Search

Open in new tab Download slide OBJECTIVES Relevant paravalvular leakage (PVL) due to prosthesis dislodgement is a rare but potentially severe complication after transcatheter mitral valve implantation (TMVI). Due to the epicardial anchoring mechanism of the Tendyne® TMVI system, repositioning of the valve stent may be possible by retensioning of the tether. This multicentre study aimed to investigate the procedural and short-term safety as well as efficacy of retensioning manoeuvres. METHODS From 2017 to 2021, N  = 18 patients who underwent secondary tether retensioning were identified. Baseline, procedural and follow-up data were available from N  = 11 patients and analysed according to the Mitral Valve Research Consortium definitions. Continuous variables are shown as median with interquartile range. RESULTS All patients [age 75 years (73.5, 85.0), 64% male (N  = 7), EuroSCORE II 6.2% (5.8, 11.6)] presented with post-procedural PVL [63.6% (N  = 7) with PVL ≥3+]. Of these, 54% (N  = 6) showed signs of haemolysis. The majority were severely symptomatic [New York Heart Association ≥III (91%, N  = 10)]. Procedural outcomes revealed no acute complications and no mortality. At discharge, PVL was completely eliminated in 91% (N  = 10) of patients with 1 case of remaining moderate PVL. At 30 days, Mitral Valve Research Consortium device success was achieved in 82% (N  = 9) of patients. Two patients required open surgical mitral valve replacement due to persistent and recurrent PVL. In 89% (N  = 8) of patients with successful retensioning procedure, New York Heart Association class was I/II. There was no 30-day mortality. CONCLUSIONS This multicentre study demonstrates technical feasibility, procedural safety and acute efficacy of retensioning procedures in the majority of patients. The potential to retension the tether in transapical TMVI may provide additional management advantages in populations at high surgical risk. [ABSTRACT FROM AUTHOR]

Background: The high‐density microarray patch (HD‐MAP) promises to be a robust vaccination platform with clear advantages for future global societal demands for health care management. The method of action has its base not only in efficient delivery of vaccine but also in the reliable induction of a local innate physical inflammatory response to adjuvant the vaccination process. The application process needs to induce levels of reactivity, which are acceptable to the vaccine, and from which the skin promptly recovers. Materials and methods: 1 × 1 cm HD‐MAP patches containing 5000, 250‐μm long microprojections were applied to the skin in 12 healthy volunteers. The return of skin barrier function was assessed by transepidermal water loss (TEWL) and reaction to topical histamine challenge. Results: Skin barrier recovery by 48 h was confirmed for all HD‐MAP sites by recovered resistance to the effects of topical histamine application. Conclusions: Our previous observation, that the barrier disruption indicator TEWL returns to normal by 48 h, is supported by this paper's demonstration of return of skin resistance to topical histamine challenge in twelve healthy subjects. [ABSTRACT FROM AUTHOR]

This expert Position Statement is a description of the requirements for Accreditation for transcatheter mitral valve therapy (TMVT) in Australia. The requirements include the need for a multidisciplinary Heart Team review of individual cases, mandatory reporting of outcome data to a national TMVT Registry, and accreditation of individuals and institutions by the Conjoint Accreditation Committee, the assigned accreditation authority. [ABSTRACT FROM AUTHOR]

Background: Transcatheter mitral valve replacement (TMVR) is feasible for selected patients with severe mitral regurgitation (MR) who are poor candidates for valve surgery. Intermediate-term to long-term TMVR outcomes have not been reported.Objectives: This study sought to evaluate the safety and effectiveness through 2-year follow-up of TMVR in high-surgical-risk patients with severe MR.Methods: The first 100 patients enrolled in the Expanded Clinical Study of the Tendyne Mitral Valve System, an open-label, nonrandomized, prospective study of transapical TMVR, were followed for 2 years.Results: The patients (aged 74.7 ± 8.0 years, 69.0% male) had symptomatic (66.0% New York Heart Association [NYHA] functional class III or IV) grade 3+ or 4+ MR that was secondary or mixed in 89 (89.0%). Prostheses were successfully implanted in 97 (97.0%) patients. At 2 years, all-cause mortality was 39.0%; 17 (43.6%) of 39 deaths occurred during the first 90 days. Heart failure hospitalization (HFH) fell from 1.30 events per year preprocedure to 0.51 per year in the 2 years post-TMVR (P < 0.0001). At 2 years, 93.2% of surviving patients had no MR. No patient had >1+ MR. The improvement in symptoms at 1 year (88.5% NYHA functional class I or II) was sustained to 2 years (81.6% NYHA functional class I or II). Among survivors, the left ventricular ejection fraction was 45.6 ± 9.4% at baseline and 39.8 ± 9.5% at 2 years (P = 0.0012). Estimated right ventricular systolic pressure decreased from 47.6 ± 8.6 mm Hg to 32.5 ± 10.4 mm Hg (P < 0.005).Conclusions: In this study, the impact of TMVR on severity of MR, reduction in HFH rate, and improvement in symptoms was sustained through 2 years. All-cause mortality and the need for HFH was highest in the first 3 months postprocedure. (Expanded Clinical Study of the Tendyne Mitral Valve System; NCT02321514). [ABSTRACT FROM AUTHOR]

As the early epicenter of the COVID-19 pandemic, New York City's medical schools experienced dramatic disruptions in every aspect of medical education. Remote learning was created, seemingly overnight, clerkships were disrupted, licensing examinations were cancelled, teaching faculty were redeployed, student volunteers rallied, and everyone was required to shelter at home. Seismic changes were required to adapt the authors' educational programs to a constantly evolving, unpredictable, and ever-worsening public health crisis. Entirely new communication strategies were adopted and thousands of decisions had to be made, often with little time to carefully reflect on the consequences of those decisions. What allowed each school to navigate these treacherous waters was a set of guiding principles that were used to ground each conversation, and inform every decision. While the language varied somewhat between schools, the core principles were universal and framed a way forward at a time when information, data, precedent, and best practices did not exist. The authors share these guiding principles in the hope that colleagues at other medical schools will find them to be a useful framework as we all continue to cope with the impact of COVID-19 on the future of medical education. [ABSTRACT FROM AUTHOR]

