Miracle-dz/UniFAR-FTUs huggingface dataset:
Diabetes‐free survival after extended distal pancreatectomy and islet auto transplantation for benign or borderline/malignant lesions of the pancreas

Islet autotransplant is particularly attractive to prevent diabetes after extended pancreatectomy for benign or borderline/malignant pancreas disease. Between 2008 and 2018, 25 patients underwent left extended pancreatectomy (>60%) and islet autotransplant for a neoplasm located in the pancreatic neck or proximal body. Overall, disease‐free and diabetes‐free survivals were estimated and compared with those observed in 68 nondiabetic patients who underwent distal pancreatectomy for pancreatic neoplasms without islet autotransplant. Median follow‐up was 4 years. We observed no deaths and a low morbidity (nonserious procedure‐related complications in 2 of 25 patients). Patient and insulin‐independent survival rates at 4 years were 100% and 96%, respectively. Glucose homeostasis remained within a nondiabetic range at all times for 19 (73%) of 25 patients. Preoperative glycemic level and insulin resistance were major predictors of diabetes development in these patients. Patients undergoing islet autotransplant had a longer diabetes‐free survival than did patients without islet autotransplant (P = .04). In conclusion, islet autotransplant after extended pancreatic resection for neoplasms is a safe and successful procedure for preventing diabetes.
Impact of Genetic Variation on Pravastatin Systemic Exposure in Pediatric Hypercholesterolemia

This study investigated the impact of SLCO1B1 genotype on pravastatin systemic exposure in children and adolescents with hypercholesterolemia. Participants (8–20 years) with at least one allelic variant of SLCO1B1 c.521T>C (521TC, n = 15; 521CC, n = 2) and wild‐type controls (521TT, n = 15) completed a single oral dose pharmacokinetic study. Interindividual variability of pravastatin acid (PVA) exposure within SLCO1B1 genotype groups exceeded the approximately twofold difference in mean PVA exposure observed between SLCO1B1 genotype groups (P > 0.05, q > 0.10). The 3′α‐iso‐pravastatin acid and lactone isomer formation in the acidic environment of the stomach prior to absorption also was variable and affected PVA exposure in all genotype groups. The SLCO1B1 c.521 gene variant contributing to variability in systemic exposure to PVA in our pediatric cohort was comparable to previous studies in adults. However, other demographic and physicochemical factors seem to also contribute to interindividual variability in the dose–exposure relationship.
AN AD-HOC DATA NETWORK FOR MEDICAL DATA COLLECTION AND REDUCTION

This paper presents an ad-hoc network that provides for fast and accurate telemetric channeling of data from medical monitoring devices in an outpatient environment. The network is used to analyze the concept of sedentary state that helps providing a model of sedentary state by the pharmaceutical employees. Prevention and treatment of sedentary state are priorities in healthcare providers serving all developmental groups.
Profound, durable and MGMT‐independent sensitivity of glioblastoma cells to cyclin‐dependent kinase inhibition

TG02 is a novel cyclin‐dependent kinase (CDK) inhibitor and thought to act mainly via CDK‐9 inhibition‐dependent depletion of short‐lived oncoproteins such as MCL‐1 or c‐MYC. We studied the activity of TG02 in 9 human long‐term glioma cell lines (LTC) and 5 glioma‐initiating cell lines (GIC) using various cell death assays in vitro and in the LN‐229 LTC and ZH‐161 GIC models in vivo. TG02 exhibits strong anti‐tumor cell activity with EC50 concentrations in the nanomolar range. Median survival in the LN‐229 and ZH‐161 models was moderately prolonged by TG02. Neither constitutive CDK levels nor those of MCL‐1 or c‐MYC correlated with sensitivity to TG02. Cdk‐9 or cdk‐5 gene silencing alone did not fully reproduce the effects of TG02. C‐myc gene silencing inhibited cell growth, but did not modulate TG02 activity. Electron microscopy revealed cell death to be essentially apoptotic. High concentrations of TG02 induced annexin V binding and minor caspase 3 cleavage, but the pan‐caspase inhibitor, zVAD‐fmk, or BCL‐2 or MCL‐1 gene transfer only moderately attenuated TG02‐induced cell death, and caspase inhibition did not prevent loss of MCL‐1 or c‐MYC. TG02 activity was independent of O6‐methylguanine DNA methyltransferase expression. Repetitive exposure to TG02 did not generate an acquired TG02 resistance phenotype, but accumulation of MCL‐1, loss of c‐MYC, or senescence. TG02 is a highly potent apoptosis‐inducing agent in glioma cells in vitro. Caspase inhibition does not rescue TG02‐treated cells and repetitive exposure fails to confer acquired resistance, supporting the clinical evaluation of TG02 in glioblastoma.
Clinical trial design and new therapies for pulmonary arterial hypertension

