The utility and impact of digital endpoints for improving breast cancer outcomes.

INTRODUCTION: In breast cancer clinical trials utilizing digital endpoints, wearable sensors record participants' health information during activities of daily living.  These sensors are worn on the wrist or finger, placed as a skin patch or headband, or embedded on clothing. Data collected from wearable sensors form the basis of a digital endpoint, useful for determining effects of novel treatments on health outcomes, particularly quality-of-life outcomes. AREAS COVERED: References for this article were selected from a PubMed search spanning from 1 January 2017,to 1 July 2024, using the terms 'wearable sensors,' 'digital endpoints,' 'virtualtrials,' 'breast cancer.'  Additional articles from the authors' personal collection of papers and reviewers suggestions were also used. EXPERT OPINION: Digital endpoints must be validated as proper surrogate measures for healthcare outcomes, prior to their use in breast cancer trials.  Wearable sensors may introduce biases, such as 'missing not-at-random bias,' and perhaps even exacerbate disparities in healthcare outcomes if patients not comfortable with their use are excluded from clinical trials, or if the accuracy of sensors varies between racial and ethnic groups. Therefore, before embarking on trials with digital endpoints, validation studies are required, and limitations and risks of such trials need to be addressed.

Student Perspectives on the Undergraduate Medical Student Research Experience at a Single United States Allopathic Institution.

Introduction The purpose of this study was to identify student-reported institutional facilitators and barriers to successful research experiences at a single United States allopathic institution. Residency applications have increasingly become more competitive, and with the United States Medical Licensing Examination (USMLE) Step 1 exam's transition to pass/fail, factors such as research experience and outcomes may become more important to increase residency application competitiveness. This study sought to explore factors that impact successful research experiences leading to tangible outcomes for medical students at our medical school, the Joe R. & Teresa Lozano Long School of Medicine. Methods  A cross-sectional survey was developed and administered via REDCap to 853 students in May 2022. Survey question domains included demographics, past and present research participation, perceived barriers/facilitators to research, tangible outcomes (e.g., publications and posters), and overall satisfaction with research comparing subjectively "best" and "worst" experiences. The Institutional Review Board (IRB) deemed this project as non-regulated research.  Results We had a 24% (n = 204/853) response rate. The responses were distributed equally among the four classes. A big portion of the participants (71%, n = 59/83) identified a tangible outcome as the most important measure of success. Regarding facilitators, students identified having a mentor (89%, n = 165/184) and departmental connections (85%, n = 156/184) as the most important when looking for a project. Barriers included SMART goals (Specific, Measurable, Achievable, Relevant, and Time-Bound) lacking in 31% (n = 24/75) of worst projects, followed by a clear timeline in 29% (n = 22/76) and hours of commitment in 27% (n = 21/78). The best projects were more likely to have resulted in a publication (61% (27/44) vs. 32% (14/44)) or have a poster (64% (28/44) vs. 36% (16/44)). Conclusions Medical students are interested in participating in research, with important facilitators including mentorship and departmental connections. Modifiable variables include lack of clear timelines, well-defined roles and responsibilities, and time commitments. This information may be useful for faculty who mentor medical students or medical schools interested in designing medical student research programs.

Glycolytic lactate in diabetic kidney disease.

Lactate elevation is a well-characterized biomarker of mitochondrial dysfunction, but its role in diabetic kidney disease (DKD) is not well defined. Urine lactate was measured in patients with type 2 diabetes (T2D) in 3 cohorts (HUNT3, SMART2D, CRIC). Urine and plasma lactate were measured during euglycemic and hyperglycemic clamps in participants with type 1 diabetes (T1D). Patients in the HUNT3 cohort with DKD had elevated urine lactate levels compared with age- and sex-matched controls. In patients in the SMART2D and CRIC cohorts, the third tertile of urine lactate/creatinine was associated with more rapid estimated glomerular filtration rate decline, relative to first tertile. Patients with T1D demonstrated a strong association between glucose and lactate in both plasma and urine. Glucose-stimulated lactate likely derives in part from proximal tubular cells, since lactate production was attenuated with sodium-glucose cotransporter-2 (SGLT2) inhibition in kidney sections and in SGLT2-deficient mice. Several glycolytic genes were elevated in human diabetic proximal tubules. Lactate levels above 2.5 mM potently inhibited mitochondrial oxidative phosphorylation in human proximal tubule (HK2) cells. We conclude that increased lactate production under diabetic conditions can contribute to mitochondrial dysfunction and become a feed-forward component to DKD pathogenesis.

