Sex-specific independent risk factors of urinary incontinence in acute stroke patients: A multicentre registry-based cohort study.

BACKGROUND: The presence of urinary incontinence (UI) in acute stroke patients indicates poor outcomes in men and women. However, there is a paucity and inconsistency of data on UI risk factors in this group and hence we conducted a sex-specific analysis to identify risk factors. METHODS: Data were collected prospectively (2014-2016) from the Sentinel Stroke National Audit Program for patients admitted to four UK hyperacute stroke units. Relevant risk factors for UI were determined by stepwise multivariable logistic regression, presented as odds ratios (OR) and 95% confidence intervals (CI). RESULTS: The mean (±SD) age of UI onset in men (73.9 year ± 13.1; n = 1593) was significantly earlier than for women (79.8 year ± 12.9; n = 1591: p < 0.001). Older age between 70 and 79 year in men (OR = 1.61: CI = 1.24-2.10) and women (OR = 1.55: CI = 1.12-2.15), or ≥80 year in men (OR = 2.19: CI = 1.71-2.81), and women (OR = 2.07: CI = 1.57-2.74)-reference: <70 year-both predicted UI. In addition, intracranial hemorrhage (reference: acute ischemic stroke) in men (OR = 1.64: CI = 1.22-2.20) and women (OR = 1.75: CI = 1.30-2.34); and prestroke disability (mRS scores ≥ 4) in men (OR = 1.90: CI = 1.02-3.5) and women (OR = 1.62: CI = 1.05-2.49) (reference: mRS scores < 4); and stroke severity at admission: NIHSS scores = 5-15 in men (OR = 1.50: CI = 1.20-1.88) and women (OR = 1.72: CI = 1.37-2.16), and NIHSS scores = 16-42 in men (OR = 4.68: CI = 3.20-6.85) and women (OR = 3.89: CI = 2.82-5.37) (reference: NIHSS scores = 0-4) were also significant. Factors not selected were: a history of congestive heart failure, hypertension, atrial fibrillation, diabetes and previous stroke. CONCLUSIONS: We have identified similar risk factors for UI after stroke in men and women including age >70 year, intracranial hemorrhage, prestroke disability and stroke severity.

Impact of healthcare-associated infections within 7-days of acute stroke on health outcomes and risk of care-dependency: a multi-centre registry-based cohort study.

Healthcare-associated infections (HCAIs) in patients admitted with acute conditions remain a major challenge to healthcare services. Here, we assessed the impact of HCAIs acquired within 7-days of acute stroke on indicators of care-quality outcomes and dependency. Data were prospectively collected (2014-2016) from the Sentinel Stroke National Audit Programme for 3309 patients (mean age = 76.2 yr, SD = 13.5) admitted to four UK hyperacute stroke units (HASU). Associations between variables were assessed by multivariable logistic regression (odds ratios, 95% confidence intervals), adjusted for age, sex, co-morbidities, pre-stroke disability, swallow screening, stroke type and severity. Within 7-days of admission, urinary tract infection (UTI) and pneumonia occurred in 7.6% and 11.3% of patients. Female (UTI only), older age, underlying hypertension, atrial fibrillation, previous stroke, pre-stroke disability, intracranial haemorrhage, severe stroke, and delay in swallow screening (pneumonia only) were independent risk factors of UTI and pneumonia. Compared to patients without UTI or pneumonia, those with either or both of these HCAIs were more likely to have prolonged stay (> 14-days) on HASU: 5.1 (3.8-6.8); high risk of malnutrition: 3.6 (2.9-4.5); palliative care: 4.5 (3.4-6.1); in-hospital mortality: 4.8 (3.8-6.2); disability at discharge: 7.5 (5.9-9.7); activity of daily living support: 1.6 (1.2-2.2); and discharge to care-home: 2.3 (1.6-3.3). In conclusion, HCAIs acquired within 7-days of an acute stroke led to prolonged hospitalisation, adverse health consequences and risk of care-dependency. These findings provide valuable information for timely intervention to reduce HCAIs, and minimising subsequent adverse outcomes.

Adreno-Muscarinic Synergy of Contractile Responses From Human Hyperplastic Prostate.

