During the first postnatal month glutamatergic synapses between layer 5 pyramidal cells in the rodent neocortex switch from an immature state exhibiting a high probability of neurotransmitter release, large unitary amplitude and synaptic depression to a mature state with decreased probability of release, smaller unitary amplitude and synaptic facilitation. Using paired recordings, we demonstrate that the developmental shift in release probability at synapses between rat somatosensory layer 5 thick-tufted pyramidal cells is mediated by a higher and more heterogeneous activation of presynaptic adenosine A1 receptors. Immature synapses under control conditions exhibited distributions of coefficient of variation, failure rate and release probability that were almost coincident with the A1 receptor blocked condition; however, mature synapses under control conditions exhibited much broader distributions that spanned those of both the A1 receptor agonized and antagonized conditions. Immature and mature synapses expressed A1 receptors with no observable difference in functional efficacy and therefore the heterogeneous A1 receptor activation seen in the mature neocortex appears due to increased adenosine concentrations that vary between synapses. Given the central role demonstrated for A1 receptor activation in determining synaptic amplitude and the statistics of transmission between mature layer 5 pyramidal cells, the emplacement of adenosine sources and sinks near the synaptic terminal could constitute a novel form of long-term synaptic plasticity.
To identify patterns and correlates of developmental trajectories of DSM-IV nicotine dependence criteria from adolescence to early adulthood.
The analytical sample of lifetime smokers (N = 877) is from a longitudinal cohort of 6th–10th graders drawn from an urban school system. Subjects were interviewed 5 times at 6-month intervals and once 4.5 years later. Growth mixture models were estimated to identify trajectories of DSM-IV nicotine dependence criteria over ages 12–23.
A four-class solution fitted the data best: No dependence criteria (Class 1, 32.0%); Early onset/Chronic course (Class 2, 26.1%); Early onset/Remission (Class 3, 15.4%); Late onset (Class 4, 26.5%). There appeared to be three critical periods. At ages 12–15, symptoms increased rapidly. As of age 16, the Early onset/Chronic class stabilized at high levels of symptoms, the Early onset/Remission class started its symptomatic decline, and the Late onset class experienced a sharp increase in symptoms. At age 20, there was a convergence in the prevalence of symptoms experienced at high (Classes 2 and 4) and low levels (Classes 1 and 3). Extensiveness of smoking and marijuana use were associated with higher baseline levels of nicotine dependence criteria. Anxiety disorders were associated with all three symptomatic trajectories. Parental smoking and nicotine dependence were associated specifically with the Early/Chronic class, while pleasant initial sensitivity and earlier onset ages of cigarette and marijuana use characterized the two early onset classes (2 and 3).
Trajectories of dependence criteria constitute an advantageous phenotype for research and intervention over static summaries of smoking behaviors.
Nicotine dependence criteria; Developmental trajectories; Growth mixture modeling; Adolescence
We describe rates of unintended pregnancy among HIV positive couples in Lusaka, Zambia. We also identify factors associated with unintended pregnancy among oral contraceptive pill (OCP) using couples in this cohort.
Data were analyzed from couples randomized in a factorial design to two family planning intervention videos.
Rates of unintended pregnancy were stratified by contraceptive method used at time of pregnancy. Predictors of time to unintended pregnancy among OCP users were determined via multivariate Cox modeling.
The highest rates of unintended pregnancy were observed among couples requesting condoms only (26.4/100CY) or OCPs (20.7/100CY); these rates were not significantly different. OCP users accounted for 37% of the couple-years (CY) observed and 87% of unintended pregnancies. Rates of unintended pregnancy for injectable (0.7/100CY) and intrauterine device (1.6/100CY) users were significantly lower relative to condom only users. No pregnancies occurred among contraceptive implant users or after tubal ligation. Factors associated (p<0.05) with time to unintended pregnancy among OCP users in multivariate analysis included the man wanting more children, the woman being HIV negative versus having stage IV HIV disease, and the woman reporting: younger age, no previous OCP use, missed OCPs, or sex without a condom.
Long-acting reversible contraceptive methods were effective in the context of integrated couples HIV prevention and contraceptive services. Injectable methods were also effective in this context. Given the high user failure rate of OCPs, family planning efforts should promote longer-acting methods among OCP users wishing to avoid pregnancy. Where other methods are not available or acceptable, OCP adherence counseling is needed, especially among younger and new OCP users.
