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BACKGROUND: Non-alcoholic fatty liver disease (NAFLD), often associated with obesity and metabolic syndrome, manifests itself as steatosis, hepatic fibrosis, cirrhosis, or even end-stage liver disease. NAFLD causes inflammation, insulin resistance and cardiovascular complications. The current study aimed to evaluate the beneficial effects of bariatric surgery on biochemical parameters of hepatic functions in obese patients by comparing them before and one-year after the surgery. METHODS: A total of 72 morbidly obese patients underwent bariatric surgery between 2016 and 2018. The incidence of diabetes mellitus in this group was 29%, median body weight was 124.5 kg (109.0-140.0) and mean body mass index (BMI) was 44.38 ± 6.770 kg/m2. The used surgical procedures included gastric bypass, sleeve gastrectomy, laparoscopic gastric plication, and single anastomosis duodeno-ileal bypass-sleeve gastrectomy. Biochemical parameters including ALT/AST ratio (AAR), NAFLD fibrosis score (NFS), hepatic fibrosis index (FIB-4) and Fatty Liver Index (FLI) were evaluated in all patients at the time of surgery and one year after the intervention. RESULTS: Significant improvement after the intervention was observed in 64 patients. A significant reduction in body weight (P, University of Ostrava in The Czech Republic

Multiple myeloma (MM) measurable residual disease (MRD) persisting after treatment is an adverse prognostic factor for progression free survival (PFS) and overall survival.1Genomic mutations occurred in the remaining clonal aberrant plasma cells (A-PCs) are linked to the development of drug resistance and disease relapse.2 Thus, personalised treatment based on the genomic profile of MRD could be highly beneficial and ultimately increase patients’ survival. However, while large-scale sequencing studies have characterised the genome of many malignancies including MM,3–8 the genomic mutations present in MM MRD are at the beginning of investigation.9 Here, we set up an exome sequencing analysis to identify genomic mutations characteristic for MM MRD and explore if they could mediate drug response, resistance or disease progression.

Background Attrition is a major obstacle for lifestyle interventions sustained for the medium-to-long term and can have significant consequences on the internal validity of a trial. When the degree of attrition differs between active and control arms this is termed differential attrition and is an important consideration during initial stages of trial planning. Objectives The primary research question of this study was: what is the differential attrition between treatment arms in lifestyle interventions for prevalent chronic diseases? Methods We performed a systematic review and meta-analysis of 23 studies involving a lifestyle intervention component in cohorts with chronic diseases. The search accessed three databases: Scopus, Medline Ovid and Web of Science. Attrition between treatment arms was analysed using a random-effects model and examined the relationship between the relative attrition and potential moderators, such as time to final follow-up, time to first follow-up, type of disease, type of control, type of intervention and length of treatment. Results The pooled risk ratio was 1.00 (95% CI 0.97 – 1.03) and only one study fell outside this range. A univariable association was described between the pooled risk ration and length (years) to final follow-up, which did not remain in the multivariable model. Conclusions Ultimately, we found no evidence of differential attrition in medium-to-long term lifestyle intervention studies for chronic disease, increasing confidence in conducting such studies with minimal potential of attrition bias. Trial registration PROSPERO registration number CRD42018084495.

AIM This prospective in vivo study aimed to optimize the assessment of pulpal contrast-enhancement (PCE) on dental magnetic resonance imaging (dMRI) and investigate physiological PCE patterns. METHODOLOGY In 70 study participants, 1585 healthy teeth were examined using 3-Tesla dMRI before and after contrast agent administration. For all teeth, the quotient of post- and pre-contrast pulp signal intensity (Q-PSI) was calculated to quantify PCE. First, pulp chambers were analysed in 10 participants to compare the coefficient of variation of mean versus maximum Q-PSI values (Q-PSImean versus Q-PSImax ). Second, dynamic PCE was evaluated in 10 subjects to optimize the time interval between contrast agent application and image acquisition. Finally, 50 participants (age groups: 20-29, 30-39, 40-49, 50-59 and 60-69 years) were examined to analyse age, gender, tooth types and maxilla versus mandible as independent factors of PCE. Statistical analysis was performed using Wilcoxon signed rank test and linear mixed models. RESULTS PCE assessment based on Q-PSImax was associated with a significantly smaller coefficient of variation compared with Q-PSImean , with median values of 0.17 versus 0.21 (p = .002). Analysis of dynamic PCE revealed an optimal timing interval for image acquisition 4 min after contrast media application. No significant differences in PCE were observed by comparing age groups, female versus male participants and maxillary versus mandibular teeth (p > .05). Differences between tooth types were small (median Q-PSImax values of 2.52/2.32/2.30/2.20 for molars/premolars/canines/incisors) but significant (p

Multiple myeloma (MM) is characterized by malignant plasma cell infiltration of the bone marrow. In extramedullary multiple myeloma (EMD), a subclone of these cells migrates out of the bone marrow. Out of 4 985 MM patients diagnosed between 2005 and 2017 in the Czech Republic, we analyzed 234 secondary EMD patients to clarify risk factors of secondary EMD development. We found younger age [65 years; odds ratio (OR) 4·38, 95% confidence interval (CI): 2·46-7·80, P 0·0001], high lactate dehydrogenase (LDH) levels (5 μkat/l; OR 2·07, 95% CI: 1·51-2·84, P 0·0001), extensive osteolytic activity (OR 2·21, 95% CI: 1·54-3·15, P 0·001), and immunoglobulin A (IgA; OR 1·53, 95% CI: 1·11-2·11, P = 0·009) or the non-secretory type of MM (OR 2·83; 95% CI: 1·32-6·04, P = 0·007) at the time of MM diagnosis to be the main risk factors for secondary EMD development. Newly diagnosed MM (NDMM) patients with subsequent EMD had inferior median progression-free (PFS) and overall (OS) survival when compared to NDMM patients without future EMD [mPFS: 13·8 months (95% CI: 11·4-16·3) vs 18·8 months (95% CI: 17·7-19·9), P = 0·006; mOS: 26·7 months (95% CI: 18·1-35·4) vs 58·7 months (95% CI: 54·8-62·6), P 0·001]. We found that NDMM patients with specific risk factors associated with secondary EMD development have a more aggressive disease course before secondary EMD develops.

The non-alcoholic fatty liver disease (NAFLD) is the predominant etiological factor for liver disease. There is a risk of the development of hepatocellular carcinoma (HCC) in patients suffering from NAFLD. Non-alcoholic steatohepatitis (NASH) is one of the risk factors for the development of HCC. The aim is to discuss an association of NAFLD and HCC in the adult population. HCC is one of the debilitating complications of NAFLD/NASH and obesity is a causative factor for NAFLD/NASH. Various clinical data suggest that obesity appears to be a causative factor in the progression of NAFLD/NASH to HCC. We searched data from the PubMed/Medline and Google Scholar databases including various studies and review articles. Significantly, an increased number of HCC patients with cryptogenic liver disease had well-differentiated tumors than in HCC patients with chronic viral hepatitis and alcoholism. HCC is one of the debilitating complications of NAFLD/NASH and obesity is a causative factor for NAFLD/NASH. Various preclinical and clinical data suggest that obesity appears to be an important causative factor in the progression of NAFLD/NASH to HCC.

Abstract. Cognitive dysfunction among individuals with depression is associated with reduced functional status, and cognitive improvement is often an important treatment goal. We compared changes in cognitive performance over four weeks among 45 inpatients with a unipolar depressive disorder completing inpatient treatment to that of 20 controls on measures of processing speed and set-shifting (Trail Making Test), as well as selective attention (Test d2). In the patients, depressive symptoms improved significantly and with a large effect over the treatment period ( d = 1.22–1.81). Among the three cognitive domains examined, the most pronounced reductions among patients compared to controls were observed in cognitive flexibility (Group effect: ηp2 = .04). The effect of Group; however, was not significant. Likewise, there were no significant improvements in cognitive flexibility over time, and changes in cognitive flexibility over the four-week period did not differ between the two groups (Group x Time interaction). Performances in selective attention and processing speed improved over the four-week period, though neither the effect of Group nor the interaction (Group x Time) was significant regarding these performances. Change in cognitive performance was not associated with changes in symptom severity (incl. remission status). Taken together, the significant improvements in selective attention and processing speed were largely attributable to practice effects. Our findings lend further support to the notion that cognitive flexibility, selective attention, and processing speed are independent of improvements in depressive symptoms. This study underscores the importance of including comparison groups to control for practice effects when examining cognitive change, and providing treatments specifically aimed at improving cognitive symptoms.

