Tacrolimus Formulation, Exposure Variability, and Outcomes in Kidney Transplant Recipients.

INTRODUCTION: Few studies have compared within-patient variability measures of tacrolimus trough levels by formulation and assessed within-patient variability on outcomes of kidney transplant recipients. RESEARCH QUESTIONS: (1) To compare within-patient variability of trough levels when converting from twice-daily to once-daily tacrolimus using standard deviation, coefficient of variation, and intrapatient variability percent. (2) To use the 3 measures of variability to examine the relationship between tacrolimus once-daily within-patient variability and total graft failure (i.e., return to chronic dialysis, pre-emptive retransplant, death with graft function). DESIGN: In this observational cohort study, within-patient variability of trough levels pre- and post-conversion from twice-daily to once-daily tacrolimus were compared using Wilcoxon matched-pairs signed-rank test. Graft outcomes were analyzed using Kaplan-Meier curves and multivariable Cox proportional hazards models. RESULTS: In 463 patients, within-patient variability differences pre- and post-conversion of median standard deviation, coefficient of variation, and intrapatient variability percent were -0.16 (P = 0.09), -0.01 (P = 0.52), and -1.41 (P = 0.32), respectively. Post-conversion, every 1 unit increase in within-patient variability standard deviation and intrapatient variability percent and every 0.1 unit increase in the coefficient of variation was associated with an increased hazard ratio [1.19 (P = 0.004), 1.02 (P = 0.030), 1.13 (P = 0.001), respectively] of total graft failure. Post-conversion, within-patient variability above cohort medians using standard deviation and coefficient of variation had a significantly higher risk of total graft failure. DISCUSSION: Under a program-wide conversion, no significant difference was observed in within-patient variability post-conversion from twice-daily to once-daily tacrolimus using the three measures of variability. High within-patient variability was associated with adverse transplant outcomes post-conversion.

Evaluation of Spin in the Abstracts of Systematic Reviews and Meta-analyses of Treatments for Glaucoma.

PURPOSE: Spin - the misrepresentation of the study's actual findings - carries the ability to distort a reader's perception of a treatments' full benefits and risks. Recent studies have suggested that spin is common in abstracts of randomized controlled trials and systematic reviews focused on treatments for a variety of medical disorders. Therefore, our primary objective was to evaluate the prevalence of spin in the abstracts of systematic reviews and meta-analyses related to glaucoma treatments. We further assessed whether specific study characteristics were associated with spin, including the methodological quality of a study. PATIENTS AND METHODS: We used a cross-sectional study design searching MEDLINE and Embase databases all for systematic reviews and meta-analyses focused on glaucoma treatments. Each abstract was assessed for the nine most severe - severity determined by likelihood of distorting a reader's perception - types of spin that occur in systematic review abstracts. The screening and data extraction was performed in a duplicate, masked fashion. The methodological quality of each review was assessed using A MeaSurement Tool to Assess Systematic Reviews (AMSTAR-2) instrument. To evaluate relationships between spin, AMSTAR-2 appraisals, and other study characteristics, we used unadjusted odds ratios and Fisher's exact test. RESULTS: Only three of the 102 abstracts contained spin, with spin type 5 being the most prevalent. No abstracts contained spin types 1, 2, 3, 4, 6, or 8, and no association was found between the presence of spin in an abstract and any particular study characteristic. Using the AMSTAR-2 quality appraisal instrument, 35 (34.3%) of the studies received a methodological quality rating as high, 42 (41.2%) as moderate, 11 (10.8%) as low, and 14 (13.7%) as critically low. CONCLUSIONS: We found that's pin is present in only a small proportion of systematic reviews and meta-analyses covering the treatment of glaucoma. In comparison to studies in other fields of medicine, ophthalmology appears to be a leader in publishing systematic reviews and meta-analyses with low rates of spin occurring in the abstract.

Local School Wellness Policy as a Means to Advance Whole School, Whole Community, Whole Child: Assessing Alignment in Los Angeles County.

BACKGROUND: District wellness policies provide an avenue to advance the Whole School, Whole Community, Whole Child (WSCC) model. The extent to which wellness policies currently align with WSCC is unclear; to-date, tools have been unavailable to examine this issue. METHODS: We reviewed written health-focused policies among 37 school districts in Los Angeles County in 2017 utilizing a 54-item tool designed to examine the quality of policies in the 10 WSCC domains. Descriptive analyses explored overall and domain-specific comprehensiveness and strength; simple negative binomial regression models examined differences in the policy quality and structure by legislated status. RESULTS: Approximately half of expected policies were present in wellness policies (mean comprehensiveness score = 52.65, ±18.09), < 20% were strong (mean strength score = 16.97, ±8.05). Content in WSCC domains addressed by legislative mandates was significantly more comprehensive and stronger, and more frequently located within the wellness policies, relative to content in non-legislated domains. CONCLUSIONS: Opportunities exist for better alignment of wellness policies with WSCC. Education and health practitioners can utilize the tool developed for this study to identify priority areas where policy support is needed in their jurisdictions. Additional efforts are needed to help schools facilitate and document practice gains around WSCC-aligned policies.

