An online Sexual Health and Rehabilitation eClinic (TrueNTH SHAReClinic) for prostate cancer patients: a feasibility study.

PURPOSE: The primary objective was to determine the feasibility of implementing the TrueNTH SHAReClinic as a pan-Canadian sexual health and rehabilitation intervention for patients treated for localized prostate cancer. METHODS: The feasibility study was designed to evaluate the accessibility and acceptability of the intervention. Participants from five institutions across Canada were enrolled to attend one pre-treatment and five follow-up online clinic visits over 1 year following their prostate cancer (PC) treatment. RESULTS: Sixty-five patients were enrolled in the intervention. Website analytics revealed that 71% completed the intervention in its entirety, including the educational modules, with an additional 10% completing more than half of the intervention. Five thousand eighty-three views of the educational modules were made along with 654 views of the health library items. Over 1500 messages were exchanged between participants and their sexual health coaches. At 12 months, the intervention received an overall average participant rating of 4.1 out of 5 on a single item satisfaction measure. CONCLUSION: Results support the TrueNTH SHAReClinic as highly acceptable to participants as defined by intervention adherence and engagement. The TrueNTH SHAReClinic demonstrated promise for being a feasible and potentially resource-efficient approach to effectively improving the sexual well-being of patients after PC treatment.

Systemic dendrimer nanotherapies for targeted suppression of choroidal inflammation and neovascularization in age-related macular degeneration.

Inflammation and neovascularization are key pathological events in human age-related macular degeneration (AMD). Activated microglia/macrophages (mi/ma) and retinal pigmented epithelium (RPE) play an active role in every stage of disease progression. Systemic therapies that can target these cells and address both inflammation and neovascularization will broaden the impact of existing therapies and potentially open new avenues for early AMD where there are no viable therapies. Utilizing a clinically relevant rat model of AMD that mirrors many aspects that of human AMD pathological events, we show that systemic hydroxyl-terminated polyamidoamine dendrimer-triamcinolone acetonide conjugate (D-TA) is selectively taken up by the injured mi/ma and RPE (without the need for targeting ligands). D-TA suppresses choroidal neovascularization significantly (by >80%, >50-fold better than free drug), attenuates inflammation in the choroid and retina, by limiting macrophage infiltration in the pathological area, significantly suppressing pro-inflammatory cytokines and pro-angiogenic factors, with minimal side effects to healthy ocular tissue and other organs. In ex vivo studies on human postmortem diabetic eyes, the dendrimer is also taken up into choroidal macrophages. These results suggest that the systemic hydroxyl dendrimer-drugs can offer new avenues for therapies in treating early/dry AMD and late/neovascular AMD alone, or in combination with current anti-VEGF therapies. This hydroxyl dendrimer platform but conjugated to a different drug is undergoing clinical trials for severe COVID-19, potentially paving the way for faster clinical translation of similar compounds for ocular and retinal disorders.

Risk of re-operation after outpatient distal hypospadias repair in a large, multistate cohort.

BACKGROUND: Repair of distal hypospadias is one of the most common pediatric urology procedures in the US. However, the risk of postsurgical complications has been reported primarily from single-institution and tertiary center studies, with short duration of patient follow-up. OBJECTIVE: The aim of the study was to examine the incidence of re-operation and risk factors for re-operation following outpatient distal hypospadias repair in a large, representative sample of US children. METHODS: A retrospective cohort study of patients aged 0-18 years undergoing single-stage distal hypospadias repair was conducted. Data were obtained from the State Ambulatory Surgery and Services Databases of 9 participating states. Patients who underwent outpatient surgery in 2008-2013 were identified using Current Procedural Terminology (CPT) codes. Patients with records suggesting prior surgery for hypospadias (CPT) were excluded, as were patients who underwent the initial repair <2 years before the end of state data availability. Return outpatient surgery visits across institutions within each of the 9 states were tracked to identify re-operations after the single-stage repair, using CPT codes for surgical treatment of hypospadias complications in 2008-2015. Time-to-event analyses were used to estimate the probability (risk) of re-operation over time and to examine whether patient and institutional characteristics were predictive of re-operation (age, race/ethnicity, health insurance, facility ownership, and institutional volume of hypospadias repair). RESULTS: A total of 4673 children treated across 148 institutions were included. The median follow-up time was 4.1 years (range: 2-7.9). Most patients were <1 year of age at the time of initial repair (53%). The risk of re-operation was 2.6% (95% confidence interval [CI]: 2.1-3.0%) at 1 year and 6.7% (95% CI: 6.0-7.5%) at 5 years after initial repair (Figure). Approximately 13% of re-operation patients had the re-operation at a different institution. None of the patient or institutional factors examined was a significant predictor of the risk of re-operation. DISCUSSION: In this population-based cohort, the estimated 5-year risk of re-operation following single-stage distal hypospadias repair was 6.7% (95% CI: 6.0-7.5). Most re-operations occurred after the first year, informing long-term expectations about postoperative complications. This study was limited by a lack of data on severity of hypospadias and surgeon characteristics and the inability to track re-operations outside of the state in which the original repair was performed. CONCLUSION: Approximately 7% of children undergoing distal hypospadias repair undergo a re-operation within 5 years. None of the factors studied were predictive of re-operations.