BACKGROUND AND PURPOSE: Modifiable lifestyle factors, including diet, may affect clinical outcomes in multiple sclerosis (MS). This study assessed the relationships between diet, and disability, fatigue, and depression risk in people with MS. METHODS: Participants from the Health Outcomes and Lifestyle In a Sample of people with Multiple sclerosis (HOLISM) international cohort were assessed over 2.5 years. Dietary data were obtained using a modified Diet Habits Questionnaire (DHQ), disability using the calculated Patient-determined MS Severity Score (P-MSSS), fatigue using the Fatigue Severity Scale, and depression risk using the Patient Health Questionnaire-2. Participants reported whether they were experiencing symptoms due to a recent relapse. Cross-sectional and prospective relationships of diet and disease outcomes were explored, adjusted for relevant confounders. RESULTS: Among 1,346 participants, higher DHQ scores showed significant dose-dependent associations with lower frequencies of severe disability, fatigue, and depression risk, cross-sectionally. Prospectively, higher baseline DHQ scores were associated with a lower risk of increasing disability, those above the median having 41% and 36% lower risk of increasing disability, and 0.30 P-MSSS points less disability progression, but were not associated with fatigue or depression risk. Meat consumption was associated with 0.22 P-MSSS points higher disability cross-sectionally, while prospectively, baseline meat consumption was associated with 76% higher risk of increasing disability and 0.18 P-MSSS points higher disability progression. Dairy consumption showed mixed associations cross-sectionally and prospectively. CONCLUSIONS: These results show that better quality of diet, as well as not consuming meat, were associated with reduced disability progression in people with MS. Substantiation of these findings in other settings may inform opportunities to manage disability progression in people with MS using dietary modifications.

Travelling with chronic diseases is no longer unusual. More and more chronically ill people are embarking on long-distance trips, sometimes under thoroughly adventurous conditions. Tour operators have long adapted to this need and are constantly offering new destinations. The experiences of the last decades have led to a considerable increase in safety standards and care for travelers. Today, an averagely mobile person can travel to almost any destination in the world. Nevertheless, the more relevant chronic illnesses are, the greater the health risks of a trip. Particularly due to reduced body defenses, infectious diseases pose an increased health risk during long-distance travel. In this overview, exemplary diseases are discussed.Reisen mit Vorerkrankungen sind heute keine Besonderheit mehr. Mehr und mehr chronisch kranke Menschen begeben sich auf immer weitere Fernreisen, zum Teil unter durchaus abenteuerlichen Bedingungen. Reiseveranstalter haben sich diesem Bedürfnis schon seit Langem angepasst und bieten immer neue Ziele an. Die Erfahrungen der letzten Jahrzehnte haben zu einer erheblichen Steigerung der Sicherheitsstandards und der Betreuung von Reisenden geführt. Heute kann ein durchschnittlich mobiler Mensch nahezu jedes Ziel der Welt ansteuern. Dennoch ist die Belastung einer Reise umso größer, je relevanter die chronischen Erkrankungen sind. Vor allem auch durch die reduzierten körperlichen Abwehrkräfte stellen Infektionskrankheiten bei Fernreisen ein erhöhtes Gesundheitsrisiko dar. In dieser Übersicht werden exemplarische Erkrankungen diskutiert.

Objectives This study compared the use of bortezomib in different combination regimens in newly diagnosed multiple myeloma (NDMM) patients who were transplant ineligible. Patients and methods We analyzed data from the Registry of Monoclonal Gammopathies (RMG) of the Czech Myeloma Group (CMG) to provide real-world evidence of outcome for 794 newly diagnosed MM transplant ineligible patients. The most frequently used regimen was VCd (bortezomib-cyclophosphamide-dexamethasone) (47.5%) over VMP (bortezomib-melphalan-prednisone) (21.7%), BDd (bortezomib-doxorubicin-dexamethasone) (9.8%) and VTd (bortezomib-thalidomide-dexamethasone) (2.9%). Results The overall response rate (ORR) was 69.2% (478/691), including 12.6% (≥ CR); 34.7% very good partial responses (VGPR); 21.9% partial responses (PR). Among triplet regimens, VMP was the most effective regimen compared to VCd, BDd and VTd. Median PFS was 22.3 vs. 18.5 vs. 13.7 vs. 13.8 months, (p=0.275), respectively and median OS was 49 vs. 41.7 vs. 37.9 vs. 32.2 months (p=0.004), respectively. The most common grade 3-4 toxicities were anemia in 17.4% and infections in 18% of patients. Conclusion Our study confirmed that bortezomib-based treatment is effective and safe in NDMM transplant ineligible patients; especially VMP, which was identified as superior between bortezomib-based induction regimens not only in clinical trials, but also in real clinical practice.

BACKGROUND AND PURPOSE: Several modifiable lifestyle factors have been associated with the onset and health outcomes of multiple sclerosis (MS), including clinically significant fatigue. A combined lifestyle score approach represents one method of assessing their relationship with clinical outcomes. The aim was to examine the association of two lifestyle scores with clinically significant fatigue and change thereof over 2.5 years' follow-up using inverse probability treatment weighting (IPTW). METHODS: Data on sociodemographic, lifestyle, and clinical characteristics surveyed from an international cohort of people with MS at baseline and at 2.5-year follow-up were used. Fatigue was defined by the Fatigue Severity Scale (FSS >5) and healthy lifestyle by the Healthy Lifestyle Index Score (HLIS) and the Smoking, Nutrition, Alcohol Consumption and Physical Activity (SNAP) score. Analyses were by IPTW accounting for age, sex, MS type, disability, treated comorbidity number, immunomodulatory medication use, prescription antifatigue medication use, and ongoing relapse symptoms. RESULTS: In total, 1268 participants completed the FSS at both time points; approximately 62% had fatigue. Using doubly robust IPTW, high (>11/20) HLIS (odds ratio [OR] 0.90, 95% confidence interval [CI] 0.81-0.98) and high (>3/5) SNAP (OR 0.82, 95% CI 0.73-0.90) were each associated with lower risk of fatigue at follow-up. Evaluating change in fatigue, a higher SNAP score was associated with a lower risk of fatigue (OR 0.89, 95% CI 0.80-0.97) but the score for HLIS did not reach statistical significance (OR 0.93, 95% CI 0.85-1.01). CONCLUSION: These results suggest a robust role for key lifestyle factors in preventing clinically significant fatigue and may represent a place for lifestyle modification in improving clinical outcomes in MS.

Cardiac autonomic dysfunction in idiopathic Parkinson’s disease (PD) manifests as reduced heart rate variability (HRV). In the present study, we explored the deceleration capacity of heart rate (DC) in patients with idiopathic PD, an advanced HRV marker that has proven clinical utility. Standard and advanced HRV measures derived from 7-min electrocardiograms in 20 idiopathic PD patients and 27 healthy controls were analyzed. HRV measures were compared using regression analysis, controlling for age, sex, and mean heart rate. Significantly reduced HRV was found only in the subcohort of PD patients older than 60 years. Low- frequency power and global HRV measures were lower in patients than in controls, but standard beat-to-beat HRV markers (i.e., rMSSD and high-frequency power) were not significantly different between groups. DC was significantly reduced in the subcohort of PD patients older than 60 years compared to controls. Deceleration-related oscillations of HRV were significantly reduced in the older PD patients compared to healthy controls, suggesting that short-term DC may be a sensitive marker of cardiac autonomic dysfunction in PD. DC may be complementary to traditional markers of short-term HRV for the evaluation of autonomic modulation in PD. Further study to examine the association between DC and cardiac adverse events in PD is needed to clarify the clinical relevance of DC in this population.

The treatment of multiple myeloma (MM) has changed substantially during the past two decades. The incorporation of novel agents into therapeutic strategies has resulted in prolonged overall survival of MM patients with approximately 15% of them being considered operationally cured.

The COVID-19 pandemic has been associated with an increase in obsessive-compulsive disorder/symptoms (OCD/OCS). However, knowledge is limited regarding the trajectories of OCS during the pandemic, as well as their predictors and mechanisms (e.g., experiential avoidance, EA). The aim of this study was to describe the trajectories of OCS and the identification of associated factors. We assessed 1207 participants of the general population in March 2020 (t1) and June 2020 (t2). Pre-pandemic data was available from March 2014 for a subsample (n = 519). To define trajectories, we determined OCS status (OCS+/−). We performed a hierarchical multinomial logistic regression to investigate predictors of trajectories. Between t1 and t2, 66% of participants had an asymptomatic trajectory (OCS−/OCS−); 18% had a continuously symptomatic trajectory (OCS+/OCS+). Ten percent had a delayed-onset trajectory (OCS−/OCS+), and the recovery trajectory group (OCS+/OCS−) was the smallest group (6%). Higher education reduced the odds of an OCS+/OCS− trajectory. OCS in 2014 was associated with increased odds of showing an OCS+/OCS+ or OCS−/OCS+ trajectory. When EA at t1 and change in EA from t1 to t2 were added to the model, higher EA at t1 was associated with increased odds of scoring above the cut score on one or more of the assessments. A higher decrease in EA from t1 to t2 reduced the probability of showing an OCS+/OCS+ and an OCS−/OCS+ trajectory. While the current data supports a slight increase in OCS during the pandemic, trajectories differed, and EA seems to represent an important predictor for an unfavorable development.

