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.

Tracking Cancer Evolution Reveals Constrained Routes to Metastases: TRACERx Renal.

Clear-cell renal cell carcinoma (ccRCC) exhibits a broad range of metastatic phenotypes that have not been systematically studied to date. Here, we analyzed 575 primary and 335 metastatic biopsies across 100 patients with metastatic ccRCC, including two cases sampledat post-mortem. Metastatic competence was afforded by chromosome complexity, and we identify 9p loss as a highly selected event driving metastasis and ccRCC-related mortality (p = 0.0014). Distinct patterns of metastatic dissemination were observed, including rapid progression to multiple tissue sites seeded by primary tumors of monoclonal structure. By contrast, we observed attenuated progression in cases characterized by high primary tumor heterogeneity, with metastatic competence acquired gradually and initial progression to solitary metastasis. Finally, we observed early divergence of primitive ancestral clones and protracted latency of up to two decades as a feature of pancreatic metastases.

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.

Fc-Optimized Anti-CD25 Depletes Tumor-Infiltrating Regulatory T Cells and Synergizes with PD-1 Blockade to Eradicate Established Tumors.

CD25 is expressed at high levels on regulatory T (Treg) cells and was initially proposed as a target for cancer immunotherapy. However, anti-CD25 antibodies have displayed limited activity against established tumors. We demonstrated that CD25 expression is largely restricted to tumor-infiltrating Treg cells in mice and humans. While existing anti-CD25 antibodies were observed to deplete Treg cells in the periphery, upregulation of the inhibitory Fc gamma receptor (FcγR) IIb at the tumor site prevented intra-tumoral Treg cell depletion, which may underlie the lack of anti-tumor activity previously observed in pre-clinical models. Use of an anti-CD25 antibody with enhanced binding to activating FcγRs led to effective depletion of tumor-infiltrating Treg cells, increased effector to Treg cell ratios, and improved control of established tumors. Combination with anti-programmed cell death protein-1 antibodies promoted complete tumor rejection, demonstrating the relevance of CD25 as a therapeutic target and promising substrate for future combination approaches in immune-oncology.

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.

Contemporary surgical management of renal oncocytoma: a nation's outcome.

OBJECTIVE: To report on the contemporary UK experience of surgical management of renal oncocytomas. PATIENTS AND METHODS: Descriptive analysis of practice and postoperative outcomes of patients with a final histological diagnosis of oncocytoma included in The British Association of Urological Surgeons (BAUS) nephrectomy registry from 01/01/2013 to 31/12/2016. Short-term outcomes were assessed over a follow-up of 60 days. RESULTS: Over 4 years, 32 130 renal surgical cases were recorded in the UK, of which 1202 were oncocytomas (3.7%). Most patients were male (756; 62.9%), the median (interquartile range [IQR]) age was 66.8 (13) years. The median (IQR; range) lesion size was 4.1 (3; 1-25) cm, 43.5% were ≤4 cm and 30.3% were 4-7 cm lesions. In all, 35 patients (2.9%) had preoperative renal tumour biopsy. Most patients had minimally invasive surgery, either radical nephrectomy (683 patients; 56.8%), partial nephrectomy (483; 40.2%) or other procedures (36; 3%). One in five patients (243 patients; 20.2%) had in-hospital complications: 48 were Clavien-Dindo classification grade ≥III (4% of the total cohort), including three deaths. Two additional deaths occurred within 60 days of surgery. The analysis is limited by the study's observational nature, not capturing lesions on surveillance or ablated after biopsy, possible underreporting, short follow-up, and lack of central histology review. CONCLUSION: We report on the largest surgical series of renal oncocytomas. In the UK, the complication rate associated with surgical removal of a renal oncocytoma was not negligible. Centralisation of specialist services and increased utilisation of biopsy may inform management, reduce overtreatment, and change patient outcomes for this benign tumour.

Contemporary role of ureterolysis in retroperitoneal fibrosis: treatment of last resort or first intent? An analysis of 50 cases.