Background Obesity has been positively associated with upper gastrointestinal cancers, but prospective data by subtype/subsite are limited. Obesity influences hormonal factors, which may play a role in these cancers. We examined anthropometry, body fat and reproductive factors in relation to oesophageal and gastric cancer by subtype/subsite in the UK Biobank cohort. Methods Among 458,713 UK Biobank participants, 339 oesophageal adenocarcinomas, 124 oesophageal squamous cell carcinomas, 137 gastric cardia and 92 gastric non-cardia cancers were diagnosed during a mean of 6.5 years follow-up. Cox models estimated multivariable hazard ratios (HRs) and 95% confidence intervals (CIs). Results Body mass index (BMI), hip circumference, waist circumference, waist-to-hip ratio, waist-to-height ratio, total body fat and trunk fat were positively associated with oesophageal adenocarcinoma (highest vs lowest category: HR = 2.33, 95%-CI:1.65-3.28; HR = 1.56, 95%-CI:1.15-2.13; HR = 2.30, 95%-CI:1.47-3.57; HR = 1.71, 95%-CI:1.01-2.90; HR = 2.87, 95%-CI:1.88-4.38; HR = 1.96, 95%-CI:1.30-2.96; HR = 2.34, 95%-CI:1.70-3.22, respectively). Although there were no statistically significant associations in combined sex analyses, BMI (HR = 1.83, 95%-CI:1.00-3.37), waist circumference (HR = 2.21, 95%-CI:1.27-3.84) and waist-to-hip ratio (HR = 1.92, 95%-CI:1.11-3.29) were associated with gastric cardia cancer in men; however, mutual adjustment attenuated the associations for BMI and waist-to-hip ratio. For oesophageal squamous cell carcinoma, statistically significant inverse associations were observed among women for BMI, hip circumference, waist circumference, waist-to-height ratio, total body fat and trunk fat, although they were based on small numbers. In addition, older age at first (HR = 0.44, 95%-CI:0.22-0.88) and last live birth (HR = 0.44, 95%-CI:0.22-0.87) were inversely associated with oesophageal squamous cell carcinoma and having a stillbirth/miscarriage/termination was positively associated (HR = 1.84, 95%-CI:1.10-3.07). Conclusions Obesity and abdominal obesity specifically may be a risk factor for oesophageal adenocarcinoma and gastric cardia cancer in men. Some reproductive factors may be associated with oesophageal squamous cell carcinoma in women. [ABSTRACT FROM AUTHOR]

Purpose: The evidence from the literature regarding the association of dietary factors and risk of prostate cancer is inconclusive. Methods: A nutrient-wide association study was conducted to systematically and comprehensively evaluate the associations between 92 foods or nutrients and risk of prostate cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC). Cox proportional hazard regression models adjusted for total energy intake, smoking status, body mass index, physical activity, diabetes and education were used to estimate hazard ratios and 95% confidence intervals for standardized dietary intakes. As in genome-wide association studies, correction for multiple comparisons was applied using the false discovery rate (FDR < 5%) method and suggested results were replicated in an independent cohort, the Netherlands Cohort Study (NLCS). Results: A total of 5916 and 3842 incident cases of prostate cancer were diagnosed during a mean follow-up of 14 and 20 years in EPIC and NLCS, respectively. None of the dietary factors was associated with the risk of total prostate cancer in EPIC (minimum FDR-corrected P, 0.37). Null associations were also observed by disease stage, grade and fatality, except for positive associations observed for intake of dry cakes/biscuits with low-grade and butter with aggressive prostate cancer, respectively, out of which the intake of dry cakes/biscuits was replicated in the NLCS. Conclusions: Our findings provide little support for an association for the majority of the 92 examined dietary factors and risk of prostate cancer. The association of dry cakes/biscuits with low-grade prostate cancer warrants further replication given the scarcity in the literature. [ABSTRACT FROM AUTHOR]

The contrast due to a strain field at an amorphous silicon/crystalline silicon (a-Si/c-Si) interface relative to the bulk crystal is studied with a scanning transmission electron microscope equipped with a low angle annular dark field (LAADF) detector and a high angle ADF (HAADF) detector. Experimental observations suggest that strain contrast depends closely on sample thickness and collection angle. For a thin sample (<100 Å) strain contrast is negative in both the LAADF and HAADF images. For a thick sample (>150 Å) strain contrast is positive in the LAADF image and negative in the HAADF image. Theoretical calculations of the effect of a random strain field are carried out. First, a simple model based on atomic scattering with an extra Debye–Waller factor is employed. It predicts a positive strain contrast in the LAADF image and no contrast in the HAADF image. The simple model fails for the HAADF contrast because it does not consider the propagation process of the electron beam inside the sample. Therefore multislice simulations including propagation details are carried out. The multislice simulation results agree well with the experimental observations. A measure of the strain amplitude is attained by comparing the experimental data with multislice simulation results. Quantitative measurements of strain contrast are only possible if the sample thickness is known. © 2004 American Institute of Physics. [ABSTRACT FROM AUTHOR]

This article disambiguates an unanswered question from Australian history: why was the Kimberley Plan, a scheme that would have opened the East Kimberley region of Western Australia to large-scale, foreign Jewish settlement during the era of the Holocaust, rejected by the Australian government? [ABSTRACT FROM AUTHOR]

