2023 AHA/ACC/ACCP/ASPC/NLA/PCNA Guideline for the Management of Patients With Chronic Coronary Disease: A Report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines.

AIM: The "2023 AHA/ACC/ACCP/ASPC/NLA/PCNA Guideline for the Management of Patients With Chronic Coronary Disease" provides an update to and consolidates new evidence since the "2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS Guideline for the Diagnosis and Management of Patients With Stable Ischemic Heart Disease" and the corresponding "2014 ACC/AHA/AATS/PCNA/SCAI/STS Focused Update of the Guideline for the Diagnosis and Management of Patients With Stable Ischemic Heart Disease." METHODS: A comprehensive literature search was conducted from September 2021 to May 2022. Clinical studies, systematic reviews and meta-analyses, and other evidence conducted on human participants were identified that were published in English from MEDLINE (through PubMed), EMBASE, the Cochrane Library, Agency for Healthcare Research and Quality, and other selected databases relevant to this guideline. STRUCTURE: This guideline provides an evidenced-based and patient-centered approach to management of patients with chronic coronary disease, considering social determinants of health and incorporating the principles of shared decision-making and team-based care. Relevant topics include general approaches to treatment decisions, guideline-directed management and therapy to reduce symptoms and future cardiovascular events, decision-making pertaining to revascularization in patients with chronic coronary disease, recommendations for management in special populations, patient follow-up and monitoring, evidence gaps, and areas in need of future research. Where applicable, and based on availability of cost-effectiveness data, cost-value recommendations are also provided for clinicians. Many recommendations from previously published guidelines have been updated with new evidence, and new recommendations have been created when supported by published data.

Early Conversion to Everolimus Within 180 Days of Living Donor Liver Transplantation.

BACKGROUND: Early conversion to Everolimus (EVR) post deceased donor liver transplant has been associated with improved renal function but increased rejection. Early EVR conversion has not been evaluated after living donor liver transplant (LDLT). A retrospective cohort study was conducted to compare the rate of rejection and renal function in patients converted to EVR early post-LDLT to patients on calcineurin inhibitors (CNIs). METHODS: This was a single center retrospective cohort study of adult LDLT recipients between January 2012 and July 2019. Patients converted to EVR within 180 days of transplant were compared to patients on CNIs. The primary endpoint was biopsy proven acute rejection (BPAR) at 24 months posttransplant. Key secondary endpoints included eGFR at 24 months, change in eGFR, adverse events, and all-cause mortality. RESULTS: From a total of 173 patients involved in the study: 58 were included in the EVR group and 115 in the CNI group. Median conversion to EVR was 26 days post-LDLT. At 24 months, there was no difference in BPAR (22.7% EVR vs. 19.1% CNI, p = 0.63). Median eGFR at 24 months posttransplant was not significantly different (68.6 [24.8 to 112.4] mL/min EVR vs. 75.9 [35.6-116.2] mL/min CNI, p = 0.103). Change in eGFR from baseline was worse in the EVR group (-13.0 [-39.9 to 13.9] mL/min EVR vs. -5.0 [-31.2 to 21.2] mL/min CNI, p = 0.047). Median change from conversion to 24 months posttransplant (EVR group only) was -3.43 mL/min/1.73 m2 (-21.0 to 9.6). CONCLUSIONS: Early EVR conversion was not associated with increased risk of rejection among LDLT recipients. Renal function was not impacted. EVR may be considered as an alternative after LDLT in patients intolerant of CNIs.

Outcomes from Partner2Lose: a randomized controlled trial to evaluate 24-month weight loss in a partner-assisted intervention.

