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Lower limb amputations represent a high social, economic and health burden. Most of them are preventable and reflect areas for improvement in health care, making it essential to know their epidemiology.This is a retrospective population-based cross-sectional analysis on all lower limb amputations performed in public hospitals in Sao Paulo between 2009 and 2020, the most populous Brazilian state, with 46 million inhabitants. Using a public database, we evaluated types, rates and trends of the amputations performed, main etiologies leading to the indication for amputation, hospital length of stay and in-hospital mortality rates, demographics of the amputees and procedure costs.In total, 180,595 lower limb amputations and surgical revision of amputations were performed, with toe amputations (45%) and major amputations (33%) being the most frequent types of surgeries, with a recent significant increase in the rates for both these procedures. Peripheral artery disease was the most frequent etiology, followed by diabetes mellitus, with both showing an upward trend over the years. Most patients were male (69.3%), Caucasians (55.6%) and elderly. August was the month with the highest number of amputations in all years. Overall in-hospital mortality after lower limb amputations was 6.6%. Total reimbursed by the government was US$ 67,675,875.55.Peripheral artery disease is the most frequent underlying diagnosis for lower limb amputations, followed by diabetes mellitus, with both showing an upward trend over the years. We observed seasonality in procedure rates, with peaks in August in all years.

Purpose PERSEUS-IT (NCT02289924) was a prospective, observational, 2-year study evaluating the effectiveness and treatment patterns of intravitreal aflibercept (IVT-AFL) in patients with neovascular age-related macular degeneration (nAMD) in routine clinical practice in Italy. Methods Treatment-naïve patients with nAMD receiving IVT-AFL per routine clinical practice were enrolled. The primary endpoint was mean change in visual acuity (VA; decimals) from baseline to month (M) 12 and M24. Outcomes were evaluated for the overall study population and independently for the 2 treatment cohorts: regular (3 initial monthly doses, ≥ 7 injections by M12, and ≥ 4 injections between M12 and M24) and irregular (any other pattern). Results Of 813 patients enrolled, 709 were included in the full analysis set (FAS); VA assessments were available for 342 patients at M12 (FAS1Y, 140 regular and 202 irregular) and 233 patients at M24 (FAS2Y, 37 regular and 196 irregular). In the overall FAS, the mean ± SD change in VA from baseline to M12 and M24 was + 0.09 ± 0.24 and + 0.02 ± 0.25 decimals, and there was a statistically significant difference between the regular and irregular cohorts in both FAS1Y (p = 0.0034) and FAS2Y (p = 0.0222). Ocular treatment-emergent adverse events were reported in 4.1% (n = 33/810 [safety set]) of patients. Conclusion In PERSEUS-IT, clinically relevant functional and anatomic improvements were observed within the first 12 months of IVT-AFL treatment in routine clinical practice in Italy in patients with treatment-naïve nAMD. These gains were generally maintained across the 2-year study. The safety profile of IVT-AFL was consistent with prior studies. Trial registration number ClinicalTrials.gov Identifier: NCT02289924. Date of registration November 13, 2014.

Background: Population aging has increased together with the need for cardiovascular care. Understanding the relevance of cardiovascular conditions in the very old is crucial to developing a specific and rationale therapeutic approach. Centenarians can be considered a model of successful aging, although the impact of cardiovascular disease in this population is still unclear. Aim: To evaluate the cardiovascular health status of a subset of centenarians enrolled in the Centenari a Trieste study and living in the province of Trieste to describe the prevalence of cardiovascular conditions among them. Methods: The current study included 20 individuals born before 1919 and living in the province of Trieste as of 1 May 2019. All centenarians were able to give consent and were subjected to an in-home complete clinical assessment focused on cardiovascular conditions, ECG and echocardiography. Results: The majority of centenarians were women (85%) and were not taking any chronic cardiovascular medication (55%). No centenarians had a history of ischemic heart disease while about one-third had signs suggestive of heart failure at examination (20%). Atrial fibrillation was present in 20% of individuals and conduction disorders were uncommon. Although the majority of individuals had a preserved left ventricular function, diastolic function was abnormal in 80% of enrolled centenarians that, however, was mild in 73% of cases. Conclusion: This is the second study to perform in-home echocardiography in centenarians and the first to characterize the cardiovascular status of centenarians living in Trieste. The majority of centenarians had asymptomatic diastolic dysfunction and were naïve from cardiovascular therapy. The recruitment of new individuals from the Trieste area is continuing to perform analyses on clinical, genetic and environmental factors that may predict greater longevity in this geographical context and unveil mechanisms that regulate cardiac aging associated with increased lifespan.

Biologics are revolutionizing the treatment of chronic diseases, such as cancer and monogenic disorders, by overcoming the limits of classic therapeutic approaches using small molecules. However, the clinical use of biologics is limited for cardiovascular diseases (CVDs) , which are the primary cause of morbidity and mortality worldwide. Here, we review the state-of-the-art use of biologics for cardiac disorders and provide a framework for understanding why they still struggle to enter the field. Some limitations are common and intrinsic to all biological drugs, whereas others depend on the complexity of cardiac disease. In our opinion, delineating these struggles will be valuable in developing and accelerating the approval of a new generation of biologics for CVDs.

Purpose The study of air pressure in the vocal tract is essential to understanding vocal function. Changes in vocal tract shape during different phonatory gestures are hypothesized to produce nonuniform air pressure across lower vocal tract locations. Current methods of air pressure measurement, however, are limited to a single location in the anterior oral cavity. The purposes of this study were (a) to assess the feasibility of a novel method of simultaneously measuring phonatory air pressure at multiple locations across the lower vocal tract using high-resolution pharyngeal manometry (HRM) and (b) to compare pressure across locations and among phonatory tasks. Method Two subjects underwent HRM while performing phonatory tasks. A catheter was passed transnasally and air pressure was measured simultaneously at five locations between the velopharyngeal port and the upper esophageal sphincter. Descriptive statistics were calculated for each location by task, and for each task averaged across locations. Results HRM was well tolerated, and air pressures from multiple locations in the lower vocal tract were able to be obtained simultaneously. During vocal tract semi-occlusion tasks, air pressures differed by location. Pressures averaged across locations demonstrated a pattern of increasing pressure with increasing semi-occlusion. Conclusions HRM is feasible for measuring air pressure simultaneously at multiple locations in the lower vocal tract during phonation with high spatial and temporal resolution, providing rich data to augment understanding of vocal function. The high spatial and temporal resolution yielded by this new method, paired with preliminary evidence that pressures change by location as a function of phonatory task, may be useful in future assays exploring differences in lower vocal tract air pressures between normal and disordered populations.

Antegrade access for infrainguinal endovascular intervention can be achieved through the common femoral artery (CFA) or superficial femoral artery (SFA). A few studies with small sample sizes have shown similar efficacy and safety for antegrade puncture of the CFA and SFA. In the present study, we analyzed the feasibility of SFA access and the occurrence of complications between SFA and CFA ipsilateral access in a broader cohort.In the present retrospective study, we analyzed data from 462 patients with peripheral arterial disease (PAD) who had undergone peripheral angioplasty from 2009 to 2016. The inclusion criteria were PAD at Rutherford stage 3 to 6 and use of an endovascular approach. Patients with coagulation disorders, those receiving anticoagulant therapy, cases with deployment of closure devices, cases with more than one access on the same limb, and patients with inadequate bed rest after the procedure were excluded. A systematic analysis of all patients' electronic medical records was performed to evaluate the demographic aspects and technical success and identify the possible complications associated with CFA and SFA access.Of the 462 patients, 290 had undergone SFA puncture and 172, CFA puncture. The demographic evaluation of both groups revealed no differences between the two groups, except that more patients with diabetes were in the CFA group and more patients with dyslipidemia and an advanced clinical presentation were in the SFA group. First puncture access was successful in 99.7% of the SFA group and 96.5% of the CFA group (P = .01). The hematoma rate in the SFA and CFA groups was 20.3% and 11%, respectively (P = .01). The incidence of major bleeding and clinically relevant nonmajor bleeding was not significantly different between the two groups (P = .215). Only three patients had developed a pseudoaneurysm, two of whom were in the SFA group. Female sex (odds ratio [OR], 2.572; 95% confidence interval [CI], 1.520-4.354; P .001] and older age (OR, 1.034; 95% CI, 1.009-1.059; P = .007) were associated with an increased hematoma rate.SFA access was associated with a higher overall rate of hematoma compared with CFA access. However, no significant difference was found in the incidence of major bleeding between the two access sites. Planned SFA access should be considered as an alternative to CFA access.

