Network-level encoding of local neurotransmitters in cortical astrocytes.

Astrocytes, the most abundant non-neuronal cell type in the mammalian brain, are crucial circuit components that respond to and modulate neuronal activity through calcium (Ca2+) signalling1-7. Astrocyte Ca2+ activity is highly heterogeneous and occurs across multiple spatiotemporal scales-from fast, subcellular activity3,4 to slow, synchronized activity across connected astrocyte networks8-10-to influence many processes5,7,11. However, the inputs that drive astrocyte network dynamics remain unclear. Here we used ex vivo and in vivo two-photon astrocyte imaging while mimicking neuronal neurotransmitter inputs at multiple spatiotemporal scales. We find that brief, subcellular inputs of GABA and glutamate lead to widespread, long-lasting astrocyte Ca2+ responses beyond an individual stimulated cell. Further, we find that a key subset of Ca2+ activity-propagative activity-differentiates astrocyte network responses to these two main neurotransmitters, and may influence responses to future inputs. Together, our results demonstrate that local, transient neurotransmitter inputs are encoded by broad cortical astrocyte networks over a minutes-long time course, contributing to accumulating evidence that substantial astrocyte-neuron communication occurs across slow, network-level spatiotemporal scales12-14. These findings will enable future studies to investigate the link between specific astrocyte Ca2+ activity and specific functional outputs, which could build a consistent framework for astrocytic modulation of neuronal activity.

A systematic review of the surgical management of apical pelvic organ prolapse.

INTRODUCTION AND HYPOTHESIS: This systematic review (PROSPERO:CRD42022275789) is aimed at comparing qualitatively the success, recurrence, and complication rates of sacrocolpopexy with concomitant hysterectomy, hysteropexy, sacrospinous fixation (SSF) with and without vaginal hysterectomy (VH) and uterosacral fixation (USF) with and without VH. METHODS: A systematic search was performed using Embase, PubMed, Scopus, and Cochrane databases for studies published from 2011, on women with apical pelvic organ prolapse requiring surgical interventions. Risk of bias was assessed via the National Institutes of Health study quality assessment tool. The primary outcomes are the success and recurrence rate of each technique, for ≥12 months' follow-up. Findings were summarised qualitatively. RESULTS: A total of 21 studies were included. Overall significant findings for a high success and low recurrence rate are summarised as: minimally invasive sacrocolpopexy (MISC) is superior to abdominal sacrocolpopexy (ASC); sacrospinous hysteropexy (SSHP) is superior to USF + VH, which is superior to uterosacral hysteropexy and mesh hysteropexy (MHP). Significant findings related to complications include: MISC recorded a lower overall complication rate than ASC except in mesh exposure; USF + VH tends to perform better than SSHP and SSF, with SSHP performing better than MHP in faecal incontinence and overactive bladder rates. CONCLUSION: There is no evidence to conclude that hysterectomy is superior to uterine-sparing approaches. MISC should be considered over ASC given similar efficacy and reduced complications. Superiority of MHP is unproven against native tissue hysteropexy. Further studies under standardised settings are required for direct comparisons between the surgical management methods.

The Asia-Pacific AMS800 artificial urinary sphincter consensus statement.

This Asia-Pacific (AP) AMS 800™ artificial urinary sphincter (AUS) consensus statement aims to provide a set of practical recommendations to assist surgeons with the AMS 800 device surgery. The AP consensus committee consisted of key opinion leaders with extensive experience with AMS 800 surgery across several AP countries. The panel reviewed and discussed relevant findings with emphasis on locoregional and specific clinical challenges relevant to the AP region. Recommendations were made in key areas namely (1) patient selection and informed consent process; (2) preoperative assessment; (3) dealing with co-existing urological disorders; (4) surgical principles and intraoperative troubleshooting; (5) postoperative care; (6) special populations; and (7) cost analysis and comparative review. The AMS 800 device should be offered to males with moderate to severe stress urinary incontinence (SUI). Full informed consent should be undertaken, and emphasis is placed on surgical contraindications and high-risk candidates. The presence of a surgical mentor or referral to experts is recommended in complex AUS candidates. Preoperative cystoscopy with or without multichannel urodynamic study is necessary and patients with pre-existing urological disorders should be treated adequately and clinically stable before surgery. Adherence to strict patient selection and safe surgical principles are critical to ensure excellent clinical outcomes and minimize complications. Given that InhibiZone-coated device is not available in many AP countries, the use of prophylactic antibiotics pre-and post-operatively are recommended. The AMS 800 device should be prepared according to the manufacturer's guidelines and remains a cost-effective treatment for male SUI. The AMS 800 device remains the surgical benchmark for male SUI but is associated with certain mechanical limitations and a unique set of complications.

