Pharmacological therapies for male infertility.

Male factor infertility is a multifaceted problem that affects approximately 50% of couples suffering from infertility. Causes of male infertility include endocrine disturbances, gonadotoxins, genetic abnormalities, varicocele, malignancies, infections, congenital or acquired urogenital abnormalities, iatrogenic factors, immunological factors, and idiopathic reasons. There are a variety of treatment options for male infertility, depending on the underlying cause(s). These can include surgical treatments, medical/hormonal therapies, and assisted reproductive techniques (ART), which can be combined with surgical sperm retrieval (SSR) if necessary. In this review article, the pharmacological therapies for male infertility are grouped by their underlying causes. Some of these therapies are targeted and specific, while others are used empirically to treat idiopathic male infertility. This will include treatments to optimize infertility in patients who have hypogonadism, ejaculatory dysfunction, infections, or idiopathic male infertility. Finally, we will provide an overview of the future directions of pharmacological therapies for male infertility. Significance Statement Male infertility is a significant worldwide problem. Detailed knowledge of the pharmacological therapies available will ensure the prescription of appropriate therapy and avoid the use of unnecessary or harmful treatments.

Impact of the COVID-19 pandemic on delivery of prostate cancer care in Australia: An interrupted time series analysis.

The COVID-19 pandemic led to a major disruption to health services across the world. The aim of this population-based study was to assess the downstream effects of the pandemic on diagnostic tests and treatment activities related to prostate cancer (PC). The Australian Government Department of Health Medicare Benefits Schedule and the Pharmaceutical Benefits Scheme databases were queried from January 2010 to June 2022. Two interrupted time series were performed Pre-COVID (January 2010 to February 2020) and peri-COVID (March 2020 to June 2022). Temporal modeling was performed to account for seasonal variation. Pre-COVID-19, monthly prostate-specific antigen (PSA) testing showed a declining trend and testing decreased by 81 tests per 100 000 annually. A single-month 38% drop in PSA testing was observed in April 2020; this corresponded to Australia's first wave. No change was observed in the rate of prostate biopsies. Peri-COVID-19 outbreaks, there was a slight shift toward the use of long-acting androgen deprivation therapy (ADT) at 4% with a predilection still for short-acting agents. with no registered change in the overall volume of radiotherapy or surgery. There were no deficits in the number of diagnostic and treatment activities for men with PC. Aside from a slight shift toward long-acting ADT use during the pandemic, no other patterns were observed. The longer-term impact such as missed diagnosis or late presentation affecting chances of survival due to COVID-19 is yet to be ascertained.

Systematic review and network meta-analysis of re-intervention rates of new surgical interventions for benign prostatic hyperplasia.

OBJECTIVE: To assess the re-intervention rates of new surgical benign prostatic hyperplasia (BPH) interventions, as the clinical durability of new surgical interventions for BPH is not widely known. METHODS: A critical review of new surgical BPH therapies namely 'UroLift®', 'Aquablation', 'Rezum', 'prostatic artery embolisation (PAE)' and 'temporary implantable nitinol device (iTIND)' was performed on PubMed, the Cochrane Library, and Embase databases between May 2010 and December 2022 according to the Preferred Reporting Items for Systematic Review and Meta-analyses (PRISMA) statement. All relevant articles were reviewed, and the risk of bias was evaluated using the Cochrane risk assessment tool and Newcastle-Ottawa Scale. RESULTS: Of the 32 studies included, there were 10 randomised controlled trials and 22 prospective observational cohorts. A total of 2400 participants were studied with a median patient age of 66 years, a median prostate volume of 51.9 mL, and a median International Prostate Symptom Score of 22. The lowest re-intervention rate at 12 months was for Aquablation at 0.01%, followed by Rezum at 0.02%, iTIND at 0.03%, and PAE at 0.05%. Network meta-analysis (NMA) showed that the best-ranked treatment at 12 months was transurethral resection of the prostate (TURP), followed by Aquablation, iTIND, Rezum, and UroLift. Re-intervention rates with these new BPH interventions are comparable, although some interventions reported better outcomes than TURP in the shorter term. CONCLUSIONS: While this systematic review and NMA showed that the re-intervention rate with these new surgical BPH interventions appears to be comparable to TURP in the short term, further studies are required to directly compare these various BPH procedures.

Safety and efficacy of an α1 -blocker plus mirabegron compared with an α1 -blocker plus antimuscarinic in men with lower urinary tract symptoms secondary to benign prostatic hyperplasia and overactive bladder: A systematic review and network meta-analysis.

