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BACKGROUND: Immediate initiation of antiretroviral therapy (ART) regardless of CD4 cell count reduces risk for AIDS and non-AIDS-related events in asymptomatic, HIV-positive persons and is the standard of care. However, most HIV-positive persons initiate ART when their CD4 count decreases below 500 × 10 9 cells/L. Consequences of delayed ART on risk for non-AIDS-defining and AIDS-defining cancer, one of the most common reasons for death in HIV, are unclear. OBJECTIVE: To estimate the long-term risk difference for cancer with the immediate ART strategy.DESIGN: Multinational prospective cohort study.SETTING: The D:A:D (Data collection on Adverse events of anti-HIV Drugs) study, which included HIV-positive persons from Europe, Australia, and the United States.PARTICIPANTS: 8318 HIV-positive persons with at least 1 measurement each of CD4 cell count and viral load while ART-naive (study period, 2006 to 2016).MEASUREMENTS: The parametric g-formula was used, with adjustment for baseline and time-dependent confounders (CD4 cell count and viral load), to assess the 10-year risk for non-AIDS-defining and AIDS-defining cancer of immediate versus deferred (at CD4 counts RESULTS: During 64 021 person-years of follow-up, 231 cases of non-AIDS-defining cancer and 272 of AIDS-defining cancer occurred among HIV-positive persons with a median age of 36 years (interquartile range, 29 to 43 years). With immediate ART, the 10-year risk for non-AIDS-defining cancer was 2.97% (95% CI, 2.37% to 3.50%) and that for AIDS-defining cancer was 2.50% (CI, 2.37% to 3.38%). Compared with immediate ART initiation, the 10-year absolute risk differences when deferring ART to CD4 counts less than 500 × 10 9 cells/L and less than 350 × 10 9 cells/L were 0.12 percentage point (CI, -0.01 to 0.26 percentage point) and 0.29 percentage point (CI, -0.03 to 0.73 percentage point), respectively, for non-AIDS-defining cancer and 0.32 percentage point (CI, 0.21 to 0.44 percentage point) and 1.00 percentage point (CI, 0.67 to 1.44 percentage points), respectively, for AIDS-defining cancer. LIMITATION: Potential residual confounding due to observational study design.CONCLUSION: In this young cohort, effects of immediate ART on 10-year risk for cancer were small, and further supportive data are needed for non-AIDS-defining cancer.PRIMARY FUNDING SOURCE: Highly Active Antiretroviral Therapy Oversight Committee.

The subtleties of human perception, as measured by vision scientists through the use of psychophysics, are important clues to the internal workings of visual recognition. For instance, measured reaction time can indicate whether a visual stimulus is easy for a subject to recognize, or whether it is hard. In this paper, we consider how to incorporate psychophysical measurements of visual perception into the loss function of a deep neural network being trained for a recognition task, under the assumption that such information can enforce consistency with human behavior. As a case study to assess the viability of this approach, we look at the problem of handwritten document transcription. While good progress has been made towards automatically transcribing modern handwriting, significant challenges remain in transcribing historical documents. Here we describe a general enhancement strategy, underpinned by the new loss formulation, which can be applied to the training regime of any deep learning-based document transcription system. Through experimentation, reliable performance improvement is demonstrated for the standard IAM and RIMES datasets for three different network architectures. Further, we go on to show feasibility for our approach on a new dataset of digitized Latin manuscripts, originally produced by scribes in the Cloister of St. Gall in the the 9th century.

Most available firearm violence data are summary and they lack sufficient incident and victim details to inform policy and practice. The lack of a national definition for a nonfatal shooting also hinders research. There is evidence to suggest that law enforcement data are a valid and reliable sources for firearm violence data. This exploratory study uses law enforcement data to examine unintentional nonfatal shooting incident and victim characteristics in a large Midwestern city. Data for this project come from law enforcement sources and include all unintentional nonfatal shooting incidents (n=177) occurring between January 1, 2017 and December 31, 2019. Exploratory analyses were conducted to describe incidents and victims. Incidents most commonly occurred in the fall season, during nighttime hours, and at a residence. Victims were most likely male, non-white, and 18-34 years old. When injury cause was known, injuries resulted from improper firearm handling. The majority of victims were wounded in their extremities and did not engage emergency medical services before arriving at the emergency department. This study demonstrates the utility of law enforcement data as a source for additional context surrounding unintentional nonfatal shooting incidents. Findings suggest two policy implications: requiring a gun safety course as part of the permitting process and treating gun safety as a life skill by advocating for gun safety courses in schools. Further research is needed to determine why some victims choose not to engage public safety or emergency services prior to arriving at emergency departments.

Introduction Breast conservation surgery (BCS) is the treatment of choice for unifocal, early-stage breast cancer. The ability to offer BCS to a wider subset of patients, including those with multifocal/multicentric cancer as well as extensive ductal carcinoma in situ, has emerged over time, especially in those undergoing joint oncoplastic reconstruction and those treated with neoadjuvant therapy. However, localization techniques using multiple radioactive seeds for bracketing in this patient subset have not been validated. Materials and Methods A single-institution retrospective review was conducted of all patients with breast cancer who underwent BCS, guided by multiple bracketed iodine I 125 radioactive seeds between January 2014 and April 2017. Results Bracketing of breast cancer using 2 or more radioactive seeds was performed in 157 breasts in 156 patients. Negative margins were achieved in 124 of 157 (79%) breasts, including 33 cases (21%) that underwent targeted margin reexcision at the time of surgery after intraoperative, multidisciplinary margin assessment. Thirty-three cases (21%) resulted in close or positive margins, of which 11 (7%) and 10 (6.4%) underwent completion mastectomy or repeat lumpectomy, respectively. Twelve patients (7.6%) did not undergo reexcision. En bloc resection was successful in 134 of 157 (85.4%) lumpectomies. Eighty-nine percent of the procedures were coupled with oncoplastic reconstruction. Conclusion Bracketing techniques using multiple radioactive seeds expands the indications for breast conservation therapy in patients who would have traditionally required mastectomy. Intraoperative margin assessment improves surgical and pathologic success. Larger defects created by multifocal resection are optimally managed in concert with oncoplastic reconstruction to minimize asymmetries and aesthetic defects.

Objective The impact of disrupted sleep on the effectiveness of prolonged exposure (PE) therapy for posttraumatic stress disorder (PTSD) is not well understood. Researchers have suggested that comorbid sleep disorders contribute to nonresponse by impairing therapeutic mechanisms such as emotional processing of trauma memories and extinction in cued fear conditioning. Several studies indicate daytime sleepiness, insomnia, and nightmares are correlated with PTSD symptom severity. However, a recent randomized controlled trial found that these sleep disorder symptoms did not affect PTSD symptom change over the course of massed PE (i.e., daily sessions across 2 weeks). Method The current study used an ecologically valid clinical sample to examine whether daytime sleepiness, insomnia, and nightmares interfere with the slope of symptom change in massed PE. Results Results indicate that all 3 sleep disorder symptoms correlate with PTSD symptom severity on the first day of treatment but were not associated with symptom change. Conclusions These findings are consistent with the expectation that the daily structure of massed PE may enhance treatment engagement in patients who are typically drowsy or not well-rested, thus facilitating fear extinction. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

The clinical spectrum of injuries in crevasse accidents can range from benign to life-threatening, even including death. To date, little is known about incidence and causes.We retrospectively analyzed mountain rescue missions that included crevasse accidents and took place in Switzerland from 2010 to 2020. Demographic and epidemiological data were collected. Injury severity was graded according to the National Advisory Committee for Aeronautics (NACA) score. Winter season was defined as December to May, and summer season as June to November.A total of 321 victims of crevasse falls were included in the study. The median age of victims was 41.2 years (interqauartile range [IQR] 31.3 to 51.6), with 82% (n=260) being male and 59% (n=186) foreigners. The typical altitude range at which rescue missions were performed was between 3000 and 3499m (44% of all cases). The median depth of the fall was 15 meters (IQR 8 to 20) during the winter season compared to 8 meters (IQR 5 to 10) during the summer, p0.001. Overall mortality was 6.5%. The NACA score was ≥4 for 9.4% (n=30) of the victims. 55% (n=177) had a NACA score of 0 or 1. There was a significant positive correlation between the depth of fall and the injury severity (Pearson`s correlation r=0.35, 95%- confidence interval: 0.18 to 0.51), p0.001.More than half of victims fallen into a crevasse are uninjured or sustain mild injury. Life-threathening injuries were found in about 10% of victims and the crevasse fall was fatal in 6.5% of cases. Injury severity positively correlates with the depth of fall, which is higher during winter season.

