Predictors for selection of outpatient single-port robot-assisted laparoscopic radical prostatectomy.

OBJECTIVE: To evaluate the different perioperative variables that may serve as important clinical predictors when selecting patients for outpatient single-port robot-assisted radical prostatectomy (SP-RARP). PATIENTS AND METHODS: A retrospective review was performed on the Institutional Review Board-approved, prospectively maintained database to identify 485 consecutive patients who underwent SP-RARP between 2018 and 2023. A comparison analysis was performed on patients who were managed as outpatients vs inpatients following their respective SP-RARP. A separate analysis was performed after excluding patients with pre-planned admissions to identify the risk factors for unplanned admissions. RESULTS: All procedures were successfully completed without any conversion or additional ports. After excluding patients with pre-planned admissions, outpatient SP-RARP was successfully achieved in 86.6% with a median (interquartile range) length of stay of 4.6 (3.8-6.1) hours. Our multivariate regression analysis identified cardiac comorbidity and preoperative International Prostate Symptom Score (IPSS) as predictors of outpatient SP-RARP. In addition, the absence of cardiac comorbidity, previous abdominal surgery, and lower postoperative pain score were protective against the risk of unplanned admission. Furthermore, both inpatient and outpatient encounters had comparable 90-day rates of postoperative complication (P = 0.136) and hospital re-admission (P = 0.942). CONCLUSION: Outpatient management models could be successfully achieved in most patients who underwent SP-RARP (86.6%) while maintaining similarly low perioperative morbidity profile. Nevertheless, appropriate patient selection based on the baseline clinicodemographic characteristics remains essential to ensure the safety and ongoing success of outpatient SP-RARP.

Adherence and persistence of HIV pre-exposure prophylaxis use in the United States.

PURPOSE: To describe medication adherence and persistence of HIV PrEP overall and compare between sex and age groups of commercially insured individuals in the United States. METHODS: We conducted a national retrospective cohort study of the Merative MarketScan Claims Database from 2011 to 2019 to describe adherence and persistence of PrEP overall and compared between sex and age groups. High adherence was defined as ≥80% of proportion of days covered and persistence was measured in days from initiation to the first day of a 60-day treatment gap. RESULTS: A total of 29 689 new PrEP users identified. Overall adherence was high (81.9%; 95% confidence interval [CI]: 81.5%-82.3%). Females were more adherent than males (adjusted odds ratio [aOR] 1.87; 95% CI: 1.50-2.34), while those ≥45-years were less adherent than individuals <45-years (aOR 0.87: 95% CI: 0.81-0.93). More than half of individuals discontinued therapy within the first year (median 238.0 days; interquartile range 99.0-507.0 days). Females were less persistent than males (hazard ratio [HR] 1.49; 95% CI: 1.34-1.65), and people ≥45-years old were more persistent (i.e., lower risk of discontinuation) than those <45-years (HR 0.43; 95% CI: 0.33-0.55). CONCLUSIONS: These findings show adherence to daily PrEP is high among commercially insured individuals but the majority still discontinue in the first year. Future research should investigate what factors influence PrEP discontinuation among this population and ways to reduce barriers to therapy maintenance to ensure the population-level benefits of PrEP treatment.

Convolutional neural network deep learning model accurately detects rectal cancer in endoanal ultrasounds.

BACKGROUND: Imaging is vital for assessing rectal cancer, with endoanal ultrasound (EAUS) being highly accurate in large tertiary medical centers. However, EAUS accuracy drops outside such settings, possibly due to varied examiner experience and fewer examinations. This underscores the need for an AI-based system to enhance accuracy in non-specialized centers. This study aimed to develop and validate deep learning (DL) models to differentiate rectal cancer in standard EAUS images. METHODS: A transfer learning approach with fine-tuned DL architectures was employed, utilizing a dataset of 294 images. The performance of DL models was assessed through a tenfold cross-validation. RESULTS: The DL diagnostics model exhibited a sensitivity and accuracy of 0.78 each. In the identification phase, the automatic diagnostic platform achieved an area under the curve performance of 0.85 for diagnosing rectal cancer. CONCLUSIONS: This research demonstrates the potential of DL models in enhancing rectal cancer detection during EAUS, especially in settings with lower examiner experience. The achieved sensitivity and accuracy suggest the viability of incorporating AI support for improved diagnostic outcomes in non-specialized medical centers.

Non-contrast computed tomography findings for identification of chronically occluded coronary artery bypass grafts.

