Five-year outcomes of fractionated stereotactic body radiotherapy for oligometastatic prostate cancer from the TRANSFORM phase II trial.

Metastasis-directed therapy (MDT) for oligometastatic prostate cancer (PCa), including stereotactic body radiotherapy (SBRT), has shown promise but is still considered investigational. This is the 5-year analysis of the TRANSFORM trial, the largest prospective cohort of men with oligometastatic PCa treated with SBRT-based MDT. The primary endpoint was 5-year treatment escalation-free survival (TE-FS), defined as freedom from any new cancer therapy other than further SBRT. In total, 199 men received SBRT; 76.4% were hormone-naïve at baseline. The rate of 5-year TE-FS was 21.7% (95% confidence interval [CI]: 15.7%-28.7%) overall and 25.4% (95% CI: 18.1%-33.9%) in the hormone-naïve subgroup. The subgroups with International Society of Urological Pathology Grade Groups 4-5 disease (hazard ratio [HR] = 1.48, 95% CI: 1.05-2.01, p = .026), a higher baseline prostate-specific antigen (PSA) (HR = 1.06, 95% CI: 1.03-1.09, p < .001) and those who received prior androgen deprivation therapy (ADT) (HR = 2.13, 95% CI: 1.40-3.26, p < .001), were at greater risk of treatment escalation. Outcomes for participants with four or five initial lesions were comparable to those with one to three lesions. At last follow-up, 18.9% (95% CI: 13.2%-25.7%) of participants were free from treatment escalation (median follow-up of 67.9 months) and two participants had an undetectable PSA level. No treatment-related grade three or higher adverse events were reported. The findings of this study demonstrate that SBRT-based MDT is an effective option for delaying systemic treatment escalation in the context of oligometastatic PCa. Future randomised trials comparing SBRT-based MDT to standard-of-care ADT-based approaches are required to evaluate the impact of delaying ADT on survival.

Genomic evolution shapes prostate cancer disease type.

The development of cancer is an evolutionary process involving the sequential acquisition of genetic alterations that disrupt normal biological processes, enabling tumor cells to rapidly proliferate and eventually invade and metastasize to other tissues. We investigated the genomic evolution of prostate cancer through the application of three separate classification methods, each designed to investigate a different aspect of tumor evolution. Integrating the results revealed the existence of two distinct types of prostate cancer that arise from divergent evolutionary trajectories, designated as the Canonical and Alternative evolutionary disease types. We therefore propose the evotype model for prostate cancer evolution wherein Alternative-evotype tumors diverge from those of the Canonical-evotype through the stochastic accumulation of genetic alterations associated with disruptions to androgen receptor DNA binding. Our model unifies many previous molecular observations, providing a powerful new framework to investigate prostate cancer disease progression.

Location location location: a carbon footprint calculator for transparent travel to the UN Climate Conference 2022.

Addressing the large carbon footprint of conferences such as the United Nations Climate Change Convention Conference of the Parties (COP) will be important for maintaining public confidence in climate policy. Transparency is also a vital aspect of creating equitable outcomes in climate policies, as those most likely to be affected or who can create change on the ground are often unable to attend in person because of the high financial costs as well as having a large carbon footprint. The selection of host locations for the regular meetings of the UN Climate Change Convention is based on a rotation amongst the five UN regions, which for 2022 was Africa. Here, we present a carbon footprint calculator for travel to COP 27 in Sharm El-Sheikh, Egypt, weighing the benefits of certain routes and modes of transport. The calculator demonstrates the well-known carbon efficiency of coach and rail over flights but shows that these benefits were partly diminished in the case of COP 27 due to insufficient transport links from Europe to the conference location. However, we also highlight some of the benefits of hosting a COP in the Global South, particularly in the context of climate justice. Users of the calculator are invited to consider all their options for travel and acknowledge the issue of climate justice through careful selection of carbon offsets.

Africa and climate justice at COP27 and beyond: impacts and solutions through an interdisciplinary lens.

