Miracle-dz/UniFAR-FTUs huggingface dataset:
Effects of an Updated Preventive Home Visit Program Based on a Systematic Structured Assessment of Care Needs for Ambulatory Frail Older Adults in Japan: A Randomized Controlled Trial.

BACKGROUND The aim of this randomized controlled trial was to determine the effects on functional parameters of an updated preventive home visit program for frail older adults in the Japanese Long-term Care Insurance (LTCI) system. METHODS The program included home visits by nurses or care managers every 3 months for 24 months, with a systematic assessment of care needs to prevent functional decline. Eligible participants (N = 360) were randomly assigned to the visit (VG: n = 179) or control group (CG: n = 181). Functional parameters were gathered via mail questionnaires at baseline and at 12- and 24-month follow-ups. Care-need levels in the LTCI were obtained at 12-, 24-, and 36-month follow-ups and the utilization of the LTCI service through 36 months. RESULTS Participants in VG were significantly more likely to maintain their activities of daily living (ADL) functioning (p = .0113) and less likely to increase care-needs level, compared with CG participants, over 24 months. A generalized linear model showed that the estimate of the effect on increase in care-needs level (ie, functional decline) was -0.53 (p = .042) over 36 months. CONCLUSIONS These results suggest that the updated preventive home visit program could be effective for the prevention of ADL and care-needs deterioration, and these effects could continue up to 1 year after program completion.
Nanocurcumin restores aberrant miRNA expression profile in multiple sclerosis, randomized, double‐blind, placebo‐controlled trial

In the current study, we aimed to identify nanocurcumin effects on microRNAs (miRNAs) in the peripheral blood of patients with relapsing‐remitting multiple sclerosis (RRMS). We intended to investigate the expression pattern of these miRNAs in experimental settings in vivo. The expression levels of the selected 27 miRNAs known to be involved in the regulation of immune responses were analyzed in 50 RRMS patients and 35 healthy controls. The miRNA expression profiles were investigated by quantitative PCR (qPCR) at baseline and after 6 months of nanocurcumin therapy. Our data revealed that the expression of a number of microRNAs including miR‐16, miR‐17‐92, miR‐27, miR‐29b, miR‐126, miR‐128, miR‐132, miR‐155, miR‐326, miR‐550, miR‐15a, miR‐19b, miR‐106b, miR‐320a, miR‐363, miR‐31, miR‐150, and miR‐340 is regulated by nanocurcumin. The results of the current work indicate that nanocurcumin is able to restore the expression pattern of dysregulated miRNAs in MS patients. We discovered that some miRNAs are deregulated in untreated patients compared with healthy controls and nanocurcumin‐treated patients. This is a new finding that might represent the potential contribution of these miRNAs to MS pathogenesis. Taken together, these data provide novel insights into miRNA‐dependent regulation of the function of B and T cells in MS disease and enrich our understanding of the effects mediated by a therapeutic approach that targets B and T cells.
Integrated Assessment of Pharmacological and Nutritional Cardiovascular Risk Management: Blood Pressure Control in the DIAbetes and LifEstyle Cohort Twente (DIALECT)

Cardiovascular risk management is an integral part of treatment in Type 2 Diabetes Mellitus (T2DM), and requires pharmacological as well as nutritional management. We hypothesize that a systematic assessment of both pharmacological and nutritional management can identify targets for the improvement of treatment quality. Therefore, we analysed blood pressure (BP) management in the DIAbetes and LifEstyle Cohort Twente (DIALECT). DIALECT is an observational cohort from routine diabetes care, performed at the ZGT Hospital (Almelo and Hengelo, The Netherlands). BP was measured for 15 min with one minute intervals. Sodium and potassium intake was derived from 24-hour urinary excretion. We determined the adherence to pharmacological and non-pharmacological guidelines in patients with BP on target (BP-OT) and BP not on target (BP-NOT). In total, 450 patients were included from August 2009 until January 2016. The mean age was 63 ± 9 years, and the majority was male (58%). In total, 53% had BP-OT. In those with BP-NOT, pharmacological management was suboptimal (zero to two antihypertensive drugs) in 62% of patients, and nutritional guideline adherence was suboptimal in 100% of patients (only 8% had a sodium intake on target, 66% had a potassium intake on target, 3% had a sodium-to-potassium ratio on target, and body mass index was <30 kg/m2 in 35%). These data show pharmacological undertreatment and a low adherence to nutritional guidelines. Uncontrolled BP is common in T2DM, and our data show a window of opportunity for improving BP control, especially in nutritional management. To improve treatment quality, we advocate to incorporate the integrated monitoring of nutritional management in quality improvement cycles in routine care.
Pharmacotherapeutic approaches for treating psoriasis in difficult-to-treat areas

