Miracle-dz/UniFAR-FTUs huggingface dataset:
The Blood Pressure Pendulum following Spinal Cord Injury: Implications for Vascular Cognitive Impairment

Cognitive impairment following spinal cord injury (SCI) has received considerable attention in recent years. Among the various systemic effects of SCI that contribute towards cognitive decline in this population, cardiovascular dysfunction is arguably one of the most significant. The majority of individuals with a cervical or upper-thoracic SCI commonly experience conditions called orthostatic hypotension and autonomic dysreflexia, which are characterized by dangerous fluctuations in systemic blood pressure (BP). Herein, we review the potential impact of extreme BP lability on vascular cognitive impairment (VCI) in individuals with SCI. Albeit preliminary in the SCI population, there is convincing evidence that chronic hypotension and hypertension in able-bodied individuals results in devastating impairments in cerebrovascular health, leading to VCI. We discuss the pertinent literature, and while drawing mechanistic comparisons between able-bodied cohorts and individuals with SCI, we emphasize the need for additional research to elucidate the mechanisms of cognitive impairment specific to the SCI population. Lastly, we highlight the current and potential future therapies to manage and treat BP instability, thereby possibly mitigating VCI in the SCI population.
CT-based radiomic signatures for prediction of pathologic complete response in esophageal squamous cell carcinoma after neoadjuvant chemoradiotherapy

Abstract The objective of this study was to build models to predict complete pathologic response (pCR) after neoadjuvant chemoradiotherapy (nCRT) in esophageal squamous cell carcinoma (ESCC) patients using radiomic features. A total of 55 consecutive patients pathologically diagnosed as having ESCC were included in this study. Patients were divided into a training cohort (44 patients) and a testing cohort (11 patients). The logistic regression analysis using likelihood ratio forward selection was performed to select the predictive clinical parameters for pCR, and the least absolute shrinkage and selection operator (LASSO) with logistic regression to select radiomic predictors in the training cohort. Model performance in the training and testing groups was evaluated using the area under the receiver operating characteristic curves (AUC). The multivariate logistic regression analysis identified no clinical predictors for pCR. Thus, only radiomic features selected by LASSO were used to build prediction models. Three logistic regression models for pCR prediction were developed in the training cohort, and they were able to predict pCR well in both the training (AUC, 0.84–0.86) and the testing cohorts (AUC, 0.71–0.79). There were no differences between these AUCs. We developed three predictive models for pCR after nCRT using radiomic parameters and they demonstrated good model performance.
Trends in Incidence and Stage at Diagnosis of Colorectal Cancer in Adults Aged 40 Through 49 Years, 1975-2015.

Trends in Incidence and Stage at Diagnosis of Colorectal Cancer in Adults Aged 40 Through 49 Years, 1975-2015 Evidence suggests that incidence of colorectal cancer (CRC) is increasing among adults younger than 50 years in the United States.1 The underlying causes of the increased incidence are unclear. If the increase is the result of earlier detection due to increased use of colonoscopy, earlier stage at diagnosis would be expected, whereas if the increased incidence is the result of true increases in risk, relatively later stage at diagnosis would be expected. We investigated trends in CRC incidence by stage in adults younger than 50 years. We focused our study on adults aged 40 through 49 years, who account for almost 3 of 4 youngonset cases.
Electrophysiologic and anatomic factors predictive of a need for touch‐up radiofrequency application for complete pulmonary vein isolation: Comparison between hot balloon‐ and cryoballoon‐based ablation

Although electrophysiologic and anatomic factors associated with the need for touch‐up radiofrequency (RF) applications after cryoballoon ablation (CBA) for atrial fibrillation (AF) have been well described, those associated with the need for such touch‐up after hot balloon ablation (HBA) have not. We aimed to identify factors predictive of the need for touch‐up applications following HBA.
PARP Inhibitors in Ovarian Cancer: The Route to “Ithaca”