BACKGROUND: Detecting occlusions of coronary artery bypass grafts using non-contrast computed tomography (CT) series is understudied and underestimated. PURPOSE: To evaluate morphological findings for the diagnosis of chronic coronary artery bypass graft occlusion on non-contrast CT and investigate performance statistics for potential use cases. MATERIAL AND METHODS: Seventy-three patients with coronary artery bypass grafts who had CT angiography of the chest (non-contrast and arterial phases) were retrospectively included. Two readers applied pre-set morphologic findings to assess the patency of a bypass graft on non-contrast series. These findings included vessel shape (linear-band like), collapsed lumen and surgical graft marker without a visible vessel. Performance was tested using the simultaneously acquired arterial phase series as the ground truth. RESULTS: The per-patient diagnostic accuracy for occlusion was 0.890 (95% confidence interval = 0.795-0.951). Venous grafts overall had an 88% accuracy. None of the left internal mammary artery to left anterior descending artery arterial graft occlusions were detected. The negative likelihood ratio for an occluded graft that is truly patent was 0.121, demonstrating a true post-test probability of 97% for identifying a patent graft as truly patent given a prevalence of 20% occlusion at a median 8.4 years post-surgery. Neither years post-surgery, nor number of vessels was associated with a significant decrease in reader accuracy. CONCLUSION: Evaluation of coronary bypass grafts for chronic occlusion on non-contrast CT based off vessel morphology is feasible and accurate for venous grafts. Potential use cases include low-intermediate risk patients with chest pain or shortness of breath for whom non-contrast CT was ordered, or administration of iodine-based contrast is contraindicated.

Surgical outcomes of minimally invasive trephine surgery for pilonidal sinus disease with and without laser therapy: a comparative study.

BACKGROUND: Over the last decades, novel therapeutic options have emerged for the surgical treatment of pilonidal sinus disease (PSD). The aim of this study was to evaluate the outcomes of trephine/pit excision surgery with or without laser therapy in patients with PSD. METHODS: A retrospective cohort study was conducted at a large tertiary medical center, including all adult patients with PNS who underwent trephine surgery with/without laser therapy between 2016 and 2021[AUTHORS TO INSERT MONTH]. Propensity score matching was used to address confounding factors, and the primary outcome was the 1-year recurrence rate. RESULTS: The study included 221 patients with PSD, with a mean age of 23.73 years (87.7% male). In the unmatched cohort (130 trephine surgery alone, 91 trephine surgery + laser therapy), significant differences were observed in mean age (23 vs. 25 years; p < 0.01)[AUTHROS TO USE MEDIAN PLUS RANGE OR ADD SD] and surgeons' experience (p = 0.014). Propensity score matching was applied to overcome confounding factors, resulting in a matched cohort including 73 patients in each group. The addition of laser therapy demonstrated a significantly lower recurrence rate (8.2% vs. 32.9%; p < 0.001) compared to pit excision without laser therapy. Logistic regression analysis showed that the addition of laser was significantly associated with a lower risk for recurrence (OR 0.23; 95% CI 0.089-0.633; p < 0.01). CONCLUSION: The incorporation of laser therapy along with trephine/pit excision surgery significantly reduces the recurrence rate in patients with PNS. Further prospective studies are needed to confirm our findings.

Left atrial calcification on chest CT: atrial ablation replaces rheumatic heart disease as the most identified etiology.

Purpose: Left atrial calcification (LAC), a primarily radiologic diagnosis, has been associated with rheumatic heart disease (RHD) and rheumatic fever (RF). However, left atrial calcification continues to be observed despite a significant decrease in the prevalence of rheumatic heart disease. The purpose of this study was to investigate other possible etiologies of left atrial calcification. Material and methods: This retrospective, observational single-center study included patients from 2017 to 2022 identified as having left atrial calcification as well as age- and sex-matched controls. The prevalence of rheumatic heart disease, atrial ablation, and mitral valve disease was compared, and odds ratios were calculated for each independent variable. Results: Sixty-two patients with left atrial calcifications were included and compared with 62 controls. 87.1% of patients in the left atrial calcifications cohort had a history of atrial fibrillation compared with 21% in the control cohort (p < 0.001). 16.1% of patients in the calcifications cohort presented a history of rheumatic fever compared with zero in the control cohort (p = 0.004). 66.1% of the left atrial calcifications cohort had a history of atrial ablation compared with 6.5% of the control group (p < 0.001). The odds ratio for left atrial calcification was 19.0 vs. 4.8 for rheumatic fever (comparative odds = 4.0 for atrial ablation vs. rheumatic fever). Multivariable log model found atrial ablation to explain 79.8% of left atrial calcifications identified. Conclusions: Our study found a 4-fold higher association between history of atrial ablation and left atrial calcification compared with rheumatic heart disease, suggesting a potential shift in etiology.

