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Introduction The lived experiences of individuals with insomnia and comorbid nocturia are not properly understood. This study explored the lived experiences of individuals with insomnia and comorbid nocturia to identify relevant concepts that could be reflected in patient-reported outcome (PRO) endpoints in clinical studies. Methods This was a cross-sectional, qualitative observational study. Data were collected from a sample of 10 adult subjects from the US suffering from insomnia disorder (DSM-5) and comorbid nocturia (≥2 nocturnal voids). Interviews were conducted using semi-structured guides, lasted 60–90 minutes, and assessed patient-relevant concepts of interest for their insomnia and nocturia. Institutional review board approval and web-based informed consent were obtained prior to the interviews. Results Overall, 10 participants were included, and the mean age was 61 years (SD=6). Most participants were female (8/10), White (9/10), and lived with a partner/spouse, family, or friends (8/10). Almost all participants experienced insomnia symptoms at least 5 nights per week (9/10), most often impacting their emotional (10/10), social (10/10), physical (9/10), cognitive (9/10), and work and productivity (6/10) functioning. Almost all participants reported that decreasing the impact of insomnia would be meaningful (8/10), most often mentioning improvements in physical impacts such as having more energy or feeling less exhausted (7/10). All participants experienced nocturia at least 6 nights per week (10/10), often impacting their emotional (7/10), social (6/10), physical (6/10), cognitive (4/10), and work and productivity (4/10) functioning. Participants reported that going to the bathroom less often (i.e., two times per night, once per night, or not at all; each 2/10) and being able to sleep through the night (2/10) would be meaningful improvements. Conclusion Individuals with insomnia and nocturia experience disrupted sleep patterns that impact their emotional, social, physical, cognitive, and work functioning. Feeling less tired, being able to sleep through the night, and getting up less often to use the bathroom would be meaningful to patients living with both conditions. Support (if any) Funded by Idorsia Pharmaceuticals Ltd.

Nocturia (ie, awakening to void one or more times per night) is common in adults, with increasing prevalence in older age. Nocturia is associated with increased risk of falls and fractures, cognitive impairment, and depressed mood. In general, mechanisms for nocturia fall into one of four categories: increased nighttime urine production, decreased storage ability, incomplete bladder emptying, or primary sleep disorder. Although screening for nocturia currently is not recommended, patients reporting bothersome symptoms should be evaluated and treated. Initial workup includes assessing urinary symptoms, fluid intake, and comorbidities. Using validated nocturia questionnaires and frequency-volume charts (bladder diaries) can aid in diagnosis. A urinalysis should be performed for all patients. Lifestyle modifications and treatment of underlying comorbidities are first-line therapies for nocturia. Limitation of fluid intake, especially in the evening; addressing timing of diuretic intake; and sleep hygiene are recommended. Pharmacotherapy should be reserved for those unresponsive to lifestyle modifications and adequate treatment of comorbidities. Pharmacotherapy should target the etiology of nocturia, such as nocturnal polyuria, overactive bladder, benign prostatic hyperplasia, and genitourinary syndrome of menopause. Patients with refractory symptoms should be referred for further treatment (eg, onabotulinumtoxinA injection, sacral neuromodulation, surgical management of benign prostatic hyperplasia).

Background Modeling studies using large datasets from men with lower urinary tract symptoms/benign prostate enlargement (LUTS/BPE) can predict changes in International Prostate Symptom Score (IPSS) and risk of acute urinary retention/surgery under different treatment regimens and according to predictors (baseline characteristics) that commonly define risk of progression. We assessed the impact of treatments on different symptom types (storage, voiding, and nocturia), quality of life (QoL; IPSS Q8), and BPH Impact Index [BII]). Methods Generalized least squares models were used to predict each outcome. Data from the CombAT study were used to predict outcomes for active treatments (dutasteride, tamsulosin, combination therapy). Predictors included: age; IPSS total, storage, voiding, nocturia and QoL (IPSS Q8) scores; BII; prostate volume; maximum urine flow rate (Qmax), prostate-specific antigen, postvoid residual urine (PVR); alpha-blocker usage within 12 months. Data from phase III dutasteride monotherapy studies were used to predict placebo outcomes. Results were visualized using an interactive web-based tool ( www.bphtool.com ). Results Combination therapy provided greater predicted benefit than either monotherapy for all five outcomes for most patient profiles within the CombAT inclusion criteria. PVR and corresponding subscores were significant predictors of change in both storage and voiding subscores. Alpha-blocker use within 12 months, age (storage subscore), and Qmax (voiding subscore) were also significant predictors. PVR, age, Qmax, and nocturia score were significant predictors of change in nocturia. PVR, Qmax, previous alpha-blocker use, total IPSS, and QoL (IPSS Q8) score were significant predictors of change in QoL (IPSS Q8) score. For BII, significant predictors were PVR, age, total IPSS, and BII score. The multivariable effect of covariates and treatments is best visualized through the interactive web-based tool. Conclusions This predictive modeling study informs our understanding of how risk factors for disease progression interact and affect treatment impact on different symptom types and QoL scores.

