Validation of the Brief Screen for Depression in a Jamaican cohort.
Research on depression in Jamaicans has been limited by the absence of a psychometrically sound measure of depression. This project attempts to rectify this problem by exploring the concurrent and discriminant validity of the Brief Screen for Depression (BSD) using a sample of 244 students attending the University of the West Indies, Mona, Jamaica. Participants were administered the BSD along with the Beck Depression Inventory (BDI), the Center for Epidemiologic Studies Depression scale (CES-D) the University of California at Los Angeles (UCLA) Loneliness Scale - Revised, (UCLA-R) and the Responding Desirably on Attitudes and Opinions scale (RD16). Overall, the BSD was found to have an acceptable level of concurrent validity as evidenced by high correlations with scores on the BDI (0.64) and the CES-D (0.62), and an acceptable level of discriminant validity as demonstrated through moderate correlations with the UCLA Loneliness Scale (0.40). In addition, the BSD was found to possess a moderate degree of sensitivity in identifying individuals who may be experiencing clinically significant symptoms of depression.


Nucleotide modulation of pinacidil stimulation of the cloned K(ATP) channel Kir6.2/SUR2A.
ATP-sensitive K(+) channels are the target for K(+) channel openers such as pinacidil. These channels are formed from pore-forming Kir6. 2 and regulatory sulfonylurea receptor (SUR) subunits. Pinacidil activates channels containing SUR2A (heart, skeletal muscle), but not those containing SUR1 (beta cells). Surprisingly, binding of the pinacidil analog [(3)H]P1075 is dependent on added nucleotides, yet in electrophysiological studies, pinacidil is effective in the absence of intracellular nucleotides. To determine the reason for this anomaly, we examined the functional interactions between pinacidil (or P1075) and nucleotides by expressing cloned Kir6. 2/SUR2A channels in Xenopus laevis oocytes. Both pinacidil and P1075 activated macroscopic Kir6.2/SUR2A currents in the absence of added nucleotide, but the presence of intracellular ATP or ADP slowed the off-rate of the response. Mutation of the Walker A lysine in a single nucleotide binding domain (NBD) of SUR2A (K707A in NBD1, K1348A in NBD2), abolished this action of nucleotide. The K1348A mutation prevented stimulation by MgADP but had little effect on the amplitude of the pinacidil response. In contrast, Kir6.2/SUR2A-K707A currents were activated by MgADP, but only responded to pinacidil in the presence of Mg-nucleotide. Off-rates in the absence (or presence) of nucleotide were slower for the pinacidil analog P1075 than for pinacidil, consistent with the higher affinity of P1075. We suggest that slowing of P1075 dissociation by nucleotide enables binding to be detected.


Demonstrating Bioequivalence of Locally Acting Orally Inhaled Drug Products (OIPs): Workshop Summary Report.
This March 2009 Workshop Summary Report was sponsored by Product Quality Research Institute (PQRI) based on a proposal by the Inhalation and Nasal Technology Focus Group (INTFG) of the American Association of Pharmaceutical Scientists (AAPS). Participants from the pharmaceutical industry, academia and regulatory bodies from the United States, Europe, India, and Brazil attended the workshop with the objective of presenting, reviewing, and discussing recommendations for demonstrating bioequivalence (BE) that may be considered in the development of orally inhaled drug products and regulatory guidances for new drug applications (NDAs), abbreviated NDAs (ANDAs), and postapproval changes. The workshop addressed areas related to in vitro approaches to demonstrating BE, biomarker strategies, imaging techniques, in vivo approaches to establishing local delivery equivalence and device design similarity. The workshop presented material that provided a baseline for the current understanding of orally inhaled drug products (OIPs) and identified gaps in knowledge and consensus that, if answered, might allow the design of a robust, streamlined method for the BE assessment of locally acting inhalation drugs. These included the following: (1) cascade impactor (CI) studies are not a good 2 predictor of the pulmonary dose; more detailed studies on in vitro/in vivo correlations (e.g., suitability of CI studies for assessing differences in the regional deposition) are needed; (2) there is a lack of consensus on the appropriate statistical methods for assessing in vitro results; (3) fully validated and standardized imaging methods, while capable of providing information on pulmonary dose and regional deposition, might not be applicable to the BE of inhaled products mainly due to the problems of having access to radiolabeled innovator product; (4) if alternatives to current methods for establishing local delivery BE of OIPs cannot be established, biomarkers (pharmacodynamic or clinical endpoints) with a sufficiently steep dose-response need to be identified and validated for all relevant drug classes; and (5) the utility of pharmacokinetic studies for evaluating "local pulmonary delivery" equivalence deserves more attention. A summary of action items for seminars and working groups to address these topics in the future is also presented.


