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Objectives. To compare the effectiveness of 3 approaches for communicating opioid risk during an emergency department visit for a common painful condition. Methods. This parallel, multicenter randomized controlled trial was conducted at 6 geographically disparate emergency department sites in the United States. Participants included adult patients between 18 and 70 years of age presenting with kidney stone or musculoskeletal back pain. Participants were randomly assigned to 1 of 3 risk communication strategies: (1) a personalized probabilistic risk visual aid, (2) a visual aid and a video narrative, or 3) general risk information. The primary outcomes were accuracy of risk recall, reported opioid use, and treatment preference at time of discharge. Results. A total of 1301 participants were enrolled between June 2017 and August 2019. There was no difference in risk recall at 14 days between the narrative and probabilistic groups (43.7% vs 38.8%; absolute risk reduction = 4.9%; 95% confidence interval [CI] = −2.98, 12.75). The narrative group had lower rates of preference for opioids at discharge than the general risk information group (25.9% vs 33.0%; difference = 7.1%; 95% CI = 0.64, 0.97). There were no differences in reported opioid use at 14 days between the narrative, probabilistic, and general risk groups (10.5%, 10.3%, and 13.3%, respectively; P = .44). Conclusions. An emergency medicine communication tool incorporating probabilistic risk and patient narratives was more effective than general information in mitigating preferences for opioids in the treatment of pain but was not more effective with respect to opioid use or risk recall. Trial Registration. Clinical Trials.gov identifier: NCT03134092. (Am J Public Health. 2022;112(S1):S45–S55. https://doi.org/10.2105/AJPH.2021.306511 )

Adjuvant therapy; Breast cancer; Olaparib Terapia adyuvante; Cáncer de mama; Olaparib Teràpia adjuvant; Càncer de mama; Olaparib Background The randomized, double-blind OlympiA trial compared 1 year of the oral poly(adenosine diphosphate-ribose) polymerase inhibitor, olaparib, to matching placebo as adjuvant therapy for patients with pathogenic or likely pathogenic variants in germline BRCA1 or BRCA2 (gBRCA1/2pv) and high-risk, human epidermal growth factor receptor 2-negative, early breast cancer (EBC). The first pre-specified interim analysis (IA) previously demonstrated statistically significant improvement in invasive disease-free survival (IDFS) and distant disease-free survival (DDFS). The olaparib group had fewer deaths than the placebo group, but the difference did not reach statistical significance for overall survival (OS). We now report the pre-specified second IA of OS with updates of IDFS, DDFS, and safety. Patients and methods One thousand eight hundred and thirty-six patients were randomly assigned to olaparib or placebo following (neo)adjuvant chemotherapy, surgery, and radiation therapy if indicated. Endocrine therapy was given concurrently with study medication for hormone receptor-positive cancers. Statistical significance for OS at this IA required P < 0.015. Results With a median follow-up of 3.5 years, the second IA of OS demonstrated significant improvement in the olaparib group relative to the placebo group [hazard ratio 0.68; 98.5% confidence interval (CI) 0.47-0.97; P = 0.009]. Four-year OS was 89.8% in the olaparib group and 86.4% in the placebo group (Δ 3.4%, 95% CI −0.1% to 6.8%). Four-year IDFS for the olaparib group versus placebo group was 82.7% versus 75.4% (Δ 7.3%, 95% CI 3.0% to 11.5%) and 4-year DDFS was 86.5% versus 79.1% (Δ 7.4%, 95% CI 3.6% to 11.3%), respectively. Subset analyses for OS, IDFS, and DDFS demonstrated benefit across major subgroups. No new safety signals were identified including no new cases of acute myeloid leukemia or myelodysplastic syndrome. Conclusion With 3.5 years of median follow-up, OlympiA demonstrates statistically significant improvement in OS with adjuvant olaparib compared with placebo for gBRCA1/2pv-associated EBC and maintained improvements in the previously reported, statistically significant endpoints of IDFS and DDFS with no new safety signals. Funding for this work, which was conducted as a collaborative partnership among the Breast International Group, NRG Oncology, Frontier Science, AstraZeneca, and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, U.S.A. (MSD), was provided by the National Institutes of Health (grant numbers: U10CA 180868, UG1CA 189867, and U10CA 180822) and by AstraZeneca as part of an alliance between AstraZeneca and MSD. Provision of olaparib and placebo was from AstraZeneca.

The microbiome plays a fundamental role in maintaining intestinal stem cell (ISC)-niche equilibrium. In this issue of Immunity, Kim and colleagues uncover a mechanism by which the microbiota drives macrophage WNT ligand-release to maintain ISC-niche homeostasis during early postnatal development.

