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Aims Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection has had a serious worldwide impact on human health. On December 2020, an immunization campaign with a COVID-19 mRNA vaccine (Comirnaty-BNT162b2 Pfizer-BioNTech) was started in Italy, first targeting healthcare workers (HCWs). This study aims to investigate the antibodies that are response against SARS-CoV-2 vaccine. Methods and Results The kinetics and the persistence of both anti-S1/S2 IgGs and neutralizing antibodies (Nt-Abs) were investigated in 76 HCWs through a 4-month follow-up with multiple testing points starting at the first dose. Temporal analysis of SARS-CoV-2 Abs titre kinetics showed three different stages, with an initial slow growth in the anti-S1/S2 IgGs and Nt-Abs titres, corresponding to the first 4 weeks after the first dose of vaccine, followed by a second stage with peaks in titres, around 35 days after the first dose, and by a third stage (38 to 90–120 days after the first dose) showing a steady decrease in anti-S1/S2 IgGs while Nt-Abs are maintained at stable levels. Moreover, the levels of specific Nt-Abs to SARS-CoV-2 Spike protein are correlated to the anti-S1/S2 IgG titre (R-squared = 0.47; p < 0.001). Conclusions The levels of specific Nt-Abs to SARS-CoV-2 Spike protein are correlated to the anti-S1/S2 IgG titre, although Nt-Abs could maintain a more stable titre over the time despite declining IgG Abs titre. Significance and Impact This study highlights the kinetics and the persistence of Nt-Abs in HCWs vaccinated with Comirnaty (BNT162b2) Pfizer-BioNTech, and compared the Nt-Abs levels with anti-SARS-CoV-2 S1/S2 IgGs titres during a 4-month follow-up starting at the first dose of vaccine.

Aims: To validate an SPE-ultra-HPLC-MS/MS method for thalidomide (THD) measurement in dried plasma spot (DPS). Methods: Extraction included acetonitrile/water clean-up and online SPE. The LOD, LLOQ, linearity, precision, accuracy, recovery, matrix effect, process efficiency, carryover, stability, drug interference and dilution integrity were assessed. Results: The method was linear from 50 to 2000 ng/ml with a LOD of 20 ng/ml and LLOQ of 50 ng/ml. The coefficient of variation for precision was 0.4–7.9% for intra-assay and 1.3–8.9% for interassay, and accuracy was 81.4–97.1%. Adequate matrix effect (100.6–107.0%), recovery (88.7–105.0%) and process efficiency (91.3–109.3%) were registered. DPS was stable for 14 days at room temperature and 45°C ,and for 4 months at -80°C. The method was applied to quantify THD in both wet plasma and DPS from patients with cutaneous lupus receiving THD treatment. The difference between THD wet plasma and DPS concentration was

Finding reliable parameters to identify patients with heart failure (HF) that will respond to cardiac resynchronization therapy (CRT) represents a major challenge. We and others have observed post-translational modifications of Ryanodine Receptor (RyR) in several tissues (including skeletal muscle and circulating lymphocytes) of patients with advanced HF. We designed a prospective study to test the hypothesis that RyR1 glycation in circulating lymphocytes could predict CRT responsiveness in patients with non-ischemic HF. We enrolled 94 patients who underwent CRT and 30 individuals without HF, examining RyR1 glycation in peripheral lymphocytes at enrollment and after 1 year. We found that baseline RyR1 glycation independently predicts CRT response at 1 year after adjusting for age, diabetes, QRS duration and morphology, echocardiographic dyssynchrony, and hypertension. Moreover, RyR1 glycation in circulating lymphocytes significantly correlated with pathologic intracellular calcium leak. Taken together, our data show for the first time that RyR1 glycation in circulating lymphocytes represents a novel biomarker to predict CRT responsiveness.

Background. The global need for efficient and cost-effective use of healthcare resources in low-income countries has led to the introduction of lay health workers (LHWs) as a link of the community to healthcare services. As such, the LHWs perform a variety of tasks such as education, support for care delivery, and social support across all disease types. However, little is known about their ability to support dementia care and management in the community. Purpose. The goal of the pilot intervention was to evaluate the 5-day training intervention for LHWs in rural southwestern Uganda in community-based care and management of people with dementia, and implementation of the knowledge and skills gained. Methods. This was a “pre” and “post” pilot intervention study which involved a qualitative assessment of LHWs’ knowledge on community-based management and care for people with dementia. We focused on four core competency domains in the WHO dementia toolkit. The intervention included a five-day training of the LHWs on dementia care, eight weeks of implementation, and an evaluation of the experiences. Analysis focused on the needs assessment, early detection and management, community engagement, support for people with dementia; and evaluation of the eight weeks implementation. Results. Before the training, the LHWs did not know much about what dementia-related support to provide in the community. Activities were limited to general support, including nutrition, and health education. After the training, LHWs had a basic understanding of dementia and began sensitizing the communities. They felt more comfortable working with people with dementia and reported a notable change in the attitude of family members. However, they reported challenges in differentiating the signs of early dementia from superstitious beliefs. Conclusion. With enhanced capacity, LHWs may be able to support community-based management for people with dementia. A larger study is needed to explore potential roles for LHWs and further assess effectiveness of the LHWs’ skills.

Nephropathy in Diabetes type 2 (NID-2) study is an open-label cluster randomized clinical trial that demonstrated that multifactorial intensive treatment reduces Major Adverse Cardiac Events (MACEs) and overall mortality versus standard of care in type 2 diabetic subjects with albuminuria and no history of cardiovascular disease. Aim of the present post-hoc analysis of NID- 2 study is to evaluate whether the number of risk factors on target associates with patient outcomes.Intervention phase lasted four years and subsequent follow up for survival lasted 10 years. To the aim of this post-hoc analysis, the whole population has been divided into 3 risk groups: 0-1 risk factor (absent/low); 2-3 risk factors (intermediate); 4 risk factors (high). Primary endpoint was a composite of fatal and non-fatal MACEs, the secondary endpoint was all-cause death at the end of the follow-up phase.Absent/low risk group included 166 patients (52.4%), intermediate risk group 128 (40.4%) and high-risk group 23 (7.3%). Cox model showed a significant higher risk of MACE and death in the high-risk group after adjustment for confounding variables, including treatment arm (HR 1.91, 95% CI 1.04-3.52, P = 0.038 and 1.96, 95%CI 1.02-3.8, P = 0,045, respectively, vs absent/low risk group).This post-hoc analysis of the NID-2 trial indicates that the increase in the number of risk factors at target correlates with better cardiovascular-free survival in patients with type 2 diabetes at high CV risk.ClinicalTrials.gov number, NCT00535925. https://clinicaltrials.gov/ct2/show/NCT00535925.

SUMMARY OBJECTIVE: The objective of this study was to analyze the association between orthostatic changes in blood pressure and mortality in elderly cardiopath patients. METHODS: A cohort of 455 elderly cardiopath patients, monitored at a referral outpatient cardiology clinic in Pernambuco, Brazil, from October 2015 to July 2018. The exposure groups were formed according to their orthostatic changes in blood pressure following the requirements of the Brazilian Guidelines for Hypertension. RESULTS: Orthostatic hypotension was present in 46 patients (10.1%), 91 had orthostatic hypertension (20%), and 318 had no orthostatic alterations (69.9%). There were 52 deaths during follow-up. The results demonstrated that there was no statistically significant association between orthostatic hypotension and overall mortality (HR 1.30; 95%CI 0.53–3.14; p=0.567) nor between orthostatic hypertension and overall mortality (HR 0.95; 95%CI 0.65–1.39; p=0.34). Survival in relation to the exposure groups presented no statistically significant difference (p=0.504). CONCLUSION: There was a low frequency of orthostatic hypotension and a mild high frequency of orthostatic hypertension when compared with previous studies, and no association was observed with overall mortality or with the survival time of elderly patients with heart disease.

We evaluated whether Angiotensin receptor/Neprilysin inhibitors (ARNI) reduce heart failure (HF) hospitalizations and deaths in cardiac resynchronization therapy with defibrillator (CRTd) non-responders patients at 12 months of follow-up, modulating microRNAs (miRs) implied in adverse cardiac remodeling.adverse cardiac remodeling characterized by left ventricle ejection fraction (LVEF) reduction, left ventricular end-systolic volume (LVESv) increase, and the 6-minute walking test (6MWT) reduction are relevant pathological mechanisms in CRTd non-responders and could be linked to changes in miRNAs (miRs), regulating cardiac fibrosis, apoptosis, and hypertrophy.miRs levels and clinical outcomes (LVEF, cardiac deaths, and 6MWT) were evaluated at baseline and one year of follow-up in CRTd non-responders divided into ARNI-users and Non-ARNI users.At baseline, there were no differences in levels of inflammatory markers, miR-18, miR-145, and miR-181 (p 0.05) between Non-ARNI users (n 106) and ARNI-users (n 312). At one year of follow-up, ARNI-users vs. Non-ARNI users showed lowest inflammatory markers (p 0.01) and miR-181 levels (p 0.01) and higher values of miR-18 (p 0.01)and miR-145 (p 0.01). At one year of follow-up, ARNI-users had a higher increase of LVEF (p 0.01) and 6MWT (p 0.01) along with a more significant reduction of LVESv (p 0.01) compared to Non-ARNI users. Cox regression analysis evidenced that ARNI-based therapies increase the probability of anti-remodeling effects of CRTd. Based on symptomatic improvements, echocardiographic and functional classification improvements, 37 (34.9%) patients among ARNI-users became responders, while only twenty (6.4%) patients became responders among Non-ARNi-users.ARNI might influence epigenetic mechanisms modulating miRs implicated in the adverse cardiac remodeling responses to CRTd.