AIM: Antimuscarinics and the ß3-adrenoreceptor agonist, mirabegron, are commonly used for treating patients with overactive bladder (OAB) and α1 -adrenoreceptor antagonists (α1 -blockers) are the main pharmacological agents used for treating lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH). As these conditions commonly occur together, the aim of this systematic review was to identify publications that compared the use of an α1 -blocker plus mirabegron with an α1 -blocker plus antimuscarinic in men with LUTS secondary to BPH and OAB. A meta-analysis was subsequently conducted to explore the safety and efficacy of these combinations. METHODS: Included records had to be from a parallel-group, randomized clinical trial that was ≥8 weeks in duration. Participants were male with LUTS secondary to BPH and OAB. The indirect analyses that were identified compared an α1 -blocker plus OAB agent with an α1 -blocker plus placebo. The PubMed/Medical Literature Analysis and Retrieval System Online, the Excerpta Medica Database, the Cochrane Central Register of Controlled Trials, and the ClinicalTrials.gov registry were searched for relevant records up until March 5, 2020. Safety outcomes included incidences of overall treatment-emergent adverse events (TEAEs) and urinary retention, postvoid residual volume, and maximum urinary flow (Qmax ). Primary efficacy outcomes were micturitions/day, incontinence episodes/day, and urgency episodes/day, and secondary outcomes were Overactive Bladder Symptom Score and International Prostate Symptom Score. A Bayesian network meta-analysis approach was used for the meta-analysis. RESULTS: Out of a total of 1039 records identified, 24 were eligible for inclusion in the meta-analysis. There were no statistically significant differences between the α1 -blocker plus mirabegron and α1 -blocker plus antimuscarinic groups in terms of the comparisons identified for all the safety and efficacy analyses conducted. Numerically superior results were frequently observed for the α1 -blocker plus mirabegron group compared with the α1 -blocker plus antimuscarinic group for the safety parameters, including TEAEs, urinary retention, and Qmax . For some of the efficacy parameters, most notably micturitions/day, numerically superior results were noted for the α1 -blocker plus antimuscarinic group. Inconsistency in reporting and study variability were noted in the included records, which hindered data interpretation. CONCLUSION: This systematic review and meta-analysis showed that an α1 -blocker plus mirabegron and an α1 -blocker plus antimuscarinic have similar safety and efficacy profiles in male patients with LUTS secondary to BPH and OAB. Patients may, therefore, benefit from the use of either combination within the clinical setting.

Seroprevalence and contributing factors of transboundary animal diseases in sheep and goats: a study in Peninsular Malaysia.

Diseases caused by small ruminant lentiviruses, Mycobacterium avium ssp. paratuberculosis (MAP), Schmallenberg virus, and peste des petits ruminants virus (PPR) is globally recognised as serious threats to the ruminant industry due to their potential to spread rapidly across boundaries. Despite their global distribution and negative impacts on ruminant production, there is a gap in knowledge of the current trends in their epidemiology among sheep and goat populations in Peninsular Malaysia. This study was therefore designed to fill the gap of knowledge concerning the seroprevalence and contributing factors of CAEV, paratuberculosis, SBV, and PPRV among small ruminants from selected flocks in Selangor, Negeri Sembilan, and Pahang states in Peninsular Malaysia. A cross-sectional study design was used to collect animal data and blood samples for serological assays simultaneously. The ID Screen (ID.VET, France) indirect ELISA screening tests were used to detect serum antibodies directed against CAEV/MVV (VISNAS Ver 0922), paratuberculosis (PARAS Ver 0516), SBV (SBVC Ver 1114) and PPRV (PPRC Ver 0821). There was 45.4% (95% CI = 40.74-50.74), 6.8% (95% CI = 4.66-9.69), 27.8% (95% CI = 23.35-32.77), and 2.6% (95% CI = 1.11-0.51) true seroprevalence for CAEV, paratuberculosis, SBV, and PPR, respectively. Geographical location and species were the risk factors for CAEV and paratuberculosis, while the management system and age of small ruminants were the risk factors for SBV. The present study is the first to document a large-scale seroprevalence of MAP and PPR infection among sheep and goat flocks in Peninsular Malaysia. The presence of PPRV and MAP antibodies among small ruminant flocks is signalling current or previous exposure to the pathogens or cross reactions with similar antigens. This finding further suggests the potential for future outbreaks of these devastating diseases among sheep and goats in Malaysia. The high seroprevalence of CAEV and SBV among small ruminants indicates high levels of exposure to the viruses in the environment, which is a potential threat to production.

Initial safety outcomes for the Rigicon Infla10® inflatable penile prosthesis.

