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Background The SARS-CoV-2 pandemic is still ongoing and a major challenge for health care services worldwide. In the first WSES COVID-19 emergency surgery survey, a strong negative impact on emergency surgery (ES) had been described already early in the pandemic situation. However, the knowledge is limited about current effects of the pandemic on patient flow through emergency rooms, daily routine and decision making in ES as well as their changes over time during the last two pandemic years. This second WSES COVID-19 emergency surgery survey investigates the impact of the SARS-CoV-2 pandemic on ES during the course of the pandemic. Methods A web survey had been distributed to medical specialists in ES during a four-week period from January 2022, investigating the impact of the pandemic on patients and septic diseases both requiring ES, structural problems due to the pandemic and time-to-intervention in ES routine. Results 367 collaborators from 59 countries responded to the survey. The majority indicated that the pandemic still significantly impacts on treatment and outcome of surgical emergency patients (83.1% and 78.5%, respectively). As reasons, the collaborators reported decreased case load in ES (44.7%), but patients presenting with more prolonged and severe diseases, especially concerning perforated appendicitis (62.1%) and diverticulitis (57.5%). Otherwise, approximately 50% of the participants still observe a delay in time-to-intervention in ES compared with the situation before the pandemic. Relevant causes leading to enlarged time-to-intervention in ES during the pandemic are persistent problems with in-hospital logistics, lacks in medical staff as well as operating room and intensive care capacities during the pandemic. This leads not only to the need for triage or transferring of ES patients to other hospitals, reported by 64.0% and 48.8% of the collaborators, respectively, but also to paradigm shifts in treatment modalities to non-operative approaches reported by 67.3% of the participants, especially in uncomplicated appendicitis, cholecystitis and multiple-recurrent diverticulitis. Conclusions The SARS-CoV-2 pandemic still significantly impacts on care and outcome of patients in ES. Well-known problems with in-hospital logistics are not sufficiently resolved by now; however, medical staff shortages and reduced capacities have been dramatically aggravated over last two pandemic years.

Respiratory and digestive mucosal surfaces are continually exposed to common environmental antigens, which include potential allergens. Although innocuous in healthy individuals, allergens cause allergy in predisposed subjects and do so by triggering a pathologic T

Background Clinical evidence is commonly obtained through individual trials that are time-, cost- and resource-consuming, and which often leave unanswered clinically relevant questions. Umbrella studies have been developed to address the need for more efficient and flexible trial structures, predominantly for cancer treatments. The umbrella concept foresees data collection within a unifying trial structure, to which one or more substudies may be added at any time to address product- or therapy-specific questions. To our knowledge, the umbrella concept has not yet been used in the medical device area, but it may offer similar advantages as in other settings, particularly in areas where multiple therapies are available within one large treatment area. Methods The MANTRA study (NCT05002543) is a prospective, global, post-marketing clinical follow-up study. The aim is to collect safety and device performance data covering the Corcym cardiac surgery portfolio for the treatment of aortic, mitral, and tricuspid valve diseases. The study uses a master protocol that outlines the main common parameters, and the specific questions are addressed in three substudies. The primary endpoints are device success at 30 days. Secondary endpoints include safety- and device performance-related data at 30 days, 1 year, and then annually through to 10 years. All endpoints are defined according to the more recent guidelines for heart valve procedures. Additionally, procedure and hospitalization information are collected, including Enhanced Recovery after Surgery in sites using such protocols, and patient outcome measures such as New York Heart Association classification and quality-of-life questionnaires. Results The study started in June 2021. Enrollment in all three substudies is ongoing. Conclusions The MANTRA study will provide contemporary information on the long-term outcomes of medical devices for the treatment of aortic, mitral, and tricuspid heart valve diseases in routine clinical practice. The umbrella approach adopted in the study has the potential of longitudinally assessing long-term efficacy of the devices and the flexibility to investigate new research questions as they arise.

The lateral cutaneous branch of the iliohypogastric nerve (LCBIN) block combined with the lateral femoral cutaneous, superior cluneal and subcostal nerve blocks has been shown to provide complete anaesthetic coverage for the incisions used for hip arthroplasty. Successful ultrasound-guided selective nerve blocks have been described for these nerves, except for the LCBIN. The objective of this cadaveric study was to determine the position of the LCBIN in order to provide the anatomical basis for an ultrasound-guided nerve block approach. Furthermore, we aimed to evaluate the spread of injected dye after using the ultrasound-guided nerve block approach.The LCBIN and its relationship with iliac crest (IC) was assessed bilaterally in 27 adult cadaveric dissections. Bilaterally, in two cadavers, an ultrasound transducer was applied transversely above the IC and moved in caudal or cranial direction to identify the LCBIN. A needle was inserted in-plane and 3 ml of a solution with methylene blue was injected and confirmed by dissection.The mean distance from the anterior superior iliac spine to the point where the LCBIN crossed the IC was 9.74 ± 0.84 cm. The mean distance from the point where the nerve pierced the aponeurosis of the external oblique muscle to the point where it crossed the IC was 0.59 ± 0.77 cm. The nerve was easily visualised in 3 out of 4 sides using ultrasound. However, the nerve was coloured in all cases.The present study showed that the LCBIN has a constant location and is sonographically easy visualized in a well-defined anatomical space. Thus, the ultrasound guided LCBIN block may be an alternative to the blind injection technique.

Leigh disease, or subacute necrotizing encephalomyelopathy, a genetically heterogeneous condition consistently characterized by defective mitochondrial bioenergetics, is the most common oxidative-phosphorylation related disease in infancy. Both neurological signs and pathological lesions of Leigh disease are mimicked by the ablation of the mouse mitochondrial respiratory chain subunit Ndufs4−/−, which is part of, and crucial for, normal Complex I activity and assembly, particularly in the brains of both children and mice. We previously conveyed the human NDUFS4 gene to the mouse brain using either single-stranded adeno-associated viral 9 recombinant vectors or the PHP.B adeno-associated viral vector. Both these approaches significantly prolonged the lifespan of the Ndufs4−/− mouse model but the extension of the survival was limited to a few weeks by the former approach, whereas the latter was applicable to a limited number of mouse strains, but not to primates. Here, we exploited the recent development of new, self-complementary adeno-associated viral 9 vectors, in which the transcription rate of the recombinant gene is markedly increased compared with the single-stranded adeno-associated viral 9 and can be applied to all mammals, including humans. Either single intra-vascular or double intra-vascular and intra-cerebro-ventricular injections were performed at post-natal Day 1. The first strategy ubiquitously conveyed the human NDUFS4 gene product in Ndufs4−/− mice, doubling the lifespan from 45 to ≈100 days after birth, when the mice developed rapidly progressive neurological failure. However, the double, contemporary intra-vascular and intra-cerebroventricular administration of self-complementary-adeno-associated viral NDUFS4 prolonged healthy lifespan up to 9 months of age. These mice were well and active at euthanization, at 6, 7, 8 and 9 months of age, to investigate the brain and other organs post-mortem. Robust expression of hNDUFS4 was detected in different cerebral areas preserving normal morphology and restoring Complex I activity and assembly. Our results warrant further investigation on the translatability of self-complementary-adeno-associated viral 9 NDUFS4-based therapy in the prodromal phase of the disease in mice and eventually humans.