Until 20 years ago the treatment of pulmonary arterial hypertension (PAH) was based on case reports and small series, and was largely ineffectual. As a deeper understanding of the pathogenesis and pathophysiology of PAH evolved over the subsequent two decades, coupled with epidemiological studies defining the clinical and demographic characteristics of the condition, a renewed interest in treatment development emerged through collaborations between international experts, industry and regulatory agencies. These efforts led to the performance of robust, high-quality clinical trials of novel therapies that targeted putative pathogenic pathways, leading to the approval of more than 10 novel therapies that have beneficially impacted both the quality and duration of life. However, our understanding of PAH remains incomplete and there is no cure. Accordingly, efforts are now focused on identifying novel pathogenic pathways that may be targeted, and applying more rigorous clinical trial designs to better define the efficacy of these new potential treatments and their role in the management scheme. This article, prepared by a Task Force comprised of expert clinicians, trialists and regulators, summarises the current state of the art, and provides insight into the opportunities and challenges for identifying and assessing the efficacy and safety of new treatments for this challenging condition. State of the art and research perspectives in clinical trial design and new therapies for pulmonary arterial hypertension http://ow.ly/VHQ030mfRxc
Simultaneous liver kidney transplantation

Kidney injury is frequently seen in patients with end‐stage liver disease from cirrhosis and liver failure. Among selected patients, simultaneous liver kidney (SLK) transplantation provides improved post‐transplant graft and patient outcomes compared to liver transplantation (LT) alone. We conducted the review of the existing literature on SLK transplant criteria and outcomes. Since the introduction of the model for end‐stage disease (MELD) score in 2002, there has been an increased use of SLK transplantation. The criteria for SLK allocation are relatively homogeneous among patients with end‐stage renal disease with cirrhosis and among patients with cirrhosis and chronic kidney disease. However, these are quite heterogeneous among patients with cirrhosis and acute kidney injury (AKI), mainly because of inability to accurately differentiate cause of AKI, especially hepatorenal syndrome versus intrarenal aetiology. Clearly, there is an unmet need of urine biomarkers of tubular injury and/or clinical models to accurately stratify AKI aetiology and to predict renal recovery after LT as basis to best utilize the scarce donor kidney pool. In this regard, it remains to be seen whether recently implemented policies by the organ procurement transplant network can fulfil the goal of saving donor kidneys and optimal allocation of SLK.
JAK2 regulates mismatch repair protein‐mediated epigenetic alterations in response to oxidative damage

