Preserved striatal innervation maintains motor function despite severe loss of nigral dopaminergic neurons.

Degeneration of dopaminergic neurons in the substantia nigra and their striatal axon terminals causes cardinal motor symptoms of Parkinson's disease. In idiopathic cases, high levels of mitochondrial DNA alterations leading to mitochondrial dysfunction are a central feature of these vulnerable neurons. Here we present a mouse model expressing the K320E-variant of the mitochondrial helicase Twinkle in dopaminergic neurons, leading to accelerated mitochondrial DNA mutations. These K320E-TwinkleDaN mice showed normal motor function at 20 months of age, although ∼70% of nigral dopaminergic neurons had perished. Remaining neurons still preserved ∼75% of axon terminals in the dorsal striatum and enabled normal dopamine release. Transcriptome analysis and viral tracing confirmed compensatory axonal sprouting of the surviving neurons. We conclude that a small population of substantia nigra dopaminergic neurons is able to adapt to the accumulation of mitochondrial DNA mutations and maintain motor control.

Constitutive nuclear accumulation of endogenous alpha-synuclein in mice causes motor impairment and cortical dysfunction, independent of protein aggregation.

A growing body of evidence suggests that nuclear alpha-synuclein (αSyn) plays a role in the pathogenesis of Parkinson's disease (PD). However, this question has been difficult to address as controlling the localization of αSyn in experimental systems often requires protein overexpression, which affects its aggregation propensity. To overcome this, we engineered SncaNLS mice, which localize endogenous αSyn to the nucleus. We characterized these mice on a behavioral, histological and biochemical level to determine whether the increase of nuclear αSyn is sufficient to elicit PD-like phenotypes. SncaNLS mice exhibit age-dependent motor deficits and altered gastrointestinal function. We found that these phenotypes were not linked to αSyn aggregation or phosphorylation. Through histological analyses, we observed motor cortex atrophy in the absence of midbrain dopaminergic neurodegeneration. We sampled cortical proteomes of SncaNLS mice and controls to determine the molecular underpinnings of these pathologies. Interestingly, we found several dysregulated proteins involved in dopaminergic signaling, including Darpp32, Pde10a and Gng7, which we further confirmed was decreased in cortical samples of the SncaNLS mice compared with controls. These results suggest that chronic endogenous nuclear αSyn can elicit toxic phenotypes in mice, independent of its aggregation. This model raises key questions related to the mechanism of αSyn toxicity in PD and provides a new model to study an underappreciated aspect of PD pathogenesis.

Urology HEIRS: A Feasibility and Acceptability Study for Video-Based Research on Physician-Family Communication in Pediatric Urology Visits.

PURPOSE: Patient- and family-centered communication is essential to health care equity. However, less is known about how urologists implement evidence-based communication and dynamics involved in caring for diverse pediatric patients and caregivers. We sought to evaluate the feasibility and acceptability using video-based research to characterize physician-family communication in pediatric urology. MATERIALS AND METHODS: We assembled a multidisciplinary team to conduct a multiphase learning health systems project to establish the Urology HEIRS (Health Experiences and Interactions in Real-time Studies) corpus for research and interventions. This paper reports the first phase, evaluating feasibility and acceptability based on consent rate, patient diversity, and qualitative identification of verbal and paraverbal features of physician-family communication. We used applied conversation analysis methodology to identify salient practices across 8 pediatric urologists. RESULTS: We recruited 111 families at 2 clinic sites; of these 82 families (N = 85 patients, ages 0-20 years) participated in the study with a consent rate of 73.9%. The racial/ethnic composition of the sample was 45.9% non-Hispanic White, 30.6% any race of Hispanic origin, 16.5% non-Hispanic Black/African American, 4.7% any ethnicity of Asian/Asian American, and 2.3% some other race/ethnicity; 24.7% of families used interpreters. We identified 11 verbal and paraverbal communication practices that impacted physician-family dynamics, including unique challenges with technology-mediated interpreters. CONCLUSIONS: Video-based research is feasible and acceptable with diverse families in pediatric urology settings. The Urology HEIRS corpus will enable future systematic studies of physician-family communication in pediatric urology and provides an empirical basis for specialty-specific training in patient- and family-centered communication.

Modulating Excited State Properties and Ligand Ejection Kinetics in Ruthenium Polypyridyl Complexes Designed to Mimic Photochemotherapeutics.

