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The benefits of testosterone therapy (TTh) in the hypogonadal male can be dramatic. Historically, TTh has been contraindicated in prostate cancer (PCa). Current evidence has redefined our understanding of the influence serum testosterone has on prostatic androgen activity. Increasing numbers of hypogonadal men with coexisting PCa emphasizes the importance of describing those who may safely receive TTh. This review aims to present literature that evaluates the efficacy and safety of TTh in men with coexisting PCa.Our study, a comprehensive review of published literature regarding TTh in men with a history of PCa, consisted of studies conducted from the 1940s to 2022. Our review discusses evidence in accordance with previous studies that TTh has a role in patients with localized PCa as it has not been reported to increase rates of recurrence or progression of PCa.The use of TTh in hypongonadal men with a localized PCa has been shown to have positive clinical outcomes without increasing the rate of disease progression or recurrence. Further research, in a randomized controlled setting, is warranted.

In adults, alcohol intoxication is associated with prolongation of the QT interval corrected for heart rate (QTc). The QTc is influenced by age and sex. Although alcohol intoxication is increasingly common in adolescents, there are no data on the prevalence of QTc prolongation in adolescents with alcohol intoxication. This study aimed to determine the prevalence of QTc prolongation in adolescents with alcohol intoxication and identify at-risk adolescents. In this observational study including adolescents aged 10–18 years, heart rate and QT interval were automatically assessed from an electrocardiogram (ECG) at alcohol intoxication using a validated algorithm. The QTc was calculated using both the Bazett formula (QTcB) and Fridericia formula (QTcF). If present, an ECG recorded within 1 year of the date of admission to the emergency department was obtained as a reference ECG. A total of 317 adolescents were included; 13.3% had a QTcB and 7.9% a QTcF longer than the sex- and age-specific 95th-percentile. None of the adolescents had a QTcB or QTcF > 500 ms, but 11.8% of the adolescents with a reference ECG had a QTcB prolongation of > 60 ms, while no adolescents had a QTcF prolongation of > 60 ms. QTc prolongation was mainly attributable to an increase in heart rate rather than QT prolongation, which underlies the differences between QTcB and QTcF. Male sex and hypokalaemia increased the likelihood of QTc prolongation.Conclusion: QTc prolongation was seen in approximately 10% of the adolescents presenting with alcohol intoxication, and although no ventricular arrhythmias were observed in this cohort, QTc prolongation increases the potential for malignant QT-related arrhythmias. Clinicians must be aware of the possibility of QTc prolongation during alcohol intoxication and make an effort to obtain an ECG at presentation, measure the QT interval, and give an adequate assessment of the findings. We advocate admitting adolescents with alcohol intoxication and QTc prolongation. During hospital admission, we recommend limiting exposure to QTc-prolonging medication, increasing potassium levels to a high-normal range (4.5–5.0 mmol/L) and obtaining a reference ECG at discharge. What is Known:• One out of five deaths in adolescents is alcohol-related. Alcohol intoxication has been related to cardiac arrhythmias and sudden cardiac death.•In adults, alcohol intoxication is associated with QTc prolongation. What is New:•Approximately 10% of the adolescents with alcohol intoxication had a QTc longer than the age- and sexspecific cut-off. In contrast to adults, in adolescents with alcohol intoxication, QTc prolongation is attributable to an increase in heart rate, rather than a prolongation of the QT interval.•Especially males and adolescents with hypokalaemia are at risk of QTc prolongation.

BACKGROUND Autologous haematopoietic stem-cell transplantation (HSCT) in first remission is the current standard treatment in fit patients with mantle cell lymphoma. In this long-term follow-up study, we aimed to evaluate the efficacy of autologous HSCT versus interferon alfa maintenance after chemotherapy without or with rituximab in patients with primary advanced-stage mantle cell lymphoma. METHODS We did a post-hoc, long-term analysis of an open-label, multicentre, randomised, phase 3 trial done in 121 participating hospitals or practices across six European countries. Patients who were aged 18-65 years with previously untreated stage III-IV mantle cell lymphoma and an ECOG performance score of 0-2 were eligible for participation. Patients were randomly assigned (1:1) to receive either myeloablative radiochemotherapy (fractionated total body irradiation with 12 Gy/day 6-4 days before autologous HSCT and cyclophosphamide 60 mg/kg per day intravenously 3-2 days before autologous HSCT) followed by autologous HSCT (the autologous HSCT group) or interferon alfa maintenance (the interferon alfa maintenance group; 6 × 106 IU three times a week subcutaneously until progression) after completion of CHOP-like induction therapy (cyclophosphamide 750 mg/m2 intravenously on day 1, doxorubicin 50 mg/m2 intravenously on day 1, vincristine 1·4 mg/m2 maximum 2 mg intravenously on day 1, and prednisone 100 mg/m2 orally on days 1-5; repeated every 21 days for up to 6 cycles) without or with rituximab (375 mg/m2 intravenously on day 0 or 1 of each cycle; R-CHOP). The primary outcome was progression-free survival from end of induction until progression or death among patients who had a remission and the secondary outcome was overall survival from the end of induction until death from any cause. We did comparisons of progression-free survival and overall survival according to the intention-to-treat principle between both groups among responding patients and explored efficacy in subgroups according to induction treatment without or with rituximab. Hazard ratios (HRs) were adjusted for the mantle cell lymphoma international prognostic index (MIPI) numerical score, and in the total group also for rituximab use (adjusted HR aHR). This trial was started before preregistration was implemented and is therefore not registered, recruitment is closed, and this is the final evaluation. FINDINGS Between Sept 30, 1996, and July 1, 2004, 269 patients were randomly assigned to receive either autologous HSCT or interferon alfa maintenance therapy. The median follow-up was 14 years (IQR 10-16), with the intention-to-treat population consisting of 174 patients (93 53{\%} in the autologous HSCT group and 81 47{\%} in the interferon alfa maintenance group) who responded to induction therapy. The median age was 55 years (IQR 47-60), and R-CHOP was used in 68 (39{\%}) of 174 patients. The median progression-free survival was 3·3 years (95{\%} CI 2·5-4·3) in the autologous HSCT group versus 1·5 years (1·2-2·0) in the interferon alfa maintenance group (log-rank p{\textless}0·0001; aHR 0·50 95{\%} CI 0·36-0·69). The median overall survival was 7·5 years (95{\%} CI 5·7-12·0) in the autologous HSCT group versus 4·8 years (4·0-6·6) in the interferon alfa maintenance group (log-rank p=0·019; aHR 0·66 95{\%} CI 0·46-0·95). For patients treated without rituximab, the progression-free survival adjusted HR for autologous HSCT versus interferon alfa was 0·40 (0·26-0·61), in comparison to 0·72 (0·42-1·24) for patients treated with rituximab. For overall survival, the adjusted hazard ratio for HSCT versus interferon alfa was 0·52 (0·33-0·82) without rituximab and 1·05 (0·55-1·99) for patients who received rituximab. INTERPRETATION Our results confirm the long-term efficacy of autologous HSCT to treat mantle cell lymphoma established in the pre-rituximab era. The suggested reduced efficacy after immunochemotherapy supports the need for its re-evaluation now that antibody maintenance, high-dose cytarabine, and targeted treatments have changed the standard of care for patients with mantle cell lymphoma. FUNDING Deutsche Krebshilfe, the European Community, and the Bundesministerium f{\"u}r Bildung und Forschung, Kompetenznetz Maligne Lymphome.

The Ad26.COV2.S vaccine is a recombinant, replication-incompetent human adenovirus type 26 vector encoding full-length severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein in a prefusion-stabilized conformation.In an international, randomized, double-blind, placebo-controlled, phase 3 trial, we randomly assigned adult participants in a 1:1 ratio to receive a single dose of Ad26.COV2.S (5×10The per-protocol population included 19,630 SARS-CoV-2-negative participants who received Ad26.COV2.S and 19,691 who received placebo. Ad26.COV2.S protected against moderate to severe-critical Covid-19 with onset at least 14 days after administration (116 cases in the vaccine group vs. 348 in the placebo group; efficacy, 66.9%; adjusted 95% confidence interval [CI], 59.0 to 73.4) and at least 28 days after administration (66 vs. 193 cases; efficacy, 66.1%; adjusted 95% CI, 55.0 to 74.8). Vaccine efficacy was higher against severe-critical Covid-19 (76.7% [adjusted 95% CI, 54.6 to 89.1] for onset at ≥14 days and 85.4% [adjusted 95% CI, 54.2 to 96.9] for onset at ≥28 days). Despite 86 of 91 cases (94.5%) in South Africa with sequenced virus having the 20H/501Y.V2 variant, vaccine efficacy was 52.0% and 64.0% against moderate to severe-critical Covid-19 with onset at least 14 days and at least 28 days after administration, respectively, and efficacy against severe-critical Covid-19 was 73.1% and 81.7%, respectively. Reactogenicity was higher with Ad26.COV2.S than with placebo but was generally mild to moderate and transient. The incidence of serious adverse events was balanced between the two groups. Three deaths occurred in the vaccine group (none were Covid-19-related), and 16 in the placebo group (5 were Covid-19-related).A single dose of Ad26.COV2.S protected against symptomatic Covid-19 and asymptomatic SARS-CoV-2 infection and was effective against severe-critical disease, including hospitalization and death. Safety appeared to be similar to that in other phase 3 trials of Covid-19 vaccines. (Funded by Janssen Research and Development and others; ENSEMBLE ClinicalTrials.gov number, NCT04505722.).

