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The dynamic interaction between depressive symptoms, mechanisms proposed in the metacognitive-therapy model, and loneliness across a 9-month period was investigated. Four data waves 2 months apart were delivered by a representative population sample of 4,361 participants during the COVID-19 pandemic in Norway. Networks were estimated using the newly developed panel graphical vector-autoregression method. In the temporal network, use of substance to cope with negative feelings or thoughts positively predicted threat monitoring and depressed mood. In turn, threat monitoring positively predicted suicidal ideation. Metacognitive beliefs that thoughts and feelings are dangerous positively predicted anhedonia. Suicidal ideation positively predicted sleep problems and worthlessness. Loneliness was positively predicted by depressed mood. In turn, more loneliness predicted more control of emotions. The findings point at the theory-derived variables, threat monitoring, beliefs that thoughts and feelings are dangerous, and use of substance to cope, as potential targets for intervention to alleviate long-term depressive symptoms.

Exercise is an important component of rehabilitation care for patients with heart failure with preserved ejection fraction (HFpEF). However, it is unclear which type of physical rehabilitation exercise is most effective. Thus, the aim of this study was to determine the relative effects of different types of exercise interventions on aerobic capacity measured by peak oxygen consumption (VO2peak; in mL/kg·min) in patients with HFpEF. We searched different electronic databases until December 2020 for randomized controlled trials that evaluated the effects of different types of exercise interventions on VO2peak of patients with HFpEF. Mean difference, standardized mean difference (SMD), and 95% confidence intervals (CIs) were calculated. Fixed and random-effects Bayesian network meta-analysis was used to compare the relative effectiveness of the different exercise interventions. Nineteen studies met the study criteria, including 720 patients. Comparing the physical rehabilitation interventions with usual care (control group), inspiratory muscle training was the highest ranked exercise intervention with an SMD of 3.6 mL/kg·min (95% CI, 2.3–4.8), followed by the group undergoing high-intensity interval training with a significant pooled improvement in VO2peak 3.5 (95% CI, 2.6–4.4) and combined aerobic and resistance exercise with an SMD of 3.2 (95% CI, 1.4–5.0). The inspiratory muscle training, high-intensity interval training, and combined aerobic and resistance exercise were the highest ranked physical rehabilitation intervention to improve VO2peak. These interventions should be considered as a component in the care of patients with HFpEF. Registration: https://www.crd.york.ac.uk/PROSPERO/; Unique identifier: CRD42021256442.

The current study evaluated whether or not there were significant differences in psychopathological traits between three groups of individuals. The first was a group of patients seeking bariatric surgery diagnosed as being affected by Binge Eating Disorder (BED), according to the new criteria of the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders. This group (NEW BED group) did not meet BED diagnosis following the previous criteria listed in the DSM-IV-TR. The second group of individuals was composed of severely obese patients seeking bariatric surgery not affected by an eating disorder, according to the diagnostic criteria of the DSM-5 (OB group). The third group was composed of individuals within a healthy weight range (Control group). 94 severely obese patients (33 in the NEW BED group and 61 in the OB group) were compared to the Control group including 41 participants on depression, anxiety and eating habits. The NEW BED scored significantly higher than the OB group on the Beck Depression Inventory, both the subscales of the State Trait Anxiety Inventory, on disinhibition and hunger subscales of the Three-Factor Eating Questionnaire and on many subscales of the Eating Disorders Inventory. The new, less restrictive diagnostic criteria for BED of the DSM-5 are useful in identifying obese patients affected by severe psychopathology and dysfunctional eating habits.

This article presents systematic pathways to model the thermal stability factor for magneto-resistive random access memories using atomistic simulations. The model involves constraint Monte Carlo solver to estimate the change in anisotropy energy as a function of the angle of magnetization from the easy axis at real temperatures. The reported modeling methodology has been validated against the hardware (HW) data of GlobalFoundries on the 22FDX technology node. We have clearly explained the routes for proper estimation of the input parameters along with the identification of important tuning parameters in the model. The model is based on a single effective free layer approximation of the magnetic tunnel junction (MTJ) and captures the variations of the thermal stability factor with the variations in free layer thickness, the diameter of the MTJ pillars, and the processing routes.

Whether coeliac disease in adults can be diagnosed with serology alone remains controversial. We aimed to evaluate the accuracy of serum anti-tissue transglutaminase IgA (tTG-IgA) in the diagnosis of coeliac disease.