Patients with type 2 diabetes (T2D) are characterized by blunted immune responses, which are affected by glycaemic control. Whether glycaemic control influences the response to COVID-19 vaccines and the incidence of SARS-CoV-2 breakthrough infections is unknown. Here we show that poor glycaemic control, assessed as mean HbA1c in the post-vaccination period, is associated with lower immune responses and an increased incidence of SARS-CoV-2 breakthrough infections in T2D patients vaccinated with mRNA-BNT162b2. We report data from a prospective observational study enroling healthcare and educator workers with T2D receiving the mRNA-BNT162b2 vaccine in Campania (Italy) and followed for one year (5 visits, follow-up 346 ± 49 days) after one full vaccination cycle. Considering the 494 subjects completing the study, patients with good glycaemic control (HbA1c one-year mean < 7%) show a higher virus-neutralizing antibody capacity and a better CD4 + T/cytokine response, compared with those with poor control (HbA1c one-year mean ≥ 7%). The one-year mean of HbA1c is linearly associated with the incidence of breakthrough infections (Beta = 0.068; 95% confidence interval [CI], 0.032-0.103; p p = 0.008). Among other factors, only smoking (HR = 0.290, CI 0.146-0.576 for non-smokers; p p

Background The inflammatory response occurring in acute myocardial infarction (AMI) has been proposed as a potential pharmacological target. Sodium-glucose co-transporter 2 inhibitors (SGLT2-I) currently receive intense clinical interest in patients with and without diabetes mellitus (DM) for their pleiotropic beneficial effects. We tested the hypothesis that SGLT2-I have anti-inflammatory effects along with glucose-lowering properties. Therefore, we investigated the link between stress hyperglycemia, inflammatory burden, and infarct size in a cohort of type 2 diabetic patients presenting with AMI treated with SGLT2-I versus other oral anti-diabetic (OAD) agents. Methods In this multicenter international observational registry, consecutive diabetic AMI patients undergoing percutaneous coronary intervention (PCI) between 2018 and 2021 were enrolled. Based on the presence of anti-diabetic therapy at the admission, patients were divided into those receiving SGLT2-I (SGLT-I users) versus other OAD agents (non-SGLT2-I users). The following inflammatory markers were evaluated at different time points: white-blood-cell count, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), neutrophil-to-platelet ratio (NPR), and C-reactive protein. Infarct size was assessed by echocardiography and by peak troponin levels. Results The study population consisted of 583 AMI patients (with or without ST-segment elevation): 98 SGLT2-I users and 485 non-SGLT-I users. Hyperglycemia at admission was less prevalent in the SGLT2-I group. Smaller infarct size was observed in patients treated with SGLT2-I compared to non-SGLT2-I group. On admission and at 24 h, inflammatory indices were significantly higher in non-SGLT2-I users compared to SGLT2-I patients, with a significant increase in neutrophil levels at 24 h. At multivariable analysis, the use of SGLT2-I was a significant predictor of reduced inflammatory response (OR 0.457, 95% CI 0.275–0.758, p = 0.002), independently of age, admission creatinine values, and admission glycemia. Conversely, peak troponin values and NSTEMI occurrence were independent predictors of a higher inflammatory status. Conclusions Type 2 diabetic AMI patients receiving SGLT2-I exhibited significantly reduced inflammatory response and smaller infarct size compared to those receiving other OAD agents, independently of glucose-metabolic control. Our findings are hypothesis generating and provide new insights on the cardioprotective effects of SGLT2-I in the setting of coronary artery disease. Trial Registration: Data are part of the ongoing observational registry: SGLT2-I AMI PROTECT. ClinicalTrials.gov Identifier: NCT 05261867.

Background The African Surgical OutcomeS-2 (ASOS-2) trial tested an enhanced postoperative surveillance intervention to reduce postoperative mortality in Africa. We undertook a concurrent evaluation to understand the process of intervention delivery. Methods Mixed-methods process evaluation, including field notes, interviews, and post-trial questionnaire responses. Qualitative analysis used the framework method with subsequent creation of comparative case studies, grouping hospitals by intervention fidelity. A post-trial questionnaire was developed using initial qualitative analyses. Categorical variables were summarised as count (%) and continuous variables as median (inter-quartile range [IQR]). Odds ratios (OR) were used to rank influences by impact on fidelity. Results The dataset included eight in-depth case studies, and 96 questionnaire responses (response rate 67%) plus intervention fidelity data for each trial site. Overall, 57% (n=55/96) of hospitals achieved intervention delivery using an inclusive definition of fidelity. Delivery of the ASOS-2 interventions and data collection presented a significant burden to the investigators, outstripping limited resources. The influences most associated with fidelity were: surgical staff enthusiasm for the trial (OR=3.0; 95% confidence interval [CI], 1.3–7.0); nursing management support of the trial (OR=2.6; 95% CI, 1.1–6.5); performance of a dummy run (OR=2.6; 95% CI, 1.1–6.1); nursing colleagues seeing the value of the intervention(s) (OR=2.1; 95% CI, 0.9–5.7); and site investigators' belief in the effectiveness of the intervention (OR=3.2; 95% CI, 1.2–9.4). Conclusions ASOS-2 has proved that coordinated interventional research across Africa is possible, but delivering the ASOS-2 interventions was a major challenge for many investigators. Future improvement science efforts must include better planning for intervention delivery, additional support to investigators, and promotion of strong inter-professional teamwork. Clinical trial registration ClinicalTrials gov NCT03853824.

Background COVID-19 pandemic has disrupted health services, including vaccination demand. We describe the impact of the COVID-19 pandemic on routine pediatric vaccination in Brazil. Methods We conducted a retrospective analysis of all vaccine doses provided to children aged 0-6 years from January 2019 to December 2020. We obtained data stratified by age group (0 to 2 years and >2 to 6 years) and Brazilian region. Difference-in-difference (DiD) analyses were performed to compare vaccine uptake in the pre-pandemic (January-February), stay-at-home (March-June), and reopening (July-December) periods. Results The number of vaccine doses administered declined in the stay-at-home period. For children aged 0 to 2 years, the highest reductions were recorded in the North (-25.3%), Northeast (-16.8%) and Central-West (-10.2%) regions. For children aged >2 to 6 years, the highest decline was observed in the North (DiD = -27.2%) and South (DiD = -14.0%) regions. The number of vaccine doses administered in the reopening period has slightly increased in all regions. Conclusions Vaccination decreased during the COVID-19 pandemic. Although the number of doses recovered in part during the reopening phase, additional strategies, such as increased public awareness and vaccination booster campaigns are required.

Background The most common Italian rickettsiosis is Mediterranean Spotted Fever (MSF). MSF is commonly associated with a symptom triad consisting of fever, cutaneous rash, and inoculation eschar. The rash is usually maculopapular but, especially in severe presentations, may be petechial. Other typical findings are arthromyalgia and headache. Herein, we describe for the first time an unusual case of Israeli spotted fever (ISF) associated with interstitial pneumonia and pleural effusion in which R. conorii subsp. israelensis was identified by molecular methods in the blood, as well as in the pleural fluid. Case presentation A 72-year-old male presented with a 10-day history of remittent fever. On admission, the patient’s general condition appeared poor with confusion and drowsiness; the first assessment revealed a temperature of 38.7°, blood pressure of 110/70 mmHg, a blood oxygen saturation level of 80% with rapid, frequent, and superficial breathing using accessory muscles (28 breaths per minute), and an arrhythmia with a heart rate of 90 beats per minute. qSOFA score was 3/3. Chest CT revealed ground-glass pneumonia with massive pleural effusion. Petechial exanthema was present diffusely, including on the palms and soles, and a very little eschar surrounded by a violaceous halo was noted on the dorsum of the right foot. Awaiting the results of blood cultures, broad-spectrum antibiotic therapy with meropenem 1 g q8h, ciprofloxacin 400 mg q12h, and doxycycline 100 mg q12h was initiated. Doxycycline was included in the therapy because of the presence of petechial rash and fever, making us consider a diagnosis of rickettsiosis. This suspicion was confirmed by the positivity of polymerase chain reaction on whole blood for R. conorii subsp. israelensis. Thoracentesis was performed to improve alveolar ventilation. R. conorii subsp. israelensis was again identified in the pleural fluid by PCR technique. On day 4 the clinical condition worsened. Blood exams showed values suggestive of secondary hemophagocytic lymphohistiocytosis; 4 out of 8 diagnostic criteria were present and empirical treatment with prednisone was started resulting in a gradual improvement in general condition. Conclusions Israeli spotted fever may be a severe disease. A high index of suspicion is required to promptly start life-saving therapy. Pleural effusion and interstitial pneumonia may be part of the clinical picture of severe rickettsial disease and should not lead the physician away from this diagnosis.