BACKGROUND: Partner support is associated with better weight loss outcomes in observational studies, but randomized trials show mixed results for including partners. Unclear is whether teaching communication skills to couples will improve weight loss in a person attempting weight loss (index participant). PURPOSE: To compare the efficacy of a partner-assisted intervention versus participant-only weight management program on 24-month weight loss. METHODS: This community-based study took place in Madison, WI. Index participants were eligible if they met obesity guideline criteria to receive weight loss counseling, were aged 18-74 years, lived with a partner, and had no medical contraindications to weight loss; partners were aged 18-74 years and not underweight. Couples were randomized 1:1 to a partner-assisted or participant-only intervention. Index participants in both arms received an evidence-based weight management program. In the partner-assisted arm, partners attended half of the intervention sessions, and couples were trained in communication skills. The primary outcome was index participant weight at 24 months, assessed by masked personnel; secondary outcomes were 24-month self-reported caloric intake and average daily steps assessed by an activity tracker. General linear mixed models were used to compare group differences in these outcomes following intent-to-treat principles. RESULTS: Among couples assigned to partner-assisted (n = 115) or participant-only intervention (n = 116), most index participants identified as female (67%) and non-Hispanic White (87%). Average baseline age was 47.27 years (SD 11.51 years) and weight was 106.55 kg (SD 19.41 kg). The estimated mean 24-month weight loss was similar in the partner-assisted (2.66 kg) and participant-only arms (2.89 kg) (estimated mean difference, 0.23 kg [95% CI, -1.58, 2.04 kg], p=0.80). There were no differences in 24-month average daily caloric intake (estimated mean difference 50 cal [95% CI: -233, 132 cal], p=0.59) or steps (estimated mean difference 806 steps [95% CI: -1675, 64 steps], p=0.07). The percentage of participants reporting an adverse event with at least possible attribution to the intervention did not differ by arm (partner-assisted: 9%, participant-only, 3%, p = 0.11). CONCLUSIONS: Partner-assisted and individual weight management interventions led to similar outcomes in index participants. TRIAL REGISTRATION: Clinicaltrials.gov NCT03801174, January 11, 2019.

Women Veterans' Barriers to Care-Seeking for Cardiovascular Disease Prevention.

BACKGROUND: Women veterans have a high prevalence of traditional and nontraditional risks for cardiovascular disease (CVD) including obesity and posttraumatic stress disorder. Experts from the U.S. Department of Veterans Affairs have called for actions to improve the cardiovascular health of this population. One approach is to assess women veterans' barriers to care-seeking for CVD prevention, to inform future intervention research. OBJECTIVE: The objective of this study was to describe women veterans' barriers to care-seeking for CVD prevention, guided by the theory of care-seeking behavior and concept awareness. METHODS: Using a cross-sectional, descriptive design, a national sample of 245 women veterans participated in an online survey about barriers to care-seeking. Participants provided narrative responses to open-ended items, endorsements to closed-ended items, and rankings of their top five barriers. Researchers conducted poststratification weighting of numerical data to reflect the women veteran population. RESULTS: Narrative responses described unaffordable and inaccessible services, feeling harassed or not respected in healthcare settings, and lack of awareness of risks for CVD. Frequently endorsed barriers were unaffordable and inaccessible services. Frequently ranked barriers were feeling not respected in healthcare settings and clinicians not recommending CVD prevention. DISCUSSION: Findings support concepts in theory of care-seeking behavior and concept awareness. Understanding women veterans' barriers to care-seeking for CVD prevention can inform clinicians and researchers as they address these barriers.

Effects of vehicle traffic on space use and road crossings of caribou in the Arctic.

Assessing the effects of industrial development on wildlife is a key objective of managers and conservation practitioners. However, wildlife responses are often only investigated with respect to the footprint of infrastructure, even though human activity can strongly mediate development impacts. In Arctic Alaska, there is substantial interest in expanding energy development, raising concerns about the potential effects on barren-ground caribou (Rangifer tarandus granti). While caribou generally avoid industrial infrastructure, little is known about the role of human activity in moderating their responses, and whether managing activity levels could minimize development effects. To address this uncertainty, we examined the influence of traffic volume on caribou summer space use and road crossings in the Central Arctic Herd within the Kuparuk and Milne Point oil fields on the North Slope of Alaska. We first modeled spatiotemporal variation in hourly traffic volumes across the road system from traffic counter data using gradient-boosted regression trees. We then used generalized additive models to estimate nonlinear step selection functions and road-crossing probabilities from collared female caribou during the post-calving and insect harassment seasons, when they primarily interact with roads. Step selection analyses revealed that caribou selected areas further from roads (~1-3 km) during the post-calving and mosquito seasons and selected areas with lower traffic volumes during all seasons, with selection probabilities peaking when traffic was <5 vehicles/h. Using road-crossing models, we found that caribou were less likely to cross roads during the insect seasons as traffic increased, but that response dissipated as insect harassment became more severe. Past studies suggested that caribou exhibit behavioral responses when traffic exceeds 15 vehicles/h, but our results demonstrate behavioral responses at much lower traffic levels. Our results illustrate that vehicle activity mediates caribou responses to road infrastructure, information that can be used in future land-use planning to minimize the behavioral responses of caribou to industrial development in sensitive Arctic landscapes.

