Biomarkers of Neurodegeneration and Alzheimer's Disease Neuropathology in Adolescents and Young Adults with Youth-Onset Type 1 or Type 2 Diabetes: A Proof-of-Concept Study.

Adult-onset diabetes increases one's risk of neurodegenerative disease including Alzheimer's disease (AD); however, the risk associated with youth-onset diabetes (Y-DM) remains underexplored. We quantified plasma biomarkers of neurodegeneration and AD in participants with Y-DM from the SEARCH cohort at adolescence and young adulthood (Type 1, n = 25; Type 2, n = 25; 59% female; adolescence, age = 15 y/o [2.6]; adulthood, age = 27.4 y/o [2.2]), comparing them with controls (adolescence, n = 25, age = 14.8 y/o [2.7]; adulthood, n = 21, age = 24.9 y/o [2.8]). Plasma biomarkers, including glial fibrillary acidic protein (GFAP), neurofilament light chain protein (NfL), phosphorylated tau-181 (pTau181), and amyloid beta (Aß40, Aß42), were measured via Simoa. A subset of participants (n = 7; age = 27.5 y/o [5.7]) and six controls (age = 25.1 y/o [4.5]) underwent PET scans to quantify brain amyloid and tau densities in AD sensitive brain regions. Y-DM adolescents exhibited lower plasma levels of Aß40, Aß42, and GFAP, and higher pTau181 compared to controls (p < 0.05), a pattern persisting into adulthood (p < 0.001). All biomarkers showed significant increases from adolescence to adulthood in Y-DM (p < 0.01), though no significant differences in brain amyloid or tau were noted between Y-DM and controls in adulthood. Preliminary evidence suggests that preclinical AD neuropathology is present in young people with Y-DM, indicating a potential increased risk of neurodegenerative diseases.

Kidney Energetics and Cyst Burden in Autosomal Dominant Polycystic Kidney Disease: A Pilot Study.

RATIONALE & OBJECTIVE: In this pilot study, we hypothesized that autosomal dominant polycystic kidney disease (ADPKD) is characterized by impaired kidney oxidative metabolism that associates with kidney size and cyst burden. STUDY DESIGN: Cross-sectional study. SETTING & PARTICIPANTS: Twenty adults with ADPKD (31±6 years of age, 65% women, BMI: 26.8 [22.7, 30.4] kg/m2, eGFR (2021 CKD-EPI Creatinine): 103±18 ml/min/1.73m2, height-adjusted total kidney volume [HtTKV]: 731±370 ml/m, Mayo Classifications: 1B [5%], 1C [42%], 1D [21%], 1E [32%]) and 11 controls in normal weight category (NWC; 25±3 years of age, 45% women, BMI: 22.5 [21.7, 24.2] kg/m2, eGFR: 113±15 ml/min/1.73m2, HtTKV: 159±31 ml/m) at the University of Colorado Anschutz Medical Campus. PREDICTORS: ADPKD status (yes/no) and severity (Mayo Classifications). OUTCOMES: HtTKV and cyst burden by MRI, kidney oxidative metabolism and perfusion by 11C-acetate PET/CT, insulin sensitivity by hyperinsulinemic-euglycemic clamps (presented as ratio of M-value of steady state insulin concentration [M/I]). ANALYTICAL APPROACH: Chi-square/Fisher's exact tests used for categorical variables and t-tests/ Mann-Whitney U tests for continuous variables. Pearson correlation used to estimate the relationships between variables. RESULTS: Compared to NWC, participants with ADPKD exhibited lower mean±SD M/I ratio (0.586±0.205 vs. 0.424±0.171 (mg/kg lean/min) / (µIU/mL), p=0.04), lower median [p25, p75] cortical perfusion (1.93 [1.80, 2.09 vs. 0.68 [0.47, 1.04] mL/min/g, p<0.001) and lower median [p25, p75] total kidney oxidative metabolism (0.17 [0.16,0.19] vs. 0.14 [0.12, 0.15] min-1, p=0.001) in voxel-wise models excluding cysts. HtTKV correlated inversely with cortical perfusion (r:-0.83, p<0.001), total kidney oxidative metabolism (r:-0.61, p<0.001) and M/I (r:-0.41, p=0.03). LIMITATIONS: Small sample size and cross-sectional design. CONCLUSION: Adults with ADPKD and preserved kidney function exhibited impaired renal perfusion and kidney oxidative metabolism across a wide range of cysts and kidney enlargements.

