Miracle-dz/UniFAR-FTUs huggingface dataset:
Milk intake is not associated with low risk of diabetes or overweight-obesity: a Mendelian randomization study in 97,811 Danish individuals.

BACKGROUND High dairy/milk intake has been associated with a low risk of type 2 diabetes observationally, but whether this represents a causal association is unknown. OBJECTIVE We tested the hypothesis that high milk intake is associated with a low risk of type 2 diabetes and of overweight-obesity, observationally and genetically. DESIGN In 97,811 individuals from the Danish general population, we examined the risk of incident type 2 diabetes and of overweight-obesity by milk intake observationally and by LCT-13910 C/T genotype [polymorphism (rs4988235) upstream from the lactase (LCT) gene], where TT and TC genotypes are associated with lactase persistence and CC with nonpersistence. RESULTS Observationally for any compared with no milk intake, the HR for type 2 diabetes was 1.10 (95% CI: 0.98, 1.24; P = 0.11), whereas the OR for overweight-obesity was 1.06 (1.02, 1.09; P = 0.002). Median milk intake was 5 glasses/wk (IQR: 0-10) for lactase TT/TC persistence and 3 (0-7) for CC nonpersistence. Genetically for lactase TT/TC persistence compared with CC nonpersistence, the OR was 0.96 (0.86, 1.08; P = 0.50) for type 2 diabetes and 1.06 (1.00, 1.12; P = 0.04) for overweight-obesity. In a stratified analysis for type 2 diabetes, corresponding values in those with and without milk intake were 0.88 (0.76, 1.03; P = 0.11) and 1.35 (1.07, 1.70; P = 0.01) (P-interaction: 0.002), whereas no gene-milk interaction on overweight-obesity was found. For a 1-glass/wk higher milk intake, the genetic risk ratio for type 2 diabetes was 0.99 (0.93, 1.06), and the corresponding observational risk was 1.01 (1.00, 1.01). For overweight-obesity, the corresponding values were 1.01 (1.00, 1.02) genetically and 1.00 (1.00, 1.01) observationally. CONCLUSIONS High milk intake is not associated with a low risk of type 2 diabetes or overweight-obesity, observationally or genetically via lactase persistence. The higher risk of type 2 diabetes in lactase-persistent individuals without milk intake likely is explained by collider stratification bias.
Urban and Rural Differences: Unmet Needs for Symptom Management in People Living With HIV in China

Abstract Access to HIV care has increased in China, but regional disparities for the unmet symptom management needs of people living with HIV remain. Little attention has been paid to these disparities, especially in rural areas. We describe unmet symptom management needs in 1,214 people living with HIV from five HIV hospitals in the eastern coast, middle, and southern regions of China. Insomnia, abnormal dreams, and fatigue were the most common unmet needs of patients in urban China, whereas cognitive problems and blurry vision were the most common in rural China. Self-management capacity, discrimination, and symptom severity predicted more unmet symptom management needs for patients in urban areas. Medication adherence, basic function, and symptom severity predicted more unmet needs among patients in rural areas. Our results have implications for nurses in HIV care and HIV policymakers. Separate interventions targeting the urban and rural areas must be implemented to meet patient symptom management needs.
Yifei Tongluo, a Chinese Herbal Formula, Suppresses Tumor Growth and Metastasis and Exerts Immunomodulatory Effect in Lewis Lung Carcinoma Mice

This study was aimed to investigate the anti-tumor, anti-metastasis and immunomodulatory effects of Yifei Tongluo (YFTL), a Chinese herbal formula, in Lewis lung carcinoma mice and to explore the underlying mechanisms. LLC cells were inoculated subcutaneously in C57BL/6 mice to establish the Lewis lung carcinoma model. We observed that YFTL effectively inhibited tumor growth and prolonged the overall survival of tumor-bearing mice. Additionally, YFTL treatment resulted in a significantly decreased number of surface lung metastatic lesions compared with the model control group. Meanwhile, TUNEL staining confirmed that the tumors from YFTL-treated mice exhibited a markedly higher apoptotic index. The results suggest that Akt and mitogen-activated protein kinase (MAPKs) pathways may be involved in YFTL-induced apoptosis. The results show that YFTL also inhibited the vascular endothelial growth factor (VEGF), matrix metalloproteinases (MMP)-2, MMP-9, N-cadherin, and Vimentin expression, but increased E-cadherin expression. Mechanistic studies indicated that YFTL could suppress the angiogenesis and the epithelial-mesenchymal transition (EMT) of the tumor through Akt/ERK1/2 and TGFβ1/Smad2 pathways. In addition, YFTL also showed immunomodulatory activities in improving the immunosuppressive state of tumor-bearing mice. Therefore, our findings could support the development of YFTL as a potential antineoplastic agent and a potentially useful anti-metastatic agent for lung carcinoma therapy.
Non-Clear Cell Renal Cell Carcinoma - Pathology and Treatment Options

