Miracle-dz/UniFAR-FTUs huggingface dataset:
Women with fair phenotypes seem to confer a survival advantage in a low UV milieu. A nested matched case control study

Background Sun exposure in combination with skin pigmentation is the main determinant for vitamin D status. Human skin color seems to be adapted and optimized for regional sun ultraviolet (UV) intensity. However, we do not know if fair, UV-sensitive skin is a survival advantage in regions with low UV radiation. Methods A population-based nested case–control study of 29,518 Caucasian women, ages 25 to 64 years from Southern Sweden who responded to a questionnaire regarding risk-factors for malignant melanoma in 1990 and followed for 25 years. For each fair woman, defined as having red hair or freckles (n = 11,993), a control was randomly selected from all non-fair women from within the cohort of similar age, smoking habits, education, marital status, income, and comorbidity, i.e., 11,993 pairs. The main outcome was the difference in all-cause mortality between fair and non-fair women in a low UV milieu, defined as living in Sweden and having low-to-moderate sun exposure habits. Secondary outcomes were mortality by sun exposure, and among those non-overweight. Results In a low UV milieu, fair women were at a significantly lower all-cause mortality risk as compared to non-fair women (log rank test p = 0.04) with an 8% lower all-cause mortality rate (hazard ratio [HR] = 0.92, 95% CI 0.84‒1.0), including a 59% greater risk of dying from skin cancer among fair women (HR 1.59, 95% CI 1.26‒2.0). Thus, it seem that the beneficial health effect from low skin coloration outweigh the risk of skin cancer at high latitudes. Conclusion In a region with low UV milieu, evolution seems to improve all-cause survival by selecting a fair skin phenotype, i.e., comprising fair women with a survival advantage.
A collaborative approach to developing sustainable behaviour change interventions for childhood obesity prevention: Development of the Choosing Healthy Eating for Infant Health (CHErIsH) intervention and implementation strategy.

OBJECTIVES AND DESIGN There is growing recognition of the need for effective behaviour change interventions to prevent chronic diseases that are feasible and sustainable and can be implemented within routine health care systems. Focusing on implementation from the outset of intervention development, and incorporating multiple stakeholder perspectives to achieve this, is therefore essential. This study explores the development of the Choosing Healthy Eating for Infant Health (CHErIsH) childhood obesity prevention intervention and implementation strategy to improve infant feeding behaviours. METHODS Five qualitative and quantitative evidence syntheses, two primary qualitative studies, and formal/informal consultations were conducted with practice, policy, research, and parent stakeholders. The Behaviour Change Wheel was used to guide the integration of findings. RESULTS The CHErIsH intervention targets parent-level behaviour change and comprises (1) brief verbal messages and (2) trustworthy resources, to be delivered by health care professionals (HCPs) during routine infant vaccination visits. The implementation strategy targets HCP-level behaviour change and comprises (1) a local opinion leader, (2) incentivized training, (3) HCP resources and educational materials, (4) electronic delivery prompts, (5) awareness-raising across all primary care HCPs, and (6) local technical support. CONCLUSIONS This study provides a rigorous example of the development of an evidence-based intervention aimed at improving parental infant feeding behaviours, alongside an evidence-based behaviour change strategy to facilitate implementation and sustainability in primary care. This approach demonstrates how to systematically incorporate multiple stakeholder perspectives with existing literature and move from multiple evidence sources to clearly specified intervention components for both the intervention and implementation strategy. Statement of Contribution What is already known? Incorporating insights from practice, policy, and public/patient stakeholders plays a key role in developing behaviour change interventions that are feasible and sustainable and can be implemented within routine health care systems. However, there are limited examples that provide in-depth guidance of how to do this using a systematic approach. What this study adds? This study describes an innovative use of the Behaviour Change Wheel to integrate multiple sources of evidence collected from practice, policy, research, and parent stakeholders to concurrently develop an evidence-based intervention to improve parental infant feeding behaviours and an implementation strategy to facilitate sustainable delivery by health care professionals in routine primary care.
A Review of Donor Acute Kidney Injury and Posttransplant Outcomes.