Context: Despite the well-known positive effects of exercise in hypertensive patients, the best mode of exercise is still under discussion.Objective: A systematic review of the literature, synthesizing data on the effects of high-intensity interval training (HIIT) on peak oxygen consumption (VO2peak), blood pressure (BP), cardiac autonomic modulation, and resting heart rate (HR) in patients with hypertension.Data Sources: MEDLINE (via PubMed), CENTRAL, PEDro database, and SciELO (from the earliest date available to December 31, 2020).Study Selection: Randomized controlled trials (RCTs) that evaluated the effects of HIIT in hypertensive patients.Study Design: Systematic review and meta-analysis.Level of Evidence: Level 2.Data Extraction: Mean differences (MDs) with a 95% CI were calculated, and heterogeneity was assessed using the I2test.Results: Nine RCTs encompassing 569 patients met the eligibility criteria and were included in the systematic review. Five trials compared supervised HIIT with moderate-intensity continuous training (MICT) and a control; 1 trial compared HIIT with MICT, and 3 compared HIIT with a control. In comparison with MICT, HIIT improved VO2peak MD (3.3 mL.kg-1.min-1; 95% CI, 1.4-5.3; N = 130). In comparison with controls, HIIT improved VO2peak MD (4.4 mL.kg-1.min-1; 95% CI, 2.5-6.2; N = 162).Conclusion: Despite the low quality of the evidence, HIIT is superior to MICT in improving VO2peak in patients with hypertension. HIIT effectively improved VO2peak, BP, and resting HR when compared with controls. HIIT appears to be safe only when performed in a supervised manner for stage 1 hypertension patients without associated risk factors.

Context: Despite increasing use of reference values in isokinetic measurements and increasing importance, there is no systematic review of the reference values for lower and upper limb isokinetic muscle strength.Objective: A systematic review to analyze studies on the reference values and protocols for the measurement for upper and lower limb isokinetic muscle strength in an untrained and noninjured healthy population.Data Sources: MEDLINE, Scopus, Scielo, and CINAHL (from the earliest date available to June 2020).Study Selection: Studies that measured a set of reference values for isokinetic muscle strength.Study Design: Systematic review.Level of Evidence: Level 3.Data Extraction: Two reviewers selected studies independently. Data related to participants characteristics, outcomes of interest, isokinetic parameters, reference values for isokinetic muscle strength, and quality of evidence assessment were systematically reviewed independently by 2 authors.Results: A total of 31 studies met the study criteria. The included studies were used to synthesize the isokinetic muscle strength data according to age-group and sex. We extracted 1845 normative data related to isokinetic strength. Of these, 1181 items referred to lower limbs and 664 items to upper limbs.Conclusion: In general, agonist muscle groups are stronger than antagonist muscles, and the men tend to obtain higher strength values than women. The angular velocity varied from 10 to 300 deg/s. The reference values identified can be useful for professionals to obtain during the isokinetic evaluation of the diagnostic parameters of muscle deficiency.

Background: Only limited studies analyzed a possible relationship between frailty and infections. Our aim was to investigate the possible association between higher multidimensional prognostic index (MPI) values, a tool for evaluating multidimensional frailty, and the prevalence of infectious diseases, including antibiotics’ cost and the prevalence of MDR (multidrug resistance) pathogens. Methods: Older patients, affected by COVID-19, were enrolled in the hospital of Palermo over four months. Results: 112 participants (mean age 77.6, 55.4% males) were included. After adjusting for potential confounders, frailer participants had a higher odds of any positivity to pathogens (prevalence: 61.5%, odds ratio = 15.56, p< 0.0001) compared to a prevalence of 8.6% in more robust, including MDR, and a higher costs in antibiotics. Conclusions: Higher MPI values, indicating frailer subjects, were associated with a higher prevalence of infections, particularly of MDR pathogens, and a consequent increase in antibiotics’ cost.

This study aims to estimate the burden, trends, forecasts, and disparities of early musculoskeletal (MSK) disorders among individuals ages 15 to 39 years.

AbstractBackgroundMental pain has been proposed as a global person-centered outcome measure. The aim of this cross-sectional study was to test an essential requisite of such a measure, namely that mental pain incorporates independent contributions from a range of discrete but disparate outcome measures.MethodsTwo hundred migraine patients were assessed concerning migraine disability, psychosomatic syndromes, mental pain, depression, anxiety, and psychosocial dimensions. General linear models were tested to verify which measures would individually make unique contributions to overall mental pain.ResultsThe final model, accounting for 44% of variance, identified that higher mental pain was associated with more severe depressive symptoms, higher migraine disability, lower well-being, and poorer quality of life.ConclusionIn this sample, mental pain was shown to behave as expected of a global outcome measure, since multiple measures of symptomatology and quality of life showed modest but significant bivariate correlations with mental pain and some of these measures individually made unique contributions to overall mental pain.

Turner's syndrome (TS) is one of the most common sex chromosome disorders caused by numeric or structural abnormalities of the X chromosome. A case of TS and Systemic Sclerosis (SSc) is reported, along with a summary of all associated TS/autoimmune diseases described in English literature from 1948 to 2020, using a search in MEDLINE (Pubmed). A 32-year-old woman affected by TS was seen due to inflammatory arthralgia in small joints and dysphagia, as well as a two-year history of Raynaud's phenomenon and puffy hands. Biohumoural laboratory tests and severity scales revealed changes that allowed us to diagnose SSc. This case report emphasises the role played by sex hormones and chromosomal abnormalities in the pathogenesis of autoimmune disorders, and to our knowledge, this is the only case described in literature of a TS patient who developed SSc.