Climate justice is not just a financial transaction to protect the environment. It needs to be seen as the protection of the most vulnerable in society after centuries of resource exploitation. African countries disproportionately face impacts of climate change on their environments, their economies, their resources and their infrastructure. This leads to greater vulnerability and increased exposure to the negative effects of a changing climate. In this article, we highlight the importance of climate justice and its role within the United Nations negotiations, and ultimately in concrete action. We discuss current climate impacts across key sectors in the African region, with a focus on health, infrastructure, food and water scarcity, energy and finance. All sectors are affected by climate change. They are interconnected and under threat. This triggers a ripple effect, where threats in one sector have a knock-on effect on other sectors. We find that the current set of intergovernmental institutions have failed to adequately address climate justice. We also contend that a siloed approach to climate action has proven to be ineffective. As we head towards the next set of negotiations (COP27), this paper argues that the economic and social conditions in Africa can be addressed through financial and collaborative support for adaptation and localised solutions, but that this will only be achieved if climate justice is prioritised by the decision makers. This needs to include a global-scale transition in how climate finance is assessed and accessed. Climate justice underpins real, effective and sustainable solutions for climate action in Africa.

A polygenic two-hit hypothesis for prostate cancer.

Prostate cancer is one of the most heritable cancers. Hundreds of germline polymorphisms have been linked to prostate cancer diagnosis and prognosis. Polygenic risk scores can predict genetic risk of a prostate cancer diagnosis. Although these scores inform the probability of developing a tumor, it remains unknown how germline risk influences the tumor molecular evolution. We cultivated a cohort of 1250 localized European-descent patients with germline and somatic DNA profiling. Men of European descent with higher genetic risk were diagnosed earlier and had less genomic instability and fewer driver genes mutated. Higher genetic risk was associated with better outcome. These data imply a polygenic "two-hit" model where germline risk reduces the number of somatic alterations required for tumorigenesis. These findings support further clinical studies of polygenic risk scores as inexpensive and minimally invasive adjuncts to standard risk stratification. Further studies are required to interrogate generalizability to more ancestrally and clinically diverse populations.

Same day discharge for robot-assisted radical prostatectomy: a prospective cohort study documenting an Australian approach.

BACKGROUND: The introduction of robotic surgical systems has significantly impacted urological surgery, arguably more so than other surgical disciplines. The focus of our study was length of hospital stay - patients have traditionally been discharged day 1 post-robot-assisted radical prostatectomy (RARP), however, during the ongoing COVID-19 pandemic and consequential resource limitations, our centre has facilitated a cohort of same-day discharges with initial success. METHODS: We conducted a prospective tertiary single-centre cohort study of a series of all patients (n = 28) - undergoing RARP between January and April 2021. All patients were considered for a day zero discharge pathway which consisted of strict inclusion criteria. At follow-up, each patient's perspective on their experience was assessed using a validated post-operative satisfaction questionnaire. Data were reviewed retrospectively for all those undergoing RARP over the study period, with day zero patients compared to overnight patients. RESULTS: Overall, 28 patients 20 (71%) fulfilled the objective criteria for day zero discharge. Eleven patients (55%) agreed pre-operatively to day zero discharge and all were successfully discharged on the same day as their procedure. There was no statistically significant difference in age, BMI, ASA, Charlson score or disease volume. All patients indicated a high level of satisfaction with their procedure. Median time from completion of surgery to discharge was 426 min (7.1 h) in the day zero discharge cohort. CONCLUSION: Day zero discharge for RARP appears to deliver high satisfaction, oncological and safety outcomes. Therefore, our study demonstrates early success with unsupported same-day discharge in carefully selected and pre-counselled patients.

Transferability of robotic console skills by early robotic surgeons: a multi-platform crossover trial of simulation training.