Instances in which natural selection maintains genetic variation in a population over millions of years are thought to be extremely rare. We conducted a genome-wide scan for long-lived balancing selection by looking for combinations of SNPs shared between humans and chimpanzees. In addition to the major histocompatibility complex (MHC), we identified 125 regions in which the same haplotypes are segregating in the two species, all but two of which are non-coding. In six cases, there is evidence for an ancestral polymorphism that persisted to the present in humans and chimpanzees. Regions with shared haplotypes are significantly enriched for membrane glycoproteins, and a similar trend is seen among shared coding polymorphisms. These findings indicate that ancient balancing selection has shaped human variation and point to genes involved in host-pathogen interactions as common targets.
We sought to examine perinatal outcomes in women with a body mass index (BMI) of 25 kg/m2 comparing those whose weight gain met 2009 IOM guidelines to women meeting 1990 IOM guidelines.
This is a retrospective cohort study utilizing birth records linked to hospital discharge data for all term, singleton infants born to overweight, Missouri residents (2000–2006) with a BMI of 25 kg/m2. We excluded congenital anomalies, mothers with diabetes, hypertension, or previous cesarean delivery.
Fourteen thousand nine hundred fifty-five women gained 25–35 lbs (1990 guidelines); 1.6% delivered low birth weight (LBW) infants and 1.1% delivered macrosomic infants. Eight thousand three hundred fifty women gained 15–25 lbs (2009 guidelines); 3.4% delivered LBW infants and 0.6% delivered macrosomic infants. Women who gained 15–25 lbs were 1.99 (95% CI 1.67, 2.38) times more likely to have a LBW infant and 0.59 (95% CI 0.40, 0.76) times less likely to deliver a macrosomic infant.
Limiting weight gain in women with a BMI of 25 kg/m2, per the 2009 guidelines, increases the risk of LBW deliveries and decreases the risk of macrosomia but does not reduce associated adverse perinatal outcomes. Further studies should explore the optimal weight gain to reduce these outcomes.
Gestational weight gain; infant outcomes
Previous studies suggest that alcohol-use disorder severity, defined by the number of criteria met, provides a more informative phenotype than dichotomized DSM-IV diagnostic measures of alcohol use disorders. Therefore, this study examined whether alcohol-use disorder severity predicted first-incident depressive disorders, an association that has never been found for the presence or absence of an alcohol use disorder in the general population.
In a national sample of persons who had never experienced a major depressive disorder (MDD), dysthymia, manic or hypomanic episode (n=27 571), we examined whether a version of DSM-5 alcohol-use disorder severity (a count of three abuse and all seven dependence criteria) linearly predicted first-incident depressive disorders (MDD or dysthymia) after 3-year follow-up. Wald tests were used to assess whether more complicated models defined the relationship more accurately.
First-incidence of depressive disorders varied across alcohol-use disorder severity and was 4.20% in persons meeting no alcohol-use disorder criteria versus 44.47% in persons meeting all 10 criteria. Alcohol-use disorder severity significantly predicted first-incidence of depressive disorders in a linear fashion (odds ratio 1.14, 95% CI 1.06–1.22), even after adjustment for sociodemographics, smoking status and predisposing factors for depressive disorders, such as general vulnerability factors, psychiatric co-morbidity and subthreshold depressive disorders. This linear model explained the relationship just as well as more complicated models.
Alcohol-use disorder severity was a significant linear predictor of first-incident depressive disorders after 3-year follow-up and may be useful in identifying a high-risk group for depressive disorders that could be targeted by prevention strategies.
Alcohol use disorders; depressive disorders; DSM-5; NESARC; severity
Comparing self-rating health responses across individuals and cultures is misleading due to different reporting behaviors. Anchoring vignettes is a technique that allows identifying and adjusting self-rating responses for reporting heterogeneity (RH).
This article aims to test two crucial assumptions of vignette equivalence (VE) and response consistency (RC) that are required to be met before vignettes can be used to adjust self-rating responses for RH.
We used self-ratings, vignettes, and objective measures covering domains of mobility and cognition from the WHO study on global AGEing and adult health, administered to older adults aged 50 years and above from eight low- and middle-income countries in Africa and Asia. For VE, we specified a hierarchical ordered probit (HOPIT) model to test for equality of perceived vignette locations. For RC, we tested for equality of thresholds that are used to rate vignettes with thresholds derived from objective measures and used to rate their own health function.