The short and long-term outcomes of children with anti-Ro/La-related congenital heart block treated with a combined maternal-neonatal therapy protocol were compared with those of controls treated with other therapies.Sixteen mothers were treated during pregnancy with a therapy consisting of daily oral fluorinated steroids, weekly plasma exchange and fortnightly intravenous immunoglobulins and their neonates with intravenous immunoglobulins (study group); 19 mothers were treated with fluorinated steroids alone or associated to intravenous immunoglobulins or plasma exchange (control group).The combined-therapy children showed a significantly lower progression rate from 2nd to 3rd degree block at birth, a significant increase in heart rate at birth and a significantly lower number of pacemaker implants during post-natal follow-up with respect to those treated with the other therapies.The combined therapy produced better short and long term outcomes with respect to the other therapies studied.

Aims Multisystem inflammatory syndrome in children (MIS-C) with cardiovascular manifestations are frequent. However, there is lacking evidence regarding cardiological follow-up of this cohort of patients. The aim of our study was to describe the early and mid-term cardiac abnormalities assessed by standard and speckle-tracking echocardiography (STE), and cardiac MRI (CMR). Methods and results We enrolled 32 patients (21 male, 11 female), mean age 8.25 ± 4years, with diagnosis of MIS-C. During admission, all children underwent TTE, STE with analysis of left ventricle global longitudinal strain (GLS) and CMR. Patients underwent cardiological evaluation at 2 (T1) and 6 months (T2) after discharge. Cardiac MRI was repeated at 6 months after discharge. Mean left ventricular ejection fraction (LVEF) at baseline was 58.8 ± 10% with 10 patients (31%) below 55%. Speckle-tracking echocardiography showed reduced mean LV GLS (−17.4 ± 4%). On CMR, late gadolinium enhancement (LGE) with non-ischaemic pattern was evident in 8 of 23 patients (35%). Follow-up data showed rapid improvement of LVEF at T1 (62.5 ± 7.5 vs. 58.8 ± 10.6%, P-value 0.044) with only three patients (10%) below ≤ 55% at T1. Left ventricular (LV) GLS remained impaired at T1 (−17.2 ± 2.7 vs.−17.4 ± 4, P-value 0.71) and significantly improved at T2 (−19 ± 2.6% vs. −17.4 ± 4%, P-value 0.009). LV GLS was impaired (>−18%) in 53% of patients at baseline and T1, whereas only 13% showed persistent LV GLS reduction at T2. Follow-up CMR showed LGE persistence in 33.4% of cases. Conclusion Early cardiac involvement significantly improves during follow-up of MIS-C patients. However, subclinical myocardial dysfunction seems to be still detectable after 6 months of follow-up in a not negligible proportion of them.

Cell migration depends on the dynamic organization of the actin cytoskeleton and assembly and disassembly of focal adhesions (FA). However the precise mechanisms coordinating these processes remain poorly understood. We previously identified the estrogen-related receptor α (ERRα) as a major regulator of cell migration. Here, we show that loss of ERRα leads to abnormal accumulation of actin filaments that is associated with an increase in the level of inactive form of the actin-depolymerizing factor cofilin. We further show that ERRα depletion decreases cell adhesion and promotes defective FA formation and turnover. Interestingly, specific inhibition of the RhoA-ROCK-LIMK-cofilin pathway rescues the actin polymerization defects resulting from ERRα silencing, but not cell adhesion. Instead we found that MAP4K4 is a direct target of ERRα and down-regulation of its activity rescues cell adhesion and FA formation in the ERRα-depleted cells. Altogether, our results highlight a crucial role of ERRα in coordinating the dynamic of actin network and focal adhesion through the independent regulation of the RhoA and MAP4K4 pathways.

Objectives Launched in 2011 by the Public Health Agency of Canada, the Canadian Diabetes Risk Questionnaire (CANRISK) is a self-assessment tool validated in a Canadian sample, but its uptake has never been assessed. We sought to determine the level of current use of the CANRISK tool, identify common facilitators and barriers to its use and recommend future improvements. Methods Ten professional allied health organizations across Canada were contacted for in-depth interviews. Contextual content and thematic analysis were used to analyze the qualitative data set. Results According to allied health professionals, the tool is widely used, appealing and needed, and is being used for risk screening and health promotion. Respondents also identified the need to provide support and next steps for users identified as high risk. Still, several barriers to implementation were found, including readability, offensive or confusing language and difficulty ascertaining body measurements. Conclusions The CANRISK is a valuable diabetes risk assessment tool in Canada, particularly for allied health organizations.

In patients with acute intermittent porphyria (AIP), induction of delta aminolevulinic acid synthase 1 (ALAS1) leads to haem precursor accumulation that may cause recurring acute attacks. In a recent phase III trial, givosiran significantly reduced the attack rate in severe AIP patients. Frequent adverse events were injection-site reaction, fatigue, nausea, chronic kidney disease and increased alanine aminotransferase.To describe the efficacy and safety of givosiran based on a personalized medical approach.We conducted a retrospective patient file study in 25 severe AIP patients treated with givosiran in France. We collected data on clinical and biochemical efficacy along with reports of adverse events.Givosiran drastically reduced the attack rate in our cohort, as 96% were attack-free at the time of the study. The sustained efficacy of givosiran in most patients allowed us to personalize dosing frequency. In 42%, givosiran was only given when haem precursor levels were increasing. Our data suggest that givosiran is most effective when given early in the disease course. We confirmed a high prevalence of adverse events. One patient discontinued treatment due to acute pancreatitis. All patients had hyperhomocysteinemia, and all patients with initial homocysteine levels available showed an increase under treatment. In this context, one patient was diagnosed with pulmonary embolism.The sustained effect of givosiran allowed a decrease in dosing frequency without compromising treatment efficacy. The high prevalence of adverse events emphasizes the importance of restricting the treatment to severe AIP and administering the minimum effective dose for each patient.

A growing number of emerging SARS-CoV-2 variants is being identified worldwide, potentially impacting the effectiveness of current vaccines. We report the data obtained in several Italian regions involved in the SARS-CoV-2 variant monitoring from the beginning of the epidemic and spanning the period from October 2020 to March 2021.

Skin and soft-tissue infections (SSTIs) encompass a variety of pathological conditions that involve the skin and underlying subcutaneous tissue, fascia, or muscle, ranging from simple superficial infections to severe necrotizing infections.Together, the World Society of Emergency Surgery, the Global Alliance for Infections in Surgery, the Surgical Infection Society-Europe, The World Surgical Infection Society, and the American Association for the Surgery of Trauma have jointly completed an international multi-society document to promote global standards of care in SSTIs guiding clinicians by describing reasonable approaches to the management of SSTIs.An extensive non-systematic review was conducted using the PubMed and MEDLINE databases, limited to the English language. The resulting evidence was shared by an international task force with different clinical backgrounds.

