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AbstractCompared with the general population, hematopoietic cell transplantation (HCT) survivors are at elevated risk for developing solid subsequent neoplasms (SNs). The Center for International Blood and Marrow Transplant Research (CIBMTR) is a key resource for quantifying solid SN incidence following HCT, but the completeness of SN ascertainment is uncertain. Within a cohort of 18 450 CIBMTR patients linked to the California Cancer Registry (CCR), we evaluated the completeness of solid SN data reported to the CIBMTR from 1991 to 2018 to understand the implications of using CIBMTR data alone or combined with CCR data to quantify the burden of solid SNs after HCT. We estimated the cumulative incidence of developing a solid SN, accounting for the competing risk of death. Within the cohort, solid SNs were reported among 724 patients; 15.6% of these patients had an SN reported by CIBMTR only, 36.9% by CCR only, and 47.5% by both. The corresponding cumulative incidence of developing a solid SN at 10 years following a first HCT was 4.0% (95% confidence interval [CI], 3.5-4.4) according to CIBMTR data only, 5.3% (95% CI, 4.9-5.9) according to CCR data only, and 6.3% (95% CI, 5.7-6.8) according to both sources combined. The patterns were similar for allogeneic and autologous HCT recipients. Linking detailed HCT information from CIBMTR with comprehensive SN data from cancer registries provides an opportunity to optimize SN ascertainment for informing follow-up care practices and evaluating risk factors in the growing population of HCT survivors.

BACKGROUND: Claims-based measures of multimorbidity, which evaluate the presence of a defined list of diseases, are limited in their ability to predict future outcomes. We evaluated whether claims-based markers of disease severity could improve assessments of multimorbid burden. METHODS: We developed 7 dichotomous markers of disease severity which could be applied to a range of diseases using claims data. These markers were based on the number of disease-associated outpatient visits, emergency department visits, and hospitalizations made by an individual over a defined interval; whether an individual with a given disease had outpatient visits to a specialist who typically treats that disease; and ICD-9 codes which connote more versus less advanced or symptomatic manifestations of a disease. Using Medicare claims linked with Health and Retirement Study data, we tested whether including these markers improved ability to predict ADL decline, IADL decline, hospitalization, and death compared to equivalent models which only included the presence or absence of diseases. RESULTS: Of 5012 subjects, median age was 76 years and 58% were female. For a majority of diseases tested individually, adding each of the 7 severity markers yielded minimal increase in c-statistic (≤0.002) for outcomes of ADL decline and mortality compared to models considering only the presence versus absence of disease. Gains in predictive power were more substantial for a small number of individual diseases. Inclusion of the most promising marker in multi-disease multimorbidity indices yielded minimal gains in c-statistics (

BACKGROUND: Measuring multimorbidity in claims data is used for risk adjustment and identifying populations at high risk for adverse events. Multimorbidity indices such as Charlson and Elixhauser scores have important limitations. We sought to create a better method of measuring multimorbidity using claims data by incorporating geriatric conditions, markers of disease severity, and disease-disease interactions, and by tailoring measures to different outcomes. METHODS: Health conditions were assessed using Medicare inpatient and outpatient claims from subjects age 67 and older in the Health and Retirement Study. Separate indices were developed for ADL decline, IADL decline, hospitalization, and death, each over 2 years of follow-up. We validated these indices using data from Medicare claims linked to the National Health and Aging Trends Study. RESULTS: The development cohort included 5012 subjects with median age 76 years; 58% were female. Claims-based markers of disease severity and disease-disease interactions yielded minimal gains in predictive power and were not included in the final indices. In the validation cohort, after adjusting for age and sex, c-statistics for the new multimorbidity indices were 0.72 for ADL decline, 0.69 for IADL decline, 0.72 for hospitalization, and 0.77 for death. These c-statistics were 0.02-0.03 higher than c-statistics from Charlson and Elixhauser indices for predicting ADL decline, IADL decline, and hospitalization, and

Adolescents involved in the juvenile justice system face a variety of risk factors that are associated with more frequent and severe experiences of aggression within romantic relationships as compared to community samples. The current study examines the nature and characteristics of adolescent dating violence (ADV) among first-time offense court-involved non-incarcerated (CINI) adolescents. A sample of 199 male and female CINI adolescents (58% male; M age = 15.05) who had a first-time, open status (e.g., truancy, curfew violation) and/or delinquent petition (e.g., assault, breaking, and entering). Overall, CINI adolescents reported prevalence rates of ADV consistent with community samples of adolescents. Females reported higher perpetration than did males in the sample of physical abuse and social networking abuse, as well as higher victimization of social networking abuse. Only one difference was found by offense type. CINI females report an increased risk for dating violence, though the cause of these gender differences is unclear. Findings also highlight that risk for ADV does not differ by offense type, suggesting that prevention efforts targeting ADV at the earliest possible intervention point, regardless of first-time offense type or severity, may be especially impactful.