Trends in surgical management of multicystic dysplastic kidney at USA children's hospitals.

INTRODUCTION AND OBJECTIVE: Multicystic dysplastic kidney (MCDK) is a congenital renal cystic disease often incidentally diagnosed in children. Historically, children with MCDK underwent early nephrectomy because of concerns for the development of hypertension or malignancy. Over the last decade, management recommendations have not supported routine early surgical removal of MCDK. The study authors sought to determine the current trends in the use of nephrectomy for MCDK in US children's hospitals because national practice patterns have not been investigated. METHODS: A population-based retrospective cohort study using the Pediatric Health Information System (PHIS) was conducted. The study population was comprised of patients aged 0-18 years with a diagnosis of MCDK (International Classification of Diseases-9th revision, code 753.19) admitted to the inpatient department of the study hospital between January 2006 and September 2015. Patients with additional renal anomalies including polycystic kidney, medullary cystic kidney, and medullary sponge kidney were excluded, as were patients treated in a hospital that did not contribute data to the PHIS continuously throughout the study period. Trends in the annual proportion of nephrectomies performed were analyzed among admissions in the study population, along with patient clinical and demographic information. RESULTS: A total of 3792 MCDK admissions, in 34 hospitals, were included in the study. Overall, 569 nephrectomies were performed during the study period. The proportion of nephrectomy decreased annually by 9.2% on average, from 22.1% in 2006 to 7.3% in the first 3 quarters of 2015. No significant trends were observed in the annual number of overall MCDK admissions or patient age at procedure among patients who had a nephrectomy. Among nephrectomies, 84.2% were open and 15.8% were minimally invasive procedures (laparoscopic non-robotic, 10% and robotic, 5.8%). The proportion of minimally invasive nephrectomies increased annually by 13.7%, from 8% in 2006 to 29% in 2015. DISCUSSION: Trends in the use of nephrectomy for MCDK at a national level have not been previously reported. This study is limited by the use of inpatient discharge data, which did not allow estimating the true rate of nephrectomy in patients born with MCDK. CONCLUSIONS: During the study period, there has been a decrease in the use of nephrectomy for MCDK in pediatric hospitals, along with a concurrent increase in utilization of minimally invasive techniques to perform nephrectomies. These results suggest that in general, urologists at freestanding children's hospitals are heeding recommendations for observation and against routine early surgical removal of these kidneys; although trends in the use of nephrectomy varied between hospitals, there is room for continued improvement in following these recommendations.

Knowledge of vesicoureteral reflux obtained by screening voiding cystourethrogram in children with multicystic dysplastic kidney does not change patient management or prevent febrile urinary tract infection.

