Evaluation of implementation of risk management guidelines for carriers of pathogenic variants in mismatch repair genes: a nationwide audit of familial cancer clinics.

INTRODUCTION: This nationwide study assessed the impact of Lynch syndrome-related risk management guidelines on clinicians' recommendations of risk management strategies to carriers of pathogenic variants in mismatch repair genes and the extent to which carriers took up strategies in concordance with guidelines. MATERIALS AND METHODS: Clinic files of 464 carriers (with and without colorectal cancer) were audited for carriers who received their genetic testing results in July 2008-July 2009 (i.e. before guideline release), July 2010-July 2011 and July 2012-July 2013 (both after guideline release) at 12 familial cancer clinics (FCCs) to ascertain the extent to which carriers were informed about risk management in accordance with guidelines. All carriers captured by the audit were invited to participate in interviews; 215 were interviewed to assess adherence to recommended risk management guidelines. RESULTS: The rates of documentation in clinic files increased significantly from pre- to post-guideline for only two out of eight risk management strategies. The strategies with the highest compliance of carriers post-guidelines were: uptake of one or two-yearly colonoscopy (87%), followed by hysterectomy to prevent endometrial cancer (68%), aspirin as risk-reducing medication (67%) and risk-reducing salpingo-oophorectomy (63%). Interrater reliability check for all guidelines showed excellent agreement (k statistics = 0.89). CONCLUSION: These results indicate that there is scope to further increase provision of advice at FCCs to ensure that all carriers receive recommendations about evidence-based risk management. A multi-pronged behaviour change and implementation science approach tailored to specific barriers is likely to be needed to achieve optimal clinician behaviours and outcomes for carriers.

Inhalational versus propofol-based total intravenous anaesthesia: practice patterns and perspectives among Australasian anaesthetists.

Increasing evidence suggests that total intravenous anaesthesia (TIVA) may be the preferred anaesthetic for cancer resection surgery. To assist the preparation of a randomised controlled trial (RCT) examining Volatile (versus TIVA) Anaesthesia and Perioperative Outcomes Related to Cancer (VAPOR-C) we developed an 18-question electronic survey to investigate practice patterns and perspectives (emphasising indications, barriers, and impact on cancer outcomes) of TIVA versus inhalational general anaesthesia in Australasia. The survey was emailed to 1,000 (of 5,300 active Fellows) randomly selected Australian and New Zealand College of Anaesthetists (ANZCA) Fellows. The response rate was 27.5% (n=275). Of the respondents, 18% use TIVA for the majority of cases. In contrast, 46% use TIVA 20% of the time or less. Respondents described indications for TIVA as high risk of nausea, neurosurgery, and susceptibility to malignant hyperthermia. Lack of equipment, lack of education and cost were not considered barriers to TIVA use, and a significant proportion (41%) of respondents would use TIVA more often if setup were easier. Of the respondents, 43% thought that TIVA was associated with less cancer recurrence than inhalational anaesthesia, while 46% thought that there was no difference. Yet, only 29% of respondents reported that they use TIVA often or very often for cancer surgery. In Australasia, there is generally a low frequency of TIVA use despite a perception of benefit when compared with inhalational anaesthesia. Anaesthetists are willing to use TIVA for indications where sufficient evidence supports a meaningful level of improvement in clinical outcome. The survey explores attitudes towards use of TIVA for cancer surgery and demonstrates equipoise in anaesthetists' opinions regarding this indication. The inconsistent use of TIVA in Australasia, minimal barriers to its use, and the equipoise in anaesthetists' opinions regarding the effect of TIVA versus inhalational anaesthesia on cancer outcomes support the need for a large prospective RCT.

Effect of beta-blockers on cancer recurrence and survival: a meta-analysis of epidemiological and perioperative studies.