Gene expression in oligodendrocytes during remyelination reveals cholesterol homeostasis as a therapeutic target in multiple sclerosis.

Regional differences in neurons, astrocytes, oligodendrocytes, and microglia exist in the brain during health, and regional differences in the transcriptome may occur for each cell type during neurodegeneration. Multiple sclerosis (MS) is multifocal, and regional differences in the astrocyte transcriptome occur in experimental autoimmune encephalomyelitis (EAE), an MS model. MS and EAE are characterized by inflammation, demyelination, and axonal damage, with minimal remyelination. Here, RNA-sequencing analysis of MS tissues from six brain regions suggested a focus on oligodendrocyte lineage cells (OLCs) in corpus callosum. Olig1-RiboTag mice were used to determine the translatome of OLCs in vivo in corpus callosum during the remyelination phase of a chronic cuprizone model with axonal damage. Cholesterol-synthesis gene pathways dominated as the top up-regulated pathways in OLCs during remyelination. In EAE, remyelination was induced with estrogen receptor-ß (ERß) ligand treatment, and up-regulation of cholesterol-synthesis gene expression was again observed in OLCs. ERß-ligand treatment in the cuprizone model further increased cholesterol synthesis gene expression and enhanced remyelination. Conditional KOs of ERß in OLCs demonstrated that increased cholesterol-synthesis gene expression in OLCs was mediated by direct effects in both models. To address this direct effect, ChIP assays showed binding of ERß to the putative estrogen-response element of a key cholesterol-synthesis gene (Fdps). As fetal OLCs are exposed in utero to high levels of estrogens in maternal blood, we discuss how remyelinating properties of estrogen treatment in adults during injury may recapitulate normal developmental myelination through targeting cholesterol homeostasis in OLCs.

The International Continence Society (ICS) report on the terminology for adult male lower urinary tract and pelvic floor symptoms and dysfunction.

INTRODUCTION: In the development of terminology of the lower urinary tract, due to its increasing complexity, the terminology for male lower urinary tract and pelvic floor symptoms and dysfunction needs to be updated using a male-specific approach and via a clinically-based consensus report. METHODS: This report combines the input of members of the Standardisation Committee of the International Continence Society (ICS) in a Working Group with recognized experts in the field, assisted by many external referees. Appropriate core clinical categories and a subclassification were developed to give a numeric coding to each definition. An extensive process of 22 rounds of internal and external review was developed to exhaustively examine each definition, with decision-making by collective opinion (consensus). RESULTS: A Terminology Report for male lower urinary tract and pelvic floor symptoms and dysfunction, encompassing around 390 separate definitions/descriptors, has been developed. It is clinically-based with the most common diagnoses defined. Clarity and user-friendliness have been key aims to make it interpretable by practitioners and trainees in all the different specialty groups involved in male lower urinary tract and pelvic floor dysfunction. Male-specific imaging (ultrasound, radiology, CT, and MRI) has been a major addition whilst appropriate figures have been included to supplement and help clarify the text. CONCLUSIONS: A consensus-based Terminology Report for male lower urinary tract and pelvic floor symptoms and dysfunction has been produced aimed at being a significant aid to clinical practice and a stimulus for research.

Pelvic floor ultrasound in the diagnosis of sling complications.