Despite fluorescent cell-labelling being widely employed in biomedical studies, some of its drawbacks are inevitable, with unsuitable fluorescent probes or probes inducing a functional change being the main limitations. Consequently, the demand for and development of label-free methodologies to classify cells is strong and its impact on precision medicine is relevant. Towards this end, high-throughput techniques for cell mechanical phenotyping have been proposed to get a multidimensional biophysical characterization of single cells. With this motivation, our goal here is to investigate the extent to which an unsupervised machine learning methodology, which is applied exclusively on morpho-rheological markers obtained by real-time deformability and fluorescence cytometry (RT-FDC), can address the difficult task of providing label-free discrimination of reticulocytes from mature red blood cells. We focused on this problem, since the characterization of reticulocytes (their percentage and cellular features) in the blood is vital in multiple human disease conditions, especially bone-marrow disorders such as anemia and leukemia. Our approach reports promising label-free results in the classification of reticulocytes from mature red blood cells, and it represents a step forward in the development of high-throughput morpho-rheological-based methodologies for the computational categorization of single cells. Besides, our methodology can be an alternative but also a complementary method to integrate with existing cell-labelling techniques., 13 pages, 3 figures, 4 tables

Background The low cost and rapidity of microsatellite analysis have led to the development of several markers for many species. Because in non-invasive genetics it is recommended to genotype individuals using few loci, generally a subset of markers is selected. The choice of different marker panels by different research groups studying the same population can cause problems and bias in data analysis. A priority issue in conservation genetics is the comparability of data produced by different labs with different methods. Here, we compared data from previous and ongoing studies to identify a panel of microsatellite loci efficient for the long-term monitoring of Apennine brown bears (Ursus arctos marsicanus), aiming at reducing genotyping uncertainty and allowing reliable individual identifications overtimes. Results We examined all microsatellite markers used up to now and identified 19 candidate loci. We evaluated the efficacy of 13 of the most commonly used loci analyzing 194 DNA samples belonging to 113 distinct bears selected from the Italian national biobank. We compared data from 4 different marker subsets on the basis of genotyping errors, allelic patterns, observed and expected heterozygosity, discriminatory powers, number of mismatching pairs, and probability of identity. The optimal marker set was selected evaluating the low molecular weight, the high discriminatory power, and the low occurrence of genotyping errors of each primer. We calibrated allele calls and verified matches among genotypes obtained in previous studies using the complete set of 13 STRs (Short Tandem Repeats), analyzing six invasive DNA samples from distinct individuals. Differences in allele-sizing between labs were consistent, showing a substantial overlap of the individual genotyping. Conclusions The proposed marker set comprises 11 Ursus specific markers with the addition of cxx20, the canid-locus less prone to genotyping errors, in order to prevent underestimation (maximizing the discriminatory power) and overestimation (minimizing the genotyping errors) of the number of Apennine brown bears. The selected markers allow saving time and costs with the amplification in multiplex of all loci thanks to the same annealing temperature. Our work optimizes the available resources by identifying a shared panel and a uniform methodology capable of improving comparisons between past and future studies.

Objective Serous endometrial cancer (USC) is a challenging malignancy associated with metastasis, recurrence and poor outcome. To identify clinically relevant prognostic biomarkers, we focused on a panel of proteins selected after a comprehensive literature review, for tumour profiling of a homogeneous cohort of USC patients. Methods Protein levels and localization were assessed by immunohistochemistry analysis in 36 hysterectomy samples. Tissue sections were stained with the following antibodies: Aurora A, phospho (T288) Aurora A, BRCA1, CHK1, CIP2A, Cyclin B1, Cyclin E, E2F-1, phospho (S364) E2F-1, FBXW7, FOXM1, phospho (S9) GSK3Beta, PLK1, phospho (T210) PLK1, PPP2R1B, p73, RAD51. Each marker was evaluated as a continuously-scaled variable for association with disease progression and death, using Cox proportional hazards models. The sample consisted of 36 patients with USC, half with stage III or IV disease. Results Results showed that higher CHK1 (Checkpoint kinase 1) expression was associated with a decreased risk of progression and death, after adjusting for stage. Interestingly, analysis of a TCGA data set of 109 USC patients corroborates our results showing a favourable prognostic role of CHEK1 after adjusting for stage. Higher FBXW7 (F-box and WD repeat domain containing 7) expression and higher cytoplasmic expression of PPP2R1B (Protein Phosphatase 2 A, Scaffold Subunit Abeta) were each associated with a decreased risk of progression, after adjusting for stage. Conclusions In conclusion, results from the present study identify new clinically relevant biomarkers and potential drug targets for uterine serous endometrial cancer.

Whereas numerous studies on large carnivores have focused on analyzing spatial patterns and habitat use, the temporal dimension of their activity has been relatively little investigated, making this a topic of growing interest, especially in human-dominated landscapes. Relict and isolated Apennine brown bears (Ursus arctos marsicanus) have been living in a human-modified landscape since millennia, but no information is available on their activity patterns. By means of GPS telemetry (26,880 GPS locations collected from 18 adult Apennine brown bears) we investigated their circadian rhythms, using hourly movement rates as an index of bear activity. Based on a Bayesian modeling approach, circadian activity of Apennine brown bears was described by a bimodal curve, with peaks of activity around sunrise and sunset. We revealed seasonal effects, with bears exhibiting higher movement rates throughout the mating season, but no relevant influence of sex. In addition, bears increased their movement rate at distances

Despite many improvements in ovarian cancer diagnosis and treatment, until now, conventional chemotherapy and new biological drugs have not been shown to cure the disease, and the overall prognosis remains poor. Over 90% of ovarian malignancies are categorized as epithelial ovarian cancers (EOC), a collection of different types of neoplasms with distinctive disease biology, response to chemotherapy, and outcome. Advances in our understanding of the histopathology and molecular features of EOC subtypes, as well as the cellular origins of these cancers, have given a boost to the development of clinically relevant experimental models. The overall goal of this review is to provide a comprehensive description of the available preclinical investigational approaches aimed at better characterizing disease development and progression and at identifying new therapeutic strategies. Systems discussed comprise monolayer (2D) and three-dimensional (3D) cultures of established and primary cancer cell lines, organoids and patient-derived explants, animal models, including carcinogen-induced, syngeneic, genetically engineered mouse, xenografts, patient-derived xenografts (PDX), humanized PDX, and the zebrafish and the laying hen models. Recent advances in tumour-on-a-chip platforms are also detailed. The critical analysis of strengths and weaknesses of each experimental model will aid in identifying opportunities to optimize their translational value.