Social media is a central context in which teens interact with their peers, creating opportunities for them to view, post, and engage with alcohol content. Because adolescent peer interactions largely occur on social media, perceptions of peer alcohol content posting may act as potent risk factors for adolescent alcohol use. Accordingly, the preregistered aims of this study were to (1) compare perceived friend, typical person, and an adolescent's own posting of alcohol content to social media and (2) examine how these perceptions prospectively relate to alcohol willingness, expectancies, and use after accounting for offline perceived peer alcohol use.This longitudinal study included 435 adolescents (MConsistent with preregistered hypotheses, adolescents reported that 60.3% of the typical person their age and 30.6% of their friends post alcohol content on social media. By contrast, only 7% of participants reported that they themselves posted such content to social media. After accounting for offline perceived peer drinking norms, neither perceived friend nor typical person alcohol content social media posts were prospectively associated with willingness to drink or positive or negative alcohol expectancies. Perceived friend alcohol content posts were prospectively positively associated with past 30-day alcohol consumption even after controlling for offline perceived peer drinking norms.Adolescents misperceived the frequency of alcohol-related posting to social media among their peers, and perceptions of friend alcohol content posts prospectively predicted alcohol use. Given the results from the current study and the ubiquity of social media among adolescents, prevention efforts may benefit from addressing misperceptions of alcohol-related posting to social media.

To investigate severe autoimmune encephalitis (AE) in the intensive care unit (ICU) with regard to standard treatment in responsive patients and additional escalation therapies for treatment-refractory cases.This retrospective, single-center study analyzed medical records of ICU-dependent AE patients for clinical characteristics, treatments, prognostic factors, and neurological outcome as quantified by modified Rankin Scale (mRS) and Clinical Assessment Scale for Autoimmune Encephalitis (CASE).From 40 enrolled patients (median age = 52 years; range = 16-89 years) with AE mediated by neuronal surface antibodies (nsAb; 90%) and AE with onconeuronal antibodies (10%), 98% received first-line therapy. Of those, 62% obtained additional second-line therapy, and 33% received escalation therapy with bortezomib and/or daratumumab. Good neurological outcome, defined as mRS = 0-2, was observed in 47% of AE with nsAb (CASE = 5), 77% of anti-N-methyl D-aspartate receptor encephalitis patients (CASE = 1), whereas AE patients with onconeuronal antibodies had the poorest outcome (mRS = 6, 100%). Treatment-refractory AE patients with nsAb requiring escalation therapy achieved similarly good recovery (mRS = 0-2, 39%, CASE = 3) as patients improving without (mRS = 0-2, 54%, CASE = 4), although they presented a higher disease severity at disease maximum (mRS = 5 100% versus 68%, CASE = 24 versus 17; p = 0.0036), had longer ICU stays (97 versus 23 days; p = 0.0002), and a higher survival propability during follow-up (p = 0.0203). Prognostic factors for good recovery were younger age (p = 0.025) and lack of preexisting comorbidities (p = 0.011).Our findings suggest that treatment-refractory AE patients with nsAb in the ICU can reach similarly good outcomes after plasma cell-depleting escalation therapy as patients already responding to standard first- and/or second-line therapies.

Allogeneic hematopoietic stem cell transplantation (HSCT) is the gold standard curative therapy for infants and children with many inborn errors of immunity (IEI), but adolescents and adults with IEI are rarely referred for transplant. Lack of published HSCT outcome data outside small, single-center studies and perceived high risk of transplant-related mortality have delayed the adoption of HSCT for IEI patients presenting or developing significant organ damage later in life. This large retrospective, multicenter HSCT outcome study reports on 329 IEI patients (age range, 15-62.5 years at HSCT). Patients underwent first HSCT between 2000 and 2019. Primary endpoints were overall survival (OS) and event-free survival (EFS). We also evaluated the influence of IEI-subgroup and IEI-specific risk factors at HSCT, including infections, bronchiectasis, colitis, malignancy, inflammatory lung disease, splenectomy, hepatic dysfunction, and systemic immunosuppression. At a median follow-up of 44.3 months, the estimated OS at 1 and 5 years post-HSCT for all patients was 78% and 71%, and EFS was 65% and 62%, respectively, with low rates of severe acute (8%) or extensive chronic (7%) graft-versus-host disease. On univariate analysis, OS and EFS were inferior in patients with primary antibody deficiency, bronchiectasis, prior splenectomy, hepatic comorbidity, and higher hematopoietic cell transplant comorbidity index scores. On multivariable analysis, EFS was inferior in those with a higher number of IEI-associated complications. Neither age nor donor had a significant effect on OS or EFS. We have identified age-independent risk factors for adverse outcome, providing much needed evidence to identify which patients are most likely to benefit from HSCT. ispartof: BLOOD vol:140 issue:14 pages:1635-1649 ispartof: location:United States status: published