Optimal Tai Chi forms in knee osteoarthritis: An exploration from biomechanical rationale to pain reduction.

Objectives: Tai Chi (TC) shows some beneficial effects in reducing pain in knee osteoarthritis (OA). However, the selection of criteria TC forms in previous studies were unclear and inconsistent, possibly accounting for the varying outcomes and rendering the training effects suboptimal. We have selected four optimal TC (OTC) forms based on the knee joint load and its association with pain. This pilot study sought to examine the effect of the OTC forms on reducing knee pain in individuals with knee OA. Methods: Fifteen knee OA participants were recruited. Their knee joint pain level was rated by using the Visual Analogue Scale before and after two weeks of OTC training and compared between these two assessments. Results: The two-week OTC training course was well accepted by our participants. The knee OA pain showed a significant reduction (median pain score: 5 â€‹cm before training and 1 â€‹cm post-training, Wilcoxon p â€‹< â€‹0.001) after the two-week training program. Conclusions: Our pilot results revealed that the 2-week four-form-based OTC program could significantly reduce the knee pain level in people with knee OA. Additionally, our OTC program appears to be about 50% more effective in reducing knee pain than the existing TC-based program, which uses 10 â€‹TC forms over 12 weeks (1.59 vs. 1.06 in Hedge's g). The findings in this study may inform the development of OTC-based knee pain reduction programs and the design of relevant clinical trials to establish OTC's effectiveness, safety, and dose-response relationship in easing knee OA pain.

The Gehan test identifies life-extending compounds overlooked by the log-rank test in the NIA Interventions Testing Program: Metformin, Enalapril, caffeic acid phenethyl ester, green tea extract, and 17-dimethylaminoethylamino-17-demethoxygeldanamycin hydrochloride.

The National Institute on Aging Interventions Testing Program (ITP) has so far identified 12 compounds that extend the lifespan of genetically heterogeneous mice using the log-rank test. However, the log-rank test is relatively insensitive to any compound that does not uniformly reduce mortality across the lifespan. This test may thus miss compounds that only reduce mortality before midlife, for example, a plausible outcome if a compound only mitigates risk factors before midlife or if its efficacy is reduced at later ages. We therefore reanalyzed all data collected by the ITP from 2004-2022 using the Gehan test, which is more sensitive to mortality differences earlier in the life course and does not assume a uniformly reduced mortality hazard across the lifespan. The Gehan test identified 5 additional compounds, metformin, enalapril, 17-dimethylaminoethylamino-17-demethoxygeldanamycin hydrochloride (17-DMAG), caffeic acid phenethyl ester (CAPE), and green tea extract (GTE), which significantly increased survival but were previously missed by the log-rank test. Three (metformin, enalapril, and 17-DMAG) were only effective in males and two (CAPE and GTE) were only effective in females. In addition, 1,3-butanediol, which by log-rank analysis increased survival in females but not males, increased survival in males by the Gehan test. These results suggest that statistical tests sensitive to non-uniformity of drug efficacy across the lifespan should be included in the standard statistical testing protocol to minimize overlooking geroprotective interventions.

Erratum: Toward standardization, harmonization, and integration of social determinants of health data: A Texas Clinical and Translational Science Award institutions collaboration - CORRIGENDUM.

[This corrects the article DOI: 10.1017/cts.2024.2.].

Increasing and sustaining discharges by noon - a multi-year process improvement project.