B cells, which are critical for intestinal homeostasis, remain understudied in ulcerative colitis (UC). In this study, we recruited three cohorts of patients with UC (primary cohort, n = 145; validation cohort 1, n = 664; and validation cohort 2, n = 143) to comprehensively define the landscape of B cells during UC-associated intestinal inflammation. Using single-cell RNA sequencing, single-cell IgH gene sequencing and protein-level validation, we mapped the compositional, transcriptional and clonotypic landscape of mucosal and circulating B cells. We found major perturbations within the mucosal B cell compartment, including an expansion of naive B cells and IgG(+) plasma cells with curtailed diversity and maturation. Furthermore, we isolated an auto-reactive plasma cell clone targeting integrin αvβ6 from inflamed UC intestines. We also identified a subset of intestinal CXCL13-expressing TFH-like T peripheral helper cells that were associated with the pathogenic B cell response. Finally, across all three cohorts, we confirmed that changes in intestinal humoral immunity are reflected in circulation by the expansion of gut-homing plasmablasts that correlates with disease activity and predicts disease complications. Our data demonstrate a highly dysregulated B cell response in UC and highlight a potential role of B cells in disease pathogenesis.

Objective. The main objective of this study was to describe the perceived quality of life (QoL) in patients living with AIDS (PLWA) and their chosen coping strategies in a cohort of individuals managed with HAART. Methods. This is a prospective cohort study conducted at the Medication Dispensing Unit of a university hospital (MDU-UH) located in southeastern Brazil. Study population comprised HIV/AIDS patients starting antiretroviral treatment at MDU. The final sample comprised 99 participants. Patients were followed up for 24 months from their recruitment. We used a face-to-face questionnaire to determine sociodemographic and behavioural variables. Quality of life (QoL) and coping strategies (CS) were measured through validated instruments. Results. Regarding the QoL dimensions, the general perception of QoL among these participants was considered good. Regarding CS, the adherent patients scored higher than the nonadherents. Conclusions. The present study revealed that the perceived QoL can be maintained in individuals treated for HIV/AIDS. There is an association between high score of coping strategies and adherence to HAART.

Abstract. We present the case of a 72-year-old woman who was diagnosed with Hashimoto’s thyroiditis and who developed a low-grade fever, fatigue, and weight loss that prompted to perform a thyroid biopsy to rule out an underlying primary thyroid lymphoma. This case report offers the opportunity to review the association between Hashimoto’s thyroiditis and primary thyroid lymphoma. Furthermore, it underlines the importance of considering the diagnosis of lymphoma when a thyroid mass is found in patients with an underlying Hashimoto’s disease, as the timely management is essential for survival with this rare thyroid condition.

Somatic hypermutation (SHM) is an important diversification mechanism that plays a part in the creation of immune memory. Immunoglobulin (Ig) variable region gene lineage trees were used over the last four decades to model SHM and the selection mechanisms operating on B cell clones. We hereby present IgTreeZ (Immunoglobulin Tree analyZer), a python-based tool that analyses many aspects of Ig gene lineage trees and their repertoires. Using simulations, we show that IgTreeZ can be reliably used for mutation and selection analyses. We used IgTreeZ on empirical data, found evidence for different mutation patterns in different B cell subpopulations, and gained insights into antigen-driven selection in corona virus disease 19 (COVID-19) patients. Most importantly, we show that including the CDR3 regions in selection analyses - which is only possible if these analyses are lineage tree-based - is crucial for obtaining correct results. Overall, we present a comprehensive lineage tree analysis tool that can reveal new biological insights into B cell repertoire dynamics. HN was supported by a Bar-Ilan University President’s Scholarship. AC is supported by the Spanish Ministry of Economy and Competitiveness (MINECO) grant RTI2018-093894-B-100. GM is supported by Spanish Institute of Health Carlos III (Miguel Servet grant 2020-2024).

A serious form of social withdrawal, initially described within Japan as hikikomori, has received increasing attention from the international scientific community during the last decade. The 25-item Hikikomori Questionnaire (HQ-25) was initially developed and validated in Japan. To date, data on its psychometric properties in other populations where cases of hikikomori have been described are still scarce. Thus, the aims of this study were to (1) translate, adapt, and validate the Italian version of the HQ-25 analyzing its psychometric properties; and (2) verify the association between hikikomori and personality functioning, social support, and problematic Internet use. A sample of 372 Italian adults aged 18 to 50 years completed the HQ-25 and measures of psychoticism, personality dysfunction, social support, and problematic Internet use were employed to test the convergent validity of the HQ-25. The data showed a satisfactory fit for a three-factor model, significantly better than a one-factor model. The three factors (socialization, isolation, and emotional support, as in the original study on the HQ-25) correlated positively with psychoticism, personality dysfunction, and problematic Internet use, and correlated negatively with social support. A lifetime history of hikikomori was present in 1.1% of the sample (n = 4). This is the first study to use the Italian validated version of the HQ-25 with an adult population. The findings from this study provide evidence of the satisfactory psychometric properties of the Italian version of the HQ-25 and support further investigation of the HQ-25 as an instrument to help screen for and investigate the presence of hikikomori.

The aims of this study were to characterize new SARS-CoV-2 genomes sampled all over Italy and to reconstruct the origin and the evolutionary dynamics in Italy and Europe between February and June 2020. The cluster analysis showed only small clusters including < 80 Italian isolates, while most of the Italian strains were intermixed in the whole tree. Pure Italian clusters were observed mainly after the lockdown and distancing measures were adopted. Lineage B and B.1 spread between late January and early February 2020, from China to Veneto and Lombardy, respectively. Lineage B.1.1 (20B) most probably evolved within Italy and spread from central to south Italian regions, and to European countries. The lineage B.1.1.1 (20D) developed most probably in other European countries entering Italy only in the second half of March and remained localized in Piedmont until June 2020. In conclusion, within the limitations of phylogeographical reconstruction, the estimated ancestral scenario suggests an important role of China and Italy in the widespread diffusion of the D614G variant in Europe in the early phase of the pandemic and more dispersed exchanges involving several European countries from the second half of March 2020.

Despite findings from previous studies, there is still little consistent knowledge regarding the co-occurrence patterns of somatic, depressive and anxiety symptoms in childhood and adolescence. Moreover, functional disability due to somatic symptoms at different concomitant levels of depression and anxiety is understudied. The present study examined the co-occurrence patterns of somatic symptoms and symptoms of depression and anxiety, in children and adolescents using two-step cluster analysis. Differences in functional disability due to somatic symptoms were tested with ANCOVA controlling for gender and age. The sample comprised 1127 Italian children and adolescents (48.7% males, n = 549) aged 8–16 years (Mage = 11.7, SD = 2.37). Data were collected using the Children Somatization Inventory-24, the Children Depression Inventory, the Screen for Child Anxiety Related Emotional Disorders, and the Functional Disability Inventory. A four-cluster solution based on the co-occurrence of internalizing symptoms best fit the data. The four clusters were labelled as follows: cluster 1: “High somatic symptoms and average depression/anxiety”; cluster 2: “High somatic symptoms and high depression/anxiety”; cluster 3: “Average somatic symptoms and above average depression/anxiety”; and cluster 4: “Low somatic symptoms and low depression/anxiety”. Significant differences between the four groups according to gender and age were shown. Participants with high levels of somatic, depressive, and anxiety symptoms reported greater functional disability due to somatic symptoms than the other three groups. Our findings indicate that children and adolescents who demonstrate high symptoms of depression and anxiety also reported higher levels of disability in daily life due to somatic symptoms.

