Exercise improves respiratory function, body fluid and nitric oxide in hemodialysis patients.

Emerging evidence suggests that resistance training (RT) can mitigate respiratory muscle weakness in hemodialysis (HD) patients. However, the underlying mechanisms responsible for these beneficial effects remain unclear. The purpose of this study was to assess the impact of periodized RT on respiratory muscle strength and its relationship with handgrip strength (HGS), fat-free mass (FFM), nitric oxide (NO), and interdialytic weight gain (IWG) in HD patients. Thirty-three patients were randomly assigned to two groups: control (CTL; n=18) and RT (n=15). RT group did not perform any additional exercise training specific to the respiratory tract. Maximal inspiratory (MIP) and expiratory (MEP) pressures, peak expiratory flow (PEF), HGS, FFM, NO, and IWG were measured before and after the intervention period. Participants in the RT group engaged in a 24-week RT program, three times per week. RT resulted in significant improvements in MIP, MEP, PEF, as well as enhancements in HGS, FFM, NO, and IWG (p<0.05). Notably, inverse correlations were observed between MIP (r= -0.37, p=0.03) and PEF (r= -0.4, p=0.02) with IWG. Thus, the amelioration of HGS and FFM coincided with a reduction in respiratory muscle weakness among HD patients. Decreased IWG and increased circulating NO are plausible mechanisms contributing to these improvements.

Intestinal FGF15 regulates bile acid and cholesterol metabolism but not glucose and energy balance.

Fibroblast growth factor 15/19 (FGF15/19, mouse/human ortholog) is expressed in the ileal enterocytes of the small intestine and released postprandially in response to bile acid absorption. Previous reports of FGF15-/- mice have limited our understanding of gut-specific FGF15's role in metabolism. Therefore, we studied the role of endogenous gut-derived FGF15 in bile acid, cholesterol, glucose, and energy balance. We found that circulating levels of FGF19 were reduced in individuals with obesity and comorbidities, such as type 2 diabetes and metabolic dysfunction-associated fatty liver disease. Gene expression analysis of ileal FGF15-positive cells revealed differential expression during the obesogenic state. We fed standard chow or a high-fat metabolic dysfunction-associated steatohepatitis-inducing diet to control and intestine-derived FGF15-knockout (FGF15INT-KO) mice. Control and FGF15INT-KO mice gained similar body weight and adiposity and did not show genotype-specific differences in glucose, mixed meal, pyruvate, and glycerol tolerance. FGF15INT-KO mice had increased systemic bile acid levels but decreased cholesterol levels, pointing to a primary role for gut-derived FGF15 in regulating bile acid and cholesterol metabolism when exposed to obesogenic diet. These studies show that intestinal FGF15 plays a specific role in bile acid and cholesterol metabolism regulation but is not essential for energy and glucose balance.

Preexisting antibody assays for gene therapy: Considerations on patient selection cutoffs and companion diagnostic requirements.

Recombinant adeno-associated virus (AAV) vectors are the leading delivery vehicle used for in vivo gene therapies. Anti-AAV antibodies (AAV Abs) can interact with the viral capsid component of an AAV-based gene therapy (GT). Therefore, patients with preexisting AAV Abs (seropositive patients) are often excluded from GT trials to prevent treatment of patients who are unlikely to benefit1 or may have a higher risk for adverse events outweighing treatment benefits. On the contrary, unnecessary exclusion of patients with high unmet medical need should be avoided. Instead, a risk-benefit assessment that weighs the potential risks due to seropositivity vs. severity of disease and available treatment options, should drive the decision if patient selection is required. Assays for patient selection must be validated according to their intended use following national regulations/standards for diagnostic assays in appropriate laboratories. In this review, we summarize the current process of patient selection, including assay cutoff criteria and related assay validation approaches. We further provide considerations on regulatory requirements for the development of in vitro diagnostic tests supporting market authorization of a corresponding GT.

Transcriptomic analysis of benign prostatic hyperplasia identifies critical pathways in prostatic overgrowth and 5-alpha reductase inhibitor resistance.

