Protocol for a randomized, double blind, placebo controlled, crossover trial of Melatonin for treatment of Nocturia in adults with Multiple Sclerosis (MeNiMS).

BACKGROUND: Nocturia (the symptom of needing to wake up to pass urine) is common in progressive Multiple Sclerosis (MS) patients. Moderate-to-severe nocturia affects quality of life, can exacerbate fatigue and may affect capacity to carry out daily activities. Melatonin is a natural hormone regulating circadian cycles, released by the pineal gland at night-time, and secretion is impaired in MS. Melatonin levels can be supplemented by administration in tablet form at bedtime. The aim of this study is to evaluate the effect of melatonin on mean number of nocturia episodes per night in MS patients. Secondary outcome measures will assess impact upon quality of life, urinated volumes, lower urinary tract symptoms (LUTS), cognition, sleep quality and sleep disturbance of partners. METHODS: A randomized, double blind, placebo controlled, crossover trial consisting of two, six week treatment phases (active drug melatonin 2 mg or placebo), with a 1 month wash-out period in between. The primary outcome (change in nocturia episodes per night) in this two arm, two treatment, two period crossover design, will be objectively measured using frequency volume charts (FVC) at baseline and following both treatment phases. Questionnaires will be used to assess quality of life, sleep quality, safety and urinary tract symptoms. Qualitative interviews of participants and partners will explore issues including quality of life, mechanisms of sleep disturbance and impact of nocturia on partners. DISCUSSION: This study will evaluate whether melatonin reduces the frequency of nocturia episodes in MS patients, and therefore whether 'Circadin' has the potential to reduce LUTS and fatigue, and improve cognition and overall quality of life. TRIAL REGISTRATION: (EudraCT reference) 2012-00418321 registered: 25/01/13. ISRCTN Registry: ISRCTN38687869.

Observational study comparing non-invasive blood pressure measurement at the arm and ankle during caesarean section.

Upper-arm non-invasive blood pressure measurement during caesarean section can be uncomfortable and unreliable because of movement artefact in the conscious parturient. We aimed to determine whether ankle blood pressure measurement could be used instead in this patient group by comparing concurrent arm and ankle blood pressure measured throughout elective caesarean section under regional anaesthesia in 64 term parturients. Bland-Altman analysis of mean difference (95% limits of agreement [range]) between the ankle and arm was 11.2 (-20.3 to +42.7 [-67 to +102]) mmHg for systolic arterial pressure, -0.5 (-21.0 to +19.9 [-44 to +91]) mmHg for mean arterial pressure and -3.8 (-25.3 to +17.8 [-41 to +94]) mmHg for diastolic arterial pressure. Although ankle blood pressure measurement is well tolerated and allows greater mobility of the arms than measurement from the arm, the degree of discrepancy between the two sites is unacceptable to allow routine use of ankle blood pressure measurement, especially for systolic arterial pressure. However, ankle blood pressure measurement may be a useful alternative in situations where arm blood pressure measurement is difficult or impossible.

Proper understanding of recurrent stress urinary incontinence treatment in women (PURSUIT): a randomised controlled trial of endoscopic and surgical treatment.

BACKGROUND: Women with stress urinary incontinence (SUI) experience urine leakage with physical activity. Currently, the interventional treatments for SUI are surgical, or endoscopic bulking injection(s). However, these procedures are not always successful, and symptoms can persist or come back after treatment, categorised as recurrent SUI. There are longstanding symptoms and distress associated with a failed primary treatment, and currently, there is no consensus on how best to treat women with recurrent, or persistent, SUI. METHODS: A two-arm trial, set in at least 20 National Health Service (NHS) urology and urogynaecology referral units in the UK, randomising 250 adult women with recurrent or persistent SUI 1:1 to receive either an endoscopic intervention (endoscopic bulking injections) or a standard NHS surgical intervention, currently colposuspension, autologous fascial sling or artificial urinary sphincter. The aim of the trial is to determine whether surgical treatment is superior to endoscopic bulking injections in terms of symptom severity at 1 year after randomisation. This primary outcome will be measured using the patient-reported International Consultation on Incontinence Questionnaire - Urinary Incontinence - Short Form (ICIQ-UI-SF). Secondary outcomes include assessment of longer-term clinical impact, improvement of symptoms, safety, operative assessments, sexual function, cost-effectiveness and an evaluation of patients' and clinicians' views and experiences of the interventions. DISCUSSION: There is a lack of high-quality, randomised, scientific evidence for which treatment is best for women presenting with recurrent SUI. The PURSUIT study will benefit healthcare professionals and patients and provide robust evidence to guide further treatment and improve symptoms and quality of life for women with this condition. TRIAL REGISTRATION: International Standard Randomised Controlled Trials Number (ISRCTN) registry ISRCTN12201059. Registered on 09 January 2020.