Data are limited regarding the immune status of CD40 ligand (CD40L)–deficient carriers and hematopoietic stem cell transplantation (HSCT) outcomes using them as donors for CD40L-deficient patients. Therefore, we studied the immune profiles of 7 carriers, 4 of whom were HSCT donors for family members with CD40L deficiency, and we characterized their HSCT outcomes. Immunoglobulin profiles, CD4, CD8, circulating T-follicular helper (cTfh) cells, and regulatory T cells (Tregs) in carriers were comparable to those in healthy controls. CD40L expression in carriers ranged from 37% to 78%. cTfh cells from carriers expressed higher CD40L compared with total CD4 cells or the memory CD4 compartment, suggesting a potential advantage to CD40L-expressing cTfh cells. Tregs had minimal CD40L expression in carriers and healthy controls. So we postulated that HSCT using donors who were CD40L carriers may result in excellent immune reconstitution without immune dysregulation. Four CD40L-deficient patients underwent HSCT from carriers who had CD40L expression from 37% to 63%. All patients engrafted, achieved excellent immune reconstitution with lack of opportunistic infections, graft-versus-host disease, and immune dysregulation; stable CD40L expression mimicked that of donors 1 to 5 years after HSCT. Immunoglobulin independence was achieved in 3 of the 4 patients. We demonstrated higher CD40L expression in the cTfh compartment of carriers and excellent immune reconstitution using donors who were CD40L carriers in CD40L-deficient patients.

Adjacent segment disease (ASD) is a potential complication following lumbar spinal fusion.This study aimed to demonstrate the demographic, clinical, and operative risk factors associated with ASD development following lumbar fusion.Systematic review and meta-analysis.We identified 35 studies that reported risk factors for ASD, with a total number of 7,374 patients who had lumbar spine fusion.We investigated the demographic, clinical, and operative risk factors for ASD after lumbar fusion.A literature search was done using PubMed, Embase, Medline, Scopus, and the Cochrane library databases from inception to December 2019. The methodological index for non-randomized studies (MINORS) criteria was used to assess the methodological quality of the included studies. A meta-analysis was done to calculate the odds ratio (OR) with the 95% confidence interval (CI) for dichotomous data and mean difference (MD) with 95% CI for continuous data.Thirty-five studies were included in the qualitative analysis, and 22 studies were included in the meta-analyses. The mean quality score based on the MINORS criteria was 12.4±1.9 (range, 8-16) points. Significant risk factors included higher preoperative body mass index (BMI) (mean difference [MD]=1.97 kg/mThe overall level of evidence was low to very low. Higher preoperative BMI, floating fusion, superior facet joint violation, and decompression outside fusion construct are significant risk factors of development of ASD following lumbar fusion surgeries.

Funder: Charité - Universitätsmedizin Berlin, PURPOSE: Six to 19% of critically ill COVID-19 patients display circulating auto-antibodies against type I interferons (IFN-AABs). Here, we establish a clinically applicable strategy for early identification of IFN-AAB-positive patients for potential subsequent clinical interventions. METHODS: We analyzed sera of 430 COVID-19 patients from four hospitals for presence of IFN-AABs by ELISA. Binding specificity and neutralizing activity were evaluated via competition assay and virus-infection-based neutralization assay. We defined clinical parameters associated with IFN-AAB positivity. In a subgroup of critically ill patients, we analyzed effects of therapeutic plasma exchange (TPE) on the levels of IFN-AABs, SARS-CoV-2 antibodies and clinical outcome. RESULTS: The prevalence of neutralizing AABs to IFN-α and IFN-ω in COVID-19 patients from all cohorts was 4.2% (18/430), while being undetectable in an uninfected control cohort. Neutralizing IFN-AABs were detectable exclusively in critically affected (max. WHO score 6-8), predominantly male (83%) patients (7.6%, 18/237 for IFN-α-AABs and 4.6%, 11/237 for IFN-ω-AABs in 237 patients with critical COVID-19). IFN-AABs were present early post-symptom onset and at the peak of disease. Fever and oxygen requirement at hospital admission co-presented with neutralizing IFN-AAB positivity. IFN-AABs were associated with lower probability of survival (7.7% versus 80.9% in patients without IFN-AABs). TPE reduced levels of IFN-AABs in three of five patients and may increase survival of IFN-AAB-positive patients compared to those not undergoing TPE. CONCLUSION: IFN-AABs may serve as early biomarker for the development of severe COVID-19. We propose to implement routine screening of hospitalized COVID-19 patients for rapid identification of patients with IFN-AABs who most likely benefit from specific therapies.