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Background High-grade serous ovarian cancer (HGSOC) has poor survival rates due to a combination of diagnosis at advanced stage and disease recurrence as a result of chemotherapy resistance. In BRCA1 (Breast Cancer gene 1) - or BRCA2-wild type (BRCAwt) HGSOC patients, resistance and progressive disease occur earlier and more often than in mutated BRCA. Identification of biomarkers helpful in predicting response to first-line chemotherapy is a challenge to improve BRCAwt HGSOC management. Methods To identify a gene signature that can predict response to first-line chemotherapy, pre-treatment tumor biopsies from a restricted cohort of BRCAwt HGSOC patients were profiled by RNA sequencing (RNA-Seq) technology. Patients were sub-grouped according to platinum-free interval (PFI), into sensitive (PFI > 12 months) and resistant (PFI Results RNA-seq identified a 42-gene panel discriminating sensitive and resistant BRCAwt HGSOC patients and pathway analysis pointed to the immune system as a possible driver of chemotherapy response. From the extended cohort analysis of the 42 DEGs (differentially expressed genes), a statistical approach combined with the random forest classifier model generated a ten-gene signature predictive of response to first-line chemotherapy. The ten-gene signature included: CKB (Creatine kinase B), CTNNBL1 (Catenin, beta like 1), GNG11 (G protein subunit gamma 11), IGFBP7 (Insulin-like growth factor-binding protein 7), PLCG2 (Phospholipase C, gamma 2), RNF24 (Ring finger protein 24), SLC15A3 (Solute carrier family 15 member 3), TSPAN31 (Tetraspanin 31), TTI1 (TELO2 interacting protein 1) and UQCC1 (Ubiquinol-cytochrome c reductase complex assembly factor). Cytotoxicity assays, combined with gene-expression analysis in primary HGSOC cell lines, allowed to define CTNNBL1, RNF24, and TTI1 as cell-autonomous contributors to tumor resistance. Conclusions Using machine-learning techniques we have identified a gene signature that could predict response to first-line chemotherapy in BRCAwt HGSOC patients, providing a useful tool towards personalized treatment modalities.

International audience; Facilitating coexistence between people and large carnivores is critical for large carnivore conservation in human-dominated landscapes, when their presence impacts negatively on human interests. Such situations will often require novel ways of mediating between different values, worldviews and opinions about how carnivores should be managed. We report on such a process in an agricultural area of recent wolf recovery in central Italy where unsolved social tensions over wolf presence have radicalized opinions on either side of the wolf debate, resulting in a stalemate. Where previous mitigation policies based on top-down damage compensation have failed, we tested the potential for applying a participatory approach to engage different stakeholder groups in a dialogue aimed at sharing a deep understanding of the problem and co-creating potential solutions. We based our approach on the theory of meta-consensus, using a decision support tool known as Multi Criteria Decision Analysis (MCDA). Over the course of three months, we carried out five workshops with stakeholder representatives from farming, hunting and environmental associations, and one biologist. Stakeholders shared several objectives and agreed over many management interventions, including the management of free-ranging dogs, the implementation of damage prevention measures, and a damage compensation system suitable for farmers. The process facilitated agreement over actions aimed at improving relations between stakeholders and enhancing the state of knowledge on the issues at stake. Most importantly, we recorded positive social and relationship outcomes from the workshops, and observed a willingness from participants to engage in further discussions over disputed management preferences. Overall, we found MCDA to be a useful tool for laying the groundwork for further participatory and deliberative processes on wolf management. However, challenges ahead included the involvement of a larger number of representatives of different social sectors, and a simplification of the methodology which some participants found too complicated and time consuming.

Background Despite the vagueness and uncertainty that is intrinsic in any medical act, interpretation and decision (including acts of data reporting and representation of relevant medical conditions), still little research has focused on how to explicitly take this uncertainty into account. In this paper, we focus on the representation of a general and wide-spread medical terminology, which is grounded on a traditional and well-established convention, to represent severity of health conditions (for instance, pain, visible signs), ranging from Absent to Extreme. Specifically, we will study how both potential patients and doctors perceive the different levels of the terminology in both quantitative and qualitative terms, and if the embedded user knowledge could improve the representation of ordinal values in the construction of machine learning models. Methods To this aim, we conducted a questionnaire-based research study involving a relatively large sample of 1,152 potential patients and 31 clinicians to represent numerically the perceived meaning of standard and widely-applied labels to describe health conditions. Using these collected values, we then present and discuss different possible fuzzy-set based representations that address the vagueness of medical interpretation by taking into account the perceptions of domain experts. We also apply the findings of this user study to evaluate the impact of different encodings on the predictive performance of common machine learning models in regard to a real-world medical prognostic task. Results We found significant differences in the perception of pain levels between the two user groups. We also show that the proposed encodings can improve the performances of specific classes of models, and discuss when this is the case. Conclusions In perspective, our hope is that the proposed techniques for ordinal scale representation and ordinal encoding may be useful to the research community, and also that our methodology will be applied to other widely used ordinal scales for improving validity of datasets and bettering the results of machine learning tasks.

Purpose: This is a retrospective, single-center, non randomized interventional real life study, investigating the correlation between variability of central retinal thickness (CRT) and functional outcomes during 2 years of anti-VEGF therapy in patients treated for neovascular age related macular degeneration (nAMD). Background: CRT fluctuations can depend on various factors such as the correct timing of injections, the therapeutic algorithm, and the number of injections (NI) performed; it is important to understand if CRT fluctuations are responsible for worse visual outcomes and consequently to identify the correct ways to avoid or reduce them. Methods: Forty-one patients were treated for nAMD with aflibercept: 0.5 mg intravitreal aflibercept was administered every 4 weeks during the first 3 months, then bimonthly over the first year, and after the first year adopting a PRN regimen. Standard deviation of CRT (CRT/SD), BCVA, and NI were recorded. Correlation studies were performed by Pearson’s test, Ancova, and Principal Component Analysis. Results: A negative correlation was found between CRT/SD and final BCVA. In patients who lost more than 15 letters, CRT/SD mean was significantly higher in comparison with patients who lost less than 15 letters. Patients with final BCVA >65 letters showed lower CRT/SD values compared to patients with final BCVA ⩽65 letters. Multivariate analysis confirmed that in patients with higher baseline BCVA, improvement of BCVA was correlated to NI, and lower values of CRT fluctuations were observed. Conclusions: CRT fluctuations, even after an appropriate NI given per year, significantly influence BCVA; a proactive treatment algorithm appears crucial when treating patients with nAMD.

SUMMARY Most current tumor immunotherapy strategies leverage cytotoxic CD8+ T cells. Despite evidence for clinical potential of CD4+ tumor-infiltrating lymphocytes (TILs), their functional diversity limits our ability to harness their activity. Here, we use single-cell mRNA sequencing to analyze the response of tumor-specific CD4+ TILs and draining lymph node (dLN) T cells. Computational approaches to characterize subpopulations identify TIL transcriptomic patterns strikingly distinct from acute and chronic anti-viral responses and dominated by diversity among T-bet-expressing T helper type 1 (Th1)-like cells. In contrast, the dLN response includes T follicular helper (Tfh) cells but lacks Th1 cells. We identify a type I interferon-driven signature in Th1-like TILs and show that it is found in human cancers, in which it is negatively associated with response to checkpoint therapy. Our study provides a proof-of-concept methodology to characterize tumor-specific CD4+ T cell effector programs. Targeting these programs should help improve immunotherapy strategies., In Brief CD4+ T cells contribute to immune responses to tumors, but their functional diversity has hampered their utilization in clinical settings. Magen et al. use single-cell RNA sequencing to dissect the heterogeneity of CD4+ T cell responses to tumor antigens and reveal molecular divergences between anti-tumor and anti-viral responses., Graphical Abstract

The present study investigated the bidirectional effects between callous-unemotional (i.e., CU) traits, student-teacher relationship quality, and bonds with school. A sample of 301 middle school students (156 girls; M age = 12.96 years, SD = 0.94) completed the Inventory of Callous-Unemotional Traits and the Student-Teacher Relationship Questionnaire, along with measures of both externalizing and internalizing problems, both in the first and second part of the school year (i.e., a time frame of 6 months). They also completed a peer-nominated measure of social preference within their peer group at the beginning of the school year. Results from a cross-lagged panel model suggested that, controlling for measures of both externalizing and internalizing problems, levels of affiliation with teachers were negatively related to levels of CU traits in students with low levels of social preference among peers. Moreover, a synergistic effect of high levels of both bonds with school and social preference emerged in predicting lower levels of CU traits. Similar results emerged with regard to externalizing problems, over and above the role of CU traits and internalizing problems. No effects of CU traits predicting student-teacher relationship quality emerged. Overall, the findings highlighted the teachers' role as emotion socializers and role models for the students who can promote students' emotional and relational prosperity over the development of maladaptive outcomes, including CU traits. They also stressed the importance of considering multiple environmental determinants in examining the pathways to CU traits, suggesting the need to integrate and expand previous research on parenting.