Cancers are the leading cause of death in England. We aimed to estimate trends in mortality from leading cancers from 2002 to 2019 for the 314 districts in England. We did a high-resolution spatiotemporal analysis of vital registration data from the UK Office for National Statistics using data on all deaths from the ten leading cancers in England from 2002 to 2019. We used a Bayesian hierarchical model to obtain robust estimates of age-specific and cause-specific death rates. We used life table methods to calculate the primary outcome, the unconditional probability of dying between birth and age 80 years by sex, cancer cause of death, local district, and year. We reported Spearman rank correlations between the probability of dying from a cancer and district-level poverty in 2019. In 2019, the probability of dying from a cancer before age 80 years ranged from 0·10 (95% credible interval [CrI] 0·10–0·11) to 0·17 (0·16–0·18) for women and from 0·12 (0·12–0·13) to 0·22 (0·21–0·23) for men. Variation in the probability of dying was largest for lung cancer among women, being 3·7 times (95% CrI 3·2–4·4) higher in the district with the highest probability than in the district with the lowest probability; and for stomach cancer for men, being 3·2 times (2·6–4·1) higher in the district with the highest probability than in the one with the lowest probability. The variation in the probability of dying was smallest across districts for lymphoma and multiple myeloma (95% CrI 1·2 times [1·1–1·4] higher in the district with the highest probability than the lowest probability for women and 1·2 times [1·0–1·4] for men), and leukaemia (1·1 times [1·0–1·4] for women and 1·2 times [1·0–1·5] for men). The Spearman rank correlation between probability of dying from a cancer and district poverty was 0·74 (95% CrI 0·72–0·76) for women and 0·79 (0·78–0·81) for men. From 2002 to 2019, the overall probability of dying from a cancer declined in all districts: the reductions ranged from 6·6% (95% CrI 0·3–13·1) to 30·1% (25·6–34·5) for women and from 12·8% (7·1–18·8) to 36·7% (32·2–41·2) for men. However, there were increases in mortality for liver cancer among men, lung cancer and corpus uteri cancer among women, and pancreatic cancer in both sexes in some or all districts with posterior probability greater than 0·80. Cancers with modifiable risk factors and potential for screening for precancerous lesions had heterogeneous trends and the greatest geographical inequality. To reduce these inequalities, factors affecting both incidence and survival need to be addressed at the local level. Wellcome Trust, Imperial College London, UK Medical Research Council, and the National Institute of Health Research. [ABSTRACT FROM AUTHOR]

Infection with any of the 4 dengue virus serotypes results in a diverse range of symptoms, from mild undifferentiated fever to life-threatening hemorrhagic fever and shock. Given that dengue virus infection elicits such a broad range of clinical symptoms, early and accurate laboratory diagnosis is essential for appropriate patient management. Virus detection and serological conversion have been the main targets of diagnostic assessment for many years, however cross-reactivity of antibody responses among the flaviviruses has been a confounding issue in providing a differential diagnosis. Furthermore, there is no single, definitive diagnostic biomarker that is present across the entire period of patient presentation, particularly in those experiencing a secondary dengue infection. Nevertheless, the development and commercialization of point-of-care combination tests capable of detecting markers of infection present during different stages of infection (viral nonstructural protein 1 and immunoglobulin M) has greatly simplified laboratory-based dengue diagnosis. Despite these advances, significant challenges remain in the clinical management of dengue-infected patients, especially in the absence of reliable biomarkers that provide an effective prognostic indicator of severe disease progression. This review briefly summarizes some of the complexities and issues surrounding clinical dengue diagnosis and the laboratory diagnostic options currently available. [ABSTRACT FROM AUTHOR]

Background Symptomatic mitral regurgitation (MR) is associated with high morbidity and mortality that can be ameliorated by surgical valve repair or replacement. Despite this, many patients with MR do not undergo surgery. Transcatheter mitral valve replacement (TMVR) may be an option for selected patients with severe MR. Objectives This study aimed to examine the effectiveness and safety of TMVR in a cohort of patients with native valve MR who were at high risk for cardiac surgery. Methods Patients underwent transcatheter, transapical delivery of a self-expanding mitral valve prosthesis and were examined in a prospective registry for short-term and 30-day outcomes. Results Thirty patients (age 75.6 ± 9.2 years; 25 men) with grade 3 or 4 MR underwent TMVR. The MR etiology was secondary (n = 23), primary (n = 3), or mixed pathology (n = 4). The Society of Thoracic Surgeons Predicted Risk of Mortality was 7.3 ± 5.7%. Successful device implantation was achieved in 28 patients (93.3%). There were no acute deaths, strokes, or myocardial infarctions. One patient died 13 days after TMVR from hospital-acquired pneumonia. Prosthetic leaflet thrombosis was detected in 1 patient at follow-up and resolved after increased oral anticoagulation with warfarin. At 30 days, transthoracic echocardiography showed mild (1+) central MR in 1 patient, and no residual MR in the remaining 26 patients with valves in situ. The left ventricular end-diastolic volume index decreased (90.1 ± 28.2 ml/m 2 at baseline vs. 72.1 ± 19.3 ml/m 2 at follow-up; p = 0.0012), as did the left ventricular end-systolic volume index (48.4 ± 19.7 ml/m 2 vs. 43.1 ± 16.2 ml/m 2 ; p = 0.18). Seventy-five percent of the patients reported mild or no symptoms at follow-up (New York Heart Association functional class I or II). Successful device implantation free of cardiovascular mortality, stroke, and device malfunction at 30 days was 86.6%. Conclusions TMVR is an effective and safe therapy for selected patients with symptomatic native MR. Further evaluation of TMVR using prostheses specifically designed for the mitral valve is warranted. This intervention may help address an unmet need in patients at high risk for surgery. (Early Feasibility Study of the Tendyne Mitral Valve System [Global Feasibility Study]; NCT02321514 ) [ABSTRACT FROM AUTHOR]

High-conductivity undoped GaN/AlN 2D hole gases (2DHGs), the p-type dual of the AlGaN/GaN 2D electron gases (2DEGs), have offered valuable insights into hole transport in GaN and enabled the first GaN GHz RF p-channel FETs. They are an important step toward high-speed and high-power complementary electronics with wide-bandgap semiconductors. These technologically and scientifically relevant 2D hole gases are perceived to be not as robust as the 2DEGs because structurally similar heterostructures exhibit wide variations of the hole density over Δ p s > --> 7 × 10 13 cm − 2 , and low mobilities. In this work, we uncover that the variations are tied to undesired dopant impurities such as silicon and oxygen floating up from the nucleation interface. By introducing impurity blocking layers (IBLs) in the AlN buffer layer, we eliminate the variability in 2D hole gas densities and transport properties, resulting in a much tighter control over the 2DHG density variations to Δ p s ≤ 1 × 10 13 cm − 2 across growths, and a 3 × boost in the Hall mobilities. These changes result in a 2–3 × increase in hole conductivity when compared to GaN/AlN structures without IBLs. [ABSTRACT FROM AUTHOR]

