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Posttraumatic stress disorder (PTSD) and traumatic brain injury (TBI) demonstrate high prevalence and comorbidity among post-9/11 veterans. Veterans with this comorbidity often present with multiple co-occurring healthcare needs and increased clinical complexity. The current case report describes the clinical presentation of a veteran with mild TBI and PTSD, both before, during, and after treatment within a multidisciplinary 2-week intensive outpatient program involving prolonged exposure, evidence-based PTSD treatment, and Cognitive Symptom Management and Rehabilitation Therapy, evidence-based treatment for postconcussive symptoms. Mr. A was a 25-year-old White, transgender male who presented with a complex mental health history. At intake, presenting complaints included anxiety, panic attacks, nightmares, and depression secondary to military sexual trauma, as well as reported cognitive difficulties secondary to a concussion. He met current criteria for PTSD as well as panic disorder with agoraphobia. Head injury history consisted of a motor vehicle collision with less than 30 seconds loss of consciousness, brief posttraumatic amnesia, and alterations of consciousness. Mr. A demonstrated habituation during individual exposure sessions as assessed via skin conductance during imaginal exposures and decreased subjective ratings during in vivo exposures, as well as a decrease in trauma-potentiated startle response to trauma cues. Posttreatment data indicates significant reduction in neurobehavioral, posttraumatic stress, and depression symptoms and significant improvement in subjective cognitive functioning. The current findings support the feasibility and efficacy of short-term integrated treatment for complex clinical presentations and the need for larger scale research investigating combined PTSD and TBI intervention.

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.

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.

Mild traumatic brain injury (mTBI) and posttraumatic stress disorder (PTSD) are pervasive consequences of the post-9/11 conflicts. Treatment of PTSD and mTBI has historically occurred separately and sequentially, which does not reflect the overlapping etiology of symptoms and may attenuate or delay recovery. This paper describes an integrated 2-week treatment program using prolonged exposure and cognitive symptom management and rehabilitation therapy to comprehensively treat PTSD and cognitive complaints attributed to mTBI, regardless of etiology. To minimize potential iatrogenic effects of treating presumed mTBI-related symptoms, a central focus of the program was to instill expectations of full recovery. Thirty patients with full or subclinical PTSD and self-reported TBI history completed the PTSD+TBI treatment program. Results indicated that self-reported PTSD, depression, and neurobehavioral symptoms significantly decreased following treatment, while satisfaction with participation in social roles increased. These preliminary effectiveness data indicate that PTSD complicated by mTBI history can be effectively treated within a 2-week intensive outpatient program.

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).

Early transcribed membrane proteins form a unique protein family in malaria parasites. These molecules are expressed during Plasmodium intracellular phases and inserted at the parasite parasitophorus vacuole membrane, which constitutes the host–parasite interface. Upregulated in infectious sporozoites 4 (UIS4) is an essential early transcribed membrane protein of liver stages of the murine malaria model parasite Plasmodium berghei. Despite its relevance for liver stage maturation, the molecular functions of UIS4 remain elusive, and UIS4 orthologs in human malaria parasites have not yet been identified. In order to characterise functional domains of UIS4, we generated P. berghei parasites carrying a carboxy-terminally truncated version of UIS4. We observed that uis4Δc parasites are severely impaired in liver stage development, similar to uis4(−) parasites, indicating an important role of the C-terminal domain for UIS4 function. To test whether members of the P. falciparum early transcribed membrane protein family are potential UIS4 orthologs, we selected candidates based on structural homology and parasitophorous vacuole membrane localization. We generated transgenic P. berghei parasites where UIS4 was replaced by Plasmodium falciparum ETRAMP8 or ETRAMP10.3. Both early transcribed membrane proteins were expressed in transgenic parasite lines, but liver stage maturation was impaired, indicating that the selected early transcribed membrane proteins failed to substitute the function of UIS4. As a control, we included the UIS4 ortholog from the murine parasite Plasmodium chaubaudi. We observed that PcUIS4 successfully restores UIS4 function in P. berghei. Together, these results suggest that Plasmodium parasites express tailor-made parasitophorous vacuole membrane proteins that might at least partially explain the narrow host range of malaria parasites.

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.

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...

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.

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.

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.

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.

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.

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.

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.

Background Gilles de la Tourette Syndrome (GTS) is a neurodevelopmental disorder with a peak of symptom severity around late childhood and early adolescence. Previous findings in adult GTS suggest that changes in perception-action integration, as conceptualized in the theory of event coding framework, are central for the understanding of GTS. However, the neural mechanisms underlying these processes in adolescence are elusive. Methods A total of 59 children/adolescents aged 9 to 18 years (n = 32 with GTS, n = 27 typically developing youths) were examined using a perception-action integration task (event file task) derived from the theory of event coding. Event-related electroencephalogram recordings (theta and beta band activity) were analyzed using electroencephalogram–beamforming methods. Results Behavioral data showed robust event file binding effects in both groups without group differences. Neurophysiological data showed that theta and beta band activity were involved in event file integration in both groups. However, the functional neuroanatomical organization was markedly different for theta band activity between the groups. The typically developing group mainly relied on superior frontal regions, whereas the GTS group engaged parietal and inferior frontal regions. A more consistent functional neuroanatomical activation pattern was observed for the beta band, engaging inferior parietal and temporal regions in both groups. Conclusions Perception-action integration processes lag behind in persisting GTS but not in the GTS population as a whole, underscoring differences in developmental trajectories and the importance of longitudinal investigations for the understanding of GTS. The findings corroborate known differences in the functional/structural brain organization in GTS and suggest an important role of theta band activity in these patients.

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.

