The SUB-urothelial DUrvalumab InjEction-1 (SUBDUE-1) trial: first-in-human trial in patients with bladder cancer.

OBJECTIVES: To assess the safety of sub-urothelial injection of durvalumab and examine the impact on tissue and circulating immune cell populations. PATIENTS AND METHODS: The patients were chemotherapy and immunotherapy naïve (bacille Calmette-Guérin allowed) with non-metastatic muscle-invasive bladder cancer or non-muscle-invasive bladder cancer planned for radical cystectomy (RC). The study was a Phase Ib 3 + 3 dose-escalation design with sub-urothelial injection of durvalumab at three pre-determined doses (25, 75, 150 mg) diluted in 25 mL normal saline, injected at 25 locations (25 × 1 mL injections), at least 2 weeks before RC. RESULTS: A total of 11 patients were recruited (10 male, one female). No significant changes were reported on American Urological Association Symptom Score or O'Leary Interstitial Cystitis Scale. In all, 14 adverse events (AEs) were reported (10 Grade 1, three Grade 2, one Grade 3), none considered immune-related. No Grade 4 or 5 AEs were recorded. All the patients underwent RC. Tissue immune populations changed following durvalumab injection (P = 0.012), with a statistically significant increase in M2-macrophage (CD163) when comparing the 25-150 mg dose (P = 0.021). Basal/mixed cancers showed a larger CD163 increase than luminal cancers (P = 0.033). CONCLUSION: Sub-urothelial injection of durvalumab is feasible and safe without immune-related AEs and shows local immunological effects.

Malignant ureteral obstruction: comparison of metallic, 8 French and 6 French ureteric stents after failure of initial ureteric stent.

PURPOSE: Malignant ureteric obstruction is a significant management challenge. The failure of ureteric stents often leads to long-term nephrostomy tubes. This is delayed for as long as possible due to its' associated morbidity. Several types of ureteric stents are available, however there is little evidence demonstrating which stents are better for preventing progression to nephrostomy tubes. This study looked to determine whether a new 6 French (Fr) polymer stent, 8Fr polymer stent or metallic stent achieved a longer functional duration once the initial polymer ureteric stent failed. METHODS: A retrospective, longitudinal study was performed at a single tertiary institution. All patients who underwent ureteric stenting with a 6Fr polymer stent for malignancy between 2010 and 2020 were included. Patients were followed up until death with ureteric stent in situ or permanent nephrostomy tube insertion. RESULTS: A total of 46 patients (66 ureters) had ureteric stents inserted for malignancy. From initial ureteric stent failure, 10 stents were changed to a new 6Fr polymer stent, 42 were changed to an 8Fr polymer stent and 14 were changed to a Resonance® 6Fr metallic stent. The Resonance 6Fr metallic stent had the longest median functional duration of 14 months (p = 0.012). CONCLUSION: Resonance® 6Fr metallic stents appear to have a significantly longer functional duration than a new 6Fr polymer stent or 8Fr polymer stent, which may allow patients to enjoy a better quality of life and delay permanent nephrostomy tube insertion.

Voluntary Medical Male Circumcisions for HIV Prevention - 13 Countries in Eastern and Southern Africa, 2017-2021.

In 2007, voluntary medical male circumcision (VMMC) was endorsed by the World Health Organization (WHO) and the Joint United Nations Programme on HIV/AIDS after it was found to be associated with approximately a 60% reduction in the risk for female-to-male transmission of HIV (1). As a result of this endorsement, the U.S. President's Emergency Plan for AIDS Relief (PEPFAR), through partnerships with U.S. government agencies, including CDC, the U.S. Department of Defense, and the U.S. Agency for International Development, started supporting VMMCs performed in prioritized countries in southern and eastern Africa. During 2010-2016, CDC supported 5,880,372 VMMCs in 12 countries (2,3). During 2017-2021, CDC supported 8,497,297 VMMCs performed in 13 countries. In 2020, the number of VMMCs performed declined 31.8% compared with the number in 2019, primarily because of COVID-19-related disruptions to VMMC service delivery. PEPFAR 2017-2021 Monitoring, Evaluation, and Reporting data were used to provide an update and describe CDC's contribution to the scale-up of the VMMC program, which is important to meeting the 2025 Joint United Nations Programme on HIV/AIDS (UNAIDS) target of 90% of males aged 15-59 years having access to VMMC services in prioritized countries to help end the AIDS epidemic by 2030 (4).

