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Introduction: Cytoreductive surgery has been used a part of multimodality treatment in patients with malignant pleural mesothelioma (MPM). The residual microscopic disease that remains will lead to disease progression in the majority of patients. Delivery of hyperthermic intrathoracic chemotherapy at the time of surgery has been used to address this microscopic disease, however it's effect and place in the multimodality treatment sphere is unknown. The aim of this systematic review was to assess the effect of surgery and hyperthermic intrathoracic chemotherapy in patients with MPM on overall survival and disease-free interval., Methods: Ovid MEDLINE, Embase, Web of Science and the Cochrane Database of Systematic Reviews were searched from database inception through to June 2021. Studies reporting overall survival and/or disease-free interval in patients with MPM undergoing cytoreductive surgery with hyperthermic intrathoracic chemotherapy were considered. Study quality was assessed using the Newcastle-Ottawa Scale. A narrative review was performed., Results: Fifteen studies were eligible for inclusion comprising 598 patients. Surgery with hyperthermic intrathoracic chemotherapy was associated with a median overall survival and disease-free interval ranging from 11 to 75 months and 7.2 to 57 months, respectively. These appeared to be superior to patients not receiving hyperthermic intrathoracic chemotherapy (overall survival: 5-36 months and disease-free interval: 12.1-21 months). A higher dose of hyperthermic intrathoracic chemotherapy was associated with an improvement in overall survival compared with a lower dose: 18-31 months versus 6-18 months, respectively. The most common morbidity was atrial fibrillation followed by renal complications., Conclusion: Surgery with hyperthermic intrathoracic chemotherapy offers a safe and effective therapy with an improvement in disease-free interval and overall survival, particularly when hyperthermic intrathoracic chemotherapy is administered at a higher dose., Prospero Registration Number: CRD42019129002., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

The tumour suppressor BRCA1-associated protein 1 (BAP1) is the most frequently mutated cancer gene in mesothelioma. Here we report novel functions for BAP1 in mitotic progression highlighting the relationship between BAP1 and control of genome stability in mesothelioma cells with therapeutic implications. Depletion of BAP1 protein induced proteasome-mediated degradation of BRCA1 in mesothelioma cells while loss of BAP1 correlated with BRCA1 loss in mesothelioma patient tumour samples. BAP1 loss also led to mitotic defects that phenocopied the loss of BRCA1 including spindle assembly checkpoint failure, centrosome amplification and chromosome segregation errors. However, loss of BAP1 also led to additional mitotic changes that were not observed upon BRCA1 loss, including an increase in spindle length and enhanced growth of astral microtubules. Intriguingly, these consequences could be explained by loss of expression of the KIF18A and KIF18B kinesin motors that occurred upon depletion of BAP1 but not BRCA1, as spindle and astral microtubule defects were rescued by re-expression of KIF18A and KIF18B, respectively. We therefore propose that BAP1 inactivation causes mitotic defects through BRCA1-dependent and independent mechanisms revealing novel routes by which mesothelioma cells lacking BAP1 may acquire genome instability and exhibit altered responses to microtubule-targeted agents., (© 2022. The Author(s).)

Pure red cell aplasia caused by true thymic hyperplasia is extremely rare. We report the case of a 25-year-old female diagnosed with pure red cell aplasia. Following a thymectomy confirming true thymic hyperplasia and corticosteroid therapy, complete response was achieved. Patients diagnosed with pure red cell aplasia should be investigated with a computerized tomographic scan to assess for thymic pathology and if present, this should be resected. Follow-up is essential to monitor for recurrence., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery.)