Ruthenium(II) polypyridyl complexes have gained significant interest as photochemotherapeutics (PCTs) due to their synthetic viability, strong light absorption, well understood excited state properties, and high phototoxicity indexes. Herein, we report the synthesis, characterization, electrochemical, spectrochemical, and preliminary cytotoxicity analyses of three series of ruthenium(II) polypyridyl complexes designed to mimic PCTs. The three series have the general structure of [Ru(bpy)2(N-N)]2+ (Series 1), [Ru(bpy)(dmb)(N-N)]2+ (Series 2), and [Ru(dmb)2(N-N)]2+ (Series 3, where N-N is a bidentate polypyridyl ligand, bpy = 2,2'-bipyridine, and dmb = 6,6'-dimethyl-2,2'-bipyridine). In the three series, the N-N ligand was systematically modified to incorporate increased conjugation and/or electronegative heteroatoms to increase dπ-π* backbonding, red-shifting the lowest energy metal-to-ligand charge transfer (MLCT) absorptions from λmax = 454 to λmax = 580 nm, nearing the therapeutic window for PCTs (600-1100 nm). In addition, steric bulk was systematically introduced through the series, distorting the Ru(II) octahedra, making the dissociative 3dd* state thermally accessible at room and body temperatures. This resulted in a 4 orders of magnitude increase in photoinduced ligand ejection kinetics, and demonstrates the ability to modulate both the MLCT* and dd* manifolds in the complexes, which is critical in PCT drug design. Preliminary cell viability assays suggest that the increased steric bulk to lower the 3dd* states may interfere with the cytotoxicity mechanism, limiting photoinitiated toxicity of the complexes. This work demonstrates the importance of understanding both the MLCT* and dd* manifolds and how they impact the ability of a complex to act as a PCT agent.

A Thirteen-Year Analysis of Facial Fractures among Professional Soccer Players.

This study aims to identify the epidemiology and effects of facial fractures on return to play (RTP) in Major League Soccer (MLS) and the English Premier League (EPL). A total of 39 MLS players and 40 EPL players who sustained facial fractures from 2007 to 2019 were identified. Data on player demographics, the injury, and the impact of their injury on RTP were collected. Elbow-to-head was the most common mechanism of injury (20.3%). The most common fracture involved the nasal bone (48.3%). Most players (90%) RTP the same season. Players who sustained nasal fractures missed significantly fewer games (p < 0.001) than those who suffered other craniofacial fractures. Players treated surgically missed significantly more games (3.21 vs. 0.71, p = 0.006) and days (30.1 vs. 8.70, p = 0.002) than those managed nonoperatively. Significantly more EPL players who sustained facial fractures wore headgear upon RTP compared to MLS players (82% vs. 56%, p <0 .01). Most professional soccer players who sustain a facial fracture RTP the same season, but their recovery time can vary depending on the type of fracture, injury management, or injury severity. Our findings can help inform future craniofacial injury management as well as guidelines on player safety and fracture prevention.

Solo and Partnered Sexual Behavior Among an International Sample of Adults With Spina Bifida.

BACKGROUND: Spina bifida (SB) may differentially impact adults' participation in solo and partnered sexual behaviors, but little research investigates this topic. AIM: Describe solo and partnered sexual behaviors among an international sample of adult men and women with SB. MAIN OUTCOME MEASURES: Ever participated (no/yes) and recent participation (>1 year ago/within last year) in solo masturbation, cuddled with a partner, held hands with a partner, kissed a partner, touched a partner's genital, had genitals touched by a partner, gave a partner oral sex, received oral sex from a partner, vaginal sex, anal sex, and sex toy use. METHODS: Data were drawn from a larger cross-sectional, internet-based survey assessing the sexual behaviors of an international sample of men and women with SB. We used logistic regression to examine the impact of background (gender, age, independent living, and relationship status) and health (shunt status, ambulation, and genital sensation) factors on each outcome. RESULTS: The sample consisted of 345 respondents aged 18-73 years from 26 nations. Very few (<3%) had no lifetime experience with any solo or partnered behaviors; 25.0% reported participating in all behaviors at some point in their lives. The median number of past year sexual behaviors (of 16 total) was 7. Lifetime and recent participation were associated with demographic and health factors. CLINICAL IMPLICATIONS: Despite impairment, adults with spina bifida do participate in solo and partnered sexual behaviors. Medical personnel who work with this population should include discussions about sexuality as part of routine care. STRENGTHS & LIMITATIONS: Although this research measured solo and partnered sexual behavior in large international sample of adults with spina bifida, it is limited by its cross-sectional retrospective design and non-clinical convenience sample. CONCLUSION: Despite disability, many adults with SB participate in solo and partnered sexual behavior. Medical and psychosocial supports are needed to help adults in this population enjoy sexuality in a healthy and safe manner. Hensel DJ, Misseri R, Wiener JS, et al. Solo and Partnered Sexual Behavior Among an International Sample of Adults With Spina Bifida. J Sex Med 2022;19:1766-1777.