OBJECTIVE: To determine the outcomes of open ureterolysis in a contemporary cohort of patients presenting with ureteric obstruction secondary to retroperitoneal fibrosis (RPF). PATIENTS AND METHODS: We conducted a prospective analysis of 50 patients undergoing open ureterolysis and omental wrap between January 2012 and January 2016 in a single centre, managed by a multi-disciplinary RPF team. Patients had a minimum follow-up of 1 year. Indications were: nephrostomy-dependent drainage (n = 5); stent failure as evidenced by persistent hydronephrosis (n = 20); severe stent symptoms (n = 22); and patient choice/pre-emptive (n = 3). Outcome measures were stent-free rate; change in renal function post-ureterolysis; operating variables (operating time, blood loss, complications, length of hospital stay); and need for further intervention. RESULTS: Of the 50 patients, 48 (96%) were stent-free at 3 months and 47/50 (94%) were stent-free at 12 months. The median (interquartile range [IQR]) changes in glomerular filtration rate, according to these indication groups, at 1 year were: overall +6 (-4 to +22)% (P < 0.05); stent failure +25 (+5 to +27)% (P < 0.001); stent symptoms +0 (-17 to +6)% (P = 0.834); nephrostomy-dependent drainage -10 (-19 to -2)% (P = 0.731); and pre-emptive 0 (0 to +8)% (P = 0.5). A total of 11/50 patients (22%) underwent additional procedures: nephrectomy, n = 7; uretero-ureterostomy, n = 1; aneurysm repair, n = 1; 1 Boari flap, n = 1; and ureteric re-implant, n = 1. Serious complications (Clavien III or IV) occurred in 12% of patients. The median (IQR) blood loss was 390 (20-1,200) mL and the median (IQR) length of hospital stay was 8 (3-21) days. CONCLUSIONS: This study suggests that for patients with ureteric obstruction caused by RPF, contemporary ureterolysis performed by a high-volume specialist team can successfully render patients stent- or nephrostomy-free without compromising renal function. The results suggest that ureterolysis should be considered in all patients who present with ureteric obstruction caused by RPF that does not respond quickly to standard treatment.

Contemporary retroperitoneal lymph node dissection (RPLND) for testis cancer in the UK - a national study.

OBJECTIVES: To undertake a comprehensive prospective national study of the outcomes of retroperitoneal lymph node dissection (RPLND) for testis cancer over a 1-year period in the UK. PATIENTS AND METHODS: Data were submitted online using the British Association of Urological Surgeons Section of Oncology Data and Audit System. All new patients undergoing RPLND for testis cancer between March 2012 and February 2013 were studied prospectively. Data were analysed using Tableau software and case ascertainment compared with Hospital Episode Statistics data. RESULTS: In all, 162 men underwent RPLND by 20 surgeons in 17 centres. The mean (range) case volume per centre was 9 (2-32) and the median (range) case volume per surgeon was 6 (1-30). Indications included: residual mass after chemotherapy (73%), primary treatment (6%), relapse (14%), and salvage (7%). The median time to surgery after chemotherapy was 8-12 weeks (<4 - >12 weeks) and 91% of procedures utilised open surgery. The median operating time was 3-4 h (<1.5 - >6 h). Nerve sparing was performed in 67% of patients (19% bilateral, 48% unilateral). The dissection was template in 81% and lumpectomy in 16%; 25% required additional intraoperative procedures including 11% synchronous planned nephrectomy. In all, 157/160 (98%) of recorded RPLND operations were completed. One was terminated due to bleeding and in two the mass could not be removed. There were no deaths within 30 days of surgery. In all, 75% of the men did not require a blood transfusion, 15% required 1-2 units and 10% received >2 units. There were postoperative complications in 10% of the men (Clavien-Dindo Grade I, seven men; Grade II, seven; and Grade III, one). The mean (range) length of stay was 5.5 (1-59) days. Histology showed necrosis in 22%; teratoma differentiated in 42%; and residual cancer in 36%. CONCLUSIONS: This prospective collaborative national study describes for the first time the surgical outcomes after RPLND across the UK. The quality of RPLND in the UK appears high. The study can act as a benchmark for this type of surgery across the world.

