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.

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.

Randomized Controlled Trial of Acupressure for Perception of Stress and Health-Related Quality of Life Among Health Care Providers During the COVID-19 Pandemic: The Self-Acupressure for Stress (SAS) Trial.

Background: The efficacy of providing self-acupressure educational materials in reducing stress and improving health-related quality of life (HRQOL) is uncertain. Evidence-based data to recommend for or against self-acupressure as an intervention for reducing stress and improving HRQOL is needed. Objective: The Self-Acupressure for Stress (SAS) trial evaluates whether providing self-acupressure educational materials would reduce stress and improve HRQOL among health care providers (HCPs). Design: Randomized behavioral clinical trial. Setting: The entire study took place remotely. Participants: One hundred fifty-nine adult HCPs with no prior experience or training in acupressure. Intervention: The intervention group received self-acupressure educational materials. Measurements: Primary outcomes were perception of stress measured by the Perceived Stress Scale (PSS), as well as scores on the physical and mental components of the 12-item Short Form Health Survey version 2 (SF-12v2). Results: From the baseline to midpoint evaluations, the intervention group significantly reduced their PSS score (P ≤ .001) and increased their SF-12v2 Mental score (P = .002) but not their SF-12v2 Physical score (P = .55). These findings persisted at the final follow-up (both PSS and SF-12v2 Mental changes from baseline P < .001). However the control group also significantly improved their SF-12v2 Mental from baseline to midpoint (P = .01) which was maintained at final follow-up (P = .02), whereas PSS and SF-12v2 Physical did not significantly change from baseline at either mid or final. Finally, the intervention group improved by significantly more than the control group from baseline to final follow-up for both PSS (P = .007) and SF-12v2 Mental (P = .02) HRQOL measures. Limitation: The trial was not blinded. Conclusion: Among HCPs during the coronavirus disease 2019 (COVID-19) pandemic, the provision of self-acupressure educational materials safely improved self-reported assessments of perception of stress and mental health. Self-acupressure represents a promising intervention for other populations. The study findings support the use of self-acupressure to reduce stress and improve HRQOL. Trial Registration: ClinicalTrials.gov: NCT04472559.

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.

'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.

Norepinephrine links astrocytic activity to regulation of cortical state.

Cortical state, defined by population-level neuronal activity patterns, determines sensory perception. While arousal-associated neuromodulators-including norepinephrine (NE)-reduce cortical synchrony, how the cortex resynchronizes remains unknown. Furthermore, general mechanisms regulating cortical synchrony in the wake state are poorly understood. Using in vivo imaging and electrophysiology in mouse visual cortex, we describe a critical role for cortical astrocytes in circuit resynchronization. We characterize astrocytes' calcium responses to changes in behavioral arousal and NE, and show that astrocytes signal when arousal-driven neuronal activity is reduced and bi-hemispheric cortical synchrony is increased. Using in vivo pharmacology, we uncover a paradoxical, synchronizing response to Adra1a receptor stimulation. We reconcile these results by demonstrating that astrocyte-specific deletion of Adra1a enhances arousal-driven neuronal activity, while impairing arousal-related cortical synchrony. Our findings demonstrate that astrocytic NE signaling acts as a distinct neuromodulatory pathway, regulating cortical state and linking arousal-associated desynchrony to cortical circuit resynchronization.

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.

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.

Dopamine activates astrocytes in prefrontal cortex via α1-adrenergic receptors.

The prefrontal cortex (PFC) is a hub for cognitive control, and dopamine profoundly influences its functions. In other brain regions, astrocytes sense diverse neurotransmitters and neuromodulators and, in turn, orchestrate regulation of neuroactive substances. However, basic physiology of PFC astrocytes, including which neuromodulatory signals they respond to and how they contribute to PFC function, is unclear. Here, we characterize divergent signaling signatures in mouse astrocytes of the PFC and primary sensory cortex, which show differential responsiveness to locomotion. We find that PFC astrocytes express receptors for dopamine but are unresponsive through the Gs/Gi-cAMP pathway. Instead, fast calcium signals in PFC astrocytes are time locked to dopamine release and are mediated by α1-adrenergic receptors both ex vivo and in vivo. Further, we describe dopamine-triggered regulation of extracellular ATP at PFC astrocyte territories. Thus, we identify astrocytes as active players in dopaminergic signaling in the PFC, contributing to PFC function though neuromodulator receptor crosstalk.

Twenty-Five Years of the Midurethral Sling: Lessons Learned.