Association between COVID-19 and subsequent vascular events in primary care patients in Germany.

OBJECTIVES: The aim of this study was to investigate the relationship between COVID-19 diagnosis and the risk of developing a first-ever vascular event (VE) compared with the same risk in those with respiratory tract infection (RTI). STUDY DESIGN: This was a retrospective cohort study. METHODS: This study using data from Disease Analyzer Database (IQVIA) included patients aged ≥18 years with at least one visit to a German practice during the index period. VEs were defined as cardiovascular or cerebrovascular events. Two cohorts were created: patients with a diagnosis of COVID-19 and those diagnosed with RTI. These were matched using propensity scores. Kaplan-Meier curves were created for the purposes of time to event analysis. A Poisson model was used to calculate incidence rates and derive incidence rate ratios (IRRs). RESULTS: A total of 58,904 patients were matched. There was no significant association between COVID-19 diagnosis and increased incidence of VE events among females (IRR [95% confidence interval (CI)]: 0.96 [0.82-1.11] and 1.30 [0.88-1.81]) or males (IRR, 95% CI: 0.91 [0.78-1.05] and 1.13 [0.80-1.62]). Overall, no significant association between COVID-19 diagnosis and incidence of VE was observed across age categories except for cardiovascular vascular events in the age category ≥70 years (IRR [95% CI]: 0.78 [0.67-0.94]). CONCLUSIONS: Overall, our study suggests that COVID-19 diagnosis was not associated with an increased risk of developing VE compared with RTI diagnosis. However, further research in a variety of healthcare settings and regions is needed to confirm these preliminary findings from our cohort, which is a good reflection of routine clinical practice in Germany.

Neuronal Protein Tyrosine Phosphatase 1B Hastens Amyloid ß-Associated Alzheimer's Disease in Mice.

Alzheimer's disease (AD) is the most common neurodegenerative disorder, resulting in the progressive decline of cognitive function in patients. Familial forms of AD are tied to mutations in the amyloid precursor protein, but the cellular mechanisms that cause AD remain unclear. Inflammation and amyloidosis from amyloid ß (Aß) aggregates are implicated in neuron loss and cognitive decline. Inflammation activates the protein-tyrosine phosphatase 1B (PTP1B), and this could suppress many signaling pathways that activate glycogen synthase kinase 3ß (GSK3ß) implicated in neurodegeneration. However, the significance of PTP1B in AD pathology remains unclear. Here, we show that pharmacological inhibition of PTP1B with trodusquemine or selective ablation of PTP1B in neurons prevents hippocampal neuron loss and spatial memory deficits in a transgenic AD mouse model with Aß pathology (hAPP-J20 mice of both sexes). Intriguingly, while systemic inhibition of PTP1B reduced inflammation in the hippocampus, neuronal PTP1B ablation did not. These results dissociate inflammation from neuronal loss and cognitive decline and demonstrate that neuronal PTP1B hastens neurodegeneration and cognitive decline in this model of AD. The protective effect of PTP1B inhibition or ablation coincides with the restoration of GSK3ß inhibition. Neuronal ablation of PTP1B did not affect cerebral amyloid levels or plaque numbers, but reduced Aß plaque size in the hippocampus. In summary, our preclinical study suggests that targeting PTP1B may be a new strategy to intervene in the progression of AD.SIGNIFICANCE STATEMENT Familial forms of Alzheimer's disease (AD) are tied to mutations in the amyloid precursor protein, but the cellular mechanisms that cause AD remain unclear. Here, we used a mouse model expressing human amyloid precursor protein bearing two familial mutations and asked whether activation of a phosphatase PTP1B participates in the disease process. Systemic inhibition of this phosphatase using a selective inhibitor prevented cognitive decline, neuron loss in the hippocampus, and attenuated inflammation. Importantly, neuron-targeted ablation of PTP1B also prevented cognitive decline and neuron loss but did not reduce inflammation. Therefore, neuronal loss rather than inflammation was critical for AD progression in this mouse model, and that disease progression could be ameliorated by inhibition of PTP1B.

Mitochondrial Dysfunction Combined with High Calcium Load Leads to Impaired Antioxidant Defense Underlying the Selective Loss of Nigral Dopaminergic Neurons.

