Search

Aims Oxygen-pulse morphology and gas exchange analysis measured during cardiopulmonary exercise testing (CPET) has been associated with myocardial ischaemia. The aim of this analysis was to examine the relationship between CPET parameters, myocardial ischaemia and anginal symptoms in patients with chronic coronary syndrome and to determine the ability of these parameters to predict the placebo-controlled response to percutaneous coronary intervention (PCI). Methods and results Patients with severe single-vessel coronary artery disease (CAD) were randomized 1:1 to PCI or placebo in the ORBITA trial. Subjects underwent pre-randomization treadmill CPET, dobutamine stress echocardiography (DSE) and symptom assessment. These assessments were repeated at the end of a 6-week blinded follow-up period. A total of 195 patients with CPET data were randomized (102 PCI, 93 placebo). Patients in whom an oxygen-pulse plateau was observed during CPET had higher (more ischaemic) DSE score [+0.82 segments; 95% confidence interval (CI): 0.40 to 1.25, P = 0.0068] and lower fractional flow reserve (−0.07; 95% CI: −0.12 to −0.02, P = 0.011) compared with those without. At lower (more abnormal) oxygen-pulse slopes, there was a larger improvement of the placebo-controlled effect of PCI on DSE score [oxygen-pulse plateau presence (Pinteraction = 0.026) and oxygen-pulse gradient (Pinteraction = 0.023)] and Seattle angina physical-limitation score [oxygen-pulse plateau presence (Pinteraction = 0.037)]. Impaired peak VO2, VE/VCO2 slope, peak oxygen-pulse, and oxygen uptake efficacy slope was significantly associated with higher symptom burden but did not relate to severity of ischaemia or predict response to PCI. Conclusion Although selected CPET parameters relate to severity of angina symptoms and quality of life, only an oxygen-pulse plateau detects the severity of myocardial ischaemia and predicts the placebo-controlled efficacy of PCI in patients with single-vessel CAD.

Anthropogenic climate change is resulting in spatial redistributions of many species. We assessed the potential effects of climate change on an abundant and widely distributed group of diving birds, Eudyptes penguins, which are the main avian consumers in the Southern Ocean in terms of biomass consumption. Despite their abundance, several of these species have undergone population declines over the past century, potentially due to changing oceanography and prey availability over the important winter months. We used light-based geolocation tracking data for 485 individuals deployed between 2006 and 2020 across 10 of the major breeding locations for five taxa of Eudyptes penguins. We used boosted regression tree modelling to quantify post-moult habitat preference for southern rockhopper (E. chrysocome), eastern rockhopper (E. filholi), northern rockhopper (E. moseleyi) and macaroni/royal (E. chrysolophus and E. schlegeli) penguins. We then modelled their redistribution under two climate change scenarios, representative concentration pathways RCP4.5 and RCP8.5 (for the end of the century, 2071-2100). As climate forcings differ regionally, we quantified redistribution in the Atlantic, Central Indian, East Indian, West Pacific and East Pacific regions. We found sea surface temperature and sea surface height to be the most important predictors of current habitat for these penguins; physical features that are changing rapidly in the Southern Ocean. Our results indicated that the less severe RCP4.5 would lead to less habitat loss than the more severe RCP8.5. The five taxa of penguin may experience a general poleward redistribution of their preferred habitat, but with contrasting effects in the (i) change in total area of preferred habitat under climate change (ii) according to geographic region and (iii) the species (macaroni/royal vs. rockhopper populations). Our results provide further understanding on the regional impacts and vulnerability of species to climate change.

IntroductionThere is an increasing need for evaluating postintensive care syndrome in adults concerning their long-term physical, psychological, cognitive and/or social outcomes, yet there is no consensus regarding the choice of instruments to measure these. This scoping review aims to identify and examine instruments used to measure postintensive care syndrome in adults.Methods and analysisThis scoping review will be conducted following the Arksey and O’Malley and its extended framework, and the Joanna Briggs Institute guideline. It will be reported according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses extension for Scoping Review checklists. Medline via EBSCO, CINAHL complete, EMBASE, Web of Science, AME and APA PsycINFO databases and grey literature will be searched from 2010 to the present. Reference lists of included studies will be manually checked to identify additional sources. The quality of included studies will be appraised using the Crowe Critical Appraisal Tool. All review steps will involve at least two reviewers. Data charting will be performed narratively, comprising study characteristics and findings, and instrument properties. This review will also aim to identify research gaps.Ethics and disseminationThere is no ethics disclosure for this review protocol. This scoping review will identify instruments used to measure postintensive care syndrome in adults. The findings will be disseminated through professional bodies, conferences and research papers.

Graphical abstract, Highlights • Large GGGGCC repeat expansions within BAC vectors are highly unstable. • CRISPR-Cas9 screening of BAC vector clones to determine repeat length. • CRISPR-Cas9 cloning of GGGGCC repeat expansion regions into the linear pJazz vector. • pJazz dramatically stabilizes GGGGCC repeat expansions over 4 kb in length., Aberrant microsatellite repeat-expansions at specific loci within the human genome cause several distinct, heritable, and predominantly neurological, disorders. Creating models for these diseases poses a challenge, due to the instability of such repeats in bacterial vectors, especially with large repeat expansions. Designing constructs for more precise genome engineering projects, such as engineering knock-in mice, proves a greater challenge still, since these unstable repeats require numerous cloning steps in order to introduce homology arms or selection cassettes. Here, we report our efforts to clone a large hexanucleotide repeat in the C9orf72 gene, originating from within a BAC construct, derived from a C9orf72-ALS patient. We provide detailed methods for efficient repeat sizing and growth conditions in bacteria to facilitate repeat retention during growth and sub-culturing. We report that sub-cloning into a linear vector dramatically improves stability, but is dependent on the relative orientation of DNA replication through the repeat, consistent with previous studies. We envisage the findings presented here provide a relatively straightforward route to maintaining large-range microsatellite repeat-expansions, for efficient cloning into vectors.

Background Most people who begin statins abandon them, most commonly because of side effects. Objectives The purpose of this study was to assess daily symptom scores on statin, placebo, and no treatment in participants who had abandoned statins. Methods Participants received 12 1-month medication bottles, 4 containing atorvastatin 20 mg, 4 placebo, and 4 empty. We measured daily symptom intensity for each using an app (scale 1-100). We also measured the “nocebo” ratio: the ratio of symptoms induced by taking statin that was also induced by taking placebo. Results A total of 60 participants were randomized and 49 completed the 12-month protocol. Mean symptom score was 8.0 (95% CI: 4.7-11.3) in no-tablet months. It was higher in statin months (16.3; 95% CI: 13.0-19.6; P < 0.001), but also in placebo months (15.4; 95% CI: 12.1-18.7; P < 0.001), with no difference between the 2 (P = 0.388). The corresponding nocebo ratio was 0.90. In the individual-patient daily data, neither symptom intensity on starting (OR: 1.02; 95% CI: 0.98-1.06; P = 0.28) nor extent of symptom relief on stopping (OR: 1.01; 95% CI: 0.98-1.05; P = 0.48) distinguished between statin and placebo. Stopping was no more frequent for statin than placebo (P = 0.173), and subsequent symptom relief was similar between statin and placebo. At 6 months after the trial, 30 of 60 (50%) participants were back taking statins. Conclusions The majority of symptoms caused by statin tablets were nocebo. Clinicians should not interpret symptom intensity or timing of symptom onset or offset (on starting or stopping statin tablets) as indicating pharmacological causation, because the pattern is identical for placebo. (Self-Assessment Method for Statin Side-effects Or Nocebo [SAMSON]; NCT02668016), Central Illustration

Cystoscopic visualization of bladder cancer is an essential method for initial bladder cancer detection and diagnosis, transurethral resection, and monitoring for recurrence. We sought to develop a new intravesical imaging agent that is more specific and sensitive using a polypeptide based NIR (near-infrared) probe designed to detect cells bearing epidermal growth factor receptors (EGFR) that are overexpressed in 80% of urothelial carcinoma (UC) cases. The NIR imaging agent consisted of an elastin like polypeptide (ELP) fused with epidermal growth factor (EGF) and conjugated to Cy5.5 to give Cy5.5-N24-EGF as a NIR contrast agent. In addition to evaluation in human cells and tissues, the agent was tested in canine cell lines and tissue samples with naturally occurring invasive UC. Flow cytometry and confocal microscopy were used to test cell-associated fluorescence of the probe in T24 human UC cells, and in K9TCC-SH (high EGFR expression) and K9TCC-Original (low EGF expression) canine cell lines. The probe specifically engages these cells through EGFR within 15 min of incubation and reached saturation within a clinically relevant 1 h timeframe. Furthermore