ABSTRACT Introduction: Despite great therapeutic advancements in psoriasis, four notable difficult-to-treat areas including the scalp, nails, intertriginous (including genitals), and palmoplantar regions, pose a challenge to both physicians and patients. Localized disease of these specific body regions inflicts a significant burden on patients’ quality of life and requires an adequate selection of treatments. Areas covered: This manuscript discusses appropriate therapies and important treatment considerations for these difficult-to-treat areas based on the available clinical data from the literature. Expert opinion: Clinical trials assessing therapies for the difficult-to-treat areas have been inadequate. With the first biological clinical trial for genital psoriasis pending publication, it is with hope that other biological agents will be evaluated for region-specific psoriasis. A greater understanding of the genetic and immunologic aspects of regional psoriasis, as well as identification of unique biomarkers, will further guide management decisions. For example, the recent discovery of the IL-36 receptor gene for generalized pustular psoriasis may prove valuable for other forms of psoriasis. Ultimately, identification of the most beneficial treatments for each psoriasis subtype and difficult-to-treat area will provide patients with maximal quality of life.
Perturbation of manganese metabolism disrupts cell division in Streptococcus pneumoniae

Manganese (Mn) is an essential micronutrient and required cofactor in bacteria. Despite its importance, excess Mn can impair bacterial growth, the mechanism of which remains largely unexplored. Here, we show that proper Mn homeostasis is critical for cellular growth of the major human respiratory pathogen Streptococcus pneumoniae. Perturbations in Mn homeostasis genes, psaBCA, encoding the Mn importer, and mntE, encoding the Mn exporter, lead to Mn sensitivity during aerobiosis. Mn‐stressed cells accumulate iron and copper, in addition to Mn. Impaired growth is a direct result of Mn toxicity and does not result from iron‐mediated Fenton chemistry, since cells remain sensitive to Mn during anaerobiosis or when hydrogen peroxide biogenesis is significantly reduced. Mn‐stressed cells are significantly elongated, whereas Mn‐limitation imposed by zinc addition leads to cell shortening. We show that Mn accumulation promotes aberrant dephosphorylation of cell division proteins via hyperactivation of the Mn‐dependent protein phosphatase PhpP, a key enzyme involved in the regulation of cell division. We discuss a mechanism by which cellular Mn:Zn ratios dictate PhpP specific activity thereby regulating pneumococcal cell division. We propose that Mn‐metalloenzymes are particularly susceptible to hyperactivation or mismetallation, suggesting the need for exquisite cellular control of Mn‐dependent metabolic processes.
Fibroblast Growth Factor 23, Mineral Metabolism, and Adiposity in Normal Kidney Function

Context Obesity is associated with poor bone mineralization and quality. Fibroblast growth factor 23 (FGF23) plays an important role in skeletal physiology. Objective To test hypothesis that greater adiposity results in higher FGF23 levels among individuals with normal estimated glomerular filtration rate (eGFR). Design, Setting, Participants Cross-sectional analyses among participants with eGFR ≥60 mL/min/1.73m2. We assessed the association between crude [body mass index (BMI), waist circumference (WC), and waist-to-hip ratio (WHR); n = 5610] and refined (abdominal adipose tissue area by computed tomography; n = 1313) measures of adiposity and FGF23 using multivariable linear regression. Main Outcome Measure Serum FGF23. Results FGF23 was higher across BMI categories (BMI <25: 37.7; BMI 25 to 29.99: 38.7; BMI 30 to 39.99: 39.8; BMI ≥40: 40.9 pg/mL, unadjusted P trend < 0.0001). The association between BMI and FGF23 was independent of known confounders of FGF23 (adjusted β = +7.2% higher FGF23 per 10 kg/m2; P < 0.0001). Similar results were observed using WC and WHR. Abdominal adipose tissue area was also independently associated with higher FGF23 (P < 0.01). Notably, the positive associations between FGF23 and adiposity were observed despite the fact that eGFR did not decline and serum phosphate levels did not increase with adiposity. Conclusion In a large cohort with normal kidney function, adiposity was associated with higher FGF23 levels independent of known confounders, including eGFR and phosphate. Further studies are needed to evaluate the causes of higher FGF23 in settings of greater adiposity and the potential impact on skeletal health.
Perceived need for care and mental health service utilization among college students with suicidal ideation