BACKGROUND: The medical therapy of prostatic symptoms (MTOPS) trial randomized men with symptoms of benign prostatic hyperplasia (BPH) and followed response of treatment with a 5α-reductase inhibitor (5ARI), an alpha-adrenergic receptor antagonist (α-blocker), the combination of 5ARI and α-blocker or no medical therapy (none). Medical therapy reduced risk of clinical progression by 66% but the reasons for nonresponse or loss of therapeutic response in some patients remains unresolved. Our previous work showed that prostatic glucocorticoid levels are increased in 5ARI-treated patients and that glucocorticoids can increased branching of prostate epithelia in vitro. To understand the transcriptomic changes associated with 5ARI treatment, we performed bulk RNA sequencing of BPH and control samples from patients who received 5ARI versus those that did not. Deconvolution analysis was performed to estimate cellular composition. Bulk RNA sequencing was also performed on control versus glucocorticoid-treated prostate epithelia in 3D culture to determine underlying transcriptomic changes associated with branching morphogenesis. METHOD: Surgical BPH (S-BPH) tissue was defined as benign prostatic tissue collected from the transition zone (TZ) of patients who failed medical therapy while control tissue termed Incidental BPH (I-BPH) was obtained from the TZ of men undergoing radical prostatectomy for low-volume/grade prostatic adenocarcinoma confined to the peripheral zone. S-BPH patients were divided into four subgroups: men on no medical therapy (none: n = 7), α-blocker alone (n = 10), 5ARI alone (n = 6) or combination therapy (α-blocker and 5ARI: n = 7). Control I-BPH tissue was from men on no medical therapy (none: n = 8) or on α-blocker (n = 6). A human prostatic cell line in 3D culture that buds and branches was used to identify genes involved in early prostatic growth. Snap-frozen prostatic tissue taken at the time of surgery and 3D organoids were used for RNA-seq analysis. Bulk RNAseq data were deconvoluted using CIBERSORTx. Differentially expressed genes (DEG) that were statistically significant among S-BPH, I-BPH, and during budding and branching of organoids were used for pathway analysis. RESULTS: Transcriptomic analysis between S-BPH (n = 30) and I-BPH (n = 14) using a twofold cutoff (p < 0.05) identified 377 DEG (termed BPH377) and a cutoff < 0.05 identified 3377 DEG (termed BPH3377). Within the S-BPH, the subgroups none and α-blocker were compared to patients on 5ARI to reveal 361 DEG (termed 5ARI361) that were significantly changed. Deconvolution analysis of bulk RNA seq data with a human prostate single cell data set demonstrated increased levels of mast cells, NK cells, interstitial fibroblasts, and prostate luminal cells in S-BPH versus I-BPH. Glucocorticoid (GC)-induced budding and branching of benign prostatic cells in 3D culture was compared to control organoids to identify early events in prostatic morphogenesis. GC induced 369 DEG (termed GC359) in 3D culture. STRING analysis divided the large datasets into 20-80 genes centered around a hub. In general, biological processes induced in BPH supported growth and differentiation such as chromatin modification and DNA repair, transcription, cytoskeleton, mitochondrial electron transport, ubiquitination, protein folding, and cholesterol synthesis. Identified signaling pathways were pooled to create a list of DEG that fell into seven hubs/clusters. The hub gene centrality was used to name the network including AP-1, interleukin (IL)-6, NOTCH1 and NOTCH3, NEO1, IL-13, and HDAC/KDM. All hubs showed connections to inflammation, chromatin structure, and development. The same approach was applied to 5ARI361 giving multiple networks, but the EGF and sonic hedgehog (SHH) hub was of particular interest as a developmental pathway. The BPH3377, 5ARI363, and GC359 lists were compared and 67 significantly changed DEG were identified. Common genes to the 3D culture included an IL-6 hub that connected to genes identified in BPH hubs that defined AP1, IL-6, NOTCH, NEO1, IL-13, and HDAC/KDM. CONCLUSIONS: Reduction analysis of BPH and 3D organoid culture uncovered networks previously identified in prostatic development as being reinitiated in BPH. Identification of these pathways provides insight into the failure of medical therapy for BPH and new therapeutic targets for BPH/LUTS.

Factors Affecting Holmium Laser Efficiency: Comparison of Laryngeal Mask Airway and Endotracheal Intubation During Ureteroscopy for Renal Stones.