Experimental studies into the beam parameter product ( BPP ) of 940–980 nm GaAs-based high-power diode lasers are presented. Such lasers exhibit broadening far field and narrowing near field with increasing bias, with BPP increasing tenfold over the diffraction limit. First, spectrally-resolved beam profile measurements of lasers with monolithically-integrated gratings are presented, showing that a reproducible series of spatially-extended optical modes makes up the optical field. Then, changes to the device construction are presented, enabling effects limiting BPP to be inferred and addressed. Process- and package-induced effects can be minimized by design, while the effects of carrier, gain and temperature profiles dominate. Self-heating within the laser stripe raises the refractive index, forming a thermal lens, and the variation in curvature of this lens with bias and device construction directly affects BPP . Temperature non-uniformity along the resonator is also shown to strongly degrade BPP . Moreover, current spreading and the resulting lateral carrier accumulation (LCA) amplify high-order, high- BPP modes, thus degrading BPP for any given thermal lens. This LCA-induced degradation is shown to be suppressed by regrown lateral current-blocking structures. Finally, a flatter thermal lens and lower BPP can be achieved using thermal engineering, via changes to the epitaxial design or device layout.

Please see the Editorial Comment by Candice Bolan discussing this article. The treatment of rectal cancer centers around the distinct but related goals of management of distant metastases and manag...

Purpose: Neoadjuvant systemic treatment elicits a pathologic complete response (pCR) in an average of 35% of women with breast cancer. In such cases, breast surgery may be considered overtreatment. However, imaging and vacuum-assisted biopsy (VAB) alone showed high rates of missed cancer compared to standard breast surgery. We therefore evaluated multivariate algorithms using patient, tumor, and VAB variables to accurately identify patients with breast pCR. Methods: We developed and tested three multivariate approaches: elastic net regression, Support Vector Machines (SVM), and a deep neural network. We analyzed 452 patients, randomly partitioned into training and test samples (2:1 ratio), who participated in three prospective studies assessing the feasibility of VAB to accurately detect residual disease after neoadjuvant systemic treatment (NST). The studies were conducted at 23 sites in the United States, Germany, and South Korea. The trials enrolled women who presented with clinical stage I-III breast cancer of any biological subtype and a partial or complete response to NST confirmed by ultrasonography, mammography, or magnetic resonance imaging; all patients underwent guideline-adherent surgery. We compared the performance of the multivariate algorithms to the histopathologic evaluation of disease response in the surgical specimen (reference standard) - false-negative rate (FNR, missed residual cancer) and specificity (identification of breast pCR) were the main outcome measures. The best performing algorithm on the test set with respect to sensitivity and specificity was validated using data of an independent fourth trial. We compared the performance of the multivariate approaches to the performance of imaging and/or VAB. Results: In the test set (n=152), elastic net regression, SVM and the neural network revealed an FNR of 1.2% (1 of 85 patients with missed residual disease). Specificity of the elastic net regression was 46.3% (31 of 67 women with surgically confirmed breast pCR identified), of the SVM 62.7% (42 of 67) and of the neural network 67.2% (45 of 67). All multivariate algorithms performed better than imaging or VAB: FNR 25.9% (22 of 85) and 16.5% (14 of 85), respectively. Subsequent external validation (n=50) of the neural network algorithm showed a false-negative rate of 0% (0 of 27) and a specificity of 65.2% (15 of 23). The area under the ROC curve for the deep neural network was 0.97 (95% CI, 0.94 to 1.00). Analyzing the coefficients of the elastic net regression (regularized beta; ß) showed that the lesion diameter on imaging after NST (ß = 0.31) and VAB results (ß = 0.49) were the most important variables in the prediction of residual tumor. Other variables were also important: age (ß = 0.18), in-situ in the initial diagnostic (not VAB) biopsy (ß = 0.11), difficulties during the pathologic evaluation of the VAB specimen (ß = 0.11); needle size 7G (ß = -0.06, as opposed to 8G, 9G, 10G), multicentricity on imaging after NST (ß = 0.06), hormone-receptor positivity (ß = 0.01), and a clip marker positioned within the (former) lesion (ß = -0.01, as opposed to a clip marker positioned 5mm from the lesion Conclusion: A multivariate algorithm can accurately select breast cancer patients without residual disease after neoadjuvant treatment. This finding may pave the way to study omission of breast surgery in these patients in the future. Performance of multivariate algorithms compared to imaging and vacuum-assisted biopsyFalse-negative rate - value (95% CI)Specificity - value (95% CI)Negative predictive value - value (95% CI)Positive predictive value - value (95% CI)Test set (n=152)Imaging25.9% (17.0-36.5%)61.2% (48.5-72.9%)65.1% (52.0-76.7%)70.8% (60.2-79.9%)VAB16.5% (9.3-26.1%)89.6% (79.7-95.7%)81.1% (70.3-89.3%)91.0% (82.4-96.3%)Imaging + VAB5.9% (1.9-13.2%)52.2% (39.7-64.6)87.5% (73.2-95.8%)71.4% (62.1-79.6%)Elastic net regression1.2% (0.0-6.4%)46.3% (34.0-58.9%)96.9% (83.8-99.9%)70.0% (61.0%-78.0%)Support Vector Machine1.2% (0.0-6.4%)62.7% (50.0 - 74.2%)97.7% (87.7-99.9%)77.1% (68.0-84.6%)Deep Neural Network1.2% (0.0-6.4%)67.2% (54.6-78.2%)97.8% (88.5-99.9%)79.3% (70.3-86.5%)Validation set (n=50)Deep Neural Network0.0% (0.0-12.8%)65.2% (42.7-83.6%)100% (78.2-100%)77.1% (59.9-89.6%) Citation Format: André Pfob, Chris Sidey-Gibbons, Han-Byoel Lee, Marios Konstantinos Tasoulis, Vivian Koelbel, Michael Golatta, Gaiane M. Rauch, Benjamin D. Smith, Vicente Valero, Fiona MacNeill, Wonshik Han, Walter Paul Weber, Geraldine Rauch, Henry Kuerer, Joerg Heil. Identify breast cancer patients with pathologic complete response in the breast after neoadjuvant systemic treatment - an international, multicenter analysis [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS2-42.

Objective: To compare the incidence of dyslipidemia in people with HIV receiving integrase inhibitors (INSTI) versus boosted protease inhibitors (PI/b) and nonnucleoside reverse transcriptase inhibitors (NNRTI) within RESPOND consortium of prospective cohorts. Methods: Participants were eligible if they were at least 18 years, without dyslipidemia and initiated or switched to a three-drug antiretroviral therapy (ART)-regimen consisting of either INSTI, NNRTI, or PI/b for the first time, between 1 January 2012 and 31 December 2018. Dyslipidemia was defined as random total cholesterol more than 240 mg/dl, HDL less than 35 mg/dl, triglyceride more than 200 mg/dl, or initiation of lipid-lowering therapy. Poisson regression was used to determine the adjusted incidence rate ratios. Follow-up was censored after 3 years or upon ART-regimen discontinuation or last lipid measurement or 31 December 2019, whichever occurred first. Results: Overall, 4577 people with HIV were eligible (INSTI = 66.9%, PI/b = 12.5%, and NNRTI = 20.6%), 1938 (42.3%) of whom were ART-naive. During 1.7 (interquartile range, 0.6 - 3.0) median years of follow-up, 1460 participants developed dyslipidemia [incidence rate: 191.6 per 1000 person-years, 95% confidence interval (CI) 182.0 - 201.7]. Participants taking INSTI had a lower incidence of dyslipidemia compared with those on PI/b (adjusted incidence rate ratio 0.71; CI 0.59 - 0.85), but higher rate compared with those on NNRTI (1.35; CI 1.15 - 1.58). Compared with dolutegravir, the incidence of dyslipidemia was higher with elvitegravir/cobicistat (1.20; CI 1.00 - 1.43) and raltegravir (1.24; CI 1.02 - 1.51), but lower with rilpivirine (0.77; CI 0.63 - 0.94). Conclusion: In this large consortium of heterogeneous cohorts, dyslipidemia was less common with INSTI than with PI/b. Compared with dolutegravir, dyslipidemia was more common with elvitegravir/cobicistat and raltegravir, but less common with rilpivirine.