This study aimed to translate the Interprofessional Facilitation Scale in French and validate its use for interprofessional simulation training. Experts translated the items into French and then back translated them into English. Data used for the validation were collected from interprofessional simulation trainings. Experts and observers found the scale's content validity was suitable. A principal component analysis was conducted. The Kaiser-Meyer-Olkin test value was 0.88 and two factors were identified, that explained 59.9% of the variance. They were labeled: (a) Opportunity of Interprofessional Learning and (b) Psychological Safety. The Cronbach's alpha measure of internal consistency was 0.91. The learning simulation environment explained the structure of the scale. This study provides evidence that the French version of Interprofessional Facilitation Scale can be used in the context of interprofessional simulation training.

Intra-abdominal infections (IAIs) are common surgical emergencies and have been reported as major contributors to non-trauma deaths in hospitals worldwide. The cornerstones of effective treatment of IAIs include early recognition, adequate source control, appropriate antimicrobial therapy, and prompt physiologic stabilization using a critical care environment, combined with an optimal surgical approach. Together, the World Society of Emergency Surgery (WSES), the Global Alliance for Infections in Surgery (GAIS), the Surgical Infection Society-Europe (SIS-E), the World Surgical Infection Society (WSIS), and the American Association for the Surgery of Trauma (AAST) have jointly completed an international multi-society document in order to facilitate clinical management of patients with IAIs worldwide building evidence-based clinical pathways for the most common IAIs. An extensive non-systematic review was conducted using the PubMed and MEDLINE databases, limited to the English language. The resulting information was shared by an international task force from 46 countries with different clinical backgrounds. The aim of the document is to promote global standards of care in IAIs providing guidance to clinicians by describing reasonable approaches to the management of IAIs.

Menin, encoded by the MEN1 gene, has been identified as a critical factor regulating ESR1 transcription, playing an oncogenic role in ER+ breast cancer (BC) cells. Here, we further dissected the consequences of menin inactivation in ER+ BC cells by focusing on factors within two major pathways involved in BC, mTOR and MYC. MEN1 silencing in MCF7 and T-47D resulted in an increase in phosphor-p70S6K1, phosphor-p85S6K1 and phosphor-4EBP1 expression. The use of an AKT inhibitor inhibited the activation of S6K1 and S6RP triggered by MEN1 knockdown (KD). Moreover, MEN1 silencing in ER+ BC cells led to increased formation of the eIF4E and 4G complex. Clinical studies showed that patients with menin-low breast cancer receiving tamoxifen plus everolimus displayed a trend toward better overall survival. Importantly, MEN1 KD in MCF7 and T-47D cells led to reduced MYC expression. ChIP analysis demonstrated that menin bound not only to the MYC promoter but also to its 5’ enhancer. Furthermore, E2-treated MEN1 KD MCF7 cells displayed a decrease in MYC activation, suggesting its role in estrogen-mediated MYC transcription. Finally, expression data mining in tumors revealed a correlation between the expression of MEN1 mRNA and that of several mTORC1 components and targets and a significant inverse correlation between MEN1 and two MYC inhibitory factors, MYCBP2 and MYCT1, in ER+ BC. The current work thus highlights altered mTORC1 and MYC pathways after menin inactivation in ER+ BC cells, providing insight into the crosstalk between menin, mTORC1 and MYC in ER+ BC.

Preoperative pelvic floor physiotherapy is commonly prescribed to limit postoperative stress urinary incontinence after radical prostatectomy. It can be done in different ways. The objective of this work is to achieve a description of the objectives and existing techniques.A narrative review is carried out based on a non-systematic review of the literature and on the authors' experience.Although discussed in the literature, preoperative pelvic floor therapy is essential for patient support and follow-up. It should not be limited to strengthening the pelvic floor. It includes a significant time of information, which should not be neglected and should be carried out in association with a holistic care to best prepare the patient before his intervention.

VPS13 is a eukaryotic lipid transport protein localized at membrane contact sites. Previous studies suggested that it may transfer lipids between adjacent bilayers by a bridge-like mechanism. Direct evidence for this hypothesis from a full-length structure and from electron microscopy (EM) studies in situ is still missing, however. Here, we have capitalized on AlphaFold predictions to complement the structural information already available about VPS13 and to generate a full-length model of human VPS13C, the Parkinson’s disease–linked VPS13 paralog localized at contacts between the endoplasmic reticulum (ER) and endo/lysosomes. Such a model predicts an ∼30-nm rod with a hydrophobic groove that extends throughout its length. We further investigated whether such a structure can be observed in situ at ER–endo/lysosome contacts. To this aim, we combined genetic approaches with cryo-focused ion beam (cryo-FIB) milling and cryo–electron tomography (cryo-ET) to examine HeLa cells overexpressing this protein (either full length or with an internal truncation) along with VAP, its anchoring binding partner at the ER. Using these methods, we identified rod-like densities that span the space separating the two adjacent membranes and that match the predicted structures of either full-length VPS13C or its shorter truncated mutant, thus providing in situ evidence for a bridge model of VPS13 in lipid transport.

Despite the availability of effective lipid-lowering drugs, only few high-risk patients attain their LDL cholesterol (LDL-C) guideline-recommended risk-based goal because of underprescription of combination therapy. We present an 18-month experience with variation of prescription protocols after publication of the 2019 ESC/EAS guidelines for the management of dyslipidemias.Overall, 621 consecutive patients hospitalized for acute coronary syndrome at Mauriziano Hospital in Turin, Italy, between January 2020 and June 2021 were enrolled. Lipid-lowering therapy recommended at discharge was registered to evaluate how many patients received statin monotherapy, statin plus ezetimibe combination or triple therapy with high-intensity statin plus ezetimibe and proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9i). At 6-month follow-up, the reduction in LDL-C, adverse events, compliance and cardiovascular recurrences was analyzed.Of 621 patients enrolled, 7 died during hospitalization. During the entire study period, 33% of patients received statin monotherapy, 50% were discharged on statin-ezetimibe combination, and PCSK9i (evolocumab) was prescribed to 17% of patients. Between April 2020 and June 2021, when new recommendations were introduced into clinical practice, 20% of patients received evolocumab, 56% combination therapy and only 24% were discharged on statin monotherapy. At the beginning of observation, evolocumab was prescribed to 3% of patients hospitalized for acute coronary syndrome, while at the end of the study period 27% of patients were discharged on PCSK9i, with an increase of the prescription rate by 759%; in the same period, prescription of statin monotherapy decreased by 75%. At 6-month follow-up, LDL-C reduction was 77% in patients treated with PCSK9i vs 48% in patients taking statin-ezetimibe combination therapy (p0.001). All patients on evolocumab reached the guideline-directed goals and a low rate of adverse events was reported, mainly represented by local injection site reactions. Six patients experienced acute coronary syndrome recurrence; only one of them was treated with evolocumab.Prescription of intensive lipid-lowering therapy after acute coronary syndrome, eventually with introduction of PCSK9i during hospitalization or at discharge, leads to attainment of guideline-recommended goals for all patients, with a low incidence of adverse events and optimal compliance.

Adhesion between leukocytes and brain endothelial cells, which line cerebral blood vessels, is a key event in both physiological and pathological conditions such as neuroinflammatory diseases. Leukocyte recruitment from blood into tissues is described as a multistep process involving leukocyte rolling on endothelial cells, adhesion, crawling, and diapedesis under hemodynamic shear stress. In neuroinflammatory conditions, there is an increase in leukocyte adhesion to the brain endothelial cells, activated by proinflammatory molecules such as cytokines. Here, we describe an in vitro technique to study the interaction between human leukocytes with human brain endothelial cells under shear stress mimicking the blood flow in vivo, coupled to live-cell imaging.