"They Have Shown Me It Is Possible to Thrive within STEM": Incorporating Learning Assistants in General Chemistry Enhances Student Belonging and Confidence.

Students often experience social and psychological barriers to success in General Chemistry, which is a key gateway to many students' science pathways. Learning assistants (LAs) have the potential to reduce these barriers and to strengthen students' sense of belonging in General Chemistry and STEM more broadly. Here, we used a 17-item Likert scale to determine whether incorporating LAs into General Chemistry I and II enhances students' sense of belonging in these courses. The incorporation of LAs into General Chemistry I had a significant positive effect and a medium to large effect size for students in all student groups examined: women and men; students in both racially and ethnically underrepresented and well-represented groups; first- and continuing-generation students. In General Chemistry II, similar results were observed for women and men; students in well-represented racial and ethnic groups; continuing-generation students. Further, we asked students to reflect on the impact that working with LAs had on their sense of belonging in STEM and confidence in talking about science. Sixty percent of students indicated that working with LAs had a positive impact on their STEM belonging, with five themes describing LA impacts: reducing isolation, serving as inspirational role models, providing mentoring, increasing opportunities for engagement and confidence building, and serving as accessible and approachable sources of support. Sixty-one percent of students also indicated that working with LAs increased their confidence in talking about science, with three themes emerging: fostering an environment with a lower risk of negative judgment, providing increased opportunities for feedback, and supporting students as they practiced their growing skills. Together, these results indicate that LAs can be an important means to reduce social and psychological barriers for students in gateway science courses, increasing their sense that they belong to the class and STEM more broadly.

Nickel-Catalyzed Sulfonylation of Aryl Bromides Enabled by Potassium Metabisulfite as a Uniquely Effective SO2 Surrogate.

The development and mechanistic investigation of a nickel-catalyzed sulfonylation of aryl bromides is disclosed. The reaction proceeds in good yields for a variety of substrates and utilizes an inexpensive, stench-free, inorganic sulfur salt (K2 S2 O5 ) as a uniquely effective SO2 surrogate. The active oxidative addition complex was synthesized, isolated, and fully characterized by a combination of NMR spectroscopy and X-ray crystallography analysis. The use of the isolated oxidative addition complex in both stoichiometric and catalytic reactions revealed that SO2 insertion occurs via dissolved SO2 , likely released upon thermal decomposition of K2 S2 O5 . Key to the success of the reaction is the role of K2 S2 O5 as a reservoir of SO2 that is slowly released, thus preventing catalyst poisoning.

Interaction of RIPK1 and A20 modulates MAPK signaling in murine acetaminophen toxicity.

Acetaminophen (APAP)-induced liver necrosis is a form of regulated cell death (RCD) in which APAP activates the mitogen-activated protein kinases (MAPKs) and specifically the c-Jun-N-terminal kinase (JNK) pathway, leading to necrotic cell death. Previously, we have shown that receptor interacting protein kinase-1 (RIPK1) knockdown is also protective against APAP RCD upstream of JNK. However, whether the kinase or platform function of RIPK1 is involved in APAP RCD is not known. To answer this question, we used genetic mouse models of targeted hepatocyte RIPK1 knockout (RIPK1HepCKO) or kinase dead knock-in (RIPK1D138N) and adult hepatocyte specific knockout of the cytoprotective protein A20 (A20HepCKO), known to interact with RIPK1, to study its potential involvement in MAPK signaling. We observed no difference in injury between WT and RIPK1D138N mice post APAP. However, RIPK1HepCKO was protective. We found that RIPK1HepCKO mice had attenuated pJNK activation, while A20 was simultaneously upregulated. Conversely, A20HepCKO markedly worsened liver injury from APAP. Mechanistically, we observed a significant upregulation of apoptosis signal-regulating kinase 1 (ASK1) and increased JNK activation in A20HepCKO mice compared with littermate controls. We also demonstrated that A20 coimmunoprecipitated (co-IP) with both RIPK1 and ASK1, and that in the presence of RIPK1, there was less A20-ASK1 association than in its absence. We conclude that the kinase-independent platform function of RIPK1 is involved in APAP toxicity. Adult RIPK1HepCKO mice are protected against APAP by upregulating A20 and attenuating JNK signaling through ASK1, conversely, A20HepCKO worsens injury from APAP.

