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Evidence from observational studies suggests a positive association between serum thyroid-stimulating hormone (TSH) levels and differentiated thyroid carcinoma. However, the cause-effect relationship is poorly understood, and these studies are susceptible to bias and confounding. Using Mendelian randomization (MR) methodology, this study aimed to investigate the causal role of TSH in both benign thyroid nodules and thyroid cancer in up to 451,025 participants in the UK Biobank. Hospital Episode Statistics and Cancer Registry databases were used to identify 462 patients with differentiated thyroid carcinoma and 2031 patients with benign nodular thyroid disease. MR methods using genetic variants associated with serum TSH were used to test causal relationships between TSH and the two disease outcomes. We observed evidence of an inverse association between TSH levels and both thyroid cancer and benign nodular thyroid disease. Two-sample MR suggested that one standard deviation higher genetically instrumented TSH (approximately 0.8 mlU/L) resulted in an 80% reduction of risk of benign nodular disease (OR 0.20; 95% CI 0.10–0.41) and a 50% reduction of risk of thyroid cancer (OR 0.50; 95% CI 0.27–0.92). In keeping with other recently published studies, our results refute a causal role for TSH in both benign nodular thyroid disease and thyroid cancer, with increasing genetically instrumented TSH resulting in a lower risk of both diseases.

Evidence from observational studies suggest a positive association between serum thyroid-stimulating hormone (TSH) levels and differentiated thyroid carcinoma. However, the cause–effect relationship is poorly understood and these studies are susceptible to bias and confounding. This study aimed to investigate the causal role of TSH in both benign thyroid nodules and thyroid cancer in up to 451,025 UK Biobank participants, using a genetic technique, known as Mendelian randomization (MR). Hospital Episode Statistics and Cancer Registry databases were used to identify 462 patients with differentiated thyroid carcinoma and 2031 patients with benign nodular thyroid disease. MR methods using genetic variants associated with serum TSH were used to test causal relationships between TSH and the two disease outcomes. Mendelian randomization provided evidence of a causal link between TSH and both thyroid cancer and benign nodular thyroid disease. Two-sample MR suggested that a 1 s.d. higher genetically instrumented TSH (approximately 0.8 mIU/L) resulted in 4.96-fold higher odds of benign nodular disease (95% CI 2.46–9.99) and 2.00-fold higher odds of thyroid cancer (95% CI 1.09–3.70). Our results thus support a causal role for TSH in both benign nodular thyroid disease and thyroid cancer.

Highlights • The cost-effectiveness of PBT for adult cancers is subject to considerable uncertainty. • Cost-utility analysis is the gold standard for assessing value, but quality matters. • Our review found studies lacked external validation of model outcomes. • When assessed against standard checklists, studies fell short. • Improving transparency and validation will improve credibility of results., Background and purpose With high treatment costs and limited capacity, decisions on which adult patients to treat with proton beam therapy (PBT) must be based on the relative value compared to the current standard of care. Cost-utility analyses (CUAs) are the gold-standard method for doing this. We aimed to appraise the methodology and quality of CUAs in this area. Materials and Methods We performed a systematic review of the literature to identify CUA studies of PBT in adult disease using MEDLINE, EMBASE, EconLIT, NHS Economic Evaluation Database (NHS EED), Web of Science, and the Tufts Medical Center Cost-Effectiveness Analysis Registry from 1st January 2010 up to 6th June 2018. General characteristics, information relating to modelling approaches, and methodological quality were extracted and synthesized narratively. Results Seven PBT CUA studies in adult disease were identified. Without randomised controlled trials to inform the comparative effectiveness of PBT, studies used either results from one-armed studies, or dose-response models derived from radiobiological and epidemiological studies of PBT. Costing methods varied widely. The assessment of model quality highlighted a lack of transparency in the identification of model parameters, and absence of external validation of model outcomes. Furthermore, appropriate assessment of uncertainty was often deficient. Conclusion In order to foster credibility, future CUA studies must be more systematic in their approach to evidence synthesis and expansive in their consideration of uncertainties in light of the lack of clinical evidence.

Objectives: The purpose of this investigation was to assess the pharyngeal dimensions and the craniofacial morphology of individuals with Treacher Collins syndrome (TCS) when compared to vertical skeletal class II individuals. It is our hypothesis that the upper airways of individuals with TCS are reduced in view of the skeletal pattern and the maxillomandibular dysmorphologies. Materials and Methods: Cone-beam computed tomography scans of 26 individuals had the pharyngeal volume (V) and minimal cross-sectional area (mCSA) evaluated. Study group (TCS) was formed by 13 scans of patients with TCS (7 males and 6 females; 20.2 ± 4.7 years). Control group (CG) assembled 13 scans of nonaffected individuals with the same type of skeletal pattern (2 males and 11 females; 26.6 ± 5.4 years). Cephalometric data of maxillomandibular position, maxillomandibular dimensions, and growth pattern were assessed. Statistical analysis ( P ≤ .05) included Student t test and Pearson correlation coefficient. Results: Although reduced, pharyngeal V and mCSA of TCS were not statistically different from the CG. On both groups, mCSA was mostly at the oropharyngeal level. Individuals with TCS presented retrognathic chin, reduced maxillomandibular dimensions, and increased clockwise rotation of the palatal plane. Maxillary and mandibular lengths were correlated with pharyngeal V and mCSA. Conclusions: The pharyngeal dimensions of individuals with TCS are impacted by the micrognathia and retrognathia. In association with the skeletal pattern, the reduction of the airways, although not statistically significant, may explain the increased prevalence of airways disorder in this syndrome.