Mutations in VPS13C cause early-onset, autosomal recessive Parkinson's disease (PD). We have established that VPS13C encodes a lipid transfer protein localized to contact sites between the ER and late endosomes/lysosomes. In the current study, we demonstrate that depleting VPS13C in HeLa cells causes an accumulation of lysosomes with an altered lipid profile, including an accumulation of di-22:6-BMP, a biomarker of the PD-associated leucine-rich repeat kinase 2 (LRRK2) G2019S mutation. In addition, the DNA-sensing cGAS-STING pathway, which was recently implicated in PD pathogenesis, is activated in these cells. This activation results from a combination of elevated mitochondrial DNA in the cytosol and a defect in the degradation of activated STING, a lysosome-dependent process. These results suggest a link between ER-lysosome lipid transfer and innate immune activation in a model human cell line and place VPS13C in pathways relevant to PD pathogenesis. ispartof: JOURNAL OF CELL BIOLOGY vol:221 issue:7 ispartof: location:United States status: published

Summary Background Patients on regular dialysis show a poor response to hepatitis B vaccine due to uremia. A recombinant HB vaccine (containing an improved adjuvant system AS04, HBV-AS04) has been licensed but the evidence on its efficacy and safety in dialysis population over the long term is extremely limited. Aim We have measured antibody (anti-HBs) persistence for up to 72 months in a large cohort of patients on long-term dialysis (with susceptibility to HBV infection) who underwent vaccination with HBV-AS04 vaccine. Methods Patients were prospectively recruited to receive four 20-mcg doses of HBV-AS04 by intramuscular route (deltoid muscle). Two vaccine schedules were adopted: 0,1,2, and 3 month (n = 217 patients) and 0,1,2, and 6 month (n = 31 patients). Anti-HBs antibody concentrations were tested at 1,2,3, 4, 7 and 12 months and then every year up to 72 months. Multivariate analysis was made to find the baseline parameters that were associated with the immune response to HBV-AS04 vaccine. Results Two hundred and seventy-two patients were included and 248 completed the study. At completion of vaccine schedule, the frequency of responders (anti-HBs titers ≥ 10 mIU/mL) was 81.5% (202/248) (mean anti-HBs antibody titers, 384.9 ± 391.9 mIU/mL), according to per-protocol analysis. On the grounds of univariate analysis, age was lower in responder than non- responder patients to HBV AS04 even if no statistical significance was achieved (P = 0.09). The sero-protection rate at month 72 was 77% (7/9) (anti-HBs antibody titers, 184.9 ± 360.1 mIU/mL, P = 0.001). Multivariate analysis found a relationship between sero-response rate and age (P = 0.04). No major side effects and no de novo HBV episodes were observed. Conclusions Our open-label nonrandomized trial performed in a ‘real-world’ practice showed the persistence of anti-HBs antibody among responder patients over a very long follow-up. Studies with longer observation periods are under way.

Objective: The aim of this study was to define whether rapidly reallocating health care workers not experienced with PP for performing PP in ICU is feasible and safe. Summary Background Data: In the setting of severe acute respiratory distress syndrome (ARDS), the use of prone and supine positioning procedures (PP) has been associated with improved oxygenation resulting in decreased mortality. Nevertheless, applying PP is time consuming for ICU staffs that are at risk of mental of physical exhaustion, especially with the constant surge of admitted COVID-19 patients with severe ARDS. Methods: This prospective cohort study conducted at a single regional university hospital between March 27 and April 15, 2020. Among 117 patients admitted to ICU, 67 patients (57.3%) presented with proven SARS-CoV-2 infection with severe ARDS requiring PP. After accelerated simulation training, 109 volunteers including surgeons, physicians, nurses and physiotherapists, multiple dedicated teams performed daily multiple PP following a systematic checklist. Patient demographics and PP data were collected. Patient safety and health care workers safety were assessed. Results: Among 117 patients admitted to ICU, 67 patients (57.3%) required PP. Overall, 53 (79%) were male, with a median age of 68.5 years and median body mass index of 29.3 kg/m2. A total of 384 PP were performed. Overall, complication occurred in 34 PP (8.8%) and led to PP cancelation in 4 patients (1%). Regarding health care workers safety, four health care workers presented with potential COVID-19 related symptoms and none was positive. Conclusions: To overcome the surge of critically ill COVID-19 patients, reallocating health care workers to targeted medical tasks beyond their respective expertise such as PP was safe.

BackgroundPsychological resilience – positive psychological adaptation in the context of adversity – is defined and measured in multiple ways across disciplines. However, little is known about whether definitions capture the same underlying construct and/or share similar correlates. This study examined the congruence of different resilience measures and associations with sociodemographic factors and body mass index (BMI), a key health indicator.MethodsIn a cross-sectional sample of 1429 African American adults exposed to child maltreatment, we derived four resilience measures: a self-report scale assessing resiliency (perceived trait resilience); a binary variable defining resilience as low depression and posttraumatic stress (absence of distress); a binary variable defining resilience as low distress and high positive affect (absence of distress plus positive functioning); and a continuous variable reflecting individuals' deviation from distress levels predicted by maltreatment severity (relative resilience). Associations between resilience measures, sociodemographic factors, and BMI were assessed using correlations and regressions.ResultsResilience measures were weakly-to-moderately correlated (0.27–0.69), though similarly patterned across sociodemographic factors. Women showed higher relative resilience, but lower perceived trait resilience than men. Only measures incorporating positive affect or resiliency perceptions were associated with BMI: individuals classified as resilient by absence of distress plus positive functioning had lower BMI than non-resilient (β = −2.10, p = 0.026), as did those with higher perceived trait resilience (β = −0.63, p = 0.046).ConclusionRelatively low congruence between resilience measures suggests studies will yield divergent findings about predictors, prevalence, and consequences of resilience. Efforts to clearly define resilience are needed to better understand resilience and inform intervention and prevention efforts.