As the act of deglutition involves much of the central and peripheral nervous systems, neurologic disease can affect swallowing behaviors ranging from mild to profound in severity. The key in working with neurogenic dysphagia is to have a solid foundation in normal swallowing processes, including neural control. Within this framework, then, understanding how the neurologic condition affects neural control will guide hypothesis-based assessment and evidence-based treatment. The purpose of this article is to provide an overview of evaluation and treatment of neurogenic dysphagia in adult populations as well to propose assessment of co-occurring speech, language, and airway compromise. Furthermore, it is vital to be familiar with ethical decision making and end-of-life issues. Continuing education in the form of research articles, conferences, and professional discussion boards is useful in maintaining a high level of service delivery. Whenever possible, an inter- or transdisciplinary approach is recommended.

Although severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines have shown efficacy against SARS-CoV-2, it is unknown if coronavirus vaccines can also protect against other coronaviruses that may infect humans in the future. Here, we show that coronavirus vaccines elicited cross-protective immune responses against heterologous coronaviruses. In particular, we show that a severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) vaccine developed in 2004 and known to protect against SARS-CoV-1 conferred robust heterologous protection against SARS-CoV-2 in mice. Similarly, prior coronavirus infections conferred heterologous protection against distinct coronaviruses. Cross-reactive immunity was also reported in patients with coronavirus disease 2019 (COVID-19) and in individuals who received SARS-CoV-2 vaccines, and transfer of plasma from these individuals into mice improved protection against coronavirus challenges. These findings provide the first demonstration to our knowledge that coronavirus vaccines (and prior coronavirus infections) can confer broad protection against heterologous coronaviruses and establish a rationale for universal coronavirus vaccines.

Background A better understanding of locally advanced cervical cancer (LACC) is mandatory for further improving the rates of disease control, since a significant proportion of patients still fail to respond or undergo relapse after concurrent chemoradiation treatment (CRT), and survival for these patients has generally remained poor. Methods To identify specific markers of CRT response, we compared pretreatment biopsies from LACC patients with pathological complete response (sensitive) with those from patients showing macroscopic residual tumor (resistant) after neoadjuvant CRT, using a proteomic approach integrated with gene expression profiling. The study of the underpinning mechanisms of chemoradiation response was carried out through in vitro models of cervical cancer. Results We identified annexin A2 (ANXA2), N-myc downstream regulated gene 1 (NDRG1) and signal transducer and activator of transcription 1 (STAT1) as biomarkers of LACC patients’ responsiveness to CRT. The dataset collected through qPCR on these genes was used as training dataset to implement a Random Forest algorithm able to predict the response of new patients to this treatment. Mechanistic investigations demonstrated the key role of the identified genes in the balance between death and survival of tumor cells. Conclusions Our results define a predictive gene signature that can help in cervical cancer patient stratification, thus providing a useful tool towards more personalized treatment modalities. Electronic supplementary material The online version of this article (10.1186/s13046-019-1268-y) contains supplementary material, which is available to authorized users.

Pathophysiologic conditions of neurodegenerative diseases are unquestionably related to protein misfolding. The accumulation of misfolded proteins into relatively ordered structures such as fibrillar intracellular and extracellular amyloids results in tissue lesions that lead to neuronal loss and brain damage. In these pathologies, the occurrence of protein aggregates suggests certain inefficient or insufficient cellular response of those molecular chaperones that should properly assist the folding of the client proteins. In this regard, all the experimental models for neurodegenerative diseases have demonstrated that the overexpression of molecular chaperones provide effective neuroprotection. A subset of these molecular chaperones corresponds to a group of proteins that exhibit peptidylprolyl isomerase enzymatic activity, the immunophilins. Most of the family members of the latter group were first described as responsible of the immunosuppressive response or they were reported as members of the chaperone complex associated with HSP90 in steroid receptor oligomers. In this article we review some aspects of the liaison between molecular chaperones and neurodegenerative diseases, in particular heat-shock proteins and immunophilins with demonstrated influence in the proper function of mitochondria. This article is intended to address a field that represents a yet critical unmet clinical need for the development of neuroprotective molecules focused on potentially novel molecular targets. Fil: Daneri Becerra, Cristina del Rosario. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Ciucci, Sol Micaela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina Fil: Mazaira, Gisela Ileana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina Fil: Galigniana, Mario Daniel. Universidad de Buenos Aires; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina

OBJECTIVES Within-individual movement variability occurs in most motor domains. However, it is unknown how pharyngeal swallowing pressure varies in healthy individuals. We hypothesized that: 1) variability would differ among pharyngeal regions; 2) variability would decrease with increased bolus volume; 3) variability would increase with age; and 4) there would be no sex differences. STUDY DESIGN Case series. METHODS We used pharyngeal high-resolution manometry to measure swallowing pressure in the following regions: velopharynx, tongue base, hypopharynx, and upper esophageal sphincter. Data were collected from 97 healthy adults (41 male) aged 21 to 89 years during thin liquid swallows: 2 mL, 10 mL, and participant-selected comfortable volume. Pressure variability was measured using coefficient of variation. Repeated measures analysis of variance was used to assess impacts of region, bolus volume, age, and sex on pressure variability. RESULTS There was a significant region × volume interaction (P

The stomach is inhabited by diverse microbial communities, co-existing in a dynamic balance. Long-term use of drugs such as proton pump inhibitors (PPIs), or bacterial infection such as Helicobacter pylori, cause significant microbial alterations. Yet, studies revealing how the commensal bacteria re-organize, due to these perturbations of the gastric environment, are in early phase and rely principally on linear techniques for multivariate analysis. Here we disclose the importance of complementing linear dimensionality reduction techniques with nonlinear ones to unveil hidden patterns that remain unseen by linear embedding. Then, we prove the advantages to complete multivariate pattern analysis with differential network analysis, to reveal mechanisms of bacterial network re-organizations which emerge from perturbations induced by a medical treatment (PPIs) or an infectious state (H. pylori). Finally, we show how to build bacteria-metabolite multilayer networks that can deepen our understanding of the metabolite pathways significantly associated to the perturbed microbial communities., Drug use or bacterial infection can cause significant alterations of gastric microbiome. Here, the authors show how advanced pattern recognition by nonlinear machine intelligence can help disclose a bacteria-metabolite network which enlightens mechanisms behind such perturbations.

Background In spite of great progress in the surgical and clinical management, until now no significant improvement in overall survival of High-Grade Serous Ovarian Cancer (HGSOC) patients has been achieved. Important aspects for disease control remain unresolved, including unclear pathogenesis, high heterogeneity and relapse resistance after chemotherapy. Therefore, further research on molecular mechanisms involved in cancer progression are needed to find new targets for disease management. The Krüppel-like factors (KLFs) are a family of transcriptional regulators controlling several basic cellular processes, including proliferation, differentiation and migration. They have been shown to play a role in various cancer-relevant processes, in a context-dependent way. Methods To investigate a possible role of KLF family members as prognostic biomarkers, we carried out a bioinformatic meta-analysis of ovarian transcriptome datasets in different cohorts of late-stage HGSOC patients. In vitro cellular models of HGSOC were used for functional studies exploring the role of KLF7 in disease development and progression. Finally, molecular modelling and virtual screening were performed to identify putative KLF7 inhibitors. Results Bioinformatic analysis highlighted KLF7 as the most significant prognostic gene, among the 17 family members. Univariate and multivariate analyses identified KLF7 as an unfavourable prognostic marker for overall survival in late-stage TCGA-OV and GSE26712 HGSOC cohorts. Functional in vitro studies demonstrated that KLF7 can play a role as oncogene, driving tumour growth and dissemination. Mechanistic targets of KLF7 included genes involved in epithelial to mesenchymal transition, and in maintaining pluripotency and self-renewal characteristics of cancer stem cells. Finally, in silico analysis provided reliable information for drug-target interaction prediction. Conclusions Results from the present study provide the first evidence for an oncogenic role of KLF7 in HGSOC, suggesting it as a promising prognostic marker and therapeutic target.