High hospital occupancy degrades emergency department performance by increasing wait times, decreasing patient satisfaction, and increasing patient morbidity and mortality. Late discharges contribute to high hospital occupancy by increasing emergency department (ED) patient length of stay (LOS). We share our experience with increasing and sustaining early discharges at a 650-bed academic medical center in the United States. Our process improvement project followed the Institute of Medicine Model for Improvement of successive Plan‒Do‒Study‒Act cycles. We implemented multiple iterative interventions over 41 months. As a result, the proportion of discharge orders before 10 am increased from 8.7% at baseline to 22.2% (p < 0.001), and the proportion of discharges by noon (DBN) increased from 9.5% to 26.8% (p < 0.001). There was no increase in balancing metrics because of our interventions. RA-LOS (Risk Adjusted Length Of Stay) decreased from 1.16 to 1.09 (p = 0.01), RA-Mortality decreased from 0.65 to 0.61 (p = 0.62) and RA-Readmissions decreased from 0.92 to 0.74 (p < 0.001). Our study provides a roadmap to large academic facilities to increase and sustain the proportion of patients discharged by noon without negatively impacting LOS, 30-day readmissions, and mortality. Continuous performance evaluation, adaptability to changing resources, multidisciplinary engagement, and institutional buy-in were crucial drivers of our success.

Deciphering the Timing and Impact of Life-extending Drugs: A Novel Analytic Approach that Differentiates Early, Midlife, and Senescence Phase Efficacies.

Evidence that life-extending interventions are not uniformly effective across the lifespan calls for an analytic tool that can estimate age-specific treatment effects on mortality hazards. Here we report such a tool, applying it to mouse data from 42 agents tested in the NIA Interventions Testing Program. This tool identified agents that either reduced (22) or increased (16) mortality hazards or did both (6), all with marked variation in the duration of efficacy and magnitude of effect size. Only 7 reduced mortality hazards after the 90% mortality, when the burden of senescence is greatest. Sex differences were apparent in all parameters. This new analytic tool complements the commonly used log-rank test. It detects more potential life-extending candidates (22 versus 10) and indicates when during the life course they are effective. It also uncovers adverse effects. Most importantly, it identifies agents that specifically reduce mortality hazards during the senescent phase of life.

Facilitators of and barriers to gastric cancer and precursor diagnosis among South Texas residents: Social determinants of health.

BACKGROUND: Latinos/Hispanics are at higher risk for developing gastric cancer (GC) compared with non-Hispanic whites, and social determinants of health (SDoH) are thought to contribute. AIMS/MATERIALS AND METHODS: This study addressed SDoH and their interactions contributing to disparities in the testing and treatment of Helicobacter pylori (HP) infection and diagnosis of GC and its known precursors, among Latinos/Hispanics relative to non-Latinos at two affiliated but independent health systems in San Antonio, Texas, using a mixed methods approach. RESULTS: Secondary data abstraction and analysis showed that GCs represented 2.6% (n = 600) of our population. Men and older individuals were at higher GC risk. Individuals with military insurance were 2.7 times as likely to be diagnosed as private insurance. Latinos/Hispanics had significantly (24%) higher GC risk than Whites. Poverty and lack of insurance contributed to GC risk among the minorities classified as other (Asians, Native Americans, Multiracial; all p < 0.01). All SDoH were associated with H. pylori infection (p < 0.001). Qualitative analysis of patient and provider interviews showed providers reporting insurance as a major care barrier; patients reported appointment delays, and lack of clinic staff. Providers universally agreed treatment of H. pylori was necessary, but disagreed on its prevalence. Patients did not report discussing H. pylori or its cancer risk with providers. DISCUSSION/CONCLUSION: These data indicate the importance of considering SDoH in diagnosis and treatment of GC and its precursors, and educating providers and patients on H. pylori risks for GC.

Cannabis Use and Biomarkers of Inflammation, Immune Activation, and Microbial Translocation in Persons with HIV.

