Scaling up area-based conservation to implement the Global Biodiversity Framework's 30x30 target: The role of Nature's Strongholds.

The Global Biodiversity Framework (GBF), signed in 2022 by Parties to the Convention on Biological Diversity, recognized the importance of area-based conservation, and its goals and targets specify the characteristics of protected and conserved areas (PCAs) that disproportionately contribute to biodiversity conservation. To achieve the GBF's target of conserving a global area of 30% by 2030, this Essay argues for recognizing these characteristics and scaling them up through the conservation of areas that are: extensive (typically larger than 5,000 km2); have interconnected PCAs (either physically or as part of a jurisdictional network, and frequently embedded in larger conservation landscapes); have high ecological integrity; and are effectively managed and equitably governed. These areas are presented as "Nature's Strongholds," illustrated by examples from the Congo and Amazon basins. Conserving Nature's Strongholds offers an approach to scale up initiatives to address global threats to biodiversity.

Altered lipid homeostasis is associated with cerebellar neurodegeneration in SNX14 deficiency.

Dysregulated lipid homeostasis is emerging as a potential cause of neurodegenerative disorders. However, evidence of errors in lipid homeostasis as a pathogenic mechanism of neurodegeneration remains limited. Here, we show that cerebellar neurodegeneration caused by Sorting Nexin 14 (SNX14) deficiency is associated with lipid homeostasis defects. Recent studies indicate that SNX14 is an interorganelle lipid transfer protein that regulates lipid transport, lipid droplet (LD) biogenesis, and fatty acid desaturation, suggesting that human SNX14 deficiency belongs to an expanding class of cerebellar neurodegenerative disorders caused by altered cellular lipid homeostasis. To test this hypothesis, we generated a mouse model that recapitulates human SNX14 deficiency at a genetic and phenotypic level. We demonstrate that cerebellar Purkinje cells (PCs) are selectively vulnerable to SNX14 deficiency while forebrain regions preserve their neuronal content. Ultrastructure and lipidomic studies reveal widespread lipid storage and metabolism defects in SNX14-deficient mice. However, predegenerating SNX14-deficient cerebella show a unique accumulation of acylcarnitines and depletion of triglycerides. Furthermore, defects in LD content and telolysosome enlargement in predegenerating PCs suggest lipotoxicity as a pathogenic mechanism of SNX14 deficiency. Our work shows a selective cerebellar vulnerability to altered lipid homeostasis and provides a mouse model for future therapeutic studies.

Factors associated with weight loss and health gains in a structured lifestyle modification programme for adults with severe obesity: a prospective cohort study.

Background: Individual responses to behavioural weight loss interventions can vary significantly, and a better understanding of the factors associated with successful treatment might help to target interventions for those who will benefit the most. We sought to identify demographic and clinical characteristics that predicted intervention "success" (defined as ≥5% weight loss) and other health gains in patients with severe obesity attending a ten-week structured lifestyle modification programme. Methods: We conducted a prospective cohort study of all 1122 patients (751 (66.9%) female, mean age 47.3 ± 11.9 years, mean body mass index (BMI) 46.7 ± 7.8 kgm-2) referred from our hospital-based obesity clinic, who started the structured lifestyle programme between 2012-2019. We compared routine clinical measures such as weight, fitness, blood pressure, lipids and HbA1c at baseline and follow-up. We also used validated questionnaires to quantify anxiety, depression and health-related quality of life. Results: Of 1122 patients who started, 877 (78.2%) completed the programme and attended for follow up. Of these, 12.8% lost ≥5% body weight. The amount of weight lost was a strong and consistent predictor of improvements in metabolic, cardiovascular, and mental health, even after adjusting for age, sex, programme attendance and baseline fitness. Older age, male sex, being physically active and having lower anxiety and depression scores at baseline predicted greater weight loss. Younger age, depression and longer wait time to start the intervention were associated with drop-out. Conclusions: In adults with severe obesity completing a structured lifestyle modification programme, older age and good mental health were associated with programme completion and attaining ≥5% weight loss. The magnitude of weight lost was a strong predictor of improvements in cardiovascular, metabolic and mental health associated with programme completion.