Mitochondrial dysfunction is critically involved in Parkinson's disease, characterized by loss of dopaminergic neurons (DaNs) in the substantia nigra (SNc), whereas DaNs in the neighboring ventral tegmental area (VTA) are much less affected. In contrast to VTA, SNc DaNs engage calcium channels to generate action potentials, which lead to oxidant stress by yet unknown pathways. To determine the molecular mechanisms linking calcium load with selective cell death in the presence of mitochondrial deficiency, we analyzed the mitochondrial redox state and the mitochondrial membrane potential in mice of both sexes with genetically induced, severe mitochondrial dysfunction in DaNs (MitoPark mice), at the same time expressing a redox-sensitive GFP targeted to the mitochondrial matrix. Despite mitochondrial insufficiency in all DaNs, exclusively SNc neurons showed an oxidized redox-system, i.e., a low reduced/oxidized glutathione (GSH-GSSG) ratio. This was mimicked by cyanide, but not by rotenone or antimycin A, making the involvement of reactive oxygen species rather unlikely. Surprisingly, a high mitochondrial inner membrane potential was maintained in MitoPark SNc DaNs. Antagonizing calcium influx into the cell and into mitochondria, respectively, rescued the disturbed redox ratio and induced further hyperpolarization of the inner mitochondrial membrane. Our data therefore show that the constant calcium load in SNc DaNs is counterbalanced by a high mitochondrial inner membrane potential, even under conditions of severe mitochondrial dysfunction, but triggers a detrimental imbalance in the mitochondrial redox system, which will lead to neuron death. Our findings thus reveal a new mechanism, redox imbalance, which underlies the differential vulnerability of DaNs to mitochondrial defects.SIGNIFICANCE STATEMENT Parkinson's disease is characterized by the preferential degeneration of dopaminergic neurons (DaNs) of the substantia nigra pars compacta (SNc), resulting in the characteristic hypokinesia in patients. Ubiquitous pathological triggers cannot be responsible for the selective neuron loss. Here we show that mitochondrial impairment together with elevated calcium burden destabilize the mitochondrial antioxidant defense only in SNc DaNs, and thus promote the increased vulnerability of this neuron population.

Tyrosine phosphatase PTP1B impairs presynaptic NMDA receptor-mediated plasticity in a mouse model of Alzheimer's disease.

Mutations in the beta-amyloid protein (APP) cause familial Alzheimer's disease. In hAPP-J20 mice expressing mutant APP, pharmacological inhibition or genetic ablation of the tyrosine phosphatase PTP1B prevents CA3 hippocampus neuron loss and cognitive decline. However, how targeting PTP1B affects the cellular mechanisms underlying these cognitive deficits remains unknown. Changes in synaptic strength at the hippocampus can affect information processing for learning and memory. While prior studies have focused on post-synaptic mechanisms to account for synaptic deficits in Alzheimer's disease models, presynaptic mechanisms may also be affected. Here, using whole cell patch-clamp recording, coefficient of variation (CV) analysis suggested a profound presynaptic deficit in long-term potentiation (LTP) of CA3:CA1 synapses in hAPP-J20 mice. While the membrane-impermeable ionotropic NMDA receptor (NMDAR) blocker norketamine in the post-synaptic recording electrode had no effect on LTP, additional bath application of the ionotropic NMDAR blockers MK801 could replicate the deficit in LTP in wild type mice. In contrast to LTP, the paired-pulse ratio and short-term facilitation (STF) were aberrantly increased in hAPP-J20 mice. These synaptic deficits in hAPP-J20 mice were associated with reduced phosphorylation of NMDAR GluN2B and the synaptic vesicle recycling protein NSF (N-ethylmaleimide sensitive factor). Phosphorylation of both proteins, together with synaptic plasticity and cognitive function, were restored by PTP1B ablation or inhibition by the PTP1B-selective inhibitor Trodusquemine. Taken together, our results indicate that PTP1B impairs presynaptic NMDAR-mediated synaptic plasticity required for spatial learning in a mouse model of Alzheimer's disease. Since Trodusquemine has undergone phase 1/2 clinical trials to treat obesity, it could be repurposed to treat Alzheimer's disease.

What Do Patients and Parents Say About Parents' Ability to Choose Early Genital Surgery for Girls with Congenital Adrenal Hyperplasia?