Female Urgency, Trial of Urodynamics as Routine Evaluation (FUTURE study): a superiority randomised clinical trial to evaluate the effectiveness and cost-effectiveness of invasive urodynamic investigations in management of women with refractory overactive bladder symptoms.

BACKGROUND: Overactive bladder (OAB) syndrome is a symptom complex affecting 12-14% of the UK adult female population. Symptoms include urinary urgency, with or without urgency incontinence, increased daytime urinary frequency and nocturia. OAB has a negative impact on women's social, physical, and psychological wellbeing. Initial treatment includes lifestyle modifications, bladder retraining, pelvic floor exercises and pharmacological therapy. However, these measures are unsuccessful in 25-40% of women (refractory OAB). Before considering invasive treatments, such as Botulinum toxin injection or sacral neuromodulation, most guidelines recommend urodynamics to confirm diagnosis of detrusor overactivity (DO). However, urodynamics may fail to show evidence of DO in up to 45% of cases, hence the need to evaluate its effectiveness and cost-effectiveness. FUTURE (Female Urgency, Trial of Urodynamics as Routine Evaluation) aims to test the hypothesis that, in women with refractory OAB, urodynamics and comprehensive clinical assessment is associated with superior patient-reported outcomes following treatment and is more cost-effective, compared to comprehensive clinical assessment only. METHODS: FUTURE is a pragmatic, multi-centre, superiority randomised controlled trial. Women aged ≥ 18 years with refractory OAB or urgency predominant mixed urinary incontinence, and who have failed/not tolerated conservative and medical treatment, are considered for trial entry. We aim to recruit 1096 women from approximately 60 secondary/tertiary care hospitals across the UK. All consenting women will complete questionnaires at baseline, 3 months, 6 months and 15 months post-randomisation. The primary outcome is participant-reported success at 15 months post-randomisation measured using the Patient Global Impression of Improvement. The primary economic outcome is incremental cost per quality-adjusted life year gained at 15 months. The secondary outcomes include adverse events, impact on other urinary symptoms and health-related quality of life. Qualitative interviews with participants and clinicians and a health economic evaluation will also be conducted. The statistical analysis of the primary outcome will be by intention-to-treat. Results will be presented as estimates and 95% CIs. DISCUSSION: The FUTURE study will inform patients, clinicians and policy makers whether routine urodynamics improves treatment outcomes in women with refractory OAB and whether it is cost-effective. TRIAL REGISTRATION: ISRCTN63268739 . Registered on 14 September 2017.

Neural control of the lower urinary and gastrointestinal tracts: supraspinal CNS mechanisms.

Normal urinary function is contingent upon a complex hierarchy of CNS regulation. Lower urinary tract afferents synapse in the dorsal horn of the spinal cord and ascend to the midbrain periaqueductal gray (PAG), with a separate nociception path to the thalamus. A spino-thalamo-cortical sensory pathway is present in some primates, including humans. In the brainstem, the pontine micturition center (PMC) is a convergence point of multiple influences, representing a co-ordinating center for voiding. Many PMC neurones have characteristics necessary to categorize the center as a pre-motor micturition nucleus. In the lateral pontine brainstem, a separate region has some characteristics to suggest a "continence center." Cerebral control determines that voiding is permitted if necessary, socially acceptable and in a safe setting. The frontal cortex is crucial for decision making in an emotional and social context. The anterior cingulate gyrus and insula co-ordinate processes of autonomic arousal and visceral sensation. The influence of these centers on the PMC is primarily mediated via the PAG, which also integrates bladder sensory information, thereby moderating voiding and storage of urine, and the transition between the two phases. The parabrachial nucleus in the pons is also important in behavioral motivation of waste evacuation. Lower urinary tract afferents can be modulated at multiple levels by corticolimbic centers, determining the interoception of physiological condition and the consequent emotional motor responses. Alterations in cognitive modulation, descending modulation, and hypervigilance are important in functional (symptom-based) clinical disorders.