Background Preterm birth is common in twins and accounts for significant mortality and morbidity. There are no effective preventative treatments. Some studies have suggested that, in twin pregnancy complicated by a short cervix, the Arabin pessary, which fits around the cervix and can be inserted as an outpatient procedure, reduces preterm birth and prevents neonatal morbidity. Objective STOPPIT 2 aimed to evaluate the clinical utility of the Arabin cervical pessary in preventing preterm birth in women with a twin pregnancy and a short cervix. Design STOPPIT 2 was a pragmatic, open label, multicentre randomised controlled trial with two treatment group – the Arabin pessary plus standard care (intervention) and standard care alone (control). Participants were initially recruited into the screening phase of the study, when cervical length was measured. Women with a measured cervical length of ≤ 35 mm were then recruited into the treatment phase of the study. An economic evaluation considered cost-effectiveness and a qualitative substudy explored the experiences of participants and clinicians. Setting Antenatal clinics in the UK and elsewhere in Europe. Participants Women with twin pregnancy at Interventions Ultrasound scan to establish cervical length. Women with a cervical length of ≤ 35 mm at 18+ 0–20+ 6 weeks’ gestation were randomised to standard care or Arabin pessary plus standard care. Randomisation was performed by computer and accessed through a web-based browser. Main outcome measures Obstetric – all births before 34+ 0 weeks’ gestation following the spontaneous onset of labour; and neonatal – composite of adverse outcomes, including stillbirth or neonatal death, periventricular leukomalacia, early respiratory morbidity, intraventricular haemorrhage, necrotising enterocolitis or proven sepsis, all measured up to 28 days after the expected date of delivery. Results A total of 2228 participants were recruited to the screening phase, of whom 2170 received a scan and 503 were randomised: 250 to Arabin pessary and 253 to standard care alone. The rate of the primary obstetric outcome was 18.4% (46/250) in the intervention group and 20.6% (52/253) in the control group (adjusted odds ratio 0.87, 95% confidence interval 0.55 to 1.38; p = 0.54). The rate of the primary neonatal outcome was 13.4% (67/500) and 15.0% (76/506) in the intervention group and control group, respectively (adjusted odds ratio 0.86, 95% confidence interval 0.54 to 1.36; p = 0.52). The pessary was largely well tolerated and clinicians found insertion and removal ‘easy’ or ‘fairly easy’ in the majority of instances. The simple costs analysis showed that pessary treatment is no more costly than standard care. Limitations There was the possibility of a type II error around smaller than anticipated benefit. Conclusions In this study, the Arabin pessary did not reduce preterm birth or adverse neonatal outcomes in women with a twin pregnancy and a short cervix. The pessary either is ineffective at reducing preterm birth or has an effect size of Future work Women with twin pregnancy remain at risk of preterm birth; work is required to find treatments for this. Trial registration Current Controlled Trials ISRCTN98835694 and ClinicalTrials.gov NCT02235181. Funding This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 44. See the NIHR Journals Library website for further project information.

Background The significant variation in the clinical behaviour of sporadic medullary thyroid carcinoma (sMTC) causes uncertainty when planning the management of these patients. Several tumour genetic and epigenetic markers have been described, but their clinical usefulness remains unclear. The aim of this review was to evaluate the evidence for the use of molecular genetic and epigenetic profiles in the risk stratification and management of sMTC. Methods MEDLINE and Embase databases were searched using the MeSH terms "medullary carcinoma", "epigenetics", "molecular genetics", "microRNAs"; and free text terms "medullary carcinoma", "sporadic medullary thyroid cancer", "sMTC", "RET", "RAS" and "miR". Articles containing less than ten subjects, not focussing on sMTC, or not reporting clinical outcomes were excluded. Risk of bias was assessed using a modified version of the Newcastle-Ottawa Scale. Results Twenty-three studies met the inclusion criteria, and key findings were summarized in themes according to the genetic and epigenetic markers studied. There is good evidence that somatic RET mutations predict higher rates of lymph node metastasis and persistent disease, and worse survival. There are also several good quality studies demonstrating associations between certain epigenetic markers such as tumour miR-183 and miR-375 expression and higher rates of lymph node and distant metastasis, and worse survival. Conclusions There is a growing body of evidence that tumour genetic and epigenetic profiles can be used to risk stratify patients with sMTC. Further research should focus on the clinical applicability of these findings by investigating the possibility of tailoring management to an individual's tumour mutation profile.

I argue for the view that some we-thoughts are immune to error through misidentification (IEM) relative to the first-person plural pronoun. To prepare the ground for this argument I defend an account of the semantics of ‘we’ and note the variety of different uses of that term. I go on to defend the IEM of a certain range of we-thoughts against a number of objections.

Background Subacute cutaneous lupus erythematosus (SCLE) lacks consensus diagnostic criteria and the pathogenesis is poorly understood. There are increasing reports of SCLE induced by monoclonal antibodies (mAbs), but there are limited data on the aetiology, clinical characteristics and natural course of this disease. Methods We devised a set of diagnostic criteria for SCLE in collaboration with a multinational, multispecialty panel. This systematic review employed a two-layered search strategy of five databases for cases of mAb-induced SCLE (PROSPERO registered protocol CRD42019116521). To explore the relationship between relative mAb use and the number of SCLE cases reported, the estimated number of mAb users was modelled from 2013 to 2018 global commercial data and estimated annual therapy costs. Results From 40 papers, we identified 52 cases of mAb-induced SCLE, occurring in a cohort that was 73% female and with a median age of 61 years. Fifty percent of cases were induced by anti-tumour necrosis factor (TNF)-ɑ agents. A median of three drug doses preceded SCLE onset and the lesions lasted a median of 7 weeks after drug cessation. Oral and topical corticosteroids were most frequently used. Of the licensed mAbs, adalimumab, denosumab, rituximab, etanercept and infliximab were calculated to have the highest relative number of yearly users based on global sales data. Comparing the number of mAb-induced SCLE cases with estimated yearly users, the checkpoint inhibitors pembrolizumab and nivolumab showed strikingly high rates of SCLE relative to their global use, but ipilimumab did not. Conclusion We present the first systematic review characterising mAb-induced SCLE with respect to triggers, clinical signs, laboratory findings, prognosis and treatment approaches. We identify elevated rates associated with the use of checkpoint inhibitors and anti-TNFɑ agents. Electronic supplementary material The online version of this article (10.1007/s40268-020-00320-5) contains supplementary material, which is available to authorized users.