Pseudoxanthoma elasticum (PXE), a heritable multisystem ectopic calcification disorder, is predominantly caused by inactivating mutations in ABCC6. The encoded protein, ABCC6, is a hepatic efflux transporter and a key regulator of extracellular inorganic pyrophosphate (PPi). Recent studies demonstrated that deficiency of plasma PPi, a potent endogenous calcification inhibitor, is the underlying cause of PXE. This study examined whether restoring plasma PPi levels by INZ-701, a recombinant human ENPP1 protein, the principal PPi-generating enzyme, prevents ectopic calcification in an Abcc6(−/−) mouse model of PXE. Abcc6(−/−) mice, at 6 weeks of age, the time of earliest stages of ectopic calcification, were injected subcutaneously with INZ-701 at 2 or 10 mg/kg for 2 or 8 weeks. INZ-701 at both doses increased steady-state plasma ENPP1 activity and PPi levels. In the 8-week treatment study, histopathologic examination and quantification of the calcium content in INZ-701-treated Abcc6(−/−) mice revealed significantly reduced calcification in the muzzle skin containing vibrissae, a biomarker of the calcification process in these mice. The extent of calcification corresponds to the local expression of two calcification inhibitors, osteopontin and fetuin-A. These results suggest that INZ-701 might provide a therapeutic approach for PXE, a disease with high unmet needs and no approved treatment.

Background Non-surgical multidisciplinary management is often the first pathway of care for patients with chronic low back pain (LBP). This study explores if patient characteristics recorded at the initial service examination have an association with a poor response to this pathway of care in an advanced practice physiotherapist-led tertiary service. Methods Two hundred and forty nine patients undergoing non-surgical multidisciplinary management for their LBP across 8 tertiary public hospitals in Queensland, Australia participated in this prospective longitudinal study. Generalised linear models (logistic family) examined the relationship between patient characteristics and a poor response at 6 months follow-up using a Global Rating of Change measure. Results Overall 79 of the 178 (44%) patients completing the Global Rating of Change measure (28.5% loss to follow-up) reported a poor outcome. Patient characteristics retained in the final model associated with a poor response included lower Formal Education Level (ie did not complete school) (Odds Ratio (OR (95% confidence interval)) (2.67 (1.17–6.09), p = 0.02) and higher self-reported back disability (measured with the Oswestry Disability Index) (OR 1.33 (1.01–1.77) per 10/100 point score increase, p = 0.046). Conclusions A low level of formal education and high level of self-reported back disability may be associated with a poor response to non-surgical multidisciplinary management of LBP in tertiary care. Patients with these characteristics may need greater assistance with regard to their comprehension of health information, and judicious monitoring of their response to facilitate timely alternative care if no benefits are attained.

Obesity-related complications including visceral fat, metabolic abnormalities, nutrient deficiencies, and immune perturbations are interdependent but have been individually associated with childhood asthma.We sought to endotype childhood obesity-related asthma by quantifying contributions of obesity-related complications to symptoms and pulmonary function.Multiomics analysis using Similarity Network Fusion followed by mediation analysis were performed to quantify prediction of obese asthma phenotype by different combinations of anthropometric, metabolic, nutrient, and TTwo clusters (n = 28 and 26) distinct in their anthropometric (neck and midarm circumference, waist to hip ratio [WHR], and body mass index [BMI] z score), metabolic, nutrient, and TAnthropometric, metabolic, nutrient, and immune perturbations have individual but interdependent contributions to obese asthma phenotype, with the most consistent effect of WHR, highlighting the role of truncal adiposity in endotyping childhood obesity-related asthma.

Taxi driving, a male-dominated occupation, is associated with an increased risk of cardiovascular disease (CVD). The increased risk is linked to a high prevalence of modifiable CVD risk factors including overweight/obesity, poor nutrition, smoking, excessive alcohol consumption and physical inactivity. Behaviour change interventions may prove advantageous, yet little research has been conducted to reduce CVD risk in this population. The purpose of this study was to co-design an eHealth intervention, ‘ManGuard’, to reduce CVD risk in male taxi drivers. The IDEAS framework was utilised to guide the development of the eHealth intervention, with the Behaviour Change Wheel (BCW) incorporated throughout to ensure the intervention was underpinned by behaviour change theory. Development and refinement of ManGuard was guided by current literature, input from a multidisciplinary team, an online survey, a systematic review and meta-analysis, and focus groups (n = 3) with male taxi drivers. Physical inactivity was identified as the prime behavior to change in order to reduce CVD risk in male taxi drivers. Male taxi drivers indicated a preference for an eHealth intervention to be delivered using smartphone technology, with a simple design, providing concise, straightforward, and relatable content, and with the ability to track and monitor progress.

N-of-1 Trial of a Statin, Placebo, or No Treatment Patients who had discontinued statins because of side effects received four bottles of a statin, four bottles of placebo, and four empty bottles, ...

Neurodegenerative disease encompasses a wide range of disorders afflicting the central and peripheral nervous systems and is a major unmet biomedical need of our time. There are very limited treatments, and no cures, for most of these diseases, including Alzheimer’s Disease, Parkinson's Disease, Huntington Disease, and Motor Neuron Diseases. Mouse and other animal models provide hope by analysing them to understand pathogenic mechanisms, to identify drug targets, and to develop gene therapies and stem cell therapies. However, despite many decades of research, virtually no new treatments have reached the clinic. Increasingly, it is apparent that human heterogeneity within clinically defined neurodegenerative disorders, and between patients with the same genetic mutations, significantly impacts disease presentation and, potentially, therapeutic efficacy. Therefore, stratifying patients according to genetics, lifestyle, disease presentation, ethnicity, and other parameters may hold the key to bringing effective therapies from the bench to the clinic. Here, we discuss genetic and cellular humanised mouse models, and how they help in defining the genetic and environmental parameters associated with neurodegenerative disease, and so help in developing effective precision medicine strategies for future healthcare.

Refereed/Peer-reviewed

Summary Background ANRS IPERGAY found that on-demand pre-exposure prophylaxis (PrEP) with oral tenofovir disoproxil fumarate plus emtricitabine was associated with an 86% relative reduction of HIV-1 incidence compared with placebo among men who have sex with men at high risk of HIV. We aimed to investigate whether on-demand PrEP was similarly effective among individuals with lower exposure to HIV risk. Methods Participants in the ANRS IPERGAY trial were randomly assigned to receive PrEP (fixed-dose combination of 300 mg tenofovir disoproxil fumarate and 200 mg emtricitabine per pill) or placebo. The primary endpoint was the diagnosis of HIV-1 infection. Pill uptake was assessed by counting returned pills at each follow-up and by estimating tenofovir concentration from frozen plasma samples. Participants were interviewed at each visit to assess the pattern of PrEP use. All participants enrolled in the modified intention-to-treat population of the double-blind phase of the ANRS IPERGAY trial were eligible for this post-hoc analysis. We calculated the total follow-up time for periods of less frequent sexual intercourse with high PrEP adherence (15 pills or fewer per month taken systematically or often during sexual intercourse). To estimate the time of HIV acquisition, fourth-generation HIV-1/2 ELISA assays, plasma HIV-1 RNA assays, and western blot analyses were done with use of frozen samples, and the stage of HIV infection was defined according to Fiebig staging. HIV incidence was compared between the two treatment groups among individuals who had less frequent sexual intercourse with high PrEP adherence. The ANRS IPERGAY trial is registered with ClinicalTrials.gov , NCT01473472 . Findings 400 participants who were randomly assigned to receive PrEP (n=199) or placebo (n=201) between Feb 22, 2012, and Oct 17, 2014, were included in this analysis. 270 participants had at least one period of less frequent sexual intercourse with high PrEP adherence during the study, representing 134 person-years of follow-up and 31% of the total study follow-up. During these periods, participants in both groups reported a median of 5·0 (IQR 2·0–10·0) episodes of sexual intercourse per month and used a median of 9·5 (6·0–13·0) pills per month. Six HIV-1 infections were diagnosed in the placebo group (HIV incidence of 9·2 per 100 person-years; 95% CI 3·4–20·1) and none were diagnosed in the tenofovir disoproxil fumarate plus emtricitabine arm (HIV incidence of 0 per 100 person-years; 0–5·4; p=0·013), with a relative reduction of HIV incidence of 100% (95% CI 39–100). Interpretation A choice between daily or on-demand PrEP regimens could be offered to men who have sex with men who have less frequent sexual intercourse. Funding ANRS (France Recherche Nord and Sud Sida-HIV Hepatites), the Canadian HIV Trials Network, Fonds Pierre Berge (Sidaction), Gilead Sciences, and the Bill & Melinda Gates Foundation.