The socioeconomic impact of tuberculosis on children and adolescents: a scoping review and conceptual framework.

BACKGROUND: Tuberculosis (TB) has been repeatedly shown to have socioeconomic impacts in both individual-level and ecological studies; however, much less is known about this effect among children and adolescents and the extent to which being affected by TB during childhood and adolescence can have life-course implications. This paper describes the results of the development of a conceptual framework and scoping review to review the evidence on the short- and long-term socioeconomic impact of tuberculosis on children and adolescents. OBJECTIVES: To increase knowledge of the socioeconomic impact of TB on children and adolescents. METHODS: We developed a conceptual framework of the socioeconomic impact of TB on children and adolescents, and used scoping review methods to search for evidence supporting or disproving it. We searched four academic databases from 1 January 1990 to 6 April 2021 and conducted targeted searches of grey literature. We extracted data using a standard form and analysed data thematically. RESULTS: Thirty-six studies (29 qualitative, five quantitative and two mixed methods studies) were included in the review. Overall, the evidence supported the conceptual framework, suggesting a severe socioeconomic impact of TB on children and adolescents through all the postulated pathways. Effects ranged from impoverishment, stigma, and family separation, to effects on nutrition and missed education opportunities. TB did not seem to exert a different socioeconomic impact when directly or indirectly affecting children/adolescents, suggesting that TB can affect this group even when they are not affected by the disease. No study provided sufficient follow-up to observe the long-term socioeconomic effect of TB in this age group. CONCLUSION: The evidence gathered in this review reinforces our understanding of the impact of TB on children and adolescents and highlights the importance of considering effects during the entire life course. Both ad-hoc and sustainable social protection measures and strategies are essential to mitigate the socioeconomic consequences of TB among children and adolescents.

Prevalence and distribution of high-risk prescription opioid use in the United States, 2011-2016.

PURPOSE: Despite the efforts of many stakeholders to reduce the risk of opioid overdose, there is limited information on the prevalence of high-risk prescription opioid use in the US. METHODS: Descriptive analysis of a nationally representative 5% random sample of anonymized, longitudinal, individual-level prescription claims from IQVIA LRx between January 1, 2011 and December 31, 2016 among individuals ages 18 years or older that used a retail pharmacy. High-risk opioid use was defined as ≥50 morphine milligram equivalents per day and/or having concurrent dispensing of a benzodiazepine based on overlapping days of coverage. RESULTS: The prevalence of high-risk opioid use among adults in the US decreased from 12.0% in 2011 to 9.4% in 2016 (p < 0.01). Declines were most pronounced among individuals ages 18-35 years (10.9%-7.0%, 36.2% decline; p < 0.01) compared to individuals age 65 years or greater (10.5%-9.8%, 6.7% decline; p < 0.01). Declines in high-risk use prevalence were observed across 49 states, with only South Dakota experiencing an increase (+13.7% relative increase). Similar to earlier years, in 2016 50.9% of all high-risk use opioid users received all their opioid prescriptions from a single prescriber, and 71.1% used a single pharmacy to fill them. CONCLUSION: Despite clinically significant declines in high-risk opioid use, in 2016 nearly 1 in 10 adult retail pharmacy users remained at high-risk for opioid overdose in the US. Future clinical and policy interventions should consider targeting older adults with Medicare Part-D, including those using a single pharmacy to fill their opioid prescriptions.

Telepharmacy and medication adherence in urban areas.

BACKGROUND: Telepharmacies, which dispense medications on-site under the supervision of an off-site pharmacist using telecommunication technologies, have been proposed as a means to ameliorate the impact of pharmacy closures and improve access to medications. OBJECTIVES: To examine whether adherence varies among individuals filling prescription medications through a telepharmacy versus a traditional pharmacy in an urban neighborhood. METHODS: We conducted a retrospective cohort study using dispensing records of a traditional pharmacy and a telepharmacy, located in the same low-income Chicago neighborhood, from January 2016 to December 2018. We focused on individuals using statins (n = 1044), angiotensin-converting enzyme inhibitors (ACEs)/angiotensin II receptor blockers (ARBs) (n = 1003), or noninsulin diabetes medications (NIDMs) (n = 692). We defined adherence as a proportion of days covered greater than 80% over 12-months. We examined the association between telepharmacy use and medication adherence using logistic regressions adjusted for demographics (age and sex) and index prescription characteristics (method of payment, e-prescription, 90-day supply). RESULTS: Telepharmacy users were less adherent to statins (37.6% vs. 54.3%, adjusted odds ratio 0.54 [95% CI 0.38-0.76], P < 0.01) and ACEs/ARBs (41.4% vs, 56.5%, 0.61 [0.44-0.84], P < 0.01) than users of the traditional pharmacy. However, adherence to NIDMs was similar among users of the tele- and traditional pharmacies (65.5% vs. 60.1%, 1.47 [0.92-2.35], P = 0.11). Our findings were similar when we conducted a series of sensitivity analyses, including restricting our cohorts to those who only used their index pharmacy and analyzing cohorts of new rather than continuing users of these medications. CONCLUSION: In this analysis, medication adherence was lower among users of telepharmacy than users of a traditional pharmacy in some but not all drug classes examined. Further research is needed to identify whether other interventions to improve adherence, such as longer hours of operation, at-home delivery, or 90-day supply, may be coupled with telepharmacies to increase their use in urban areas.