BACKGROUND: Zika virus (ZIKV) may cause severe congenital disease after maternal-fetal transmission. No vaccine is currently available. OBJECTIVE: To assess the safety and immunogenicity of Ad26.ZIKV.001, a prophylactic ZIKV vaccine candidate. DESIGN: Phase 1 randomized, double-blind, placebo-controlled clinical study. (ClinicalTrials.gov: NCT03356561). SETTING: United States. PARTICIPANTS: 100 healthy adult volunteers. INTERVENTION: Ad26.ZIKV.001, an adenovirus serotype 26 vector encoding ZIKV M-Env, administered in 1- or 2-dose regimens of 5 × 1010 or 1 × 1011 viral particles (vp), or placebo. MEASUREMENTS: Local and systemic adverse events; neutralization titers by microneutralization assay (MN50) and T-cell responses by interferon-I³ enzyme-linked immunospot and intracellular cytokine staining; and protectivity of vaccine-induced antibodies in a subset of participants through transfer in an exploratory mouse ZIKV challenge model. RESULTS: All regimens were well tolerated, with no safety concerns identified. In both 2-dose regimens, ZIKV neutralizing titers peaked 14 days after the second vaccination, with geometric mean MN50 titers (GMTs) of 1065.6 (95% CI, 494.9 to 2294.5) for 5 × 1010 vp and 956.6 (595.8 to 1535.8) for 1 × 1011 vp. Titers persisted for at least 1 year at a GMT of 68.7 (CI, 26.4-178.9) for 5 × 1010 vp and 87.0 (CI, 29.3 to 258.6) for 1 × 1011 vp. A 1-dose regimen of 1 × 1011 vp Ad26.ZIKV.001 induced seroconversion in all participants 56 days after the first vaccination (GMT, 103.4 [CI, 52.7 to 202.9]), with titers persisting for at least 1 year (GMT, 90.2 [CI, 38.4 to 212.2]). Env-specific cellular responses were induced. Protection against ZIKV challenge was observed after antibody transfer from participants into mice, and MN50 titers correlated with protection in this model. LIMITATION: The study was conducted in a nonendemic area, so it did not assess safety and immunogenicity in a flavivirus-exposed population. CONCLUSION: The safety and immunogenicity profile makes Ad26.ZIKV.001 a promising candidate for further development if the need reemerges. PRIMARY FUNDING SOURCE: Janssen Vaccines and Infectious Diseases.

Human visual cortex contains many retinotopic and category-specific regions. These brain regions have been the focus of a large body of functional magnetic resonance imaging research, significantly expanding our understanding of visual processing. As studying these regions requires accurate localization of their cortical location, researchers perform functional localizer scans to identify these regions in each individual. However, it is not always possible to conduct these localizer scans. Here, we developed and validated a functional region of interest (ROI) atlas of early visual and category-selective regions in human ventral and lateral occipito-temporal cortex. Results show that for the majority of functionally defined ROIs, cortex-based alignment results in lower between-subject variability compared to nonlinear volumetric alignment. Furthermore, we demonstrate that 1) the atlas accurately predicts the location of an independent dataset of ventral temporal cortex ROIs and other atlases of place selectivity, motion selectivity, and retinotopy. Next, 2) we show that the majority of voxel within our atlas is responding mostly to the labeled category in a left-out subject cross-validation, demonstrating the utility of this atlas. The functional atlas is publicly available (download.brainvoyager.com/data/visfAtlas.zip) and can help identify the location of these regions in healthy subjects as well as populations (e.g., blind people, infants) in which functional localizers cannot be run.

This paper presents a low power, high dynamic range (DR), reconfigurable light-to-digital converter (LDC) for photoplethysmogram (PPG), and near-infrared spectroscopy (NIRS) sensor readouts. The proposed LDC utilizes a current integration and a charge counting operation to directly convert the photocurrent to a digital code, reducing the noise contributors in the system. This LDC consists of a latched comparator, a low-noise current reference, a counter, and a multi-function integrator, which is used in both signal amplification and charge counting based data quantization. Furthermore, a current DAC is used to further increase the DR by canceling the baseline current. The LDC together with LED drivers and auxiliary digital circuitry are implemented in a standard 0.18 μm CMOS process and characterized experimentally. The LDC and LED drivers consume a total power of 196 μW while achieving a maximum 119 dB DR. The charge counting clock, and the pulse repetition frequency of the LED driver can be reconfigured, providing a wide range of power-resolution trade-off. At a minimum power consumption of 87 μW, the LDC still achieves 95 dB DR. The LDC is also validated with on-body PPG and NIRS measurement by using a photodiode (PD) and a silicon photomultiplier (SIPM), respectively. ispartof: IEEE TRANSACTIONS ON BIOMEDICAL CIRCUITS AND SYSTEMS vol:14 issue:4 pages:800-810 ispartof: location:JAPAN, Nara status: published

A safe and effective vaccine for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may be required to end the coronavirus disease 2019 (COVID-19) pandemic1-8. For global deployment and pandemic control, a vaccine that requires only a single immunization would be optimal. Here we show the immunogenicity and protective efficacy of a single dose of adenovirus serotype 26 (Ad26) vector-based vaccines expressing the SARS-CoV-2 spike (S) protein in non-human primates. Fifty-two rhesus macaques (Macaca mulatta) were immunized with Ad26 vectors that encoded S variants or sham control, and then challenged with SARS-CoV-2 by the intranasal and intratracheal routes9,10. The optimal Ad26 vaccine induced robust neutralizing antibody responses and provided complete or near-complete protection in bronchoalveolar lavage and nasal swabs after SARS-CoV-2 challenge. Titres of vaccine-elicited neutralizing antibodies correlated with protective efficacy, suggesting an immune correlate of protection. These data demonstrate robust single-shot vaccine protection against SARS-CoV-2 in non-human primates. The optimal Ad26 vector-based vaccine for SARS-CoV-2, termed Ad26.COV2.S, is currently being evaluated in clinical trials.

The long-term outcomes of surgery followed by delirium after multimodal prehabilitation program are largely unknown. We conducted this study to assess the effects of prehabilitation on 1-year mortality and of postoperative delirium on 1-year mortality and functional outcomes. The subjects of this study were patients aged ≥ 70 years who underwent elective surgery for abdominal aortic aneurysm (AAA) or colorectal cancer (CRC) between January 2013, and June 2018. A prehabilitation program was implemented in November 2015, which aimed to optimize physical health, nutritional status, factors of frailty and preoperative anemia prior to surgery. The outcomes were assessed as mortality after 6 and 12 months, compared between the two treatment groups; and mortality and functional outcomes, compared between patients with and those without delirium. There were 627 patients (controls N = 360, prehabilitation N = 267) included in this study. Prehabilitation did not reduce mortality after 1 year (HR 1.31 [95% CI 0.75–2.30]; p = 0.34). Delirium was significantly associated with 1-year mortality (HR 4.36 [95% CI 2.45–7.75]; p

BackgroundProspective research in the field of cochlear implants is hampered by methodological issues and small sample sizes. The ELEPHANT study presents an alternative clinical trial design with a daily randomized approach evaluating individualized tonotopical fitting of a cochlear implant (CI).MethodsA single-blinded, daily-randomized clinical trial will be implemented to evaluate a new imaging-based CI mapping strategy. A minimum of 20 participants will be included from the start of the rehabilitation process with a 1-year follow-up period. Based on a post-operative cone beam CT scan (CBCT), mapping of electrical input will be aligned to natural place-pitch arrangement in the individual cochlea. The CI’s frequency allocation table will be adjusted to match the electrical stimulation of frequencies as closely as possible to corresponding acoustic locations in the cochlea. A randomization scheme will be implemented whereby the participant, blinded to the intervention allocation, crosses over between the experimental and standard fitting program on a daily basis, and thus effectively acts as his own control, followed by a period of free choice between both maps to incorporate patient preference. With this new approach the occurrence of a first-order carryover effect and a limited sample size is addressed.DiscussionThe experimental fitting strategy is thought to give rise to a steeper learning curve, result in better performance in challenging listening situations, improve sound quality, better complement residual acoustic hearing in the contralateral ear and be preferred by recipients of a CI. Concurrently, the suitability of the novel trial design will be considered in investigating these hypotheses.Trial registrationClinicalTrials.gov:NCT03892941. Registered 27 March 2019.

Pattern separation is a hippocampal process in which highly similar stimuli are recognized as separate representations, and deficits could lead to memory impairments in neuropsychiatric disorders such as schizophrenia. The 5-HT1A receptor (5-HT1AR) is believed to be involved in these hippocampal pattern separation processes. However, in the dorsal raphe nucleus (DRN), the 5-HT1AR is expressed as a somatodendritic autoreceptor, negatively regulates serotonergic signaling, and could thereby counteract the effects of hippocampal postsynaptic 5-HT1A receptors. Therefore, this study aims to identify how pre- and post-synaptic 5-HT1AR activity affects pattern separation. Object pattern separation (OPS) performance was measured in male Wistar rats after both acute and chronic treatment (i.p.) with 5-HT1AR biased agonists F13714 (0.0025 mg/kg acutely, 0.02 mg/kg/day chronically) or NLX-101 (0.08 mg/kg acutely, 0.32 mg/kg/day chronically), which preferentially activate autoreceptors or postsynaptic receptors respectively, for 14 days. Body temperature - a functional correlate of hypothalamic 5-HT1AR stimulation - was measured daily. Additionally, 5-HT1AR density (DRN) and plasticity markers (hippocampus) were assessed. Acute treatment with F13714 impaired OPS performance, whereas chronic treatment normalized this, and a drop in body temperature was found from day 4 onwards. NLX-101 enhanced OPS performance acutely and chronically, and caused an acute drop in body temperature. Chronic NLX-101 treatment increased doublecortin positive neurons in the dorsal hippocampus, while chronic treatment with F13714 resulted in a downregulation of 5-HT1A autoreceptors, which likely reversed the acute impairment in OPS performance. Chronic treatment with NLX-101 appears to have therapeutic potential to improve brain plasticity and OPS performance.