The meteorite-asteroid connection: the infrared spectra of eucrites, shergottites, and vesta.

Infrared reflectance spectra have been obtained for the meteorites Shergotty and Allan Hills (ALHA) 77005, a unique achondrite apparently related to the shergottites. Comparisons with the reflectance spectra of eucrites and asteroid 4 Vesta indicate that the surface of Vesta is covered with eucrite-like basalts and that, if shergottite-like basalts are present on the surface of Vesta, they must be a minor rock type. The paradox that both the eucrite and shergottite parent bodies should presently exist is examined. The preferred solution is that both eucrites and shergottites are derived from Vesta, and that this asteroid is compositionally and isotopically heterogeneous; however, other possible solutions cannot be ruled out.

Europium anomaly in plagioclase feldspar: experimental results and semiquantitative model.

The partition of europium between plagioclase feldspar and magmatic liquid is considered in terms of the distribution coefficients for divalent and trivalent europium. A model equation is derived giving the europium anomaly in plagioclase as a function of temperature and oxygen fugacity. The model explains europium anomalies in plagioclase synthesized under controlled laboratory conditions as well as the variations of the anomaly observed in natural terrestrial and extraterrestrial igneous rocks.

High-pressure and high-temperature experiments on core-mantle segregation in the accreting Earth.

The abundances of siderophile elements in the Earth's silicate mantle are too high for the mantle to have been in equilibrium with iron in the core if equilibrium occurred at low pressures and temperatures. It has been proposed that this problem may be solved if equilibrium occurred at high pressures and temperatures. Experimental determination of the distribution of siderophile elements between liquid metal and liquid silicate at 100 kilobar and 2000 degrees C demonstrates that it is unlikely that siderophile element abundances were established by simple metal-silicate equilibrium, which indicates that the segregation of the core from the mantle was a complex process.

Petrology of a fine-grained igneous rock from the sea of tranquillity.

All phases in a thin section of sample 10022 have been analyzed by electron microprobe. Augite grains show strong iron enrichment in the outer 15 to 20 microns. Pigeonite cores occur within augite grains. The plagioclase has an anorthite content of between 73 and 81 mole percent and is high in Si and low in Al compared to stoichiometric feldspar. Residual phases include microcrystalline Fe-rich "pyroxene," plagioclase, K-rich alkali feldspar, silica, and rare areas rich in P and Zr with concentrations of Ba, Y, and rare earth elements. The density, viscosity, and crystallization history of the lava of sample 10022 are discussed.

The effect of consultant outcome publication on surgeon behaviour: a systematic review and narrative synthesis.

Introduction Surgeon-specific outcome data, or consultant outcome publication, refers to public access to named surgeon procedural outcomes. Consultant outcome publication originates from cardiothoracic surgery, having been introduced to US and UK surgery in 1991 and 2005, respectively. It has been associated with an improvement in patient outcomes. However, there is concern that it may also have led to changes in surgeon behaviour. This review assesses the literature for evidence of risk-averse behaviour, upgrading of patient risk factors and cessation of low-volume or poorly performing surgeons. Materials and methods A systematic literature review of Embase and Medline databases was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. Original studies including data on consultant outcome publication and its potential effect on surgeon behaviour were included. Results Twenty-five studies were identified from the literature search. Studies suggesting the presence of risk-averse behaviour and upgrading of risk factors tended to be survey based, with studies contrary to these findings using recognised regional and national databases. Discussion and conclusion Our review includes instances of consultant outcome publication leading to risk-averse behaviour, upgrading of risk factors and cessation of low-volume or poorly performing surgeons. As UK data on consultant outcome publication matures, further research is essential to ensure that high-risk patients are not inappropriately turned down for surgery.

Muscarinic stimulation of the mouse isolated whole bladder: physiological responses in young and ageing mice.