Oral Pretreatment with Galantamine Effectively Mitigates the Acute Toxicity of a Supralethal Dose of Soman in Cynomolgus Monkeys Posttreated with Conventional Antidotes.

Earlier reports suggested that galantamine, a drug approved to treat mild-to-moderate Alzheimer's disease (AD), and other centrally acting reversible acetylcholinesterase (AChE) inhibitors can serve as adjunct pretreatments against poisoning by organophosphorus compounds, including the nerve agent soman. The present study was designed to determine whether pretreatment with a clinically relevant oral dose of galantamine HBr mitigates the acute toxicity of 4.0×LD50 soman (15.08 µg/kg) in Macaca fascicularis posttreated intramuscularly with the conventional antidotes atropine (0.4 mg/kg), 2-pyridine aldoxime methyl chloride (30 mg/kg), and midazolam (0.32 mg/kg). The pharmacokinetic profile and maximal degree of blood AChE inhibition (∼25%-40%) revealed that the oral doses of 1.5 and 3.0 mg/kg galantamine HBr in these nonhuman primates (NHPs) translate to human-equivalent doses that are within the range used for AD treatment. Subsequent experiments demonstrated that 100% of NHPs pretreated with either dose of galantamine, challenged with soman, and posttreated with conventional antidotes survived 24 hours. By contrast, given the same posttreatments, 0% and 40% of the NHPs pretreated, respectively, with vehicle and pyridostigmine bromide (1.2 mg/kg, oral), a peripherally acting reversible AChE inhibitor approved as pretreatment for military personnel at risk of exposure to soman, survived 24 hours after the challenge. In addition, soman caused extensive neurodegeneration in the hippocampi of saline- or pyridostigmine-pretreated NHPs, but not in the hippocampi of galantamine-pretreated animals. To our knowledge, this is the first study to demonstrate the effectiveness of clinically relevant oral doses of galantamine to prevent the acute toxicity of supralethal doses of soman in NHPs. SIGNIFICANCE STATEMENT: This is the first study to demonstrate that a clinically relevant oral dose of galantamine effectively prevents lethality and neuropathology induced by a supralethal dose of the nerve agent soman in Cynomolgus monkeys posttreated with conventional antidotes. These findings are of major significance for the continued development of galantamine as an adjunct pretreatment against nerve agent poisoning.

Efficacy of an intermittent energy restriction diet in a primary care setting.

PURPOSE: Intermittent energy restriction (IER) is a popular weight loss (WL) strategy; however, its efficacy in clinical practice remains unknown. The present study compared the effects of IER compared to continuous energy restriction (CER) on WL and cardiometabolic risk factors in primary care. METHODS: A (self-selected) cohort study was conducted at the Rotherham Institute for Obesity (RIO), a primary care-based weight management service. 197(24% male) obese patients volunteered to participate and selected their diet group. IER participants (n = 99) consumed ~ 2600 kJ for two days/week. CER participants (n = 98) restricted their diet by ~ 2100 kJ/day below estimated requirements. Both interventions were delivered alongside RIO standard care. Changes in anthropometry and cardiometabolic disease risk markers (fasting biochemistry and blood pressure) were assessed after a 6-month intervention period and then participants were followed up again 6 months later (month 12). RESULTS: 27 IER patients (27%) and 39 CER patients (40%) completed the 6-month weight loss phase. Among completers, mean (SEM) WL was greater in the IER group at 6 months (5.4 ± 1.1% versus 2.8 ± 0.6%; p = 0.01), as were reductions in fat mass (p < 0.001) and improvements in systolic blood pressure (p < 0.001). Fasting insulin (p = 0.873) and diastolic blood pressure (p = 0.701) were reduced similarly in both groups. However, in the IER group, changes in anthropometry and blood pressure in the IER group had reverted to baseline by 12-month follow-up, whilst the CER group maintained weight loss but showed an increase in blood pressure. CONCLUSIONS: Among completers, IER resulted in superior short-term changes in anthropometry and some cardiometabolic risk factors. However, rates of attrition and weight regain were higher compared with standard care, providing important insights in the implementations of IER within a "real-life" NHS setting. TRIAL REGISTRATION NUMBER: ISRCTN31465600.

