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Background this study compares diuresis rate, sodium clearance and free water clearance (FWC) by age and time of day (nighttime vs. daytime) in subjects with and without nocturnal polyuria (NP) to determine whether these variables affect the phenotype of NP. Methods post hoc analysis of two prospective observational studies. Eight urine samples collected at 3-h intervals and a single blood sample were used to calculate daytime (10a/1p/4p/7p/10p) and nighttime (1a/4a/7a) diuresis rates, sodium clearance and FWC. Three mixed linear models were constructed for diuresis rate, sodium clearance and FWC using four predictor variables: NP status (present [nocturnal urine production >90 ml/h] vs. absent [≤90 ml/h]), time of day, age and study identification. Results subjects with NP experienced higher nighttime versus daytime diuresis rates, sodium clearance and FWC. Regardless of NP status, increased age was accompanied by an increase in the ratio of nighttime/daytime diuresis rate, nighttime sodium clearance and daytime sodium clearance. FWC showed a complex age effect, which was independent of time of day or NP status. Conclusions age-related increases in nighttime/daytime diuresis rate, 24-h sodium clearance and 24-h FWC are not specific to subjects with NP. The age-related surge in either nocturnal sodium clearance or nocturnal FWC may represent the relevant substrate for behavioural or pharmacologic interventions targeting sodium diuresis or free water diuresis, respectively. Increases in FWC in older age groups may reflect impaired circadian rhythmicity of endogenous AVP or changes in responsiveness of the aged nephron to water clearance.

Pathogenic variants in the RBM10 gene cause a rare X-linked disorder described as TARP (Talipes equinovarus, Atrial septal defect, Robin sequence, and Persistent left vena cava superior) syndrome. We report two novel patients with truncating RBM10 variants in view of the literature, presenting a total of 26 patients from 15 unrelated families. Our results illustrate the highly pleiotropic nature of RBM10 pathogenic variants, beyond the classic TARP syndrome features. Major clinical characteristics include severe developmental delay, failure to thrive, brain malformations, neurological symptoms, respiratory issues, and facial dysmorphism. Minor features are growth retardation, cardiac, gastrointestinal, limb, and skeletal abnormalities. Additional recurrent features include genital and renal abnormalities as well as hearing and visual impairment. Thus, RBM10 loss of function variants typically cause an intellectual disability and congenital malformation syndrome that requires assessment of multiple organ systems at diagnosis and for which provided clinical features might simplify diagnostic assessment. Furthermore, evidence for an RBM10-related genotype-phenotype correlation is emerging, which can be important for prognosis. ispartof: CLINICAL GENETICS vol:99 issue:3 pages:449-456 ispartof: location:Denmark status: published

IQSEC2 mutations are associated with IQSEC2-related intellectual disability (ID). Phenotypic spectrum has been better defined in the last few years by the increasing number of reported cases although the genotype-phenotype relationship for IQSEC2 remains overall complex. As for IQSEC2-related ID a wide phenotypic diversity has been described in Rett syndrome (RTT). Several patients harboring IQSEC2 mutations present with clinical symptoms similar to RTT and some cases meet most of the criteria for classic RTT. With the aim of establishing a genotype-phenotype correlation, we collected data of 16 patients harboring IQSEC2 point mutations (15 of them previously unreported) and of five novel patients carrying CNVs encompassing IQSEC2. Most of our patients surprisingly shared a moderate-to-mild phenotype. The similarities in the clinical course between our mild cases and patients with milder forms of atypical RTT reinforce the hypothesis that also IQSEC2 mutated patients may lay under the wide clinical spectrum of RTT and thus IQSEC2 should be considered in the differential diagnosis. Our data confirm that position, type of variant and gender are crucial for IQSEC2-associated phenotype delineation.

Objectives: The objective of the study is to evaluate the use of an experimental smart diaper as an indicator of saturation for diaper change in persons with dementia living in nursing homes. Methods: A multicenter prospective study was conducted in 3 nursing homes amongst 18 residents with dementia. For each resident, a frequency-volume urine chart (FVUC) was kept for 24 h including voided volume and diaper weights, wearing smart diapers. A comparative study was set up between results obtained by smart diapers and data registered in FVUCs. Results: Analysis based on quantification of the agreement between saturation calculated by smart diaper and determined by FVUC indicates that measurements reported by sensor do not correspond with measurements based on FVUC. For the regular diaper, the saturation measured by sensor may be 26% below or 39% above saturation based on FVUC and for the super diaper, respectively, 34% below or 30% above. Discussion: This study indicates that the sensor detects and notifies wetness but is not sensitive enough for using it as an indicator for diaper change in people with severe dementia.

