Miracle-dz/UniFAR-FTUs huggingface dataset:
Long‐term zidovudine reduces neurocognitive deficits in HIV‐1 infection

ObjectiveTo determine the efficacy of zidovudine (ZDV) in preventing decline of neurocognitive functions in HIV-1 infection. DesignRetrospective evaluation of subjects enrolled in a natural history study. Two analyses were made to evaluate the effect of (1) current ZDV, irrespective of length of treatment and (2) long-term ZDV treatment for at least 1 year. SettingSubjects were recruited from HIV out-patient clinics. PatientsHIV-1 -seropositive subjects were assigned to one of three groups according to the Centers for Disease Control and Prevention classification: asymptomatic infection (n = 60), symptomatic infection but without AIDS (n = 51), and AIDS (n = 32). Main outcome measuresStandardized neuropsychological and neurophysiological measures [electroencephalogram (EEG) and long-latency evoked potentials]. ResultsLong-term ZDV use was associated with improved cognitive performance in subjects with early symptomatic HIV-1 infection and AIDS, compared to subjects in the same clinical stage but without previous ZDV treatment. This was corroborated by neurophysiological evidence of reduced slow-wave EEG amplitude in the ZDV-treated subjects. The advantage of ZDV treatment was evident despite lower immune status in most treated subjects. ConclusionsThe findings in this natural history study indicate that long-term ZDV treatment may be an effective prophylactic to reduce neurocognitive deficits in symptomatic HIV-1 infection, thereby lowering the risk for developing HIV-1-associated dementia.
The clinical result of arterialized venous free flaps for the treatment of soft tissue defect of the fingers

Abstract The purpose of this study is to report the clinical results of the arterialized venous free flaps in reconstructing soft tissue defects of the finger and to extend the indications for the use of the flaps based on clinical experiences of the authors. We retrospectively reviewed the records of 35 patients who underwent an arterialized venous free flaps for a finger reconstruction, between May 2007 and August 2015. The mean size of flap was 4.8 ± 1.23 × 3.1 ± 0.84 cm. The donor site was the ipsilateral volar aspect of the distal forearm in all cases. There were 17 (48.6%) cases of venous skin flaps, 9 (25.7%) cases of innervated venous flaps, 7 (20%) cases of tendocu taneous flaps, and 2 (5.7%) case of innervated tendocutaneous flap. The vascularity of recipient beds was good except 8 (22.9%) cases (partial devascularity in 3, more than 50% avascularity [bone cement] in 3, and chronic infected bed in 2). Of the 35 cases, 29 (82.9%) cases (including 3 cases who had more than 50% avascularity recipient bed) showed complete survival. 3 (8.6%) cases, which had partially devascularity of distal phalanx in recipient bed, showed partial necrosis (P = .015). The mean number of included veins was 2.4 ± 0.5 for a flap. A forearm arterialized venous free flap is a useful procedure for single-stage reconstructing of a soft tissue or combined defect of a finger, we consider that this technique could be applied to fingers despite an avascular or insufficient vascular recipient bed if the periphery of recipient bed vascularity was good and if the recipient beds were free from infection.
Tumorigenesis and Neoplastic Progression Biological Role of Anaplastic Lymphoma Kinase in Neuroblastoma

Anaplastic lymphoma kinase (ALK) is a tyrosine kinase receptor originally identified as part of the chi-meric nucleophosmin-ALK protein in the t(2;5) chromosomal rearrangement associated with anaplastic large cell lymphoma. We recently demonstrated that the ALK kinase is constitutively activated by gene amplification at the ALK locus in several neuroblastoma cell lines. Forming a stable complex with hyperphosphorylated ShcC, activated ALK modifies the respon-siveness of the mitogen-activated protein kinase pathway to growth factors. In the present study, the biological role of activated ALK was examined by suppressing the expression of ALK kinase in neuroblastoma cell lines using an RNA interference technique. The suppression of activated ALK in neuroblastoma cells by RNA interference significantly reduced the phosphorylation of ShcC, mitogen-activated protein kinases, and Akt, inducing rapid apoptosis in the cells. By immunohistochemical analysis, the cytoplasmic expression of ALK was detected in most of the samples of neuroblastoma tissues regardless of the stage of the tumor,
Long‐Term Exposure to Elevated Systolic Blood Pressure in Predicting Incident Cardiovascular Disease: Evidence From Large‐Scale Routine Electronic Health Records