Background: The relationship between cannabis and inflammation among persons with HIV (PWH) remains unclear. We examined whether the cannabis metabolite 11-nor-9-carboxy THC (THC-COOH) is associated with lower levels of plasma biomarkers of inflammation, immune activation, and microbial translocation in PWH. We hypothesized that cannabis use would be associated with lower levels of plasma inflammatory biomarkers than noncannabis use. Methods: We quantified THC-COOH in plasma, with THC-COOH levels between 5.1-69.9 µg/L and ≥70 µg/L being classified as moderate and heavy cannabis use, respectively, with noncannabis use defined as undetected THC-COOH. We measured a panel of plasma biomarkers of inflammation (interleukin [IL]-1-ß, tumor necrosis factor-alpha, IL-18, IL-6, and C-reactive protein), immune activation (CD14 and CD163), and microbial translocation (iFABP2 and lipopolysaccharide binding protein [LBP]), with all biomarkers collected on the same day. We used a cross-sectional design and linear regression models to test whether cannabis use is associated with lower biomarker levels. Results: Participants were (N=107) sexual minority men with HIV (median age=32 years, IQR=28, 38), of whom 65% were virally suppressed; 36%, 44%, and 20% were classified as nonuse, moderate, and heavy cannabis, respectively. In linear regression models adjusted for viral suppression, stimulant use, and CD4 counts, heavy cannabis use was significantly associated with lower levels of log10 LBP (ß=-0.14, 95% confidence interval: -0.24 to -0.04; false discovery rate=0.0029; partial eta squared=0.07) than noncannabis users. No precise associations were observed for other biomarkers (all p>0.05). Conclusions: Our findings suggest that cannabis use may be associated with lower plasma LBP. Further work is needed to clarify the relationship between cannabis use and biomarkers of microbial translocation in PWH.

Toward standardization, harmonization, and integration of social determinants of health data: A Texas Clinical and Translational Science Award institutions collaboration.

Introduction: The focus on social determinants of health (SDOH) and their impact on health outcomes is evident in U.S. federal actions by Centers for Medicare & Medicaid Services and Office of National Coordinator for Health Information Technology. The disproportionate impact of COVID-19 on minorities and communities of color heightened awareness of health inequities and the need for more robust SDOH data collection. Four Clinical and Translational Science Award (CTSA) hubs comprising the Texas Regional CTSA Consortium (TRCC) undertook an inventory to understand what contextual-level SDOH datasets are offered centrally and which individual-level SDOH are collected in structured fields in each electronic health record (EHR) system potentially for all patients. Methods: Hub teams identified American Community Survey (ACS) datasets available via their enterprise data warehouses for research. Each hub's EHR analyst team identified structured fields available in their EHR for SDOH using a collection instrument based on a 2021 PCORnet survey and conducted an SDOH field completion rate analysis. Results: One hub offered ACS datasets centrally. All hubs collected eleven SDOH elements in structured EHR fields. Two collected Homeless and Veteran statuses. Completeness at four hubs was 80%-98%: Ethnicity, Race; < 10%: Education, Financial Strain, Food Insecurity, Housing Security/Stability, Interpersonal Violence, Social Isolation, Stress, Transportation. Conclusion: Completeness levels for SDOH data in EHR at TRCC hubs varied and were low for most measures. Multiple system-level discussions may be necessary to increase standardized SDOH EHR-based data collection and harmonization to drive effective value-based care, health disparities research, translational interventions, and evidence-based policy.

Causes of death in individuals with trisomy 18 after the first year of life.

Mortality in individuals with trisomy 18 has significantly decreased over the past 20 years, but there is scant literature addressing the prognosis and cause of death in individuals with trisomy 18 and survival past the first year of life (YOL). This study analyzed factors associated with mortality and cause of death in a retrospective cohort of 174 individuals with trisomy 18 and survival past the first YOL, the largest such series to date. Data were collected via retrospective survey of parents of affected individuals. Prenatal diagnosis of trisomy 18; postnatal respiratory distress; maternal age > 35 years; birthweight <2000 g; brain and spinal cord defect(s); atrial and/or ventricular septal defect(s); inability to feed orally without medical assistance; and failure to meet sitting and rolling milestones were associated with mortality in this sample. Cause of death was compared between our cohort of individuals with trisomy 18 and existing literature on those with mortality before the first YOL. Individuals with trisomy 18 with mortality after the first YOL demonstrated a predominance of infectious (n = 10/22) and postoperative (n = 6/22) contributing causes of death, in contrast to the existing literature, which shows a predominance of cardiopulmonary causes of death (e.g., cardiopulmonary arrest, pulmonary hypertension). These findings demonstrate that individuals with trisomy 18 and survival past the first YOL have unique medical needs, but further research is needed to develop clinical guidelines for this growing population.