Purpose: To assess the contributions of circulating metabolites for improving upon the performance of the risk of ovarian malignancy algorithm (ROMA) for risk prediction of ovarian cancer among women with ovarian cysts. Experimental Design: Metabolomic profiling was performed on an initial set of sera from 101 serous and nonserous ovarian cancer cases and 134 individuals with benign pelvic masses (BPM). Using a deep learning model, a panel consisting of seven cancer-related metabolites [diacetylspermine, diacetylspermidine, N-(3-acetamidopropyl)pyrrolidin-2-one, N-acetylneuraminate, N-acetyl-mannosamine, N-acetyl-lactosamine, and hydroxyisobutyric acid] was developed for distinguishing early-stage ovarian cancer from BPM. The performance of the metabolite panel was evaluated in an independent set of sera from 118 ovarian cancer cases and 56 subjects with BPM. The contributions of the panel for improving upon the performance of ROMA were further assessed. Results: A 7-marker metabolite panel (7MetP) developed in the training set yielded an AUC of 0.86 [95% confidence interval (CI): 0.76–0.95] for early-stage ovarian cancer in the independent test set. The 7MetP+ROMA model had an AUC of 0.93 (95% CI: 0.84–0.98) for early-stage ovarian cancer in the test set, which was improved compared with ROMA alone [0.91 (95% CI: 0.84–0.98); likelihood ratio test P: 0.03]. In the entire specimen set, the combined 7MetP+ROMA model yielded a higher positive predictive value (0.68 vs. 0.52; one-sided P < 0.001) with improved specificity (0.89 vs. 0.78; one-sided P < 0.001) for early-stage ovarian cancer compared with ROMA alone. Conclusions: A blood-based metabolite panel was developed that demonstrates independent predictive ability and complements ROMA for distinguishing early-stage ovarian cancer from benign disease to better inform clinical decision making.

ImportanceDespite similar histologic appearance among high-grade serous ovarian cancers (HGSOCs), clinical observations suggest vast differences in gross appearance. There is currently no systematic framework by which to classify HGSOCs according to their gross morphologic characteristics.ObjectiveTo develop and characterize a gross morphologic classification system for HGSOC.Design, Setting, and ParticipantsThis cohort study included patients with suspected advanced-stage ovarian cancer who presented between April 1, 2013, and August 5, 2016, to the University of Texas MD Anderson Cancer Center, a large referral center. Patients underwent laparoscopic assessment of disease burden before treatment and received a histopathologic diagnosis of HGSOC. Researchers assigning morphologic subtype and performing molecular analyses were blinded to clinical outcomes. Data analysis was performed between April 2020 and November 2021.ExposuresGross tumor morphologic characteristics.Main Outcomes and MeasuresClinical outcomes and multiomic profiles of representative tumor samples of type I or type II morphologic subtypes were compared.ResultsOf 112 women (mean [SD] age 62.7 [9.7] years) included in the study, most patients (84% [94]) exhibited a predominant morphologic subtype and many (63% [71]) had a uniform morphologic subtype at all involved sites. Compared with those with uniform type I morphologic subtype, patients with uniform type II morphologic subtype were more likely to have a favorable Fagotti score (83% [19 of 23] vs 46% [22 of 48]; P = .004) and thus to be triaged to primary tumor reductive surgery. Similarly, patients with uniform type II morphologic subtype also had significantly higher mean (SD) estimated blood loss (639 [559; 95% CI, 391-887] mL vs 415 [527; 95% CI, 253-577] mL; P = .006) and longer mean (SD) operative time (408 [130; 95% CI, 350-466] minutes vs 333 [113; 95% CI, 298-367] minutes; P = .03) during tumor reductive surgery. Type I tumors had enrichment of epithelial-mesenchymal transition (false discovery rate [FDR] q-value, 3.10 × 10−24), hypoxia (FDR q-value, 1.52 × 10−5), and angiogenesis pathways (FDR q-value, 2.11 × 10−2), whereas type II tumors had enrichment of pathways related to MYC signaling (FDR q-value, 2.04 × 10−9) and cell cycle progression (FDR q-value, 1.10 × 10−5) by integrated proteomic and transcriptomic analysis. Abundances of metabolites and lipids also differed between the 2 morphologic subtypes.Conclusions and RelevanceThis study identified 2 novel, gross morphologic subtypes of HGSOC, each with unique clinical features and molecular signatures. The findings may have implications for triaging patients to surgery or chemotherapy, identifying outcomes, and developing tailored therapeutic strategies.

Background Low-grade serous ovarian cancer (LGSOC) is a rare disease that occurs more frequently in younger women than those with high-grade disease. The current treatment is suboptimal and a better understanding of the molecular pathogenesis of this disease is required. In this study, we compared the proteogenomic analyses of LGSOCs from short- and long-term survivors (defined as 60 months, respectively). Our goal was to identify novel mutations, proteins, and mRNA transcripts that are dysregulated in LGSOC, particularly in short-term survivors. Methods Initially, targeted sequencing of 409 cancer-related genes was performed on 22 LGSOC and 6 serous borderline ovarian tumor samples. Subsequently, whole-genome sequencing analysis was performed on 14 LGSOC samples (7 long-term survivors and 7 short-term survivors) with matched normal tissue samples. RNA sequencing (RNA-seq), quantitative proteomics, and phosphoproteomic analyses were also performed. Results We identified single-nucleotide variants (SNVs) (range: 5688–14,833 per sample), insertion and deletion variants (indels) (range: 880–1065), and regions with copy number variants (CNVs) (range: 62–335) among the 14 LGSOC samples. Among all SNVs and indels, 2637 mutation sites were found in the exonic regions. The allele frequencies of the detected variants were low (median12%). The identified recurrent nonsynonymous missense mutations included KRAS, NRAS, EIF1AX, UBR5, and DNM3 mutations. Mutations in DNM3 and UBR5 have not previously been reported in LGSOC. For the two samples, somatic DNM3 nonsynonymous missense mutations in the exonic region were validated using Sanger sequencing. The third sample contained two missense mutations in the intronic region of DNM3, leading to a frameshift mutation detected in RNA transcripts in the RNA-seq data. Among the 14 LGSOC samples, 7754 proteins and 9733 phosphosites were detected by global proteomic analysis. Some of these proteins and signaling pathways, such as BST1, TBXAS1, MPEG1, HBA1, and phosphorylated ASAP1, are potential therapeutic targets. Conclusions This is the first study to use whole-genome sequencing to detect somatic mutations in LGSOCs with matched normal tissues. We detected and validated novel mutations in DNM3, which were present in 3 of the 14 samples analyzed. Additionally, we identified novel indels, regions with CNVs, dysregulated mRNA, dysregulated proteins, and phosphosites that are more prevalent in short-term survivors. This integrated proteogenomic analysis can guide research into the pathogenesis and treatment of LGSOC.

Herpes simplex virus type 1 (HSV-1) is a persistent human pathogen, and the emergence of strains resistant to Acyclovir (ACV, reference drug) shows the urgency to develop new treatments. We report the antiherpetic mechanism of the action of lasiodiplodan (LAS-N, (1 → 6)-β-d-glucan) and its sulfonated derivative (LAS-S3) in vitro and in vivo. LAS-S3 showed anti-HSV-1 action with high selectivity indices for HSV-1 KOS (88.1) and AR (189.2), sensitive and resistant to ACV, respectively. LAS-S3 inhibitedgt;80% of HSV-1 infection in different treatment protocols (virucidal, adsorption inhibition, and post-adsorption effects), even at low doses, and showed a preventive effect and DNA and protein synthesis inhibition. The antiherpetic effect was confirmed in vivo by the cosmetic LAS-S3-CRÈME decreasing cutaneous lesions of HSV-1, including the AR strain. LAS-S3 possessed a broad-spectrum mechanism of action acting in the early and post-adsorption stages of HSV-1 infection, and LAS-S3-CRÈME is a potential antiherpetic candidate for patients infected by HSV-1-resistant strains.

HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a neurodegenerative disease that leads to motor impairment due to a chronic inflammatory process in the central nervous system (CNS). However, the HAM/TSP pathogenesis is not completely clear, and biomarkers to define the disease prognosis are still necessary. Thus, we aimed to identify biomarkers for HAM/TSP and potential mechanisms involved in disease development. To that end, the concentrations of VILIP-1, BDNF, VEGF, β-NGF, TGF-β1, fractalkine/CX3CL1, IL-6, IL-18, and TNF-α, and the soluble forms of TREM-1, TREM-2, and RAGE, were assessed using a multiplex bead-based immunoassay in paired cerebrospinal fluid (CSF) and serum samples from HAM/TSP patients (n = 20), asymptomatic HTLV-1 carriers (AC) (n = 13), and HTLV-1-seronegative individuals (n = 9), with the results analyzed according to the speed of HAM/TSP progression. HAM/TSP patients had elevated fractalkine in the serum but not in the CSF, particularly those with low neuroinflammatory activity (CSF/serum ratio of neopterin

Background Due to improved coverage and scale-up of antiretroviral therapy (ART), patients are increasingly transferring between ART-providing sites. Self-transfers may constitute a high proportion of patients considered lost to follow-up (LTFU), and if overlooked when reporting patients who have dropped out of HIV care, may result in an incorrect estimation of retention. We determined the prevalence of self-transfers, and successful tracing, and identified associated factors among people living with HIV (PLHIV) LTFU from care at public health facilities in Sheema District, Southwestern Uganda. Methods We conducted a cross-sectional retrospective medical records review during February and March 2022. We included records of all PLHIV who were LTFU from 2017 to 2021, and who were registered at government-owned ART clinics in Sheema District. LTFU was considered for those who were not taking ART refills for a period of ≥ 3 months. We abstracted demographic and clinical data from medical records at the selected clinics. Participants were traced via phone calls or in-person to ascertain the outcomes of LTFU. We performed multivariate modified Poisson regression to identify factors associated with self-transfer, and successful tracing. Results Overall, 740 patients were identified as LTFU from three ART-providing clinics; of these, 560 (76%) were self-transfers. The mean age was 30 (SD ± 10) years, and most (69%, n = 514) were female; the majority (87%, 641/740) were successfully traced. Age (adjusted prevalence ratio [aPR] = 1.13, 95% CI 1.01–1.25, P = 0.026 for those aged 18–30 years compared to > 30 years), female sex (aPR = 1.18, 95% CI 1.11–1.25, P P P = 0.026) was associated with successful tracing of the patients considered LTFU. Conclusion Self-transfers accounted for the majority of patients recorded as LTFU, highlighting the need to account for self-transfers among patients considered LTFU, to accurately estimate retention in care. ART-providing facilities should regularly update contact information for PLHIV to enable successful tracing, in the event that the patients are LTFU. This calls for a health-tracking system that easily identifies self-transfers across ART-providing clinics using unique patient identifiers.

Background Suicide is one of the leading causes of death globally, with over 75% of all suicides occurring in low-and middle-income Countries. Although 25% of people have contact with their health care workers before suicide attempts, most never receive proper suicide assessment and management. We explored primary care health workers' knowledge, attitudes, and experiences in evaluating and managing suicidality in structured primary healthcare services in Uganda. Methods This was a cross-sectional qualitative study among health workers in southwestern Uganda from purposively selected health facilities. A semi-structured interview guide was used, and data were analyzed using thematic analysis. Results The in-depth interviews were conducted with 18 individuals (i.e., five medical doctors, two clinical officers, two midwives, and nine nurses) from 12 health facilities in the five selected districts. Four themes emerged from the discussions: a) Knowledge and attitudes of primary healthcare workers in the assessment and management of suicidality, b) Experiences in the assessment and management of suicidality, c) challenges faced by primary healthcare workers while assessing and managing suicidality, and d) Recommendations for improving assessment and management of suicidality in PHC. Most participants were knowledgeable about suicide and the associated risk factors but reported challenges in assessing and managing individuals with suicide risk. The participants freely shared individual experiences and attitudes in the assessment and management of suicide. They also proposed possible ways to improve the evaluation and management of suicidality in PHC, such as setting up a system of managing suicidality, regularizing community sensitization, and training health workers. Conclusion Suicidality is commonly encountered by primary health care workers in Uganda who struggle with its assessment and management. Improving the knowledge and attitudes of primary health care workers would be a big step towards ensuring equitable services.

Background and aims Diabetic retinopathy (DR) is the most common microvascular complication of diabetes. Diabetic macroangiopathies, particularly cardiovascular (CV) diseases, seem closely related to diabetes microvascular complications. Aspirin represents the most prescribed compound in CV prevention. Aspirin impact on DR is still object of debate. As it is already recommended among diabetics at high CV risk, aim of this study was to assess a potential relationship between DR and aspirin therapy, in a type 2 diabetes cohort of patients screened through telemedicine. Methods and results NO Blind is a cross-sectional, multicenter, observational study, which involved nine Italian outpatient clinics. Primary endpoint was the assessment of the relationship between aspirin treatment and DR. 2068 patients were enrolled in the study, subsequently split in two subpopulations according to either the presence or absence of DR. Overall, 995 subjects were under aspirin therapy. After adjusting for most common potential confounders, age and gender, aspirin reveals significantly associated with DR (OR: 1.72, 95%CI: 1.58–2.89, p = 0.002) and proliferative DR (PDR) (OR: 1.89, 95%CI: 1.24–2.84, p = 0.003). Association comes lost further adjusting for MACEs (OR: 1.28, 95%CI: 0.85–1.42, p = 0.157) (Model 4) and eGFR (OR: 0.93; 95%CI: 0.71–1.22; p = 0.591) (Model 5). Conclusion In this multicenter cross-sectional study including a large sample of outpatients with T2DM, we showed that aspirin was not associated with DR after adjustment for several cardio-metabolic confounders. However, as partially confirmed by our findings, and related to the well-known pro-hemorrhagic effect of aspirin, its use should be individually tailored, even by telemedicine tools.

OBJECTIVE An important prognostic factor in any form of infection seems to be glucose control in patients with type 2 diabetes. There is no information about the effects of tight glycemic control on coronavirus disease 2019 (COVID-19) outcomes in patients with hyperglycemia. Therefore, we examined the effects of optimal glycemic control in patients with hyperglycemia affected by COVID-19. RESEARCH DESIGN AND METHODS Fifty-nine patients with COVID-19 hospitalized with moderate disease were evaluated. On the basis of admission glycemia >7.77 mmol/L, patients were divided into hyperglycemic and normoglycemic groups. Interleukin 6 (IL-6) and D-dimer levels were evaluated at admission and weekly during hospitalization. The composite end point was severe disease, admission to an intensive care unit, use of mechanical ventilation, or death. RESULTS Thirty-four (57.6%) patients were normoglycemic and 25 (42.4%) were hyperglycemic. In the hyperglycemic group, 7 (28%) and 18 (72%) patients were diagnosed with diabetes already before admission, and 10 (40%) and 15 (60%) were treated without and with insulin infusion, respectively. The mean of glycemia during hospitalization was 10.65 ± 0.84 mmol/L in the no insulin infusion group and 7.69 ± 1.85 mmol/L in the insulin infusion group. At baseline, IL-6 and D-dimer levels were significantly higher in the hyperglycemic group than in the normoglycemic group (P < 0.001). Even though all patients were on standard treatment for COVID-19 infection, IL-6 and D-dimer levels persisted higher in patients with hyperglycemia during hospitalization. In a risk-adjusted Cox regression analysis, both patients with hyperglycemia and patients with diabetes had a higher risk of severe disease than those without diabetes and with normoglycemia. Cox regression analysis evidenced that patients with hyperglycemia treated with insulin infusion had a lower risk of severe disease than patients without insulin infusion. CONCLUSIONS Insulin infusion may be an effective method for achieving glycemic targets and improving outcomes in patients with COVID-19.

Background High glycated-hemoglobin (HbA1c) levels correlated with an elevated risk of adverse cardiovascular outcomes despite renin-angiotensin system (RAS) inhibition in type-2 diabetic (T2DM) patients with reduced ejection fraction. Using the routine biopsies of non-T2DM heart transplanted (HTX) in T2DM recipients, we evaluated whether the diabetic milieu modulates glycosylated ACE2 (GlycACE2) levels in cardiomyocytes, known to be affected by non-enzymatic glycosylation, and the relationship with glycemic control. Objectives We investigated the possible effects of GlycACE2 on the anti-remodeling pathways of the RAS inhibitors by evaluating the levels of Angiotensin (Ang) 1–9, Ang 1–7, and Mas receptor (MasR), Nuclear-factor of activated T-cells (NFAT), and fibrosis in human hearts. Methods We evaluated 197 first HTX recipients (107 non-T2DM, 90 T2DM). All patients were treated with angiotensin-converting enzyme inhibitor (ACE-I) or angiotensin receptor blocker (ARB) at hospital discharge. Patients underwent clinical evaluation (metabolic status, echocardiography, coronary CT-angiography, and endomyocardial biopsies). Biopsies were used to evaluate ACE2, GlycACE2, Ang 1–9, Ang 1–7, MasR, NAFT, and fibrosis. Results GlycACE2 was higher in T2DM compared tonon-T2DM cardiomyocytes. Moreover, reduced expressions of Ang 1–9, Ang 1–7, and MasR were observed, suggesting impaired effects of RAS-inhibition in diabetic hearts. Accordingly, biopsies from T2DM recipients showed higher fibrosis than those from non-T2DM recipients. Notably, the expression of GlycACE2 in heart biopsies was strongly dependent on glycemic control, as reflected by the correlation between mean plasma HbA1c, evaluated quarterly during the 12-month follow-up, and GlycACE2 expression. Conclusion Poor glycemic control, favoring GlycACE2, may attenuate the cardioprotective effects of RAS-inhibition. However, the achievement of tight glycemic control normalizes the anti-remodeling effects of RAS-inhibition. Trial registration: https://clinicaltrials.gov/ NCT03546062.