At sites of chronic inflammation epithelial cells undergo aberrant DNA methylation that contributes to tumorigenesis. Inflammation is associated with an increase in reactive oxygen species (ROS) that cause oxidative DNA damage, which has also been linked to epigenetic alterations. We previously demonstrated that in response to ROS, mismatch repair proteins MSH2 and MSH6 recruit epigenetic silencing proteins DNA methyltransferase 1 (DNMT1) and polycomb repressive complex 2 (PRC2) members to sites of DNA damage, resulting in transcriptional repression of tumor suppressor genes (TSGs). However, it was unclear what signal is unique to ROS that results in the chromatin binding of MSH2 and MSH6. Herein, we demonstrate that in response to hydrogen peroxide (H2O2), JAK2 localizes to the nucleus and interacts with MSH2 and MSH6. Inhibition or knockdown of JAK2 reduces the H2O2‐induced chromatin interaction of MSH2, MSH6, DNMT1, and PRC2 members, reduces H2O2‐induced global increase in trimethylation of lysine 27 of histone H3 (H3K27me3), and abrogates oxidative damage‐induced transcriptional repression of candidate TSGs. Moreover, JAK2 mRNA expression is associated with CpG island methylator phenotype (CIMP) status in human colorectal cancer. Our findings provide novel insight into the connection between kinase activation and epigenetic alterations during oxidative damage and inflammation. Environ. Mol. Mutagen. 60:308–319, 2019. © 2018 Wiley Periodicals, Inc.
Lenalidomide‐based response‐adapted therapy for older adults without high risk myeloma

Combined lenalidomide and dexamethasone is a standard‐of‐care therapy for the treatment of older adults with multiple myeloma. Lenalidomide monotherapy has not been evaluated in newly diagnosed myeloma patients. We conducted a phase II study, evaluating a response‐adapted therapy for older adults newly diagnosed with multiple myeloma without high‐risk features who were ineligible for high‐dose therapy and stem cell transplant. Patients were started on single‐agent lenalidomide, and low‐dose dexamethasone was added in the event of progressive disease, in a response‐adapted approach. The primary endpoint was progression‐free survival (PFS), and the International Myeloma Working Group's uniform response criteria were used to assess response and progression. Twenty‐seven patients were enrolled, and 20 (74%) experienced a partial response or better to this response‐adapted therapy. After a median follow‐up of 69 months, the median PFS was 36 months [95% confidence interval (CI), 29·8 to not reached], and the median overall survival was 65 months (95% CI, 35·3 to not reached). Grade 3/4 adverse events were mainly haematological in nature. This response‐adapted therapy in this patient population is feasible and results in durable responses that compare favourably with concurrent lenalidomide and dexamethasone. These results should be validated in prospective studies.
Chronic Musculoskeletal Pain, Self-Reported Health and Quality of Life among Older Populations in South Africa and Uganda

Chronic musculoskeletal pain (CMP) is a serious health concern especially among the elderly population and has significant bearing on health and quality of life. Not much is known about the relationship between chronic pain with self-reported health and quality of life among older populations in low-resource settings. Based on sub-national data from South Africa and Uganda, the present study aimed to explore whether the older population living with CMP report health and quality of life differently compared to those with no CMP complaints. This study was based on cross-sectional data on 1495 South African and Ugandan men and women collected from the SAGE Well-Being of Older People Study. Outcome variables were self-reported physical and mental health and quality of life (QoL). Mental health was assessed by self-reported depressive symptoms during the last 12 months. CMP was assessed by self-reported generalised pain as well as back pain. Multivariable logistic regression models were used to measure the association between health and QoL with CMP by adjusting for potential demographic and environmental confounders. The prevalence of poor self-rated health (61.2%, 95% CI = 51.7, 70.0), depression (37.2%, 95% CI = 34.8, 39.6) and QoL (80.5%, 95% CI = 70.8, 87.5) was considerably high in the study population. Mild/moderate and Severe/extreme generalised pain were reported respectively by 34.5% (95% CI = 28.9, 40.5) and 15.7% (95% CI = 12.2, 19.9) of the respondents, while back pain was reported by 53.3% (95% CI = 45.8, 60.4). The prevalence of both types was significantly higher among women than in men (p < 0.001). In the multivariate analysis, both generalised pain and back pain significantly predicted poor health, depression and QoL, however, it varied between the two different populations. Back pain was associated with higher odds of poor self-rated health [OR = 1.813, 95% CI = 1.308, 2.512], depression [1.640, 95% CI = 1.425, 3.964] and poor QoL [1.505, 95% CI = 1.028, 2.202] in South Africa, but not in Uganda. Compared to having no generalised pain, having Mild/Moderate [OR = 2.309, 95% CI = 1.219, 7.438] and Severe/Extreme [OR = 2.271, 95% CI = 1.447, 4.143] generalised pain was associated with significantly higher odds of poor self-rated health in South Africa. An overwhelmingly high proportion of the sample population reported poor health, quality of life and depression. Among older individuals, health interventions that address CMP may help promote subjective health and quality and life and improve psychological health.
Validation of CollaboRATE and SURE – two short questionnaires to measure shared decision making during CPAP initiation