PURPOSE: Adreno-muscarinic synergy, a supra-additional contractile response to simultaneous application of α-adrenoreceptor and muscarinic receptor agonists, is a feature of several lower urinary tract regions that have dual sympathetic and parasympathetic innervation. We tested the hypothesis that synergy is also a feature of prostate tissue obtained from men with benign prostatic enlargement. METHODS: Isolated tissue strips were dissected from prostate 'chips', collected after transurethral prostate resection procedures for in vitro experiments, to measure isometric tension at 36°C. RESULTS: Added separately to the superfusate, phenylephrine and carbachol generated contractions with mean pEC50 (-log10EC50) values of 5.36 and 5.58, respectively, although phenylephrine maximal responses were about six-fold greater. In the presence of carbachol, the mean phenylephrine pEC50 was significantly increased to 5.84 and maximal response increased by 28%; overall, a significant synergistic response was demonstrated. The synergistic response was reduced by muscarinic receptor antagonists, most potently by the M3-selective agent 4-DAMP (1,1-dimethyl-4-diphenylacetoxypiperidinium iodide), and less so by M2 and M1-selective inhibitors gallamine and pirenzepine, but with an overall profile indicating M3/M2 mediation of the synergistic response. The magnitude of the synergistic response was variable between prostate chips that provided isolated preparations suggesting regional heterogenicity, although their zonal origin could not be determined. CONCLUSION: These experiments show that adreno-muscarinic contractile synergy is a feature of human hyperplastic prostate tissue. This has implications for the use of a combination therapy of α-blockers and anti-muscarinic agent to relieve secondary symptoms associated with benign prostatic hyperplasia, at least in men who can tolerate antimuscarinics without a risk of retention.

Urinary incontinence indicates mortality, disability, and infections in hospitalised stroke patients.

OBJECTIVES: To assess the impact of urinary incontinence (UI) on health outcomes over the entire spectrum of acute stroke severity (National Institutes of Health Stroke Scale [NIHSS] scores: 0-42), due to a paucity of data on patients with milder strokes. PATIENTS AND METHODS: Data were prospectively collected (2014-2016) from the Sentinel Stroke National Audit Programme (1593 men, 1591 women; mean [SD] age 76.8 [13.3] years) admitted to four UK hyperacute stroke units (HASUs). Relationships between variables were assessed by multivariable logistic regression. Data were adjusted for age, sex, comorbidities, pre-stroke disability and intra-cranial haemorrhage, and presented as odds ratios with 95% confidence intervals. RESULTS: Amongst patients with no symptoms or a minor stroke (NIHSS scores of 0-4), compared to patients without UI, patients with UI had significantly greater risks of poor outcomes including: in-hospital mortality; disability at discharge; in-hospital pneumonia; urinary tract infection within 7 days of admission; prolonged length of stay on the HASU; palliative care by discharge; activity of daily living (ADL) support, and new discharge to care home. In patients with more moderate stroke (NIHSS score of 5-15) the same outcomes were identified; being at greater risk for patients with UI, except for palliative care by discharge and ADL support. With the highest stroke severity group (NIHSS score of 16-48) all outcomes were identified except in-patient mortality, pneumonia, and ADL support. However, odds ratios diminished as NIHSS scores increased. CONCLUSIONS: Urinary incontinence is a useful indicator of poor short-term outcomes in older patients with an acute stroke, but irrespective of stroke severity. This provides valuable information to healthcare professionals to identify at-risk individuals.

Determination of independent risk factors for early healthcare-associated infections acquired after acute stroke admission: A multi-centre registry-based cohort study.

OBJECTIVE: Healthcare-associated infections (HCAIs) in patients admitted with acute conditions pose a serious risk to patients and a major challenge to healthcare services. However, there is a lack of consistency in reporting aetiological risk factors, particularly in acute stroke patients. Here, we determined independent risk factors of two common HCAIs (urinary tract infection and pneumonia) acquired within 7-days of admission after an acute stroke. METHODS: Data were prospectively collected (2014-2016) from the Sentinel Stroke National Audit Programme for 3,309 patients (mean age=76.2yr, SD=13.5) admitted to four UK hyperacute stroke units. Associations between variables were assessed by forward stepwise multivariable logistic regression (odds ratios, 95 % confidence intervals). RESULTS: The rate of urinary tract infection and/or pneumonia occurring within 7-days of admission was 15.0 %. The risk of urinary tract infection and/or pneumonia was increased amongst women: OR = 1.35 (1.08-1.68); patients from ethnic minority backgrounds: OR = 1.77 (1.01-3.10); patients aged 70-79 years: OR = 2.08 (1.42-3.06), and ≥80 years: OR = 3.20 (2.26-4.55); history of hypertension: OR = 1.59 (1.27-1.98); history of atrial fibrillation: OR = 1.67 (1.32-2.12); pre-stroke disability: OR = 2.08 (1.44-3.00); intracranial haemorrhage: OR = 1.41 (1.07-1.86); severe stroke: OR = 3.21 (2.32-4.45); swallow screening within 4-72 h: OR = 1.42 (1.08-1.86); swallow screening beyond 72 h: OR = 1.70 (1.08-2.70). History of congestive heart failure, diabetes and previous stroke did not significantly associate with HCAIs. CONCLUSIONS: A profile of independent risk factors for two common HCAIs in acute stroke was identified. These findings provide valuable information for timely intervention to reduce HCAIs, and the ability to minimise subsequent adverse outcomes.