Objective Diagnostic germline RET analysis is offered to all patients with a diagnosis of medullary thyroid carcinoma (MTC), or other conditions associated with multiple endocrine neoplasia type 2 (MEN2) in the United Kingdom. Here, we report the experience of a single centre's germline RET analysis over a 21-year period. Design Retrospective case-note review. Patients All index patients referred to the Exeter Genomics Laboratory for diagnostic germline RET analysis between 1997 and 2018, and unaffected family members, undergoing predictive testing. Measurements The rate and nature of pathogenic variant detection were recorded, as well as the indication for testing. Results 1,058 index patients and 551 unaffected family members were tested. The overall rate of pathogenic variant detection was 10.2% amongst index patients and 29% amongst unaffected family members. The commonest indication was isolated MTC, and amongst the 690 patients with isolated MTC, 68 (9.9%) were found to harbour a RET pathogenic variant. Of those with presumed sporadic MTC, 8.5% were found to harbour germline RET pathogenic variants, compared with 36.4% of those with a family history of MEN2-associated conditions. Pathogenic variants were identified in 3.6% and 0% of patients with isolated phaeochromocytoma and primary hyperparathyroidism, respectively. Conclusions Although the detection rate of RET germline pathogenic variants in patients with presumed sporadic MTC was significant, the overall detection rate in those with MTC was lower than expected in this series. Advances in RET analysis in response to reports of new variants over the last two decades are likely to have improved the pick-up rate in recent years.

Background Nurse migration is increasingly seen as an appropriate response to address nursing shortages in overburdened health systems. This paper aims to analyse the situation in Germany, the UK and Australia and identify similarities and differences in the dimensions, perceptions and processing of nurse migration in different health systems. Methods A rapid evidence assessment and comparative situation analysis of routine data obtained from public health, education and labour market reporting systems, and academic and grey literature were carried out in Jan-Feb 2020. Primary outcome measures were key data of nurse population and migration, barriers and opportunities, and educational initiatives to support migrating nurses to meet the requirements to work in the destination country. Results Germany, the UK and Australia are confronted with an ageing and increasingly chronically ill population and severe nursing shortages. Skilled migration is seen as an opportunity to address these problems, but each country is faced with different contextual conditions and requirements. Data on the nurse workforce obtained from public health, educational and labour market reporting systems are more differentiated and extensive in the UK and Australia than in Germany. Furthermore, there is a substantial amount of published literature in the UK (n = 65) and Australia (n = 87) on nurse migration and on how the countries address challenges in this area; in comparison to the German context, where such research is limited (n = 7). Available research focuses on the economic, epidemiological and geographical impact and distribution of nurse migration. Qualitative dimensions and educational requirements are less well discussed. Conclusions Evidence on nursing migration is strongly based on quantitative factors and may not reflect current needs. More information about qualitative aspects of nurse migration is required to develop recommendations that support enhanced nursing workforce migration. Key messages Nurse Migration presents many challenges that have not yet been fully researched. Results of a comparative analysis of three countries offer the opportunity to highlight missed opportunities.

Background Impaction of a soft food bolus in the oesophagus causes dysphagia and regurgitation. If the bolus does not pass spontaneously, then the patient is at risk of aspiration, dehydration, perforation, and death. Definitive management is with endoscopic intervention, recommended within 24 hours. Prior to endoscopy, many patients undergo a period of observation, awaiting spontaneous disimpaction, or may undergo enteral or parenteral treatments to attempt to dislodge the bolus. There is little consensus as to which of these conservative strategies is safe and effective to be used in this initial period, before resorting to definitive endoscopic management for persistent impaction. Objectives To evaluate the efficacy of non-endoscopic conservative treatments in the management of soft food boluses impacted within the oesophagus. Search methods We searched the following databases, using relevant search terms: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase and CINAHL. The date of the search was 18 August 2019. We screened the reference lists of relevant studies and reviews on the topic to identify any additional studies. Selection criteria We included randomised controlled trials of the management of acute oesophageal soft food bolus impaction, in adults and children, reporting the incidence of disimpaction (confirmed radiologically or clinically by return to oral diet) without the need for endoscopic intervention. We did not include studies focusing on sharp or solid object impaction. Data collection and analysis We used standard methodological procedures recommended by Cochrane. Main results We identified 890 unique records through the electronic searches. We excluded 809 clearly irrelevant records and retrieved 81 records for further assessment. We subsequently included one randomised controlled trial that met the eligibility criteria, which was conducted in four Swedish centres and randomised 43 participants to receive either intravenous diazepam followed by glucagon, or intravenous placebos. The effect of the active substances compared with placebo on rates of disimpaction without intervention is uncertain, as the numbers from this single study were small, and the rates were similar (38% versus 32%; risk ratio 1.19, 95% confidence interval 0.51 to 2.75, P = 0.69). The certainty of the evidence using GRADE for this outcome is low. Data on adverse events were lacking. Authors' conclusions There is currently inadequate data to recommend the use of any enteral or parenteral treatments in the management of acute oesophageal soft food bolus impaction. There is also inadequate data regarding potential adverse events from the use of these treatments, or from potential delays in definitive endoscopic management. Caution should be exercised when using any conservative management strategies in these patients.