Midurethral slings (MUS) are widely accepted for the surgical treatment of stress urinary incontinence (SUI) in cases where conservative treatment has failed. They have been shown to be a safe and effective surgical treatment for the management of SUI. However, there have recently been growing concerns regarding the safety profile of mesh procedures, generating international debate and leading to national inquiries into the effectiveness and safety of mesh implants. A multitude of clinical, technical, manufacturer-related, and other health jurisdictional factors are involved in the outcomes of MUS. Appropriate patient selection and informed consent to all treatment options, with proper guidance from healthcare providers, are critical for empowering women to choose an appropriate treatment option based on a personalized decision.

Desmoid fibromatosis involving the ureter: A rare presentation with intraoperative challenges.

Following failed retrograde and antegrade ureteric stenting, a 35-year-old male patient underwent an elective boari flap for marked proximal hydroureteronephrosis due to a periureteric mass in the right iliac fossa. Intraoperative vascular surgical assistance was required for control of arterial bleeding due to friable vessel wall. Histopathology demonstrated desmoid fibromatosis.

Lower Urinary Tract Functional Assessment of Men Undergoing Radical Prostatectomy: Correlation of Preoperative Clinical and Urodynamic Parameters.

PURPOSE: To assess baseline clinical and urodynamic profiles of a contemporary cohort of men undergoing radical prostatectomy (RP) as part of the ROSE (Robotic and Open Surgery for Prostate Cancer: A Prospective, Multi-centre, Comparative Study of Functional and Oncological Outcomes) study. METHODS: Men with localized prostate cancer undergoing RP were prospectively recruited to undergo clinical assessment and urodynamic testing prior to surgery as part of a clinical trial. The International Prostate Symptoms Score (IPSS) was used to determine participants' degree of lower urinary tract symptoms (LUTS). RESULTS: Eighty-five men with a median age of 64.5 years and a median prostate-specific antigen level of 6.3 ng/mL were prospectively recruited. Of patients with complete baseline data, 36 (50.7%), 28 (39.4%), and 7 (9.9%) had mild (IPSS<8), moderate (IPSS 8-19), and severe (IPSS>20) LUTS, respectively. Obstruction was identified in 18 men (29.5%), and 9 (14.8%) showed detrusor underactivity. Of the 15 patients with detrusor overactivity, 12 (80%) reported overactive bladder (OAB). Of men with urodynamic obstruction, 5 (31.3%), 10 (62.5%), and 1 (6.3%) reported mild, moderate, and severe LUTS, respectively. Of men without OAB, 4 (11.8%, P=0.002) showed filling phase abnormalities, 13 (46.4%, P=0.611) had flow rates of <15 mL/sec, and 7 (30.4%, P=0.767) showed obstruction. Of men with mild or no LUTS, 5 (20%, P=0.072) showed obstruction and 4 (16%, P=0.524) showed poor contractility. CONCLUSION: LUTS and OAB were common in men with localized prostate cancer undergoing RP. Detrusor overactivity and urodynamic filling phase abnormalities were strongly correlated with OAB. IPSS did not show a strong correlation with bladder outflow obstruction or detrusor underactivity. Urodynamic filling abnormalities were found in 11.8% of men without OAB. Symptomatic and functional assessment may therefore have a role in the preoperative counselling of patients and possibly guide postoperative management of LUTS, especially if OAB is present.

Expression and Activity of Dysregulated miRNAs in T-ALL Development and Progression.

OBJECTIVES: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological disease caused by genetic abnormalities that manifest during the development of T-cell precursors, encompassing 15% of pediatric and 25% of adult ALL cases. While T-ALL and its heterogeneous genomic landscape has been well-characterized by establishing different subtypes and risk stratification for patients, the expression and activity of microRNAs (miRNAs) in T-ALL have not been investigated as extensively as cytogenetic and genomic abnormalities. miRNAs are prospective biomarkers that can be critical in improving diagnostic measures for T-ALL, expanding risk categorizations of patients for select therapies, and as target candidates for interventional treatments. Certain miRNAs have been found to be dysregulated as a result of mechanisms underlying T-ALL pathophysiology, including aberrant signaling pathways and epigenetics. Through the implementation of more robust bioinformatics such as miRNA target prediction tools, next-generation sequencing, and standard molecular techniques, recent research has underscored the significant contribution of miRNAs toward the development and progression of T-ALL by altering canonical signaling pathways associated with T-ALL such as NOTCH1, mTOR, and PI3K/AKT. In this review, we summarize the recent findings surrounding the expression and activity of dysregulated miRNAs and how they contribute to the onset and course of disease in T-ALL. As dysregulated miRNAs have been shown to elicit positive and negative responses, the dual effects of miRNAs demand additional research to elucidate miRNAs for target treatments in addition to profiling T-ALL further as a malignant disease.

T-Cell Acute Lymphoblastic Leukemia: A Cytogenomic Update.