OBJECTIVE: To analyse data from patient information forms (PIFs) submitted to the manufacturer of a new three-piece inflatable penile prosthesis (IPP), the Rigicon Infla10®, to summarize early outcomes. METHODS: A retrospective review of PIFs from 319 patients implanted with the IPP between 6 January 2019 and 31 December 2021 was performed to assess device durability and rates of reoperation for infection, mechanical failure or medical reasons. RESULTS: The mean ± sd (range) follow-up was 21.2 ± 11 (5-36) months and the mean ± sd patient age was 58.5 ± 8.7 years. Of the total, 4.4% of devices required removal or revision. Complications included mechanical failure (2.5%) and component migration (0.7%). No infections were observed in this series. One patient (0.4%) required revision for inadequate straightening of Peyronie's disease. Three patients (0.9%) requested device removal because of dissatisfaction. A total of 95.6% of the Rigicon Infla10 devices were free from explant or revision 21 months after the original implant date. Kaplan-Meier analysis showed the rates of cumulative survival of the device at 12, 24, 36 months were 95.6%, 94.7% and 93.7%, respectively. CONCLUSIONS: The vast majority of the early Rigicon Infla10 IPPs implanted prior to January 2022 were included in this retrospective analysis of volunteered PIFs. These early results demonstrate initial durability from reoperation equivalent to that of other contemporary devices.

Postvaricocele Embolization Pain Syndrome: A Case Series Report and Review of Current Treatment Strategies.

BACKGROUND: Orchialgia is not an uncommon complaint among men with varicocele, but postvaricocele embolization-related testicular pain has not been widely investigated. This study evaluates the phenomenon of postvaricocele embolization pain (PVEP) syndrome and examines the current strategies to treat this unusual complication. METHODS AND MATERIALS: A prospectively collected database of patients with PVEP who presented to a tertiary center was analyzed between January 2011 and January 2020 following internal ethics approval. Patient demographics, including other complications related to embolization, analgesic requirements, and pain scores (on a 10-point visual analog score), treatment strategies, Patient Global Impression of Improvement (PGI-I) score and overall satisfaction score (on a 5-point scale), were reviewed. All patients were reviewed for a minimum of 12 months. RESULTS: A total of 20 men with a mean age of 33.8 (18-45) years old, presented with PVEP over 10 years. Most men received embolization on an average of 26.6 (18-48) months. The reasons for varicocele embolization include either isolated or combined orchialgia (15 men), subfertility (5 men), and cosmesis (6 men). Eighteen (90%) men underwent microscopic spermatic cord denervation (MSCD) and 2 patients elected for conservative measures. The average pain scores pre-MSCD and post-MSCD were 6.9 (4-9) and 1.4 (0-4) (p<0.001) with a significant reduction in analgesia requirements. Immediate improvement in pain score was reported in all the patients and this persisted at the 12 months review. Most men reported a high satisfaction score (of 4/5) and only one patient reported no change in symptoms after MSCD. CONCLUSION: PVEP is a unique complication and patients should be counseled on the potential risk of persistent orchialgia following embolization for varicocele. The MSCD appears to be an effective treatment option with high success and satisfaction rates.

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.

Pro-inflammatory cytokines and reproductive hormone responses in bucks post-challenge with Mannheimia haemolytica A2 and its outer membrane protein.

The lipopolysaccharide (LPS) endotoxin and outer membrane protein (OMP) are among the virulence factors of Gram-negative bacteria responsible for inducing pathogenicity in the infected host. OMP and LPS occur on the outer membrane of M. haemolytica A2, the primary aetiological agent of pneumonic mannheimiosis in small ruminants. While the LPS is known to mediate Gram-negative bacterial infection by activating downstream inflammatory pathways, the potential role of OMP during inflammatory responses remained unclear. Hence, this study determined the effect of the OMP of M. haemolytica A2 on the serum concentration of pro-inflammatory cytokines and the male reproductive hormones (testosterone and Luteinizing Hormone). We randomly assigned twelve bucks to three groups (n = 4 bucks each): Group 1 was challenged with 2 mL PBS buffer (pH 7.0) intranasally; Group 2 received 2 mL of 1.2 X 109 CFU/mL whole M. haemolytica A2 intranasally; and Group 3 received 2 mL of OMP extract obtained from 1.2 X 109 CFU/mL M. haemolytica A2 intramuscularly. Serum samples collected at pre-determined intervals were used for the quantitative determination of the pro-inflammatory cytokines (IL-1ß, IL-6, and TNFα) and reproductive hormones (testosterone and LH) using commercial sandwich enzyme-linked immunosorbent assay (ELISA). The serum concentration of IL1ß was initially increased within the first-hour post-challenge in Groups 2 and 3, followed by a significant decrease in concentration at 21d and 35d (p < 0.05) in Group 3. Only mild fluctuations in IL-6 occurred in group 2, as opposed to the 1.7-fold rapid increase in TNFα within 2 h post-challenge before decreasing at 6 h. An increase in pro-inflammatory cytokines was accompanied by an acute febrile response of 39.5 ± 0.38 °C (p < 0.05) at 2 h and 40.1 ± 0.29 °C (p < 0.05) at 4 h in Group 2 and Group 3, respectively. Serum testosterone decreased significantly (p < 0.05) in both treatment groups but remained significantly (p > 0.05) lower than in Group 1 throughout the study. There was a moderate negative association between testosterone and IL1ß (r = -0.473; p > 0.05) or TNFα (r = -0.527; p < 0.05) in Group 2. Serum LH also showed moderate negative associations with TNFα in Group 2 (r = -0.63; p < 0.05) and Group 3 (r = -0.54; p > 0.05). The results of this study demonstrated that M. haemolytica A2 and its OMP produced marked alterations in serum levels of pro-inflammatory cytokines and male reproductive hormones. The negative correlations between serum testosterone and inflammatory cytokines would suggest the potential role of OMP in causing male infertility by mediating innate inflammatory responses to suppress testosterone production in bucks.