Audit, Feedback, and Education to Improve Quality and Outcomes in Transurethral Resection and Single-Instillation Intravesical Chemotherapy for Nonmuscle Invasive Bladder Cancer Treatment: Protocol for a Multicenter International Observational Study With an Embedded Cluster Randomized Trial.

BACKGROUND: Nonmuscle invasive bladder cancer (NMIBC) accounts for 75% of bladder cancers. It is common and costly. Cost and detriment to patient outcomes and quality of life are driven by high recurrence rates and the need for regular invasive surveillance and repeat treatments. There is evidence that the quality of the initial surgical procedure (transurethral resection of bladder tumor [TURBT]) and administration of postoperative bladder chemotherapy significantly reduce cancer recurrence rates and improve outcomes (cancer progression and mortality). There is surgeon-reported evidence that TURBT practice varies significantly across surgeons and sites. There is limited evidence from clinical trials of intravesical chemotherapy that NMIBC recurrence rate varies significantly between sites and that this cannot be accounted for by differences in patient, tumor, or adjuvant treatment factors, suggesting that how the surgery is performed may be a reason for the variation. OBJECTIVE: This study primarily aims to determine if feedback on and education about surgical quality indicators can improve performance and secondarily if this can reduce cancer recurrence rates. Planned secondary analyses aim to determine what surgeon, operative, perioperative, institutional, and patient factors are associated with better achievement of TURBT quality indicators and NMIBC recurrence rates. METHODS: This is an observational, international, multicenter study with an embedded cluster randomized trial of audit, feedback, and education. Sites will be included if they perform TURBT for NMIBC. The study has four phases: (1) site registration and usual practice survey; (2) retrospective audit; (3) randomization to audit, feedback, and education intervention or to no intervention; and (4) prospective audit. Local and national ethical and institutional approvals or exemptions will be obtained at each participating site. RESULTS: The study has 4 coprimary outcomes, which are 4 evidence-based TURBT quality indicators: a surgical performance factor (detrusor muscle resection); an adjuvant treatment factor (intravesical chemotherapy administration); and 2 documentation factors (resection completeness and tumor features). A key secondary outcome is the early cancer recurrence rate. The intervention is a web-based surgical performance feedback dashboard with educational and practical resources for TURBT quality improvement. It will include anonymous site and surgeon-level peer comparison, a performance summary, and targets. The coprimary outcomes will be analyzed at the site level while recurrence rate will be analyzed at the patient level. The study was funded in October 2020 and began data collection in April 2021. As of January 2023, there were 220 hospitals participating and over 15,000 patient records. Projected data collection end date is June 30, 2023. CONCLUSIONS: This study aims to use a distributed collaborative model to deliver a site-level web-based performance feedback intervention to improve the quality of endoscopic bladder cancer surgery. The study is funded and projects to complete data collection in June 2023. TRIAL REGISTRATION: ClinicalTrials.org NCT05154084; https://clinicaltrials.gov/ct2/show/NCT05154084. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/42254.

Protocol for a MULTI-centre feasibility study to assess the use of 99mTc-sestaMIBI SPECT/CT in the diagnosis of kidney tumours (MULTI-MIBI study).