1 Peripheral autonomous bladder activity is an incompletely understood property that may be important both in normal bladder function and in functional problems of the lower urinary tract. We describe how a muscarinic agonist, arecaidine, influences intravesical pressure and intramural bladder contractions in the isolated mouse and how response varies in ageing mice. 2 A group of 12 mice aged 3-4 months was compared with an 'ageing' group of 12 mice age 28-34 months. Bladders were microsurgically removed and mounted in whole organ tissue baths. The effects of the muscarinic agonist arecaidine on intravesical pressure and intramural contractions were performed at different bladder volumes. 3 In normal mice, arecaidine elicited tonic and phasic contractions, the latter showing a more substantial increase in amplitude with bladder distension. Localized 'micromotion' contractions were seen in the bladder wall, with regional differences arising after exposure to arecaidine. A background release of acetylcholine was inferred from the pressure increase induced by the cholinesterase inhibitor physostigmine. 4 Both micromotion activity and the phasic component of the arecaidine response were substantially reduced in ageing mice; the tonic component was preserved in the same specimens. 5 We conclude that the enhanced pressure fluctuations seen at high bladder volumes may act as a peripheral determinant of bladder capacity, and that changes in such activity may contribute to altered functional capacity and lower urinary tract symptoms in ageing individuals.

Physiological and pathophysiological implications of micromotion activity in urinary bladder function.

'Micromotions' is a term signifying the presence of localized microcontractions and microelongations, alongside non-motile areas. The motile areas tend to shift over the bladder surface with time, and the intravesical pressure reflects moment-by-moment summation of the interplay between net contractile force generated by micromotions and general bladder tone. Functionally, the bladder structure may comprise modules with variable linkage, which supports presence of localized micromotions (no functional linkage between modules), propagating contractions (where emergence of linkage allows sequential activation) and the shifting of micromotions over time. Detrusor muscle, interstitial cells and intramural innervation have properties potentially relevant for initiating, coordinating and modulating micromotions. Conceptually, such activity could facilitate the generation of afferent activity (filling state reporting) in the absence of intravesical pressure change and the ability to transition to voiding at any bladder volume. This autonomous activity is an intrinsic property, seen in various experimental contexts including the clinical setting of human (female) overactive bladder. 'Disinhibited autonomy' may explain the obvious micromotions in isolated bladders and perhaps contribute clinically in neurological disease causing detrusor overactivity. Furthermore, any process that could increase the initiation or propagation of microcontractions might be anticipated to have a functional effect, increasing the likelihood of urinary urgency and detrusor overactivity respectively. Thus, models of bladder outlet obstruction, neurological trauma and ageing provide a useful framework for detecting cellular changes in smooth muscle, interstitial cells and innervation, and the consequent effects on micromotions.

Urodynamics for Prostate Surgery Trial; Randomised Evaluation of Assessment Methods (UPSTREAM) for diagnosis and management of bladder outlet obstruction in men: study protocol for a randomised controlled trial.

BACKGROUND: Lower urinary tract symptoms (LUTS) comprise storage symptoms, voiding symptoms and post-voiding symptoms. Prevalence and severity of LUTS increase with age and the progressive increase in the aged population group has emphasised the importance to our society of appropriate and effective management of male LUTS. Identification of causal mechanisms is needed to optimise treatment and uroflowmetry is the simplest non-invasive test of voiding function. Invasive urodynamics can evaluate storage function and voiding function; however, there is currently insufficient evidence to support urodynamics becoming part of routine practice in the clinical evaluation of male LUTS. DESIGN: A 2-arm trial, set in urology departments of at least 26 National Health Service (NHS) hospitals in the United Kingdom (UK), randomising men with bothersome LUTS for whom surgeons would consider offering surgery, between a care pathway based on urodynamic tests with invasive multichannel cystometry and a care pathway based on non-invasive routine tests. The aim of the trial is to determine whether a care pathway not including invasive urodynamics is no worse for men in terms of symptom outcome than one in which it is included, at 18 months after randomisation. This primary clinical outcome will be measured with the International Prostate Symptom Score (IPSS). We will also establish whether inclusion of invasive urodynamics reduces rates of bladder outlet surgery as a main secondary outcome. DISCUSSION: The general population has an increased life-expectancy and, as men get older, their prostates enlarge and potentially cause benign prostatic obstruction (BPO) which often requires surgery. Furthermore, voiding symptoms become increasingly prevalent, some of which may not be due to BPO. Therefore, as the population ages, more operations will be considered to relieve BPO, some of which may not actually be appropriate. Hence, there is sustained interest in the diagnostic pathway and this trial could improve the chances of an accurate diagnosis and reduce overall numbers of surgical interventions for BPO in the NHS. The morbidity, and therapy costs, of testing must be weighed against the cost saving of surgery reduction. TRIAL REGISTRATION: Controlled-trials.com - ISRCTN56164274 (confirmed registration: 8 April 2014).