Background: Genetically stratified therapy for malignant mesothelioma is unavailable. Mesotheliomas frequently harbour loss of the chromosome 9p21.3 locus (CDKN2A-MTAP), which is associated with shorter overall survival due to loss of the tumour suppressor p16ink4A, an endogenous suppressor of cyclin-dependent kinase (CDK)4 and CDK6. Genetic restoration of p16ink4A suppresses mesothelioma in preclinical models, underpinning the rationale for targeting CDK4 and CDK6 in p16ink4A-negative mesothelioma. We developed a multicentre, stratified, phase 2 trial to test this hypothesis., Methods: The MiST2 study was a single-arm, open-label, phase 2 clinical trial done two UK centres. Patients older than 18 years with any histologically confirmed subtype of mesothelioma (pleural or peritoneal) with radiological progression after at least one course of platinum-based chemotherapy were molecularly screened by immunohistochemistry for p16ink4A. Patients with p16ink4A-negative mesothelioma were eligible for inclusion in the study. Patients were required to have measurable disease by modified Response Evaluation Criteria in Solid Tumours version 1.1 for malignant mesothelioma, a predicted life expectancy of at least 12 weeks, and an Eastern Cooperative Oncology Group performance status score of 0-1. Patients received oral abemaciclib 200 mg twice daily, administered in 28-day cycles for 24 weeks. The primary endpoint was the disease control rate (patients with complete responses, partial responses, or stable disease) at 12 weeks. The null hypothesis could be rejected if at least 11 patients had disease control. The efficacy and safety populations were defined as all patients who received at least one dose of the study drug. The study is registered with ClinicalTrials.gov, NCT03654833, and is ongoing (but MiST2 is now closed)., Findings: Between Sept 31, 2019, and March 2, 2020, 27 eligible patients consented to molecular screening. The median follow-up was 18·4 weeks (IQR 6·7-23·9). One patient was excluded before treatment because of a serious adverse event before study drug allocation. 26 (100%) of 26 treated patients were p16ink4A deficient and received at least one dose of abemaciclib. Disease control at 12 weeks was reported in 14 (54%) of 26 patients (95% CI 36-71). Grade 3 or worse treatment-related adverse events (of any cause) occurred in eight (27%) of 26 patients (diarrhoea, dyspnoea, thrombocytopenia, vomiting, urinary tract infection, increased alanine aminotransferase, ascites, chest infection or suspected chest infection, neutropenic sepsis, alopecia, blood clot left calf, fall [broken neck and collar bone], haemoptysis, lower respiratory tract infection, and pulmonary embolism). Grade 3 or worse treatment-related adverse events occurred in three (12%) of 26 patients (diarrhoea, thrombocytopenia, vomiting, increased alanine aminotransferase, and pulmonary embolism). Serious adverse events occurred in six (23%) of 26 patients, leading to treatment discontinuation in one (4%) patient (diarrhoea, urinary tract infection, chest infection, neutropenic sepsis, fall [broken neck and collar bone], haemoptysis, lower respiratory tract infection, and pulmonary embolism). One patient had a serious adverse event related to abemaciclib (diarrhoea). One (4%) of 26 patients died from an adverse event (neutropenic sepsis)., Interpretation: This study met its primary endpoint, showing promising clinical activity of abemaciclib in patients with p16ink4A-negative mesothelioma who were previously treated with chemotherapy, and warrants its further investigation in a randomised study as a targeted stratified therapy., Funding: University of Leicester, Asthma UK and British Lung Foundation Partnership, and the Victor Dahdaleh Foundation., Competing Interests: Declaration of interests DAF reports grants from Astex Therapeutics, Boehringer Ingelheim, MSD, and Bayer; personal fees from Aldeyra, Inventiva, and Paredox; non-financial support from Clovis, Eli Lilly, and BMS; and personal fees and non-financial support from Roche, during the conduct of the study. AT reports personal fees from Amgen, outside the submitted work. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Malignant mesothelioma remains an incurable cancer, with no effective treatments in the setting of relapsed disease. Homologous recombination deficiency predicts sensitivity to poly (ADP-ribose) polymerase (PARP) inhibitors. In mesothelioma, BRCA1-associated protein 1 carboxy-terminal hydrolase (BAP1), which regulates DNA repair, is frequently mutated. We aimed to test the hypothesis that BAP1-deficient or BRCA1-deficient mesotheliomas would be sensitive to PARP inhibition by rucaparib., Methods: We did a single-centre, open-label, single-arm, phase 2a trial in Leicester, UK, with prospective molecular stratification (Mesothelioma-Stratified Therapy 1 [MiST1]). Patients aged 18 years or older who had radiologically progressing, histologically confirmed, malignant mesothelioma after at least one course of systemic treatment; with cytoplasmic-BAP1-deficient or BRCA1-deficient mesothelioma (pleural or peritoneal or other primary localisation), and who met the other inclusion criteria, were deemed eligible. All eligible patients who consented to take part were given rucaparib 600 mg twice a day orally, for six cycles of 28 days, or until disease progression, unacceptable toxicity, withdrawal of consent, or death. Response was measured by CT scan every 6 weeks. The primary outcome was disease control (complete response, partial response, or stable disease) at 12 weeks in all patients who received study drug; secondary outcomes were the safety and toxicity profile, objective response rate (proportion of complete or partial responses), and disease control rate at 24 weeks. Recruitment is now closed. This trial is registered with ClinicalTrials.gov, NCT03654833., Findings: Between Feb 9 and June 10, 2019, we enrolled 26 molecularly and clinically eligible patients. Ten (38%) of 26 patients were BAP1 negative and BRCA1 negative, 23 patients (89%) were BAP1 negative, and 13 patients (50%) were BRCA1 negative. Disease control rate at 12 weeks was 58% (95% CI 37-77; 15 of 26 patients), and at 24 weeks was 23% (9-44; six of 26 patients). Rucaparib was well tolerated, with 15 (9%) of 166 adverse events being grade 3 or 4, which were seen in nine (35%) of 26 patients, and there were no deaths. The most common grade 1-2 adverse events were nausea (18 [69%] of 26 patients), fatigue (14 patients [54%]), and decreased appetite (ten patients [38%]). The most common grade 3-4 adverse events were upper respiratory tract infection (three patients [12%]) and anaemia (three patients [12%]). All six cycles of rucaparib were received by eight (31%) of 26 patients. One or more dose reductions occurred in nine patients (35%)., Interpretation: Rucaparib in patients with BAP1-negative or BRCA1-negative mesothelioma met the prespecified criteria for success, showing promising activity with manageable toxicity. Further investigation of homologous recombination deficiency mutations is planned to refine the identification of predictive biomarkers for PARP inhibition in mesothelioma., Funding: University of Leicester (Leicester, UK), Asthma UK and British Lung Foundation Partnership, and the Victor Dahdaleh Foundation (Toronto, ON, Canada)., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Metastatic renal cell carcinoma with involvement through the pulmonary veins to the left atrium is very rare. We report the case of a 70-year-old male with metastatic renal cell carcinoma to the right lower lobe of the lung abutting the inferior pulmonary vein with extension to the left atrium without pre-operative evidence. Surgical resection was achieved through a posterolateral thoracotomy. Lung masses that abut the pulmonary veins should prompt further investigation with a pre-operative transoesophageal echocardiogram to minimize unexpected intraoperative findings., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