Glycoprotein Acetyls Associate With Intraglomerular Hemodynamic Dysfunction, Albuminuria, Central Adiposity, and Insulin Resistance in Youth With Type 1 Diabetes.

OBJECTIVES: Glycoprotein acetyls (GlycA's) are biomarkers of systemic inflammation and cardiovascular disease, yet little is known about their role in type 1 diabetes (T1D). In this study we examined the associations among GlycA's, central adiposity, insulin resistance, and early kidney injury in youth with T1D. METHODS: Glomerular filtration rate and renal plasma flow by iohexol and p-aminohippurate clearance, urine albumin-to-creatinine ratio (UACR), central adiposity by dual-energy x-ray absorptiometry, and estimated insulin sensitivity were assessed in 50 youth with T1D (16±3.0 years of age, 50% female, glycated hemoglobin 8.7±1.3%, T1D duration 5.7±2.6 years). Concentrations of GlycA were quantified by targeted nuclear magnetic resonance spectroscopy. Correlation and multivariable linear regression analyses were performed. RESULTS: GlycA's were higher in girls vs boys (1.05±0.26 vs 0.84±0.15 mmol/L, p=0.001) and in participants living with overweight/obesity vs normal weight (1.12±0.23 vs 0.87±0.20 mmol/L, p=0.0004). GlycA's correlated positively with estimated intraglomerular pressure (r=0.52, p=0.001), UACR (r=0.53, p<0.0001), and trunk mass (r=0.45, p=0.001), and inversely with estimated insulin sensitivity (r=-0.36, p=0.01). All relationships remained significant after adjustment for age, sex, and glycated hemoglobin. CONCLUSIONS: As biomarker of inflammation, GlycA's were higher in girls and those with overweight or obese body habitus in T1D. GlycA's associated with parameters of early kidney dysfunction, central adiposity, and insulin resistance.

Insulin Secretion, Sensitivity, and Kidney Function in Young Individuals With Type 2 Diabetes.

OBJECTIVE: ß-Cell dysfunction and insulin resistance magnify the risk of kidney injury in type 2 diabetes. The relationship between these factors and intraglomerular hemodynamics and kidney oxygen availability in youth with type 2 diabetes remains incompletely explored. RESEARCH DESIGN AND METHODS: Fifty youth with type 2 diabetes (mean age ± SD 16 ± 2 years; diabetes duration 2.3 ± 1.8 years; 60% female; median HbA1c 6.4% [25th, 75th percentiles 5.9, 7.6%]; BMI 36.4 ± 7.4 kg/m2; urine albumin-to-creatinine ratio [UACR] 10.3 [5.9, 58.0] mg/g) 21 control participants with obesity (OCs; age 16 ± 2 years; 29% female; BMI 37.6 ± 7.4 kg/m2), and 20 control participants in the normal weight category (NWCs; age 17 ± 3 years; 70% female; BMI 22.5 ± 3.6 kg/m2) underwent iohexol and p-aminohippurate clearance to assess glomerular filtration rate (GFR) and renal plasma flow, kidney MRI for oxygenation, hyperglycemic clamp for insulin secretion (acute C-peptide response to glucose [ACPRg]) and disposition index (DI; ×103 mg/kg lean/min), and DXA for body composition. RESULTS: Youth with type 2 diabetes exhibited lower DI (0.6 [0.0, 1.6] vs. 3.8 [2.4, 4.5] × 103 mg/kg lean/min; P < 0.0001) and ACPRg (0.6 [0.3, 1.4] vs. 5.3 [4.3, 6.9] nmol/L; P < 0.001) and higher UACR (10.3 [5.9, 58.0] vs. 5.3 [3.4, 14.3] mg/g; P = 0.003) and intraglomerular pressure (77.8 ± 11.5 vs. 64.8 ± 5.0 mmHg; P < 0.001) compared with OCs. Youth with type 2 diabetes and OCs had higher GFR and kidney oxygen availability (relative hyperoxia) than NWCs. DI was associated inversely with intraglomerular pressure and kidney hyperoxia. CONCLUSIONS: Youth with type 2 diabetes demonstrated severe ß-cell dysfunction that was associated with intraglomerular hypertension and kidney hyperoxia. Similar but attenuated findings were found in OCs.