Optimizing thermal anneals of Si-implanted β-Ga2O3 is critical for low resistance contacts and selective area doping. We report the impact of annealing ambient, temperature, and time on the activation of room temperature ion-implanted Si in β-Ga2O3 at concentrations from 5 × 1018 to 1 × 1020 cm−3, demonstrating full activation (>80% activation, mobilities >70 cm2/V s) with contact resistances below 0.29 Ω mm. Homoepitaxial β-Ga2O3 films, grown by plasma-assisted molecular beam epitaxy on Fe-doped (010) substrates, were implanted at multiple energies to yield 100 nm box profiles of 5 × 1018, 5 × 1019, and 1 × 1020 cm−3. Anneals were performed in an ultra-high vacuum-compatible quartz furnace at 1 bar with well-controlled gas compositions. To maintain β-Ga2O3 stability, pO2 must be greater than 10−9 bar. Anneals up to pO2 = 1 bar achieve full activation at 5 × 1018 cm−3, while 5 × 1019 cm−3 must be annealed with pO2 ≤ 10−4 bar, and 1 × 1020 cm−3 requires pO2 < 10−6 bar. Water vapor prevents activation and must be maintained below 10−8 bar. Activation is achieved for anneal temperatures as low as 850 °C with mobility increasing with anneal temperatures up to 1050 °C, though Si diffusion has been reported above 950 °C. At 950 °C, activation is maximized between 5 and 20 min with longer times resulting in decreased carrier activation (over-annealing). This over-annealing is significant for concentrations above 5 × 1019 cm−3 and occurs rapidly at 1 × 1020 cm−3. Rutherford backscattering spectrometry (channeling) suggests that damage recovery is seeded from remnant aligned β-Ga2O3 that remains after implantation; this conclusion is also supported by scanning transmission electron microscopy showing retention of the β-phase with inclusions that resemble the γ-phase. [ABSTRACT FROM AUTHOR]

Background: Life expectancy is increasing in Europe, yet a substantial proportion of adults still die prematurely before the age of 70 years. We sought to estimate the joint and relative contributions of tobacco smoking, hypertension, obesity, physical inactivity, alcohol and poor diet towards risk of premature death.Methods: We analysed data from 264,906 European adults from the EPIC prospective cohort study, aged between 40 and 70 years at the time of recruitment. Flexible parametric survival models were used to model risk of death conditional on risk factors, and survival functions and attributable fractions (AF) for deaths prior to age 70 years were calculated based on the fitted models.Results: We identified 11,930 deaths which occurred before the age of 70. The AF for premature mortality for smoking was 31 % (95 % confidence interval (CI), 31-32 %) and 14 % (95 % CI, 12-16 %) for poor diet. Important contributions were also observed for overweight and obesity measured by waist-hip ratio (10 %; 95 % CI, 8-12 %) and high blood pressure (9 %; 95 % CI, 7-11 %). AFs for physical inactivity and excessive alcohol intake were 7 % and 4 %, respectively. Collectively, the AF for all six risk factors was 57 % (95 % CI, 55-59 %), being 35 % (95 % CI, 32-37 %) among never smokers and 74 % (95 % CI, 73-75 %) among current smokers.Conclusions: While smoking remains the predominant risk factor for premature death in Europe, poor diet, overweight and obesity, hypertension, physical inactivity, and excessive alcohol consumption also contribute substantially. Any attempt to minimise premature deaths will ultimately require all six factors to be addressed. [ABSTRACT FROM AUTHOR]

Background: Although smoking and HPV infection are recognized as important risk factors for oropharyngeal cancer, how their joint exposure impacts on oropharyngeal cancer risk is unclear. Specifically, whether smoking confers any additional risk to HPV-positive oropharyngeal cancer is not understood.Methods: Using HPV serology as a marker of HPV-related cancer, we examined the interaction between smoking and HPV16 in 459 oropharyngeal (and 1445 oral cavity and laryngeal) cancer patients and 3024 control participants from two large European multi-centre studies. Odds ratios and credible intervals [CrI], adjusted for potential confounders, were estimated using Bayesian logistic regression.Results: Both smoking [odds ratio (OR [CrI]: 6.82 [4.52, 10.29]) and HPV seropositivity (OR [CrI]: 235.69 [99.95, 555.74]) were independently associated with oropharyngeal cancer. The joint association of smoking and HPV seropositivity was consistent with that expected on the additive scale (synergy index [CrI]: 1.32 [0.51, 3.45]), suggesting they act as independent risk factors for oropharyngeal cancer.Conclusions: Smoking was consistently associated with increase in oropharyngeal cancer risk in models stratified by HPV16 seropositivity. In addition, we report that the prevalence of oropharyngeal cancer increases with smoking for both HPV16-positive and HPV16-negative persons. The impact of smoking on HPV16-positive oropharyngeal cancer highlights the continued need for smoking cessation programmes for primary prevention of head and neck cancer. [ABSTRACT FROM AUTHOR]

Adequate access to effective and affordable vaccines is essential for the prevention of mortality due to infectious disease. Pneumonia – a consequence of Streptococcus pneumoniae infection – is the world's leading cause of death in children aged under 5 years. The development of a needle-free, thermostable pneumococcal-conjugate vaccine (PCV) could revolutionise the field by reducing cold-chain and delivery constraints. Skin patches have been used to deliver a range of vaccines, with some inducing significantly higher vaccine-specific immunogenicity than needle-injected controls in pre-clinical models, though they have yet to be used to deliver a PCV. We dry-coated a licensed PCV onto a microprojection-based patch (the Nanopatch) and delivered it to mouse skin. We analysed resulting anti-polysaccharide IgG responses. With and without adjuvant, anti-polysaccharide IgG titres induced by Nanopatch immunisation were significantly higher than dose-matched intramuscular controls. These improved responses were primarily obtained against pneumococcal serotypes 4 and 14. Importantly, capsule-specific IgG correlated with functionality in an opsonophagocytic killing assay. We demonstrate enhanced anti-PCV immunogenicity when delivered by Nanopatch over intramuscular injection. As the first study of a PCV delivered by a skin vaccination technology, this report indicates the potential for reduced costs and greater global distribution of such a vaccine. [ABSTRACT FROM AUTHOR]