BackgroundGirls have unique developmental pathways to substance use and justice system involvement, warranting gender-responsive intervention. We tested the efficacy of VOICES (a 12-session, weekly trauma-informed, gender-responsive substance use intervention) in reducing substance use and HIV/STI risk behaviors among justice- and school-referred girls.MethodsParticipants were 113 girls (Mage = 15.7 years, SD = 1.4; 12 % White, 19 % Black, 15 % multi-racial; 42 % Latinx) with a history of substance use referred from juvenile justice (29 %) and school systems (71 %). Study assessments were completed at baseline, 3-, 6- and 9-months follow-up. Primary outcomes included substance use and HIV/STI risk behaviors; secondary outcomes included psychiatric symptoms (including posttraumatic stress) and delinquent acts. We hypothesized that girls randomized to the VOICES (n = 51) versus GirlHealth (attention control; n = 62) condition would report reduced alcohol, cannabis and other substance use, HIV/STI risk behaviors, psychiatric symptoms, and delinquent acts.ResultsGirls randomized to VOICES reported significantly less cannabis use over 9-month follow-up relative to the control condition (time by intervention, p < .01), but there were no between group differences over time in HIV/STI risk behavior. Girls in both conditions reported fewer psychiatric symptoms and delinquent acts over time.ConclusionsData support the use of a trauma-informed, gender-responsive intervention to reduce cannabis use among girls with a substance use history and legal involvement; reducing cannabis use in this population has implications for preventing future justice involvement and improving public health outcomes for girls and young women, who are at disproportionate health and legal risk relative to their male counterparts.

Acute traumatic spinal cord injury (SCI) can result in severe, lifelong neurological deficits. After SCI, Rho activation contributes to collapse of axonal growth cones, failure of axonal regeneration, and neuronal loss. This randomized, double-blind, placebo-controlled phase 2b/3 study evaluated the efficacy and safety of Rho inhibitor VX-210 (9 mg) in patients after acute traumatic cervical SCI. The study enrolled patients 14-75 years of age with acute traumatic cervical SCIs, C4-C7 (motor level) on each side, and American Spinal Injury Association Impairment Scale (AIS) Grade A or B who had spinal decompression/stabilization surgery commencing within 72 h after injury. Patients were randomized 1:1 with stratification by age (

BackgroundThe association of community factors and outcomes after hematopoietic cell transplantation (HCT) has not been comprehensively described. Using the County Health Rankings and Roadmaps (CHRR) and the Center for International Blood and Marrow Transplant Research (CIBMTR), this study evaluated the impact of community health status on allogeneic HCT outcomes.MethodsThis study included 18,544 adult allogeneic HCT recipients reported to the CIBMTR by 170 US centers in 2014-2016. Sociodemographic, environmental, and community indicators were derived from the CHRR, an aggregate community risk score was created, and scores were assigned to each patient (patient community risk score [PCS]) and transplant center (center community risk score [CCS]). Higher scores indicated less healthy communities. The impact of PCS and CCS on patient outcomes after allogeneic HCT was studied.ResultsThe median age was 55 years (range, 18-83 years). The median PCS was -0.21 (range, -1.37 to 2.10; standard deviation [SD], 0.42), and the median CCS was -0.13 (range, -1.04 to 0.96; SD, 0.40). In multivariable analyses, a higher PCS was associated with inferior survival (hazard ratio [HR] per 1 SD increase, 1.04; 99% CI, 1.00-1.08; P = .0089). Among hematologic malignancies, a tendency toward inferior survival was observed with a higher PCS (HR, 1.04; 99% CI, 1.00-1.08; P = .0102); a higher PCS was associated with higher nonrelapse mortality (NRM; HR, 1.08; 99% CI, 1.02-1.15; P = .0004). CCS was not significantly associated with survival, relapse, or NRM.ConclusionsPatients residing in counties with a worse community health status have inferior survival as a result of an increased risk of NRM after allogeneic HCT. There was no association between the community health status of the transplant center location and allogeneic HCT outcomes.

Background: Nonagenarians and centenarians (NCs) are an extremely fragile population, particularly in regard to their physical and cognitive function. The aim of this study was to define the neurocognitive profiles among 29 NCs and their 49 younger cohabitants aged 50-75 years from The Cilento Initiative on Aging Outcomes (CIAO) Pilot study in the South of Italy that had provided initial hypotheses regarding positive psychological traits related to exceptional longevity. Methods: During the home visits, lifestyle information with specific questionnaires, functional autonomy and the neuropsychological Mini Mental Scale Examination (MMSE), and the Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog) scale were obtained by qualified study personnel. The total blood oxidative capacity was also determined by testing the reactive derivative of oxygen metabolites (d-ROM) and by the Biological Antioxidant Potential (BAP). In all individuals, the APOE genotype determination was also performed. Results: All the subjects in both groups showed high adherence to the Mediterranean Diet. None of the NCs had severe cognitive impairment, and a very low incidence of dementia was found. The data obtained on the Activities ed Instrumental Activities of Daily Living (ADL-IADL) scale showed that the majority of NCs (16/29) were autonomous in daily life activities. The comparative assessment of NCs and cohabitants showed no significant differences in the laboratory assessment of oxidative stress and APOE genotype. Conclusion: In the Cilento Region of Southern Italy, NCs seemed to have good cognitive status when compared to younger cohabitants aging 50-65 years without significant differences in oxidative stress markers or APOE genotype. These results might be related to optimal adherence to the Mediterranean diet, although other lifestyle factors and positive personality traits may also contribute to their healthy aging. Further studies on a larger population should be performed to confirm the results of this pilot study.