We hypothesized that small molecule transcriptional perturbation could be harnessed to target a cellular dependency involving protein arginine methyltransferase 5 (PRMT5) in the context of methylthioadenosine phosphorylase (MTAP) deletion, seen frequently in malignant pleural mesothelioma (MPM). Here we show, that MTAP deletion is negatively prognostic in MPM. In vitro, the off-patent antibiotic Quinacrine efficiently suppressed PRMT5 transcription, causing chromatin remodelling with reduced global histone H4 symmetrical demethylation. Quinacrine phenocopied PRMT5 RNA interference and small molecule PRMT5 inhibition, reducing clonogenicity in an MTAP-dependent manner. This activity required a functional PRMT5 methyltransferase as MTAP negative cells were rescued by exogenous wild type PRMT5, but not a PRMT5E444Q methyltransferase-dead mutant. We identified c-jun as an essential PRMT5 transcription factor and a probable target for Quinacrine. Our results therefore suggest that small molecule-based transcriptional perturbation of PRMT5 can leverage a mutation-selective vulnerability, that is therapeutically tractable, and has relevance to 9p21 deleted cancers including MPM.

Malignant Pleural Mesothelioma (MPM) is typically diagnosed 20-50 years after exposure to asbestos and evolves along an unknown evolutionary trajectory. To elucidate this path, we conducted multi-regional exome sequencing of 90 tumour samples from 22 MPMs acquired at surgery. Here we show that exomic intratumour heterogeneity varies widely across the cohort. Phylogenetic tree topology ranges from linear to highly branched, reflecting a steep gradient of genomic instability. Using transfer learning, we detect repeated evolution, resolving 5 clusters that are prognostic, with temporally ordered clonal drivers. BAP1/-3p21 and FBXW7/-chr4 events are always early clonal. In contrast, NF2/-22q events, leading to Hippo pathway inactivation are predominantly late clonal, positively selected, and when subclonal, exhibit parallel evolution indicating an evolutionary constraint. Very late somatic alteration of NF2/22q occurred in one patient 12 years after surgery. Clonal architecture and evolutionary clusters dictate MPM inflammation and immune evasion. These results reveal potentially drugable evolutionary bottlenecking in MPM, and an impact of clonal architecture on shaping the immune landscape, with potential to dictate the clinical response to immune checkpoint inhibition.

Mesothelioma is a universally lethal cancer lacking effective therapy. The spindle poison vinorelbine exhibits clinical activity in the relapsed setting, and in preclinical models requires BRCA1 to initiate apoptosis. However, the mechanisms underlying this regulation and the clinical implications have not been explored. Here, we show that BRCA1 silencing abrogated vinorelbine-induced cell-cycle arrest, recruitment of BUBR1 to kinetochores, and apoptosis. BRCA1 silencing led to codepletion of MAD2L1 at the mRNA and protein levels consistent with its status as a transcriptional target of BRCA1 Silencing of MAD2L1 phenocopied BRCA1 and was sufficient to confer resistance to vinorelbine. This was recapitulated in cell lines selected for resistance to vinorelbine, which acquired loss of both BRCA1 and MAD2L1 expression. Following ex vivo vinorelbine in 20 primary tumor explants, apoptotic response rate was 59% in BRCA1/MAD2L1 -positive explants compared with 0% in BRCA1/MAD2L1 -negative explants. In 48 patients, BRCA1 and/or MAD2L1 loss of expression was not prognostic; however, in a subset of patients treated with vinorelbine, survival was shorter for patients lacking BRCA1/MAD2L1 expression compared with double-positive patients (5.9 vs. 36.7 months, P = 0.03). Our data implicate BRCA1/MAD2L1 loss as a putative predictive marker of resistance to vinorelbine in mesothelioma and warrant prospective clinical evaluation., (©2020 American Association for Cancer Research.)

Gold shops in artisanal and small-scale gold mining communities represent major point sources of airborne mercury pollution. Concentrations of elemental mercury (Hg 0 ) emitted by these shops can be determined using a portable atomic absorbance spectrometer (AAS) with Zeeman correction. These measured Hg 0 concentrations can then be correlated to position as determined by a hand-held GPS unit, and the resulting data mapped using a Geographic Information System (GIS). A detailed method for obtaining and analyzing data collected near gold shops in Mazuko, Peru is provided. Maps generated using this method were employed to identify point sources of Hg 0 contamination originating from gold shops in ASGM communities and were shared with local city managers to assist in urban planning.•A detailed method is provided to collect and process data, ultimately generating a map that allows for the screening of a community to identify point sources of Hg 0 contamination.•Raw data is provided, as well as a video detailing data processing and mapping using a common spreadsheet program and an open-source GIS.•The generated map can be used for determining areas where people may be exposed to elevated Hg 0 concentrations and/or occupational mercury vapor exposure, targeted enforcement, or outreach to limit Hg 0 pollution., Competing Interests: The Authors confirm that there are no conflicts of interest., (© 2020 The Authors. Published by Elsevier B.V.)