Adherence to continuous positive airway pressure (CPAP) treatment tends to be low. Brief validated instruments focusing on shared decision making have not been used in a CPAP context. The aim was to investigate factorial structure, categorical functioning of the response scale and differential item functioning across sub‐populations of the CollaboRATE and Sure questionnaires among patients with obstructive sleep apnea (OSA) before CPAP treatment is initiated. A prospective design, including 193 objectively diagnosed (polygraphy) OSA patients (68% men, 59.7 years, SD 11.5) from two CPAP clinics was used. Data were collected with the following questionnaires; Sure, CollaboRATE, Attitudes to CPAP Inventory, Epworth sleepiness scale, minimal insomnia symptoms scale, and hospital anxiety and depression scale. Objective CPAP use was collected after 6 months; 49% demonstrated decisional conflict on SURE and 51% scored low levels of shared decision making on CollaboRATE. Unidimensionality was found for both CollaboRATE (one factor explaining 57.4%) and SURE (one factor explaining 53.7%), as well as local independence. Differential item functioning showed both to be invariant across both male and female patients. Internal consistency (Cronbach's alpha 0.83) and composite reliability (0.89) were good. Latent class analyses showed that patients with low decisional conflict and high shared decision making were more adherent to CPAP treatment. CollaboRATE and SURE provided good validity and reliability scores to measure shared decision making and decisional conflict in relation to CPAP treatment. The questionnaires can be used by healthcare personnel as a tool to simplify the assessment of shared decision making.
Predictive value of oncogenic driver subtype, programmed death‐1 ligand (PD‐L1) score, and smoking status on the efficacy of PD‐1/PD‐L1 inhibitors in patients with oncogene‐driven non–small cell lung cancer

This multicenter, retrospective study explored the value of oncogene driver subtype, programmed death‐1 ligand (PD‐L1) status, and smoking status for predicting which patients with oncogene‐driven non–small cell lung cancer (NSCLC) would benefit from treatment with programmed death‐1 (PD‐1)/PD‐L1 inhibitors.
Dietary Fat Intake and Risk of Colorectal Cancer: A Systematic Review and Meta-Analysis of Prospective Studies

Dietary fat intake is associated with the risk of colorectal cancer (CRC); however, the results of epidemiological studies on this are controversial. Therefore, this study aimed to summarize the available scientific evidence regarding the association between dietary fat and the risk of CRC. We conducted a systematic search of PubMed, Web of Science, and the Cochrane library for articles related to dietary fat and the risk of CRC. The summary relative risks with 95% confidence intervals (CI) were calculated via a random effect model. Begg’s test was used to detect publication bias. A total of 18 articles were identified. The pooled relative risk with 95% CI for the risk of CRC were 1.00 (95% CI: 0.90–1.12), 0.97 (95% CI: 0.86–1.10), 1.08 (95% CI: 0.92–1.26), and 0.99 (95% CI: 0.93–1.04) for total fat, saturated fatty acid, monounsaturated fatty acid, and polyunsaturated fatty acid, respectively. No significant associations were found in subgroup analyses. Begg’s test for all exposures revealed no publication bias (total fat, p = 0.3; saturated fatty acid, p = 0.1; monounsaturated fatty acid, p = 0.08; polyunsaturated fatty acid, p = 0.2). The studies included in this review and meta-analysis revealed that dietary fats and fatty acids had no effects on the risk of CRC.
In vitro fertilisation/intracytoplasmic sperm injection beyond 2020