Background Neoadjuvant systemic treatment elicits a pathologic complete response (pCR) in about 35% of women with breast cancer. In such cases, breast surgery may be considered overtreatment. We evaluated multivariate algorithms using patient, tumor, and vacuum-assisted biopsy (VAB) variables to identify patients with breast pCR. Methods We developed and tested four multivariate algorithms: a logistic regression with elastic net penalty, an Extreme Gradient Boosting (XGBoost) tree, Support Vector Machines (SVM), and neural network. We used data from 457 women, randomly partitioned into training and test set (2:1), enrolled in three trials with stage 1–3 breast cancer, undergoing VAB before surgery. False-negative rate (FNR) and specificity were the main outcome measures. The best performing algorithm was validated in an independent fourth trial. Results In the test set (n = 152), the logistic regression with elastic net penalty, XGboost tree, SVM, and neural network revealed an FNR of 1.2% (1 of 85 patients with missed residual cancer). Specificity of the logistic regression with elastic net penalty was 52.2% (35 of 67 women with surgically confirmed breast pCR identified), of the XGBoost tree 55.2% (37 of 67), of SVM 62.7% (42 of 67), and of the neural network 67.2% (45 of 67). External validation (n = 50) of the neural network showed an FNR of 0% (0 of 27) and a specificity of 65.2% (15 of 23). Area under the ROC curve for the neural network was 0.97 (95% CI, 0.94–1.00). Conclusion A multivariate algorithm can accurately select breast cancer patients without residual cancer after neoadjuvant treatment.

Objectives Imaging evaluation is an essential part of treatment planning for patients with ovarian cancer. Variation in the terminology used for describing ovarian cancer on computed tomography (CT) and magnetic resonance (MR) imaging can lead to ambiguity and inconsistency in clinical radiology reports. The aim of this collaborative project between Society of Abdominal Radiology (SAR) Uterine and Ovarian Cancer (UOC) Disease-focused Panel (DFP) and the European Society of Uroradiology (ESUR) Female Pelvic Imaging (FPI) Working Group was to develop an ovarian cancer reporting lexicon for CT and MR imaging. Methods Twenty-one members of the SAR UOC DFP and ESUR FPI working group, one radiology clinical fellow, and two gynecologic oncology surgeons formed the Ovarian Cancer Reporting Lexicon Committee. Two attending radiologist members of the committee prepared a preliminary list of imaging terms that was sent as an online survey to 173 radiologists and gynecologic oncologic physicians, of whom 67 responded to the survey. The committee reviewed these responses to create a final consensus list of lexicon terms. Results An ovarian cancer reporting lexicon was created for CT and MR Imaging. This consensus-based lexicon has 6 major categories of terms: general, adnexal lesion-specific, peritoneal carcinomatosis-specific, lymph node-specific, metastatic disease -specific, and fluid-specific. Conclusions This lexicon for CT and MR imaging evaluation of ovarian cancer patients has the capacity to improve the clarity and consistency of reporting disease sites seen on imaging. Key points • This reporting lexicon for CT and MR imaging provides a list of consensus-based, standardized terms and definitions for reporting sites of ovarian cancer on imaging at initial diagnosis or follow-up. • Use of standardized terms and morphologic imaging descriptors can help improve interdisciplinary communication of disease extent and facilitate optimal patient management. • The radiologists should identify and communicate areas of disease, including difficult to resect or potentially unresectable disease that may limit the ability to achieve optimal resection.

Purpose The new active transcutaneous partially implantable osseointegrated system Cochlear™ Osia® System is indicated in case of conductive or mixed hearing loss (CHL/MHL) with a maximum average bone conduction hearing loss of 55 dB, or in single-sided deafness (SSD). The implant directly stimulates the bone via a piezoelectric transducer and is directed by an external sound processor. We conducted a monocentric retrospective longitudinal within-subject clinical study at our tertiary academic referral center. The aim was to investigate long-term data (2017–2021) on audiological outcomes and hearing-related quality of life for the Osia system. Methods Between 2017 and 2020, 22 adults (18: CHL/MHL; 3: SSD) were implanted with the Osia100 implant; seven received bilateral implants. As of 10/2020, the sound processor was upgraded to Osia 2. Results Mean Osia system use by 04/2021 was 30.9 ± 8.6 months (range 17–40 months). Unaided bone conduction thresholds were unchanged postoperatively. One patient had to be explanted because of prolonged wound infection. Aided hearing thresholds were significantly lower compared to the unaided thresholds preoperatively, along with a marked increase in speech recognition in quiet. Speech processor upgrade resulted in a stable benefit. Patients with CHL/MHL and SSD showed a similar improvement in self-rated hearing performance revealed by SSQ, APHAB, and HUI questionnaires. Conclusion The Osia system is a safe, effective and sustainable option for treatment of conductive and mixed hearing loss or single-sided deafness.

BACKGROUND: A better understanding of the extent to which prior occurrences of posttraumatic stress disorder (PTSD) and major depressive episode (MDE) predict psychopathological reactions to subsequent traumas might be useful in targeting post-traumatic preventive interventions. METHODS: Data come from 1,306 patients presenting to 29 U.S. emergency departments (EDs) after a motor vehicle collision (MVC) in the Advancing Understanding of RecOvery afteR traumA (AURORA) study. Patients completed self-reports in the ED and 2-weeks, 8-weeks, and 3-months post-MVC. Associations of pre-MVC probable PTSD and probable MDE histories with subsequent 3-months post-MVC probable PTSD and probable MDE were examined along with mediation through intervening peritraumatic, 2-week, and 8-week disorders. RESULTS: 27.6% of patients had 3-month post-MVC probable PTSD and/or MDE. Pre-MVC lifetime histories of these disorders were not only significant (relative-risk=2.6–7.4) but were dominant (63.1% population attributable risk proportion [PARP]) predictors of this 3-month outcome, with 46.6% prevalence of the outcome among patients with pre-MVC disorder histories versus 9.9% among those without such histories. The associations of pre-MVC lifetime disorders with the 3-month outcome were mediated largely by 2-week and 8-week probable PTSD and MDE (PARP decreasing to 22.8% with controls for these intervening disorders). Decomposition showed that pre-MVC lifetime histories predicted both onset and persistence of these intervening disorders as well as higher conditional prevalence of the 3-month outcome in the presence of these intervening disorders. CONCLUSIONS: Assessments of pre-MVC PTSD and MDE histories and follow-ups at 2-weeks and 8-weeks could help target early interventions for psychopathological reactions to MVCs.

Zur Gestaltung zukunftsrobuster Fabriken ist es erforderlich, langfristige Trends und Entwicklungen in die Fabrikplanung einzubeziehen. Die Zukunftsforschung befasst sich mit der systematischen Erkundung der Zukunft und verfügt zu diesem Zweck über eine Vielzahl an Methoden. Im vorliegenden Beitrag wird ausgehend von den Anforderungen der Fabrikplanung hergeleitet, welche Methoden für den Anwendungsfall geeignet sind. Weiterhin wird dargestellt, inwiefern diese Methoden an die Anforderungen der Fabrikplanung angepasst werden müssen.

Vascular perturbations and cerebral hypometabolism are emerging as important components of Alzheimer’s disease (AD). While various in vivo imaging modalities have been designed to detect changes of cerebral perfusion and metabolism in AD patients and animal models, study results were often heterogenous with respect to imaging techniques and animal models. We therefore evaluated cerebral perfusion and glucose metabolism of two popular transgenic AD mouse strains, TgCRND8 and 5xFAD, at 7 and 12 months-of-age under identical conditions and analyzed possible molecular mechanisms underlying heterogeneous cerebrovascular phenotypes. Results revealed disparate findings in these two strains, displaying important aspects of AD progression. TgCRND8 mice showed significantly decreased cerebral blood flow and glucose metabolism with unchanged cerebral blood volume (CBV) at 12 months-of-age whereas 5xFAD mice showed unaltered glucose metabolism with significant increase in CBV at 12 months-of-age and a biphasic pattern of early hypoperfusion followed by a rebound to normal cerebral blood flow in late disease. Finally, immunoblotting assays suggested that VEGF dependent vascular tone change may restore normoperfusion and increase CBV in 5xFAD.

Primary vaginal cancer is rare, comprising 1% to 2% of gynecologic malignancies and 20% of all malignancies involving the vagina. More frequently, the vagina is involved secondarily by direct invasion from malignancies originating in adjacent organs or by metastases from other pelvic or extrapelvic primary malignancies. Data on the use of imaging in vaginal cancer are sparse. Insights are derived from the study of imaging in cervical cancer and have reasonable generalizability to vaginal cancer due to similar tumor biology. Given the trend toward definitive chemoradiation for both cancers in all but early stage lesions, principles of postchemoradiation tumor response evaluation are largely analogous. Accordingly, many of the recommendations outlined here are informed by principles translated from the literature on cervical cancer. For pretreatment assessment of local tumor burden and in the case of recurrent vaginal cancer, MRI is the preferred imaging modality. PET/CT has demonstrated utility for the detection of nodal metastatic and unexpected distant metastatic disease. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.