Introduction: The incidental early-stage thymic mass presents a diagnostic challenge. Video-assisted thoracoscopic (VAT) thymectomy is an attractive but potentially morbid solution. The aim was to show it can be safely applied as a first-line modality in those with undiagnosed thymic enlargement with acceptable long-term results., Methods: A total of 45 patients were identified (24 male, median age 52 interquartile range [IQR]: 41-66 years) in a 14-year experience who had CT evidence of an enlarged, possibly malignant thymic mass, but no tissue diagnosis before undertaking VAT thymectomy. The clinical outcomes of both benign and malignant diagnoses were compared., Results: Myasthenic symptoms were present in 20 patients (44%), whereas 15 (33%) were asymptomatic. Benign lesions were resected in 27 patients (60%): thymic hyperplasia (56%), thymic cyst (33%), lipoma (7%) and xanthogranulomatous inflammation (4%). Of the 18 malignant patients, 82% had thymoma (three had Masaoka Stage I, 11 Stage II and one Stage III), 6% thymic carcinoma, 6% teratoma and 6% seminoma. Seven patients required radiotherapy for R1 resection. There was no difference in median hospital stay in either group: Benign group: 4 versus 5 days (P = 0.07). One patient in both groups required conversion to open. Two patients in the malignant group had significant morbidity (one myocardial infarction and one pulmonary embolism). There were no cases of tumour recurrence or mortality at a median follow-up of 6.6 years (IQR: 4.4-9.5 years)., Conclusion: Right-sided diagnostic VAT thymectomy is a safe and effective first-line approach to suspected malignant thymic enlargement. At 5-year follow-up, there were no cases of recurrence in the malignant group.

Randomized surgical trials are of the most difficult to design and recruit, however, they are the only robust method available to establish a new surgical procedure. Mesothelioma is a disease with a perceived poor prognosis for which surgical intervention has relatively high complications and not insignificant mortality. This review will consider the mesothelioma and radical surgery (MARS) 1 and 2 trials, SAKK 17/04 trial and the EORTC 1205 trial all aimed at assessing the potential benefit of radical surgery for malignant pleural mesothelioma. In addition, MesoVATS and MesoTRAP will be explored assessing the value of debulking surgery for malignant pleural mesothelioma. We also endeavour to identify the mistakes made and the lessons learned which will inform future randomized controlled clinical trials in the field of malignant pleural mesothelioma. Despite the insurmountable problems with randomized controlled clinical trials, we show that they are possible and continuing with uncontrolled experiments will perpetuate unproven and potentially harmful operations., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Introduction : To evaluate an aortic pericardial valve for pulmonary valve (PV) regurgitation after repair of congenital heart defects. Methods : From July 2012 to June 2016 71 patients, mean age 24 ± 13 years (four to years) underwent PV implantation of aortic pericardial valve, mean interval after previous repair = 21 ± 10 years (two to 47 years). Previous surgery at mean age 3.2 ± 7.2 years (one day to 49 years): tetralogy of Fallot repair in 83% (59/71), pulmonary valvotomy in 11% (8/71), relief of right ventricular outflow tract (RVOT) obstruction in 6% (4/71). Pre-operative echocardiography and MRI showed severe PV regurgitation in 97% (69/71), moderate in 3% (2/71) with associated RVOT obstruction. MRI and knowledge-based reconstruction 3D volumetry (KBR-3D-volumetry) showed mean PV regurgitation = 42 ± 9% (20-58%), mean indexed RV end-diastolic volume = 169 ± 33 (130-265) ml m -2 BSA and mean ejection fraction (EF) = 46 ± 8% (33-61%). Cardio-pulmonary exercise showed mean peak O 2 /uptake = 24 ± 8 ml kg -1  min -1 (14-45 ml kg -1  min -1 ), predicted max O 2 /uptake 66 ± 17% (26-97%). Pre-operative NYHA class was I in 17% (12/71) patients, II in 70% (50/71) and III in 13% (9/71). Results : Mean cardio-pulmonary bypass duration was 95 ± 30' (38-190'), mean aortic cross-clamp in 23% (16/71) 46 ± 31' (8-95'), with 77% (55/71) implantations without aortic cross-clamp. Size of implanted PV: 21 mm in seven patients, 23 mm in 33, 25 mm in 23, and 27 mm in eight. The z -score of the implanted PV was -0.16 ± 0.80 (-1.6 to 2.5), effective orifice area indexed (for BSA) of native PV was 1.5 ± 0.2 (1.2 to -2.1) vs. implanted PV 1.2 ± 0.3 (0.76 to -2.5) ( p  = ns). In 76% (54/71) patients surgical RV modelling was associated. Mean duration of mechanical ventilation was 6 ± 5 h (0-26 h), mean ICU stay 21 ± 11 h (12-64 h), mean hospital stay 6 ± 3 days (three to 19 days). In mean follow-up = 25 ± 14 months (six to 53 months) there were no early/late deaths, no need for cardiac intervention/re-operation, no valve-related complications, thrombosis or endocarditis. Last echocardiography showed absent PV regurgitation in 87.3% (62/71) patients, trivial/mild degree in 11.3% (8/71), moderate degree in 1.45% (1/71), mean max peak velocity through RVOT 1.6 ± 0.4 (1.0-2.4) m s -1 . Mean indexed RV end-diastolic volume at MRI/KBR-3D-volumetry was 96 ± 20 (63-151) ml m -2 BSA, lower than pre-operatively ( p  < 0.001), and mean EF = 55 ± 4% (49-61%), higher than pre-operatively ( p  < 0.05). Almost all patients (99% = 70/71) remain in NYHA class I, 1.45% = 1/71 in class II. Conclusion : (a) Aortic pericardial valve is implantable in PV position with an easy and reproducible surgical technique; (b) valve size adequate for patient BSA can be implanted with simultaneous RV remodelling; (c) medium-term outcomes are good with maintained PV function, RV dimensions significantly reduced and EF significantly improved; (d) adequate valve size will allow later percutaneous valve-in-valve implantation.