The efficacy of sacral neuromodulation in the treatment of low anterior resection syndrome: a systematic review and meta-analysis.

BACKGROUND: Sacral neuromodulation (SNM) has become one of the main treatment options in patients with fecal incontinence. The aim of this study was to determine the efficacy of sacral neuromodulation in the treatment of low anterior resection syndrome (LARS). METHODS: A systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. The search was conducted using the Pubmed, Embase, Ovid, and Cochrane databases, restricted to the English language and to articles published from 2000 to November 2018. RESULTS: A total of 434 articles on the efficacy of SNM in the treatment of LARS were retrieved, and 13 studies were included in the final analysis, with a total of 114 patients treated with SNM for LARS The overall success rate excluding study heterogeneity was 83.30% [95% CI (71.33-95.25%)]. Improvement in anal continence was seen in several clinical and functional parameters, including the Wexner Score [10.78 points, 95% CI (8.55-13.02), p < 0.0001], manometric maximum resting pressure [mean improvement of 6.37 mm/Hg, 95% CI (2.67-10.07), p = 0.0007], maximum squeeze pressure [mean improvement of 17.99 mm/Hg, 95% CI (17.42-18.56), p < 0.0001] and maximum tolerated volume [mean improvement of 22.74 ml, 95% CI (10.65-34.83), p = 0.0002]. Quality of life questionnaires also demonstrated significant improvement in patients' quality of life, but were reported only in a small group of included patients. CONCLUSIONS: SNM significantly improves symptoms and quality of life in patients suffering from fecal incontinence following low anterior resection.

Magnetic imaging defecography results are comparable to high-resolution manometry and conventional X-ray defecography in the assessment of functional pelvic floor disorders.

BACKGROUND: X-ray defecography or magnetic resonance defecography (MRD) and high-resolution anorectal manometry (HR-ARM) are essential for the diagnosis of pelvic floor disorders (PFD). However, there is only scarce information available about the accuracy of MRD in the functional assessment of the pelvic floor. The aim of this study was to examine the accuracy of MRD in the diagnosis of pelvic floor disorders by examining the intra-test agreement with x-ray defecography and HR-ARM in patients with PFD. METHODS: The study population included adults referred to our institution in January 2018-February 2020 for MRD as part of their evaluation of PFD. The MRD results were compared with X-ray defecography and HR-ARM. RESULTS: Forty-two patients were included in the study (36 female, 86%, mean age 56.9 years ± 15.8, range 19-86 years). When compared to X-ray defecography, the sensitivity of MRD for the evaluation of normal rest and squeeze pressures was high (0.83 and 1, respectively). High sensitivity rates were observed for the detection of pelvic organ prolapse and pelvic floor dyssynergia (0.84-1). When compared to HR-ARM, the sensitivity of MRD for the evaluation of squeeze and dyssynergia was very good (0.92and 1, respectively), and good for the evaluation of rest pressure (0.6). Inter-test agreement was high (0.5, 0.6, 0.6 for rest, squeeze and dyssynergia). Excellent rates of sensitivity as well as almost perfect intra-test agreement was found between abnormal balloon expulsion test and the diagnosis of dyssynergia and pelvic organ prolapse on MRD (1, 0.81). CONCLUSIONS: This study demonstrated substantial diagnostic agreement between HR-ARM and MRD in the diagnosis of pathological etiologies for functional pelvic floor disorders, mainly obstructed defecation syndrome.

Recombinant human granulocyte- colony stimulating factor in women with unexplained recurrent pregnancy losses: a randomized clinical trial.

