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Desmopressin is a synthetic analog of the endogenous peptide hormone arginine vasopressin, or antidiuretic hormone. The drug was initially developed in 1967 with the intention of creating a molecule that could treat central diabetes insipidus, a condition characterized by a deficiency of ADH and results in the production of large volumes of dilute urine (Zaoral et al., 1967). In the years since, therapeutic use of desmopressin has expanded beyond central diabetes insipidus to include the treatment of many other conditions, notably nocturnal polyuria in children with enuresis (bed wetting), adult nocturia, congenital bleeding disorders, and more. The purpose of the present narrative review is to recount the history of desmopressin, review its key therapeutic indications, and discuss important pharmacologic and pharmacokinetic considerations of this medication.

Purpose:: Sleep-related factors, such as snoring or sleep duration may be causes for or consequence of nocturia. The purpose of this study was to evaluate the associations between sleep-related factors and nocturia in the absence of sleep disorders. Materials and Methods:: Using the National Health and Nutrition Examination Survey (NHANES) database from 2005/06 to 2017/18, we analyzed respondents who completed the kidney conditions and sleep disorders questionnaires. Respondents who reported a physician-diagnosed sleep disorder, did not provide an answer to this sleep disorder question, or had other conditions impacting nocturia were excluded. After sample weighing, the prevalence of nocturia for responses to sleep-related factors (hours of sleep, work schedule, snoring, snorting or stopping breathing, and sleepiness) was analyzed using chi-square analysis and the association of sleep-related factors to nocturia, accounting for age, gender, race, and BMI, was determined using univariate and multivariate regression. Results:: From the 2005/06–2017/18NHANES database, 23,895 respondents (11,672 males and 12,223 females; mean age, SD = 45.2, 20.1 years) were included. For sleep-related factors, greatest nocturia prevalence was seen in those sleeping 8 h (38.0%), snoring ≥5 nights per week (33.4%), snorting or stopping breathing ≥5 nights per week (38.7%), and feeling sleepy 16–30 times per month (44.7%). Work schedule differences (morning, evening/night, rotating) showed no differences in nocturia prevalence (21.1–22.5%) or significant odds of nocturia. On univariate analysis, nocturia was associated with age (OR = 1.035, p < 0.001), BMI (OR = 1.038, p < 0.001), sleeping 8 h (OR = 1.673, p < 0.001), snoring ≥5 nights per week (OR = 1.192, p = 0.004), snorting or stopping breathing 3–4 nights (OR = 1.425, p < 0.001) to ≥5 nights per week (OR = 1.528, p < 0.001), and feeling sleepy 5–15 times (OR = 1.579, p < 0.001) to 16–30 times per month (OR = 1.970, p < 0.001). On multivariate analysis, only age (OR = 1.035, p < 0.001), BMI (OR = 1.032, p < 0.001), and sleepiness (OR = 1.169, p < 0.001) showed an association with nocturia. Conclusion:: While most sleep-related factors showed increasing prevalence of nocturia at their extremes, only sleepiness showed an association to nocturia on multivariate analysis. Further examination of sleep issues related to nocturia elucidating causality are warranted.

Purpose Nocturia significantly impacts patients’ quality of life but remains insufficiently evaluated and treated. The “Sleep C.A.L.M.” system categorizes the factors thought to collectively reflect most underlying causes of nocturia (Sleep disorders, Comorbidities, Actions [i.e., modifiable patient behaviors such as excess fluid intake], Lower urinary tract dysfunction, and Medications). The purpose of this study was to assess the association of nocturia with the Sleep C.A.L.M. categories using a nationally representative dataset. Methods Retrospective analysis of the National Health and Nutrition Examination Survey from 2013/14–2017/18 cycles was conducted. Pertinent questionnaire, laboratory, dietary, and physical examination data were used to ascertain the presence of Sleep C.A.L.M. categories in adults ≥20 years of age. Nocturia was defined as ≥2 nighttime voids. Results A total of 12,274 included subjects were included (51.6% female; median age, 49.0 years [interquartile range, 34.0–62.0 years]; 27.6% nocturia). Among subjects with nocturia, the prevalence of 0, ≥1, and ≥2 Sleep C.A.L.M. categories was 3.5% (95% confidence interval [CI], 2.8%–4.4%), 96.5% (95% CI, 95.6%–97.2%), and 81.2% (95% CI, 78.9%–83.3%), respectively. Compared to those with 0–1 Sleep C.A.L.M. categories, the adjusted odds of nocturia in subjects with 2, 3, and 4–5 Sleep C. A.L.M. categories were 1.77 (95% CI, 1.43–2.21), 2.33 (1.89–2.87), and 3.49 (2.81–4.35), respectively (P

Purpose The pathophysiology of nocturia and nocturnal polyuria (NP), conditions that become more prevalent with aging, may in part be explained by changes in hormones involved in water homeostasis. The purpose of this study was to analyze the impact of aging on urinary natriuretic peptides in nocturia and NP. Methods Patients aged ≥18 years completed 24-hour bladder diaries for assessment of nocturia and NP. They were divided into subgroups of ≥65 years old and

Purpose To conduct a systematic review of preclinical and clinical peer-reviewed evidence linking alterations in oxidative stress biomarkers or outcome measures that were also prevalent in specific age-related lower urinary tract (LUT) disorders. Methods PubMed, Scopus, CINAHL, and Embase were searched for peer-reviewed studies published between January 2000 and March 2021. Animal and human studies that reported on the impact of oxidative stress in age-related LUT disorders through structural or functional changes in the LUT and changes in biomarkers were included. The PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) protocol was followed. Results Of 882 articles identified, 21 studies (13 animal; 8 human) met inclusion criteria. Across LUT disorders, common structural changes were increased bladder and prostate weights, ischemic damage, nerve damage and detrusor muscle hypertrophy; common functional changes included decreased bladder contraction, increased bladder sensation and excitability, decreased perfusion, and increased inflammation. The disorders were associated with increased levels of biomarkers of oxidative stress that provided evidence of either molecular damage, protective mechanisms against oxidative stress, neural changes, or inflammation. In all cases, the effect on biomarkers and enzymes was greater in aged groups compared to younger groups. Conclusions Increased oxidative stress, often associated with mitochondrial dysfunction, plays a significant role in the pathogenesis of age-related LUT disorders and may explain their increasing prevalence. This systematic review identifies potential markers of disease progression and treatment opportunities; further research is warranted to evaluate these markers and the mechanisms by which these changes may lead to age-related LUT disorders.