Poly (ADP-ribose) polymerase (PARP) inhibitors are a novel class of therapeutic agents that target tumors with deficiencies in the homologous recombination DNA repair pathway. Genomic instability characterizes high-grade serous ovarian cancer (HGSOC), with one half of all tumors displaying defects in the important DNA repair pathway of homologous recombination. Early studies have shown significant efficacy for PARP inhibitors in patients with germline breast related cancer antigens 1 and 2 (BRCA1/2) mutations. It has also become evident that BRCA wild-type patients with other defects in the homologous recombination repair pathway benefit from this treatment. Companion homologous recombination deficiency (HRD) scores are being developed to guide the selection of patients that are most likely to benefit from PARP inhibition. The choice of which PARP inhibitor is mainly based upon the number of prior therapies and the presence of a BRCA mutation or HRD. The identification of patients most likely to benefit from PARP inhibitor therapy in view of HRD and other biomarker assessments is still challenging. The aim of this review is to describe the current evidence for PARP inhibitors in ovarian cancer, their mechanism of action, and the outstanding issues, including the rate of long-term toxicities and the evolution of resistance.
Role of Macrophages in Cardioprotection

Cardiovascular diseases are the leading cause of mortality worldwide. It is widely known that non-resolving inflammation results in atherosclerotic conditions, which are responsible for a host of downstream pathologies including thrombosis, myocardial infarction (MI), and neurovascular events. Macrophages, as part of the innate immune response, are among the most important cell types in every stage of atherosclerosis. In this review we discuss the principles governing macrophage function in the healthy and infarcted heart. More specifically, how cardiac macrophages participate in myocardial infarction as well as cardiac repair and remodeling. The intricate balance between phenotypically heterogeneous populations of macrophages in the heart have profound and highly orchestrated effects during different phases of myocardial infarction. In the early “inflammatory” stage of MI, resident cardiac macrophages are replaced by classically activated macrophages derived from the bone marrow and spleen. And while the macrophage population shifts towards an alternatively activated phenotype, the inflammatory response subsides giving way to the “reparative/proliferative” phase. Lastly, we describe the therapeutic potential of cardiac macrophages in the context of cell-mediated cardio-protection. Promising results demonstrate innovative concepts; one employing a subset of yolk sac-derived, cardiac macrophages that have complete restorative capacity in the injured myocardium of neonatal mice, and in another example, post-conditioning of cardiac macrophages with cardiosphere-derived cells significantly improved patient’s post-MI diagnoses.
Milk in the prevention and management of type 2 diabetes: The potential role of milk proteins

Globally, diabetes mellitus is not only considered a leading cause of mortality and morbidities but has also created a substantial economic burden. There is growing evidence that foods and their components can be implemented in the prevention and management of type 2 diabetes mellitus (T2DM). Increased dairy consumption has been linked to a lower risk of T2DM. The protective role of dairy foods in the development of T2DM is thought to be largely attributable to dairy nutrients, one of them being dairy protein. There is considerable evidence that milk proteins increase the postprandial insulin response and lower the postprandial blood glucose response in both healthy subjects and patients with T2DM. The exact mechanisms by which milk proteins lower postprandial glucose levels are yet to established; however, the amino acids and bioactive peptides derived from milk proteins are thought to modify a physiological milieu, which includes delayed gastric emptying and the enhancement of incretin and insulin responses, consequently leading to lower postprandial glucose levels. The present review will focus on providing a clear presentation of the potential implementation of milk proteins as a dietary supplement in the prevention and management of T2DM by summarizing the relevant supporting evidence for this particular topic.
Mycobacterium tuberculosis ECF sigma factor sigC is required for lethality in mice and for the conditional expression of a defined gene set