The triarchic model of psychopathy includes a disinhibition dimension related to externalizing outcomes, a meanness dimension pertaining to callous-unemotional traits, and a boldness dimension referring to emotional stability and high confidence in peer relationships. Some dimensions of psychopathy have been extensively investigated in samples of children and adolescents; in particular, the callous-unemotional (meanness) dimension has been associated with aggression and bullying in numerous studies. However, the other dimensions of the triarchic model have been relatively unexplored in samples of adolescents. Thus, we tested for associations between the triarchic dimensions and bullying and cyberbullying behaviors (i.e., proactive, goal-directed, and repetitive aggressive behaviors) in a sample of 580 high school students aged 14 to 19 years. Logistic regression analyses showed that (a) meanness and disinhibition scores were uniquely associated with traditional bullying, whereas only meanness was uniquely associated with cyberbullying; (b) boldness scores moderated the relationship between disinhibition and cyberbullying, such that disinhibition was related to cyberbullying only at low levels of boldness; and (c) these patterns were maintained when accounting for overall levels of conduct problems and were not moderated by the experience of victimization. Our findings suggest that the triarchic model of psychopathy can contribute to an understanding of youth engagement in bullying and cyberbullying.

Background: Continuous subcutaneous insulin infusion (CSII) is increasing worldwide, mostly because of improved technology. The aim of this study was to evaluate the current status of CSII in Italy. Materials and Methods: Physicians from 272 diabetes centers received a questionnaire investigating clinical features, pump technology, and management of patients on CSII. Results: Two hundred seventeen centers (79.8%) joined the study and, by the end of April 2013, gave information about 10,152 patients treated with CSII: 98.2% with type 1 diabetes mellitus, 81.4% adults, 57% female, and 61% with a conventional pump versus 39% with a sensor-augmented pump. CSII advanced functions were used by 68% of patients, and glucose sensors were used 12 days per month on average. Fifty-eight percent of diabetes centers had more than 20 patients on CSII, but there were differences among centers and among regions. The main indication for CSII was poor glucose control. Dropout was mainly due to pump wearability or nonoptimal glycemic control. Twenty-four hour assistance was guaranteed in 81% of centers. A full diabetes team (physician+ nurse + dietician + psychologist) was available in 23% of adult-care diabetes centers and in 53%of pediatric diabetes units. Conclusions: CSII keeps increasing in Italy. More work is needed to ensure uniform treatment strategies throughout the country and to improve pump use.

Abstract. Background: The endovascular management of arterial injuries has resulted in reduced operating time, blood loss, hospital mortality, lower incidence of sepsis, and decrease in mortality rates. For penetrating trauma, however, the benefits of endovascular therapy are questionable. Patients and methods: Data were obtained by retrospective analysis of electronic medical records. All patients with vascular trauma seeking care at our institution from January 2010 to December 2015 were reviewed. A total of 223 vascular trauma patients were enrolled. Of these, 18 patients (8 %) were treated with endovascular techniques. The data related to clinical presentation, patient characteristics, technical aspects of the treatment, and follow-up were analysed. Results: The mean patient age was 35.4 ± 17.8 years, 94 % were male. The mean injury severity score was 10.4 ± 2.5. The most commonly observed trauma mechanism was a gunshot in 10 cases (55 %), followed by lesions provoked by arterial catheter misplacement in five cases (27 %), and stab wounds in three cases (16.6 %). The main injury site was the subclavian artery, accounting for eight cases (44 %), followed by the superficial femoral artery and the tibiofibular trunk in two cases, respectively (18 %). The anterior tibial, fibular artery, axillary, common carotid, superior mesenteric, and profunda femoris were each affected once. Arteriovenous fistula was detected in nine cases (50 %), pseudoaneurysms in nine cases (50 %), and short occlusion in two cases (11 %). The mean follow-up duration was 753 days. The primary patency rate was 92.3 and 61.5 % after one and two years, respectively. The survival rate was 94.4 % after one and two years. Infection of the stents or limb amputations were not identified at follow-up. Conclusions: The endovascular treatment of penetrating arterial injuries with covered stents is feasible. However, the criteria used to choose the best method must be individualized. Keywords: Trauma, endovascular, stent graft, gunshot, stab wound

In Italy, drug expenditure governance is achieved by setting caps based on the percentage increase in hospital spending compared to the previous year. This method is ineffective in identifying issues and opportunities as it does not consider an analysis of the number of treated cases and per capita consumption in local and regional settings. The IRCCS (Scientific hospitalization and treatment institute) Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori” in Meldola, has developed and adopted an effective management model designed to oversee pharmaceutical expenditure, guarantee prescription appropriateness and quality of care to patients. The budget setting follows a structured process which evaluates determining factors of the expenditure such as expected patients calculated according to the epidemiology and to national and regional indications of appropriateness, mean cost per patient calculated on the average period of demonstrated efficacy of the drug and use of drugs with the best cost-effectiveness ratio. Strict monitoring and integrated purchasing processes allow for immediate corrective actions on expenditures, as well as a continuous dialogue with the region in order to guarantee consistent funding of IRST activities. The model, presented in this article is efficient and implements concepts beyond the conventional “silos” approach and national and regional governance tools, in terms of patient centricity.

Objective Low-grade serous ovarian carcinomas (LGSOCs) are a histological subtype of epithelial ovarian tumors, accounting for fewer than 5% of all cases of ovarian carcinoma. Due to the chemoresistant nature of this subtype a search for more effective systemic therapies is actively ongoing, hormonal therapy showing some degree of activity in this clinical setting. The present study ought to investigate the hormone receptor status of LGSOCs, as a strategy to provide molecular support for patient-tailored hormonal treatments. Methods Estrogen receptor α (ERα), ERβ isoforms (i.e. ERβ1, ERβ2 and ERβ5), progesterone and androgen receptor (PR, AR) expression was evaluated by immunohistochemistry in 25 untreated LGSOC primary tumors, 6 matched metastases and 6 micropapillary variant of serous borderline tumors (micropapillary SBOTs). In vitro cellular models were used to provide insights into clinical observations. Results Our results showed prominent expression of nuclear ERα, ERβ2, ERβ5 and PR in LGSOC primary tissues, while metastatic lesions also exhibit considerable cytoplasmic ERβ2 levels. Notably, a higher expression of ERβ1 protein was determined in micropapillary SBOTs compared to LGSOCs. In vitro experiments on LGSOC cell lines (i.e. HOC-7 and VOA-1056) revealed low/absent ERα, PR and AR protein expression, whereas the three ERβ isoforms were all present. Proliferation of HOC-7 and VOA-1056 was not modulated by either the endogenous or the selective synthetic ligands. Conclusions These novel findings highlight the need of assessing relative levels of ERα and ERβ isoforms in the total receptor pool in future clinical studies investigating molecular predictors of response to hormonal therapy in LGSOC.