Aim Nocturia frequency has been used as a measure of treatment efficacy for nocturia even though fluctuation of the symptom over time has been well described in the literature. Additionally, given the multifactorial causal pathway and clinically relevant comorbidities, frequency alone may be an insufficient marker of treatment direction. The aim of this study was to investigate factors associated with nocturia-related bother to identify additional variables that may capture the impact of nocturia, direct clinical care and have potential to quantify treatment outcome. Methods Prospective data from tertiary hospital Urology and Continence cohorts were matched for identical variables to generate a sample of 204 datasets. Descriptive statistics were obtained to describe the two cohorts. Characteristics of patients were evaluated across levels of nocturia frequency and nocturia-related bother using nonparametric methods; statistically significant differences between groups in each cohort were established. Results Nocturia frequency alone does not comprehensively reflect attributable bother. Five sleep variables (poor quality sleep, short time to first awakening to void, less than 7 hours of total sleep, primary sleep latency, and daytime sleepiness) and daily urinary urgency were significantly associated with high nocturia-related bother. Attributable bother, despite high-frequency nocturia, was minimized by male gender, lack of daily urinary urgency and good sleep quality. Poor health status, urinary urgency and sleep latency were associated with nocturia frequency. Conclusions Items of importance to individuals with nocturia have been identified from patient data. These variables have the potential to sit alongside change in nocturia frequency as potential markers of treatment response.

Background Resistance mechanisms in the androgen receptor (AR) signaling pathway remain key drivers in the progression to castration-resistant prostate cancer (CRPC) and relapse under antihormonal therapy. Materials and Methods We evaluated the circulating AR gene copy number (CN) gain using droplet digital polymerase chain reaction in 21 control and 91 prostate cancer serum samples and its prognostic and therapeutic implications in prostate cancer. Results In CRPC, AR CN gain was associated with faster progression to CRPC (P = .026), a greater number of previous treatments (P = .045), and previous chemotherapy (P = .016). Comparing patients with and without CN gain, the median progression-free survival (PFS) in the abiraterone subgroup was 1.7 months versus not reached (P = .004), and the median overall survival (OS) was 7 months versus 20.9 months (P = .020). In the enzalutamide subgroup, PFS was 1.7 versus 10.8 months (P = .006), and OS was 6.1 versus 16.5 months (P = .042). In the taxane subgroup, PFS was 3.2 versus 6.5 months (P = .093), and OS was 3.9 months versus not reached (P = .026). The presence of more AR copies correlated with shorter androgen deprivation (P = .002), abiraterone (P = .022), enzalutamide (P = .008), and taxane (P = .039) therapy. Conclusion Circulating AR CN gain predicts for a poor prognosis in CRPC. It is a promising biomarker predetermining rapid CRPC progression and predicting worse abiraterone and enzalutamide outcomes. Furthermore, it is associated with multiple previous treatments and previous chemotherapy.

Objectives To explore the mismatch between functional bladder capacity and nocturnal urine production, and to study the pathophysiology of an increased nocturnal urine production in older patients with urinary incontinence. Methods The present prospective observational study included adults aged ≥65 years with urinary incontinence. Participants completed questionnaires, frequency volume charts and renal function profiles. The nocturnal lower urinary tract symptom index was defined as nocturnal urine output/maximum voided volume; the nocturnal polyuria index as nocturnal/24 h urine output. Results The median age (n = 95) was 74 years (69–79), 87% were women and 73% had nocturnal lower urinary tract symptoms (nocturnal urinary incontinence or nocturia ≥2). Participants with nocturnal lower urinary tract symptoms had a significantly higher nocturnal urine output (809 mL vs 650 mL; P = 0.001) and no significant difference in maximum voided volume (350 mL vs 437 mL; P = 0.079) compared with participants without nocturnal lower urinary tract symptoms. Participants (nocturnal polyuria index >33% [n = 56], nocturnal polyuria index >40% [n = 42], nocturnal lower urinary tract symptom index >1.87 [n = 51]) showed higher night-time diuresis rates, free water and sodium clearance compared with during the daytime. Controls (nocturnal polyuria index ≤33% [n = 26], nocturnal polyuria index ≤40% [n = 40], nocturnal lower urinary tract symptom index ≤1.87 [n = 44]) had no circadian rhythm in their diuresis rate or sodium clearance, but more nocturnal free water clearance compared with during the daytime. Conclusions The majority of older adults with urinary incontinence present nocturnal lower urinary tract symptoms. An increased nocturnal sodium diuresis seems to be the only mechanism differentiating patients with nocturnal lower urinary tract symptoms from controls.