Non-clear cell renal cell carcinomas (nccRCC) are rare diseases with heterogeneous histopathologically and genetically defined entities. The clinical data on optimal systemic treatments of nccRCC is rather limited. In this review, the current World Health Organization (WHO) classification of nccRCC based on histopathologic and genetic findings is reported. Regarding systemic treatment options, the most commonly used agents are mTOR inhibitors like everolimus or temsirolimus, or tyrosine kinase inhibitors like sunitinib. 2 small randomized clinical trials with nccRCC comparing sunitinib with everolimus revealed a trend towards a better progression-free survival (PFS) and overall survival (OS) in favor of sunitinib. In RCC with predominant sarcomatoid features, both chemotherapy and targeted agents are reported without any preference for outcome. For subsequent lines of therapy, some case reports describe promising effects of PD-1 or PD-L1 inhibitors in nccRCC including sarcomatoid subtype and Bellini duct carcinoma. Currently, nccRCCs are treated similarly to clear cell RCC or, whenever possible, within clinical trials. Clinical trials with immune checkpoint inhibitors are ongoing.
Recovery as the new medical model for psychiatry.

Treatment grounded in recovery principles is often viewed as not being based on the "medical model. " In this Open Forum the author asserts that recovery from mental illness is entirely compatible with concepts of recovery from medical illness and with new approaches to medical treatment. Three ways of conceptualizing recovery are defined: clinical recovery, illness management, and personal recovery. Basing treatment on recovery principles is supported by research that has shown significant remission rates over time among persons with schizophrenia. The author uses examples of public figures and of one family with physical disabilities to illustrate the progress society has made toward accepting and including people with physical illness and disability. Recovery-oriented mental health treatment parallels the move in other medical specialties toward person-centered care. A clinical approach to promote recovery is discussed.
Investigating accuracy of 3D printed liver models with computed tomography.

Background The aim of this study was to evaluate the accuracy of three-dimensional (3D) printed liver models developed by a cost-effective approach for establishing validity of using these models in a clinical setting. Methods Fifteen patients undergoing laparoscopic liver resection in a single surgical department were included. Patient-specific, 1-1 scale 3D printed liver models including the liver, tumor, and vasculature were created from contrast-enhanced computed tomography (CT) images using a cost-effective approach. The 3D models were subsequently CT scanned, 3D image post-processing was performed, and these 3D computer models (MCT) were compared to the original 3D models created from the original patient images (PCT). 3D computer models of each type were co-registered using a point set registration method. 3D volume measurements of the liver and lesions were calculated and compared for each set. In addition, Hausdorff distances were calculated and surface quality was compared by generated heatmaps. Results The median liver volume in MCT was 1,281.84 [interquartile range (IQR) =296.86] cm3, and 1,448.03 (IQR =413.23) cm3 in PCT. Analysis of differences between surfaces showed that the median value of mean Hausdorff distances for liver parenchyma was 1.92 mm. Bland-Altman plots revealed no significant bias in liver volume and diameters of hepatic veins and tumor location. Median errors of all measured vessel diameters were smaller than CT slice height. There was a slight trend towards undersizing anatomical structures, although those errors are most likely due to source imaging. Conclusions We have confirmed the accuracy of 3D printed liver models created by using the low-cost method. 3D models are useful tools for pre-operative planning and intra-operative guidance. Future research in this field should continue to move towards clinical trials for assessment of the impact of these models on pre-surgical planning decisions and perioperative outcomes.
Venetoclax plus R- or G-CHOP in non-Hodgkin lymphoma: results from the CAVALLI phase 1b trial.