A randomized placebo-controlled trial of nicotinamide riboside in older adults with mild cognitive impairment.

Nicotinamide riboside (NR) increases blood levels of NAD+, a cofactor central to energy metabolism, and improves brain function in some rodent models of neurodegeneration. We conducted a placebo-controlled randomized pilot study with the primary objective of determining safety of NR in older adults with mild cognitive impairment (MCI). Twenty subjects with MCI were randomized to receive placebo or NR using dose escalation to achieve, and maintain, a final dose of 1 g/day over a 10-week study duration. The primary outcome was post-treatment change from baseline measures of cognition (Montreal Cognitive Assessment, MoCA). Predefined secondary outcomes included post-treatment changes in cerebral blood flow (CBF); blood NAD+ levels; and additional neurocognitive, psychometric, and physical performance tests. DNA methylation was assessed in peripheral blood mononuclear cells (PBMCs) as an exploratory outcome. The target NR dose was safely achieved as evidenced by a 2.6-fold increase in blood NAD+ in the NR group (p < 0.001, 95% CI [17.77, 43.49]) with no between-group difference in adverse event reporting. MoCA and other neurocognitive and psychometric metrics remained stable throughout the study. NR reduced CBF in the default mode network (DMN) with greatest differences observed in the left inferior parietal lobe (IPL) (DMN p = 0.013, µ = 0.92, 95% CI [0.23, 1.62]; left IPL p = 0.009, µ = 1.66, 95% CI [0.5, 2.82]). Walking speed in the placebo group significantly improved across the study duration suggestive of a practice effect but did not change in the NR group (p = 0.0402 and p = 0.4698, respectively). Other secondary outcome measures remained stable. Global methylation analyses indicated a modest NR-associated increase in DNA methylation and concomitant reduction in epigenetic age as measured by PhenoAge and GrimAge epigenetic clock analyses. In summary, NR significantly increased blood NAD+ concentrations in older adults with MCI. NR was well tolerated and did not alter cognition. While CBF was reduced by NR treatment, statistical significance would not have withstood multiple comparisons correction. A larger trial of longer duration is needed to determine the potential of NR as a strategy to improve cognition and alter CBF in older adults with MCI. ClinicalTrials.gov NCT02942888.

Extracellular Delivery of Functional Mitochondria Rescues the Dysfunction of CD4+ T Cells in Aging.

Mitochondrial dysfunction alters cellular metabolism, increases tissue oxidative stress, and may be principal to the dysregulated signaling and function of CD4+ T lymphocytes in the elderly. In this proof of principle study, it is investigated whether the transfer of functional mitochondria into CD4+ T cells that are isolated from old mice (aged CD4+ T cells), can abrogate aging-associated mitochondrial dysfunction, and improve the aged CD4+ T cell functionality. The results show that the delivery of exogenous mitochondria to aged non-activated CD4+ T cells led to significant mitochondrial proteome alterations highlighted by improved aerobic metabolism and decreased cellular mitoROS. Additionally, mito-transferred aged CD4+ T cells showed improvements in activation-induced TCR-signaling kinetics displaying markers of activation (CD25), increased IL-2 production, enhanced proliferation ex vivo. Importantly, immune deficient mouse models (RAG-KO) showed that adoptive transfer of mito-transferred naive aged CD4+ T cells, protected recipient mice from influenza A and Mycobacterium tuberculosis infections. These findings support mitochondria as targets of therapeutic intervention in aging.

Comparative Effectiveness Randomized Clinical Trial Using Next-generation Microbial Sequencing to Direct Prophylactic Antibiotic Choice Before Urologic Stone Lithotripsy Using an Interprofessional Model.

