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Clinical, biomedical, and translational science has reached an inflection point in the breadth and diversity of available data and the potential impact of such data to improve human health and well-being. However, the data are often siloed, disorganized, and not broadly accessible due to discipline-specific differences in terminology and representation. To address these challenges, the Biomedical Data Translator Consortium has developed and tested a pilot knowledge graph-based "Translator" system capable of integrating existing biomedical data sets and "translating" those data into insights intended to augment human reasoning and accelerate translational science. Having demonstrated feasibility of the Translator system, the Translator program has since moved into development, and the Translator Consortium has made significant progress in the research, design, and implementation of an operational system. Herein, we describe the current system's architecture, performance, and quality of results. We apply Translator to several real-world use cases developed in collaboration with subject-matter experts. Finally, we discuss the scientific and technical features of Translator and compare those features to other state-of-the-art, biomedical graph-based question-answering systems.

BackgroundChronic pain and opioid use disorder (OUD) individually represent a risk to health and well-being. Concerningly, there is evidence that they are frequently co-morbid. While few treatments exist that simultaneously target both conditions, preliminary work has supported the feasibility of an integrated behavioral treatment targeting pain interference and opioid misuse. This treatment combined Acceptance and Commitment Therapy (ACT) and Mindfulness-Based Relapse Prevention (ACT+MBRP). This paper describes the protocol for the adequately powered efficacy study of this integrated treatment.MethodsA multisite randomized controlled trial will examine the efficacy of ACT+MBRP in comparison to a parallel education control condition, focusing on opioid safety and pain education. Participants include veterans (n = 160; 21–75 years old) recruited from three Veterans Administration (VA) Healthcare Systems with chronic pain who are on a stable dose of buprenorphine. Both conditions include twelve weekly 90 min group sessions delivered via telehealth. Primary outcomes include pain interference (Patient Reported Outcome Measurement Information System - Pain Interference) and hazardous opioid use (Current Opioid Misuse Measure), which will be examined at the end of the active treatment phase and through 12 months post-intervention. Secondary analyses will evaluate outcomes including pain intensity, depression, pain-related fear, and substance use, as well as treatment mechanisms.ConclusionThis study will determine the efficacy of an integrated behavioral treatment program for pain interference and hazardous opioid use among veterans with chronic pain and OUD who are prescribed buprenorphine, addressing a critical need for more integrated treatments for chronic pain and OUD.Trial registrationClinicalTrials.gov Identifier: NCT04648228

CYP2A6 activity, phenotyped by the nicotine metabolite ratio (NMR), is a predictor of several smoking behaviors, including cessation and smoking‐related disease risk. The heritability of the NMR is 60–80%, yet weighted genetic risk scores (wGRSs) based on common variants explain only 30–35%. Rare variants (minor allele frequency

The missense variant, breast cancer resistance protein (BCRP) p.Q141K, which encodes a reduced function BCRP, has been linked to poor response to allopurinol. Using a multifaceted approach, we aimed to characterize the relationship(s) between BCRP p.Q141K, the pharmacokinetics (PK) and pharmacodynamics (PD) of oxypurinol (the active metabolite of allopurinol), and serum uric acid (SUA) levels. A prospective clinical study (NCT02956278) was conducted in which healthy volunteers were given a single oral dose of 300mg allopurinol followed by intensive blood sampling. Data were analyzed using noncompartmental analysis and population PK/PD modeling. Additionally, electronic health records were analyzed to investigate whether clinical inhibitors of BCRP phenocopied the effects of the p.Q141K variant with respect to SUA. Subjects homozygous for p.Q141K had a longer half-life (34.2±12.2h vs. 19.1±1.42h) of oxypurinol. The PK/PD model showed that women had a 24.8% lower volume of distribution. Baseline SUA was affected by p.Q141K genotype and renal function; that is, it changed by 48.8% for every 1mg/dl difference in serum creatinine. Real-world data analyses showed that patients prescribed clinical inhibitors of BCRP have higher SUA levels than those that have not been prescribed inhibitors of BCRP, consistent with the idea that BCRP inhibitors phenocopy the effects of p.Q141K on uric acid levels. This study identified important covariates of oxypurinol PK/PD that could affect its efficacy for the treatment of gout as well as a potential side effect of BCRP inhibitors on increasing uric acid levels, which has not been described previously.

Anaphylaxis is a serious systemic hypersensitivity reaction that is usually rapid in onset and may cause death. It is characterised by the rapid development of airway and/or breathing and/or circulation problems. Intramuscular adrenaline is the most important treatment, although, even in healthcare settings, many patients do not receive this intervention contrary to guidelines. The Resuscitation Council UK published an updated guideline in 2021 with some significant changes in recognition, management, observation and follow-up of patients with anaphylaxis. This is a concise version of the updated guideline.

Coccidioidomycosis is a fungal infection of the Western hemisphere that is endemic to the soil in areas with limited rainfall. Human and animal infections result with inhalation of arthroconidia. Most often, this is an asymptomatic event. When illness occurs, it is primarily a pneumonic presentation. A small minority of infections eventuate in disseminated disease. Predominately, this presents as meningitis or osteoarticular or integumentary disease. Treatment may not be required for the mildest illness. Azoles are commonly prescribed. Severe infections may require amphotericin B.

Chronic coronary syndromes (CCS) and stable angina are a growing clinical burden worldwide. This is of particular concern in the Gulf region given its high prevalence of cardiovascular risk factors, especially diabetes mellitus and smoking. Despite recommendations on the use of first- and second-line anti-anginal medication, management challenges remain. Current guidelines for pharmacologic treatment are not determined by the range of pathophysiological mechanisms of ischaemia and consequent angina, which may occur either in isolation or co-exist. In this article, we highlight the need to improve knowledge of the epidemiology of chronic coronary syndromes in the Middle East and Gulf region, and the need for studies of stratified pharmacologic approaches to improve symptomatic angina and quality of life in the large and growing number of patients with coronary artery disease from this region. We discuss the role of nicorandil, currently recommended as a second-line anti-anginal drug in CCS patients, and suggest that this may be a particularly useful add-on therapy for patients in the Gulf region.

Graft function is crucial for successful kidney transplantation. Many factors may affect graft function or cause delayed graft function (DGF), which decreases the prognosis for graft survival. This study was designed to evaluate whether the perioperative use of dexmedetomidine (Dex) could improve the incidence of function of graft kidney and complications after kidney transplantation. A total of 780 patients underwent kidney transplantations, 315 received intravenous Dex infusion during surgery, and 465 did not. Data were adjusted with propensity scores and multivariate logistic regression was used. The primary outcomes are major adverse complications, including DGF and acute rejection in the early post-transplantation phase. The secondary outcomes included length of hospital stay (LOS), infection, overall complication, graft functional status, post-transplantation serum creatinine values, and estimated glomerular filtration rate (eGFR). Dex use significantly decreased DGF (19.37% vs. 23.66%; adjusted odds ratio, 0.744; 95% confidence interval, 0.564-0.981; P=0.036), risk of infection, risk of acute rejection in the early post-transplantation phase, the risk of overall complications, and LOS. However, there were no statistical differences in 90-day graft functional status or 7-day, 30-day, and 90-day eGFR. Perioperative Dex use reduced incidence of DGF, risk of infection, risk of acute rejection, overall complications, and LOS in patients who underwent kidney transplantation.