Purpose This study investigated the feasibility of a new image analysis technique (radiomics) on conventional MRI for the computer-aided diagnosis of Menière’s disease. Materials and methods A retrospective, multicentric diagnostic case–control study was performed. This study included 120 patients with unilateral or bilateral Menière’s disease and 140 controls from four centers in the Netherlands and Belgium. Multiple radiomic features were extracted from conventional MRI scans and used to train a machine learning-based, multi-layer perceptron classification model to distinguish patients with Menière’s disease from controls. The primary outcomes were accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of the classification model. Results The classification accuracy of the machine learning model on the test set was 82%, with a sensitivity of 83%, and a specificity of 82%. The positive and negative predictive values were 71%, and 90%, respectively. Conclusion The multi-layer perceptron classification model yielded a precise, high-diagnostic performance in identifying patients with Menière’s disease based on radiomic features extracted from conventional T2-weighted MRI scans. In the future, radiomics might serve as a fast and noninvasive decision support system, next to clinical evaluation in the diagnosis of Menière’s disease.

Background Atrial fibrillation (AF) is the most common arrhythmia after cardiac surgery, yet the precise incidence and significance of arrhythmias after discharge home need to be better defined. Photoplethysmography (PPG)-based smartphone apps are promising tools to enable early detection and follow-up of arrhythmias. Objective By using a PPG-based smartphone app, we aimed to gain more insight into the prevalence of AF and other rhythm-related complications upon discharge home after cardiac surgery and evaluate the implementation of this app into routine clinical care. Methods In this prospective, single-center trial, patients recovering from cardiac surgery were asked to register their heart rhythm 3 times daily using a Food and Drug Administration–approved PPG-based app, for either 30 or 60 days after discharge home. Patients with permanent AF or a permanent pacemaker were excluded. Results We included 24 patients (mean age 60.2 years, SD 12 years; 15/23, 65% male) who underwent coronary artery bypass grafting and/or valve surgery. During hospitalization, 39% (9/23) experienced postoperative AF. After discharge, the PPG app reported AF or atrial flutter in 5 patients. While the app notified flutter in 1 patient, this was a false positive, as electrocardiogram revealed a 2nd-degree, 2:1 atrioventricular block necessitating a permanent pacemaker. AF was confirmed in 4 patients (4/23, 17%) and interestingly, was associated with an underlying postoperative complication in 2 participants (pneumonia n=1, pericardial tamponade n=1). A significant increase in the proportion of measurements indicating sinus rhythm was observed when comparing the first to the second month of follow-up (P Conclusions Implementation of smartphone-based PPG technology enables detection of AF and other rhythm-related complications after cardiac surgery. An association between AF detection and an underlying complication was found in 2 patients. Therefore, smartphone-based PPG technology may supplement rehabilitation after cardiac surgery by acting as a sentinel for underlying complications, rhythm-related or otherwise.

Cardiovascular diseases (CVD) are often characterized by their multifactorial complexity. This makes remote monitoring and ambulatory cardiac rehabilitation (CR) therapy challenging. Current wearable multimodal devices enable remote monitoring. Machine learning (ML) and artificial intelligence (AI) can help in tackling multifaceted datasets. However, for clinical acceptance, easy interpretability of the AI models is crucial. The goal of the present study was to investigate whether a multi-parameter sensor could be used during a standardized activity test to interpret functional capacity in the longitudinal follow-up of CR patients. A total of 129 patients were followed for 3 months during CR using 6-min walking tests (6MWT) equipped with a wearable ECG and accelerometer device. Functional capacity was assessed based on 6MWT distance (6MWD). Linear and nonlinear interpretable models were explored to predict 6MWD. The t-distributed stochastic neighboring embedding (t-SNE) technique was exploited to embed and visualize high dimensional data. The performance of support vector machine (SVM) models, combining different features and using different kernel types, to predict functional capacity was evaluated. The SVM model, using chronotropic response and effort as input features, showed a mean absolute error of 42.8 m (&plusmn, 36.8 m). The 3D-maps derived using the t-SNE technique visualized the relationship between sensor-derived biomarkers and functional capacity, which enables tracking of the evolution of patients throughout the CR program. The current study showed that wearable monitoring combined with interpretable ML can objectively track clinical progression in a CR population. These results pave the road towards ambulatory CR.

Pattern separation is a hippocampal process in which highly similar stimuli are recognized as separate representations, and deficits could lead to memory impairments in neuropsychiatric disorders such as schizophrenia. The 5-HT

The purpose of this study was to compare the functional exercise capacity of patients with alcohol use disorders (AUD) with an age-, gender-, and body mass index (BMI)-matched healthy control group. Thirty patients (22 males, 40.4 ± 10.5 years, illness duration = 9.7 ± 9.3 years) and healthy control subjects (22 males, 40.2 ± 10.7 years) participated. Participants performed a 6-min walk test (6MWT) to assess their functional exercise capacity, were asked about musculoskeletal problems and dyspnea, executed a standing broad jump to assess their muscular strength, and completed the International Physical Activity Questionnaire (IPAQ). Patients also filled in the Positive Affect and Negative Affect Schedule (PANAS) and Alcohol Use Disorders Identification Test (AUDIT). Our data show that patients with AUD walked a significantly shorter distance on the 6MWT (649.0 ± 72.9 m vs. 724.4 ± 89.0 m, p = 0.001). In patients with AUD, the variance in standing broad jump score explained 43.6% of the variance in the 6MWT score. The current study demonstrates that impaired muscle strength is negatively associated with functional outcomes in patients with AUD. Exercise interventions should be investigated in order to assess whether they can ameliorate muscle strength and daily life functioning of this vulnerable population. ispartof: ALCOHOL vol:82 pages:47-52 ispartof: location:United States status: published

Highlights • TH-302 combined with RT enhances tumor growth delay in esophageal cancer models. • This combination does not increase normal tissue toxicity on the short and long term. • The increased therapeutic index (1.38) paves the way for future clinical trials., Background and purpose Esophageal cancer incidence is increasing and is rarely curable. Hypoxic tumor areas cause resistance to conventional therapies, making them susceptible for treatment with hypoxia-activated prodrugs (HAPs). We investigated in vivo whether the HAP evofosfamide (TH-302) could increase the therapeutic ratio by sensitizing esophageal carcinomas to radiotherapy without increasing normal tissue toxicity. Materials and methods To assess therapeutic efficacy, growth of xenografted esophageal squamous cell (OE21) or adeno (OE19) carcinomas was monitored after treatment with TH-302 (50 mg/kg, QD5) and irradiation (sham or 10 Gy). Short- and long-term toxicity was assessed in a gut mucosa and lung fibrosis irradiation model, sensitive to acute and late radiation injury respectively. Mice were injected with TH-302 (50 mg/kg, QD5) and the abdominal area (sham, 8 or 10 Gy) or the upper part of the right lung (sham, 20 Gy) was irradiated. Damage to normal tissues was assessed 84 hours later by histology and blood plasma citrulline levels (gut) and for up to 1 year by non-invasive micro CT imaging (lung). Results The combination treatment of TH-302 with radiotherapy resulted in significant tumor growth delay in OE19 (P = 0.02) and OE21 (P = 0.03) carcinomas, compared to radiotherapy only. Irradiation resulted in a dose-dependent decrease of crypt survival (P

Background The primary objective of this study is to determine whether age at first alcohol use is a determinant for adolescent acute alcohol intoxication characteristics, such as age at first acute alcohol intoxication and blood alcohol concentration (BAC) at hospital admission. Around the world, as in the Netherlands, a key aim of alcohol policy is to postpone the age at first alcohol use. This is based on cohort studies that indicate a relationship between a younger age at first alcohol use and subsequent adult alcohol use disorders. Methods This study was conducted using a cohort of data comprising individuals under 18 years of age. Data were collected between 2007 and 2017 by the Dutch Pediatric Surveillance System (NSCK) in order to monitor trends in admissions for acute alcohol intoxication. Multivariate linear regression analyses were used to determine the association between age at first alcohol use and acute alcohol intoxication characteristics, such as age at first acute alcohol intoxication and BAC at admission. Results This study indicates that among adolescents admitted for acute alcohol intoxication, adolescents who started drinking at ≤ 14 years of age are significantly more often female, lower educated, and raised in nontraditional family structures than adolescents who started drinking between 15 and 18 years of age. Multiple linear regression analyses indicated that age at first alcohol use, corrected for covariates, significantly predicted the age at acute alcohol intoxication and BAC at admission. The association between age at first alcohol use and age at intoxication was also found to be clinically relevant. Conclusions Although causation cannot be implied based on the results of these analyses, the results of this study suggest that interventions delaying the age at first alcohol use could be successful in increasing the average age that adolescents are admitted to the hospital for acute alcohol intoxication.