V.P. was fnancially supported by (1) the Excellence Project CGL2017-82782-P financed by the Spanish Ministry of Science, Innovation and Universities, the Agencia Estatal de Investigación (AEI) and the Fondo Europeo de Desarrollo Regional (FEDER, EU), and (2) Modalidad Grupos de Investigación Consolidados, Principado de Asturias (IDI/2018/000151). M.M.D. was fnancially supported by the Spanish Ramon y Cajal grant RYC-2014-16263. N.S., C.B. and A.G. were partly supported by the National Centre for Research and Development (GLOBE POL-NOR/198352/85/2013) and the National Science Centre in Poland (DEC-2013/08/M/NZ9/00469; 2016/22/Z/NZ8/00121; 2017/25/N/NZ8/02861). E.R., J.N., A.F., N.S., and C.B. were supported by the Agencia Estatal de Investigación from the Ministry of Economy, Industry and Competitiveness, Spain (project CGL2017-83045-R AEI/FEDER EU, co-fnanced with FEDER)., Bombieri, G., Naves, J., Penteriani, V., Selva, N., Fernández-Gil, A., López-Bao, J.V., Ambarli, H., Bautista, C., Bespalova, T., Bobrov, V., Bolshakov, V., Bondarchuk, S., Camarra, J.J., Chiriac, S., Ciucci, P., Dutsov, A., Dykyy, I., Fedriani, J.M., García-Rodríguez, A., Garrote, P.J., Gashev, S., Groff, C., Gutleb, B., Haring, M., Härkönen, S., Huber, D., Kaboli, M., Kalinkin, Y., Karamanlidis, A.A., Karpin, V., Kastrikin, V., Khlyap, L., Khoetsky, P., Kojola, I., Kozlow, Y., Korolev, A., Korytin, N., Kozsheechkin, V., Krofel, M., Kurhinen, J., Kuznetsova, I., Larin, E., Levykh, A., Mamontov, V., Männil, P., Melovski, D., Mertzanis, Y., Meydus, A., Mohammadi, A., Norberg, H., Palazón, S., Pătrașcu, L.M., Pavlova, K., Pedrini, P., Quenette, P.Y., Revilla, E., Rigg, R., Rozhkov, Y., Russo, L.F., Rykov, A., Saburova, L., Sahlén, V., Saveljev, A.P., Seryodkin, I.V., Shelekhov, A., Shishikin, A., Shkvyria, M., Sidorovich, V., Sopin, V., Støen, O., Stofik, J., Swenson, J.E., Tirski, D., Vasin, A., Wabakken, P., Yarushina, L., Zwijacz-Kozica, T., Delgado, M.M.

The triarchic model of psychopathy was advanced to reconcile differing historic conceptions of this condition and alternative approaches for assessing it. The current study was undertaken to expand the empirical evidence base for the triarchic model by examining its correlates in adolescents, with measures of particular relevance to developmental theories of antisocial behavior. Self-report scales assessing the triarchic constructs were administered along with measures of conduct problems, callous-unemotional traits, attachment style dimensions, negative emotionality, and hyperactivity/inattention to 608 Italian adolescents (272 girls; M age = 16.70 years). The disinhibition dimension of the triarchic model was related most highly to general externalizing outcomes, such as conduct problems and hyperactivity-inattention, in this adolescent sample. The meanness dimension was selectively related to callous-unemotional traits and other measures of limited prosocial emotions and to affiliation motives that emphasize social gain. Triarchic boldness was associated with greater emotional stability and greater confidence in peer relationships. Of interest, an interaction between meanness and boldness was evident in predicting a lower need to understand one's own and others' emotions. These results provide a valuable illustration of the potential of the triarchic model to help advance developmental models of antisocial behavior in youth. Public Significance Statement This study examined how dimensions of psychopathy described by the triarchic model relate to measures of problem behaviors and affective-interpersonal style in an adolescent sample. Scores on the three triarchic dimensions-disinhibition, meanness, and boldness-showed meaningful contrasting relations with conduct problems, hyperactivity/inattention, callous-unemotional traits, emotional proclivities, and attachment style dimensions. This work illustrates how the triarchic model conceptualization can help advance developmental models of the emergence of antisocial behavior.

A dimer of the heat-shock protein of 90-kDa (Hsp90) represents the critical core of the chaperone complex associated to the glucocorticoid receptor (GR) oligomer. The C-terminal end of the Hsp90 dimer shapes a functional acceptor site for co-chaperones carrying tetratricopeptide repeat (TPR) domains, where they bind in a mutually exclusive and competitive manner. They impact on the biological properties of the GR•Hsp90 complex and are major players of the GR transport machinery. Recently, we showed that the overexpression of a chimeric TPR peptide influences the subcellular distribution of GR. In this study, the functional role of endogenous proteins carrying TPR or TPR-like sequences on GR subcellular distribution was characterized. It is demonstrated that, contrarily to the positive influence of FKBP52 on GR nuclear accumulation, FKBP51 and 14-3-3 impaired this property. While SGT1α showed no significant effect, the overexpression of the Ser/Thr phosphatase PP5 resulted in a nearly equal nuclear-cytoplasmic redistribution of GR rather than its typical cytoplasmic localization in the absence of steroid. This observation led to analyse the influence of the phosphorylation status of GR, which resulted not linked to its nucleo-cytoplasmic shuttling mechanism. Nonetheless, it was evidenced that both PP5 and FKBP52 are related to the anchorage of the GR to nucleoskeleton structures. The influence of these TPR domain proteins on the steroid-dependent transcriptional activity of GR was also characterized. It is postulated that the pleiotropic actions of the GR in different cell types may be the consequence of the relative abundance of different TPR-domain interacting co-chaperones.

Dysphagia evaluation and management has rapidly become the primary practice area of medical speech pathologists since its adoption in our field less than three decades ago. As a specialty, swallowing and swallowing disorders comprise the largest represented discipline with 10,059 specialty interest group members within the American Speech-Language-Hearing Association and 298 board-certified specialists in the American Speech Hearing Association. There are national and international organizations, such as the Dysphagia Research Society and its interdisciplinary journal Dysphagia, that provide continuing education for clinicians and a platform for dysphagia researchers. Despite this rapid growth, herein we identify some significant needs for improving the science and practice of dysphagia clinical care, including a deeper understanding of physiology and neurophysiology, standardization of evaluation, consensus on core sets of dysphagia parameters for clinical and research reporting, personalized algorithms for implementation of evidenced-based practice, metrics for therapy efficacy, and increased buy-in and funding from agencies. The goals of this article are to summarize the status quo of dysphagia research, evaluation, and treatment as well as to make predictions about the future. Medical trends that we speculate will influence dysphagia research and care in the future include, among others, imaging advances, personalized medicine, regenerative medicine, and telehealth.

Parkinson disease (PD) has detrimental effects on swallowing function. Treatment options are largely behavioral; thus, patients would benefit from an earlier start to therapy. Early swallowing changes in PD are not well-known, so patients do not typically receive swallowing treatment until later in the progression of PD.We used predictive modeling to determine what quantitative swallowing variables best differentiate individuals with early to mid-stage PD from healthy controls.Participants included twenty-six individuals with early to mid-stage PD and 26 healthy, age- and sex-matched controls. Swallowing was evaluated by simultaneous high-resolution manometry and videofluoroscopy as well as the Sydney Swallow Questionnaire (SSQ). Binomial logistic regression was performed on 4 sets of data: 1) high-resolution manometry only; 2) videofluoroscopy only; 3) SSQ only; and 4) all data combined.A model from a combined data set had the highest accuracy in differentiating individuals with PD from controls. The model included maximum pressure in the velopharynx (soft palate), pressure variability in the velopharynx, and the SSQ item concerning difficulty with swallowing saliva. No significant models could be generated using the videofluoroscopy data.Individuals with PD show quantitative changes in pressure generation and are able to self-assess aspects of swallowing function in the early and mid-stages of PD, even in the absence of swallowing changes seen on videofluoroscopy. A multimodal approach for the assessment of swallowing may be more accurate for determining subtle swallowing changes that occur in the early stages of PD.

The notion that menopausal estrogen replacement therapy increases ovarian cancer risk, but only for the two more common types (i.e. serous and endometrioid), while possibly decreasing risk for clear cell tumors, is strongly suggestive of causality. However, whether estradiol (E2) is tumorigenic or promotes development of occult preexisting disease is unknown. The present study investigated molecular and cellular mechanisms by which E2 modulates the growth of high grade serous ovarian cancer (HGSOC). Results showed that ERα expression was necessary and sufficient to induce the growth of HGSOC cells in in vitro models. Conversely, in vivo experimental studies demonstrated that increasing the levels of circulating estrogens resulted in a significant growth acceleration of ERα-negative HGSOC xenografts, as well. Tumors from E2-treated mice had significantly higher proliferation rate, angiogenesis, and density of tumor-associated macrophage (TAM) compared to ovariectomized females. Accordingly, immunohistochemical analysis of ERα-negative tissue specimens from HGSOC patients showed a significantly greater TAM infiltration in premenopausal compared to postmenopausal women. This study describes novel insights into the impact of E2 on tumor microenvironment, independently of its direct effect on tumor cell growth, thus supporting the idea that multiple direct and indirect mechanisms drive estrogen-induced tumor growth in HGSOC.