Who is at risk of death from nephrectomy? An analysis of thirty-day mortality after 21 380 nephrectomies in 3 years of the British Association of Urological Surgeons (BAUS) National Nephrectomy Audit.

OBJECTIVE: To ascertain contemporary overall and differential thirty-day mortality (TDM) rates after all types of nephrectomy in the UK, and to identify potential new risk factors for death. PATIENTS AND METHODS: We conducted a retrospective analysis of the 110 deaths that occurred within 30 days of surgery out of the total of 21 380 nephrectomies performed, and calculated the odds ratio (OR) and 95% confidence interval (CI) for TDM based on peri-operative characteristics. RESULTS: The overall TDM rate was 110/21380 (0.5%). The TDM rates after radical, partial, simple nephrectomy and nephro-ureterectomy were 0.6% (63/11057), 0.1% (4/3931), 0.4% (11/2819) and 0.9% (28/3091), respectively. TDM increased with age, stage, estimated blood loss (EBL), operating time and performance status. EBL of 1-2 L was associated with a greater risk of TDM than EBL of 2-5 L (OR 1.38; 95% CI 1.03-2.24). Conversion from minimally invasive surgery was associated with higher risk than non-conversion (OR 2.53; 95% CI 1.14-4.51. Curative surgery was safer than cytoreductive surgery (OR 0.31; 95% CI 0.18-0.54). There was an association between surgical volume and TDM. CONCLUSIONS: This study provides contemporary insights into the true risks of all types of nephrectomy. The TDM rate after nephrectomy in the UK appears acceptably low at 0.5%. Established risk factors were confirmed and the following novel risk factors were identified: modest EBL (1-2 L) and conversion from minimally invasive surgery.

Raised preoperative international normalised ratio (INR) identifies patients at high risk of perioperative death after simultaneous renal and cardiac surgery for tumours involving the peri-diaphragmatic inferior vena cava and right atrium.

OBJECTIVE: To identify preoperative factors that predict 30-day mortality in patients undergoing simultaneous cardiac and renal surgery for urological tumours involving the peri-diaphragmatic vena cava and right atrium- The ability to predict mortality and therefore avoid surgery in those patients likely to die would be valuable. PATIENTS AND METHODS: We retrospectively reviewed perioperative outcomes in patients managed between December 2007 and January 2016 by a single team. The relationships of outcome measurements were analysed using Fisher's exact and Mann-Whitney U-tests. RESULTS: Of the 46 patients identified, 41 (89%) underwent surgery (20 males and 21 females). The median (range) age was 65 (17-95) years. Histology confirmed 37 renal cell cancers, one adrenal cancer, two primitive neuroectodermal tumours, and one leiomyosarcoma. The overall 30-day mortality rate was 7% (three of 41 patients). The international normalised ratio (INR), age, and estimated glomerular filtration rate (eGFR) correlated significantly with 30-day mortality. The mortality rate was high in patients with an INR ≥1.5 and <1.5 (with three of the five patients dying) compared to those with an INR <1.5 (0/36 patients died; 30 day mortality 0%). The INR correlated with serious complications (≥Clavien-Dindo Grade III), which occurred in all five patients with an INR ≥1.5 and <1.5 vs 12/36 (33%) with an INR <1.5 (P < 0.002). The median (range) eGFR in those that died was 36 (26-37) mL/min/1.73 m2 compared to 52 (24-154) mL/min/1.73 m2 in those that survived (P = 0.018). CONCLUSIONS: In patients undergoing combined cardiac and renal tumour surgery raised preoperative INR is associated with a high risk of 30-day mortality when the patient is elderly (>70 years) and of significant post-operative complications in younger patients (<70 years). Surgery in patients with a normal INR is challenging but much safer.

Sequential bacillus Calmette-Guérin/Electromotive Drug Administration of Mitomycin C as the Standard Intravesical Regimen in High Risk Nonmuscle Invasive Bladder Cancer: 2-Year Outcomes.