This paper reports on the research methods used in five different projects aimed at supporting people living with dementia in their everyday lives and activities of daily living. In all five projects, people living with dementia and their informal carers were involved. Applied methods ranged from passive involvement in the form of observations to very active involvement consisting of consultation rounds and think-aloud sessions. The projects highlighted that people living with dementia can still contribute to the development of solutions that support them in the self-management of their symptoms and challenges, as well as technological solutions that support them in daily living. LinkedIn: https://www.linkedin.com/in/jvhoof1980/

Objective: The number of refugees worldwide is unprecedented in recent history. Little is known, however, about profiles of psychological symptoms following persecution and displacement. Methods: This study reports on a latent class analysis that identified profiles of posttraumatic stress disorder (PTSD), depression and anxiety symptoms in a nationally representative sample of 1625 refugees in Australia. The association between specific symptom profiles, exposure to potentially traumatic events and post-migration stressors, and overall health and help-seeking was examined. Results: Latent class analysis yielded an optimal five-class solution. These classes comprised the Pervasive Symptom class (19.2%), the High PTSD Symptom class (17.1%), the High Depression/Anxiety Symptom class (16.4%), the Moderate PTSD Symptom class (16.2%) and the Low Symptom class (31.1%). Participants in the symptomatic classes were more likely to be female, older and report greater post-migration stressors than those in the Low Symptom class. In addition, individuals in classes characterized by PTSD symptoms had been exposed to more types of potentially traumatic events. Membership in symptomatic classes was associated with poorer overall heath and greater help-seeking. Conclusion: Qualitatively distinct symptom profiles were observed in a nationally representative sample of refugees. In addition to a group of people who reported high symptoms across psychological disorders and may warrant clinical intervention, we identified two subclinical classes who may be missed by existing diagnostic classification systems. Post-migration stressors play an important role in influencing refugee symptom profiles over and above exposure to potentially traumatic events. Clinicians should consider specific symptom profiles and contextual factors when planning interventions with refugees.

Based on the embodied cognition framework and research addressing transfer effects between visual perception and taste, the point of departure for this study is the widespread association between vertical orientation and connotations related to luxury and (economic) power. Specifically, this study tests whether vertical orientation not only affects impressions of product luxury, but also influences actual taste evaluations, including perceptions of taste strength (intensity) and taste liking. Results confirm these predictions by showing that participants in a Dutch coffee house gave higher ratings on these constructs when they were exposed to an ad display depicting vertically-oriented rather than horizontally-oriented visual cues during a coffee sample test. Findings furthermore stress the influence of design cues as opposed to more traditional product claims. Implications for marketing and design practice are discussed.

Light therapy for older persons with dementia is often administered with light boxes, even though indoor ambient light may more comfortably support the diverse lighting needs of this population. Our objective is to investigate the influence of indoor daylight and lighting on the health of older adults with dementia living in long-term care facilities. A systematic literature search was performed within PubMed, CINAHL, PsycINFO, Web of Science and Scopus databases. The included articles (n=37) were published from 1991 to 2020. These articles researched the influence of existing and changed indoor light conditions on health and resulted in seven categories of health outcomes. Although no conclusive evidence was found to support the ability of indoor light to decrease challenging behaviors or improve circadian rhythms, findings of two studies indicate that exposure to (very) cool light of moderate intensity diminished agitation. Promising effects of indoor light were to reduce depressive symptoms and facilitate spatial orientation. Furthermore, there were indications that indoor light improved one’s quality of life. Despite interventions with dynamic lighting having yielded little evidence of its efficacy, its potential has been insufficiently researched among this study population. This review provides a clear and comprehensive description of the impact of diverse indoor light conditions on the health of older adults with dementia living in long-term care facilities. Variation was seen in terms of research methods, (the description of) light conditions, and participants’ characteristics (types and severity of dementia), thus confounding the reliability of the findings. The authors recommend further research to corroborate the beneficial effects of indoor light on depression and to clarify its role in supporting everyday activities of this population. An implication for practice in long-term care facilities is raising the awareness of the increased lighting needs of aged residents. Original article at: https://doi.org/10.2147/CIA.S297865

In line with other countries from wealthier parts of the world, the Netherlands shows clear trends of less alcohol use and less binge drinking by youth since the millennium shift.1 Contrary to these trends, the number of underage patients who are admitted to a hospital with alcohol intoxication characteristics is an ongoing and stable health concern in the country.2 Knowledge about what time of day patients are brought into the hospital is important for the development of efficient prevention policies. The primary aim of this repeated cross-sectional study was to investigate how time of day variation (morning, afternoon, evening and night) was associated with patient and intoxication characteristics in Dutch adolescents admitted for alcohol intoxication. Furthermore, we also examined how …

Importance Control of the global COVID-19 pandemic will require the development and deployment of safe and effective vaccines. Objective To evaluate the immunogenicity of the Ad26.COV2.S vaccine (Janssen/Johnson & Johnson) in humans, including the kinetics, magnitude, and phenotype of SARS-CoV-2 spike-specific humoral and cellular immune responses. Design, Setting, and Participants Twenty-five participants were enrolled from July 29, 2020, to August 7, 2020, and the follow-up for this day 71 interim analysis was completed on October 3, 2020; follow-up to assess durability will continue for 2 years. This study was conducted at a single clinical site in Boston, Massachusetts, as part of a randomized, double-blind, placebo-controlled phase 1 clinical trial of Ad26.COV2.S. Interventions Participants were randomized to receive 1 or 2 intramuscular injections with 5 × 1010viral particles or 1 × 1011viral particles of Ad26.COV2.S vaccine or placebo administered on day 1 and day 57 (5 participants in each group). Main Outcomes and Measures Humoral immune responses included binding and neutralizing antibody responses at multiple time points following immunization. Cellular immune responses included immunospot-based and intracellular cytokine staining assays to measure T-cell responses. Results Twenty-five participants were randomized (median age, 42; age range, 22-52; 52% women, 44% male, 4% undifferentiated), and all completed the trial through the day 71 interim end point. Binding and neutralizing antibodies emerged rapidly by day 8 after initial immunization in 90% and 25% of vaccine recipients, respectively. By day 57, binding and neutralizing antibodies were detected in 100% of vaccine recipients after a single immunization. On day 71, the geometric mean titers of spike-specific binding antibodies were 2432 to 5729 and the geometric mean titers of neutralizing antibodies were 242 to 449 in the vaccinated groups. A variety of antibody subclasses, Fc receptor binding properties, and antiviral functions were induced. CD4+ and CD8+ T-cell responses were induced. Conclusion and Relevance In this phase 1 study, a single immunization with Ad26.COV2.S induced rapid binding and neutralization antibody responses as well as cellular immune responses. Two phase 3 clinical trials are currently underway to determine the efficacy of the Ad26.COV2.S vaccine. Trial Registration ClinicalTrials.gov Identifier:NCT04436276

BACKGROUND: Efficacious vaccines are urgently needed to contain the ongoing coronavirus disease 2019 (Covid-19) pandemic of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A candidate vaccine, Ad26.COV2.S, is a recombinant, replication-incompetent adenovirus serotype 26 (Ad26) vector encoding a full-length and stabilized SARS-CoV-2 spike protein. METHODS: In this multicenter, placebo-controlled, phase 1-2a trial, we randomly assigned healthy adults between the ages of 18 and 55 years (cohort 1) and those 65 years of age or older (cohort 3) to receive the Ad26.COV2.S vaccine at a dose of 5×1010 viral particles (low dose) or 1×1011 viral particles (high dose) per milliliter or placebo in a single-dose or two-dose schedule. Longer-term data comparing a single-dose regimen with a two-dose regimen are being collected in cohort 2; those results are not reported here. The primary end points were the safety and reactogenicity of each dose schedule. RESULTS: After the administration of the first vaccine dose in 805 participants in cohorts 1 and 3 and after the second dose in cohort 1, the most frequent solicited adverse events were fatigue, headache, myalgia, and injection-site pain. The most frequent systemic adverse event was fever. Systemic adverse events were less common in cohort 3 than in cohort 1 and in those who received the low vaccine dose than in those who received the high dose. Reactogenicity was lower after the second dose. Neutralizing-antibody titers against wild-type virus were detected in 90% or more of all participants on day 29 after the first vaccine dose (geometric mean titer [GMT], 212 to 354), regardless of vaccine dose or age group, and reached 96% by day 57 with a further increase in titers (GMT, 288 to 488) in cohort 1a. Titers remained stable until at least day 71. A second dose provided an increase in the titer by a factor of 2.6 to 2.9 (GMT, 827 to 1266). Spike-binding antibody responses were similar to neutralizing-antibody responses. On day 15, CD4+ T-cell responses were detected in 76 to 83% of the participants in cohort 1 and in 60 to 67% of those in cohort 3, with a clear skewing toward type 1 helper T cells. CD8+ T-cell responses were robust overall but lower in cohort 3. CONCLUSIONS: The safety and immunogenicity profiles of Ad26.COV2.S support further development of this vaccine candidate. (Funded by Johnson & Johnson and the Biomedical Advanced Research and Development Authority of the Department of Health and Human Services; COV1001 ClinicalTrials.gov number, NCT04436276.). ispartof: The New England Journal of Medicine vol:384 issue:19 ispartof: location:United States status: published

Segmentation of anatomical structures is valuable in a variety of tasks, including 3D visualization, surgical planning, and quantitative image analysis. Manual segmentation is time-consuming and deals with intra and inter-observer variability. To develop a deep-learning approach for the fully automated segmentation of the inner ear in MRI, a 3D U-net was trained on 944 MRI scans with manually segmented inner ears as reference standard. The model was validated on an independent, multicentric dataset consisting of 177 MRI scans from three different centers. The model was also evaluated on a clinical validation set containing eight MRI scans with severe changes in the morphology of the labyrinth. The 3D U-net model showed precise Dice Similarity Coefficient scores (mean DSC-0.8790) with a high True Positive Rate (91.5%) and low False Discovery Rate and False Negative Rates (14.8% and 8.49% respectively) across images from three different centers. The model proved to perform well with a DSC of 0.8768 on the clinical validation dataset. The proposed auto-segmentation model is equivalent to human readers and is a reliable, consistent, and efficient method for inner ear segmentation, which can be used in a variety of clinical applications such as surgical planning and quantitative image analysis.