Impending and complete pathologic fractures often necessitate surgical fixation. Traditional orthopedic implants are commonly used, achieving clinically acceptable outcomes, but their metallic composition can impair radiographic evaluation and affect radiation treatments. Recognition of these concerns led to the development of radiolucent implants such as the minimally invasive Photodynamic Bone Stabilization System (PBSS; IlluminOss Medical Inc), featuring a light cured polymer contained within an inflatable balloon catheter. Two participating hospitals in one health care system reviewed cases using the PBSS implant. Twenty-five patients with 29 impending or pathologic fractures in the proximal radius or humerus from metastatic carcinoma, myeloma, lymphoma, and melanoma were identified. Clinical charts and imaging were reviewed to determine the status of the implant at final follow-up as well as complications. For analysis, a chi-square test was used for nominal variables and a t test was used for continuous variables. Eleven of the 25 patients were alive with disease at the time of analysis. Eight of 29 (27.5%) implants failed. Five of 25 (20%) patients required repeat surgery due to complications, including 3 revision open reduction and internal fixations, 1 open reduction and internal fixation for a periprosthetic fracture, and 1 screw removal. Five of the 9 cases (56%) ( P =.03) with lesions in the distal humeral shaft had breakage of the implant by final follow-up, compared with 3 of 20 cases (15%) ( P =.03) elsewhere in the humerus; no failures were seen in the radius. One of 4 patients (25%) also had failure in the surgical neck, although this did not reach significance. Five patients were noted to have progression of disease on follow-up radiographs, with 4 failures in patients with progression. The PBSS implants potentially allow improved surveillance of fracture healing and tumor recurrence along with decreased scattering of radiation during treatment. Unfortunately, there may be a higher rate of mechanical failures, particularly for lesions involving the distal humerus. This may be due to decreased cross-sectional area of the implant in this region as compared with the metaphyseal and proximal regions. Caution should be exercised when treating distal humeral pathologic fractures with large lytic lesions where the underlying disease process is not well controlled. [ Orthopedics . 2021;44(3):154–159.]

Background: European travellers to endemic countries are at risk of malaria and may be affected by a different range of co-morbidities than natives of endemic regions. The safety profile, especially cardiac issues, of artenimol (previously dihydroartemisinin)–piperaquine (APQ) Eurartesim® during treatment of uncomplicated imported falciparum malaria is not adequately described due to the lack of longitudinal studies in this population. The present study was conducted to partially fill this gap. Methods: Participants were recruited through Health Care Provider’s safety registry in 15 centres across 6 European countries in the period 2013–2016. Adverse events (AE) were collected, with a special focus on cardiovascular safety by including electrocardiogram QT intervals evaluated after correction with either Bazett’s (QTcB) or Fridericia’s (QTcF) methods, at baseline and after treatment. QTcB and/or QTcF prolongation were defined by a value > 450 ms for males and children and > 470 ms for females. Results: Among 294 participants, 30.3% were women, 13.7% of Caucasian origin, 13.5% were current smoker, 13.6% current alcohol consumer and 42.2% declared at least one illness history. The mean (SD) age and body mass index were 39.8 years old (13.2) and 25.9 kg/m2 (4.7). Among them, 75 reported a total of 129 AE (27 serious), 46 being suspected to be related to APQ (11 serious) and mostly labelled as due to haematological, gastrointestinal, or infection. Women and Non-African participants had significantly (p < 0.05) more AEs. Among AEs, 21 were due to cardiotoxicity (7.1%), mostly QT prolongation, while 6 were due to neurotoxicity (2.0%), mostly dizziness. Using QTcF correction, QT prolongation was observed in 17/143 participants (11.9%), only 2 of them reporting QTcF > 500 ms (milliseconds) but no clinical symptoms. Using QTcB correction increases of > 60 ms were present in 9 participants (6.3%). A trend towards increased prolongation was observed in those over 65 years of age but only a few subjects were in this group. No new safety signal was reported. The overall efficacy rate was 255/257 (99.2%). Conclusions: APQ appears as an effective and well-tolerated drug for treatment of malaria in patients recruited in European countries. AEs and QT prolongation were in the range of those obtained in larger cohorts from endemic countries. Trial registration This study has been registered in EU Post-Authorization Studies Register as EUPAS6942, SCOPUS: ar.j, info:eu-repo/semantics/published

Background: Currently, most available data on the medication adherence of patients with chronic heart failure are based on indirect methods. We examined the level of adherence to medical therapy using a direct method - serum drug level testing. Methods: We carried out a prospective single-centre registry of patients with chronic heart failure (LEVEL-CHF registry), in whom we analysed serum levels of the medications prescribed for the treatment of heart failure: angiotensin converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers and mineralocorticoid receptor antagonists. We labelled a patient as non-adherent if at least one serum level of a prescribed drug was unmeasurable (below the detection limit). Patients with all tested drugs identifiable in serum were labelled as adherent. We enrolled 274 patients (208 men and 66 women) mean age 62 years. Results: 82.5% of patients were adherent and 17.5% non-adherent to prescribed medications. 3.6% were completely non-adherent without any detectable drugs in serum. Patients aged

Although awareness of side effects over the course of psychotherapy is growing, side effects are still not always reported. The purpose of the present study was to examine side effects in a randomized controlled trial comparing Metacognitive Training for Depression (D-MCT) and a cognitive remediation training in patients with depression. 84 patients were randomized to receive either D-MCT or cognitive remediation training (MyBrainTraining) for 8 weeks. Side effects were assessed after the completion of each intervention (post) using the Short Inventory of the Assessment of Negative Effects (SIAN) and again 6 months later (follow-up) using the Negative Effects Questionnaire (NEQ). D-MCT and MyBrainTraining did not differ significantly in the number of side effects. At post assessment, 50% of the D-MCT group and 59% of the MyBrainTraining group reported at least one side effect in the SIAN. The most frequently reported side effect was disappointment in subjective benefit of study treatment. At follow-up, 52% reported at least one side effect related to MyBrainTraining, while 34% reported at least one side effect related to the D-MCT in the NEQ. The most frequently reported side effects fell into the categories of “symptoms” and “quality”. Our NEQ version was missing one item due to a technical error. Also, allegiance effects should be considered. The sample size resulted in low statistical power. The relatively tolerable number of side effects suggests D-MCT and MyBrainTraining are safe and well-received treatment options for people with depression. Future studies should also measure negative effects to corroborate our results.

Objectives: The purpose of this study was to set an optimal fit of the estimated LVEF at hourly intervals from 24-hour ECG recordings and compare it with the fit based on two gold-standard guidelines. Methods: Support vector regression (SVR) models were applied to estimate LVEF from ECG derived heart rate variability (HRV) data in one-hour intervals from 24-hour ECG recordings of patients with either preserved, mid-range, or reduced LVEF, obtained from the Intercity Digital ECG Alliance (IDEAL) study. A step-wise feature selection approach was used to ensure the best possible estimations of LVEF levels. Results: The experimental results have shown that the lowest Root Mean Square Error (RMSE) between the original and estimated LVEF levels was during 3–4 am, 5–6 am and 6–7 pm. Conclusion: The observations suggest these hours as possible times for intervention and optimal treatment outcomes. In addition, LVEF classifications following the ACCF/AHA guidelines leads to a more accurate assessment of mid-range LVEF. Significance: This study paves the way to explore the use of HRV features in the prediction of LVEF percentages as an indicator of disease progression, which may lead to an automated classification process for CAD patients.

While autopsy-repository programs with a variety of pediatric central nervous system (CNS) tumor types are a critical resource for preclinical neuro-oncology research, few exist and there is no published guidance on how to develop one. The goal of this prospective Pediatric Brain Tumor Repository (PBTR) study was to develop such a program at Cincinnati Children’s Hospital Medical Center (CCHMC) and then publish the quantitative and experiential data as a guide to support the development of similar programs. Protocols and infrastructure were established—to educate oncologists and families, establish eligibility, obtain consent, address pre- and post-autopsy logistics (e.g., patient and tissue transportation), process and authenticate tissue samples, and collect and analyze data. Of the 129 pediatric CNS tumor patients at CCHMC who died between 2013 and 2018, 109 were eligible for our study. Of these, 74% (81 of 109) were approached for PBTR donation, and 68% (55 of 81) consented. In the final year of the study, approach and consent rates were 93% and 85%, respectively. Median time from death to autopsy (postmortem interval, PMI) was 10 h (range, 1.5–30). In the outpatient setting, PMI increased with distance (from the hospice/home where the patient died to CCHMC). In all patients, PMI appeared to be lower, when consent was obtained more than 24 h before death. Procurement of autopsy specimens need not be a barrier in neuro-oncology research. Regional centers, strict timing-of-consent, patient education, and dedicated staff are all needed to minimize PMI and, thereby, increase the value of the procured tissue for an array of basic and translational research applications.