BACKGROUND: The biological perturbation associated with psychological and surgical stress is implicated in cancer recurrence. Preclinical evidence suggests that beta-blockers can be protective against cancer progression. We undertook a meta-analysis of epidemiological and perioperative clinical studies to investigate the association between beta-blocker use and cancer recurrence (CR), disease-free survival (DFS), and overall survival (OS). METHODS: Databases were searched until September 2017, reported hazard ratios (HRs) pooled, and 95% confidence intervals (CIs) calculated. Comparative studies examining the effect of beta-blockers (selective and non-selective) on cancer outcomes were included. The Newcastle Ottawa Scale was used to assess methodological quality and bias. RESULTS: Of the 27 included studies, nine evaluated the incidental use of non-selective beta-blockers, and ten were perioperative studies. Beta-blocker use had no effect on CR. Within subgroups of cancer, melanoma was associated with improved DFS (HR 0.03, 95% CI 0.01-0.17) and OS (HR 0.04, 95% CI 0.00-0.38), while endometrial cancer had an associated reduction in DFS (HR 1.40, 95% CI 1.10-1.80) and OS (HR 1.50, 95% CI 1.12-2.00). There was also reduced OS seen with head and neck and prostate cancer. Non-selective beta-blocker use was associated with improved DFS and OS in ovarian cancer, improved DFS in melanoma, but reduced OS in lung cancer. Perioperative studies showed similar variable effects across cancer types, albeit from a limited data pool. CONCLUSION: Beta-blocker use had no evident effect on CR. The beneficial effect of beta-blockers on DFS and OS in the epidemiological or perioperative setting remains variable, tumour-specific, and of low-level evidence at present.

The effects of ambient temperature and heatwaves on daily Campylobacter cases in Adelaide, Australia, 1990-2012.

Campylobacter spp. is a commonly reported food-borne disease with major consequences for morbidity. In conjunction with predicted increases in temperature, proliferation in the survival of microorganisms in hotter environments is expected. This is likely to lead, in turn, to an increase in contamination of food and water and a rise in numbers of cases of infectious gastroenteritis. This study assessed the relationship of Campylobacter spp. with temperature and heatwaves, in Adelaide, South Australia. We estimated the effect of (i) maximum temperature and (ii) heatwaves on daily Campylobacter cases during the warm seasons (1 October to 31 March) from 1990 to 2012 using Poisson regression models. There was no evidence of a substantive effect of maximum temperature per 1 °C rise (incidence rate ratio (IRR) 0·995, 95% confidence interval (95% CI) 0·993-0·997) nor heatwaves (IRR 0·906, 95% CI 0·800-1·026) on Campylobacter cases. In relation to heatwave intensity, which is the daily maximum temperature during a heatwave, notifications decreased by 19% within a temperature range of 39-40·9 °C (IRR 0·811, 95% CI 0·692-0·952). We found little evidence of an increase in risk and lack of association between Campylobacter cases and temperature or heatwaves in the warm seasons. Heatwave intensity may play a role in that notifications decreased with higher temperatures. Further examination of the role of behavioural and environmental factors in an effort to reduce the risk of increased Campylobacter cases is warranted.

The effect of temperature on different Salmonella serotypes during warm seasons in a Mediterranean climate city, Adelaide, Australia.

Changing trends in foodborne disease are influenced by many factors, including temperature. Globally and in Australia, warmer ambient temperatures are projected to rise if climate change continues. Salmonella spp. are a temperature-sensitive pathogen and rising temperature can have a substantial effect on disease burden affecting human health. We examined the relationship between temperature and Salmonella spp. and serotype notifications in Adelaide, Australia. Time-series Poisson regression models were fit to estimate the effect of temperature during warmer months on Salmonella spp. and serotype cases notified from 1990 to 2012. Long-term trends, seasonality, autocorrelation and lagged effects were included in the statistical models. Daily Salmonella spp. counts increased by 1·3% [incidence rate ratio (IRR) 1·013, 95% confidence interval (CI) 1·008-1·019] per 1 °C rise in temperature in the warm season with greater increases observed in specific serotype and phage-type cases ranging from 3·4% (IRR 1·034, 95% CI 1·008-1·061) to 4·4% (IRR 1·044, 95% CI 1·024-1·064). We observed increased cases of S. Typhimurium PT9 and S. Typhimurium PT108 notifications above a threshold of 39 °C. This study has identified the impact of warm season temperature on different Salmonella spp. strains and confirms higher temperature has a greater effect on phage-type notifications. The findings will contribute targeted information for public health policy interventions, including food safety programmes during warmer weather.