Introduction: Holmium laser lithotripsy is a standard energy source used for treatment of kidney stones during flexible ureteroscopy. Efficiency of laser surgery may be affected by patient and operator characteristics or perioperative management. Here, we sought to examine intraoperative data from patients undergoing high frequency dusting with high-powered holmium laser lithotripsy to evaluate surgical and demographic factors associated with lasing efficiency (LE). Methods: A total of 82 intraoperative reports were analyzed from an ongoing laser lithotripsy clinical trial evaluating the Lumenis Pulse™ 120H holmium laser with renal stones up to 20 mm in diameter with and without Moses 2.0 technology. For each case, the total pause time between lasing activations was corrected to remove lengthy pauses and divided by the total lasing time to calculate an efficiency percentage. This was then compared with patient demographics, anesthesia administration, stone burden, postoperative complications, and stone-free rates using both univariate and multivariate analyses. Results: Of the 82 included patients, 36 received endotracheal tube (ETT) intubation and 46 had a laryngeal mask airway (LMA). Patients with ETT had significantly higher LE (78.7%) compared to those with an LMA (73.3%) in our univariate analysis (p < 0.01) as well as in the multivariate model that adjusted for maximum stone size, number of stones, stone density, and patient body mass index (p < 0.05). There was also significantly higher mean LE in patients with no postoperative complications (76.3%) compared to those with any grade (I-V) Clavien-Dindo complication within 30 days after surgery (70.0%) (p < 0.05). Conclusions: Flexible ureteroscopy and laser lithotripsy cases with higher LE are associated with lower rates of postoperative complications. The data also support the use of ETT over LMA to improve overall LE; however, this remains one consideration among many for choosing anesthesia administration. Clinical Trial Registration number: NCT04505956.

From Consensus to Validation: A Multicenter Study for Design and Development of a Holmium Laser Enucleation of the Prostate Hydrogel Simulation Platform.

Background: Holmium laser enucleation of the prostate (HoLEP) has emerged as a new gold standard for treatment of benign prostatic hyperplasia; however, its steep learning curve hinders generalization of this technique. Therefore, there is a need for a benchtop HoLEP simulator to reduce this learning curve and provide training. We have developed a nonbiohazardous HoLEP simulator using modern education theory and validated it in a multicenter study. Materials and Methods: Six experts established key components for a HoLEP simulator through a Delphi consensus over three rounds including 250 questions. After consensus, a digital design was created and approved by experts, then used to fabricate a physical prototype using three-dimensional printing and hydrogel molding. After a process of iterative prototype testing, experts completed a survey assessing the simulator with a 5-point Likert scale for final approval. The approved model was validated with 56 expert and novice participants at seven institutions using subjective and objective performance metrics. Results: Consensus was reached on 85 of 250 questions, and experts found the physical model to adequately replicate 82.5% of required features. Objective metrics were statistically significant (p < 0.0001) when comparing experts and novices for enucleation time (37.4 ± 8.2 vs 16.7 ± 6.8 minutes), adenoma weight (79.6 ± 20.4 vs 36.2 ± 9.9 g), and complications (6 vs 22), respectively. Conclusion: We have effectively completed a multicenter study to develop and validate a nonbiohazardous benchtop simulator for HoLEP through modern education theory. A training curriculum including this simulator is currently under development.

Nonopioid Pain Management Pathways for Stone Disease.

Introduction: New opioid dependency after urologic surgery is a serious adverse outcome that is well-described in the literature. Patients with stone disease often require multiple procedures because of recurrence of disease and hence are at greater risk for repeat opioid exposures. Despite this, opioid prescribing after urologic surgery remains highly variable and in an emergency setting, opioids are still used commonly in management of acute renal colic. Methods: Two literature searches were performed using PubMed. First, we searched available literature concerning opioid-sparing pathways in acute renal colic. Second, we searched available literature for opioid-sparing pathways in ureteroscopy and percutaneous nephrolithotomy (PCNL). Abstracts were reviewed for inclusion in our narrative review. Results: In the setting of acute renal colic, multiple randomized control trials have shown that nonsteroidal anti-inflammatory drugs (NSAIDs) attain greater reduction in pain scores, decreased need for rescue medications, and decreased vomiting events in comparison with opioids. NSAIDs also form a core component in management of postureteroscopy pain and have been demonstrated in randomized trials to have equivalent to improved pain control outcomes compared with opioids. Multiple opioid-free pathways have been described for postureteroscopy analgesia with need for rescue narcotics falling under 20% in most studies, including in patients with ureteral stents. Enhanced Recovery After Surgery protocols after percutaneous nephrolithotomy are less well described but have yielded a reduction in postoperative opioid requirements. Conclusions: In select patients, both acute renal colic and after kidney stone surgery, adequate pain management can usually be obtained with minimal or no opioid medication. NSAIDs form the core of most described opioid-sparing pathways for both ureteroscopy and PCNL, with the contribution of other components to postoperative pain outcomes limited because of lack of head-to-head comparisons. However, medications aimed specifically at targeting stent-related discomfort form a key component of most multimodal postsurgical pain management pathways. Further investigation is needed to develop pathways in patients unable to tolerate NSAIDs.