There was evidence of RH in self-rating responses for difficulty in mobility and cognition. Assumptions of VE and RC between countries were violated driven by age, sex, and education. However, within a country context, assumption of VE was met in some countries (mainly in Africa, except Tanzania) and violated in others (mainly in Asia, except India).
We conclude that violation of assumptions of RC and VE precluded the use of anchoring vignettes to adjust self-rated responses for RH across countries in Asia and Africa.
reporting heterogeneity; mobility; cognition; self-rating; anchoring vignettes; vignette equivalence; response consistency
Clinical trials are typically designed to test the effect of a specific treatment on a single diagnostic entity. However, because common internalizing disorders are highly correlated (‘co-morbid ’), we sought to establish a practical and parsimonious method to characterize and quantify changes in a broad spectrum of internalizing psychopathology targeted for treatment in a clinical trial contrasting two transdiagnostic psychosocial interventions.
Alcohol dependence treatment patients who had any of several common internalizing disorders were randomized to a six-session cognitive-behavioral therapy (CBT) experimental treatment condition or a progressive muscle relaxation training (PMRT) comparison treatment condition. Internalizing psychopathology was characterized at baseline and 4 months following treatment in terms of the latent structure of six distinct internalizing symptom domain surveys.
Exploratory structural equation modeling (ESEM) identified a two-factor solution at both baseline and the 4-month follow-up : Distress (measures of depression, trait anxiety and worry) and Fear (measures of panic anxiety, social anxiety and agoraphobia). Although confirmatory factor analysis (CFA) demonstrated measurement invariance between the time-points, structural models showed that the latent means of Fear and Distress decreased substantially from baseline to follow-up for both groups, with a small but statistically significant advantage for the CBT group in terms of Distress (but not Fear) reduction.
The approach demonstrated in this study provides a practical solution to modeling co-morbidity in a clinical trial and is consistent with converging evidence pointing to the dimensional structure of internalizing psychopathology.
Anxiety disorder; clinical trial; internalizing; latent variable structural equation modeling; psychopathology
Previous studies have shown a higher incidence of biliary complications following donation after cardiac death (DCD) liver transplantation compared with donation after brain death (DBD) liver transplantation. The endoscopic management of ischemic type biliary strictures in patients who have undergone DCD liver transplants needs to be characterized further.
A retrospective institutional review of all patients who underwent DCD liver transplant from January 2006 to September 2011 was performed. These patients were compared with all patients who underwent DBD liver transplantation in the same time period. A descriptive analysis of all DCD patients who developed biliary complications and their subsequent endoscopic management was also performed.
Of the 36 patients who received DCD liver transplants, 25% developed biliary complications compared with 13% of patients who received DBD liver transplants (P=0.062). All DCD allograft recipients who developed biliary complications became symptomatic within three months of transplantation. Ischemic type biliary strictures in DCD allograft recipients included disseminated biliary strictures in two patients, biliary strictures of the hepatic duct bifurcation in three patients and biliary strictures of the donor common hepatic duct in three patients.
There was a trend toward increasing incidence of total biliary complications in recipients of DCD liver allografts compared with those receiving DBD livers, and the rate of diffuse ischemic cholangiopathy was significantly higher. Focal ischemic type biliary strictures can be treated effectively in DCD liver transplant recipients with favourable results. Diffuse ischemic type biliary strictures in DCD liver transplant recipients ultimately requires retransplantation.
Donation after cardiac death; ERCP; Ischemic cholangiopathy; Ischemic type biliary strictures; Stenting; Warm ischemia time
Craniosynostosis, the premature fusion of the cranial sutures, is a heterogeneous disorder with a prevalence of ~1 in 2,200 (refs. 1,2). A specific genetic etiology can be identified in ~21% of cases3, including mutations of TWIST1, which encodes a class II basic helix-loop-helix (bHLH) transcription factor, and causes Saethre-Chotzen syndrome, typically associated with coronal synostosis4-6. Starting with an exome sequencing screen, we identified 38 heterozygous TCF12 mutations in 347 samples from unrelated individuals with craniosynostosis. The mutations predominantly occurred in patients with coronal synostosis and accounted for 32% and 10% of subjects with bilateral and unilateral pathology, respectively. TCF12 encodes one of three class I E-proteins that heterodimerize with class II bHLH proteins such as TWIST1. We show that TCF12 and TWIST1 act synergistically in a transactivation assay, and that mice doubly heterozygous for loss-of-function mutations in Tcf12 and Twist1 exhibit severe coronal synostosis. Hence, the dosage of TCF12/TWIST1 heterodimers is critical for coronal suture development.