Determining factors that contribute to interindividual and intra-individual variability in pharmacokinetics (PKs) and drug metabolism is essential for the optimal use of drugs in humans. Intestinal microbes are important contributors to variability; however, such gut microbe-drug interactions and the clinical significance of these interactions are still being elucidated. Traditional PKs can be complemented by untargeted mass spectrometry coupled with molecular networking to study the intricacies of drug metabolism. To show the utility of molecular networking on metabolism we investigated the impact of a 7-day course of cefprozil on cytochrome P450 (CYP) activity using a modified Cooperstown cocktail and assessed plasma, urine, and fecal data by targeted and untargeted metabolomics and molecular networking in healthy volunteers. This prospective study revealed that cefprozil decreased the activities of CYP1A2, CYP2C19, and CYP3A, decreased alpha diversity and increased interindividual microbiome variability. We further demonstrate a relationship between the loss of microbiome alpha diversity caused by cefprozil and increased drug and metabolite formation in fecal samples. Untargeted metabolomics/molecular networking revealed several omeprazole metabolites that we hypothesize may be metabolized by both CYP2C19 and bacteria from the gut microbiome. Our observations are consistent with the hypothesis that factors that perturb the gut microbiome, such as antibiotics, alter drug metabolism and ultimately drug efficacy and toxicity but that these effects are most strongly revealed on a per individual basis.

The effect of nintedanib on slowing the rate of decline in forced vital capacity (FVC) has been investigated in randomized placebo-controlled trials in subjects with idiopathic pulmonary fibrosis (IPF), other progressive fibrosing interstitial lung diseases (ILDs), and ILD associated with systemic sclerosis (SSc-ILD). We assessed the consistency of the effect of nintedanib on the rate of decline in FVC over 52 weeks across four placebo-controlled phase III trials. Methods: We used data on FVC decline from the INPULSIS-1 and INPULSIS-2 trials in subjects with IPF, the INBUILD trial in subjects with progressing fibrosing ILDs other than IPF, and the SENSCIS trial in subjects with SSc-ILD. In each trial, the primary endpoint was the annual rate of decline in FVC (mL/year) assessed over 52 weeks. We performed fixed effect and random effects meta-analyses based on the relative treatment effect of nintedanib versus placebo on the rate of decline in FVC (mL/year) over 52 weeks. Heterogeneity of the relative treatment effect of nintedanib across populations was assessed using the I2 statistic, τ2 and corresponding p value from a Q test for heterogeneity. The combined analysis comprised 1257 subjects treated with nintedanib and 1042 subjects who received placebo. Nintedanib reduced the rate of decline in FVC (mL/year) over 52 weeks by 51.0% (95% CI 39.1, 63.0) compared with placebo. The relative effect (95% CI) was the same using the fixed effect and random effects models. There was no evidence of heterogeneity in the relative treatment effect of nintedanib across the populations studied (I2 = 0%, τ2 = 0, p = 0.93). Conclusions: A meta-analysis of data from four placebo-controlled trials demonstrated that nintedanib approximately halved the rate of decline in FVC over 52 weeks across subjects with different forms of pulmonary fibrosis, with no evidence of heterogeneity in its relative treatment effect across patient populations, Open Access funding enabled and organized by Projekt DEAL. The INPULSIS, SENSCIS and INBUILD trials were funded by Boehringer Ingelheim International GmbH (BI)

Purpose: This literature review is aimed at examining the benefits of lifestyle modifications in preventing recurrent gestational diabetes (GDM). Worldwide GDM affects approximately 16.2% of all pregnancies with significant maternal, fetal and neonatal complications. Almost two thirds of pregnant women with GDM will develop type 2 diabetes mellitus (T2DM) in the years following pregnancy. The proportion of women affected by GDM is on the rise and reflects increasing trends in T2DM as well as adult and childhood obesity. Methods: Using predefined subject headings, we searched for relevant articles from the PubMed, Scopus, and Cochrane databases. Results: For high-risk women lifestyle modifications, such as dietary and exercise changes, are the mainstay of treatment to reduce negative outcomes for both women and their pregnancies. This includes reducing the incidence of recurrent GDM and future T2DM by intervening during pregnancy and in the postnatal period. Conclusion: This review provides an overview of the literature to date, discusses different targeted approaches and how these interventions can optimise their benefits, and where further research is required.

International audience; Introduction : Il n'existe actuellement aucun traitement approuvé uniquement pour la maladie pulmonaire interstitielle inclassable (uILD) ; cependant, un essai récent a montré que cette population peut bénéficier de la pirfénidone. Nous rapportons une analyse de sous-groupe de cet essai pour évaluer les effets des immunomodulateurs (mycophénolate mofétil [MMF] concomitant et/ou corticostéroïdes antérieurs) avec la pirfénidone chez les patients atteints d'uILD.Méthodes : Il s'agissait d'un essai de phase II multicentrique, international, en double aveugle, randomisé et contrôlé par placebo portant sur des patients atteints d'uILD fibrosante progressive ( NCT03099187 ). Les patients ont été randomisés (1:1) pour recevoir de la pirfénidone 2403 mg/jour ou un placebo. Cette analyse a évalué la variation de la capacité vitale forcée (CVF) par rapport à la ligne de base mesurée à l'aide de la spirométrie du site (critère d'évaluation secondaire clé) et la sécurité sur 24 semaines par l'utilisation concomitante de MMF lors de la randomisation (analyse pré-spécifiée) et/ou l'utilisation antérieure de corticostéroïdes (analyse post hoc).Résultats: Au total, 253 patients ont été randomisés, dont 45 (17,8%) patients (pirfénidone, n = 23 ; placebo, n = 22) recevant de manière concomitante du MMF avec/sans corticoïdes (sous-groupe MMF) ; 79 (31,2 %) patients (pirfénidone, n = 44 ; placebo, n = 35) ayant déjà reçu des corticostéroïdes sans MMF (sous-groupe corticostéroïdes/sans MMF) ; et 129 (51,0 %) patients (pirfénidone, n = 60 ; placebo, n = 69) ne recevant pas de MMF concomitante ou de corticoïdes antérieurs (sous-groupe sans corticoïdes/sans MMF). À 24 semaines, la différence de variation moyenne (intervalle de confiance à 95 %) de la CVF par rapport à la ligne de base entre la pirfénidone et le placebo était de - 55,4 ml (- 206,7, 96,0 ; P = 0,4645) dans le sous-groupe MMF ; 128,4 mL (- 6,4 ; 263,3 ; P = 0,0617) dans le sous-groupe corticoïdes/sans MMF ; et 115,5 ml (35,1 195,9 ; P = 0,0052) dans le sous-groupe sans corticostéroïdes/sans MMF.Conclusion : Bien que limitée par la conception et la petite taille des échantillons, cette analyse suggère que la pirfénidone peut être moins efficace chez les patients atteints d'uILD recevant du MMF en concomitance, alors qu'un effet thérapeutique bénéfique a été observé chez les patients ne recevant pas de MMF en concomitance, indépendamment de l'utilisation antérieure de corticostéroïdes. La pirfénidone a été bien tolérée indépendamment de l'utilisation de MMF et/ou de corticostéroïdes.

Background Clonal immunoglobulin and T-cell receptor rearrangements serve as tumor-specific markers that have become mainstays of the diagnosis and monitoring of lymphoid malignancy. Next-generation sequencing (NGS) techniques targeting these loci have been successfully applied to lymphoblastic leukemia and multiple myeloma for minimal residual disease detection. However, adoption of NGS for primary diagnosis remains limited. Methods We addressed the bioinformatics challenges associated with immune cell sequencing and clone detection by designing a novel web tool, CloneRetriever (CR), which uses machine-learning principles to generate clone classification schemes that are customizable, and can be applied to large datasets. CR has 2 applications—a “validation” mode to derive a clonality classifier, and a “live” mode to screen for clones by applying a validated and/or customized classifier. In this study, CR-generated multiple classifiers using 2 datasets comprising 106 annotated patient samples. A custom classifier was then applied to 36 unannotated samples. Results The optimal classifier for clonality required clonal dominance ≥4.5× above background, read representation ≥8% of all reads, and technical replicate agreement. Depending on the dataset and analysis step, the optimal algorithm yielded sensitivities of 81%–90%, specificities of 97%–100%, areas under the curve of 91%–94%, positive predictive values of 92–100%, and negative predictive values of 88%–98%. Customization of the algorithms yielded 95%–100% concordance with gold-standard clonality determination, including rescue of indeterminate samples. Application to a set of unknowns showed concordance rates of 83%–96%. Conclusions CR is an out-of-the-box ready and user-friendly software designed to identify clonal rearrangements in large NGS datasets for the diagnosis of lymphoid malignancies.