PURPOSE: We assessed opinions of females with congenital adrenal hyperplasia and their parents about the parent's ability to choose early genital surgery for these patients. MATERIALS AND METHODS: We conducted an online survey of females with congenital adrenal hyperplasia (46XX,16+ years old) and independently recruited parents (2019-2020) diagnosed in first year of life in the United States. A multidisciplinary medical team, women with congenital adrenal hyperplasia and parents drafted the survey. Fisher exact test was used. RESULTS: Of 57 females with congenital adrenal hyperplasia (median age 39 years), 93.0% underwent genital surgery (median 1-2 years old). Most females (79.0%) believed legislation prohibiting surgery in childhood would cause harm. Most (64.9%) believed a ban "would have been harmful to me" (24.6% not harmful, 10.5% neutral). Most females (70.2%) believed a ban undermined parental rights to make medical decisions in their child's best interest. While 75.4% did not believe a ban was in the best interest of females with congenital adrenal hyperplasia, 14.0% did (10.5% neutral). For 132 parents of females with congenital adrenal hyperplasia (parent/child median age 40/11 years), 78.8% of children underwent surgery (median <1 year old). Most parents (93.9%) believed legislation prohibiting surgery in childhood would cause harm. Most (77.3%) believed a ban "would have harmed my daughter" (12.1% no harm, 5.3% neutral, 5.3% no answer). Parents were more likely than females with congenital adrenal hyperplasia to oppose a ban (p ≤0.02). Most parents (90.9%) believed a ban undermined parental rights. While 93.9% did not believe a ban was in the best interest of females with congenital adrenal hyperplasia, 3.8% did (2.3% neutral). CONCLUSIONS: The majority of females with congenital adrenal hyperplasia and their parents support the parents' ability to decide about potential genital surgery, opposing moratoria on surgery in childhood.

Development and Validation of the Japanese Version of Quality of Life Assessment of Spina Bifida in Children (QUALAS-C-J).

BACKGROUND: We previously developed the Japanese version of The Quality of Life Assessment of Spina Bifida in Teenagers, a health-related quality-of-life instrument specific to children aged 13-17 years with spina bifida (SB). The Quality of Life Assessment of Spina Bifida in Children is a version of this questionnaire for children aged 8-12 years. The purpose of this study was to develop a Japanese version of the Quality of Life Assessment of Spina Bifida in Children (QUALAS-C-J) and verify its reliability and validity. METHODS: Three urologists specializing in SB, 2 nurses, and 1 statistician developed the QUALAS-C-J and conducted a pilot and main survey. Participants included children with SB and non-disabled (ND) children. Participants completed the QUALAS-C-J and the Japanese version of KIDSCREEN-27 (J-KIDSCREEN) without parental help. RESULTS: Five children with SB participated in the pilot study and provided face and content validity. Sixty-three children with SB and 40 age- and sex-matched ND children participated in the main survey. The intraclass correlation coefficient in the retest was 0.80, and Cronbach's alpha in each domain was 0.73. The validity was verified by factor analysis, convergent / divergent validity, and known-groups validity. Factor analysis converged to the same two-factor structure as the original version. The correlation between QUALAS-C-J and J-KIDSCREEN-27 was weak (r=-0.06-0.30). The scores of both groups for the two domains of the QUALAS-C-J were significantly lower in SB than ND children. CONCLUSIONS: QUALAS-C-J is easy to answer, suitable for Japanese children with SB, reliable, and valid. It can be a communication tool for children with SB, medical staff, families, communities, and school teachers.

Additional Surgeries after Bladder Augmentation in Patients with Spina Bifida in the 21st Century.

PURPOSE: We determined the long-term risks of additional surgery after bladder augmentation in a modern spina bifida cohort accounting for differential followup. MATERIALS AND METHODS: We retrospectively reviewed patients with spina bifida who were born after 1972 and were followed at our institution after augmentation surgery performed between 1979 and 2018. Outcomes included diversion, bladder stones, perforation, reaugmentation, laparotomy for bowel obstruction, and benign and malignant bladder tumors. Survival analysis was used for the entire cohort and the modern cohort (detubularized and reconfigured ileocystoplasty beginning in 2000). RESULTS: A total of 413 patients were included in the study. At a median followup of 11.2 years 80.9% of the patients had undergone ileocystoplasty and 44.1% had undergone 370 additional surgeries. Ten-year risk of any reoperation was 43.9%, with 17.4% of patients undergoing 2 or more and 9.9% undergoing 3 or more additional surgeries. Outcomes included conversion to a diversion (2.7% at 10-year followup) and bladder stones (28.2% with recurrence in 52.4%) irrespective of detubularized reconfigured status (p ≥0.20). Bladder perforation risk was 9.6% for patients undergoing vs 23.7% for those not undergoing detubularized reconfigured ileocystoplasty (p=0.01). Similarly reaugmentation rate was 5.3% for patients undergoing vs 15.2% for those not undergoing detubularized reconfigured ileocystoplasty (p=0.001). Finally, 10-year reperforation risk was 32.1% for patients undergoing vs 73.8% for those not undergoing detubularized reconfigured ileocystoplasty (p=0.053). Other risks included bowel obstruction (4.5% with recurrence in 15.8%), nephrogenic adenoma (2.2% with regrowth in 48.2%) and malignancy (0.0% at 20 years). For 222 patients in the modern cohort (median followup 9.1 years) 10-year risk of any reoperation was 46.0%, which consisted of diversion in 4.0%, stones in 32.9% (recurrence in 44.5%), perforation in 8.8% (recurrence in 42.2%), reaugmentation in 4.3%, obstruction in 4.9% (recurrence in 10.0%), adenoma in 4.7% (regrowth in 40.0%) and cancer in 0.0%. CONCLUSIONS: Bladder augmentation is long-lasting. While benefiting continence and renal outcomes, this operation frequently requires additional surgeries, necessitating close followup. Since survival analysis based risks of alternative management options such as incontinent diversion are unavailable, comparisons with augmentation are unfeasible.