Bacterial alternative RNA polymerase sigma factors are key global adaptive response regulators with a likely role in Mycobacterium tuberculosis pathogenesis. We constructed a mutant lacking the sigma factor gene, sigC, by allelic exchange, in the virulent CDC1551 strain of M. tuberculosis and compared the resulting mutant with the isogenic wild‐type strain and complemented mutant strain. In vitro, compared to the wild‐type and complemented strains, the mutant was found to have similar ability to survive in both murine bone marrow‐derived macrophages and activated J774 macrophages. In time‐to‐death experiments in the mouse model, the ΔsigC mutant was significantly attenuated, causing no death in infected mice whereas the wild‐type and complemented strains caused 100% mortality within 235 days after aerosol infection with a median time to death of 170 days. Mouse organ bacterial burdens indicated that the mutant proliferated and persisted at the same level as the wild‐type and complemented strains in lung tissue and was able to persist in mice without causing death for > 300 days. A complete genomic microarray study demonstrated that SigC modulates the expression of several key virulence‐associated genes including hspX, senX3 and mtrA, encoding the α‐crystallin homologue, a two‐component sensor kinase and a two‐component response regulator respectively. Altered expression of a subset of these genes was confirmed by quantitative RT‐PCR analysis. Analysis of genes modulated by SigC also revealed a putative consensus DNA recognition sequence for SigC of SSSAAT–N16−20–CGTSSS (S = C or G). Promoter recognition for one of these genes was confirmed by in vitro transcription analysis after purification of recombinant SigC and reconstitution of an EσC RNA polymerase holoenzyme. These data indicate that the M. tuberculosis transcription factor SigC governs expression of an important M. tuberculosis regulon and is essential for lethality in mice, but is not required for bacterial survival in this species. These observations place the ΔsigC mutant in a class of M. tuberculosis mutants which persist in tissues but are attenuated in their ability to elicit lethal immunopathology.
Arterial hypertension and diastolic blood pressure associate with aortic stenosis

Abstract Objectives. Due to age-related differences in aortic valve structure, it is likely that the pathophysiology of aortic stenosis (AS) and associated risk factors differ between age groups. Here we prospectively studied the influence of traditional cardiovascular risk factors on AS development requiring surgery among patients without concomitant coronary artery disease (CAD) and stratified for age. Design. This study included 322 patients, who had prior to surgery for AS participated in population-based surveys, and 131 of them had no visible CAD upon preoperative coronary angiogram. For each case, we selected four referents matched for age, gender, and geographic area. To identify predictors for surgery, we used multivariable conditional logistic regression with a model including arterial hypertension (or measured blood pressure and antihypertensive medication), cholesterol levels, diabetes, body mass index (BMI), and smoking. Results. In patients without CAD, future surgery for AS was associated with arterial hypertension and elevated levels of diastolic blood pressure in patients younger than 60 years at surgery (odds ratio [95% confidence interval]), (3.40 [1.45–7.93] and 1.60 [1.09–2.37], respectively), and with only impaired fasting glucose tolerance in patients 60 years or older at surgery (3.22 [1.19–8.76]). Conclusion. Arterial hypertension and elevated diastolic blood pressure are associated with a risk for AS requiring surgery in subjects below 60 years of age. Strict blood pressure control in this group is strongly advocated to avoid other cardiovascular diseases correlated to hypertension. If hypertension and elevated diastolic blood pressure are risk factors for developing AS requiring surgery need further investigations. Notably, elevated fasting glucose levels were related to AS requiring surgery in older adults without concomitant CAD.
The History of Pancreas Transplantation: Past, Present and Future