Knowledge of axillary nodal status is highly important for correct staging and treatment planning in patients with breast cancer. Axillary US is a recognized highly specific and cost-effective tool for assessing nodal status and guiding appropriate treatment. Axillary US imaging with US-guided biopsy is routinely performed throughout the world. However, because of recent developments in the surgical management of the axilla in patients with newly diagnosed breast cancer (American College of Surgeons Oncology Group [ACOSOG] Z0011 trial) and in patients with breast cancer receiving neoadjuvant systemic therapy (ACOSOG Z1071, SENTinel NeoAdjuvant [SENTINA] and Sentinel Node biopsy aFter NeoAdjuvant Chemotherapy [SN FNAC] trials), some have questioned the utility of axillary US for nodal staging. Here, we review the evidence to date supporting the additional value of axillary US for patients with breast cancer. Nodal US in patients with newly diagnosed breast cancer is useful for staging; in a significant proportion of patients, nodal US identifies additional axillary level II or level III nodal disease, which allows for appropriate treatment of disease. Furthermore, ongoing clinical trials may show that axillary surgery can be omitted in patients with negative findings on axillary US. In patients with lymph node–positive disease undergoing neoadjuvant systemic therapy, nodal US can guide the approach to axillary surgery. A more personalized patient approach, taking into the account tumor biology, among other factors, may help to mitigate the controversy surrounding the role of axillary US in breast cancer patients.

Purpose: When patients with advanced cancer have minor children (age < 18), their health-related quality of life is closely linked to their concerns about the impact of progressive illness and death on their children. The Parenting Concerns Questionnaire (PCQ), a validated measure for parents with cancer, does not capture the full range of concerns in advanced cancer. The aim of this was study was to adapt and establish psychometrics for the PCQ for advanced disease (PCQ-AD). Methods: After generating an initial item-bank, we conducted concept elicitation interviews with clinicians (n = 8) and cognitive interviews with patients (n = 23) for face validity. New items addressed concerns about impact of parental death, making every moment count, communication, and financial impact of cancer on children. We administered 21 candidate items to 151 parents with advanced cancer. We conducted confirmatory factor analysis (CFA), calculated internal consistency, and assessed convergent and known-groups validity. Results: We removed 8 redundant items due to residual covariation between items. CFA of the 13-item PCQ-AD demonstrated satisfactory fit (CFI = 0.971, TLI = 0.966, RMSEA = 0.081) and high internal consistency (Cronbach’s alpha = 0.94, composite reliability = 0.95). The PCQ-AD demonstrated convergent validity and known-groups validity; patients with poor functional status reported higher scores than patients with better functional status (Cohen’s d = 0.56, p = 0.002). Conclusion: Adaptation of the PCQ yielded the addition of constructs important in advanced cancer. The PCQ-AD appears to be a reliable and valid measure of parenting concerns in advanced cancer, but future studies are needed to examine measure performance in diverse populations and responsiveness of the PCQ-AD to interventions.

This study describes the identification of two new mutations of the fibrinogen beta-chain in patients with inherited fibrinogen deficiency. Modelling of the impact of the mutations predict that these single amino acid substitutions are sufficient to abolish secretion of the mutant chains into the circulation, resulting in low fibrinogen levels in the patients. In addition, whole exome sequencing identified genetic modifiers for both patients which could contribute to the patients' global hemostatic function. Our results yield clinically relevant information for the personalised management of patients and eventually precision medicine for fibrinogen disorders.

Dizziness is a common complaint in otolaryngology clinics and can present a diagnostic challenge. A thorough history including onset, duration, and exacerbating and alleviating factors, along with physician persistence, can help differentiate between otologic and nonotologic forms of dizziness. An otologic and neurotologic physical examination, including vestibulo-ocular reflex and cranial nerve function evaluation and postural examination, can shed further light on symptom etiology. Otologic forms of dizziness often result in vertigo and may be associated with unilateral symptoms of hearing loss, aural fullness, or tinnitus. Primary causes of dizziness are more often constant and insidious in onset.

Retroperitoneale Weichgewebssarkome (RPS) umfassen Tumoren mesenchymalen Ursprungs mit teils gut charakterisierten, histologischen Subtypen und heterogener Prognose. Die STRASS-Studie, welche den Stellenwert einer neoadjuvanten Radiotherapie beim primaren RPS untersuchte, lieferte zum ersten Mal Daten in einer Phase-III-Studie. Das primare Ziel der vorliegenden Arbeit ist es, den Stellenwert der neoadjuvanten Strahlentherapie beim RPS nach Veroffentlichung der STRASS-Studie aufzuzeigen. Wir fuhrten eine nichtsystematische Literatursuche durch, die Ergebnisse retrospektiver Arbeiten wurden in Bezug zu der kurzlich erschienenen STRASS-Studie gesetzt. In den zwei grosten, die amerikanischen Datenbanken National Cancer Database (NCDB) und Surveillance, Epidemiology, and End Results Program (SEER) umfassenden Analysen konnte eine Verbesserung des Gesamtuberlebens durch die Radiotherapie beim RPS gezeigt werden. Entgegen diesen Ergebnissen fiel die STRASS-Studie fur den kombinierten Endpunkt des abdominal-rezidivfreien 3‑Jahres-Uberlebens negativ aus. Hier konnten lediglich initial ungeplante Subgruppenanalysen einen Trend fur einen Vorteil fur Liposarkome sowie niedriggradige Sarkome zeigen, welcher nicht fur Leiomyo- und hochgradige Sarkome nachgewiesen werden konnte. Auch bei so seltenen Tumoren wie den RPS ist eine randomisierte Studie wie die STRASS-Studie dank internationaler Kooperation moglich. Die Ergebnisse der STRASS-Studie haben den Stellenwert der neoadjuvanten Radiotherapie in der Gesamtheit der Behandlung von RPS relativiert. Ein langeres Follow-up ist insbesondere zur weiteren Beurteilung des Stellenwertes der Radiotherapie bei den Liposarkomen wunschenswert.

Bachmann-Bupp syndrome (BABS) is a rare syndrome caused by gain-of-function variants in the C-terminus of ornithine decarboxylase (ODC coded by the ODC1 gene). BABS is characterized by developmental delay, macrocephaly, macrosomia, and an unusual pattern of non-congenital alopecia. Recent diagnosis of four more BABS patients provides further characterization of the phenotype of this syndrome including late-onset seizures in the oldest reported patient at 23 years of age, representing the first report for this phenotype in BABS. Neuroimaging abnormalities continue to be an inconsistent feature of the syndrome. This may be related to the yet unknown impact of ODC/polyamine dysregulation on the developing brain in this syndrome. Variants continue to cluster, providing support to a universal biochemical mechanism related to elevated ODC protein, enzyme activity, and abnormalities in polyamine levels. Recommendations for medical management can now be suggested as well as the potential for targeted molecular or metabolic testing when encountering this unique phenotype. The natural history of this syndrome will evolve with difluoromethylornithine (DFMO) therapy and raise new questions for further study and understanding.

Background More patients with left-hemispheric than right-hemispheric strokes are admitted to hospitals. This is due to the easier recognition of cortical symptoms of the dominant-hemisphere. The thalamus constitutes a “micro-model” of the brain cortex with structure-function relationships known to be asymmetric, especially for language, memory, and visuo-spatial neurocognitive functions. The goal of this study was to characterize clinical symptoms and lesion distribution patterns of patients with acute isolated thalamic stroke (ITS) and to evaluate whether left-sided lesions are overrepresented in the hospital. Methods We performed a radiological database search including all brain scans performed in the Center of Neurology and Neurosurgery of the University Hospital Frankfurt between 2010 and 2019. A total of 5733 patients presenting with acute ischemic stroke were screened for ITS. Based on the MRI data, a lesion-overlap map was then generated to visualize the ITS lesion distribution. Results Fifty-eight patients with unilateral ITS were identified. A majority of 38 patients (65.5%) showed left-sided ITS, whereas only 20 patients (34.5%) had right-sided ITS (p = 0.012). A particular difference was found for ITS lesions in the anterior thalamus of the anterolateral (n = 10) and anteromedian (n = 3) vascular territory, which were located in the left thalamus in 85% of patients (p = 0.011). No distribution difference was found for ITS lesions in the inferomedial (n = 7), central (n = 8), inferolateral (n = 23) and posterior (n = 7) vascular territories. The neuropsychological symptoms of thalamic aphasia (n = 8), neurocognitive impairment (n = 6), behavioral changes (n = 2), neglect (n = 2) and memory deficits (n = 3) were described predominantly in patients with left-sided ITS (p Conclusions The better recognizability of left anterior compared to right anterior thalamic stroke symptoms may have an impact on the frequency in which ITS patients are admitted to the hospital. Clinical characteristics of right anterior thalamic stroke should therefore be further investigated, and diagnostic instruments towards their detection be identified.