Purpose:: The main goal of this study was to determine the effects of arginine vasopressin (AVP) and desmopressin on bladder contractility and to examine whether the effects of these vasopressin receptor (VR) agonists differ in young versus aged animals. These aims were addressed using urinary bladders from young (3 months) and aged (24 month) female Fischer 344 rats that were isolated and dissected into strips for isometric tension recordings. Bladder strips were exposed to AVP and desmopressin through the perfusate, and tension changes recorded. Results:: In young rat bladders, AVP, an agonist at both vasopressin-1 receptors (V1Rs) and vasopressin-2 receptor (V2Rs), concentration-dependently caused contraction of bladder strips with a sensitivity that was greater in young versus aged bladder strips. Removal of the mucosa did not alter the sensitivity of young bladder strips to AVP yet enhanced the AVP sensitivity of aged bladder strips. The differential sensitivity to AVP between young denuded and aged denuded bladder strips was similar. In contrast to AVP, desmopressin (V2R selective agonist) relaxed bladder strips. This response was reduced by removal of the mucosa in young, but not aged, bladder strips. Conclusion:: These findings support a direct role for VRs in regulating detrusor tone with V1Rs causing contraction and V2Rs relaxation. In aged bladders, the contractile response to V1R activation is attenuated due to release of a mucosal factor that attenuates V1R-induced contractions. Also in aged bladders, the relaxation response to V2R activation is attenuated by lack of release of a mucosal factor that contributes to V2R-induced relaxation. Thus age-associated changes in the bladder mucosa impair the effects of VRs on bladder tone. Because the V2R signaling system is impaired in the older bladder, administering an exogenous V2R agonist (e.g., desmopressin) could counteract this defect. Thus, desmopressin could potentially increase nighttime bladder capacity through detrusor relaxation in concert with decreased urine production, reducing nocturnal voiding frequency.

Objective:: To retrospectively review a cohort of adult patients with single ectopic ureter, a rare congenital abnormality where one ureter terminates in an abnormal position outside of the trigone of the bladder. Methods:: We identified 5 patients diagnosed with a single ectopic ureter over a single surgeon’s career over 35 years and 2 institutions. Clinical symptoms, medical history, interventions, available radiologic imaging, and urodynamic features were analyzed. Results:: Median age at diagnosis was 53 years (range 18–85 years). The majority were male (80%). All patients were noted to have a solitary functioning kidney. A diminutive contralateral kidney and ureter was found in 1 (20%) patient. All patients were symptomatic, with the most common presenting symptoms being chronic dysuria (60%) and chronic prostatitis (40%). Physical examination findings were identified in 3 (60%) patients. Interventions were principally dependent upon the type and severity of each patient’s symptoms, and included observation, drainage of ectopic structures, vaginal marsupialization, and laparoscopic nephroureterectomy. The 3 (60%) patients that underwent intervention remained symptom free and the 2 (40%) patients that decided on observation were minimally symptomatic. Conclusions:: Single ectopic ureter is a complex embryological abnormality that can result in a wide array of anatomic variations and clinical findings in both men and women. Given the rarity of this entity in adult patients, a high index of suspicion must be held by the clinician for this diagnosis. Ultimately, treatment options for these patients will be dependent upon symptom severity, anatomic presentation, and patient quality of life.

Purpose Low nocturnal urine production (NUP) may be sufficient to rule out global polyuria (GP) in men. This study determines the sensitivity of indices for nocturnal polyuria (NP), defined as nocturnal polyuria index (NPi; nocturnal urine volume/24-hour urine volume) ≥0.33 or NUP ≥90 mL/hr, for detecting GP in women. Methods Data were analyzed from 2 prospective protocols involving subjects recruited from a urology ambulatory care unit and a continence clinic. Women ≥18 years with nocturia were included if they met either of 2 common criteria for GP: (1) ≥40 mL/kg/24 hr or (2) ≥3,000 mL/24 hr. Results Thirty-one women were included (NPi, 28.6 [21.3–40.7]; NUP, 100.8 [68.3–135.8] mL/hr). At the ≥40 mL/kg/24-hr cutoff, 40% and 63% of women reporting ≥1 nocturnal void(s) (n=30) had NPi ≥0.33 and NUP ≥90 mL/hr, respectively. Additionally, 53% and 71% of subjects reporting ≥2 nocturnal voids (n=17) had NPi ≥0.33 and NUP ≥90 mL/hr, respectively. At the ≥3,000 mL/24-hr cutoff, 38% and 69% of women reporting ≥1 nocturnal void(s) (n=13) had NPi ≥0.33 and NUP ≥90 mL/hr, respectively, and 63% and 88% of subjects reporting ≥2 nocturnal voids (n=8) had NPi ≥0.33 and NUP ≥90 mL/hr, respectively. By extension, 37%–62% of women with nocturia and GP did not have NP by NPi ≥0.33 criteria, and 12%–37% did not have NP by NUP ≥90 mL/hr criteria. Conclusions Indices of excess nighttime urination do not reliably predict GP in women. A full-length voiding diary may be particularly important in the evaluation of women with nocturia. Nocturia in women merits further consideration as a distinct entity.

