An Eight-Week Trial Investigating the Efficacy and Tolerability of Atorvastatin for Children and Adolescents With Heterozygous Familial Hypercholesterolemia

This study aimed to assess the efficacy and tolerability of atorvastatin in Tanner stage (TS) 1 patients ages 6 to 10 years and TS ≥2 patients ages 10 to <18 years with genetically confirmed heterozygous familial hypercholesterolemia (HeFH) and a low density lipoprotein cholesterol (LDL-C) level of 4 mmol/l (155 mg/dl) or higher. In this open-label, 8-week study, 15 TS 1 children were treated initially with atorvastatin 5 mg/day and 24 TS ≥2 children with 10 mg/day. Doses were doubled at week 4 if the LDL-C target (<3.35 mmol/l [130 mg/dl]) was not achieved. The efficacy variables were the percentage change from baseline in LDL-C, total cholesterol (TC), triglycerides (TG), high density lipoprotein cholesterol (HDL-C), very low density lipoprotein cholesterol (VLDL-C), and apolipoprotein (Apo) A-I and Apo B. Safety evaluations included clinical monitoring, subject-reported adverse events (AEs), vital signs, and clinical laboratory tests. The mean values for LDL-C, TC, VLDL-C, and Apo B decreased by week 2 among all TS 1 and TS ≥2 patients, whereas TG, HDL-C, and Apo A-I varied considerably from week to week. After 8 weeks, the mean reduction in LDL-C was −40.7% ± 8.4 for the TS 1 children and −39.7% ± 10.3 for the TS ≥2 children. For the TS 1 patients, the mean reductions were −34.1% ± 6.9 for TC and −6.0% ± 32.1 for TG. The corresponding changes for the TS ≥2 patients were −35.6% ± 9.5 for TC and −21.1% ± 29.7 for TG. Four patients experienced mild to moderate treatment-related AEs. No serious AEs or discontinuations were reported. Overall, no difference in safety or tolerability was observed between the younger and older cohorts. Across the range of exposures after atorvastatin 5 to 10 mg (TS 1) or atorvastatin 10 to 20 mg (TS ≥2) doses for 8 weeks, clinically meaningful reductions in LDL-C, TC, VLDL-C, and Apo were observed with atorvastatin in pediatric patients who had HeFH. Atorvastatin also was well tolerated in this population

Circulating Levels of Insulin-like Growth Factor 1 and Insulin-like Growth Factor Binding Protein 3 Associate With Risk of Colorectal Cancer Based on Serologic and Mendelian Randomization Analyses

BACKGROUND & AIMS: Human studies examining associations between circulating levels of insulin-like growth factor 1 (IGF1) and insulin-like growth factor binding protein 3 (IGFBP3) and colorectal cancer risk have reported inconsistent results. We conducted complementary serologic and Mendelian randomization (MR) analyses to determine whether alterations in circulating levels of IGF1 or IGFBP3 are associated with colorectal cancer development. METHODS: Serum levels of IGF1 and other proteins were measured in blood samples collected from 397,380 participants from the UK Biobank, from 2006 through 2010. Incident cancer cases and cancer cases recorded first in death certificates were identified through linkage to national cancer and death registries. Complete follow-up was available through March 31, 2016. For the MR analyses, we identified genetic variants associated with circulating levels of IGF1 and IGFBP3. The association of these genetic variants with colorectal cancer was examined with 2-sample MR methods using genome-wide association study consortia data (52,865 cases with colorectal cancer and 46,287 individuals without [controls]) RESULTS: After a median follow-up period of 7.1 years, 2665 cases of colorectal cancer were recorded. In a multivariable-adjusted model, circulating level of IGF1 level associated with colorectal cancer risk (hazard ratio per 1 standard deviation increment of IGF1, 1.11; 95% confidence interval [CI] 1.05-1.17). Similar associations were found by sex, follow-up time, and tumor subsite. In the MR analyses, a 1 standard deviation increment in IGF1 level, predicted based on genetic factors, was associated with a higher risk of colorectal cancer risk (odds ratio 1.08; 95% CI 1.03-1.12; P = 3.3 × 10-4). Level of IGFBP3, predicted based on genetic factors, was associated with colorectal cancer risk (odds ratio per 1 standard deviation increment, 1.12; 95% CI 1.06-1.18; P = 4.2 × 10-5). Colorectal cancer risk was associated with only 1 variant in IGFBP3 (rs11977526), which also associated with anthropometric traits and circulating level of IGF2. CONCLUSIONS: In an analysis of blood samples from almost 400,000 participants in the UK Biobank, we found an association between circulating level of IGF1 and colorectal cancer. Using genetic data from 52,865 cases with colorectal cancer and 46,287 controls, a higher level of IGF1, determined by genetic factors, was associated with colorectal cancer. Further studies are needed to determine how this signaling pathway might contribute to colorectal carcinogenesis