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.

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.

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.

Protease-activated receptor 1 (PAR1) is widely expressed in humans and mice, and is activated by a variety of proteases, including thrombin. Recently, we showed that PAR1 contributes to the innate immune response to viral infection. Mice with a global deficiency of PAR1 expressed lower levels of CXCL10 and had increased Coxsackievirus B3 (CVB3)-induced myocarditis compared with control mice. In this study, we determined the effect of cell type-specific deletion of PAR1 in cardiac myocytes (CMs) and cardiac fibroblasts (CFs) on CVB3-induced myocarditis. Mice lacking PAR1 in either CMs or CFs exhibited increased CVB3 genomes, inflammatory infiltrates, macrophages and inflammatory mediators in the heart and increased CVB3-induced myocarditis compared with wild-type controls. Interestingly, PAR1 enhanced poly I:C induction of CXCL10 in rat CFs but not in rat neonatal CMs. Importantly, activation of PAR1 reduced CVB3 replication in murine embryonic fibroblasts and murine embryonic cardiac myocytes. In addition, we showed that PAR1 reduced autophagy in murine embryonic fibroblasts and rat H9c2 cells, which may explain how PAR1 reduces CVB3 replication. These data suggest that PAR1 on CFs protects against CVB3-induced myocarditis by enhancing the anti-viral response whereas PAR1 on both CMs and fibroblasts inhibits viral replication.

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.

Roy, Steven, Inigo Soteras, Alison Sheets, Richard Price, Kazue Oshiro, Simon Rauch, Don McPhalen, Maria Antonia Nerin, Giacomo Strapazzon, Myron Allen, Alistair Read, and Peter Paal. Guidelines for mountain rescue during the COVID-19 pandemic: official guidelines of the International Commission for Alpine Rescue. High Alt Med Biol. 22: 128–141, 2021. Background: In mountain rescue, uncertainty exists on the best practice to prevent coronavirus disease 2019 (COVID-19) transmission. The aim of this work was to provide a state-of-the-art overview of the challenges caused by the COVID-19 pandemic in mountain rescue. Methods: Original articles or reviews, published until December 27, 2020 in Cochrane COVID-19 Study Register, EMBASE, PubMed, and Google Scholar were included. Articles were limited to English, French, German, or Spanish with the article topic COVID-19 or other epidemics, addressing transmission, transport, rescue, or cardiopulmonary resuscitation. Results: The literature search yielded 6,190 articles. A total of 952 were duplicates and 5,238 were unique results. After exclusion of duplicates and studies that were not relevant to this work, 249 articles were considered for this work. Finally, 72 articles and other sources were included. Conclusions: Recommendations are provided for protection of the rescuer (including screening, personal protective equipment [PPE], and vaccination), protection of the patient (including general masking if low risk, specific PPE if high risk), equipment hygiene (including disinfection after every mission), use of single-use products, training and medical measures under COVID-19 precautions, and psychological wellbeing of rescuers during the COVID-19 pandemic. Adapted COVID-19 precautions for low-and-medium-income countries are also discussed.

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.

Located in the critical 1p36 microdeletion region, the chromodomain helicase DNA-binding protein 5 (CHD5) gene encodes a subunit of the nucleosome remodeling and deacetylation (NuRD) complex required for neuronal development. Pathogenic variants in six of nine chromodomain (CHD) genes cause autosomal dominant neurodevelopmental disorders, while CHD5-related disorders are still unknown. Thanks to GeneMatcher and international collaborations, we assembled a cohort of 16 unrelated individuals harboring heterozygous CHD5 variants, all identified by exome sequencing. Twelve patients had de novo CHD5 variants, including ten missense and two splice site variants. Three familial cases had nonsense or missense variants segregating with speech delay, learning disabilities, and/or craniosynostosis. One patient carried a frameshift variant of unknown inheritance due to unavailability of the father. The most common clinical features included language deficits (81%), behavioral symptoms (69%), intellectual disability (64%), epilepsy (62%), and motor delay (56%). Epilepsy types were variable, with West syndrome observed in three patients, generalized tonic–clonic seizures in two, and other subtypes observed in one individual each. Our findings suggest that, in line with other CHD-related disorders, heterozygous CHD5 variants are associated with a variable neurodevelopmental syndrome that includes intellectual disability with speech delay, epilepsy, and behavioral problems as main features.

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

BACKGROUND Heterogeneity exists in the response of triple-negative breast cancer (TNBC) to standard anthracycline (AC)/taxane-based neoadjuvant systemic therapy (NAST), with 40% to 50% of patients having a pathologic complete response (pCR) to therapy. Early assessment of the imaging response during NAST may identify a subset of TNBCs that are likely to have a pCR upon completion of treatment. The authors aimed to evaluate the performance of early ultrasound (US) after 2 cycles of neoadjuvant NAST in identifying excellent responders to NAST among patients with TNBC. METHODS Two hundred fifteen patients with TNBC were enrolled in the ongoing ARTEMIS (A Robust TNBC Evaluation Framework to Improve Survival) clinical trial. The patients were divided into a discovery cohort (n = 107) and a validation cohort (n = 108). A receiver operating characteristic analysis with 95% confidence intervals (CIs) and a multivariate logistic regression analysis were performed to model the probability of a pCR on the basis of the tumor volume reduction (TVR) percentage by US from the baseline to after 2 cycles of AC. RESULTS Overall, 39.3% of the patients (42 of 107) achieved a pCR. A positive predictive value (PPV) analysis identified a cutoff point of 80% TVR after 2 cycles; the pCR rate was 77% (17 of 22) in patients with a TVR ≥ 80%, and the area under the curve (AUC) was 0.84 (95% CI, 0.77-0.92; P < .0001). In the validation cohort, the pCR rate was 44%. The PPV for pCR with a TVR ≥ 80% after 2 cycles was 76% (95% CI, 55%-91%), and the AUC was 0.79 (95% CI, 0.70-0.87; P < .0001). CONCLUSIONS The TVR percentage by US evaluation after 2 cycles of NAST may be a cost-effective early imaging biomarker for a pCR to AC/taxane-based NAST.