Evaluating the Efficacy of Hyperbaric Oxygen Therapy in Digital Frostbite.

Frostbite is a limb threatening, cold-induced tissue injury most commonly affecting the extremities. Hyperbaric oxygen therapy (HBOT) is a proposed adjunctive treatment for this condition, which acts by increasing cellular oxygen availability in damaged tissues. Currently, there is a lack of data regarding the effectiveness of HBOT. Therefore, the purpose of this study is to further the research as one of the largest retrospective comparative cohort studies to date. We evaluated the efficacy of HBOT in the treatment of digital frostbite compared to a non-HBOT-treated group, with a focus on amputation outcomes between each group. A multicenter retrospective cohort study was performed from January 2016 to August 2021 observing patients seen for frostbite. Amputation characteristics and encounter outcomes of patients treated with HBOT were compared to those in patients treated without HBOT. A one-to-one matching of HBOT-treated and non-HBOT-treated patients was also performed, followed by chi-square and Fisher's exact test statistical analysis. The results of the study found a low overall amputation rate of 5.2% across both cohorts. Comparison between groups identified no statistical difference between HBOT and non-HBOT groups regarding amputation characteristics through matched cohort analysis. However, an increased length of hospital stay in patients treated with HBOT (22.2 days) compared to the non-HBOT group (6.39 days) was identified. Based on this study, recommendations for future HBOT studies should evaluate the efficacy of HBOT for more severe cases of frostbite, with additional consideration for cost analysis studies.

Intracellular Islatravir-Triphosphate in Dried Blood Spots and Peripheral Blood Mononuclear Cells from Pig-Tailed Macaques.

The purpose of this study was to evaluate the relationship between intracellular islatravir-triphosphate (ISL-TP) in paired peripheral blood mononuclear cells (PBMCs) and dried blood spots (DBS). Three pig-tailed macaques (PMs) were dosed with a single intravaginal extended-release ISL-etonogestrel film for a period of 31 days. After extraction and quantification, repeated measures correlation (rrm) was assessed between log-transformed DBS and PBMC ISL-TP concentrations. Twenty-six paired PBMC/DBS samples were included. Peak ISL-TP concentrations in DBS ranged from 262 to 913 fmol/punches, PBMC Cmax ranged from 427 to 857 fmol/106 cells. Repeated measures correlation yielded an rrm value of 0.96 (95% confidence interval 0.92-0.98; p < .0001). Importantly, ISL-TP was quantifiable in DBS and its pharmacokinetics were similar to PBMC in PMs. Human studies should evaluate DBS applications in clinical pharmacokinetic studies to help define ISL's place in the antiretroviral drug armamentarium.

Changing Characteristics of Children With COVID-19 in Colorado Admitted During Different Variant Periods.

BACKGROUND: Data are lacking on the impact of different severe acute respiratory syndrome coronavirus 2 variants in children and on pediatric vaccine effectiveness. We examined differences among children requiring hospital admission associated with coronavirus disease 2019 (COVID-19) during wild type, Delta and Omicron variant periods and calculated vaccine effectiveness at preventing symptomatic hospitalization during the Delta and Omicron variant periods. METHODS: We conducted a retrospective review of children younger than 21 years of age hospitalized with symptomatic COVID-19. Characteristics were compared between variant periods using Kruskal-Wallis or generalized Fisher exact tests. We estimated vaccine effectiveness in preventing symptomatic hospitalization. RESULTS: We included 115 children admitted during the wild type period, 194 during Delta and 226 during the Omicron periods. Median age (years) decreased (12.2 wild type, 5.9 Delta, 1.3 Omicron periods, P < 0.0001) over time. Children were less likely to have a comorbid condition, including diabetes or obesity, and had shorter admissions during Omicron compared with the wild type and Delta periods. Intensive care unit admissions and respiratory support requirements were highest during the Delta period ( P = 0.05). Among children ≥12 years, adjusted vaccine effectiveness at preventing symptomatic hospitalization was 86% during Delta and 45% during Omicron periods. CONCLUSIONS: Children hospitalized with COVID-19 during later variant periods were younger and less likely to have comorbidities. Children admitted during the Delta variant period required more intensive care and respiratory support compared to other variant periods. Vaccination was less effective at preventing symptomatic hospital admission during the Omicron period compared to the Delta period.