INTRODUCTION: While children with multicystic dysplastic kidneys (MCDK) are predisposed to contralateral kidney (CK) vesicoureteral reflux (VUR), it is unknown if this results in an increased risk of urinary tract infection (UTI). The authors hypothesized that knowledge of VUR via voiding cystourethrogram (VCUG) would enable altered practices to prevent UTI and thus reduce the number of febrile urinary tract infections (fUTIs). METHODS: The authors performed a retrospective chart review of all patients at their institution of multiple providers caring for patients with a diagnosis of MCDK from 1/1/07 to 7/14/17. Patients were evaluated for age, sex, circumcision status, race, imaging results on renal ultrasound (RUS) and/or VCUG, occurrence of fUTI, and prophylactic antibiotic (ppx) use. RESULTS: One hundred sixty-five patients were identified; 70% of patients were diagnosed with MCDK on prenatal imaging. Seventy-seven (47%) patients had a screening VCUG after diagnosis of MCDK. Eighteen patients with VCUG had VUR with 13 (17%) having VUR in the CK. Only children undergoing VCUG were placed on ppx with no difference in the use of ppx in patients with and without dilating VUR (45% vs 43%; p = 0.91). Overall, 11 patients experienced a fUTI. There was no significant difference in fUTI between those children who underwent VCUG compared with those who did not (10% vs 3%; p = 0.07). Use of ppx and presence of CK renal anomaly on RUS had no impact on incidence of subsequent fUTI. CONCLUSION: Knowledge of VUR based on VCUG results did not reduce the rate of fUTI or predict ppx use in the practice of multiple providers. The authors feel this confirms the low utility of VCUG in the practical management of otherwise healthy children with MCDK.

Benefits of spinal anesthesia for urologic surgery in the youngest of patients.

INTRODUCTION: Increasing concerns regarding potential negative effects of early use of inhalational and intravenous anesthetics on neurocognitive development have led to a growing interest in alternative forms of anesthesia in infants. The study institution's outcomes with spinal anesthesia (SA) for urologic surgery in infants aged less than 90 days are reported and their outcomes with a matched cohort of patients who underwent general anesthesia (GA) are compared. METHODS: This is a retrospective single-center analysis. Patients aged less than 90 days who underwent SA for four urologic surgeries (inguinal hernia repair, scrotal exploration, posterior urethral valve ablation, and ureterocele puncture) were identified from the study institution's SA database. An age- and procedure-matched control cohort was identified from a list of patients who underwent the aforementioned four procedures under GA since 2013. Outcomes of interest included success rate of SA, complications from spinal placement, narcotic use, need for supplemental medications and oxygen, and length of hospital stay. RESULTS: Forty patients were identified; 20 in the SA and 20 in the GA group. Mean patient age was 54 (standard deviation, 35) days. There were no significant differences between the groups in age, gender, weight, history of prematurity, or presence of comorbidities. Eighty percent of SA patients had successful SA; reasons for conversion to GA included failure of spinal needle placement (75%) and agitation during operative procedure (25%). Ninety-six percent of patients who received GA (primarily or converted) had an endotracheal tube (ETT) placed. No patient in the SA group had a complication from spinal needle placement. Patients in the SA group were less likely to receive narcotics during the operative procedure (P = 0.001) and also had a lower mean morphine equivalent dose/kilogram (P = 0.002). Patients in the SA group were also less likely to receive any supplemental medications during the operative procedure (P = 0.001), particularly intravenous corticosteroids (P < 0.001). There were no significant differences in the length of hospital stay. CONCLUSIONS: The use of SA has clear advantages for this medically vulnerable population. For the majority of patients, it obviates the need for ETT placement and airway management and avoids the potential negative effects of GA on neurocognitive development. It also decreases the use of narcotics and other supplemental medications. In scenarios in which the benefit of surgery must be weighed against the risk of GA, such as neonatal torsion, SA may allow a paradigm shift in the timing of surgery.

Urinary antimicrobial peptides: Potential novel biomarkers of obstructive uropathy.