Background: In an apparent paradox, morbidity and mortality are lower in obese patients undergoing cardiac surgery, although the nature of this association is unclear. We sought to determine whether the obesity paradox observed in cardiac surgery is attributable to reverse epidemiology, bias, or confounding., Methods: Data from the National Adult Cardiac Surgery registry for all cardiac surgical procedures performed between April 2002 and March 2013 were extracted. A parallel systematic review and meta-analysis (MEDLINE, Embase, SCOPUS, Cochrane Library) through June 2015 were also accomplished. Exposure of interest was body mass index categorized into 6 groups according to the World Health Organization classification., Results: A total of 401 227 adult patients in the cohort study and 557 720 patients in the systematic review were included. A U-shaped association between mortality and body mass index classes was observed in both studies, with lower mortality in overweight (adjusted odds ratio, 0.79; 95% confidence interval, 0.76-0.83) and obese class I and II (odds ratio, 0.81; 95% confidence interval, 0.76-0.86; and odds ratio, 0.83; 95% confidence interval, 0.74-0.94) patients relative to normal-weight patients and increased mortality in underweight individuals (odds ratio, 1.51; 95% confidence interval, 1.41-1.62). In the cohort study, a U-shaped relationship was observed for stroke and low cardiac output syndrome but not for renal replacement therapy or deep sternal wound infection. Counter to the reverse epidemiology hypotheses, the protective effects of obesity were less in patients with severe chronic renal, lung, or cardiac disease and greater in older patients and in those with complications of obesity, including the metabolic syndrome and atherosclerosis. Adjustments for important confounders did not alter our results., Conclusions: Obesity is associated with lower risks after cardiac surgery, with consistent effects noted in multiple analyses attempting to address residual confounding and reverse causation., (© 2016 American Heart Association, Inc.)

Not all patients who have a rupture of the anterior cruciate ligament (ACL) elect to have surgical reconstruction. The aim of this study was to assess the short-to-medium-term results of patients who chose conservative management in comparison to patients who had reconstructive surgery within the same time period. Sixty-three patients with an ACL injury were retrospectively studied. Forty patients were managed, according to patient choice, with ACL reconstruction and 23 conservatively. Four validated questionnaires were used to assess general and knee-specific function in a cohort with a median age of 32 years and a median follow-up period of 38 months. Patients were matched on demographic variables except for gender. There were no statistically significant differences in the outcome measures, and the majority of patients would proceed with the same treatment in the event the control leg became injured. Patients who elect to have conservative management of an ACL rupture can achieve similar function and satisfaction to those who elect to have reconstruction. Until a large randomized controlled trial is conducted, patients need to be made aware of the merits of both management strategies and the lack of evidence of superiority of one over the other., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was 'Is the placement of an Amplatzer septal occluder device across a post-infarction ventricular septal defect a suitable alternative for patients not eligible for surgical repair?' Altogether, 31 papers were found using the reported search, of which 17 represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. We conclude that the insertion of an Amplatzer occluder device in patients with a post-infarction ventricular septal defect (VSD) not amenable to surgical repair can offer benefit in selected patients. Patients with cardiogenic shock frequently have an unfavourable outcome and closure should be considered cautiously. From the literature available, patients have a better outcome if the intervention is delayed by 2 weeks or more possibly due to the maturation of the VSD and recovery of myocardial function. In certain situations, device closure may be complicated by device dislocation or embolization, residual shunting or a tortuous course not amenable to device implantation. In such settings, surgical repair is the only option. In patients who proceed straight to surgical repair with no attempt at percutaneous closure, the overall mortality lies in the region of 43% and similar to percutaneous closure, there is an association observed between those operated within 7 days of the VSD occurrence and those greater than this time. Patients presenting in cardiogenic shock experienced an increased risk of death and if the timing of myocardial infarction to VSD closure could be delayed by 3 weeks, there was a statistically significant reduction in operative mortality. Percutaneous closure of a post-infarction VSD may avoid the requirement for surgical closure. However, in some cases, it provides time to allow the VSD to mature and the patient to stabilize and be optimized acting as a bridge to surgery to offer the best possible outcome for the patient., (© The Author 2014. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

The mechanism by which inhaled anesthetics work is not fully understood, although they have been extensively used. Much research has been done showing the likelihood that there is more than one pathway or mechanism of action. A long-term goal of our laboratory is to decipher these mechanisms using Drosophila melanogaster, an excellent model organism for this purpose. In order to do this, we have modified and constructed an apparatus called the inebriometer to quantitatively analyze the response of flies to inhaled anesthetics. While the inebriometer is not new to the fly community, our updated design provides a relatively low-labor, high-throughput means for performing screens in search of genes involved in the anesthetic mechanism. Here we describe our construction of an airtight inebriometer that we have designed for this purpose. We also provide data that validates this apparatus and establishes a procedure for its use.

Congenital abnormalities of the internal carotid artery (ICA) are infrequent and can be associated with aberrations of the Circle of Willis. A 47-year-old gentleman presented with transient neurological symptoms and cerebral infarction and carotid Doppler showed a stenotic right ICA. Subsequent computed tomographic angiography showed a hypoplastic ICA with a low-lying bifurcation at the C6 level and aplasia of the anterior communicating artery. This patient was commenced on aggressive medical therapy and at 7-month follow-up was symptom-free. This case report highlights the need for a centralized registry with long-term follow-up data in order to identify optimal management., (Copyright © 2012 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.)