This narrative review synthesizes current evidence on the medical management of nocturnal polyuria, including antidiuretic replacement therapy as well as other emerging modalities, with particular emphasis on areas of active investigation and future research directions. Relative to earlier formulations, the pharmacological profiles of novel desmopressin acetate nasal spray and orally disintegrating tablet formulations appear favorable in optimizing the balance between efficacy and safety. Additionally, several highly selective small-molecule arginine vasopressin 2 receptor agonists are under active development, while appropriately timed short-acting diuretics, pharmacotherapy for hypertension, nonsteroidal anti-inflammatory drugs, and sex hormone replacement therapy are also a focal point of extensive ongoing nocturnal polyuria research. Emerging laboratory technologies now make feasible a sub-stratification of nocturnal polyuria patients into substrate-based phenotypes for individualized treatment. An increasingly refined understanding of the pathogenesis of nocturnal polyuria, and arginine vasopressin dysregulation in particular, has also introduced new opportunities for point-of-care testing in patients with nocturnal polyuria.

A large number of falls in hospitals occur on the way to the toilet. Accordingly, a literature search was conducted in Web of Science, PubMed, Embase, and the Cochrane Library to identify fall risk screening and assessment metrics published between 1980 and 2019 and to study the inclusion of lower urinary tract symptoms (LUTS) and their related parameters in these screening tools. In addition, the literature was searched to explore the relationship between toilet-related falls and LUTS. In total, 23 fall risk scales were selected, from which 11 were applicable for in-hospital patients. In nine of the 11 scales for in-hospital patients, a LUTS or LUTS-related parameter was included. In the 12 risk assessment tools for community-dwelling older people, there were no LUTS included. Frequency, urinary incontinence, and nocturia were mostly reported in the literature as a potential fall risk parameter. It is recommended to create greater awareness of nocturia and other LUTS among caregivers of hospitalized patients to prevent falls.

Background Hypertension is assumed to be asymptomatic. Yet, clinically significant nocturia (≥2 nightly voids) constitutes a putative symptom of uncontrolled hypertension. Black men with hypertension may be prone to nocturia because of blunted nocturnal blood pressure (BP) dipping, diuretic drug use for hypertension, and comorbidity that predisposes to nocturia. Here, we test the hypothesis that nocturia is a common and potentially reversible symptom of uncontrolled hypertension in black men. Methods and Results We determined the strength of association between nocturia (≥2 nightly voids) and high BP (≥135/85 mm Hg) by conducting in‐person health interviews and measuring BP with an automated monitor in a large community‐based sample of black men in their barbershops. Because nocturia is prevalent and steeply age‐dependent after age 50 years, we studied men aged 35 to 49 years. Among 1673 black men (mean age, 43±4 years [SD]), those with hypertension were 56% more likely than men with normotension to have nocturia after adjustment for diabetes mellitus and sleep apnea (adjusted odds ratio, 1.56; 95% CI, 1.25–1.94 [P

Background: Primary small cell carcinoma of the kidney (PSCCK) is exceedingly rare and data on disease characteristics and outcomes are sparse. This study examines a nationally-representative cancer registry to better characterize PSCCK. Methods: We queried the National Cancer Database to identify patients with histology-confirmed PSCCK from 2004 to 2015. Adjusted Cox proportional hazards regression and Kaplan–Meier analyses were employed to assess predictors of mortality and estimate median survival time, respectively. Results: A total of 110 patients were included (47:53% female:male, 77% ≥60 years of age, 86% Caucasian). Significant predictors of mortality included female sex, age 60–69 years, treatment at an Integrated Network Cancer Program, stage cM1, and lack of surgical and chemoradiotherapy treatment. Independent protective factors were high socioeconomic status and treatment at an Academic Research Program. The estimated median overall survival time was 9.31 (95% CI 7.28–10.98) months for all patients. No differences in estimated survival time were observed across individual treatment modalities among those patients who underwent treatment (p = 0.214). Conclusions: PSCCK is an aggressive malignancy with a median survival time of less than one year. Future studies that correlate clinical tumor staging with specific treatment modalities are needed to optimize and individualize management.

ABSTRACTIntroduction:The Foley catheter has been widely assumed to be an effective means of draining the bladder. However, recent studies have brought into question its efficacy. The objective of our study is to further assess the adequacy of Foley catheter for complete drainage of the bladder.Materials and Methods:Consecutive catheterized patients were identified from a retrospective review of contrast enhanced and non-contrast enhanced computed tomo-graphic (CT) abdomen and pelvis studies completed from 7/1/2011-6/30/2012. Residual urine volume (RUV) was measured using 5mm axial CT sections as follows: The length (L) and width (W) of the bladder in the section with the greatest cross sectional area was combined with bladder height (H) as determined by multiplanar reformatted images in order to calculate RUV by applying the formula for the volume (V) of a sphere in a cube: V=(ϖ/6)*(L*W*H).Results:RUVs of 167 (mean age 67) consecutively catheterized men (n=72) and women (n=95) identified by CT abdomen and pelvis studies were calculated. The mean RUV was 13.2 mL (range: 0.0 mL-859.1 mL, standard deviation: 75.9 mL, margin of error at 95% confidence:11.6 mL). Four (2.4%) catheterized patients had RUVs of >50 mL, two of whom had an improperly placed catheter tip noted on their CT-reports.Conclusions:Previous studies have shown that up to 43% of catheterized patients had a RUV greater than 50 mL, suggesting inadequacy of bladder drainage via the Foley catheter. Our study indicated that the vast majority of patients with Foley catheters (97.6%), had adequately drained bladders with volumes of

Nocturia is a widespread condition that can negatively impact quality of sleep and overall health. This condition is multifactorial in nature and is best approached through the analysis of frequency volume charts. Through these charts, clinicians may classify each individual case of nocturia into one of four distinct categories: global polyuria, nocturnal polyuria, reduced bladder capacity, and mixed. Treatments should then be tailored to each individual based upon the category of their nocturia. In some cases, appropriate therapy will consist of behavioral modification techniques or addressing underlying systemic diseases. In other cases, medical therapy may be necessary, but, to date, medications have shown limited efficacy at treating nocturia.