A mutual relationship between nocturia and sleep disturbances is assumed; however, evidence for these associations in the general population remains limited, particularly regarding sleep-promoting lifestyle habits. This cross-sectional internet study examined associations between nocturia, sleep issues, and lifestyle habits perceived as promoting sleep in 3,317 participants in July 2019. The prevalence of nocturia increased with age, while overall sleep satisfaction tended to improve with age. However, individuals with more frequent nocturnal voids reported lower sleep satisfaction. Sleep dissatisfaction was significantly correlated with nocturnal urinary frequency in both men ( r  = 0.16) and women ( r  = 0.18, p  < 0.001), emphasizing the impact of nocturia on sleep quality. Furthermore, it revealed that nocturia was associated with various sleep issues. In men, mid-wakefulness (OR = 3.32, p  < 0.001) and difficulty falling asleep (OR = 1.37, p  < 0.050) were key factors, whereas in women, mid-wakefulness (OR = 11.2, p  < 0.001) and shallow sleep (OR = 1.77, p  = 0.010) were significant. Notably, it was found that lifestyle habits, such as drinking tea or alcohol, which can exacerbate nocturia and reduce sleep quality, are undertaken with intention of promoting good sleep. Conversely, good bedding (OR = 0.75, p  = 0.010) was associated with fewer nocturnal voids. These findings highlight the complex interplay between nocturia, sleep issues, and lifestyle behaviors, providing valuable insights for addressing these interconnected issues.

Introduction The Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ) is validated to measure daytime functioning in individuals with insomnia disorder. This study assessed the content validity of the IDSIQ through cognitive interviews in individuals with insomnia and comorbid nocturia. Methods This was a cross-sectional, qualitative observational study. Data were collected from 10 adult subjects from the US suffering from insomnia disorder (DSM-5) and comorbid nocturia (≥2 nocturnal voids). One-on-one, web-based interviews were conducted using semi-structured guides and lasted 60–90 minutes. Based on the stage of the study, all participants examined the content validity of the IDSIQ as part of 1) hybrid concept elicitation and cognitive interviews (n=5; Stage 1), or 2) cognitive interviews (n=5; Stage 2). Institutional review board approval and web-based informed consent were obtained prior to the patient interviews. Results The mean age of participants was 59.5 years (SD=4.3) and 62.2 years (SD=8.5) in the hybrid and cognitive interview groups, respectively. All individuals in the hybrid interviews were female, whereas all individuals in the cognitive interviews were male. Participants’ overall impressions were positive (10/10), describing the IDSIQ as straightforward (5/10), good (1/10), simple (1/10), very precise (1/10), very specific (1/10), clear (1/10), and aligned with their experience (3/10). The items were understood by all participants (10/10) except Item 1, which was understood by almost all participants (9/10). One participant suggested that the responses to questions on the IDSIQ may vary depending on the time the survey is administered, and the amount of sleep obtained the previous night. All 10 participants reported that they could answer all questions. Of the nine participants who were asked, all stated that the IDSIQ was relevant to their experience of their condition. Most participants reported that there were no missing items, whereas two participants stated that an item assessing the impact of insomnia on personal relationships (including family) was missing. Conclusion The content of the IDSIQ was easy to understand by patients that suffer from insomnia and comorbid nocturia. The study provides evidence for the content validity of the IDSIQ and its applicability in this population. Support (if any) Funded by Idorsia Pharmaceuticals Ltd.