Preserving Families of Children in Child Welfare with Fetal Alcohol Spectrum Disorders: Challenges and Opportunities.

The mission of child welfare is to ensure children's safety, permanency, and well-being. It is also charged with preserving and strengthening families and with avoiding the removal of children who can be kept at home safely. This paper addresses some of the challenges in meeting these concurrent goals in work with children prenatally exposed to alcohol and their families. Current child welfare practices are unlikely to identify prenatal alcohol exposure or children with fetal alcohol spectrum disorders (FASD). Yet if this exposure is identified when families come into contact with child welfare, a jurisdiction's laws and safety and risk assessment processes may lead to unnecessary removal of children from their homes, particularly for Black and American Indian/Alaska Native families. Drawing from research and discourse in the field, strategies are described that could help the child welfare system care for children who may be impacted by FASD while preserving their families. A crucial strategy is partnering with key child and family service providers to identify and respond to FASD.

Retention and weight outcomes after transitioning an intensive behavioral weight management program from an in-person to a virtual format.

Background: Virtual care offers many potential advantages over traditional in-person care for people with chronic diseases including obesity. Before the COVID-19 pandemic, virtual care was not broadly implemented because of regulatory, legal, and reimbursement barriers. Objective: To evaluate the impact of the transition from an entirely in-person format to a virtual format during the COVID-19 pandemic on retention and weight reduction in a 2-year, structured, intensive behavioral weight management program for people with moderate to severe obesity. Methods: Retrospective cohort study of 1313 program participants stratified according to the phase of the program during which the transition to virtual visits occurred. Results: Age, sex, and baseline weight were independent predictors of program retention. Transition to virtual visits was associated with greater 2-year program retention. Retention but not mode of program delivery was associated with reduction in weight at 2-year. Conclusions: Transition from in-person to virtual program delivery improved retention and by doing so, indirectly improved weight loss at 2 years. Telemedicine has the potential to overcome many of the limitations associated with traditional in-person weight loss interventions. Clinical Trial Registration: This research was reviewed and approved by the University of Michigan Institutional Review Board and registered on ClinicalTrials.gov (NCT02043457). All participants provided written informed consent.

Saturated Fat Intake and the Prevention and Management of Cardiovascular Disease in Adults: An Academy of Nutrition and Dietetics Evidence-Based Nutrition Practice Guideline.

Cardiovascular disease (CVD) is the leading cause of death in the United States and globally and is largely attributable to atherosclerosis. Evidence indicates that multiple dietary components contribute to the complex causes of CVD and associated events and mortality. Public health authorities and scientific organizations have recommended reduced saturated fatty acid (SFA) intake for decades to promote cardiovascular health, which is linked to favorable impacts on established and emerging atherosclerotic CVD risk factors. Recently, a debate has emerged about whether SFA intake should be reduced for CVD prevention, which has contributed to confusion among health care professionals, including registered dietitian nutritionists (RDNs), and the general public, and necessitates the critical evaluation of the evidence. The objective of this evidence-based nutrition practice guideline is to provide health care and public health professionals, particularly RDNs, with evidence-based recommendations on how to address SFA intake in adults within an individualized healthy dietary pattern. Moderate evidence supports the reduction of SFA intake for CVD event reduction, low- to moderate-certainty evidence supports prioritization of replacement of SFAs with polyunsaturated fatty acids, and low-certainty evidence supports focusing on reducing the total amount of SFA rather than specific food sources of SFA. Guideline implementation should include consideration of individual preferences; principles of inclusion, diversity, equity, and access; and potential nutritional deficiencies that may occur with reduced SFA intake. Future research is needed to address gaps that were identified and provide high-quality evidence to support stronger future recommendations based on the relationship between SFA and CVD.