Factors Beyond Compensation Associated with Uptake of Voluntary Medical Male Circumcision in Zambia.

Voluntary medical male circumcision (VMMC) provides partial protection against female-to-male transmission of HIV. The Maximizing the Impact of Voluntary Medical Male Circumcision in Zambia (MAXZAM) project was a phased implementation of a demand generation strategy for VMMC through economic compensation. Previously published findings showed increased uptake of VMMC when compensation was provided. This paper is a follow-up evaluation of the MAXZAM project exploring additional factors associated with uptake of VMMC. Factors found associated include the outreach setting in which men were approached, number of information sources seen, heard, or read about VMMC, their self-reported HIV risk behaviors, their self-reported intention to go through the procedure, and their behavioral-psychographic profile. The findings highlight the importance of considering general (e.g., intensifying mass communications and targeting specific settings) and person-centered demand generation approaches (e.g., considering the client's psychographic profile and HIV risk level) to maximize effect on VMMC uptake.

Effects of COVID-19 Pandemic on Voluntary Medical Male Circumcision Services for HIV Prevention, Sub-Saharan Africa, 2020.

Beginning in March 2020, to reduce COVID-19 transmission, the US President's Emergency Plan for AIDS Relief supporting voluntary medical male circumcision (VMMC) services was delayed in 15 sub-Saharan African countries. We reviewed performance indicators to compare the number of VMMCs performed in 2020 with those performed in previous years. In all countries, the annual number of VMMCs performed decreased 32.5% (from 3,898,960 in 2019 to 2,631,951 in 2020). That reduction is largely attributed to national and local COVID-19 mitigation measures instituted by ministries of health. Overall, 66.7% of the VMMC global annual target was met in 2020, compared with 102.0% in 2019. Countries were not uniformly affected; South Africa achieved only 30.7% of its annual target in 2020, but Rwanda achieved 123.0%. Continued disruption to the VMMC program may lead to reduced circumcision coverage and potentially increased HIV-susceptible populations. Strategies for modifying VMMC services provide lessons for adapting healthcare systems during a global pandemic.

The association between mosaicism type and cognitive and behavioral functioning among males with fragile X syndrome.

Mosaicism in fragile X syndrome (FXS) refers to two different FMR1 allele variations: size mosaicism represents different numbers of CGG repeats between the two alleles, such that in addition to a full mutation allele there is an allele in the normal or premutation range of CGG repeats, while methylation mosaicism indicates whether a full-mutation allele is fully or partially methylated. The present study explored the association between mosaicism type and cognitive and behavioral functioning in a large sample of males 3 years and older (n = 487) with FXS, participating in the Fragile X Online Registry with Accessible Research Database. Participants with methylation mosaicism were less severely cognitively affected as indicated by a less severe intellectual disability rating, higher intelligence quotient and adaptive behavior score, and lower social impairment score. In contrast, the presence of size mosaicism was not significantly associated with better cognitive and behavioral outcomes than full mutation. Our findings suggest that methylation mosaicism is associated with better cognitive functioning and adaptive behavior and less social impairment. Further research could assess to what extent these cognitive and behavioral differences depend on molecular diagnostic methods and the impact of mosaicism on prognosis of individuals with FXS.

Defining the Global Research and Programmatic Agenda and Priority Actions for Voluntary Medical Male Circumcision for HIV Prevention.

PURPOSE OF REVIEW: Since 2007, voluntary medical male circumcision (VMMC) programs have been associated with substantially reduced HIV incidence across 15 prioritized countries in Eastern and Southern Africa. Drawing on the programmatic experience of global VMMC leaders, this report reviews progress made in the first 15 years of the program, describes programmatic and research gaps, and presents considerations to maximize the impact of VMMC. RECENT FINDINGS: Overall, key programmatic and research gaps include a lack of robust male circumcision coverage estimates due to limitations to the data and a lack of standardized approaches across programs; challenges enhancing VMMC uptake include difficulties reaching populations at higher risk for HIV infection and men 30 years and older; limitations to program and procedural quality and safety including variations in approaches used by programs; and lastly, sustainability with limited evidence-based practices. Considerations to address these gaps include the need for global guidance on estimating coverage, conducting additional research on specific sub-populations to improve VMMC uptake, implementation of responsive and comprehensive approaches to adverse event surveillance, and diversifying financing streams to progress towards sustainability. This report's findings may help establish a global VMMC research and programmatic agenda to inform policy, research, and capacity-building activities at the national and global levels.