Turner's syndrome (TS) is one of the most common sex chromosome disorders caused by numeric or structural abnormalities of the X chromosome. A case of TS and Systemic Sclerosis (SSc) is reported, along with a summary of all associated TS/autoimmune diseases described in English literature from 1948 to 2020, using a search in MEDLINE (Pubmed). A 32-year-old woman affected by TS was seen due to inflammatory arthralgia in small joints and dysphagia, as well as a two-year history of Raynaud's phenomenon and puffy hands. Biohumoural laboratory tests and severity scales revealed changes that allowed us to diagnose SSc. This case report emphasises the role played by sex hormones and chromosomal abnormalities in the pathogenesis of autoimmune disorders, and to our knowledge, this is the only case described in literature of a TS patient who developed SSc.

Introduction: The hemangioma is the most common vascular tumor, involving the head and neck in 60% of cases. It is rare in the larynx. In children, hemangiomas are more frequent on the subglottis, whereas in adults the most common site is the supraglottis. Laryngeal hemangioma with cavernous features isolated to the free edge of the vocal fold is a very rare clinical finding. We present 2 cases of glottic hemangioma. Both patients reported severe hoarseness.Cases: In the first patient, an extensive blue-purple mass was seen on the right vocal cord. The patient was posted for microlaryngeal surgery with carbon dioxide (CO2) laser. Second patient had a large, smooth, flesh-colored polypoid mass emanating from the left vocal cord. The patient was posted for microlaryngeal surgery. After 2 months, both patients showed a considerable voice improvement.Discussion: Vocal cord hemangiomas are very rare, and they usually cause problem in the voice of the patient. A vascular lesion that may mimic a hemangioma may sometimes result from an organizing hematoma following a hemorrhage on the vocal cords due to voice abuse. Laryngeal hemangiomas also need to be distinguished pathologically from polypoidal vascular granulation tissue that may be produced by laryngeal biopsy, intubation, or trauma. Indirect endoscopy is enough to diagnosis. No active treatment is advised for adult laryngeal hemangiomas unless the lesions are symptomatic or show a tendency to involve other parts. There is no uniformly accepted treatment of head and neck hemangiomas. Surgical excision with laser CO2microlaryngoscopic techniques gives satisfactory results.

Vaccination, particularly against pneumococcus and influenza, is a low-cost primary prevention, useful to avoid hard complications, particularly among frail older people. In this pilot study, we aimed to assess the effect of a strategy for influenza and pneumococcal vaccination for outpatients mainly affected by cognitive or endocrinological conditions, evaluating what could stimulate or demotivate vaccination among older people. This study was conducted during the 2023–2024 influenza season at the outpatient clinics in Palermo, Italy. A total 76 patients were included. More than half of the patients could be considered as pre-frail and about 20% frail, according to a comprehensive geriatric evaluation. Among patients, 46.05% received only vaccination against pneumococcus, 28.95% both vaccinations, and 25.0% only against influenza. Compared with the previous seasons, a 19.5% increase of influenza and 90.2% of pneumococcal vaccine uptake was observed. Side effects of vaccination were the main reason of the previous rejection, namely 76.9% for influenza and 53.8% for anti-pneumococcal vaccination. In conclusion, our study indicates how a new vaccination strategy in different settings could be feasible. Proposing influenza and pneumococcal vaccination for frail older outpatients could be an effective instrument to improve immunization coverage that is still low among older people.

Background: Osteoporosis is a common concern in the elderly that leads to fragile bones. Calcium supplementation plays a crucial role in improving bone health, reducing fracture risk, and supporting overall skeletal strength in this vulnerable population. However, there is conflicting evidence on the safety of calcium supplements in elderly individuals. Aim: The aim of this study was to evaluate the adherence, safety and tolerability of calcium citrate supplementation in elderly osteopenic subjects. Methods: In this non-interventional, prospective, multicenter study, subjects received daily 500 mg calcium citrate supplementation for up to one year. Adherence was calculated based on compliance and persistence. Safety was assessed through adverse reactions (ARs), deaths, and clinical laboratory evaluations. Results: A total of 268 Caucasian subjects (91.4% female, mean age 70 ± 4.5 years) participated in the study. Mean adherence to treatment was 76.6 ± 29.5% and half of subjects had an adherence of 91% and ~ 33% of participants achieved complete (100%) adherence. ARs were reported by nine (3.9%) subjects, primarily gastrointestinal disorders, with no serious ARs. The frequency of all adverse events (including ARs) was significantly higher in subjects with adherence of < 80% (41.6%; 32/77) vs. those with adherence ≥ 80% (11%; 16/145, p < 0.0001). Both systolic and diastolic blood pressure decreased from baseline to follow-up visit (change of -2.8 ± 13.9 mmHg, p = 0.0102 and -2.1 ± 10.4 mmHg, p = 0.0116, respectively). Conclusion: This study demonstrated favorable adherence to calcium citrate supplementation in elderly osteopenic subjects. The occurrence of ARs, though generally mild, were associated with lower adherence to calcium supplementation.