Prospective cohort studies have found that prediagnostic circulating vitamin B6 is inversely associated with both risk of kidney cancer and kidney cancer prognosis. We investigated whether circulating concentrations of vitamin B6 at kidney cancer diagnosis are associated with risk of death using a case-cohort study of 630 renal cell carcinoma (RCC) patients. Blood was collected at the time of diagnosis, and vitamin B6 concentrations were quantified using LC-MS/MS. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated using Cox regression models. After adjusting for stage, age, and sex, the hazard was 3 times lower among those in the highest compared to the lowest fourth of B6 concentration (HR4vs1 0.33, 95% CI [0.18, 0.60]). This inverse association was solely driven by death from RCC (HR4vs1 0.22, 95% CI [0.11, 0.46]), and not death from other causes (HR4vs1 0.89, 95% CI [0.35, 2.28], p-interaction = 0.008). These results suggest that circulating vitamin B6 could provide additional prognostic information for kidney cancer patients beyond that afforded by tumour stage. [ABSTRACT FROM AUTHOR]

Background Incidence of renal cell carcinoma (RCC) is two-fold higher in men compared with women. This ratio has been remarkably stable, both geographically and over time. We investigated whether established risk factors for RCC can explain the higher incidence in men. Methods 230,399 participants in the EPIC cohort study with complete data for BMI, history of hypertension, and smoking variables were included. Cox regression models with age as the time-scale were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for sex. Results We identified 690 incident RCC cases. The marginal HR [95% CI] for men versus women was 2.30 [1.98, 2.69]. There was no strong evidence for interactions between hypertension, BMI, or smoking status and sex. Adjusting for BMI, hypertension and smoking variables did not materially affect the estimate (HR: 2.18 [1.85, 2.56]), accounting for only 10% of the observed excess risk. In contrast, smoking factors alone could account for 88% of the observed excess risk of lung cancer for men (marginal HR: 2.19 [2.02, 2.38]; adjusted HR: 1.14 [1.04, 1.25]) Conclusions The two-fold higher incidence of RCC in men compared with women cannot be explained by established risk factors. Key messages Whilst obesity, hypertension, and smoking are established risk factors for RCC, they cannot account for the greater incidence among men compared with women. This indicates the presence of as yet unknown factors to which men are more susceptible than women. [ABSTRACT FROM AUTHOR]

Mitral regurgitation is the most common valve abnormality worldwide and its prevalence is expected to increase in the future due to aging of the population. Percutaneous mitral valve repair therapies may offer an opportunity to treat severe MR in the elderly or other high-risk groups who would otherwise be ineligible for surgery. The MitraClip system uses edge-to-edge coaptation of the mitral leaflets to create a double-orifice valve and reduce MR. It has been performed in over 10 000 patients to date, and as experience has improved, procedural times have shortened from over 200 minutes to less than 100 minutes, with increasing numbers of patients being left with ≤ grade 2+ MR. This review will focus on the literature available on MitraClip and other novel percutaneous techniques that are being developed for the treatment of severe MR. [ABSTRACT FROM AUTHOR]

Herein we demonstrate the use of a wearable device that can selectively capture two distinct circulating protein biomarkers (recombinant P. falciparum rPfHRP2 and total IgG) from the intradermal fluid of live mice in situ, for subsequent detection in vitro. The device comprises a microprojection array that, when applied to the skin, penetrates the outer skin layers to interface directly with intradermal fluid. Because of the complexity of the biological fluid being sampled, we investigated the effects of solution conditions on the attachment of capture antibodies, to optimize the assay detection limit both in vitro and on live mice. For detection of the target antigen diluted in 20% serum, immobilization conditions favoring high antibody surface density (low pH, low ionic strength) resulted in 100-fold greater sensitivity in comparison to standard conditions, yielding a detection limit equivalent to the plate enzyme-linked immunosorbent assay (ELISA). We also show that blocking the device surface to reduce nonspecific adsorption of target analyte and host proteins does not significantly change sensitivity. After injecting mice with rPfHRP2 via the tail vein, we compared analyte levels in both plasma and skin biopsies (cross-sectional area same as the microprojection array), observing that skin samples contained the equivalent of ~8 μL of analyte-containing plasma. We then applied the arrays to mice, showing that surfaces coated with a high density of antibodies captured a significant amount of the rPfHRP2 target while the standard surface showed no capture in comparison to the negative control. Next, we applied a triplex device to both control and rPfHRP2-treated mice, simultaneously capturing rPfHRP2 and total IgG (as a positive control for skin penetration) in comparison to a negative control device. We conclude that such devices can be used to capture clinically relevant, circulating protein biomarkers of infectious disease via the skin, with potential applications as a minimally invasive and lab-free biomarker detection platform. [ABSTRACT FROM AUTHOR]

Normal renal function is essential for vitamin D metabolism, but it is unclear whether circulating vitamin D is associated with risk of renal cell carcinoma (RCC). We assessed whether 25-hydroxyvitamin D3 (25(OH)D3) was associated with risk of RCC and death after RCC diagnosis in the European Prospective Investigation into Cancer and Nutrition (EPIC). EPIC recruited 385,747 participants with blood samples between 1992 and 2000. The current study included 560 RCC cases, 557 individually matched controls, and 553 additional controls. Circulating 25(OH)D3 was assessed by mass spectrometry. Conditional and unconditional logistic regression models were used to calculate odds ratios and 95% confidence intervals. Death after RCC diagnosis was assessed using Cox proportional hazards models and flexible parametric survival models. A doubling of 25(OH)D3 was associated with 28% lower odds of RCC after adjustment for season of and age at blood collection, sex, and country of recruitment (odds ratio = 0.72, 95% confidence interval: 0.60, 0.86; P = 0.0004). This estimate was attenuated somewhat after additional adjustment for smoking status at baseline, circulating cotinine, body mass index (weight (kg)/height (m)2), and alcohol intake (odds ratio = 0.82, 95% confidence interval: 0.68, 0.99; P = 0.038). There was also some indication that both low and high 25(OH)D3 levels were associated with higher risk of death from any cause among RCC cases. [ABSTRACT FROM PUBLISHER]

The article offers information on the suicide of medical students who ended her life by jumping from her apartment window. It mentions that she was found by surgical interns who take her to the hospital to attend for their patients. It mentions that classmates, on his surgery subinternship, was with them. It mentions that she ended her life in the emergency department (ED).