Mechanotransduction is the process by which cells convert physical forces into electrochemical responses. On a molecular scale, these forces are detected by mechanically activated ion channels, which constitute the basis for hearing, touch, pain, cold, and heat sensation, among other physiological processes. Exciting high-resolution structural details of these channels are currently emerging that will eventually allow us to delineate the molecular determinants of gating and ion permeation. However, our structural-functional understanding across the family remains limited. Piezo1 is one of the largest and least understood of these channels, with various structurally identified features within its trimeric assembly. This study seeks to determine the modularity and function of Piezo1 channels by constructing deletion proteins guided by cryo EM structural knowledge. Our comprehensive functional study identified, for the first time, the minimal amino acid sequence of the full-length Piezo1 that can fold and function as the channel's pore domain between E2172 and the last residue E2547. While the addition of an anchor region has no effect on permeation properties. The Piezo1 pore domain is not pressure-sensitive and the appending of Piezo Repeat-A did not restore pressure-dependent gating, hence the sensing module must exist between residues 1 to 1952. Our efforts delineating the permeation and gating regions within this complex ion channel have implications in identifying small molecules that exclusively regulate the activity of the channel's pore module to influence mechanotransduction and downstream processes.

As experience managing coronavirus disease 2019 (COVID-19) increased in early 2020, it became evident that patients infected with severe acute respiratory syndrome coronavirus 2 were at increased risk of developing AKI. In large United States cohorts studied at the beginning of the pandemic, 28%–46% of those hospitalized with COVID-19 developed AKI, and rates were markedly higher among patients requiring admission/transfer to the intensive care unit (ICU; 61%–78%) (1⇓⇓⇓–5). In a retrospective study in New York, patients admitted with COVID-19 were at 130% increased risk for AKI compared with a historical cohort in the same centers (6). The burden of COVID-19–associated AKI is superimposed upon the nearly 4 million cases of AKI reported annually among United States adults in a pre–COVID-19 environment (7). Given the absence of uniformly effective therapy directed against severe acute respiratory syndrome coronavirus 2, supportive management and RRT are the primary treatments for AKI (8,9). For hemodynamically unstable and critically ill patients, continuous RRT (CRRT) is generally the preferred RRT (9). Alternative modalities for hemodynamically unstable patients include sustained low-efficiency dialysis (SLED), prolonged intermittent RRT (PIRRT), and peritoneal dialysis (PD), whereas intermittent hemodialysis (IHD) is a primary option for more hemodynamically stable patients. The widespread nature of the current pandemic placed enormous demands on the need for RRT across the United States. In the pre–COVID-19 era, 23,105 patients were treated for AKI with RRT annually (7). The need for RRT among patients with COVID-19 appears to be five-fold higher than that observed in historical populations (4.9% versus 0.9%) (6). In datasets of community cohorts, 5%–15% of patients hospitalized with COVID-19 required dialytic support (1,2,5). In certain United States centers, the population requiring CRRT increased 370% over typical levels (10). During the first 6 months of …

Introduction The ORBITA trial of percutaneous coronary intervention (PCI) versus a placebo procedure for patients with stable angina was conducted across six sites in the United Kingdom via home monitoring and telephone consultations. Patients underwent detailed assessment of medication adherence which allowed us to measure the efficacy of the implementation of the optimization protocol and interpretation of the main trial endpoints. Methods Prescribing data were collected throughout the trial. Self‐reported adherence was assessed, and urine samples collected at pre‐randomization and at follow‐up for direct assessment of adherence using high‐performance liquid chromatography with tandem mass spectrometry (HPLC MS/MS). Results Self‐reported adherence was >96% for all drugs in both treatment groups at both stages. The percentage of samples in which drug was detected at pre‐randomization and at follow‐up in the PCI versus placebo groups respectively was: clopidogrel, 96% versus 90% and 98% versus 94%; atorvastatin, 95% versus 92% and 92% versus 91%; perindopril, 95% versus 97% and 85% versus 100%; bisoprolol, 98% versus 99% and 96% versus 97%; amlodipine, 99% versus 99% and 94% versus 96%; nicorandil, 98% versus 96% and 94% versus 92%; ivabradine, 100% versus 100% and 100% versus 100%; and ranolazine, 100% versus 100% and 100% versus 100%. Conclusions Adherence levels were high throughout the study when quantified by self‐reporting methods and similarly high proportions of drug were detected by urinary assay. The results indicate successful implementation of the optimization protocol delivered by telephone, an approach that could serve as a model for treatment of chronic conditions, particularly as consultations are increasingly conducted online., Medical therapy for patients with stable angina optimised over 6 weeks of tele‐ health clinic visits. Treatment titrated to home blood pressure and heart rate measurements. Medication adherence confirmed using HPLC MS/MS and patient self‐reporting. Patients subsequently randomised to PCI or placebo procedure in the ORBITA trial. Adherence reassessed at final follow‐up. Self‐reported adherence was >96% for all drugs in both treatment groups at both stages. Proportion of expected drug detected was >90% for all first‐choice, protocol‐directed medicines at both stages. No significant between group differences at pre‐ randomisation or at follow‐up and medication taking patterns did not change following treatment with PCI. The study uses a simple model for optimisation of medical therapy in clinical practice using a telehealth approach with high levels of adherence.

Summary Background Although metformin is increasingly being used in women with type 2 diabetes during pregnancy, little data exist on the benefits and harms of metformin use on pregnancy outcomes in these women. We aimed to investigate the effects of the addition of metformin to a standard regimen of insulin on neonatal morbidity and mortality in pregnant women with type 2 diabetes. Methods In this prospective, multicentre, international, randomised, parallel, double-masked, placebo-controlled trial, women with type 2 diabetes during pregnancy were randomly assigned from 25 centres in Canada and four in Australia to receive either metformin 1000 mg twice daily or placebo, added to insulin. Randomisation was done via a web-based computerised randomisation service and stratified by centre and pre-pregnancy BMI ( ClinicalTrials.gov , NCT01353391 . Findings Between May 25, 2011, and Oct 11, 2018, we randomly assigned 502 women, 253 (50%) to metformin and 249 (50%) to placebo. Complete data were available for 233 (92%) participants in the metformin group and 240 (96%) in the placebo group for the primary outcome. We found no significant difference in the primary composite neonatal outcome between the two groups (40% vs 40%; p=0·86; relative risk [RR] 1·02 [0·83 to 1·26]). Compared with women in the placebo group, metformin-treated women achieved better glycaemic control (HbA1c at 34 weeks' gestation 41·0 mmol/mol [SD 8·5] vs 43·2 mmol/mol [–10]; 5·90% vs 6·10%; p=0·015; mean glucose 6·05 [0·93] vs 6·27 [0·90]; difference −0·2 [–0·4 to 0·0]), required less insulin (1·1 units per kg per day vs 1·5 units per kg per day; difference −0·4 [95% CI −0·5 to −0·2]; p Interpretation We found several maternal glycaemic and neonatal adiposity benefits in the metformin group. Along with reduced maternal weight gain and insulin dosage and improved glycaemic control, the lower adiposity and infant size measurements resulted in fewer large infants but a higher proportion of small-for-gestational-age infants. Understanding the implications of these effects on infants will be important to properly advise patients who are contemplating the use of metformin during pregnancy. Funding Canadian Institutes of Health Research, Lunenfeld-Tanenbaum Research Institute, University of Toronto.