Objective Web-based treatments address many of the logistical and stigma-related barriers to in-person behavioral health care. Prior studies of web-based treatments for posttraumatic stress disorder (PTSD) did not employ gold-standard treatments and have not compared to in-person therapy. Method We compared a web version of Prolonged Exposure Therapy, "Web-PE," to in-person Present-Centered Therapy (PCT) in a randomized controlled trial (RCT) with 40 military personnel with PTSD seeking treatment at Fort Hood, Texas. Due to recruitment challenges, we terminated the RCT and subsequently examined the effects of Web-PE in an uncontrolled open trial with 34 service members and veterans recruited nationwide. Both studies assessed PTSD, depressive symptoms, and health functioning at baseline and 1 and 3 months posttreatment; the RCT also included a 6-month assessment. Results Results of the RCT showed no differential impact for Web-PE and PCT, although more PCT participants achieved clinically significant change at one of the follow-up assessments. Both treatment conditions significantly reduced self-reported and blind independent interviewer-assessed symptoms of PTSD. Results of the open trial showed that Web-PE was associated with significant reductions in self-reported PTSD symptoms, with a much larger effect size than in the RCT. Conclusions Web-PE significantly reduced PTSD symptoms in both studies, although the reductions in PTSD symptoms were greater among open trial participants, who were specifically seeking a web-based treatment. Future research should evaluate Web-PE relative to another web-based treatment. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Background Cognitive diseases with Lewy bodies occur in two forms: dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD), which follows the progression of Parkinson's disease. There is currently no curative treatment for these cognitive diseases with Lewy bodies. Therapeutic trials in DLB are rare, due to the recent description of the disease as well as its first international diagnostic criteria (1996). Method This article proposes a synthesis of the therapeutic trials carried out in DLB in the last 5 years, including PDD patients with DLB patients, using the Clinicaltrials.gov and Pubmed.gov databases. Results We identified 35 therapeutic trials on Clinical Trials and 14 on PubMed. According to our temporal criteria, 21 trials were analyzed. Among the 11 completed trials with reported results, two molecules showed positive results: two trials with zonisamide (phase 2 and 3) showed a gain on parkinsonism and one trial with neflamapimod (phase 2) a gain on cognition and walking. Conclusion In recent years, there has been an increase in the therapeutic research effort in DLB, which is consistent with the prevalence of this disease - approximately 200,000 patients in France. Compared to other cognitive neurodegenerative diseases, therapeutic research is largely insufficient, whereas the proportion of positive trials is important. An effective disease modifying would have strong consequences for the patient and the relatives.

Objective The World Health Organization’s (WHO) Rehabilitation 2030 initiative is working to develop a set of evidence-based interventions selected from clinical practice guidelines for Universal Health Coverage. As an initial step, the WHO Rehabilitation Programme and Cochrane Rehabilitation convened global content experts to conduct systematic reviews of clinical practice guidelines for 20 chronic health conditions, including cerebral palsy. Data Sources Six scientific databases (Pubmed, EMBASE, Scopus, Web of Science, PEDro, CINAHL), Google Scholar, guideline databases, and professional society websites were searched. Study Selection A search strategy was implemented to identify clinical practice guidelines for cerebral palsy across the lifespan published within 10 years in English. Standardized spreadsheets were provided for process documentation, data entry, and tabulation of the Appraisal of Guidelines for Research and Evaluation (AGREE II) tool. Each step was completed by 2 or more group members, with disagreements resolved by discussion. Initially, 13 guidelines were identified. Five did not meet the AGREE II established threshold or criteria for inclusion. Further review by the WHO eliminated 3 more, resulting in 5 remaining guidelines. Data Extraction All 339 recommendations from the 5 final guidelines, with type (assessment, intervention, or service), strength, and quality of evidence, were extracted, and an International Classification of Functioning, Disability and Health Functioning (ICF) category was assigned to each. Data Synthesis Most guidelines addressed mobility functions, with comorbid conditions and lifespan considerations also included. However, most were at the level of body functions. No guideline focused specifically on physical or occupational therapies to improve activity and participation, despite their prevalence in rehabilitation. Conclusions Despite the great need for high quality guidelines, this review demonstrated the limited number and range of interventions and lack of explicit use of the ICF during development of guidelines identified here. A lack of guidelines, however, does not necessarily indicate a lack of evidence. Further evidence review and development based on identified gaps and stakeholder priorities are needed.

Contains fulltext : 249977.pdf (Publisher’s version ) (Closed access) BACKGROUND: It is important to evaluate whether a new treatment for heart failure with reduced ejection fraction (HFrEF) provides additive benefit to background foundational treatments. As such, we aimed to evaluate the efficacy and safety of empagliflozin in patients with HFrEF in addition to baseline treatment with specific doses and combinations of disease-modifying therapies. METHODS: We performed a post-hoc analysis of the EMPEROR-Reduced randomised, double-blind, parallel-group trial, which took place in 520 centres (hospitals and medical clinics) in 20 countries in Asia, Australia, Europe, North America, and South America. Patients with New York Heart Association (NYHA) classification II-IV with an ejection fraction of 40% or less were randomly assigned (1:1) to receive the addition of either oral empagliflozin 10 mg per day or placebo to background therapy. The primary composite outcome was cardiovascular death and heart failure hospitalisation; the secondary outcome was total heart failure hospital admissions. An extended composite outcome consisted of inpatient and outpatient HFrEF events was also evaluated. Outcomes were analysed according to background use of angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs) or angiotensin receptor neprilysin inhibitors (ARNIs), as well as β blockers and mineralocorticoid receptor antagonists (MRAs) at less than 50% or 50% or more of target doses and in various combinations. This study is registered with ClinicalTrials.gov, NCT03057977. FINDINGS: In this post-hoc analysis of 3730 patients (mean age 66·8 years [SD 11·0], 893 [23·9%] women; 1863 [49·9%] in the empagliflozin group, 1867 [50·1%] in the placebo group) assessed between March 6, 2017, and May 28, 2020, empagliflozin reduced the risk of the primary outcome (361 in 1863 participants in the empagliflozin group and 462 of 1867 in the placebo group; HR 0·75 [95% CI 0·65-0·86]) regardless of background therapy or its target doses for ACE inhibitors or ARBs at doses of less than 50% of the target dose (HR 0·85 [0·69-1·06]) and for doses of 50% or more of the target dose (HR 0·67 [0·52-0·88]; p(interaction)=0·18). A similar result was seen for β blockers at doses of less than 50% of the target dose (HR 0·66 [0·54-0·80]) and for doses of 50% or more of the target dose (HR 0·81 [0·66-1·00]; p(interaction)=0·15). Empagliflozin also reduced the risk of the primary outcome irrespective of background use of triple therapy with an ACE inhibitor, ARB, or ARNI plus β blocker plus MRA (given combination HR 0·73 [0·61-0·88]; not given combination HR 0·76 [0·62-0·94]; p(interaction)=0·77). Similar patterns of benefit were observed for the secondary and extended composite outcomes. Empagliflozin was well tolerated and rates of hypotension, symptomatic hypotension, and hyperkalaemia were similar across all subgroups. INTERPRETATION: Empagliflozin reduced serious heart failure outcomes across doses and combinations of disease-modifying therapies for HFrEF. Clinically, these data suggest that empagliflozin might be considered as a foundational therapy in patients with HFrEF regardless of their existing background therapy. FUNDING: Boehringer Ingelheim and Eli Lilly and Company.

Zusammenfassung Hintergrund Kraniomandibuläre Dysfunktionen (CMD) können auch im hohen Alter auftreten. Die Prävalenz von CMD-Symptomen bei Senioren wurde bisher nur wenig untersucht. Ziel der Arbeit Ziel dieser Untersuchung war es, die Prävalenz von Symptomen einer CMD bei Senioren nach Befunderhebung mit den Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD) zu bestimmen. Dabei sollten die Prävalenzwerte von jüngeren (60 bis 74 Jahren) und älteren (≥ 75 Jahre) Senioren verglichen werden. Material und Methoden Im Rahmen der Interdisziplinären Längsschnittstudie des Erwachsenenalters (ILSE) wurden Probanden nach repräsentativen Gesichtspunkten rekrutiert. Während der vierten Nachverfolgungswelle im Zeitraum von 2014 bis 2016 im Bereich des Studienzentrums Leipzig wurden die Probanden auf das Vorliegen von anamnestischen und klinischen CMD-Symptomen untersucht. Ergebnisse Anamnestische CMD-Symptome bei Senioren (n = 192) waren v. a. durch Schmerzen im Gesichtsbereich (13,0 %) gekennzeichnet. Das häufigste klinische CMD-Symptom waren Kiefergelenkgeräusche mit einer Prävalenz bis zu 35,5 %. Frauen gaben anamnestisch häufiger Kopfschmerzen/Migräne an. Kiefergelenkgeräusche und eine limitierte Mundöffnung wurden klinisch häufiger bei weiblichen Teilnehmenden beobachtet. Statistisch signifikante Unterschiede zeigten sich bei dem Vergleich von jüngeren und älteren Senioren hinsichtlich der Prävalenz von Kopfschmerzen/Migräne, jedoch nicht bei klinischen Symptomen. Schlussfolgerung Anamnestisch werden Gesichtsschmerzen von 13,0 % der Senioren angegeben. Kiefergelenkgeräusche werden bei jedem dritten Älteren klinisch beobachtet. CMD-Symptome scheinen bei jüngeren und älteren Senioren im ähnlichen Maße ausgeprägt zu sein.