Stroke remains one of the main causes of mortality and morbidity worldwide. Immediately after stroke, a neuroinflammatory process starts in the brain, triggering a systemic immunodepression mainly through excessive activation of the autonomous nervous system. Manifestations of immunodepression include lymphopenia but also dysfunctional innate and adaptive immune cells. The resulting impaired antibacterial defenses render patients with stroke susceptible to infections. In addition, other risk factors like stroke severity, dysphagia, impaired consciousness, mechanical ventilation, catheterization, and older age predispose stroke patients for infections. Most common infections are pneumonia and urinary tract infection, both occur in ≈10% of the patients. Especially pneumonia increases unfavorable outcome and mortality in patients with stroke; systemic effects like hypotension, fever, delay in rehabilitation are thought to play a crucial role. Experimental and clinical data suggest that systemic infections enhance autoreactive immune responses against brain antigens and thus negatively affect outcome but convincing evidence is lacking. Prevention of poststroke infections by preventive antibiotic therapy did not improve functional outcome after stroke. Immunomodulatory approaches counteracting immunodepression to prevent stroke-associated pneumonia need to account for neuroinflammation in the ischemic brain and avoid further tissue damage. Experimental studies discovered interesting targets, but these have not yet been investigated in patients with stroke. A better understanding of the pathobiology may help to develop optimized approaches of preventive antibiotic therapy or immunomodulation to effectively prevent stroke-associated pneumonia while improving long-term outcome after stroke. In this review, we aim to characterize epidemiology, risk factors, cause, diagnosis, clinical presentation, and potential treatment of poststroke immunosuppression and associated infections.

Myasthenia gravis (MG) is an antibody-mediated disease that develops in the majority of patients mainly as a result of acetylcholine receptor (AChR) autoantibodies. This process is mediated by a series of immunoregulatory events. Therapeutic targets for MG include suppression of circulating antibodies or antibody production, suppression of complement activation, and immunomodulation of cytokines or T cells. Intravenous immunoglobulin (IVIg) has an effect on all of these mechanisms.This narrative review explores the broad immunomodulatory effects of IVIg in MG and provides an update on IVIg treatment for MG.IVIg has a range of immunomodulatory effects on therapeutic targets relevant to the immunopathogenesis of MG. An emerging area of research is the pharmacogenomics of IVIg in MG related to FcRn and IgG catabolism. New data suggest that the FcRn

Most patients with COVID-19 are asked to self-isolate and monitor their symptoms at home. However, their conditions may decline rapidly and unpredictably. The authors studied the use of a remote patient monitoring service via text messaging with clinical support to facilitate emergency department and hospital care for patients who require it., Visual Abstract. Outcomes of Automated Home Monitoring for COVID-19. Most patients with COVID-19 are asked to self-isolate and monitor their symptoms at home. However, their conditions may decline rapidly and unpredictably. The authors studied the use of a remote patient monitoring service via text messaging with clinical support to facilitate emergency department and hospital care for patients who require it., Background: Although most patients with SARS-CoV-2 infection can be safely managed at home, the need for hospitalization can arise suddenly. Objective: To determine whether enrollment in an automated remote monitoring service for community-dwelling adults with COVID-19 at home (“COVID Watch”) was associated with improved mortality. Design: Retrospective cohort analysis. Setting: Mid-Atlantic academic health system in the United States. Participants: Outpatients who tested positive for SARS-CoV-2 between 23 March and 30 November 2020. Intervention: The COVID Watch service consists of twice-daily, automated text message check-ins with an option to report worsening symptoms at any time. All escalations were managed 24 hours a day, 7 days a week by dedicated telemedicine clinicians. Measurements: Thirty- and 60-day outcomes of patients enrolled in COVID Watch were compared with those of patients who were eligible to enroll but received usual care. The primary outcome was death at 30 days. Secondary outcomes included emergency department (ED) visits and hospitalizations. Treatment effects were estimated with propensity score–weighted risk adjustment models. Results: A total of 3488 patients enrolled in COVID Watch and 4377 usual care control participants were compared with propensity score weighted models. At 30 days, COVID Watch patients had an odds ratio for death of 0.32 (95% CI, 0.12 to 0.72), with 1.8 fewer deaths per 1000 patients (CI, 0.5 to 3.1) (P = 0.005); at 60 days, the difference was 2.5 fewer deaths per 1000 patients (CI, 0.9 to 4.0) (P = 0.002). Patients in COVID Watch had more telemedicine encounters, ED visits, and hospitalizations and presented to the ED sooner (mean, 1.9 days sooner [CI, 0.9 to 2.9 days]; all P < 0.001). Limitation: Observational study with the potential for unobserved confounding. Conclusion: Enrollment of outpatients with COVID-19 in an automated remote monitoring service was associated with reduced mortality, potentially explained by more frequent telemedicine encounters and more frequent and earlier presentation to the ED. Primary Funding Source: Patient-Centered Outcomes Research Institute.