BackgroundThe Cilento region of southern Italy has a high prevalence of nonagenarians and centenarians. Few studies of the oldest old have included echocardiographic and/or electrocardiographic data, in a home-based setting.ObjectivesThe objective of this pilot study was to delineate the key lifestyle, medical, echocardiographic, and electrocardiographic features of a sample of nonagenarians and centenarians and their younger cohabitants from Cilento, via a comprehensive, home-based cardiovascular assessment. The ultimate aim is to identify the cardiovascular profile and lifestyle factors associated with longevity.MethodsTwenty-six nonagenarians and centenarians (mean age 94 ± 3 years) and 48 younger cohabitants aged 50-75 years (mean 62 ± 5) underwent a comprehensive cardiovascular evaluation in their homes.ResultsIn contrast to their younger cohabitants, nonagenarians and centenarians did not smoke, had lower fasting glucose levels, and lower LDL cholesterol despite being half as likely to be taking statins, and showing similar adherence to a Mediterranean diet. Over half of nonagenarians and centenarians (15/26) remained autonomous with their activities of daily living. Prevalence of self-reported coronary artery disease and stroke among nonagenarians and centenarians was low (11.5%), though a significant number had atrial fibrillation (31%) or congestive heart failure (27%). Although 62% of nonagenarians and centenarians had at least moderate valvular disease on echocardiography, less than 25% of those affected reported dyspnea.ConclusionNonagenarians and centenarians in the Cilento region had a healthy metabolic profile and a low prevalence of clinical cardiovascular disease. Even among nonagenarians and centenarians with structural heart abnormalities, report of symptoms is low. Larger studies in the Cilento population may help elucidate the mechanisms underlying cardiovascular health in the oldest old.

BACKGROUND: Millions of traumatized refugees worldwide have resettled in the United States. For one of the largest, the Cambodian community, having their mental health needs met has been a continuing challenge. A multicomponent health information technology screening tool was designed to aid provider recognition and treatment of major depressive disorder and posttraumatic stress disorder (PTSD) in the primary care setting. METHODS: In a clustered randomized controlled trial, 18 primary care providers were randomized to receive access to a multicomponent health information technology mental health screening intervention, or to a minimal intervention control group; 390 Cambodian American patients empaneled to participating providers were assigned to the providers randomized group. RESULTS: Electronic screening revealed that 65% of patients screened positive for depression and 34% screened positive for PTSD. Multilevel mixed effects logistic models, accounting for clustering structure, indicated that providers in the intervention were more likely to diagnose depression [odds ratio (OR), 6.5; 95% confidence interval (CI), 1.48-28.79; P=0.013] and PTSD (OR, 23.3; 95% CI, 2.99-151.62; P=0.002) among those diagnosed during screening, relative to the control group. Providers in the intervention were more likely to provide evidence-based guideline (OR, 4.02; 95% CI, 1.01-16.06; P=0.049) and trauma-informed (OR, 15.8; 95% CI, 3.47-71.6; P

Although donation of bone marrow (BM) or peripheral blood stem cells (PBSCs) from children to family members undergoing allogeneic transplantation are well-established procedures, studies detailing levels of pain, symptoms, and long-term recovery are lacking. To address this lack, we prospectively enrolled 294 donors age 20% of females and males age 13 to 17 years do not return to baseline pain levels by 1 year after BM donation. Studies aimed at decreasing symptoms and improving recovery in older children are warranted.

Unlike unrelated donor registries, transplant centers lack uniform approaches to related donor assessment and deferral. To test whether related donors are at increased risk for donation-related toxicities, we conducted a prospective observational trial of 11,942 related and unrelated donors aged 18-60 years. Bone marrow (BM) was collected at 37 transplant and 78 National Marrow Donor Program centers, and peripheral blood stem cells (PBSC) were collected at 42 transplant and 87 unrelated donor centers in North America. Possible presence of medical comorbidities was verified prior to donation, and standardized pain and toxicity measures were assessed pre-donation, peri-donation, and one year following. Multivariate analyses showed similar experiences for BM collection in related and unrelated donors; however, related stem cell donors had increased risk of moderate [odds ratios (ORs) 1.42; P

The development of reduced-intensity approaches for allogeneic hematopoietic cell transplantation has resulted in growing numbers of older related donors (RDs) of peripheral blood stem cells (PBSCs). The effects of age on donation efficacy, toxicity, and long-term recovery in RDs are poorly understood. To address this we analyzed hematologic variables, pain, donation-related symptoms, and recovery in 1211 PBSC RDs aged 18 to 79 enrolled in the Related Donor Safety Study. RDs aged > 60 had a lower median CD34+ level before apheresis compared with younger RDs (age > 60, 59 × 106/L; age 41 to 60, 81 × 106/L; age 18 to 40, 121 × 106/L; P < .001). This resulted in older donors undergoing more apheresis procedures (49% versus 30% ≥ 2 collections, P < .001) and higher collection volumes (52% versus 32% > 24 L, P < .001), leading to high percentages of donors aged > 60 with postcollection thrombocytopenia