Latent Profile Analysis of Physical Activity Motivation during Behavioral Weight Loss Treatment.

Participants in behavioral weight loss (BWL) treatment often struggle to meet and maintain physical activity (PA) prescriptions; improving participants' motivation for the behavior is a potential intervention strategy. Self-Determination Theory (SDT) outlines a continuum of qualitatively different dimensions of motivation, suggesting that more self-determined forms of motivation should predict more PA, whereas less self-determined forms of motivation should be unrelated or negatively related to PA. Although SDT has ample empirical support, most existing research in this area has used statistical analyses that oversimplify the complex, interdependent relationships between dimensions of motivation and behavior. This study's purpose was to explore commonly occurring motivational "profiles" for PA based on the SDT dimensions of motivation (amotivation, external, introjected, integrated/identified, and intrinsic motivation) and how these profiles relate to PA behavior among participants with overweight/obesity (N=281, 79.4% female) at baseline and six months into BWL treatment. Latent profile analysis determined that three motivational profiles fit the data best at both timepoints and the profile characterized by high self-determined (i.e., integrated/identified and intrinsic) motivation and moderate introjected motivation was by far the most common. There were no differences in physical activity behavior across motivational profiles, which contrasts previous literature. Findings suggest that participants who take the initiative to sign up for intensive BWL programs may have sufficiently high PA motivation, which may be a poor predictor of their actual behavior. Future research should examine these relationships later in treatment, when motivation may have more variability, as well as among participants who initiate lower-commitment weight loss programs (e.g., self-help).

Quick Sequential Organ Failure Assessment Score Is a Better Predictor of Septic Shock After Percutaneous Nephrolithotomy: A Secondary Analysis of Two Multicenter Prospective Trials.

Introduction: Recent retrospective literature suggests that the quick sequential organ failure assessment (qSOFA) scoring tool is a potentially superior tool over use of the systemic inflammatory response syndrome (SIRS) criteria to predict septic shock after percutaneous nephrolithotomy (PCNL) surgery. Here we examine use of qSOFA and SIRS to predict septic shock within data series collected prospectively on PCNL patients as part of a greater study of infectious complications. Materials and Methods: We performed a secondary analysis of two prospective multicenter studies including PCNL patients across nine institutions. Clinical signs informing SIRS and qSOFA scores were collected no later than postoperative day 1. The primary outcome was sensitivity and specificity of SIRS and qSOFA (high-risk score of greater-or-equal to two points) in predicting admission to the intensive care unit (ICU) for vasopressor support. Results: A total of 218 cases at 9 institutions were analyzed. One patient required vasopressor support in the ICU. The sensitivity/specificity was 100%/72.4% (McNemar's test p < 0.001) for SIRS and was 100%/90.8% (McNemar's test p < 0.001) for qSOFA. Conclusion: Although positive predictive value for both qSOFA and SIRS in prediction of post-PCNL septic shock is low, prospectively collected data demonstrate use of qSOFA may offer greater specificity than SIRS criteria when predicting post-PCNL septic shock.

Barriers and facilitators of naloxone and safe injection facility interventions to reduce opioid drug-related deaths: A qualitative analysis.

BACKGROUND: Opioid drug-related deaths continue to be a significant public health concern in the Republic of Ireland (ROI) and Northern Ireland (NI). While both regions have implemented naloxone to reduce drug related deaths, there remains a gap in the implementation of a supervised injection facility (SIF). This study aimed to identify barriers and facilitators to implementing naloxone and a SIF to reduce opioid drug-related deaths in ROI and NI. METHODS: Semi-structured interviews (n=23) were conducted in ROI and NI with experts by experience (n=8), staff from low threshold services (n=9), and individuals involved in policy making (n= 6). Data were analyzed using coding reliability Thematic Analysis and were informed by the Risk Environmental Framework. RESULTS: The findings illustrated that stigma within the media, health centers, and the community was a significant barrier to naloxone distribution and SIF implementation. Policing and community intimidation were reported to hinder naloxone carriage in both the ROI and NI, while threats of paramilitary violence towards people who use drugs were unique to NI. Municipal government delays and policy maker apathy were reported to hinder SIF implementation in the ROI. Participants suggested peer-to-peer naloxone delivery and amending legislation to facilitate non-prescription naloxone would increase naloxone uptake. Participants recommended using webinars, Town Halls, and a Citizens' Assembly as tools to advocate for SIF implementation. CONCLUSION: Local and regional stigma reduction campaigns are needed in conjunction with policy changes to advance naloxone and a SIF. Tailoring stigma campaigns to incorporate the lived experience of people who use drugs, their family members, and the general community can aid in educating the public and change negative perceptions. This study highlights the need for ongoing efforts to reduce stigma and increase accessibility to evidence-based interventions to address opioid drug-related deaths in the ROI, NI, and internationally.