The management of estrogen receptor positive (ER+)/HER2- and lymph node (LN) negative breast cancers can be influenced by Oncotype DX recurrence score (RS) in the USA. However, the benefit of RS in T1 tumors (≤ 1 cm) is not clear.We retrieved 199 T1 ER+/HER2-/LN- breast cancer diagnosed between 1993 and 2016 that had undergone RS testing. The median follow-up time was 51 months. We examined the disease-free survival (DFS) and distant metastasis and their association with RS and other clinicopathologic features.Of the 199 cases, 40 were T1a (≤ 0.5 cm) and 159 were T1b ( 0.5 cm to 1 cm) tumors. In the 40 T1a tumors, 11 would benefit from chemotherapy by the TAILORx study results. Of these T1a tumors, 36 were Nottingham grade 1/2, 3 were grade 3, and 1 was microinvasive carcinoma; 2 (5%) had local recurrence and 1 (2.5%) had distant metastasis to the bone. The only patient with T1a tumor (Nottingham grade 3, RS = 42) and distant metastasis to bone had received adjuvant chemotherapy. In the 159 T1b tumors, 25 would benefit chemotherapy by the TAILORx results. Of the T1b tumors, 149 were Nottingham grade 1/2 and 10 were grade 3. Nine (5.7%) had local recurrence and 2 (1.3%) had distant metastasis to bone and mediastinum, respectively. The two T1b tumors with distant metastasis had a RS 20 and Nottingham grade 2, and RS 27 and Nottingham grade 3, respectively. Both patients received adjuvant chemotherapy. In multivariate analysis of the entire cohort (T1a and T1b tumors), Nottingham tumor grade and receiving chemotherapy were significantly associated with DFS. In univariate analysis of the entire cohort, Nottingham tumor grade, receiving adjuvant chemotherapy, and RS were significantly associated with distant metastasis.This study demonstrates that the metastatic rate of T1a and T1b ER+/HER2-/LN- breast cancer is very low. Patients with low grade (1 or 2), T1a ER+/HER2-/LN- breast cancer may not need RS for treatment decision-making; however, in patients with high-grade T1a or T1b ER+/HER2-/LN- breast cancer, RS analysis should be strongly considered.

In the U.S., overdoses have become a health crisis in both public and private places. We describe the impact of the overdose crisis in public libraries across five U.S. states, and the front-line response of public library workers. We conducted a cross-sectional survey, inviting one worker to respond at each public library in five randomly selected states (CO, CT, FL, MI, and VA), querying participants regarding substance use and overdose in their communities and institutions, and their preparedness to respond. We describe substance use and overdose patterns, as well as correlates of naloxone uptake, in public libraries. Participating library staff (N = 356) reported witnessing alcohol use (45%) and injection drug use (14%) in their libraries in the previous month. Across states surveyed, 12% of respondents reported at least one on-site overdose in the prior year, ranging from a low of 10% in MI to a high of 17% in FL. There was wide variation across states in naloxone uptake at libraries, ranging from 0% of represented libraries in FL to 33% in CO. Prior on-site overdose was associated with higher odds of naloxone uptake by the library (OR 2.5, 95% CI 1.1-5.7). Although 24% of respondents had attended a training regarding substance use in the prior year, over 90% of respondents wanted to receive additional training on the topic. Public health professionals should partner with public libraries to expand and strengthen substance use outreach and overdose prevention efforts.

ObjectivesMyasthenia gravis (MG) is a rare, chronic, autoimmune neuromuscular disease which can affect functional and mental aspects of health and health-related quality of life (HRQoL). This study aims to obtain detailed knowledge of the impact of MG on HRQoL in a broad population from the perspective of the patient.DesignProspective, observational, digital, longitudinal real-world study.SettingAdult patients with MG from seven countries (USA, Japan, Germany, UK, Italy, Spain and Canada) downloaded a mobile application onto their phones and entered data about themselves and their MG.Outcome measuresData was collected using the following general and disease-specific patient-reported outcome measurements: EuroQol 5 Domains Health-Related Quality of Life Questionnaire (EQ-5D-5L), Myasthenia Gravis Activities of Daily Living (MG-ADL), Myasthenia Gravis Quality of Life 15-item revised scale (MG-QoL-15r), Hospital Anxiety and Depression Scale (HADS) and Health Utilities Index III (HUI3). Patients were categorised by their self-assessed Myasthenia Gravis Foundation of America (MGFA) class (I–V).ResultsBaseline results of 841 participants (mean age 47 years, 70% women) are reported . The distribution across the MGFA classes was: 13.9%, 31.0%, 38.1%, 15.5% and 1.6% for classes I–V. The MGFA class was a strong predictor of all aspects of HRQoL, measured with disease-specific and with generic instruments. The domains in which patients with MG most frequently mentioned problems were usual activities, anxiety and depression, tiredness, breathing and vision. The mean total MG-ADL Score was positively associated with increasing MGFA classes: 2.7, 4.4, 6.3 and 8.4 for MGFA classes I–IV. Mean baseline EQ-5D-5L utility was also associated with MGFA classes and was 0.817, 0.766, 0.648 and 0.530 for MGFA class I–IV.ConclusionsMG has a large impact on key aspects of health and HRQoL. The impact of this disease increases substantially with increasing disease severity.