INTRODUCTION: Antimicrobial peptides (AMPs) have historically been evaluated for their role in protecting against uropathogens. However, there is mounting evidence to support their expression in noninfectious injury, with unclear meaning as to their function. It is possible that AMPs represent urothelial injury. Urinary tract obstruction is known to alter the urothelium; however, AMPs have not been evaluated for expression in this noninfectious injury. OBJECTIVE: A pilot study to compare urinary AMP expression in children undergoing surgical intervention for ureteropelvic junction obstruction (UPJO) with nonobstructed controls. STUDY DESIGN: Bladder urine was collected from consenting/assenting pediatric patients with UPJO at intervention. Control bladder urines were obtained from age-matched and sex-matched healthy children without known obstruction or infection. Enzyme-linked immunosorbent assays were run for the following AMPs: ß defense 1 (BD-1), neutrophil gelatinase-associated lipocalin (NGAL), cathelicidin (LL-37), hepatocarcinoma-intestine-pancreas/pancreatitis-associated protein (HIP/PAP), and human α defensin 5 (HD-5); and normalized to urine creatinine. Results were analyzed with Student's t-test or Mann-Whitney U test, when appropriate, and receiver operating characteristic curves. A P-value of <0.05 was considered significant. RESULTS: Thirty bladder urine samples were obtained from children with UPJO at the time of decompressive intervention. Mean patient age was 4.7 years (range 0.3-18.4); 20 (67%) patients were male. Fifteen bladder urine samples were obtained from age-matched and sex-matched controls. Urinary AMP levels were significantly higher in UPJO patients than controls for BD-1 (P = 0.015), NGAL (P < 0.001), LL-37 (P < 0.001), and HIP/PAP (P = 0.046). Optimal threshold values of these AMPs were determined, with each demonstrating significant odds ratios of predicting urinary obstruction. DISCUSSION: Certain urinary AMPs are altered even in noninfectious urinary tract pathology. This represents a novel induction of AMP expression, as the current study is the first to report elevations in BD-1 and HIP/PAP in urinary tract obstruction. This suggests other roles for these AMPs outside of their antimicrobial properties, and likely is a reflection of the urothelial and tubular stress resulting from obstructive uropathy. CONCLUSIONS: Induction of AMPs BD-1, NGAL, LL-37, and HIP/PAP was found to occur in urinary tract obstruction. Further evaluation of AMP expression as a biomarker of uroepithelial injury outside of infection is indicated.

Breaking the biomarker code: PD-L1 expression and checkpoint inhibition in advanced NSCLC.

BACKGROUND: Lung cancer is the most common cause of cancer-related death among males and the second leading cause among females globally. Checkpoint inhibitors re-engage the immune system to fight cancer. This review evaluates phase III data on the use of checkpoint inhibitors in the treatment of advanced NSCLC and addresses PD-L1 expression in predicting efficacy. METHODS: Six phase III clinical trials investigating checkpoint inhibitors for NSCLC were identified through a search of PubMed (to November 15, 2016) and conference databases, with findings updated from a directed search of eligible studies conducted in January 2018. RESULTS: Significant reductions in the risk of death ranging from 27% to 41% and were observed second-line and beyond. A relationship between PD-L1 expression and survival was apparent in most trials with optimal benefit for the highest expression levels (≥50%). Benefit was also observed at low or no PD-L1 expression levels and in third-line in some studies. Significantly improved PFS was observed for pembrolizumab at high PD-L1 expression levels (≥50%) first-line. Immune-related adverse events associated with checkpoint inhibitors are tolerable and rates of pneumonitis may be lower among PD-L1 inhibitors. Use of checkpoint inhibitors for tumors with driver mutations should only be considered after all appropriate targeted therapy and chemotherapy have been exhausted. PD-L1 testing presents a valuable tool to guide treatment sequencing and we recommend use of agent-specific PD-L1 tests and respective scoring systems until a standardized, convenient and broadly applicable test is identified. CONCLUSIONS: Checkpoint inhibitors represent a major advance in the treatment of advanced NSCLC and PD-L1 status can inform treatment decisions.

Development of the hyaloid, choroidal and retinal vasculatures in the fetal human eye.