PURPOSE: Sequential bacillus Calmette-Guérin/electromotive drug administration of mitomycin C is reported to be superior to bacillus Calmette-Guérin alone but it has not been widely adopted. We aimed to determine the efficacy and tolerability of sequential bacillus Calmette-Guérin/electromotive drug administration of mitomycin C in high risk, nonmuscle invasive bladder cancer. MATERIALS AND METHODS: Starting in 2009 bacillus Calmette-Guérin/electromotive drug administration of mitomycin C was introduced as the standard induction regime in patients with high risk, nonmuscle invasive bladder cancer undergoing bladder conservation. As induction bacillus Calmette-Guérin was administered in weeks 1 and 2. Mitomycin C was administered in electromotive fashion (40 mg and 20 mA current for 30 minutes) in week 3 and repeated thrice for a total of 9 weeks. As maintenance 3 doses of bacillus Calmette-Guérin were given 3 months after induction and then every 6 months for 3 years. Outcome measures were disease recurrence at first check, 1 and 2-year cystoscopy, and treatment tolerability. RESULTS: Of the 151 patients with high risk, nonmuscle invasive bladder cancer treated between June 2009 and 2013, 44 underwent primary cystectomy and 107 received sequential bacillus Calmette-Guérin/electromotive drug administration of mitomycin C. Disease was high grade Ta/T1 in 86 patients (80%), of whom 34 (32%) also had carcinoma in situ. A total of 19 patients (18%) had primary carcinoma in situ and 2 had recurrent large volume, low grade disease. Of 107 patients 104 underwent first check cystoscopy, including 90 (87%) who were clear. Of the 90 complete responders 86 underwent 1-year cystoscopy, including 74 (86%) who were recurrence-free. Of the 74 patients 71 underwent 2-year cystoscopy, of whom 66 (93%) remained recurrence-free. The full induction schedule was not completed in 30 patients (28%), including 16 and 14 with minor and major schedule alterations, respectively. There was no difference in recurrence between patients who received a full vs a reduced induction schedule. CONCLUSIONS: This study confirms the excellent oncologic efficacy of sequential bacillus Calmette-Guérin/electromotive drug administration of mitomycin C in cases of high risk, nonmuscle invasive bladder cancer. Tolerability is a challenge but alterations to the 9-week schedule appeared to have a negligible impact on outcomes.

Nephron-sparing surgery across a nation - outcomes from the British Association of Urological Surgeons 2012 national partial nephrectomy audit.

OBJECTIVE: To determine the scope and outcomes of nephron-sparing surgery (NSS), i.e. partial nephrectomy, across the UK and in so doing set a realistic benchmark and identify fresh contemporary challenges in NSS. PATIENTS AND METHODS: In 2012 reporting of outcomes of all types of nephrectomy became mandatory in the UK. In all, 148 surgeons in 86 centres prospectively entered data on 6 042 nephrectomies undertaken in 2012. This study is a retrospective analysis of the NSS procedures in the dataset. RESULTS: A total of 1 044 NSS procedures were recorded and the median (range) surgical volume was 4 (1-39) per consultant and 8 (1-59) per centre. In all, 36 surgeons and 10 centres reported on only one NSS. The indications for NSS were: elective with a tumour of ≤4.5 cm in 59%, elective with a tumour of >4.5 cm in 10%, relative in 7%, imperative in 12%, Von Hippel-Lindau in 1%, and unknown in 11%. The median (range) tumour size was 3.4 (0.8-30) cm. The technique used was minimally invasive surgery in 42%, open in 58%, with conversions in 4%. The histology results were: malignant in 80%, benign in 18%, and unknown in 2%. In patients aged <40 years 36% (36/101) had benign histology vs 17% (151/874) of those aged ≥40 years (P < 0.01). In patients with tumours of <2.5 cm 29% (69/238) had benign histology vs 14% (57/410) with tumours of 2.5-4 cm vs 8% (16/194) with tumours of ≥4 cm (P = 0.02). In patients aged <40 years with of tumours of <2.5 cm 44% (15/34) were benign. The 30-day mortality was 0.1% (1/1 044). There were major complications (Clavien-Dindo grade of ≥IIIa) in 5% (53/1 044). There was an increased risk of complications after extended elective NSS of 19% (19/101) vs elective at 12% (76/621) (relative risk [RR] 1.54; P < 0.01). Margins were recorded in 68% (709/1 044) of the patients, with positive margins identified in 7% (51/709). Positive surgical margins after NSS for pathological T3 (pT3) tumours were found in 47.8% (11/23) vs 6.1% (32/523) for pT1a, tumours (RR 5.61; P < 0.01). In all, 14% (894/6 042) of the patients underwent surgery for T1a tumours: 55% (488/894) by NSS, 42% (377/894) by radical nephrectomy (RN), and in 3% (29/894) the procedure used was unknown. Major complications after occurred in 4.9% (24/488) of NSS vs 1.3% (5/377) of RN (P < 0.01). Limitations included poor reporting of renal function data and no data on tumour complexity. CONCLUSIONS: In its first year, mandatory national reporting has provided several challenging contemporary insights into NSS.