Background How measures of long‐term exposure to elevated blood pressure might add to the performance of “current” blood pressure in predicting future cardiovascular disease is unclear. We compared incident cardiovascular disease risk prediction using past, current, and usual systolic blood pressure alone or in combination. Methods and Results Using data from UK primary care linked electronic health records, we applied a landmark cohort study design and identified 80 964 people, aged 50 years (derivation cohort=64 772; validation cohort=16 192), who, at study entry, had recorded blood pressure, no prior cardiovascular disease, and no previous antihypertensive or lipid‐lowering prescriptions. We used systolic blood pressure recorded up to 10 years before baseline to estimate past systolic blood pressure (mean, time‐weighted mean, and variability) and usual systolic blood pressure (correcting current values for past time‐dependent blood pressure fluctuations) and examined their prospective relation with incident cardiovascular disease (first hospitalization for or death from coronary heart disease or stroke/transient ischemic attack). We used Cox regression to estimate hazard ratios and applied Bayesian analysis within a machine learning framework in model development and validation. Predictive performance of models was assessed using discrimination (area under the receiver operating characteristic curve) and calibration metrics. We found that elevated past, current, and usual systolic blood pressure values were separately and independently associated with increased incident cardiovascular disease risk. When used alone, the hazard ratio (95% credible interval) per 20–mm Hg increase in current systolic blood pressure was 1.22 (1.18–1.30), but associations were stronger for past systolic blood pressure (mean and time‐weighted mean) and usual systolic blood pressure (hazard ratio ranging from 1.39–1.45). The area under the receiver operating characteristic curve for a model that included current systolic blood pressure, sex, smoking, deprivation, diabetes mellitus, and lipid profile was 0.747 (95% credible interval, 0.722–0.811). The addition of past systolic blood pressure mean, time‐weighted mean, or variability to this model increased the area under the receiver operating characteristic curve (95% credible interval) to 0.750 (0.727–0.811), 0.750 (0.726–0.811), and 0.748 (0.723–0.811), respectively, with all models showing good calibration. Similar small improvements in area under the receiver operating characteristic curve were observed when testing models on the validation cohort, in sex‐stratified analyses, or by using different landmark ages (40 or 60 years). Conclusions Using multiple blood pressure recordings from patients’ electronic health records showed stronger associations with incident cardiovascular disease than a single blood pressure measurement, but their addition to multivariate risk prediction models had negligible effects on model performance.
Belimumab, an anti-BLyS human monoclonal antibody for potential treatment of inflammatory autoimmune diseases

Background: B lymphocyte stimulator (BLyS) is a factor determining the survival of B cells, and elevated levels in serum or locally have been observed in rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) patients. Belimumab (LymphoStat-B), a human monoclonal antibody that inhibits BlyS, was developed for the treatment of these diseases. Objective: To summarize preclinical development, efficacy and safety of belimumab in treatment of RA and SLE. Methods: Articles found in a PubMed search and data presented in abstract form at international conferences up to August 2008 are described. Results/conclusions: Belimumab was well tolerated in treatment of RA over 24 weeks and SLE over 3 years. It significantly decreased rheumatoid factor (RF) levels, and modestly reduced symptoms of RA, especially in some subgroups such as patients with high disease activity, positive RF and no anti-TNF treatment experience. It also significantly reduced symptoms of SLE, and decreased anti-double-stranded DNA autoantibodies among patients with positive baseline anti-double-stranded DNA or antinuclear antibodies during a long-period treatment. These results suggest that careful patient selection is necessary to achieve optimal outcomes.
Genetic risk scores in lipid disorders.