The development of the ocular vasculatures is perfectly synchronized to provide the nutritional and oxygen requirements of the forming human eye. The fetal vasculature of vitreous, which includes the hyaloid vasculature, vasa hyaloidea propria, and tunica vasculosa lentis, initially develops around 4-6 weeks gestation (WG) by hemo-vasculogenesis (development of blood and blood vessels from a common progenitor, the hemangioblast). This transient fetal vasculature expands around 12 WG by angiogenesis (budding from primordial vessels) and remains until a retinal vasculature begins to form. The fetal vasculature then regresses by apoptosis with the assistance of macrophages/hyalocytes. The human choroidal vasculature also forms by a similar process and will supply nutrients and oxygen to outer retina. This lobular vasculature develops in a dense collagenous tissue juxtaposed with a cell constitutively producing vascular endothelial growth factor (VEGF), the retinal pigment epithelium. This epithelial/endothelial relationship is critical in maintaining the function of this vasculature throughout life and maintaining it's fenestrated state. The lobular capillary system (choriocapillaris) develops first by hemo-vasculogenesis and then the intermediate choroidal blood vessels form by angiogenesis, budding from the choriocapillaris. The human retinal vasculature is the last to develop. It develops by vasculogenesis, assembly of CXCR4+/CD39+ angioblasts or vascular progenitors perhaps using Muller cell Notch1 or axonal neuropilinin-1 for guidance of semaphorin 3A-expressing angioblasts. The fovea never develops a retinal vasculature, which is probably due to the foveal avascular zone area of retina expressing high levels of antiangiogenic factors. From these studies, it is apparent that development of the mouse ocular vasculatures is not representative of the development of the human fetal, choroidal and retinal vasculatures.

The modified Ulaanbaatar procedure: Reduced complications and enhanced cosmetic outcome for the most severe cases of hypospadias.

INTRODUCTION/OBJECTIVE: Proximal hypospadias is one of the most challenging conditions that pediatric urologists have to deal with. Many procedures have been devised over the years, but nothing has been proven to be the best option. Although there have been some attempts at correcting severe hypospadias in one procedure, most have advocated a staged approach. The classic approach - laying penile skin or a graft within a split glans followed by glanuloplasty at the second stage - by definition requires two operations on the glans. In the Ulaanbaatar procedure the distal glanular urethra is constructed at the first stage, allowing for a single glans procedure and thus potentially better cosmetic outcomes. The present study discusses experience with the Ulaanbaatar procedure for severe hypospadias. STUDY DESIGN: The study retrospectively reviewed every child who underwent both stages of this procedure at the present institution. It reviewed age, associated diagnoses, surgical technique and outcomes. SURGICAL TECHNIQUE: The first stage was analogous to a classic first-stage procedure with regard to division of the urethral plate and correction of penile curvature. However, an island flap of preputial skin was mobilized and tubularized to create the glanular urethra. No attempt was made to bridge the native meatus and this reconstructed urethra, and the remaining penile skin was placed between the two. The second stage was performed 6 months later by tubularizing the penile skin between the two meatuses. RESULTS: The series consisted of 34 boys. Mean age at surgery was 18.3 months (range 6-118). Nineteen underwent evaluation for genital ambiguity at birth (56%). Thirty (88%) received pre-operative testosterone or human chorionic gonadotropin (HCG). After urethral plate transection, persistent curvature was addressed during the first stage, with dorsal plication in 12 (35%), urethral plate transection alone in six (18%) or ventral grafting with small intestinal submucosa in 16 (47%). Twenty-three boys (67%) had the neourethra tunneled through the glans, and 11 (33%) had the glans split followed by glanuloplasty. Average time between the two stages was 7 months (range 4.0-13.9). Four patients (12%) developed urethral diverticula that required repair. One developed recurrent epididymitis related to an abnormal ejaculatory duct (no stricture) and underwent vasectomy. No patient developed a fistula. Mean length of follow-up was 15.2 months (range 0.3-55.5). DISCUSSION: This modification of the classic staged hypospadias repair may allow for better cosmetic outcome, since the majority of boys required no formal glanuloplasty. There were reduced complications, perhaps because the urethral defect acted like a controlled fistula, allowing for better tissue healing prior to final urethral reconstruction.

Distribution and Quantification of Choroidal Macrophages in Human Eyes With Age-Related Macular Degeneration.