Background Nursing homes (NH) for the elderly have been particularly affected by the Covid-19 pandemic mainly due to their hosted vulnerable populations and poor outbreak preparedness. In Belgium, the medical humanitarian organization Médecins Sans Frontières (MSF) implemented a support project for NH including training on infection prevention and control (IPC), (re)-organization of care, and psychosocial support for NH staff. As psychosocial and mental health needs of NH residents in times of Covid-19 are poorly understood and addressed, this study aimed to better understand these needs and how staff could respond accordingly. Methods A qualitative study adopting thematic content analysis. Eight focus group discussions with direct caring staff and 56 in-depth interviews with residents were conducted in eight purposively and conveniently selected NHs in Brussels, Belgium, June 2020. Results NH residents experienced losses of freedom, social life, autonomy, and recreational activities that deprived them of their basic psychological needs. This had a massive impact on their mental well-being expressed in feeling depressed, anxious, and frustrated as well as decreased meaning and quality of life. Staff felt unprepared for the challenges posed by the pandemic; lacking guidelines, personal protective equipment and clarity around organization of care. They were confronted with professional and ethical dilemmas, feeling ‘trapped’ between IPC and the residents’ wellbeing. They witnessed the detrimental effects of the measures imposed on their residents. Conclusion This study revealed the insights of residents’ and NH staff at the height of the early Covid-19 pandemic. Clearer outbreak plans, including psychosocial support, could have prevented the aggravated mental health conditions of both residents and staff. A holistic approach is needed in NHs in which tailor-made essential restrictive IPC measures are combined with psychosocial support measures to reduce the impact on residents’ mental health impact and to enhance their quality of life.

Cultural tightness-looseness represents the degree to which a particular culture possesses strong behavioral norms, and the degree to which members of that culture are likely to sanction individuals who deviate from those norms. While tightness-looseness has been quantified for a large and growing number of countries around the world, there are many countries where a tightness-looseness score has yet to be determined, thus impeding the inclusion of those countries in cross-cultural research with a tightness-looseness focus. There is a dearth of research on cultural tightness-looseness in South America in particular. We report results from a national survey of 1,265 Ecuadorian residents which provided quantification of the relatively tight culture of Ecuador.

Although hyperglycemia is associated with worse outcomes after aneurysmal subarachnoid hemorrhage (aSAH), there is no consensus on the optimal glucose control metric, acceptable in-hospital glucose ranges, or suitable insulin regimens in this population. In this single-center retrospective cohort study of aSAH patients, admission glucose, and hospital glucose mean (MHG), minimum (MinG), maximum (MaxG), and variability were compared. Primary endpoints (mortality, complications, and vasospasm) were assessed using multivariate logistic regressions. Of the 217 patients included, complications occurred in 83 (38.2%), 124 (57.1%) had vasospasm, and 41 (18.9%) died. MHG was independently associated with (p

Background Haemodialysis (HD) patients are burdened by frequent fluid shifts which amplify their comorbidities. Bioimpedance (bioZ) is a promising technique to monitor changes in fluid status. The aim of this study is to investigate if the thoracic bioZ signal can track fluid changes during a HD session. Methods Prevalent patients from a single centre HD unit were monitored during one to six consecutive HD sessions using a wearable multi-frequency thoracic bioZ device. Ultrafiltration volume (UFV) was determined based on the interdialytic weight gain and target dry weight set by clinicians. The correlation between the bioZ signal and UFV was analysed on population level. Additionally regression models were built and validated per dialysis session. Results 66 patients were included, resulting in a total of 133 HD sessions. Spearman correlation between the thoracic bioZ and UFV showed a significant strong correlation of 0.755 (p on population level. Regression analysis per session revealed a strong relation between the bioZ value and the UFV (R2 = 0.982). The fluid extraction prediction error of the leave-one-out cross validation was very small (56.2 ml [− 121.1–194.1 ml]) across all sessions at all frequencies. Conclusions This study demonstrated that thoracic bioZ is strongly correlated with fluid shifts during HD over a large range of UFVs. Furthermore, leave-one-out cross validation is a step towards personalized fluid monitoring during HD and could contribute to the creation of autonomous dialysis.

The COVID-19 pandemic is a stark reminder of the heavy toll that emerging infectious diseases (EIDs) with epidemic and pandemic potential can inflict. Vaccine development, scale-up, and commercialization is a long, expensive, and risky enterprise that requires substantial upfront planning and offers no guarantee of success. EIDs are a particularly challenging target for global health preparedness, including for vaccine development. Insufficient attention has been given to challenges, lessons learned, and potential solutions to support and sustain vaccine industry engagement in vaccine development for EIDs. Drawing from lessons from the most recent Ebola epidemic in the Democratic Republic of the Congo, as well as the 2009 H1N1 influenza, 2014-2016 Ebola, and 2015-16 Zika outbreaks preceding it, we offer our perspective on challenges facing EID vaccine development and recommend additional solutions to prioritize in the near term. The 6 recommendations focus on reducing vaccine development timelines and increasing business certainty to reduce risks for companies. The global health security community has an opportunity to build on the current momentum to design a sustainable model for EID vaccines.

Background: A dimensional approach of psychopathology focuses on features and risk factors that are shared across diagnoses. In support for this dimensional approach, studies point to a general psychopathology factor (GPF) associated with risk for multiple psychiatric disorders. It is, however, unknown how GPF relates to white matter integrity (WMI). In the current diffusion tensor imaging (DTI) study, we examined how GPF relates to abnormalities in a skeleton representation of white matter tracts, taking into account a trans-diagnostic risk factor: unresolved-disorganized attachment (Ud) resulting from loss or trauma. Methods: Unique associations between GPF, Ud, and WMI were examined in a combined sample of adolescents (N = 63) with childhood sexual abuse-related posttraumatic stress disorder (N = 18), anxiety and depressive disorders (N = 26) and without psychiatric disorder (N = 19). WMI was measured using DTI. Ud was measured using the Adult Attachment Interview. We controlled for puberty stage, gender, age, and IQ. Results: Controlling for GPF, Ud was associated with reduced fractional anisotropy (FA) in the splenium and inferior fronto-occipital fasciculus (IFOF). Controlling for Ud, GPF was associated with reduced FA in the genu and body of the corpus callosum. Conclusions: Decreasing WMI in the genu and body with increasing psychopathology across diagnoses suggests demyelinization in these areas and may underlie comorbidity and presence of symptoms that transcend psychopathological diagnoses. In contrast, trauma-related WMI reductions in the splenium and IFOF may account for heterogeneity within diagnostic categories as a function of childhood trauma. These findings support the importance of a dimensional approach in addition to traditional diagnostic classifications in clinical research and practice. Keywords: Adversity, Child abuse, Psychopathology, Attachment, Brain imaging

BACKGROUND: Occupational incidents and accidents are still commonplace in the contemporary workplace, despite increased understandings of safety. OBJECTIVE: This article aims to yield new insights into safety-related thinking, decisions and behaviours through the application of an institutional logics perspective. METHOD: Semi-structured interviews with twenty-two managers in a railroad construction and maintenance organisation were conducted, in which a variety of topics related to occupational safety and management were discussed. RESULTS: The results illustrate that an institutional logics perspective provides useful insights into the different logics of the market, profession, and corporation in the occupational safety context. Furthermore, the results demonstrate contradictory viewpoints, so-called complexity, between these three logics and subsequent management approaches. CONCLUSIONS: We demonstrate that viewing occupational safety through the lens of institutional logics leads to a better understanding of safety and reveals various rationales for safety attitudes and behaviours that otherwise may have been dismissed as irrational. Understanding and possessing the discourse of logics can help managers and safety professionals with analysis and prevention of accidents.