Background We have performed a head to head comparison of all-oral triplet combination of ixazomib, lenalidomide and dexamethasone (IRD) versus lenalidomide and dexamethasone (RD) in patients with relapsed and refractory multiple myeloma (RRMM) in the routine clinical practice. Methods A total of 344 patients treated with IRD (N = 127) or RD (N = 217) were selected for analysis from the Czech Registry of Monoclonal Gammopathies (RMG). Descriptive statistics were used to assess patient’s characteristics associated with the respective therapy. The primary endpoint was progression free survival (PFS), secondary end points included response rates and overall survival (OS). Survival endpoints were plotted using Kaplan-Meier methodology at 95% Greenwood confidence interval. Univariable and multivariable Cox proportional hazards models were used to evaluate the effect of treatment regimens and the significance of uneven variables. Statistical tests were performed at significance level 0.05. Results In the whole cohort, median PFS for IRD was 17.5 and for RD was 11.5 months favoring the all-oral triplet, p = 0.005; in patients within relapse 1–3, the median PFS was 23.1 vs 11.6 months, p = 0.001. The hazard ratio for PFS was 0.67 (95% confidence interval [CI] 0.51–0.89, p = 0.006). The PFS advantage translated into improved OS for patients treated with IRD, median 36.6 months vs 26.0 months (p = 0.008). The overall response rate (ORR) was 73.0% in the IRD group vs 66.2% in the RD group with a complete response rate (CR) of 11.1% vs 8.8%, and very good partial response (VGPR) 22.2% vs 13.9%, IRD vs RD respectively. The IRD regimen was most beneficial in patients ≤75 years with ISS I, II, and in the first and second relapse. Patients with the presence of extramedullary disease did not benefit from IRD treatment (median PFS 6.5 months). Both regimens were well tolerated, and the incidence of total as well as grade 3/4 toxicities was comparable. Conclusions Our analysis confirms the results of the TOURMALINE-MM1 study and shows benefit of all-oral triplet IRD treatment versus RD doublet. It demonstrates that the addition of ixazomib to RD improves key survival endpoints in patients with RRMM in a routine clinical setting.

Analysis of heart failure is important in clinical practice to ensure coronary artery disease (CAD) patients will be provided with appropriate timely treatment. The current gold-standard, echocardiography, although reliable, provides a once-off left ventricular ejection fraction (LVEF) measurement and does not provide information about heart function disturbances during day/night cardiac cycles. Additionally, the discrimination between heart failure with preserved and mid-range ejection fraction remains challenging in echocardiography tests. In this vein, this study was sought to investigate the ability of heart rate variability (HRV) in categorizing CAD patients into multiple LVEF groups throughout the 24-hour circadian cycle and checking its agreement with established gold-standard echocardiography-based guidelines. A total of 92 CAD patients who have suffered from heart failure were included in this study. The newly introduced index, HRV ejection fraction (HRVEF), was based on optimizing indices extracted from HRV data, which are correlated with the sympathetic and parasympathetic nervous systems, to form group membership of the preserved (HFpEF), mid-range (HFmEF), and reduced (HFrEF) LVEF categories. HRVEF groups optimized on hourly basis through Jenks natural breaks algorithm exhibited a consistent pattern with a goodness of variance fit (GVF) of more than 70% accuracy during the late-night to early-morning (01:00-08:00) and evening (17:00-23:00) time periods. At these hours, several HRV indices were found significant (p-value ≤0.05) in differentiating between HRVEF groups using statistical analysis of variance (ANOVA) test. These features include the successive differences between normal heartbeats (RMSSD), low and high frequency (LF, HF) power, standard deviation of normal heartbeats (SD2), short-term scaling exponent (alpha1), and percentage of normal heartbeats in alternation segments (PAS). The findings of this study suggest HRV as a promising supplementary tool to the once-off echocardiography for timely LVEF measurements and heart failure prognosis. It paves the way towards multi-time HRV-based estimations for LVEF according to the association between LVEF and HRV indices to better demonstrate the circadian cardiac function at different LVEF levels in CAD patients.

Biopsy site changes in mediastinal lymph nodes (LNs) attributable to prior endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) have not been studied in a systematic manner. Twenty-four contributors from 14 institutions in 5 countries collaborated via social media (Twitter) to retrospectively review consecutive cases of resected mediastinal LNs from patients with prior EBUS-TBNA. Resected LNs were reexamined by submitting pathologists for changes attributable to EBUS-TBNA. Patients who received neoadjuvant therapy were excluded. Cases with suspected biopsy site changes underwent central review by 5 pathologists. A total of 297 mediastinal LN resection specimens from 297 patients (183 male/114 female, mean age: 65 y, range: 23 to 87) were reviewed. Biopsy site changes were most common in station 7 (10 cases) followed by 11R, 4R, and 10R, and were found in 34/297 (11.4%) cases, including displacement of tiny cartilage fragments into LN parenchyma in 26, intranodal or perinodal scars in 7, and hemosiderin in 1. Cartilage fragments ranged from 0.26 to 1.03 mm in length and 0.18 to 0.62 mm in width. The mean interval between EBUS-TBNA and LN resection was 38 days (range: 10 to 112) in cases with biopsy site changes. A control group of 40 cases without prior EBUS-TBNA, including 193 mediastinal LN stations, showed no evidence of biopsy site changes. Biopsy site changes are identified in a subset of resected mediastinal LNs previously sampled by EBUS-TBNA. The location of the abnormalities, temporal association with prior EBUS-TBNA, and the absence of such findings in cases without prior EBUS-TBNA support the contention that they are caused by EBUS-TBNA.

Das Ziel des Artikels ist es, den neuesten Stand zum effektiven Einsatz von Verhaltensexperimenten im Rahmen der Psychotherapie für Zwangsstörungen darzulegen. Dazu werden im ersten Teil die evidenzbasierten Psychotherapien zur Behandlung von Zwangsstörungen vorgestellt sowie die Probleme bei der Implementierung dieser Verfahren aufgezeigt. Dabei zeigt sich, dass trotz der guten Evidenzlage die Verfahren zu selten eingesetzt werden und so die Forschungs-Praxis-Lücke fördern. Im Anschluss werden die zugrundeliegenden Rationale zur Durchführung von Verhaltensexperimenten erläutert, in Bezug zu aktuellen Forschungsarbeiten gestellt und damit die Bedeutung von Verhaltensexperimenten in der Therapie von Zwangsstörungen unterstrichen. Daraus werden Empfehlungen für die effektive Umsetzung von Verhaltensexperimenten in der Praxis abgeleitet. Die Funktionsanalyse der zwangsspezifischen Symptomatik stellt das zentrale Element im Rahmen der Behandlung von Zwangsstörungen dar. Dabei müssen die Verhaltensexperimente an die individuell befürchtete Konsequenz bei Unterlassen von Ritualen und Sicherheitsverhalten (d.h. die furchtbasierte Überzeugung) ausgerichtet sein, um eine maximale Erwartungsverletzung zu ermöglichen. Klinische Fallbeispiele werden skizziert, anhand deren effektive Verhaltensexperimente anschaulich und praxisnah dargestellt werden. Abschließend werden noch Hinweise, Tipps und Fallstricke für Praktiker zur Durchführung von effektiven Verhaltensexperimenten beleuchtet und die Grenzen von Verhaltensexperimenten benannt.