Abstract The first attempt to cure type 1 diabetes by pancreas transplantation was done at the University of Minnesota, in Minneapolis, on December 17, 1966, followed by a series of whole pancreas transplantation. Due to the lack of potent immunosuppressive drugs, rejections and infections, it was concluded that pancreas was less antigenic than the kidney which was less antigenic than the duodenum. It opened the door to a period, between the mid 70’s to mid 80’s where only segmental pancreatic grafts were used in the recipient. Numerous techniques for diverting or dealing with the pancreas juice secretion were described, none of them being satisfactory. In the late 70ȉs - early 80’s, three major events happened and boosted the development of pancreas transplantation: firstly the introduction of Cyclosporine A in the clinical field, secondly the organization on March 1980, of the first international meeting on Pancreas Transplantation with the first report of the International Pancreas Transplantation Registry (IPTR) and finally in 1982, the organization of the first informal so-called Spitzingsee meetings where pancreas transplantation successes but mainly failures were discussed which precluded the onset of IPITA (International Pancreas and Islet Transplantation Association), EuroSPK (European Study Group for simultaneous Pancreas and Kidney Transplantation) and EPITA (European Pancreas and Islet Transplantation Association). During one of the Spitzingsee meetings, participants had the idea to renew the urinary drainage technique of the exocrine secretion of the pancreatic graft with segmental graft and eventually with whole pancreaticoduodenal transplant. That was clinically achieved during the mid 80’s and remained the mainstay technique during the next decade. In parallel, the Swedish group developed the whole pancreas transplantation technique with enteric diversion. It was the onset of the whole pancreas reign. The enthusiasm for the technique was rather moderated in its early phase due to the rapid development of liver transplantation and the need for sharing vascular structures between both organs, liver and pancreas. During the modern era of immunosuppression, the whole pancreas transplantation technique with enteric diversion became the gold standard for simultaneous pancreas and kidney transplantation (SPK), with portal drainage of the venous effluent of the pancreas, even for pancreas after kidney (PAK) or pancreas transplantation alone (PTA). Today, there remains room for improvement: safety of using the duodeno-duodenal anastomosis technique must be confirmed by prospective analysis while preventing ischemic reperfusion injuries, using specific drugs; that must be assessed in new trials.
Nociceptors Are Interleukin-1β Sensors

A cardinal feature of inflammation is heightened pain sensitivity at the site of the inflamed tissue. This results from the local release by immune and injured cells of nociceptor sensitizers, including prostaglandin E2, bradykinin, and nerve growth factor, that reduce the threshold and increase the excitability of the peripheral terminals of nociceptors so that they now respond to innocuous stimuli: the phenomenon of peripheral sensitization. We show here that the proinflammatory cytokine interleukin-1β (IL-1β), in addition to producing inflammation and inducing synthesis of several nociceptor sensitizers, also rapidly and directly activates nociceptors to generate action potentials and induce pain hypersensitivity. IL-1β acts in a p38 mitogen-activated protein kinase (p38 MAP kinase)-dependent manner, to increase the excitability of nociceptors by relieving resting slow inactivation of tetrodotoxin-resistant voltage-gated sodium channels and also enhances persistent TTX-resistant current near threshold. By acting as an IL-1β sensor, nociceptors can directly signal the presence of ongoing tissue inflammation.
Perspectives of Individuals With Serious Mental Illness on a Reverse-Colocated Care Model: A Qualitative Study.

OBJECTIVE Individuals with serious mental illness experience excess mortality related to general medical comorbidities. Reverse-integrated and reverse-colocated models of care have been proposed as a system-level solution. Such models integrate primary care services within behavioral health settings. Further understanding of consumer perspectives on these models is needed to ensure that models adequately engage consumers on the basis of their expressed needs. This qualitative study examined the perspectives of English- and Spanish-speaking individuals with serious mental illness on their current experience with the management of their medical care and on a hypothetical reverse-colocated care model. METHODS Semistructured interviews were conducted in a purposive sample of 30 individuals with serious mental illness recruited from two outpatient mental health clinics affiliated with a comprehensive community-based program. The interview assessed the participant's current experience with the management of their health care, followed by a vignette describing a reverse--colocated care model and questions to elicit the participant's reaction to the vignette. An inductive thematic analysis was employed. RESULTS Consumers expressed positive views of the potential for working with trusted staff, increased communication, and access to care through reverse colocation. Reflections on current health management experience were notable for an emphasis on self-efficacy and receipt of support for self-management strategies from mental health clinicians. CONCLUSIONS Study findings add to prior literature indicating support for assistance with management of general medical health in the mental health setting among individuals with serious mental illness. Key themes similar to those in previous studies generate hypotheses for further evaluation.
Role of socioeconomic status and housing conditions in geriatric depression in rural China: a cross-sectional study