PURPOSE: The mid-urethral synthetic sling (MUS) procedure has become the standard of care for treatment of female stress urinary incontinence. However, a small number of patients will have complications following MUS including failure, obstructive voiding, sling erosion, or chronic pain. This paper discusses the role of 2D and 3D ultrasound imaging in the evaluation of the female patient with complications following placement of a synthetic mid-urethral sling. RESULTS: The MUS is easily visualized as an echogenic structure on ultrasound and can be imaged by transperineal, transvaginal and introital approaches. Ultrasound allows dynamic assessment of the sling and can assist in the diagnosis of sling failure, obstruction, erosion and mesh related pain. CONCLUSIONS: Pelvic floor ultrasound has an emerging role in the assessment of complications following MUS surgery. 3D ultrasound can assist the clinician in assessment of the complex patient with multiple slings or meshes in situ.

Prevalence and factors of self-corrective intention among Hong Kong secondary school students who are self-assessed Internet addiction cases.

BACKGROUND: Adolescent Internet addiction (IA) is prevalent. No study, however, has applied the health belief model (HBM) to investigate issues on IA nor investigated factors associated with intention to correct one's perceived IA problem (self-corrective intention). Such information facilitates design of related interventions, which are warranted. METHODS: This cross-sectional study surveyed 9,618 Chinese secondary school students in Hong Kong; 4,111 (42.7%) self-assessed that they had IA (self-assessed IA cases); 1,145 of these self-assessed IA cases (27.9%) were also classified as IA cases (concordant IA cases), as their Chen Internet Addiction Scale score exceeded 63. RESULTS: The prevalence of self-corrective intention among these two subsamples was only 28.2% and 34.1%, respectively. In the self-assessed IA subsample, the HBM constructs including perceived susceptibility to IA [adjusted odds ratio (ORa) = 1.24, 95% CI = 1.16, 1.34], perceived severity of IA (ORa = 2.28, 95% CI = 2.09, 2.48), perceived benefits for reducing Internet use (ORa = 1.21, 95% CI = 1.18, 1.24), self-efficacy to reduce Internet use (ORa = 1.07, 95% CI = 1.03, 1.11), and cues to action to reduce Internet use (ORa = 1.15, 95% CI = 1.11, 1.20) were positively, while perceived barriers for reducing Internet use (ORa = 0.95, 95% CI = 0.94, 0.97) were negatively, associated with self-corrective intention. Similar factors were identified in the concordant IA subsample. CONCLUSIONS: A large proportion of the students perceived that they had IA but only about one-third intended to correct the problem. Future interventions may consider altering students' HBM constructs, and focus on the segment of concordant IA with self-corrective intention, as they show readiness for changes.

Mid-term outcomes of a male retro-urethral, transobturator synthetic sling for treatment of post-prostatectomy incontinence: Impact of radiotherapy and storage dysfunction.

PURPOSE: To determine mid-term durability of the AdVance sling for post-prostatectomy incontinence (PPI) and impact of prior radiotherapy and storage dysfunction. METHOD: Eighty men undergoing AdVance sling for PPI during 2008-2013 were reviewed. Pre-op urodynamics, pre and post-op pad usage, prior radiotherapy, and PGI-I scores were recorded. RESULT: Mean follow-up was 36 months (range 14-72). Twelve men had radiotherapy pre-op, 10 had detrusor overactivity (DO), and 20 reduced compliance. Pre-op mean 24-hr pad weight was 264 g and mean pads-per-day (PPD) 2.60 ± 0.29. In the early post-op period (3-6 months), mean PPD was 0.40 (SD 0.16); at mid-term follow-up mean PPD was 1.02 ± 0.31. Radiotherapy and DO were independently predictive of poor mid-term outcome. Men with DO or radiotherapy were using 1.03 ± 0.42 (P = 0.019) and 1.17 ± 0.41 (P = 0.02) more PPD, respectively than men without these factors. At mid-term follow-up, men without radiotherapy or DO were using 1.98 ± 0.28 less PPD compared to pre-operatively (P < 0.0001); with radiotherapy or DO men were using 0.73 ± 0.38 (P = 0.057) and 0.72 ± 0.43 (P = 0.092) less PPD, respectively. PGI-I score for men without radiotherapy or DO was 1.98 ± 0.40 ("much better"); with radiotherapy or DO PGI-I score was 3.80 ± 0.49 ("no difference"). CONCLUSION: The AdVance sling provides mid-term improvement in men with PPI. However, men with radiotherapy or DO have significantly poorer outcomes with mid-term results indicating a return to baseline degree of incontinence. Caution should be taken when considering the AdVance sling in these men. Pre-op urodynamics in men with radiotherapy and/or overactive bladder may be important when considering men for AdVance sling. Neurourol. Urodynam. 36:1147-1150, 2017. © 2016 Wiley Periodicals, Inc.