Drug-induced bladder and urinary disorders. Incidence, prevention and management.

The bladder is vulnerable to the adverse effects of drugs because of its complex control and the frequent excretion of drug metabolites in the urine. Incontinence results when bladder pressure exceeds sphincter resistance. Stress incontinence because of sphincter weakness occurs with antipsychotics and alpha-blockers, especially in women. Urge incontinence and irritative symptoms may be caused by drugs. Anticholinergics, anaesthetics and analgesics cause urinary retention because of failure of bladder contraction. They are more likely to cause retention in men because of prostatic enlargement. Cyclophosphamide and tiaprofenic acid can cause chemical cystitis, and should be withdrawn if a patient develops irritative symptoms or haematuria. Cyclophosphamide may also induce bladder tumours. Adverse effects of cyclophosphamide can be reduced with prophylactic administration of mesna and adequate hydration. Mitomycin, doxorubicin or bacillus Calmette-Guerin (BCG) instilled locally to treat bladder tumours can cause cystitis, contracture and calcification. Their administration should be limited to 1 hour per week for a maximum of 8 weeks. Retroperitoneal fibrosis and urine discolouration may be caused by drugs. Ureteric calculi may result from any drug causing nephrolithiasis.

Tamsulosin/solifenacin fixed-dose combination tablet for the treatment of male lower urinary tract symptoms.

Men reporting mixed storage and voiding lower urinary tract symptoms (LUTS) often experience persisting storage LUTS after initial treatment. Combination therapy of an alpha-adrenergic antagonist and an antimuscarinic is increasingly recognized as a therapy option. Clinical trials have combined tamsulosin (0.4 mg) with different doses of solifenacin. In the SATURN study, greater efficacy benefits were observed for moderate to severe storage symptoms. Single tablet administration may offer improved compliance. Accordingly, the NEPTUNE study researched fixed-dose combination (FDC) therapy for mixed LUTS, using tamsulosin (oral controlled administration system formulation), with solifenacin (6 or 9 mg). The FDC containing tamsulosin and solifenacin 6 mg improved storage and voiding LUTS, with no additional benefit from the higher solifenacin dose. During the open-label extension study, symptom improvement was maintained. Adverse events reflected the known effects of the component therapies. Acute urinary retention, an adverse event of special interest, was seen in only a small number of treated men.

An artificial model for studying fluid dynamics in the obstructed and stented ureter.

Fluid dynamics in the obstructed and stented ureter represents a non-trivial subject of investigation since, after stent placement, the urine can flow either through the stent lumen or in the extra-luminal space located between the stent wall and the ureteric inner wall. Fluid dynamic investigations can help understanding the phenomena behind stent failure (e.g. stent occlusions due to bacterial colonization and encrustations), which may cause kidney damage due to the associated high pressures generated in the renal pelvis. In this work a microfluidic-based transparent device (ureter model, UM) has been developed to simulate the fluid dynamic environment in a stented ureter. UM geometry has been designed from measurements on pig ureters. Pressure in the renal pelvis compartment has been measured against three variables: fluid viscosity (µ), volumetric flow rate (Q) and level of obstruction (OB%). The measurements allowed a quantification of the critical combination of µ, Q and OB% values which may lead to critical pressure levels in the kidney. Moreover, an example showing the possibility of applying particle image velocimetry (PIV) technology to the developed microfluidic device is provided.

A first-principles characterization of water adsorption on forsterite grains.

Numerical simulations examining chemical interactions of water molecules with forsterite grains have demonstrated the efficacy of nebular gas adsorption as a viable mechanism for water delivery to the terrestrial planets. Nevertheless, a comprehensive picture detailing the water-adsorption mechanisms on forsterite is not yet available. Towards this end, using accurate first-principles density functional theory, we examine the adsorption mechanisms of water on the (001), (100), (010) and (110) surfaces of forsterite. While dissociative adsorption is found to be the most energetically favourable process, two stable associative adsorption configurations are also identified. In dual-site adsorption, the water molecule interacts strongly with surface magnesium and oxygen atoms, whereas single-site adsorption occurs only through the interaction with a surface Mg atom. This results in dual-site adsorption being more stable than single-site adsorption.