STUDY QUESTION: Does administration of recombinant human granulocyte colony stimulating factor (rhG-CSF) in the first trimester improve pregnancy outcomes, among women with a history of unexplained recurrent pregnancy loss? SUMMARY ANSWER: rhG-CSF administered in the first trimester of pregnancy did not improve outcomes among women with a history of unexplained recurrent pregnancy loss. WHAT IS KNOWN ALREADY: The only previous randomized controlled study of granulocyte colony stimulating factor in recurrent miscarriage in 68 women with unexplained primary recurrent miscarriage found a statistically significant reduction in miscarriage and improvement in live birth rates. A further four observational studies where G-CSF was used in a recurrent miscarriage population were identified in the literature, two of which confirmed statistically significant increase in clinical pregnancy and live birth rates. STUDY DESIGN, SIZE, DURATION: A randomized, double-blind, placebo controlled clinical trial involving 150 women with a history of unexplained recurrent pregnancy loss was conducted at 21 sites with established recurrent miscarriage clinics in the United Kingdom between 23 June 2014 and 05 June 2016. The study was coordinated by University of Birmingham, UK. PARTICIPANTS/MATERIALS, SETTING, METHODS: One hundred and fifty women with a history of unexplained recurrent pregnancy loss: 76 were randomized to rhG-CSF and 74 to placebo. Daily subcutaneous injections of recombinant human granulocyte - colony stimulating factor 130 µg or identical appearing placebo from as early as three to five weeks of gestation for a maximum of 9 weeks. The trial used central randomization with allocation concealment. The primary outcome was clinical pregnancy at 20 weeks of gestation, as demonstrated by an ultrasound scan. Secondary outcomes included miscarriages, livebirth, adverse events, stillbirth, neonatal birth weight, changes in clinical laboratory variables following study drug exposure, major congenital anomalies, preterm births and incidence of anti-drug antibody formation. Analysis was by intention to treat. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 340 participants were screened for eligibility of which 150 women were randomized. 76 women (median age, 32[IQR, 29-34] years; mean BMI, 26.3[SD, 4.2]) and 74 women (median age, 31[IQR, 26-33] years; mean BMI, 25.8[SD, 4.2]) were randomized to placebo. All women were followed-up to primary outcome, and beyond to live birth. The clinical pregnancy rate at 20 weeks, as well as the live birth rate, was 59.2% (45/76) in the rhG-CSF group, and 64.9% (48/74) in the placebo group, giving a relative risk of 0.9 (95% CI: 0.7-1.2; P = 0.48). There was no evidence of a significant difference between the groups for any of the secondary outcomes. Adverse events (AEs) occurred in 52 (68.4%) participants in rhG-CSF group and 43 (58.1%) participants in the placebo group. Neonatal congenital anomalies were observed in 1/46 (2.1%) of babies in the rhG-CSF group versus 1/49 (2.0%) in the placebo group (RR of 0.9; 95% CI: 0.1-13.4; P = 0.93). LIMITATIONS, REASONS FOR CAUTION: This trial was conducted in women diagnosed with unexplained recurrent pregnancy loss and therefore no screening tests (commercially available) were performed for immune dysfunction related pregnancy failure/s. WIDER IMPLICATIONS OF THE FINDINGS: To our knowledge, this is the first multicentre study and largest randomized clinical trial to investigate the efficacy and safety of granulocyte human colony stimulating factor in women with recurrent miscarriages. Unlike the only available single center RCT, our trial showed no significant increase in clinical pregnancy or live births with the use of rhG-CSF in the first trimester of pregnancy. STUDY FUNDING/COMPETING INTEREST(S): This study was sponsored and supported by Nora Therapeutics, Inc., 530 Lytton Avenue, 2nd Floor, Palo Alto, CA 94301, USA. Darryl Carter was the co-founder and VP of research, Nora Therapeutics, Inc. and held shares in the company. He holds a patent for the use of recombinant human granulocyte colony stimulating factor to reduce unexplained recurrent pregnancy loss. Mark Joing, Paul Kwon and Jeff Tong were or are employees of Nora Therapeutics, Inc. No other potential conflict of interest relevant to this article was reported. TRIAL REGISTRATION NUMBER: EUDRACT No: 2014-000084-40; ClinicalTrials.gov Identifier: NCT02156063. TRIAL REGISTRATION DATE: 31 Mar 2014. DATE OF FIRST PATIENT'S ENROLMENT: 23 Jun 2014.

Clinical and physiological risk factors for fecal incontinence in chronically constipated women.

BACKGROUND: Fecal incontinence (FI) and chronic constipation (CC) are disabling symptoms that cause a significant public health problem. The pathophysiology of combined constipation and FI is not fully understood. Our aim was to delineate the clinical, physiological and anatomical factors that may contribute to the association of FI and CC. METHODS: A retrospective study was performed in a pelvic floor unit in a tertiary medical center. Consecutive female patients diagnosed with CC were included, and further divided into two groups according to the co-occurrence of FI. Demographic characteristics, anorectal physiology (obtained by manometry) and pelvic anatomical pathology (as assessed by dynamic pelvic ultrasound) were recorded and subsequently compared. RESULTS: A total of 267 women were included in the study. Of those, 62 patients (23%) had an associated FI (CCFI). The CCFI group had higher body mass index (BMI) levels and a trend toward younger average age as compared to the group without FI (CCNFI). The number of vaginal and instrumental deliveries was similar in both groups. Anal resting and squeeze pressures were significantly lower in the CCFI group (64 ± 21 vs 48 ± 18, p = 0.004 and 141 ± 136.2 vs. 97.5 ± 38.6, p = 0.02, respectively). Rectal sensation abnormalities were common, but did not differ between both groups. Dyssynergic defecation and rectocele were more common in the CCNFI group (68% vs. 51%, p = 0.04 and 39% vs. 24%, p = 0/045, respectively. CONCLUSIONS: Lower anal pressures and higher BMI were found among women with coexisting FI and CC. Pelvic floor anatomical and functional abnormalities are common in women diagnosed with CC and FI, but dyssynergia and diagnosis of significant rectocele, which cause obstructed defecation, were more common in the CCNFI group.