Although over 90 000 people are on the kidney transplant waitlist in the United States, some kidneys that are viable for transplantation are discarded. Transplant surgeons are more likely to discard deceased donors with acute kidney injury (AKI) versus without AKI (30% versus 18%). AKI is defined using changes in creatinine from baseline. Transplant surgeons can use DonorNet data, including admission, peak, and terminal serum creatinine, and biopsy data when available to differentiate kidneys with AKI from those with chronic injury. While chronic kidney disease is associated with reduced graft survival, an abundance of literature has demonstrated similar graft survival for deceased donors with AKI versus donors without AKI. Donors with AKI are more likely to undergo delayed graft function (DGF) but have similar long-term outcomes as donors without AKI. The mechanism for similar graft survival is unclear. Some hypothesized mechanisms include a) ischemic preconditioning; b) posttransplant and host factors playing a greater role in long-term survival than donor factors; and c) selection bias of transplanting only relatively healthy donor kidneys with AKI. Existing literature suggests transplanting more donor kidneys with Stage 1 and 2 AKI, and cautious utilization of Stage 3 AKI donors, may increase the pool of viable kidneys. Doing so can reduce the number of people who die on the waitlist by over 500 every year.
A Phase I/II Trial of 5-Fraction Stereotactic Radiosurgery with 5-mm Margins with Concurrent Temozolomide in Newly Diagnosed Glioblastoma: Primary Outcomes.

BACKGROUND We sought to determine the maximum tolerated dose (MTD) of 5-fraction stereotactic radiosurgery (SRS) with 5-mm margins delivered with concurrent temozolomide in newly diagnosed glioblastoma. METHODS We enrolled adult patients with newly diagnosed glioblastoma to 5 days of SRS in a 3+3 design on 4 escalating dose levels: 25, 30, 35, and 40 Gy. Dose limiting toxicity (DLT) was defined as CTCAE Grade 3-5 acute or late CNS toxicity, including adverse radiation effect (ARE), the imaging correlate of radiation necrosis. RESULTS From 2010 to 2015, 30 patients were enrolled. The median age was 66 years (range 51-86 years). The median target volume was 60 cm3 (range 14.7-137.3 cm3). DLT occurred in 2 patients: one for post-treatment cerebral edema and progressive disease at 3 weeks (Grade 4, Dose 40 Gy); another patient died 1.5 weeks following SRS from post-operative complications (Grade 5, Dose 40 Gy). Late grade 1-2 ARE occurred in 8 patients at a median of 7.6 months (range 3.2-12.6 months). No grade 3-5 ARE occurred. With a median follow-up of 13.8 months (range 1.7-64.4 months), the median survival times were: PFS 8.2 months (95%CI 4.6-10.5), OS 14.8 months (95%CI 10.9-19.9), MGMT hypermethylated 19.9 months (95%CI 10.5-33.5) vs. 11.3 months (95%CI 8.9-17.6) for no/unknown hypermethylation (p=0.03), and 27.2 months (95%CI 11.2-48.3) if late ARE occurred vs. 11.7 months (95%CI 8.9-17.6) for no ARE (p=0.08). CONCLUSIONS The per-protocol MTD of 5-fraction SRS with 5-mm margins with concurrent temozolomide was 40 Gy in 5 fractions. ARE was limited to grade 1-2 and did not statistically impact survival.
Cardiovascular Acute Effects of Traditional vs. Paired Set Resistance Training in Patients With Liver Cirrhosis

ABSTRACT Purpose: This study compared the acute effects of two different resistance training methods on heart rate variability, blood pressure, and rating of perceived exertion in patients with liver cirrhosis. Methods: Ten patients with Child-Pugh A (seven women and three men) participated in two experimental sessions, in random order: The traditional set condition consisted of three sets of six exercises performed in a sequential manner, while the paired set condition consisted of alternating sets between two exercises (three pairs of exercises). Ten repetitions were performed for each set with 70% of a 10 repetition maximum load and with 2 min rest between sets. Blood pressure and heart rate variability were assessed pre-workout and for 60 min post-workout. The rating of perceived exertion was assessed at the end of the third set for each exercise. Results: Significant alterations in heart rate variability were observed when considering the lowest value obtained during recovery, in which the SDNN was reduced in both the traditional set and paired set conditions, as well as the root mean square of standard deviation for the traditional set condition (p < .05). Additionally, for the paired set condition, there was a significant reduction in the HFnu band and a significant increase in the LFnu band (p < .05). Effect size showed reductions in diastolic and mean blood pressure until 30 min in a small magnitude for traditional sets. Conclusion: Similar cardiovascular responses were observed between methods eliciting normal physiological responses within safe limits for patients with liver cirrhosis.
Impaired death receptor signaling in leukemia causes antigen-independent resistance by inducing CAR T cell dysfunction.