How does the lower urinary tract contribute to bladder sensation? ICI-RS 2023.

AIM: Bladder sensation is critical for coordinating voluntary micturition to maintain healthy bladder function. Sensations are initiated by the activation of sensory afferents that innervate throughout the bladder wall. However, the physiological complexity that underlies the initiation of bladder sensory signaling in health and disease remains poorly understood. This review summarises the latest knowledge of the mechanisms underlying the generation of bladder sensation and identifies key areas for future research. METHODS: Experts in bladder sensory signaling reviewed the literature on how the lower urinary tract contributes to bladder sensation and identified key research areas for discussion at the 10th International Consultation on Incontinence-Research Society. RESULTS: The importance of bladder sensory signals in maintaining healthy bladder function is well established. However, better therapeutic management of bladder disorders with exaggerated bladder sensation, including overactive bladder syndrome (OAB) and interstitial cystitis/bladder pain syndrome (IC/BPS) is limited by a lack of knowledge in a number of key research areas including; the contribution of different nerves (pudendal, pelvic, hypogastric) to filling sensations in health and disease; the relative contribution of stretch sensitive (muscular) and stretch-insensitive (mucosal) afferents to bladder sensation in health and disease; the direct and indirect contributions of the muscularis mucosae to bladder contraction and sensation; and the impact of manipulating urothelial release factors on bladder sensation. CONCLUSION: Disturbances in bladder sensory signaling can have severe consequences for bladder sensation and function including the development of OAB and IC/BPS. Advancing therapeutic treatments for OAB and IC/BPS requires a deeper understanding of the mechanisms underlying the generation of bladder sensation, and key areas for future research have been identified.

Nitric oxide signaling pathways in the normal and pathological bladder: Do they provide new pharmacological pathways?-ICI-RS 2023.

AIMS: The nitric oxide (NO•)/soluble guanylate cyclase/cyclic-GMP (cGMP) signaling pathway is ubiquitous and regulates several functions in physiological systems as diverse as the vascular, nervous, and renal systems. However, its roles in determining normal and abnormal lower urinary tract functions are unclear. The aim was to identify potential therapeutic targets associated with this pathway to manage lower urinary tract functional disorders. METHODS: This review summarizes a workshop held under the auspices of ICI-RS with a view to address these questions. RESULTS: Four areas were addressed: NO• signaling to regulate neurotransmitter release to detrusor smooth muscle; its potential dual roles in alleviating and exacerbating inflammatory pathways; its ability to act as an antifibrotic mediator; and the control by nitrergic nerves of lower urinary tract vascular dynamics and the contractile performance of muscular regions of the bladder wall. Central to much of the discussion was the role of the NO• receptor, soluble guanylate cyclase (sGC) in regulating the generation of the enzyme product, the second messenger cGMP. The redox state of sGC is crucial in determining its enzymic activity and the role of a class of novel agents, sGC activators, to optimize activity and to potentially alleviate the consequences of lower urinary tract disorders was highlighted. In addition, the consequences of a functional relationship between nitrergic and sympathetic nerves to regulate vascular dynamics was discussed. CONCLUSIONS: Several potential NO•-dependent drug targets in the lower urinary tract were identified that provide the basis for future research and translation to clinical trials.

Influences of the COVID-19 pandemic on admissions and clinical outcomes in mental health disorders and self-poisoning: Age- and sex-specific analysis.