Effects of an eight-week supervised, structured lifestyle modification programme on anthropometric, metabolic and cardiovascular risk factors in severely obese adults.

BACKGROUND: Lifestyle modification is fundamental to obesity treatment, but few studies have described the effects of structured lifestyle programmes specifically in bariatric patients. We sought to describe changes in anthropometric and metabolic characteristics in a cohort of bariatric patients after participation in a nurse-led, structured lifestyle programme. METHODS: We conducted a retrospective, observational cohort study of adults with a body mass index (BMI) ≥ 40 kgm(-2) (or ≥ 35 kgm(-2) with significant co-morbidity) who were attending a regional bariatric service and who completed a single centre, 8-week, nurse-led multidisciplinary lifestyle modification programme. Weight, height, waist circumference, blood pressure, HbA1c, fasting glucose and lipid profiles as well as functional capacity (Incremental Shuttle Walk Test) and questionnaire-based anxiety and depression scores before and after the programme were compared in per-protocol analyses. RESULTS: Of 183 bariatric patients enrolled, 150 (81.9%) completed the programme. Mean age of completers was 47.9 ± 1.2 years. 34.7% were male. There were statistically significant reductions in weight (129.6 ± 25.9 v 126.9 ± 26.1 kg, p < 0.001), BMI (46.3 ± 8.3 v 44.9 ± 9.0 kgm(-2), p < 0.001), waist circumference (133.0 ± 17.1 v 129.3 ± 17.5 cm in women and 143.8 ± 19.0 v 135.1 ± 17.9 cm in men, both p < 0.001) as well as anxiety and depression scores, total- and LDL-cholesterol and triglyceride levels, with an increase in functional capacity (5.9 ± 1.7 v 6.8 ± 2.1 metabolic equivalents of thermogenesis (METS), p < 0.001) in completers at the end of the programme compared to the start. Blood pressure improved, with reductions in systolic and diastolic blood pressure from 135 ± 16.2 to 131.6 ± 17.1 (p = 0.009) and 84.7 ± 10.2 to 81.4 ± 10.9 mmHg (p < 0.001), respectively. The proportion of patients achieving target blood pressure increased from 50.3 to 59.3% (p = 0.04). The proportion of patients with diabetes achieving HbA1c <53 mmol/mol increased from 28.6 to 42.9%, p = 0.02. CONCLUSIONS: Bariatric patients completing an 8 week, nurse-led structured lifestyle programme had improved adiposity, fitness, lipid profiles, psychosocial health, blood pressure and glycaemia. Further assessment of this programme in a pragmatic randomised controlled trial seems warranted.

Community participation in health service reform: the development of an innovative remote Aboriginal primary health-care service.