This study aimed at investigating the SGLT2 expression in human cardiomyocytes. Human studies evaluating cardiomyocyte SGLT2s expression are limited. To better clarify this issue, SGLT2 protein expression was assessed in human hearts of diabetic and non-diabetic patients, and in AC16 human cardiomyocyte cell line. A prospective study with a follow-up of patients who underwent their first heart transplant (HTX) was performed. Explanted heart, basal (1 week after HTX), and final (48 weeks after HTX) endomyocardial biopsies (EMBs) from patients were evaluated for SGLT2 occurrence in cardiomyocyte with immunohistochemistry, immunofluorescence and SGLT2 quantization with both real-time reverse transcription-polymerase chain reaction and Western blot analysis. The immunofluorescence co-localization of SGLT2 in cardiomyocyte evidenced that an increased expression in the explanted heart from diabetic patients compared to non-diabetic (p&nbsp

Made available in DSpace on 2022-05-01T08:44:34Z (GMT). No. of bitstreams: 0 Previous issue date: 2021-01-01 Constraining knee flexion of non-disabled individuals could further our understanding regarding the importance of knee joint during gait, which is a common disturbance in individuals with gait impairment. In this study we investigated whether a mechanical constraint of knee flexion in non-disabled adults would lead to compensatory strategies. Eleven non-disabled male adults walked without and with an orthosis that permitted full extension and limited knee flexion up to either 45° or 30°. We analyzed the temporal organization of lower limb kinematics and electromyograms of the rectus femoris, vastus medialis and lateralis, tibialis anterior, semitendinosus, biceps femoris, and gastrocnemius medialis and lateralis. Non-disabled adults compensated for the reduced knee flexion by increasing hip and ankle joint excursions and ankle flexor activation amplitude. Also, these adults shortened pre-swing and lengthened swing duration in the constrained limb and increased the activity of bifunctional hip extensor and knee flexor muscles in the constrained limb in relation to the unconstrained limb. The use of an orthosis that limited knee flexion in non-disabled adults leaded to compensatory strategies in the temporal organization of joint excursions and muscle activations in the constrained limb. The compensatory effects were correlated with the extent of knee flexion constraint. Institute of Physical Activity and Sport Sciences Cruzeiro do Sul University Department of Physical Education São Paulo State University Department of Human Performance–Exercise Physiology School of Medicine West Virginia University Department of Biomedical Engineering Benjamin M. Statler College of Engineering and Mineral Resources West Virginia University Rockefeller Neuroscience Institute School of Medicine West Virginia University Mechanical and Aerospace Engineering Benjamin M. Statler College of Engineering and Mineral Resources West Virginia University Department of Neuroscience School of Medicine West Virginia University Department of Physical Education São Paulo State University

Purpose Insulin pump therapy has become the preferential treatment for type 1 diabetes (T1D) as it mimics the physiological secretion of insulin better than multiple daily injections. However, not all patients improve with insulin pump therapy. This study aims to determine the predictors of the effectiveness of insulin pumps in T1D. Methods We conducted a retrospective observational study of patients who started insulin pumps. Data from four timepoints (before, at 6, 12 and 36 months) were evaluated for outcomes of glycemic control and safety. The association of baseline predictors with outcomes was analyzed using linear and logistic regression models. Results We evaluated 136 patients (57.4% females, age 36 ± 12 years, duration of T1D 14 ± 9 years). During the follow-up, there was a mean decrease of HbA1c of 0.9 ± 1.2%. The improvement in HbA1c was independent of sex, age and duration of T1D. Higher baseline HbA1c, family history of diabetes and not being treated with statins were predictors of improvement in HbA1c. Not being treated with statins and higher baseline HbA1c predicted improvement in HbA1c without worsening hypoglycemia. History of hypoglycemia was a predictor of severe hypoglycemia. Family history, higher baseline HbA1c and psychological/psychiatric disorders were predictors of ketoacidosis. Conclusion Benefits of insulin pump were independent of sex, age, and duration of T1D. Baseline HbA1c, family history of diabetes, treatment with statins, history of hypoglycemia and psychological/psychiatric disorders were predictors of outcomes and may allow the identification of patients who benefit most from insulin pump therapy or who are at increased risk of complications.

Summary Background Risk of mortality following surgery in patients across Africa is twice as high as the global average. Most of these deaths occur on hospital wards after the surgery itself. We aimed to assess whether enhanced postoperative surveillance of adult surgical patients at high risk of postoperative morbidity or mortality in Africa could reduce 30-day in-hospital mortality. Methods We did a two-arm, open-label, cluster-randomised trial of hospitals (clusters) across Africa. Hospitals were eligible if they provided surgery with an overnight postoperative admission. Hospitals were randomly assigned through minimisation in recruitment blocks (1:1) to provide patients with either a package of enhanced postoperative surveillance interventions (admitting the patient to higher care ward, increasing the frequency of postoperative nursing observations, assigning the patient to a bed in view of the nursing station, allowing family members to stay in the ward, and placing a postoperative surveillance guide at the bedside) for those at high risk (ie, with African Surgical Outcomes Study Surgical Risk Calculator scores ≥10) and usual care for those at low risk (intervention group), or for all patients to receive usual postoperative care (control group). Health-care providers and participants were not masked, but data assessors were. The primary outcome was 30-day in-hospital mortality of patients at low and high risk, measured at the participant level. All analyses were done as allocated (by cluster) in all patients with available data. This trial is registered with ClinicalTrials.gov , NCT03853824 . Findings Between May 3, 2019, and July 27, 2020, 594 eligible hospitals indicated a desire to participate across 33 African countries; 332 (56%) were able to recruit participants and were included in analyses. We allocated 160 hospitals (13 275 patients) to provide enhanced postoperative surveillance and 172 hospitals (15 617 patients) to provide standard care. The mean age of participants was 37·1 years (SD 15·5) and 20 039 (69·4%) of 28 892 patients were women. 30-day in-hospital mortality occurred in 169 (1·3%) of 12 970 patients with mortality data in the intervention group and in 193 (1·3%) of 15 242 patients with mortality data in the control group (relative risk 0·96, 95% CI 0·69–1·33; p=0·79). 45 (0·2%) of 22 031 patients at low risk and 309 (5·6%) of 5500 patients at high risk died. No harms associated with either intervention were reported. Interpretation This intervention package did not decrease 30-day in-hospital mortality among surgical patients in Africa at high risk of postoperative morbidity or mortality. Further research is needed to develop interventions that prevent death from surgical complications in resource-limited hospitals across Africa. Funding Bill & Melinda Gates Foundation and the World Federation of Societies of Anaesthesiologists. Translations For the Arabic, French and Portuguese translations of the abstract see Supplementary Materials section.

Background and Purpose: The AFFINITY trial (Assessment of Fluoxetine in Stroke Recovery) reported that oral fluoxetine 20 mg daily for 6 months after acute stroke did not improve functional outcome and increased the risk of falls, bone fractures, and seizures. After trial medication was ceased at 6 months, survivors were followed to 12 months post-randomization. This preplanned secondary analysis aimed to determine any sustained or delayed effects of fluoxetine at 12 months post-randomization. Methods: AFFINITY was a randomized, parallel-group, double-blind, placebo-controlled trial in adults (n=1280) with a clinical diagnosis of stroke in the previous 2 to 15 days and persisting neurological deficit who were recruited at 43 hospital stroke units in Australia (n=29), New Zealand (4), and Vietnam (10) between 2013 and 2019. Participants were randomized to oral fluoxetine 20 mg once daily (n=642) or matching placebo (n=638) for 6 months and followed until 12 months after randomization. The primary outcome was function, measured by the modified Rankin Scale, at 6 months. Secondary outcomes for these analyses included measures of the modified Rankin Scale, mood, cognition, overall health status, fatigue, health-related quality of life, and safety at 12 months. Results: Adherence to trial medication was for a mean 167 (SD 48) days and similar between randomized groups. At 12 months, the distribution of modified Rankin Scale categories was similar in the fluoxetine and placebo groups (adjusted common odds ratio, 0.93 [95% CI, 0.76–1.14]; P =0.46). Compared with placebo, patients allocated fluoxetine had fewer recurrent ischemic strokes (14 [2.18%] versus 29 [4.55%]; P =0.02), and no longer had significantly more falls (27 [4.21%] versus 15 [2.35%]; P =0.08), bone fractures (23 [3.58%] versus 11 [1.72%]; P =0.05), or seizures (11 [1.71%] versus 8 [1.25%]; P =0.64) at 12 months. Conclusions: Fluoxetine 20 mg daily for 6 months after acute stroke had no delayed or sustained effect on functional outcome, falls, bone fractures, or seizures at 12 months poststroke. The lower rate of recurrent ischemic stroke in the fluoxetine group is most likely a chance finding. Registration: URL: http://www.anzctr.org.au/ ; Unique identifier: ACTRN12611000774921.