Responses of selected biomarkers, female reproductive hormones and tissue changes in non-pregnant does challenged with Mannheimia haemolytica serotype A2 and its outer membrane protein (OMP) immunogen.

BACKGROUND: Mannheimia haemolytica causative agent of pneumonic mannheimiosis, a common respiratory disease of goat and sheep, which cause huge economic losses to farmers worldwide. Pneumonic mannheimiosis caused by M. haemolytica serotype A2 has been reported among small ruminants in Malaysia. The lipopolysaccharide (LPS) and outer membrane protein (OMP) are major virulence determinants for M. haemolytica serotype A2. Although pneumonic mannheimiosis is known to cause poor reproductive performance in small ruminants under field conditions, there is a dearth of published information on the specific effects of M. haemolytica serotype A2 infection on the female reproductive physiology. In this experiment, we explored the impact of M. haemolytica serotype A2 and its OMP immunogen on selected pro-inflammatory cytokines, acute phase proteins, female reproductive hormones, and cellular changes in visceral and female reproductive organs of non-pregnant does. METHODOLOGY: Twelve healthy, non-pregnant, Boer crossbreds does were divided equally into three groups (n = 4); Group 1 served as the negative control and was challenged with 2 ml of sterile PBS intranasally. Group 2 served as the positive control and was challenged with 2 ml of 109 colonies forming unit (CFU) of M. haemolytica serotype A2 suspension intranasally. Group 3 was challenged with 2 ml of OMP extracted from 109 CFU of M. haemolytica A2 intramuscularly. The experimental does were monitored for clinical signs and responses periodically. Blood samples were collected at 0, 1, 2, 4, 6, 12 and 24 h and 3, 7, 21, 35 and 56 days post treatment for serological analyses. All does were euthanised using the halal slaughter method on day 60 post challenge/treatment. Tissues from the uterus, liver, lung and associated bronchial lymph nodes were collected and fixed in 10% formalin for 14 days for histopathological study. RESULTS: Compared to the control group, the challenged/treated groups showed significant (p < 0.05) increase in the rectal temperature, respiratory rate, heart rate, and rumen motility. Serum analyses revealed that the concentrations of progesterone and estrogen hormones were significantly (p < 0.05) decreased in groups 2 & 3. In contrast, the concentrations of pro-inflammatory cytokines (IL-1ß and IL-6) and acute phase proteins (Hp and SAA) were significantly increased (p < 0.05) in the challenged/treated groups compared to the control group. Histopathological lesion scoring revealed mild to moderate cellular changes characterised by congestion, haemorrhage, degeneration, leucocytic cellular infiltration, and cellular necrosis in the tissues of does from the OMP treatment and bacterial challenge groups compared to the control group. CONCLUSION: The findings from this study suggests that M. haemolytica serotype A2 and its OMP immunogen induced mild to moderate inflammatory and degenerative changes which may potentially interfere with fertilization through hormonal imbalances and cause temporary loss of fertility in infected does.

Pathologic primary tumor factors associated with risk of lymph node involvement in patients with non-endometrioid endometrial cancer.