Conjoint Urological Society of Australia and New Zealand (USANZ) and Urogynaecological Society of Australasia (UGSA) Guidelines on the management of adult non-neurogenic overactive bladder.

Due to the myriad of treatment options available and the potential increase in the number of patients afflicted with overactive bladder (OAB) who will require treatment, the Female Urology Special Advisory Group (FUSAG) of the Urological Society of Australia and New Zealand (USANZ), in conjunction with the Urogynaecological Society of Australasia (UGSA), see the need to move forward and set up management guidelines for physicians who may encounter or have a special interest in the treatment of this condition. These guidelines, by utilising and recommending evidence-based data, will hopefully assist in the diagnosis, clinical assessment, and optimisation of treatment efficacy. They are divided into three sections: Diagnosis and Clinical Assessment, Conservative Management, and Surgical Management. These guidelines will also bring Australia and New Zealand in line with other regions of the world where guidelines have been established, such as the American Urological Association, European Association of Urology, International Consultation on Incontinence, and the National Institute for Health and Care Excellence guidelines of the UK.

Voiding dysfunction in older men.

PURPOSE OF REVIEW: Voiding dysfunction in older men is an important health issue, with significant morbidity and biosocioeconomic burden. Treatment decisions are increasingly complex as many older men also suffer concurrent comorbidities and polypharmacy. A relatively sparse number of publications specifically examine this relevant topic. RECENT FINDINGS: Common geriatric voiding syndromes include overactive bladder (OAB) and underactive bladder, with nocturia and incontinence often the most bothersome lower urinary tract symptoms, and may represent a falls risk together with OAB and incontinence. The combination of detrusor overactivity and impaired contractility may coexist in older patients and can be particularly difficult to diagnose and treat clinically. A small but not insignificant proportion of older men experience spontaneous remission of OAB symptoms without treatment, and 'watchful waiting' may be a reasonable option. OAB treatment with mirabegron may have a preferable side-effect profile compared with anticholinergics in older men. Intravesical onabotulinum toxin A is effective but risk of retention is greater in the older adults. Benign prostatic obstruction (BPO) and underactive bladder may lead to urinary retention, necessitating surgery or catheterization. BPO surgery is a reasonable option in older men, with realistic counselling of postoperative expectations. Combination BPO surgery and medical OAB treatment is suitable for detrusor overactivity and impaired contractility. Stress incontinence in older patients is usually iatrogenic and treatment can include continence applicances, urethral bulking agents, suburethral sling or artificial urinary sphincter. SUMMARY: Management of voiding dysfunction in older patients need to take into account multiple factors including symptomatic and functional impairment, cognition, comorbidities and polypharmacy. Future research examining pathophysiology and treatment outcomes of voiding dysfunction in the older patient population is increasingly relevant.

Botulinum toxin (OnabotulinumtoxinA) in the male non-neurogenic overactive bladder: clinical and quality of life outcomes.

OBJECTIVE: To assess the efficacy of OnabotulinumtoxinA (BTXA) injections in men with drug-refractory non-neurogenic overactive bladder (NNOAB). PATIENTS AND METHODS: A total of 43 men received BTXA injections for NNOAB from 2004 to 2012. Patient Global Impression of Improvement (PGI-I) score was obtained. For men with wet NNOAB, change in number of pads per day was also assessed. RESULTS: Forty-three men with a mean age of 69 (range 37-85) received at least one injection. Of the 43 men, 20 (47%) had prior prostate surgery: 11 had radical prostatectomy (RP) and nine had transurethral resection of prostate (TURP). Overall, average PGI-I score was 2.7. Comparing PGI-I score in men who had prior prostate surgery with men who have not: 2.6 ± 0.5 vs 2.8 ± 0.5 respectively (average ± 95% CI), P = 0.6. Comparing PGI-I score in men who had previous TURP with men who had previous RP: PGI-I score: 3.3 ± 0.8 vs 2.0 ± 0.5 respectively, P < 0.05. Men who had RP experienced a reduction in pad use (from 3.5 ± 1.7 to 1.6 ± 0.9 pads/day, P < 0.05) while this was not the case amongst men who had TURP (from 1.7 ± 1.5 to 1.4 ± 1.5 pads/day, P = 0.4). CONCLUSION: Overall, BTXA injection in men with drug-refractory NNOAB does provide a symptomatic benefit. Amongst men who have had prior prostate surgery, men who have had RP experience a greater benefit than men who have had TURP, both in regards to PGI-I score and pad use.