Background: Next-generation sequencing (NGS) methods for microbial profiling have increased sensitivity to detect urinary pathogens. Objective: To determine whether NGS microbial profiling can be used to guide antibiotic prophylaxis and reduce infection compared with the standard of care. Design setting and participants: A prospective randomized controlled clinical trial of patients undergoing urologic stone interventions at an academic health center from December 2019 to January 2022 was conducted. Urine was collected at the preoperative visit for standard culture and intervention NGS diagnostics. Evaluable patients were culture negative, met 2-wk follow-up, and did not cancel surgery. Of 240 individuals (control = 121, intervention = 119), 83 control and 74 intervention patients were evaluable. Intervention: Microbial findings (paired quantitative polymerase chain reaction and NGS) were sent to an infectious disease pharmacist to recommend prophylactic antimicrobial regimen. Outcome measurements and statistical analysis: The primary outcome was postoperative urinary infection within the follow-up period (Fisher's exact test). The primary outcome was analyzed by modified intent-to-treat (mITT) and per-protocol analyses. Secondary endpoints considered included positive culture concordance, antibiotic use, and adverse events. Additional post hoc analyses investigated factors contributing to infection (univariate logistic regression). Results and limitations: The intervention significantly reduced postsurgical urinary infection risk by 7.1% (-0.73%, 15%) compared with the standard of care in the mITT analysis (1.4% vs 8.4%, p = 0.045) or by 8.5% (0.88%, 16%) compared with the per-protocol analysis (0% vs 8.5%, p = 0.032). NGS-guided treatment altered the distribution of antibiotics used (p = 0.025), and antibiotics poorly matched with NGS findings were associated with increased infection odds (odds ratio [OR] = 5.9, p = 0.046). Women were at greater odds to develop infection (OR = 10, p = 0.03) and possessed differentiated microbial profiles (p < 0.001). Conclusions: Urinary microbial NGS-guided antibiotic prophylaxis before endoscopic urologic stone lithotripsy improves antibiotic selection to reduce healthcare-associated urinary infections; however, treatment efficacy may be limited by the ability to adhere to the recommended protocol. Patient summary: We investigated whether microbial DNA sequencing could improve the selection of antibiotics before kidney stone surgery in patients not known to have any bacteria in the urine on standard culture. We found that using microbe DNA to guide antibiotic choices decreased postoperative infection rate and may encourage individualized use of available antibiotics.

Effects of vortioxetine on hippocampal-related cognitive impairment induced in rats by androgen deprivation as a model of prostate cancer treatment.

Advances in prostate cancer treatment have significantly improved survival, but quality of life for survivors remains an under-studied area of research. Androgen deprivation therapy (ADT) is a foundational treatment for advanced prostate cancer and is used as an adjuvant for prolonged periods in many high-risk, localized tumors. More than half of patients treated with ADT experience debilitating cognitive impairments in domains such as spatial learning and working memory. In this study, we investigated the effects of androgen deprivation on hippocampal-mediated cognition in rats. Vortioxetine, a multimodal antidepressant, has been shown to improve cognition in depressed patients. Thus, we also tested the potential efficacy of vortioxetine in restoring impaired cognition after ADT. We further investigated mechanisms that might contribute to these effects, measuring changes in the circuitry and gene expression within the dorsal hippocampus. ADT via surgical castration induced impairments in visuospatial cognition on the novel object location test and attenuated afferent-evoked local field potentials recorded in the CA1 region of the dorsal hippocampus. Chronic dietary administration of vortioxetine effectively reversed these deficits. Castration significantly altered gene expression in the hippocampus, whereas vortioxetine had little effect. Pathway analysis revealed that androgen depletion altered pathways related to synaptic plasticity. These results suggest that the hippocampus may be vulnerable to ADT, contributing to cognitive impairment in prostate cancer patients. Further, vortioxetine may be a candidate to improve cognition in patients who experience cognitive decline after androgen deprivation therapy for prostate cancer and may do so by restoring molecular and circuit-level plasticity-related mechanisms compromised by ADT.

High burden of sexually transmitted infections among under-resourced populations in the Dominican Republic.