Background The incidence of thyroid cancer is rising, and relatively little is known about modifiable risk factors for the condition. Observational studies have suggested a link between adiposity and thyroid cancer; however, these are subject to confounding and reverse causality. Here, we used data from the UK Biobank and Mendelian randomization approaches to investigate whether adiposity causes benign nodular thyroid disease and differentiated thyroid cancer. Methods We analyzed data from 379 708 unrelated participants of European ancestry in the UK Biobank and identified 1812 participants with benign nodular thyroid disease and 425 with differentiated thyroid carcinoma. We tested observational associations with measures of adiposity and type 2 diabetes mellitus. One and 2-sample Mendelian randomization approaches were used to investigate causal relationships. Results Observationally, there were positive associations between higher body mass index (odds ratio [OR], 1.15; 95% confidence interval [CI], 1.08-1.22), higher waist-hip ratio (OR, 1.16; 95% CI, 1.09-1.23), and benign nodular thyroid disease, but not thyroid cancer. Mendelian randomization did not support a causal link for obesity with benign nodular thyroid disease or thyroid cancer, although it did provide some evidence that individuals in the highest quartile for genetic liability of type 2 diabetes had higher odds of thyroid cancer than those in the lowest quartile (OR, 1.45; CI, 1.11-1.90). Conclusions Contrary to the findings of observational studies, our results do not confirm a causal role for obesity in benign nodular thyroid disease or thyroid cancer. They do, however, suggest a link between type 2 diabetes and thyroid cancer.

Purpose of review Medullary thyroid carcinoma (MTC) represents a wide spectrum of tumours with differing biology, behaviour and natural history. The only current available curative treatment is surgery in the form of thyroidectomy with or without ipsilateral or bilateral neck dissection. There is a lack of consensus in the available published guidelines on the optimum extent of initial surgery, and there is significant variation in clinical practice. This review focuses on the most recently published evidence. Recent findings Many patients with limited disease do not receive total thyroidectomy and central neck compartment dissection as recommended by international guidelines. Despite this, 5-year disease-specific survival is over 90% in those without distant metastases at presentation. Over 20% of patients may harbour occult lateral compartment nodal metastases, and baseline calcitonin alone (>1000 pg/ml) is not a good predictor of nodal metastasis. Although delayed lateral neck compartment dissection results in similar survival outcomes to prophylactic neck dissection for clinically node-negative patients, there is an underappreciated psychological effect of having biochemical evidence of persistent disease following limited surgery. Summary No single currently available prognostic indicator is sufficient to predict disease behaviour and evidence of occult nodal metastases. In clinically ad radiologically node-negative patients, the extent of neck dissection at initial operation, therefore, needs to be planned and executed on an individual patient basis.

Introduction Warthin's tumor (WT) is a common benign salivary gland neoplasm with a negligible risk of malignant transformation. However, there is a risk of malignant tumors being misdiagnosed as WT on cytology and inappropriately managed conservatively. Methods Patients from nine centers in Italy and the United Kingdom undergoing parotid surgery for cytologically diagnosed WT were included in this multicenter retrospective series. Definitive histology was compared with preoperative cytological diagnoses. Surgical complications were recorded. Results A total of 496 tumors were identified. In 88.9%, the final histological diagnosis was WT. In 21 cases (4.2%) a malignant neoplasm was diagnosed, which had been incorrectly labeled as WT on cytology. Conclusions The risk of undiagnosed malignancy should be balanced against surgical risks when considering the management of WT. Although nonsurgical management remains an appropriate option, there may be a rationale for serial clinical or radiological evaluation if surgical excision is not performed.

Traditionally, subgroup analyses are used to assess whether patient characteristics moderate treatment effectiveness with general disregard for issues of multiplicity. Using data from The Action for Health in Diabetes (Look AHEAD) trial in the United States, we aim to identify a subgroup where all of its types of members experience a treatment benefit defined as reducing the likelihood of a major cardiovascular event under an intensive lifestyle and weight-loss intervention. We apply the credible subgroups method to a Bayesian logistic model with a conservative prior that is sceptical of large treatment effect heterogeneity. The covariate profiles for which there is sufficient evidence of treatment benefit are, coarsely, middle-aged women, in poor subjective general health and with moderately to poorly controlled diabetes. There is at least 80% posterior probability that the conditional average treatment effect is positive for all covariate profiles fitting this description, which account for 0.5% of trial participants. Conversely, the covariate profiles that are likely to be associated with no benefit are middle aged and older men in excellent subjective general health, with well-controlled diabetes. These profiles apply to less than 2% of trial participants. More information is required to determine treatment benefit or no benefit for the remainder of the trial population.

Ecosystem restoration planning requires an integrated approach considering many components of the natural system when prioritizing where and what to restore. Toronto and Region Conservation Authority and partners have developed a multi-discipline and multi-benefit approach to restoration planning that facilitates effective restoration works, which contribute to realizing regional watershed objectives pertaining to natural system functions. Through various long term monitoring and modeling initiatives, Toronto and Region Conservation Authority has amassed a wealth of knowledge on terrestrial biodiversity, aquatic ecosystems, hydrology, and headwater conditions. The aim of Integrated Restoration Prioritization is to identify impairments and threats to ecosystem function as a means to improve the delivery of ecological goods and services. Consolidating data and comparing discrete areas based on different parameters and thresholds can help direct decision making for future restoration initiatives. The first iteration of the Integrated Restoration Prioritization analyzed existing datasets, identified gaps, and made recommendations for future monitoring. This approach will assist with delisting Beneficial Use Impairments #14 Loss of Fish and Wildlife Habitat and #3 Degradation of Fish and Wildlife Populations within the Toronto Remedial Action Plan area. Further, the Integrated Restoration Prioritization will assist in implementing the recommendations made in watershed planning documents pertaining to fisheries and natural heritage management. Specifically, the Integrated Restoration Prioritization will identify where impairments to ecological function are located, ensure habitats and corridor linkages are protected or restored, and prioritize local and upstream catchments that could contribute most to improving the natural system if restored.