Minimizing the deconditioning of burn injury through early rehabilitation programs (RP) in the intensive care unit (ICU) is of importance for improving the recovery time. The aim of this study was to assess current standard of care (SOC) for early ICU exercise programs in major burn centers. We designed a survey investigating exercise RP on the ICU for burn patients with >30% total burned surface area. The survey was composed of 23 questions and submitted electronically via SurveyMonkey® to six major (pediatric and adult) burn centers in Texas and California. All centers responded and reported exercise as part of their RP on the ICU. The characteristics of exercises implemented were not uniform. All centers reported to perform resistive and aerobic exercises but only 83% reported isotonic and isometric exercises. Determination of intensity of exercise varied with 50% of centers using patient tolerance and 17% using vital signs. Frequency of isotonic, isometric, aerobic, and resistive exercise was reported as daily by 80%, 80%, 83%, and 50% of centers, respectively. Duration for all types of exercises was extremely variable. Mobilization was used as a form of exercise by 100% of burn centers. Our results demonstrate that although early RP seem to be integral during burn survivors ICU stay, no SOC exists. Moreover, early RP are inconsistently administered and large variations exist in frequency, intensity, duration, and type of exercise. Thus, future prospective studies investigating the various components of exercise interventions are needed to establish a SOC and determine how and if early exercise benefits the burn survivor.

BACKGROUND: In inflammatory bowel disease (IBD), many scenarios call for fecal diversion, leaving behind defunctionalized bowel. The theoretical risk of colorectal cancer (CRC) in this segment is frequently cited as a reason for resection. To date, no studies have characterized the incidence of neoplasia in the diverted colorectal segments of IBD patients. METHODS: A retrospective cohort analysis was conducted for IBD patients identified through a tertiary care center pathology database. Patients that had undergone colorectal diversion and were diverted for ≥ 1 year were included. Incidence of diverted dysplasia/CRC was calculated for Crohns disease (CD) and ulcerative colitis (UC) with respect to diverted patient-years (dpy) and patient-years of disease (pyd). RESULTS: In total, 154 patients comprising 754 dpy and 1984 pyd were analyzed. Only 2 cases of diverted colorectal dysplasia (CD 1, UC 1) and 1 case of diverted CRC (UC) were observed. In the UC cohort (n = 75), the rate of diversion-associated CRC was 4.5 cases/1000 dpy (95% CI 0.11-25/1000) or 1.5 cases/1000 pyd (95% CI 0.04-8.2/1000). In the CD cohort (n = 79), no patients developed CRC, although a dysplasia rate of 1.9 cases/1000 dpy (95% CI 0.05-11/1000) or 0.77 cases/1000 pyd (95% CI 0.02-4.3/1000) was observed. All patients developing neoplasia had disease duration > 10 years and microscopic inflammation. CONCLUSIONS: Diverted dysplasia occurred infrequently with rates overlapping those reported in registries for IBD-based rectal cancers. Neoplasia was undetected in patients with < 10 pyd, regardless of diversion duration, suggesting low yield for endoscopic surveillance before this time.

Iron-sulfur (Fe-S) clusters are ubiquitous cofactors essential to various cellular processes, including mitochondrial respiration, DNA repair, and iron homeostasis. A steadily increasing number of disorders are being associated with disrupted biogenesis of Fe-S clusters. Here, we conducted whole-exome sequencing of patients with optic atrophy and other neurological signs of mitochondriopathy and identified 17 individuals from 13 unrelated families with recessive mutations in FDXR, encoding the mitochondrial membrane-associated flavoprotein ferrodoxin reductase required for electron transport from NADPH to cytochrome P450. In vitro enzymatic assays in patient fibroblast cells showed deficient ferredoxin NADP reductase activity and mitochondrial dysfunction evidenced by low oxygen consumption rates (OCRs), complex activities, ATP production and increased reactive oxygen species (ROS). Such defects were rescued by overexpression of wild-type FDXR. Moreover, we found that mice carrying a spontaneous mutation allelic to the most common mutation found in patients displayed progressive gait abnormalities and vision loss, in addition to biochemical defects consistent with the major clinical features of the disease. Taken together, these data provide the first demonstration that germline, hypomorphic mutations in FDXR cause a novel mitochondriopathy and optic atrophy in humans.

Tourette syndrome (TS) is a model neuropsychiatric disorder thought to arise from abnormal development and/or maintenance of cortico-striato-thalamo-cortical circuits. TS is highly heritable, but its underlying genetic causes are still elusive, and no genome-wide significant loci have been discovered to date. We analyzed a European ancestry sample of 2,434 TS cases and 4,093 ancestry-matched controls for rare (< 1% frequency) copy-number variants (CNVs) using SNP microarray data. We observed an enrichment of global CNV burden that was prominent for large (> 1 Mb), singleton events (OR = 2.28, 95% CI [1.39-3.79], p = 1.2 × 10-3) and known, pathogenic CNVs (OR = 3.03 [1.85-5.07], p = 1.5 × 10-5). We also identified two individual, genome-wide significant loci, each conferring a substantial increase in TS risk (NRXN1 deletions, OR = 20.3, 95% CI [2.6-156.2]; CNTN6 duplications, OR = 10.1, 95% CI [2.3-45.4]). Approximately 1% of TS cases carry one of these CNVs, indicating that rare structural variation contributes significantly to the genetic architecture of TS.