The occurrence and persistence of thoughts of suicide, self-harm and death in family caregivers of people with dementia: a longitudinal data analysis over 2 years.
Family caregivers of people with dementia often report high levels of stress and depression, but little is known about those who contemplate suicide or self-harm. This study explores thoughts of suicide, self-harm and death in dementia caregivers and investigates the characteristics that distinguish them from those without such thoughts. Data were collected every 3 months, for 24 months, from 192 family caregivers of people with dementia living in the Netherlands. Caregivers did not have a clinical depression or anxiety disorder at baseline. Suicide-related thoughts were measured with an item from the Mini International Neuropsychiatric Interview, a diagnostic instrument for DSM-IV mental disorders. Fisher exact, analysis of variance or Kruskal-Wallis tests compared the characteristics of caregivers who had contemplated suicide with two comparison groups. Within 24 months, 76 caregivers reported symptoms of a potential depression and were further assessed for suicidal thoughts. Nine carers (11.8%, 4.7% of the total sample) reported suicidal thoughts with three of those at multiple points. Caregivers with suicidal thoughts had more severe depressive and anxious symptoms, had a lower sense of competence and mastery, felt less happy and experienced more health problems, less family support and more feelings of loneliness than caregivers who had not. Suicidal thoughts are present in dementia caregivers and can persist across the care trajectory. Various psychological and social characteristics significantly distinguish caregivers with suicidal thoughts from those without. More research is needed to enable the identification of high-risk caregivers and provide an evidence base for the development of preventive strategies and interventions. © 2017 The Authors. International Journal of Geriatric Psychiatry Published by John Wiley & Sons Ltd.


Classifying child and adolescent psychiatric disorder by problem checklists and standardized interviews.
This paper discusses the need for research on the psychometric adequacy of self-completed problem checklists to classify child and adolescent psychiatric disorder based on proxy assessments by parents and self-assessments by adolescents. We put forward six theoretical arguments for expecting checklists to achieve comparable levels of reliability and validity with standardized diagnostic interviews for identifying child psychiatric disorder in epidemiological studies and clinical research. Empirically, the modest levels of test-retest reliability exhibited by standardized diagnostic interviews - 0.40 to 0.60 based on kappa - should be achievable by checklists when thresholds or cut-points are applied to scale scores to identify a child with disorder. The few studies to conduct head-to-head comparisons of checklists and interviews in the 1990s concurred that no construct validity differences existed between checklist and interview classifications of disorder, even though the classifications of youth with psychiatric disorder only partially overlapped across instruments. Demonstrating that self-completed problem checklists can classify disorder with similar reliability and validity as standardized diagnostic interviews would provide a simple, brief, flexible way to measuring psychiatric disorder as both a categorical or dimensional phenomenon as well as dramatically lowering the burden and cost of assessments in epidemiological studies and clinical research.