Secular trends in earlier initiation of puberty have been observed in recent decades. One risk factor appears to be increases in adiposity, as measured by body mass index. This trend is particularly notable among Latino populations, who have higher rates of overweight/obesity compared with non-Latino White youth. Previous research has focused primarily on White girls, resulting in data gaps regarding male puberty and among potentially high-risk populations. Using data from the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS) study, we examined body mass index at age 5 years (2005–2006) and multiple markers of pubertal onset, assessed repeatedly and longitudinally at 7 in-person visits, starting at age 9 and continuing through age 14 (2009–2015), among 336 Mexican Americans in Salinas, California. We observed no associations among boys, but found significantly earlier thelarche in overweight (HR = 1.7, 95% CI: 1.1, 2.7) and obese girls (HR = 1.5, 95% CI: 1.0, 2.4), menarche in overweight girls (HR = 1.6; CI: 1.0, 2.4), and pubarche in obese girls (HR = 1.9; CI: 1.2, 3.0), compared with normal-weight girls. This study examined an understudied population and included key covariates, such as birth weight and early adverse events, which are typically omitted in studies.

Background Hypotension is associated with worse outcome in patients with traumatic brain injury (TBI) and maintaining a systolic blood pressure (SBP) ≥110 mmHg is recommended. The aim of this study was to assess the incidence of TBI in patients suffering multiple trauma in mountain areas; to describe associated factors, treatment and outcome compared to non-hypotensive patients with TBI and patients without TBI; and to evaluate pre-hospital variables to predict admission hypotension. Methods Data from the prospective International Alpine Trauma Registry including mountain multiple trauma patients (ISS ≥ 16) collected between 2010 and 2019 were analysed. Patients were divided into three groups: 1) TBI with hypotension, 2) TBI without hypotension and 3) no TBI. TBI was defined as Abbreviated Injury Scale (AIS) of the head/neck ≥3 and hypotension as SBP Results A total of 287 patients were included. Fifty (17%) had TBI and hypotension, 92 (32%) suffered TBI without hypotension and 145 (51%) patients did not have TBI. Patients in group 1 were more severely injured (mean ISS 43.1 ± 17.4 vs 33.3 ± 15.3 vs 26.2 ± 18.1 for group 1 vs 2 vs 3, respectively, p p p p = 0.029). The rate of hypothermia on hospital arrival was different between the groups (p = 0.029). Patients in group 1 had the highest mortality (24% vs 10% vs 1%, p Conclusion Multiple trauma in the mountains goes along with severe TBI in almost 50%. One third of patients with TBI is hypotensive on hospital arrival and this is associated with a worse outcome. No single variable or set of variables easily obtainable at scene was able to predict admission hypotension in TBI patients.

Many observational studies and some randomized trials demonstrate how fetal growth can be influenced by environmental insults (for example, maternal infections)1 and preventive interventions (for example, multiple-micronutrient supplementation)2 that can have a long-lasting effect on health, growth, neurodevelopment and even educational attainment and income in adulthood3. In a cohort of pregnant women (n = 3,598), followed-up between 2012 and 2019 at six sites worldwide4, we studied the associations between ultrasound-derived fetal cranial growth trajectories, measured longitudinally from

Objectives The objective was to describe the physical and psychosocial features of patients attending a specialized consultation hour for temporomandibular disorders (TMD). This investigation focused on those patients who did not receive a diagnosis according to the Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD). Materials and methods From 2004 to 2017, patients seeking care during a TMD-specialized consultation hour were consecutively recruited. Each patient completed a TMD-related questionnaire, psychosocial questionnaires (Graded Chronic Pain Scale, Hospital Anxiety and Depression Scale, Beschwerden-Liste), and the Oral Health Impact Profile-49. The clinical examination was performed according to the RDC/TMD. Results The mean age of the 1020 patients was 43.3 years (75.3% female). According to the RDC/TMD decision trees, 351 patients were categorized without a TMD diagnosis (NoTMDdx). The most frequent reasons for seeking care were orofacial pain/TMJ pain or headaches revealing an OR of 1.89 (for TMDdx group). A relevant proportion of patients was categorized as positive for anxiety (NoTMDdx/TMDdx 30.8/41.2%; p = 0.072), depression (20.8/23.9%; p = 0.433), non-specific physical symptoms (31.4/44.1%; p < 0.001), or dysfunctional chronic pain (11.5/18.2%; p < 0.001). In both patient groups, the oral health-related quality of life was impaired (42.9/52.7 points; p < 0.001), and the frequency of therapy measures prior to the consultation hour was high. Conclusions Patients seeking care from TMD specialists were usually referred with TMD-associated symptoms. Of those, a relevant proportion did not receive a diagnosis according to RDC/TMD decision trees. Clinical relevance Psychosocial screening and the avoidance of overtreatment are recommended for patients with TMD-related symptoms.