Retinal vein occlusions may decrease visual acuity. There is no known therapy to treat ocular thrombosis. The authors used fondaparinux, an ultra-low-molecular-weight heparin, to treat 13 consecutive cases of recent-onset retinal vein occlusions. Two patients with renal insufficiency were not included. Eight central retinal vein occlusions and 5 branch retinal vein occlusions in 13 patients were treated with subcutaneous fondaparinux 2.5 mg once a day. The patients were seen every 2 weeks. Macular edema was treated with intravitreal injections of anti-vascular endothelial growth factor or steroids. Two patients elected to discontinue treatment. Of the remaining 11, 9 occlusions resolved in 1.5 to 13.5 months with rapid resolution of retinal edema and hemorrhage as soon as the occlusions resolved. One patient had a retinal vein that was still occluded after 8 months of therapy and 1 had retinal vein occlusion that partially resolved after 15 months of treatment. Of the 9 eyes with occlusions that resolved, visual acuity improved in 7. In 2, visual acuity decreased due to macular ischemia. Occlusion recurred in 1 2.5 months after the suspension of initial treatment. This patient is again being treated with fondaparinux 2.5 mg. No hemorrhaging occurred. Fondaparinux 2.5 mg can be given subcutaneously once a day to patients with recent-onset retinal vein occlusions without renal insufficiency. An occlusion may take a number of months to resolve. Once the vein occlusion has resolved, retinal edema and hemorrhage rapidly resolve and vision improves. Macular edema should be treated while waiting for the vein occlusion to resolve.

αβ lineage T cells, most of which are CD4(+) or CD8(+) and recognize MHC I or MHC II-presented antigens, are essential for immune responses and develop from CD4(+)CD8(+) thymocytes. The absence of in vitro models and the heterogeneity of αβ thymocytes have hampered analyses of their intrathymic differentiation. Here, combining single-cell RNA- and ATAC- (chromatin accessibility) sequencing, we identified mouse and human αβ thymocyte developmental trajectories. We demonstrated asymmetric emergence of CD4(+) and CD8(+) lineages, matched differentiation programs of agonist-signaled cells to their MHC specificity, and identified correspondences between mouse and human transcriptomic and epigenomic patterns. Through computational analysis of single cell data and binding sites for the CD4(+)lineage transcription factor Thpok, we inferred transcriptional networks associated with CD4(+)- or CD8(+)lineage differentiation, and with expression of Thpok or of the CD8(+)-lineage factor Runx3. Our findings provide insight into the mechanisms of CD4(+) and CD8(+) T cell differentiation, and a foundation for mechanistic investigations of αβ T cell development.

In Italy, the coronavirus disease 2019 (COVID-19) emergency took hold in Lombardy and Veneto at the end of February 2020 and spread unevenly among the other regions in the following weeks. In Tuscany, the progressive increase of hospitalized COVID-19 patients required the set-up of a regional task force to prepare for and effectively respond to the emergency. In this case report, we aim to describe the key elements that have been identified and implemented in our center, a 1082-bed hospital located in the Pisa district, to rapidly respond to the COVID-19 outbreak in order to guarantee safety of patients and healthcare workers.

Memory CD4(+) T cells mediate long term immunity, and their generation is a key objective of vaccination strategies. However, the transcriptional circuitry controlling the emergence of memory cells from early CD4(+) antigen-responders remains poorly understood. Here, using single-cell RNAseq to study the transcriptome of virus-specific CD4(+) T cells, we identified a gene signature distinguishing potential memory precursors from effector cells. We found that both that signature and the emergence of memory CD4(+) T cells required the transcription factor Thpok. We further demonstrated that Thpok cell-intrinsically protected memory cells from a dysfunctional, effector-like transcriptional program, similar to but distinct from the exhaustion pattern of cells responding to chronic infection. Mechanistically, Thpok bound genes encoding the transcription factors Blimp1 and Runx3, and acted by antagonizing their expression. Thus, a Thpok-dependent circuitry both promotes the differentiation and functional fitness of memory CD4(+) T cells, two previously unconnected critical attributes of adaptive immunity.

High-resolution manometry has traditionally been utilized in gastroenterology diagnostic clinical and research applications. Recently, it is also finding new and important applications in speech pathology and laryngology practices. A High-Resolution Pharyngeal Manometry International Working Group was formed as a grass roots effort to establish a consensus on methodology, protocol, and outcome metrics for high-resolution pharyngeal manometry (HRPM) with consideration of impedance as an adjunct modality. The Working Group undertook three tasks (1) survey what experts were currently doing in their clinical and/or research practice; (2) perform a review of the literature underpinning the value of particular HRPM metrics for understanding swallowing physiology and pathophysiology; and (3) establish a core outcomes set of HRPM metrics via a Delphi consensus process. Expert survey results were used to create a recommended HRPM protocol addressing system configuration, catheter insertion, and bolus administration. Ninety two articles were included in the final literature review resulting in categorization of 22 HRPM-impedance metrics into three classes: pharyngeal lumen occlusive pressures, hypopharyngeal intrabolus pressures, and upper esophageal sphincter (UES) function. A stable Delphi consensus was achieved for 8 HRPM-Impedance metrics: pharyngeal contractile integral (CI), velopharyngeal CI, hypopharyngeal CI, hypopharyngeal pressure at nadir impedance, UES integrated relaxation pressure, relaxation time, and maximum admittance. While some important unanswered questions remain, our work represents the first step in standardization of high-resolution pharyngeal manometry acquisition, measurement, and reporting. This could potentially inform future proposals for an HRPM-based classification system specifically for pharyngeal swallowing disorders.

Research on human memory has shown that monetary incentives can enhance hippocampal memory consolidation and thereby protect memory traces from forgetting. However, it is not known whether initial reward may facilitate the recovery of already forgotten memories weeks after learning. Here, we investigated the influence of monetary reward on later relearning. Nineteen healthy human participants learned object-location associations, for half of which we offered money. Six weeks later, most of these associations had been forgotten as measured by a test of declarative memory. Yet, relearning in the absence of any reward was faster for the originally rewarded associations. Thus, associative memories encoded in a state of monetary reward motivation may persist in a latent form despite the failure to retrieve them explicitly. Alternatively, such facilitation could be analogous to the renewal effect observed in animal conditioning, whereby a reward-associated cue can reinstate anticipatory arousal, which would in turn modulate relearning. This finding has important implications for learning and education, suggesting that even when learned information is no longer accessible via explicit retrieval, the enduring effects of a past prospect of reward could facilitate its recovery.

The outcomes of endovascular treatment of femoropopliteal atherosclerotic lesions have been improving recently. Although open repair is indicated for class D femoropopliteal lesions based on the TransAtlantic Inter-Society Consensus II (TASC II) document, in some cases, it is reasonable to use the endovascular approach for these lesions. The aim of this study was to retrospectively analyze the technical aspects and outcomes of treating TASC II D femoropopliteal disease with endovascular approaches.In total, 91 procedures between January 2011 and December 2016 were retrospectively analyzed. We collected data corresponding to the technical aspects and outcomes of treatment from an electronic database. Images and videos of all procedures were reviewed. Among the 91 procedures, 70 were for popliteal artery occlusions involving the trifurcation vessels, and 12 were for superficial femoral artery (SFA) occlusions of20 cm in length; 9 procedures for occlusions meeting both criteria were also performed. The χApproximately 44.4% of all patients were male. The mean age was 67.3 ± 20.7 years. Hypertension, diabetes, current smoker, kidney impairment, coronary disease, and cardiac insufficiency were identified in 92.3%, 66.6%, 21.7%, 7.6%, 25.6%, and 62.8% of the patients, respectively. All included patients had critical limb ischemia (11.5%, 84.6%, and 3.8% of cases corresponding to Rutherford categories 4, 5, and 6, respectively). Technical failure was observed in three patients (3.3%). The mean number of stents used was 0.7 ± 0.65 per patient. Primary patency at 30 days, 1 year, 2 years, and 3 years was 91%, 60.1%, 55.7%, and 50.6%, respectively. Limb salvage at 30 days, 1 year, 2 years, 3 years, and 4 years was 95.2%, 82.2%, 76.9%, 71.8%, and 63.7%, respectively. Reinterventions were necessary in 11.1% of the patients. Comparison of curves revealed significant differences in the 60-day primary patency for the SFA and popliteal groups (standard error, 10%; log-rank, P = .039). Analysis of the risk and technical factors affecting primary patency, limb salvage, and overall survival indicated that female sex was associated with poor survival (odds ratio, 8.942; 95% confidence interval, 1.105-72.36) and that the use of stents was associated with high rates of limb loss in the popliteal group (log-rank, P = .033).For endovascular treatment of TASC II D femoropopliteal lesions, primary patency was better in patients with popliteal artery occlusions involving the trifurcation vessels than in those with SFA occlusions20 cm in length. Female sex was associated with the risk of major amputations, and the use of stents in patients with popliteal occlusions was associated with major limb loss.

