% confidence intervals. We created a multivariable logistic regression model and measured predictive power with the area under the curve (AUC). In the multivariable model, age group, race, and ethnicity were included a priori due to increased risk for HIV among specific demographic groups. RESULTS: The following clinical diagnoses were significant at the bivariate level and were included in the model: pregnancy (OR 1.96 (1.00, 3.84)), hepatitis C (OR 5.73 (1.24, 26.51)), substance use (OR 3.12 (1.12, 8.65)) and sexually transmitted infections (STIs) chlamydia, gonorrhoea, or syphilis. We also a priori included demographic factors that are associated with HIV. Our final model had an AUC of 0.74 and included healthcare site, age group, race, ethnicity, pregnancy, hepatitis C, substance use, and STI diagnosis. CONCLUSIONS: Our predictive model showed acceptable discrimination between those who were and were not newly diagnosed with HIV. We identified risk factors such as recent pregnancy, recent hepatitis C diagnosis, and substance use in addition to the traditionally used recent STI diagnosis that can be incorporated by health systems to detect women who are vulnerable to HIV and would benefit from preexposure prophylaxis (PrEP).

Predictive Modeling of Lapses in Care for People Living with HIV in Chicago: Algorithm Development and Interpretation.

BACKGROUND: Reducing care lapses for people living with HIV is critical to ending the HIV epidemic and beneficial for their health. Predictive modeling can identify clinical factors associated with HIV care lapses. Previous studies have identified these factors within a single clinic or using a national network of clinics, but public health strategies to improve retention in care in the United States often occur within a regional jurisdiction (eg, a city or county). OBJECTIVE: We sought to build predictive models of HIV care lapses using a large, multisite, noncurated database of electronic health records (EHRs) in Chicago, Illinois. METHODS: We used 2011-2019 data from the Chicago Area Patient-Centered Outcomes Research Network (CAPriCORN), a database including multiple health systems, covering the majority of 23,580 people with an HIV diagnosis living in Chicago. CAPriCORN uses a hash-based data deduplication method to follow people across multiple Chicago health care systems with different EHRs, providing a unique citywide view of retention in HIV care. From the database, we used diagnosis codes, medications, laboratory tests, demographics, and encounter information to build predictive models. Our primary outcome was lapses in HIV care, defined as having more than 12 months between subsequent HIV care encounters. We built logistic regression, random forest, elastic net logistic regression, and XGBoost models using all variables and compared their performance to a baseline logistic regression model containing only demographics and retention history. RESULTS: We included people living with HIV with at least 2 HIV care encounters in the database, yielding 16,930 people living with HIV with 191,492 encounters. All models outperformed the baseline logistic regression model, with the most improvement from the XGBoost model (area under the receiver operating characteristic curve 0.776, 95% CI 0.768-0.784 vs 0.674, 95% CI 0.664-0.683; P<.001). Top predictors included the history of care lapses, being seen by an infectious disease provider (vs a primary care provider), site of care, Hispanic ethnicity, and previous HIV laboratory testing. The random forest model (area under the receiver operating characteristic curve 0.751, 95% CI 0.742-0.759) revealed age, insurance type, and chronic comorbidities (eg, hypertension), as important variables in predicting a care lapse. CONCLUSIONS: We used a real-world approach to leverage the full scope of data available in modern EHRs to predict HIV care lapses. Our findings reinforce previously known factors, such as the history of prior care lapses, while also showing the importance of laboratory testing, chronic comorbidities, sociodemographic characteristics, and clinic-specific factors for predicting care lapses for people living with HIV in Chicago. We provide a framework for others to use data from multiple different health care systems within a single city to examine lapses in care using EHR data, which will aid in jurisdictional efforts to improve retention in HIV care.

eFluorination Using Cheap and Readily Available Tetrafluoroborate Salts.

A practical electrochemical method for the rapid, safer, and mild synthesis of tertiary hindered alkyl fluorides from carboxylic acids has been developed without the need for hydrofluoric acid salts or non-glass reactors. In this anodic fluorination, collidinium tetrafluoroborate acts as both the supporting electrolyte and fluoride donor. A wide range of functional groups has been shown to be compatible, and the possibility of scale-up using flow electrochemistry has also been demonstrated.

No-show Prediction Model Performance Among People With HIV: External Validation Study.