Objectives The primary aim of this study was to describe the socioeconomic status (SES), housing conditions and depression of the elderly in rural China, as well as to examine the associations between depression and SES and housing conditions using the China Health and Retirement Longitudinal Study (CHARLS). Design This is a cross-sectional study. Setting A nationally representative sample of elderly in rural China. Participants A total of 4585 elderly adults in 2015 in rural China. Outcome measures Prevalence and risk factors of depression among rural elderly. Results Among the participants in this study, approximately 46.15% (2116/4585) reported depressive symptoms (10-item Center for Epidemiologic Studies Depression Scale [CESD-10] score >10) in rural China. The results revealed significant associations between higher scores on CESD-10 (indicating more symptoms of depression) and lowest personal annual income (OR=1.63, 95% CI 1.290 to 2.060), polluting cooking fuel (OR=1.16, 95% CI 1.018 to 1.321), toilet without seat (OR=1.273, 95% CI 1.056 to 1.535), as well as having no bath facility (OR=1.172, 95% CI 1.025 to 1.341) after adjustment for confounders. Conclusion Elderly in rural China experienced severe depressive symptoms. Lowest personal annual income, polluting cooking fuel, toilet without seat and having no bath facility were significantly associated with more depressive symptoms. Caution needs to be taken in generalising the findings of this study to the rest of the population in China since its highly selected sample.
Ontogenetic and Pathogenetic Views on Somatic Chromosomal Mosaicism

Intercellular karyotypic variability has been a focus of genetic research for more than 50 years. It has been repeatedly shown that chromosome heterogeneity manifesting as chromosomal mosaicism is associated with a variety of human diseases. Due to the ability of changing dynamically throughout the ontogeny, chromosomal mosaicism may mediate genome/chromosome instability and intercellular diversity in health and disease in a bottleneck fashion. However, the ubiquity of negligibly small populations of cells with abnormal karyotypes results in difficulties of the interpretation and detection, which may be nonetheless solved by post-genomic cytogenomic technologies. In the post-genomic era, it has become possible to uncover molecular and cellular pathways to genome/chromosome instability (chromosomal mosaicism or heterogeneity) using advanced whole-genome scanning technologies and bioinformatic tools. Furthermore, the opportunities to determine the effect of chromosomal abnormalities on the cellular phenotype seem to be useful for uncovering the intrinsic consequences of chromosomal mosaicism. Accordingly, a post-genomic review of chromosomal mosaicism in the ontogenetic and pathogenetic contexts appears to be required. Here, we review chromosomal mosaicism in its widest sense and discuss further directions of cyto(post)genomic research dedicated to chromosomal heterogeneity.
Early Alterations of the Receptor-Binding Properties of H1, H2, and H3 Avian Influenza Virus Hemagglutinins after Their Introduction into Mammals

ABSTRACT Interspecies transmission of influenza A viruses circulating in wild aquatic birds occasionally results in influenza outbreaks in mammals, including humans. To identify early changes in the receptor binding properties of the avian virus hemagglutinin (HA) after interspecies transmission and to determine the amino acid substitutions responsible for these alterations, we studied the HAs of the initial isolates from the human pandemics of 1957 (H2N2) and 1968 (H3N2), the European swine epizootic of 1979 (H1N1), and the seal epizootic of 1992 (H3N3), all of which were caused by the introduction of avian virus HAs into these species. The viruses were assayed for their ability to bind the synthetic sialylglycopolymers 3′SL-PAA and 6′SLN-PAA, which contained, respectively, 3′-sialyllactose (the receptor determinant preferentially recognized by avian influenza viruses) and 6′-sialyl(N-acetyllactosamine) (the receptor determinant for human viruses). Avian and seal viruses bound 6′SLN-PAA very weakly, whereas the earliest available human and swine epidemic viruses bound this polymer with a higher affinity. For the H2 and H3 strains, a single mutation, 226Q→L, increased binding to 6′SLN-PAA, while among H1 swine viruses, the 190E→D and 225G→E mutations in the HA appeared important for the increased affinity of the viruses for 6′SLN-PAA. Amino acid substitutions at positions 190 and 225 with respect to the avian virus consensus sequence are also present in H1 human viruses, including those that circulated in 1918, suggesting that substitutions at these positions are important for the generation of H1 human pandemic strains. These results show that the receptor-binding specificity of the HA is altered early after the transmission of an avian virus to humans and pigs and, therefore, may be a prerequisite for the highly effective replication and spread which characterize epidemic strains.