Urodynamic testing: physiological background, setting-up, calibration and artefacts.

Urodynamics (UDS) is an interactive diagnostic study of lower urinary tract function. It is composed of several tests that can be used to obtain functional information about urine storage and expulsion. Its main goal is to reproduce the patients' symptoms and determine their cause. The present article is a review of the physiological concepts behind UDS, and explains the various normal and abnormal forces and parameters that are measured and used during the tests to assist the physician in making a diagnosis. It outlines the importance and methods of the calibration of UDS equipment to optimise diagnostic accuracy and reliability, which would have a crucial impact over the treatment's decision, and consequently the patient's outcome.

Durability of Memokath™ urethral stent for stabilisation of recurrent bulbar urethral strictures -- medium-term results.

OBJECTIVE: To examine the durability after 3 months deployment of a urethral (Memokath™) stent in conjunction with endoscopic treatment of recurrent bulbar urethral strictures, as repeated endoscopic treatment of urethral strictures can cause worsening of underlying spongiofibrosis. PATIENTS AND METHODS: Prospective series of 22 patients with recurrent bulbar strictures requiring repeat endoscopic treatment were included. The median age was 38 years and the mean stricture length was 2.4 cm. The median number of previous dilatation or direct visual internal urethrotomy (DVIU) procedures was three with a mean time to stricture recurrence of 2 months. After endoscopic dilatation or DVIU, the urethral (Memokath™) stent was deployed and left situ for 3 months. Re-stricture rates were examined with uroflowmetry at 3, 6 and 12 months and confirmed with 17-F cystoscopy at 1 year after stent removal. A telephone survey was conducted at >1-year follow-up. RESULTS: Five of the 22 (22%) patients had stricture recurrence after stent removal. In all, 17/22 (78%) patients remained stricture-free at a median (range) follow-up of 23 (9-31) months. Uroflowmetry showed significantly improved flow rates, which were sustained at 12 months after stent removal. On Kaplan-Meier analysis, there was a significant delay (23 vs 2 months) in stricture or symptom recurrence after stent removal. CONCLUSION: The medium term results of temporary urethral stent placement are encouraging with 78% of patients remaining stricture-free at a median follow-up of 23 months.

What to do about recurrent urinary tract infections: A review of evidence behind emerging therapies.

BACKGROUND: Recurrent urinary tract infections (rUTIs) can be debilitating for patients and pose an increasing challenge in the primary care setting. An efficient approach enables timely access and effective care for patients. Recent research and pharmaceutical developments have provided new avenues for treating this common condition. OBJECTIVE: A narrative review was conducted to provide a targeted overview of contemporary management strategies in rUTIs to assist primary care physicians in managing patients with rUTIs efficiently and effectively. DISCUSSION: Recurrent urinary tract infections require investigation and risk factor identification. Appropriate patient education in the primary care setting, behavioural modifications and commencement of non-antibiotic treatment might reduce rUTI. Certain patients might require referral to a urologist for consideration of other treatment strategies and further investigation.

Global or local: The future of biotech.

Biotech start-ups often begin as domestic companies relying on local resources and talent, but this approach might not be effective in achieving rapid growth and long-term success, particularly for developing new therapeutics that require significant resources and extensive commitment. Here, we argue that born-global biotechs are better equipped to tackle major industry challenges, such as innovation, resource constraints, and limited talent diversity, especially in current challenging times. We also highlight the importance of capital efficiency in maximizing the benefits of being a born-global biotech, and provide an operational framework, based on the FlyWheel concept, for becoming a successful born-global biotech.

'Feel like going crazy': Mental health discourses in an online support group for mothers during COVID-19.