Toward Optimal High Continuous Positive Airway Pressure as Postextubation Support in Preterm Neonates: A Retrospective Cohort Study.

OBJECTIVE: This study aimed to evaluate whether the initial pressure level on high continuous positive airway pressure (CPAP; ≥9 cm H2O), in relation to preextubation mean airway pressure (Paw), influences short-term clinical outcomes in preterm neonates. STUDY DESIGN: In this retrospective cohort study, preterm neonates <29 weeks' gestational age (GA) extubated from mean Paw ≥9 cm H2O and to high CPAP (≥9 cm H2O) were classified into "higher level CPAP" (2-3 cm H2O higher than preextubation Paw) and "equivalent CPAP" (-1 to +1 cm H2O in relation to preextubation Paw). Only the first eligible extubation per infant was analyzed. The primary outcome was failure within ≤7 days of extubation, defined as any one or more of (1) need for reintubation, (2) escalation to an alternate noninvasive respiratory support mode, or (3) use of CPAP >preextubation Paw + 3 cm H2O. Secondary outcomes included individual components of the primary outcome, along with other clinical and safety outcomes. RESULTS: Over a 10-year period (Jan 2011-Dec 2020), 175 infants were extubated from mean Paw >9 cm H2O to high CPAP pressures. Twenty-seven patients (median GA = 24.7, [interquartile range (IQR)]: (24.0-26.4) weeks and chronological age = 31, IQR: [21-40] days) were classified into the "higher level CPAP" group while 148 infants (median GA = 25.4, IQR: [24.6-26.6] weeks and chronological age = 26, IQR: [10-39] days) comprised the "equivalent CPAP" group. There was no difference in the primary outcome (44 vs. 51%; p = 0.51), including postadjustment for confounders (adjusted OR [aOR] = 0.47 [95% confidence interval (CI): 0.17-1.29; p = 0.14]). However, reintubation risk within 7 days was lower with higher level CPAP (7 vs. 37%; p < 0.01), including postadjustment (aOR = 0.07; 95% CI: 0.02-0.35; p < 0.01). CONCLUSION: In this cohort, use of initial distending CPAP pressures 2 to 3 cm H2O higher than preextubation Paw did not alter the primary outcome of failure but did lower the risk of reintubation. The latter is an interesting hypothesis-generating finding that requires further confirmation. KEY POINTS: · Use of high CPAP pressures (≥9 cm H2O) is gradually increasing in the care of preterm neonates.. · This study compares higher level versus equivalent CPAP in relation to preextubation Paw.. · The findings demonstrate no difference in failure as defined with use of higher level CPAP pressures..

Establishment and evaluation of scalable COVID-19 vaccine clinics at a large university.

BACKGROUND: Previous large-scale vaccination clinics have been successful before the coronavirus disease 2019 (COVID-19) pandemic; however, owing to the strict storage requirements and pharmaceutical preparation needed for the COVID-19 vaccines, careful thought and planning were necessary to successfully deploy these clinics immediately after vaccine availability. The focus of this manuscript is to describe the development and implementation of COVID-19 vaccination clinics in a large public university, using professionals from within and outside of its health sciences schools. OBJECTIVES: The primary objective of this project was to (1) implement COVID-19 vaccination clinics for university faculty, staff, students, and community members. Additional objectives of the clinics were to (2) actively incorporate pharmacy, nursing, and medical students into the clinic workflow; (3) promote interprofessional collaboration among faculty and students; and (4) assess patient satisfaction. PRACTICE DESCRIPTION: The School of Pharmacy faculty, in conjunction with the Office of Strategic Initiatives, planned and coordinated COVID-19 vaccination clinics from December 2020 to July 2021. Students and faculty from schools of pharmacy, nursing, and medicine were used. COVID-19 vaccinations were offered to university faculty, staff, and students and community members based on the Centers for Disease Control and Prevention priority groups. The clinic processes were designed such that they could be scaled from 100 to 2,000 participants per day. PRACTICE INNOVATION: The School of Pharmacy led approach was adjustable depending on the number of patients, continuously monitored and adaptable. The importance of pharmacists as part of the interprofessional health care team was exemplified by faculty and students involved. EVALUATION METHODS: All patients receiving COVID-19 vaccinations at the clinics were e-mailed anonymous surveys for assessment of the quality of the vaccination encounter after completion of their primary vaccine series. RESULTS: More than 15,000 COVID-19 vaccinations were provided through the clinics from December 2020 to July 2021. Professional staffing totaled 3352 hours for the 48 clinics. Thirty-eight percent of the vaccinated patients responded to the clinic satisfaction survey with predominately excellent ratings. CONCLUSION: COVID-19 vaccination clinics can be successfully planned and implemented in a scalable fashion in a large university setting using an interprofessional team approach.