Background: Controversy persists about the role of hepatitis C as a risk factor for developing kidney disease in the general population. Some authors have evaluated the effect of antiviral therapy for HCV on the risk of kidney disease. Study Aims and Design: A systematic review of the published medical literature was performed to assess whether antiviral therapy for HCV has an independent impact on kidney survival in the adult general population. A random effects model was used to generate an overall estimate of the risk of kidney disease after anti-HCV therapy across the published studies. Meta-regression and stratified analysis were also carried out. Results: Fifteen studies were eligible (n = 356, 285 patients) and separate meta-analyses were conducted according to the outcome. Pooling studies based on viral responses (n = 7; 34,763 individual patients) demonstrated a relationship between sustained viral response and lower frequency of kidney disease; the overall estimate for adjusted risk of kidney disease was 2.50 (95% CI, 1.41; 4.41) (p = 0.0016) and between-study heterogeneity was found (p-value by Q test = 0.004). Aggregation of studies comparing treated vs untreated cohorts (n = 8, n = 333,312 patients) revealed an association between anti-HCV therapy and lower risk of kidney disease. The overall estimate for adjusted risk of kidney disease across the eight studies was 0.39 (95% CI, 0.25; 0.612) (p = 0.0001). Meta-regression showed that the effectiveness of antiviral therapy in reducing the frequency of kidney disease diminishes as cirrhosis (p = 0.02) and HBV infection (p = 0.0001) increase among HCV-infected individuals. Conclusions: Antiviral therapy for HCV lowers the risk of kidney disease among HCV-infected individuals. Studies to understand the mechanisms underlying this association are ongoing. Resumen: Antecedentes: Sigue existiendo controversia acerca del rol de la hepatitis C como factor de riesgo de desarrollo de enfermedades renales en la población general. Algunos autores han evaluado el efecto de la terapia antiviral para el VHC en el riesgo de enfermedad renal. Objetivos y diseño del estudio: Se realizó una revisión sistemática de la literatura médica publicada, para evaluar si la terapia antiviral para el VHC tenía un impacto independiente en la supervivencia renal en la población adulta general. Se utilizó un modelo de efectos aleatorios para generar una estimación general del riesgo de enfermedad renal tras la terapia anti-VHC, entre los estudios publicados. También se realizaron análisis de meta-regresión y estratificados. Resultados: Quince estudios resultaron elegibles (n = 356, 285 pacientes), realizándose meta-análisis separados con arreglo al resultado. Los estudios agrupados basados en las respuestas virales (n = 7; 34.763 pacientes individuales) demostraron una relación entre la respuesta viral sostenida y la menor frecuencia de enfermedad renal; la estimación general para el riesgo ajustado de enfermedad renal fue de 2,5 (95% IC, 1,41; 4,41) (p = 0,0016), encontrándose una heterogeneidad entre estudios (valor p con prueba Q = 0,004). La suma de estudios comparativos de cohortes tratadas vs no tratadas (n = 8, n = 333.312 pacientes) reveló una asociación entre la terapia anti-VHC y el menor riesgo de enfermedad renal. La estimación general para el riesgo ajustado de enfermedad renal entre ocho estudios fue de 0,39 (95% IC, 0,25; 0,612) (p = 0,0001). La meta-regresión reflejó que la efectividad de la terapia antiviral para reducir la frecuencia de enfermedad renal disminuye a medida que aumentan los casos de cirrosis (p = 0,02) e infección por VHB (p = 0,0001) entre los individuos infectados de VHC. Conclusiones: La terapia antiviral para el VHC disminuye el riesgo de enfermedad renal entre los individuos infectados de VHC. Son continuos los estudios para comprender los mecanismos subyacentes a esta asociación.

Background Goal directed therapy (GDT) is able to improve mortality and reduce complications in selected high-risk patients undergoing major surgery. The aim of this study is to compare two different strategies of perioperative hemodynamic optimization: one based on optimization of preload using dynamic parameters of fluid-responsiveness and the other one based on estimated oxygen extraction rate (O2ER) as target of hemodynamic manipulation. Methods This is a multicenter randomized controlled trial. Adult patients undergoing elective major open abdominal surgery will be allocated to receive a protocol based on dynamic parameters of fluid-responsiveness or a protocol based on estimated O2ER. The hemodynamic optimization will be continued for 6 h postoperatively. The primary outcome is difference in overall postoperative complications rate between the two protocol groups. Fluids administered, fluid balance, utilization of vasoactive drugs, hospital length of stay and mortality at 28 day will also be assessed. Discussion As a predefined target of cardiac output (CO) or oxygen delivery (DO2) seems to be not adequate for every patient, a personalized therapy is likely more appropriate. Following this concept, dynamic parameters of fluid-responsiveness allow to titrate fluid administration aiming CO increase but avoiding fluid overload. This approach has the advantage of personalized fluid therapy, but it does not consider if CO is adequate or not. A protocol based on O2ER considers this second important aspect. Although positive effects of perioperative GDT have been clearly demonstrated, currently studies comparing different strategies of hemodynamic optimization are lacking. Trial registration ClinicalTrials.gov, NCT04053595. Registered on 12/08/2019.

Background After several decades, cisplatin continues to be an essential drug for the treatment of several tumors, however, its potential nephrotoxicity is still a clinically relevant issue. Identification of predisposing factors for renal toxicity could be of value to warrant prophylactic measures. Methods We analyzed data from 198 patients with various tumor types, treated with cisplatin containing regimens in our regional cancer center in a two-years period. Assessed variables included age, gender, smoking status, alcohol consumption, tumor type, prior or concomitant anticancer treatment, cisplatin dose, time-interval between cycles, number of cycles, concomitant nephrotoxic drugs or radiotherapy and co-morbidities. We divided cisplatin nephrotoxicity in two categories: transient and permanent. Univariable and multivariable analyses were performed in order to define statistical associations. Results Cisplatin discontinuation rate was 27,7%, of which, 8.1% was due to renal toxicity. A total of 74 and 21 patients developed transient and permanent nephrotoxicity, respectively. At univariable analysis cirrhosis (p = 0.027), hypertension (p = 0.020), alcohol intake (p = 0.030) and number of cycles < 4 (p = 0.002) were significantly associated with transient renal toxicity, while at the multivariable analysis, a statistical significance was detected for cirrhosis (p = 0.009), hypertension (p = 0.009) and a total number of cycles < 4 (p = 0.003). Regarding permanent renal toxicity, a concomitant administration of NSAIDs was significant at univariable analysis (p = 0.002). Conclusions Relevant risk factors for the development of transient nephrotoxicity were defined. Patients presenting these baseline characteristics may require more frequent post-cycle check-up visits and hydration treatment should be guaranteed as soon as a reduction of creatinine clearance is detected.

BACKGROUND: Patient blood management (PBM) promotes the routine detection and treatment of anaemia before surgery, optimising the management of bleeding disorders, thus minimising iatrogenic blood loss and pre-empting allogeneic blood utilisation. PBM programmes have expanded from the elective surgical setting to nonsurgical patients, including those in intensive care units (ICUs), but their dissemination in a whole country is unknown. METHODS: We performed a cross-sectional, anonymous survey (10 October 2018 to 13 March 2019) of all ordinary medical members of the Swiss Society of Intensive Care Medicine and the registered ICU nurses from the 77 certified adult Swiss ICUs. We analysed PBM-related interventions adopted in Swiss ICUs and related them to the spread of PBM in Swiss hospitals. We explored blood test ordering policies, blood-sparing strategies and red blood cell-related transfusion practices in ICUs. RESULTS: A total of 115 medical doctors and 624 nurses (response rates 27% and 30%, respectively) completed the surveys. Hospitals had implemented a PBM programme according to 42% of physicians, more commonly in Switzerland’s German-speaking regions (Odds Ratio [OR] 3.39, 95% confidence interval [CI] 1.23–9.35; p = 0.018) and in hospitals with more than 500 beds (OR 3.91, 95% CI 1.48–10.4; p = 0.006). The PBM programmes targeted the detection and correction of anaemia before surgery (79%), minimising perioperative blood loss (94%) and optimising anaemia tolerance (98%). Laboratory tests were ordered in 70.4% by the intensivist during morning rounds; the nurses performed arterial blood gas analyses autonomously in 48.4%. Blood-sparing techniques were used by only 42.1% of nurses (263 of 624, missing: 6) and 47.0% of physicians (54 of 115). Approximately 60% of respondents used an ICU-specific transfusion guideline. The reported haemoglobin threshold for the nonbleeding ICU population was 70 g/l and, therefore, was at the lower limit of current guidelines. CONCLUSIONS: Based on this survey, the estimated proportion of the intensivists working in hospitals with a PBM initiative is 42%, with significant variability between regions and hospitals of various sizes. The risk of iatrogenic anaemia is relevant due to liberal blood sample collection practices and the underuse of blood-sparing techniques. The reported transfusion threshold suggests excellent adherence to current international ICU-specific transfusion guidelines.