We measured rates of hospital admissions for mental health disorders and self-poisoning during the pandemic in patients without COVID-19, compared to those admitted before the pandemic. Data were collected from 01/04/2019 to 31/03/2021, including the pandemic period from 01/03/2020. There were 10 173 (47.7% men) from the pre-pandemic and 11 019 (47.5% men) from the pandemic periods; mean age = 68.3 year. During the pandemic, admission rates for mental health disorders and self-poisoning were higher for any given age and sex. Self-poisoning was increased with toxic substances, sedatives and psychotropic drugs, but reduced with nonopioid analgesics. Patients admitted with mental health disorders had lower readmission rates within 28 days during the pandemic, but did not differ in other outcomes. Outcomes from self-poisoning did not change between the two study periods.

Adverse stroke outcomes amongst UK ethnic minorities: a multi-centre registry-based cohort study of acute stroke.

OBJECTIVE: Socioeconomic and health inequalities persist in multicultural western countries. Here, we compared outcomes following an acute stroke amongst ethnic minorities with Caucasian patients. METHODS: Data were prospectively collected (2014-2016) from the Sentinel Stroke National Audit Programme for 3309 patients who were admitted with an acute stroke in four UK hyperacute stroke units. Associations between variables were examined by chi-squared tests and multivariable logistic regression, adjusted for age, sex, prestroke functional limitations and co-morbidities, presented as odds ratios (OR) with 95% CI. RESULTS: There were 3046 Caucasian patients, 95 from ethnic minorities (mostly South Asians, Blacks, mixed race and a few in other ethnic groups) and 168 not stated. Compared with Caucasian patients, those from ethnic minorities had a proportionately higher history of diabetes (33.7% vs 15.4%, P < 0.001), but did not differ in other chronic conditions, functional limitations or sex distribution. Their age of stroke onset was younger both in women (76.8 year vs 83.2 year, P < 0.001) and in men (69.5 year vs 75.9 year, P = 0.002). They had greater risk for having a stroke before the median age of 79.5 year: OR = 2.15 (1.36-3.40) or in the first age quartile (< 69 year): OR = 2.91 (1.86-4.54), requiring palliative care within the first 72 h: OR = 3.88 (1.92-7.83), nosocomial pneumonia or urinary tract infection within the first 7 days of admission: OR = 1.86 (1.06-3.28), and in-hospital mortality: OR = 2.50 (1.41-4.44). CONCLUSIONS: Compared with Caucasian patients, those from ethnic minorities had earlier onset of an acute stroke by about 5 years and a 2- to fourfold increase in many stroke-related adverse outcomes and death.

Evaluation of independent risk factors associated with surgical site infections from caesarean section.

BACKGROUND: The present study assessed factors associated with the risk of surgical site infections (SSI) after a caesarean section (C-section). METHODS: Data were collected in 1682 women undergoing elective (53.9%) and emergency (46.1%) C-sections between 1st August 2020, and 30th December 2021, at a National Health Service hospital (Surrey, UK). RESULTS: At the time of C-section, the mean age was 33.1 yr (SD ± 5.2). Compared to women with BMI < 30 kg/m2, those with a BMI ≥ 35 kg/m2 had a greater risk of SSI, OR 4.07 (95%CI 2.48-6.69). Women with a history of smoking had a greater risk of SSI than those who had never smoked, OR 1.69 (95%CI 1.05-2.27). Women with a BMI ≥ 30 kg/m2 and had a smoking history or emergency C-section had 3- to tenfold increases for these adverse outcomes. Ethnic minority, diabetes or previous C-section did not associate with any of the outcomes. CONCLUSIONS: High BMI, smoking, and emergency C-section are independent risk factors for SSI from C-section. Women planning conception should avoid excess body weight and smoking. Women with diabetes and from ethnic minority backgrounds did not have increased risks of SSI, indicating a consistent standard of care for all patients.

Reduction of adverse outcomes from cesarean section by surgical-site infection prevention care bundles in maternity.