The problem of malaria and malaria control in pregnancy in sub-Saharan Africa.
Plasmodium falciparum infection in pregnant women frequently leads to placental infection and low birth weight (< 2,500 grams) of the infant, particularly in the areas of high malaria transmission found in sub-Saharan Africa. Low birth weight is widely known to be an important risk factor for early infant mortality. To reduce the risk that maternal infection poses to child survival, many antenatal clinic programs recommend and provide antimalarial chemoprophylaxis, often with chloroquine (CQ) as a recommended element for antenatal care. Prior to the 1980s, despite widespread advocacy for this intervention, little was known about the effect of this intervention strategy. As an introduction to the Mangochi Malaria Research Project, which examined the efficacy of several antimalarial regimens using CQ or mefloquine in pregnant women in Malawi, we describe the background of knowledge regarding malaria infection in pregnant African women and the important elements of an intervention and prevention strategy.


Visual context modulates the subjective vertical in neglect: evidence for an increased rod-and-frame-effect.
Patients with spatial hemi-neglect display systematic deviations of the subjective vertical. The magnitude of such deviations was shown to be modulated by internal factors mediating the perception of verticality, including head-orientation. The present study investigated whether and how spatial orientation deficits are modulated by external, contextual changes in neglect patients. In a classic rod-and-frame task, we analyzed effects of frame orientation on the subjective visual vertical (SVV) in neglect patients, control patients with left- or right-sided brain damage without neglect and healthy participants. We found that neglect patients, but not brain-damaged control patients, generally display a systematic counterclockwise (CCW) tilt in their SVV judgments. Furthermore, all participant groups displayed a typical rod-and-frame effect (RFE), that is, a modulation of the SVV as a function of frame tilt. However, in the control groups, this modulation was only moderate whereas in the neglect group SVV judgments were substantially and systematically modulated by frame orientation: with CCW frame tilts, the spatial bias of neglect patients increased as a function of the magnitude of the tilt whereas with clockwise (CW) frame tilts, the spatial bias was decreased in case of moderate frame tilts and even reversed in case of stronger frame tilts, resulting in a substantial CW spatial bias. This dramatically enhanced RFE might be caused by a pathologically increased influence of contextual cues on the subjective vertical in neglect patients as a consequence of impaired processing of gravitational information. The results indicate a systematic bias of the subjective vertical along with an impairment of spatial orientation constancy which leads to severe perturbations of subjective space as well as an increased reliance on internal and external cues mediating the perception of verticality in neglect.


Association of total-mixed-ration chemical composition with milk, fat, and protein yield lactation curves at the individual level.
The objective of this study was to examine the effect of the chemical composition of a total mixed ration (TMR) tested quarterly from March 2006 through December 2008 for milk, fat, and protein yield curves for 27 herds in Ragusa, Sicily. Before this study, standard yield curves were generated on data from 241,153 test-day records of 9,809 animals from 42 herds in Ragusa province collected from 1995 to 2008. A random regression sire-maternal grandsire model was used to develop variance components for yields. The model included parity, age at calving, year at calving, and stage of pregnancy as fixed effects. Random effects were herd × test date, sire and maternal grandsire additive genetic effect, and permanent environmental effect modeled using third-order Legendre polynomials. Model fitting was carried out using ASReml. Subsequently, the model with estimated variance components was used to examine the influence of TMR crude protein, soluble N, acid detergent lignin, neutral detergent fiber, acid detergent fiber, starch, and ash on milk, fat, and protein yield curves. The data set contained 46,531 test-day milk yield records from 3,554 cows in the 27 herds recorded during the study period. Initially, an analysis was performed using one dietary component (one-component analysis) within each model as a fixed effect associated with the test-day record closest to the months the TMR was sampled within each herd. An interaction was included with the nutrient component and days in milk. The effect of the TMR chemical component(s) was modeled using a ninth-order Legendre polynomial. The conditional Wald F-statistic for the fixed effects revealed significant effects for acid detergent fiber, neutral detergent fiber, crude protein, starch, and their interactions with days in milk on milk, fat, and protein yield. On the basis of these results, a multicomponent analysis was performed in which crude protein, neutral detergent fiber, and starch were simultaneously included in the model with days in milk interactions. Although both analyses revealed that diet composition influenced production responses depending on lactation stage, the multiple-component analysis showed more pronounced effects of starch and neutral detergent fiber relative to crude protein for all traits throughout lactation.