PURPOSE OF REVIEW Extensive work has gone into understanding the genetics of cardiovascular disease (CVD) and implicating genes involved in hyperlipidaemia. Translation into routine practise involves using genetic risk scores (GRS) to identify high-risk individuals in the general population. Some of these risk scores are beginning to disentangle the complex nature of CVD and inherited dyslipidaemias. RECENT FINDINGS GRS of varying complexity have been used to identify high-risk groups of patients with polygenic CVD including some individuals with risk equivalent to monogenic disease. In phenotypic familial hypercholesterolaemia a six or 12 gene lipid GRS may identify polygenic cases that comprise up to 50% of cases. In high triglyceride syndromes including even cases of familial chylomicronaemia syndrome more than 80% of cases are polygenic and not even associated with rare variants. In both familial hypercholesterolaemia and familial chylomicronaemia syndrome individuals with polygenic disease have a lower risk than those with monogenic disease. SUMMARY GRS show promise in identifying individuals with high risks of CVD. They have a close relationship with imaging markers. It is unclear whether GRS, imaging or both will be used to identify individuals at high risk of future events.
Impact of red blood cell transfusion dose density on progression-free survival in patients with lower-risk myelodysplastic syndromes

Progression-free survival (PFS) of patients with lower-risk myelodysplastic syndromes (MDS) treated with red blood cell transfusions is usually reduced, but it is unclear whether transfusion dose density is an independent prognostic factor. The European MDS Registry collects prospective data at 6-monthly intervals from newly diagnosed lower-risk myelodysplastic syndromes patients in 16 European countries and Israel. Data on the transfusion dose density - the cumulative dose received at the end of each interval divided by the time since the beginning of the interval in which the first transfusion was received - were analyzed using proportional hazards regression with time-varying co-variates, with death and progression to higher-risk MDS/acute myeloid leukemia as events. Of the 1,267 patients included in the analyses, 317 died without progression; in 162 patients the disease had progressed. PFS was significantly associated with age, EQ-5D index, baseline World Health Organization classification, bone marrow blast count, cytogenetic risk category, number of cytopenias, and country. Transfusion dose density was inversely associated with PFS (P<1×10−4): dose density had an increasing effect on hazard until a dose density of 3 units/16 weeks. The transfusion dose density effect continued to increase beyond 8 units/16 weeks after correction for the impact of treatment with erythropoiesis-stimulating agents, lenalidomide and/or iron chelators. In conclusion, the negative effect of transfusion treatment on PFS already occurs at transfusion densities below 3 units/16 weeks. This indicates that transfusion dependency, even at relatively low dose densities, may be considered as an indicator of inferior PFS. This trial was registered at www.clinicaltrials. gov as #NCT00600860.
Nursing workload: influence of indirect care interventions.

OBJECTIVE To evaluate nurses' perception of the degree of interference of indirect care interventions on the team's workload and to verify the association between these interventions and the professional and institutional variables. METHOD A research survey through e-mail conducted with clinical nurses, unit managers and service managers from eight Brazilian states. A questionnaire containing 28 indirect care interventions and their definitions proposed by the Nursing Interventions Classification was applied. RESULTS A total of 151 clinical nurses participated, and a response rate of 14.8% was obtained. The indirect care interventions reported as those which most increase the workload were: Preceptor: employee (M = 3.2), Employee Development (M = 3.1), Physician Support (M = 3.0) and Conflict mediation (M = 3.0). Statistically significant associations between the investigated interventions and the institutional variables (legal nature and size) were evidenced. CONCLUSION Nurses in different practice scenarios perceive that indirect care interventions influence the workload in a differentiated way, with emphasis on the demands related to the monitoring and qualification of employees.
Screening key genes and signaling pathways in colorectal cancer by integrated bioinformatics analysis