Craniocervical abnormalities in osteogenesis imperfecta (OI) such as basilar invagination or cervical kyphosis can cause severe neurological morbidity. These abnormalities may be more frequent in OI type V compared with other OI subtypes of similar disease severity, underlining the importance of screening in this group. Craniocervical abnormalities in osteogenesis imperfecta (OI) can cause severe neurological morbidity. Although radiological cranial base abnormalities in OI have been well described in the literature, there are limited data on these abnormalities in OI type V and their association with clinical sequelae. A retrospective case series on patients with craniocervical abnormalities in OI type V at our institution. Craniocervical abnormalities were present in 7 of 37 patients with OI type V (19%). For 5 patients (age at last follow-up: 5 to 26 years; 2 females), sufficient information was available for inclusion in the case series. All had genetically confirmed OI type V. Age range at diagnosis of the craniocervical abnormality was 1 day to 18 years. Basilar invagination was present in 3 patients; 2 had cervical kyphosis. Dysplasia of upper cervical vertebrae or base of skull was seen in 3 patients. The severity of the craniocervical abnormality did not clearly correlate with the severity of the OI phenotype. Three patients required surgical intervention (ages 7, 11, and 26 years) due to compression of the spinal cord or brainstem. Craniocervical abnormalities were detected incidentally or on screening in 3 patients, and only 2 had significant positive findings on neurological examination. A variety of craniocervical abnormalities are seen in OI type V including dysplasia of the cervical vertebrae. These cases highlight the importance of screening patients with OI type V with lateral skull and cervical spine x-rays throughout childhood and after skeletal maturity.

Objective To describe the effect of robotic locomotor training (RLT) and activity-based training (ABT) on cardiovascular indices during various physiological positions in individuals with spinal cord injury. Design Randomized controlled pilot study. Setting Private practice: Therapy & Beyond Centre - Walking with Brandon Foundation, Sports Science Institute of South Africa, Cape Town, South Africa. Participants Participants with chronic traumatic motor incomplete tetraplegia (N=16) who resided in the Western Cape, South Africa. Intervention Robotic locomotor training (Ekso GT) and activity-based training over a 24-week intervention. Main Outcome Measures Brachial and ankle blood pressure, heart rate, heart rate variability, and cardiovascular efficiency during 4 physiological positions. Results No differences between groups or over time were evident in resting systolic and diastolic blood pressure, ankle systolic pressure, ankle brachial pressure index, and heart rate variability. Standing heart rate at 24 weeks was significantly higher in the ABT group (95.58±12.61 beats/min) compared with the RLT group (75.14±14.96 beats/min) (P=.05). In the RLT group, no significant changes in heart rate variability (standard deviation R-R interval and root mean square of successive differences) was found between the standing and 6-minute walk test physiological positions throughout the intervention. Cardiovascular efficiency in the RLT group during the 6-minute walk test improved from 11.1±2.6 at baseline to 7.5±2.8 beats per meter walked at 6 weeks and was maintained from 6 to 24 weeks. Conclusions Large effect sizes and significant differences between groups found in this pilot study support the clinical effectiveness of RLT and ABT for changing cardiovascular indices as early as 6 weeks and up to 24 weeks of rehabilitation. RLT may be more effective than ABT in improving cardiac responses to orthostatic stress. Based on heart rate variability metrics, the stimulus of standing has comparable effects to RLT on the parasympathetic nervous system. Cardiovascular efficiency of exoskeleton walking improved, particularly over the first 6 weeks. Both the RLT and ABT interventions were limited in their effect on brachial and ankle blood pressure. A randomized controlled trial with a larger sample size is warranted to further examine these findings.

The onset of the COVID‐19 pandemic disrupted many aspects of daily life and required a rapid and unprecedented shift in psychotherapy delivery from in‐person to telemental health. In the present study, we explored the impact of the pandemic on individuals’ ability to participate in posttraumatic stress disorder (PTSD) psychotherapy and the association between the impact of COVID‐19 impact on health and financial well‐being and psychotherapy participation. Participants (N = 161, 63.2% male, M age = 42.7 years) were United States military veterans (n = 108), active duty military personnel (n = 12), and civilians (n = 6), who were participating in one of nine PTSD treatment trials. The results indicate a predominately negative COVID‐19 impact on therapy participation, although some participants (26.1%) found attending therapy sessions through telehealth to be easier than in‐person therapy. Most participants (66.7%) reported that completing in vivo exposure homework became harder during the pandemic. Moreover, the impact of the pandemic on PTSD symptom severity and daily stress were each associated with increased difficulty with aspects of therapy participation. The findings highlight the unique challenges to engaging in PTSD treatment during the pandemic as well as a negative impact on daily stress and PTSD severity, both of which were related to treatment engagement difficulties.

Sludge recirculation mixing in anaerobic digesters is essential for the stable operation of the digestion process. While often neglected, the configuration of the sludge inlet has a substantial influence on the efficiency of the mixing process. The fluid is either injected directly into the enclosed fluid domain or splashes onto the free surface of the slurry flow. In this paper, the aim was to investigate the effect of the inlet configuration by means of computational fluid dynamics—using ANSYS Fluent. Single-phase and multi-phase models are applied for a submerged and splashing inlet, respectively. To reduce the high computational demand, we also develop surrogate single-phase models for the splashing inlet. The digester mixing is analyzed by comparing velocity contours, velocity profiles, mixing time and dead volume. The non-Newtonian characteristics of the sludge is considered, and a $$k-\varepsilon $$ k - ε model is employed for obtaining turbulence closure. Our method is validated by means of a previous study on the same geometry. Applying a submerged inlet configuration, the resulting dead volume in the tank is estimated around 80 times lower than for the case of a splashing inlet. Additionally, by emulating the multi-phase model for splashing inlet configurations with a single-phase one, the simulation clock time reduced to 15%.

Purpose: Increasing tumor-infiltrating lymphocytes (TIL) is associated with higher rates of pathologic complete response (pCR) to neoadjuvant therapy (NAT) in patients with triple-negative breast cancer (TNBC). However, the presence of TILs does not consistently predict pCR, therefore, the current study was undertaken to more fully characterize the immune cell response and its association with pCR. Experimental Design: We obtained pretreatment core-needle biopsies from 105 patients with stage I–III TNBC enrolled in ARTEMIS (NCT02276443) who received NAT from Oct 22, 2015 through July 24, 2018. The tumor-immune microenvironment was comprehensively profiled by performing T-cell receptor (TCR) sequencing, programmed death-ligand 1 (PD-L1) IHC, multiplex immunofluorescence, and RNA sequencing on pretreatment tumor samples. The primary endpoint was pathologic response to NAT. Results: The pCR rate was 40% (42/105). Higher TCR clonality (median = 0.2 vs. 0.1, P = 0.03), PD-L1 positivity (OR: 2.91, P = 0.020), higher CD3+:CD68+ ratio (median = 14.70 vs. 8.20, P = 0.0128), and closer spatial proximity of T cells to tumor cells (median = 19.26 vs. 21.94 μm, P = 0.0169) were associated with pCR. In a multivariable model, closer spatial proximity of T cells to tumor cells and PD-L1 expression enhanced prediction of pCR when considered in conjunction with clinical stage. Conclusions: In patients receiving NAT for TNBC, deep immune profiling through detailed phenotypic characterization and spatial analysis can improve prediction of pCR in patients receiving NAT for TNBC when considered with traditional clinical parameters.