The safety of novel therapeutics and vaccines are typically assessed in early phase clinical trials involving “healthy volunteers.” Abnormalities in such individuals can be difficult to interpret and may indicate previously unrecognized medical conditions. The frequency of incidental findings (IFs) in healthy volunteers who attend for clinical trial screening is unclear. To assess this, we retrospectively analyzed data for 1838 “healthy volunteers” screened for enrolment in a UK multicenter, phase I/II severe acute respiratory syndrome‐coronavirus 2 (SARS‐COV‐2) vaccine trial. Participants were predominantly White (89.7%, 1640/1828) with a median age of 34 years (interquartile range [IQR] = 27–44). There were 27.7% of participants (510/1838) who had at least one IF detected. The likelihood of identifying evidence of a potential, new blood‐borne virus infection was low (1 in 238 participants) compared with identification of an elevated alanine transaminase (ALT; 1 in 17 participants). A large proportion of participants described social habits that could impact negatively on their health; 21% consumed alcohol in excess, 10% were current smokers, 11% described recreational drug use, and only 48% had body weight in the ideal range. Our data demonstrate that screening prior to enrollment in early phase clinical trials identifies a range of IFs, which should inform discussion during the consent process. Greater clarity is needed to ensure an appropriate balance is struck between early identification of medical problems and avoidance of exclusion of volunteers due to spurious or physiological abnormalities. Debate should inform the role of the trial physician in highlighting and advising about unhealthy social habits.

The global pandemic of severe acute respiratory syndrome coronavirus 2 (SARS‐Co‐V‐2) has resulted in a critical need to rapidly develop new pharmacologic interventions and disseminate information. This has led to confusing and conflicting information on drug efficacy. Remdesivir has emerged as a promising treatment for SARS‐Co‐V‐2 infection yet published clinical pharmacology and drug interaction studies are limited. Additional studies of the disposition of remdesivir, its active metabolite (GS‐441524), and its triphosphate metabolite (GS‐443902) are needed.

Although immunoassays are the most widely used protein measurement method, aptamer-based methods such as the SomaScan platform can quantify up to 7000 proteins per biosample, creating new opportunities for unbiased discovery. However, there is limited research comparing the consistency of biomarker-disease associations between immunoassay and aptamer-based platforms. In a substudy of the TRIBE-AKI cohort, preoperative and postoperative plasma samples from 294 patients with previous immunoassay measurements were analyzed using the SomaScan platform. Inter-platform Spearman correlations (rs) and biomarker-AKI associations were compared across 30 preoperative and 34 postoperative immunoassay-aptamer pairs. Possible factors contributing to inter-platform differences were examined including target protein characteristics, immunoassay, and SomaScan coefficients of variation, other assay characteristics, and sample storage time. The median rs was 0.54 (interquartile range [IQR] 0.34-0.83) in postoperative samples and 0.41 (IQR 0.21-0.69) in preoperative samples. We observed a trend of greater rs in biomarkers with greater concentrations; the Spearman correlation between the concentration of protein and the inter-platform correlation was 0.64 in preoperative pairs and 0.53 in postoperative pairs. Of proteins measured by immunoassays, we observed significant biomarker-AKI associations for 13 proteins preop and 24 postop; of all corresponding aptamers, 8 proteins preop and 12 postop. All proteins significantly associated with AKI as measured by SomaScan were also significantly associated with AKI as measured by immunoassay. All biomarker-AKI odds ratios were significantly different (P < 0.05) between platforms in 14% of aptamer-immunoassay pairs, none of which had high (rs > 0.50) inter-platform correlations. Although similar biomarker-disease associations were observed overall, biomarkers with high physiological concentrations tended to have the highest-confidence inter-platform operability in correlations and biomarker-disease associations. Aptamer assays provide excellent precision and an unprecedented coverage and promise for disease associations but interpretation of results should keep in mind a broad range of correlations with immunoassays.

An expert committee was formed to reach consensus on the use of tilt table testing (TTT) in the diagnosis of disorders that may cause transient loss of consciousness (TLOC) and to outline when other provocative cardiovascular autonomic tests are needed. While TTT adds to history taking, it cannot be a substitute for it. An abnormal TTT result is most meaningful if the provoked event is recognised by patients or eyewitnesses as similar to spontaneous events. The minimum requirements to perform TTT are a tilt table, a continuous beat-to-beat blood pressure monitor, at least one ECG lead, protocols for the indications stated below and trained staff. This basic equipment lends itself to the performance of (1) additional provocation tests, such as the active standing test, carotid sinus massage and autonomic function tests; (2) additional measurements, such as video, EEG, transcranial Doppler, NIRS, end-tidal CO2 or neuro-endocrine tests; and (3) tailor-made provocation procedures in those with a specific and consistent trigger of TLOC. TTT and other provocative cardiovascular autonomic tests are indicated if the initial evaluation does not yield a definite or highly likely diagnosis, but raises a suspicion of (1) reflex syncope, (2) the three forms of orthostatic hypotension (OH), i.e. initial, classic and delayed OH, as well as delayed orthostatic blood pressure recovery, (3) postural orthostatic tachycardia syndrome or (4) psychogenic pseudosyncope. A therapeutic indication for TTT is to teach patients with reflex syncope and OH to recognise hypotensive symptoms and to perform physical counter manoeuvres.

Background Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease characterized by an unpredictable decline in lung function. Predicting IPF progression from the early changes in lung function tests have known to be a challenge due to acute exacerbation. Although it is unpredictable, the neighboring regions of fibrotic reticulation increase during IPF's progression. With this clinical information, quantitative characteristics of high-resolution computed tomography (HRCT) and a statistical learning paradigm, the aim is to build a model to predict IPF progression. Design A paired set of anonymized 193 HRCT images from IPF subjects with 6–12 month intervals were collected retrospectively. The study was conducted in two parts: (1) Part A collects the ground truth in small regions of interest (ROIs) with labels of “expected to progress” or “expected to be stable” at baseline HRCT and develop a statistical learning model to classify voxels in the ROIs. (2) Part B uses the voxel-level classifier from Part A to produce whole-lung level scores of a single-scan total probability's (STP) baseline. Methods Using annotated ROIs from 71 subjects' HRCT scans in Part A, we applied Quantum Particle Swarm Optimization–Random Forest (QPSO-RF) to build the classifier. Then, 122 subjects' HRCT scans were used to test the prediction. Using Spearman rank correlations and survival analyses, we ascertained STP associations with 6–12 month changes in quantitative lung fibrosis and forced vital capacity. Conclusion This study can serve as a reference for collecting ground truth, and developing statistical learning techniques to predict progression in medical imaging.

Objectives To explore knowledge and attitude about Covid‐19, among Syrian refugee mothers in the Governorate of Irbid, where the first outbreak of Covid‐19 in Jordan took place. Methods This is a cross‐section study among Syrian refugee mothers, who were pregnant or having had children. Data was collected through an online questionnaire. The survey link was distributed in April 2020, through the social network's messaging services Facebook and WhatsApp. Contact information was obtained from local community centres and non‐governmental organisations in the town of Irbid, the north of Jordan. Results In total, 389 Syrian refugee mothers participated in the study. It showed that 66% of mother's access information regarding Covid‐19. The main sources of information were Facebook 87%, WhatsApp 69%, television 53%, while 21% indicated that they access professional databases or government websites. In general, Syrian refugee mothers were knowledgeable about Covid‐19 transmission and prevention. However, they lacked adequate knowledge about transmission of Covid‐19 between the mother and the child, and smoking risks associated with Covid‐19. Conclusions There are gaps in the knowledge and attitude of Syrian refugee mothers in the Governorate of Irbid in relation to the Covid‐19 pandemic. There is a need for further health education measures.