Advancing Quality Improvement in Public Health by Exploring CQI in Alabama's Home Visiting Program.

Continuous Quality Improvement (CQI) is the use of a deliberate and defined improvement process to advance organizational systems. Quality improvement in public health is increasingly widespread, but there are still limited examples of success or descriptions of developmental trajectories for building CQI capacity. The goal of this article is to add to the extant knowledge on the topic by describing one state's implementation of evidence-based CQI in the Maternal, Infant, and Early Childhood Home Visiting program between 2014 and 2019. On the basis of a systematic review of Annual Yearly Progress reports and semistructured key informant interviews, analysis yielded 3 themes that facilitated successful implementation of CQI in Alabama: starting small and building capacity; engaging in continuous and supported learning; and establishing and maintaining a culture of quality. This project demonstrates that CQI can help public health practitioners refine processes and grow capacity to best serve clients' diverse needs.

A competency roadmap for advanced practice nursing education using PRIME-NP.

BACKGROUND: Clinical competency validation is essential for nurse practitioner (NP) education and public accountability. While there has been robust discussion around what constitutes clinical competency and assessment, clear and consistent definitions and measurements remain elusive. PURPOSE: This article describes the PRIME-NP clinical competency model that is scalable, reproducible and accurately documents NP student competency across clinical courses. METHODS: To develop the model, work in 5 discrete domains was necessary: (a) model development, (b) assessment tool to be used in Objective Structured Clinical Exams (OSCE), (c) rubrics to accompany the OSCE exam, (d) faculty education, and (e) evaluating the model use. FINDINGS: Faculty and student outcomes reveal that the model and assessment tool acceptability and effectiveness of the model, especially for early identification for at risk students. CONCLUSION: The PRIME-NP offered faculty the opportunity to identify at-risk students, identify a more nuanced remediation plan, and assess student competency in simulated environments.

Spring phenology drives range shifts in a migratory Arctic ungulate with key implications for the future.

Annual variation in phenology can have profound effects on the behavior of animals. As climate change advances spring phenology in ecosystems around the globe, it is becoming increasingly important to understand how animals respond to variation in the timing of seasonal events and how their responses may shift in the future. We investigated the influence of spring phenology on the behavior of migratory, barren-ground caribou (Rangifer tarandus), a species that has evolved to cope with short Arctic summers. Specifically, we examined the effect of spring snow melt and vegetation growth on the current and potential future space-use patterns of the Porcupine Caribou Herd (PCH), which exhibits large, inter-annual shifts in their calving and post-calving distributions across the U.S.-Canadian border. We quantified PCH selection for snow melt and vegetation phenology using machine learning models, determined how selection resulted in annual shifts in space-use, and then projected future distributions based on climate-driven phenology models. Caribou exhibited strong, scale-dependent selection for both snow melt and vegetation growth. During the calving season, caribou selected areas at finer scales where the snow had melted and vegetation was greening, but within broader landscapes that were still brown or snow covered. During the post-calving season, they selected vegetation with intermediate biomass expected to have high forage quality. Annual variation in spring phenology predicted major shifts in PCH space-use. In years with early spring phenology, PCH predominately used habitat in Alaska, while in years with late phenology, they spent more time in Yukon. Future climate conditions were projected to advance spring phenology, shifting PCH calving and post-calving distributions further west into Alaska. Our results demonstrate that caribou selection for habitat in specific phenological stages drive dramatic shifts in annual space-use patterns, and will likely affect future distributions, underscoring the importance of maintaining sufficient suitable habitat to allow for behavioral plasticity.