BackgroundBipolar disorder (BD) and schizophrenia (SZ) show substantial overlap. It has been suggested that a subgroup of patients might contribute to these overlapping features. This study employed a cross-diagnostic cluster analysis to identify subgroups of individuals with shared cognitive phenotypes.Method143 participants (68 BD patients, 39 SZ patients and 36 healthy controls) completed a battery of EEG and performance assessments on perception, nonsocial cognition and social cognition. A K-means cluster analysis was conducted with all participants across diagnostic groups. Clinical symptoms, functional capacity, and functional outcome were assessed in patients.ResultsA two-cluster solution across 3 groups was the most stable. One cluster including 44 BD patients, 31 controls and 5 SZ patients showed better cognition (High cluster) than the other cluster with 24 BD patients, 35 SZ patients and 5 controls (Low cluster). BD patients in the High cluster performed better than BD patients in the Low cluster across cognitive domains. Within each cluster, participants with different clinical diagnoses showed different profiles across cognitive domains.LimitationsAll patients are in the chronic phase and out of mood episode at the time of assessment and most of the assessment were behavioral measures.ConclusionsThis study identified two clusters with shared cognitive phenotype profiles that were not proxies for clinical diagnoses. The finding of better social cognitive performance of BD patients than SZ patients in the Lowe cluster suggest that relatively preserved social cognition may be important to identify disease process distinct to each disorder.

Inherited retinal disease is a common cause of visual impairment and represents a highly heterogeneous group of conditions. Here, we present findings from a cohort of 722 individuals with inherited retinal disease, who have had whole-genome sequencing (n = 605), whole-exome sequencing (n = 72), or both (n = 45) performed, as part of the NIHR-BioResource Rare Diseases research study. We identified pathogenic variants (single-nucleotide variants, indels, or structural variants) for 404/722 (56%) individuals. Whole-genome sequencing gives unprecedented power to detect three categories of pathogenic variants in particular: structural variants, variants in GC-rich regions, which have significantly improved coverage compared to whole-exome sequencing, and variants in non-coding regulatory regions. In addition to previously reported pathogenic regulatory variants, we have identified a previously unreported pathogenic intronic variant in CHM in two males with choroideremia. We have also identified 19 genes not previously known to be associated with inherited retinal disease, which harbor biallelic predicted protein-truncating variants in unsolved cases. Whole-genome sequencing is an increasingly important comprehensive method with which to investigate the genetic causes of inherited retinal disease.

Preclinical animal models are indispensable tools for translational research for which behavioral characterization and phenotyping are essential to testing hypotheses and for evaluating the potential of novel therapeutic agents to treat diseases. The methods employed for comprehensive behavioral phenotyping and pharmacological experiments are complex and should be conducted exclusively by trained technicians with demonstrated proficiency. The ultimate goal is to identify disease-relevant and translational behavioral endpoints that are robust, reliable, and reproducible, and that can be employed to evaluate potential of novel therapeutic agents to treat disease. The intent of the present article is to provide a pragmatic outline for establishing and optimizing behavioral assays and phenotyping batteries, ensuring that the assays and the data are reliable such that they can be reproduced within and across technicians and laboratories and, more importantly, that the data is translatable to the clinic. © 2016 by John Wiley & Sons, Inc.

Anterior segment dysgeneses (ASDs) comprise a spectrum of developmental disorders affecting the anterior segment of the eye. Here, we describe three unrelated families affected by a previously unclassified form of ASD. Shared ocular manifestations include bilateral iris hypoplasia, ectopia lentis, corectopia, ectropion uveae, and cataracts. Whole-exome sequencing and targeted Sanger sequencing identified mutations in CPAMD8 (C3 and PZP-like alpha-2-macroglobulin domain-containing protein 8) as the cause of recessive ASD in all three families. A homozygous missense mutation in the evolutionarily conserved alpha-2-macroglobulin (A2M) domain of CPAMD8, c.4351T>C (p. Ser1451Pro), was identified in family 1. In family 2, compound heterozygous frameshift, c.2352_2353insC (p.Arg785Glnfs∗23), and splice-site, c.4549-1G>A, mutations were identified. Two affected siblings in the third family were compound heterozygous for splice-site mutations c.700+1G>T and c.4002+1G>A. CPAMD8 splice-site mutations caused aberrant pre-mRNA splicing in vivo or in vitro. Intriguingly, our phylogenetic analysis revealed rodent lineage-specific CPAMD8 deletion, precluding a developmental expression study in mice. We therefore investigated the spatiotemporal expression of CPAMD8 in the developing human eye. RT-PCR and in situ hybridization revealed CPAMD8 expression in the lens, iris, cornea, and retina early in development, including strong expression in the distal tips of the retinal neuroepithelium that form the iris and ciliary body, thus correlating CPAMD8 expression with the affected tissues. Our study delineates a unique form of recessive ASD and defines a role for CPAMD8, a protein of unknown function, in anterior segment development, implying another pathway for the pathogenicity of ASD.

Leber's hereditary optic neuropathy (LHON) is typically characterized by vascular alterations in the acute phase. The aim of this study was to evaluate choroidal changes occurring in asymptomatic, acute and chronic stages of LHON. We enrolled 49 patients with LHON, 19 with Dominant Optic Atrophy (DOA) and 22 healthy controls. Spectral Domain-Optical Coherence Tomography (SD-OCT) scans of macular and peripapillary regions were performed in all subjects, to evaluate macular and peripapillary choroidal thickness, and retinal nerve fiber layer (RNFL) thicknes. Macular and peripapillary choroidal thicknesses were significantly increased in the acute LHON stage. On the contrary, macular choroidal thickness was significantly reduced in the chronic stage. Furthermore, peripapillary choroidal thickness was decreased in chronic LHON and in DOA. Both RNFL and choroid had the same trend (increased thickness, followed by thinning), but RNFL changes preceded those affecting the choroid. In conclusion, our study quantitatively demonstrated the involvement of the choroid in LHON pathology. The increase in choroidal thickness is a feature of the LHON acute stage, which follows the thickening of RNFL. Conversely, thinning of the choroid is the common outcome in chronic LHON and in DOA.