Primary resistance to CD19-directed chimeric antigen receptor T cell therapy (CART19) occurs in 10-20% of patients with acute lymphoblastic leukemia (ALL), however the mechanisms of this resistance remain elusive. Using a genome-wide loss-of-function screen, we identified that impaired death receptor signaling in ALL led to rapidly progressive disease despite CART19 treatment. This was mediated by an inherent resistance to T cell cytotoxicity which permitted antigen persistence and was subsequently magnified by the induction of CAR T cell functional impairment. These findings were validated using samples from two CAR T cell clinical trials in ALL, where we found that reduced expression of death receptor genes was associated with worse overall survival and reduced T cell fitness. Our findings suggest that inherent dysregulation of death receptor signaling in ALL directly leads to CAR T cell failure by impairing T cell cytotoxicity and promoting progressive CAR T cell dysfunction.
Ketotic cows display a different serum nonesterified fatty acid composition

Abstract The experiments reported in this research communication aimed to compare the serum nonesterified fatty acid (NEFA) composition in ketotic cows and healthy cows during the perinatal period. NEFAs play significant roles in etiology and pathology of ketosis. We hypothesized that ketotic cows will display a different serum NEFA composition compared to healthy controls, and fatty acid related indicators for ketosis prediction can be screened. Pre-partum healthy cows were recruited, and blood samples were collected on −7, 3, 7, 14 and 21 d postpartum. Cows were further divided into a healthy control group (C group, n = 6) and a ketosis group (K group, n = 6) if blood β-hydroxybutyric acid levels exceeded 1.2 mm during the experiment. NEFA composition was then analyzed by means of Gas Chromatography-Mass Spectrometer (GC-MS). Only C12 : 0% was significantly higher in C group than K group on 7 d pre-partum (P < 0.05), when the cows were not diagnosed with ketosis. Five fatty acids displayed statistical differences in composition between C and K group (P < 0.05), namely C12 : 0, C16 : 0, C17 : 0, C18 : 1n9 and C22 : 1n9. Saturates%, unsaturates%, mono-unsaturates% and saturates/unsaturates were also different between C and K group (P < 0.05). Of note, C18 : 1n9/C12 : 0 and C18 : 1n9/C22 : 1n9 in K group were significantly higher than those in controls on 7 d pre-partum (P < 0.05). It is suggested that the ratios show potential as indicators for prediction of ketosis.
Eccentric and Isometric Exercises in Achilles Tendinopathy Evaluated by the VISA-A Score and Shear Wave Elastography

Background: Apart from eccentric exercises (EE), isometric exercises (ISO) might be a treatment option for Achilles tendinopathy. Shear wave elastography (SWE) provides information for diagnosis and for monitoring tissue elasticity, which is altered in symptomatic tendons. Hypothesis: Isometric exercises will have a beneficial effect on patients’ outcome scores. Based on SWE, insertional and midportion tendon parts will differ in their elastic properties according to current symptoms. Study Design: Randomized clinical trial. Level of Evidence: Level 2. Methods: Group 1 (EE; n = 20; 12 males, 8 females; mean age, 52 ± 8.98 years) and group 2 (EE + ISO; n = 22; 15 males, 7 females; mean age, 47 ± 15.11 years) performed exercises for 3 months. Measurement points were before exercises were initiated as well as after 1 and 3 months using the Victorian Institute of Sports Assessment–Achilles (VISA-A) score, American Orthopaedic Foot & Ankle Society score, and SWE (insertion and midportion). Results: Both groups improved significantly, but there were no significant interindividual differences (VISA-A; P = 0.362) between group 1 (n = 15; +15 VISA-A) and group 2 (n = 15; +15 VISA-A). The symptomatic insertion (symptomatic, 136.89 kPa; asymptomatic, 174.68 kPa; P = 0.045) and the symptomatic midportion of the Achilles tendon (symptomatic, 184.40 kPa; asymptomatic, 215.41 kPa; P = 0.039) had significantly lower Young modulus compared with the asymptomatic tendons. The midportion location had significantly higher Young modulus than the insertional part of the tendon (P = 0.005). Conclusion: Isometric exercises do not have additional benefit when combined with eccentric exercises, as assessed over a 3-month intervention period. SWE is able to distinguish between insertional and midportion tendon parts in a symptomatic and asymptomatic state. Clinical Relevance: The present study shows no additional effect of ISO when added to baseline EE in treating Achilles tendinopathy. Different elastic properties of the insertional and midportion tendon have to be taken into consideration when rating a tendon as pathologic.
Cardio-respiratory fitness estimation from heart rate and body movement in daily life.