Background Assessing why the spread of the COVID 19 virus slowed down in many countries in March through to May of 2020 is of great significance. The relative role of restrictions on behaviour (”lockdowns”) and of a natural slowing for other reasons is difficult to asses when mass testing was not widely done. This paper assesses the evolution of the spread of the COVID 19 virus over this period when there was not data on test results for a large, random sample of the population. Method We estimate a version of the SIR model applied to data on the numbers who were tested positive in several countries over the period when the virus spread very fast and then its spread slowed sharply. Up to the end of April 2020 test data came from non random samples of populations who were overwhelmingly those who displayed symptoms. Using data from a period when the criteria used for testing (which was that people had clear symptoms) was relatively consistent is important in drawing out the message from test results. We use this data to assess two things: how large might be the group of those infected who were not recorded; how effective were lockdown measures in slowing the spread of the infection. Results We find that to match data on daily new cases of the virus, the estimated model favours high values for the number of people infected but not recorded. Conclusions Our findings suggest that the infection may have spread far enough in many countries by April 2020 to have been a significant factor behind the fall in measured new cases. Government restrictions on behavior ‐ lockdowns ‐ were only one factor behind slowing in the spread of the virus.

PURPOSE:This study explored the characteristics associated with the use of self-care products and practices by people rehabilitating from stroke. MATERIALS AND METHODS:A cross-sectional sub-study of the Sax Institute's 45 and Up Study in which 1300 participants who had indicated a doctor had diagnosed them as having had a stroke were mailed a sub-study survey. The survey instrument included questionnaire items on demographics, self-care products and practices, health status, and stroke status. RESULTS:The survey was completed by 576 (44.3%) of those eligible. At least one self-care product or practice was used by 39.9% of participants. Female participants were more likely than males to use self-care products (p=

The SARS-CoV-2 (COVID-19) pandemic has caused unprecedented morbidity, mortality and global disruption. Following the initial surge of infections, focus shifted to managing the longer-term sequelae of illness in survivors. ‘Post-acute COVID’ (known colloquially as ‘long COVID’) is emerging as a prevalent syndrome. It encompasses a plethora of debilitating symptoms (including breathlessness, chest pain, palpitations and orthostatic intolerance) which can last for weeks or more following mild illness. We describe a series of individuals with symptoms of ‘long COVID’, and we posit that this condition may be related to a virus- or immune-mediated disruption of the autonomic nervous system resulting in orthostatic intolerance syndromes. We suggest that all physicians should be equipped to recognise such cases, appreciate the symptom burden and provide supportive management. We present our rationale for an underlying impaired autonomic physiology post-COVID-19 and suggest means of management.

Introduction Patients with asthma typically increase short-acting β2-agonists (SABA) use with worsening symptoms. Excessive SABA use may lead to a higher risk of adverse outcomes. We evaluated, in a large population cohort, an association between SABA inhaler use and asthma exacerbations and healthcare utilization. Methods As part of the SABINA (SABA use IN Asthma) global program, we conducted a retrospective longitudinal observational study (SABINA I) using UK primary care electronic healthcare records (Clinical Practice Research Datalink; 2007–2017) from asthma patients aged ≥ 12 years. SABA inhaler use was classified as ‘high use ’ 3 canisters/year versus ‘low use’, 0–2 canisters/year. Taking into consideration all their asthma prescriptions, patients were categorized into a treatment step according to 2016 British Thoracic Society (BTS) asthma management guidelines. Multivariable regression assessed the association of SABA inhaler use by BTS treatment steps (grouped as BTS steps 1/2 and 3–5), separately, and with outcomes of exacerbations or asthma-related healthcare utilization (primary care and hospital outpatient consultations); only patients with linked hospital data were included in this analysis. Results Of the 574,913 patients included, 218,365 (38%) had high SABA inhaler use. Overall, 336,412 patients had linked hospital data. High SABA inhaler use was significantly associated with an increased risk of exacerbations [adjusted hazard ratio, 95% confidence interval (CI): BTS steps 1/2 = 1.20, 1.16–1.24; BTS steps 3–5 = 1.24, 1.20–1.28], asthma-related primary care consultations [adjusted incidence rate ratio (IRR), 95% CI: BTS steps 1/2 = 1.24, 1.23–1.26; BTS steps 3–5 = 1.13, 1.11–1.15), and asthma-related hospital outpatient consultations (adjusted IRR, 95% CI: BTS steps 1/2 = 1.19, 1.12–1.27; BTS steps 3–5 = 1.19, 1.13–1.26). Conclusion High SABA inhaler use was frequent across BTS steps and was associated with a significant increase in exacerbations and asthma-related healthcare utilization.

Myocardial infarction (MI) is one of the leading causes of global mortality. Over the last decade, acute MI mortality has significantly decreased; however, fatal heart failure remains a common complication for post-MI survivors.[1][1] Lack of oxygen due to MI causes cardiac tissue necrosis and, as a

Introduction Systemic sclerosis-associated interstitial lung disease (SSc-ILD) places a substantial burden on patients and healthcare systems. The objectives of this study were to describe clinical characteristics and assess healthcare resource utilization and costs of patients with SSc-ILD in England, compared with patients with non-pulmonary organ involvement related to SSc (SSc-OOI). Methods This population-based retrospective study used data from the Clinical Practice Research Datalink linked to Hospital Episode Statistics. Data were extracted from medical records dated January 1, 2005 to March 31, 2016. Patients with SSc were identified and placed in subgroups based on organ involvement: SSc-ILD, SSc-OOI, and both (SSc-ILD-OOI). Patients with SSc-ILD-OOI were included in both the SSc-ILD and SSc-OOI subgroups. All-cause healthcare costs, excluding medication costs, were calculated to 2016 British pounds sterling (£). Results This study included 675 patients with SSc: 174 (26%) had neither ILD nor other organ involvement (OOI); 127 (19%) had SSc-ILD; 477 (71%) had SSc-OOI; 103 (15%) had SSc-ILD-OOI. Age-weighted median [interquartile range (IQR)] annual healthcare costs per patient were: £1496 (£664–£2817) in SSc only; £6375 (£3451–£15,041) in SSc-ILD; £4084 (£1454–£10,105) in SSc-OOI; £6632 (£4023–£17,009) in SSc-ILD-OOI. In multivariate analysis, older age at diagnosis, diagnosis of anemia, and number of comorbid diseases were associated with higher yearly healthcare costs. Conclusion The annual healthcare cost for patients with SSc-ILD is substantial, and higher than that of patients with SSc-OOI or SSc only. These results quantify the economic burden of SSc-ILD in a real-world setting, and highlight the need for treatment of this disease. Electronic supplementary material The online version of this article (10.1007/s12325-020-01330-0) contains supplementary material, which is available to authorized users., Plain Language Summary SSc is a rare disease that causes fibrosis, or thickening, of the skin. In some patients, SSc can also affect the lungs (‘SSc-ILD’) or other organs, e.g., the heart (‘SSc-OOI’). Patients with SSc-ILD typically have high healthcare costs; however, it is not clear how costs for SSc-ILD compare with those for SSc-OOI. To investigate this, we evaluated the costs associated with SSc-ILD and compared them with those for SSc only or SSc-OOI. In this England-based study, the annual healthcare costs for patients with SSc-ILD were approximately 50% higher than for those without lung disease (SSc only) or SSc-OOI. These results highlight the importance of promptly diagnosing and treating patients with lung fibrosis complicating SSc. Electronic supplementary material The online version of this article (10.1007/s12325-020-01330-0) contains supplementary material, which is available to authorized users.