The knowledge of electronic properties of matter is the key to the understanding of its properties and to propose useful applications. To model hybrid organic/inorganic systems with the plane-wave approach, large supercells with many atoms are usually necessary to minimize artificial interactions between periodic images. For such systems, accurate approximations to the exchange-correlation functional of density functional theory, such as hybrid functionals, become computationally expensive, and cheaper approaches need to be considered. Here, we apply the local modified Becke-Johnson exchange-correlation potential to free molecules and surfaces and study its accuracy for calculated ionization potentials. This quantity being important to understand the band alignment of composite heterogeneous systems, we demonstrate the application of the potential to the electronic structure calculation of an exemplary composite semiconductor/molecule system, namely, a F6-TCNNQ molecule adsorbed on a hydrogenated Si(111) surface.

BACKGROUND The literature on white matter anatomy underlying the human orbitofrontal cortex (OFC) is scarce in spite of its relevance for glioma surgery. OBJECTIVE To describe the anatomy of the OFC and of the underlying white matter fiber anatomy, with a particular focus on the surgical structures relevant for a safe and efficient orbitofrontal glioma resection. Based on anatomical and radiological data, the secondary objective was to describe the growth pattern of OFC gliomas. METHODS The study was performed on 10 brain specimens prepared according to Klingler's protocol and dissected using the fiber microdissection technique modified according to U.T., under the microscope at high magnification. RESULTS A detailed stratigraphy of the OFC was performed, from the cortex up to the frontal horn of the lateral ventricle. The interposed neural structures are described together with relevant neighboring topographic areas and nuclei. Combining anatomical and radiological data, it appears that the anatomical boundaries delimiting and guiding the macroscopical growth of OFC gliomas are as follows: the corpus callosum superiorly, the external capsule laterally, the basal forebrain and lentiform nucleus posteriorly, and the gyrus rectus medially. Thus, OFC gliomas seem to grow ventriculopetally, avoiding the laterally located neocortex. CONCLUSION The findings in our study supplement available anatomical knowledge of the OFC, providing reliable landmarks for a precise topographical diagnosis of OFC lesions and for perioperative orientation. The relationships between deep anatomic structures and glioma formations described in this study are relevant for surgery in this highly interconnected area.

PUPs B-LONG evaluated the safety and efficacy of recombinant factor IX Fc fusion protein (rFIXFc) in previously untreated patients (PUPs) with hemophilia B. In this open-label, phase 3 study, male PUPs (age 85%) bleeding episodes required only 1 infusion for bleed resolution. In this first study reporting results with rFIXFc in pediatric PUPs with hemophilia B, rFIXFc was well tolerated, with the adverse event profile as expected in a pediatric hemophilia population. rFIXFc was effective, both as prophylaxis and in the treatment of bleeding episodes. This trial was registered at www.clinicaltrials.gov as #NCT02234310.

While there is broad evidence to suggest that individual stress increases, and that high couple relationship quality reduces the risk for psychological distress, our understanding of these associations in couples dealing with infertility remains limited. In this cross-sectional study, we used dyadic data-analysis (Actor-Partner Interdependence Model; APIM) to examine the effects of infertility-related distress (experienced as an individual risk factor) and couple relationship quality (experienced as a couple-based resource), on psychological distress in a sample of 116 infertile couples. 59% of women and 23% of men reported clinical levels of psychological distress, 71% of women and 45% of men reported infertility-related distress, and 3% of participants reported low couple relationship quality. Infertility-related distress predicted psychological distress at the individual level ('actor effects') while men's infertility-related distress predicted women's psychological distress (partner effect'). Women without medically assisted reproduction (MAR) treatment exposure reported significantly higher couple relationship quality than women with MAR exposure, and men without treatment exposure reported significantly lower infertility-related distress than men with exposure. The level of psychological distress depended on whether both or neither of the partners, or only one partner reported infertility-related distress. Couple relationship quality was not associated with distress, which may imply that dyadic dimensions other than overall satisfaction could be relevant in supporting couples facing infertility.

CSNK2B has recently been implicated as a disease gene for neurodevelopmental disability (NDD) and epilepsy. Information about developmental outcomes has been limited by the young age and short follow-up for many of the previously reported cases, and further delineation of the spectrum of associated phenotypes is needed. We present 25 new patients with variants in CSNK2B and refine the associated NDD and epilepsy phenotypes. CSNK2B variants were identified by research or clinical exome sequencing, and investigators from different centers were connected via GeneMatcher. Most individuals had developmental delay and generalized epilepsy with onset in the first 2 years. However, we found a broad spectrum of phenotypic severity, ranging from early normal development with pharmacoresponsive seizures to profound intellectual disability with intractable epilepsy and recurrent refractory status epilepticus. These findings suggest that CSNK2B should be considered in the diagnostic evaluation of patients with a broad range of NDD with treatable or intractable seizures.

Purpose According to the principle of equivalence of care, health care in prison has to be of the same standard and quality as in the general population. This study aims to determine the geographic accessibility of dialysis services for older prisoners and the older general population in Switzerland and whether accessibility and availability of dialysis care are equivalent. Design/methodology/approach Spatial accessibility analysis incorporated four different data types: population data, administrative data, street network data and addresses of prisons and hemodialysis services. Findings Analysis revealed that the average travel time to the nearest dialysis service was better for prisoners (11.5 min) than for the general population (14.8 min). However, dialysis service for prisoners is hampered by the necessary lead-time in correctional settings, which, ultimately, leads to longer overall access times (36.5 min). Accordingly, the equivalence of dialysis care for older Swiss prisoners is not entirely respected for availability and accessibility. Originality/value The strength of the study lies in the combination of ethical principles and the highly tangible results of a spatial accessibility analysis. The ethics-driven empirical analysis provides arguments for policy-makers to review the current practices.

ZusammenfassungGliflozine (Inhibitoren der „sodium-dependent glucose cotransporter“, SGLT) sind Arzneistoffe, die ursprünglich zur Behandlung des Diabetes mellitus eingesetzt und der Gruppe der Antidiabetika zugeordnet wurden. Seit November 2020 ist mit Dapagliflozin erstmalig ein SGLT2-Inhibitor zur Behandlung von Patienten mit Herzinsuffizienz (mit reduzierter linksventrikulärer Funktion), unabhängig vom Diabetesstatus, zugelassen worden. Das Präparat Empagliflozin hat gerade – im Juni 2021 – von der europäischen Arzneimittelbehörde (EMA) eine Zulassung für die Therapie der Herzinsuffizienz mit reduzierter Ejektionsfraktion erhalten. Somit stehen verschiedene Gliflozine nicht nur zur Behandlung des Diabetes mellitus, sondern auch der Herzinsuffizienz zur Verfügung. Der vorliegende Beitrag vermittelt Grundlagenkenntnisse zu den Gliflozinen und bietet eine Übersicht zur ihrer Bedeutung sowohl in der Behandlung des Diabetes mellitus Typ 2 als auch aufgrund ihrer kardio- und nephroprotektiven Funktion.

Additive Manufacturing (AM), consists of depositing material in successive layers to obtain the desired part. The parts produced by AM can thus adopt geometries inaccessible by conventional manufacturing means, for example hollow or lattice structures which considerably reduce their weight while keeping or even improving their mechanical properties. Among the many existing processes, Wire Arc Additive Manufacturing (WAAM) is particularly well suited to the manufacture of large metallic parts. It is characterized by a supply of heat in the form of an electric arc (produced by a welding generator) and a supply of material in the form of wire. This paper will discuss the impact of additive manufacturing to enhance the performances of high value components, based on naval application: the manufacturing of a hollow propeller blade demonstrator of 1.5 m high realized in the laboratory.

BackgroundInternet cognitive behavioural therapy (iCBT) is a viable delivery format of CBT for depression. However, iCBT programmes include training in a wide array of cognitive and behavioural skills via different delivery methods, and it remains unclear which of these components are more efficacious and for whom.MethodsWe did a systematic review and individual participant data component network meta-analysis (cNMA) of iCBT trials for depression. We searched PubMed, PsycINFO, Embase, and the Cochrane Library for randomised controlled trials (RCTs) published from database inception to Jan 1, 2019, that compared any form of iCBT against another or a control condition in the acute treatment of adults (aged ≥18 years) with depression. Studies with inpatients or patients with bipolar depression were excluded. We sought individual participant data from the original authors. When these data were unavailable, we used aggregate data. Two independent researchers identified the included components. The primary outcome was depression severity, expressed as incremental mean difference (iMD) in the Patient Health Questionnaire-9 (PHQ-9) scores when a component is added to a treatment. We developed a web app that estimates relative efficacies between any two combinations of components, given baseline patient characteristics. This study is registered in PROSPERO, CRD42018104683.FindingsWe identified 76 RCTs, including 48 trials contributing individual participant data (11 704 participants) and 28 trials with aggregate data (6474 participants). The participants' weighted mean age was 42·0 years and 12 406 (71%) of 17 521 reported were women. There was suggestive evidence that behavioural activation might be beneficial (iMD −1·83 [95% credible interval (CrI) −2·90 to −0·80]) and that relaxation might be harmful (1·20 [95% CrI 0·17 to 2·27]). Baseline severity emerged as the strongest prognostic factor for endpoint depression. Combining human and automated encouragement reduced dropouts from treatment (incremental odds ratio, 0·32 [95% CrI 0·13 to 0·93]). The risk of bias was low for the randomisation process, missing outcome data, or selection of reported results in most of the included studies, uncertain for deviation from intended interventions, and high for measurement of outcomes. There was moderate to high heterogeneity among the studies and their components.InterpretationThe individual patient data cNMA revealed potentially helpful, less helpful, or harmful components and delivery formats for iCBT packages. iCBT packages aiming to be effective and efficient might choose to include beneficial components and exclude ones that are potentially detrimental. Our web app can facilitate shared decision making by therapist and patient in choosing their preferred iCBT package.FundingJapan Society for the Promotion of Science.