A Genetic Locus within the FMN1/GREM1 Gene Region Interacts with Body Mass Index in Colorectal Cancer Risk

Colorectal cancer risk can be impacted by genetic, environmental, and lifestyle factors, including diet and obesity. Geneenvironment interactions (G x E) can provide biological insights into the effects of obesity on colorectal cancer risk. Here, we assessed potential genome-wide G x E interactions between body mass index (BMI) and common SNPs for colorectal cancer risk using data from 36,415 colorectal cancer cases and 48,451 controls from three international colorectal cancer consortia (CCFR, CORECT, and GECCO). The G x E tests included the conventional logistic regression using multiplicative terms (one degree of freedom, 1DF test), the two-step EDGE method, and the joint 3DF test, each of which is powerful for detecting G x E interactions under specific conditions. BMI was associated with higher colorectal cancer risk. The two-step approach revealed a statistically significant GxBMI interaction located within the Formin 1/Gremlin 1 (FMN1/GREM1) gene region (rs58349661). This SNP was also identified by the 3DF test, with a suggestive statistical significance in the 1DF test. Among participants with the CC genotype of rs58349661, overweight and obesity categories were associated with higher colorectal cancer risk, whereas null associations were observed across BMI categories in those with the TT genotype. Using data from three large international consortia, this study discovered a locus in the FMN1/GREM1 gene region that interacts with BMI on the association with colorectal cancer risk. Further studies should examine the potential mechanisms through which this locus modifies the etiologic link between obesity and colorectal cancer

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Quality of life and service satisfaction in outpatients with severe or non-severe mental illness diagnoses

Purpose Our study investigated quality of life (QoL) in patients with severe or non-severe mental illness diagnoses (SMI and non-SMI) and the association between QoL and service satisfaction measured as patients’ perception of continuity of care (CoC), therapeutic relationship, and unmet service needs. Methods We conducted a national cross-sectional survey among 3836 mental health outpatients, of whom 1327 (34.6%)responded. We assessed QoL with the Manchester Short Assessment of Quality of Life (MANSA), CoC with the CONTINUUM, the therapeutic relationship with the Therapeutic Relationship in Community Mental Health Care (STAR-P) and developed a simple scale to measure unmet service needs. Results Outpatients with SMI (n = 155) reported significantly better QoL than those with non-SMI (n = 835) (p = 0.003). In both groups, QoL was positively associated with cohabitation (p = 0.007 for non-SMI and p = 0.022 for SMI), good contact with family and friends (p < 0.001 for both) and positive ratings of CoC (p < 0.001 for non-SMI and p = 0.008 for SMI). A positive association between QoL and therapeutic relationship (p = 0.001) and a negative association between QoL and unmet needs for treatment (p = 0.009) and activity (p = 0.005) was only found in the non-SMI group. Conclusion Our study highlights the important differences between those with SMI and those with non-SMI in their reported QoL and in the relationship between QoL and service satisfaction, with only non-SMI patients’ QoL influenced by the therapeutic relationship and unmet needs for treatment and activity. It also shows the importance of continuity of care and social factors for good QoL for both groups.publishedVersio

AKTIVITAS SITOTOKSIK EKSTRAK KARANG LUNAK Xenia sp. DARI TELUK MANADO, PROVINSI SULAWESI UTARA

Bioactive compounds from the sea which are generally in the form of secondary metabolites have the potential to be developed as medicinal ingredients. Marine life can be used as an object of research and development, considering the many benefits that can be taken from the secondary metabolite compounds contained in it, especially compounds that have bioactivity. Soft corals are marine biota that have bioactivity, extracts from sost coral contain bioactive compounds that have cytotoxic, anti-tumor, anti-viral, anti-inflammatory, anti-fungal, anti-leukemic, and enzyme activity inhibitory properties. Some of the research results show that marine soft corals have a variety of structures and biological activities including antioxidant substances. Soft corals were extracted by maceration method and then evaporated. The cytotoxic activity of soft coral extract was tested using the BLSA method and then analyzed the data to find the concentration of mortality (LC50). The purpose of this study was to test the cytotoxic activity of soft coral Xenia sp. The results of this study were testing the cytotoxic activity of the sample Xenia sp., amounting to 20.89 ppm, and having strong toxic properties. Key words: BLSA, Soft coral Xenia sp., LC50, Cytotoxi