PURPOSE/OBJECTIVES: Lymph node (LN) involvement is an important factor in guiding adjuvant treatment for patients with endometrial cancer. Risk factors for LN involvement are fairly well-established for endometrial adenocarcinoma, but it is not as well defined whether these factors similarly predict LN positivity in less common histologies. MATERIALS/METHODS: Patients diagnosed with pathologic T1-T2 carcinosarcoma, clear cell, uterine papillary serous carcinoma (UPSC), and mixed histologic type endometrial cancer between 2004 and 2016 undergoing primary surgery with at least 1 lymph node sampled in the National Cancer Data Base were identified. Logistic regression was performed to identify primary pathologic tumor predictors of LN positivity. Nomograms were created to predict overall, pelvic only, and paraaortic with or without pelvic LN involvement. RESULTS: Among 11,390 patients included, 1950 (18%) were node positive. On multivariable analysis, increasing pathologic tumor stage (pT2 versus pT1a, odds ratio [OR] 3.63, 95% confidence interval [CI] 3.15-4.18, p < 0.001), increase in tumor size per centimeter (OR 1.08, 95% CI 1.06-1.10, p < 0.001), and the presence of lymphovascular invasion (LVI) (OR 4.97, 95% CI 4.43-5.57, p < 0.001) were predictive of overall LN positivity. Relative to carcinosarcoma, both clear cell (OR 1.54, 95% CI 1.22-1.95, p < 0.001) and UPSC (OR 1.73, 95% CI 1.48-2.02, p < 0.001) histology were significantly associated with a higher risk of LN positivity while mixed histology was not (OR 1.07, 95% CI 0.92-1.24, p = 0.42). CONCLUSION: Among patients with non-endometrioid endometrial cancer, predictors of LN positivity are similar to endometrial adenocarcinoma. The nomograms provided could be helpful in making adjuvant treatment decisions for these less common histologies.

Quality Improvement Report: Safety Program for Prevention of Central Line-associated Bloodstream Infections.

The increasing usage of peripherally inserted central catheters (PICCs) in medical imaging departments has led to a corresponding increase in cases of central line-associated bloodstream infection (CLABSI). However, this condition is preventable with proper monitoring and use of aseptic techniques. A Comprehensive Unit-based Safety Program (CUSP) is a quality improvement (QI) measure implemented by health care institutions to reduce the incidence of CLABSI. However, effective strategies have yet to be established. The authors describe a QI project that evaluated the implementation of CUSP at a teaching hospital to reduce PICC-associated bloodstream infection (BSI). The framework consists of a five-step process: understand and train staff on the science of safety, assemble a team, engage senior executives, identify defects through sensemaking, and implement teamwork and communication strategies in a series of related and sequential steps that use QI tools. Targets were identified for improvement from existing processes, and the workflow was reengineered. Nine months after the start of the CUSP intervention, PICC-associated BSI incidence in the hospital had been reduced from 3.4 to 2.7 per 1000 central lines days after intervention. The incidence of BSI was also reduced correspondingly from 8.8% to 5.9%. The QI processes in this study may be adopted by other hospitals, as they involve minimal cost with significant impact on patient safety and well-being. The QI sequential steps described capture the implementation processes that can be modified for use in other department settings where patient safety could be compromised. Online supplemental material is available for this article. ©RSNA, 2022.

International Continence Society (ICS) report on the terminology for sexual health in men with lower urinary tract (LUT) and pelvic floor (PF) dysfunction.

INTRODUCTION: The terminology for sexual health in men with lower urinary tract (LUT) and pelvic floor (PF) dysfunction has not been defined and organized into a clinically based consensus terminology report. The aim of this terminology report is to provide a definitional document within this context that will assist clinical practice and research. METHODS: This report combines the input of the members of sexual health in men with LUT and PF Dysfunction working group of the International Continence Society (ICS), assisted at intervals by external referees. Appropriate core clinical categories and a sub-classification were developed to give coding to definitions. An extensive process of 18 rounds of internal and external review was involved to exhaustively examine each definition, with decision-making by collective opinion (consensus). The Committee retained evidence-based definitions, identified gaps, and updated or discarded outdated definitions. Expert opinions were used when evidence was insufficient or absent. RESULTS: A terminology report for sexual health in men with LUT and PF dysfunction, encompassing 198 (178 NEW) separate definitions, 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 speciality groups involved. Conservative and surgical managements are major additions and appropriate figures have been included to supplement and clarify the text. Emerging concepts and measurements, in use in the literature and offering further research potential, but requiring further validation, have been included as an appendix. Interval (5-10 years) review is anticipated to keep the document updated. CONCLUSION: A consensus-based terminology report for sexual health in men with LUT and PF dysfunction has been produced to aid clinical practice and research. The definitions that have been adopted are those that are most strongly supported by the literature at this time or are considered clinical principles or consensus of experts' opinions.