Pregnancy induces a variety of physiologic changes in the urinary tract. When such changes become accentuated the physiologic becomes the pathologic and symptoms arise, at times of significance enough to threaten the well being of mother and/or fetus. This article intends to describe the basis for urinary physiology and its pathologic counterparts during pregnancy. Such a background may then facilitate a rational management protocol for various urologic problems in the gravid state.

Introduction. Penile cancer is a rare malignancy often treated with neoadjuvant chemotherapy followed by surgery. However, the utility of neoadjuvant chemoradiation, particularly when the tumor is resistant to chemotherapy alone, has not been established. In this study, we report a case of pT3cN3M0 penile squamous cell carcinoma with progression of nodal disease on chemotherapy, which was cured with use of neoadjuvant concurrent chemoradiation. Case Report. A 65-year-old male presented with a fixed left inguinal lymph node with associated firmness of the penile glans. Biopsies of both sites revealed evidence of squamous cell carcinoma. The patient underwent partial penectomy for the primary lesion and began neoadjuvant chemotherapy to reduce the size of the unresectable left inguinal node. However, he displayed disease progression in the left inguinal node. As such, we attempted concurrent chemoradiation therapy with regression of his nodal disease. The patient was able to undergo left inguinal node dissection and has no evidence of disease 18 months since his initial surgery. Conclusion. The use of neoadjuvant chemoradiation for bulky cN2-3 disease seems appropriate in the setting of progressive disease. Further studies are necessary to assess the utility of concurrent chemoradiation both in the neoadjuvant and salvage setting.

Nocturia is a common and bothersome condition experienced by both men and women. Studies have suggested that nocturia contributes a level of morbidity to those who suffer from the condition, both young and old. Desmopressin has historically been utilized to treat conditions such as central diabetes insipidus, certain bleeding disorders and primary nocturnal enuresis. Recently, interest has increased as to the use of desmopressin (a vasopressin analog) in the treatment of adult nocturia, for whom nocturnal polyuria is prevalent. While desmopressin has been traditionally administered in tablet and bioequivalent high dose melt formulations, newer low-dose orally disintegrating sublingual desmopressin has been recently studied to determine safe and efficacious dosing strategies. In this review, nocturia and its associated morbidities are discussed, followed by a contemporary literature review regarding the safety and efficacy of desmopressin for its treatment.

ABSTRACT Objectives To compare the surgical outcomes of men with bladder outlet obstruction (BOO) due to benign prostatic obstruction (BPO) to those with detrusor underactivity (DU) or acontractile detrusor (DA). Materials and Methods This retrospective, IRB approved study included men who underwent BPO surgery for refractory LUTS or urinary retention. Patients were grouped based on videourodynamic (VUDS) findings: 1) men with BOO, 2) men with DU and 3) men with DA. The primary outcome measure was the Patient Global Impression of Improvement (PGII). Secondary outcome measures included uroflow (Qmax), post-void residual volume (PVR) and the need for clean intermittent catheterization (CIC). Results One hundred and nineteen patients were evaluated: 1) 34 with BOO, 2) 62 with DU and 3) 23 with DA. Subjective success rate (PGII) was highest in the BOO group (97%) and those with DU (98%), while DA patients had a PGII success of 26%, (p

ABSTRACT Introduction: We compared characteristics of patients undergoing prostate biopsy in a high-risk inner city population before and after the 2012 USPSTF recommendation against PSA based prostate cancer screening to determine its effect on prostate biopsy practices. Materials and Methods: This was a retrospective study including patients who received biopsies after an abnormal PSA measurement from October 2008-December 2015. Patients with previously diagnosed prostate cancer were excluded. Chi-square tests of independence, two sample t-tests, Mann-Whitney U tests, and Fisher's exact tests were performed. Results: There were 202 and 208 patients in the pre-USPSTF and post-USPSTF recommendation cohorts, respectively. The post-USPSTF cohort had higher median PSA (7.8 versus 7.1ng/mL, p=0.05), greater proportion of patients who were black (96.6% versus 90.5%, p=0.01), and greater percentage of biopsy cores positive for disease (58% versus 29.5%, p

Aim: This narrative review investigates the effect of dietary intake on nocturnal voiding severity. The primary aims of this review are to provide a framework for future research and ultimately contribute to more comprehensive, lifestyle-centered guidelines for the management of nocturia. Methods: A literature search was conducted in Web of Science, PubMed, and Google Scholar databases using the keywords “nocturia”, “diuresis”, “natriuresis”, “food”, “diet”, and “nutrients”. Results: High fruit and vegetable consumption was negatively associated with nocturia. High intake of tea and dietary sodium showed a positive association with nocturia. Several foods have also been directly linked to changes in diuresis rate, glycemic control, and endogenous serum melatonin concentration, offering potential mechanisms for this observed effect. Overall quality of the evidence was low. Conclusion : At present, there is limited evidence to suggest that certain foods, electrolytes, and specific compounds may contribute to the pathogenesis of nocturia. A greater understanding of the impact of food and nutrients on body fluid metabolism is needed to further refine the evaluation and treatment of nocturia.