•Gender differences may influence the response to CPAP treatment.•Sleepy males and females showed a low adherence rate to CPAP treatment.•Sleeping females are older, obese and have cognitive symptoms, possibly caused by a greater experience of nocturnal hypoxaemia.•Sleepy males report more symptoms and history of multimorbidity.

When coronavirus disease 2019 (COVID-19) became a national health crisis, the local government of the Cagayan de Oro City (CDOC) did not implement total lockdown. The COVID-19 Adjustment Measure Program adopted by the local government probably affected the April 2020 Labor Force Survey that showed that Region 10 posted an employment rate of 88.9%, which is higher than the national average of 82.3% (Department of Labor and Employment, Region Office No. X (DOLE-X). NorMin secures highest employment rate amid COVID 19. 2020. Available from: https://pia.gov.ph/news/articles/1044898[Accessed 9th May 2021]). Despite the regional figure being 6.6 percentage points higher than the national one, there is a decrease in employed persons by around 400,000 from 2.302 million persons employed in April 2019 to 1.883 million in April 2020 (Department of Labor and Employment, Region Office No. X (DOLE-X). NorMin secures highest employment rate amid COVID 19. 2020. Available from: https://pia.gov.ph/news/articles/1044898[Accessed 9th May 2021]). Hence, the study determines the effect of COVID-19 protective measures implemented by the government on the economy of CDOC. Using the barangay-level and selected sectoral-level data on business registration, and employment data between 2010 and 2019, the study estimates that one-week lockdown means a ₱1,825 loss of income for a minimum-wage employee. One-month lockdown costs ₱7,300 foregone income, while one-quarter lockdown (or a half of six months) is equivalent to ₱21,900 income loss. We recommend 10 policy interventions, but the government should also think big and invest its resources into programs that create a multiplier effect on the economy. Multipliers are interventions that create ripples or positive impacts on other sectors and/or economic participants.

Supplemental Digital Content is available in the text.

AbstractBackgroundPain has been qualified under four categories: nociception, perception of pain, suffering, and pain behaviors. Most of the literature on migraine has devoted attention to the first two. The aim of the present cohort study was to investigate patients with migraine enrolled at a tertiary care unit to study suffering and mental pain and identify potential risk factors for migraine.MethodsAn observational cross-sectional study was carried out on patients with chronic migraine (CM) and episodic migraine (EM), and healthy subjects (HS). The three groups were matched for age and sex. A comprehensive assessment of migraine disability, pain, psychiatric disorders, psychosomatic syndromes, depressive and anxious symptoms, euthymia, psychosocial variables, mental pain, and pain-proneness (PP) was performed.ResultsThree hundred subjects were enrolled (100 CM, 100 EM, and 100 HS). Based on the multiple regression analyses, those presenting PP (social impairment: odds ratio [OR] = 3.59, 95% confidence interval [CI] = 1.14-11.29; depressive symptoms: OR = 3.82, 95% CI = 1.74-8.41) were more likely to be CM than HS. Those with higher levels of PP (social impairment: OR = 4.04, 95% CI = 1.60-10.22; depressive symptoms: OR = 2.02, 95% CI = 1.26-3.24) were more likely to be EM than HS. Those presenting higher levels of mental pain were more likely to be CM than EM (OR = 1.45, 95% CI = 1.02-2.07).ConclusionMigraine is an unpleasant sensory and emotional experience associated with psychosocial manifestations that might contribute to the level of suffering of the individuals. Mental pain resulted to be the variable that most differentiated patients with CM from EM.

•The HMob scale showed excellent internal consistency and reliability.•The HMOB scale presents concurrent validity with the FSS and FIM scales.•The HMOB scale can be used in daily practice to measure mobility in hospital.

Supplemental Digital Content is available in the text.

DNA methylation can play a pathogenic role in the early stages of hyperglycemia linking homeostasis imbalance and vascular damage.

SARS-CoV-2 betacoronavirus is responsible for the Corona Virus Disease 2019 (COVID-19) which has relevant pathogenic implications for the cardiovascular system. Incidence and severity of COVID-19 are higher in the elderly population (65 years and older). This may be due to higher frequency of comorbidities, but increased frailty and immunosenescence linked with aging may also contribute. Moreover, in elderly individuals, SARS-CoV-2 may adopt different molecular strategies to strongly impact on cardiac aging that culminate in exacerbating a pro-inflammatory state (cytokine storm activation), which, in turn, may lead to pulmonary vascular endothelialitis, microangiopathy, diffuse thrombosis, myocarditis, heart failure, cardiac arrhythmias, and acute coronary syndromes. All these events are particularly relevant in elderly patients, and deserve targeted cardiovascular treatments and specific management of repurposed drugs against COVID-19. We discuss current evidence about the cardiovascular involvement during COVID-19, and elaborate on clinical implications in elderly patients.