Novel strategies, such as chemosensitization with targeted agents, that build on the success of standard immunochemotherapy show promise for the treatment of non-Hodgkin lymphoma (NHL). Here, we report a phase 1b study investigating dose escalation of the BCL2 inhibitor, venetoclax, in combination with rituximab or obinutuzumab and cyclophosphamide, doxorubicin, vincristine, and prednisone (R-/G-CHOP) chemotherapy in B-cell NHL. Objectives included safety assessment and determination of a recommended phase 2 dose (RP2D). Fifty-six patients were enrolled, most with follicular lymphoma (43%) or diffuse large B-cell lymphoma (DLBCL; 32%). Dose-limiting toxicities were reported in 3/14 patients at the first venetoclax dose (200 mg/d), after which dosing was changed from daily to 10 days per cycle and escalated to 800 mg. A further reduction to 5 days per cycle occurred at the 800-mg dose level in the G-CHOP arm. Cytopenias were predominant among grade 3/4 events and reported at a higher rate than expected, particularly in the G-CHOP arm; however, safety was manageable. Overall response rates were 87.5% (R-CHOP and G-CHOP combinations); complete response (CR) rates were 79.2% and 78.1%, respectively. Most double-expressor (BCL2+ and MYC+) DLBCL patients (87.5%; n = 7/8) achieved CR. Although the maximum tolerated dose was not reached, the RP2D for venetoclax with R-CHOP was established at 800 mg days 4 to 10 of cycle 1 and days 1 to 10 of cycles 2 to 8; higher doses were not explored, and this dosing schedule demonstrated an acceptable safety profile. This regimen is subsequently being evaluated in first-line DLBCL in the phase 2 portion of the study. This trial was registered at www.clinicaltrials. gov as #NCT02055820.
Association of non‐surgical periodontal therapy on patients' oral health‐related quality of life—A multi‐centre cohort study

AIM The aim of this multi-centre cohort study was to investigate the association of non-surgical periodontal therapy (NST) on the oral health-related quality of life (OHRQoL) in general and related to severity of periodontal disease and treatment modalities. MATERIALS AND METHODS One hundred and seventy-two patients with periodontal disease from 18 dental practices were measured before and 6-8 weeks after NST using a standardized and validated OHRQoL instrument (Oral Health Impact Profile-G14, OHIP-G14). Another questionnaire was filled out by the dentists to evaluate the influence of treatment modalities and disease severity. RESULTS Overall, the mean value of the OHIP baseline improved significantly after NST (p < 0.0001). Furthermore, a significant negative association between the severity of periodontitis and OHRQoL could be detected, and only patients with moderate and severe periodontitis showed a significant improvement of OHIP mean values (p < 0.0001). The results also indicated a significant association of the practitioners (p = 0.0362) as well as treatment modalities (favouring systemic antibiotics, p = 0.0066) regarding the improvement of the patients' OHRQoL. CONCLUSION This study showed that NST is positively associated with patients' oral health-related quality of life. This association seems to depend on the disease severity and caregiver and treatment modality.
Vitamin D supplementation and total cancer incidence and mortality: a meta-analysis of randomized controlled trials.

BACKGROUND Previous meta-analyses of randomized controlled trials (RCTs) of vitamin D supplementation and total cancer incidence and mortality found inconsistent results, and most included trials administered generally low doses of vitamin D (≤1100 IU/day). We updated the meta-analysis by incorporating recent RCTs that have tested higher doses of vitamin D supplements. MATERIALS AND METHODS PubMed and Embase were searched from the inception to November 2018. Summary relative risks (RRs) and 95% confidence intervals (CIs) were estimated using a random-effects model. RESULTS For total cancer incidence, 10 trials were included [6537 cases; 3-10 years of follow-up; 54-135 nmol/l of attained levels of circulating 25(OH) vitamin D [25(OH)D] in the intervention group]. The summary RR was 0.98 (95% CI, 0.93-1.03; P = 0.42; I2 = 0%). The results remained null across subgroups tested, including even when attained 25(OH)D levels exceeded 100 nmol/l (RR, 0.95; 95% CI, 0.83-1.09; P = 0.48; I2 = 26%). For total cancer mortality, five trials were included [1591 deaths; 3-10 years of follow-up; 54-135 nmol/l of attained levels of circulating 25(OH)D in the intervention group]. The summary RR was 0.87 (95% CI, 0.79-0.96; P = 0.005; I2 = 0%), which was largely attributable to interventions with daily dosing (as opposed to infrequent bolus dosing). No statistically significant heterogeneity was observed by attained levels of circulating 25(OH)D (Pheterogeneity = 0.83), with RR being 0.88 (95% CI, 0.78-0.98; P = 0.02; I2 = 0%) for ≤100 nmol/l and 0.85 (95% CI, 0.70-1.03; P = 0.11; I2 = 0%) for >100 nmol/l. CONCLUSIONS In an updated meta-analysis of RCTs, vitamin D supplementation significantly reduced total cancer mortality but did not reduce total cancer incidence.
Missing value estimation methods for DNA methylation data