INTRODUCTION: The incidence of renal tumours is increasing and anatomic imaging cannot reliably distinguish benign tumours from renal cell carcinoma. Up to 30% of renal tumours are benign, with oncocytomas the most common type. Biopsy has not been routinely adopted in many centres due to concerns surrounding non-diagnostic rate, bleeding and tumour seeding. As a result, benign masses are often unnecessarily surgically resected. 99mTc-sestamibi SPECT/CT has shown high diagnostic accuracy for benign renal oncocytomas and other oncocytic renal neoplasms of low malignant potential in single-centre studies. The primary aim of MULTI-MIBI is to assess feasibility of a multicentre study of 99mTc-sestamibi SPECT/CT against a reference standard of histopathology from surgical resection or biopsy. Secondary aims of the study include obtaining estimates of 99mTc-sestamibi SPECT/CT sensitivity and specificity and to inform the design and conduct of a future definitive trial. METHODS AND ANALYSIS: A feasibility prospective multicentre study of participants with indeterminate, clinical T1 renal tumours to undergo 99mTc-sestamibi SPECT/CT (index test) compared with histopathology from biopsy or surgical resection (reference test). Interpretation of the index and reference tests will be blinded to the results of the other. Recruitment rate as well as estimates of sensitivity, specificity, positive and negative predictive value will be reported. Semistructured interviews with patients and clinicians will provide qualitative data to inform onward trial design and delivery. Training materials for 99mTc-sestamibi SPECT/CT interpretation will be developed, assessed and optimised. Early health economic modelling using a decision analytic approach for different diagnostic strategies will be performed to understand the potential cost-effectiveness of 99mTc-sestamibi SPECT/CT. ETHICS AND DISSEMINATION: Ethical approval has been granted (UK HRA REC 20/YH/0279) protocol V.5.0 dated 21/6/2022. Study outputs will be presented and published nationally and internationally. TRIAL REGISTRATION NUMBER: ISRCTN12572202.

Epidemiology of Renal Cell Carcinoma: 2022 Update.

CONTEXT: International variations in the rates of kidney cancer (KC) are considerable. An understanding of the risk factors for KC development is necessary to generate opportunities to reduce its incidence through prevention and surveillance. OBJECTIVE: To retrieve and summarize global incidence and mortality rates of KC and risk factors associated with its development, and to describe known familial syndromes and genetic alterations that represent biologic risk factors. EVIDENCE ACQUISITION: A systematic review was conducted via Medline (PubMed) and Scopus to include meta-analyses, reviews, and original studies regarding renal cell carcinoma, epidemiology, and risk factors. EVIDENCE SYNTHESIS: Our narrative review provides a detailed analysis of KC incidence and mortality, with significant variations across time, geography, and sex. In particular, while KC incidence has continued to increase, mortality models have leveled off. Among the many risk factors, hypertension, obesity, and smoking are the most well established. The emergence of new genetic data coupled with observational data allows for integrated management and surveillance strategies for KC care. CONCLUSIONS: KC incidence and mortality rates vary significantly by geography, sex, and age. Associations of the development of KC with modifiable and fixed risk factors such as obesity, hypertension, smoking, and chronic kidney disease (CKD)/end-stage kidney disease (ESKD) are well described. Recent advances in the genetic characterization of these cancers have led to a better understanding of the germline and somatic mutations that predispose patients to KC development, with potential for identification of therapeutic targets that may improve outcomes for these at-risk patients. PATIENT SUMMARY: We reviewed evidence on the occurrence of kidney cancer (KC) around the world. Currently, the main avoidable causes are smoking, obesity, and high blood pressure. Although other risk factors also contribute, prevention and treatment of these three factors provide the best opportunities to reduce the risk of developing KC at present.

Spatial patterns of tumour growth impact clonal diversification in a computational model and the TRACERx Renal study.

Genetic intra-tumour heterogeneity fuels clonal evolution, but our understanding of clinically relevant clonal dynamics remain limited. We investigated spatial and temporal features of clonal diversification in clear cell renal cell carcinoma through a combination of modelling and real tumour analysis. We observe that the mode of tumour growth, surface or volume, impacts the extent of subclonal diversification, enabling interpretation of clonal diversity in patient tumours. Specific patterns of proliferation and necrosis explain clonal expansion and emergence of parallel evolution and microdiversity in tumours. In silico time-course studies reveal the appearance of budding structures before detectable subclonal diversification. Intriguingly, we observe radiological evidence of budding structures in early-stage clear cell renal cell carcinoma, indicating that future clonal evolution may be predictable from imaging. Our findings offer a window into the temporal and spatial features of clinically relevant clonal evolution.