Background: Sexually transmitted infections (STIs) are a major health issue, exacerbated by limited financial and infrastructural resources in developing countries. Methods: Prevalence of STIs was assessed in two urban centers of the Dominican Republic (DR) among populations at high risk for STIs: pregnant youth, men who have sex with men (MSM), trans women (TG), batey residents, female sex workers, and people living with human immunodeficiency virus (HIV). We conducted a cross-sectional survey and biological specimen collection to screen for Chlamydia trachomatis, Neisseria gonorrhea, Mycoplasma genitalium, Trichomonas vaginalis (trichomoniasis), Treponema pallidum (syphilis), HIV, hepatitis B and C, and human papillomavirus (HPV) among at-risk populations between 2015 and 2018. Ureaplasma urealyticum testing was also conducted even though it is not considered a STI. A non-probability community sample was recruited. Descriptive statistics examined the prevalence of STIs by population. Results: A total of 1991 subjects participated in the study. The median age was 26 years (range: 18-65). Most participants were female (65.3%), heterosexual (76.7%), and were not partnered (55.7%). Most of the participants reported unprotected vaginal sex in the last 6 months (54%); among MSM and TG almost half of the participants reported unprotected anal sex in the last 6 months and 17.6% reported drug use in the last 6 months. Almost half of the participants (49%) tested positive for one or more STIs. The most prevalent STI was Chlamydia trachomatis (12.8%), and human papillomavirus (11.9%). Among transgender women, 65.3% tested positive for an STI, 64.8% of female sex workers tested positive for an STI, and 53.8% of pregnant adolescents tested positive for an STI. Conclusion: There is a high prevalence of STIs among key and under resourced populations in the DR. Our findings highlight the need to conduct further research to optimize prevention and care strategies for structurally vulnerable and under resourced populations in the DR.

Endogenous adenine mediates kidney injury in diabetic models and predicts diabetic kidney disease in patients.

Diabetic kidney disease (DKD) can lead to end-stage kidney disease (ESKD) and mortality; however, few mechanistic biomarkers are available for high-risk patients, especially those without macroalbuminuria. Urine from participants with diabetes from the Chronic Renal Insufficiency Cohort (CRIC) study, the Singapore Study of Macro-angiopathy and Micro-vascular Reactivity in Type 2 Diabetes (SMART2D), and the American Indian Study determined whether urine adenine/creatinine ratio (UAdCR) could be a mechanistic biomarker for ESKD. ESKD and mortality were associated with the highest UAdCR tertile in the CRIC study and SMART2D. ESKD was associated with the highest UAdCR tertile in patients without macroalbuminuria in the CRIC study, SMART2D, and the American Indian study. Empagliflozin lowered UAdCR in nonmacroalbuminuric participants. Spatial metabolomics localized adenine to kidney pathology, and single-cell transcriptomics identified ribonucleoprotein biogenesis as a top pathway in proximal tubules of patients without macroalbuminuria, implicating mTOR. Adenine stimulated matrix in tubular cells via mTOR and stimulated mTOR in mouse kidneys. A specific inhibitor of adenine production was found to reduce kidney hypertrophy and kidney injury in diabetic mice. We propose that endogenous adenine may be a causative factor in DKD.

Role of endogenous adenine in kidney failure and mortality with diabetes.

Diabetic kidney disease (DKD) can lead to end-stage kidney disease (ESKD) and mortality, however, few mechanistic biomarkers are available for high risk patients, especially those without macroalbuminuria. Urine from participants with diabetes from Chronic Renal Insufficiency Cohort (CRIC), Singapore Study of Macro-Angiopathy and Reactivity in Type 2 Diabetes (SMART2D), and the Pima Indian Study determined if urine adenine/creatinine ratio (UAdCR) could be a mechanistic biomarker for ESKD. ESKD and mortality were associated with the highest UAdCR tertile in CRIC (HR 1.57, 1.18, 2.10) and SMART2D (HR 1.77, 1.00, 3.12). ESKD was associated with the highest UAdCR tertile in patients without macroalbuminuria in CRIC (HR 2.36, 1.26, 4.39), SMART2D (HR 2.39, 1.08, 5.29), and Pima Indian study (HR 4.57, CI 1.37-13.34). Empagliflozin lowered UAdCR in non-macroalbuminuric participants. Spatial metabolomics localized adenine to kidney pathology and transcriptomics identified ribonucleoprotein biogenesis as a top pathway in proximal tubules of patients without macroalbuminuria, implicating mammalian target of rapamycin (mTOR). Adenine stimulated matrix in tubular cells via mTOR and stimulated mTOR in mouse kidneys. A specific inhibitor of adenine production was found to reduce kidney hypertrophy and kidney injury in diabetic mice. We propose that endogenous adenine may be a causative factor in DKD.