MOTIVATION DNA methylation is a stable epigenetic mark with major implications in both physiological (development, aging) and pathological conditions (cancers and numerous diseases). Recent research involving methylation focuses on the development of molecular age estimation methods based on DNA methylation levels (mAge). An increasing number of studies indicate that divergences between mAge and chronological age may be associated to age-related diseases. Current advances in high-throughput technologies have allowed the characterization of DNA methylation levels throughout the human genome. However, experimental methylation profiles often contain multiple missing values, that can affect the analysis of the data and also mAge estimation. Although several imputation methods exist, a major deficiency lies in the inability to cope with large datasets, such as DNA methylation chips. Specific methods for imputing missing methylation data are therefore needed. RESULTS We present a simple and computationally efficient imputation method, metyhLImp, based on linear regression. The rationale of the approach lies in the observation that methylation levels show a high degree of inter-sample correlation. We performed a comparative study of our approach with other imputation methods on DNA methylation data of healthy and disease samples from different tissues. Performances have been assessed both in terms of imputation accuracy and in terms of the impact imputed values have on mAge estimation. In comparison to existing methods, our linear regression model proves to perform equally or better and with good computational efficiency. The results of our analysis provide recommendations for accurate estimation of missing methylation values. AVAILABILITY AND IMPLEMENTATION The R package methyLImp is freely available at https://github.com/pdilena/methyLImp. SUPPLEMENTARY INFORMATION Supplementary data are available at Bioinformatics online.
Genome‐Wide Interaction Analysis of Air Pollution Exposure and Childhood Asthma with Functional Follow‐up

Rationale: The evidence supporting an association between traffic‐related air pollution exposure and incident childhood asthma is inconsistent and may depend on genetic factors. Objectives: To identify gene‐environment interaction effects on childhood asthma using genome‐wide single‐nucleotide polymorphism (SNP) data and air pollution exposure. Identified loci were further analyzed at epigenetic and transcriptomic levels. Methods: We used land use regression models to estimate individual air pollution exposure (represented by outdoor NO2 levels) at the birth address and performed a genome‐wide interaction study for doctors’ diagnoses of asthma up to 8 years in three European birth cohorts (n = 1,534) with look‐up for interaction in two separate North American cohorts, CHS (Children's Health Study) and CAPPS/SAGE (Canadian Asthma Primary Prevention Study/Study of Asthma, Genetics and Environment) (n = 1,602 and 186 subjects, respectively). We assessed expression quantitative trait locus effects in human lung specimens and blood, as well as associations among air pollution exposure, methylation, and transcriptomic patterns. Measurements and Main Results: In the European cohorts, 186 SNPs had an interaction P < 1 × 10−4 and a look‐up evaluation of these disclosed 8 SNPs in 4 loci, with an interaction P < 0.05 in the large CHS study, but not in CAPPS/SAGE. Three SNPs within adenylate cyclase 2 (ADCY2) showed the same direction of the interaction effect and were found to influence ADCY2 gene expression in peripheral blood (P = 4.50 × 10−4). One other SNP with P < 0.05 for interaction in CHS, rs686237, strongly influenced UDP‐Gal:betaGlcNAc &bgr;‐1,4‐galactosyltransferase, polypeptide 5 (B4GALT5) expression in lung tissue (P = 1.18 × 10−17). Air pollution exposure was associated with differential discs, large homolog 2 (DLG2) methylation and expression. Conclusions: Our results indicated that gene‐environment interactions are important for asthma development and provided supportive evidence for interaction with air pollution for ADCY2, B4GALT5, and DLG2.
Plant-Parasitic Nematodes Infecting Grapevine in Southern Spain and Susceptible Reaction to Root-Knot Nematodes of Rootstocks Reported as Moderately Resistant.