Summary Background Symptomatic relief is the primary goal of percutaneous coronary intervention (PCI) in stable angina and is commonly observed clinically. However, there is no evidence from blinded, placebo-controlled randomised trials to show its efficacy. Methods ORBITA is a blinded, multicentre randomised trial of PCI versus a placebo procedure for angina relief that was done at five study sites in the UK. We enrolled patients with severe (≥70%) single-vessel stenoses. After enrolment, patients received 6 weeks of medication optimisation. Patients then had pre-randomisation assessments with cardiopulmonary exercise testing, symptom questionnaires, and dobutamine stress echocardiography. Patients were randomised 1:1 to undergo PCI or a placebo procedure by use of an automated online randomisation tool. After 6 weeks of follow-up, the assessments done before randomisation were repeated at the final assessment. The primary endpoint was difference in exercise time increment between groups. All analyses were based on the intention-to-treat principle and the study population contained all participants who underwent randomisation. This study is registered with ClinicalTrials.gov, number NCT02062593. Findings ORBITA enrolled 230 patients with ischaemic symptoms. After the medication optimisation phase and between Jan 6, 2014, and Aug 11, 2017, 200 patients underwent randomisation, with 105 patients assigned PCI and 95 assigned the placebo procedure. Lesions had mean area stenosis of 84·4% (SD 10·2), fractional flow reserve of 0·69 (0·16), and instantaneous wave-free ratio of 0·76 (0·22). There was no significant difference in the primary endpoint of exercise time increment between groups (PCI minus placebo 16·6 s, 95% CI −8·9 to 42·0, p=0·200). There were no deaths. Serious adverse events included four pressure-wire related complications in the placebo group, which required PCI, and five major bleeding events, including two in the PCI group and three in the placebo group. Interpretation In patients with medically treated angina and severe coronary stenosis, PCI did not increase exercise time by more than the effect of a placebo procedure. The efficacy of invasive procedures can be assessed with a placebo control, as is standard for pharmacotherapy. Funding NIHR Imperial Biomedical Research Centre, Foundation for Circulatory Health, Imperial College Healthcare Charity, Philips Volcano, NIHR Barts Biomedical Research Centre.

Background Shanfield first described a simple ureteric implantation technique involving a U-stitch anchoring the spatulated end of the transplant ureter to the interior of the intact bladder through a small stab wound. We present an extrapolation of this principle to Mitrofanoff channels and native ureteric reimplantations and further extend it to a laparoscopic approach in some. Methods A retrospective case-note reviewing the Shanfield ureteric reimplantation in fifteen children between October 2014 and May 2017 was performed. Results Fifteen children (females n = 9), median age 6 years (range 8 months–15 years), underwent a Shanfield anastomosis for ureteric (n = 3) or Mitrofanoff (n = 12) implantation into the bladder. Their diagnoses were: vesicoureteric reflux (n = 2), vesicoureteric obstruction (n = 1), neuropathic bladder (n = 4), exstrophy (n = 2, bladder and cloacal), nonneuropathic bladder (n = 3), cloaca (n = 2), and one with failed urethral reconstruction of a Y-duplication. Two ureteric reimplantations and one appendix-Mitrofanoff were undertaken entirely laparoscopically. The bladder was not opened in 9/15, with the remaining six in an ileocystoplasty and one complex cloaca. Fourteen patients were available for follow-up at a median 18.2 (5.8–43.3) months. There was no anastomotic leakage in any, and one stenosis was successfully managed with simple dilatation. One complex patient required a new Mitrofanoff channel. Conclusion Our preliminary data suggest that the Shanfield anastomosis offers a safe, robust, and simple antireflux implantation technique without the need to formally open the bladder. The technique offers several advantages as it allows overcoming the problem of inadequate tunnelling when the bladder template is deficient. Meanwhile, its simplicity permits it to be faithfully reproduced with laparoscopy in select patients. Type of study Treatment study. Level of evidence IV.

Summary Background In blinded randomised controlled trials, statin therapy has been associated with few adverse events (AEs). By contrast, in observational studies, larger increases in many different AEs have been reported than in blinded trials. Methods In the Lipid-Lowering Arm of the Anglo-Scandinavian Cardiac Outcomes Trial, patients aged 40–79 years with hypertension, at least three other cardiovascular risk factors, and fasting total cholesterol concentrations of 6·5 mmol/L or lower, and who were not taking a statin or fibrate, had no history of myocardial infarction, and were not being treated for angina were randomly assigned to atorvastatin 10 mg daily or matching placebo in a randomised double-blind placebo-controlled phase. In a subsequent non-randomised non-blind extension phase (initiated because of early termination of the trial because efficacy of atorvastatin was shown), all patients were offered atorvastatin 10 mg daily open label. We classified AEs using the Medical Dictionary for Regulatory Activities. We blindly adjudicated all reports of four prespecified AEs of interest—muscle-related, erectile dysfunction, sleep disturbance, and cognitive impairment—and analysed all remaining AEs grouped by system organ class. Rates of AEs are given as percentages per annum. Results The blinded randomised phase was done between February, 1998, and December, 2002; we included 101 80 patients in this analysis (5101 [50%] in the atorvastatin group and 5079 [50%] in the placebo group), with a median follow-up of 3·3 years (IQR 2·7–3·7). The non-blinded non-randomised phase was done between December, 2002, and June, 2005; we included 9899 patients in this analysis (6409 [65%] atorvastatin users and 3490 [35%] non-users), with a median follow-up of 2·3 years (2·2–2·4). During the blinded phase, muscle-related AEs (298 [2·03% per annum] vs 283 [2·00% per annum]; hazard ratio 1·03 [95% CI 0·88–1·21]; p=0·72) and erectile dysfunction (272 [1·86% per annum] vs 302 [2·14% per annum]; 0·88 [0·75–1·04]; p=0·13) were reported at a similar rate by participants randomly assigned to atorvastatin or placebo. The rate of reports of sleep disturbance was significantly lower among participants assigned atorvastatin than assigned placebo (149 [1·00% per annum] vs 210 [1·46% per annum]; 0·69 [0·56–0·85]; p=0·0005). Too few cases of cognitive impairment were reported for a statistically reliable analysis (31 [0·20% per annum] vs 32 [0·22% per annum]; 0·94 [0·57–1·54]; p=0·81). We observed no significant differences in the rates of all other reported AEs, with the exception of an excess of renal and urinary AEs among patients assigned atorvastatin (481 [1·87%] per annum vs 392 [1·51%] per annum; 1·23 [1·08–1·41]; p=0·002). By contrast, during the non-blinded non-randomised phase, muscle-related AEs were reported at a significantly higher rate by participants taking statins than by those who were not (161 [1·26% per annum] vs 124 [1·00% per annum]; 1·41 [1·10–1·79]; p=0·006). We noted no significant differences between statin users and non-users in the rates of other AEs, with the exception of musculoskeletal and connective tissue disorders (992 [8·69% per annum] vs 831 [7·45% per annum]; 1·17 [1·06–1·29]; p=0·001) and blood and lymphatic system disorders (114 [0·88% per annum] vs 80 [0·64% per annum]; 1·40 [1·04–1·88]; p=0·03), which were reported more commonly by statin users than by non-users. Interpretation These analyses illustrate the so-called nocebo effect, with an excess rate of muscle-related AE reports only when patients and their doctors were aware that statin therapy was being used and not when its use was blinded. These results will help assure both physicians and patients that most AEs associated with statins are not causally related to use of the drug and should help counter the adverse effect on public health of exaggerated claims about statin-related side-effects. Funding Pfizer, Servier Research Group, and Leo Laboratories.

Introduction. Carbon dioxide is the standard insufflation gas for laparoscopy. However, in many areas of the world, bottled carbon dioxide is not available. Laparoscopy offers advantages over open surgery and has been practiced using filtered room air insufflation since 2006 at Bongolo Hospital in Gabon, Africa. Objective. Our primary goal was to evaluate the safety of room air insufflation related to intraoperative and postoperative complications. Our secondary aim was to review the types of cases performed laparoscopically at our institution. Methods. This retrospective review evaluates laparoscopic cases performed at Bongolo Hospital between January 2006 and December 2013. Demographic and perioperative information for patients undergoing laparoscopic procedures was collected. Insufflation was achieved using a standard, oil-free air compressor using filtered air and a standard insufflation regulator. Results. A total of 368 laparoscopic procedures were identified within the time period. The majority of cases were gynecologic (43%). There was a 2% (8/368) complication rate with one perioperative death. The 2 complications related to insufflation were episodes of hypotension responsive to standard corrective measures. No intracorporeal combustion events were observed in any cases in which the use of diathermy and room air insufflation were combined. The other complications and the death were unrelated to the use of insufflation with air. Conclusion. Insufflation complications with room air occurred in our study. However, the complications related to insufflation with room air in our study were no different than those described in the literature using carbon dioxide. As room air is less costly than carbon dioxide and readily available, confirming the safety of room air insufflation in prospective studies is warranted. Room air appears to be safe for establishing and maintaining pneumoperitoneum, making laparoscopic surgery more accessible to patients in low-resource settings.