Introduction Combination therapy for melanoma brain metastases (MM) using stereotactic radiosurgery (SRS) and immune checkpoint-inhibition (ICI) or targeted therapy (TT) is currently of high interest. In this collective, time evolution and incidence of imaging findings indicative of pseudoprogression is sparsely researched. We therefore investigated time-course of MRI characteristics in these patients. Methods Data were obtained retrospectively from 27 patients (12 female, 15 male; mean 61 years, total of 169 MMs). Single lesion volumes, total MM burden and edema volumes were analyzed at baseline and follow-up MRIs in 2 months intervals after SRS up to 24 months. The occurrence of intralesional hemorrhages was recorded. Results 17 patients (80 MM) received ICI, 8 (62 MM) TT and 2 (27 MM) ICI + TT concomitantly to SRS. MM-localization was frontal (n = 89), temporal (n = 23), parietal (n = 20), occipital (n = 10), basal ganglia/thalamus/insula (n = 10) and cerebellar (n = 10). A volumetric progression of MM 2–4 months after SRS was observed in combined treatment with ICI (p = 0.028) and ICI + TT (p = 0.043), whereas MMs treated with TT showed an early volumetric regression (p = 0.004). Edema volumes moderately correlated with total MM volumes (r = 0.57; p Conclusion Reversible volumetric increases in terms of pseudoprogression are observed 2–4 months after SRS in patients with MM concomitantly treated with ICI and ICI + TT, rarely after TT. Edema volumes mirror total MM volumes. Medical treatment type does not significantly affect rates of intralesional hemorrhage.

Visual Abstract, Highlights • FYCO1, a component of the autophagic machinery, is highly expressed in the heart and a potent inducer of cardiomyocyte autophagy. • Loss of FYCO1 in vivo inhibits adaptation to starvation or biomechanical stress of the heart by an abrogated increase of autophagic flux and results in contractile dysfunction. • Heart specific overexpression of FYCO1 improves autophagic flux and rescues contractile dysfunction following pressure overload., Summary Autophagy is a cellular degradation process that has been implicated in diverse disease processes. The authors provide evidence that FYCO1, a component of the autophagic machinery, is essential for adaptation to cardiac stress. Although the absence of FYCO1 does not affect basal autophagy in isolated cardiomyocytes, it abolishes induction of autophagy after glucose deprivation. Likewise, Fyco1-deficient mice subjected to starvation or pressure overload are unable to respond with induction of autophagy and develop impaired cardiac function. FYCO1 overexpression leads to induction of autophagy in isolated cardiomyocytes and transgenic mouse hearts, thereby rescuing cardiac dysfunction in response to biomechanical stress.

OBJECTIVE Cognitive symptoms in patients with vestibular disorders are far from rare, but identification of patients at risk for cognitive impairment remains poor. The Dizziness Handicap Inventory (DHI) is a widely used patient-reported outcome questionnaire for dizzy patients with several questions that address cognitive function. However, the relationship between subjective cognitive symptomatology in patients with vestibular disorders and performance on DHI is poorly characterized. STUDY DESIGN Retrospective cohort study. SETTING Tertiary care vestibular clinic. SUBJECTS Individuals with diagnoses of vestibular migraine (VM), Meniere's disease (MD), and concomitant vestibular migraine and Meniere's disease (VMMD) presenting to clinic between January 2007 and December 2019. RESULTS Of 761 subjects, 365 had VM, 311 had MD, and 85 had VMMD. Symptoms of brain fog and chronic fatigue occurred more frequently in the VM and VMMD groups compared with the MD group (χ2 (df = 2, n = 761) = 67.8, 20.9, respectively, p

BackgroundAlmost half of the patient with initially metastatic axillary node, treated with neoadjuvantchemotherapy (NAC) for a large operable breast cancer, has no axillary lymph node involvementat the time of surgery after NAC. Sentinel lymph node detection (SLND), performed after NAC,has a high false negative rate (FNR) when compared to FNR after primary surgery. GANEA 3 isa French prospective multi institutional ongoing trial, aimed at assessing the impact of targeting,before NAC, the initially positive node and removing it after NAC. The main objective of GANEA3 trial is the accuracy of this initially positive node to predict pathological status of the otheraxillary nodes after NAC. A total of 385 patients are required.ObjectiveThe current abstract assessed preliminary results of the detection rate of the clipped node and thedifferent methods to find it during axillary surgery based on the first 41 patients.Patients and MethodThis study is part of GANEA 3 Trial validated by scientific national board (clinicialtrials.gov:NCT03630913).Inclusion criteria: TNM stage T1-T3 N1 infiltrating breast carcinoma, indication of NAC, andsigned consent form,Exclusion criteria: more than 5 suspicious axillary nodes, inflammatory cancer, local relapse,mental disorder, pregnancy or no contraceptive method, contra-indication to NAC, NACinterrupted due to progressive disease.Design: Patients treated for an early breast cancer with NAC, axillary sonography with fine needlecytology before NAC to select patients with a proven lymph node involvement. Initially positive node identification warranted, for example with a clip. After NAC patients underwent the removalof the clipped node, a SLN detection with the combined method (patent blue and technetium) andan axillary lymph node dissection (ALND). In order to find the clipped node, during surgery thesurgeon attempted to find it with palpation and sonography. Each surgical specimen was then x-rayed before pathological examination.Studied parameters were clipped node and SLND detection rate, and the methods used to find theclipped node.ResultsFrom January 2019, to November 2019, 41 patients were enrolled, from 13 institutions, withinitially positive axillary node clipped, NAC courses and surgery after NAC.Median age was 53 (31-75), pathological subtype infiltrative ductal carcinoma (n=40) andinfiltrative lobular carcinoma (n=1), a median of 7 courses of NAC (1-16).SLN detection rate was 90% (37/41). A median number of 2 sentinel nodes were removed (1-7).The clipped node was removed in 100% of cases. The clipped node was identified by thesurgeon palpation (n=11), an axillary wire (n=13), per operative axillary sonography (n=4),surgical specimen radiography (n=11), the pathologist (n=2).The clipped node was part of SLN in 29 cases (70%). It was part of axillary lymphadenectomyspecimen in 6 cases (14.5%) and was find alone as an isolated node in 6 cases (14.5%).ConclusionThe clipped node was always found after NAC. It was mostly always part of SLN or ALNDspecimens. Further studies are needed in order to help the surgeon to remove only the clippednode. Citation Format: Celine Renaudeau, Roman Rouzier, Pierre Gimbergues, Marian Gutowski, Eva Jouve, Philippe Rauch, Charles Coutant, Christelle Faure, Catherine Uzan, Pierre-François Dupré, Vivien Ceccato, Charlotte N'go, Augustin Reynard, Isabelle Doutriaux, Loic Campion, Jean-Marc Classe. Axillary surgery after neoadjuvant chemotherapy in patients treated for an operable breast cancer with a proven initially positive axillary node: Preliminary results of identification and removal of the initially positive axillary node [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 PS1-43.