The molecular mechanisms that underlie oncogene-induced genomic damage are still poorly understood. To understand how oncogenes affect chromatin architecture, it is important to visualize fundamental processes such as DNA replication and transcription in intact nuclei and quantify the alterations of their spatiotemporal organization induced by oncogenes. Here, we apply superresolution microscopy in combination with image cross correlation spectroscopy to the U937-PR9 cell line, an in vitro model of acute promyelocytic leukemia that allows us to activate the expression of the PML-RARα oncogene and analyze its effects on the spatiotemporal organization of functional nuclear processes. More specifically, we perform Tau-stimulated emission depletion imaging, a superresolution technique based on the concept of separation of photons by lifetime tuning. Tau-stimulated emission depletion imaging is combined with a robust image analysis protocol that quickly produces a value of colocalization fraction on several hundreds of single cells and allows observation of cell-to-cell variability. Upon activation of the oncogene, we detect a significant increase in the fraction of transcription sites colocalized with PML/PML-RARα. This increase of colocalization can be ascribed to oncogene-induced disruption of physiological PML bodies and the abnormal occurrence of a relatively large number of PML-RARα microspeckles. We also detect a significant cell-to-cell variability of this increase of colocalization, which can be ascribed, at least in part, to a heterogeneous response of the cells to the activation of the oncogene. These results prove that our method efficiently reveals oncogene-induced alterations in the spatial organization of nuclear processes and suggest that the abnormal localization of PML-RARα could interfere with the transcription machinery, potentially leading to DNA damage and genomic instability.

Background: Cancer incidence in the world is predicted to increase in the next decade. While progress has been in diagnosis and treatment, much still remains to be done to improve cancer pain therapy, mainly in underserved communities in low-income countries. Objective: To determine knowledge, beliefs, and barriers regarding pain management in both high- and low-income countries (according to the WHO classification); and to learn about ways to improve the current state of affairs. Design: Descriptive survey. Setting/Subjects: Fifty-six countries worldwide; convenience sample of 1639 consisted of 36.8% physicians; 45.1% nurses, and 4.5% pharmacists employed in varied settings. Results: Improved pain management services are key elements. Top barriers include religion factors, lack of appropriate education and training at all levels, nonadherence to guidelines, patients' reluctance to report on pains, over regulation associated with prescribing and access to opioid analgesics, fear of addiction to opioids, and lack of discussions around prognosis and treatment planning. Conclusion: The majority of patients with cancer in low-income countries are undertreated for their pain. Promoting cancer pain accredited program of training and education on pain management for physicians and nurses is crucial, as well as advocating policymakers and the public at large. Keywords: cancer; global; management; opioids; pain.

The devastation caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has made clear the importance of pandemic preparedness. To address future zoonotic outbreaks due to related viruses in the sarbecovirus subgenus, we identified a human monoclonal antibody, 10-40, that neutralized or bound all sarbecoviruses tested in vitro and protected against SARS-CoV-2 and SARS-CoV in vivo. Comparative studies with other receptor-binding domain (RBD)–directed antibodies showed 10-40 to have the greatest breadth against sarbecoviruses, suggesting that 10-40 is a promising agent for pandemic preparedness. Moreover, structural analyses on 10-40 and similar antibodies not only defined an epitope cluster in the inner face of the RBD that is well conserved among sarbecoviruses but also uncovered a distinct antibody class with a common CDRH3 motif. Our analyses also suggested that elicitation of this class of antibodies may not be overly difficult, an observation that bodes well for the development of a pan-sarbecovirus vaccine.

This clinical study evaluated the survival of monolithic lithium disilicate (ML) (IPS Emax, Ivoclar Vivadent) restorations bonded to complete-arch CAD/CAM made titanium or zirconia frameworks. Between August 2007 and December 2009, 15 patients (7 female, 8 male; mean age: 56.8 years old) received 30 implant-supported screw-retained rehabilitations with ML restorations cemented to CAD/CAM made titanium (T) (n=6) or zirconia (Z) frameworks (n=24) adhesively (Multilink Automix, RelyX Unicem) and followed up until December 2015. The evaluation protocol involved technical failures (chipping, debonding or fracture of crown/framework, screw loosening), Californian Dental Association (CDA) quality criteria (Romeo: Excellent; Sierra: Acceptable; Tango: Retrievable; Victor: Not acceptable) and biological failures (mucositis, peri-implantitis). Mean observation time was 60.3 months. No implants were lost, and all the prostheses were in situ. Four mechanical failures occurred in the form of minor chipping (n=3 in ML-Z, n=1 in ML-T) and major fracture in ML crown (n=1 in ML-Z). Romeo scores (N=370) decreased until final observation (N=347) and 23 Sierra scores were given to the restorations. Mucositis was observed in 3 patients and peri-implantitis in one patient. Complete-arch implant-borne FDPs made of monolithic lithium disilicate bonded to titanium or zirconia frameworks could be a promising alternative.

Estrogen related receptors are orphan members of the nuclear receptor superfamily acting as transcription factors (TFs). In contrast to classical nuclear receptors, the activities of the ERRs are not controlled by a natural ligand. Regulation of their activities thus relies on availability of transcriptional co-regulators. In this paper, we focus on ERRα, whose involvement in cancer progression has been broadly demonstrated. We propose a new approach to identify potential co-activators, starting from previously identified ERRα-activated genes in a breast cancer (BC) cell line. Considering mRNA gene expression from two sets of human BC cells as major endpoint, we used sparse partial least squares modeling to uncover new transcriptional regulators associated with ERRα. Among them, DDX21, MYBBP1A, NFKB1, and SETD7 are functionally relevant in MDA-MB-231 cells, specifically activating the expression of subsets of ERRα-activated genes. We studied SET7 in more details and showed its co-localization with ERRα and its ERRα-dependent transcriptional and phenotypic effects. Our results thus demonstrate the ability of a modeling approach to identify new transcriptional partners from gene expression. Finally, experimental results show that ERRα cooperates with distinct co-regulators to control the expression of distinct sets of target genes, thus reinforcing the combinatorial specificity of transcription.