Objective Adult granulosa cell tumor (AGCT) is a rare form of sex-cord stromal ovarian tumors. Due to their origin, AGCTs secrete estrogens, and thus, estrogen receptor (ER)-mediated signaling has been considered as a possible target for therapy. The aim of the present study was to get insights into estrogen receptor status and activity in AGCTs, as a strategy to provide molecular support for personalized hormonal treatments. Methods We evaluated by immunohistochemistry the expression of ERα, ERβ isoforms (i.e. ERβ1, ERβ2 and ERβ5), progesterone and androgen receptor (PR, AR) in 20 untreated AGCTs and 12 unmatched recurrent lesions. Thereafter, we visualized by immunofluorescence, the subcellular distribution of cytoplasmic receptors, and by the proximity ligation assays (PLA) we characterized in situ their ability to interact with other proteins involved in the apoptotic cascade. Results Primary AGCTs predominantly expressed ERβ isoforms, along with PR and AR, while only 30% of patients showed ERα expression. Recurrent tumors were associated with a decrease in AR levels. From mechanistic studies it emerges that ERβ2, and to a lesser extent ERβ1 and AR, are mitochondrial components in cancer cells and that ERβ2 can act as a binding partner of proteins involved in the apoptotic cascade, in turn potentially inhibiting apoptosis. Conclusions As in other endocrine tumors, ERβ may play a role in the pathogenesis of AGCT; it is crucial to understand estrogen receptor-mediated pathways before planning hormonal treatment strategies in AGCT.

Background Albuminuria has been classically considered a marker of kidney damage progression in diabetic patients and it is routinely assessed to monitor kidney function. However, the role of a mild GFR reduction on the development of stage ≥3 CKD has been less explored in type 1 diabetes mellitus (T1DM) patients. Aim of the present study was to evaluate the prognostic role of kidney disease measures, namely albuminuria and reduced GFR, on the development of stage ≥3 CKD in a large cohort of patients affected by T1DM. Methods A total of 4284 patients affected by T1DM followed-up at 76 diabetes centers participating to the Italian Association of Clinical Diabetologists (Associazione Medici Diabetologi, AMD) initiative constitutes the study population. Urinary albumin excretion (ACR) and estimated GFR (eGFR) were retrieved and analyzed. The incidence of stage ≥3 CKD (eGFR 30% from baseline was evaluated. Results The mean estimated GFR was 98 ± 17 mL/min/1.73m2 and the proportion of patients with albuminuria was 15.3% (n = 654) at baseline. About 8% (n = 337) of patients developed one of the two renal endpoints during the 4-year follow-up period. Age, albuminuria (micro or macro) and baseline eGFR 90 ml/min/1.73m2 and normoalbuminuria, those with albuminuria at baseline had a 1.69 greater risk of reaching stage 3 CKD, while patients with mild eGFR reduction (i.e. eGFR between 90 and 60 mL/min/1.73 m2) show a 3.81 greater risk that rose to 8.24 for those patients with albuminuria and mild eGFR reduction at baseline. Conclusions Albuminuria and eGFR reduction represent independent risk factors for incident stage ≥3 CKD in T1DM patients. The simultaneous occurrence of reduced eGFR and albuminuria have a synergistic effect on renal function worsening. Electronic supplementary material The online version of this article (10.1186/s12882-018-1136-6) contains supplementary material, which is available to authorized users.

The anatomic research of the lymphatic system has been a very controversial subject throughout due to the complexity of the methods for its visualization. More than 30 years ago, together with Prof. Caplan, we began the vascular anatomy research, focusing on the lymphatic anatomy, developing and adapting different techniques of injection. On the third Normal Anatomy Chair of Buenos Aires University, we summarized the lymphatic drainage of the breast and the limbs to interpret the anatomic bases of lymphedema.

Callous-unemotional (CU) traits are associated with aggressive behavior but preliminary research suggests this relationship is modified by patterns of emotional processing. This study examined whether attentional orienting to emotional faces moderated the association between CU traits and peer-nominated aggression in 251 middle school students (53% females, mean age = 13.24 years, SD = 0.73). Attentional orienting was assessed using an emotional faces (i.e., angry, fearful, happy, sad, and neutral) variant of the dot-probe task. Students also completed a self-report measure of CU traits and their classmates made peer nominations of aggression. Logistic regression analyses showed that peer-nominated aggression was positively related to CU traits at low levels of attentional orienting to angry faces, whereas aggression was unrelated to CU traits at high levels of attentional orienting to angry faces. That is, peer-nominated aggression was greatest for youth high on CU traits who were not engaged by angry faces. These findings support the importance of considering different patterns of emotional responding when studying the association between CU traits and aggressive behavior in youth.

The inpatient burden of dysphagia has primarily been evaluated in patients with stroke. It is unclear whether dysphagia, irrespective of cause, is associated with worse clinical outcomes and higher costs compared to inpatients with similar demographic, hospital, and clinical characteristics without dysphagia. The aim of this study is to assess how a dysphagia diagnosis affects length of hospital stay (LOS), costs, discharge disposition, and in-hospital mortality among adult US inpatients. Annual and overall dysphagia prevalence, LOS, hospital charges, inpatient care costs, discharge disposition, and in-hospital mortality were measured using the AHRQ Healthcare Cost and Utilization Project (HCUP) National Inpatient Sample (2009-2013). Patients aged 45 years or older with ≤180 days of stay in hospital with and without dysphagia were included. Multivariable survey regression methods with propensity weighting were used to assess associations between dysphagia and different outcomes. Overall, 2.7 of 88 million (3.0%) adult US inpatients had a dysphagia diagnosis (50.2% male, 72.4% white, 74.6% age 65-90 years) and prevalence increased from 408,035 (2.5% of admissions) in 2009 to 656,655 (3.3%) in 2013. After inverse probability of treatment weighting adjustment, mean hospital LOS in patients with dysphagia was 8.8 days (95% CI 8.66-8.90) compared to 5.0 days (95% CI 4.97-5.05) in the non-dysphagia group (P < 0.001). Total inpatient costs were a mean $6,243 higher among those with dysphagia diagnoses ($19,244 vs. 13,001, P < 0.001). Patients with dysphagia were 33.2% more likely to be transferred to post-acute care facility (71.9% vs. 38.7%, P < 0.001) with an adjusted OR of 2.8 (95% CI 2.73-2.81, P < 0.001). Compared to non-cases, adult patients with dysphagia were 1.7 times more likely to die in the hospital (95% CI 1.67-1.74). Dysphagia affects 3.0% of all adult US inpatients (aged 45-90 years) and is associated with a significantly longer hospital length of stay, higher inpatient costs, a higher likelihood of discharge to post-acute care facility, and inpatient mortality when compared to those with similar patient, hospital size, and clinical characteristics without dysphagia. Dysphagia has a substantial health and cost burden on the US healthcare system.