Robotic surgical training is undergoing a period of transition now that new robotic operating platforms are entering clinical practice. As this occurs, training will need to be adapted to include strategies to train across various consoles. These new consoles differ in multiple ways, with some new vendors using flat screen open source 3D enhanced vision with glasses and differences in design will require surgeons to learn new skills. This process has parallels with aviation credentialling across different aircraft described as type rating. This study was designed to test the hypothesis that technical robotic console operating skills are transferrable across different robotic operating platforms. Ten participants sequentially completed four Mimic®(Surgical Science) simulation exercises on two different robotic operating platforms (DaVinci®, Intuitive Surgical and HUGO™ RAS, Medtronic). Ethical approval and informed consent were obtained for this study. Groups were balanced for key demographics including previous robotic simulator experience. Data for simulation metrics and time to proficiency were collected for each attempt at the simulated exercise and analysed. Qualitative feedback on multi-platform learning was sought via unstructured interviews and a questionnaire. Participants were divided into two groups of 5. Group 1 completed the simulation exercises on console A first then repeated these exercises on console B. Group 2 completed the simulated exercises on console B first then repeated these exercises on console A. Group 1 candidates adapted quicker to the second console and Group 2 candidates reached proficiency faster on the first console. Participants were slower on the second attempt of the final exercise regardless of their allocated group. Quality and efficiency metrics and risk and safety metrics were equivalent across consoles. The data from this investigation suggests that console operating skills are transferrable across different platforms. Overall risk and safety metrics are within acceptable limits regardless of the order of progression of console indicating that training can safely occur across multiple consoles contemporaneously. This data has implications for the design of training and certification as new platforms progress to market and supports a proficiency-based approach.

Children in All Policies (CAP) 2030 Citizen Science for Climate Change Resilience: a cross-sectional pilot study engaging adolescents to study climate hazards, biodiversity and nutrition in rural Nepal.

Background: Young people will suffer most from climate change yet are rarely engaged in dialogue about it. Citizen science offers a method for collecting policy-relevant data, whilst promoting awareness and capacity building. We tested the feasibility and acceptability of engaging Nepalese adolescents in climate change and health-related citizen science. Methods: We purposively selected 33 adolescents from two secondary schools in one remote and one relatively accessible district of Nepal. We contextualised existing apps and developed bespoke apps to survey climate hazards, waste and water management, local biodiversity, nutrition and sociodemographic information. We analysed and presented quantitative data using a descriptive analysis. We captured perceptions and learnings via focus group discussions and analysed qualitative data using thematic analysis. We shared findings with data collectors using tables, graphs, data dashboards and maps. Results: Adolescents collected 1667 biodiversity observations, identified 72 climate-change related hazards, and mapped 644 geolocations. They recorded 286 weights, 248 heights and 340 dietary recalls. Adolescents enjoyed learning how to collect the data and interpret the findings and gained an appreciation of local biodiversity which engendered 'environmental stewardship'. Data highlighted the prevalence of failing crops and landslides, revealed both under- and over-nutrition and demonstrated that children consume more junk foods than adults. Adolescents learnt about the impacts of climate change and the importance of eating a diverse diet of locally grown foods. A lack of a pre-established sampling frame, multiple records of the same observation and spurious nutrition data entries by unsupervised adolescents limited data quality and utility. Lack of internet access severely impacted feasibility, especially of apps which provide online feedback. Conclusions: Citizen science was largely acceptable, educational and empowering for adolescents, although not always feasible without internet access. Future projects could improve data quality and integrate youth leadership training to enable climate-change advocacy with local leaders.

Lymphovascular Invasion at the Time of Radical Prostatectomy Adversely Impacts Oncological Outcomes.