Background: Because athletes rely on sports physicians as a source of information, physicians must be included in research relating to doping prevention. According to several studies, the level of knowledge of sports physicians with regard to doping prevention seems to be inadequate. It is crucial for them to have a comprehensive understanding of doping regulations, substances and the side effects, as well as the procedure for issuing Therapeutic Use Exemptions (TUE). Research questions: (1) to evaluate the knowledge of Austrian sports physicians regarding doping substances, doping methods and side effects and (2) to provide ideas on efficient strategies to educate this target group. Methods: An online questionnaire was distributed to all registered Austrian physicians who hold a Supplementary Diploma in Sports Medicine (n = 1,543). The questionnaire was administered over four months and structured into eight areas of interest. Chi-Square tests, as well as descriptive statistics, were used to analyse the data. Results: A total of 152 physicians returned the questionnaire (response rate of 9.8%). Some 53.7% subjectively believed that they were poorly informed about the topic, and 43% reported that they knew of the World Anti-Doping Agency (WADA) 2011 Prohibited List. Knowledge deficits regarding substances (especially insulin, recombinant human erythropoietin, stimulants) and strong uncertainties with regard to prohibited doping methods and the side effects of specific substances were reported. This low level of knowledge stood in contrast to the high interest in the topic that the physicians self-reported. In general, physicians had a very positive anti-doping attitude. Conclusion: Results of this study are comparable with previous studies conducted in Germany and France. Despite the low response rate, this study demonstrated high interest from sports physicians regarding doping, and showed some of the deficits in their knowledge of doping. Integrating anti-doping related information within educational material may assist increasing the knowledge of sports physicians and gain their support for wider anti-doping strategies. [ABSTRACT FROM AUTHOR]

A literary criticism of the play "Tartuff" by play writer Molière is presented. It outlines the characters and explores the symbolic significance of these characters. It emphasizes the met dramatic performativity and theatricality inherent in the conception of the play and the neoclassical dramatic theory may have prohibited the excessive use of stage objects.

Highlights: [•] We review the vast array of activities reported for the enigmatic NS1 protein. [•] NS1 is a major player in diagnosis, viral replication, protection and pathogenesis. [•] NS1 is found in cell-associated membrane forms as well as a secreted lipoparticle. [•] NS1 engages with a range of complement factors to subvert the immune response. [Copyright &y& Elsevier]

Objectives: This report aimed to assess whether second to fourth digit ratio (2D:4D) is associated with adult anthropometric measures and, in particular, measurements of adiposity. Methods: Height, weight, waist circumference, hip circumference and bioelectrical resistance and reactance were measured at baseline attendance of the Melbourne Collaborative Cohort Study. 2D:4D was measured from photocopies of participants' hands that were taken at a recent follow-up of the cohort. Complete anthropometric and 2D:4D data were available for 8840 women and 6076 men. Linear regression models adjusted for age at baseline and country of birth were used to estimate the expected mean increment in anthropometric measures for a standard deviation increment in 2D:4D. Results: No substantial association was found between any assessed anthropometric measure, including those of adiposity and 2D:4D. Conclusions: 2D:4D is not strongly associated with adult anthropometric measures, including those of adiposity. [ABSTRACT FROM AUTHOR]

Abstract: Increased oxidative stress has been implicated in both the onset and the progression of diabetes mellitus and its complications. The development of easy to measure biomarkers of oxidative stress would, therefore, help in determining in a prospective manner the impact of glycemic control on oxidative stress and macrovascular disease in patients with diabetes. We report the development and validation of a novel method to directly measure the urinary concentrations of the conjugated metabolites of vitamin E (α-tocopherol) and investigate whether the oxidized metabolite α-tocopheronolactone (α-TL) could be used as a biomarker of oxidative stress in children with type 1 diabetes. A novel method using liquid chromatography–tandem mass spectrometry was developed and used to measure directly and rapidly the urinary concentrations of the glucuronidated and sulfated metabolites of α-tocopherol in 32 young patients with type 1 diabetes and age-matched controls. The mean concentrations of the glucuronidated and sulfated conjugates of α-TL were all highly significantly increased in the children with type 1 diabetes (p<0.001). The results suggest that the measurement of the urinary concentrations of α-TL conjugates may provide a useful biomarker of oxidative stress in diabetes and possibly in other clinical conditions in which oxidative stress has been implicated. [Copyright &y& Elsevier]

Abstract: Mono-atomic-layer membranes such as graphene offer new opportunities for imaging and detecting individual light atoms in transmission electron microscopes (TEM). For such applications where multiple scattering and diffraction effects are weak, we evaluate the detection efficiency and interpretability of single atom images for the most common detector geometries using quantitative quantum mechanical simulations. For well-resolved and atomically-thin specimens, the low angle annular dark field (LAADF) detector can provide a significant increase in signal-to-noise over other common detector geometries including annular bright field and incoherent bright field. This dramatically improves the visibility of organic specimens on atomic-layer membranes. Simulations of Adenosine Triphosphate (ATP) imaged under ideal conditions indicate the minimal dose requirements for elastic imaging by STEM or conventional TEM still exceed previously reported dose limits. [Copyright &y& Elsevier]

A personal narrative from David Muller, the dean for medical education at the Mount Sinai School of Medicine in New York, is presented, which explores his experience with an old patient in his nineties, who voluntarily stopped eating and drinking in order to have a hastened death.