In amyotrophic lateral sclerosis (ALS) caused by superoxide dismutase 1 (SOD1) gene mutations (SOD1-ALS), the antisense oligonucleotide tofersen had been investigated in a phase III study (VALOR) and subsequently introduced in an expanded access program. In this study we assess neurofilament light chain (NfL) before and during tofersen treatment.In six SOD1-ALS patients treated with tofersen at three specialized ALS centers in Germany, NfL in cerebrospinal fluid (CSF-NfL) and/or serum (sNfL) were investigated using the ALS Functional Rating Scale Revised (ALSFRS-R) and ALS progression rate (ALS-PR), defined by monthly decline of ALSFRS-R.Three of the six SOD1-ALS patients reported a negative family history. Three patients harbored a homozygous c.272A > C, p.(Asp91Ala) mutation. These and two other patients showed slower progressing ALS (defined by ALS-PR

Patients with COVID-19 can have a variety of neurological symptoms, but the active involvement of central nervous system (CNS) in COVID-19 remains unclear. While routine cerebrospinal fluid (CSF) analyses in patients with neurological manifestations of COVID-19 generally show no or only mild inflammation, more detailed data on inflammatory mediators in the CSF of patients with COVID-19 are scarce. We studied the inflammatory response in paired CSF and serum samples of patients with COVID-19 (n = 38). Patients with herpes simplex virus encephalitis (HSVE, n = 10) and patients with non-inflammatory, non-neurodegenerative neurological diseases (n = 28) served as controls. We used proteomics, enzyme-linked immunoassays, and semiquantitative cytokine arrays to characterize inflammatory proteins. Autoantibody screening was performed with cell-based assays and native tissue staining. RNA sequencing of long-non-coding RNA and circular RNA was done to study the transcriptome. Proteomics on single protein level and subsequent pathway analysis showed similar yet strongly attenuated inflammatory changes in the CSF of COVID-19 patients compared to HSVE patients with, e.g., downregulation of the apolipoproteins and extracellular matrix proteins. Protein upregulation of the complement system, the serpin proteins pathways, and other proteins including glycoproteins alpha-2 and alpha-1 acid. Importantly, calculation of interleukin-6, interleukin-16, and CXCL10 CSF/serum indices suggest that these inflammatory mediators reach the CSF from the systemic circulation, rather than being produced within the CNS. Antibody screening revealed no pathological levels of known neuronal autoantibodies. When stratifying COVID-19 patients into those with and without bacterial superinfection as indicated by elevated procalcitonin levels, inflammatory markers were significantly (p

Background and aims Myasthenia Gravis requires expert treatment from specialized neurologists. In Germany, this treatment is mainly provided by 18 Integrated Myasthenia Centers (iMZ) accredited by the German Myasthenia Gravis Association (DMG). The DMG is a large and well-organized patient organisation that is regarded as a trusted source for disease-specific information. The aim of this study was to analyse the type of requests that each of these institutions receives in order to identify any potential unmet needs regarding the availability of advice for patients and caregivers. This data can then be used in further research to tailor modern digital communication tools to the specific needs of MG patients. Methods Counselling requests sent via e-mail to both institutions were extracted for defined examination periods and divided into a period ‘before COVID-19 pandemic’ (01.07.2019–31.12.2019) and ‘during COVID-19 pandemic’ (01.07.2020–31.12.2020). Requests were then analysed using four main categories: medical requests, organisational issues, COVID-19 and social legislation inquiries. Results One thousand seven hundred eleven requests for advice were addressed to DMG and iMZ Charité. Most inquiries directed to the DMG (47%; n = 750) were related to medical issues, most frequently to side effects of medications (n = 325; 20%) and questions about treatment (n = 263; 16%), followed by inquiries regarding organisational issues (26%; n = 412). About half of the inquiries (n = 69; 58%) to the iMZ Charité were related to medical issues and almost one in three inquiries concerned organisational issues (n = 37; 30%). About one in ten inquiries concerned socio-legal matters (iMZ: n = 7; 6% and DMG: n = 177; 11%). During the pandemic, COVID-19 related issues accounted for 8% (n = 6) of inquiries at iMZ, and 16% (n = 253) at DMG. Conclusions MG sufferers have a high demand for timely advice. In the current setting, they address their requests to both iMZs and the DMG via e-mail. Our findings confirm that the DMG is highly trusted by patients and caregivers and is used to obtain second opinions. A relevant proportion of requests to the iMZ could be answered more effectively through standardized responses or improved process management. The implementation of modern digital solutions, including telemedicine, for communication between patient and specialist should be evaluated in further research.