Perioperative management including dual cell salvage in a Jehovah's Witness patient undergoing major urological surgery.

Complex surgery associated with major hemorrhage presents particular risks for Jehovah's Witnesses who do not accept transfusion of blood products. Intraoperative use of two cell saver machines simultaneously can maximize the yield of salvaged blood from both the operative field and from washed surgical swabs and can potentially be life-saving.

Publishing Individual Surgeons' Outcomes in Urology: Empowering Patient Choice and Improving Safety.

It has been demonstrated that publication of individual surgeons' outcomes has improved patient safety and choice. Taking into consideration the lack of negative impact on patient selection and surgical training, it is difficult to argue that surgeons' outcomes should not be openly available in urology.

Selection of metastasis competent subclones in the tumour interior.

The genetic evolutionary features of solid tumour growth are becoming increasingly well described, but the spatial and physical nature of subclonal growth remains unclear. Here, we utilize 102 macroscopic whole-tumour images from clear cell renal cell carcinoma patients, with matched genetic and phenotypic data from 756 biopsies. Utilizing a digital image processing pipeline, a renal pathologist marked the boundaries between tumour and normal tissue and extracted positions of boundary line and biopsy regions to X and Y coordinates. We then integrated coordinates with genomic data to map exact spatial subclone locations, revealing how genetically distinct subclones grow and evolve spatially. We observed a phenotype of advanced and more aggressive subclonal growth in the tumour centre, characterized by an elevated burden of somatic copy number alterations and higher necrosis, proliferation rate and Fuhrman grade. Moreover, we found that metastasizing subclones preferentially originate from the tumour centre. Collectively, these observations suggest a model of accelerated evolution in the tumour interior, with harsh hypoxic environmental conditions leading to a greater opportunity for driver somatic copy number alterations to arise and expand due to selective advantage. Tumour subclone growth is predominantly spatially contiguous in nature. We found only two cases of subclone dispersal, one of which was associated with metastasis. The largest subclones spatially were dominated by driver somatic copy number alterations, suggesting that a large selective advantage can be conferred to subclones upon acquisition of these alterations. In conclusion, spatial dynamics is strongly associated with genomic alterations and plays an important role in tumour evolution.

The Impact of the COVID-19 Pandemic on Genitourinary Cancer Care: Re-envisioning the Future.

CONTEXT: The coronavirus disease 2019 (COVID-19) pandemic necessitated rapid changes in medical practice. Many of these changes may add value to care, creating opportunities going forward. OBJECTIVE: To provide an evidence-informed, expert-derived review of genitourinary cancer care moving forward following the initial COVID-19 pandemic. EVIDENCE ACQUISITION: A collaborative narrative review was conducted using literature published through May 2020 (PubMed), which comprised three main topics: reduced in-person interactions arguing for increasing virtual and image-based care, optimisation of the delivery of care, and the effect of COVID-19 in health care facilities on decision-making by patients and their families. EVIDENCE SYNTHESIS: Patterns of care will evolve following the COVID-19 pandemic. Telemedicine, virtual care, and telemonitoring will increase and could offer broader access to multidisciplinary expertise without increasing costs. Comprehensive and integrative telehealth solutions will be necessary, and should consider patients' mental health and access differences due to socioeconomic status. Investigations and treatments will need to maximise efficiency and minimise health care interactions. Solutions such as one stop clinics, day case surgery, hypofractionated radiotherapy, and oral or less frequent drug dosing will be preferred. The pandemic necessitated a triage of those patients whose treatment should be expedited, delayed, or avoided, and may persist with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in circulation. Patients whose demographic characteristics are at the highest risk of complications from COVID-19 may re-evaluate the benefit of intervention for less aggressive cancers. Clinical research will need to accommodate virtual care and trial participation. Research dissemination and medical education will increasingly utilise virtual platforms, limiting in-person professional engagement; ensure data dissemination; and aim to enhance patient engagement. CONCLUSIONS: The COVID-19 pandemic will have lasting effects on the delivery of health care. These changes offer opportunities to improve access, delivery, and the value of care for patients with genitourinary cancers but raise concerns that physicians and health administrators must consider in order to ensure equitable access to care. PATIENT SUMMARY: The coronavirus disease 2019 (COVID-19) pandemic has dramatically changed the care provided to many patients with genitourinary cancers. This has necessitated a transition to telemedicine, changes in threshold or delays in many treatments, and an opportunity to reimagine patient care to maintain safety and improve value moving forward.