Successful implementation of the National Radiation Oncology Registry should improve the quality of care for patients with cancer treated with radiation.
The National Radiation Oncology Registry (NROR), sponsored by the Radiation Oncology Institute and the American Society for Radiation Oncology, is designed to collect standardized information on cancer care delivery among patients treated with radiotherapy in the United States and will focus on patients with prostate cancer. Stakeholders were engaged through a forum that emphasized the need for patient-centered outcomes, minimal data burden, and maximal connectivity to existing registries and databases. An electronic infrastructure is under development to provide connectivity across radiation oncology and hospital information systems. The NROR Gateway features automatic abstraction as well as aggregation of treatment and outcome data. The prostate cancer data dictionary provides standardized elements in four domains: facility, physician, patient, and treatment. The pilot phase will consist of clinical centers chosen to provide a representative mix of radiation treatment modalities, facility types, population-based settings, and regional locations. The initial set of radiation practice metrics includes physician board certification and maintenance, ordering of staging scans, active surveillance discussion, dose prescriptions for low-risk/high-risk disease, radiation fields for low-risk/high-risk disease, image-guided radiation therapy use, androgen deprivation therapy use, post-brachytherapy implant computed tomography dosimetry, collection of toxicity assessments, and longitudinal patient follow-up. The NROR pilot study will provide the framework for expansion to a nationwide electronic registry for radiation oncology.
The extracellular signal-related kinases (ERK1/2) are key proteins mediating mitogen-activated protein kinase signaling downstream of RAS: phosphorylation of ERK1/2 leads to nuclear uptake and modulation of multiple targets1. Here we show that reduced dosage of ERF, which encodes an inhibitory ETS transcription factor directly bound by ERK1/2 (refs 2-7), causes complex craniosynostosis (premature fusion of the cranial sutures) in humans and mice. Features of this newly recognized clinical disorder include multiple suture synostosis, craniofacial dysmorphism, Chiari malformation and language delay. Mice with functional Erf reduced to ~30% of normal exhibit postnatal multisuture synostosis; by contrast, embryonic calvarial development appears mildly delayed. Using chromatin immunoprecipitation in mouse embryonic fibroblasts and high-throughput sequencing, we find that ERF binds preferentially to distal regulatory elements containing RUNX or AP1 motifs. This work identifies ERF as a novel regulator of osteogenic stimulation by RAS-ERK signaling, potentially by competing with activating ETS factors in multifactor transcriptional complexes.
A number of changes have been proposed and investigated in the criteria for substance use disorders in DSM-5. However, although clinical utility of DSM-5 is a high priority, relatively little of the empirical evidence supporting the changes was obtained from samples of substance abuse patients.
Proposed changes were examined in 663 patients in treatment for substance use disorders, evaluated by experienced clinicians using the Psychiatric Research Interview for Substance and Mental Disorders (PRISM). Factor and item response theory analysis was used to investigate the dimensionality and psychometric properties of alcohol, cannabis, cocaine and heroin abuse and dependence criteria, and craving.
The seven dependence criteria, three of the abuse criteria (hazardous use; social/interpersonal problems related to use; neglect of roles to use), and craving form a unidimensional latent trait for alcohol, cannabis, cocaine and heroin. Craving did not add significantly to the total information offered by the dependence criteria, but adding the three abuse criteria and craving together did significantly increase total information for the criteria sets associated with alcohol, cannabis and heroin.
Among adult patients in treatment for substance disorders, the alcohol, cannabis, cocaine and heroin criteria for dependence, abuse (with the exception of legal problems), and craving measure a single underlying dimension. Results support the proposal to combine abuse and dependence into a single diagnosis in the DSM-5, omitting legal problems. Mixed support was provided for the addition of craving as a new criterion, warranting future studies of this important construct in substance use disorders.