Objectives To report the results of the systematic search performed to identify interventions and related evidence for rehabilitation of individuals with amputation based on the current evidence from clinical practice guidelines (CPG). Data Sources Pubmed, Pedro, CINAHL, Embase, Google Scholar, and multiple guideline databases (date restriction, 2008-2018). Study Selection Exclusion criteria were no CPG, not reporting on rehabilitation, published before 2008, developed for health conditions other than amputation, presence of conflict of interest (financial or nonfinancial), lack of information on the strength of the recommendation, and lack of quality assessed by the “Appraisal of Guidelines for Research and Evaluation.” Data Extraction Data extraction was done using a standardized form, which comprised information on the recommendation, the strength of recommendation and the quality of the evidence used to inform the recommendation. Data Synthesis We included 4 guidelines, providing a total of 217 recommendations (20 on assessments, 131 on interventions, and 66 on service provision). Most recommendations concerned pain management, education, pre- and postoperative management, and residual limb care. The strength of recommendation was generally weak to intermediate. The level of evidence mostly compromised expert opinions, with only 6.9% (15 of 217) being provided by randomized controlled trials, systematic reviews, or meta-analyses. Conclusions The field of amputation is well covered for recommended interventions, but the level of evidence is generally low and is based mostly on expert opinion. Some important domains are not covered (eg, vocation and education, sexual and/or intimate relationships, activities of daily living or leisure activities, education concerning socket/liner fitting). There is also a lack of description of the contents of training and rehabilitation programs. This should be taken into account for the development of future guidelines.

Background The Cochlear™ Osia® System leaves a retroauricular bump that can cause discomfort and poor aesthetic outcome. Method To reduce the retroauricular bump, we introduced an implant well in the bone behind the ear for the transducer. We used cutting and diamond drills to create the implant well with an average depth of 4–5 mm. The surgical time including the implant well (40 min) was within the range of reported average surgical time (52 min). Conclusion Introduction of an implant well resulted in a better aesthetic outcome and improved patients’ comfort. The reduced distance between BI300 and ear canal might improve audiological outcome.

The aim of this study was to evaluate the hearing outcome of cochlear implantation in patients deafened by Ménière's disease.Retrospective single-institution study.Tertiary medical center.Our institutional database of 1400 patients with cochlear implants was reviewed to identify cases with deafness due to Ménière's disease. Twenty-nine patients were identified: 24 with unilateral and 5 with sequential bilateral cochlear implants. Pre- and postoperative speech recognition scores and medical data were extracted from the medical record and analyzed.Overall the mean difference between pre- and postoperative speech recognition after1 year was 56% (95% CI, 47.08%-64.92%). The mean preoperative monosyllabic word score was 9.5%, and the mean postoperative scores at 1 month, 3 months, 6 months, 1 year, and1 year were 37.1%, 46.1%, 54.1%, 59.1%, and 66.8%, respectively. Cochlear implantation resulted in improved word scores in all patients regardless of prior medical or surgical treatment (endolymphatic sac, labyrinthectomy). The mean postoperative hearing improvement in patients aged70 and ≥70 years was 65.26% (95% CI, 54.79%-75.73%) and 40.00% (95% CI, 27.22%-52.77%). Postoperative word scores in patients with bilateral cochlear implants were not significantly different between the first and second implanted ears or between the monoaural and binaural testing conditions.Cochlear implant in patients deafened by Ménière's disease significantly improves word recognition scores regardless of whether medical or surgical treatment is used prior to implantation. The potential improvement in word recognition scores decreases after age 70 years.

IRET During the ongoing coronavirus disease (COVID-19) pandemic, farmworkers in the United States are consid ered essential personnel and continue in-person work. We conducted prospective surveillance for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and antibody prevalence among farmwork ers in Salinas Valley, California, during June 15–No vember 30, 2020. We observed 22.1% (1,514/6,864) positivity for SARS-CoV-2 infection among farmwork ers compared with 17.2% (1,255/7,305) among other adults from the same communities (risk ratio 1.29, 95% CI 1.20–1.37). In a nested study enrolling 1,115 farm workers, prevalence of current infection was 27.7% among farmworkers reporting >1 COVID-19 symptom and 7.2% among farmworkers without symptoms (ad justed odds ratio 4.16, 95% CI 2.85–6.06). Prevalence of SARS-CoV-2 antibodies increased from 10.5% (95% CI 6.0%–18.4%) during July 16–August 31 to 21.2% (95% CI 16.6%–27.4%) during November 1–30. High SARS-CoV-2 infection prevalence among farmworkers underscores the need for vaccination and other pre ventive interventions. Durante la pandemia actual de la enfermedad por coronavirus (COVID-19), los trabajadores agrícolas en los Estados Unidos son considerados personal esencial y continúan trabajando en persona. Realizamos una vigilancia prospectiva de la infección por coronavirus 2 (SARS-CoV-2) del síndrome respiratorio agudo severo y la prevalencia de anticuerpos entre los trabajadores agrícolas en Salinas Valley, California, del 15 de junio al 30 de noviembre de 2020. Observamos 22.1% (1,514 / 6,864) positividad para la infección por SARS-CoV-2 entre los trabajadores agrícolas en comparación con el 17.2% (1.255 / 7.305) entre otros adultos de las mismas comunidades (razón de riesgo 1.29, IC del 95%: 1.20–1.37). En un estudio anidado que inscribió a 1115 trabajadores agrícolas, la prevalencia de la infección actual fue del 27,7% entre los trabajadores agrícolas que informaron> 1 síntoma de COVID-19 y del 7,2% entre los trabajadores agrícolas sin síntomas (razón de probabilidades ajustada 4,16, IC del 95%: 2,85–6,06). La prevalencia de anticuerpos contra el SARS-CoV-2 aumentó del 10,5% (IC del 95%: 6,0% al 18,4%) del 16 de julio al 31 de agosto al 21,2% (IC del 95%: 16,6% al 27,4%) del 1 al 30 de noviembre. La alta prevalencia de la infección por SARS-CoV-2 entre los trabajadores agrícolas subraya la necesidad de vacunación y otras intervenciones preventivas. Universidad de California, Estados Unidos. Universidad Nacional, Costa Rica. Clínica de Salud del Valle de Salinas, Estados Unidos. Escuela de Higiene y Medicina Tropical de Londres, Reino Unido. Universidad de Arizona, Estados Unidos. Instituto Regional de Estudios en Sustancias Tóxicas

OBJECTIVES We previously demonstrated an association between tenofovir disoproxil fumarate (TDF) and chronic liver enzyme elevation in the D:A:D study. The objective of the study was to assess changes in alanine aminotransferase (ALT) levels after switching from TDF to tenofovir alafenamide (TAF). METHODS We included Swiss HIV Cohort Study participants who switched from TDF to TAF with two or more ALT values in the 24 months before and two or more values in the 24 months after replacing TDF with TAF. Individuals with replicating viral hepatitis were excluded. Uni- and multivariable linear mixed models were used to explore changes in ALT values associated with switching from TDF to TAF, and to assess potential modifying effects. RESULTS A total of 1712 participants were included, contributing 6169 ALT values before and 5482 after switching. Median (interquartile range, IQR) age was 50 (42-57) years, and 75% were male. Median (IQR) ALT was 28 (22-38) U/L before and 24 (19-32) U/L after replacing TDF with TAF. ALT values decreased by 3.7 U/L (95% confidence interval: 3.2-4.2) after the switch. The median drop was larger in patients with chronic ALT elevation (defined as two or more elevated values for ≥ 6 months) compared with patients with normal ALT values (17.8 vs. 3.3 U/L, P