OBJECTIVE: To reduce average surgical-site infection (SSI) rates to less than 7.5%, as well as other complications by incrementally implementing an SSI prevention care bundle in maternity: (1) ChloraPrep; (2) PICO dressings, performing elective cesarean sections in a main theater rather than a labor ward and warming blankets; (3) vaginal cleansing; and (4) Hibiscrub. METHODS: In this prospective cohort study, the association between categorical variables was assessed by χ2 tests, temporal trends in the monthly percentage change of SSI were measured using the Joinpoint Regression Program v4.7.0.0. RESULTS: In all, 1682 women (mean age 33.1 ± 5.2 years) underwent either elective (53.9%) or emergency (46.1%) cesarean section. After a small initial increase (10.0%-11.8%), SSI progressively declined to 4.4% (χ2  = 22.1, P < 0.001), as did sepsis, reoperation or readmission for SSI: from 12.5% to 0.5% (χ2  = 90.1, P < 0.001). The rates of SSI fell progressively with the cumulative introduction care bundle components. The average monthly percentage change was -14.0% (95% confidence interval -21.8% to -5.4%, P = 0.004), and the average SSI rate was kept below 7.5% for the last 12 months of the study. CONCLUSION: The maternal SSI prevention care bundle is simple and inexpensive; it effectively reduces SSI after a cesarean section and should be offered routinely to women undergoing cesarean section.

Selective reduction of neurotransmitter release by cAMP-dependent pathways in mouse detrusor.

Parasympathetic nerve-mediated contractions of detrusor smooth muscle are generated by ATP and acetylcholine (ACh) release from efferent nerve terminals. In humans, ACh is responsible for detrusor contractions in normal human bladders, whereas ATP has an additional role in overactive bladder pathologies. The ATP metabolite, adenosine, relaxes nerve-mediated contractions, with a potential action via presynaptic adenosine A1 receptor activation and subsequent suppression of neuronal ATP release. We investigated the effect of A1 receptor activation and downstream cAMP-dependent pathways on nerve-mediated ATP and ACh release, and detrusor contraction in mouse detrusor. Bladders from male C57BL/6 mice (12 wk) were used for in vitro experiments. Upon electrical field stimulation of intact preparations (detrusor and mucosal layers), ATP or ACh release was measured simultaneously with tension recordings. Activation of A1 receptors by adenosine or exogenous agonists reduced the lower frequency component of nerve-mediated contractions and neuronal ATP release. The A1 receptor antagonist abolished these effects. A1 receptor activation inhibits adenylyl cyclase (AC) activity and cAMP generation. The effect of A1 receptor activation was mimicked by a PKA antagonist but not by modulators of exchange proteins activated by cAMP, demonstrating that modulation of nerve-mediated ATP release is via PKA. Adenosine had no effect on ACh release or the higher frequency component of nerve-mediated contractions. Differential regulation of neurotransmitter release is possible at the detrusor nerve-muscle junction, as demonstrated by A1 receptor activation, and downstream inhibition of AC, cAMP generation, and PKA. The ability to specifically attenuate ATP release offers a potential to target purinergic motor pathways enhanced in overactive bladder pathologies.

Cytoplasmic anion/cation imbalances applied across the membrane capacitance may form a significant component of the resting membrane potential of red blood cells.

Electrical aspects of cell function manifest in many ways. The most widely studied is the cell membrane potential, Vm, but others include the conductance and capacitance of the membrane, the conductance of the enclosed cytoplasm, as well as the charge at the cell surface (an electrical double layer) producing an extracellular electrical potential, the ζ-potential. Empirical relationships have been identified between many of these, but not the mechanisms that link them all. Here we examine relationships between Vm and the electrical conductivities of both the cytoplasm and extracellular media, using data from a suspensions of red blood cells. We have identified linear relationships between extracellular medium conductivity, cytoplasm conductivity and Vm. This is in contrast to the standard model of a resting membrane potential which describes a logarithmic relationship between Vm and the concentration of permeable ions in the extracellular medium. The model here suggests that Vm is partially electrostatic in origin, arising from a charge imbalance at an inner electrical double-layer, acting across the membrane and double-layer capacitances to produce a voltage. This model describes an origin for coupling between Vm and ζ, by which cells can alter their electrostatic relationship with their environment, with implications for modulation of membrane ion transport, adhesion of proteins such as antibodies and wider cell-cell interactions.

Identification of preoperative factors and postoperative outcomes in relation to delays in surgery for hip fractures.