Urological Society of Australia and New Zealand (USANZ) and Australasian Chapter of Sexual Health Medicine (AChSHM) for the Royal Australasian College of Physicians (RACP) clinical guidelines on the management of erectile dysfunction.

INTRODUCTION: These clinical practice recommendations by the Urological Society of Australia and New Zealand (USANZ) and the Australasian Chapter of Sexual Health Medicine (AChSHM) for the Royal Australasian College of Physicians (RACP) provide evidence-based clinical guidelines on the management of erectile dysfunction (ED) in Australia. MAIN RECOMMENDATIONS: A comprehensive clinical history and a tailored physical examination are essential (Level of evidence [LoE] 3; GRADE B). Laboratory testing should include fasting glucose, lipid profile and total testosterone level (LoE 3; GRADE A). Specialised diagnostic tests are recommended in selected cases and the patient should be counselled accordingly (LoE 4; GRADE B). Lifestyle changes and optimisation of existing medical conditions should accompany all ED treatment regimens (LoE 1; GRADE A). Oral phosphodiesterase type 5 inhibitor (PDE5i) is an effective first line medical therapy (LoE 1; GRADE A). Intracavernosal injections and vacuum erection devices are recommended as second line therapy (LoE 1; GRADE B). A penile prosthesis implant can be considered in men who are medically refractory or unable to tolerate the side effects of medical therapy (LoE 4; GRADE B). Pro-erectile regenerative therapy remains largely experimental (LoE 3; GRADE B). CHANGES IN MANAGEMENT AS A RESULT OF THESE GUIDELINES: Modification of lifestyle behaviour, management of reversible risk factors and optimisation of existing medical conditions remain pivotal, and existing standard ED therapies are often effective and safe following cardiovascular risk stratification. Caution should be exercised on the use of regenerative technology in ED due to unknown long term outcomes.

Fundoplication in children with esophageal atresia: preoperative workup and outcome.

Up to 45% of esophageal atresia (EA) patients undergo fundoplication during childhood. Their esophageal dysmotility may predispose to worse fundoplication outcomes compared with patients without EA. We therefore compared fundoplication outcomes and symptoms pre- and post-fundoplication in EA patients with matched patients without EA. A retrospective review of patients with- and without EA who underwent a fundoplication was performed between 2006 and 2017. Therapeutic success was defined as complete sustained resolution of symptoms that were the reason to perform fundoplication. Fundoplication indications of 39 EA patients (49% male; median age 1.1 [0.1-17.0] yrs) and 39 non-EA patients (46% male; median age 1.3 [0.3-17.0] yrs) included respiratory symptoms, brief resolved unexplained events, typical symptoms of gastroesophageal reflux disease, recurrent strictures and respiratory problems. Post-fundoplication, therapeutic success was achieved in 5 (13%) EA patients versus 29 (74%) non-EA patients (P<0.001). Despite therapeutic success, all 5 (13%) EA patients developed postoperative sustained symptoms/complications versus 12 (31%) non-EA patients. Eleven (28%) EA patients versus 3 (8%) non-EA patients did not achieve any therapeutic success (P=0.036). Remaining patients achieved partial therapeutic success. EA patients suffered significantly more often from postoperative sustained dysphagia (41% vs. 13%; P=0.039), gagging (33% vs. 23%; P<0.001) and bloating (40% vs. 17%; P=0.022). Fundoplication outcomes in EA patients are poor and EA patients are more susceptible to post-fundoplication sustained symptoms and complications compared with patients without EA. The decision to perform fundoplication in EA patients with proven gastroesophageal reflux disease needs to be made with caution after thorough multidisciplinary evaluation.

Seminal and histopathological alterations in bucks challenged with Mannheimia haemolytica serotype a2 and its LPS endotoxin.