Item response theory; Substance abuse; Substance dependence; Craving; DSM-IV; DSM-5
β cell pseudoislets (PIs) are used for the in vitro study of β-cells in a three-dimensional (3-D) configuration. Current methods of PI induction require unique culture conditions and extensive mechanical manipulations. Here we report a novel co-culture system consisting of high passage β-cells and islet-derived endothelial cells (iECs) that results in a rapid and spontaneous formation of free-floating PIs. PI structures were formed as early as 72 h following co-culture setup and were preserved for more than 14 d. These PIs, composed solely of β-cells, were similar in size to that of native islets and showed an increased percentage of proinsulin-positive cells, increased insulin gene expression in response to glucose stimulation, and restored glucose-stimulated insulin secretion when compared to β-cells cultured as monolayers. Key extracellular matrix proteins that were absent in β-cells cultured alone were deposited by iECs on PIs and were found in and around the PIs. iEC-induced PIs are a readily available tool for examining β cell function in a native 3-D configuration and can be used for examining β-cell/iEC interactions in vitro.
Increased transcription of ribosomal RNA genes (rDNA) by RNA Polymerase I is a common feature of human cancer, but whether it is required for the malignant phenotype remains unclear. We show that rDNA transcription can be therapeutically targeted with the small molecule CX-5461 to selectively kill B-lymphoma cells in vivo while maintaining a viable wild-type B cell population. The therapeutic effect is a consequence of nucleolar disruption and activation of p53-dependent apoptotic signaling. Human leukemia and lymphoma cell lines also show high sensitivity to inhibition of rDNA transcription that is dependent on p53 mutational status. These results identify selective inhibition of rDNA transcription as a therapeutic strategy for the cancer specific activation of p53 and treatment of hematologic malignancies.
Although significant progress has been achieved in developing sensory augmentation methods to improve standing balance, attempts to extend this research to locomotion have been quite limited in scope. The goal of this study was to characterize the effects of two real-time feedback displays on locomotor performance during four gait-based tasks ranging in difficulty.
Seven subjects with vestibular deficits used a trunk-based vibrotactile feedback system that provided real-time feedback regarding their medial-lateral (M/L) trunk tilt when they exceeded a subject-specific predefined tilt threshold during slow and self-paced walking, walking along a narrow walkway, and walking on a foam surface. Two feedback display configurations were evaluated: the continuous display provided real-time continuous feedback of trunk tilt, and the gated display provided feedback for 200 ms during the period immediately following heel strike. The root-mean-square (RMS) trunk tilt and percentage of time below the tilt thresholds were calculated for all locomotor tasks.
Use of continuous feedback resulted in significant decreases in M/L trunk tilt and increases in percentage times below the tilt thresholds during narrow and foam trials. The gated display produced generally smaller changes.
This preliminary study demonstrated that use of continuous vibrotactile feedback during challenging locomotor tasks allowed subjects with vestibular deficits to significantly decrease M/L RMS trunk tilt. Analysis of the results also showed that continuous feedback was superior.
Balance; Gait; Locomotion; Vibrotactile; Biofeedback; Vestibular; Sensory augmentation; Balance aid
HPV4 is approved as a series of three timed doses expected to result in efficacy against specific HPV infections. Completion rates in the US are quite low at the same time the structure of health care delivery is changing. The aim of this study was to determine how the patient-, clinic- and systems-level characteristics facilitate or hinder the timely completion of three HPV4 doses in both adolescent and adult female populations in a high-risk safety net population.
This is a retrospective study in which patient-, clinic- and systems-level data are abstracted from the electronic medical record (EMR) for all females 10–26 years of age receiving at least one dose of HPV4 between July 1, 2006 and October 1, 2009.
Adults were more likely to complete the three dose series if they had at least one health care visit in addition to their HPV4 visit, (aOR = 1.54 (95% CI:1.10, 2.15). Adults were less likely to complete the three dose series if they received their second HPV4 dose at an acute health care, preventive care or postpartum visits compared to an HPV4-only visit (aOR = 0.31 (95% CI: 0.13, 0.72), 0.12 (0.04, 0.35), 0.30 (0.14, 0.62), respectively). Hispanic adults were less likely than whites to complete the series (aOR = 0.24 (95% CI:0.10, 0.59). 39% of adolescents who completed two doses completed the series.