Background: Dobutamine stress echocardiography is widely used to test for ischemia in patients with stable coronary artery disease. In this analysis, we studied the ability of the prerandomization stress echocardiography score to predict the placebo-controlled efficacy of percutaneous coronary intervention (PCI) within the ORBITA trial (Objective Randomised Blinded Investigation With Optimal Medical Therapy of Angioplasty in Stable Angina). Methods: One hundred eighty-three patients underwent dobutamine stress echocardiography before randomization. The stress echocardiography score is broadly the number of segments abnormal at peak stress, with akinetic segments counting double and dyskinetic segments counting triple. The ability of prerandomization stress echocardiography to predict the placebo-controlled effect of PCI on response variables was tested by using regression modeling. Results: At prerandomization, the stress echocardiography score was 1.56±1.77 in the PCI arm (n=98) and 1.61±1.73 in the placebo arm (n=85). There was a detectable interaction between prerandomization stress echocardiography score and the effect of PCI on angina frequency score with a larger placebo-controlled effect in patients with the highest stress echocardiography score ( P interaction =0.031). With our sample size, we were unable to detect an interaction between stress echocardiography score and any other patient-reported response variables: freedom from angina ( P interaction =0.116), physical limitation ( P interaction =0.461), quality of life ( P interaction =0.689), EuroQOL 5 quality-of-life score ( P interaction =0.789), or between stress echocardiography score and physician-assessed Canadian Cardiovascular Society angina class ( P interaction =0.693), and treadmill exercise time ( P interaction =0.426). Conclusions: The degree of ischemia assessed by dobutamine stress echocardiography predicts the placebo-controlled efficacy of PCI on patient-reported angina frequency. The greater the downstream stress echocardiography abnormality caused by a stenosis, the greater the reduction in symptoms from PCI. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02062593.

Background: There are no data on how fractional flow reserve (FFR) and instantaneous wave-free ratio (iFR) are associated with the placebo-controlled efficacy of percutaneous coronary intervention (PCI) in stable single-vessel coronary artery disease. Methods: We report the association between prerandomization invasive physiology within ORBITA (Objective Randomised Blinded Investigation With Optimal Medical Therapy of Angioplasty in Stable Angina), a placebo-controlled trial of patients who have stable angina with angiographically severe single-vessel coronary disease clinically eligible for PCI. Patients underwent prerandomization research FFR and iFR assessment. The operator was blinded to these values. Assessment of response variables, treadmill exercise time, stress echocardiography score, symptom frequency, and angina severity were performed at prerandomization and blinded follow-up. Effects were calculated by analysis of covariance. The ability of FFR and iFR to predict placebo-controlled changes in response variables was tested by using regression modeling. Results: Invasive physiology data were available in 196 patients (103 PCI and 93 placebo). At prerandomization, the majority had Canadian Cardiovascular Society class II or III symptoms (150/196, 76.5%). Mean FFR and iFR were 0.69±0.16 and 0.76±0.22, respectively; 97% had ≥1 positive ischemia tests. The estimated effect of PCI on between-arm prerandomization-adjusted total exercise time was 20.7 s (95% confidence interval [CI], –4.0 to 45.5; P =0.100) with no interaction of FFR ( P interaction =0.318) or iFR ( P interaction =0.523). PCI improved stress echocardiography score more than placebo (1.07 segment units; 95% CI, 0.70–1.44; P P interaction P interaction P =0.072) with no detectable evidence of interaction with FFR ( P interaction =0.849) or iFR ( P interaction =0.783). However, PCI resulted in more patient-reported freedom from angina than placebo (49.5% versus 31.5%; odds ratio, 2.47; 95% CI, 1.30–4.72; P =0.006) but neither FFR ( P interaction =0.693) nor iFR ( P interaction =0.761) modified this effect. Conclusions: In patients with stable angina and severe single-vessel disease, the blinded effect of PCI was more clearly seen by stress echocardiography score and freedom from angina than change in treadmill exercise time. Moreover, the lower the FFR or iFR, the greater the magnitude of stress echocardiographic improvement caused by PCI. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02062593.

The hyperaccumulation of trace elements is a widely characterized phenomenon in plants, bacteria, and fungi, but has received little attention in animals. However, there are numerous examples of animals that specifically and facultatively accumulate trace elements in the absence of elevated environmental concentrations. Metal hyperaccumulating animals are usually marine invertebrates, likely owing to environmental (e.g. constant exposure via the water) and physiological (e.g. osmoconforming and reduced integument permeability) factors. However, there are examples of terrestrial animals (insect larvae) and marine vertebrates (e.g. squirrelfish) that accumulate high body and/or tissue metal burdens. This review examines examples of animal hyperaccumulation of the elements arsenic, copper, iron, titanium, vanadium and zinc, describing mechanisms by which accumulation occurs and, where possible, hypothesizing functional roles. Groups such as the ascidians (sea squirts), molluscs (gastropods, bivalves and cephalopods) and polychaete annelids feature prominently as animals with hyperaccumulating capacity. Many of these species are potential model organisms offering insight into fundamental processes underlying metal handling, with relevance to human disease and aquatic metal toxicity, and some offer promise in applied fields such as bioremediation.

There are no data on how fractional flow reserve (FFR) and instantaneous wave-free ratio (iFR) are associated with the placebo-controlled efficacy of percutaneous coronary intervention (PCI) in stable single-vessel coronary artery disease.We report the association between prerandomization invasive physiology within ORBITA (Objective Randomised Blinded Investigation With Optimal Medical Therapy of Angioplasty in Stable Angina), a placebo-controlled trial of patients who have stable angina with angiographically severe single-vessel coronary disease clinically eligible for PCI. Patients underwent prerandomization research FFR and iFR assessment. The operator was blinded to these values. Assessment of response variables, treadmill exercise time, stress echocardiography score, symptom frequency, and angina severity were performed at prerandomization and blinded follow-up. Effects were calculated by analysis of covariance. The ability of FFR and iFR to predict placebo-controlled changes in response variables was tested by using regression modeling.Invasive physiology data were available in 196 patients (103 PCI and 93 placebo). At prerandomization, the majority had Canadian Cardiovascular Society class II or III symptoms (150/196, 76.5%). Mean FFR and iFR were 0.69±0.16 and 0.76±0.22, respectively; 97% had ≥1 positive ischemia tests. The estimated effect of PCI on between-arm prerandomization-adjusted total exercise time was 20.7 s (95% confidence interval [CI], -4.0 to 45.5; P=0.100) with no interaction of FFR ( PIn patients with stable angina and severe single-vessel disease, the blinded effect of PCI was more clearly seen by stress echocardiography score and freedom from angina than change in treadmill exercise time. Moreover, the lower the FFR or iFR, the greater the magnitude of stress echocardiographic improvement caused by PCI.URL: https://www.clinicaltrials.gov . Unique identifier: NCT02062593.

ObjectivesCumulative radiation exposure is associated with increased risk of malignancy. This is important in cystic fibrosis (CF) as frequent imaging is required to monitor disease progression and diagnose complications. Previous estimates of cumulative radiation are outdated as the imaging was performed on older equipment likely to deliver higher radiation. Our objectives were to determine the radiation dose delivered to children during common radiological investigations using modern equipment and to identify the number of such investigations performed in a cohort of children with CF to calculate their cumulative radiation exposure.Design, setting and participantsData including age at investigation and radiation exposure measured as estimated effective dose (EED) were collected on 2827 radiological studies performed on children at one UK paediatric centre. These were combined with the details of all radiological investigations performed on 65 children with CF attending the same centre to enable calculation of each child’s cumulative radiation exposure.ResultsThe mean EED for the common radiological investigations varied according to age. The range was 0.01–0.02 mSv for chest X-rays, 0.03–0.11 mSv for abdominal X-rays, 0.57–1.69 mSv for CT chest, 2.9–3.9 mSv for abdominal and pelvic CT, 0.20–0.21 mSv for sinus CT and 0.15–0.52 mSv for fluoroscopy-guided procedures. The mean EED was three to five times higher for helical compared with axial chest CT scans. The mean annual cumulative EED for our cohort of children with CF was 0.15 mSv/year with an estimated cumulative paediatric lifetime EED (0–18 years) of 3.5 mSv.ConclusionsThis study provides up-to-date estimations of the radiation exposure when using common radiological investigations. These doses and the estimates of cumulative radiation exposure in children with CF are lower than previously reported. This reflects the reduced EED associated with modern equipment and the use of age-specific scanning protocols.