Undiagnosed hypertension in a rural district in Bangladesh: The Bangladesh Population-based Diabetes and Eye Study (BPDES).

Hypertension is mainly asymptomatic and remains undiagnosed until the disease progresses. The objective of the study was to determine the prevalence of and risk factors for hypertension in rural Bangladesh. Using a population-based cluster random sampling strategy, 3096 adults aged ⩾30 years were recruited from a rural district in Bangladesh. Data collected included two blood pressure (BP) measurements, fasting blood glucose, socio-demographic and anthropometric measurements. Hypertension was defined as systolic BP (SBP) ⩾140 mm Hg or diastolic BP (DBP) ⩾90 mm Hg or self-reported diagnosed hypertension. Logistic regression techniques were used for data analyses. The crude prevalence of hypertension was 40% (95% confidence interval (CI) 38-42%) of which 82% were previously undiagnosed. People from lower socio-economic status (SES) had a significantly higher percentage of undiagnosed hypertension compared with people with higher SES (P<0.001). There was no significant gender difference in severity of hypertension. Males with higher education level compared with no education had a higher prevalence of hypertension (odds ratio 2.34, 95% CI 1.49-3.69). Older age and waist circumference in both genders, and diabetes, lack of physical activity in females were found to be associated with higher prevalence of hypertension. Our research suggests the prevalence of undiagnosed hypertension was higher in the rural area in Bangladesh than that reported from the rural area in neighbouring India and China. Lower SES was associated with a higher risk of undiagnosed hypertension. Public health programs at the grass-roots level must emphasise the provision of primary care and preventive services in managing this non-communicable disease.

Clinical outcomes of elderly patients receiving neoadjuvant chemoradiation for locally advanced rectal cancer.

BACKGROUND: Studies of clinical outcomes of elderly patients treated with neoadjuvant chemoradiation (nCRT) for locally advanced rectal cancer (LARC) are limited. Our aim was to assess the impact of age on clinical outcomes in a large multi-institutional database. PATIENTS AND METHODS: Data for patients diagnosed with LARC who received nCRT and curative-intent surgery between 2005 and 2012 were collected from five major Canadian cancer centers. Age was analyzed as a continuous and dichotomous variable (< 70 versus ≥ 70 years) and correlated with disease-free survival (DFS), cancer-specific survival (CSS) and overall survival (OS). Cox regression models were used to adjust for important prognostic factors. RESULTS: Of 1172 patients included, 295 (25%) were ≥ 70 years, and they were less likely to receive adjuvant chemotherapy (ACT; 60% versus 79%, P < 0.0001), oxaliplatin-based ACT (12% versus 31%, P < 0.0001), less likely to complete nCT (76% versus 86%, P < 0.001), and more likely to be anemic at initiation of nCRT (42% versus 30%, P = 0.0004). In multivariate analyses, age ≥ 70 years was associated with similar DFS [hazard ratio (HR) 0.93, 95% confidence interval (CI) 0.68-1.26, P = 0.63], similar CSS (HR 0.81, 95% CI 0.46-1.41, P = 0.45), and similar OS (HR 1.28, 95% CI 0.88-1.86, P = 0.20), compared with the younger age group. As a continuous variable, increasing age was not predictive of DFS (HR 1.00, 95% CI 0.99-1.02, P = 0.49) or CSS (HR 1.002, 95% CI 0.98-1.02, P = 0.88); however, it correlated with an inferior OS (HR 1.02, 95% CI 1.00-1.03, P = 0.04). CONCLUSIONS: Elderly patients (≥ 70 years) who receive nCRT followed by surgery appear to have similar outcomes compared with younger patients. Decisions regarding eligibility for nCRT and surgery should not be based on age alone.

Relevance of chronic hepatitis E in liver transplant recipients: a real-life setting.