Sharing digital self-monitoring data with others to enhance long-term weight loss: A randomized controlled trial.

BACKGROUND: Participants in behavioral weight loss (BWL) programs increasingly use digital tools to self-monitor weight, physical activity, and dietary intake. Data collected with these tools can be systematically shared with other parties in ways that might support behavior change. METHODS: Adults age 18 to 70 with overweight/obesity (BMI 27-50 kg/m2) will enroll in a remotely delivered, 24-month BWL program designed to produce and maintain a 10% weight loss. Participants will be asked to use a wireless body weight scale, wearable activity sensor, and dietary intake app daily. All participants will receive individual and group counseling, engage in text messaging with members of their group, and appoint a friend or family member to serve in a support role. A 2x2x2 factorial design will test the effects of three types of data sharing partnerships: 1) Coach Share: The behavioral coach will regularly view digital self-monitoring data and address data observations. 2) Group Share: Participants will view each other's self-monitoring data in small-group text messages. 3) Friend/Family Share: A friend or family member will view the participant's data via automated message. The primary outcome is weight loss at 24 months. Mediators and moderators of intervention effects will be tested. CONCLUSION: This study will provide a clear indication of whether data sharing can improve long-term weight loss. This study will be the first to discern the mechanisms of action through which each type of data sharing may be beneficial, and elucidate conditions under which the benefits of data sharing may be maximized.

The Fate of Residual Fragments After Percutaneous Nephrolithotomy: Results from the Endourologic Disease Group for Excellence Research Consortium.

Background: Residual fragments (RFs) after percutaneous nephrolithotomy (PCNL) have a significant impact on patients' quality of life and clinical course. There is a paucity of studies that evaluate the natural history of RFs after PCNL. The objective of this study is to compare rates of reintervention, complications, stone growth, and passage in patients with RFs >4, ≤4, and ≤2 mm after PCNL. Methods: Sites from the Endourologic Disease Group for Excellence (EDGE) research consortium examined data of PCNL patients from 2015 to 2019 with at least 1-year follow-up. RF passage, regrowth, reintervention, and complications were recorded and RFs were stratified into >4 and ≤4 mm groups, as well as >2 and ≤2 mm groups. Potential predictors for stone-related events after PCNL were determined using multivariable logistic regression analysis. It was hypothesized that larger RF thresholds would result in lower passage rates, faster regrowth, and greater clinically significant events (complications and reinterventions) than smaller RF thresholds. Results: A total of 439 patients with RFs >1 mm on CT postoperative day 1 were included in this study. For RFs >4 mm, rates of reintervention were found to be significantly higher and Kaplan-Meier curve analysis showed significantly higher rates of stone-related events. Passage and RF regrowth were not found to be significantly different compared with RFs ≤4 mm. However, RFs ≤2 mm had significantly higher rates of passage, and significantly lower rates of fragment regrowth (>1 mm), complications, and reintervention compared with RFs >2 mm. On multivariable analysis, older age, body mass index, and RF size were found to be predictive of stone-related events. Conclusions: With the largest cohort to date, this study by the EDGE research consortium further confirms that clinically insignificant residual fragment is problematic for patients after PCNL, particularly in older more obese patients with larger RFs. Our study underscores the importance of complete stone clearance post-PCNL and challenges the use of Clinically insignificant residual fragment (CIFR).

17⍺-Estradiol Protects against HIV-1 Tat-Induced Endolysosome Dysfunction and Dendritic Impairments in Neurons.