Introduction Behavioral therapy has proved effective for insomnia in older adults. However, its efficacy has not been examined among those with nocturia (awakening to urinate) which is the most common cause of insomnia in this age group. Thus we assessed the impact of behavioral sleep treatment on sleep in older adults with nocturia. Methods Fifty-six community-dwelling older adults (mean age, 72±6 years; 64% women) with nocturia frequency ≥2 per night were randomized to receive Brief Behavioral Treatment for Insomnia (BBTI) or information-only control (IC). We determined the impact of BBTI on sleep, sleep quality, and nocturia as assessed by a 3-day voiding and sleep diary. Participants concurrently wore a single-channel, EEG device Z-machine® for objective in-home sleep assessment. Insomnia Severity Index (ISI) was used to assess insomnia symptoms. Results Participants had a mean nocturia frequency of 2.2±0.7/night at baseline. Time in bed (TIB) decreased by 42±76 minutes among the BBTI group, but total sleep time (TST) increased by 20±95. Significant differences ± standard error between BBTI and IC in pre- to post-intervention changes were observed for TIB (-41±18 minutes, p=.03) but not TST (27±18, p=.14). Compared to the IC group, the BBTI group also showed a greater improvement in ISI (-3.3±1.4, p=.02) as well as objectively measured sleep onset latency (-9.8±3.5, p=.008), latency to deep sleep (-19±11, p=.08), and percentage of total sleep time spent in deep sleep (8.4±3.1, p=.01). BBTI also decreased nocturia frequency to a greater extent (-0.49±0.20, p=.02) Conclusion BBTI improves insomnia symptoms, objective sleep measures, and nocturia in older adults with frequent sleep interruptions related to nocturia. Treatment for insomnia may be an important addition to current treatments for nocturia. Support (if any) NIA AG 060292

Nocturnal enuresis in children and nocturia in the elderly are two highly prevalent clinical conditions characterized by a mismatch between urine production rate in the kidneys and storage in the urinary bladder during the sleep phase. Here we demonstrate, using a novel method for automated recording of mouse micturition, that connexin43, a bladder gap junction protein, is a negative regulator of functional bladder capacity. Bladder connexin43 levels and functional capacity show circadian oscillations in wild-type mice, but such rhythms are completely lost in Cry -null mice having a dysfunctional biological clock. Bladder muscle cells have an internal clock, and show oscillations of connexin43 and gap junction function. A clock regulator, Rev-erbα, upregulates connexin43 transcription as a cofactor of Sp1, using Sp1 cis -elements of the promoter. Therefore, circadian oscillation of connexin43 is associated with the biological clock and contributes to diurnal changes in bladder capacity, which avoids disturbance of sleep by micturition. Humans and rodents normally store more urine in the bladder when fast asleep than when awake. In this study, the production of the gap junction protein connexin43, a regulator of bladder capacity, is shown to oscillate in mouse urinary bladder muscle in synchrony with the circadian clock.

Abstract Introduction In nocturia, longer FUSP (time to first void) correlates with better quality sleep (Bliwise et al, JCSM 2015;11:53-5) and, with treatment, longer FUSP is associated with decreased nightly voids (Epstein et al, Neurourol Urodyn 2018;37:186-91). We examined urologic correlates of FUSP in an outpatient nocturia population without comorbidities (CHF, OSA, ESRD, diuretics). Methods Participants (n=119; men) kept a home flow/volume diary, tracking clock time and quantity of each urination across a 24-hr period. FUSP was defined as time between going to bed and time of first void. We analyzed the urine volume at first nocturnal void (FNVV) (i.e., at end of FUSP). We also analyzed all nighttime volumes and divided by reported hours of sleep to impute nocturnal urine production (NUP) (in ml/hr, classified as high [>90 ml/hr] [n=49] vs low [<90 ml/hr] [n=60])—a measure correlated with number of nocturia episodes (van Doorn et al, J Urol 2014;191:1034-9). Nocturnal maximal voided volume (NMVV) at any single nocturnal void defined maximal functional nocturnal bladder capacity. Data were analyzed non-parametrically. Results For 53 of 119 patients, FNVV was identical to NMVV. This was more likely in patients with NUP >90 ml/hr vs <90 ml/hr (59% vs 40%, p=.046). High (vs low) NUP rates were also associated with higher FNVV (300 [225-420] vs 135 [100-200] ml, p<.001), as well as higher number of voids (3 vs. 2, p=.03). Conclusion For nearly half of these nocturia patients, the volume at first void occurred at their maximal nocturnal volume. In nocturia, higher FNVV also reflects greater overall nocturnal volume of urine produced, and excess urine volume (as opposed to insufficient bladder capacity) likely plays a central role in the pathogenesis of nocturia in these patients. The extent to which these higher initial volumes represent free-water vs solute-driven clearance is currently under investigation. Support N/A