Electronic Health Record–Driven Approaches in Primary Care to Strengthen Hypertension Management Among Racial and Ethnic Minoritized Groups in the United States: Systematic Review

BackgroundManaging hypertension in racial and ethnic minoritized groups (eg, African American/Black patients) in primary care is highly relevant. However, evidence on whether or how electronic health record (EHR)–driven approaches in primary care can help improve hypertension management for patients of racial and ethnic minoritized groups in the United States remains scarce. ObjectiveThis review aims to examine the role of the EHR in supporting interventions in primary care to strengthen the hypertension management of racial and ethnic minoritized groups in the United States. MethodsA search strategy based on the PICO (Population, Intervention, Comparison, and Outcome) guidelines was utilized to query and identify peer-reviewed articles on the Web of Science and PubMed databases. The search strategy was based on terms related to racial and ethnic minoritized groups, hypertension, primary care, and EHR-driven interventions. Articles were excluded if the focus was not hypertension management in racial and ethnic minoritized groups or if there was no mention of health record data utilization. ResultsA total of 29 articles were included in this review. Regarding populations, Black/African American patients represented the largest population (26/29, 90%) followed by Hispanic/Latino (18/29, 62%), Asian American (7/29, 24%), and American Indian/Alaskan Native (2/29, 7%) patients. No study included patients who identified as Native Hawaiian/Pacific Islander. The EHR was used to identify patients (25/29, 86%), drive the intervention (21/29, 72%), and monitor results and outcomes (7/29, 59%). Most often, EHR-driven approaches were used for health coaching interventions, disease management programs, clinical decision support (CDS) systems, and best practice alerts (BPAs). Regarding outcomes, out of 8 EHR-driven health coaching interventions, only 3 (38%) reported significant results. In contrast, all the included studies related to CDS and BPA applications reported some significant results with respect to improving hypertension management. ConclusionsThis review identified several use cases for the integration of the EHR in supporting primary care interventions to strengthen hypertension management in racial and ethnic minoritized patients in the United States. Some clinical-based interventions implementing CDS and BPA applications showed promising results. However, more research is needed on community-based interventions, particularly those focusing on patients who are Asian American, American Indian/Alaskan Native, and Native Hawaiian/Pacific Islander. The developed taxonomy comprising “identifying patients,” “driving intervention,” and “monitoring results” to classify EHR-driven approaches can be a helpful tool to facilitate this

Dendritic mesoporous silica nanoparticles for pH-stimuli-responsive drug delivery of TNF-alpha

Tumor necrosis factor-alpha (TNF-α) is a pleiotropic immune stimulatory cytokine and natural endotoxin that can induce necrosis and regression in solid tumors. However, systemic administration of TNF-α is not feasible due to its short half-life and acute toxicity, preventing its widespread use in cancer treatment. Dendritic mesoporous silica nanoparticles (DMSN) are used coated with a pH-responsive block copolymer gate system combining charged hyperbranched polyethylenimine and nonionic hydrophilic polyethylenglycol to encapsulate TNF-α and deliver it into various cancer cell lines and dendritic cells. Half-maximal effective concentration (EC) for loaded TNF-α is reduced by more than two orders of magnitude. Particle stability and premature cargo release are assessed with enzyme-linked immunosorbent assay. TNF-α-loaded particles are stable for up to 5 d in medium. Tumor cells are grown in vitro as 3D fluorescent ubiquitination-based cell cycle indicator spheroids that mimic in vivo tumor architecture and microenvironment, allowing real-time cell cycle imaging. DMSN penetrate these spheroids, release TNF-α from its pores, preferentially affect cells in S/G2/M phase, and induce cell death in a time- and dose-dependent manner. In conclusion, DMSN encapsulation is demonstrated, which is a promising approach to enhance delivery and efficacy of antitumor drugs, while minimizing adverse side effects