PURPOSE: Increasing evidence suggests a role for macrophages in the pathogenesis of age-related macular degeneration (AMD). This study examined choroidal macrophages and their activation in postmortem eyes from subjects with and without AMD. METHODS: Choroids were incubated with anti-ionized calcium-binding adapter molecule 1 (anti-IBA1) to label macrophages, anti-human leukocyte antigen-antigen D-related (anti-HLA-DR) as a macrophage activation marker, and Ulex europaeus agglutinin lectin to label blood vessels. Whole mounts were imaged using confocal microscopy. IBA1- and HLA-DR-positive (activated) cells were counted in submacula, paramacula, and nonmacula, and cell volume and sphericity were determined using computer-assisted image analysis. RESULTS: In aged control eyes, the mean number of submacular IBA1+ and HLA-DR+ macrophages was 433/mm2 and 152/mm2, respectively. In early AMD eyes, there was a significant increase in IBA1+ and HLA-DR+ cells in submacula compared to those in controls (P = 0.0015 and P = 0.008, respectively). In eyes with neovascular AMD, there were significantly more HLA-DR+ cells associated with submacular choroidal neovascularization (P = 0.001). Mean cell volume was significantly lower (P ≤ 0.02), and sphericity was significantly higher (P ≤ 0.005) in all AMD groups compared to controls. CONCLUSIONS: The average number of IBA1+ macrophages in submacular and paramacular choroid was significantly higher in early/intermediate AMD compared to that in aged controls. HLA-DR+ submacular macrophages were significantly increased in all stages of AMD, and they were significantly more round and smaller in size in the submacular AMD choroid, suggesting their activation. These findings support the concept that AMD is an inflammatory disease.

Segmental arterial mapping during pediatric robot-assisted laparoscopic heminephrectomy: A descriptive series.

INTRODUCTION: The incidence of innocent moiety injury during heminephrectomy is estimated to be 4-5%. This complication can have long-term consequences for the child. Selective arterial mapping (SAM) with indocyanine green (ICG)-aided near infrared fluorescence (NIRF) imaging using the Firefly™ system on the da Vinci(®) surgical robotic console has proven to be valuable in robotic partial nephrectomy for adult renal tumors. However, there is nothing in the literature for using this technique in pediatric robot-assisted laparoscopic heminephrectomy (RALHN). OBJECTIVE: To present a descriptive series of children who had SAM RALHN using ICG-aided NIRF imaging. To determine the feasibility of using ICG-aided NIRF SAM during RALHN, and to study if real-time delineation of the selective arterial anatomy of the upper and lower moieties would be helpful or change the immediate outcomes of the surgery. STUDY DESIGN: A descriptive series of six children who received RALHN at the present institution. RESULTS: Selective arterial mapping was performed safely without toxicity or vascular complications; it did not extend the operative time and did not change the complexity of the operation. As shown in the summary table below, SAM added value by increasing safety of the operation. The individual operation cost increase of using SAM was only related to the single-use vial of ICG. DISCUSSION: Inadvertent injury to the innocent moiety in pediatric heminephrectomy is seldom noted intraoperatively, and many times only becomes evident postoperatively when there is acute ischemia or a chronic reduction in renal function. Although there is no replacement for good surgical technique and judgment, SAM during RALHN is a useful real-time way of alerting the surgeon to unexpected anatomy, and possible unintended or occult injury to the innocent moiety that could have devastating short-term and long-term consequences to the child, despite immediate recovery from surgery. CONCLUSIONS: This report achieved its aim of reporting the feasibility of SAM on a small descriptive series of children who had RALHN.

The D-Health Trial: A randomized trial of vitamin D for prevention of mortality and cancer.

BACKGROUND: Vitamin D, specifically serum 25(OH)D has been associated with mortality, cancer and multiple other health endpoints in observational studies, but there is a paucity of clinical trial evidence sufficient to determine the safety and effectiveness of population-wide supplementation. We have therefore launched the D-Health Trial, a randomized trial of vitamin D supplementation for prevention of mortality and cancer. Here we report the methods and describe the trial cohort. METHODS: The D-Health Trial is a randomized placebo-controlled trial, with planned intervention for 5years and a further 5years of passive follow-up through linkage with health and death registers. Participants aged 65-84years were recruited from the general population of Australia. The intervention is monthly oral doses of 60,000IU of cholecalciferol or matching placebo. The primary outcome is all-cause mortality. Secondary outcomes are total cancer incidence and colorectal cancer incidence. RESULTS: We recruited 21,315 participants to the trial between February 2014 and May 2015. The participants in the two arms of the trial were well-balanced at baseline. Comparison with Australian population statistics shows that the trial participants were less likely to report being in fair or poor health, to be current smokers or to have diabetes than the Australian population. However, the proportion overweight or with health conditions such as arthritis and angina was similar. CONCLUSIONS: Observational data cannot be considered sufficient to support interventions delivered at a population level. Large-scale randomized trials such as the D-Health Trial are needed to inform public health policy and practice.