Investigational medications in 9,638 hospitalized patients with severe COVID-19: lessons from the "fail-and-learn" strategy during the first two waves of the pandemic in 2020.

BACKGROUND: The early surge of the novel coronavirus disease 2019 (COVID-19) pandemic introduced a significant clinical challenge due to the high case-fatality rate in absence of evidence-based recommendations. The empirical treatment modalities were relegated to historical expertise from the traditional management of acute respiratory distress syndrome (ARDS) in conjunction with off-label pharmaceutical agents endorsed under the "emergency use authorization" (EUA) paradigm by regulatory agencies. This study was designed to evaluate the insights from the "fail-and-learn" strategy in 2020 before the availability of COVID-19 vaccines and access to reliable insights from high-quality randomized controlled trials. METHODS: A retrospective, multicenter, propensity-matched, case-control study was performed on a data registry comprising 186 hospitals from a national health care system in the United States, designed to investigate the efficacy of empirical treatment modalities during the early surge of the COVID-19 pandemic in 2020. Reflective of the time-windows of the initial two surges of the pandemic in 2020, patients were stratified into "Early 2020" (March 1-June 30) versus "Late 2020" (July 1-December 31) study cohorts. Logistic regression was applied to determine the efficacy of prevalent medications (remdesivir, azithromycin, hydroxychloroquine, corticosteroids, tocilizumab) and supplemental oxygen delivery modalities (invasive vs. non-invasive ventilation) on patient outcomes. The primary outcome measure was in-hospital mortality. Group comparisons were adjusted for covariates related to age, gender, ethnicity, body weight, comorbidities, and treatment modalities pertinent to organ failure replacement. RESULTS: From a total of 87,788 patients in the multicenter data registry screened in this study, 9,638 patients were included who received 19,763 COVID-19 medications during the first two waves of the 2020 pandemic. The results showed a minimal, yet statistically significant, association with hydroxychloroquine in "Early 2020" and remdesivir in "Late 2020" with reduced odds of mortality (odds ratios 0.72 and 0.76, respectively; P = 0.01). Azithromycin was the only medication associated with decreased odds of mortality during both study time-windows (odds ratios 0.79 and 0.68, respectively; P < 0.01). In contrast, the necessity for oxygen supply showed significantly increased odds of mortality beyond the effect of all investigated medications. Of all the covariates associated with increased mortality, invasive mechanical ventilation had the highest odds ratios of 8.34 in the first surge and 9.46 in in the second surge of the pandemic (P < 0.01). CONCLUSION: This retrospective multicenter observational cohort study on 9,638 hospitalized patients with severe COVID-19 during revealed that the necessity for invasive ventilation had the highest odds of mortality, beyond the variable effects observed by administration of the prevalent EUA-approved investigational drugs during the first two surges of the early 2020 pandemic in the United States.

Nursing opinions on collaborating with residents in new and legacy OB/GYN programs.

Collaboration among physicians and nurses is vital and has shown to lead to better patient care and improve outcomes. Our study surveyed two groups of Labor and Delivery nurses in two regionally similar community hospitals in midwestern United States: one group from a new Obstetrics and Gynecology (OB/GYN) residency program (n = 49) and another from an established (legacy) OB/GYN residency program (n = 49). The survey asked nurses from the hospital with new and legacy residency program about preparedness for working with residents, perceptions of nurse-resident-patient relationships, collaboration and opinions about how resident physicians impact patient safety. Most nurses from the legacy residency program showed positive perceptions of collaboration with the residency and institutional support. In the new OB/GYN residency program, nurses were generally neutral and showed skepticism about collaboration with OB/GYN resident physicians and institutional support. Nurses from both hospitals felt similarly in their comfort escalating issues to administration and in their satisfaction with interprofessional collaboration within Labor and Delivery units. Providing nurses with opportunities to learn about the role of new medical residents in their patient care setting as well as intentional collaboration between nursing and residency program administration might result in more effective collaboration between physician residents and nursing staff.