The chronic course of hepatitis E virus (HEV) infections in orthotopic liver transplant (OLT) recipients has been described previously, but prospectively collected data are rare. We aimed to study the role of chronic hepatitis E in OLT in a real-life setting. Therefore, 287 adult OLT recipients (169 male [59%], median age 56 years) were prospectively tested by HEV polymerase chain reaction assay (lower level of detection = 10 IU/mL), irrespective of their level of liver enzymes. In 4 patients (1.4%), chronic HEV infection was diagnosed. All 4 patients were male, and their age (median 48.5 years), the time since transplantation (median 45.5 months), and bilirubin level (median 0.6 mg/dL) did not differ significantly from the total cohort. However, alanine transaminase and aspartame transaminase levels were significantly higher in HEV-infected patients (75-646 U/L, median 216 U/L and 68-317 U/L, median 108 U/L) than in non-infected patients (6-617 U/L, median 41 and 6-355 U/L, median 36; P = 0.004 and 0.040, Mann-Whitney test). In 3 patients, liver biopsy was performed and revealed signs of inflammation and chronic liver disease, as enlarged densely infiltrated portal tracts with mild-to-moderate interface hepatitis. All infected patients were treated with ribavirin with the starting dose adjusted to renal function (400-800 mg/day). In 2 patients, dose reduction was necessary. Transaminases normalized in all 4 patients, and all patients cleared their infection within 3 months of ribavirin treatment. However, 1 patient experienced viral relapse 12 weeks after discontinuation. Ribavirin medication was re-started and viral clearance occurred within 8 weeks and persisted. Sequence analysis of the HEV genome of this patient revealed that he was infected with an HEV variant, which recently has been shown to have a reduced response to ribavirin in cell culture. The risk of chronic HEV infections in OLT recipients in low-endemic countries should not be overestimated. No case of chronic hepatitis E was observed in patients with normal liver enzymes, indicating that general screening of all OLT recipients is not necessary. However, if chronic hepatitis E develops, it can be treated efficiently with ribavirin.

Does Co-morbidity provide significant improvement on age adjustment when predicting medical outcomes?

OBJECTIVE: Using three risk-adjustment methods we evaluated whether co-morbidity derived from electronic hospital patient data provided significant improvement on age adjustment when predicting major outcomes following an elective total joint replacement (TJR) due to osteoarthritis. METHODS: Longitudinal data from 819 elderly men who had had a TJR were integrated with hospital morbidity data (HMD) and mortality records. For each participant, any morbidity or health-related outcome was retrieved from the linked data in the period 1970 through to 2007 and this enabled us to better account for patient co-morbidities. Co-morbidities recorded in the HMD in all admissions preceding the index TJR admission were used to construct three risk-adjustment methods, namely Charlson co-morbidity index (CCI), Elixhauser's adjustment method, and number of co-morbidities. Postoperative outcomes evaluated included length of hospital stay, 90-day readmission, and 1-year and 2-year mortality. These were modelled using Cox proportional hazards regression as a function of age for the baseline models, and as a function of age and each of the risk-adjustment methods. The difference in the statistical performance between the models that included age alone and those that also included the co-morbidity adjustment method was assessed by measuring the difference in the Harrell's C estimates between pairs of models applied to the same patient data using Bootstrap analysis with 1000 replications. RESULTS: Number of co-morbidities did not provide any significant improvement in model discrimination when added to baseline models observed in all outcomes. CCI significantly improved model discrimination when predicting post-operative mortality but not when length of stay or readmission was modelled. For every one point increase in CCI, postoperative 1- and 2-year mortality increased by 37% and 30%, respectively. Elixhauser's method outperformed the other two providing significant improvement on age adjustment in all outcomes. CONCLUSION: The predictive performance of co-morbidity derived from electronic hospital data is outcome and risk-adjustment method specific.

Perioperative epidural analgesia reduces cancer recurrence after gastro-oesophageal surgery.