To perform a multicenter assessment of the CT Pneumonia Analysis prototype for predicting disease severity and patient outcome in COVID-19 pneumonia both without and with integration of clinical information. Our IRB-approved observational study included consecutive 241 adult patients (> 18 years; 105 females; 136 males) with RT-PCR-positive COVID-19 pneumonia who underwent non-contrast chest CT at one of the two tertiary care hospitals (site A: Massachusetts General Hospital, USA; site B: Firoozgar Hospital Iran). We recorded patient age, gender, comorbid conditions, laboratory values, intensive care unit (ICU) admission, mechanical ventilation, and final outcome (recovery or death). Two thoracic radiologists reviewed all chest CTs to record type, extent of pulmonary opacities based on the percentage of lobe involved, and severity of respiratory motion artifacts. Thin-section CT images were processed with the prototype (Siemens Healthineers) to obtain quantitative features including lung volumes, volume and percentage of all-type and high-attenuation opacities (≥ −200 HU), and mean HU and standard deviation of opacities within a given lung region. These values are estimated for the total combined lung volume, and separately for each lung and each lung lobe. Multivariable analyses of variance (MANOVA) and multiple logistic regression were performed for data analyses. About 26% of chest CTs (62/241) had moderate to severe motion artifacts. There were no significant differences in the AUCs of quantitative features for predicting disease severity with and without motion artifacts (AUC 0.94–0.97) as well as for predicting patient outcome (AUC 0.7–0.77) (p > 0.5). Combination of the volume of all-attenuation opacities and the percentage of high-attenuation opacities (AUC 0.76–0.82, 95% confidence interval (CI) 0.73–0.82) had higher AUC for predicting ICU admission than the subjective severity scores (AUC 0.69–0.77, 95% CI 0.69–0.81). Despite a high frequency of motion artifacts, quantitative features of pulmonary opacities from chest CT can help differentiate patients with favorable and adverse outcomes.

Malignant mesothelioma is an aggressive cancer associated with prior exposure to asbestos and dismal prognosis. Immune checkpoint inhibitor therapy is currently approved by the Food and Drug Administration for pre-treated malignant pleural mesothelioma. We describe a 75-year-old patient with disseminated, progressive malignant mesothelioma receiving 2 cycles of pembrolizumab who presented with generalized muscle weakness, shortness of breath, double vision and ptosis. There was no previous history of cardiovascular disease. The clinical picture, supported by the detection of anti-titin autoantibodies suggested myasthenia gravis (MG). Also, cardiac biomarkers were elevated. Echocardiography showed new severely reduced ejection fraction. A 12-lead resting electrocardiogram (ECG) revealed ST segment elevation in the posterior leads with polymorphic ventricular extrasystoles. Because cardiac catheterization revealed no relevant coronary lesions, immune checkpoint inhibitor-associated myocarditis and MG were suspected. Management and Outcome: The patient was started on steroids. Within a few days of presentation respiratory failure set in and the patient was intubated. Recurrent arrhythmias followed, which were treated by repeated emergency electrical cardioversion. In order to relieve myasthenic symptoms, plasma exchange was initiated and 10 cycles were carried out. This consequently also led to an improvement of myocarditis. Upon discharge, the ejection fraction recovered. The patient recovered and was alive at 1-year follow-up, without relevant limitations to his quality of life. Discussion and Conclusion: The article further discusses the use of plasma exchange for immune checkpoint inhibitor-associated myocarditis based on a review of literature. We conclude that patients showing no improvement after steroid therapy for immune checkpoint inhibitor-related myocarditis should be evaluated for plasma exchange, which appears to be an effective treatment option.