Cardiovascular diseases (CVD) remain the leading cause of mortality worldwide. Although major diagnostic and therapeutic advances have significantly improved the prognosis of patients with CVD in the past decades, these advances have less benefited women than age-matched men. Noninvasive cardiac imaging plays a key role in the diagnosis of CVD. Despite shared imaging features and strategies between both sexes, there are critical sex disparities that warrant careful consideration, related to the selection of the most suited imaging techniques, to technical limitations, and to specific diseases that are overrepresented in the female population. Taking these sex disparities into consideration holds promise to improve management and alleviate the burden of CVD in women. In this review, we summarize the specific features of cardiac imaging in four of the most common presentations of CVD in the female population including coronary artery disease, heart failure, pregnancy complications, and heart disease in oncology, thereby highlighting contemporary strengths and limitations. We further propose diagnostic algorithms tailored to women that might help in selecting the most appropriate imaging modality.

PURPOSE Total body irradiation (TBI) before allogeneic hematopoietic stem cell transplantation (HSCT) in pediatric patients with acute lymphoblastic leukemia (ALL) is efficacious, but long-term side effects are concerning. We investigated whether preparative combination chemotherapy could replace TBI in such patients. PATIENTS AND METHODS FORUM is a randomized, controlled, open-label, international, multicenter, phase III, noninferiority study. Patients ≤ 18 years at diagnosis, 4-21 years at HSCT, in complete remission pre-HSCT, and with an HLA-compatible related or unrelated donor were randomly assigned to myeloablative conditioning with fractionated 12 Gy TBI and etoposide versus fludarabine, thiotepa, and either busulfan or treosulfan. The noninferiority margin was 8%. With 1,000 patients randomly assigned in 5 years, 2-year minimum follow-up, and one-sided alpha of 5%, 80% power was calculated. A futility stopping rule would halt random assignment if chemoconditioning was significantly inferior to TBI (EudraCT: 2012-003032-22; ClinicalTrials.gov: NCT01949129 ). RESULTS Between April 2013 and December 2018, 543 patients were screened, 417 were randomly assigned, 212 received TBI, and 201 received chemoconditioning. The stopping rule was applied on March 31, 2019. The median follow-up was 2.1 years. In the intention-to-treat population, 2-year overall survival (OS) was significantly higher following TBI (0.91; 95% CI, 0.86 to 0.95; P < .0001) versus chemoconditioning (0.75; 95% CI, 0.67 to 0.81). Two-year cumulative incidence of relapse and treatment-related mortality were 0.12 (95% CI, 0.08 to 0.17; P < .0001) and 0.02 (95% CI, < 0.01 to 0.05; P = .0269) following TBI and 0.33 (95% CI, 0.25 to 0.40) and 0.09 (95% CI, 0.05 to 0.14) following chemoconditioning, respectively. CONCLUSION Improved OS and lower relapse risk were observed following TBI plus etoposide compared with chemoconditioning. We therefore recommend TBI plus etoposide for patients > 4 years old with high-risk ALL undergoing allogeneic HSCT.

Significance Ischemic stroke triggers peripheral immunosuppression, increasing the susceptibility to poststroke pneumonia that is linked with poor survival. The poststroke brain initiates intensive communication with the immune system, and acetylcholine contributes to these messages; but the responsible molecules are yet unknown. We discovered a “changing of the guards,” where microRNA levels decreased but small transfer RNA fragments increased in poststroke blood. This molecular switch may rebalance acetylcholine signaling in CD14+ monocytes by regulating their gene expression and modulating poststroke immunity. Our observations point to transfer RNA fragments as molecular regulators of poststroke immune responses that may be potential therapeutic targets., Stroke is a leading cause of death and disability. Recovery depends on a delicate balance between inflammatory responses and immune suppression, tipping the scale between brain protection and susceptibility to infection. Peripheral cholinergic blockade of immune reactions fine-tunes this immune response, but its molecular regulators are unknown. Here, we report a regulatory shift in small RNA types in patient blood sequenced 2 d after ischemic stroke, comprising massive decreases of microRNA levels and concomitant increases of transfer RNA fragments (tRFs) targeting cholinergic transcripts. Electrophoresis-based size-selection followed by qRT-PCR validated the top six up-regulated tRFs in a separate cohort of stroke patients, and independent datasets of small and long RNA sequencing pinpointed immune cell subsets pivotal to these responses, implicating CD14+ monocytes in the cholinergic inflammatory reflex. In-depth small RNA targeting analyses revealed the most-perturbed pathways following stroke and implied a structural dichotomy between microRNA and tRF target sets. Furthermore, lipopolysaccharide stimulation of murine RAW 264.7 cells and human CD14+ monocytes up-regulated the top six stroke-perturbed tRFs, and overexpression of stroke-inducible tRF-22-WE8SPOX52 using a single-stranded RNA mimic induced down-regulation of immune regulator Z-DNA binding protein 1. In summary, we identified a “changing of the guards” between small RNA types that may systemically affect homeostasis in poststroke immune responses, and pinpointed multiple affected pathways, which opens new venues for establishing therapeutics and biomarkers at the protein and RNA level.