The aim of the present study was to identify potential key genes associated with the progression and prognosis of colorectal cancer (CRC). Differentially expressed genes (DEGs) between CRC and normal samples were screened by integrated analysis of gene expression profile datasets, including the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis was conducted to identify the biological role of DEGs. In addition, a protein-protein interaction network and survival analysis were used to identify the key genes. The profiles of GSE9348, GSE22598 and GSE113513 were downloaded from the GEO database. A total of 405 common DEGs were identified, including 236 down- and 169 upregulated. GO analysis revealed that the downregulated DEGs were mainly enriched in ‘detoxification of copper ion’ [biological process, (BP)], ‘oxidoreductase activity, acting on CH-OH group of donors, NAD or NADP as acceptor’ [molecular function, (MF)] and ‘brush border’ [cellular component, (CC)]. Upregulated DEGs were mainly involved in ‘nuclear division’ (BP), ‘snoRNA binding’ (MF) and ‘nucleolar part’ (CC). KEGG pathway analysis revealed that DEGs were mainly involved in ‘mineral absorption’, ‘nitrogen metabolism’, ‘cell cycle’ and ‘caffeine metabolism’. A PPI network was constructed with 268 nodes and 1,027 edges. The top one module was selected, and it was revealed that module-related genes were mainly enriched in the GO terms ‘sister chromatid segregation’ (BP), ‘chemokine activity’ (MF), and ‘condensed chromosome (CC)’. The KEGG pathway was mainly enriched in ‘cell cycle’, ‘progesterone-mediated oocyte maturation’, ‘chemokine signaling pathway’, ‘IL-17 signaling pathway’, ‘legionellosis’, and ‘rheumatoid arthritis’. DNA topoisomerase II-α (TOP2A), mitotic arrest deficient 2 like 1 (MAD2L1), cyclin B1 (CCNB1), checkpoint kinase 1 (CHEK1), cell division cycle 6 (CDC6) and ubiquitin conjugating enzyme E2 C (UBE2C) were indicated as hub genes. Furthermore, survival analysis revealed that TOP2A, MAD2L1, CDC6 and CHEK1 may serve as prognostic biomarkers in CRC. The present study provided insights into the molecular mechanism of CRC that may be useful in further investigations.
CSF biomarkers distinguish idiopathic normal pressure hydrocephalus from its mimics

Objective To examine the differential diagnostic significance of cerebrospinal fluid (CSF) biomarkers reflecting Alzheimer’s disease-related amyloid β (Aβ) production and aggregation, cortical neuronal damage, tau pathology, damage to long myelinated axons and astrocyte activation, which hypothetically separates patients with idiopathic normal pressure hydrocephalus (iNPH) from patients with other neurodegenerative disorders. Methods The study included lumbar CSF samples from 82 patients with iNPH, 75 with vascular dementia, 70 with Parkinson’s disease, 34 with multiple system atrophy, 34 with progressive supranuclear palsy, 15 with corticobasal degeneration, 50 with Alzheimer’s disease, 19 with frontotemporal lobar degeneration and 54 healthy individuals (HIs). We analysed soluble amyloid precursor protein alpha (sAPPα) and beta (sAPPβ), Aβ species (Aβ38, Aβ40 and Aβ42), total tau (T-tau), phosphorylated tau, neurofilament light and monocyte chemoattractant protein 1 (MCP-1). Results Patients with iNPH had lower concentrations of tau and APP-derived proteins in combination with elevated MCP-1 compared with HI and the non-iNPH disorders. T-tau, Aβ40 and MCP-1 together yielded an area under the curve of 0.86, differentiating iNPH from the other disorders. A prediction algorithm consisting of T-tau, Aβ40 and MCP-1 was designed as a diagnostic tool using CSF biomarkers. Conclusions The combination of the CSF biomarkers T-tau, Aβ40 and MCP-1 separates iNPH from cognitive and movement disorders with good diagnostic sensitivity and specificity. This may have important implications for diagnosis and clinical research on disease mechanisms for iNPH.
Cost and cost-effectiveness studies in heart failure research.

BACKGROUND Heart failure is a major and increasing cause of death and disability and accounts for significant resource use. In the United States alone, the prevalence is 4.6 million, with an incidence rate of 550,000 new cases a year and approximately 957,000 hospitalizations a year. METHODS AND RESULTS Methods of evaluating cost and outcome and of comparing cost with outcome are reviewed. Economic and cost-effectiveness studies in heart failure research, especially those related to clinical trials, are reviewed in the therapeutic areas of digoxin, angiotension-converting enzyme inhibition, beta blockers, disease management, and transplantation. CONCLUSION In an era in which economic constraints on medical resource use limit the ability to give all services to all patients, economic studies can help guide more rational decision making. Economic studies in heart failure can be expected to improve and so help society to make better, more informed choices.
Multilevel regression and poststratification as a modeling approach for estimating population quantities in large population health studies: A simulation study