Backgrounds and aimsLow concentrations of plasma HDL-C are associated with the development of atherosclerotic cardiovascular diseases and type 2 diabetes. Here we aimed to explore the relationship between the in vivo fractional synthesis of triglycerides (fTG) in subcutaneous (s.q.) abdominal adipose tissue (AT), HDL-C concentrations and HDL particle size composition in non-diabetic humans.MethodsThe fTG in s.q. abdominal AT was measured in 16 non-diabetic volunteers (7 women, 9 men; Age: 49 ± 20 years; BMI: 31 ± 5 kg/m; Fasting Plasma Glucose: 90 ± 10 mg/dl) after (2)H2O labeling. HDL-C concentration and subclasses, large (L-HDL), intermediate (I-HDL) and small (S-HDL) were measured.ResultsLinear regression analyses demonstrated significant associations of fTG with plasma concentration of HDL-C (r = 0.625,p = 0.009) and percent contribution of L-HDL (r = 0.798,p

Altered knee kinematics following ACL reconstruction may predispose patients to the development of early onset post-traumatic osteoarthritis. The goal of our study was to examine the longitudinal interrelationship between altered tibial position relative to the femur and cartilage health measured by quantitative T1ρ MRI. Twenty-five patients with isolated unilateral ACL injury underwent kinematic and cartilage T1ρ MRI at baseline prior to ACL reconstruction and then at 1-year post-reconstruction. Tibial position relative to the femur in the anterior-posterior plane was calculated as well as cartilage T1ρ relaxation values in the injured and uninjured knee. At baseline prior to ACL reconstruction, the tibia was in a significantly more anterior position relative to the femur in the ACL deficient knee compared to the healthy contralateral knee. This difference was no longer present at 1-year follow-up. Additionally, the side-side difference in tibial position correlated to increased cartilage T1ρ relaxation values in the medial compartment of the knee 1-year post-reconstruction. Altered tibial position following ACL reconstruction is correlated with detectable cartilage degeneration as soon as 1 year following ACL reconstruction.

Rett syndrome is a monogenic disease due to de novo mutations in either MECP2 or CDKL5 genes. In spite of their involvement in the same disease, a functional interaction between the two genes has not been proven. MeCP2 is a transcriptional regulator; CDKL5 encodes for a kinase protein that might be involved in the regulation of gene expression. Therefore, we hypothesized that mutations affecting the two genes may lead to similar phenotypes by dysregulating the expression of common genes. To test this hypothesis we used induced pluripotent stem (iPS) cells derived from fibroblasts of one Rett patient with a MECP2 mutation (p.Arg306Cys) and two patients with mutations in CDKL5 (p.Gln347Ter and p.Thr288Ile). Expression profiling was performed in CDKL5-mutated cells and genes of interest were confirmed by real-time RT-PCR in both CDKL5- and MECP2-mutated cells. The only major change in gene expression common to MECP2- and CDKL5-mutated cells was for GRID1, encoding for glutamate D1 receptor (GluD1), a member of the δ-family of ionotropic glutamate receptors. GluD1 does not form AMPA or NMDA glutamate receptors. It acts like an adhesion molecule by linking the postsynaptic and presynaptic compartments, preferentially inducing the inhibitory presynaptic differentiation of cortical neurons. Our results demonstrate that GRID1 expression is downregulated in both MECP2- and CDKL5-mutated iPS cells and upregulated in neuronal precursors and mature neurons. These data provide novel insights into disease pathophysiology and identify possible new targets for therapeutic treatment of Rett syndrome.

BackgroundThe Nutrition Facts label can facilitate healthy dietary practices. There is a dearth of research on Latinos' utilization and comprehension of the Nutrition Facts label.ObjectiveTo measure use and comprehension of the Nutrition Facts label and to identify correlates among Latinos in East Los Angeles, CA.DesignCross-sectional interviewer-administered survey using computer-assisted personal interview software, conducted in either English or Spanish in the participant's home.Participants/settingEligibility criteria were: living in a household within the block clusters identified, being age 18 years or older, speaking English or Spanish, identifying as Latino and as the household's main food purchaser and preparer. Analyses were based on 269 eligible respondents.Statistical analyses performedχ(2) test and multivariate logistic regression analysis assessed the associations among the main outcomes and demographics. Multiple imputations addressed missing data.ResultsSixty percent reported using the label; only 13% showed adequate comprehension of the label. Utilization was associated with being female, speaking Spanish, and being below the poverty line. Comprehension was associated with younger age, not being married, and higher education. Utilization was not associated with comprehension.ConclusionsLatinos who are using the Nutrition Facts label are not correctly interpreting the available information. Targeted education is needed to improve use and comprehension of the Nutrition Facts label to directly improve diet, particularly among males, older Latinos, and those with less than a high school education.