We evaluated factors and outcomes associated with elapsed time to surgery (ETTS) in 1,081 men and 2,891 women (mean age 83.5 years ±9.1) undergoing hip fracture surgery (from 2009-2019). Mortality rates were 4.8%, 6.3%, 6.2% and 10.3% (chi-squared 19.0; p<0.001), and hospital length of stay (LOS) >19 days were 31.9%, 32.8%, 33.8% and 43.2% (chi-squared 18.5; p<0.001) for ETTS <24 hours, 24-35 hours, 36-47 hours and ≥48 hours, respectively. There were no differences between ETTS categories for failure to mobilise within 1 day of surgery, pressure ulcers or discharge to nursing care. After adjustment for age, sex, American Society of Anesthesiologists' score and years of data collection, compared with Sunday, the risk of ETTS ≥36 hours was highest on Friday (odds ratio (OR) 3.50; 95% confidence interval (CI) 2.43-5.03) and Saturday (OR 4.70; 95% CI 3.26-6.76). Compared with ETTS <24 hours, there were increases in the risk of death when ETTS ≥48 hours (OR 2.31; 95% CI 1.47-3.65) and LOS >19 days (OR 1.34; 95% CI 1.02-1.75). The median (interquartile range (IQR)) LOS for ETTS <24 hours was 12.7 days (IQR 8.0-23.0), 24-35 hours was 13.5 days (IQR 8.4-22.9), 36-47 hours was 14.1 days (IQR 8.9-23.3) and ≥48 hours was 16.9 (IQR 10.8-27.0; p<0.001). The 10-year period of collection did not change the conclusion. Admissions towards the end of the week are associated with delayed ETTS for hip fractures, while delay in surgery, particularly beyond 48 hours, is associated with increased risk of mortality and prolonged LOS.

Comparison of characteristics, management and outcomes in hospital-onset and community-onset stroke: a multi-centre registry-based cohort study of acute stroke.

OBJECTIVE: Hospital-onset stroke (HOS) is associated with poorer outcomes than community-onset stroke (COS). Previous studies have variably documented patient characteristics and outcome measures; here, we compare in detail characteristics, management and outcomes of HOS and COS. METHODS: A total of 1656 men (mean age ± SD = 73.1 years ± 13.2) and 1653 women (79.3 years ± 13.0), with data prospectively collected (2014-2016) from the Sentinel Stroke National Audit Programme, were admitted with acute stroke in four UK hyperacute stroke units (HASU). Associations between variables were examined by chi-squared tests and multivariable logistic regression (COS as reference). RESULTS: There were 272 HOS and 3037 COS patients with mean ages of 80.2 years ± 12.5 and 76.4 years ± SD13.5 and equal sex distribution. Compared to COS, HOS had higher proportions ≥ 80 years (64.0% vs 46.4%), congestive heart failure (16.9% vs 4.9%), atrial fibrillation (25.0% vs 19.7%) and pre-stroke disability (9.6% vs 5.1%), and similar history of stroke, hypertension, diabetes, stroke type and severity of stroke. After age, sex and co-morbidities adjustments, HOS had greater risk of pneumonia: OR (95%CI) = 1.9 (1.3-2.6); malnutrition: OR = 2.2 (1.7-2.9); immediate thrombolysis complications: OR = 5.3 (1.5-18.2); length of stay on HASU > 3 weeks: OR = 2.5 (1.8-3.4); post-stroke disability: OR = 1.8 (1.4-2.4); and in-hospital mortality: OR = 1.8 (1.2-2.4), as well as greater support at discharge including palliative care: OR = 1.9 (1.3-2.8); nursing care: OR = 2.0 (1.3-4.0), help for daily living activities: OR = 1.6 (1.1-2.2); and joint-care planning: OR = 1.5 (1.1-1.9). CONCLUSIONS: This detailed analysis of underlying differences in subject characteristics between patients with HOS or COS and adverse consequences provides further insights into understanding poorer outcomes associated with HOS.

Frequency-dependent characteristics of nerve-mediated ATP and acetylcholine release from detrusor smooth muscle.