Introduction Total knee arthroplasty (TKA) reduces joint symptoms, but habitual movement compensations persist years after surgery. Preliminary research on movement training interventions have signaled initial efficacy for remediating movement compensations and restoring knee joint loading symmetry during dynamic functional tasks after TKA. The purpose of this clinical trial is to determine if physical rehabilitation that includes movement training restores healthy movement patterns after TKA and reduces the risk of osteoarthritis (OA) progression in the contralateral knee. Methods/design 150 participants will be enrolled into this randomized controlled trial. Participants will be randomly allocated to one of two dose-equivalent treatment groups: standard rehabilitation plus movement training (MOVE) or standard rehabilitation without movement training (CONTROL). Movement training will promote between-limb symmetry and surgical knee loading during activity-based exercises. Movement training strategies will include real-time biofeedback using in-shoe pressure sensors and verbal, visual, and tactile cues from the physical therapist. The primary outcome will be change in peak knee extension moment in the surgical knee during walking, from before surgery to six months after surgery. Secondary outcomes will include lower extremity movement symmetry during functional tasks, physical function, quadriceps strength, range of motion, satisfaction, adherence, contralateral knee OA progression, and incidence of contralateral TKA. Discussion This study will provide insights into the efficacy of movement training after unilateral TKA, along with mechanisms for optimizing long-term physical function and minimizing negative sequelae of compensatory movement patterns.

Canaloplasty is a relatively new non-penetrating surgery for the reduction of intraocular pressure in patients affected by glaucoma. The technique uses a microcatheter to perform a 360 o cannulation of Schlemm's canal and leaves in place a tension suture providing an inward distension. It aims to restore the physiological outflow pathways of the aqueous humour and is independent of external wound healing. Several studies have shown that canaloplasty is effective in reducing intraocular pressure and has a low rate of complications, especially compared with trabeculectomy, the gold standard for glaucoma surgery. Currently, canaloplasty is indicated in patients with open-angle glaucoma, having a mild to moderate disease, and the combination with cataract phacoemulsification may provide further intraocular pressure reduction. This article reviews canaloplasty indications, results and complications and analyses its outcomes compared with traditional penetrating and non-penetrating techniques.

Despite negative association between 25-hydroxy vitamin D and incidence of many chronic respiratory diseases, this feature was not well studied in sarcoidosis. Current study investigated the association between 25-hydroxy vitamin D deficiency with sarcoidosis chronicity, disease activity, extra-pulmonary skin manifestations, urine calcium level and pulmonary function status in Iranian sarcoidosis patients. Results of this study along with future studies, will supply more effective programs for sarcoidosis treatment.Eighty sarcoidosis patients in two groups of insufficient serum level and sufficient serum level of 25-hydroxy vitamin D were studied. Course of sarcoidosis was defined as acute and chronic sarcoidosis. Pulmonary function test (PFT) was assessed by spirometry. Skin involvements were defined as biopsy proven skin sarcoidosis. 24-hour urine calcium level was used to specify the disease activity. Stages of lung involvements were obtained by CT-scan and chest X-ray. The statistical analyses were evaluated using Statistical Package for the Social Sciences.A significant negative correlation was obtained between vitamin D deficiency in sarcoidosis patients and disease chronic course and stages two to four of lung involvements. Considering other parameters of the disease and vitamin D deficiency, no significant correlation was detected.In conclusion, results of the current study implies in the role of vitamin 25(OH)D deficiencies in predicting the course of chronic sarcoidosis. Furthermore, it was concluded that vitamin 25(OH)D deficiency can direct pulmonary sarcoidosis toward stage 2-4 of lung involvements.Uprkos negativnoj povezanosti između 25-hidroksi vitamina D i učestalosti brojnih hroničnih respiratornih oboljenja, ovaj uticaj još uvek nije ispitivan u sarkoidozi. Ova istraživanja izučavaju vezu između deficijencije 25-hidroksi vitamina D sa stepenom hroničnosti kod sarkoidoze, aktivnosti oboljenja, ekstra pulmonalnih kožnih manifestacija, nivoa kalcijuma u urinu i statusa pulmonalne funkcije kod Iranskih pacijenata sa sarkoidozom. Rezultati ovih izučavanja sa budućim istraživanjima mogu ukazati na mnogo bolji uspeh u tretmanu sarkoidoze.Proučavano je osamdeset pacijenata sa sarkoidozom podeljenih u dve grupe u odnosu na insuficijentni i zadovoljavajući nivo 25-hidroksi vitamina D. Stepen sarkoi doze je definisan kao akutna i hronična sarkoidoza. Pulmonalni fnkcionalni test (PFT) je izveden spirometrijom. Uključenost kože je definisana biopsijom. Nivo kalcijuma u 24-urinu je korišćen za dokazivanje stepena aktivnosti oboljenja. Stepen uključenosti promena na plućima je dobijen primenom CT-skenera i snimanjem pluća rendgenski. Za statističku procenu rezultata korišćen je statistički program Social Sciences (SPSS).Dobijena je značajno negativna korelacija između deficijencije vitamina D kod pacijenata sa sarkoidozom i hroničnog toka bolesti i stupnjeva u dva do četiri plućna stepena. Nije nađena značajna korelacija između drugih parametara oboljenja i deficijencije vitamina D.Može se zaključiti da dobijeni rezultati ukazuju na ulogu deficijencije vitamina 25(OH)D u predviđanju toka hronične sarkoidoze. Takođe, može se zaključiti da deficijencija vitamina 25(OH)D može ukazati na pulmonalnu sarkoidozu sa uključenjem pluća stepena 2–4.

This paper gives a brief overview of common non-invasive techniques for body composition analysis and a more in-depth review of a body composition assessment method based on fat-referenced quantitative magnetic resonance imaging (MRI). Earlier published studies of this method are summarized, and a previously un-published validation study, based on 4.753 subjects from the UK Biobank imaging cohort, comparing the quantitative MRI method with dual-energy x-ray absorptiometry (DXA) is presented. For whole-body measurements of adipose tissue (AT) or fat and lean tissue (LT), DXA and quantitative MRI show excellent agreement with linear correlation of 0.99 and 0.97, and coefficient of variation (CV) of 4.5 % and 4.6 % for fat (computed from AT) and lean tissue respectively, but the agreement was found significantly lower for visceral adipose tissue, with a CV of more than 20 %. The additional ability of MRI to also measure muscle volumes, muscle AT infiltration and ectopic fat in combination with rapid scanning protocols and efficient image analysis tools make quantitative MRI a powerful tool for advanced body composition assessment.

BACKGROUND Continuous peripheral nerve blocks can be administered as continuous infusion, patient-controlled boluses, automated boluses, or a combination of these modalities. MATERIAL AND METHODS Ten patients undergoing either ankle (5) or distal radius (5) open reduction and internal fixation received single-injection ropivacaine sciatic nerve block or infraclavicular brachial plexus block and catheter. Infusion pumps were set to begin administering additional ropivacaine 6 h following the initial block as automated boluses supplemented with patient-controlled boluses. RESULTS Patients had similar pain scores when compared to previously published controls; however, local anesthetic consumption was lower in the patients, resulting in increased infusion and analgesia duration by 1 or more days in each group. CONCLUSIONS For infraclavicular and popliteal sciatic catheters, automated boluses may provide a longer duration of analgesia than continuous infusions following painful hand and ankle surgeries, respectively.