BACKGROUND Low cardiorespiratory fitness (CRF) increases risk of all-cause mortality and cardiovascular events. Periodic CRF assessment can have an important preventive function. OBJECTIVE To develop a protocol-free method to estimate CRF in daily life based on heart rate (HR) and body acceleration measurements. METHODS Acceleration and HR data were collected from 37 subjects (M=49%) while performing a standardized laboratory activity protocol (sitting, walking, running, cycling) and during a 5-days free-living monitoring period. CRF was determined by oxygen uptake (VO2max) during maximal exercise testing. A doubly-labeled water validated equation was used to predict total energy expenditure (TEE) from acceleration data. A fitness index was defined as the ratio between TEE and HR (TEE-pulse). Activity recognition techniques were used to process acceleration features and classify sedentary, ambulatory and other activity types. Regression equations based on TEE-pulse data from each activity type were developed to predict VO2max. RESULTS TEE-pulse measured within each activity type of the laboratory protocol was highly correlated to VO2max (r from 0.74 to 0.91). Averaging the outcome of each activity-type specific equation based on TEE-pulse from the laboratory data led to accurate estimates of VO2max (RMSE: 300.0 mlO2/min or 10%). The difference between laboratory and free-living determined TEE-pulse was 3.7 ± 11% (r =0.85). The prediction method preserved the prediction accuracy when applied to free-living data (RMSE: 367 mlO2/min or 12%). CONCLUSIONS Measurements of body acceleration and HR can be used to predict VO2max in daily life. Activity-specific prediction equations are needed to achieve highly accurate estimates of CRF.
Causes of mortality in Non-Alcoholic Fatty Liver Disease (NAFLD) and Alcohol related Fatty Liver Disease (AFLD).

Non-alcoholic fatty liver disease (NAFLD) and alcohol related fatty liver disease (AFLD) both represent a spectrum of liver disease severity from hepatic steatosis to fibrosis and cirrhosis. Both NAFLD and AFLD are common diseases in the general population. NAFLD affects ~25% of the adult global population whilst AFLD has become the commonest indication for liver transplantation in the United States. It is often not possible to distinguish between NAFLD and AFLD on examination of liver histology, consequently, differentiation between NAFLD and AFLD is heavily reliant on a history of alcohol consumption. Age, smoking, alcohol consumption and sex appear to influence risk of mortality in NAFLD or AFLD. In NAFLD and AFLD, the key causes of increased liver-related mortality are advanced liver fibrosis and cirrhosis leading to complications such as hepatocellular carcinoma and decompensated cirrhosis. NAFLD and AFLD are also associated with an increased risk of all-cause mortality including an increased risk of extra-hepatic malignancy. Non-invasive biomarkers of liver disease severity in NAFLD and AFLD perform poorly to predict mortality. However, alanine aminotransferase, gamma-glutamyl transpeptidase, FIB-4 and the NAFLD Fibrosis Score are independently associated with increased mortality in NAFLD. Both NAFLD and AFLD are associated with extra-hepatic risk factors and complications such as metabolic syndrome encompassing obesity, hypertension, type 2 diabetes mellitus, and chronic kidney disease. AFLD is associated with hypertension and cardiovascular disease as well as other organ damage. This narrative review discusses the associations, risk factors and diagnostic biomarkers linking NAFLD and AFLD with increased mortality.
Acute Treatment of Pediatric Migraine

The purpose of the Research to Practice column is to review and critique current research articles that directly affect the practice of the advanced practice nurse (APN) in the emergency department. This review examines the findings of M. Oskoui et al. (2019) from their article, “Practice guideline update summary: Acute treatment of migraine in children and adolescents: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology and the American Headache Society. ” The authors completed an extensive literature review and created eight recommendations for the acute treatment of pediatric migraine focusing on medication selection, dosing, patient education, and patient counseling. By applying the evidence-based guidelines presented in this study, the urgent care or emergency department APN can confidently recognize and treat acute migraine symptoms and reduce patient risks from unnecessary testing and overuse of acute migraine medications.
New Insights Into Intestinal Failure–Associated Liver Disease in Children