The length of hospital stays of patients undergoing orthognathic surgery depends on related local and systemic factors. Hematological changes resulting from orthognathic surgery, followed up in the postoperative period until hospital discharge, have neither yet been established for specific cases, nor for normal situations. This study aimed to describe the hemodynamic parameters of patients undergoing orthognathic surgery, considering a prediction of hospital discharge. A prospective analytical study was carried out on a sample of convenience for this purpose.The erythrogram, leukogram, and platelet count were assessed 24 and 72 hours after surgery and compared with preoperative values. Intraoperative volume loss was also assessed. Inferential statistical analyses were performed as analysis of variance or Friedman test, paired Wilcoxon test, Mann-Whitney test, and 2-tailed Spearman correlation.The red blood cell count (mean ± standard deviation [median]); (4.60 ± 0.24 [4.56]), hemoglobin (12.82 ± 1.03 [12.75]), hematocrit (39.51 ± 3.47 [39.60]), and red cell distribution with (32.60 ± 0.88 [33.05]) were higher preoperatively (P 0.001). Mean corpuscular volume (83.87 ± 5.63 [83.10]), mean corpuscular hemoglobin (27.50 ± 1.47 [28.00]), leukocytes (6262.00 ± 1448.36 [6380.00]). The volume loss varied between 463.87 and 752.13 mL (608.00 ± 144.13 [630.00]).The results of the hematological evaluations corroborate the expectation of standard discharge from the hospital, with reflected changes resulting from volume loss and intense postoperative inflammatory response, even under the anti-inflammatory pharmacological effect.

Objectives In latest years GII.4[P16] and GII.2[P16] noroviruses have become predominant in some temporal/geographical settings. In parallel with the emergence of the GII.P16 polymerase type, norovirus surveillance activity in Italy experienced increasing difficulties in generating sequence data on the RNA polymerase genomic region A, using the widely adopted JV12A/JV13B primer set. Two sets of modified primers (Deg1 and Deg2) were tested in order to improve amplification and typing of the polymerase gene. Methods Amplification and typing performance of region A primers was assessed in RT-PCR on 452 GII norovirus positive samples obtained from 2194 stool samples collected in 2016–2019 from children hospitalized with acute gastroenteritis. Results The use of Deg1 increased the rate of samples types in region A from 49.5% to 81.4% and from 21.9% to 69.7% in 2016 and 2017, respectively. The rate of Deg1 typed samples remained high in 2018 (90.1%), but sharply decreased to 11.8% in 2019. The second primers set, Deg2, was able to increase to 64.9% the rate of 2019 samples typed in region A, while typing efficiently 73.2%, 69%, and 86.4% of samples collected in 2016, 2017 and 2018, respectively. Conclusions The plasticity of norovirus genomes requires continuous updates of the primers used for strain characterization.

Worldwide, thyroid cancer accounts for some 10% of total cancer incidence, most markedly for females. Thyroid cancer radiotherapy, typically using 131I (T1/2 8.02 days; β− max energy 606 keV, branching ratio 89.9%), is widely adopted as an adjunct to surgery or to treat inoperable cancer and hyperthyroidism. With staff potentially receiving significant doses during source preparation and administration, radiation protection and safety assessment are required in ensuring practice complies with international guidelines. The present study, concerning a total of 206 patient radioiodine therapies carried out at King Faisal Specialist Hospital and Research Center over a 6-month period, seeks to evaluate patient and occupational exposures during hospitalization, measuring ambient doses and estimating radiation risk. Using calibrated survey meters, patient exposure dose-rate estimates were obtained at a distance of 30-, 100- and 300 cm from the neck region of each patient. Occupational and ambient doses were measured using calibrated thermoluminescent dosimeters. The mean and range of administered activity (AA, in MBq) for the thyroid cancer and hyperthyroidism treatment groups were 4244 ± 2021 (1669–8066), 1507.9 ± 324.1 (977.9–1836.9), respectively. The mean annual occupational doses were 1.2 mSv, that for ambient doses outside of the isolation room corridors were found to be 0.2 mSv, while ambient doses at the nursing station were below the lower limit of detection. Exposures to staff from patients being treated for thyroid cancer were less compared to hyperthyroidism patients. With a well-defined protocol, also complying with international safety requirements, occupational exposures were found to be relatively high, greater than most reported in previous studies.

SUMMARY OBJECTIVE: To evaluated calcification of the coronary arteries and its association with visceral fat and 25-hydroxyvitamin D (25(OH)D) serum levels. METHODS: A cross sectional study involving 140 individuals without any previous diagnosis of cardiovascular disease. A biochemical analysis of vitamin D serum levels was carried out, as well as computed tomography to measure coronary artery calcium score and visceral adipose tissue. RESULTS: The mean age of the individuals was 55.9 (±12.4). Coronary artery calcium was observed in 40.7% of the population. Vitamin D presented median serum levels of 30.4 ng/ml (IQ24.5–39.1), with 14,1 and 33.7% of the individuals presenting deficiency and insufficiency, respectively. In the univariate analysis, the calcium score was more prevalent in aged patients (p

Heart Period (H) results from the activity of several coexisting control mechanisms, involving Systolic Arterial Pressure (S) and Respiration (R), which operate across multiple time scales encompassing not only short-term dynamics but also long-range correlations. In this work, multiscale representation of Transfer Entropy (TE) and of its decomposition in the network of these three interacting processes is obtained by extending the multivariate approach based on linear parametric VAR models to the Vector AutoRegressive Fractionally Integrated (VARFI) framework for Gaussian processes. This approach allows to dissect the different contributions to cardiac dynamics accounting for the simultaneous presence of short and long term dynamics. The proposed method is first tested on simulations of a benchmark VARFI model and then applied to experimental data consisting of H, S and R time series measured in healthy subjects monitored at rest and during mental and postural stress. The results reveal that the proposed method can highlight the dependence of the information transfer on the balance between short-term and long-range correlations in coupled dynamical systems.

In patients with type 2 diabetes mellitus (T2DM) the vaso-vagal syncope (VVS) recurrence could be due to the alteration of autonomic system function, evaluated by heart rate variability (HRV), and by 123I-metaiodobenzylguanidine (123I-mIBG) myocardial scintigraphy indexes: Heart to Mediastinum ratio (H/MIn a prospective multicenter study, after propensity score matching, we studied a population of 324 T2DM patients with VVS, divided into 161 SGLT2-I-users vs. 163 Non-SGLT2-I users. In these patients as SGLT2-I-users vs. Non-SGLT2-I users, we investigated the HRV and 123I-MIBG modifications and VVS recurrence at 12 months of follow-up.At follow-up end, the SGLT2-I-users vs. Non-SGLT2-I users had best glucose homeostasis and lower values of inflammatory markers, and resting heart rate (p 0.05). The SGLT2-I-users vs. Non-SGLT2-I users evidenced the lowest low frequency/high frequency ratio (LF/HFr), a significant difference for all the indexes of autonomic dysfunction via ECG Holter analysis, and higher values of H/MNon-SGLT2-I users vs. SGLT2-I-users had alterations of the autonomic nervous system, with a higher rate of VVS recurrence at 1 year of follow-up. The indexes of cardiac denervation predicted the VVS recurrence, while the SGLT2-I reduced the risk of VVS recurrence.NCT03717207.

Background Uganda Ministry of Health (UMOH) embraced the World Health Organization recommendation for people living with human immunodeficiency virus with a detectable viral load (VL) exceeding 1000 copies/mL to receive intensive adherence counselling (IAC). The IAC framework was developed as a step-by-step guide for healthcare providers to systematically support persons with non-suppressed VL to develop a comprehensive plan for adhering to treatment. The objective of this study was to explore the current practice of the healthcare providers when providing IAC, and identify the barriers and facilitators to the utilization of the UMOH IAC framework at two health centers IV level in rural Uganda. Methods This was a descriptive cross-sectional qualitative study that explored the current practices of the healthcare providers when providing IAC, and identified the barriers and facilitators to the utilization of the UMOH IAC framework. We used an interview guide with unstructured questions about what the participants did to support the clients with non-suppressed VL, and semi-structured questions following a checklist of categories of barriers and facilitators that affect ‘providers of care’ as provided by the Supporting the Use of Research Evidence for policy in African health systems (SURE) framework. Current practice as well as the categories of barriers and facilitators formed the a priori themes which guided data collection and analysis. In this study we only included healthcare providers (i.e., medical doctors, clinical officer, nurses, and counsellors) as ‘providers of care’ excluding family members because we were interested in the health system. Results A total of 19 healthcare providers took part in the interviews. The healthcare providers reported lack of sufficient knowledge on the UMOH IAC framework; most of them did not receive prior training or sensitization when it was first introduced. They indicated that they lacked counselling and communication skills to effectively utilize the IAC framework, and they were not motivated to utilize it because of the high workload at the clinics compounded by the limited workforce. Conclusions Although the UMOH IAC framework is a good step-by-step guide for the healthcare providers, there is need to understand their context and assess readiness to embrace the new behavior before expecting spontaneous uptake and utilization.