Objectives There are no approved pharmacologic therapies for chronic sensorineural hearing loss (SNHL). The combination of CHIR99021+valproic acid (CV, FX-322) has been shown to regenerate mammalian cochlear hair cells ex vivo. The objectives were to characterize the cochlear pharmacokinetic profile of CV in guinea pigs, then measure FX-322 in human perilymph samples, and finally assess safety and audiometric effects of FX-322 in humans with chronic SNHL. Study designs Middle ear residence, cochlear distribution, and elimination profiles of FX-322 were assessed in guinea pigs. Human perilymph sampling following intratympanic FX-322 dosing was performed in an open-label study in cochlear implant subjects. Unilateral intratympanic FX-322 was assessed in a Phase 1b prospective, randomized, double-blinded, placebo-controlled clinical trial. Setting Three private otolaryngology practices in the US. Patients Individuals diagnosed with mild to moderately severe chronic SNHL (≤70 dB standard pure-tone average) in one or both ears that was stable for ≥6 months, medical histories consistent with noise-induced or idiopathic sudden SNHL, and no significant vestibular symptoms. Interventions Intratympanic FX-322. Main outcome measures Pharmacokinetics of FX-322 in perilymph and safety and audiometric effects. Results After intratympanic delivery in guinea pigs and humans, FX-322 levels in the cochlear extended high-frequency region were observed and projected to be pharmacologically active in humans. A single dose of FX-322 in SNHL subjects was well tolerated with mild, transient treatment-related adverse events (n = 15 FX-322 vs 8 placebo). Of the six patients treated with FX-322 who had baseline word recognition in quiet scores below 90%, four showed clinically meaningful improvements (absolute word recognition improved 18-42%, exceeding the 95% confidence interval determined by previously published criteria). No significant changes in placebo-injected ears were observed. At the group level, FX-322 subjects outperformed placebo group in word recognition in quiet when averaged across all time points, with a mean improvement from baseline of 18.9% (p = 0.029). For words in noise, the treated group showed a mean 1.3 dB signal-to-noise ratio improvement (p = 0.012) relative to their baseline scores while placebo-treated subjects did not (-0.21 dB, p = 0.71). Conclusions Delivery of FX-322 to the extended high-frequency region of the cochlea is well tolerated and enhances speech recognition performance in multiple subjects with stable chronic hearing loss.

Coronavirus SARS-CoV-2; COVID-19; 2019-nCoV; Hipertensió gestacional; Preeclampsia Coronavirus SARS-CoV-2; COVID-19; 2019-nCoV; Hipertension gestacional; Preeclampsia Coronavirus SARS-CoV-2; COVID-19; 2019-nCoV; Gestational hypertension; Preeclampsia Background It is unclear whether the suggested link between COVID-19 during pregnancy and preeclampsia is an independent association or if these are caused by common risk factors. Objective This study aimed to quantify any independent association between COVID-19 during pregnancy and preeclampsia and to determine the effect of these variables on maternal and neonatal morbidity and mortality. Study Design This was a large, longitudinal, prospective, unmatched diagnosed and not-diagnosed observational study assessing the effect of COVID-19 during pregnancy on mothers and neonates. Two consecutive not-diagnosed women were concomitantly enrolled immediately after each diagnosed woman was identified, at any stage during pregnancy or delivery, and at the same level of care to minimize bias. Women and neonates were followed until hospital discharge using the standardized INTERGROWTH-21 st protocols and electronic data management system. A total of 43 institutions in 18 countries contributed to the study sample. The independent association between the 2 entities was quantified with the risk factors known to be associated with preeclampsia analyzed in each group. The outcomes were compared among women with COVID-19 alone, preeclampsia alone, both conditions, and those without either of the 2 conditions. Results We enrolled 2184 pregnant women; of these, 725 (33.2%) were enrolled in the COVID-19 diagnosed and 1459 (66.8%) in the COVID-19 not-diagnosed groups. Of these women, 123 had preeclampsia of which 59 of 725 (8.1%) were in the COVID-19 diagnosed group and 64 of 1459 (4.4%) were in the not-diagnosed group (risk ratio, 1.86; 95% confidence interval, 1.32–2.61). After adjustment for sociodemographic factors and conditions associated with both COVID-19 and preeclampsia, the risk ratio for preeclampsia remained significant among all women (risk ratio, 1.77; 95% confidence interval, 1.25–2.52) and nulliparous women specifically (risk ratio, 1.89; 95% confidence interval, 1.17–3.05). There was a trend but no statistical significance among parous women (risk ratio, 1.64; 95% confidence interval, 0.99–2.73). The risk ratio for preterm birth for all women diagnosed with COVID-19 and preeclampsia was 4.05 (95% confidence interval, 2.99–5.49) and 6.26 (95% confidence interval, 4.35–9.00) for nulliparous women. Compared with women with neither condition diagnosed, the composite adverse perinatal outcome showed a stepwise increase in the risk ratio for COVID-19 without preeclampsia, preeclampsia without COVID-19, and COVID-19 with preeclampsia (risk ratio, 2.16; 95% confidence interval, 1.63–2.86; risk ratio, 2.53; 95% confidence interval, 1.44–4.45; and risk ratio, 2.84; 95% confidence interval, 1.67–4.82, respectively). Similar findings were found for the composite adverse maternal outcome with risk ratios of 1.76 (95% confidence interval, 1.32–2.35), 2.07 (95% confidence interval, 1.20–3.57), and 2.77 (95% confidence interval, 1.66–4.63). The association between COVID-19 and gestational hypertension and the direction of the effects on preterm birth and adverse perinatal and maternal outcomes, were similar to preeclampsia, but confined to nulliparous women with lower risk ratios. Conclusion COVID-19 during pregnancy is strongly associated with preeclampsia, especially among nulliparous women. This association is independent of any risk factors and preexisting conditions. COVID-19 severity does not seem to be a factor in this association. Both conditions are associated independently of and in an additive fashion with preterm birth, severe perinatal morbidity and mortality, and adverse maternal outcomes. Women with preeclampsia should be considered a particularly vulnerable group with regard to the risks posed by COVID-19. The study was supported by the COVID-19 Research Response Fund from the University of Oxford (Ref 0009083). A.T.P. is supported by the Oxford Partnership Comprehensive Biomedical Research Centre with funding from the National Institute for Health Research (NIHR) Biomedical Research Centre funding scheme. The funding organization had no involvement in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript, and decision to submit the manuscript for publication.