Extracellular matrix (ECM) collagen density and fibril anisotropy are thought to affect the development of new vasculatures during pathologic and homeostatic angiogenesis. Computational simulation is emerging as a tool to investigate the role of matrix structural configurations on cell guidance. However, prior computational models have only considered the orientation of collagen as a model input. Recent experimental evidence indicates that cell guidance is simultaneously influenced by the direction and intensity of alignment (i.e., degree of anisotropy) as well as the local collagen density. The objective of this study was to explore the role of ECM collagen anisotropy and density during sprouting angiogenesis through simulation in the AngioFE and FEBio modeling frameworks. AngioFE is a plugin for FEBio (Finite Elements for Biomechanics) that simulates cell-matrix interactions during sprouting angiogenesis. We extended AngioFE to represent ECM collagen as deformable 3D ellipsoidal fibril distributions (EFDs). The rate and direction of microvessel growth were modified to depend simultaneously on the ECM collagen anisotropy (orientation and degree of anisotropy) and density. The sensitivity of growing neovessels to these stimuli was adjusted so that AngioFE could reproduce the growth and guidance observed in experiments where microvessels were cultured in collagen gels of varying anisotropy and density. We then compared outcomes from simulations using EFDs to simulations that used AngioFE's prior vector field representation of collagen anisotropy. We found that EFD simulations were more accurate than vector field simulations in predicting experimentally observed microvessel guidance. Predictive simulations demonstrated the ability of anisotropy gradients to recruit microvessels across short and long distances relevant to wound healing. Further, simulations predicted that collagen alignment could enable microvessels to overcome dense tissue interfaces such as tumor-associated collagen structures (TACS) found in desmoplasia and tumor-stroma interfaces. This approach can be generalized to other mechanobiological relationships during cell guidance phenomena in computational settings.

OBJECTIVES Students often express uncertainty regarding changing their answers on multiple choice tests despite multiple studies quantitatively showing the benefits of changing answers. METHODS Data was collected from 86 first-year podiatric medical students over one semester for the course of Biochemistry, as shown in electronic testing data collected via ExamSoft's® Snapshot Viewer. Quantitative analysis was performed comparing frequency of changing answers and whether students changed their answers from incorrect-to-correct, correct-to-incorrect, or incorrect-to-incorrect. A correlation analysis was performed to assess the relationship between the frequency of each type of answer change and class rank. Independent-sample t -tests were used to assess differences in the pattern of changing answers amongst the top and bottom performing students in the class. RESULTS The correlation between total changes made from correct-to-incorrect per total answer changes and class rank yielded a positive correlation of r = 0.218 ( P = .048). There was also a positive correlation of r = 0.502 ( P

Purpose:: Pregnancy has been associated with long-term lower urinary tract symptoms such as nocturia. The purpose of this study was to explore potential associations between delivery modality and fetal size during pregnancy and the presence of nocturia. Materials and Methods:: Using the National Health and Nutrition Examination Survey (NHANES) database from 2005/06-2017/18, we categorized females by status of prior delivery modalities: nulligravida, vaginal deliveries, and cesarean deliveries. Groups were weighed and case-control matched for age, race, BMI, and number of deliveries. The association of delivery modality and fetal size (≥9 pounds or

Early lung cancer lesions develop within a unique microenvironment that undergoes constant cyclic stretch from respiration. While tumor stiffening is an established driver of tumor progression, the contribution of stress and strain to lung cancer is unknown. We developed tissue scale finite element models of lung tissue to test how early lesions alter respiration-induced strain. We found that an early tumor, represented as alveolar filling, amplified the strain experienced in the adjacent alveolar walls. Tumor stiffening further increased the amplitude of the strain in the adjacent alveolar walls and extended the strain amplification deeper into the normal lung. In contrast, the strain experienced in the tumor proper was less than the applied strain, although regions of amplification appeared at the tumor edge. Measurements of the alveolar wall thickness in clinical and mouse model samples of lung adenocarcinoma (LUAD) showed wall thickening adjacent to the tumors, consistent with cellular response to strain. Modeling alveolar wall thickening by encircling the tumor with thickened walls moved the strain amplification radially outward, to the next adjacent alveolus. Simulating iterative thickening in response to amplified strain produced tracks of thickened walls. We observed such tracks in early-stage clinical samples. The tracks were populated with invading tumor cells, suggesting that strain amplification in very early lung lesions could guide pro-invasive remodeling of the tumor microenvironment. The simulation results and tumor measurements suggest that cells at the edge of a lung tumor and in surrounding alveolar walls experience increased strain during respiration that could promote tumor progression.

Background: In 2017, The Respectful and Equitable Access to Comprehensive Healthcare (REACH) Program at Mount Sinai Hospital became a registered Opioid Overdose Prevention Program (OOPP) and received funding from the New York City Department of Health and Mental Hygiene to develop a program to provide overdose education and naloxone distribution (OEND) training to at risk population and bystanders. We report on the programmatic quality improvement initiatives conducted.Methods: From April 2017 to December 2020, the REACH OOPP conducted 290 opioid overdose reversal trainings, throughout the Mount Sinai Health System and in multiple other community settings. OEND training was at times offered alone and in other settings alongside Hepatitis C Virus point of care testing. Additionally, a “train the trainer” model was implemented whereby medical students and nurses at outpatient clinics were trained to train others.Results: There were 4235 naloxone kits distributed to 3,906 participants. The training venues included hospital settings (patients and medical staff), public events, substance use programs, educational facilities, homeless prevention programs, faith-based organizations, alternative to incarceration programs, and community-based organizations. We implemented two types of training. During outreach sessions, we utilized one-on-one personalized sessions to train bystanders. When training clinic staff in the “train the trainer” model we utilized a standardized didactic presentation with slides. The two top reasons participants reported for being trained were “Just in case I see someone overdose” (59.3%) and “I'm worried that someone I know will overdose OR that I will overdose” (20.2%).Conclusion: The REACH program at Mount Sinai Hospital developed an effective model to train community bystanders and health care staff by leveraging administrative support and building on broader programmatic initiatives to promote drug user health and stigma-free care for people who use drugs. Hospitals do not currently mandate staff training or keeping naloxone stocked at inpatient units or outpatients clinics posing a challenge when implementing an OEND program in this setting. A recommended policy change needed to decrease overdose deaths is for hospitals to be required to implement systematic naloxone education and access for all health care personal and at risk patients.