Aneurysmal subarachnoid hemorrhage (aSAH) is devastating, with delayed cerebral ischemia (DCI) significantly contributing to the high morbidity and mortality rates. Cholesterol has been studied as a measure of nutritional status in other neurological pathologies, but reports examining cholesterol's effects on aSAH outcomes are sparse. This study aimed to elucidate the effect of low total cholesterol (TC) and high density lipoprotein (HDL) on mortality and DCI following aSAH.We performed a retrospective cohort study at a quaternary academic medical center between June 2014 and July 2018. All patients had aSAH confirmed by digital subtraction angiography and had TC measured on admission. Primary outcomes were mortality and DCI. Secondary outcome was radiographic vasospasm. Univariate and multivariate logistic regressions were performed.There were 75 aSAH patients, with an average age of 58.7 ± 1.7 (range: 14-89) and HuntHess score of 2.8 ± 0.1, included for analysis. Those with a low TC 160 mg/dL had 3 times increased odds of DCI (OR = 3.4; 95 %CI: 1.3-9.0; p = 0.0175) and a nearly 5 times increased odds of death (OR = 4.9; 95 %CI: 1.1-18.3; p = 0.0339). Low HDL 40 mg/dL was associated with 12 times increased odds of DCI (OR = 12.3; 95 %CI: 2.7-56.4; p = 0.0003) but no significant differences in death (p = 0.2205). In multivariate analysis, low TC was an independent risk factor for increased mortality (OR = 5.6; 95 %CI: 1.2-27.6; p = 0.0335) while low HDL was associated with increased risk for DCI (OR = 17.9; 95 %CI: 3.1-104.4; p = 0.0013). There was no effect of TC or HDL on radiographic vasospasm.Low TC and HDL are independent predictors of increased mortality and DCI, respectively, following aSAH. Low TC and HDL may be markers of poor overall health, in addition to having some pathophysiological effect on cerebral vasculature. These results may have practical implications for the improvement of aSAH prognostication and management.

This paper presents a sub-mW ASIC for multimodal brain monitoring. The ASIC is co-integrated with electrode(s) and optodes (i.e., optical source and detector) as an active sensor to measure electroencephalography (EEG), bio-impedance (BioZ), and near-infrared spectroscopy (NIRS) on scalp. The target is to build a wearable EEG-NIRS headset for low-cost functional brain imaging. The proposed NIRS readout utilizes the near-infrared light to measure the pulse oximetry and blood oxygen saturation (SpO2). While traditional photodiodes are supported, the readout also allows the use of silicon photomultipliers (SiPMs) as optical detectors. The SiPM improves optical sensitivity while significantly reducing the average power of two LEDs to 150 μW. On circuit level, a SAR-based calibration compensates maximum 40 μA current from ambient light, while digital DC-servo loops reduces the baseline static SiPM current up to 400 μA, leading to an overall dynamic range of 87 dB. The EEG readout exhibits 720 MΩ input impedance at 50 Hz. The BioZ readout has 3 mΩ/√(Hz) impedance sensitivity by employing dynamic circuit techniques. When EEG, BioZ, and NIRS are enabled at the same time, one ASIC consumes 665 μW including the power of LEDs.

BACKGROUND AND OBJECTIVE: Intraoperative rupture of a cerebral aneurysm during neurosurgery can be a devastating event that increases perioperative morbidity and mortality. Rapid ventricular pacing (RVP) is a technique to obtain flow arrest for short periods of time during dissection or rupture of the aneurysm. The objective of this study was to evaluate the neurological and cardiac effects of repetitive periods of RVP during cerebrovascular surgery. METHODS: Data from patients who underwent repetitive RVP during craniotomy for cerebrovascular disorders were retrospectively analyzed from a single-center medical records database (Cegeka Medical Health Care Systems). We compared preoperative and postoperative troponin levels (cTnl) to assess cardiac ischemia. Preoperative and postoperative magnetic resonance imaging (MRI) results were screened for RVP-induced infarcts by evaluating diffusion restriction in the hemisphere contralateral to the operated side and the fossa posterior. RESULTS: A total of 37 patients were analyzed. An immediate decrease of systolic arterial blood pressure (

Summary Background In the LYM-3002 study, the efficacy and safety of frontline bortezomib plus rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP) and rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) were compared in transplant-ineligible patients with untreated, newly diagnosed, mantle cell lymphoma. We report the final overall survival and safety outcomes for patients in the long-term follow-up phase after the primary progression-free-survival endpoint was met. Methods LYM-3002 was a randomised, open-label, phase 3 study done at 128 clinical centres in 28 countries in Asia, Europe, North America, and South America. Adult patients with confirmed stage II–IV previously untreated mantle cell lymphoma, Eastern Cooperative Oncology Group performance status score of 2 or less, who were ineligible for bone marrow transplantation, were randomly assigned (1:1) to receive six or eight 21-day cycles of VR-CAP (intravenous rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and bortezomib 1·3 mg/m2, plus oral prednisone 100 mg/m2) or R-CHOP (intravenous vincristine 1·4 mg/m2 [2 mg maximum], rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, and doxorubicin 50 mg/m2, plus oral prednisone 100 mg/m2). Randomisation was done according to a computer-generated randomisation schedule prepared by the sponsor; permuted blocks central randomisation was used (block size of 4), and was stratified by International Prognostic Index score and disease stage at diagnosis. The primary endpoint of this final analysis was overall survival, which was analysed in the intention-to-treat population. This study is registered with ClinicalTrials.gov , number NCT00722137 , and is closed to new participants with follow-up completed. Findings Between May 22, 2008, and Dec 5, 2011, 487 patients were enrolled and randomly assigned. 268 patients (140 in the VR-CAP group and 128 in the R-CHOP group) were included in the follow-up analysis, which included patients with data available after the primary analysis clinical cutoff date of Dec 2, 2013. After median follow-up of 82·0 months (IQR 74·1–94·2), median overall survival was significantly longer in the VR-CAP group than in the R-CHOP group (90·7 months [95% CI 71·4 to not estimable] vs 55·7 months [47·2 to 68·9]; hazard ratio 0·66 [95% CI 0·51–0·85]; p=0·001). Three new adverse events were reported since the primary analysis cutoff (one each of grade 4 lung adenocarcinoma and grade 4 gastric cancer in the VR-CAP group, and one case of grade 2 pneumonia in the R-CHOP group). 103 (42%) of 243 patients in the VR-CAP group, and 138 (57%) of 244 in the R-CHOP group died; the most common cause of death was progressive disease. Interpretations Compared with R-CHOP, VR-CAP was associated with significantly longer survival, and had a manageable and expected safety profile. Our results support further assessment of VR-CAP in patients with previously untreated mantle cell lymphoma. Funding Janssen Research & Development.

Exacerbations in Chronic obstructive pulmonary disease (COPD) are often accompanied by pulmonary and systemic inflammation, and are associated with an increased susceptibility to weight loss and muscle wasting. As the emphysematous phenotype in COPD appears prone to skeletal muscle wasting, the aims of this study were to evaluate in emphysematous compared to control mice following repetitive exacerbations (1) changes in muscle mass and strength and, (2) whether muscle mass recovery and its underlying processes are impaired. Emphysema was induced by intra-tracheal (IT) elastase instillations, followed by three weekly IT-LPS instillations to mimic repetitive exacerbations. Loss of muscle mass and strength were measured, and related to analyses of muscle protein turnover and myogenesis signaling in tissue collected during and following recovery. Emphysematous mice showed impaired muscle mass recovery in response to pulmonary inflammation-induced muscle atrophy. Proteolysis and protein synthesis signaling remained significantly higher in emphysematous mice during recovery from LPS. Myogenic signaling in skeletal muscle was altered, and fusion capacity of cultured muscle cells treated with plasma derived from LPS-treated emphysematous mice was significantly decreased. In conclusion, repetitive cycles of pulmonary inflammation elicit sustained muscle wasting in emphysematous mice due to impaired muscle mass recovery, which is accompanied by aberrant myogenesis.

International audience; BACKGROUND:Rituximab plus chemotherapy has been shown to be effective in patients with advanced-stage, previously untreated follicular lymphoma; nevertheless, most patients will have a relapse. Combination immunotherapy with lenalidomide and rituximab is an immunomodulatory regimen that has shown promising activity in patients with indolent B-cell non-Hodgkin's lymphoma.METHODS:We conducted this multicenter, international, phase 3 superiority trial to evaluate rituximab plus lenalidomide, as compared with rituximab plus chemotherapy, in patients with previously untreated follicular lymphoma. Patients were randomly assigned to receive one of the two regimens, followed by maintenance monotherapy with rituximab. Treatment with rituximab plus lenalidomide consisted of 18 cycles of the two drugs, followed by rituximab maintenance therapy every 8 weeks for 12 cycles (six additional doses). Treatment with rituximab plus chemotherapy consisted of the investigator's choice of one of three rituximab-based regimens, followed by maintenance monotherapy with rituximab every 8 weeks for 12 cycles. The primary end points were complete response (confirmed or unconfirmed) at 120 weeks and progression-free survival.RESULTS:A total of 1030 patients were randomly assigned to receive rituximab plus lenalidomide (513 patients) or rituximab plus chemotherapy (517 patients). The rate of confirmed or unconfirmed complete response at 120 weeks was similar in the two groups: 48% (95% confidence interval [CI], 44 to 53) in the rituximab-lenalidomide group and 53% (95% CI, 49 to 57) in the rituximab-chemotherapy group (P=0.13). The interim 3-year rate of progression-free survival was 77% (95% CI, 72 to 80) and 78% (95% CI, 74 to 82), respectively. A higher percentage of patients in the rituximab-chemotherapy group had grade 3 or 4 neutropenia (32% vs. 50%) and febrile neutropenia of any grade (2% vs. 7%), and a higher percentage of patients in the rituximab-lenalidomide group had grade 3 or 4 cutaneous reactions (7% vs. 1%).CONCLUSIONS:Among patients with previously untreated follicular lymphoma, efficacy results were similar with rituximab plus lenalidomide and rituximab plus chemotherapy (with both regimens followed by rituximab maintenance therapy). The safety profile differed in the two groups. (Funded by Celgene; RELEVANCE ClinicalTrials.gov numbers, NCT01476787 and NCT01650701 , and EudraCT number, 2011-002792-42 .).