Increased choroidal mast cells and their degranulation in age-related macular degeneration.

BACKGROUND/AIMS: Inflammation has been implicated in age-related macular degeneration (AMD). This study investigates the association of mast cells (MCs), a resident choroidal inflammatory cell, with pathological changes in AMD. METHODS: Human donor eyes included aged controls (n=10), clinically diagnosed with early AMD (n=8), geographic atrophy (GA, n=4) and exudative AMD (n=11). The choroids were excised and incubated for alkaline phosphatase (APase; blood vessels) and non-specific esterase activities (MCs). Degranulated (DG) and non-degranulated MCs in four areas of posterior choroid (nasal, non-macular, paramacular and submacular) were counted in flat mounts (4-6 fields/area). Choroids were subsequently embedded in JB-4 and sectioned for histological analyses. RESULTS: The number of MCs was significantly increased in all choroidal areas in early AMD (p=0.0006) and in paramacular area in exudative AMD (139.44±55.3 cells/mm(2); p=0.0091) and GA (199.08±82.0 cells/mm(2); p=0.0019) compared with the aged controls. DG MCs were also increased in paramacular (p=0.001) and submacular choroid (p=0.02) in all forms of AMD. Areas with the greatest numbers of DG MCs had loss of choriocapillaris (CC). Sections revealed that the MCs were widely distributed in Sattler's and Haller's layer in the choroidal stroma in aged controls, whereas MCs were frequently found in close proximity with CC in GA and exudative AMD and in choroidal neovascularisation (CNV). CONCLUSION: Increased MC numbers and degranulation were observed in all AMD choroids. These results suggest that MC degranulation may contribute to the pathogenesis of AMD: death of CC and retinal pigment epithelial and CNV formation. The proteolytic enzymes released from MC granules may result in thinning of AMD choroid.

A randomised controlled trial of perineural vs intravenous dexamethasone for foot surgery.

We used 20 ml ropivacaine 0.75% for ankle blocks before foot surgery in 90 participants who we allocated in equal numbers to: perineural dexamethasone 8 mg and intravenous saline 0.9%; perineural saline 0.9% and intravenous dexamethasone 8 mg; or perineural and intravenous saline 0.9%. Dexamethasone increased the median (IQR [range]) time for the return of some sensation or movement, from 14.6 (10.8-18.8 [5.5-38.0]) h with saline to 24.1 (19.3-29.3 [5.0-44.0]) h when given perineurally, p = 0.00098, and to 20.9 (18.3-27.8 [8.8-31.3]) h when given intravenously, p = 0.0067. Dexamethasone increased the median (IQR [range]) time for the return of normal neurology, from 17.6 (14.0-21.0 [9.5-40.5]) h with saline to 27.5 (22.0-36.3 [7.0-53.0]) h when given perineurally, p = 0.00016, and to 24.0 (20.5-32.3 [13.0-42.5]) h when given intravenously, p = 0.0022. Dexamethasone did not affect the rates of block success, postoperative pain scores, analgesic use, or nausea and vomiting. The route of dexamethasone administration did not alter its effects.

Increasing thyroid cancer incidence in Queensland, Australia 1982-2008 - true increase or overdiagnosis?

BACKGROUND: Thyroid cancer incidence has been increasing worldwide. Some suggest greater ascertainment of indolent tumours is the only driver, but others suggest there has been a true increase. Increases in Australia appear to have been among the largest in the world, so we investigated incidence trends in the Australian state of Queensland to help understand reasons for the rise. METHODS: Thyroid cancers diagnoses in Queensland 1982-2008 were ascertained from the Queensland Cancer Registry. We calculated age-standardized incidence rates (ASR) and used Poisson regression to estimate annual percentage change (APC) in thyroid cancer incidence by socio-demographic and tumour-related factors. RESULTS: Thyroid cancer ASR in Queensland increased from 2·2 to 10·6/100 000 between 1982 and 2008 equating to an APC of 5·5% [95% confidence interval (CI) 4·7-6·4] in men and 6·1% (95% CI 5·5-6·6) in women. The rise was evident, and did not significantly differ, across socio-economic and remoteness-of-residence categories. The largest increase seen was in the papillary subtype in women (APC 7·9%, 95% CI 7·3-8·5). Incidence of localized and more advanced-stage cancers rose over time although the increase was greater for early-stage cancers. CONCLUSION: There has been a marked increase in thyroid cancer incidence in Queensland. The increase is evident in men and women across all adult age groups, socio-economic strata and remoteness-of-residence categories as well as in localized and more advanced-stage cancers. Our results suggest 'overdiagnosis' may not entirely explain rising incidence. Contemporary aetiological data and individual-level information about diagnostic circumstances are required to further understand reasons for rising thyroid cancer incidence.