Microstimulation in the somatosensory cortex can evoke artificial tactile percepts and can be incorporated into bidirectional brain–computer interfaces (BCIs) to restore function after injury or disease. However, little is known about how stimulation parameters themselves affect perception. Here, we stimulated through microelectrode arrays implanted in the somatosensory cortex of two human participants with cervical spinal cord injury and varied the stimulus amplitude, frequency, and train duration. Increasing the amplitude and train duration increased the perceived intensity on all tested electrodes. Surprisingly, we found that increasing the frequency evoked more intense percepts on some electrodes but evoked less-intense percepts on other electrodes. These different frequency–intensity relationships were divided into three groups, which also evoked distinct percept qualities at different stimulus frequencies. Neighboring electrode sites were more likely to belong to the same group. These results support the idea that stimulation frequency directly controls tactile perception and that these different percepts may be related to the organization of somatosensory cortex, which will facilitate principled development of stimulation strategies for bidirectional BCIs.

Here, the authors compare gene expression signatures in rectal tissues of African green monkeys (AGMs) and rhesus macaques (RMs) acutely infected with simian immunodeficiency virus and find that AGMs rapidly activate and maintain evolutionarily conserved regenerative wound healing mechanisms.

Oceanic flows self-organize into coherent vortices, which strongly influence their transport and mixing properties. Counter-rotating vortex pairs can travel long distances and carry trapped fluid as they move. These structures are often modeled as hetons, viz. counter-rotating quasigeostrophic point vortex pairs with equal circulations. Here, we investigate the structure of the transport induced by a single three-dimensional heton. The transport is determined by the Hamiltonian structure of the velocity field induced by the heton’s component vortices. The dynamics display a sequence of bifurcations as one moves through the heton-induced velocity field in height. These bifurcations create and destroy unstable fixed points whose associated invariant manifolds bound the trapped volume. Heton configurations fall into three categories. Vertically aligned hetons, which are parallel to the vertical axis and have zero horizontal separation, do not move and do not transport fluid. Horizontally aligned hetons, which lie on the horizontal plane and have zero vertical separation, have a single parameter, the horizontal vortex half-separation Y, and simple scaling shows the dimensional trapped volume scales as Y3. Tilted hetons are described by two parameters, Y and the vertical vortex half-separation Z, rendering the scaling analysis more complex. A scaling theory is developed for the trapped volume of tilted hetons, showing that it scales as Z4/Y for large Z. Numerical calculations illustrate the structure of the trapped volume and verify the scaling theory.

Vascular connectivity between adjacent vessel beds within and between tissue compartments is essential to any successful neovascularization process. To establish new connections, growing neovessels must locate other vascular elements during angiogenesis, often crossing matrix and other tissue-associated boundaries and interfaces. How growing neovessels traverse any tissue interface, whether part of the native tissue structure or secondary to a regenerative procedure (e.g., an implant), is not known. In this study, we developed an experimental model of angiogenesis wherein growing neovessels must interact with a 3D interstitial collagen matrix interface that separates two distinct tissue compartments. Using this model, we determined that matrix interfaces act as a barrier to neovessel growth, deflecting growing neovessels parallel to the interface. Computational modeling of the neovessel/matrix biomechanical interactions at the interface demonstrated that differences in collagen fibril density near and at the interface are the likely mechanism of deflection, while fibril alignment guides deflected neovessels along the interface. Interestingly, stromal cells facilitated neovessel interface crossing during angiogenesis via a vascular endothelial growth factor (VEGF)-A dependent process. However, ubiquitous addition of VEGF-A in the absence of stromal cells did not promote interface invasion. Therefore, our findings demonstrate that vascularization of a tissue via angiogenesis involves stromal cells providing positional cues to the growing neovasculature and provides insight into how a microvasculature is organized within a tissue.

Collagen denaturation is thought to occur during tissue mechanical damage, but its role in damage initiation is still unclear. Here, the authors use a collagen hybridizing peptide to provide insights into the molecular mechanisms leading to collagen unfolding during tendon mechanical stretch.

The unprecedented 2013–2016 outbreak of Ebola virus (EBOV) resulted in over 11,300 human deaths. Host resistance to RNA viruses requires RIG-I-like receptor (RLR) signaling through the adaptor protein, mitochondrial antiviral signaling protein (MAVS), but the role of RLR-MAVS in orchestrating anti-EBOV responses in vivo is not known. Here we apply a systems approach to MAVS−/− mice infected with either wild-type or mouse-adapted EBOV. MAVS controlled EBOV replication through the expression of IFNα, regulation of inflammatory responses in the spleen, and prevention of cell death in the liver, with macrophages implicated as a major cell type influencing host resistance. A dominant role for RLR signaling in macrophages was confirmed following conditional MAVS deletion in LysM+ myeloid cells. These findings reveal tissue-specific MAVS-dependent transcriptional pathways associated with resistance to EBOV, and they demonstrate that EBOV adaptation to cause disease in mice involves changes in two distinct events, RLR-MAVS antagonism and suppression of RLR-independent IFN-I responses.

Thorough understanding of growth and evolution of tissue vasculature is fundamental to many fields of medicine including cancer therapy, wound healing, and tissue engineering. Angiogenesis, the growth of new vessels from existing ones, is dynamically influenced by a variety of environmental factors, including mechanical and biophysical factors, chemotactic factors, proteolysis, and interaction with stromal cells. Yet, dynamic interactions between neovessels and their environment are difficult to study with traditional fixed time imaging techniques. Advancements in imaging technologies permit time-series and volumetric imaging, affording the ability to visualize microvessel growth over 3D space and time. Time-lapse imaging has led to more informative investigations of angiogenesis. The environmental factors implicated in angiogenesis span a wide range of signals. Neovessels advance through stromal matrices by forming attachments and pulling and pushing on their microenvironment, reorganizing matrix fibers, and inducing large deformations of the surrounding stroma. Concurrently, neovessels secrete proteolytic enzymes to degrade their basement membrane, create space for new vessels to grow, and release matrix-bound cytokines. Growing neovessels also respond to a host of soluble and matrix-bound growth factors, and display preferential growth along a cytokine gradient. Lastly, stromal cells such as macrophages and mesenchymal stem cells (MSCs) interact directly with neovessels and their surrounding matrix to facilitate sprouting, vessel fusion, and tissue remodeling. This review highlights how time-lapse imaging techniques advanced our understanding of the interaction of blood vessels with their environment during sprouting angiogenesis. The technology provides means to characterize the evolution of microvessel behavior, providing new insights and holding great promise for further research on the process of angiogenesis.