BACKGROUND: Recent interest has focused on the role of perioperative epidural analgesia in improving cancer outcomes. The heterogeneity of studies (tumour type, stage and outcome endpoints) has produced inconsistent results. Clinical practice also highlights the variability in epidural effectiveness. We considered the novel hypothesis that effective epidural analgesia improves cancer outcomes following gastro-oesophageal cancer surgery in patients with grouped pathological staging. METHODS: Following institutional approval, a database analysis identified 140 patients, with 2-year minimum follow-up after gastro-oesophageal cancer surgery. All patients were operated on by a single surgeon (2005-2010). Information pertaining to cancer and survival outcomes was extracted. RESULTS: Univariate analysis demonstrated a 1-year 14% vs. 33% (P = 0.01) and 2-year 27% vs. 40% [hazard ratio (HR)=0.59; 95% CI, 0.32-1.09, P = 0.087] incidence of cancer recurrence in patients with (vs. without) effective (> 36 h duration) epidural analgesia, respectively. Multivariate analysis demonstrated increased time to cancer recurrence (HR = 0.33; 95% CI: 0.17-0.63, P < 0.0001) and overall survival benefit (HR = 0.42; 95% CI: 0.21-0.83, P < 0.0001) at 2-year follow-up following effective epidural analgesia. Subgroup analysis identified epidural-related cancer recurrence benefit in patients with oesophageal cancer (HR = 0.34; 95% CI: 0.16-0.75, P = 0.005) and in patients with tumour lymphovascular space infiltration (LVSI), (HR = 0.49; 95% CI: 0.26-0.94, P = 0.03). Effective epidural analgesia improved estimated median time to death (2.9 vs. 1.8 years, P = 0.029) in patients with tumour LVSI. CONCLUSIONS: This study found an association between effective post-operative epidural analgesia and medium-term benefit on cancer recurrence and survival following oesophageal surgery. A prospective study that controls for disease type, stage and epidural effectiveness is warranted.

A systematic review of surgical biopsy for LCIS found at core needle biopsy - do we have the answer yet?

BACKGROUND: The natural history of lobular carcinoma in-situ (LCIS) suggests that women are at increased risk of subsequent invasive breast cancer. Questions of effective management for women with this lesion have led to the need for evidence-based guidance and, in particular, guidance regarding management after LCIS is found at core needle biopsy (CNB). METHODS: A systematic review was conducted to determine the most appropriate management for women with LCIS found at CNB. A comprehensive search of the scientific literature was conducted to identify the literature pertaining to this population. Critical appraisal of the literature, data extraction and a narrative synthesis of the results were conducted. The outcome of interest was upgrade of diagnosis to invasive breast cancer or ductal carcinoma in-situ (DCIS). RESULTS: Sparse data, with limited generalisability and considerable uncertainty, are available for women with LCIS at CNB. Nine studies were identified that met pre-specified inclusion criteria. The reported estimates of upgrade of diagnosis from LCIS to invasive breast cancer or DCIS ranged from 2% to 25%. The body of evidence was limited by its retrospective nature, risk of selection bias and poor generalisability to all women with LCIS at CNB. Further, higher quality research is required to determine the best approach for women with LCIS at CNB with any certainty.

Symmetrically reduced stiffness and increased extensibility in compression and tension at the mineralized fibrillar level in rachitic bone.

In metabolic bone diseases, the alterations in fibrillar level bone-material quality affecting macroscopic mechanical competence are not well-understood quantitatively. Here, we quantify the fibrillar level deformation in cantilever bending in a mouse model for hereditary rickets (Hpr). Microfocus in-situ synchrotron small-angle X-ray scattering (SAXS) combined with cantilever bending was used to resolve nanoscale fibril strain in tensile- and compressive tissue regions separately, with quantitative backscattered scanning electron microscopy used to measure microscale mineralization. Tissue-level flexural moduli for Hpr mice were significantly (p<0.01) smaller compared to wild-type (~5 to 10-fold reduction). At the fibrillar level, the fibril moduli within the tensile and compressive zones were significantly (p<0.05) lower by ~3- to 5-fold in Hpr mice compared to wild-type mice. Hpr mice have a lower mineral content (24.2±2.1Cawt.% versus 27.4±3.3Ca wt.%) and its distribution was more heterogeneous compared to wild-type animals. However, the average effective fibril modulus did not differ significantly (p>0.05) over ages (4, 7 and 10weeks) between tensile and compressive zones. Our results indicate that incompletely mineralized fibrils in Hpr mice have greater deformability and lower moduli in both compression and tension, and those compressive and tensile zones have similar moduli at the fibrillar level.