Assessing Nursing Sentiments on Nurse-Resident Physician Collaboration and Administrative Support in the Labor and Delivery Setting: Development and Validation of a Novel Instrument.

OBJECTIVE: To develop a survey instrument that: 1) investigates the dynamics of collaboration in multidisciplinary care units such as labor and delivery (L&D); and (2) uniquely determines the collaborative relationships between nurses and resident physicians. BACKGROUND: An effective interprofessional collaboration between healthcare providers is considered a critical component in delivering high-quality care to patients and lies at the root of ensuring positive patient outcomes. METHODS: Two samples of responses (n = 98) were collected from L&D nurses working in 2 hospitals: 1 with novel obstetrics and gynecology (OB/GYN) residency program and 1 with legacy OB/GYN residency program. Descriptive statistics and reliability statistics (Cronbach's α and item-total correlations) were calculated for each sample. RESULTS: Reliability analysis revealed strong internal consistency of the survey items in both samples even after completing single-item deletion analysis. CONCLUSIONS: Findings suggest that our 11-item instrument shows promise in effectively assessing nursing sentiments toward collaboration with resident physicians.

Data Mining Framework for Discovering and Clustering Phenotypes of Atypical Diabetes.

CONTEXT: Some individuals present with forms of diabetes that are "atypical" (AD), which do not conform to typical features of either type 1 diabetes (T1D) or type 2 diabetes (T2D). These forms of AD display a range of phenotypic characteristics that likely reflect different endotypes based on unique etiologies or pathogenic processes. OBJECTIVE: To develop an analytical approach to identify and cluster phenotypes of AD. METHODS: We developed Discover Atypical Diabetes (DiscoverAD), a data mining framework, to identify and cluster phenotypes of AD. DiscoverAD was trained against characteristics of manually classified patients with AD among 278 adults with diabetes within the Cameron County Hispanic Cohort (CCHC) (Study A). We then tested DiscoverAD in a separate population of 758 multiethnic children with T1D within the Texas Children's Hospital Registry for New-Onset Type 1 Diabetes (TCHRNO-1) (Study B). RESULTS: We identified an AD frequency of 11.5% in the CCHC (Study A) and 5.3% in the pediatric TCHRNO-1 (Study B). Cluster analysis identified 4 distinct groups of AD in Study A: cluster 1, positive for the 65 kDa glutamate decarboxylase autoantibody (GAD65Ab), adult-onset, long disease duration, preserved beta-cell function, no insulin treatment; cluster 2, GAD65Ab negative, diagnosed at age ≤21 years; cluster 3, GAD65Ab negative, adult-onset, poor beta-cell function, lacking central obesity; cluster 4, diabetic ketoacidosis (DKA)-prone participants lacking a typical T1D phenotype. Applying DiscoverAD to the pediatric patients with T1D in Study B revealed 2 distinct groups of AD: cluster 1, autoantibody negative, poor beta-cell function, lower body mass index (BMI); cluster 2, autoantibody positive, higher BMI, higher incidence of DKA. CONCLUSION: DiscoverAD can be adapted to different datasets to identify and define phenotypes of participants with AD based on available clinical variables.

Oncogenic Role of Exosomal Circular and Long Noncoding RNAs in Gastrointestinal Cancers.

Circular RNAs (circRNAs) and long noncoding RNAs (lncRNAs) are differentially expressed in gastrointestinal cancers. These noncoding RNAs (ncRNAs) regulate a variety of cellular activities by physically interacting with microRNAs and proteins and altering their activity. It has also been suggested that exosomes encapsulate circRNAs and lncRNAs in cancer cells. Exosomes are then discharged into the extracellular environment, where they are taken up by other cells. As a result, exosomal ncRNA cargo is critical for cell-cell communication within the cancer microenvironment. Exosomal ncRNAs can regulate a range of events, such as angiogenesis, metastasis, immune evasion, drug resistance, and epithelial-to-mesenchymal transition. To set the groundwork for developing novel therapeutic strategies against gastrointestinal malignancies, a thorough understanding of circRNAs and lncRNAs is required. In this review, we discuss the function and intrinsic features of oncogenic circRNAs and lncRNAs that are enriched within exosomes.