Individuals with schizophrenia often show substantial deficits in social cognitive abilities, which are strongly associated with social functioning. To advance our understanding of the genetic variation that is associated with social cognitive deficits in schizophrenia, we genotyped 74 schizophrenia outpatients who completed social cognitive performance measures assessing mentalizing, social perception, and emotional intelligence, as well as clinical symptoms. We assessed seven single nucleotide polymorphisms (SNPs) of the oxytocin receptor (OXTR) previously found to show replicable associations with socio-emotional processes. For one of the seven SNPs, rs2268493, the 'T' allele was significantly associated with poorer performance on a composite social cognition index, as well as specific tests of mentalizing and social perception. None of the SNPs were associated with clinical symptoms. Though the sample size is small, these findings provide initial support for the involvement of genetic variants of the OXTR in social cognitive impairments in schizophrenia.

Schizophrenia is associated with motivational deficits that interfere with a wide range of goal directed activities. Despite their clinical importance, our current understanding of these motivational impairments is limited. Furthermore, different types of motivational problems are commonly seen among individuals within the broad diagnosis of schizophrenia. The goal of the current study was to examine whether clinically meaningful subgroups could be identified based on approach and avoidance motivational tendencies. We measured these tendencies in 151 individuals with schizophrenia. Although prior studies demonstrate elevated BIS sensitivity in schizophrenia at the overall group level, none have explored various combinations of BIS/BAS sensitivities within this disorder. Cluster analyses yielded five subgroups with different combinations of low, moderate, or high BIS and BAS. The subgroups had interpretable differences in clinically rated negative symptoms and self-reported anhedonia/socio-emotional attitudes, which were not detectable with the more commonly used linear BIS/BAS scores. Two of the subgroups had significantly elevated negative symptoms but different approach/avoidance profiles: one was characterized by markedly low BIS, low BAS and an overall lack of social approach motivation; the other had markedly high BIS but moderate BAS and elevated social avoidance motivation. The two subgroups with relatively good clinical functioning showed patterns of BAS greater than BIS. Our findings indicate that there are distinct motivational pathways that can lead to asociality in schizophrenia and highlight the value of considering profiles based on combined patterns of BIS and BAS in schizophrenia.

Schizophrenia is associated with motivational deficits that interfere with a wide range of goal directed activities. Despite their clinical importance, our current understanding of these motivational impairments is limited. Furthermore, different types of motivational problems are commonly seen among individuals within the broad diagnosis of schizophrenia. The goal of the current study was to examine whether clinically meaningful subgroups could be identified based on approach and avoidance motivational tendencies. We measured these tendencies in 151 individuals with schizophrenia. Although prior studies demonstrate elevated BIS sensitivity in schizophrenia at the overall group level, none have explored various combinations of BIS/BAS sensitivities within this disorder. Cluster analyses yielded five subgroups with different combinations of low, moderate, or high BIS and BAS. The subgroups had interpretable differences in clinically rated negative symptoms and self-reported anhedonia/socio-emotional attitudes, which were not detectable with the more commonly used linear BIS/BAS scores. Two of the subgroups had significantly elevated negative symptoms but different approach/avoidance profiles: one was characterized by markedly low BIS, low BAS and an overall lack of social approach motivation; the other had markedly high BIS but moderate BAS and elevated social avoidance motivation. The two subgroups with relatively good clinical functioning showed patterns of BAS greater than BIS. Our findings indicate that there are distinct motivational pathways that can lead to asociality in schizophrenia and highlight the value of considering profiles based on combined patterns of BIS and BAS in schizophrenia.

Young female offenders represent a growing number of young offenders. Studies have shown that youth in the juvenile justice system, particularly young females, report higher rates of lifetime sexual abuse than their nonoffending peers. The aim of this study was to examine gender differences in risk factors for recidivism, including a history of sexual abuse, among a juvenile court clinic sample. Findings suggest that, even after accounting for previously identified risk factors for recidivism such as prior legal involvement and conduct problems, a history of sexual abuse is the most salient predictor of recidivism for young female offenders, but not for males. The development of gender-responsive interventions to reduce juvenile recidivism and continued legal involvement into adulthood may be warranted.

This study identifies differences in health insurance predictors and investigates the main reported reasons for lacking health insurance coverage between short-stayed (≤ 10 years) and long-stayed (>10 years) US immigrant adults to parse the possible consequences of the Affordable Care Act among immigrants by length of stay and documentation status. Foreign-born adults (18-64 years of age) from the 2009 California Health Interview Survey are the study population. Health insurance coverage predictors and the main reasons for being uninsured are compared across cohorts and by documentation status. A logistic-regression two-part multivariate model is used to adjust for confounding factors. The analyses determine that legal status is a strong health insurance predictor, particularly among long-stayed undocumented immigrants. Immigration status is the main reported reason for lacking health insurance. Although long-stayed documented immigrants are likely to benefit from the Affordable Care Act implementation, undocumented immigrants and short-stayed documented immigrants may encounter difficulties getting health insurance coverage.