Viscerosensory input drives angiotensin II type 1A receptor-expressing neurons in the solitary tract nucleus.

Homeostatic regulation of visceral organ function requires integrated processing of neural and neurohormonal sensory signals. The nucleus of the solitary tract (NTS) is the primary sensory nucleus for cranial visceral sensory afferents. Angiotensin II (ANG II) is known to modulate peripheral visceral reflexes, in part, by activating ANG II type 1A receptors (AT1AR) in the NTS. AT1AR-expressing NTS neurons occur throughout the NTS with a defined subnuclear distribution, and most of these neurons are depolarized by ANG II. In this study we determined whether AT1AR-expressing NTS neurons receive direct visceral sensory input, and whether this input is modulated by ANG II. Using AT1AR-GFP mice to make targeted whole cell recordings from AT1AR-expressing NTS neurons, we demonstrate that two-thirds (37 of 56) of AT1AR-expressing neurons receive direct excitatory, visceral sensory input. In half of the neurons tested (4 of 8) the excitatory visceral sensory input was significantly reduced by application of the transient receptor potential vallinoid type 1 receptor agonist, capsaicin, indicating AT1AR-expressing neurons can receive either C- or A-fiber-mediated input. Application of ANG II to a subset of second-order AT1AR-expressing neurons did not affect spontaneous, evoked, or asynchronous glutamate release from visceral sensory afferents. Thus it is unlikely that AT1AR-expressing viscerosensory neurons terminate on AT1AR-expressing NTS neurons. Our data suggest that ANG II is likely to modulate multiple visceral sensory modalities by altering the excitability of second-order AT1AR-expressing NTS neurons.

Nurse-led primary health care for homeless men: a multimethods descriptive study.

AIM: To explore the primary healthcare needs and health service use of homeless men in inner Sydney. BACKGROUND: People experiencing homelessness have greater health needs than the general population and place high demands on tertiary care, which is expensive and may not be the optimum service for their needs. Accessible, approachable and affordable primary healthcare services could improve the health of homeless persons and potentially decrease costs to the healthcare system. METHODS: A multimethod design using a cross-sectional survey (n = 40) and administrative data (n = 2 707 daily summaries) collected from a nurse-led primary healthcare clinic for homeless men in Sydney. FINDINGS: Survey respondents were aged 27-76 years. Health problems reflected multimorbidity, with mental health issues present in almost all respondents. The majority had attended the clinic more than 20 times in the past year and said the services, treatments and referrals helped them avoid the emergency department. Administrative data indicated that medication administration was the most frequent service provided. Referrals to other health services doubled over the 7-year period. DISCUSSION: Multiple morbidities, particularly mental health issues, are associated with homelessness. A proactive approach by nurses including preventative services appeared to overcome barriers to health service use. CONCLUSION: This nurse-led primary healthcare clinic highlights the importance of providing services to homeless men with multiple comorbidities. Respect and trust in addition to easy access to health services appear to be important facilitators of health service use. IMPLICATIONS FOR NURSING, AND IMPLICATIONS FOR HEALTH POLICY: A greater number of primary health services that collaborate with specialist services, including nurse-led clinics, may facilitate health care for persons who are homeless, reducing the burden on acute services.

Functional and neurochemical characterization of angiotensin type 1A receptor-expressing neurons in the nucleus of the solitary tract of the mouse.