ABSTRACTBackground: Immune-checkpoint inhibitors have radically changed the treatment landscape of Non-Small-Cell Lung Cancer (NSCLC). It is still unclear whether specific clinical characteristics might identify those patients benefiting from immunotherapy more than others. The aim of this study was to identify clinical characteristics associated with disease-specific survival (DSS), time-to-treatment failure (TTF), objective responses (OR) and progressive disease (PD) in NSCLC patients treated with Nivolumab.Methods: This was a multicenter retrospective study conducted on 294 patients treated with Nivolumab for advanced NSCLC.Results: Of the more than 50 variables analyzed, five showed a significant correlation with DSS: ECOG PS, size of the biggest brain metastasis, number of metastatic sites, toxicity, and malignant pleural effusion. Three variables significantly correlated with TTF: malignant pleural effusion, number of metastatic sites, number of liver metastases. Malignant pleural effusion was the only variable showing a significant correlation with OR, as well as the only one correlating with all the endpoints of the study.Conclusions: This study identified clinical characteristics associated with survival and response during treatment with Nivolumab in NSCLC patients. The unfavorable association between malignant pleural effusion and objective response is a novel finding with important translational implications.

Introduction: Guidelines recommend hemodialysis graft screening to identify and repair significant (>50%) stenosis at high risk of thrombosis, but there is insufficient evidence to prefer one or other screening tool due to the lack of studies comparing all available options.Methods: Seeking an optimal screening approach, we compared the performance of all currently used tools (duplex ultrasound to detect significant stenosis (StD) and measure access blood flow (QaD), ultrasound dilution access blood flow (QaU), static venous intra-access pressure ratio (VAPR), dynamic arterial and venous pressures measurement, and monitoring) for diagnosing significant angiography-proven stenosis (StA) and predicting incipient thrombosis (occurring within 4 months) in 62 grafts. All thrombotic and symptomatic acute hypotension episodes were recorded during follow-up.Results: VAPR > 0.70 and QaU < 1600 mL/min were the best indicators to angiography for those aiming to identify the majority of StA (91% sensitivity) and QaU < 1000 mL/min or StD for those aiming to avoid unnecessary angiograms (95%–93% positive predictive value). At Cox’s analysis, the only significant thrombosis predictors were acute hypotension episodes (relative risk = 4.4 (95% confidence interval = 2.2–8.8), p < 0.0001) and QaU or QaD (14% (95% confidence interval = 8–21) or 16% (95% confidence interval = 6–25) increased risk per 100 mL/min drop in Qa, p < 0.003). Thrombosis risk (adjusted for acute hypotension) became significantly higher at QaU = 1000–700 mL/min (relative risk = 3.6 (95% confidence interval = 1.6–8.2), p < 0.001) and QaD = 1300–1000 mL/min (relative risk = 3.1 (95% confidence interval = 1.1–12.8), p = 0.031). The proportion of thromboses attributable to acute hypotension was 40% (95% confidence interval = 24–57).Conclusions: Our comparative study showed that an effective screening for graft stenosis and short-term thrombosis risk can rely on Qa surveillance alone, and suggested that avoiding acute hypotension and correcting stenosis at QaU < 1000 mL/min or QaD < 1300 mL/min can contain thrombosis risk.

Dilated cardiomyopathy (DCM) represents a common genetic cause of mechanical and/or electrical dysfunction leading to heart failure (HF) onset for which truncating variants in titin (TTN) gene result in the most frequent mutations. Moreover, myocyte and endothelial cell apoptosis is a key endophenotype underlying cardiac remodelling. Therefore, a deeper knowledge about molecular networks leading to acute injury and apoptosis may reveal novel circulating biomarkers useful to better discriminate HF phenotypes, patients at risk of heart transplant as well as graft reject in order to improve personalised therapy. Remarkably, increased plasma levels of cell-free DNA (cfDNA) may reflect the extent of cellular damage, whereas circulating mitochondrial DNA (mtDNA) may be a promising biomarker of poor prognosis in patients with HF. Furthermore, some panels of circulating miRNAs may improve the stratification of natural history of disease. For example, a combination of miR-558, miR-122* and miR-520d-5p, as well as miR-125a-5p, miR-550a-5p, miR-638 and miR-190a, may aid to discriminate different phenotypes of HF ranging from preserved to reduced ejection fraction. We give update on the most relevant genetic determinants involved in DCM and discuss the putative role of non-invasive biomarkers to overcome current limitations of the reductionist approach in HF management.