Protocol for a single patient therapy plan: A randomised, double-blind, placebo-controlled N-of-1 trial to assess the efficacy of cannabidiol in patients with intractable epilepsy.

AIM: This paper describes the use of the single patient therapy plan (SPTP). The SPTP has been designed to assess the efficacy at an individual level of a commercially available cannabinoid product, cannabidiol, in reducing seizure frequency in paediatric patients with intractable epilepsy. METHODS: The SPTP is a randomised, double-blind, placebo-controlled N-of-1 trial designed to assess the efficacy of treatment in a neurology outpatient setting. The primary objective of the SPTP is to assess the efficacy of cannabidiol in reducing seizure frequency in each patient with intractable epilepsy, with change in seizure frequency being the primary outcome of interest. The analysis adopts a Bayesian approach, which provides results in the form of posterior probabilities that various levels of benefit (based on the primary outcome measure, seizure frequency) have been achieved under active treatment compared to placebo, accompanied by decision rules that provide thresholds for deciding whether treatment has been successful in the individual patient. The SPTP arrangement is most accurately considered part of clinical practice rather than research, since it is aimed at making clinical treatment decisions for individual patients and is not testing a hypothesis or collecting aggregate data. Therefore, Human Research Ethics Committee approval was considered not to be required, although it is recommended that hospital Clinical Ethics Committees provide ethical oversight. CONCLUSION: These SPTP resources are made available so that they may inform clinical practice in the treatment of severe epilepsy or adapted for use in other conditions.

Pathologic root migration secondary to vertical root fracture and full-coverage crowns: a report of 3 cases.

Occasionally, tooth fractures may demonstrate exaggerated pathologic root migration (PRM), often resulting in tooth loss. The early propagation of the root fracture may not be readily identifiable through clinical inspection and conventional radiographic imaging. Ultimately, increased root separation, isolated deep periodontal probing depth, and characteristic radiolucent changes may facilitate the diagnosis. This article describes 3 patients with unusual presentations of PRM in endodontically treated teeth restored with full-coverage crowns. One case illustrates the use of cone beam computed tomography for restorative assessment following root separation. Although it is efficacious to place crowns on most posterior endodontically treated teeth to maintain structural integrity, patients may remain at risk for catastrophic PRM and tooth loss. Timely extraction of teeth with hopeless PRM may minimize underlying bone resorption and the need for osseous regenerative procedures, ultimately improving the dental implant recipient site.

Increase in Meningococcal Serogroup W Disease, Victoria, Australia, 2013-2015.

In Victoria, Australia, invasive meningococcal disease caused by Neisseria meningitidis serogroup W increased from 4% of all cases in 2013 to 30% in 2015. This increase resulted largely from strains similar to those in the serogroup W sequence type 11 clonal complex, previously described in the United Kingdom and South America.

Rise in invasive serogroup W meningococcal disease in Australia 2013-2015.

Since 2013, there has been an increase in the number of notified cases of invasive meningococcal disease (IMD) due to serogroup W (MenW) in Australia. In response to this observed increase, the Communicable Diseases Network Australia convened a working group in 2015 to collate and analyse the epidemiology of MenW disease nationally. Enhanced surveillance data collected by jurisdictions were collated and analysed, and whole genome sequencing (WGS) of MenW isolates assessed the genomic relatedness of strains between 2012 and 2015. This report describes that epidemiology. Since 2013, the incidence and proportion of MenW has increased in Australia, rising from an average of 2% of all IMD cases annually (range 0% to 5%) between 1991 and 2012; to 8% (12/149) of cases in 2013, 10% (17/169) in 2014, and 19% (34/182) in 2015. Victoria has been the main affected state, with 50% (17/34) of national cases in 2015. MenW has affected older populations, with a median age between 2003 and 2015 being 44 years. During this period, case fatality was 10.7% (17/159), 2.3 times higher than for all IMD serogroups combined (4.7%, 173/3720). There were 7 deaths due to MenW in 2015 (CFR 21%). WGS has found the majority of Australian isolates cluster within a group of W:P1.5,2:F1-1:ST11 isolates from the United Kingdom and South America, regions where rapid spread and endemic transmission has occurred since 2009. The recent increase in incidence of MenW in Australia is evolving and is being closely monitored. Lessons learned from the international experience will be important in informing the public health response.