BACKGROUND Malignant peritoneal mesothelioma is an unusual disease process characterized radiologically by ascites and infiltration of the peritoneum by multiple small tumor nodules. Both parietal and visceral peritoneum are involved by the multiple malignant tumor nodules. Computed tomography (CT) has been used to identify the anatomic pathology induced by the progression of this malignant process. AIM To identify and then describe unusual CT images in patients with malignant peritoneal mesothelioma. Recognition of these unusual radiologic findings can cause the radiologist to be suspicious of this rare malignant process. METHODS In 100 patients who were to undergo definitive treatment of malignant peritoneal mesothelioma, the findings on preoperative CT scans were catalogued. Many of these changes were repeatedly noted on the CT scans. Other pathologic CT images were less common. These unusual radiologic presentations were specially studied in this manuscript. RESULTS Eight unusual radiologic presentations of malignant peritoneal mesothelioma were selected for study. These unusual findings included a mass occurring within a Spigelian hernia, infiltration of the splenic parenchyma by spherical mesothelioma masses, infiltration of the lower mediastinum by tumor, a mesothelioma mass within a left inguinal canal, enlarged cardiophrenic angle lymph nodes, pleural plaques associated with the progression of malignant peritoneal mesothelioma, splenic notches caused by disease surrounding the spleen, and a mass greater than 5 cm associated with the proximal jejunum and directly adjacent to the anatomic location of the Treitz ligament. CONCLUSION There are unusual radiologic presentations of malignant peritoneal mesothelioma that are important to recognize in order to accurately diagnose this disease by CT.

Remarkable advances have been achieved in the treatment of multiple myeloma (MM) in the last decade, which saw targeted immunotherapy, represented by anti-CD38 monoclonal antibodies, successfully incorporated across indications. However, myeloma is still considered curable in only a small subset of patients, and the majority of them eventually relapse. B-cell maturation antigen (BCMA) is expressed exclusively in mature B lymphocytes and plasma cells, and represents an ideal new target for immunotherapy, presented by bispecific antibody (bsAb) constructs, antibody-drug conjugates (ADCs) and chimeric antigen receptor T (CAR-T) cells. Each of them has proved its efficacy with the potential for deep and long-lasting responses as a single agent therapy in heavily pretreated patients. As a result, belantamab mafodotin was approved by the United States Food and Drug Administration for the treatment of relapsed/refractory MM, as the first anti-BCMA agent. In the present review, we focus on monoclonal antibodies targeting BCMA - bsAbs and ADCs. The data from preclinical studies as well as first-in-human clinical trials will be reviewed, together with the coverage of their constructs and mechanisms of action. The present results have laid the groundwork for the ongoing or upcoming clinical trials with combinatory regimens, which have always been a cornerstone in the treatment of MM.

This review focuses on the problem of oxidative stress in early brain injury (EBI) after spontaneous subarachnoid hemorrhage (SAH). EBI involves complex pathophysiological mechanisms, including oxidative stress. In the first section, we describe the main sources of free radicals in EBI. There are several sources of excessive generation of free radicals from mitochondrial free radicals’ generation and endoplasmic reticulum stress, to hemoglobin and enzymatic free radicals’ generation. The second part focuses on the disruption of antioxidant mechanisms in EBI. The third section describes some newly found molecular mechanisms and pathway involved in oxidative stress after EBI. The last section is dedicated to the pathophysiological mechanisms through which free radicals mediate early brain injury.

Background Many individuals with obsessive-compulsive disorder (OCD) do not receive professional treatment due to various idiosyncratic barriers. Internet-based cognitive-behavioral therapy (iCBT) is increasingly used to narrow treatment gaps, but the efficacy of such interventions without guidance of therapists has not been well studied. This study evaluated the efficacy of an unguided iCBT that includes third-wave approaches for the treatment of OCD symptoms. Methods A total of 128 individuals with self-reported OCD symptoms were randomly allocated to either an intervention group (unguided iCBT) or to a care-as-usual (CAU) control group following an anonymous baseline assessment via an online survey. Eight weeks after inclusion, a reassessment was carried out online. The Yale-Brown Obsessive-Compulsive Scale served as the primary outcome parameter for detecting symptom changes in the per-protocol sample with at least 60 minutes utilization. Results The iCBT group showed a significantly stronger reduction of OCD symptoms with a medium effect size (η²p = 0.06) compared with the control condition. This effect was moderated by the general frequency of Internet usage (η²p = 0.08); the more time per day users spent online, the less they benefited from the intervention. Secondary outcomes revealed (1) a medium effect size on self-esteem (η²p = 0.06); (2) no statistically significant effects on quality of life, depression symptoms, impulsivity, or social insecurity; and (3) good acceptability of the intervention. Conclusions The current study provides evidence that unguided iCBT for OCD may be a viable option for individuals who experience treatment barriers. As non-compliance remains a challenge, this topic needs further research.

Lipoblastoma is a rare benign neoplasm of immature fat cells in children. Imaging appearances are frequently complex, sometimes simulating liposarcoma. To characterize features of lipoblastoma on MRI and CT in comparison with recurrence risk. We identified cases via retrospective review of histopathology-proven lipoblastoma cases in a large referral database and a pediatric medical center. Two radiologists scored CT and MRI on the basis of lesion features. We included a total of 56 children (32 boys and 24 girls) with a mean age of 2.6 years (range 0.1–13 years). Extremity lesions were most common (27%), followed by neck (19%), gluteal region (18%), chest (14%) and mesentery (14%). Children most commonly presented with painless masses (73%), followed by dyspnea (9%), distension (9%) and pain (7%). Non-adipose soft-tissue components were identified on CT and MRI in 78% of cases. Significant (moderate or marked) septations were noted in 59% and enhancement in 35%. Compartmental invasion was present in 43% of cases. Of paraspinal cases, 38% involved the neural foramina or central canal. Lesion complexity did not significantly correlate with age. Recurrence was observed in 9% of cases and was significantly correlated with compartmental invasion (correlation: 0.303, P=0.009) and septation complexity (correlation: 0.227, P=0.038) on initial imaging. Although lipoblastoma is a fat-containing entity, many lesions demonstrate marked complexity and local infiltration that resemble liposarcoma, which is exceedingly rare in younger children. Compartmental invasion and thicker septations appear to confer greater risk of recurrence following resection.

This policy brief proposes a group of twenty (G20) coordinating committee for the governance of artificial intelligence (CCGAI) to plan and coordinate on a multilateral level the mitigation of AI risks. The G20 is the appropriate regime complex for such a metagovernance mechanism, given the involvement of the largest economies and their highest political representatives. Other regime complexes and international organizations, which also focus on AI governance, tend to either lack such political power or exclude major rivalry countries. However, such inclusive centrality is necessary to counter the fragmentation of the existing cyber regime complex and effectively coordinate the mitigation of AI risks on a global level. Therefore, the G20 CCGAI is proposed to complement and strengthen polycentric governance as well as AI governance networks. CCGAI’s metagovernance function is presented as a task intended to institutionalize linkages between the CCGAI and relevant actors with the G20 complex and the broader AI and cyber regime complex. While the policy brief outlines the landscape of AI risks and proposes an agenda with AI governance challenges, the focus is on the functional and organizational features of the CCGAI and how such chartered committee can foster international collaboration. Without such global coordination, AI governance risks becoming primarily an instrument of strategic competition and rivalry. An earlier and shorter version of this policy brief was included in the Think 20 (T20) communique as a recommendation to the G20 in 2020 (Jelinek Global Solutions Initiative Foundation, 2020). The T20 is a G20 engagement group that incubates and proposes policy ideas.

Background Prolonged electrocardiogram (ECG) QRS duration has been associated with increased cardiovascular risk. It is unclear whether the main predictor of cardiovascular risk, the Framingham risk score also predicts short-term changes in ECG QRS duration. Our aim is to determine whether baseline Framingham risk score is associated with baseline or changes in QRS duration. Methods A retrospective cross-sectional analysis was performed using observational data obtained from two hundred two participants. Framingham risk score was calculated using an online risk calculator. QRS duration was obtained using a 10 s trace from a Welch Allyn PC-based 12-lead ECG system. Results Average follow-up duration was 3.3 ± 1.1 years. Mean QRS change was 1.8 ± 11.4 ms. Specifically, among two hundred two participants, there are 104 subjects with a greater QRS duration at follow-up, while 98 subjects had the same or a shorter follow-up QRS duration. Baseline Framingham risk score did not significantly predict an increase in QRSd with an odds ratio of 1.04 (P = 0.230). Regression analysis of QRS duration at baseline and Framingham risk at baseline had a weak association (R2 = 0.020; P = 0.043). The Framingham risk score at follow-up was likewise has a weak association with follow-up QRS duration (R2 = 0.045; P = 0.002). Conclusions Our results do not demonstrate a statistically significant association between Framingham risk parameters and future QRS duration changes over longitudinal time. QRS duration had variable changes between baseline and follow-up. This might suggest that a longer period of follow-up is required to document more stable increases in QRS duration associated with ventricular pathology. A larger population study is needed to confirm our observations.