Lymphovascular invasion, whereby tumour cells or cell clusters are identified in the lumen of lymphatic or blood vessels, is thought to be an essential step in disease dissemination. It has been established as an independent negative prognostic indicator in a range of cancers. We therefore aimed to assess the impact of lymphovascular invasion at the time of prostatectomy on oncological outcomes. We performed a multicentre, retrospective cohort study of 3495 men who underwent radical prostatectomy for localised prostate cancer. Only men with negative preoperative staging were included. We assessed the relationship between lymphovascular invasion and adverse pathological features using multivariable logistic regression models. Kaplan-Meier curves and Cox proportional hazard models were created to evaluate the impact of lymphovascular invasion on oncological outcomes. Lymphovascular invasion was identified in 19% (n = 653) of men undergoing prostatectomy. There was an increased incidence of lymphovascular invasion-positive disease in men with high International Society of Urological Pathology (ISUP) grade and non-organ-confined disease (p < 0.01). The presence of lymphovascular invasion significantly increased the likelihood of pathological node-positive disease on multivariable logistic regression analysis (OR 15, 95%CI 9.7-23.6). The presence of lymphovascular invasion at radical prostatectomy significantly increased the risk of biochemical recurrence (HR 2.0, 95%CI 1.6-2.4). Furthermore, lymphovascular invasion significantly increased the risk of metastasis in the whole cohort (HR 2.2, 95%CI 1.6-3.0). The same relationship was seen across D'Amico risk groups. The presence of lymphovascular invasion at the time of radical prostatectomy is associated with aggressive prostate cancer disease features and is an indicator of poor oncological prognosis.

Has COVID-19 suppressed dengue transmission in Nepal?

Following the report of the first COVID-19 case in Nepal on 23 January 2020, three major waves were documented between 2020 and 2021. By the end of July 2022, 986 596 cases of confirmed COVID-19 and 11 967 deaths had been reported and 70.5% of the population had received at least two doses of a COVID-19 vaccine. Prior to the pandemic, a large dengue virus (DENV) epidemic affected 68 out of 77 districts, with 17 932 cases and six deaths recorded in 2019. In contrast, the country's Epidemiology and Disease Control Division reported 530 and 540 dengue cases in the pandemic period (2020 and 2021), respectively. Furthermore, Kathmandu reported just 63 dengue cases during 2020 and 2021, significantly lower than the 1463 cases reported in 2019. Serological assay showed 3.2% positivity rates for anti-dengue immunoglobulin M antibodies during the pandemic period, contrasting with 26.9-40% prior to it. Real-time polymerase chain reaction for DENV showed a 0.5% positive rate during the COVID-19 pandemic which is far lower than the 57.0% recorded in 2019. Continuing analyses of dengue incidence and further strengthening of surveillance and collaboration at the regional and international levels are required to fully understand whether the reduction in dengue incidence/transmission were caused by movement restrictions during the COVID-19 pandemic.

Feeding, caregiving practices, and developmental delay among children under five in lowland Nepal: a community-based cross-sectional survey.

BACKGROUND: Nurturing care, including adequate nutrition, responsive caregiving and early learning, is critical to early childhood development. In Nepal, national surveys highlight inequity in feeding and caregiving practices for young children. Our objective was to describe infant and young child feeding (IYCF) and cognitive and socio-emotional caregiving practices among caregivers of children under five in Dhanusha district, Nepal, and to explore socio-demographic and economic factors associated with these practices. METHODS: We did a cross-sectional analysis of a subset of data from the MIRA Dhanusha cluster randomised controlled trial, including mother-child dyads (N = 1360), sampled when children were median age 46 days and a follow-up survey of the same mother-child dyads (N = 1352) when children were median age 38 months. We used World Health Organization IYCF indicators and questions from the Multiple Indicator Cluster Survey-4 tool to obtain information on IYCF and cognitive and socio-emotional caregiving practices. Using multivariable logistic regression models, potential explanatory household, parental and child-level variables were tested to determine their independent associations with IYCF and caregiving indicators. RESULTS: The prevalence of feeding indicators varied. IYCF indicators, including ever breastfed (99%), exclusive breastfeeding (24-hour recall) (89%), and vegetable/fruit consumption (69%) were common. Problem areas were early initiation of breastfeeding (16%), colostrum feeding (67%), no pre-lacteal feeding (53%), timely introduction of complementary feeding (56%), minimum dietary diversity (49%) and animal-source food consumption (23%). Amongst caregiving indicators, access to 3+ children's books (7%), early stimulation and responsive caregiving (11%), and participation in early childhood education (27%) were of particular concern, while 64% had access to 2+ toys and 71% received adequate care. According to the Early Child Development Index score, only 38% of children were developmentally on track. Younger children from poor households, whose mothers were young, had not received antenatal visits and delivered at home were at higher risk of poor IYCF and caregiving practices. CONCLUSIONS: Suboptimal caregiving practices, inappropriate early breastfeeding practices, delayed introduction of complementary foods, inadequate dietary diversity and low animal-source food consumption are challenges in lowland Nepal. We call for urgent integrated nutrition and caregiving interventions, especially as interventions for child development are lacking in Nepal.