Objective: To determine where the current literature stands in regard to diet/exercise interventions on cognition in overweight or obese individuals. Data Source: A rapid review was conducted of English-language studies published in Medline from January 1965 to January 2020. Study Inclusion and Exclusion Criteria: Included studies were intervention studies lasting ≥12 weeks, with participants aged ≥65 years, with a body mass index ≥25 kg/m2 Data Extraction: Data extracted included study population, duration, intervention design, outcomes, and results. Data Synthesis: Outcomes were qualitatively measured due to paucity of RTC. Results: 1845 citations were identified, 31 full-text articles were reviewed, and 5 studies were included. Studies had usual care control groups and combined exercise/diet intervention groups with 31-3,526 participants randomized to each arm. Mean age of participants was 69.2-83.4 years. Studies reporting on cognitive changes showed marginally significant positive changes in cognition, and those that reported BMI indicated potential improvements in cognition. Conclusions: The number of interventions assessing the combined effects of both diet and exercise is low. Future studies should evaluate the impact of combined effects to ascertain whether cognitive decline may be reversed in older adults with a BMI ≥25 kg/m2.

Aims/hypothesis Many individuals who develop type 2 diabetes also display increased glucagon levels (hyperglucagonaemia), which we have previously found to be associated with the metabolic syndrome. The concept of a liver–alpha cell axis provides a possible link between hyperglucagonaemia and elevated liver fat content, a typical finding in the metabolic syndrome. However, this association has only been studied in individuals with non-alcoholic fatty liver disease. Hence, we searched for a link between the liver and the alpha cells in individuals with non-steatotic levels of liver fat content. We hypothesised that the glucagon–alanine index, an indicator of the functional integrity of the liver–alpha cell axis, would associate with liver fat and insulin resistance in our cohort of women with low levels of liver fat. Methods We analysed data from 79 individuals participating in the Prediction, Prevention and Subclassification of Type 2 Diabetes (PPSDiab) study, a prospective observational study of young women at low to high risk for the development of type 2 diabetes. Liver fat content was determined by MRI. Insulin resistance was calculated as HOMA-IR. We conducted Spearman correlation analyses of liver fat content and HOMA-IR with the glucagon–alanine index (the product of fasting plasma levels of glucagon and alanine). The prediction of the glucagon–alanine index by liver fat or HOMA-IR was tested in multivariate linear regression analyses in the whole cohort as well as after stratification for liver fat content ≤0.5% (n = 39) or >0.5% (n = 40). Results The glucagon–alanine index significantly correlated with liver fat and HOMA-IR in the entire cohort (ρ = 0.484, p ρ = 0.417, p 0.5% (liver fat, ρ = 0.550, p ρ = 0.429, p = 0.006). In linear regression analyses, the association of the glucagon–alanine index with liver fat remained significant after adjustment for age and HOMA-IR in all participants and in those with liver fat >0.5% (β = 0.246, p = 0.0.23 and β = 0.430, p = 0.007, respectively) but not in participants with liver fat ≤0.5% (β = −0.184, p = 0.286). Conclusions/interpretation We reproduced the previously reported association of liver fat content and HOMA-IR with the glucagon–alanine index in an independent study cohort of young women with low to high risk for type 2 diabetes. Furthermore, our data indicates an insulin-resistance-independent association of liver fat content with the glucagon–alanine index. In summary, our study supports the concept that even lower levels of liver fat (from 0.5%) are connected to relative hyperglucagonaemia, reflecting an imminent impairment of the liver–alpha cell axis.

Background Understanding the mechanisms in the brain’s incentive network that give rise to symptoms of major depressive disorder (MDD) during adolescence provides new perspectives to address MDD in early stages of development. This functional magnetic resonance imaging study determines whether instrumental vigor and brain responses to appetitive and aversive monetary incentives are altered in adolescent MDD and associated with symptom severity. Methods Adolescents with moderate to severe MDD (n = 30, mean age [SD] = 16.1 [1.4] years) and healthy control subjects (n = 33, mean age = 16.2 [1.9] years) matched for age, sex, and IQ performed a monetary incentive delay task. During outcome presentation, prediction error signals were used to study the response and coupling of the incentive network during learning of cue-outcome associations. A computational reinforcement model was used to assess adaptation of response vigor. Brain responses and effective connectivity to model-derived prediction errors were assessed and related to depression severity and anhedonia levels. Results Participants with MDD behaved according to a more simplistic learning model and exhibited slower learning. Effective connectivity analysis of functional magnetic resonance imaging data revealed that impaired loss error processing in the orbitofrontal cortex was associated with aberrant gain control. Anhedonia scores correlated with loss-related error signals in the posterior insula and habenula. Conclusions Adolescent MDD is selectively related to impaired processing of error signals during loss, but not reward, in the orbitofrontal cortex. Aberrant evaluation of loss outcomes might reflect an early mechanism of how negative bias and helplessness manifest in the brain. This approach sheds light on pathomechanisms in MDD and may improve early diagnosis and treatment selection., Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, 7 (3), ISSN:2451-9022, ISSN:2451-9030

Objectives Most research addressing needs and concerns of young patients with breast cancer (≤40 years) is retrospective. The HOHO European protocol is a prospective multicenter cohort study of young women with newly diagnosed breast cancer, about fertility, psychosocial and quality of life concerns. Here we report the baseline data and focus on predictors of fertility concerns. Materials and methods Patient surveys and medical record review were used. The baseline survey included sociodemographic, medical and treatment data as well as questions on fertility concerns and preservation strategies. Subscales from the CAncer Rehabilitation Evaluation System-Short Form (CARES-SF) were administered to measure specific quality of life aspects. Uni- and multivariable modeling were used to investigate predictors of greater fertility concern. Results Among 297 eligible respondents, 67% discussed fertility issues before starting therapy, 64% were concerned about becoming infertile after treatment, and 15% decided not to follow prescribed therapies. Fifty-four percent of women wished future children before diagnosis; of these, 71% still desired biologic children afterwards. In multivariable analysis, not having children was the only patient characteristic significantly associated with fertility concerns at diagnosis. Twenty-seven percent used fertility preservation strategies. Women who received chemotherapy reported greater physical (p = 0.021) and sexual difficulties (p = 0.039) than women who did not. Women who were married or had a partner reported less psychosocial problems than single women (p = 0.039). Conclusions Young women with newly diagnosed breast cancer have several concerns, including, but not limited to, fertility. The HOHO European study provides valuable information to develop targeted interventions.