COVID-19 has become a mental health pandemic. The impact on vulnerable demographic groups has been particularly severe. This paper focuses on women in employment in Hong Kong who have had to balance remote work and online schooling for over 2 years. Using semi-ethnography and theme-oriented discourse analysis, we examine 200 threads that concern members' mental health on a popular Facebook support group for mothers. We demonstrate that mental health messages are typically framed as 'troubles talk'. Other support group members actively align with a trouble-teller through 'caring responses', namely expressions of empathy and sympathy. These are realized through assessments of the trouble-teller's experience, reports of similar experiences; expressions of compassion and advice-giving. Mental health talk online is heavily mitigated, nevertheless the medium provides a space for expressing mental health troubles and providing informal psychosocial support. We advocate the importance of microanalytic discourse studies for mental health research to get insights into people's lived experiences during the pandemic.

Uro-symphyseal Fistula: A Systematic Review to Inform a Contemporary, Evidence-based Management Framework.

OBJECTIVE: To collate available data via systematic review considering etiology, presentation, and treatment of Uro-Symphyseal Fistula (USF) in order to inform a contemporary management framework. MATERIALS AND METHODS: A systematic review was performed according to the Cochrane Handbook and registered in PROSPERO (CRD42021232954). MEDLINE and CENTRAL databases were searched for manuscripts considering USF published between 2000 and 2022. Full text manuscripts were reviewed for clinical data. Univariate statistical analysis was performed where possible. RESULTS: A total of 31 manuscripts, comprising 248 USF cases, met inclusion criteria. Suprapubic pain and difficulty ambulating were common symptoms. MRI confirmed the diagnosis in 95% of cases. Radiotherapy for prostate cancer was the most common predisposing factor (93%). Among these patients, prior endoscopic bladder outlet surgery was common (83%; bladder neck incision/urethral dilatation n = 59, TURP/GLL PVP n = 34). In those with prior prostatic radiation, conservative management failed in 96% of cases. Cystectomy with urinary diversion (86% n = 184) was favored over bladder-sparing techniques (14% (n = 30) after prior radiation. In radiation naïve patients, conservative management failed in 72% of patients, resulting in either open fistula repair with flap (62%) or radical prostatectomy (28%). CONCLUSION: Prior radiotherapy is a significant risk factor for USF and almost always requires definitive major surgery (debridement, cystectomy, and urinary diversion). On the basis of the findings within this systematic review, we present management principles that may assist clinicians with these complex cases. Further research into pathogenesis, prevention, and optimal treatment approach is required.

Network-level encoding of local neurotransmitters in cortical astrocytes.

Astrocytes-the most abundant non-neuronal cell type in the mammalian brain-are crucial circuit components that respond to and modulate neuronal activity via calcium (Ca 2+ ) signaling 1-8 . Astrocyte Ca 2+ activity is highly heterogeneous and occurs across multiple spatiotemporal scales: from fast, subcellular activity 3,4 to slow, synchronized activity that travels across connected astrocyte networks 9-11 . Furthermore, astrocyte network activity has been shown to influence a wide range of processes 5,8,12 . While astrocyte network activity has important implications for neuronal circuit function, the inputs that drive astrocyte network dynamics remain unclear. Here we used ex vivo and in vivo two-photon Ca 2+ imaging of astrocytes while mimicking neuronal neurotransmitter inputs at multiple spatiotemporal scales. We find that brief, subcellular inputs of GABA and glutamate lead to widespread, long-lasting astrocyte Ca 2+ responses beyond an individual stimulated cell. Further, we find that a key subset of Ca 2+ activity-propagative events-differentiates astrocyte network responses to these two major neurotransmitters, and gates responses to future inputs. Together, our results demonstrate that local, transient neurotransmitter inputs are encoded by broad cortical astrocyte networks over the course of minutes, contributing to accumulating evidence across multiple model organisms that significant astrocyte-neuron communication occurs across slow, network-level spatiotemporal scales 13-15 . We anticipate that this study will be a starting point for future studies investigating the link between specific astrocyte Ca 2+ activity and specific astrocyte functional outputs, which could build a consistent framework for astrocytic modulation of neuronal activity.