The aim of this study was to describe the reorientation of a remote primary health-care service, in the Kimberley region of Australia, its impact on access to services and the factors instrumental in bringing about change. A unique community-initiated health service partnership was developed between a community-controlled Aboriginal health organisation, a government hospital and a population health unit, in order to overcome the challenges of delivering primary health care to a dispersed, highly disadvantaged Aboriginal population in a very remote area. The shared goals and clear delineation of responsibilities achieved through the partnership reoriented an essentially acute hospital-based service to a prevention-focussed comprehensive primary health-care service, with a focus on systematic screening for chronic disease, interdisciplinary follow up, health promotion, community advocacy and primary prevention. This formal partnership enabled the primary health-care service to meet the major challenges of providing a sustainable, prevention-focussed service in a very remote and socially disadvantaged area.

A systematic review of outcome measurements and quality of studies evaluating fixed tooth-supported restorations.

PURPOSE: The purpose of this systematic review was to review clinical studies of fixed tooth-supported prostheses, and to assess the quality of evidence with an emphasis on the assessment of the reporting of outcome measurements. Multiple hypotheses were generated to compare the effect of study type on different outcome modifiers and to compare the quality of publications before and after January 2005. MATERIALS AND METHODS: An electronic search was conducted using specific databases (MEDLINE via Ovid, EMBASE via Ovid, Cochrane Library) through July 2012. This was complemented by hand searching the past 10 years of issues of the Journal of Oral Rehabilitation, Journal of Prosthetic Dentistry, Journal of Prosthodontics, and the International Journal of Prosthodontics. All experimental and observational clinical studies evaluating survival, success, failure, and complications of tooth-supported extracoronal fixed partial dentures, crowns, and onlays were included. No restrictions on age or follow-up time were placed. RESULTS: The electronic search generated 14,869 papers, of which 206 papers were included for full-text review. Hand-searching added 23 papers. Inclusion criteria were met by 182 papers and were included for the review. The majority were retrospective studies. Only 8 (4.4%) were randomized controlled trials. The majority of the studies measured survival and failure, and few studies recorded data on success; however, more than 60% of the studies failed to define survival, success, and failure. Many studies did not use any standardized criteria for assessment of the quality of the restorations and, when standardized criteria were used, they were modified, thereby not allowing for comparisons with other studies. There was an increase of 21.8% in the number of studies evaluating outcome measurements of all-ceramic restorations in past 8 years. CONCLUSIONS: Prosthodontic literature presents with a reduced percentage of RCTs compared to other disciplines in dentistry. The overall quality of recording prosthodontic outcome measurements has not improved greatly in the past 8 years.

Role of remediation in cases of serious misconduct before UK healthcare regulators: a qualitative study.

BACKGROUND: The raison d'etre of healthcare profession regulators across the globe is to protect patients and the public from the risk of harm. In cases of serious misconduct, remediation is deemed to be an important factor when considering the risk of harm from a practitioner under investigation. Yet, we know very little about how regulators account for remediation in their decision-making, and whether it is consistent with the aim of risk reduction. This paper explores the role of remediation in decision-making in cases of serious misconduct before UK healthcare regulators. METHODS: We conducted interviews with 21 participants from across eight of the nine UK healthcare profession regulators, covering a range of roles in the decision-making process in misconduct cases. Interviews were conducted remotely by video call and digitally transcribed. Data were analysed using the framework analysis method. The initial framework was developed from existing literature and guidance documents from the regulators, and was subsequently refined through the various rounds of coding. RESULTS: Remediation influenced decision-making in three ways: (1) Some types of misconduct were deemed more inherently remediable than others. In cases involving dishonesty or sexual misconduct, remediation was less likely to serve as a mitigating factor. (2) Decision-makers often view remediation as a proxy indicator of practitioner insight. (3) Whether a practitioner had demonstrated their commitment to change through undergoing remediation was more likely to feed into decision-making at the point where current impairment was under consideration. CONCLUSIONS: Remediation plays a key role in decision-makers' judgements in cases of misconduct, particularly when these cases relate to clinical misconduct. In such cases, remediation informs judgements on the levels of practitioner insight and the risk of such misconduct being repeated. Our results suggest a need to develop remediation interventions that are explicitly geared towards the regulatory function of developing practitioner insight. Regulators should also consider the structure of their fitness to practise processes and whether there are appropriate opportunities for judgements on remediation to feed into decisions and to facilitate balanced and proportionate outcomes.

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.