Background: Stargardt Disease is the most common inherited macular degeneration, typically resulting in progressive central vision loss and legal blindness at an early age. We report regarding 34 eyes with Stargardt Disease treated in the Stem Cell Ophthalmology Treatment Study (SCOTS and SCOTS2). Methods: Autologous bone marrow was processed, separating the stem cell fraction which was provided Arms using retrobulbar, subtenons, intravitreal or subretinal and intravenous. The follow-up period was one year. Results: Of the 34 treated eyes, 21 (61.8%) improved, 8 (23.5%) remained stable, and 5 (14.7%) showed continued progression of their disease. Results were statistically significant with p = 0.0004. The average central vision improvement following treatment was 17.96% (95%CI, 16.39–19.53%) and ranged up to 80.5%. Of 17 patients treated, 13 (76.5%) showed visual acuity improvement in one or both eyes, 3 patients (17.6%) showed no net loss, and 1 worsened as a consequence of disease progression; 94.1% of patients had improved vision or remained stable. There were no adverse events. Conclusions: Patients with Stargardt Disease may potentially benefit from autologous bone marrow-derived stem cells (BMSC) as provided in SCOTS. Improvement or stabilization of vision was found to occur for the vast majority of reported patients and findings were highly statistically significant.

The Stem Cell Ophthalmology Treatment Study (SCOTS) is currently the largest-scale stem cell ophthalmology trial registered at ClinicalTrials.gov (identifier: NCT01920867). SCOTS utilizes autologous bone marrow-derived stem cells (BMSCs) to treat optic nerve and retinal diseases. Treatment approaches include a combination of retrobulbar, subtenon, intravitreal, intra-optic nerve, subretinal, and intravenous injection of autologous BMSCs according to the nature of the disease, the degree of visual loss, and any risk factors related to the treatments. Patients with Leber′s hereditary optic neuropathy had visual acuity gains on the Early Treatment Diabetic Retinopathy Study (ETDRS) of up to 35 letters and Snellen acuity improvements from hand motion to 20/200 and from counting fingers to 20/100. Visual field improvements were noted. Macular and optic nerve head nerve fiber layer typically thickened. No serious complications were seen. The increases in visual acuity obtained in our study were encouraging and suggest that the use of autologous BMSCs as provided in SCOTS for ophthalmologic mitochondrial diseases including Leber′s hereditary optic neuropathy may be a viable treatment option.

We report results in a 77-year-old male patient with visual loss from long-standing serpiginous choroidopathy treated with bone marrow derived stem cells (BMSC) within the Stem Cell Ophthalmology Treatment Study (SCOTS). SCOTS is an Institutional Review Board approved clinical trial and the largest ophthalmology stem cell study registered at the National Institutes of Health to date (ClinicalTrials.gov Identifier: NCT01920867). Eight months after treatment by a combination of retrobulbar, subtenon, intravitreal and intravenous injection of BMSC, the patient′s best corrected Snellen acuity improved from 20/80 - to 20/60 +1 in the right eye and from 20/50 - to 20/20 -3 in the left eye. The Early Treatment of Diabetic Retinopathy Study (ETDRS) visual acuity continued to improve over the succeeding 8 months and the optical coherence tomography macular volume increased. The increases in visual acuity and macular volume are encouraging and suggest that the use of BMSC as provided in SCOTS may be a viable approach to treating serpiginous choroidopathy.

Background: Dry age-related macular degeneration (AMD) is one of the leading causes of vision loss in older patients. The macula accumulates drusen with loss of retinal pigment epithelial cells and photoreceptors. Abnormal subretinal neovascularization is absent. There is no effective drug therapy for dry AMD and a large proportion of patients progress to legal blindness from macular atrophy. The Stem Cell Ophthalmology Treatment Study (SCOTS) was conducted to assess the effect of bone marrow-derived stem cells (BMSCs) on dry AMD and other retinal and optic nerve diseases. Methods: Thirty-two eyes were treated with BMSC per the protocols in SCOTS. Provision of BMSCs in Arm 1 was via retrobulbar (RB), sub-tenons (ST) and intravenous (IV); Arm 2 via intravitreal, RB, ST and IV; Arm 3 via subretinal and IV. Patient age averaged 78 years old and ranged from 69 to 90. Visual acuity preoperatively ranged from counting fingers to 20/50-2 with an average preoperative LogMAR of 1.125. Results: Following treatment, 20 of 32 (63%) of eyes experienced improvement in visual acuity averaging 27.6% on LogMAR and ranging from 2.5% to 44.6%. The mean improvement in LogMAR was 0.963 with a standard deviation (SD) of 0.42. The visual acuity remained stable in 34% of treated eyes. One eye continued to worsen as a consequence of disease progression. The results showed high statistical significance with p ≤ 0.001. The procedures were conducted safely, and no complications were observed. Conclusions: Treatment of dry AMD with BMSC using the protocols developed in the SCOTS clinical trial has shown statistically significant clinical benefit improving visual acuity and potentially delaying visual loss in the disease.