We describe a rare case of cervical necrotising fasciitis caused by mastoiditis and Bezold’s abscess. This case was complicated by a tracheostomy delaying wound healing. A novel strategy to repair the tracheotomy defect using Permacol™, an acellular porcine dermal substitute, and a local muscle flap not previously reported in the literature is described to allow the use of negative pressure wound therapy dressing. This technique may be employed in similar applications for non-healing tracheotomy wounds.

We present a case of non-surgically managed bilateral osteonecrosis of the external auditory canal with a history of long-term medical therapy for osteoporosis. A 79-year-old woman with severe osteoporosis and destructive osteoarthritis received >10 years of once weekly bisphosphonate therapy before switching to denosumab. Four months later, the patient presented with bilateral loss of hearing and right-sided otalgia. Necrotising otitis externa, cholesteatoma and malignancy were considered but with histology, microbiological and CT assessment, bilateral osteonecrosis of the external auditory canal was diagnosed. Surgical debridement with canalplasty was avoided due to our patient’s comorbidities. Treatment continued for 5 months with regular aural toilet, Terra-Cortril ointment and bismuth-iodine-paraffin paste packing. At 1-year follow-up, bilateral external auditory canals were completely re-epithelialised with no pain or affected hearing. We report the first case of bilateral osteonecrosis of the external auditory canal associated with denosumab and bisphosphonates with successful conservative management.

Salivary gland cancers are a complex group of tumours with variations in location, type and grade, all of which influence their biological behaviour. The understanding of salivary gland pathology has evolved at the molecular level in the last decade leading to identification of distinct entities, development of improved methods of diagnosis as well as identifying therapeutic targets for selected high-grade tumours. This article focuses on these advances and their impact on the management of primary salivary gland cancers.

// Timothy K. Khoo 1, * , Bing Yu 1, 2, * , Joel A. Smith 3 , Angus J. Clarke 1 , Peter P. Luk 4 , Christina I. Selinger 4 , Kate L. Mahon 1, 5 , Spiridoula Kraitsek 2 , Carsten Palme 1, 3 , Michael J. Boyer 1, 5 , Marcel E. Dinger 6 , Mark J. Cowley 6 , Sandra A. O’Toole 1, 4 , Jonathan R. Clark 1, 3, 7, * and Ruta Gupta 1, 3, 4, * 1 Central Clinical School, The University of Sydney, Australia 2 Department of Medical Genomics, Royal Prince Alfred Hospital, Sydney, Australia 3 The Sydney Head and Neck Cancer Institute, Chris O’Brien Lifehouse, Sydney, Australia 4 Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, Australia 5 The Department of Medical Oncology, Chris O’Brien Lifehouse, Sydney, Australia 6 Kinghorn Cancer Centre and Garvan Institute of Medical Research, Darlinghurst, Sydney, Australia 7 South West Clinical School, University of New South Wales, Sydney, Australia * These authors contributed equally to this work Correspondence to: Ruta Gupta, email: Ruta.Gupta@sswahs.nsw.gov.au Keywords: salivary duct carcinoma, somatic mutation analysis, targeted therapies, androgen receptor, HER2 Received: January 10, 2017 Accepted: March 20, 2017 Published: May 25, 2017 ABSTRACT Background: Salivary duct carcinomas (SDCa) are rare highly aggressive malignancies. Most patients die from distant metastatic disease within three years of diagnosis. There are limited therapeutic options for disseminated disease. Results: 11 cases showed androgen receptor expression and 6 cases showed HER2 amplification. 6 Somatic mutations with additional available targeted therapies were identified: EGFR (p.G721A: Gefitinib), PDGFRA (p.H845Y: Imatinib and Crenolanib), PIK3CA (p.H1047R: Everolimus), ERBB2 (p.V842I: Lapatinib), HRAS (p.Q61R: Selumetinib) and KIT (p.T670I: Sorafenib). Furthermore, alterations in PTEN , PIK3CA and HRAS that alter response to androgen deprivation therapy and HER2 inhibition were also seen. Materials and Methods: Somatic mutation analysis was performed on DNA extracted from 15 archival cases of SDCa using the targeted Illumina TruSeq Amplicon Cancer Panel. Potential targetable genetic alterations were identified using extensive literature and international somatic mutation database (COSMIC, KEGG) search. Immunohistochemistry for androgen receptor and immunohistochemistry and fluorescent in situ hybridization for HER2 were also performed. Conclusions: SDCa show multiple somatic mutations, some that are amenable to pharmacologic manipulation and others that confer resistance to treatments currently under investigation. These findings emphasize the need to develop testing and treatment strategies for SDCa.

Objective This study is an economic evaluation of immediate birth compared with expectant management in women with preterm prelabour rupture of the membranes near term (PPROMT). Design A cost-effectiveness analysis alongside the PPROMT randomised controlled trial. Setting Obstetric departments in 65 hospitals across 11 countries. Population Women with a singleton pregnancy with ruptured membranes between 34+0 and 36+6 weeks gestation. Methods Women were randomly allocated to immediate birth or expectant management. Costs to the health system were identified and valued. National hospital costing data from both the UK and Australia were used. Average cost per recruit in each arm was calculated and 95% confidence intervals were estimated using bootstrap re-sampling. Averages costs during antenatal care, delivery and postnatal care, and by country were estimated. Main outcomes measures Total mean cost difference between immediate birth and expectant management arms of the trial. Results From 11 countries 923 women were randomised to immediate birth and 912 were randomised to expectant management. Total mean costs per recruit were £8852 for immediate birth and £8740 for expectant delivery resulting in a mean difference in costs of £112 (95% CI: −431 to 662). The expectant management arm had significantly higher antenatal costs, whereas the immediate birth arm had significantly higher delivery and neonatal costs. There was large variation between total mean costs by country. Conclusion This economic evaluation found no evidence that expectant management was more or less costly than immediate birth. Outpatient management may offer opportunities for cost savings for those women with delayed delivery. Tweetable abstract For women with preterm prelabour rupture of the membranes, the relative benefits and harms of immediate and expectant management should inform counselling as costs are similar.