Systemic and Intravitreal Delivery of Dendrimers to Activated Microglia/Macrophage in Ischemia/Reperfusion Mouse Retina.

PURPOSE: Microglial activation and associated neuroinflammation play a key role in the pathogenesis of many diseases of the retina, including viral infection, diabetes, and retinal degeneration. Strategies to target activated microglia and macrophages and attenuate inflammation may be valuable in treating these diseases. We seek to develop dendrimer-based formulations that target retinal microglia and macrophages in a pathology-dependent manner, and deliver drugs, either intravenously or intravitreally. METHODS: Retinal uptake of cyanine dye (Cy5)-conjugated dendrimer (D-Cy5) was assessed in normal and ischemia/reperfusion (I/R) mouse eyes. Microglia/macrophage uptake of the dendrimer was assessed with immunofluorescence using rabbit Iba-1 antibody with Cy3-tagged secondary antibody (microglia/macrophage). Uptake in retina and other organs was quantified using fluorescence spectroscopy. RESULTS: Clearance of D-Cy5 from normal eyes was almost complete by 72 hours after intravitreal injection and 24 hours after intravenous delivery. In eyes with activated microglia after I/R injury, D-Cy5 was retained by activated microglia/macrophage (Iba1+ cells) up to 21 days after intravitreal and intravenous administration. In I/R eyes, the relative retention of intravitreal and intravenous D-Cy5 was comparable, if a 30-fold higher intravenous dose was used. CONCLUSIONS: Intravitreal and systemic dendrimers target activated microglia and show qualitatively similar retinal biodistribution when administered by either route. Results provide proof-of-concept insights for developing dendrimer drug formulations as treatment options for retinal diseases associated with microglia or macrophage activation such as age-related macular degeneration, diabetic retinopathy, and retinal degenerations.

Matching two independent cohorts validates DPH1 as a gene responsible for autosomal recessive intellectual disability with short stature, craniofacial, and ectodermal anomalies.

Recently, Alazami et al. (2015) identified 33 putative candidate disease genes for neurogenetic disorders. One such gene was DPH1, in which a homozygous missense mutation was associated with a 3C syndrome-like phenotype in four patients from a single extended family. Here, we report a second homozygous missense variant in DPH1, seen in four members of a founder population, and associated with a phenotype initially reminiscent of Sensenbrenner syndrome. This postpublication "match" validates DPH1 as a gene underlying syndromic intellectual disability with short stature and craniofacial and ectodermal anomalies, reminiscent of, but distinct from, 3C and Sensenbrenner syndromes. This validation took several years after the independent discoveries due to the absence of effective methods for sharing both candidate phenotype and genotype data between investigators. Sharing of data via Web-based anonymous data exchange servers will play an increasingly important role toward more efficient identification of the molecular basis for rare Mendelian disorders.

Disrupted auto-regulation of the spliceosomal gene SNRPB causes cerebro-costo-mandibular syndrome.

Elucidating the function of highly conserved regulatory sequences is a significant challenge in genomics today. Certain intragenic highly conserved elements have been associated with regulating levels of core components of the spliceosome and alternative splicing of downstream genes. Here we identify mutations in one such element, a regulatory alternative exon of SNRPB as the cause of cerebro-costo-mandibular syndrome. This exon contains a premature termination codon that triggers nonsense-mediated mRNA decay when included in the transcript. These mutations cause increased inclusion of the alternative exon and decreased overall expression of SNRPB. We provide evidence for the functional importance of this conserved intragenic element in the regulation of alternative splicing and development, and suggest that the evolution of such a regulatory mechanism has contributed to the complexity of mammalian development.