HPV4 is more likely to be effectively administered to adults in a safety net population if multiple health care needs can be met within the health care system.
Sagittal craniosynostosis is the most common form of craniosynostosis, affecting approximately one of 5,000 newborns. We conducted the first genome-wide association study (GWAS) for non-syndromic sagittal craniosynostosis (sNSC) using 130 non-Hispanic white (NHW) case-parent trios. Robust associations were observed in a 120 kb region downstream of BMP2, flanked by rs1884302 (P = 1.13 × 10−14; odds ratio [OR] = 4.58) and rs6140226 (P = 3.40 × 10−11; OR = 0.24) and within a 167 kb region of BBS9 between rs10262453 (P = 1.61 × 10−10; OR=0.19) and rs17724206 (P = 1.50 × 10−8; OR = 0.22). We replicated the associations to both loci [rs1884302 (P = 4.39 × 10−31); rs10262453 (P = 3.50 × 10−14)] in an independent NHW population of 172 unrelated sNSC probands and 548 controls. Both BMP2 and BBS9 are genes with a role in skeletal development warranting functional studies to further understand the etiology of sNSC.
genome-wide association study; non-syndromic sagittal craniosynostosis; BMP2; BBS9; meta-analysis; nonsyndromic
Volar plating for distal radius fractures has caused extensor tendon ruptures secondary to dorsal screw prominence. This study was designed to determine the biomechanical impact of placing unicortical distal locking screws and pegs in an extra-articular fracture model.
Volar-locking distal radius plates were applied to 30 osteoporotic distal radius models. Radii were divided into 5 groups based on distal locking fixation: bicortical locked screws, 3 lengths of unicortical locked screws (abutting the dorsal cortex [full length], 75% length, and 50% length to dorsal cortex), and unicortical locked pegs. Distal radius osteotomy simulated a dorsally comminuted, extra-articular, fracture. Each constructs stiffness was determined under physiologic loads (axial compression, dorsal bending volar bending) before and after 1000 cycles of axial conditioning and prior to axial loading to failure (2mm of displacement) and subsequent catastrophic failure.
Cyclic conditioning did not alter constructs stiffness. Stiffness to volar bending and dorsal bending forces were similar between groups. Final stiffness(N/mm) under axial load was statistically equivalent for all groups: bicortical screws(230), full-length unicortical screws(227), 75% length unicortical screws(226), 50% length unicortical screws(187), unicortical pegs(226). Force(N) at 2 mm displacement was significantly less for 50% length unicortical screws(311) compared to bicortical screws(460), full-length unicortical screws(464), 75% length unicortical screws(400), and unicortical pegs(356). Force(N) to catastrophic fracture was statistically equivalent between groups but mean values for pegs(749) and 50% length unicortical(702) screws were 16-21% less than means for bicortical(892), full-length unicortical(860), and 75% length(894) unicortical constructs.
Locked unicortical distal screws of at least 75% length produce construct stiffness similar to bicortical fixation. Unicortical distal fixation for extra-articular distal radius fractures should be entertained to avoid extensor tendon injury since it does not appear to compromise initial fixation.
Biomechanical comparison of distal fixation techniques during volar locked plating for distal radius fracture.
Bicortical; Biomechanical; Distal radius; Fracture; Volar locking plate
Despite prophylaxis with immunosuppressive agents or a variety of other approaches, many patients suffer from acute graft-versus-host disease after allogeneic hematopoietic cell transplantation. Although consensus has emerged supporting the use of high-dose methylprednisolone or prednisone for initial treatment of acute GVHD, practices differ among centers with respect to the initial glucocorticoid dose, the use of additional immunosuppressive agents, and the approach to withdrawal of treatment after initial improvement. Despite many studies, practices vary considerably with respect to the selection of agents for treatment of glucocorticoid-resistant or refractory GVHD. Investigators and clinicians have recognized the lack of progress and lamented the absence of an accepted standard of care for secondary treatment of acute GVHD. The American Society of Blood and Marrow Transplantation has developed recommendations for treatment of acute GVHD to be considered by care providers, based on a comprehensive and critical review of published reports. Since the literature provides little basis for a definitive guideline, this review also provides a framework for the interpretation of previous studies and the design of future studies.
acute graft-versus-host disease; hematopoietic cell transplantation; treatment