peer-reviewed Quantifying the value of investment in medical research can inform decision-making on the prioritisation of research programmes. Existing methodologies to estimate the rate of return of medical research are inappropriate for early-phase translational research due to censoring of health benefits and time lags. A strategy to improve the process of translational research for patient benefit has been initiated as part of the UK National Institute for Health Research (NIHR) investment in Biomedical Research Centres (BRCs) in England. By providing a platform for partnership between universities, NHS trusts and industry, successful BRCs should reduce time lags within translational research whilst also providing an impetus for local economic growth through industry collaboration. We present a novel contribution in the assessment of early-phase biomedical research by estimating the impact of the Oxford Biomedical Research Centre (OxBRC) on income and job creation following the initial NIHR investment. We adopt a macroeconomic assessment approach using Input-Output Analysis to estimate the value of medical research in terms of income and job creation during the early pathway towards translational biomedical research. Inter-industry linkages are assessed by building a model economy for the South East England region to estimate the return on investment of the OxBRC. The results from the input-output model estimate that the return on investment in biomedical research within the OxBRC is 46%. Each £1 invested in the OxBRC generates an additional £0.46 through income and job creation alone. Multiplicative employment effects following a marginal investment in the OxBRC of £98m during the period 2007-2017 result in an estimated additional 196 full time equivalent positions being created within the local economy on top of direct employment within OxBRC. Results from input-output analyses can be used to inform the prioritisation of biomedical research programmes when compared against national minimum thresholds of investment

IntroductionThe STOPPIT-2 study aims to determine the clinical utility of the Arabin cervical pessary in preventing preterm birth in women with a twin pregnancy and a short cervix, about which there is current uncertainty. STOPPIT-2 will resolve uncertainty around effectiveness for women with a twin pregnancy and a cervical length of 35 mm or less, define adverse effects, ascertain acceptability and estimate National Health Service costs and savings.MethodsSTOPPIT-2 is a pragmatic multicentre open-label randomised controlled trial. Consenting women with twin pregnancy will have an transvaginal ultrasound scan of their cervical length performed between 18+0 and 20+6 weeks’ gestation by an accredited practitioner: women with a cervical length of ≤35 mm will be eligible for inclusion in the treatment phase of the study. The intervention by the insertion of the Arabin cervical pessary will be compared with standard treatment (no pessary).The primary outcomes are (obstetric) spontaneous onset of labour for the mother leading to delivery before 34 weeks’ gestation and (neonatal) a composite of specific adverse outcomes or death occurring up to the end of the first 4 weeks after the estimated date of delivery to either or both babies.We plan to recruit 500 women in the treatment phase of the study. Assuming a treatment effect of 0.6, and background rates of 35% and 18%, respectively, for each of the primary outcomes, our study has 85% power to detect a difference between the intervention and the control groups.AnalysisData will be analysed on the intention-to-treat principle.EthicsSTOPPIT-2 was approved by the South East Scotland Ethics Committee 02 on 29 August 2014, reference number 14/SS/1031 IRAS ID 159610.DisseminationPeer reviewed journals, presentations at national and international scientific meetings.Trial registration numberNCT98835694andNCT02235181.

BACKGROUND: As the health care education landscape in the UK changes rapidly and dramatically, collaboration across institutions bridging undergraduate and postgraduate fields is increasingly necessary. Collaboration entails both risks and benefits. There is a paucity of advice on how to ensure collaborative projects in medical education are effective. There is a paucity of advice on how to ensure collaborative projects in medical education are effective CONTEXT: In 2011 three medical schools began a collaborative project along with NHS Education for Scotland (NES) to modify, develop and deliver a medical school version of the NES foundation programme ePortfolio, called UMeP. The underlying principal was the introduction of an authentic ePortfolio early in undergraduate life. The challenge of three diverse medical schools with significantly different curricula and assessment approaches working together with a single postgraduate ePortfolio was complex and demanding. DISCUSSION: We reveal the complexities of collaboration on education projects and draw on our experiences to provide illustrative examples of collaboration. Despite the increased complexity and need for compromise, we argue that successful collaborative partnerships are key to maximising the circumstances in which education innovation can be successful, and create the potential for robust evaluation and research.

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To evaluate the efficacy of non‐procedural interventions in the management of soft food boluses impacted within the oesophagus.

Background Comparisons of outcomes of health care in different systems can be used to inform health policy. The EuroHOPE (European Healthcare Outcomes, Performance and Efficiency) project investigated the feasibility of comparing routine data on selected conditions including breast cancer across participating European countries. Methods Routine data on incidence, treatment and mortality by age and clinical characteristics for breast cancer in women over 24 years of age were obtained (for a calendar year) from linked hospital discharge records, cancer and death registers from Finland, the Turin metropolitan area, Scotland and Sweden (all 2005), Hungary (2006) and Norway (2009). Age-adjusted breast cancer incidence and 1-year survival were estimated for each country/region. Results In total, 24 576 invasive breast cancer cases were identified from cancer registries from over 13 million women. Age-adjusted incidence ranged from 151.1 (95%CI 147.2-155.0) in Hungary to 234.7 (95%CI 227.4-242.0)/100 000 in Scotland. One-year survival ranged from 94.1% (95%CI 93.5-94.7%) in Scotland to 97.1% (95%CI 96.2-98.1%) in Italy. Scotland had the highest proportions of poor prognostic factors in terms of tumour size, nodal status and metastases. Significant variations in data completeness for prognostic factors prevented adjustment for case mix. Conclusion Incidence of and survival from breast cancer showed large differences between countries. Substantial improvements in the use of internationally recognised common terminology, standardised data coding and data completeness for prognostic indicators are required before international comparisons of routine data can be used to inform health policy.