Background Myasthenia gravis (MG) leads to exertion-dependent muscle weakness, but also psychological and social well-being are limited. We aim to describe the burden of disease in MG including sociodemographic, economical, psychosocial as well as clinical aspects, to compare health-related quality of life (HRQoL) of patients with MG to the general population (genP) and to explore risk factors for a lower HRQoL. Methods This case–control study was conducted with MG patients of the German Myasthenia Association. A questionnaire-based survey included sociodemographic and clinical data as well as standardized questionnaires, e.g. the Short Form Health (SF-36). HRQoL was compared to genP in a matched-pairs analysis. Participants of the German Health Interview and Examination Survey for Adults (DEGS1) served as control group. Results In our study, 1660 MG patients participated and were compared to 2556 controls from the genP. Patients with MG showed lower levels of physical functioning (SF-36 mean 56.0, SD 30.3) compared to the genP (mean 81.8, SD 22.1, adjusted difference: 25, 95% CI 22–29) and lower mental health sub-score (SF-36 mean 67.3, SD 19.8, vs. 74.1, SD 16.7, adjusted difference: 5, 95% CI 2–8). Female gender, higher age, low income, partnership status, lower activities of daily life, symptoms of depression, anxiety and fatigue and self-perceived low social support were associated with a lower HRQoL in MG patients. Discussion HRQoL is lower in patients with MG compared to genP. The burden of MG on patients includes economic and social aspects as well as their emotional well-being. New therapies must achieve improvements for patients in these areas. Trial registration information Clinicaltrials.gov, NCT03979521, submitted: June 7, 2019, first patient enrolled: May 1, 2019, https://clinicaltrials.gov/ct2/show/NCT03979521

Objective Simultaneous use of alcohol and cannabis is common among young adults, but little research has examined social ties and their relation to simultaneous use. This study investigated the social network characteristics of college students at two time points in the first year of college. Participants were categorized into those who used alcohol and cannabis, such that their effects overlap (simultaneous users), those who used both substances without overlapping effects (concurrent users), and those who used alcohol only. Method First-year college students (N = 1,294) completed online questionnaires during the fall and spring semester. At both assessments, participants nominated up to 10 important peers in their class, reported on peers' alcohol and cannabis use, and reported their own use of alcohol or cannabis with each peer. Results Concurrent and simultaneous users reported a greater proportion of drinking buddies than those who used alcohol only. A greater proportion of friends who used alcohol or cannabis, but not the proportion who were "drinking buddies" or "cannabis buddies," was associated with increased odds of simultaneous use relative to concurrent use. Participants nominated network ties that paralleled their own substance use (e.g., the majority of simultaneous users' networks ties were also simultaneous users). Conclusion Having a larger percentage of friends who use cannabis and alcohol is associated with increased odds of using both substances at the same time, perhaps because it gives access to both substances at the same time. Interventions should account for amount of exposure to alcohol and cannabis use from network members. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Background: Psychiatric comorbidities are relevant in patients with Myasthenia gravis (MG). Also, MG patients experience a reduced health related quality of life (HRQoL). We aimed to quantify the impact of depression as well as self-perceived MG severity on HRQoL and caregivers' burden.Methods: In this cross-sectional study, we used a survey encompassing demographic, disease-related information and standardized questionnaires to assess depression, anxiety, HRQoL (MG Quality of Life scale; MG-QoL15) and caregiver burden (Burden Scale for Family Caregivers; BSFC).Results: Data from 1399 participating patients (96%) and 1042 caregivers (65%) were eligible for further analysis. Depression and anxiety disorder were indicated by 31% and 36% of patients. Self-reported MG severity and MG-QoL15 scores were strongly associated (estimated marginal means for severe vs. mild MG severity= 18 95% CI [16; 21]; p≤0.001). Adjusting for depression decreased the estimated strength of this association (estimated marginal means for severe vs. mild MG severity= 15 [13; 17]; p≤0.001). Caregiver burden is associated to MG disease severity (estimated marginal means for severe vs. mild MG severity= 0.16 [0.13; 0,19); p≤0.001) and also negatively influenced by depression (estimated marginal means= 0.12 [0.09; 0.15]).Conclusion: Depression and anxiety disorder in MG are frequent. Beyond MG severity, depression has negative effects on HRQoL as well as on caregivers’ burden. Diagnosis and treatment of psychiatric comorbidities should be considered as an important element in MG care. Screening tools for mental health conditions should be implemented at least in specialized MG centers.