Pneumonic mannheimiosis is a widespread respiratory bacterial disease of small ruminants caused by Mannheimia haemolytica serotype A2. The disease is known to affect the respiratory organs of infected animals, but its effect on other vital and reproductive organs has not been fully explored. Previous studies have demonstrated increased serum pro-inflammatory cytokine concentration post-challenge with M. haemolytica A2 and its LPS, indicating systemic inflammation in the host. This study determined the potential tissue changes and alterations of sperm parameters due to infection of M. haemolytica A2 and its LPS endotoxin. In this study, twelve experimental bucks were randomly assigned to three groups of four bucks each: group 1 (control group) were intranasally inoculated with 2 mL of PBS pH 7.0, group 2 received 2 mL of 1.2 × 109 CFU/mL M. haemolytica A2 intranasally, and group 3 received 2 mL of LPS extracted from 1.2 × 109 CFU/mL of M. haemolytica A2 intravenously. Semen samples were collected at pre-determined intervals using an electro-ejaculator and analysed immediately after collection. All experimental bucks were slaughtered via exsanguination on day 60 to collect their vital and reproductive organs at necropsy, and the samples were processed and analysed for histopathological changes. The current study has revealed that bucks challenged with M. haemolytica A2 and its LPS exhibited alterations in semen parameters such as motility, wave pattern, viability, and morphological abnormalities. Mild to moderate histopathological changes of the lung, liver, testis, epididymis, vas deferens, prostate, and lymph nodes were also observed in both challenged groups. Therefore, this study revealed the potential harmful effects of respiratory mannheimiosis on the reproductive organs of the infected bucks and sheds light on the expanse of systemic effects of this disease.

Effect of Brachiaria decumbens as a novel supplementation on the production performance of broiler chickens.

The primary goal of this research was to elucidate the novel influence of Brachiaria decumbens supplementation on broiler chicken growth performance, nutritional digestibility, cecal microbiota, intestinal histomorphology, carcass characteristics, and meat quality. A total of 300 male day-old Ross 308 broiler chickens were randomly subjected to six different treatment groups having five replicates per treatment with 10 birds in each replicate. In treatment 1, broiler chickens were fed commercial diets with no added additives; in treatment 2, broiler chickens were offered commercial diets containing 100 mg/kg of the antibiotic oxytetracycline. However, in treatments 3, 4, 5, and 6, broiler chickens received similar commercial diets supplemented with 25 mg/kg, 50 mg/kg, 75 mg/kg, and 100 mg/kg of B. decumbens ground leaf powder, respectively, without antibiotics. Throughout the 42-day trial, the body weight gain and total feed intake for each replicate were recorded every week to determine the growth performance. Then, on 21th and 42nd day, ten broilers from each treatment (two in each replicate) were randomly selected and slaughtered to assess the digestibility of nutrients, histomorphology of the small intestine, the population of the cecal microbiota, carcass characteristics, as well as quality of both breast and drumstick muscle. There were differences (p < 0.05) in the growth performance, apparent ileal nutrient digestibility, intestinal histomorphology, carcass characteristics, and meat quality. Animals supplemented with 25 mg/kg of B. decumbens had higher growth performance and better ileal nutrient digestibility of protein, fiber, and ether extract, as well as higher villi height and carcass percentage with superior meat quality. Besides, the growth of E. faecalis during the starter phase was inhibited. In summary, B. decumbens supplementation at 25 mg/kg may be suggested as an optimal dose of as a prophylactic as well as an alternative for antibiotic growth promoter in stimulating the productivity of commercial broilers. This unconventional phytobiotic supplementation could be the key to replacing unnecessary antibiotics used in poultry feed.

Changes in selected cytokines, acute-phase proteins, gonadal hormones and reproductive organs of non-pregnant does challenged with Mannheimia haemolytica serotype A2 and its LPS endotoxin.

Previous investigations have revealed that lipopolysaccharide (LPS) endotoxin from certain Gram-negative bacteria could adversely affect the reproductive system of female animals. However, it is unknown whether LPS endotoxin of Mannheimia haemolytica serotype A2, the principal causative bacteria that cause pneumonic mannheimiosis in small ruminants, may also induce similar insidious effects. Therefore, this study aimed to investigate the effects of M. haemolytica serotype A2 and its LPS endotoxin on the responses of female gonadal hormones (progesterone and oestrogen), pro-inflammatory cytokines (interleukin-1ß, interleukin-6), acute-phase proteins (haptoglobin and serum amyloid A) and cellular changes via histopathology study of female reproductive organs of the treatment does. Twelve clinically healthy, non-pregnant, crossbred does were randomly allocated into three equal groups. Group 1 was administered intranasally with 2 ml of sterile phosphate-buffered saline (PBS) and served as a negative control group. Group 2 was challenged intranasally with 2 ml of bacterial inoculum containing 109 colony-forming units (CFU)/ml of M. haemolytica serotype A2, while Group 3 was challenged intravenously with 2 ml of LPS endotoxin extracted from 109 CFU/ml of M. haemolytica serotype A2. Following that, blood samples were collected serially at pre-determined intervals for serological analyses. All does were euthanised 60 days post-challenges, and tissue samples from the ovaries, oviducts, uterine horns, uterine body, cervix and vagina were collected for histopathological study. The serological result revealed a significant increase (p < 0.05) in the mean concentrations of progesterone, oestrogen, interleukin-1ß, interleukin-6, haptoglobin and serum amyloid A for both challenged groups. Histopathologically, all reproductive organs (except the cervix and vagina) from both challenged groups displayed significant cellular alterations (p < 0.05) characterised by haemorrhage and congestion, necrosis and degeneration, inflammatory cell infiltration and oedema. This study provides new information that elucidates the potential role of pneumonic mannheimiosis in the pathogenesis of female infertility amongst small ruminants.