Probability of Bladder Augmentation, Diversion and Clean Intermittent Catheterization in Classic Bladder Exstrophy: A 36-Year, Multi-Institutional, Retrospective Cohort Study.

PURPOSE: We assessed the probability of bladder augmentation/diversion and clean intermittent catheterization in classic bladder exstrophy in a multi-institutional cohort. MATERIALS AND METHODS: We included children born from 1980 to 2016 with bladder exstrophy and treated across 5 centers (exclusion criteria less than 1 year followup after birth, isolated epispadias, bladder exstrophy variants etc). Outcomes were probability of bladder augmentation/diversion after bladder closure and proportion of patients performing clean intermittent catheterization at last followup. Survival analysis was used. RESULTS: Of 216 patients 63.4% were male (median followup 14.4 years). Overall 4 patients (1.9%) underwent primary diversion and 212 underwent primary closure (72.6% in first week of life). After primary closure 50.9% underwent augmentation, 4.7% diversion and 44.8% neither. By age 18 years 88.5% underwent a bladder neck procedure (synchronous augmentation 27.3%). On survival analysis the probability of bladder augmentation/diversion was 14.9% by age 5 years, 50.7% by 10 years and 70.1% by 18 years. Probability of bladder augmentation/diversion varied significantly between centers (p=0.01). Probability of bladder augmentation/diversion was 60.7% 10 years after bladder neck procedure. At last followup of the entire cohort 67.4% performed clean intermittent catheterization. Among 95 patients with intact native bladders 30.5% performed clean intermittent catheterization (channel 72.4%). Among 76 adults without a diversion 85.5% performed clean intermittent catheterization (augmented bladder 100.0% clean intermittent catheterization, native bladder 31.3%). Fifteen patients underwent diversion (continent 8, ureterosigmoidostomy 5, incontinent 2). CONCLUSIONS: On long-term followup probability of bladder augmentation/diversion increased with age, with 1 in 2 patients by age 10 years and the majority in adulthood. Probability of bladder augmentation/diversion differed among institutions. Almost a third of patients, including adults, with a closed native bladder performed clean intermittent catheterization. Considering all adults only 14% did not perform clean intermittent catheterization.

Risk of Reaugmentation after Enterocystoplasty Using a Reconfigured Bowel Segment in Patients with Spina Bifida: A Bi-Institutional Cohort Study.

PURPOSE: Reaugmentation cystoplasty rates vary in the literature but have been reported as high as 15%. It is likely that bladders augmented with detubularized and reconfigured bowel are less likely to require reaugmentation. We assessed the incidence of reaugmentation among patients with spina bifida at 2 high volume reconstruction centers. MATERIALS AND METHODS: We retrospectively reviewed medical records of patients with spina bifida who underwent enterocystoplasty before age 21 years (1987 to 2017). Those who did not undergo augmentation with a detubularized and reconfigured bowel segment were excluded from analysis. Data on demographic and surgical variables were collected. Reaugmentation was the main outcome. One analysis was performed using the entire cohort and another analysis was restricted to patients with ileocystoplasty performed in the last 15 years (2002 to 2017). Survival analysis was used. RESULTS: A total of 289 patients were identified. Enterocystoplasty was performed in patients at a median age of 8.1 years (median followup 11.3, IQR 5.2-14.9). Most initial augmentations were performed using ileum (93.4%), followed by sigmoid (6.2%). Seven patients underwent reaugmentation, including 6 with initial augmentation using ileum and 1 with initial augmentation using sigmoid. On survival analysis risk of reaugmentation was 1.1% at 5 years and 3.3% at 10 years after the original surgery. All reaugmentations occurred within the first 9 years of followup. In the more contemporary cohort (162, median followup 7.0 years) only 1 patient underwent reaugmentation at 2.0 years. CONCLUSIONS: The risk of reaugmentation after enterocystoplasty with a detubularized and reconfigured bowel in the spina bifida population is lower than that reported in initial series.