Defining Prostatic Vascular Pedicle Recurrence and the Anatomy of Local Recurrence of Prostate Cancer on Prostate-specific Membrane Antigen Positron Emission Tomography/Computed Tomography.

Background: The term local recurrence in prostate cancer is considered to mean persistent local disease in the prostatic bed, most commonly at the site of the vesicourethral anastomosis (VUA). Since the introduction of prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) and magnetic resonance imaging for assessment of early biochemical recurrence (BCR), we have found histologically confirmed prostate cancer in the prostatic vascular pedicle (PVP). If a significant proportion of local recurrences are distant to the VUA, it may be possible to alter adjuvant and salvage radiation fields in order to reduce the potential morbidity of radiation in selected patients. Objective: To describe PVP local recurrence and to map the anatomic pattern of prostate bed recurrence on PSMA PET/CT. Design setting and participants: This was a retrospective multicentre study of 185 patients imaged with PSMA PET/CT following radical prostatectomy (RP) between January 2016 and November 2018. All patient data and clinical outcomes were prospectively collected. Recurrences were documented according to anatomic location. For patients presenting with local recurrence, the precise location of the recurrence within the prostate bed was documented. Intervention: PSMA PET/CT for BCR following RP. Results and limitations: A total of 43 local recurrences in 41/185 patients (22%) were identified. Tumour recurrence at the PVP was found in 26 (63%), VUA in 15 (37%), and within a retained seminal vesicle and along the anterior rectal wall in the region of the neurovascular bundle in one (2.4%) each. Histological and surgical evidence of PVP recurrence was acquired in two patients. The study is limited by its retrospective nature with inherent selection bias. This is an observational study reporting on the anatomy of local recurrence and does not include follow-up for patient outcomes. Conclusions: Our study showed that prostate cancer can recur in the PVP and is distant to the VUA more commonly than previously thought. This may have implications for RP technique and for the treatment of selected patients in the local recurrence setting. Patient summary: We investigated more precise identification of the location of tumour recurrence after removal of the prostate for prostate cancer. We describe a new definition of local recurrence in an area called the prostatic vascular pedicle. This new concept may alter the treatment recommended for recurrent disease.

How an Outbreak of COVID-19 Circulated Widely in Nepal: A Chronological Analysis of the National Response to an Unprecedented Pandemic.

Coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The first COVID-19 case was reported in Wuhan, China, in December 2019. In March 2020, the World Health Organization (WHO) declared COVID-19 a global pandemic. The first COVID-19 case in Nepal was reported in January 2020 in a Nepalese man who had returned from Wuhan to Nepal. This study aims to evaluate the government of Nepal's (GoN) response to the COVID-19 pandemic and explore ways to prevent COVID-19 and other pandemic diseases in the future. As of May 2022, a total of 979,140 cases and 11,951 deaths associated with COVID-19 have been reported in Nepal. To prevent the spread of the virus, the GoN initiated various preventive and control measures, including lockdown strategies. The effects of COVID-19 are expected to persist for many years; the best strategies a resource-limited country such as Nepal can implement to control pandemic diseases such as COVID-19 in the pre-vaccine stage are to increase testing, tracing, and isolation capacity.