The market demand for a low-cost transportation system that operates efficiently in a circulatory environment is significant. In this paper, we propose a solution, EcoPRT, a two person, electric, autonomous, low cost, adaptable system that solves the circulatory problem, being ideal for areas that are too far to walk but too short to drive. The key advantages of the proposed system are: narrow footprint, low weight, low cost, no delays en route, and adaptable installation. A pilot run of the vehicle is expected during the first part of 2017 on the campus of NC State University. To date an operating prototype and test track have been completed. An overview of the mechanical and electrical vehicle design is presented. Additionally, we discuss the major navigation and sensing subsystems including the development of a low-cost 3D LIDAR unit for navigation and collision avoidance. Further, three different solutions for vision-based navigation are compared qualitatively for effectiveness. In summary, a functional platform vehicle is presented on which we expect to further develop and refine an effective, low cost, automated transportation solution.

Metastases to the parotid gland are the commonest cause of parotid malignancies in many regions of the world including Australia. The most common etiology of these metastases is head and neck cutaneous squamous cell carcinoma (HNcSCC) followed by melanoma of the head and neck. This article focuses on the management of the aforementioned pathologies including Merkel cell carcinoma (MCC).

The seventh edition tumor, node metastasis (TNM) classifies tumors

Background: The susceptibility to type 2 diabetes of people of south Asian descent is established, but there is little trial-based evidence for interventions to tackle this problem. We assessed a weight control and physical activity intervention in south Asian individuals in the UK. Methods: We did this non-blinded trial in two National Health Service (NHS) regions in Scotland (UK). Between July 1, 2007, and Oct 31, 2009, we recruited men and women of Indian and Pakistani origin, aged 35 years or older, with waist circumference 90 cm or greater in men or 80 cm or greater in women, and with impaired glucose tolerance or impaired fasting glucose determined by oral glucose tolerance test. Families were randomised (using a random number generator program, with permuted blocks of random size, stratified by location [Edinburgh or Glasgow], ethnic group [Indian or Pakistani], and number of participants in the family [one vs more than one]) to intervention or control. Participants in the same family were not randomised separately. The intervention group received 15 visits from a dietitian over 3 years and the control group received four visits in the same period. The primary outcome was weight change at 3 years. Analysis was by modified intention to treat, excluding participants who died or were lost to follow-up. We used linear regression models to provide mean differences in baseline-adjusted weight at 3 years. This trial is registered, number ISRCTN25729565. Findings: Of 1319 people who were screened with an oral glucose tolerance test, 196 (15%) had impaired glucose tolerance or impaired fasting glucose and 171 entered the trial. Participants were in 156 family clusters that were randomised (78 families with 85 participants were allocated to intervention; 78 families with 86 participants were allocated to control). 167 (98%) participants in 152 families completed the trial. Mean weight loss in the intervention group was 1·13 kg (SD 4·12), compared with a mean weight gain of 0·51 kg (3·65) in the control group, an adjusted mean difference of -1·64 kg (95% CI -2·83 to -0·44). Interpretation: Modest, medium-term changes in weight are achievable as a component of lifestyle-change strategies, which might control or prevent adiposity-related diseases. Funding: National Prevention Research Initiative, NHS Research and Development; NHS National Services Scotland NHS Health Scotland. © 2014 Bhopal et al.

In this article we present a probabilistic-based method to construct a t chart to monitor the stability of a process. Assuming that the time between events can be modeled with an exponential distribution, we show how to apply the supplementary runs rules to identify whether the process is out of control. We compare the exact average run length (ARL) when the process is stable and under control, as well as the ability of this chart to identify a shift in the process to other charts currently used to monitor the same type of processes. Similar charts are applied in health care to monitor the rate of infections and other adverse events. However, some existing methods provide undesirable behavior when attempting to detect shifts and may hide or incorrectly demonstrate the nature of such shifts.

Gas pipeline internal surface typically undergoes degradation for a variety of reasons such as fouling of the pipe inner surface, erosion, corrosion and deposits of objectionable materials that occasionally enter the gas stream at receipt points. Accurate monitoring of the pipe internal surface condition can hugely benefit the planning of cleaning activities. Theoretically the pipe wall roughness for a given pipe segment can be extracted based on measured flow data and other system parameters. The challenge lies in the fact that measured data all contain varying degrees of uncertainty, and the system becomes more complex to analyze when it contains different segments connected in series or parallel like many typical gas gathering and lateral networks. This paper demonstrates the application of the Error-in-Variable Model (EVM) using the Markov Chain Monte Carlo (MCMC) solution method in analyzing a complex pipeline network on the TransCanada NGTL System. EVM, a well-established Bayesian parameter estimation technique, accounts for uncertainties in the measured variables, such as flow and pressure data, when determining the most probable estimates of unknown parameters such as pipe internal wall surface roughness. In this work, the EVM problem is solved using the MCMC Metropolis-Hastings algorithm. The MCMC approach is demonstrated to be robust, easy to implement and capable of handling large quantities of data. It has the potential to analyze complex networks and monitor the pipe wall surface condition on-line with SCADA data. Using this method, the internal wall surface roughness for the segments of interest in this network were extracted from measured data collected before and after the pigging operation. Results demonstrate the model’s capability in estimating the degradation of the pipe wall internal surface and the effectiveness of pigging. Details on implementation and challenges in applying such methodology to analyze complex gas networks are discussed.