Review: Modelling the pathology and behaviour of frontotemporal dementia.

Frontotemporal dementia (FTD) encompasses a collection of clinically and pathologically diverse neurological disorders. Clinical features of behavioural and language dysfunction are associated with neurodegeneration, predominantly of frontal and temporal cortices. Over the past decade, there have been significant advances in the understanding of the genetic aetiology and neuropathology of FTD which have led to the creation of various disease models to investigate the molecular pathways that contribute to disease pathogenesis. The generation of in vivo models of FTD involves either targeting genes with known disease-causative mutations such as GRN and C9orf72 or genes encoding proteins that form the inclusions that characterize the disease pathologically, such as TDP-43 and FUS. This review provides a comprehensive summary of the different in vivo model systems used to understand pathomechanisms in FTD, with a focus on disease models which reproduce aspects of the wide-ranging behavioural phenotypes seen in people with FTD. We discuss the emerging disease pathways that have emerged from these in vivo models and how this has shaped our understanding of disease mechanisms underpinning FTD. We also discuss the challenges of modelling the complex clinical symptoms shown by people with FTD, the confounding overlap with features of motor neuron disease, and the drive to make models more disease-relevant. In summary, in vivo models can replicate many pathological and behavioural aspects of clinical FTD, but robust and thorough investigations utilizing shared features and variability between disease models will improve the disease-relevance of findings and thus better inform therapeutic development.

Radiographic abnormalities, bladder interventions, and bladder surgery in the first decade of life in children with spina bifida.

BACKGROUND: Spina bifida (SB) patients are at increased risk for hydronephrosis, bladder storage and emptying problems, and renal failure that may require multiple bladder surgeries. METHODS: We retrospectively reviewed patients born with SB 2005-2009, presenting to our institution within 1 year of birth. Outcomes at 8-11 years old included final renal/bladder ultrasound (RBUS) results, clean intermittent catheterization (CIC) use, anticholinergic use, surgical interventions, and final renal function. We excluded those without follow-up past age 8 and/or no RBUS or fluoroscopic urodynamic images (FUI) within the first year of life. Imaging was independently reviewed by four pediatric urologists blinded to radiologists' interpretation and initial findings compared with final outcomes. RESULTS: Of 98 children, 62 met inclusion criteria (48% male, 76% shunted). Median age at last follow-up was 9.6 years. Upon initial imaging, 74% had hydronephrosis (≥ SFU grade 1), decreasing to 5% at 10 years (p < 0.0001). Initially, 9% had ≥ SFU grade 3 hydronephrosis, decreasing to 2% (p = 0.13). CIC and anticholinergic use increased from 61% and 37% to 87% and 86%, respectively (p = 0.001 and p < 0.0001, respectively). With follow-up, 55% had surgical intervention and 23% had an augmentation. Of children with a serum creatinine/cystatin-C at 8-11 years old, one had confirmed chronic kidney disease (stage 2). CONCLUSIONS: Despite initial high incidence of hydronephrosis, this was low grade and resolved in the first decade of life. Additionally, the 8-11-year incidence of kidney disease and upper tract changes was low due to aggressive medical management.

Development and validation of the Japanese version of the Quality of Life Assessment of Spina Bifida in Teenagers (QUALAS-T-J).