Total knee replacement (TKR) may be associated with chronic limb ischemia (CLI) due to arterial injury intraoperatively. The aim of this study was to determine the incidence of CLI after TKR surgery. Patients who received a unilateral TKR in 2003-2004 were identified from our database. Patients with diabetes mellitus and preexisting peripheral arterial disease were excluded. Patient assessment was by collection of demographic details, completion of the Oxford Knee Score, Short Form-12 Health Survey, and King's College Hospital's Vascular Quality of Life Questionnaire, and measurement of the ankle brachial pressure index (ABPI). Of the 209 eligible patients, 86 (41%) participated (median age, 73 years; 50% male). Five (5.8%) patients had a reduced ABPI compared with population norms of 4.6 to 7%. Patients with reduced ABPI measurements had higher Oxford Knee Scores, but no relationships between other variables were demonstrated. TKR surgery does not appear to increase the risk of CLI.

A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was 'In patients coming to theatre with an intra aortic balloon pump (IABP), is it better to turn it off or keep it on while on bypass?' Altogether 46 papers were found using the reported search, of which 11 represented the best evidence to answer the clinical question. Nine of them were randomised controlled trials (RCTs). The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. The different RCTs were performed looking at various effects of IABP induced pulsatility during cardiopulmonary bypass (CPB) and cardioplegic arrest. These studies showed that IABP induced pulsatile perfusion results in improved perfusion to vital organs, better lung function in chronic obstructive pulmonary disease patients, ameliorates the coagulative system and lowers endothelial activation. Despite these facts a survey in the UK and Ireland showed that 80.5% of cardiac surgeons stop IABP on commencing CPB. We conclude that in patients who already have IABP in-situ whilst going on CPB there is enough evidence in the literature to suggest that it should be turned on to internal trigger mode. Although several randomised control trials in this field have conveyed considerable benefit in terms of biochemical markers measured, none of them have resulted in better clinical outcomes in terms of reduction in major morbidity or mortality. This may be largely due to the small sample size in most of these studies. Seven out of 11 papers were published by same group of authors.

A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was 'Should you place one or two chest drains in patients undergoing lobectomy?' Altogether >200 papers were found using the reported search, of which six represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. We conclude that the insertion of one chest drain confers less postoperative pain as shown by one randomised controlled trial (RCT) and one further cohort study. In addition, another RCT was able to demonstrate a lower use of non-standard analgesia in the face of no overall difference in total pain score while another RCT conveyed a significantly shorter duration of opioid and NSAID use inferring less postoperative pain. From all the studies in this area, no differences in the duration and amount of drainage or the length of hospital stay could be demonstrated with any significance. Therefore, the use of the conventional two drain method is not superior to the one drain method and may indeed cause more pain and is obviously more expensive.

A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was 'Should patients undergoing cardiac surgery with atrial fibrillation (AF) have left atrial appendage (LAA) exclusion?' Altogether 310 papers were found using the reported search, of which 12 represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. We conclude that despite finding five clinical trials including one randomised controlled trial, that studied around 1400 patients who underwent LAA occlusion, the results of these studies do not clearly show a benefit for appendage occlusion. Indeed of the five studies, only one showed a statistical benefit for LAA occlusion, with three giving neutral results and in fact one demonstrating a significantly increased risk. One reason for this may be the inability to achieve acceptably high rates of successful occlusion on echocardiography when attempting to perform this procedure. The highest success rate was only 93% but most studies reported only a 55-66% successful occlusion rate when attempting closure in a variety of methods including stapling, ligation and amputation. Currently, the evidence is insufficient to support LAA occlusion and may indeed cause harm especially if incomplete exclusion occurs.

Following the implementation of the GMC document Tomorrow's Doctors in 1993 the amount of time dedicated to anatomy in undergraduate curricula has been reduced. This has resulted in considerable disquiet among physicians and surgeons with regard to the anatomical knowledge of newly qualified doctors, and also amongst students. This study aimed to assess the perceived student need for anatomical teaching packages to support clinical attachments in the later years of the undergraduate medical curriculum. The views of two groups of students were obtained: Group A were at the beginning of their clinical attachments, whereas Group B had completed all clinical attachments and had sat the final examination. The majority of students indicated that there was a need for the development of a teaching package for anatomy (and other basic sciences) in the later stages of the undergraduate medical curriculum. A high proportion stated that the completion of these packages should be in a self-directed manner with a staff member available. There was a difference between both groups in response to the best time to offer the packages, and in the clinical areas which might be prioritized in such a development. We conclude that the vertical integration of anatomy--perhaps through clinically focused teaching packages--would be welcomed by students as part of their clinical attachments., (Copyright 2008 Wiley-Liss, Inc.)

Aim: To examine differences in morbidity and rates of hospital admission between diabetes patients and patients without diabetes in New Zealand., Methods: A 1,123 and 11,325 patients with Types 1 and 2 diabetes in the Southlink Health diabetes register were identified. Types 1 and 2 diabetes patients were matched with non-diabetic patients drawn from primary care patient registers. Hospital admission rates for diabetic complications and general medical conditions, length of stay in hospital, patients readmitted, deaths in hospital and hospital procedures were analyzed for the 3-year period from 2000 to 2002., Results: Diabetes patients were more likely to be admitted to hospital for any reason than patients without diabetes (odds ratio (OR) 2.55, 95% confidence interval (CI) 2.13-3.04, p<0.001 for Type 1 patients; OR 1.40, CI 1.33-1.48, p<0.001 for Type 2 patients). A 46% (770) of all admissions for Type 1 patients were due to complications arising from diabetes and 33% (4685) for Type 2 patients. Major complications included ischaemic heart disease, heart failure, cataracts and conditions specific to diabetes., Conclusions: Increasing prevalence of diabetes will increase demand for hospital services overall, and particularly for inpatient care related to macroangiopathy, ophthalmic and renal problems and peripheral circulatory disorders.