ABSTRACT Objective: This study aimed to identify correlates of service utilization and perceived need for care among college students with suicidal ideation. Participants: Respondents were recruited from introductory psychology courses at an undergraduate college during the Fall 2014 semester. Methods: Independent correlates of (1) mental health service utilization, (2) self-perceived need, and (3) other-perceived need for mental health services among college students (N = 190) with suicidal ideation were identified. Results: Service utilization was associated with need for care as perceived by others. Perceived need for care by others was associated with suicidal ideation intensity and suicide attempt history. Perceived need by the respondents themselves was correlated with depression severity, sex, and race but was not independently associated with actual service utilization. Conclusions: Perceived need by others was the sole significant correlate of service utilization, suggesting it is an important target for public health interventions aimed at facilitating pathways into mental health treatment.
Management of Treatment-Related Adverse Events with Agents Targeting the MAPK Pathway in Patients with Metastatic Melanoma.

Tremendous progress has been made in the clinical landscape of advanced-stage BRAF V600-mutant melanoma treatment over the past 5 years. Targeted therapies that inhibit specific steps of the mitogen-activated protein kinase pathway have been shown to provide significant overall treatment benefit in patients with this difficult-to-treat disease. Combination therapy with BRAF and MEK inhibitors (dabrafenib plus trametinib or vemurafenib plus cobimetinib, respectively) has become standard of care. These agents are administered until disease progression or unacceptable toxicity occurs; thus, some patients may remain on maintenance therapy for an extended period of time, while toxicities may result in early discontinuation in other patients. Because the goal of treatment is to prolong survival with minimal impairment of quality of life, drug-related adverse events (AEs) require prompt management to ensure that patients derive the best possible benefit from therapy. Proper management depends on an understanding of which AEs are most likely BRAF or MEK inhibitor associated, thus providing a rationale for dose modification of the appropriate drug. Additionally, the unique safety profile of the chosen regimen may influence patient selection and monitoring. This review discusses the toxicity profiles of these agents, with a focus on the most commonly reported and serious AEs. Here, we offer practical guidance derived from our clinical experience for the optimal management of key drug-related AEs. IMPLICATIONS FOR PRACTICE Targeted therapy with BRAF plus MEK inhibitors has become the standard of care for patients with advanced-stage BRAF V600-mutant metastatic melanoma. To provide optimal therapeutic benefit to patients, clinicians need a keen understanding of the toxicity profiles of these drugs. Prompt identification and an understanding of which adverse events are most likely BRAF or MEK inhibitor associated provide a rationale for appropriate therapy adjustments. Practical recommendations derived from clinical experience are provided for management of key drug-related toxicities.
TRIM28 Is an Epigenetic Barrier to Induced Pluripotent Stem Cell Reprogramming

Since the discovery of induced pluripotent stem cells there has been intense interest in understanding the mechanisms that allow a somatic cell to be reprogrammed back to a pluripotent state. Several groups have studied the alterations in gene expression that occur as somatic cells modify their genome to that of an embryonic stem cell. Underpinning many of the gene expression changes are modifications to the epigenetic profile of the associated chromatin. We have used a large‐scale shRNA screen to identify epigenetic modifiers that act as barriers to reprogramming. We have uncovered an important role for TRIM28 in cells resisting transition between somatic and pluripotent states. TRIM28 achieves this by maintaining the H3K9me3 repressed state and keeping endogenous retroviruses (ERVs) silenced. We propose that knockdown of TRIM28 during reprogramming results in more plastic H3K9me3 domains, dysregulation of genes nearby H3K9me3 marks, and up regulation of ERVs, thus facilitating the transition through reprogramming. Stem Cells 2017;35:147–157
The Role of Episodic Context in Retrieval Practice Effects