BACKGROUND: Regular medical care is important for people living with HIV. A no-show predictive model among people with HIV could improve clinical care by allowing providers to proactively engage patients at high risk of missing appointments. Epic, a major provider of electronic medical record systems, created a model that predicts a patient's probability of being a no-show for an outpatient health care appointment; however, this model has not been externally validated in people with HIV. OBJECTIVE: We examined the performance of Epic's no-show model among people with HIV at an academic medical center and assessed whether the performance was impacted by the addition of demographic and HIV clinical information. METHODS: We obtained encounter data from all in-person appointments among people with HIV from January 21 to March 30, 2022, at the University of Chicago Medicine. We compared the predicted no-show probability at the time of the encounter to the actual outcome of these appointments. We also examined the performance of the Epic model among people with HIV for only HIV care appointments in the infectious diseases department. We further compared the no-show model among people with HIV for HIV care appointments to an alternate random forest model we created using a subset of seven readily accessible features used in the Epic model and four additional features related to HIV clinical care or demographics. RESULTS: We identified 674 people with HIV who contributed 1406 total scheduled in-person appointments during the study period. Of those, we identified 331 people with HIV who contributed 440 HIV care appointments. The performance of the Epic model among people with HIV for all appointments in any outpatient clinic had an area under the receiver operating characteristic curve (AUC) of 0.65 (95% CI 0.63-0.66) and for only HIV care appointments had an AUC of 0.63 (95% CI 0.59-0.67). The alternate model we created for people with HIV attending HIV care appointments had an AUC of 0.78 (95% CI 0.75-0.82), a significant improvement over the Epic model restricted to HIV care appointments (P<.001). Features identified as important in the alternate model included lead time, appointment length, HIV viral load >200 copies per mL, lower CD4 T cell counts (both 50 to <200 cells/mm3 and 200 to <350 cells/mm3), and female sex. CONCLUSIONS: For both models among people with HIV, performance was significantly lower than reported by Epic. The improvement in the performance of the alternate model over the proprietary Epic model demonstrates that, among people with HIV, the inclusion of demographic information may enhance the prediction of appointment attendance. The alternate model further reveals that the prediction of appointment attendance in people with HIV can be improved by using HIV clinical information such as CD4 count and HIV viral load test results as features in the model.

Trends in STI testing and diagnosis rates during the COVID-19 pandemic at a large urban tertiary care center, and the role of the emergency department in STI care.

Introduction: The COVID-19 pandemic has had profound effects on access to care, including outpatient sexually transmitted infection (STI) testing and treatment. Many vulnerable populations already relied on the emergency department (ED) for much of their care prior to the pandemic. This study examines trends in STI testing and positivity before and during the pandemic at a large urban medical center and evaluates the role of the ED in providing STI care. Methods: This is a retrospective review of all gonorrhea, chlamydia, and trichomonas tests from November 1, 2018, through July 31, 2021. Demographic information and location and results of STI testing were extracted from the electronic medical record. Trends in STI testing and positivity were examined for 16 month periods before and after the COVID-19 pandemic started (March 15, 2020), with the latter divided into the early pandemic period (EPP: March 15 -July 31, 2020) and late pandemic period (LPP: August 1, 2020 - July 31, 2021). Results: Tests per month decreased by 42.4% during the EPP, but rebounded by July 2020. During the EPP, the proportion of all STI testing originating in the ED increased from 21.4% pre-pandemic to 29.3%, and among pregnant women from 45.2% to 51.5%. Overall STI positivity rate increased from 4.4% pre-pandemic to 6.2% in the EPP. Parallel trends were observed for gonorrhea and chlamydia individually. The ED represented 50.5% of overall positive tests, and as much as 63.1% of positive testing during the EPP. The ED was the source of 73.4% of positive tests among pregnant women, which increased to 82.1% during the EPP. Conclusions: STI trends from this large urban medical center paralleled national trends, with an early decrease in positive cases followed by a rebound by the end of May 2020. The ED represented an important source of testing for all patients, and especially for pregnant patients, throughout the study period, but even more so early in the pandemic. This suggests that more resources should be directed towards STI testing, education, and prevention in the ED, as well as to support linkage to outpatient primary and obstetric care during the ED visit.

Electrochemical Isothiocyanation of Primary Amines.

Isothiocyanates are ubiquitous building blocks used across the fields. Nevertheless, their classical syntheses very often rely on the use of toxic and expensive reagents. Herein, we report a new practical, mild, high-yielding, and supporting-electrolyte-free electrochemical method for the preparation of aliphatic and aromatic isothiocyanates from amine and carbon disulfide.

Measuring Retention in HIV Care in the First Year of the COVID-19 Pandemic: The Impact of Telehealth.

It is unknown how the COVID-19 pandemic impacted traditional measures of retention in HIV care. We calculated six different retention measures at an urban HIV care clinic for two time periods: pre-pandemic, and during the first year of the COVID-19 pandemic, with and without inclusion of telehealth appointments. Spearman rank correlation was used to assess correlation between different measures of retention. For both the pre-pandemic and pandemic time periods, there was strong correlation among measures of missed visits (range 0.857-0.957). More patients were considered retained in care during the pandemic when telehealth appointments were included in the analysis.

Clostridioides difficile Infection: A Clinical Review of Pathogenesis, Clinical Considerations, and Treatment Strategies.