Incidence and nematode population densities of plant-parasitic nematodes were determined in 64 samples of soil and grapevine roots collected from commercial vineyards in southern Spain between October 2003 and May 2005. In addition, a histopathological study was done of root-stock roots naturally infected by root-knot nematodes (Meloidogyne spp.). Nematodes infecting the rootstocks were identified according to conventional procedures, and the Meloidogyne spp. were furthermore identified by sequence characterized amplified region-polymerase chain reaction (SCAR-PCR) and isozyme esterase analyses. The most important plant-parasitic nematodes detected, in order of decreasing frequency of total soil infestation and root infection (percentage of samples), were Mesocriconema xenoplax (34.4%), Meloidogyne incognita (26.6%), Meloidogyne javanica (14.1%), Xiphinema index (12.5%), Xiphinema italiae (10.9%), Pratylenchus vulnus (6.3%), and Meloidogyne arenaria (1.6%). No disease symptoms were observed on aboveground plant parts of the infected grapevines, except for plants in some fields where soil was infested with the virus-vector nematodes X. index and X. italiae. Those grapevines showed a yellow mosaic pattern in leaves early in the growing season and the internode shortening characteristic of infections by Grapevine fanleaf virus. Rootstocks infected by root-knot nematodes (Meloidogyne spp.) showed distorted feeder roots and large- to moderate-sized root galls, present either singly or in clusters. Histopathology of galled roots showed a typical susceptible response to infection by root-knot nematodes: cellular alterations were induced in the cortex, endodermis, pericycle, and vascular system, including giant-cell formation and severe distortion of vascular tissues. Most Meloidogyne egg masses ocurred on the surface of the galled root tissues, a position that could facilitate dispersion of the nematode eggs and juveniles and the occurrence of secondary infections. Some of the grapevine rootstocks surveyed in this study (Paulsen 1103, Richter 110, Rupestris du Lot, and SO4) had previously been reported to be resistant to Meloidogyne spp. ; however, the population densities of these nematodes found in soil and roots sampled in the present study, as well as the compatible host-parasite relationship revealed by histopathology, indicate a susceptible response to Meloidogyne spp. from southern Spain.
Men and women, alcohol and aggression.

The purpose of this study was to examine the acute effects of alcohol on aggressive behavior in men and women in a laboratory setting. Participants were 526 (261 men and 265 women) healthy social drinkers between 21 and 35 years of age. They were randomly assigned to either an alcohol or a placebo group. Aggression was measured using a modified version of the Taylor Aggression Paradigm in which electric shocks are received from, and delivered to, a same gender fictitious opponent during a supposed competitive interpersonal task. Aggression was operationalized as the intensity and duration of shocks that participants administered to their "opponent. " Overall, men were more aggressive than women. Alcohol increased aggression for both men and women but this effect was stronger for men. This is one of the first laboratory studies to demonstrate that alcohol increases aggression in women.
A Phase II Study of Alisertib in Children with Recurrent/Refractory Solid Tumors or Leukemia: Children's Oncology Group Phase I and Pilot Consortium (ADVL0921)

Purpose: Aurora A kinase (AAK) plays an integral role in mitotic entry, DNA damage checkpoint recovery, and centrosome and spindle maturation. Alisertib (MLN8237) is a potent and selective AAK inhibitor. In pediatric preclinical models, antitumor activity was observed in neuroblastoma, acute lymphoblastic leukemia, and sarcoma xenografts. We conducted a phase 2 trial of alisertib in pediatric patients with refractory or recurrent solid tumors or acute leukemias (NCT01154816). Patients and Methods: Alisertib (80 mg/m2/dose) was administered orally, daily for 7 days every 21 days. Pharmacogenomic (PG) evaluation for polymorphisms in the AURK gene and drug metabolizing enzymes (UGT1A1*28), and plasma pharmacokinetic studies (PK) were performed. Using a 2-stage design, patients were enrolled to 12 disease strata (10 solid tumor and 2 acute leukemia). Response was assessed after cycle 1, then every other cycle. Results: A total of 139 children and adolescents (median age, 10 years) were enrolled, 137 were evaluable for response. Five objective responses were observed (2 complete responses and 3 partial responses). The most frequent toxicity was myelosuppression. The median alisertib trough concentration on day 4 was 1.3 μmol/L, exceeding the 1 μmol/L target trough concentration in 67% of patients. No correlations between PG or PK and toxicity were observed. Conclusions: Despite alisertib activity in pediatric xenograft models and cogent pharmacokinetic-pharmacodynamic relationships in preclinical models and adults, the objective response rate in children and adolescents receiving single-agent alisertib was less than 5%.