An evaluation of the safety and preliminary efficacy of peri- and post-operative treprostinil in preventing ischemia and reperfusion injury in adult orthotopic liver transplant recipients.

BACKGROUND: Orthotopic liver transplantation (OLT) is the only treatment option for various end-stage liver diseases. Ischemia and reperfusion (I/R) injury is one of the unavoidable complications/conditions in OLT. In 2019, a total of 8896 livers were transplanted of which >94% organs were procured from deceased donors. An increase in the use of extended criteria donor (ECD) livers for transplantation further unraveled the role of hepatic I/R injury on short-term and long-term graft outcomes. Despite promising outcomes with the use of antioxidants, free radical scavengers, and vasodilators; I/R-mediated liver injury persists and significantly influences the overall clinical outcomes. Treprostinil, a synthetic prostacyclin I2  (PGI2 ) analog, due to its vasodilatory property, antiplatelet activity, and its ability to downregulate pro-inflammatory cytokines can potentially minimize I/R injury. AIM: We investigated the safety and preliminary efficacy of continuous intravenous infusion of treprostinil in liver transplant recipients in a prospective, single-center, non-randomized, interventional study. MATERIAL AND METHODS: This was a dose escalation (3 + 3 design) phase 1/2 study. Deceased donor liver transplant recipients received 5 ng/kg/min for two days, or 2.5, 5, and 7.5 ng/min/kg for 5 days as a continuous infusion. Multiple blood samples were collected for biochemical parameter assessment and for measuring treprostinil levels. Indocyanine green plasma disappearance rate was used as a measure of hepatic functional capacity. RESULTS: Subjects tolerated continuous infusion of treprostinil up to 5 ng/kg/min for 120 h with no occurrence of primary graft non-function (PNF), minimized need for ventilation support, reduced hospitalization time, 100% graft and patient survival, and improved hepatobiliary excretory function comparable to normal healthy adults. DISCUSSION: Treprostinil can be administered to liver transplant patients safely during the perioperative period. CONCLUSION: Based on this phase 1/2 study, further efficacy studies of treprostinil in preventing I/R injury of liver should be conducted to potentially increase the number of livers available for transplantation.

Biocatalytic oxidation of alcohols using galactose oxidase and a manganese(III) activator for the synthesis of islatravir.

Galactose oxidase (GOase) is a Cu-dependent metalloenzyme that catalyzes the oxidation of alcohols to aldehydes. An evolved GOase variant was recently shown to catalyze a desymmetrizing oxidation as the first enzymatic step in the biocatalytic synthesis of islatravir. Horseradish peroxidase (HRP) is required to activate the GOase, introducing cost and protein burden to the process. Herein we describe that complexes of earth-abundant Mn(iii) (e.g. Mn(OAc)3) can be used at low loadings (2 mol%) as small molecule alternatives to HRP, providing similar yields and purity profiles. While an induction period is observed when using Mn(OAc)3 as the activator, employment of alternative Mn(iii) sources, such as Mn(acac)3 and K3[Mn(C2O4)3], eliminates the induction period and provides higher conversions to product. We demonstrate that use of the Mn(OAc)3 additive is also compatible with subsequent biocatalytic steps in the islatravir-forming cascade. Finally, to exhibit the wider utility of Mn(OAc)3, we show that Mn(OAc)3 functions as a suitable activator for several commercially available variants of GOase with a series of alcohol substrates.

Politics, patients, and the role of the pharmacist: Addressing social and political issues that affect health care.

Pharmacists are well-respected health care practitioners tasked with providing optimal patient care while operating under an assigned code of ethics. Pharmacists know their responsibility regarding improving patients' health in the examination room, pharmacy, and hospital, but several factors influence the well-being of a patient that are not directly related to their therapy regimens. A patient's actions regarding political and social issues can have an indirect effect on their health and the health of others. As health professionals, are pharmacists duty-bound to alert patients to the impact of public policies on the health care system and their individual health? In addition, should pharmacists be able to assess when interventions are necessary and provide this education? As a profession, pharmacy must work toward creating guidance to help practitioners identify and address these issues with patients and encourage positive outcomes for individual patients and communities as a whole. Political and social issues will continue to become intertwined in the patient-practitioner relationship, and tools must be created to best navigate these delicate topics.

Development and validation of a 25-Gene Panel urine test for prostate cancer diagnosis and potential treatment follow-up.