Juvenile offenders have disproportionately high rates of psychiatric and substance use disorders relative to their nonoffending counterparts. Less is known about the impact of psychiatric and substance use disorders on repeat juvenile justice involvement among juveniles specifically referred for forensic mental health evaluations. We describe the demographic, psychiatric, and legal history background of 404 juveniles who underwent a court clinic forensic mental health evaluation, and we examine the association between these factors and detention rates of 20 percent over a 12-month post-evaluation period. After accounting for known predictors of reoffending, such as prior offense history and externalizing disorders, dual diagnosis (i.e., co-occurring psychiatric and substance use disorders) remained a salient predictor of future detention. Consistent with prior literature on juvenile offending, substance use may greatly enhance the likelihood of subsequent detention.

The objective of this study is to identify differences in healthcare access and utilization among Mexican immigrants by documentation status. Cross-sectional survey data are analyzed to identify differences in healthcare access and utilization across Mexican immigrant categories. Multivariable logistic regression and the Blinder-Oaxaca decomposition are used to parse out differences into observed and unobserved components. Mexican immigrants ages 18 and above who are immigrants of California households and responded to the 2007 California Health Interview Survey (2,600 documented and 1,038 undocumented immigrants). Undocumented immigrants from Mexico are 27% less likely to have a doctor visit in the previous year and 35% less likely to have a usual source of care compared to documented Mexican immigrants after controlling for confounding variables. Approximately 88% of these disparities can be attributed to predisposing, enabling and need determinants in our model. The remaining disparities are attributed to unobserved heterogeneity. This study shows that undocumented immigrants from Mexico are much less likely to have a physician visit in the previous year and a usual source of care compared to documented immigrants from Mexico. The recently approved Patient Protection and Affordable Care Act will not reduce these disparities unless undocumented immigrants are granted some form of legal status.

Leber's hereditary optic neuropathy (LHON) is characterized by retinal ganglion cell (RGC) degeneration with the preferential involvement of those forming the papillomacular bundle. The optic nerve is considered the main pathological target for LHON. Our aim was to investigate the possible involvement of the post-geniculate visual pathway in LHON patients. We used diffusion-weighted imaging for in vivo evaluation. Mean diffusivity maps from 22 LHON visually impaired, 11 unaffected LHON mutation carriers and 22 healthy subjects were generated and compared at level of optic radiation (OR). Prefrontal and cerebellar white matter were also analyzed as internal controls. Furthermore, we studied the optic nerve and the lateral geniculate nucleus (LGN) in post-mortem specimens obtained from a severe case of LHON compared to an age-matched control. Mean diffusivity values of affected patients were higher than unaffected mutation carriers (P

Sjögren-Larsson syndrome is a genetic disease characterized by ichthyosis, mental retardation, spasticity and mutations in the ALDH3A2 gene coding for fatty aldehyde dehydrogenase, an enzyme necessary for oxidation of fatty aldehydes and fatty alcohols. We investigated the cutaneous abnormalities in 9 patients with Sjögren-Larsson syndrome to better understand how the enzymatic deficiency results in epidermal dysfunction. Histochemical staining for aldehyde oxidizing activity was profoundly reduced in the epidermis. Colloidal lanthanum perfusion studies showed abnormal movement of tracer into the extracellular spaces of the stratum corneum consistent with a leaky water barrier. The barrier defect could be attributed to the presence of abnormal lamellar bodies, many with disrupted limiting membranes or lacking lamellar contents. Entombed lamellar bodies were present in the cytoplasm of corneocytes suggesting blockade of lamellar body secretion. At the stratum granulosum-stratum corneum interface, non-lamellar material displaced or replaced secreted lamellar membranes, and in the stratum corneum, the number of lamellar bilayers declined and lamellar membrane organization was disrupted by foci of lamellar/non-lamellar phase separation. These studies demonstrate the presence of a permeability barrier abnormality in Sjögren-Larsson syndrome, which localizes to the stratum corneum interstices and can be attributed to abnormalities in lamellar body formation and secretion.

BackgroundWe compared access to health care, use of services, and health care experiences for Mexicans and other Latinos by citizenship and immigrant authorization status.MethodsWe acquired data from the 2003 California Health Interview Survey, with 42,044 participants representative of noninstitutionalized households. Participants were differentiated by ethnicity/race, national origin, and citizenship/immigration authorization status. Outcome measures included having a usual source of care, problems in obtaining necessary care, use of physician and emergency department care, and 3 experiences with health care. Multivariate analyses measured the associations of citizenship/immigration authorization status with the outcome measures among foreign-born Mexicans and other Latinos vs their US-born counterparts.ResultsIn multivariate analyses, undocumented Mexicans had 1.6 fewer physician visits (P < .01); compared with US-born Mexicans; other undocumented Latinos had 2.1 fewer visits (P < .01) compared with their US-born counterparts. Both undocumented groups were less likely to report difficulty obtaining necessary health care than US-born Mexicans (odds ratio, 0.68; P < .01) and other US-born Latinos (odds ratio, 0.40; P < .01), respectively. Undocumented Mexicans were less likely to have a usual source of care (odds ratio, 0.70; P < .01) and were more likely to report negative experiences than US-born Mexicans (odds ratio, 1.93; P < .01). Findings were similar for other undocumented Latinos, with the exception of having a usual source of care. Patterns of access to and use of health care services tended to improve with changing legal status.ConclusionIn this large sample, undocumented Mexicans and other undocumented Latinos reported less use of health care services and poorer experiences with care compared with their US-born counterparts, after adjustment for confounders in multivariate analyses.