Development of intestinal failure–associated liver disease (IFALD) is a common complication of long‐term parenteral nutrition (PN) in children and adults. The molecular and cellular mechanisms and the phases of IFALD are now being delineated. Components of PN lipid emulsions, including plant sterols, interact with hepatic innate immune activation promoted by products of gut bacterial overgrowth/dysbiosis and altered intestinal barrier function (gut‐liver axis) and by episodes of sepsis to cause cholestasis and IFALD. New therapeutic strategies, including modifications of intravenous lipid emulsions to reduce pro‐inflammatory fatty acids and plant sterol content, can lower the risk of IFALD, reverse cholestasis, and reduce complications, although the significance of persisting hepatic fibrosis is unknown. This review will provide an update on advances in the pathogenesis of IFALD, newer therapeutic and preventative strategies, and challenges that confront managing patients with IFALD.
The GTPase KRAS suppresses the p53 tumor suppressor by activating the NRF2-regulated antioxidant defense system in cancer cells

In human cancer cells that harbor mutant KRAS and WT p53 (p53), KRAS contributes to the maintenance of low p53 levels. Moreover, KRAS depletion stabilizes and reactivates p53 and thereby inhibits malignant transformation. However, the mechanism by which KRAS regulates p53 is largely unknown. Recently, we showed that KRAS depletion leads to p53 Ser-15 phosphorylation (P-p53) and increases the levels of p53 and its target p21/WT p53-activated fragment 1 (WAF1)/CIP1. Here, using several human lung cancer cell lines, siRNA-mediated gene silencing, immunoblotting, quantitative RT-PCR, promoter–reporter assays, and reactive oxygen species (ROS) assays, we demonstrate that KRAS maintains low p53 levels by activating the NRF2 (NFE2-related factor 2)–regulated antioxidant defense system. We found that KRAS depletion led to down-regulation of NRF2 and its targets NQO1 (NAD(P)H quinone dehydrogenase 1) and SLC7A11 (solute carrier family 7 member 11), decreased the GSH/GSSG ratio, and increased ROS levels. We noted that the increase in ROS is required for increased P-p53, p53, and p21Waf1/cip1 levels following KRAS depletion. Downstream of KRAS, depletion of RalB (RAS-like proto-oncogene B) and IκB kinase–related TANK-binding kinase 1 (TBK1) activated p53 in a ROS- and NRF2-dependent manner. Consistent with this, the IκB kinase inhibitor BAY11-7085 and dominant-negative mutant IκBαM inhibited NF-κB activity and increased P-p53, p53, and p21Waf1/cip1 levels in a ROS-dependent manner. In conclusion, our findings uncover an important role for the NRF2-regulated antioxidant system in KRAS-mediated p53 suppression.
Identifying cytochrome P450s involved in oxidative metabolism of synthetic cannabinoid N‐(adamantan‐1‐yl)‐1‐(5‐fluoropentyl)‐1H‐indole‐3‐carboxamide (STS‐135)

Synthetic cannabinoids (SCBs), designer drugs marketed as legal alternatives to marijuana, act as ligands to cannabinoid receptors; however, they have increased binding affinity and potency, resulting in toxicity symptoms such as cardiovascular incidents, seizures, and potentially death. N‐(adamantan‐1‐yl)‐1‐(5‐fluoropentyl)‐1H‐indole‐3‐carboxamide (STS‐135) is a third generation SCB. When incubated with hepatocytes, it undergoes oxidation, hydrolysis, and glucuronidation, resulting in 29 metabolites, with monohydroxy STS‐135 (M25) and dihydroxy STS‐135 (M21) being the predominant metabolites. The enzymes responsible for this oxidative metabolism were unknown. Thus, the aim of this study was to identify the cytochrome P450 (P450s or CYPs) enzymes involved in the oxidative metabolism of STS‐135. In this study, STS‐135 was incubated with liver, intestinal, and brain microsomes and recombinant P450s to determine the enzymes involved in its metabolism. Metabolite quantification was carried out using ultra‐performance liquid chromatography. STS‐135 was extensively metabolized in HLMs and HIMs. Screening assays indicated CYP3A4 and CYP3A5 could be responsible for STS‐135’s oxidation. Through incubations with genotyped HLMs, CYP3A4 was identified as the primary oxidative enzyme. Interestingly, CYP2J2, a P450 isoform expressed in cardiovascular tissues, showed high activity towards the formation of M25 with a Km value of 11.4 μmol/L. Thus, it was concluded that STS‐135 was primarily metabolized by CYP3A4 but may have extrahepatic metabolic pathways as well. Upon exposure to STS‐135, individuals with low CYP3A4 activity could retain elevated blood concentration, resulting in toxicity. Additionally, CYP2J2 may aid in protecting against STS‐135‐induced cardiovascular toxicity.