Over-the-counter access to levonorgestrel emergency contraception in South Texas: Does Over-the-counter mean ready to buy?

OBJECTIVE: To determine the percentage of pharmacies in Hidalgo County, Texas, with unrestricted over-the-counter access to levonorgestrel emergency contraceptive pills (ECPs). Unrestricted over-the-counter access means product is available directly to consumer on store shelf, in-stock the day of data collection, and with no security barriers present (such as locked cabinet or individual locked product container), and to compare this access to that of other reproductive health items. STUDY DESIGN: We conducted in-person secret shopper surveys from October 2018 to March 2019, recording in-stock over-the-counter availability of levonorgestrel ECPs, security barriers, and price. We collected the same information for condom multipacks, ovulation prediction test kits, and pregnancy tests. RESULTS: Out of the 76 pharmacies surveyed, 31 (40.8%) sold levonorgestrel ECPs over-the-counter, 23 (30.3%) had product in-stock over-the-counter and two (2.6%) had unrestricted over-the-counter access. Other reproductive health items such as condom multipacks, ovulation prediction test kits and pregnancy tests had unrestricted over-the-counter access in at least 33 (43.4%, p < 0.01) pharmacies. Of the chain pharmacies, 30 (73.2%) sold levonorgestrel ECPs over-the-counter with and without security barriers, while only one (2.9%) of the 35 independent pharmacies sold levonorgestrel ECPs over-the-counter with security barriers (p < 0.001). CONCLUSIONS: While previous research has noted high prevalence of levonorgestrel ECP availability in pharmacies, potential purchasers of over-the-counter levonorgestrel ECPs encounter access barriers not associated with other reproductive health products. These additional access barriers to levonorgestrel ECPs may increase consumer discomfort, decrease privacy, and delay access. IMPLICATIONS: Advocacy efforts may be needed to promote unrestricted access to over-the-counter emergency contraceptives on par with other reproductive health items.

Reduction of dislocations in α-Ga2O3 epilayers grown by halide vapor-phase epitaxy on a conical frustum-patterned sapphire substrate.

The compound α-Ga2O3 is an ultra-wide-bandgap semiconductor and possesses outstanding properties such as a high breakdown voltage and symmetry compared with other phases. It has been studied for applications in high-performance power devices. However, it is difficult to obtain a high-quality thin films because α-Ga2O3 can only grow heteroepitaxially, which results in residual stress generation owing to lattice mismatch and thermal expansion between the substrate and α-Ga2O3. To overcome this, α-Ga2O3 was grown on a conical frustum-patterned sapphire substrate by halide vapor-phase epitaxy. The surface morphology was crack-free and flat. The α-Ga2O3 grown on a frustum-patterned substrate and a conventional sapphire substrate at 500°C exhibited full-width at half-maxima of 961 and 1539 arcsec, respectively, for 10-12 diffraction. For the former substrate, lateral growth on the pattern and threading dislocation bending towards the pattern suppressed the propagation of threading dislocations generated at the interface, which reduced the threading dislocation propagation to the surface by half compared with that on the latter conventional substrate. The results suggest that conical frustum-patterned sapphire substrates have the potential to produce high-quality α-Ga2O3 epilayers.

Life Experiences with Using Community Care among People with Severe Physical Disabilities: A Comparative Analysis between South Korea and Japan.

This study identified the pathways chosen by people with severe physical disabilities (PWSPD) in South Korea and Japan in using community care throughout their life and compared their experiences while navigating these pathways from their perspective. A concurrent nested mixed-method design was adopted. Quantitative data analysis included pathway mapping of facilities and services used throughout their lives. For qualitative data, interpretative phenomenological analysis (IPA) was applied. Eleven South Korean (congenital 7, acquired 4) and nine Japanese (congenital 6, acquired 3) participants were surveyed and interviewed. Pathway mapping was conducted by classifying the participants into focus groups. South Korean participants took nine years more than the Japanese participants to reach independence and showed different pathway characteristics. Superordinate themes from the IPA provided insight into the differences in experiences between PWSPD of the two countries: (1) accessibility and continuity of medical services; (2) experience of vocational training; (3) way and degree of social support for independent living; (4) care planning for receiving comprehensive services. In developing a community care model for the PWSPD to accelerate their time to independence, the government should strive for accessibility and connectivity of medical services, strengthen vocational training, social support for independent living, and information provision for the PWSPD.