The introduction of renewables, distributed generation, microgrids, electric vehicles, and new market actors, such as aggregators, have led to a remarkable change in the power network. To address the issues that such a profound modification implies on a modern energy system, here a new hierarchical architecture is presented. Specifically, the proposed approach considers the case of an aggregator of consumers in the balancing market, in which incentives for local users (i.e., microgrids, buildings) are considered as well as flexibility assessment for demand response, and CO2emissions. The main innovation is related to the overall architecture and to the formalization of the upper level decision problem that aims at coordinating local users in a democratic way, while, at the lower level, consumers want to track the aggregator’s reference values performing demand response programs. The approach is applied to a real case study.

The characterization of intrinsically disordered regions (IDRs) in membrane-associated proteins is of crucial importance to elucidate key biochemical processes, including cellular signaling, drug targeting, or the role of post-translational modifications. These protein regions pose significant challenges to powerful analytical techniques of molecular structural investigations. We here applied magic angle spinning solid-state nuclear magnetic resonance to quantitatively probe the structural dynamics of IDRs of membrane-bound α-synuclein (αS), a disordered protein whose aggregation is associated with Parkinson’s disease (PD). We focused on the mitochondrial binding of αS, an interaction that has functional and pathological relevance in neuronal cells and that is considered crucial for the underlying mechanisms of PD. Transverse and longitudinal 15N relaxation revealed that the dynamical properties of IDRs of αS bound to the outer mitochondrial membrane (OMM) are different from those of the cytosolic state, thus indicating that regions generally considered not to interact with the membrane are in fact affected by the spatial proximity with the lipid bilayer. Moreover, changes in the composition of OMM that are associated with lipid dyshomeostasis in PD were found to significantly perturb the topology and dynamics of IDRs in the membrane-bound state of αS. Taken together, our data underline the importance of characterizing IDRs in membrane proteins to achieve an accurate understanding of the role that these elusive protein regions play in numerous biochemical processes occurring on cellular surfaces.

Interests in covalent drugs have grown in modern drug discovery as they could tackle challenging targets traditionally considered “undruggable”. The identification of covalent binders to target proteins typically involves directly measuring protein covalent modifications using high-resolution mass spectrometry. With a continually expanding library of compounds, conventional mass spectrometry platforms such as LC–MS and SPE-MS have become limiting factors for high-throughput screening. Here, we introduce a prototype high-resolution acoustic ejection mass spectrometry (AEMS) system for the rapid screening of a covalent modifier library comprising ∼10,000 compounds against a 50 kDa-sized target protein─Werner syndrome helicase. The screening samples were arranged in a 1536-well format. The sample buffer containing high-concentration salts was directly analyzed without any cleanup steps, minimizing sample preparation efforts and ensuring protein stability. The entire AEMS analysis process could be completed within a mere 17 h. An automated data analysis tool facilitated batch processing of the sample data and quantitation of the formation of various covalent protein–ligand adducts. The screening results displayed a high degree of fidelity, with a Z′ factor of 0.8 and a hit rate of 2.3%. The identified hits underwent orthogonal testing in a biochemical activity assay, revealing that 75% were functional antagonists of the target protein. Notably, a comparative analysis with LC–MS showcased the AEMS platform’s low risk of false positives or false negatives. This innovative platform has enabled robust high-throughput covalent modifier screening, featuring a 10-fold increase in library size and a 10- to 100-fold increase in throughput when compared with similar reports in the existing literature.

The persistence in therapy of rheumatoid arthritis drugs and particularly bDMARD is a limiting factor for their long-term use. The randomized controlled trials (RCTs) may not reflect real-world contexts due to strict inclusion and exclusion criteria. Baricitinib, which targets both JAK1 and JAK2, has been used in Italy for several years. The aim of this multi-center study is to assess the real world persistence on therapy of baricitinib in RA patients and to identify predictive factors of baricitinib's survival rate.

The aim of this systematic review and meta-analysis was to determine the effects of whole-body vibration training on metabolic abnormalities, mobility, balance and aerobic capacity in older adult patients with type 2 diabetes mellitus.

•RaDID-QC was developed to screen dysphagia signs and symptoms.•RaDID-QC is meant to be applied to caregivers of older people with dementia.•RaDID-QC is a simple, concise, easy-to-apply, quick, and reliable questionnaire.

•Cardiorespiratory fitness measured by cardiopulmonary exercise testing is consistently impaired in COVID-19 survivors.•The degree of reduction of cardiorespiratory fitness is inversely associated with age, time post-COVID-19, disease severity, presence of dyspnea, and reduced exercise capacity.•Future research should investigate the mechanisms of cardiorespiratory fitness reduction in addition to investigating possible therapeutic strategies to maximize fitness post COVID-19.

We performed a cross-sectional study to investigate the correlation between a plateau in the minute ventilation during cardiopulmonary exercise testing in patients with chronic obstructive pulmonary disease and its impact on cardiac performance. There is a correlation between a plateau in the minute ventilation exercise testing graph, and it impacts cardiac performance.