Introduction Papillary thyroid carcinoma is the most frequent endocrine neoplasia and its incidence has tripled over the past 35 years. Although papillary thyroid carcinoma carries a good prognosis, 10%−30% of patients still develop recurrence and metastasis. Some clinical and genetic features are associated with worse prognosis. The most frequent mutation is the BRAF p.V600E, which has been associated with many clinical features of poor prognosis. However, many studies have produced controversial results without any association between BRAF mutation and clinicopathological features of poor prognosis. Objective Since the prognostic value of BRAF mutations remains controversial, this study aims to investigate the importance of this mutation in therapeutic decisions for papillary thyroid carcinoma. Methods Therefore, we evaluated whether the presence of BRAF mutation is associated with features of poor prognosis in 85 patients with papillary thyroid carcinoma older than 45 years treated at A.C. Camargo Cancer Center, from 1980 to 2007. BRAF mutation was evaluated by pyrosequencing. Statistical analysis was performed using SPSS. Results The mean age of patients was 54 years (range: 45 − 77 years), 73 were women (85.8%) and 12 were men (14.2%). Among them, 39 cases (45.9%) presented extrathyroidal extension and 11 cases had recurrent disease. BRAF mutation was detected in 57 (67%) patients. No significant association was observed between BRAF mutation and gender (p = 0.743), age (p = 0.236), N-stage (p = 0.423), vascular and perineural infiltration (p = 0.085 or multifocality (p = 1.0). Although not statistically significant, the majority of patients with recurrent disease were BRAF positive (9 out of 11) (p = 0.325). Patients affected by BRAF mutation are associated with tumors larger than 1 cm (p = 0.034) and with extrathyroidal extension (p = 0.033). Conclusion Although BRAF testing is widely available, there are no consistent data to support improvement in outcomes from incorporating it into therapeutic decision for thyroid cancer.

The Metacognitive Awareness Inventory (MAI) is used all over the world to identify metacognitive components that are relevant to learning. However, there is not enough evidence confirming its factorial structure or the suitability of its Shortened Version, proposed by various authors. Also, to date, the MAI has not been validated in the Spanish context.After adapting the MAI to Spanish, it was administered to 1076 university students from different regions of Spain. Different structures of the MAI Shortened Version, with 19 items, were compared with the structures of the original 52-item MAI. Indexes of validity and reliability were analyzed, considering the factorial structure and relationships to other validated questionnaires.Only the MAI Shortened Version that differentiates between knowledge and regulation of cognition achieved a good fit. These two scales showed good convergent and divergent validity, high criterion validity in relation to academic achievement, high test- retest reliability, and high internal reliability.results support the traditional differentiation between knowledge of cognition and regulation of cognition, but only for the Shortened Version of the MAI. This instrument allows quick evaluations and identification of these components in Spanish contexts with adequate metric properties.

The MAP kinase and motor scaffold JIP3 prevents excess lysosome accumulation in axons of vertebrates and invertebrates. How JIP3’s interaction with dynein and kinesin-1 contributes to organelle clearance is unclear. We show that human dynein light intermediate chain (DLIC) binds the N-terminal RH1 domain of JIP3, its paralog JIP4, and the lysosomal adaptor RILP. A point mutation in RH1 abrogates DLIC binding without perturbing the interaction between JIP3’s RH1 domain and kinesin heavy chain. Characterization of this separation-of-function mutation in Caenorhabditis elegans shows that JIP3–bound dynein is required for organelle clearance in the anterior process of touch receptor neurons. Unlike JIP3 null mutants, JIP3 that cannot bind DLIC causes prominent accumulation of endo-lysosomal organelles at the neurite tip, which is rescued by a disease-associated point mutation in JIP3’s leucine zipper that abrogates kinesin light chain binding. These results highlight that RH1 domains are interaction hubs for cytoskeletal motors and suggest that JIP3–bound dynein and kinesin-1 participate in bidirectional organelle transport.

Parathyroid cysts (PCs) are rare benign lesions representing between the 0.08% and the 0.34% of the neck masses going on surgery. They should be considered in the differential diagnosis of neck masses, especially in the differential diagnosis of the cystic anterior neck masses.Approximately 300 cases of PC are reported within the international literature.The gold standard for diagnosis is the evidence of high-level intact parathyroid hormone in cystic fluid. It is important to diagnose PCs before surgery, not intraoperatively, in order to avoid unnecessary surgeries or superfluous excision of part of the thyroid gland and prevent the patient from iatrogenic hypothyroidism.A surgical approach is required in those patients with large-sized cysts, relapses despite needle aspirations or if it causes hyperparathyroidism.We describe a case report of a patient, initially misdiagnosed with a thyroid cyst swelling, who instead had a giant non-functioning PC, which produced dyspnoea or dysphagia.

Generalized additive models provide a flexible and easily-interpretable method for uncovering a nonlinear relationship between response and covariates. In many situations, the effect of a continuous covariate on the response varies across groups defined by the levels of a categorical variable. When confronted with a considerable number of groups defined by the levels of the categorical variable and a factor‐by‐curve interaction is detected in the model, it then becomes important to compare these regression curves. When the null hypothesis of equality of curves is rejected, leading to the clear conclusion that at least one curve is different, we may assume that individuals can be grouped into a number of classes whose members all share the same regression function. We propose a method that allows determining such groups with an automatic selection of their number by means of bootstrapping. The validity and behavior of the proposed method were evaluated through simulation studies. The applicability of the proposed method is illustrated using real data from an experimental study in neurology., This work was partially supported by project 2017/00001/006/001/097: Ayudas para el man tenimiento de actividades de investigaci ´on de institutos universitarios de investigaci ´on y grupos de investigaci´on de la Universidad de Oviedo para el ejercicio 2021. Luís Meira-Machado acknowledges financial support from Portuguese Funds through FCT - ”Fundação para a Ciência e a Tecnologia”, within the projects UIDB ˆ /00013/2020, UIDP/00013/2020. Javier Roca-Pardinas acknowledges financial support from Grant PID2020-118101GB-I00, Ministerio de Ciencia e Innovacion (MCIN/AEI /10.13039/501100011033).

Introduction: Immediate and delayed hypersensitivity reactions (HSR) to COVID-19 vaccines are rare adverse events that need to be prevented, diagnosed, and managed in order to guarantee adherence to the vaccination campaign. The aims of our study were to stratify the risk of HSR to COVID-19 vaccines and propose alternative strategies to complete the vaccination. Methods: 1,640 subjects were screened for vaccinal eligibility, according to national and international recommendations. Among them, we enrolled for allergy workup 152 subjects, 43 with HSR to COVID-19 vaccines and 109 at high risk of HSR to the first dose. In vivo skin tests with drugs and/or vaccines containing PEG/polysorbates were performed in all of them, using skin prick test and, when negative, intradermal tests. In a subgroup of patients resulted negative to the in vivo skin tests, the programmed dose of COVID-19 vaccine (Pfizer/BioNTech) was administered in graded doses regimen, and detection of neutralizing anti-spike antibodies was performed in these patients after 4 weeks from the vaccination, using the SPIA method. Results: Skin tests for PEG/polysorbates resulted positive in only 3% (5/152) of patients, including 2 with previous HSR to COVID-19 vaccines and 3 at high risk of HSR to the first dose. Among the 147 patients with negative skin tests, 97% (143/147) were eligible for vaccination and 87% (124/143) of them received safely the programmed COVID-19 vaccine dose. Administration of graded doses of Pfizer/BioNTech vaccine were well tolerated in 17 out of 18 patients evaluated; only 1 developed an HSR during the vaccination, less severe than the previous one, and all developed neutralizing anti-spike antibodies after 4 weeks with values comparable to those subjects who received the vaccine in unfractionated dose. Conclusion: On the whole, the usefulness of the skin tests for PEG/polysorbates seems limited in the diagnosis of HSR to COVID-19 vaccines. Graded doses regimen (Pfizer/BioNTech) is a safe and effective alternative strategy to complete the vaccinal course.