PROBLEM ADDRESSED: Timely access to specialist care is an important issue for patients with mild to moderate symptoms, and wait times for referrals are currently quite long. OBJECTIVE OF PROGRAM: To provide FPs with quick telephone access to other specialists for treatment advice for patients with nonserious conditions that they would otherwise refer to specialist care. PROGRAM DESCRIPTION: The RACE (Rapid Access to Consultative Expertise) program is a telephone hot-line providing FPs and nurse practitioners in the Vancouver, BC, area with timely access to specialist consultations. An evaluation of data from RACE found 60% of RACE calls prevented patients from visiting a specialist and 32% of calls prevented FP referrals to hospital emergency departments. CONCLUSION: Supported by RACE, FPs can more effectively remain the locus of patient care, calling on other specialist expertise when appropriate and providing better coordination of care for their patients. Evaluations to date suggest RACE helps reduce system costs by reducing unnecessary emergency department visits and face-to-face specialist consultations.

BackgroundPneumatosis intestinalis (PI) is an uncommon and poorly understood condition. Although it can be an incidental finding in asymptomatic individuals, it can also be secondary to life-threatening bowel ischaemia and sepsis. In premature infants, it is a pathognomonic sign of necrotising enterocolitis. There is no consensus regarding management and long-term outcome of children with PI.AimReview of our experience of PI in children beyond the early infantile period.MethodsRetrospective review of patient’s records and radiological images from 2013 to 2015.ResultsEighteen patients (three girls) had radiologically confirmed PI. The median age was 4.5 years (range 8 months–13 years). Background medical conditions (number): short bowel syndrome (one), congenital heart disease (two), sickle cell disease (one), epilepsy (three), cerebral palsy (six), myotonic dystrophy (four) and peroxisomal biogenesis defect (one).Six children (33%) presented with abdominal distension, four (22%) with abdominal pain, three (17%) with bilious vomiting, two (11%) with diarrhoea and one (6%) with rectal bleeding. Two (11%) were asymptomatic. One had air in portal vein and two had pneumoperitoneum.All patients with symptomatic PI were treated conservatively with successful outcome and complete resolution of PI. None required surgical intervention.ConclusionPI in children who are not on chemotherapy or immunosuppressant appears to follow a benign course and is responsive to conservative management. In contrast to adults, portal venous gas and pneumoperitoneum do not predict the need for surgical intervention.

We investigated molecular features and cellular roles of PI31 (PSMF1) on regulation of proteasome function. PI31 has a C-terminal HbYX (where Hb is a hydrophobic amino acid, Y is tyrosine, and X is any amino acid) motif characteristic of several proteasome activators. Peptides corresponding to the PI31 C terminus also bind to and activate the 20 S proteasome in an HbYX-dependent manner, but intact PI31protein inhibits in vitro 20 S activity. Binding to and inhibition of the proteasome by PI31 are conferred by the HbYX-containing proline-rich C-terminal domain but do not require HbYX residues. Thus, multiple regions of PI31 bind independently to the proteasome and collectively determine effects on activity. PI31 blocks the ATP-dependent in vitro assembly of 26 S proteasome from 20 S proteasome and PA700 subcomplexes but has no effect on in vitro activity of the intact 26 S proteasome. To determine the physiologic significance of these in vitro effects, we assessed multiple aspects of cellular proteasome content and function after altering PI31 levels. We detected no change in overall cellular proteasome content or function when PI31 levels were either increased by moderate ectopic overexpression or decreased by RNA interference (RNAi). We also failed to identify a role of PI31 ADP-ribosylation as a mechanism for regulation of overall 26 S proteasome content and function, as recently proposed. Thus, despite its in vitro effects on various proteasome activities and its structural relationship to established proteasome regulators, cellular roles and mechanisms of PI31 in regulation of proteasome function remain unclear and require future definition.

We examined the role of ATP binding by six different ATPase subunits (Rpt1–6) in the cellular assembly and molecular functions of mammalian 26 S proteasome. Four Rpt subunits (Rpt1–4) with ATP binding mutations were incompetent for cellular assembly into 26 S proteasome. In contrast, analogous mutants of Rpt5 and Rpt6 were incorporated normally into 26 S proteasomes in both intact cells and an in vitro assembly assay. Surprisingly, purified 26 S proteasomes containing either mutant Rpt5 or Rpt6 had normal basal ATPase activity and substrate gate opening for hydrolysis of short peptides. However, these mutant 26 S proteasomes were severely defective for ATP-dependent in vitro degradation of ubiquitylated and non-ubiquitylated proteins and did not display substrate-stimulated ATPase and peptidase activities characteristic of normal proteasomes. These results reveal differential roles of ATP binding by various Rpt subunits in proteasome assembly and function. They also indicate that substrate-stimulated ATPase activity and gating depend on the concerted action of a full complement of Rpt subunits competent for ATP binding and that this regulation is essential for normal proteolysis. Thus, protein substrates appear to promote their own degradation by stimulating proteasome functions involved in proteolysis. Background: ATPase subunits mediate 26 S proteasome assembly and function. Results: Defective ATP binding by some ATPase subunits inhibits proteasome assembly, and proteasomes harboring an ATP binding-defective subunit are impaired for proteolysis, substrate-stimulated gating, and ATPase activity. Conclusion: The proteasome requires normal ATP binding for assembly and function. Significance: Protein substrates promote their own degradation by inducing ATP-dependent proteasome functions.

National data on vaccine up-to-date (UTD) suggest that insufficient numbers of adolescents receive needed vaccines. This study analyzed public use data of the National Immunization Survey-Teen (NIS-Teen) from 2010 through 2013 for South Carolina (SC) adolescents and compared immunization rates to those of United States (US) adolescents. We also examined trends for each vaccine recommended for adolescents for both SC and US adolescents. UTD rates in SC adolescents for the quadrivalent meningococcal conjugate vaccine (MCV4) and the tetanus- diphtheria, acellular pertussis (Tdap) vaccine lag those of US adolescents, despite demonstrating a trend of improvement in SC adolescents from 45% to 69% for MCV and from 48% to 72% for Tdap. Human papillomavirus (HPV) vaccine UTD rates for SC adolescents demonstrated improvement over a 4 year period. HPV vaccination for SC girls improved when compared to the US, however UTD rates for both the SC and US were still well below the Healthy People 2020 goal of 80%. For all three vaccines, parental recall for a provider recommendation to vaccinate their adolescent was around or below 50%, except for HPV in females where it reached 65% in SC and 69% in the US. Differences between state and national rates may help SC providers focus on specific interventions needed to improve UTD rates.

In this paper we present an algorithm that allows for minimal end-user inputs by internally automating the creation and management of interactions amongst the objects in the scene in real-time medical simulation framework. A bi-directed graph (with nodes representing the scene objects and the connections representing the interactions) is formed based on the inputs from the user. This graph is then processed using a two stage algorithm that aims to find subgraphs that can be treated as independent sub-systems. Collision detection, collision response, assembly and solver objects are then automatically created and managed. This allows for users with limited knowledge of the underlying physics models, collision detection and contact algorithms to easily create a surgical scenario with minimal inputs.