Pharmacokinetics and renal safety of tenofovir alafenamide with boosted protease inhibitors and ledipasvir/sofosbuvir.

BACKGROUND: Ledipasvir/sofosbuvir increases tenofovir plasma exposures by up to 98% with tenofovir disoproxil fumarate (TDF), and exposures are highest with boosted PIs. There are currently no data on the combined use of the newer tenofovir prodrug, tenofovir alafenamide (TAF), boosted PIs and ledipasvir/sofosbuvir. OBJECTIVES: To compare the plasma and intracellular pharmacokinetics and renal safety of TAF with ledipasvir/sofosbuvir when co-administered with boosted PIs. METHODS: Persons with HIV between 18 and 70 years and on a boosted PI with TDF were eligible. The study was comprised of four phases: (1) TDF 300 mg with boosted PI; (2) TAF 25 mg with boosted PI; (3) TAF 25 mg with boosted PI and ledipasvir/sofosbuvir; and (4) TAF 25 mg with boosted PI. Pharmacokinetic sampling, urine biomarker collection [urine protein (UPCR), retinol binding protein (RBP) and ß2 microglobulin (ß2M) normalized to creatinine] and safety assessments occurred at the end of each phase. Plasma, PBMCs and dried blood spots were collected at each visit. RESULTS: Ten participants were enrolled. Plasma tenofovir exposures were 76% lower and tenofovir-diphosphate (TFV-DP) concentrations in PBMCs increased 9.9-fold following the switch to TAF. Neither of these measures significantly increased with ledipasvir/sofosbuvir co-administration, nor did TAF plasma concentrations. No significant changes in estimated glomerular filtration rate or UPCR occurred, but RBP:creatinine and ß2M:creatinine improved following the switch to TAF. CONCLUSIONS: Ledipasvir/sofosbuvir did not significantly increase plasma tenofovir or intracellular TFV-DP in PBMCs with TAF. These findings provide reassurance that the combination of TAF, boosted PIs and ledipasvir/sofosbuvir is safe in HIV/HCV-coinfected populations.

Development of three-dimensional articular cartilage construct using silica nano-patterned substrate.

Current strategies for cartilage cell therapy are mostly based on the use of autologous chondrocytes. However, these cells have limitations of a small number of cells available and of low chondrogenic ability, respectively. Many studies now suggest that fetal stem cells are more plastic than adult stem cells and can therefore more efficiently differentiate into target tissues. This study introduces, efficiency chondrogenic differentiation of fetal cartilage-derived progenitor cells (FCPCs) to adult cells can be achieved using a three-dimensional (3D) spheroid culture method based on silica nanopatterning techniques. In evaluating the issue of silica nano-particle size (Diameter of 300, 750, 1200 nm), each particle size was coated into the well of a 6-well tissue culture plate. FCPCs (2 x 105 cells/well in 6-well plate) were seeded in each well with chondrogenic medium. In this study, the 300 nm substrate that formed multi-spheroids and the 1200 nm substrate that showed spreading were due to the cell-cell adhesion force(via N-cadherin) and cell-substrate(via Integrin) force, the 750 nm substrate that formed the mass-aggregation can be interpreted as the result of cell monolayer formation through cell-substrate force followed by cell-cell contact force contraction. We conclude that our 3D spheroid culture system contributes to an optimization for efficient differentiation of FCPC, offers insight into the mechanism of efficient differentiation of engineered 3D culture system, and has promise for wide applications in regeneration medicine and drug discovery fields.

Muscle profile and cognition in patients with Alzheimer's disease dementia.