Objective: to determine the prevalence of radiodermatitis, severity grades and predictive factors of its occurrence in patients with anal and rectal cancer followed up by the nursing consultation, and to analyze the association of severity grades of radiodermatitis with temporary radiotherapy interruption. Method: a quantitative, cross-sectional and retrospective study, carried out with 112 medical records of patients with anal and rectal cancer undergoing curative radiotherapy followed up in the nursing consultation. Data were collected using a form and analyzed using analytical and inferential statistics. Results: 99.1% of patients had radiodermatitis, 34.8% of which were severe. The predictive factors were female sex, age greater than 65 years, anal canal tumor, treatment with cobalt device and IMRT technique. Treatment interruption occurred in 13% of patients, associated with severe radiodermatitis. Conclusion: there was a high prevalence of radiodermatitis, mainly severe, which resulted in treatment interruption. RESUMEN Objetivo: determinar la prevalencia de radiodermatitis, los grados de severidad y los factores predictores de su ocurrencia en pacientes con cáncer anal y rectal seguidos de la consulta de enfermería, y analizar la asociación de los grados de severidad de la radiodermatitis con la interrupción temporal de radioterapia. Método: investigación cuantitativa, transversal y retrospectiva, realizada con 112 prontuarios de pacientes con cáncer anal y rectal en tratamiento con radioterapia curativa seguidos en la consulta de enfermería. Los datos fueron recolectados mediante un formulario y analizados mediante estadística analítica e inferencial. Resultados: el 99,1% de los pacientes presentaban radiodermatitis, de las cuales el 34,8% eran graves. Los factores predictores fueron sexo femenino, edad mayor de 65 años, tumor del canal anal, tratamiento con aparato de cobalto y técnica de IMRT. La interrupción del tratamiento se produjo en el 13% de los pacientes, asociada a radiodermitis grave. Conclusión: hubo una alta prevalencia de radiodermatitis, principalmente severa, lo que obligó a la interrupción del tratamiento. RESUMO Objetivo: determinar a prevalência da radiodermatite, os graus de severidade e os fatores preditivos da sua ocorrência em pacientes com câncer de canal anal e reto acompanhados pela consulta de enfermagem, e analisar a associação dos graus de severidade da radiodermatite com a interrupção temporária da radioterapia. Método: pesquisa quantitativa, seccional e retrospectiva, realizada com 112 prontuários de pacientes com câncer de canal anal e reto submetidos à radioterapia curativa acompanhados na consulta de enfermagem. Dados foram coletados por formulário e analisados empregando-se estatística analítica e inferencial. Resultados: 99,1% dos pacientes apresentaram radiodermatite, sendo 34,8% graus severos. Os fatores preditivos foram sexo feminino, idade maior que 65 anos, tumor de canal anal, tratamento com aparelho de cobalto e técnica IMRT. A interrupção do tratamento ocorreu em 13% dos pacientes, associada à radiodermatite severa. Conclusão: houve alta prevalência de radiodermatite, principalmente grau severo, que resultou em interrupção do tratamento.

Background Few studies have explored the Central Nervous System (CNS) infection illness trajectory among older persons with dementia in sub-Saharan African (SSA) settings. This study explored the Caregiver’s perspectives on the Central Nervous System infection illness trajectory among the older persons with dementia in Northern Uganda. Methods This was a qualitative study conducted in Lira District northern Uganda in March 2022 amongst purposively selected 20 caregivers of the older persons aged 50 + years with a positive history of CNS infection and later life dementia. Data were collected using an in-depth interview guide. Audio recordings and field notes of the interviews were undertaken. The interviews generated data on the CNS infection illness trajectory from onset to the current demented state of the older persons. The audio-recorded interviews were transcribed verbatim before manual reflective thematic analysis. Results Older persons with a positive history of CNS infection illness and later life dementia in rural northern Uganda presented with symptoms of early life CNS infection illness ranging from neck pain, back pain, chronic headache, and fatigue. There were also manifestations of comorbidities particularly road traffic accidents involving traumatic injury to the head, neck, and spine, high blood pressure, chronic headache, and or their medications in the older person’s trajectory to later life dementia. A plurality of healthcare which included both formal and informal healthcare medicines was sought and utilized for the treatment and care of the CNS infection illness and dementia by the older persons amidst improper diagnosis and mismanagement. Conclusions and recommendations Older persons with early-life CNS infections illness and later-life dementia were reported to present with symptoms including neck pain, back pain, chronic headache, high blood pressure, and fatigue. The reported symptoms of CNS infection illness may be intertwined with co-morbidities particularly traumatic injury involving the head, neck, and spine, high blood pressure, and chronic headache. Healthcare professionals should integrate routine screening of older persons for the history of CNS infections, chronic headache, high blood pressure, trauma to the head, neck, and spine, and dementia and early treatment.

Left ventricular noncompaction (LVNC) is a congenital pathology that directly affects the lining walls of myocardial tissue, causing trabeculations with blood filling in the inner wall of the heart, concomitantly with the development of a mesocardial thinning. Although LVNC was described for the first time as long ago as 1984, our understanding of the disease with regard to its genetic pattern, diagnosis, clinical presentation and treatment is still scanty. LVNC can present as an isolated condition or associated with congenital heart disease, genetic syndromes or neuromuscular disease. This suggests that LVNC is not a distinct form of cardiomyopathy, but rather a morphological expression of different diseases. Recognition of the disease is of fundamental importance because its clinical manifestations are variable, ranging from the absence of any symptom to congestive heart failure, lethal arrhythmias and thromboembolic events. The study of this disease has emphasized its genetic aspects, as it may be of sporadic origin or hereditary, in which case it most commonly has an autosomal dominant inheritance or one linked to the X chromosome. Echocardiography is the gold standard for diagnosis, and magnetic resonance imaging may refine the identification of the disease, especially in those patients with non-conclusive echocardiography. This article sets out to review the main characteristics of LVNC and present updates, especially in the genetic pattern, diagnosis and treatment of the disease.

It has been proposed that vaccines may exert an unspecific protective effect against infectious agents, different than expected. Coronavirus disease 2019 (COVID-19) is a pandemic infection with high mortality in older patients due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The high number of vaccinations may be one of the reasons why children show a lower susceptibility to SARS-CoV-2 infection and milder severity when compared to adults. We have designed a study aimed at investigating whether the influenza vaccine may reduce the susceptibility and severity of SARS-CoV-2 infection. We retrospectively enrolled 635 patients who accessed our Emergency Department from March 1st to June 30th, 2020, and were diagnosed with COVID-19 infection confirmed by an RT-PCR on an oropharyngeal swab. Clinical data, outcomes, and influenza vaccination status were collected from the electronic medical records of our Hospital. We also used data from the Italian Health Ministry to compare the prevalence of flu vaccination among the general population of the Lazio Region and our enrolled patients. We then compared clinical outcomes between vaccinated and non-vaccinated patients, by univariate and multivariate analysis. COVID-19-positive patients older than 65 years reported a lower prevalence of flu vaccination when compared to the general population residing in the Lazio (p = 0.004). After correction for gender, age, and comorbidities, we found a lower risk of death at 60 days in patients with flu vaccination than in not vaccinated patients (p = 0.001). Our study shows that flu vaccination could reduce the mortality of COVID-19. Prospective studies are needed to confirm this result.

Introduction Thyroidectomy is the most common surgery in the cervical region. Currently, several techniques are available for intraoperative hemostasis. Objective To compare the performance of three techniques (monopolar and bipolar electrical and ultrasonic) on operative time and postoperative complications. Methods Patients submitted to total thyroidectomy without prior treatment were included in this prospective series study, using a scientific design. Results A total of 834 patients were included; 661 women (79.3%) and 173 men (20.7%). The diagnosis was malignant neoplasia in 528 patients (63.3%) and benign disease in 306 patients (36.7%). The monopolar electric scalpel was used in 280 patients (33.6%), bipolar scalpel in 210 patients (25.2%) and ultrasonic scalpel in 344 patients (41.3%). The operative time was significantly shorter with the ultrasonic or bipolar scalpel when compared to the electric scalpel. In a linear regression model, gender, malignancy diagnosis and power energy type were significant for the procedure duration. Patients who underwent surgery with an ultrasound or bipolar scalpel had a significantly lower incidence of hypoparathyroidism. Conclusion The use of ultrasonic or bipolar scalpel significantly reduces operative time and the incidence of transient hypoparathyroidism.

Background: The role of minimal extrathyroidal extension (mETE) as a risk factor for persistent papillary thyroid carcinoma (PTC) is still debated. The aim of this study was to assess the clinical impact of mETE as a predictor of worse initial treatment response in PTC patients and to verify the impact of radioiodine therapy after surgery in patients with mETE. Methods: We reviewed all records in the Italian Thyroid Cancer Observatory (ITCO) database and selected 2237 consecutive patients with PTC who satisfied the inclusion criteria (PTC with no lymph node metastases and at least 1 year of follow-up). For each case, we considered initial surgery, histological variant of PTC, tumor diameter, recurrence risk class according to the American Thyroid Association (ATA) risk stratification system, use of radioiodine therapy, and initial therapy response, as suggested by ATA guidelines. Results: At 1-year follow-up, 1831 patients (81.8%) had an excellent response, 296 (13.2%) had an indeterminate response, 55 (2.5%) had a biochemical incomplete response, and 55 (2.5%) had a structural incomplete response. Statistical analysis suggested that mETE (odds ratio [OR] 1.16, p=0.65), tumor size >2 cm (OR 1.45, p=0.34), aggressive PTC histology (OR 0.55, p=0.15), and age at diagnosis (OR 0.90, p=0.32) were not significant risk factors for a worse initial therapy response. When evaluating the combination of mETE, tumor size, and aggressive PTC histology, the presence of mETE with a >2 cm tumor was significantly associated with a worse outcome (OR 5.27, 95% CI, p=0.014). The role of radioiodine ablation in patients with mETE was also evaluated. When considering radioiodine treatment, propensity score-based matching was performed, and no significant differences were found between treated and non-treated patients (p=0.24). Conclusions: This study failed to show the prognostic value of mETE in predicting initial therapy response in a large cohort of PTC patients without lymph node metastases. The study suggests that the combination of tumor diameter and mETE can be used as a reliable prognostic factor for persistence and could be easily applied in clinical practice to manage PTC patients with low-to-intermediate risk of recurrent/persistent disease.