We aimed to describe website traffic and qualitatively analyze an e-health community discussion forum. Participants in this study were people affected by multiple sclerosis visiting the Overcoming Multiple Sclerosis (OMS) website. This mixed methods study combined descriptive analysis of website traffic over 7 years and 1 month, and qualitative analysis of 1 week of posts in the meditation topic, coded into theme groups using qualitative thematic analysis. There were 166 meditation topics posted with 21,530 initial views of primary post and 785 sub-post responses. Meditation posts and sub-posts received 368,713 replies. Number of views increased from 4,684 in 2011 to over 80,000 in 2017, a considerably greater rate of increase than overall traffic. Qualitative analysis of posts on the meditation forum identified themes of barriers and enablers to utilization of meditation resources. Enablement themes dominated, observed across six of the seven theme groups with various forms of positive social and emotional support to learn and practice meditation. One theme, negative emotion, was identified as a barrier. The OMS peer-to-peer patient online discussion forum serves important functions in encouraging, educating and enabling its growing online community. Our analysis may help improve and innovate online support for lifestyle management in many chronic diseases.

While many studies have examined the impacts of multiple sclerosis (MS) on health-related quality of life (HRQoL), none have used the SF-6D multi-attribute utility instrument in a large international cohort (> 2000 subjects) of people with MS. To derive SF-6D health state utilities (HSUs) for participants of the HOLISM (Health Outcomes and Lifestyle In a Sample of people with Multiple Sclerosis) international cohort and to describe the distribution and determinants thereof. HSUs were generated using the SF-6D for participants with sufficient SF-36 data [n = 2185/2466 (88.6%)]. Mean HSUs for sociodemographic, clinical and modifiable lifestyle factors (including diet, physical activity, supplement use) were evaluated. Determinants of HSU were then evaluated by linear regression, adjusted for age, sex, MS type, disability, fatigue, and prescription antidepressant use. Mean HSU for the sample was 0.67 (SD = 0.13) and diminished with increasing MS-related disability, robust to adjustment, supporting the SF-6D’s discriminatory power in people with MS. Severe disability and clinically significant fatigue were each associated with 11% lower HSU (95% CI = − 0.13, − 0.10 and − 0.12, − 0.10), and depression risk with 10%-lower HSU (95% CI = − 0.11, − 0.08). Employment, higher socioeconomic and married/partnered statuses, larger social-network size, greater physical activity, and vitamin D and omega-3 supplement use were associated with significantly higher HSU, and overweight/obese BMI and tobacco smoking with lower HSU. Age, sex, and education were not associated. Modifiable lifestyle factors including healthy diet, increased physical activity and supplement use were associated with higher HRQOL among people with MS. The SF-6D instrument revealed significant discriminatory power in this international cohort of people with MS.

This paper investigates the problem of minimizing data transfer between different data centers of the cloud during the neurological diagnostics of cardiac autonomic neuropathy (CAN). This problem has never been considered in the literature before. All classifiers considered for the diagnostics of CAN previously assume complete access to all data, which would lead to enormous burden of data transfer during training if such classifiers were deployed in the cloud. We introduce a new model of clustering-based multi-layer distributed ensembles (CBMLDE). It is designed to eliminate the need to transfer data between different data centers for training of the classifiers. We conducted experiments utilizing a dataset derived from an extensive DiScRi database. Our comprehensive tests have determined the best combinations of options for setting up CBMLDE classifiers. The results demonstrate that CBMLDE classifiers not only completely eliminate the need in patient data transfer, but also have significantly outperformed all base classifiers and simpler counterpart models in all cloud frameworks.

Introduction: One of the hallmarks of cancerogenesis is the ability of tumor cells to evade the immune system. They can achieve it by abusing inhibitory immune checkpoint pathways, which, under normal circumstances, maintain peripheral tolerance during infection. Immune checkpoint inhibitors, especially anti-PD-1/PD-L1 monoclonal antibodies, currently represent a widely discussed treatment option not only in solid oncology, but in hematology-oncology as well.Areas covered: The manuscript is focused on clinical research concerning PD-1/PD-L1 blockade in lymphoma and multiple myeloma in order to identify the patients who would profit the most from this treatment modality. The authors reviewed articles on the topic on PubMed and relevant clinical trials on clinicaltrials.gov before October 2019.Expert opinion: So far, nivolumab and pembrolizumab have been approved for treating patients with relapsed/refractory classical Hodgkin lymphoma and primary mediastinal B cell lymphoma. Nevertheless, monotherapy alone is not curative and a combinational approach is needed. Modern treatment strategies and combinations are comprehensively summarized in this manuscript. There is no approved immune checkpoint inhibitor for the multiple myeloma indication. Although the combination of PD-1/PD-L1 inhibitors with immunomodulatory agents initially seemed promising, unexpected immune related toxicities have stopped any further development. Novel strategies and more potent combinations in myeloma and lymphoma are further discussed in the manuscript.

Effectiveness of heart rate variability (HRV) biofeedback is dependent on the relationship between the measured respiratory-heart rate coherence (C HR) and the resonant frequency (RFB) breathing. C...

BACKGROUND There were gaps between guidelines and practice when surgery was the only treatment for aortic stenosis (AS). OBJECTIVES This study analyzed the decision to intervene in patients with severe AS in the EORP VHD (EURObservational Research Programme Valvular Heart Disease) II survey. METHODS Among 2,152 patients with severe AS, 1,271 patients with high-gradient AS who were symptomatic fulfilled a Class I recommendation for intervention according to the 2012 European Society of Cardiology guidelines; the primary end point was the decision for intervention. RESULTS A decision not to intervene was taken in 262 patients (20.6%). In multivariate analysis, the decision not to intervene was associated with older age (odds ratio [OR]: 1.34 per 10-year increase; 95% CI: 1.11 to 1.61; P = 0.002), New York Heart Association functional classes I and II versus III (OR: 1.63; 95% CI: 1.16 to 2.30; P = 0.005), higher age adjusted Charlson comorbidity index (OR: 1.09 per 1-point increase; 95% CI: 1.01 to 1.17; P = 0.03), and a lower transaortic mean gradient (OR: 0.81 per 10-mm Hg decrease; 95% CI: 0.71 to 0.92; P < 0.001). During the study period, 346 patients (40.2%, median age 84 years, median EuroSCORE II [European System for Cardiac Operative Risk Evaluation II] 3.1%) underwent transcatheter intervention and 515 (59.8%, median age 69 years, median EuroSCORE II 1.5%) underwent surgery. A decision not to intervene versus intervention was associated with lower 6-month survival (87.4%; 95% CI: 82.0 to 91.3 vs 94.6%; 95% CI: 92.8 to 95.9; P < 0.001). CONCLUSIONS A decision not to intervene was taken in 1 in 5 patients with severe symptomatic AS despite a Class I recommendation for intervention and the decision was particularly associated with older age and combined comorbidities. Transcatheter intervention was extensively used in octogenarians. (J Am Coll Cardiol 2021;78:2131-2143) (c) 2021 by the American College of Cardiology Foundation.

Background: The metabolic syndrome (MetS) is prevalent in Arabian populations. Several small-scale studies have been performed to investigate the genetic basis of MetS. This systematic review and meta-analysis aimed to examine whether candidate gene polymorphisms are associated with MetS susceptibility among ethnic groups of the Arabian world and to suggest possible directions for future research regarding genetic markers and MetS.Methods: A search was conducted for peer-reviewed articles that examined the genetic association of MetS in Arabian populations in the following databases: Medline, Embase, Scopus, Direct Science, Web of Science, ProQuest, and Google Scholar until March 31, 2021. Articles were eligible if they were case-control studies, which investigated MetS as a dichotomous outcome (MetS vs no MetS). To assess the quality of the studies, the Q-Genie tool (Quality of Genetic Association Studies) was used. A non-central chi2 (random-effect) distribution was used to determine the heterogeneity (H) of Q and I (Galassi et al., The American journal of medicine, 2006, 119, 812–819) statistics.Results: Our search strategy identified 36 studies that met our inclusion criteria. In most cases, studies were excluded due to a lack of statistical information such as odds ratios, confidence intervals, and p-values. According to the Q-Genie tool, 12 studies scored poorly (a score of≤35), 13 studies scored moderately ( >35 and≤45), and 12 studies had good quality ( >45 or higher). The most frequently studied genes were FTO and VDR (both included in four studies). Three SNPs indicated increased risk for MetS after calculating the pooled odds ratios: FTO-rs9939609 (odds ratio 1.49, 95% CI: 0.96–2.32); LEP-rs7799039 (odds ratio 1.85, 95% CI: 1.37–2.5); and SERPINA12-rs2236242 (odds ratio 1.65, 95% CI: 1.21–2.24). Meta-analysis studies showed no significant heterogeneity.Conclusion: There were many sources of heterogeneity in the study settings. Most of the studies had low to moderate quality because of sample size and power issues, not considering all potential sources of bias, and not providing details about genotyping methods and results. As most studies were small-scale, aimed to replicate findings from other populations, we did not find any unique genetic association between MetS and Arabian populations.