Numerical simulation modeling of the irreversible electroporation treatment zone for focal therapy of prostate cancer, correlation with whole-mount pathology and T2-weighted MRI sequences.

BACKGROUND: At present, it is not possible to predict the ablation zone volume following irreversible electroporation (IRE) for prostate cancer (PCa). This study aimed to determine the necessary electrical field threshold to ablate human prostate tissue in vivo with IRE. METHODS: In this prospective multicenter trial, patients with localized PCa were treated with IRE 4 weeks before their scheduled radical prostatectomy. In 13 patients, numerical models of the electrical field were generated and compared with the ablation zone volume on whole-mount pathology and T2-weighted magnetic resonance imaging (MRI) sequences. Volume-generating software was used to calculate the ablation zone volumes on histology and MRI. The electric field threshold to ablate prostate tissue was determined for each patient. RESULTS: A total of 13 patients were included for histological and simulation analysis. The median electrical field threshold was 550 V/cm (interquartile range 383-750 V/cm) for the software-generated histology volumes. The median electrical field threshold was 500 V/cm (interquartile range 386-580 V/cm) when the ablation zone volumes were used from the follow-up MRI. CONCLUSIONS: The electrical field threshold to ablate human prostate tissue in vivo was determined using whole-mount pathology and MRI. These thresholds may be used to develop treatment planning or monitoring software for IRE prostate ablation; however, further optimization of simulation methods are required to decrease the variance that was observed between patients.

Surgery for high-risk locally advanced (pT3c) renal tumours: oncological outcomes and prognostic significance of a modified International Metastatic Renal Cell Cancer Database Consortium (IMDC) score.

OBJECTIVES: To evaluate contemporary oncological outcomes and long-term survival in patients undergoing surgery for urological tumours involving the peridiaphragmatic inferior vena cava up to the level of the right atrium. To apply prognostic factors developed for metastatic renal cancer to patients with very-high-risk but apparently localized tumours, and develop a scoring system. PATIENTS AND METHODS: A retrospective cohort study of 54 patients referred between December 2007 and April 2018 to a single surgical and oncological team was conducted. Electronic patient records were used to obtain peri-operative data and oncological follow-up. For operated patients lost to follow-up, survival data were obtained from primary care physicians. We used Kaplan-Meier curves to estimate overall survival (OS) and disease-free survival. For the subgroup undergoing curative surgery (n = 32) the prognostic value of a renal cancer score developed at Guy's Hospital using five of the six criteria in the International Metastatic Renal Cell Carcinoma Database Consortium prognostic model (one point for each of anaemia, neutrophilia, thrombophilia, hypercalcaemia and Karnofsky performance status <80), in order to be relevant for M0 disease, was assessed using the log-rank test. RESULTS: The median (interquartile range [IQR]) OS of the whole cohort was 29 (11-57) months. The median (IQR) survival of the curative subgroup (n = 32) was 32 (16-57) months, vs 11 (4-upper limit not reached) months for the cytoreductive subgroup (n = 13; P = 0.14). The median (IQR) follow-up time was 14 (1-65) months for patients alive at analysis. Disease-free survival in the curative subgroup was 10 (6-30) months. The median (IQR) OS by risk category for curative cases, as defined by the Guy's renal cancer score, was not reached in the favourable risk group (score = 0 points) because there were no patient deaths, 43 (30-61) months in the intermediate-risk group (score = 1 point), and 18 months (11-32) months in the poor-risk group (score ≥ 2 points; P = 0.005). CONCLUSION: A median survival of 29 months appears to justify this type of surgery. A prognostic model, the Guy's renal cancer score, using five readily available clinical measures, appears promising in patients with very-high-risk locally advanced tumours.