Enhancing plasticity in central networks improves motor and sensory recovery after nerve damage.

Nerve damage can cause chronic, debilitating problems including loss of motor control and paresthesia, and generates maladaptive neuroplasticity as central networks attempt to compensate for the loss of peripheral connectivity. However, it remains unclear if this is a critical feature responsible for the expression of symptoms. Here, we use brief bursts of closed-loop vagus nerve stimulation (CL-VNS) delivered during rehabilitation to reverse the aberrant central plasticity resulting from forelimb nerve transection. CL-VNS therapy drives extensive synaptic reorganization in central networks paralleled by improved sensorimotor recovery without any observable changes in the nerve or muscle. Depleting cortical acetylcholine blocks the plasticity-enhancing effects of CL-VNS and consequently eliminates recovery, indicating a critical role for brain circuits in recovery. These findings demonstrate that manipulations to enhance central plasticity can improve sensorimotor recovery and define CL-VNS as a readily translatable therapy to restore function after nerve damage.

A Geospatial Analysis of Health, Mental Health, and Stressful Community Contexts in Los Angeles County.

INTRODUCTION: Despite numerous federal investments, chronic disease continues to disproportionately affect certain communities across the United States. Understanding the regional distribution (including any overlaps) of factors that extend beyond built and food environments, especially factors that may adversely affect chronic disease-related behaviors, is important. This case study of Los Angeles County's geospatial landscape sought to address these gaps in research and practice. METHODS: We examined the distributions and geographic overlaps between economic hardship, psychological distress, soda consumption, and availability of publicly funded mental health facilities in 8 Service Planning Areas in Los Angeles County. We categorized the geospatial presence of each variable as low, intermediate, or high. We imported all data, collected during 2014-2018, into ArcGIS Pro version 2.3.3 to create 5 bivariate choropleth maps. RESULTS: Levels of economic hardship were not equally distributed across communities; the county was characterized by intermediate levels of soda consumption and psychological distress. Most areas had low or intermediate availability of publicly funded mental health facilities. We also found some discordance between psychological distress and availability of publicly funded mental health facilities, and between economic hardship and availability of these facilities. CONCLUSION: The need exists to address disparities in economic hardship and to increase access to publicly funded mental health supports and providers in Los Angeles County. The information collected in this case study has policy implications for health, public health, and mental health services planning at the local level.

Higher pricing of fresh produce is more likely in SNAP-Ed eligible neighborhoods when adjacent non-program eligible neighborhoods are mixed income.

This analysis describes the socioeconomic attributes of neighborhoods adjacent to low-income neighborhoods with ≥50% of households that are Supplemental Nutrition Assistance Program Education (SNAP-Ed) eligible. It compares the pricing, availability, and quality of fresh produce between these neighborhoods in Los Angeles County. The Los Angeles County Department of Public Health utilized 2013-2014 community-level data from the Communities of Excellence in Nutrition, Physical Activity and Obesity Prevention (CX3) Project to examine the geographic patterns of fresh produce purchases and accessibility in SNAP-Ed eligible census tracts. Community indicators collected by CX3 included information on pricing, availability, and quality of fruits and vegetables from grocery stores (n = 108) in these eligible neighborhoods (n = 21). Correlation statistics were generated to explore the effects of adjacent neighborhoods' socioeconomic status on fruit and vegetable pricing, availability, and quality in the selected neighborhoods ("CX3 neighborhoods"). Poverty data were obtained from the United States Census' American Community Survey. Residents of CX3 neighborhoods that were surrounded by mixed income neighborhoods paid 43% more for fresh produce than CX3 neighborhoods surrounded by other similarly low-income neighborhoods (median produce price, $1.50 versus $1.05). Study results suggest that while quality of produce remains an issue, it is the higher pricing of fresh produce in CX3 neighborhoods - i.e., in the presence of other surrounding mixed income neighborhoods (those with relatively higher income) - that appeared to potentiate food access barriers. Future SNAP-Ed efforts should take this pricing pattern under consideration when designing, planning, and/or implementing nutrition-related programs in these neighborhoods.

Vagus Nerve Stimulation Enhances Stable Plasticity and Generalization of Stroke Recovery.

BACKGROUND AND PURPOSE: Chronic impairment of the arm and hand is a common consequence of stroke. Animal and human studies indicate that brief bursts of vagus nerve stimulation (VNS) in conjunction with rehabilitative training improve recovery of motor function after stroke. In this study, we tested whether VNS could promote generalization, long-lasting recovery, and structural plasticity in motor networks. METHODS: Rats were trained on a fully automated, quantitative task that measures forelimb supination. On task proficiency, unilateral cortical and subcortical ischemic lesions were administered. One week after ischemic lesion, rats were randomly assigned to receive 6 weeks of rehabilitative training on the supination task with or without VNS. Rats then underwent 4 weeks of testing on a task assessing forelimb strength to test generalization of recovery. Finally, the durability of VNS benefits was tested on the supination task 2 months after the cessation of VNS. After the conclusion of behavioral testing, viral tracing was performed to assess synaptic connectivity in motor networks. RESULTS: VNS enhances plasticity in corticospinal motor networks to increase synaptic connectivity to musculature of the rehabilitated forelimb. Adding VNS more than doubled the benefit of rehabilitative training, and the improvements lasted months after the end of VNS. Pairing VNS with supination training also significantly improved performance on a similar, but untrained task that emphasized volitional forelimb strength, suggesting generalization of forelimb recovery. CONCLUSIONS: This study provides the first evidence that VNS paired with rehabilitative training after stroke (1) doubles long-lasting recovery on a complex task involving forelimb supination, (2) doubles recovery on a simple motor task that was not paired with VNS, and (3) enhances structural plasticity in motor networks.