The episodic context account of retrieval-based learning proposes that retrieval enhances subsequent retention because people must think back to and reinstate a prior learning context. Three experiments directly tested this central assumption of the context account. Subjects studied word lists and then either restudied the words under intentional learning conditions or made list discrimination judgments by indicating which list each word had occurred in originally. Subjects in both conditions experienced all items for the same amount of time, but subjects in the list discrimination condition were required to retrieve details about the original episodic context in which the words had occurred. Making initial list discrimination judgments consistently enhanced subsequent free recall relative to restudying the words. Analyses of recall organization and retrieval strategies on the final test showed that retrieval practice enhanced temporal organization during final recall. Semantic encoding tasks also enhanced retention relative to restudying but did so by promoting semantic organization and semantically based retrieval strategies during final recall. The results support the episodic context account of retrieval-based learning.
Dynamic changes in the mouse skeletal muscle proteome during denervation-induced atrophy

ABSTRACT Loss of neuronal stimulation enhances protein breakdown and reduces protein synthesis, causing rapid loss of muscle mass. To elucidate the pathophysiological adaptations that occur in atrophying muscles, we used stable isotope labelling and mass spectrometry to quantify protein expression changes accurately during denervation-induced atrophy after sciatic nerve section in the mouse gastrocnemius muscle. Additionally, mice were fed a stable isotope labelling of amino acids in cell culture (SILAC) diet containing 13C6-lysine for 4, 7 or 11 days to calculate relative levels of protein synthesis in denervated and control muscles. Ubiquitin remnant peptides (K-ε-GG) were profiled by immunoaffinity enrichment to identify potential substrates of the ubiquitin-proteasomal pathway. Of the 4279 skeletal muscle proteins quantified, 850 were differentially expressed significantly within 2 weeks after denervation compared with control muscles. Moreover, pulse labelling identified Lys6 incorporation in 4786 proteins, of which 43 had differential Lys6 incorporation between control and denervated muscle. Enrichment of diglycine remnants identified 2100 endogenous ubiquitination sites and revealed a metabolic and myofibrillar protein diglycine signature, including myosin heavy chains, myomesins and titin, during denervation. Comparative analysis of these proteomic data sets with known atrogenes using a random forest approach identified 92 proteins subject to atrogene-like regulation that have not previously been associated directly with denervation-induced atrophy. Comparison of protein synthesis and proteomic data indicated that upregulation of specific proteins in response to denervation is mainly achieved by protein stabilization. This study provides the first integrated analysis of protein expression, synthesis and ubiquitin signatures during muscular atrophy in a living animal. Summary: Comprehensive proteomic profiling of protein expression, synthesis and ubiquitination during skeletal muscle atrophy reveals that complex regulatory networks are activated during muscle wasting.
Risk factors for leptospirosis seropositivity in slaughterhouse workers in western Kenya

Objectives Leptospirosis has been documented in slaughterhouse workers around the world. Risk factors include smoking and drinking at work, and performing tasks such as cleaning offal. This paper examined risk factors for leptospirosis seropositivity in slaughterhouse workers in western Kenya. Methods The study was conducted between May 2011 and October 2012. Questionnaires were used to collect information from workers on demographic data, health and hygiene practices in the slaughterhouse. A commercial ELISA detected antibodies to Leptospira spp. in serum samples and multilevel logistic regression analysis identified factors associated with leptospirosis seropositivity. Results A total of 737 workers from 142 slaughterhouses were recruited. The seroprevalence of antibodies to Leptospira spp. was 13.4% (95% CI 11.1% to 16.1%). Risk factors included: having wounds (OR 3.1; 95% CI 1.5 to 6.1); smoking (OR 1.8; 95% CI 1.1 to 2.9); eating at work (OR 2.1; 95% CI 1.2 to 3.6); cleaning the offal (OR 5.1; 95% CI 1.8 to 15.0); and having a borehole for personal water use (OR 2.3; 95% CI 1.1 to 4.7). At the slaughterhouse level, risk factors included having a roof (OR 2.6; 95% CI 1.2 to 5.6) and drawing water from a well (OR 2.2; 95% CI 1.2 to 4.0). Protective factors included working in slaughterhouses where antemortem inspection was conducted (OR 0.6; 95% CI 0.4 to 1.0) and where workers wore protective aprons (OR 0.4; 95% CI 0.2 to 0.7). Conclusions This is the first report of leptospirosis seropositivity in slaughterhouse workers in Kenya. Potential risk factors were identified and this information can be used to educate workers regarding their disease risks and ways to prevent or reduce transmission.
Gestational high-fat diet and bisphenol A exposure heightens mammary cancer risk