Progresses in liquid-based assays may provide novel useful non-invasive indicators of cardiovascular (CV) diseases. By analysing circulating cells or their products in blood, saliva and urine samples, we can investigate molecular changes present at specific time points in each patient allowing sequential monitoring of disease evolution. For example, an increased number of circulating endothelial cells may be a diagnostic biomarker for diabetic nephropathy and heart failure with preserved ejection fraction. The assessment of circulating cell-free DNA (cfDNA) levels may be useful to predict severity of acute myocardial infarction, as well as diagnose heart graft rejection. Remarkably, circulating epigenetic biomarkers, including DNA methylation, histone modifications and non-coding RNAs are key pathogenic determinants of CV diseases representing putative useful biomarkers and drug targets. For example, the unmethylated FAM101Agene may specifically trace cfDNA derived from cardiomyocyte death providing a powerful diagnostic biomarker of apoptosis during ischaemia. Moreover, changes in plasma levels of circulating miR-92 may predict acute coronary syndrome onset in patients with diabetes. Now, network medicine provides a framework to analyse a huge amount of big data by describing a CV disease as a result of a chain of molecular perturbations rather than a single defect (reductionism). We outline advantages and challenges of liquid biopsy with respect to traditional tissue biopsy and summarise the main completed and ongoing clinical trials in CV diseases. Furthermore, we discuss the importance of combining fluid-based assays, big data and network medicine to improve precision medicine and personalised therapy in this field.

IMPORTANCE: Although increasingly strong evidence suggests a role of maternal total cholesterol and low-density lipoprotein cholesterol (LDLC) levels during pregnancy as a risk factor for atherosclerotic disease in the offspring, the underlying mechanisms need to be clarified for future clinical applications. OBJECTIVE: To test whether epigenetic signatures characterize early fetal atherogenesis associated with maternal hypercholesterolemia and to provide a quantitative estimate of the contribution of maternal cholesterol level to fetal lesion size. DESIGN, SETTING, AND PARTICIPANTS: This autopsy study analyzed 78 human fetal aorta autopsy samples from the Division of Human Pathology, Department of Advanced Biomedical Sciences, Federico II University of Naples, Naples, Italy. Maternal levels of total cholesterol, LDLC, high-density lipoprotein cholesterol (HDLC), triglycerides, and glucose and body mass index (BMI) were determined during hospitalization owing to spontaneous fetal death. Data were collected and immediately processed and analyzed to prevent degradation from January 1, 2011, through November 30, 2016. MAIN OUTCOMES AND MEASUREMENTS: Results of DNA methylation and messenger RNA levels of the following genes involved in cholesterol metabolism were assessed: superoxide dismutase 2 (SOD2), low-density lipoprotein receptor (LDLR), sterol regulatory element binding protein 2 (SREBP2), liver X receptor α (LXRα), and adenosine triphosphate–binding cassette transporter 1 (ABCA1). RESULTS: Among the 78 fetal samples included in the analysis (59% male; mean [SD] fetal age, 25 [3] weeks), maternal cholesterol level explained a significant proportion of the fetal aortic lesion variance in multivariate analysis (61%; P = .001) independently by the effect of levels of HDLC, triglycerides, and glucose and BMI. Moreover, maternal total cholesterol and LDLC levels were positively associated with methylation of SREBP2 in fetal aortas (Pearson correlation, 0.488 and 0.503, respectively), whereas in univariate analysis, they were inversely correlated with SREBP2 messenger RNA levels in fetal aortas (Pearson correlation, −0.534 and −0.671, respectively). Epivariations of genes controlling cholesterol metabolism in cholesterol-treated human aortic endothelial cells were also observed. CONCLUSIONS AND RELEVANCE: The present study provides a stringent quantitative estimate of the magnitude of the association of maternal cholesterol levels during pregnancy with fetal aortic lesions and reveals the epigenetic response of fetal aortic SREBP2 to maternal cholesterol level. The role of maternal cholesterol level during pregnancy and epigenetic signature in offspring in cardiovascular primary prevention warrants further long-term causal relationship studies.

Primary lymphoma of the sphenoid is an extremely rare pathology, therefore it is difficult to hypothesize and the imaging characteristics are not well-known. Here we report the imaging features in computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET) scan of a 44-year-old patient who presented with severe headache. CT and MRI showed a sphenoid sinus mass that suggested rhinopharyngeal lesion or a chordoma. However, biopsy from the mass histologically proved it to be Diffuse large B-cell lymphoma and PET examinations revealed increased fluorodeoxyglucose uptake around the sphenoid bone and multiple spinal lesions.

Systematic review of real-world studies about repeated dexamethasone intravitreal implant (DEXi) 0.7 mg in diabetic macular edema management, in order to identify the effective window of time occurring between injections, the critical evaluation of efficacy of the treatment, and the relative long-term safety in the real life setting.