The Case for Photodynamic Diagnosis-assisted Resection Without Intravesical Single-shot Chemotherapy.

Although there is level 1 evidence for the use of intravesical chemotherapy after the transurethral resection of bladder tumour, the decision to apply it needs to be individualised. "What benefit will the patient derive from it?"

The natural history of crouch gait in bilateral cerebral palsy: A systematic review.

AIM: To systematically review the natural history of crouch gait in bilateral cerebral palsy (CP) in the absence of surgical intervention and to review any relationship between clinical variables and progression of knee crouch. METHODS: Relevant literature was identified by searching article databases (PubMed, CINAHL, EMBASE, and Web of Science). Included studies reported on participants with bilateral CP who had 3-dimensional gait analysis on at least two occasions with no surgical interventions between analyses. RESULTS: Five papers (4 retrospective cohort studies; 1 case report) comprised the final selection. Studies varied in follow-up times and participant numbers. Increased knee flexion over time was reported in the four retrospective studies with two distinct patterns of increasing knee flexion evident. Only the case-study reported improved knee extension between assessments. Four studies demonstrated increased hamstring tightness over time with the biggest increases related to longer follow-up time rather than increase in crouch. CONCLUSION AND IMPLICATIONS: The existing literature suggests that the natural history of crouch gait is towards increasing knee flexion over time. Future prospective studies of bigger groups are needed to examine the relationship between increasing crouch and clinical variables.

Timing the Landmark Events in the Evolution of Clear Cell Renal Cell Cancer: TRACERx Renal.

Clear cell renal cell carcinoma (ccRCC) is characterized by near-universal loss of the short arm of chromosome 3, deleting several tumor suppressor genes. We analyzed whole genomes from 95 biopsies across 33 patients with clear cell renal cell carcinoma. We find hotspots of point mutations in the 5' UTR of TERT, targeting a MYC-MAX-MAD1 repressor associated with telomere lengthening. The most common structural abnormality generates simultaneous 3p loss and 5q gain (36% patients), typically through chromothripsis. This event occurs in childhood or adolescence, generally as the initiating event that precedes emergence of the tumor's most recent common ancestor by years to decades. Similar genomic changes drive inherited ccRCC. Modeling differences in age incidence between inherited and sporadic cancers suggests that the number of cells with 3p loss capable of initiating sporadic tumors is no more than a few hundred. Early development of ccRCC follows well-defined evolutionary trajectories, offering opportunity for early intervention.

Deterministic Evolutionary Trajectories Influence Primary Tumor Growth: TRACERx Renal.

The evolutionary features of clear-cell renal cell carcinoma (ccRCC) have not been systematically studied to date. We analyzed 1,206 primary tumor regions from 101 patients recruited into the multi-center prospective study, TRACERx Renal. We observe up to 30 driver events per tumor and show that subclonal diversification is associated with known prognostic parameters. By resolving the patterns of driver event ordering, co-occurrence, and mutual exclusivity at clone level, we show the deterministic nature of clonal evolution. ccRCC can be grouped into seven evolutionary subtypes, ranging from tumors characterized by early fixation of multiple mutational and copy number drivers and rapid metastases to highly branched tumors with >10 subclonal drivers and extensive parallel evolution associated with attenuated progression. We identify genetic diversity and chromosomal complexity as determinants of patient outcome. Our insights reconcile the variable clinical behavior of ccRCC and suggest evolutionary potential as a biomarker for both intervention and surveillance.