The Impact of Two Los Angeles County Teen Courts on Youth Recidivism: Comparing Two Informal Probation Programs.

OBJECTIVE: This study sought to examine the impact of two Teen Courts operating in Los Angeles County, a juvenile justice system diversion program in which youth are judged by their peers and given restorative sentences to complete during a period of supervision. METHODS: A quasi-experimental design was used to compare youth who participated in Teen Court (n=112) to youth who participated in another diversion program administered by the Probation Department (the 654 Contract program) (n=194). Administrative data were abstracted from Probation records for all youth who participated in these programs between January 1, 2012 and June 20, 2014. Logistic and survival models were used to examine differences in recidivism - measured as whether the minor had any subsequent arrest or arrests for which the charge was filed. RESULTS: Comparison group participants had higher rates of recidivism than Teen Court participants, after controlling for age, gender, race/ethnicity, and risk level. While the magnitude of the program effects were fairly consistent across model specifications (odd ratios comparing Teen Court [referent] to school-based 654 Contract ranging from 1.95 to 3.07, hazard ratios ranging from 1.62 to 2.27), differences were not statistically significant in all scenarios. CONCLUSIONS: While this study provides modest support for the positive impact of Teen Court, additional research is needed to better understand how juvenile diversion programs can improve youth outcomes.

Rapid centriole assembly in Naegleria reveals conserved roles for both de novo and mentored assembly.

Centrioles are eukaryotic organelles whose number and position are critical for cilia formation and mitosis. Many cell types assemble new centrioles next to existing ones ("templated" or mentored assembly). Under certain conditions, centrioles also form without pre-existing centrioles (de novo). The synchronous differentiation of Naegleria amoebae to flagellates represents a unique opportunity to study centriole assembly, as nearly 100% of the population transitions from having no centrioles to having two within minutes. Here, we find that Naegleria forms its first centriole de novo, immediately followed by mentored assembly of the second. We also find both de novo and mentored assembly distributed among all major eukaryote lineages. We therefore propose that both modes are ancestral and have been conserved because they serve complementary roles, with de novo assembly as the default when no pre-existing centriole is available, and mentored assembly allowing precise regulation of number, timing, and location of centriole assembly.

Structure of a eukaryotic thiaminase I.

Thiaminases, enzymes that cleave vitamin B1, are sporadically distributed among prokaryotes and eukaryotes. Thiaminase I enzymes catalyze the elimination of the thiazole ring moiety from thiamin through substitution of the methylene group with a nitrogenous base or sulfhydryl compound. In eukaryotic organisms, these enzymes are reported to have much higher molecular weights than their bacterial counterparts. A thiaminase I of the single-celled amoeboflagellate Naegleria gruberi is the only eukaryotic thiaminase I to have been cloned, sequenced, and expressed. Here, we present the crystal structure of N. gruberi thiaminase I to a resolution of 2.8 Å, solved by isomorphous replacement and pseudo-two-wavelength multiwavelength anomalous diffraction and refined to an R factor of 0.231 (Rfree, 0.265). This structure was used to solve the structure of the enzyme in complex with 3-deazathiamin, a noncleavable thiamin analog and enzyme inhibitor (2.7 Å; R, 0.233; Rfree, 0.267). These structures define the mode of thiamin binding to this class of thiaminases and indicate the involvement of Asp272 as the catalytic base. This enzyme is able to use thiamin as a substrate and is active with amines such as aniline and veratrylamine as well as sulfhydryl compounds such as l-cysteine and ß-mercaptoethanol as cosubstrates. Despite significant differences in polypeptide sequence and length, we have shown that the N. gruberi thiaminase I is homologous in structure and activity to a previously characterized bacterial thiaminase I.

Photoluminescence, thermal transport, and breakdown in joule-heated GaN nanowires.

Thermal transport and breakdown in Joule-heated GaN nanowires is investigated using a combination of microphotoluminescence and in situ TEM characterization. The thermal conductivity of the nanowires is estimated to be <80 W/m.K, which is substantially below the bulk GaN value. Catastrophic breakdown in individual nanowires is observed to occur at a maximum temperature of approximately 1000 K, and nanowire morphology near the breakdown region indicates that failure occurs via thermal decomposition, a conclusion that is validated by in situ TEM images obtained during the failure process.