The presented paper deals with the use of Industry 4.0 elements in industrial metrology applied to a production cell located at the Institute of Manufacturing Machines, Systems and Robotics, Faculty of Mechanical Engineering, Brno University of Technology. Conventional machine tool measurement methods can only improve the geometric accuracy of the machine tool, but the contribution of dynamic forces and the selected technological parameters are also reflected in the working accuracy during the production of a real part. The aim is to improve the manufacturing accuracy of the machine tool by measuring the machined parts using a single-purpose measuring station. The control system of this station was designed using virtual commissioning technology on Siemens platforms (NX MCD and Simatic PLC). The resulting measured data are stored in a local database. The design includes the creation of an infrastructure where the initial data processing will be handled by edge computing and the subsequent visualization will be done in the cloud environment MindSphere from Siemens and in virtual reality (Oculus & HTC).

Background Mastery is the extent to which an individual perceives their life circumstances as being under their control and not predominantly influenced by external factors. The relationship of mastery with clinical outcomes in people with multiple sclerosis (pwMS) has not been well-researched. We assessed the relationships of mastery with fatigue, disability, relapse number, and depression risk among pwMS over 2.5 years’ follow-up. Methods Data from the Health Outcomes and Lifestyle in a Sample of people with Multiple sclerosis study, among 839 participants who completed the 2.5 and 5-year reviews, were analysed. Mastery was measured by the Pearlin Mastery Scale, fatigue by Fatigue Severity Scale, depression risk by Patient Health Questionnaire-9, and disability by Patient-Determined Disease Steps, and diagnosed relapse number in the previous 12 months was queried. Cross-sectional and prospective analyses were undertaken by log-binomial, log-multinomial, and Poisson regression, as appropriate, adjusted for relevant confounders. Results Cross-sectionally, pwMS with the highest quartile mastery (> 25/28) had 90% lower frequency of depression risk, 60% lower frequency of clinically significant fatigue, and 77% fewer had severe disability, all largely robust to adjustment. Prospectively, those in the top two quartiles of mastery (> 21–25, > 25/28) had 66% and 74% lower subsequent depression risk, robust to adjustment. No significant associations were seen prospectively for change in fatigue, disability, or relapse number, however, and no robust associations of mastery with relapse number were evident. Conclusions Prospectively, a protective relationship of mastery with subsequent risk of depression was observed, suggesting this may be a point of intervention to improve wellbeing in pwMS.

Multiple sclerosis (MS), a neuroinflammatory disorder, occurs as non-progressive or progressive phenotypes, both forms present with diverse symptoms that may reduce quality of life (QoL). Adherence to healthy lifestyle behaviors has been associated with higher QoL in people with MS, whether these associations differ based on MS phenotype is unknown. Cross-sectional self-reported observational data from 1108 iConquerMS participants were analysed. Associations between lifestyle behaviors and QoL were assessed by linear regression, and phenotype differences via moderation analyses. Diet, wellness, and physical activity, but not vitamin D or omega-3 supplement use, were associated with QoL. Specifically, certain diet types were negatively associated with QoL in relapsing-remitting MS (RRMS), and positively associated in progressive MS (ProgMS). Participation in wellness activities had mixed associations with QoL in RRMS but was not associated in ProgMS. Physical activity was positively associated with QoL in RRMS and ProgMS. Phenotype differences were observed in diet and wellness with physical QoL, and physical activity with most QoL subdomains. Our findings show lifestyle behaviors are associated with QoL and appear to differ based on MS phenotype. Future studies assessing timing, duration, and adherence of adopting lifestyle behaviors may better inform their role in MS management.

Background: Left ventricular ejection fraction (LVEF) is the gold standard for evaluating heart failure (HF) in coronary artery disease (CAD) patients. It is an essential metric in categorizing HF patients as preserved (HFpEF), mid-range (HFmEF), and reduced (HFrEF) ejection fraction but differs, depending on whether the ASE/EACVI or ESC guidelines are used to classify HF.Objectives: We sought to investigate the effectiveness of using deep learning as an automated tool to predict LVEF from patient clinical profiles using regression and classification trained models. We further investigate the effect of utilizing other LVEF-based thresholds to examine the discrimination ability of deep learning between HF categories grouped with narrower ranges.Methods: Data from 303 CAD patients were obtained from American and Greek patient databases and categorized based on the American Society of Echocardiography and the European Association of Cardiovascular Imaging (ASE/EACVI) guidelines into HFpEF (EF > 55%), HFmEF (50% ≤ EF ≤ 55%), and HFrEF (EF < 50%). Clinical profiles included 13 demographical and clinical markers grouped as cardiovascular risk factors, medication, and history. The most significant and important markers were determined using linear regression fitting and Chi-squared test combined with a novel dimensionality reduction algorithm based on arc radial visualization (ArcViz). Two deep learning-based models were then developed and trained using convolutional neural networks (CNN) to estimate LVEF levels from the clinical information and for classification into one of three LVEF-based HF categories.Results: A total of seven clinical markers were found important for discriminating between the three HF categories. Using statistical analysis, diabetes, diuretics medication, and prior myocardial infarction were found statistically significant (p < 0.001). Furthermore, age, body mass index (BMI), anti-arrhythmics medication, and previous ventricular tachycardia were found important after projections on the ArcViz convex hull with an average nearest centroid (NC) accuracy of 94%. The regression model estimated LVEF levels successfully with an overall accuracy of 90%, average root mean square error (RMSE) of 4.13, and correlation coefficient of 0.85. A significant improvement was then obtained with the classification model, which predicted HF categories with an accuracy ≥93%, sensitivity ≥89%, 1-specificity Conclusions: Our study suggests the potential of implementing deep learning-based models clinically to ensure faster, yet accurate, automatic prediction of HF based on the ASE/EACVI LVEF guidelines with only clinical profiles and corresponding information as input to the models. Invasive, expensive, and time-consuming clinical testing could thus be avoided, enabling reduced stress in patients and simpler triage for further intervention.

Over the last few years, treatment principles have been changed towards more targeted therapy for many B-cell lymphoma subtypes and in chronic lymphocytic leukemia (CLL). Immunotherapeutic modalities, namely monoclonal antibodies (mAbs), bispecific antibodies (bsAbs), antibody-drug conjugates (ADCs), and chimeric antigen receptor T (CAR-T) cell therapy, commonly use B-cell-associated antigens (CD19, CD20, CD22, and CD79b) as one of their targets. T-cell engagers (TCEs), a subclass of bsAbs, work on a similar mechanism as CAR-T cell therapy without the need of previous T-cell manipulation. Currently, several anti-CD20xCD3 TCEs have demonstrated promising efficacy across different lymphoma subtypes with slightly better outcomes in the indolent subset. Anti-CD19xCD3 TCEs are being developed as well but only blinatumomab has been evaluated in clinical trials yet. The results are not so impressive as those with anti-CD19 CAR-T cell therapy. Antibody-drug conjugates targeting different B-cell antigens (CD30, CD79b, CD19) seem to be effective in combination with mAbs, standard chemoimmunotherapy, or immune checkpoint inhibitors. Further investigation will show whether immunotherapy alone or in combinatory regimens has potential to replace chemotherapeutic agents from the first line treatment.

Introduction/Background* Resistance of cancer cells to taxanes is a serious problem preventing successful therapy. Efforts are ongoing to synthesize novel taxanes efficacious against the resistant phenotype. Stony Brook taxanes (SB-Ts) have proven to have potential, but require further preclinical testing and more detailed study of their mechanism of action. Here, we aimed to evaluate the efficacy of several promising SB-Ts in resistant ovarian cancer models in vitro, and in vivo. We also studied the role of 3 candidate genes ABCC3, CPS1, and TRIP6 in SB-Ts cell death-inducing molecular mechanisms. Methodology The NCI/ADR-RES ovarian cancer cell line was incubated with either paclitaxel or one of the second generation (SB-T-1214 and SB-T-1216) or third generation (SB-T-121402, SB-T-121605 and SB-T-121606) taxanes. Cell survival was measured as IC50 after 72 hours. Cell cycle analysis was performed using flow cytometry. Uptake of SB-Ts into cells was measured by HPLC. Female athymic mice Nude Crl: NU(NCr)-Foxn1nu (N=50) were used as the model organism for ovarian cancer by subcutaneous application of NCI/ADR-RES cells. In vivo efficacy of taxanes was measured after intraperitoneal application twice per week. Gene expression in tumour tissue was measured by RT-qPCR. Result(s)* Compared to paclitaxel, NCI/ADR-RES cells showed 30x lower resistance to SB-T-1214, SB-T-1216, and SB-T-121402 and 50x lower to the 3rd generation taxanes SB-T-121605 and SB-T-121606. Cell cycle analysis showed the “1216” family to be more cytostatic than cytotoxic compared to “1214”. Uptake of SB-T-1216 and its derivatives into cells was 6-15.5x higher than for paclitaxel. Treatment of mice (groups of 5) with regimen combining paclitaxel and SB-T-121605/-06 significantly slowed tumour growth and even reduced tumour volume after several applications. Doses of SB-Ts higher than 3 mg/kg caused severe toxicity. Both SB-T-121605 and SB-T-121606, but not paclitaxel, led to significant decrease in CPS1 and ABCC3 expression in vitro and in case of CPS1 also in vivo. Conclusion* Third generation taxanes SB-T-121605 and SB-T-121606 are highly effective in a paclitaxel-resistant ovarian carcinoma model both in vitro and in vivo and warrant further investigation. SB-T treatment led to deregulation of CPS1 and ABCC3 expression that seems to play a role in their efficacy.