OBJECTIVES: T-cell acute lymphoblastic leukemia (T-ALL) is a pervasive hematologic malignancy that arises from developmental and genetic abnormalities manifested in lymphoblasts belonging to the T-cell lineage. Responsible for 10-15% of pediatric acute lymphoblastic leukemia (ALL) and 25% of adult ALL patients, T-ALL is characterized not only by cytomorphic features, but also by the aberrant expression of specific genes critical to T-cell development. Such changes in the genome ultimately result in mutational and developmental cascades that alter the chromosomal constitution, the process of which are used to organize T-ALL cases into different subgroups according to specific gene expression signatures. Clinically, comprehensive categorizations are important in risk stratification, assessment, and treatment protocols. Notable genetic subgroups include that of TAL, TLX1, TLX3, HOXA, MYB, ETP and NKX2. Current research also recognizes phenotypic and immunologic categories, such as ALK-positive ALCL, ALK-negative ALCL, BIA ALCL, AITL, and PTCL, NOS, which has revolutionized our understanding of T-cell lymphoma. Furthermore, it has been suggested that most T-ALL patients present with abnormal NOTCH1 genes in addition to mutations involving the JAK-STAT signaling pathway. These abnormalities are associated with the regulatory malfunction of T-cell development as well as that of their respective tumor suppressors and oncogenes. While recent studies have revealed characteristic defects in T-ALL, the interactions between oncogenes and their tumor suppressors with leukemia development are not well known as the signaling pathways involved behind each genetic lesion have yet to be fully explored. Studies involving FISH, RT-PCR, aCGH, and NGS offer novel perspectives to potentially learn more about the pathogenesis and cytogenetics of T-ALL, a field that demands further attention and research.

A Case of a Lymphoplasmacytic Lymphoma with Trisomy 12 in the Lymphoid Population and Deletion 13q in the Unstimulated Cell Culture.

OBJECTIVES: Lymphoplasmacytic lymphoma (LPL, previously termed lymphoplasmacytoid lymphoma) is an uncommon mature B-cell lymphoma usually involving the bone marrow and less commonly the spleen and/or lymph nodes. The majority of patients with LPL have a circulating monoclonal immunoglobulin M (IgM) that can lead to a hyperviscosity syndrome known as Waldenström macroglobulinemia (WM). Although LPL appears to be a sporadic disease in the majority of cases, a familial predisposition is present in some cases. The main chromosomal abnormalities are trisomy 12, trisomy 3, isochromosome 6p, and 14q rearrangements involving IgH among complex karyotypes. Herein, we present an 89-year-old male patient who presents with LPL involving 80% of the marrow cellularity with circulating lymphoma cells. Chromosomal analysis detected two unrelated abnormal clonal populations: one clone has trisomy 12 as the sole abnormality in the stimulated culture, while the other clone has a 13q deletion as the sole abnormality in the cells from the non-stimulated culture. Trisomy 12 is one of the most common abnormalities in B-CLL and it is associated with an intermediate prognosis. Deletions 13q have been identified in B-cell malignancies, non-Hodgkin's lymphomas (NHL), as well as myelodysplastic syndromes and chronic myeloproliferative neoplasms (Heim and Mitelman, 2015). Trisomy 12/13q- FISH slide was reviewed looking at the segmented cells. Fifty segmented cells were scored and a 13q- pattern was detected in 36% (18/50) of the cells suggesting that this finding (the 13q- clone) may be myeloid in origin. Clinicopathologic correlation of these results was recommended.

Molecular Cytogenetic Characterization of a Complex Karyotype of a Pediatric Male Patient with B-Acute Lymphoblastic Leukemia.

OBJECTIVES: B-Acute lymphoblastic leukemia (B-ALL) is a malignant disease that arises from several cooperative genetic mutations in a single B-lymphoid progenitor, leading to altered blast cell proliferation, survival and maturation, and eventually the lethal accumulation of leukemic cells. B-ALL accounts for about 12% of all childhood and adult leukemias diagnosed in developed countries, and 60% of those diagnosed are patients younger than 20 years old. As the most common cancer in children (25% of all cases) with a peak incidence in patients between the ages of two and five years, with a second, smaller peak in the elderly, the factors predisposing children and adults to ALL remain largely unknown. Herein we present an eight-year-old male patient diagnosed with B-ALL. Chromosome studies of 20 G-banded metaphases of the bone marrow detected an abnormal male karyotype with loss of 9p [i(9)(q10)] and loss of 17p [der(17)(?::17q11.2->17p11.2::17p11.2->17qter)] within the context of a complex karyotype in eight metaphase cells. Four of these abnormal metaphases showed additional material of unknown origin on chromosome 12 at p11.2 [add(12)(p11.2)]. Metaphase FISH analysis was crucial to characterize such complex chromosomal abnormalities, underscoring the importance of molecular cytogenetics in characterizing complex karyotypes in this hematological malignancy.