Background: In clinical practice, local anesthesia with conscious sedation (CS) is performed in roughly 50% of patients undergoing transcatheter aortic valve replacement. However, no randomized data assessing the safety and efficacy of CS versus general anesthesia (GA) are available. Methods: The SOLVE-TAVI (Comparison of Second-Generation Self-Expandable Versus Balloon-Expandable Valves and General Versus Local Anesthesia in Transcatheter Aortic Valve Implantation) trial is a multicenter, open-label, 2×2 factorial, randomized trial of 447 patients with aortic stenosis undergoing transfemoral transcatheter aortic valve replacement comparing CS versus GA. The primary efficacy end point was powered for equivalence (equivalence margin 10% with significance level 0.05) and consisted of the composite of all-cause mortality, stroke, myocardial infarction, infection requiring antibiotic treatment, and acute kidney injury at 30 days. Results: The primary composite end point occurred in 27.2% of CS and 26.4% of GA patients (rate difference, 0.8 [90% CI, −6.2 to 7.8]; P equivalence =0.015). Event rates for the individual components were as follows: all-cause mortality, 3.2% versus 2.3% (rate difference, 1.0 [90% CI, −2.9 to 4.8]; P equivalence P equivalence P equivalence P equivalence =0.011); acute kidney injury, 9.0% versus 9.2% (rate difference, −0.2 [90% CI, −5.2 to 4.8]; P equivalence =0.0005). There was a lower need for inotropes or vasopressors with CS (62.8%) versus GA (97.3%; rate difference, −34.4 [90% CI, −41.0 to −27.8]). Conclusions: Among patients with aortic stenosis undergoing transfemoral transcatheter aortic valve replacement, use of CS compared with GA resulted in similar outcomes for the primary efficacy end point. These findings suggest that CS can be safely applied for transcatheter aortic valve replacement. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02737150.

Objectives Osteogenesis imperfecta type VI (OI VI) follows a progressive and severe course, yet unlike other forms of severe OI it has a later onset of fractures, and extra-skeletal findings are not part of the clinical picture. Another difference is that there is an increase in unmineralized osteoid tissue in OI VI, which hinders the effect of bisphosphonates-the current standard of treatment for OI. Therefore, the response to standard treatments in OI VI is not satisfactory. Herein, we report long-term follow-up of two cases with novel SERPINF1 mutations, who show great variation in their treatment response to bisphosphonates. Case presentation The first case was given pamidronate at the age of 15 months when he could sit independently, followed a fluctuating course under treatment, fracture rate did not decrease, however he was able to mobilize with walker at the age of 10 years. On the other hand, the second case developed severe deformities and became wheelchair-bound under pamidronate, thus the treatment was switched to denosumab. Unfortunately, there was no improvement under denosumab after 15 months too, and since bone pain increased, denosumab treatment was stopped. He was put on zoledronic acid instead. Conclusion SERPINF1 transcript amount may be an important factor to explain the variation in response to pamidronate therapy. In OI VI patients, the factors affecting the clinical course should be identified and new or combined treatment options should be established.

Catheter-guided interventional implantation of cardiac valves is one of the main developments in cardiology over the past 15 years. It is characterized by a close interdisciplinary cooperation in the heart team (H-team), which consists of cardiac anesthesiologists, cardiologists and heart surgeons. This co-responsibility for anesthesia, which is demanded by the legislator (Federal Joint Committee, G‑BA, July 2015), includes not only qualified training for the cardiac anesthesiologist, including transthoracic echocardiography (TTE) and transesophageal echocardiography (TEE) but also several years of experience in cardiac anesthesia and correlates with the recommendations of the German Society for Anaesthesiology and Intensive Care Medicine. In accompaniment with the demographic development, the number of heart valve diseases increases with age. More than 50% of all heart operations are performed on patients over the age of 70 years and nearly 20% on patients over the age of 80 years. Minimally invasive procedures are outstanding opportunities for patients who were initially classified as inoperable. Therefore, anesthesiologists must have precise knowledge of the possible complications related to the procedure itself. Additionally, it challenges the anesthesiologist with unconventional situations in the care of older patients who are exposed to a higher risk. The aforementioned risks are organic functional restrictions, increasing number of comorbidities and more severe exposure due to malnutrition and frailty; however, monitoring methods are also being developed aiming for patient-specific anesthesia management and analgesia treatment. This article discusses the interventional procedures of heart valvular diseases as well as the hemodynamic changes associated with the procedures from the anesthesiologist's point of view. To present examples, we have selected transcatheter aortic valve replacement (TAVR) and the interventional procedure of mitral and tricuspid valve insufficiency called MitraClip and TricaClip. A thorough examination of the procedural risk rate shows that despite minimizing the surgical intervention by miniaturizing the devices, the presence of an experienced cardiac anesthesiologist is obligatory.