Objectives Isatuximab (Isa) is an approved IgG1 monoclonal antibody that targets a specific epitope of CD38 and kills multiple myeloma (MM) cells via multiple mechanisms. The Phase 3 IKEMA study (NCT03275285) demonstrated that Isa plus carfilzomib (K) and dexamethasone (d) significantly improved progression-free survival (PFS) compared with Kd in patients (pts) with relapsed MM (hazard ratio [HR], 0.531; 99% CI, 0.32–0.89; p = 0.0007), leading to the approval of Isa-Kd in the US for adults with MM with 1–3 prior lines and in the EU for those with ≥1 prior therapy. The presence of soft-tissue plasmacytomas is associated with poor prognosis, and newer therapies are urgently needed. In this post hoc analysis, we evaluated the efficacy and safety of Isa-Kd vs Kd in pts with relapsed MM and pre-existing soft-tissue plasmacytomas. Material and methods Pts (n = 302) were randomized (3:2) to Isa-Kd (n = 179) or Kd (n = 123). Isa (10 mg/kg IV) was given weekly for 4 weeks, then every 2 weeks. K (20 mg/m2 days 1–2, then 56 mg/m2) was given twice-weekly 3 of 4 weeks, and d (20 mg) twice-weekly. The independent review committee assessed response based on central radiology review and central lab M-protein using the International Myeloma Working Group criteria. Results At study entry, 19 (6.3%) pts had soft-tissue plasmacytomas: 12/179 (6.7%) had Isa-Kd and 7/123 (5.7%) had Kd. Overall median (range) duration of exposure in these pts was 41.9 (2–87) weeks for Isa-Kd vs 29.9 (4–83) for Kd, with 41.7% pts still on treatment at cycle 20 in Isa-Kd vs 14.3% pts in Kd. Baseline characteristics in the plasmacytomas subgroup were similar to those in the overall IKEMA intent-to-treat (ITT) population with the exception of ISS stages II (42.1% vs 31.1%) and III (31.6% vs 15.2%), and renal function impairment (38.9% vs 22.1%) which were more prevalent in the plasmacytomas subgroup vs ITT. PFS was improved with Isa-Kd vs Kd: HR, 0.574; 95% CI, 0.125–2.640. Median PFS was 18.76 (95% CI, 4.435–not calculable [NC]) months with Isa-Kd vs NC (0.986–NC) months with Kd. Overall response rate (50.0% vs 28.6%), very good partial response or better (33.3% vs 14.3%), and complete response (25.0% vs 0%, all with minimal residual disease negativity) rates were also improved with Isa-Kd vs Kd. Grade ≥3 TEAE occurred in 12 (100%) pts with Isa-Kd vs 4 (57.1%) with Kd. Grade 5 TEAEs during study treatment occurred in 2 (16.7%) vs 1 (14.3%) pt; serious TEAEs in 9 (75.0%) vs 4 (57.1%); TEAEs leading to discontinuations were 0 (0%) vs 1 (14.3%). Grade 5 events were pneumonia (1 [8.3%], Isa-Kd) and progressive disease (1 [8.3%], Isa-Kd; 1 [14.3%], Kd). Conclusions In pts with relapsed MM and soft-tissue plasmacytomas, Isa-Kd improved PFS and depth of response compared with Kd alone, with a manageable safety profile, consistent with the benefit observed in the IKEMA study overall population. Isa-Kd is a new treatment option for pts with relapsed MM and soft-tissue plasmacytomas. Funding Sanofi.

Background and Purpose: We aimed to estimate the prevalence of perceived cognitive impairment (PCI) and explore its associations with lifestyle and disease characteristics in a large international cohort of people with multiple sclerosis (MS). Methods: This study was a cross-sectional analysis. Participants rated their cognitive function over the preceding 4 weeks using four questions in a subscale within the Multiple Sclerosis Quality of Life questionnaire (MSQOL-54). These questions assessed perceived concentration, attention and memory by the patient and family/friends. Four definitions of PCI were derived, ranging from lowest to highest specificity. Associations with PCI were assessed by log-binomial regression. Results: The prevalence of PCI in our sample ranged from 41.0% (95% confidence interval, 39.0-43.0) using the least-specific definition to 11.6% (95% confidence interval, 10.3-12.9) using the most specific definition. A number of factors were associated with PCI, increasing in magnitude as the definition specificity increased, including positive associations for smoking and body mass index, whereas physical activity, dietary quality and use of vitamin D/omega-3 supplements were inversely associated with PCI. Conclusions: Our study reports associations between healthy lifestyle behaviours and PCI in people with MS. Although reverse causality is a potential explanation for our findings, previous studies have shown comparable associations with healthy lifestyle and MS onset and progression. Subject to external validation, these results suggest benefits realized from a healthy lifestyle in people with MS.

The article presents a model for the simulation of associative reasoning. This theme has been in the spotlight for a long time, mainly due to its influence on individuals' cognitive and decision-making processes because they significantly affect the individual knowledge base. This influence arises from the history of individual's perceptions, and due to that, significant differences between individuals must be taken into account. The model's main benefit is the selected way of representing knowledge. It takes the whole input perception (observation) and metadata about it as a basic associative processing unit. The model also respects the different importance of specific objects and concepts in perception. Concrete procedures for the implementation of associative processes are also described. The aim was to achieve a state when the model will simulate the dynamics of associative reasoning and specify the so-called knowledge context, which can then serve as a basis for subsequent decision-making processes. The paper describes in detail the structure of the model and some experiments that were performed with it.

Background The global burden of neurological disorders continues to grow. Many have a long disease course and symptoms that can impact daily living and reduce quality of life. Common symptoms are reported across neurological disorders, however, have not been assessed in detail. Assessment of shared symptoms and conditions across neurological disorders may provide insight into similar risk reduction and disease management opportunities. Methods Data from an Australian cohort (n = 192,091) were analysed. Log-binomial regression assessed shared symptoms and comorbidities in ten pre-defined categories across people with Alzheimer’s disease (AD), stroke, motor neuron disease (MND), multiple sclerosis (MS), or Parkinson’s disease (PD). Then, to identify sub-categories of symptoms and conditions that were driving the shared associations across disorders. Results Positive associations shared across neurological disorders were observed for cancers, digestive system, mental health, kidney and urinary, lung and breathing, and other conditions, categories. Bladder and urinary problems, incontinence, fatigue, muscle weakness, depression, and sleep apnoea, were associated with at least 3 of 5 neurological disorders. Conclusions Six overarching symptoms and condition categories were shared across neurological disorders. Bladder and urinary problems, incontinence, fatigue, muscle weakness, depression, and sleep apnoea were associated across most neurological disorders. Key messages Shared symptoms and conditions were identified across five neurological disorders. These findings may inform risk prevention and disease management strategies with broad applicability.

At least half of all heart failure (CHF) patients will have a comorbidity that could be undertreated, requires additional speciality input and/or polypharmacy. These patients are then at risk of iatrogenic and disease-related complications and readmissions if not closely supervised. Common comorbidities of relevance are cardiorenal and cardiometabolic syndromes (DM, obesity, OSA), chronic airways disease, elderly age, and accompanying pharmacotherapies. The structure of community practice often leaves primary, speciality, and allied health care in silos. For example, cardiology speciality training in Australia creates excellent sub-specialists to deliver diagnostic and therapeutic advances. A casualty of this process has been the gradual alienation of general cardiology toward general internal medical specialists and primary care practitioners. The consequences are largely noticed in community practice. The issue is compounded by suboptimal communication of information. This review explores these issues from a cardiology sub-speciality lens; firstly cross speciality areas that are important for cardiologists to maintain their skill, and finally, to obtain a brief overview of disease management and identify game-changing common denominators such as endothelial dysfunction and self-management.