Angiotensin II acts via two main receptors within the central nervous system, with the type 1A receptor (AT1AR) most widely expressed in adult neurons. Activation of the AT1R in the nucleus of the solitary tract (NTS), the principal nucleus receiving central synapses of viscerosensory afferents, modulates cardiovascular reflexes. Expression of the AT1R occurs in high density within the NTS of most mammals, including humans, but the fundamental electrophysiological and neurochemical characteristics of the AT1AR-expressing NTS neurons are not known. To address this, we have used a transgenic mouse, in which the AT1AR promoter drives expression of green fluorescent protein (GFP). Approximately one-third of AT1AR-expressing neurons express the catecholamine-synthetic enzyme tyrosine hydroxylase (TH), and a subpopulation of these stained for the transcription factor paired-like homeobox 2b (Phox2b). A third group, comprising approximately two-thirds of the AT1AR-expressing NTS neurons, showed Phox2b immunoreactivity alone. A fourth group in the ventral subnucleus expressed neither TH nor Phox2b. In whole cell recordings from slices in vitro, AT1AR-GFP neurons exhibited voltage-activated potassium currents, including the transient outward current and the M-type potassium current. In two different mouse strains, both AT1AR-GFP neurons and TH-GFP neurons showed similar AT1AR-mediated depolarizing responses to superfusion with angiotensin II. These data provide a comprehensive description of AT1AR-expressing neurons in the NTS and increase our understanding of the complex actions of this neuropeptide in the modulation of viscerosensory processing.

Host and Potential Vector Susceptibility to an Emerging Orbivirus in the United States: Epizootic Hemorrhagic Disease Virus Serotype 6.

Epizootic hemorrhagic disease viruses (EHDVs) are orbiviruses transmitted by Culicoides biting midges to domestic and wild ruminants. EHDV-1 and EHDV-2 are endemic in the United States, where epizootic hemorrhagic disease is the most significant viral disease of white-tailed deer (WTD;Odocoileus virginianus) and reports of epizootic hemorrhagic disease in cattle are increasing. In 2006, a reassortant EHDV-6 was isolated from dead WTD in Indiana and has been detected each subsequent year over a wide geographic region. Since EHDV-6 is not a historically endemic serotype in the United States, it is important to understand infection outcome in potential hosts. Specifically, we aimed to evaluate the pathogenicity of the virus in 2 primary US ruminant hosts (WTD and cattle) and the susceptibility of a confirmed US vector (Culicoides sonorensis). Five WTD and 4 cattle were inoculated with >10(6)TCID50EHDV-6 by intradermal and subcutaneous injection. All 5 WTD exhibited moderate to severe disease, and 3 died. Viremia was first detected 3 to 5 days postinfection (dpi) with surviving animals seroconverting by 10 dpi. Two of 4 inoculated cattle had detectable viremia, 5 to 10 dpi and 7 to 24 dpi, respectively. No clinical, hematologic, or pathologic abnormalities were observed. Antibodies were detected by 10 dpi in 3 of 4 cows.C. sonorensis were fed on WTD blood spiked with EHDV-6 and held for 4 to 14 days postfeeding at 25°C. From 4 to 14 days postfeeding, 19 of 171 midges were virus isolation positive and 6 of 171 had ≥10(2.7)TCID50EHDV-6. Although outcomes varied, these studies demonstrate the susceptibility of ruminant and vector hosts in the United States for this recently emerged EHDV serotype.

Impact of HMG-CoA reductase inhibitors on the incidence of polyomavirus-associated nephropathy in renal transplant recipients with human BK polyomavirus viremia.

BACKGROUND: Up to 20% of renal transplant recipients (RTR) will develop human BK polyomavirus (BKPyV) viremia. BKPyV viremia is a pre-requisite of polyomavirus-associated nephropathy (PyVAN). Risk of BKPyV infections increases with immunosuppression. Currently, the only effective therapy against PyVAN is reductions in immunosuppression, but this may increase the risk of rejection. In vitro data have shown that pravastatin dramatically decreased caveolin-1 expression in human renal proximal tubular epithelial cells (HRPTEC) and suppressed BKPyV infection in these cells. Based on these data, we postulated that statin therapy may prevent the progression of BKPyV viremia to PyVAN. PATIENTS AND METHODS: A multicenter, retrospective study was conducted in adult RTR transplanted between July 2005 and March 2012. All patients with documented BKPyV viremia (viral load >500 copies/mL on 2 consecutive tests) were included. Group I consisted of patients taking a statin before the BKPyV viremia diagnosis (n = 32), and Group II had no statin exposure before or after the BKPyV viremia diagnosis (n = 36). The primary endpoint was the incidence of PyVAN. RESULTS: Demographic data, transplant characteristics, and the degree of immunosuppression (i.e., induction/maintenance therapies, rejection treatment) were similar between the groups, with the exception of more diabetics in Group I. The incidence of PyVAN was comparable between the 2 groups (Group I = 28.1% vs. Group II = 41.7%; P = 0.312). CONCLUSIONS: Despite the proven in vitro effectiveness of pravastatin preventing BKPyV infection in HRPTEC, statins at doses maximized for cholesterol lowering, in RTR with BKPyV viremia, did not prevent progression to PyVAN.