NEW FINDINGS: What is the central question of this study? Is the frequency dependence of co-transmitter release from postganglionic nerve fibres different for each transmitter? What is the main finding and its importance? Release of co-transmitters from the parasympathetic supply to detrusor smooth muscle can be independently regulated. This offers a targeted drug model to reduce selectively the release of transmitter associated with human pathologies (ATP) and may also be applicable to other smooth muscle-based disorders of visceral tissues. ABSTRACT: Nerve-mediated contractions of detrusor smooth muscle are mediated by acetylcholine (ACh) and ATP release in most animals. However, with the normal human bladder, only ACh is a functional transmitter, but in benign pathologies such as overactive bladder (OAB), ATP re-emerges as a secondary transmitter. The selective regulation of ATP release offers a therapeutic approach to manage OAB, in contrast to current primary strategies that target ACh actions. However, the release characteristics of nerve-mediated ACh and ATP are poorly defined and this study aimed to measure the frequency dependence of ACh and ATP release and determine if selective regulation of ATP or ACh was possible. Experiments were carried out in vitro with mouse detrusor with nerve-mediated ATP and ACh release measured simultaneously with tension recording. ATP was released in two frequency-dependent components, both at lower frequencies (mid-range 0.4 and 5.5 Hz stimulation) compared to a single compartment release of ACh at 14 Hz. Intervention with the phosphodiesterase type-5 inhibitor sildenafil attenuated ATP release, equally from both components, but had no effect on ACh release. These data demonstrate that nerve-mediated ACh and ATP release characteristics are distinct and may be separately manipulated. This offers a potential targeted drug model to manage benign lower urinary tract conditions such as OAB.

Hypothesis: Disrupted Regulation of the Intracranial Vascular and Cerebrospinal Fluid Circulations Causes Nocturia.

Nocturia is a prevalent condition and may result from nocturnal polyuria, whereby overnight urine production is excessive. Anecdotal cases of idiopathic nocturnal polyuria in which cerebrospinal fluid (CSF) disorders were identified suggest a potential mechanism. The skull constrains three circulatory systems: the CSF, interstitial fluid, and vascular supply. For each, fluid dynamics (pressure, volume, and flow) are closely regulated and adapt to changes such as recumbency and circadian variation. Pathologies disrupting this regulation, and thus impairing intracranial fluid dynamics, will place the brain environment at risk. Hence, compensatory responses are needed to maintain safe limits and prevent neurological deficits. We hypothesise that a change in the fluid dynamics for the intracranial CSF, interstitial, or vascular circulation means that positional or circadian changes during sleep trigger compensatory hormonal responses to protect the brain, but these also cause nocturnal polyuria. Natriuretic hormones are candidate mediators for protection against excess intracranial pressure or volume. PATIENT SUMMARY: A need to pass urine during the night, which is called nocturia, may be because of excessive overnight urine production. We propose that changes in fluid dynamics in the brain caused by lying down or daily body rhythms may trigger the release of hormones that could be a factor in nighttime urine production. This hypothesis should be explored in further investigations.

Adverse consequences of immediate thrombolysis-related complications: a multi-centre registry-based cohort study of acute stroke.

Complications following thrombolysis for stroke are well documented, and mostly concentrated on haemorrhage. However, the consequences of patients who experience any immediate thrombolysis-related complications (TRC) compared to patients without immediate TRC have not been examined. Prospectively collected data from the Sentinel Stroke National Audit Programme were analysed. Thrombolysis was performed in 451 patients (52.1% men; 75.3 years ± 13.2) admitted with acute ischaemic stroke (AIS) in four UK centres between 2014 and 2016. Adverse consequences following immediate TRC were assessed using logistic regression, adjusted for age, sex and co-morbidities. Twenty-nine patients (6.4%) acquired immediate TRC. Compared to patients without, individuals with immediate TRC had greater adjusted risks of: moderately-severe or severe stroke (National Institutes of Health for Stroke Scale score ≥ 16) at 24-h (5.7% vs 24.7%, OR 3.9, 95% CI 1.4-11.1); worst level of consciousness (LOC) in the first 7 days (score ≥ 1; 25.0 vs 60.7, OR 4.6, 95% CI 2.1-10.2); urinary tract infection or pneumonia within 7-days of admission (13.5% vs 39.3%, OR 3.2, 95% CI 1.3-7.7); length of stay (LOS) on hyperacute stroke unit (HASU) ≥ 2 weeks (34.7% vs 66.7%, OR 5.2, 95% CI 1.5-18.4); mortality (13.0% vs 41.4%, OR 3.7, 95% CI 1.6-8.4); moderately-severe or severe disability (modified Rankin Scale score ≥ 4) at discharge (26.8% vs 65.5%, OR 4.7, 95% CI 2.1-10.9); palliative care by discharge date (5.1% vs 24.1%, OR 5.1, 95% CI 1.7-15.7). The median LOS on the HASU was longer (7 days vs 30 days, Kruskal-Wallis test: χ2 = 8.9, p = 0.003) while stroke severity did not improve (NIHSS score at 24-h post-thrombolysis minus NIHSS score at arrival = - 4 vs 0, χ2 = 24.3, p < 0.001). In conclusion, the risk of nosocomial infections, worsening of stroke severity, longer HASU stay, disability and death is increased following immediate TRC. The management of patients following immediate TRC is more complex than previously thought and such complexity needs to be considered when planning an increased thrombolysis service.