In utero exposure to bisphenol A (BPA) increases mammary cancer susceptibility in offspring. High-fat diet is widely believed to be a risk factor of breast cancer. The objective of this study was to determine whether maternal exposure to BPA in addition to high-butterfat (HBF) intake during pregnancy further influences carcinogen-induced mammary cancer risk in offspring, and its dose–response curve. In this study, we found that gestational HBF intake in addition to a low-dose BPA (25 µg/kg BW/day) exposure increased mammary tumor incidence in a 50-day-of-age chemical carcinogen administration model and altered mammary gland morphology in offspring in a non-monotonic manner, while shortening tumor-free survival time compared with the HBF-alone group. In utero HBF and BPA exposure elicited differential effects at the gene level in PND21 mammary glands through DNA methylation, compared with HBF intake in the absence of BPA. Top HBF + BPA-dysregulated genes (ALDH1B1, ASTL, CA7, CPLX4, KCNV2, MAGEE2 and TUBA3E) are associated with poor overall survival in The Cancer Genomic Atlas (TCGA) human breast cancer cohort (n = 1082). Furthermore, the prognostic power of the identified genes was further enhanced in the survival analysis of Caucasian patients with estrogen receptor-positive tumors. In conclusion, concurrent HBF dietary and a low-dose BPA exposure during pregnancy increases mammary tumor incidence in offspring, accompanied by alterations in mammary gland development and gene expression, and possibly through epigenetic reprogramming.
Engineering and Dissecting the Glycosylation Pathway of a Streptococcal Serine-rich Repeat Adhesin*

Serine-rich repeat glycoproteins (SRRPs) are conserved in Gram-positive bacteria. They are crucial for modulating biofilm formation and bacterial-host interactions. Glycosylation of SRRPs plays a pivotal role in the process; thus understanding the glycosyltransferases involved is key to identifying new therapeutic drug targets. The glycosylation of Fap1, an SRRP of Streptococcus parasanguinis, is mediated by a gene cluster consisting of six genes: gtf1, gtf2, gly, gtf3, dGT1, and galT2. Mature Fap1 glycan possesses the sequence of Rha1–3Glc1-(Glc1–3GlcNAc1)-2,6-Glc1–6GlcNAc. Gtf12, Gtf3, and dGT1 are responsible for the first four steps of the Fap1 glycosylation, catalyzing the transfer of GlcNAc, Glc, Glc, and GlcNAc residues to the protein backbone sequentially. The role of GalT2 and Gly in the Fap1 glycosylation is unknown. In the present study, we synthesized the fully modified Fap1 glycan in Escherichia coli by incorporating all six genes from the cluster. This study represents the first reconstitution of an exogenous stepwise O-glycosylation synthetic pathway in E. coli. In addition, we have determined that GalT2 mediates the fifth step of the Fap1 glycosylation by adding a rhamnose residue, and Gly mediates the final glycosylation step by transferring glucosyl residues. Furthermore, inactivation of each glycosyltransferase gene resulted in differentially impaired biofilms of S. parasanguinis, demonstrating the importance of Fap1 glycosylation in the biofilm formation. The Fap1 glycosylation system offers an excellent model to engineer glycans using different permutations of glycosyltransferases and to investigate biosynthetic pathways of SRRPs because SRRP genetic loci are highly conserved.