Aim Nocturia impairs the quality of life in patients with type 2 diabetes mellitus. Although sodium glucose co‐transporter 2 inhibitors (SGLT2i) such as tofogliflozin increase urine volume, their impact on nocturia, in conjunction with dietary salt restriction, is less clear. Materials and Methods This multicenter, open‐label, randomized, parallel‐group trial included 80 subjects with type 2 diabetes and nocturia. The patients were divided into two groups: one receiving tofogliflozin, the shortest half‐life, without salt restriction, and the other receiving both tofogliflozin and dietary salt restriction. The primary endpoint was nocturia frequency at 12 weeks. The secondary outcomes included changes in daytime urination frequency, urine volume, and home blood pressure. Results At 12 weeks, there were no significant differences in nocturia changes between both groups. Nocturia frequency did not change in the tofogliflozin without salt restriction group from 1.5 ± 0.8 to 1.3 ± 1.1 times per night (P = 0.297), and significantly decreased from 1.6 ± 1.0 to 1.3 ± 0.7 times per night in the tofogliflozin and dietary salt restriction group (P = 0.049). There was a trend toward increased urine volume and frequency during the daytime in the group with salt restriction, indicating a time‐shift effect of the short half‐life tofogliflozin and salt restriction on urinary time. Conclusions The frequency of nocturia after tofogliflozin did not increase. Tofogliflozin reduced nocturia when combined with salt restriction. Furthermore, daytime urine volume and frequency showed an increasing trend, suggesting a shift in urine production to daytime hours due to the short half‐life of tofogliflozin. Dietary modifications can enhance the therapeutic benefits of tofogliflozin in managing nocturia in people with type 2 diabetes. The effect of tofogliflozin, an SGLT2i with the shortest half‐life, on the frequency of nocturia in patients with T2D was found that the frequency of nocturia did not increase upon tofogliflozin administration. Particularly, combining tofogliflozin administration with dietary salt restriction significantly reduced nocturia.

Summary Aim To raise awareness on nocturia disease burden and to provide simplified aetiologic evaluation and related treatment pathways. Methods A multidisciplinary group of nocturia experts developed practical advice and recommendations based on the best available evidence supplemented by their own experiences. Results Nocturia is defined as the need to void ≥1 time during the sleeping period of the night. Clinically relevant nocturia (≥2 voids per night) affects 2%‐18% of those aged 20‐40 years, rising to 28%‐62% for those aged 70‐80 years. Consequences include the following: lowered quality of life; falls and fractures; reduced work productivity; depression; and increased mortality. Nocturia‐related hip fractures alone cost approximately €1 billion in the EU and $1.5 billion in the USA in 2014. The pathophysiology of nocturia is multifactorial and typically related to polyuria (either global or nocturnal), reduced bladder capacity or increased fluid intake. Accurate assessment is predicated on frequency‐volume charts combined with a detailed patient history, medicine review and physical examination. Optimal treatment should focus on the underlying cause(s), with lifestyle modifications (eg, reducing evening fluid intake) being the first intervention. For patients with sustained bother, medical therapies should be introduced; low‐dose, gender‐specific desmopressin has proven effective in nocturia due to idiopathic nocturnal polyuria. The timing of diuretics is an important consideration, and they should be taken mid‐late afternoon, dependent on the specific serum half‐life. Patients not responding to these basic treatments should be referred for specialist management. Conclusions The cause(s) of nocturia should be first evaluated in all patients. Afterwards, the underlying pathophysiology should be treated specifically, alone with lifestyle interventions or in combination with drugs or (prostate) surgery.