Predicting Stroke Complications in Hospital and Functional Status at Discharge by Clustering of Cardiovascular Diseases a Multi-Centre Registry-Based Study of Acute Stroke.

OBJECTIVE: Indicators for outcomes following acute stroke are lacking. We have developed novel evidence-based criteria for identifying outcomes of acute stroke using the presence of clusters of coexisting cardiovascular disease (CVD). MATERIALS AND METHODS: Analysis of prospectively collected data from the Sentinel Stroke National Audit Programme (SSNAP). A total of 1656 men (mean age ±SD=73.1yrs±13.2) and 1653 women (79.3yrs±13.0) were admitted with acute stroke (83.3% ischaemic, 15.7% intracranial haemorrhagic), 1.0% unspecified) in four major UK hyperacute stroke units (HASU) between 2014 and 2016. Four categories from cardiovascular disease Congestive heart failure, Atrial fibrillation, pre-existing Stroke and Hypertension (CASH).were constructed: CASH-0 (no coexisting CVD); CASH-1 (any one coexisting CVD); CASH-2 (any two coexisting CVD); CASH-3 (any three or all four coexisting CVD). These were tested against outcomes, adjusted for age and sex. RESULTS: Compared to CASH-0, individuals with CASH-3 had greatest risks of in-hospital mortality (11.1% vs 24.5%, OR=1.8, 95%CI=1.3-2.7) and disability (modified Rankin Scale score ≥4) at discharge (24.2% vs 46.2%, OR=1.9, 95%CI=1.4-2.7), urinary tract infection (3.8% vs 14.6%, OR= 3.3, 95%CI= 1.9-5.5), and pneumonia (7.1% vs 20.6%, OR= 2.6, 95%CI= 1.7-4.0); length of stay on HASU >14 days (29.8% vs 39.3%, OR=1.8, 95%CI=1.3-2.6); and joint-care planning (20.9% vs 29.8%, OR=1.4, 95%CI=1.0-2.0). CONCLUSIONS: We present a simple tool for estimating the risk of adverse outcomes of acute stroke including death, disability at discharge, nosocomial infections, prolonged length of stay, as well as any joint care planning. CASH-0 indicates a low level and CASH-3 indicates a high level of risk of such complications after stroke.

Association of risk of malnutrition with adverse outcomes and early support on discharge in acute stroke patients without prestroke disability: A multicenter, registry-based cohort study.

BACKGROUND: Malnutrition in hospitals remains highly prevalent. As part of quality improvement initiatives, the Royal College of Physicians recommends nutrition screening for all patients admitted with acute stroke. We aimed to examine the associations of patients at risk of malnutrition with poststroke outcomes. METHODS: We analyzed prospectively collected data from four hyperacute stroke units (HASUs) (2014-2016). Nutrition status was screened in 2962 acute stroke patients without prestroke disability (1515 men, [mean ± SD] 73.5 years ± 13.1; 1447 women, 79.2 ± 13.0 years). The risk of malnutrition was tested against stroke outcomes and adjusted for age, sex, and comorbidities. RESULTS: Risk of malnutrition was identified in 25.8% of patients). Compared with well-nourished patients, those at risk of malnutrition had, within 7 days of admission, increased risk of stay on the HASU of >14 days (odds ratio [OR]: 9.9 [7.3-11.5]), disability on discharge (OR: 8.1 [6.6-10.0]), worst level of consciousness in the first 7 days (score ≥ 1) (OR: 7.5 [6.1-9.3]), mortality (OR: 5.2 [4.0-6.6], pneumonia (OR: 5.1 [3.9-6.7]), and urinary tract infection (OR: 1.5 [1.1-2.0]). They also required palliative care (OR: 12.3 [8.5-17.8]), discharge to new care home (OR: 3.07 [2.18-4.3]), activities of daily living support (OR: 1.8 [1.5-2.3]), planned joint care (OR: 1.5 [1.2-1.8]), and weekly visits (OR: 1.4 [1.1-1.8]). CONCLUSION: Patients at risk of malnutrition more commonly have multiple adverse outcomes after acute stroke and greater need for early support on discharge.