Abstract: Dengue virus is the most significant human viral pathogen spread by the bite of an infected mosquito. With no vaccine or antiviral therapy currently available, disease prevention relies largely on surveillance and mosquito control. Preventing the onset of dengue outbreaks and effective vector management would be considerably enhanced through surveillance of dengue virus prevalence in natural mosquito populations. However, current approaches to the identification of virus in field-caught mosquitoes require relatively slow and labor intensive techniques such as virus isolation or RT-PCR involving specialized facilities and personnel. A rapid and portable method for detecting dengue virus-infected mosquitoes is described. Using a hand held battery operated homogenizer and a dengue diagnostic rapid strip the viral protein NS1 was detected as a marker of dengue virus infection. This method could be performed in less than 30min in the field, requiring no downstream processing, and is able to detect a single infected mosquito in a pool of at least 50 uninfected mosquitoes. The method described in this study allows rapid, real-time monitoring of dengue virus presence in mosquito populations and could be a useful addition to effective monitoring and vector control responses. [Copyright &y& Elsevier]

While advances in assay chemistry and detection continue to improve molecular diagnostics technology, blood samples are still collected using the 150-year-old needle/syringe method. Surface modified microprojection arrays have been developed as a novel platform for in viva, needle-free biomarker capture. These devices are gold coated silicon arrays with >20,000 projections per cm², which can be applied to the skin for tunable penetration into the epidermis or dermis. The microprojection array conceptually offers several advantages over the current methods including: minimally invasive sample collection, no need for sample processing and concentration of specific markers at the device surface for sensitive detection, In this study, Microprojection arrays were coated with antibodies to capture an early marker of dengue virus infection, NSI, from the skin of live mice, We also developed a complementary "total IgG" assay which could be used as a positive control for adequate penetration of the projections. Surface modifications designed for selective extraction were tested against standard microtiter plate ELISA. We also investigated the use of Protein G-mediated antibody immobilization in order to orient capture antibodies. While we found that capture efficiency could be improved, the direct EDC-based antibody immobilization resulted in a significantly higher surface density leading to a higher degree of NS1 capture. Using mice intravenously injected with recombinant dengue virus type 2 NS1 as a pseudomodel for dengue infection, NSI was successfully extracted using microprojection arrays sampling from skin fluid, with a detection limit of 8 μg/mL [ABSTRACT FROM AUTHOR]

The essay discusses director Jacques Copeau’s 1937 staging of the French play "Bajazet" by Jean Racine performed at the Comédie-Française in Paris, France, specifically describing the scenography in the French tradition of classical tragedy. The author argues that Copeau's version of the play used the idea of palais à volonté, or a neutral palace setting without recognizable historical details, which dominated French theater for decades and became part of French theater's cultural memory.

Background: The second to fourth digit ratio (2D:4D) is used as a marker of prenatal sex hormone exposure. The objective of this study was to examine whether circulating concentrations of sex hormones and SHBG measured in adulthood was associated with 2D:4D. Methods: This analysis was based on a random sample from the Melbourne Collaborative Cohort Study. The sample consisted of of 1036 men and 620 post-menopausal women aged between 39 and 70 at the time of blood draw. Concentrations of circulating sex hormones were measured from plasma collected at baseline (1990- 1994), while digit length was measured from hand photocopies taken during a recent follow-up (2003-2009). The outcome measures were circulating concentrations of testosterone, oestradiol, dehydroepiandrosterone sulphate, androstenedione, Sex Hormone Binding Globulin, androstenediol glucoronide for men only and oestrone sulphate for women only. Free testosterone and oestradiol were estimated using standard formulae derived empirically. Predicted geometric mean hormone concentrations (for tertiles of 2D:4D) and conditional correlation coefficients (for continuous 2D:4D) were obtained using mixed effects linear regression models. Results: No strong associations were observed between 2D:4D measures and circulating concentrations of hormones for men or women. For males, right 2D:4D was weakly inversely associated with circulating testosterone (predicted geometric mean testosterone was 15.9 and 15.0 nmol/L for the lowest and highest tertiles of male right 2D:4D respectively (P-trend = 0.04). There was a similar weak association between male right 2D:4D and the ratio of testosterone to oestradiol. These associations were not evident in analyses of continuous 2D:4D. Conclusions: There were no strong associations between any adult circulating concentration of sex hormone or SHGB and 2D:4D. These results contribute to the growing body of evidence indicating that 2D:4D is unrelated to adult sex hormone concentrations. [ABSTRACT FROM AUTHOR]

A new generation of electron microscopes is able to explore the microscopic properties of materials and devices as diverse as transistors, turbine blades and interfacial superconductors. All of these systems are made up of dissimilar materials that, where they join at the atomic scale, display very different behaviour from what might be expected of the bulk materials. Advances in electron optics have enabled the imaging and spectroscopy of these buried interface states and other nanostructures with atomic resolution. Here I review the capabilities, prospects and ultimate limits for the measurement of physical and electronic properties of nanoscale structures with these new microscopes. [ABSTRACT FROM AUTHOR]

Electron energy loss fine structure near the threshold of inner-shell edges can potentially give valuable information on bonding on an atomic scale. To use near-edge structure it is essential to understand what factors influence both the occupied and unoccupied local density of states in the material of interest. Different techniques of electronic structure theory are suitable for metals, semiconductors, and ionic materials, although some methods can be applied to a wide range of systems. To extract quantitative information on bonding it is important to avoid those edges that are strongly affected by the presence of the core hole such as cations in ionic materials. [ABSTRACT FROM AUTHOR]

Objectives The purpose of this study was to develop a better understanding of how medical trainees define medical errors and what factors influence medical trainees' perceptions of medical errors. Methods We surveyed 423 medical students and house staff at an urban academic medical centre to learn about how they defined medical errors, their experiences with medical errors, their beliefs about when a patient should be informed of an error, and their attitudes towards medical errors with differing severity of outcomes. Results Trainees stated that an event could be considered an error regardless of outcome, negligence, intention or consent. Definitions did not vary according to gender or level of training. Trainees had increasing feelings of guilt and fear as the outcomes related to errors worsened. Respondents were more likely to feel guilty and angry at themselves, and be afraid of accusations of malpractice, losing their licence, damaging their reputation, or losing confidence when errors were made while working individually versus in a team setting. Female trainees were more likely than male trainees to feel guilty and angry at themselves, and were afraid of losing confidence if they made an error. Conclusions Trainees' perceptions and attitudes towards errors vary depending on whether they are in their clinical years, the severity of outcome, and whether the error is attributable to an individual or a team. These factors will have to be explored in greater depth if we are adequately to prepare young doctors for the errors they will inevitably make. [ABSTRACT FROM AUTHOR]

The author describes how even the best of patient-doctor relationships can go wrong in the face of death. The author relates his relationship with his patient during his residency training in Veterans Affairs Hospitals. According to the author, a doctor might have to take into account different opinions, different personalities and a lifetime of complicated family dynamics for any given patients.