Introduction Globally, individuals with asthma tend to overrely on short-acting β2-agonists (SABAs) and underuse inhaled corticosteroids, thereby undertreating the underlying inflammation. Such relief-seeking behavior has been reinforced by long-standing treatment guidelines, which until recently recommended SABA-only use for immediate symptom relief. We aimed to describe the current burden of SABA use among European individuals with asthma within the SABA use IN Asthma (SABINA) program. Methods Prescription and/or dispensing data during 2006–2017 from electronic medical records and/or national patient registries in the United Kingdom (UK), Germany, Italy, Spain, and Sweden were analyzed. Individuals aged at least 12 years old with a current asthma diagnosis and no other chronic respiratory conditions were included. Asthma treatment step and severity were based on treatment guidelines in use in each individual country. The proportion of individuals prescribed SABA was measured during a 12-month period. SABA overuse was defined as at least three SABA canisters per year. Results More than one million individuals with asthma were included across five European countries. Overall, the majority of individuals were over 45 years of age, except in Sweden (mean age 27.6 years) where individuals aged over 45 years were excluded to avoid a potential chronic obstructive pulmonary disease co-diagnosis. The study population was predominantly female (55–64%), except in the UK (46%). The prevalence of SABA overuse was 9% in Italy, 16% in Germany, 29% in Spain, 30% in Sweden, and 38% in the UK. In the UK, SABA overuse was greater in individuals with moderate-to-severe asthma versus individuals with mild asthma (58% versus 27%, respectively), while SABA overuse was similar in individuals with both mild (9–32%) and moderate-to-severe (8–31%) asthma in the other European countries. Conclusions The findings of this study from the SABINA program show that SABA overuse (at least three canisters per year) is common across Europe, despite the different healthcare and reimbursement policies of each country.

Cancer is a heterogeneous disease that requires a multimodal approach to diagnose, manage and treat. A better understanding of the disease biology can lead to identification of novel diagnostic/prognostic biomarkers and the discovery of the novel therapeutics with the goal of improving patient outcomes. Employing advanced technologies can facilitate this, enabling better diagnostic and treatment for cancer patients. In this regard, microfluidic technology has emerged as a promising tool in the studies of cancer, including single cancer cell analysis, modeling angiogenesis and metastasis, drug screening and liquid biopsy. Microfluidic technologies have opened new ways to study tumors in the preclinical and clinical settings. In this chapter, we highlight novel application of this technology in area of fundamental, translational and clinical cancer research.

Objective Assess achievement of low-density lipoprotein cholesterol (LDL-C) targets in European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) guidelines. Design Systematic literature review. Data Sources Medline, EMBASE, Cumulated Index to Nursing and Allied Health Literature. Eligibility Criteria Observational studies reporting LDL-C levels/target attainment, measured between 1 August 2006 to 31 August 2017, in European adults with established cardiovascular disease (CVD), diabetes with target organ damage, familial hypercholesterolaemia (FH) or 10-year risk of fatal CVD ≥ 5% (assessed by Systematic Coronary Risk Evaluation [SCORE]). Data Extraction and Synthesis Two reviewers independently extracted relevant studies and assessed study quality using the Risk of Bias for Non-Randomised Studies–Interventions (ROBINS-I) tool. Primary outcome was the proportion of patients achieving LDL-C targets in the 2011/2016 ESC/EAS guidelines. Where available, patient characteristics were presented as means weighted by sample size. The proportions of patients achieving LDL-C targets in the 5 years before and after publication of the 2011 guidelines were compared using a chi-square test. Results Across 81 eligible studies (303,534 patients), achievement of LDL-C

© 2019, The Author(s). Hematologic complete remission (CR) is achievable for most adults with B cell precursor acute lymphoblastic leukemia (BCP-ALL). However, minimal residual disease (MRD) in patients with hematologic CR is associated with increased risk of relapse, shorter survival, and poorer transplantation outcomes. This study explored the concept of cure in adults with Philadelphia chromosome-negative (Ph−) BCP-ALL by MRD status at first hematologic CR (CR1) to inform evaluation of the clinical and economic benefits of new agents, where the concept of cure is important but long-term data are not available. The study used modified Delphi methodology involving clinicians experienced in the treatment of adult ALL. Participants completed a questionnaire, which was followed by country-specific panel discussions to discuss results and identify consensus on concepts and definitions. Clinicians from France (n = 4), Germany (n = 4), and the UK (n = 5) took part. Participants described cure in terms of the probability of future relapse. Relapse-free survival (RFS) was the preferred outcome measure to describe cure for the three patient groups considered (patients with MRD at CR1; patients who become negative for MRD after further treatment; patients who continue to have MRD). Consensus was reached on definitions of cure: that cure would begin to be considered at 3 years’ RFS and/or would be highly likely at 5 years’ RFS. Participants agreed that patients with MRD should usually undergo hematopoietic stem cell transplantation to have the best chance of survival; consensus was reached that alternatives are required when transplantation is not an option. Panels agreed that patients who achieve cure have a higher mortality rate and lower health-related quality of life than the general population. This study provides quantitative and qualitative information on the concept of cure in Ph− BCP-ALL in CR by MRD status applicable to interpreting the value of new therapies. Funding: Amgen. Plain Language Summary: Plain language summary available for this article.

The present study had the purpose of evaluating the proportion of subjects with hypertension, treatment, control rates, and the relationship between blood pressure (BP) with body mass index and abdominal circumference in a cross-sectional study, as part of a worldwide study designed by International Society of Hypertension, performed during May 2017. After the protocol´s approval by the local Ethical Committee, 64 sites were included from eight Venezuelan regions. A short questionnaire was completed for each participant, including knowledge of taking antihypertensive treatment, diabetes, previous myocardial infarction or stroke, alcohol intake, and smoking. BP was measured in the sitting position three times after resting for 5 minutes, one minute apart, using mainly oscillometric devices. Height, weight and abdominal circumference were measured. Data analyses were performed by the MMM central team. 21644 individuals were screened. After multiple imputations, 10584 individuals [48.9% (50.7% male; 47.7% female)] had hypertension. Of subjects not receiving antihypertensive medication, 1538 (12.2%) were hypertensives. Of hypertensive individuals receiving antihypertensive medication, 2974 (32.9%) had uncontrolled BP. 15.6% of our sample had obesity according to their body mass index; 43.8% of women and 20.7% of men had abdominal obesity. BP was positively correlated with BMI and abdominal circumference. In this largest BP screening carried out in Venezuela, 48.9% of the individuals had elevated BP and 12.2% did not know that they had hypertension, and in one third of those with hypertension on treatment, BP was not controlled. 15.6% had obesity by BMI, and 35.1% abdominal obesity. Screening such as the MMM17 can evaluate the association between hypertension and obesity and therefore may help to inform control programs.

BACKGROUNDIn cancer patients, circulating cell-free DNA (ccfDNA) can contain tumor-derived DNA (ctDNA), which enables noninvasive diagnosis, real-time monitoring, and treatment susceptibility testing. However, ctDNA fractions are highly variable, which challenges downstream applications. Therefore, established preanalytical work flows in combination with cost-efficient and reproducible reference materials for ccfDNA analyses are crucial for analytical validity and subsequently for clinical decision-making.METHODSWe describe the efforts of the Innovative Medicines Initiative consortium CANCER-ID (http://www.cancer-id.eu) for comparing different technologies for ccfDNA purification, quantification, and characterization in a multicenter setting. To this end, in-house generated mononucleosomal DNA (mnDNA) from lung cancer cell lines carrying known TP53 mutations was spiked in pools of plasma from healthy donors generated from 2 different blood collection tubes (BCTs). ccfDNA extraction was performed at 15 partner sites according to their respective routine practice. Downstream analysis of ccfDNA with respect to recovery, integrity, and mutation analysis was performed centralized at 4 different sites.RESULTSWe demonstrate suitability of mnDNA as a surrogate for ccfDNA as a process quality control from nucleic acid extraction to mutation detection. Although automated extraction protocols and quantitative PCR-based quantification methods yielded the most consistent and precise results, some kits preferentially recovered spiked mnDNA over endogenous ccfDNA. Mutated TP53 fragments derived from mnDNA were consistently detected using both next-generation sequencing-based deep sequencing and droplet digital PCR independently of BCT.CONCLUSIONSThis comprehensive multicenter comparison of ccfDNA preanalytical and analytical work flows is an important contribution to establishing evidence-based guidelines for clinically feasible (pre)analytical work flows.