BACKGROUND: Spina bifida (SB) is the second-most common birth defect in Japan. In recent years, health-related quality of life measurements have been used to assess the psychosocial status of children with SB. The Quality of Life Assessment of Spina Bifida in Teenagers (QUALAS-T) is a self-reported questionnaire for subjects aged 13-17 years with SB. It focuses particularly on factors related to independence, bladder and bowel. The purpose of this study was to develop and validate a Japanese version of QUALAS-T (QUALAS-T-J). METHODS: Three urologists specialized in SB, two nurses, one statistician, and the author of the original version developed the QUALAS-T-J. Subjects with SB completed the QUALAS-T-J and the Japanese version of KIDSCREEN-27 (J-KIDSCREEN-27) independently from their parents. RESULTS: A pilot study involving seven adolescents with SB and confirmed face and content validity. Sixty-nine adolescents with SB participated in the main survey. The intraclass correlation coefficient in the retest was 0.77, and Cronbach's alpha in each domain was 0.83 and 0.79. Validity was verified on factor analysis and convergent/divergent validity. Five items converged in the one domain, Bladder and Bowel. The remaining five items converged in the concept of Family and Independence. The correlation between each domain of the QUALAS-T-J and J-KIDSCREEN-27 was low-moderate. CONCLUSION: The reliability and validity of the QUALAS-T-J were verified in Japanese adolescents with SB. The QUALAS-T-J would be a useful tool for communication between adolescents with SB and medical staff.

Isolation and characterization of native probiotics for fish farming.

BACKGROUND: Innovations in fish nutrition act as drivers for the sustainable development of the rapidly expanding aquaculture sector. Probiotic dietary supplements are able to improve health and nutrition of livestock, but respective bacteria have mainly been isolated from terrestrial, warm-blooded hosts, limiting an efficient application in fish. Native probiotics adapted to the gastrointestinal tract of the respective fish species will establish within the original host more efficiently. RESULTS: Here, 248 autochthonous isolates were cultured from the digestive system of three temperate flatfish species. Upon 16S rRNA gene sequencing of 195 isolates, 89.7% (n = 175) Gram-negatives belonging to the Alpha- (1.0%), Beta- (4.1%) and Gammaproteobacteria (84.6%) were identified. Candidate probiotics were further characterized using in vitro assays addressing 1) inhibition of pathogens, 2) degradation of plant derived anti-nutrient (saponin) and 3) the content of essential fatty acids (FA) and their precursors. Twelve isolates revealed an inhibition towards the common fish pathogen Tenacibaculum maritimum, seven were able to metabolize saponin as sole carbon and energy source and two isolates 012 Psychrobacter sp. and 047 Paracoccus sp. revealed remarkably high contents of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). Furthermore, a rapid and cost-effective method to coat feed pellets revealed high viability of the supplemented probiotics over 54 d of storage at 4°C. CONCLUSIONS: Here, a strategy for the isolation and characterization of native probiotic candidates is presented that can easily be adapted to other farmed fish species. The simple coating procedure assures viability of probiotics and can thus be applied for the evaluation of probiotic candidates in the future.

All Incontinence is Not Created Equal: Impact of Urinary and Fecal Incontinence on Quality of Life in Adults with Spina Bifida.

PURPOSE: We previously reported that the self-reported amount of urinary incontinence is the main predictor of lower health related quality of life in adults with spina bifida. In this study we sought to determine the impact of fecal incontinence on health related quality of life after correcting for urinary incontinence. MATERIALS AND METHODS: An international sample of adults with spina bifida was surveyed online in 2013 to 2014. We evaluated fecal incontinence in the last 4 weeks using clean intervals (less than 1 day, 1 to 6 days, 1 week or longer, or no fecal incontinence), amount (a lot, medium, a little or none), number of protective undergarments worn daily and similar variables for urinary incontinence. Validated instruments were used, including QUALAS-A (Quality of Life Assessment in Spina bifida for Adults) for spina bifida specific health related quality of life and the generic WHOQOL-BREF (WHO Quality of Life, short form). Linear regression was used (all outcomes 0 to 100). RESULTS: Mean age of the 518 participants was 32 years and 33.0% were male. Overall, 55.4% of participants had fecal incontinence, 76.3% had urinary incontinence and 46.9% had both types. On multivariate analysis fecal incontinence was associated with lower bowel and bladder health related quality of life across all amounts (-16.2 for a lot, -20.9 for medium and -18.5 for little vs none, p <0.0001) but clean intervals were not significant (-4.0 to -3.4, p ≥0.18). Conversely, health related quality of life was lower with increased amounts of urinary incontinence (-27.6 for a lot, -18.3 for medium and -13.4 for little vs none, p <0.0001). Dry intervals less than 4 hours were not associated with lower health related quality of life (-4.6, p = 0.053) but the use of undergarments was associated with it (-7.5 to -7.4, p ≤0.01). Fecal incontinence and urinary incontinence were associated with lower WHOQOL-BREF scores. CONCLUSIONS: Fecal incontinence and urinary incontinence are independent predictors of lower health related quality of life in adults with spina bifida. Health related quality of life is lower with an increasing amount of urinary incontinence. Fecal incontinence has a more uniform impact on health related quality of life regardless of frequency or amount.