BACKGROUND: Heterogeneity of prostate cancer (PCa) contributes to inaccurate cancer screening and diagnosis, unnecessary biopsies, and overtreatment. We intended to develop non-invasive urine tests for accurate PCa diagnosis to avoid unnecessary biopsies. METHODS: Using a machine learning program, we identified a 25-Gene Panel classifier for distinguishing PCa and benign prostate. A non-invasive test using pre-biopsy urine samples collected without digital rectal examination (DRE) was used to measure gene expression of the panel using cDNA preamplification followed by real-time qRT-PCR. The 25-Gene Panel urine test was validated in independent multi-center retrospective and prospective studies. The diagnostic performance of the test was assessed against the pathological diagnosis from biopsy by discriminant analysis. Uni- and multivariate logistic regression analysis was performed to assess its diagnostic improvement over PSA and risk factors. In addition, the 25-Gene Panel urine test was used to identify clinically significant PCa. Furthermore, the 25-Gene Panel urine test was assessed in a subset of patients to examine if cancer was detected after prostatectomy. RESULTS: The 25-Gene Panel urine test accurately detected cancer and benign prostate with AUC of 0.946 (95% CI 0.963-0.929) in the retrospective cohort (n = 614), AUC of 0.901 (0.929-0.873) in the prospective cohort (n = 396), and AUC of 0.936 (0.956-0.916) in the large combination cohort (n = 1010). It greatly improved diagnostic accuracy over PSA and risk factors (p < 0.0001). When it was combined with PSA, the AUC increased to 0.961 (0.980-0.942). Importantly, the 25-Gene Panel urine test was able to accurately identify clinically significant and insignificant PCa with AUC of 0.928 (95% CI 0.947-0.909) in the combination cohort (n = 727). In addition, it was able to show the absence of cancer after prostatectomy with high accuracy. CONCLUSIONS: The 25-Gene Panel urine test is the first highly accurate and non-invasive liquid biopsy method without DRE for PCa diagnosis. In clinical practice, it may be used for identifying patients in need of biopsy for cancer diagnosis and patients with clinically significant cancer for immediate treatment, and potentially assisting cancer treatment follow-up.

Five-Step Enantioselective Synthesis of Islatravir via Asymmetric Ketone Alkynylation and an Ozonolysis Cascade.

A 5-step enantioselective synthesis of the potent anti-HIV nucleoside islatravir is reported. The highly efficient route was enabled by a novel enantioselective alkynylation of an α,ß-unsaturated ketone, a unique ozonolysis-dealkylation cascade in water, and an enzymatic aldol-glycosylation cascade.

Does 24-h Activity Cycle Influence Plasma PCSK9 Concentration? A Systematic Review and Meta-Analysis.

PURPOSE OF REVIEW: Higher plasma proprotein convertase subtilisin/kexin type 9 (PCSK9) concentration has been associated with a higher risk of atherosclerotic cardiovascular disease (ASCVD). Animal and human studies have examined the relationship between 24-h activity cycles (24-HAC) and PCSK9, but conflicting results exist. Therefore, this review aimed to examine the relationship between 24-HAC and plasma PCSK9 concentration in animals and humans.Three databases (PubMed, CINAHL, and Web of Science) were searched for eligible articles. Descriptive data were summarized using network meta-analysis. The effect size was estimated using pairwise meta-analysis. RECENT FINDINGS: The interventions designed to increase moderate to vigorous physical activities (MVPA) did not significantly change plasma PCSK9 concentration (Hedges' g = 0.137; p = 0.337). However, the effect was influenced by statin therapy and intervention delivery mode. Specifically, physical activity interventions in conjunction with statin therapy significantly increased plasma PCSK9 concentration (Hedges' g = 0.275; p = 0.007). Supervised exercise training significantly increased plasma PCSK9 concentration (Hedges' g = 0.630; p = 0.001), but physical activity counseling did not (p = 0.845). The effects of MVPA on plasma PCSK9 may be moderated by statin therapy, intervention delivery mode, or other potential unknown mechanistic factors. Thus, caution should be taken when using plasma PCSK9 as an outcome indicator for physical activity interventions aimed at decreasing the risk of ASCVD. Graphical abstract.

Correction to: Does 24-h Activity Cycle Influence Plasma PCSK9 Concentration? A Systematic Review and Meta-Analysis.

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