INTRODUCTION: Neurodegenerative disease is one of the main contributing factors affecting muscle atrophy. However, this intriguing brain-muscle axis has been explained by the unsubstantial mechanisms. Although there have been several studies that have evaluated the muscle profile and its relation to cognition in patients with dementia, there is still lack of data using standardized methods and only few published studies on Korean populations. The objective of this study is to evaluate the relationship of muscle mass and strength to cognition in patients with Alzheimer's disease dementia (AD). METHODS: We recruited 91 patients with probable AD without weakness. We assessed patients' basic demographic characteristics, vascular risk, body mass index, and global cognitive assessment scores. Muscle mass was measured using body dual-energy X-ray absorptiometry. Muscle strength was assessed by isokinetic knee extensor using an isokinetic device at an angular velocity of 60°/s in nm/kg. RESULTS: The muscle mass and strength were not related to each other in both male and female groups. Only muscle strength, but not muscle mass, was negatively related to cognition. After adjusting for covariates, the relationship between muscle strength and cognition still remained in the male group, however, was attenuated in the female group. CONCLUSIONS: In patients with AD dementia, abundant muscle mass did not mean strong power. The simple lower-extremity muscle strength assessment is more effective in predicting cognition than a muscle mass measure in male patients.

Development of the Korean framework for senior-friendly hospitals: a Delphi study.

BACKGROUND: Aging is an inevitable part of life. One can maintain well-being and wellness even after discharge and/or transition if his or her functional decline is minimized, sudden decline is prevented, and functioning is promoted during hospitalization. Caring appropriately for elderly patients requires the systematic application of Senior-Friendly Hospital principles to all operating systems, including medical centres' organization and environment, as well as patient treatment processes. The Senior-Friendly Hospital framework is valid and important for patient safety and quality improvement. This study aimed to make recommendations regarding the development of the Korean Framework for Senior-Friendly Hospitals for older patients' care management, patient safety interventions, and health promotion, via a Delphi survey. METHODS: Two rounds of Delphi surveying were conducted with 15 participants who had at least 3 years' experience in accreditation surveying and medical accreditation standards, survey methods, and accreditation investigator education. In each round, we calculated statistics describing each standard's validity and feasibility. RESULTS: The Korean Framework for Senior-Friendly Hospitals included 4 Chapters, 11 categories, and 67 standards through consensus of the Senior-Friendly Hospitals task force and experts' peer review. After the two rounds of Delphi surveying, validity evaluation led to no changes in standards of the Senior-Friendly Hospitals; however, the number of standards showing adequate validity decreased from 67 to 58. Regarding feasibility, no changes were necessary in the standards; however, the number of categories showing adequate feasibility decreased from 11 to 8 and from 67 to 30, respectively. The excluded categories were 3.2, 4.2, and 4.3 (service, transportation, and signage and identification). The highest feasibility values were given to standards 2.1.1, 4.1.4, and 4.1.6. The highest feasibility score was given to standard 2.4.2. CONCLUSIONS: The Korean Framework for Senior-Friendly Hospitals needs to include 4 Chapters, 8 categories, and 30 standards. The Accreditation Program for Healthcare Organizations should include Senior-Friendly Hospitals -relevant standards considering Korea's medical environment.

Novel Compound Heterozygous Nonsense PRX Mutations in a Korean Dejerine-Sottas Neuropathy Family.

BACKGROUND: Mutations in the gene encoding periaxin (PRX) are known to cause autosomal recessive Dejerine-Sottas neuropathy (DSN) or Charcot-Marie-Tooth disease type 4F. However, there have been no reports describing Korean patients with these mutations. CASE REPORT: We examined a Korean DSN patient with an early-onset, slowly progressive, demyelinating neuropathy with prominent sensory involvement. Whole-exome sequencing and subsequent capillary sequencing revealed novel compound heterozygous nonsense mutations (p.R392X and p.R679X) in PRX. One mutation was transmitted from each of the patient's parents. No unaffected family member had both mutations, and the mutations were not found in healthy controls. CONCLUSIONS: We believe that these novel compound heterozygous nonsense mutations are the underlying cause of DSN. The clinical, electrophysiologic, and pathologic phenotypes in this family were similar to those described previously for patients with PRX mutations. We have identified the first PRX mutation in a Korean patient with DSN.