Over 8 million babies have been born following IVF (in vitro fertilisation) and other artificial reproductive technology (ART) procedures since Louise Brown's birth 40 years ago. New innovations have added much complexity to both clinical and laboratory procedures over the last four decades. Translation of novel approaches from basic science into clinical practice continues unabated, widening the applicability of ART to new groups of people and helping improve both chances of healthy live birth and patient acceptability. However, the impact of ART on the health of both patients and their offspring continues to cause concern, and many ethical challenges created by new scientific developments in this field attract widely differing opinions. What is undeniable is that there will be a sustained global growth in utilisation of ART and that reproductive tourism will allow many people to access the treatment they desire notwithstanding national regulations that may forbid some approaches. The greatest challenge is to expand access to ART to those living in the less wealthy nations who are equally deserving of its benefits.
The transcription factor POU3F2 regulates a gene coexpression network in brain tissue from patients with psychiatric disorders

POU3F2 regulates expression of key genes in postmortem brain tissue from patients with schizophrenia or bipolar disorder. Illuminating the genomic mysteries of psychiatric diseases Schizophrenia and bipolar disorder are complex psychiatric diseases with risks contributed by multiple genes. Studies by the PsychENCODE Consortium, including two in this issue (Chen et al. and Meng et al.), seek to elucidate the genomic elements and regulatory pathways that underpin several psychiatric disorders. Chen et al. analyzed transcriptome data from postmortem brain tissue from patients with schizophrenia or bipolar disorder. They report that the transcription factor POU3F2 is a core regulator of a gene coexpression network associated with these disorders. In a genome-wide analysis of control human brain samples from the adult and developing brain, Meng et al. report that the lncRNA DGCR5, which lies within the 22q11.2 deletion associated with schizophrenia risk, regulates expression of several SCZ-associated protein-coding genes. Schizophrenia and bipolar disorder are complex psychiatric diseases with risks contributed by multiple genes. Dysregulation of gene expression has been implicated in these disorders, but little is known about such dysregulation in the human brain. We analyzed three transcriptome datasets from 394 postmortem brain tissue samples from patients with schizophrenia or bipolar disorder or from healthy control individuals without a known history of psychiatric disease. We built genome-wide coexpression networks that included microRNAs (miRNAs). We identified a coexpression network module that was differentially expressed in the brain tissue from patients compared to healthy control individuals. This module contained genes that were principally involved in glial and neural cell genesis and glial cell differentiation, and included schizophrenia risk genes carrying rare variants. This module included five miRNAs and 545 mRNAs, with six transcription factors serving as hub genes in this module. We found that the most connected transcription factor gene POU3F2, also identified on a genome-wide association study for bipolar disorder, could regulate the miRNA hsa-miR-320e and other putative target mRNAs. These regulatory relationships were replicated using PsychENCODE/BrainGVEX datasets and validated by knockdown and overexpression experiments in SH-SY5Y cells and human neural progenitor cells in vitro. Thus, we identified a brain gene expression module that was enriched for rare coding variants in genes associated with schizophrenia and that contained the putative bipolar disorder risk gene POU3F2. The transcription factor POU3F2 may be a key regulator of gene expression in this disease-associated gene coexpression module.
Much Ado about N…atrium: modelling tissue sodium as a highly sensitive marker of subclinical and localized oedema

Hypertonic Na+ accumulation in peripheral tissues is a recently described phenomenon: it has been associated with ageing, hypertension, diabetes, chronic kidney disease and heart failure, but its clinical meaning has yet to be determined. This concept conflicts with the classic physiological paradigm of constant balance between salt intake and excretion, and its water-independent nature is still a matter of debate. We developed a theoretical model explaining changes in the chemical composition of tissues as a function of extracellular volume fraction and excess extracellular fluid, i.e. oedema. The model suggests that the proportional increase in absolute Na+ content and concentration due to different degrees of oedema is higher than the parallel increase in water content, thus making Na+ a more sensitive index to detect this oedema. Our model would explain some of the recent findings of high tissue Na+ content in pathological conditions. More importantly, it prompts the reappraisal of tissue Na+ analysis from being a topic of niche interest to a potential diagnostic tool with broad applicability in the investigation of subclinical systemic and localized oedema.