We present a case of a man with headache and progressive behavioural disturbance. His cognitive decline progressed over a few months such that he was unable to hold a conversation or carry out any daily tasks such as washing and dressing. He had some upper motor neurone signs in his limbs and features of brainstem dysfunction including dysarthria and ocular abnormalities. His brain magnetic resonance imaging showed signs of brain ‘sagging’. He was thought to have frontotemporal brain sagging syndrome. Prior to any treatment, he began to improve. Over the course of a week he became markedly better, was back to normal within 3 months and remains so 7 months later. We propose that resolution of spontaneous intracranial hypotension led to resolution of frontotemporal brain sagging syndrome. We believe this is the first case described where this has occurred without any intervention. It is important to recognise this condition as a potentially reversible cause of dementia.

BACKGROUND: In human body fluids, microRNA (miRNA) can be found as circulating cell-free miRNA (cfmiRNA), as well as secreted into extracellular vesicles (EVmiRNA). miRNAs are being intensively evaluated as minimally invasive liquid biopsy biomarkers in patients with cancer. The growing interest in developing clinical assays for circulating miRNA necessitates careful consideration of confounding effects of preanalytical and analytical parameters. METHODS: By using reverse transcription quantitative real-time PCR and next-generation sequencing (NGS), we compared extraction efficiencies of 5 different protocols for cfmiRNA and 2 protocols for EVmiRNA isolation in a multicentric manner. The efficiency of the different extraction methods was evaluated by measuring exogenously spiked cel-miR-39 and 6 targeted miRNAs in plasma from 20 healthy individuals. RESULTS: There were significant differences between the tested methods. Although column-based extraction methods were highly effective for the isolation of endogenous miRNA, phenol extraction combined with column-based miRNA purification and ultracentrifugation resulted in lower quality and quantity of isolated miRNA. Among all extraction methods, the ubiquitously expressed miR-16 was represented with high abundance when compared with other targeted miRNAs. In addition, the use of miR-16 as an endogenous control for normalization of quantification cycle values resulted in a decreased variability of column-based cfmiRNA extraction methods. Cluster analysis of normalized NGS counts clearly indicated a method-dependent bias. CONCLUSIONS: The choice of plasma miRNA extraction methods affects the selection of potential miRNA marker candidates and mechanistic interpretation of results, which should be done with caution, particularly across studies using different protocols.

Introduction Despite the poor prognosis for adults with relapsed or refractory (RR) Philadelphia chromosome (Ph)-negative B cell precursor acute lymphoblastic leukemia (ALL), long-term survival is possible and may even be considered as “cure”. Methods This study used a Delphi panel approach to explore concepts of cure in RR Ph-negative B cell precursor ALL. Ten European experts in this disease area participated in a survey and face-to-face panel meeting. Results Findings showed that clinicians conceptualize “cure” as a combination of three broad treatment outcomes that vary depending on the treatment stage: complete remission early in treatment (1–3 months) indicates initial success; eradicating cancer cells (minimal residual disease negative status) consolidates the early clinical response; leukemia-free survival is required in the long term. Conclusions Although such terminology remains contested, clinicians would begin considering “cure” as early as 2 years provided the patient is off therapy, with most considering the term applicable by the third year. Funding Amgen Inc. Electronic supplementary material The online version of this article (10.1007/s12325-019-00910-z) contains supplementary material, which is available to authorized users.

Of the 10 million incident cases of tuberculosis (TB) globally in 2017, around 558,000 cases were rifampicin-resistant of which 82% were multidrug-resistant (MDR) TB. In England, 5,102 cases were recorded of which 55 cases (1.8%) were MDR-TB. MDR-TB cases have worse outcomes and are a serious public health issue. Polymerase chain reaction (PCR) tests allow a faster approach to diagnose TB and predict drug susceptibility. The emerging use of whole genome sequencing may improve the diagnostic workflow compared with standard drug susceptibility testing, with more rapid molecular sensitivity results and more precise contact investigation of linked cases. Treatment of MDR-TB remains a challenge as it relies on prolonged second-line drug treatments that are less effective and more toxic than first-line treatments. Two new drug treatments have been approved; bedaquiline and delamanid. In addition, a shorter treatment regimen of 9–12 months can be considered instead of the conventional 20–24 month regimen.

BACKGROUND Genetic generalized epilepsies (GGEs) are associated with microstructural brain abnormalities that can be evaluated with diffusion tensor imaging (DTI). Available studies on GGEs have conflicting results. Our primary goal was to compare the white matter structure in a cohort of patients with video/EEG-confirmed GGEs to healthy controls (HCs). Our secondary goal was to assess the potential effect of age at GGE onset on the white matter structure. MATERIAL AND METHODS A convenience sample of 23 patients with well-characterized treatment-resistant GGEs (13 female) was compared to 23 HCs. All participants received MRI at 3T. DTI indices, including fractional anisotropy (FA) and mean diffusivity (MD), were compared between groups using Tract-Based Spatial Statistics (TBSS). RESULTS After controlling for differences between groups, abnormalities in DTI parameters were observed in patients with GGEs, including decreases in functional anisotropy (FA) in the hemispheric (left>right) and brain stem white matter. The examination of the effect of age at GGE onset on the white matter integrity revealed a significant negative correlation in the left parietal white matter region FA (R=-0.504; p=0.017); similar trends were observed in the white matter underlying left motor cortex (R=-0.357; p=0.103) and left posterior limb of the internal capsule (R=-0.319; p=0.148). CONCLUSIONS Our study confirms the presence of widespread white matter abnormalities in patients with GGEs and provides evidence that the age at GGE onset may have an important effect on white matter integrity.

© Med Sci Monit, 2016. Background: The aim of this study was to evaluate the accuracy and feasibility of an individualized thoracic pedicle screw placement guide plate produced by 3-D laser printing. Material/Methods: Thoracic pedicle samples of 3 adult cadavers were randomly assigned for 3-D CT scans. The 3-D thoracic models were established by using medical Mimics software, and a screw path was designed with scanned data. Then the individualized thoracic pedicle screw placement guide plate models, matched to the backside of thoracic vertebral plates, were produced with a 3-D laser printer. Screws were placed with assistance of a guide plate. Then, the placement was assessed. Results: With the data provided by CT scans, 27 individualized guide plates were produced by 3-D printing. There was no significant difference in sex and relevant parameters of left and right sides among individuals (P>0.05). Screws were placed with assistance of guide plates, and all screws were in the correct positions without penetration of pedicles, under direct observation and anatomic evaluation post-operatively. Conclusions: A thoracic pedicle screw placement guide plate can be produced by 3-D printing. With a high accuracy in placement and convenient operation, it provides a new method for accurate placement of thoracic pedicle screws.