BackgroundProlonged separation from parental support is a risk factor for psychopathology. This study assessed the impact of brief separation from parents during childhood trauma on adult attachment tendencies and post-traumatic stress.MethodChildren (n = 806) exposed to a major Australian bushfire disaster in 1983 and matched controls (n = 725) were assessed in the aftermath of the fires (mean age 7–8 years) via parent reports of trauma exposure and separation from parents during the fires. Participants (n = 500) were subsequently assessed 28 years after initial assessment on the Experiences in Close Relationships scale to assess attachment security, and post-traumatic stress disorder (PTSD) was assessed using the PTSD checklist.ResultsBeing separated from parents was significantly related to having an avoidant attachment style as an adult (B = −3.69, s.e. = 1.48, β = −0.23, p = 0.013). Avoidant attachment was associated with re-experiencing (B = 0.03, s.e. = 0.01, β = 0.31, p = 0.045), avoidance (B = 0.03, s.e. = 0.01, β = 0.30, p = 0.001) and numbing (B = 0.03, s.e. = 0.01, β = 0.30, p < 0.001) symptoms. Anxious attachment was associated with re-experiencing (B = 0.03, s.e. = 0.01, β = 0.18, p = 0.001), numbing (B = 0.03, β = 0.30, s.e. = 0.01, p < 0.001) and arousal (B = 0.04, s.e. = 0.01, β = 0.43, p < 0.001) symptoms.ConclusionsThese findings demonstrate that brief separation from attachments during childhood trauma can have long-lasting effects on one's attachment security, and that this can be associated with adult post-traumatic psychopathology.

The application of next-generation sequencing to fetal pathology has proved to increase the diagnostic yield in fetuses with abnormal ultrasounds. We retrospectively reviewed genetic data of 30 selected cases studied through targeted resequencing of OMIM genes. In our experience, clinical data proved to be essential to support diagnostic reasoning and enhance variants’ assessment. The molecular diagnosis was reached in 19/30 (63%) cases. Only in 7/19 cases the molecular diagnosis confirmed the initial diagnostic hypothesis, showing the relevance of the genotype-first approach. According to the genotype-phenotype correlation, we were able to divide the solved cases into three groups: i) the correlation is well established but it was missed due to lack of specificity, unusual presentation or recent description; ii) the clinical presentation is much more severe than currently known for the underlying condition; iii) the correlation does not recapitulate the entire phenotype, possibly due to the fetal presentation or multiple coexisting conditions. Moreover, we found a higher proportion of recessive diagnosis in abnormal fetuses compared to cohorts of individuals with developmental delay. Our findings suggest that fetal pathology may be enriched in rare alleles and/or in unusual combinations, counter-selected in postnatal genomes and thus contributing to both phenotypic extremeness and atypical presentation.

Although it is believed that physical activity, sedentary, and dietary behavior (i.e., energy balance-related behavior) may decrease the risk of burn-out, the association between both is currently not well understood. Therefore, the aim of this systematic review was to synthesize studies investigating the relationship between energy balance-related behavior and burn-out risk. A systematic literature search was conducted in four databases, resulting in 25 included studies (ten experimental and 15 observational studies). Nine out of ten experimental studies showed that exercise programs were effective in reducing burn-out risk. Fourteen out of fifteen observational studies found a negative association between physical activity and burn-out risk, whereas one study did not find a relation. Two of the 15 observational studies also showed that being more sedentary was associated with a higher burn-out risk, and two other studies found that a healthier diet was related to a lower burn-out risk. No experimental studies were found for the latter two behaviors. It can be concluded that physical activity may be effective in reducing burn-out risk. The few observational studies linking sedentary and dietary behavior with burn-out risk suggest that being more sedentary and eating less healthy are each associated with higher burn-out risk. More high-quality research is needed to unravel the causal relationship between these two behaviors and burn-out risk.

Intestinal worms, or soil-transmitted helminths (STHs), affect hundreds of millions of people in all tropical and subtropical regions of the world. The most prevalent STH is Ascaris lumbricoides. Through large-scale deworming programs, World Health Organization aims to reduce morbidity, caused by moderate-to-heavy intensity infections, below 2%. In order to monitor these control programs, stool samples are examined microscopically for the presence of worm eggs. This procedure requires well-trained personnel and is known to show variability between different operators interpreting the slides. We have investigated whether ABA-1, one of the excretory-secretory products of A. lumbricoides can be used as a coproantigen marker for infection with this parasite. Polyclonal antibodies were generated and a coproantigen ELISA was developed. Using this ELISA, it was found that ABA-1 in stool detected Ascaris infection with a sensitivity of 91.5% and a specificity of 95.3%. Our results also demonstrate that there is a correlation between ABA-1 levels in stool and A. lumbricoides DNA detected in stool. Using a threshold of 18.2 ng/g stool the ABA-1 ELISA correctly assigned 68.4% of infected individuals to the moderate-to-heavy intensity infection group, with a specificity of 97.1%. Furthermore, the levels of ABA-1 in stool were shown to rapidly and strongly decrease upon administration of a standard anthelminthic treatment (single oral dose of 400 mg albendazole). In an Ascaris suum infection model in pigs, it was found that ABA-1 remained undetectable until day 28 and was detected at day 42 or 56, concurrent with the appearance of worm eggs in the stool. This report demonstrates that ABA-1 can be considered an Ascaris -specific coproantigen marker that can be used to monitor infection intensity. It also opens the path for development of point-of-care immunoassay-based tests to determine A. lumbricoides infection in stool at the sample collection site., Author summary Intestinal worms are one of the most common infections in tropical and subtropical parts of the world. The roundworm Ascaris lumbricoides is the most prevalent and efforts are ongoing to use preventive chemotherapy to reduce both prevalence and intensity of this infection. To monitor these programs, stool-based microscopy is currently used. We have investigated the possibility of using ABA-1, an abundantly secreted protein from the worm, as a biomarker in stool of infected individuals. We have developed an ELISA and using this assay determined that ABA-1 as stool biomarker had a sensitivity of 91.5% and a specificity of 95.3% to detect infection with A. lumbricoides. We also showed that ABA-1 in stool rapidly and strongly decreased upon administration of a standard anthelminthic treatment. The main asset of this novel stool biomarker is its potential to be used in point-of-care immunoassay-based tests to determine A. lumbricoides infection in stool at the sample collection site.

The goal of this study was to report deep squat hip kinetics in young, athletic adults using a personalized numerical model solution based on inverse dynamics. Thirty-five healthy subjects underwent deep squat motion capture acquisitions and MRI scans of the lower extremities. Musculoskeletal models were personalized using each subject's lower limb anatomy. The average peak hip joint reaction force was 274 percent bodyweight. Average peak hip and knee flexion angles were 107 degrees and 112 degrees respectively. These new findings show that deep squatting kinetics in the younger population differ substantially from the previously reported in vivo data in older subjects.

Background: Cardiac rehabilitation (CR) is known for its beneficial effects on functional capacity and is a key component within current cardiovascular disease management strategies. In addition, a larger increase in functional capacity is accompanied by better clinical outcomes. However, not all patients respond in a similar way to CR. Therefore, a patient-tailored approach to CR could open up the possibility to achieve an optimal increase in functional capacity in every patient. Before treatment can be optimized, the differences in response of patients in terms of cardiac adaptation to exercise should first be understood. In addition, digital biomarkers to steer CR need to be identified. Objective: The aim of the study was to investigate the difference in cardiac response between patients characterized by a clear improvement in functional capacity and patients showing only a minor improvement following CR therapy. Methods: A total of 129 patients in CR performed a 6-minute walking test (6MWT) at baseline and during four consecutive short-term follow-up tests while being equipped with a wearable electrocardiogram (ECG) device. The 6MWTs were used to evaluate functional capacity. Patients were divided into high- and low-response groups, based on the improvement in functional capacity during the CR program. Commonly used heart rate parameters and cardiac digital biomarkers representative of the heart rate behavior during the 6MWT and their evolution over time were investigated. Results: All participating patients improved in functional capacity throughout the CR program (P

In the Netherlands, there is an increasing need for collective forms of housing for older people. Such housing bridges the gap between the extremes of living in an institutionalised setting and remaining in their own house. The demand is related to the closure of many residential care homes and the need for social engagement with other residents. This study focuses on housing initiatives that offer innovative and alternative forms of independent living, which deviate from mainstream housing arrangements. It draws on recent literature on healthcare &lsquo, rebels&rsquo, and further develops the concept of &lsquo, rebellion&rsquo, in the context of housing. The main research question is how founders dealt with challenges of establishing and governing &lsquo, rebellious&rsquo, innovative living arrangements for older people in the highly regulated context of housing and care in the Netherlands. Qualitative in-depth interviews with 17 founders (social entrepreneurs, directors and supervisory board members) were conducted. Founders encountered various obstacles that are often related to governmental and sectoral rules and regulations. Their stories demonstrate the opportunities and constraints of innovative entrepreneurship at the intersection of housing and care. The study concludes with the notion of &lsquo, responsible rebellion&rsquo, and practical lessons about dealing with rules and regulations and creating supportive contexts.