Protein phosphatase 2A activation as a therapeutic strategy for managing MYC-driven cancers.

The tumor suppressor protein phosphatase 2A (PP2A) is a serine/threonine phosphatase whose activity is inhibited in most human cancers. One of the best-characterized PP2A substrates is MYC proto-oncogene basic helix-loop-helix transcription factor (MYC), whose overexpression is commonly associated with aggressive forms of this disease. PP2A directly dephosphorylates MYC, resulting in its degradation. To explore the therapeutic potential of direct PP2A activation in a diverse set of MYC-driven cancers, here we used biochemical assays, recombinant cell lines, gene expression analyses, and immunohistochemistry to evaluate a series of first-in-class small-molecule activators of PP2A (SMAPs) in Burkitt lymphoma, KRAS-driven non-small cell lung cancer, and triple-negative breast cancer. In all tested models of MYC-driven cancer, the SMAP treatment rapidly and persistently inhibited MYC expression through proteasome-mediated degradation, inhibition of MYC transcriptional activity, decreased cancer cell proliferation, and tumor growth inhibition. Importantly, we generated a series of cell lines expressing PP2A-dependent phosphodegron variants of MYC and demonstrated that the antitumorigenic activity of SMAPs depends on MYC degradation. Collectively, the findings presented here indicate a pharmacologically tractable approach to drive MYC degradation by using SMAPs for the management of a broad range of MYC-driven cancers.

Biomarkers, immune responses and cellular changes in vaccinated and non-vaccinated goats during experimental infection of M. haemolytica A2 under tropical conditions.

BACKGROUND: We investigated the biomarkers, immune responses and cellular changes in vaccinated and non-vaccinated goats experimentally challenged with M. haemolytica serotype A2 under rainy and hot tropical conditions. A total of twenty-four clinically healthy, non-pregnant, female goats randomly allocated to 2 groups of 12 goats each were used for the study. The 12 goats in each season were subdivided into three groups (n = 4), which served as the control (G-NEG), non-vaccinated (G-POS), and vaccinated (G-VACC). In week-1, the G-VACC received 2 mL of alum-precipitated pasteurellosis vaccine while G-POS and G-NEG received 2 ml of sterile PBS. In week 2, the G-POS and G-VACC received 1 mL intranasal spray containing 105 CFU of M. haemolytica serotype A2. Inoculation was followed by daily monitoring and weekly bleeding for eight weeks to collect data and serum for biomarkers and immune responses using commercial ELISA test kits. The goats were humanely euthanised at the end of the experiments to collect lungs and the submandibular lymph nodes tissue samples for gross and histopathological examinations. RESULTS: Regardless of the season, we have observed a significant (p < 0.05) increase in serum concentrations of acute-phase proteins (haptoglobin, serum amyloid A), proinflammatory cytokines (interleukine-1ß, interleukin-6), antibodies (immunoglobulin M, immunoglobulin G), and stress markers (cortisol and heat shock protein 70) in the G-POS goats compared to G-VACC and G-NEG. With regards to seasons, there was a significantly (p < 0.05) higher serum concentration with 1.5, 2 and 1-folds increase in the serum interleukin (IL)-1ß, cortisol, and heat shock protein (HSP)-70 in the G-POS during rainy compared to the hot season. Histopathology of the lungs in G-POS goats revealed inflammatory cell infiltration, degeneration, haemorrhage/congestion, and pulmonary oedema in the alveoli spaces; thickening of the interstitium, and desquamation of bronchiolar epithelium. Cellular changes in the lymph node were characterized by a marked hypercellularity in G-POS goats. CONCLUSION: Host responses to pneumonic mannheimiosis based on increased serum levels of biomarkers (cortisol, HSP70, IL-1ß and IL-6) and severe cellular changes seen in the lungs and lymph nodes of G-POS goats compared to vaccinated goats and control group are influenced by the high environmental humidity recorded in the rainy season. Increased relative humidity in the rainy season is a significant stress factor for the higher susceptibility and severity of pneumonic mannheimiosis of goats in the tropics. Vaccination of goats using the alum precipitated Pasteurella multocida vaccine before the onset of the rainy season is recommended to minimise mortality due to potential outbreaks of pneumonia during the rainy season.