Author(s): Ajmera, Veeral; Thompson, Wesley K; Smith, Davey M; Malhotra, Atul; Mehta, Ravindra L; Tolia, Vaishal; Yin, Jeffrey; Sriram, Krishna; Insel, Paul A; Collier, Summer; Richards, Lisa; Loomba, Rohit | Abstract: Background and aimsRetrospective studies have shown that angiotensin-converting-enzyme (ACE) inhibitors are associated with a reduced risk of complications and mortality in persons with novel coronavirus disease 2019 (COVID-19). Thus, we aimed to examine the efficacy of ramipril, an ACE-inhibitor, in preventing ICU admission, mechanical ventilation and/or mortality while also minimizing the risk of transmission and use of personal protective equipment (PPE).MethodsRAMIC is a multicenter, randomized, double-blind, allocation-concealed, placebo-controlled trial comparing the efficacy of treatment with ramipril 2.5nmg orally daily compared to placebo for 14ndays. The study population includes adult patients with COVID-19 who were admitted to a hospital or assessed in an emergency department or ambulatory clinic. Key exclusion criteria include ICU admission or need for mechanical ventilation at screening, use of an ACE inhibitor or angiotensin-receptor-II blocker within 7ndays, glomerular filtration ratenln40nmL/min or a systolic blood pressure (BP)nln100nmmHg or diastolic BPnln65nmmHg. Patients are randomized 2:1 to receive ramipril (2.5nmg) or placebo daily. Informed consent and study visits occur virtually to minimize the risk of SARS-CoV-2 transmission and preserve PPE. The primary composite endpoint of ICU admission, invasive mechanical ventilation and death are adjudicated virtually.ConclusionsRAMIC is designed to assess the efficacy of treatment with ramipril for 14ndays to decrease ICU admission, mechanical ventilator use and mortality in patients with COVID-19 and leverages virtual study visits and endpoint adjudication to mitigate risk of infection and to preserve PPE (ClinicalTrials.gov, NCT04366050).

Precision medicine is expected to impact the care of people with asthma, given its high disease prevalence, heterogeneity of pathophysiologic mechanisms, and consequent clinical phenotypes. A novel phenotype-stratified clinical trial conducted by the NHLBI AsthmaNet Consortium, titled Steroids in Eosinophil Negative Asthma (SIENA), was a randomized, multicenter, clinical trial that prospectively stratified individuals according to their baseline level of sputum inflammation during a screening period. Two phenotypic strata were assigned based on an a priori defined extent of sputum eosinophilia (Eos Low versus Eos High). This article describes: the scientific premise for the trial design, including assumptions used for power calculations; modifications to the analysis plan implemented after the trial started due to a higher than expected prevalence of one phenotypic stratum which impacted the ability to accrue sufficient subjects within the planned budget and study period; investigator alternatives to address the strata imbalance weighing scientific impact and study feasibility; and the final modified SIENA study design and analysis plan. SIENA was successfully completed in a manner that maintained meaningful outcomes. We conclude with recommendations for incorporation of pre-specified contingency plans into phenotype-directed protocols, to address the potential for differences in observed compared to estimated prevalence of different phenotypes in a study population. These approaches can be applied to precision medicine trials for the future.

© 2019 The Authors Vaginal bacterial community composition influences pregnancy outcome. Preterm prelabor rupture of the fetal membranes (PPROM), which precedes 30% of all spontaneous preterm births, is associated with high vaginal bacterial diversity prior to rupture. The point at which vaginal bacterial diversity is established before PPROM is unknown. In this study, we use metataxonomics to longitudinally characterize the vaginal bacterial composition from as early as 6 weeks of gestation in women at high (n = 38) and low (n = 22) risk of preterm birth who subsequently experience PPROM and in women delivering at term without complications (n = 36). Reduced Lactobacillus spp. abundance and high diversity was observed prior to PPROM in 20% and 26% of women at low and high risk of preterm births respectively, but in only 3% of women who delivered at term. PPROM was associated with instability of bacterial community structure during pregnancy and a shift toward higher diversity predominately occurring during the second trimester. This was characterized by increased relative abundance of potentially pathogenic species including Prevotella, Peptoniphilus, Streptococcus, and Dialister. This study identifies reduced Lactobacillus spp. abundance and increasing vaginal bacterial diversity as an early risk factor for PPROM and highlights the need for interventional studies designed to assess the impact of modifying vaginal bacterial composition for the prevention of preterm birth.

Veterans seeking care in VA medical facilities have high rates of chronic pain, which often co-occur with mental health and substance use disorders, including prescription opioid misuse. The overall goal of the Optimizing Pain Treatment Interventions (OPTI) study was to pilot a 12-week Collaborative Care intervention to improve opioid safety, chronic pain disability, and use of non-pharmacological pain management strategies in veterans in VA primary care. Between November 2014 and January 2017, 100 veteran patients with chronic pain and high-risk prescription opioid use (e.g., high-dose therapy, early refills, etc.) were enrolled and completed an initial one-hour study visit with a primary care provider (PCP) within 4 weeks of enrollment. Study PCPs were guided by a web-based opioid management decision support program and templated notes in the VA electronic medical record. After assessment and education, study PCPs used Shared Decision-Making to formulate a Pain Care Plan aligned with a participant's personal values and goals. After the initial visit, patients randomized to Collaborative Care received one Motivational Interviewing (MI) session with a Care Manager followed by 3 Care Manager-delivered brief telephone MI sessions at 6, 8, and 12 weeks to reinforce Pain Care Plans; patients randomized to an Attention Control condition met with a Care Manager briefly, followed by 3 brief scripted telephone psychoeducation sessions at 6, 8, and 12 weeks. Masked evaluators assessed outcomes at baseline, end of intervention (12 weeks), and after eight weeks of no contact (20 weeks). We present study rationale, detailed methods, preliminary results and lessons learned.

Bile acids have important roles in the regulation of lipid, glucose and energy metabolism. Metabolic diseases linked to obesity, including type 2 diabetes mellitus and non-alcoholic fatty liver disease, are associated with dysregulation of bile acid homeostasis. Here, the basic chemistry and regulation of bile acids as well as their metabolic effects will be reviewed. Changes in circulating bile acids associated with obesity and related diseases will be reviewed. Finally, pharmaceutical manipulation of bile acid homeostasis as therapy for metabolic diseases will be outlined.

Critical illness is an aetiologically and clinically heterogeneous syndrome that is characterised by organ failure and immune dysfunction. Mortality in critically ill patients is driven by inflammation-associated organ damage and a profound vulnerability to nosocomial infection. Both factors are influenced by the activated complement protein C5a, released by unbridled activation of the complement system during critical illness. C5a exerts deleterious effects on organ systems directly and suppresses antimicrobial functions of key immune cells. Whilst several recent reports have added key knowledge of the cellular signalling pathways triggered by C5a, there remain a number of areas that are incompletely understood and therapeutic opportunities are still being evaluated. In this review, we summarise the cellular basis for C5a-induced vulnerability to nosocomial infection and organ dysfunction. We focus on cells of the innate immune system, highlighting the major areas in need of further research and potential avenues for targeted therapies.

The treatment of acute myeloid leukemia (AML) has remained relatively unchanged for the past 3–4 decades with generally poor outcomes, especially in elderly populations unfit for intensive therapy. Recent advancements, however, have identified several cytogenetic and molecular markers that have not only improved prognostication but have also led to the development of several new targeted therapies for specific subpopulations. In 2017, the US Food and Drug Administration approved four new treatments with indications for fms like tyrosine kinase 3 (FLT3)-mutated AML (midostaurin), newly diagnosed or relapsed/refractory CD33+AML (gemtuzumab ozogamicin), newly diagnosed therapy-related AML or AML with myelodysplasia-related changes (CPX-351) and relapsed/refractory AML with an isocitrate dehydrogenase (IDH)2 mutation (enasidenib). These newly approved therapies have demonstrated improved response in their target populations in several pivotal clinical trials with some also demonstrating improved overall survival. Additional novel therapies in development for AML include agents that target B cell lymphoma 2, FLT3, IDH1, the ubiquitination pathway, as well as cell therapy using engineered T cells with chimeric antigen receptors. This review provides a summary of the four newly approved therapies for AML, as well as several promising therapies currently in development.