IntroductionSmoking prevalence continues to be high over the world and smoking-induced diseases impose a heavy burden on the medical care system. As believed by many researchers, a promising way to promote healthcare and well-being at low cost for the large vulnerable smoking population is through eHealth solutions by providing self-help information about smoking cessation. But in the absence of first-hand knowledge about smoking habits in daily life settings, systems built on these methods often fail to deliver proactive and tailored interventions for different users and situations over time, thus resulting in low efficacy. To fill the gap, an observational study has been developed on the theme of objective and non-biased monitoring of smoking habits in a longitudinal and ambulatory mode. This paper presents the study protocol. The primary objective of the study is to reveal the contextual and physiological pattern of different smoking behaviours using wearable sensors and mobile phones. The secondary objectives are to (1) analyse cue factors and contextual situations of smoking events; (2) describe smoking types with regard to users’ characteristics and (3) compare smoking types between and within subjects.Methods and analysesThis is an observational study aimed at reaching 100 participants. Inclusion criteria are adults aged between 18 and 65 years, current smoker and office worker. The primary outcome is a collection of a diverse and inclusive data set representing the daily smoking habits of the general smoking population from similar social context. Data analysation will revolve around our primary and secondary objectives. First, linear regression and linear mixed model will be used to estimate whether a factor or pattern have consistent (p valueEthics and disseminationThe study was designed together by an interdisciplinary group of researchers, including psychologist, psychiatrist, engineer and user involvement coordinator. The protocol was reviewed and approved by the ethical review board of UZ Leuven on 18 April 2016, with an approval number S60078. The study will allow us to characterise the types of smokers and triggering events. These findings will be disseminated through peer-reviewed articles.

Loss and abuse in children can lead to unresolved-disorganized (UD) attachment. How this condition relates to brain structure and functional connectivity (FC) is unknown. We therefore aimed to investigate gray matter volume (GMV) and resting state functional connectivity (RSFC) correlates of UD attachment in adolescents. Based on previous neuroimaging studies of trauma effects, we hypothesized that the structure of the amygdala and hippocampus and the FC of the latter would be linked to UD attachment. Anatomical and RSFC data were collected from a mixed group of adolescents (N = 74) with symptoms of posttraumatic stress disorder (PTSD) related to childhood sexual abuse (CSA), anxiety/depressive symptoms, and without psychiatric disorder as part of the Emotional Pathways' Imaging Study in Clinical Adolescents (EPISCA). Bilateral volumes of the amygdala and hippocampus were measured using the FMRIB Software Library, and RSFC of the hippocampus was assessed using seed-based correlation. UD attachment was measured using the Adult Attachment Interview. Hierarchical regression and correlation were used to assess the associations between UD status (continuous and categorical), brain structure, and FC, adjusting for a general psychopathology factor, puberty stage, gender, age, and IQ. UD attachment was associated with a smaller left hippocampal volume, RSpanish Abstracts by Asociación Chilena de Estrés Traumático (ACET) El apego desorganizado no resuelto asociado con un menor hipocampo y un incremento de la conectividad funcional más allá de la psicopatología APEGO, HIPOCAMPO Y CONECTIVIDAD FUNCIONAL. Las pérdidas y el abuso en niños pueden conllevar a un apego desorganizado no resuelto (DN). La forma en que esta condición se relaciona con la estructura cerebral y conectividad funcional (CF) es desconocida. Por lo tanto, nuestro objetivo fue investigar el volumen de materia gris (VMG) y los correlatos de la conectividad funcional en estado de reposo (CFER) de DN en adolescentes. Basado en estudios previos de neuroimágenes sobre los efectos del trauma, hipotetizamos que la estructura de la amígdala e hipocampo y la CF de este último podría estar relacionado con DN. Los datos anatómicos y de CFER fueron recolectados de un grupo mixto de adolescentes (N = 74) con síntomas de trastorno de estrés postraumático (TEPT) relacionado con abuso sexual infantil (ASI), síntomas de ansiedad/depresión, y sin trastornos psiquiátricos, como parte del Estudio de Imágenes de Vías Emocionales en Clínica Adolescente (EPISCA en su sigla en inglés). Volúmenes bilaterales de la amígdala e hipocampo fueron evaluados usando el software de biblioteca FMRIB, y la CFER del hipocampo fue evaluada usando la correlación basada en semillas. La DN fue medido utilizando la Entrevista de Apego Adulto. Regresiones jerárquicas y correlaciones fueron utilizadas para evaluar las asociaciones entre DN (continuo y categórico), estructura cerebral, y CF, ajustando un factor general de psicopatología, etapa de pubertad, género, edad y CI. DN fue asociado con un menor volumen del hipocampo izquierdo, RTraditional and Simplified Chinese Abstracts by the Asian Society for Traumatic Stress Studies (AsianSTSS) 簡體及繁體中文撮要由亞洲創傷心理研究學會翻譯 Unresolved-disorganized attachment associated with smaller hippocampus and increased functional connectivity beyond psychopathology Traditional Chinese 標題: 未解決和錯亂依附跟海馬體較小和功能連結性提升有關, 程度超於心理疾病所致 撮要: 兒童經歷失落與虐待, 可導致有未解決和錯亂依附(UD)。可是, 我們仍不清楚這種狀況跟腦部結構與功能連結性有何關連。因此, 我們旨在探查青少年中, 作為UD的關連因素的灰質體積(GMV)及靜息態功能連結性(RSFC)。我們基於過往檢視創傷效應的神經成像研究, 假設杏仁核與海馬體的結構和後者的FC會跟UD有關。混合的青少年樣本(N = 74) 來自青少年臨床情緒路徑成像研究(EPISCA)。他們有童年性虐(CSA)相關、焦慮症/抑鬱症狀相關的創傷後壓力症(PTSD)症狀, 但無精神疾病。我們收集樣本的解剖數據和RSFC數據, 採用FMRIB Software Library來測量杏仁核與海馬體的雙邊體積, 用種子相關分析來評估海馬體的RSFC, 並以成人依附面談來測量UD。層次迴歸及相關分析用以評估UD(連續與明確的)、腦部結構、FC之間的關連;我們亦因應以下因素作調節:一個普遍的心理疾病因素、青春期、性別、年齡、IQ。UD跟左邊海馬體體積較小有關(R

OBJECTIVE: To design and evaluate a new vestibular implant and surgical procedure that should reach correct electrode placement in 95% of patients in silico.DESIGN: Computational anatomy driven implant and surgery design study.SETTING: Tertiary referral center.PARTICIPANTS: The population comprised 81 patients that had undergone a CT scan of the Mastoid region in the Maastricht University Medical Center. The population was subdivided in a vestibular implant eligible group (28) and a control group (53) without known vestibular loss.INTERVENTIONS: Canal lengths and relationships between landmarks were calculated for every patient. The relationships in group-anatomy were used to model a fenestration site on all three semicircular canals. Each patient's simulated individual distance from the fenestration site to the ampulla was calculated and compared with the populations average to determine if placement would be successful.MAIN OUTCOME MEASURES: Lengths of the semicircular canals, distances from fenestration site to ampulla (intralabyrinthine electrode length), and rate of successful electrode placement (robustness).RESULTS: The canal lengths for the lateral, posterior, and superior canal were respectively 12.1 mm ± 1.07, 18.8 mm ± 1.62, and 17.5 mm ± 1.23, the distances from electrode fenestration site to the ampulla were respectively 3.73 mm ± 0.53, 9.02 mm ± 0.90, and 5.31 mm ± 0.73 and electrode insertions were successful for each respective semicircular canal in 92.6%, 66.7%, and 86.4% of insertions in silico. The implant electrode was subsequently revised to include two more electrodes per lead, resulting in a robustness of 100%.CONCLUSIONS: The computational anatomy approach can be used to design and test surgical procedures. With small changes in electrode design, the proposed surgical procedure's target robustness was reached.

Background Rupture of a vulnerable carotid atherosclerotic plaque is an important underlying cause of ischemic stroke. Increased leaky plaque microvasculature may contribute to plaque vulnerability. These immature microvessels may facilitate entrance of inflammatory cells into the plaque. The objective of the present study is to investigate whether there is a difference in plaque microvasculature (the volume transfer coefficient K trans ) between the ipsilateral symptomatic and contralateral asymptomatic carotid plaque using noninvasive dynamic contrast‐enhanced magnetic resonance imaging. Methods and Results Eighty‐eight patients with recent transient ischemic attack or ischemic stroke and ipsilateral >2 mm carotid plaque underwent 3 T magnetic resonance imaging to identify plaque components and to determine characteristics of plaque microvasculature. The volume transfer coefficient K trans , indicative for microvascular density, flow, and permeability, was calculated for the ipsilateral and asymptomatic plaque, using a pharmacokinetic model (Patlak). Presence of a lipid‐rich necrotic core, intraplaque hemorrhage, and a thin and/or ruptured fibrous cap was assessed on multisequence magnetic resonance imaging . We found significantly lower K trans in the symptomatic carotid plaque compared with the asymptomatic side (0.057±0.002 min −1 versus 0.062±0.002 min −1 ; P =0.033). There was an increased number of slices with intraplaque hemorrhage (0.9±1.6 versus 0.3±0.8, P =0.002) and lipid‐rich necrotic core (1.4±1.9 versus 0.8±1.4, P =0.016) and a higher prevalence of plaques with a thin and/or ruptured fibrous cap (32% versus 17%, P =0.023) at the symptomatic side. Conclusions K trans was significantly lower in symptomatic carotid plaques, indicative for a decrease of plaque microvasculature in symptomatic plaques. This could be related to a larger amount of necrotic tissue in symptomatic plaques. Clinical Trial Registration URL : http://www.clinicaltrials.gov.uk . Unique identifier: NCT 01208025.