Pre-market approval and post-market direct-to-consumer advertising of medical devices in Australia: a case study of breast cancer screening and diagnostic devices.

While research investigating direct-to-consumer advertising of therapeutic goods in Australia has historically focused on prescription medicines, recent action taken by regulators against companies promoting medical devices has placed the industry into the spotlight. Despite the need to effectively regulate direct-to-consumer advertising of medical devices due to its potential harms, inadequacies in the current regulatory system have been noted. Under the present system, devices with a questionable evidence base may enter the Australian marketplace without an evaluation of their effectiveness, and regulators are reliant on industry self-regulation and consumer complaints to draw attention to cases of advertising misconduct. Although some successes in the present system have been observed, we argue that the outlined inadequacies continue to enable the promotion of medical devices to consumers without thorough or sufficient examination of evidence.

Hypophosphatemic rickets is associated with disruption of mineral orientation at the nanoscale in the flat scapula bones of rachitic mice with development.

Metabolic bone disorders such as rickets are associated with altered in vivo muscular force distributions on the skeletal system. During development, these altered forces can potentially affect the spatial and temporal dynamics of mineralised tissue formation, but the exact mechanisms are not known. Here we have used a murine model of hypophosphatemic rickets (Hpr) to study the development of the mineralised nanostructure in the intramembranously ossifying scapulae (shoulder bone). Using position-resolved scanning small angle X-ray scattering (SAXS), we quantified the degree and direction of mineral nanocrystallite alignment over the width of the scapulae, from the load bearing lateral border (LB) regions to the intermediate infraspinous fossa (IF) tissue. These measurements revealed a significant (p<0.05) increase in mineral nanocrystallite alignment in the LB when compared to the IF region, with increased tissue maturation in wild-type mice; this was absent in mice with rickets. The crystallites were more closely aligned to the macroscopic bone boundary in the LB when compared to the IF region in both wild type and Hpr mice, but the degree of alignment was reduced in Hpr mice. These findings are consistent with a correlation between the nanocrystallites within fibrils and in vivo muscular forces. Thus our results indicate a relevant mechanism for the observed increased macroscopic deformability in rickets, via a significant alteration in the mineral particle alignment, which is mediated by an altered spatial distribution of muscle forces.

Transporting live donor kidneys for kidney paired donation: initial national results.

Optimizing the possibilities for kidney-paired donation (KPD) requires the participation of donor-recipient pairs from wide geographic regions. Initially it was envisaged that donors would travel to the recipient center; however, to minimize barriers to participation and simplify logistics, recent trends have involved transporting the kidneys rather than the donors. The goal of this study was to review outcomes of this practice. KPD programs throughout the United States were directly queried about all transplants involving live donor kidney transport. Early graft function was assessed by urine output in the first 8 h, postoperative serum creatinine trend, and incidence of delayed graft function. Between April 27, 2007 and April 29, 2010, 56 live donor kidneys were transported among 30 transplant centers. Median CIT was 7.2 h (IQR 5.5-9.7, range 2.5-14.5). Early urine output was robust (>100 cc/h) in all but four patients. Creatinine nadir was <2.0 mg/dL in all (including the four with lower urine output) but one patient, occurring at a median of 3 days (IQR 2-5, range 1-49). No patients experienced delayed graft function as defined by the need for dialysis in the first week. Current evidence suggests that live donor kidney transport is safe and feasible.

A retrospective observational study examining the admission arterial to end-tidal carbon dioxide gradient in intubated major trauma patients.