Introduction: Multiple pacing modalities have been shown to individually decrease atrial fibrillation (AF) burden and relieve symptoms of AF. This investigation retrospectively evaluated whether a combination of bi-atrial pacing with dynamic atrial overdrive (DAO) AF suppression would further decrease AF burden as compared to AF suppression (DAO) alone. Methods and Results: A total of 33 patients were retrospectively evaluated. Patients (n = 16) were identified from the Deborah Heart and Lung Center pacemaker database with DAO programmed on at time of implantation. Patients (n = 17) were identified with bi-atrial pacing leads in right atrium and mid to distal coronary sinus who also had DAO programmed on at the time of implant. Evaluation of interrogated pacing data revealed Percent Time in Mode Switch (18.2%± 7.2% vs 0.59%± 0.08%) to be significantly lower (P = 0.014) in the bi-atrial paced group. In addition, there were less mode switches per day (MSPD) in the bi-atrial paced group (0.62 ± 0.43 MSPD) versus control (4.40 ± 3.24 MSPD) (P = 0.06). Conclusion: Bi-atrial pacing while used in conjunction with an adaptive pacing suppression algorithm (DAO) may successfully be used to inhibit PAF. [ABSTRACT FROM AUTHOR]

Abstract: Despite their names, the cytokines granulocyte- and granulocyte–macrophage-colony stimulating factor (G-CSF and GM-CSF respectively) have actions far beyond simply stimulating the proliferation of neutrophil and monocyte lineage cells. A comprehensive body of evidence now exists demonstrating that G-CSF and GM-CSF effectively mobilize bone-marrow-derived progenitor cells into the peripheral circulation. These mobilized progenitor cells can be conveniently harvested for use in reconstituting bone marrow by transplantation after myelo-ablative treatment of hematological malignancies. In addition, much evidence has recently emerged to suggest that these cytokines may have multiple direct and indirect beneficial cardiovascular effects—including neovascularization of ischemic myocardium and reducing the extent of myocardial damage after infarction. Based on this knowledge and a strong safety record in hematological applications, a number of early clinical trials have evaluated the use of G-CSF or GM-CSF in patients with both acute and chronic myocardial ischemia. Although the interpretation of these trials is complicated by heterogeneity in study design, small patient numbers and methodological concerns related to appropriate selection and blinding of patients, the results of ongoing larger phase II/III trials should soon be available to determine if these agents will be useful additions to the cardiovascular armamentarium. [Copyright &y& Elsevier]

Abstract: Aberration correctors correct aberrations, not instabilities. Rather, as spatial resolution improves, a microscope''s sensitivity to room environment becomes more noticeable, not less. Room design is now an essential part of the microscope installation process. Previously ignorable annoyances like computer fans, desk lamps and that chiller in the service corridor now may become the limiting factors in the microscopes performance. We discuss methods to quantitatively characterize the instrument''s response to magnetic, mechanical, acoustical and thermal disturbances and thus predict the limits that the environment places on imaging and spectroscopy. [Copyright &y& Elsevier]

In mammals, severe and chronic deficiency of vitamin E (α-tocopherol) is associated with a characteristic neurological syndrome. Previously, we have shown that this syndrome is accompanied by electrophysiological abnormalities of neural and visual function. To investigate the molecular basis of the observed abnormalities, we used microarrays to monitor the expression of ∼14,000 genes in the cerebral cortex from rats which had received diets containing 0, 1.25 and 5.0 mg/kg diet of all-rac-α-tocopheryl acetate for 14 months. Compared to the groups receiving 1.25 and 5.0 mg/kg α-tocopheryl acetate, a total of 11 genes were statistically significantly upregulated (≥1.3-fold) and 34 downregulated (≤1.3-fold) in the vitamin E-deficient group. Increased expression was observed for the genes encoding the antioxidant enzyme catalase and the axon guidance molecule tenascin-R, while decreased expression was detected for genes encoding protein components of myelin and determinants of neuronal signal propagation. Thus our observations suggest that vitamin E deficiency results in transcriptional alterations in the cerebral cortex of the rat which are consistent with the observed neurological and electrophysiological alterations. Copyright © 2006 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Abstract: This study examined rapid orthographic learning following silent reading in third-grade children as a function of number of target nonword repetitions and test delay. In each of two test sessions at least 6 days apart, children read a series of short stories, with each story containing a different nonword repeated either four or eight times. In the second session, after the stories had been read, children were asked to read short lists of target nonwords or homophonic alternatives. Children read target nonwords faster than homophones, indicating that they had formed functional orthographic representations of the target nonwords through phonologically recoding them during silent story reading. They also preferred target nonwords to homophones in an orthographic choice task in which the alternatives included the target, the homophone, and a visually similar foil, although here orthographic learning was stronger for items encountered eight times within stories and stronger for items tested immediately. These findings provide critical evidence in support of Share’s self-teaching through phonological recoding hypothesis. [Copyright &y& Elsevier]

This paper describes the introduction of a new elective, "Writing About Medicine," into the Mount Sinai School of Medicine (MSSM) curriculum, part of a new trend of developing humanities programs at medical schools. The paper will first survey two exemplary programs at other schools, and discuss their impact on students. It will then detail the development of "Writing About Medicine," including its purpose and format. Finally, it will present focus group data evaluating the course and elaborate on its role in the MSSM educational process. Five samples of student writing follow the discussion. [ABSTRACT FROM AUTHOR]

Narrates the author's experience while treating an AIDS patient. Information that the patient with advanced AIDS was admitted, comatose and hopelessly ill in the author's hospital; Information that the author spent the night helping the patient's family come to terms with his imminent death; Information about the medical case history of the patient.