Purpose: Clean intermittent self-catheterization (CISC) is now considered the gold standard for the management of urinary retention. In the literature, several articles on patients' perspectives on CISC and adherence to this technique have been published. No studies have yet explored the points of view of professional caregivers, such as nurses and doctors. The aim of this study was to explore the opinions of urologists about CISC and to evaluate the need for dedicated nurses specialized in CISC through a self-administered questionnaire. Methods: A questionnaire was developed to explore the opinions of professional caregivers about self-catheterization and to evaluate the need to provide nurses with specialized education in CISC. Questionnaires were sent to 244 urologists through email. We received 101 completed questionnaires. The response rate was 41.4%. Results: Hand function, the presence or absence of tremor, and visual acuity were rated as the most important determinants for proposing CISC to a patient. Twenty-five percent of the urologists reported that financial remuneration would give them a greater incentive to propose CISC. The lack of dedicated nurses was reported by half of the urologists as a factor preventing them from proposing CISC. A meaningful number of urologists thought that patients perceive CISC as invasive and unpleasant. Although most urologists would choose CISC as a treatment option for themselves, almost 1 urologist out of 5 would prefer a permanent catheter. Conclusions: This questionnaire gave valuable insights into urologists' perceptions of CISC, and could serve as the basis for a subsequent broader international study. Further research should also focus on the opinions of nurses and other caregivers involved in incontinence management. Apart from financial remuneration, it is also clear that ensuring sufficient expertise and time for high-quality CISC care is important. This could be a potential role for dedicated nurses.

// Shana Claeys 1, 2 , Geertrui Denecker 1, 2 , Robrecht Cannoodt 1, 2, 3, 4, 5 , Candy Kumps 1, 6 , Kaat Durinck 1, 2 , Frank Speleman 1, 2 and Katleen De Preter 1, 2 1 Center for Medical Genetics, Ghent University, Ghent, Belgium 2 Cancer Research Institute Ghent, Ghent University, Ghent, Belgium 3 Bioinformatics Institute Ghent From Nucleotides to Networks, Ghent, Belgium 4 Data Mining and Modelling for Biomedicine group, VIB Inflammation Research Center, Ghent, Belgium 5 Department of Respiratory Medicine, Ghent University, Ghent, Belgium 6 Department of Uro-Gynaecology, Ghent University Hospital, Ghent, Belgium Correspondence to: Katleen De Preter, email: Katleen.DePreter@UGent.be Keywords: neuroblastoma; ALK; ALK inhibition; ALK signaling; dynamic Received: July 28, 2017 Accepted: October 17, 2017 Published: November 06, 2017 ABSTRACT Background: Neuroblastoma is an aggressive childhood malignancy of the sympathetic nervous system. Despite multi-modal therapy, survival of high-risk patients remains disappointingly low, underscoring the need for novel treatment strategies. The discovery of ALK activating mutations opened the way to precision treatment in a subset of these patients. Previously, we investigated the transcriptional effects of pharmacological ALK inhibition on neuroblastoma cell lines, six hours after TAE684 administration, resulting in the 77-gene ALK signature, which was shown to gradually decrease from 120 minutes after TAE684 treatment, to gain deeper insight into the molecular effects of oncogenic ALK signaling. Aim: Here, we further dissected the transcriptional dynamic profiles of neuroblastoma cells upon TAE684 treatment in a detailed timeframe of ten minutes up to six hours after inhibition, in order to identify additional early targets for combination treatment. Results: We observed an unexpected initial upregulation of positively regulated MYCN target genes following subsequent downregulation of overall MYCN activity. In addition, we identified adrenomedullin (ADM), previously shown to be implicated in sunitinib resistance, as the earliest response gene upon ALK inhibition. Conclusions: We describe the early and late effects of ALK inhibitor TAE684 treatment on the neuroblastoma transcriptome. The observed unexpected upregulation of ADM warrants further investigation in relation to putative ALK resistance in neuroblastoma patients currently undergoing ALK inhibitor treatment.