Background: The effect of alteplase on patient survival after ischaemic stroke is the subject of debate. We report the effect of intravenous alteplase on long-term survival after ischaemic stroke of participants in the Third International Stroke Trial (IST-3).Methods: In IST-3, done at 156 hospitals in 12 countries (Australia, Europe, and the UK), participants (aged >18 years) were randomly assigned with a telephone voice-activated or web-based system in a 1:1 ratio to treatment with intravenous 0·9 mg/kg alteplase plus standard care or standard care alone within 6 h of ischaemic stroke. We followed up participants in the UK and Scandinavia (Sweden and Norway) for survival up to 3 years after randomisation using data from national registries and compared survival in the two groups with proportional hazards survival analysis, adjusting for key prognostic variables. IST-3 is registered with the ISRCTN registry, number ISRCTN25765518.Findings: Between May 5, 2000, and July 27, 2011, 3035 participants were enrolled in IST-3. Of these, 1948 (64%) of 3035 participants were scheduled for analysis of 3 year survival, and 1946 (>99%) of these were included in the analysis (967 [50%] in the alteplase plus standard care group and 979 [50%] in the standard care alone group). By 3 years after randomisation, 453 (47%) of 967 participants in the alteplase plus standard care group and 494 (50%) of 979 in the standard care alone group had died (risk difference 3·6% [95% CI −0·8 to 8·1]). Participants allocated to alteplase had a significantly higher hazard of death during the first 7 days (99 [10%] of 967 died in the alteplase plus standard care group vs 65 [7%] of 979 in the standard care alone group; hazard ratio 1·52 [95% CI 1·11–2·08]; p=0·004) and a significantly lower hazard of death between 8 days and 3 years (354 [41%] of 868 vs 429 [47%] of 914; 0·78 [0·68–0·90]; p=0·007).Interpretation: Alteplase treatment within 6 h after ischaemic stroke was associated with a small, non-significant reduction in risk of death at 3 years, but among individuals who survived the acute phase, treatment was associated with a significant increase in long-term survival. These results are reassuring for clinicians who have expressed concerns about the effect of alteplase on survival.Funding: Heart and Stroke Scotland, UK Medical Research Council, Health Foundation UK, Stroke Association UK, Research Council of Norway, AFA Insurance, Swedish Heart Lung Fund, Foundation of Marianne and Marcus Wallenberg, Polish Ministry of Science and Education, Australian Heart Foundation, Australian National Health and Medical Research Council, Swiss National Research Foundation, Swiss Heart Foundation, Assessorato alla Sanita (Regione dell'Umbria), and Danube University.

How is teaching introductory statistics like producing a high-quality coil of cold rolled steel? Can educators learn techniques from the manufacturing sector that make instruction more productive? ...

Background. The aim of this study was to inform an evidence-based management policy for oral dysplastic lesions. Methods. Systematic review was performed with meta-analysis. Studies reporting follow-up of patients with histologically confirmed oral dysplasia were included. Outcome measures included malignant transformation rate (MTR) and time to malignant transformation (TMT). Subgroup analysis was performed by histologic grade, clinical risk factors, and treatment modality. Heterogeneity was assessed. Results. Fourteen nonrandomized studies, reporting on 992 patients, were included. There was considerable heterogeneity between studies: mean overall MTR = 12.1% (confidence interval: 8.1%, 17.9%) and mean TMT = 4.3 years. Histologic grade significantly affected mean MTR (p < .008). Lesions that were not excised demonstrated considerably higher MTR than those that were excised (p = .003). Conclusions. Oral dysplasia showed a significant rate of transformation to cancer, which was related to grade and was decreased significantly but not eliminated by excision. This suggested the need for excision and continued surveillance. (C) 2009 Wiley Periodicals, Inc. Head Neck 31: 1600-1609, 2009

Background The CLOTS 3 trial showed that intermittent pneumatic compression (IPC) reduced the risk of DVT and improved survival after stroke. Aims To provide additional information which may help clinicians target IPC on the most appropriate patients by exploring the variation in its effects on subgroups defined by predicted prognosis. Methods A multicentre, parallel group, randomized trial enrolled immobile acute stroke patients and allocated them to IPC or no IPC. The primary outcome was proximal DVT at 30 days. Secondary outcomes at six-months included survival, disability, quality of life, and hospital costs. We stratified patients into quintiles according to their predicted prognosis at randomization, based on the Six Simple Variable model. Results Between December 2008 and September 2012, we enrolled 2876 patients in 94 UK hospitals. Patients with the best predicted outcome had the lowest absolute risk of proximal DVT (6.7%) and death by six-months (9.3%). Allocation to IPC had little effect on DVT, survival, disability, quality of life, hospital length of stay, or costs. In patients with the worst predicted outcomes, the overall risk of DVT and death was 16.0% and 51.3%, respectively. IPC reduced DVT (odds reduction 34%) and improved survival 17% and significantly increased length of stay and hospital costs. In the three intermediate quintiles, IPC reduced the odds of DVT (35-43%) and improved survival (11-13%). Disability and quality of life at six-months depended on baseline severity but was not influenced significantly by IPC. Conclusions IPC appears to reduce the risk of DVT and probably improves survival in all immobile stroke patients, other than the fifth with the best prognosis. It therefore seems reasonable to recommend that IPC should be considered in all immobile stroke patients, but that the final decision should be based on a judgment about the individual's prognosis. In some, their prognosis for survival with an acceptable quality of life will be so poor that use of IPC might be considered futile, while at the other end of the spectrum, patients’ risk of DVT, and of dying from VTE, may not be high enough to justify the modest cost and inconvenience of IPC use.

Hypoxia under general anaesthesia is a potentially life-threatening condition. A seemingly well 67-year-old man appeared hypoxic with peripheral pulse oximetric measurement during routine anaesthesia. Postoperatively, the patient admitted to daily self-prescription of apricot kernel extract for a period of 5 years. Apricot kernel is a commonly taken extract used for a range of ailments, and is associated with cyanide toxicity, which was confirmed through blood analysis. Our explanation for the hypoxic measurement was the presence of free cyanide interfering with functioning of the peripheral pulse oximeter. On cessation of the apricot kernel extract, peripheral oxygen saturations returned to normal. Cardiac and respiratory causes together with rare haemoglobinopathies were excluded. This case illustrates how chronic dosing of complementary medicines can result in harmful toxicities, which may carry potential for serious consequences and how these chronic toxicities may present to physicians in atypical ways.