To analyze SARS-CoV-2 seroprevalence and association of sociodemographic and clinical aspects in the state of Espírito Santo, Brazil.This was a serial cross-sectional study carried out in four phases, using households as the unit of analysis, from May to June 2020. Eleven municipalities were surveyed, with a sample of 4,500 households in each phase.Prevalence ranged from 2.1% (95%CI 1.7;2.5) on May 10 (first phase) to 9.6% (95%CI 8.8;10.4) on June 21 (fourth phase). In the Greater Vitória Metropolitan Region, the prevalence were 2.7% (95%CI 2.2;3.3) in the first phase, and 11.5% (95%CI 10.5;12.6) in the fourth phase; in the interior region of the state, prevalence ranged from 0.4% (95%CI 0.1;0.9) to 4.4% (95%CI 3.2;5.5) between the two phases.The increase in SARS-CoV-2 seroprevalence found in the fourth phase highlighted the high transmission of the virus, information that can support management of the pandemic.Analisar a soroprevalência de SARS-CoV-2 e sua associação com aspectos sociodemográficos e clínicos, no estado do Espírito Santo, Brasil.Estudo transversal seriado, realizado em quatro fases, no período de maio a junho de 2020, utilizando os domicílios como unidade de análise. Foram pesquisados 11 municípios, com amostra de 4.500 domicílios em cada fase.A soroprevalência de SARS-CoV-2 variou de 2,1% (IC95% 1,7;2,5), em 10 de maio (primeira etapa), a 9,6% (IC95% 8,8;10,4) em 21 de junho (quarta etapa). Na Região Metropolitana da Grande Vitória, as prevalências foram de 2,7% (IC95% 2,2;3,3), na primeira, e de 11,5% (IC95% 10,5;12,6) na quarta etapa; no interior do estado, a prevalência variou de 0,4% (IC95% 0,1;0,9) a 4,4% (IC95% 3,2;5,5) entre a primeira e a quarta etapas.O aumento da soroprevalência de SARS-CoV-2 observado na quarta fase destacou a elevada transmissão do vírus, informação que pode subsidiar a gestão da pandemia.Analizar la seroprevalencia del SARS-CoV-2 y la asociación de aspectos sociodemográficos y clínicos en el estado de Espírito Santo, Brasil.Estudio transversal seriado realizado en cuatro fases, utilizando los hogares como unidad de análisis, de mayo a junio de 2020. Se encuestaron 11 municipios, con una muestra de 4.500 hogares en cada fase.La prevalencia varió de 2,1% (IC95% 1,7;2,5) el 10 de mayo (primera etapa) a 9,6% (IC95% 8,8;10,4), el 21 de junio (cuarta etapa). En la Región Metropolitana de la Gran Vitória, las prevalencias fueron de 2,7% (IC95% 2,2;3,3), en la primera, y de 11,5% (IC95% 10,5;12,6) en la cuarta etapa; en el estado osciló entre 0,4% (IC95% 0,1;0,9) y 4,4% (IC95% 3,2;5,5).El aumento de la seroprevalencia del SARS-CoV-2 observado en la cuarta fase destacó la alta transmisión del virus, información que puede subsidiar el manejo de la pandemia.

Gastrointestinal tract diseases are characterized by an imbalance in physiological functions, which may involve inflammatory and metabolic pathways and trigger chronic, multifactorial, and idiopathic inflammatory disorders. The association of probiotics with prebiotics has the potential to remedy these afflictive conditions, because they attenuate or even block the adhesion of pathogenic microorganisms in the enteric environment. This article highlights the importance of using probiotics associated with fibers from Psyllium as prebiotics to maintain a healthy intestinal microbiota. We also present the technologies and encapsulating materials involved in coating to increase the survival rate of these strains when exposed to the gastrointestinal tract. The importance of products containing probiotics and fibers from Psyllium as prebiotics becomes increasingly evident when there is a health bias. Emerging health challenges and advances in research will drive selective approaches in biotechnology to discover and evaluate new probiotics and prebiotics that can potentially contribute to human health.

The recently reported B.1.1.529 omicron variant of SARS-CoV-2 includes 34 mutations in the spike protein relative to the Wuhan strain, including 15 mutations in the receptor binding domain (RBD). Functional studies have shown omicron to substantially escape the activity of many SARS-CoV-2-neutralizing antibodies. Here we report a 3.1 Å resolution cryo-electron microscopy (cryo-EM) structure of the omicron spike protein ectodomain. The structure depicts a spike that is exclusively in the 1-RBD-up conformation with high mobility of RBD. Many mutations cause steric clashes and/or altered interactions at antibody binding surfaces, whereas others mediate changes of the spike structure in local regions to interfere with antibody recognition. Overall, the structure of the omicron spike reveals how mutations alter its conformation and explains its extraordinary ability to evade neutralizing antibodies., Graphical Abstract, Cerutti et al. report the cryo-EM structure of the SARS-CoV-2 Omicron spike in its ligand-free form. The structure elucidates the effect of the mutations on the global and local conformation of spike and explains the antibody resistance to the Omicron variant.

Aim: This study investigated the influence of antidepressant drugs on methylation status of KCNE1, KCNH2 and SCN5A promoters and ECG parameters in adult psychiatric patients. Materials & methods: Electrocardiographic evaluation (24 h) and blood samples were obtained from 34 psychiatric patients before and after 30 days of antidepressant therapy. Methylation of promoter CpG sites of KCNE1, KCNH2 and SCN5A was analyzed by pyrosequencing. Results: Three CpG and four CpG sites of KCNE1 and SCN5A, respectively, had increased % methylation after treatment. Principal component analysis showed correlations of the methylation status with electrocardiographic variables, antidepressant doses and patient age. Conclusion: Short-term treatment with antidepressant drugs increase DNA methylation in KCNE1 and SCN5A promoters, which may induce ECG alterations in psychiatric patients.

This first pilot trial on external quality assessment (EQA) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) whole-genome sequencing, initiated by the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) Study Group for Genomic and Molecular Diagnostics (ESGMD) and the Swiss Society for Microbiology (SSM), aims to build a framework between laboratories in order to improve pathogen surveillance sequencing. Ten samples with various viral loads were sent out to 15 clinical laboratories that had free choice of sequencing methods and bioinformatic analyses. The key aspects on which the individual centers were compared were the identification of (i) single nucleotide polymorphisms (SNPs) and indels, (ii) Pango lineages, and (iii) clusters between samples. The participating laboratories used a wide array of methods and analysis pipelines. Most were able to generate whole genomes for all samples. Genomes were sequenced to various depths (up to a 100-fold difference across centers). There was a very good consensus regarding the majority of reporting criteria, but there were a few discrepancies in lineage and cluster assignments. Additionally, there were inconsistencies in variant calling. The main reasons for discrepancies were missing data, bioinformatic choices, and interpretation of data. The pilot EQA was overall a success. It was able to show the high quality of participating laboratories and provide valuable feedback in cases where problems occurred, thereby improving the sequencing setup of laboratories. A larger follow-up EQA should, however, improve on defining the variables and format of the report. Additionally, contamination and/or minority variants should be a further aspect of assessment.

The present study investigated the concurrent relations between language ability, executive difficulties, and behavior problems in a sample of 142 preschoolers ranging in age between 3 and 6 years of age. Language skills were assessed with a direct task, whereas ratings of executive difficulties and behavior problems were obtained from teachers. Regression analyses indicated that difficulties in flexibility and inhibitory self-control were positively associated with internalizing problems, and difficulties in inhibitory self-control were positively associated with externalizing problems. The associations between emergent metacognition and internalizing problems and between inhibitory self-control and externalizing problems were both moderated by sex, being stronger in boys than in girls. Lastly, language had indirect effects on internalizing problems by decreasing children's difficulties in flexibility, as well as on externalizing problems by decreasing children' difficulties in inhibitory self-control. Overall, these findings support the idea that low language skills may interfere with preschoolers' ability to exploit the executive functions of inner language to self-regulate their own behaviors, especially in boys.