Background: Given the growing use of off-label in pediatric practice, there is a growing interest on pharmacovigilance programs monitoring the occurrence of adverse drug reactions related to off-label drug prescription in childhood. Patients and Methods: The results of a one-year program of pharmacovigilance issued in the Sicilian Region, Italy, are herein presented. The study involved 6 pediatric and neonatal centres and prospectively reviewed the prescriptions of 5,060 patients, who were stratified for age (newborn, infant, children, adolescents). Results: A total of 14,916 prescriptions were issued for 5,060 patients. Among them, 454 patients [8.97%] received at least one off-label drug. Among the off-label treated patients, 255 [56.2%] were newborns. Anti-infective drugs were the most frequent off-label used drugs, followed by drugs for alimentary tract and metabolism and drugs for blood or blood forming organs. Ninety adverse drug reactions were recorded [1.78% of the total patients]. They occurred after an off-label prescription in 33 out of 90 [36.7%], while those occurring after an on-label prescription were 57 [63.3%]. Patients treated with an off-label drug had a significantly higher risk of adverse drug reactions [7.3% vs. 1.2%; p <0.01]. Conclusion: The present study indicates that children admitted to neonatal intensive care units are likely to receive an off-label medication; children who receive an off-label medication are usually more likely to be treated with more medication than the others; adverse drug reactions occur in patients admitted in neonatal intensive care and pediatrics are units are more frequently with off-label than with on-label drugs.

Heart failure (HF) is a syndrome that results in inadequate blood supply, leading to a number of structural and functional changes. Noninvasive ventilatory support (NIVS) is used as an adjuvant treatment to improve the functional capacity of these patients.

We performed a systematic review and meta-analysis to investigate the effects pulmonary rehabilitation on exercise tolerance and quality of life in patients with idiopathic pulmonary fibrosis. Pulmonary rehabilitation is effective in increasing exercise tolerance and improving quality of life in these patients.

Here we analyse genetic variation, population structure and diversity among 3,010 diverse Asian cultivated rice (Oryza sativaL.) genomes from the 3,000 Rice Genomes Project. Our results are consistent with the five major groups previously recognized, but also suggest several unreported subpopulations that correlate with geographic location. We identified 29 million single nucleotide polymorphisms, 2.4 million small indels and over 90,000 structural variations that contribute to within- and between-population variation. Using pan-genome analyses, we identified more than 10,000 novel full-length protein-coding genes and a high number of presence–absence variations. The complex patterns of introgression observed in domestication genes are consistent with multiple independent rice domestication events. The public availability of data from the 3,000 Rice Genomes Project provides a resource for rice genomics research and breeding.

To identify predictors and develop a risk score for the prediction of extubation failure in TBI patients.

Background Exercise is an effective strategy for reducing total and cardiovascular mortality in patients with coronary artery disease. However, it is not clear which modality is best. We performed a meta-analysis to investigate the effects of high-intensity interval versus moderate-intensity continuous training of coronary artery disease patients.Methods We searched MEDLINE, PEDro, LILACS, SciELO and the Cochrane Library (from the earliest date available to November 2016) for controlled trials that evaluated the effects of high-intensity interval versus moderate-intensity continuous training for coronary artery disease patients. Weighted mean differences and 95% confidence intervals were calculated, and heterogeneity was assessed using the I2test.Results Twelve studies met the study criteria, including 609 patients. High-intensity interval training resulted in improvement in peak oxygen uptake weighted mean difference (1.3?ml/kg/min, 95% confidence interval: 0.6–1.9, n?=?594) compared with moderate-intensity continuous training. No significant difference in physical, emotional, and social domain of quality of life was found for participants for participants in the high-intensity interval training group compared with the moderate-intensity continuous training group. Sub-analysis of three studies with isocaloric exercise training showed no significant difference in peak oxygen uptake weighted mean difference (0.4?ml/kg/min, 95% confidence interval: –0.1–0.9, n?=?137) for participants in the high-intensity interval training group compared with moderate-intensity continuous training group.Conclusions High-intensity interval training may improve peak oxygen uptake and should be considered as a component of care of coronary artery disease patients. However, this superiority disappeared when isocaloric protocol is compared.

Although it has been proposed that the dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis may act as a possible pathway linking early life stress to psychosis, this relationship has not yet been fully confirmed. This study aimed to investigate the relationship between childhood adversity (CA), cortisol levels, and psychosis. Eighty-five patients with psychosis and 170 control subjects were enrolled in the study. CA was evaluated using the Florence Psychiatric Interview, and Childhood Experience of Care and Abuse Questionnaire. Positive symptoms (PS) were assessed using the Positive and Negative Syndrome Scale. Cortisol levels were evaluated in saliva samples. Patients experienced more CA and showed higher cortisol levels than controls. Patients with CA showed higher morning cortisol levels and more severe PS than those without CA. Patients with higher morning cortisol levels showed severe delusions. These findings suggest that both CA and dysregulation of the HPA axis could be related to psychosis.