Background Despite the conflicting evidence about postvoid residual (PVR) and its variation in time and corresponding voided volume (VV), studies with urinary diaries and systematic measurements of PVR after each void have never been conducted in nursing home (NH) residents. Objective To describe the circadian rhythm of PVR and residual fraction (RF, the net quantity of PVR) and to identify the time window with the highest PVR and RF. Design, setting, and participants A multicentre prospective study conducted between 2014 and 2015 in 5 Belgian NHs. A convenience sample of cognitively intact residents completed a 24-hour frequency volume chart with PVR. Results Participants (n = 73) had a median age of 84 years (interquartile range 82-89) and moderate impairment of activities of daily living; 69% were women. In residents with nocturia, mean PVR was higher during the night [45 mL (26–80)] than during the day [36 mL (18–61)]. In residents without nocturia no difference was detected. In spite of the variation between diurnal and nocturnal VV and PVR in residents with nocturia, all residents emptied their bladder as effectively during daytime as during nighttime [mean RF = 20% (12–32)]. Maximum PVR and RF in residents with nocturia (n = 57) showed a circadian variation. The highest PVR and RF were found during the day. The PVR and RF of the first morning void were an indicator of the maximum nocturnal PVR and RF. Conclusions PVR and VV should be measured in NH residents during the waking hours (first morning void excepted) to detect the clinically relevant maximum PVR and RF.

Objectives: To evaluate the androgen receptor (AR) gene copy number in androgen deprivation therapy (ADT) treatment-naïve prostate cancer (PCa) patients and to evaluate the corresponding AR protein expression and assess the association between these features and prognostic factors. Materials and Methods: Chromosome X and AR gene copy number, using fluorescence-in-situ-hybridization, and epithelial-stromal AR expression, using AR immunohistochemistry, were analyzed in 62 ADT treatment-naïve PCa patients and 8 castration-refractory patients. Results: In ADT treatment-naïve PCa patients, the AR expression was higher in tumor epithelial cells versus surrounding stromal cells (p < 0.001) and versus normal epithelium in the same patient (p = 0.043). The difference between tumoral AR expression and expression in normal epithelium was higher in patients with ≥15% of tumor cells with increased AR copy number (p = 0.019). Peritumoral stroma had lower AR expression in patients with lymph-node or distant metastases compared to those without metastases (p = 0.038). Conclusions: This research evaluates the link between AR gene status, expression profile, and possible prognostic factors. Furthermore, it highlights the importance of the peritumoral environment in PCa. Additional research is needed to further clarify the role of stromal AR in PCa dissemination and identify possible therapeutic strategies to target this mechanism.

Motivation: Many high-resolution array comparative genomic hybridization tumor profiles contain a wave bias, which makes accurate detection of breakpoints in such profiles more difficult. Results: An efficient and highly effective algorithm that largely removes the wave bias from tumor profiles by regressing the tumor profile data on data of profiles from the clinical genetics practice. Results are illustrated on two independent datasets. The algorithm is shown to be robust against the presence of true copy number aberrations. Moreover, the smoothed profiles are able to recapitulate the aberration location and signal for simulated tumor profiles. Availability: Easy-to-use R scripts, user instructions and data are available from http://www.few.vu.nl/~mavdwiel/nowaves.html. Contact: mark.vdwiel@vumc.nl Supplementary information: Supplementary information are available at Bioinformatics online.

Objectives To describe the effects of cytoreductive nephrectomy (CN) on the natural course of metastatic renal cell carcinoma (mRCC). CN appears to stabilize metastatic lesions in mRCC in a subgroup of patients and we hypothesize that systemic treatment might be deferred in these patients with stable disease after CN. Subjects and methods Overall, 45 patients with mRCC who underwent CN and subsequent oncologic follow-up were included in this retrospective, single-center analysis. After CN, patients were followed at least every 3 months with clinical evaluation, contrast-enhanced computerized tomography scan of chest and abdomen, with additional imaging if needed. At 3 months, patients were radiographically evaluated and categorized into nonresponders (death or progression) or responders (stable disease or remission). Kaplan-Meier and Cox proportional hazards regression statistics were used to describe prognostic factors for overall survival (OS) and systemic therapy–free survival (STFS). Results Median OS was 31(3–121) months. Further, 24 (53.3%) and 21 (46.7%) patients were classified as responders and nonresponders at 3 months, respectively. Responders had a significant better 2-year OS compared with nonresponders (81.7% vs. 26.5%, P = 0.005). Responders also had a better 2-year STFS (40.3% vs. 6.3%, P = 0.005). On Cox regression analysis, worse OS was found to be associated with low preoperative hemoglobin levels, the absence of postoperative radiographical response, and the presence of non–clear cell pathology. The presence of postoperative radiographical response, normal preoperative lactate dehydrogenase levels, the presence of a single metastasis, and performing metastasis-directed therapy was found to be associated with a longer systemic therapy-free period. Conclusion A beneficial oncologic response is observed in approximately half of the patients undergoing CN. Absence of radiographic progression at 3 months is an important marker for OS and STFS. Therefore, systemic treatment might be postponed in selected patients.