Major trauma patients who are intubated and ventilated are exposed to the potential risk of iatrogenic hypercapnic and hypocapnic physiological stress. In the pre-hospital setting, end-tidal capnography is used as a practical means of estimating arterial carbon dioxide concentrations and to guide the adequacy of ventilation. In our study, potentially deleterious hypercapnia (mean 47 mmHg, range 26 to 83 mmHg) due to hypoventilation was demonstrated in 49% of 100 intubated major trauma patients arriving at a major Australian trauma centre. A mean gradient of 15 mmHg arterial to end-tidal carbon dioxide concentration difference was found, highlighting the limitations of capnography in this setting. Moreover, 80% of the patients in the study had a head injury. Physiological deadspace due to hypovolaemia in these patients is commonly thought to contribute to the increased arterial to end-tidal carbon dioxide gradient in trauma patients. However in this study, scene and arrival patient hypoxia was more predictive of hypoventilation and an increased arterial to end-tidal carbon dioxide gradient than physiological markers of shock. Greater vigilance for hypercapnia in intubated trauma patients is required. Additionally, a larger study may confirm that lower end-tidal carbon dioxide levels could be safely targeted in the pre-hospital and emergency department ventilation strategies of the subgroup of major trauma patients with scene hypoxia.

Exploring policy makers' perspectives on a clinical controversy: airway surgery for adult obstructive sleep apnoea.

BACKGROUND AND OBJECTIVES: Worldwide, there is increasing focus on measures to reduce ineffective healthcare practices. Upper airway surgeries for the treatment of adult obstructive sleep apnoea (OSA) represent a case-study in this area, given recent publications that draw into question their efficacy. Policy stakeholders were canvassed to assess their perspectives on this. DESIGN AND SETTING: Senior health policy stakeholders from Australia were criterion and snowball sampled (to identify opinion leaders). Participants were presented with preparatory material and took part in individual semistructured interviews. These focused on eliciting responses to recently published evidence and a relevant Cochrane review. Questions were posed relating to clinical effectiveness and associated policy implications. Interviews were taped and transcribed for thematic analysis. Participant comments were de-identified. FINDINGS: Ten stakeholders were interviewed before saturation was reached. Thematic analysis highlighted participant concern with the diversity of procedures on offer, coupled with limited effectiveness (suggesting potential clinical uncertainty) and considerations therefore of resource allocation (potential opportunity cost). Stakeholders seem aware of the methodological complexities, the ethical issues raised and the role of patients in considerations regarding appropriateness. Finally, policy stakeholders acknowledge that these procedures appear appropriate only for a minority, with consensus that policy level restrictions to government funding for these procedures may be warranted. CONCLUSION: This report highlights that this clinical controversy is of interest and relevance from a policy perspective with lessons and potential implications for clinical practice. It further highlights the need for clinical consensus on definitions of surgical "success" in treating this condition, as this forms an important pretext to policy considerations.

Genetic discontinuity between local hunter-gatherers and central Europe's first farmers.

After the domestication of animals and crops in the Near East some 11,000 years ago, farming had reached much of central Europe by 7500 years before the present. The extent to which these early European farmers were immigrants or descendants of resident hunter-gatherers who had adopted farming has been widely debated. We compared new mitochondrial DNA (mtDNA) sequences from late European hunter-gatherer skeletons with those from early farmers and from modern Europeans. We find large genetic differences between all three groups that cannot be explained by population continuity alone. Most (82%) of the ancient hunter-gatherers share mtDNA types that are relatively rare in central Europeans today. Together, these analyses provide persuasive evidence that the first farmers were not the descendants of local hunter-gatherers but immigrated into central Europe at the onset of the Neolithic.

Persistent genital arousal disorder: a review of the literature and recommendations for management.

Persistent genital arousal disorder is a newly recognized condition that is poorly understood. There is a paucity of research in this area and there are concerns as to the validity of the results of what little research there has been. This article aims to draw together current literature on this topic and provide readers with guidance on the management of this condition. This includes a working definition, an exploration of possible aetiologies within the confines of current knowledge, practical advice regarding assessment, management and auditable outcomes of practice.