There are now a growing number of applications of multilevel regression and poststratification (MRP) in population health and epidemiological studies. MRP uses multilevel regression to model individual survey responses as a function of demographic and geographic covariates. Estimated mean outcome values for each demographic–geographic respondent subtype are then weighted by the proportions of each subtype in the population to produce an overall population‐level estimate. We recently reported an extensive case study of a large nationwide survey and found that MRP performed favorably compared to conventional survey sampling weights for the estimation of population descriptive quantities in a highly selected sample. In this study, we aimed to evaluate, by way of a simulation experiment, both the accuracy and precision of MRP versus survey sampling weights in the context of large population health studies. While much of the research into MRP has been focused on U.S. political and social science, we considered an alternative population structure of smaller size and with notably fewer geographic subsets. We explored the impact on MRP performance of sample size, model misspecification, interactions, and the addition of a geographic‐level covariate. MRP was found to achieve generally superior performance in both accuracy and precision at both the national and state levels. Results were generally robust to model misspecification, and MRP performance was further improved by the inclusion of a geographic‐level covariate. These findings offer further evidence that MRP provides a promising analytic approach for addressing participation bias in the estimation of population descriptive quantities from large‐scale health surveys and cohort studies.
The Microbiome in Populations with a Low and High Prevalence of Caries

The oral microbiota was compared between Romanian adolescents with a high prevalence of caries and no dental care and Swedish caries-active and caries-free adolescents in caries prevention programs and with a low prevalence of caries. Biofilm samples were analyzed by FLX+ pyrosequencing of the V1 to V4 hypervariable regions of the 16S rRNA gene and polymerase chain reaction (PCR)/quantitative PCR (qPCR) for Streptococcus mutans and Streptococcus sobrinus. Sequences obtained blasted to 9 phyla, 66 genera, and 401 human oral taxa (HOT) in the 16S rRNA Human Oral Microbiome Database, of which 295 were represented by ≥20 sequences. The Romanian adolescents had more sequences in Firmicutes and fewer in Actinobacteria phyla and more sequences in the genera Bacteroidetes [G-3], Porphyromonas, Abiotrophia, Filifactor, Peptostreptococcaceae [11][G-4], Pseudoramibacter, Streptococcus, and Neisseria and fewer in Actinomyces, Selenomonas, Veillonella, Campylobacter, and TM7 [G-1] than the Swedish groups. Multivariate modeling employing HOT, S. sobrinus and S. mutans (PCR/qPCR), and sugar snacks separated Romanian from Swedish adolescents. The Romanian adolescents’ microbiota was characterized by a panel of streptococci, including S. mutans, S. sobrinus, and Streptococcus australis, and Alloprevotella, Leptotrichia, Neisseria, Porphyromonas, and Prevotella. The Swedish adolescents were characterized by sweet snacks, and those with caries activity were also characterized by Prevotella, Actinomyces, and Capnocytophaga species and those free of caries by Actinomyces, Prevotella, Selenomonas, Streptococcus, and Mycoplasma. Eight species including Streptococcus mitis and Streptococcus species HOT070 were prevalent in Romanian and Swedish caries-active subjects but not caries-free subjects. In conclusion, S. mutans and S. sobrinus correlated with Romanian adolescents with caries and with limited access to dental care, whereas S. mutans and S. sobrinus were detected infrequently in Swedish adolescents in dental care programs. Swedish caries-active adolescents were typically colonized by Actinomyces, Selenomonas, Prevotella, and Capnocytophaga. Hence, the role of mutans streptococci as a primary caries pathogen appears less pronounced in populations with prevention programs compared to populations lacking caries treatment and prevention strategies.
Solid Dispersion of Hydroxypropyl β‐Cyclodextrin and Ketorolac: Enhancement of In‐vitro Dissolution Rates, Improvement in Anti‐inflammatory Activity and Reduction in Ulcerogenicity in Rats

Ketorolac, is a non‐steroidal anti‐inflammatory drug, with strong analgesic activity. It is practically insoluble in water and has been implicated in causing gastrointestinal ulceration. This study describes the formulation of solid dispersions of ketorolac using hydroxypropyl β‐cyclodextrin (HPβ‐CyD) and β‐cyclodextin (β‐CyD) as carriers, to improve the aqueous solubility of the drug, thus enhancing its bioavailability. Also, reduction in ulcerogenicity was anticipated.