Aims Cardiac allograft vasculopathy (CAV) is a major cause of morbidity and mortality in cardiac transplant recipients. This study evaluates the usefulness of single photon emission computed tomography (SPECT) and various SPECT-derived diastolic variables to detect CAV in heart transplant patients. Methods and results A retrospective review of 141 SPECT studies with corresponding coronary angiograms within 12 months was performed on 99 transplant recipients. Diastolic function was assessed using computer-derived measures of peak filling rate (PFR), time to peak filling rate (TPFR), and mean first one-third filling rate (MFR/3). Angiography identified CAV in 53 of the 141 studies (38%). Of the 53, SPECT identified 7 with reversible myocardial defects (sensitivity 13%) and stress-induced electrocardiographic evidence of ischaemia was seen in one patient (sensitivity 2%). SPECT imaging was negative in 86 of the 88 negative coronary angiograms (specificity 98%). The positive predictive value and negative predictive value were 78 and 65%, respectively. If a more stringent definition of CAV was used (≥70% stenosis), the sensitivity and specificity were unchanged (14 and 98%, respectively). There was no statistical difference in diastolic variables between patients with or without angiographic evidence of CAV in regard to PFR (3.57 ± 1.14 vs. 3.18 ± 1.21 EDV/s, P = 0.90), TPFR (149 ± 32 vs. 153 ± 43 ms, P = 0.33), or MFR/3 (1.37 ± 0.43 vs. 1.27 ± 0.42 EDV/s, P = 0.94). Conclusion Adenosine stress/rest technetium-99m tetrofosmin-gated SPECT is not a sensitive test for detection of CAV in heart transplant recipients. Diastolic dysfunction, as assessed by SPECT, was not shown to be associated with development of CAV.

Summary Background Our aim was to investigate whether a nurse-coordinated multidisciplinary, family-based preventive cardiology programme could improve standards of preventive care in routine clinical practice. Methods In a matched, cluster-randomised, controlled trial in eight European countries, six pairs of hospitals and six pairs of general practices were assigned to an intervention programme (INT) or usual care (UC) for patients with coronary heart disease or those at high risk of developing cardiovascular disease. The primary endpoints—measured at 1 year—were family-based lifestyle change; management of blood pressure, lipids, and blood glucose to target concentrations; and prescription of cardioprotective drugs. Analysis was by intention to treat. The trial is registered as ISRCTN 71715857. Findings 1589 and 1499 patients with coronary heart disease in hospitals and 1189 and 1128 at high risk were assigned to INT and UC, respectively. In patients with coronary heart disease who smoked in the month before the event, 136 (58%) in the INT and 154 (47%) in the UC groups did not smoke 1 year afterwards (difference in change 10·4%, 95% CI −0·3 to 21·2, p=0·06). Reduced consumption of saturated fat (196 [55%] vs 168 [40%]; 17·3%, 6·4 to 28·2, p=0·009), and increased consumption of fruit and vegetables (680 [72%] vs 349 [35%]; 37·3%, 18·1 to 56·5, p=0·004), and oily fish (156 [17%] vs 81 [8%]; 8·9%, 0·3 to 17·5, p=0·04) at 1 year were greatest in the INT group. High-risk individuals and partners showed changes only for fruit and vegetables (p=0·005). Blood-pressure target of less than 140/90 mm Hg was attained by both coronary (615 [65%] vs 547 [55%]; 10·4%, 0·6 to 20·2, p=0·04) and high-risk (586 [58%] vs 407 [41%]; 16·9%, 2·0 to 31·8, p=0·03) patients in the INT groups. Achievement of total cholesterol of less than 5 mmol/L did not differ between groups, but in high-risk patients the difference in change from baseline to 1 year was 12·7% (2·4 to 23·0, p=0·02) in favour of INT. In the hospital group, prescriptions for statins were higher in the INT group (810 [86%] vs 794 [80%]; 6·0%, −0·5 to 11·5, p=0·04). In general practices in the intervention groups, angiotensin-converting enzyme inhibitors (297 [29%] INT vs 196 [20%] UC; 8·5%, 1·8 to 15·2, p=0·02) and statins (381 [37%] INT vs 232 [22%] UC; 14·6%, 2·5 to 26·7, p=0·03) were more frequently prescribed. Interpretation To achieve the potential for cardiovascular prevention, we need local preventive cardiology programmes adapted to individual countries, which are accessible by all hospitals and general practices caring for coronary and high-risk patients. Funding European Society of Cardiology through an unconditional educational grant from AstraZeneca.

Background There were over 36,000 new cases of kidney cancer reported in the United States in 2004, the most common type being renal cell carcinoma (RCC). Available treatments for localized RCC frequently lead to cure; however RCC patients with advanced disease have limited treatment options and low survival rates. Data on the economic burden of RCC are limited. Methods A prevalence-based model was used to estimate the aggregate annual societal cost burden of RCC in the U.S., including costs of treatment and lost productivity. Key parameters in the model include: the annual number of patients treated for RCC by age group and cancer stage; utilization of cancer treatments; unit costs; work-days missed; and wage rates. Multiplying stratum-specific distributions of treatment by annual quantities of treatments and unit costs yields estimates of RCC-related health-care costs. Multiplying stratum-specific estimates of annual workdays missed by average wage rates yields estimates of RCC-related lost productivity. Results The annual prevalence of RCC in the U.S. was estimated to be 109,500 cases. The associated annual burden (inflated to 2005 U.S.$) was approximately $4.4 billion ($40,176 per patient). Health-care costs and lost productivity accounted for 92.4% ($4.1 billion) and 7.6% ($334 million), respectively. Reflecting its higher prevalence, the total cost associated with localized RCC accounted for the greatest share (78.2%), followed by regional, distant, and unstaged RCC, at 18.3%, 2.8%, and 0.7%, respectively. Conclusions The economic burden of RCC in the U.S. is substantial. Interventions to reduce the prevalence of RCC have the potential to yield considerable economic benefits.

Background Antiretroviral preexposure prophylaxis has been shown to reduce the risk of human immunodeficiency virus type 1 (HIV-1) infection in some studies, but conflicting results have been reported among studies, probably due to challenges of adherence to a daily regimen. Methods We conducted a double-blind, randomized trial of antiretroviral therapy for preexposure HIV-1 prophylaxis among men who have unprotected anal sex with men. Participants were randomly assigned to take a combination of tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) or placebo before and after sexual activity. All participants received risk-reduction counseling and condoms and were regularly tested for HIV-1 and HIV-2 and other sexually transmitted infections. Results Of the 414 participants who underwent randomization, 400 who did not have HIV infection were enrolled (199 in the TDF-FTC group and 201 in the placebo group). All participants were followed for a median of 9.3 months (interquartile range, 4.9 to 20.6). A total of 16 HIV-1 infections occurred during follow-up, 2 in the TDF-FTC group (incidence, 0.91 per 100 person-years) and 14 in the placebo group (incidence, 6.60 per 100 person-years), a relative reduction in the TDF-FTC group of 86% (95% confidence interval, 40 to 98; P=0.002). Participants took a median of 15 pills of TDF-FTC or placebo per month (P=0.57). The rates of serious adverse events were similar in the two study groups. In the TDF-FTC group, as compared with the placebo group, there were higher rates of gastrointestinal adverse events (14% vs. 5%, P=0.002) and renal adverse events (18% vs. 10%, P=0.03). Conclusions The use of TDF-FTC before and after sexual activity provided protection against HIV-1 infection in men who have sex with men. The treatment was associated with increased rates of gastrointestinal and renal adverse events. (Funded by the National Agency of Research on AIDS and Viral Hepatitis [ ANRS] and others; ClinicalTrials.gov number, NCT01473472.)

Cystic adventitial disease of veins is a rare condition. We report the case of a 28-year-old man who presented with a swollen leg secondary to obstruction of the common femoral vein as a result of this disease. He underwent excision of the cyst and made a full recovery. The presentation, investigation, treatment and pathology of this condition is discussed.

The 26S proteasome degrades polyubiquitinated proteins by an energy-dependent mechanism. Here we define multiple roles for ATP in 26S proteasome function. ATP binding is necessary and sufficient for assembly of 26S proteasome from 20S proteasome and PA700/19S subcomplexes and for proteasome activation. Proteasome assembly and activation may require distinct ATP binding events. The 26S proteasome degrades nonubiquitylated, unstructured proteins without ATP hydrolysis, indicating that substrate translocation per se does not require the energy of hydrolysis. Nonubiquitylated folded proteins and certain polyubiquitylated folded proteins were refractory to proteolysis. The latter were deubiquitylated by an ATP-independent mechanism. Other folded as well as unstructured polyubiquitylated proteins required ATP hydrolysis for proteolysis and deubiquitylation. Thus, ATP hydrolysis is not used solely for substrate unfolding. These results indicate that 26S proteasome-catalyzed degradation of polyubiquitylated proteins involves mechanistic coupling of several processes and that such coupling imposes an energy requirement not apparent for any isolated process.