In order for brain-computer interface (BCI) systems to maximize functionality, users will need to be able to accurately modulate grasp force to avoid dropping heavy objects while also being able to handle fragile items. We present a case-study consisting of two experiments designed to identify whether intracortical recordings from the motor cortex of a person with tetraplegia could predict intended grasp force. In the first task, we were able classify neural responses to attempted grasps of four objects, each of which required similar grasp kinematics but different implicit grasp force targets, with 69% accuracy. In the second task, the subject attempted to move a virtual robotic arm in space to grasp a simple virtual object. For each trial, the subject was asked to grasp the virtual object with the force appropriate for one of the four objects from the first experiment, with the goal of measuring an implicit representation of grasp force. While the subject knew the grasp force during all phases of the trial, accurate classification was only achieved during active grasping, not while the hand moved to, transported, or released the object. In both tasks, misclassifications were most often to the object with an adjacent force requirement. In addition to the implications for understanding the representation of grasp force in motor cortex, these results are a first step toward creating intelligent algorithms to help BCI users grasp and manipulate a variety of objects that will be encountered in daily life.Clinical Trial Identifier: NCT01894802 https://clinicaltrials.gov/ct2/show/NCT01894802.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

IntroductionLiver cancer is the fastest increasing cancer in the United States and is one of the leading causes of cancer-related death in New York City (NYC), with wide disparities among neighborhoods. The purpose of this cross-sectional study was to describe liver cancer incidence by neighborhood and examine its association with risk factors. This information can inform preventive and treatment interventions.Materials and methodsPublicly available data were collected on adult NYC residents (n = 6,407,022). Age-adjusted data on liver and intrahepatic bile duct cancer came from the New York State Cancer Registry (1) (2007–2011 average annual incidence); and the NYC Vital Statistics Bureau (2015, mortality). Data on liver cancer risk factors (2012–2015) were sourced from the New York City Department of Health and Mental Hygiene: (1) Community Health Survey, (2) A1C registry, and (3) NYC Health Department Hepatitis surveillance data. They included prevalence of obesity, diabetes, diabetic control, alcohol-related hospitalizations or emergency department visits, hepatitis B and C rates, hepatitis B vaccine coverage, and injecting drug use.ResultsLiver cancer incidence in NYC was strongly associated with neighborhood poverty after adjusting for race/ethnicity (β = 0.0217, p = 0.013); and with infection risk scores (β = 0.0389, 95% CI = 0.0088–0.069, p = 0.011), particularly in the poorest neighborhoods (β = 0.1207, 95% CI = 0.0147–0.2267, p = 0.026). Some neighborhoods with high hepatitis rates do not have a proportionate number of hepatitis prevention services.ConclusionHigh liver cancer incidence is strongly associated with infection risk factors in NYC. There are gaps in hepatitis prevention services like syringe exchange and vaccination that should be addressed. The role of alcohol and metabolic risk factors on liver cancer in NYC warrants further study.

We present the results from a patient with relapsing optic neuropathy treated within the Stem Cell Ophthalmology Treatment Study (SCOTS). SCOTS is an Institutional Review Board approved clinical trial and has become the largest ophthalmology stem cell study registered at the National Institutes of Health to date (www.clinicaltrials.gov Identifier NCT 01920867). SCOTS utilizes autologous bone marrow-derived stem cells (BMSCs) for treatment of retinal and optic nerve diseases. Pre-treatment and post-treatment comprehensive eye exams of a 54 year old female patient were performed both at the Florida Study Center, USA and at The Eye Center of Columbus, USA. As a consequence of a relapsing optic neuritis, the patient′s previously normal visual acuity decreased to between 20/350 and 20/400 in the right eye and to 20/70 in the left eye. Significant visual field loss developed bilaterally. The patient underwent a right eye vitrectomy with injection of BMSCs into the optic nerve of the right eyeand retrobulbar, subtenon and intravitreal injection of BMSCs in the left eye. At 15 months after SCOTS treatment, the patient′s visual acuity had improved to 20/150 in the right eye and 20/20 in the left eye. Bilateral visual fields improved markedly. Both macular thickness and fast retinal nerve fiber layer thickness were maximally improved at 3 and 6 months after SCOTS treatment. The patient also reduced her mycophenylate dose from 1,500 mg per day to 500 mg per day and required no steroid pulse therapy during the 15-month follow up.

In this report, we present the results of a single patient with optic neuropathy treated within the Stem Cell Ophthalmology Treatment Study (SCOTS). SCOTS is an Institutional Review Board approved clinical trial and is the largest ophthalmology stem cell study registered at the National Institutes of Health to date- www.clinicaltrials.gov Identifier NCT 01920867. SCOTS utilizes autologous bone marrow-derived stem cells in the treatment of optic nerve and retinal diseases. Pre- and post-treatment comprehensive eye exams were independently performed at the Wilmer Eye Institute at the Johns Hopkins Hospital, USA. A 27 year old female patient had lost vision approximately 5 years prior to enrollment in SCOTS. Pre-treatment best-corrected visual acuity at the Wilmer Eye Institute was 20/800 Right Eye (OD) and 20/4,000 Left Eye (OS). Four months following treatment in SCOTS, the central visual acuity had improved to 20/100 OD and 20/40 OS.

Angiogenesis is regulated by the local microenvironment, including the mechanical interactions between neovessel sprouts and the extracellular matrix (ECM). However, the mechanisms controlling the relationship of mechanical and biophysical properties of the ECM to neovessel growth during sprouting angiogenesis are just beginning to be understood. In this research, we characterized the relationship between matrix density and microvascular topology in an in vitro 3D organ culture model of sprouting angiogenesis. We used these results to design and calibrate a computational growth model to demonstrate how changes in individual neovessel behavior produce the changes in vascular topology that were observed experimentally. Vascularized gels with higher collagen densities produced neovasculatures with shorter vessel lengths, less branch points, and reduced network interconnectivity. The computational model was able to predict these experimental results by scaling the rates of neovessel growth and branching according to local matrix density. As a final demonstration of utility of the modeling framework, we used our growth model to predict several scenarios of practical interest that could not be investigated experimentally using the organ culture model. Increasing the density of the ECM significantly reduced angiogenesis and network formation within a 3D organ culture model of angiogenesis. Increasing the density of the matrix increases the stiffness of the ECM, changing how neovessels are able to deform and remodel their surroundings. The computational framework outlined in this study was capable of predicting this observed experimental behavior by adjusting neovessel growth rate and branching probability according to local ECM density, demonstrating that altering the stiffness of the ECM via increasing matrix density affects neovessel behavior, thereby regulated vascular topology during angiogenesis.