Cost-effectiveness of interventions to prevent cardiovascular disease in Australia's indigenous population.

BACKGROUND: Cardiovascular disease is the leading cause of disease burden in Australia's Indigenous population, and the greatest contributor to the Indigenous 'health gap'. Economic evidence can help identify interventions that efficiently address this discrepancy. METHODS: Five interventions (one community-based and four pharmacological) to prevent cardiovascular disease in Australia's Indigenous population were subject to economic evaluation. Pharmacological interventions were evaluated as delivered either via Aboriginal Community Controlled Health Services or mainstream general practitioner services. Cost-utility analysis methods were used, with health benefit measured in disability-adjusted life-years saved. RESULTS: All pharmacological interventions produced more Indigenous health benefit when delivered via Indigenous health services, but cost-effectiveness ratios were higher due to greater health service costs. Cost-effectiveness ratios were also higher in remote than in non-remote regions. The polypill was the most cost-effective intervention evaluated, while the community-based intervention produced the most health gain. CONCLUSIONS: Local and decision-making contextual factors are important in the conduct and interpretation of economic evaluations. For Australia's Indigenous population, different models of health service provision impact on reach and cost-effectiveness results. Both the extent of health gain and cost-effectiveness are important considerations for policy-makers in light of government objectives to address health inequities and bridge the health gap.

Comparing fluorodeoxyglucose positron emission tomography with computed tomography in staging for nodal and distant metastasis in urothelial/bladder cancer.

Objectives: We aim to assess the clinical value of 18F-fluorodeoxyglucose positron (18F-FDG-PET) scan in detecting nodal and distant metastasis compared with computed tomography (CT) scan in patients with urothelial carcinoma or bladder cancer, aiming to improve staging accuracy and thereby better prognosticate and determine therapy. Methods: A retrospective review of 75 patients with invasive bladder cancer (≥T1) who were staged with both CT and 18F-FDG-PET within an 8-week interval was performed for the period between 2015 and 2020. Seventy-two per cent (54/75) had formal pelvic lymph node (LN) dissection or biopsy of lesions suspicious for metastases. FDG-PET definitions for positive sites were assessed depending on SUV Max (nodes with SUVmax >4 at any size, SUV > 2 for lymph nodes >8 mm, or any SUV if the lymph node was >10 mm on axial images). For CT scanning, enlarged LN by RECIST 1.1 criteria (>10 mm) as well as qualitative findings suggesting metastasis were considered positive. The analysis was based on the comparison of CT and 18F-FDG-PET findings to histopathology results from LN dissection or biopsies. Results: Sensitivity, specificity, positive predictive values (PPV) and negative predictive value (NPV) of CT versus FDG-PET for detecting metastasis, in patients who underwent pelvic LN dissection or biopsy of lesions suspicious of metastases, were 46.6% (95% CI: 21%-70%) versus 60% (95% CI: 32%-84%), 100% (95% CI: 91%-100%) versus 83.78% (95% CI: 69%-94%), 100% (95% CI: 63%-100%) versus 60% (95% CI: 32%-84%), and 82.2% (95% CI: 68%-92%) versus 83.78% (95% CI: 69%-94%), respectively. 7/75 (9.3%) patients avoided cystectomy due to 18F-FDG-PET features of metastases that were not detected by CT. Conclusion: FDG-PET may be more sensitive than CT for metastases in the staging of bladder cancer, which resulted in significant avoidance of aggressive local management in cases with occult metastasis.

A randomised trial of two techniques for bottle feeding preterm infants.

AIM: Preterm infants begin the transition from gastric tube feeds to sucking feeds around 34 weeks' postmenstrual age. We compared physiological stability in two bottle feeding positions, cradle hold versus side lying in preterm infants. METHODS: Randomised crossover trial of infants <34 weeks' gestation at birth, ≥34 weeks' postmenstrual age at study and receiving at least two sucking feeds/day. Two feeds were studied on successive days. A pulse oximeter measured oxygen saturation (SpO2) and heart rate (HR) before, during and 30 min after feeds. Continuous data were compared using paired t-tests and proportions using chi squared. RESULTS: Twenty-five study infants were mean (standard deviation (SD)) 37 (2.4) weeks' post-menstrual age and 2740 (589) g at study. There was little difference in mean (SD) SpO2 during feeds between the cradle-hold and side-lying position 94 (6) % versus 95 (6) %, respectively (P = 0.55, confidence interval (CI) -1.4, 5.4). During feeds, 17/25 (68%) experienced a period of SpO2 <80% in the cradle-hold position compared with 14/25 (56) % in the side-lying position (P = 0.26, CI 0.68, 4.10). There were no significant differences in the mean HR or number of episodes of bradycardia HR <100 bpm. There was a trend towards infants consuming a smaller mean (SD) proportion of their feed in the cradle-hold position compared with the side-lying position, 82 (25) % versus 87 (20) % (P = 0.08, CI -0.64, 10.00). CONCLUSIONS: There was little difference in infants' physiological stability between the two bottle feeding positions. Both methods may be appropriate for the transition from gastric tube to sucking feeds in preterm infants.