Acute cholangitis is more common in older people, and increasing age is a determinant of morbidity and mortality, as is early biliary decompression by ERCP. This study aims to identify factors that may contribute to delays in the diagnosis and treatment of older people with acute cholangitis. Case notes of 122 patients (45 aged75 years, 7775 years) with a final diagnosis of acute cholangitis who underwent ERCP were reviewed for presenting clinical features (pain, jaundice, rigors, fever, falls, incontinence, confusion), liver function tests, blood count, and the interval from admission to diagnosis, ultrasonography, and ERCP. The most common symptom at presentation was abdominal pain (81%), followed by jaundice (55%). These symptoms were no less common in older patients. Charcot's triad was present in only 15.6% of young and 18.8% of older patients. Jaundice was not detected in 16% of significantly hyperbilirubinemic older patients, but only the presence of functional symptoms was associated with significant diagnostic delay (median, 1 day [range: 0-11] vs. 9.5 days [3-25]; P0.001) and delay in performing ERCP (median: 4 days [0-24] vs. 16.5 days [2-29], P0.001). Overall mortality was 10%, and the incidence of septic shock was similar in both groups. Charcot's classical triad is infrequent in patients suffering from acute cholangitis. Given the greater difficulty assessing jaundice in older people and the confounding effect of falls, incontinence, and confusion, a routine policy of liver function tests, with further investigation of abnormal results in such presentations, may reduce delays in diagnosing and treating acute cholangitis.

Background: Pharmacoeconomic analysis is increasingly being used to assist decision makers in getting the biggest "bang for the buck" within cost-constrained health care budgets. The tools and techniques of this science,however, have scarcely been applied to neuropathic pain. Objective: To describe the basic principles of pharmacoeconomic analysis and set forth a preliminary pharmacoeconomic model of neuropathic pain. Key Findings: Applying the tools and techniques of pharmacoeconomic analysis to neuropathic pain yields several insights. First, because pain treatment predominantly benefits quality of life, the results of a pharmacoeconomic analysis of neuropathic pain treatment should be expressed in terms of the cost per quality-adjusted life-year (QALY)-gained metric. Second, because pain can fluctuate, a state-transition modeling approach should be used in constructing the pharmacoeconomic model to account for changes in pain status over time, particularly as relates to the effects of treatment. Finally, assessment of typical practice patterns in neuropathic pain suggests that the pharmacoeconomic model should account for multiple rounds of treatment (i.e., first-line therapy, second-line therapy, and so on), primary care to specialty care referral patterns, and differences in costs and outcomes between primary care physicians and pain specialists. Conclusions: Pharmacoeconomic analysis of neuropathic pain treatments can play an influential role in formulary committee deliberations, treatment algorithms, and decision making in the clinical setting. By describing the fundamental concepts and key challenges in this field, it is hoped that this article will represent a useful first step toward a pharmacoeconomic model of neuropathic pain.

Recent years have seen a dramatic rise in the prevalence of obesity in many countries, stimulating interest in the health and economic consequences of this phenomenon. In this article, we provide a systematic review of the literature on the medical-care cost burden of obesity. Relevant studies were identified using a computerized search of the medical literature for English-language articles published between 1990 and 2001. The 18 studies that met all criteria for inclusion in the review can be classified as modelling or database studies and further distinguished as cross-sectional or longitudinal in nature. The majority of studies that have been conducted are cross-sectional modelling studies, including 10 studies reporting the burden of obesity to national health systems. These suggest that obesity accounts for 5.5-7.0% of national health expenditures in the United States and 2.0-3.5% in other countries for which estimates have been reported. Other studies highlight the burden of obesity from other perspectives, including employers and health plans, as well as the impact of obesity on future disease risks and associated medical-care costs. Despite various methodological limitations, discussed herein, this body of research leads to the inescapable conclusion that obesity exacts an immense economic toll in various countries throughout the world.

In this paper, we present a systematic review of the literature on current issues in the economics of depression management, focusing on studies within three distinct areas of interest: 1) the clinical and economic outcomes of alternative patterns of antidepressant use; 2) the impact of depression and antidepressant therapy on the costs of general medical-care services; and 3) the effects of depression and associated benefits of antidepressant therapy on worker productivity. Our review suggests that 1) patterns of antidepressant use are important predictors of symptom improvement, relapse/recurrence, and costs of care, and that use patterns vary according to the antidepressant received as initial therapy; 2) patients with depression have higher costs of general medical-care services compared with their nondepressed peers, and that treatment of depression may reduce these costs; and 3) depression can result in productivity losses via increased rates of absenteeism and short-term disability as well as via impaired on-the-job performance.

Study objective Proposed national performance measures for severe sepsis or septic shock include interventions within 3 hours of emergency department (ED) arrival rather than from time of first meeting diagnostic criteria. We aim to determine the percentage of ED patients who first meet criteria greater than 3 hours after arrival. Methods We conducted a retrospective analysis of adult patients with severe sepsis or septic shock in 2 EDs (university hospital [September 2012 to June 2013] and public trauma center [December 2012 to May 2013]). Times of ED arrival and first meeting clinical criteria were collected for quality assurance programs, which differed between institutions. At the university hospital, patients with admission diagnoses consistent with infection were included. Clinical presentation was defined as time meeting 2 or more systemic inflammatory response syndrome criteria and evidence of end-organ dysfunction. At the trauma center, only patients with hospital discharge diagnoses consistent with infection were included. Clinical presentation was defined by time of end-organ dysfunction. Results Three hundred seventy-two patients met inclusion criteria at the university hospital and 133 at the trauma center. Median times from ED arrival to first meeting criteria were 68 minutes (interquartile range 34 to 130 minutes) and 31 minutes (interquartile range 8 to 73 minutes), respectively; 15.3% (95% confidence interval 11.9% to 19.3%) and 9.8% (95% confidence interval 5.5% to 15.7%) first met criteria greater than 3 hours from ED arrival, respectively. Conclusion Compliance with a performance metric for severe sepsis and septic shock within 3 hours of ED arrival would require application of this measure to patients who do not meet diagnostic criteria, potentially resulting in unnecessary interventions. Measure developers should consider these findings.

ObjectiveTo examine the use of vitamin D supplements during infancy among the participants in an international infant feeding trial.DesignLongitudinal study.SettingInformation about vitamin D supplementation was collected through a validated FFQ at the age of 2 weeks and monthly between the ages of 1 month and 6 months.SubjectsInfants (n 2159) with a biological family member affected by type 1 diabetes and with increased human leucocyte antigen-conferred susceptibility to type 1 diabetes from twelve European countries, the USA, Canada and Australia.ResultsDaily use of vitamin D supplements was common during the first 6 months of life in Northern and Central Europe (>80 % of the infants), with somewhat lower rates observed in Southern Europe (>60 %). In Canada, vitamin D supplementation was more common among exclusively breast-fed than other infants (e.g. 71 % v. 44 % at 6 months of age). Less than 2 % of infants in the USA and Australia received any vitamin D supplementation. Higher gestational age, older maternal age and longer maternal education were study-wide associated with greater use of vitamin D supplements.ConclusionsMost of the infants received vitamin D supplements during the first 6 months of life in the European countries, whereas in Canada only half and in the USA and Australia very few were given supplementation.

31P NMR was used to measure the intracellular free magnesium concentration ([Mg2+]i) in human erythrocytes while [Mg2+]i was changed between 0.01 and 1.2 mM using the divalent cationophore A23187. 13C NMR and [2-13C]glucose were used to determine the kinetic effects of [Mg2+]i by measuring the flux through several parts of the glucose pathway. Glucose utilization was strongly dependent on [Mg2+]i, with half-maximal flux occurring at 0.03 mM. The rate-limiting step was most likely at phosphofructokinase, which has a Km(Mg2+) of 0.025 mM in the purified enzyme. Phosphorylated glycolytic intermediate concentration was also strongly dependent on [Mg2+]i and [MgATP], and glucose transport plus hexokinase may have been partially rate-determining at [Mg2+]i below approximately 0.1 mM. The pentose phosphate shunt activity was too low to determine the dependence on [Mg2+]i. Phosphoglycerate kinase and 2, 3-diphosphoglycerate mutase fluxes were also measured, but were not rate-limiting for glycolysis and showed no Mg2+ dependence. Human erythrocyte [Mg2+]i varies between 0.2 mM (oxygenated) and 0.6 mM (deoxygenated), well above the measured [Mg2+]i(1/2). It is unlikely, then, that [Mg2+]i plays a regulatory role in normal erythrocyte glycolysis.