Environmental influences on sexual behavior are difficult to examine given their temporal distance from the sexual act and the cost of long-term longitudinal studies. We examined environmental influences on risky sexual behavior in young gay men using the Situational Presentation (Sitpres) methodology, where situations in which relevant environmental variables are presented as computer vignettes with the variables randomly allocated, and participants rate the likelihood of their engaging in unsafe sexual behavior. A total of 100 gay men aged between 18 and 26 years of age completed 20 situational presentations with the outcome being the likelihood of engaging in unprotected anal intercourse. On regression analysis, 3 environmental variables significantly predicted safer sex: perceived gay/bisexual men's norms toward condom use; availability of HIV prevention messages; and what one's religion says about gay sex. Not significant were family, media, legal, and work/school attitudes to homosexuality. Demographic variables that were predictors included education, age, sexual orientation, and degree of being "out" about sexual orientation. These data suggest that environmental factors can be approximated using the Sitpres methodology, and that more proximal environmental variables have a stronger impact than distal ones.

Tsunami represents one of the most potentially serious forms of coastal flood risk. Although much is known on the recorded history of tsunamis for given areas of the world, very little information is available on the occurrence of palaeotsunamis during prehistory. This is of fundamental importance in calculating tsunami flood risk for any given coastal area. Given sufficient information on past tsunami activity for a particular coastal area, the numerical calculation of aggregate coastal flood risk (including tsunami) for a coastal area is very difficult to estimate since one needs also to take into account the risk of a tsunami and a storm surge taking place simultaneously during a high tide. Estimates of coastal flood risk also need to consider future changes in relative sea level caused by the combined effects of global climate change and vertical movements of the lithosphere.

This study investigated the efficacy of oral melatonin in alleviating jet lag in flight crew after a series of international flights. The optimal time for taking melatonin in this group was also investigated. In a double-blind placebo-controlled trial, 52 international cabin crew were randomly assigned to three groups; early melatonin (5 mg started 3 days prior to arrival until 5 days after return home); late melatonin (placebo for 3 days then 5 mg melatonin for 5 days); and placebo. Daily ratings showed a trend in jet lag, mood, and sleepiness measures toward an improved recovery in the late melatonin group and a worse recovery in the early melatonin group as compared to placebo. Retrospective ratings made 6 days after arrival showed the late melatonin group reported significantly less jet lag and sleep disturbance following the flight compared to placebo. The late melatonin group also showed a significantly faster recovery of energy and alertness than the early melatonin group, which reported a worse overall recovery than placebo. These findings show melatonin may have potential benefits for international aircrew.

The effect of alpha-chlorohydrin (3-chloropropan-1,2-diol) on the metabolism of D-[U-14C]-fructose and L-[U-14C]-lactate by washed boar sperm has been investigated. Whereas alpha-chlorohydrin at concentrations as low as 0.1 mM inhibited the metabolism of fructose and led to an increase in the utilization of endogenous lactate, amounts up to 500 mM had no effect on the oxidation of added lactate. Low levels of alpha-chlorohydrin increased the cellular concentrations of fructose-1,6-bisphosphate and the triosephosphates, an effect consistent with the inhibition of glyceraldehyde-3-phosphate dehydrogenase. Although [U-14C]-glycerol was rapidly oxidized by boar sperm, [U-14C]-alpha-chlorohydrin was not metabolized to 14CO2, showing that it is not converted to glycerol. Extracts obtained by sonication of boar sperm after incubation with [3-36C1]-alpha-chlorohydrin, did not contain [3-36C1]-alpha-chlorohydrin-1-phosphate. This is contrary to the postulate that this phosphorylated compound is the inhibitory metabolite of alpha-chlorohydrin.

A method is described for the determination of chlorpromazine and some of its major metabolites in post mortem specimens by enzymic digestion of the tissues with ethyl acetate using a simple, single micro-extraction method, followed by HPLC of the extracts using a 10 micron silica column packing and a mobile phase consisting of ethanolamine:methanol:water. Separation and quantitation of 7-hydroxy-chlorpromazine, chlorpromazine, chlorpromazine sulfoxide, norchlorpromazine and norchlorpromazine sulfoxide was achieved employing mesoridazine as an internal standard.

Systems containing soluble fraction of rat liver, with or without mitochondrial fraction, oxidised [1-14C] ethanol to acetaldehyde, 14CO2 and non-volatile 14C-products of which acetate was the principal, and possibly the only, component. Ethanol oxidation was stimulated by pyruvate which served as an electron sink thereby allowing rapid regeneration of NAD. When no mitochondria were present acetaldehyde accumulated, rapidly at first but eventually reaching a plateau. The rate of ethanol oxidation in these systems was much lower than the measured maximum activity of alcohol dehydrogenase (ADH) and it was concluded that ADH was inhibited by the accumulated acetaldehyde. Mitochondria, because of their relatively high aldehyde dehydrogenase (ALDH) activity, prevented the accumulation of acetaldehyde, or quickly removed acetaldehyde already accumulated. This action was accompanied by a sharp increase in the rate of ethanol oxidation, presumably due to the deinhibition of ADH. Cyanamide, an inhibitor of mitochondrial ALDH, blocked the stimulatory effect of mitochondria on ethanol oxidation. It was concluded that, in the reconstituted systems, acetaldehyde played a dominant role in controlling the rate of ethanol oxidation. The possible importance of acetaldehyde in governing ethanol oxidation in vivo is discussed.