BACKGROUND: Clostridioides difficile infection (CDI) is a common nosocomial infection. Risk factors for developing CDI include prior hospitalization, being older than 65 years old, antibiotic use, and chronic disease. It is linked with diarrhea and colitis and can vary in severity. It is a major cause of increased morbidity and mortality among hospitalized patients. However, community-acquired CDI is also increasing. Proper diagnosis and determination of severity are crucial for the treatment of CDI. Depending on how severe the CDI is, the patient may endorse different symptoms and physical exam findings. The severity of CDI will determine how aggressively it is treated. Management and treatment: Laboratory studies can be helpful in the diagnosis of CDI. In this regard, common labs include complete blood count, stool assays, and, in certain cases, radiography and endoscopy. Mild-to-moderate colitis is treated with antibiotics, but severe colitis requires a different approach, which may include surgery. Several alternative therapies for CDI exist and have shown promising results. This review will touch upon these therapies, which include fecal transplants, intravenous immunoglobulin, and the use of cholestyramine and tigecycline. CONCLUSION: Prevention of CDI can be achieved by proper hygiene, vaccinations, and detecting the infection early. Proper hygiene is indeed noted to be one of the best ways to prevent CDI in the hospital setting. Overprescribing antibiotics is also another huge reason why CDI occurs. Proper prescription of antibiotics can also help reduce the chances of acquiring CDI.

Comparison of algorithms for identifying people with HIV from electronic medical records in a large, multi-site database.

Objective: As electronic medical record (EMR) data are increasingly used in HIV clinical and epidemiologic research, accurately identifying people with HIV (PWH) from EMR data is paramount. We sought to evaluate EMR data types and compare EMR algorithms for identifying PWH in a multicenter EMR database. Materials and Methods: We collected EMR data from 7 healthcare systems in the Chicago Area Patient-Centered Outcomes Research Network (CAPriCORN) including diagnosis codes, anti-retroviral therapy (ART), and laboratory test results. Results: In total, 13 935 patients had a positive laboratory test for HIV; 33 412 patients had a diagnosis code for HIV; and 17 725 patients were on ART. Only 8576 patients had evidence of HIV-positive status for all 3 data types (laboratory results, diagnosis code, and ART). A previously validated combination algorithm identified 22 411 patients as PWH. Conclusion: EMR algorithms that combine laboratory results, administrative data, and ART can be applied to multicenter EMR data to identify PWH.

Critical transitions in Chinese dunes during the past 12,000 years.

Dune systems can have alternative stable states that coexist under certain environmental conditions: a vegetated, stabilized state and a bare active state. This behavior implies the possibility of abrupt transitions from one state to another in response to gradual environmental change. Here, we synthesize stratigraphic records covering 12,000 years of dynamics of this system at 144 localities across three dune fields in northern China. We find side-by-side coexistence of active and stabilized states, and occasional sharp shifts in time between those contrasting states. Those shifts occur asynchronously despite the fact that the entire landscape has been subject to the same gradual changes in monsoon rainfall and other conditions. At larger scale, the spatial heterogeneity in dune dynamics averages out to produce relatively smooth change. However, our results do show different paths of recovery and collapse of vegetation at system-wide scales, implying that hysteretic behavior occurs in spatially extended systems.

A Genomic DNA Reporter Screen Identifies Squalene Synthase Inhibitors That Act Cooperatively with Statins to Upregulate the Low-Density Lipoprotein Receptor.

Hypercholesterolemia remains one of the leading risk factors for the development of cardiovascular disease. Many large double-blind studies have demonstrated that lowering low-density lipoprotein (LDL) cholesterol using a statin can reduce the risk of having a cardiovascular event by approximately 30%. However, despite the success of statins, some patient populations are unable to lower their LDL cholesterol to meet the targeted lipid levels, due to compliance or potency issues. This is especially true for patients with heterozygous familial hypercholesterolemia who may require additional upregulation of the low-density lipoprotein receptor (LDLR) to reduce LDL cholesterol levels below those achievable with maximal dosing of statins. Here we identify a series of small molecules from a genomic DNA reporter screen that upregulate the LDLR in mouse and human liver cell lines at nanomolar potencies (EC50 = 39 nM). Structure-activity relationship studies carried out on the lead compound, OX03771 [(E)-N,N-dimethyl-3-(4-styrylphenoxy)propan-1-amine], led to the identification of compound OX03050 [(E)-3-(4-styrylphenoxy)propan-1-ol], which had similar potency (EC50 = 26 nM) but a much-improved pharmacokinetic profile and showed in vivo efficacy. Compounds OX03050 and OX03771 were found to inhibit squalene synthase, the first committed step in cholesterol biosynthesis. These squalene synthase inhibitors were shown to act cooperatively with statins to increase LDLR expression in vitro. Overall, we demonstrated here a novel series of small molecules with the potential to be further developed to treat patients either alone or in combination with statins.

Surface modification imparts selectivity, facilitating redox catalytic studies: quinone mediated oxygen reduction.

Modifying a gold electrode surface with hydroxy-alkyl-thiols significantly reduces the observed rate of electron transfer. This designed and controlled decrease in electron transfer rate readily allows reversible and irreversible electrode processes to be more clearly delineated. Separation of such voltammetric responses can facilitate the direct study of redox catalytic processes, which would, under other experimental conditions be obscured. The reduction of oxygen by anthraquinone hydroxy derivatives are used as a paradigmatic example, demonstrating the importance of the hydroxyl groups in the reduction process. Specifically, the reduced form of 1,8-dihydroxy-anthraquinone is shown to be significantly more reactive towards oxygen reduction than the 1,4-dihydroxyl analogue.