Large bladder stones in an augmented bladder - An open approach to a big problem.

Bladder augmentation can be a valuable life-changing operation for patients with bladder dysfunction, however, are associated with several complications that require long-term management. One of the most common complications seen in these patients are bladder calculi. If bladder stones are left untreated, they can become extremely large and cause pain, urinary tract infections, or difficulty emptying the bladder. We present the case of a patient with an augmented bladder who had numerous large bladder stones and his management.

Torsion of an intra-abdominal testis presenting as acute abdominal pain - A rare diagnosis.

Cryptorchidism is associated with a higher risk of malignancy, infertility, and torsion. Torsion of an intra-abdominal testis is a rare cause of acute abdominal pain in the post-pubertal male but must be considered in men presenting with abdominal pain and a history of cryptorchidism. We present an unusual case of a patient with acute abdominal pain found to have torsion of a left intra-abdominal testis and his management.

Solitary fibrous tumour of the urinary bladder - A rare and potentially malignant neoplasm.

Solitary fibrous tumours (SFTs) of the urinary bladder are a rare mesenchymal neoplasm that occasionally has malignant potential. The tumour is characterised by haphazardly arranged spindle-shaped to ovoid cells, with a prominent, branching, thin-walled, dilated vasculature and NAB2-STAT6 gene rearrangement. While most SFTs are indolent in nature, difficulty arises predicting which SFTs are potentially malignant. There are now validated risk stratification tools to help identify which SFTs are likely to metastasize and help clinicians determine management. The mainstay of treatment for SFTs remains surgery, with emerging evidence in the combined use of surgery and radiotherapy.

Polyphenolic Natural Products Active In Silico Against SARS-CoV-2 Spike Receptor Binding Domains and Non-structural Proteins - A Review.

The ongoing Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pandemic has been proven to be more severe than the previous coronavirus outbreaks due to the virus' high transmissibility. With the emergence of new variants, this global phenomenon took a more dramatic turn, with many countries recently experiencing higher surges of confirmed cases and deaths. On top of this, the inadequacy of effective treatment options for COVID-19 aggravated the problem. As a way to address the unavailability of target-specific viral therapeutics, computational strategies have been employed to hasten and systematize the search. The objective of this review is to provide initial data highlighting the utility of polyphenols as potential prophylaxis or treatment for COVID-19. In particular, presented here are virtually screened polyphenolic compounds which showed potential as either antagonists to viral entry and host cell recognition through binding with various receptor-binding regions of SARS-CoV-2 spike protein or as inhibitors of viral replication and post-translational modifications through binding with essential SARS-CoV-2 non-structural proteins.

Preventing HIV Among Adolescent Boys and Young Men Through PEPFAR-Supported Voluntary Medical Male Circumcision in 15 Sub-Saharan African Countries, 2018-2021.

Voluntary medical male circumcision (VMMC) is an HIV prevention intervention that has predominantly targeted adolescent and young men, aged 10-24 years. In 2020, the age eligibility for VMMC shifted from 10 to 15 years of age. This report describes the VMMC client age distribution from 2018 to 2021, at the site, national, and regional levels, among 15 countries in southern and eastern Africa. Overall, in 2018 and 2019, the highest proportion of VMMCs were performed among 10-14-year-olds (45.6% and 41.2%, respectively). In 2020 and 2021, the 15-19-year age group accounted for the highest proportion (37.2% and 50.4%, respectively) of VMMCs performed across all age groups. Similarly, in 2021 at the site level, 68.1% of VMMC sites conducted the majority of circumcisions among men aged 15-24 years. This analysis highlights that adolescent boys and young men are the primary recipients of VMMC receiving an important lifetime reduction in HIV risk.