The levels of various metabolites were measured in freeze-clamped samples of liver from triiodothyronine-treated and control rats to which either saline or ethanol (2.5 g/kg body weight) had been administered 2 hours earlier. It was found that ethanol led to a sharp increase in the hepatic acetate concentration in both hyperthyroid and euthyroid rats whereas lactate and pyruvate concentrations were lowered in both groups. The lactate/pyruvate ratio rose significantly in euthyroid animals that had received ethanol but the ratio remained relatively low in hyperthyroid rats. The adenine nucleotide phosphorylation potential, already low in hyperthyroid rats, was further lowered by ethanol. However, the most remarkable difference between the responses of euthyroid and hyperthyroid rats to ethanol was in the hepatic concentrations of ketone bodies, particularly 3-hydroxybutyrate. In control animals, administration of ethanol did not affect either the acetoacetate or 3-hydroxybutyrate concentration but, although the level of ketone bodies in the livers of hyperthyroid rats that had not received ethanol was the same as that of controls, there was a greater than fivefold increase in the 3-hydroxybutyrate level when ethanol was given. While this increase in ethanol-dependent ketogenesis is not explicable at this stage, hyperthyroidism did not increase the activity of cytoplasmic acetyl-CoA synthetase, an enzyme that is probably involved in the formation of ketone bodies from ethanol-derived acetate.

1. The properties of membrane vesicles from the extreme thermophile Bacillus caldolyticus were investigated. 2. Vesicles prepared by exposure of spheroplasts to ultrasound contained cytochromes a, b and c, and at 50 degrees C they rapidly oxidized NADH and ascorbate in the presence of tetramethyl-p-phenylenediamine. Succinate and l-malate were oxidized more slowly, and dl-lactate, l-alanine and glycerol 1-phosphate were not oxidized. 3. In the absence of proton-conducting uncouplers the oxidation of NADH was accompanied by a net translocation of H(+) into the vesicles. Hydrolysis of ATP by a dicyclohexylcarbodi-imide-sensitive adenosine triphosphatase was accompanied by a similarly directed net translocation of H(+). 4. Uncouplers (carbonyl cyanide p-trifluoromethoxyphenylhydrazone or valinomycin plus NH(4) (+)) prevented net H(+) translocation but stimulated ATP hydrolysis, NADH oxidation and ascorbate oxidation. The last result suggested an energy-conserving site in the respiratory chain between cytochrome c and oxygen. 5. Under anaerobic conditions the reduction of cytochrome b by ascorbate (with tetramethyl-p-phenylenediamine) was stimulated by ATP hydrolysis, indicating an energy-conserving site between cytochrome b and cytochrome c. However, no reduction of NAD(+) supported by oxidation of succinate, malate or ascorbate occurred, neither did it with these substrates in the presence of ATP under anaerobic conditions, suggesting that there was no energy-conserving site between NADH and cytochrome b. 6. Succinate oxidation, in contrast with that of NADH and ascorbate, was strongly inhibited by uncouplers and stimulated by ATP hydrolysis. These effects were not observed when phenazine methosulphate, which transfers electrons from succinate dehydrogenase directly to oxygen, was present. It was concluded that in these vesicles the oxidation of succinate was energy-dependent and that the reoxidation of reduced succinate dehydrogenase was dependent on the outward movement of H(+) by the protonmotive force. 7. In support of the foregoing conclusion it was shown that the reduction of fumarate by NADH was an energy-conserving process. 8. If the activities of vesicles accurately represent those of the intact organism it appears that in B. caldolyticus the reduction of fumarate to succinate at the expense of reducing equivalents from NADH is energetically favoured over succinate oxidation even under aerobic conditions. This may be related to the need for an ample supply of succinate for haem synthesis in order to provide cytochromes for the organism.

The metabolism of isolated rat kidney tubules suspended in calcium-free physiological saline buffered with phosphate was found to be sensitive to changes in the pH of the suspending medium. Lowering the pH from 7.8 to 6.4 brought about increases in the rates of oxidation of added succinate, glutamate or glutamine as well as in the production of glucose from lactate, glutamine, succinate and fructose. The cellular ATP level was also higher in tubules incubated at pH 6.4 In contrast, the utilization of added glucose was greater at pH 7.8 than at pH 6.4, a substantial amount of lactate being produced at the higher pH. When glucose and either lactate or glutamine were provided as co-substrates glucose was the preferred fuel at pH 7.8 but the alternative substrate was the more readily utilized at pH 6.4. As a consequence of the metabolic activities of the tubules the pH of the suspending medium changed, utilization of lactate, glutamate or glutamine causing a rise in pH while conversion of glucose to lactate caused a fall in pH. In cases where two substrates were metabolized concurrently over a period of 3 h the extracellular pH tended towards a plateau level of approximately pH 7.4. It is proposed that pH-sensitive metabolism in isolated kidney tubules contributes to pH homeostasis in the cellular environment.