HIV-1 Tat continues to play an important role in the development of HIV-associated neurocognitive disorders (HAND), which persist in 15-55% of people living with HIV even with virological control. In the brain, Tat is present on neurons, where Tat exerts direct neuronal damaging effects by, at least in part, disrupting endolysosome functions, a pathological feature present in HAND. In this study, we determined the protective effects of 17α-estradiol (17αE2), the predominant form of estrogen in the brain, against Tat-induced endolysosome dysfunction and dendritic impairment in primary cultured hippocampal neurons. We demonstrated that pre-treatment with 17αE2 protected against Tat-induced endolysosome dysfunction and reduction in dendritic spine density. Estrogen receptor alpha (ERα) knockdown impairs the ability of 17αE2 to protect against Tat-induced endolysosome dysfunction and reduction in dendritic spine density. Furthermore, over-expressing an ERα mutant that fails to localize on endolysosomes impairs 17αE2's protective effects against Tat-induced endolysosome dysfunction and reduction in dendritic spine density. Our findings demonstrate that 17αE2 protects against Tat-induced neuronal injury via a novel ERα-mediated and endolysosome-dependent pathway, and such a finding might lead to the development of novel adjunct therapeutics against HAND.

Association between obstructive sleep apnea and 24-h urine chemistry risk factors for urinary stone disease.

The effect of obstructive sleep apnea (OSA) on 24-h urine parameters and resultant kidney stone risk is unknown. We sought to compare urinary lithogenic risk factors among patients with kidney stone disease with and without OSA. We performed a retrospective cohort study of adult patients with nephrolithiasis undergoing both polysomnography and 24-h urine analysis. Measures of acid load including gastrointestinal alkali absorption, urinary titratable acid, and net acid excretion were calculated from 24-h urine. We performed univariable comparisons of 24-h urine parameters between those with and without OSA and fit a multivariable linear regression model adjusting for age, sex, and BMI. Overall, there were 127 patients who underwent both polysomnography and a 24-h urine analysis from 2006 to 2018. There were 109 (86%) patients with OSA and 18 (14%) without. Patients with OSA were more commonly male, had greater BMI and had higher rates of hypertension. Patients with OSA had significantly higher levels of 24-h urinary oxalate, uric acid, sodium, potassium, phosphorous, chloride, and sulfate; higher supersaturation of uric acid; higher titratable acid, and net acid excretion; and lower urinary pH and supersaturation of calcium phosphate (p < 0.05). The difference in urinary pH and titratable acid, but not net acid excretion, remained significant when adjusting for BMI, age, and gender (both p = 0.02). OSA is associated with changes in urinary analytes that promote kidney stone formation, similar to those observed with obesity. After accounting for BMI, OSA is independently associated with lower urine pH and increased urinary titratable acid.

Kidney Stone Prevalence Based on Self-Report and Electronic Health Records: Insight into the Prevalence of Active Medical Care for Kidney Stones.

OBJECTIVE: To compare rates of patient-reported kidney stone disease to Electronic Health Records (EHR) kidney stone diagnosis using a common dataset to evaluate for socio-demographic differences, including between those with and without active care. METHODS: From the All of Us research database, we identified 21,687 adult participants with both patient-reported and EHR data. We compared differences in age, sex, race, education, employment status and healthcare access between patients with self-reported kidney stone history without EHR data to those with EHR-based diagnoses. RESULTS: In this population, the self-reported prevalence of kidney stones was 8.6% overall (n = 1877), including 4.6% (n = 1004) who had self-reported diagnoses but no EHR data. Among those with self-reported kidney stone diagnoses only, the median age was 66. The EHR-based prevalence of kidney stones was 5.7% (n = 1231), median age 67. No differences were observed in age, sex, education, employment status, rural/urban status, or ability to afford healthcare between groups with EHR diagnosis or self-reported diagnosis only. Of patients who had a self-reported history of kidney stones, 24% reported actively seeing a provider for kidney stones. CONCLUSION: Kidney stone prevalence by self-report is higher than EHR-based prevalence in this national dataset. Using either method alone to estimate kidney stone prevalence may exclude some patients with the condition, although the demographic profile of both groups is similar. Approximately 1 in 4 patients report actively seeing a provider for stone disease.