Milk-induced eczema is associated with the expansion of T cells expressing cutaneous lymphocyte antigen.
The extravasation of T cells at sites of inflammation is critically dependent on the activity of homing receptors (HR) involved in endothelial cell recognition and binding. Two such HR (the cutaneous lymphocyte antigen [CLA] and L-selectin) have been shown to be selectively involved in T cell migration to skin and peripheral lymph nodes, respectively. This study was designed to assess the relationship between the organ specificity of an allergic reaction to food and the expression of HR on T cells activated in vitro by the relevant food allergen. Peripheral blood mononuclear cells were isolated from seven milk allergic children with a history of eczema when exposed to milk. All patients had a positive prick skin test and double-blind placebo-controlled food challenge to milk. 10 children with either allergic eosinophilic gastroenteritis or milk-induced enterocolitis and 8 nonatopic adults served as controls. Five-parameter flow cytometry using monoclonal antibodies was used for detection of the specific HR on freshly isolated T cells versus T cell blasts induced by a 6-d incubation with casein, as compared with Candida albicans. After in vitro stimulation with casein, but not C. albicans, patients with milk allergy and atopic dermatitis had a significantly greater percentage of CLA+ T cells (P < 0.01) than controls with milk-induced enterocolitis, allergic eosinophilic gastroenteritis, or nonatopic healthy controls. In contrast, the percentage of L-selectin-expressing T cells did not differ significantly between these groups. These data suggest that after casein stimulation allergic patients with milk-induced skin disease have an expanded population of CLA+ T cells, as compared with nonatopics or allergic patients without skin involvement. We postulate that heterogeneity in the regulation of HR expression on antigen-specific T cells may play a role in determining sites of involvement in tissue-directed allergic responses.


[Continuous intraocular pressure measurement: First results with a pressure-sensitive contact lens].
A prototype of a pressure-sensitive contact lens (CL-DCT) based on dynamic contour tonometry (DCT) has been developed for continuous intraocular pressure (IOP) monitoring. The purpose of the present study was to assess the clinical applicability of this CL-DCT. In 24 healthy subjects continuous IOP recording with the CL-DCT for 100 s was accomplished including IOP monitoring during 2 consecutive Valsalva manoeuvres. The measurement procedure was repeated after 5 min on the same eye and compared with the initial measurement. Continuous pressure curves were recorded in 20 subjects. The CL-DCT revealed an individual increase in IOP from 0.74 to 8.26 mmHg during the Valsalva manoeuvres. Comparison of the 2 consecutive IOP measurements yielded a mean deviation of +/-0.4 mmHg. CL-DCT allows non-invasive and continuous measurements of IOP. The measured values are comparable to the expected ones. Further studies are necessary to compare the measurement accuracy of CL-DCT with that of slit lamp adapted DCT (SL-DCT).


Inclusion of PF68 Surfactant Improves Stability of rAAV Titer when Passed through a Surgical Device Used in Retinal Gene Therapy.
Recent advances in recombinant adeno-associated virus (rAAV) gene therapy for choroideremia show gene replacement to be a promising approach. It is, however, well known that contact of vector solution with plastic materials in the surgical device may result in non-specific adsorption with resulting loss of physical titer and/or level of protein expression and activity. Here we assessed the biocompatibility and stability of rAAV2-REP1 (Rab Escort Protein-1) before and following passage through the injection device over a period of time to mimic the clinical scenario. Three identical devices were screened using two concentrations of vector: high (1E+12 DNase-resistant particles [DRP]/mL) and low (1E+11 DRP/mL), to mimic high- and low-dose administrations of vector product. The low dose was prepared using either formulation buffer that contained 0.001% of a non-ionic surfactant (PF68) or balanced salt solution (BSS). We observed significant losses in the genomic titer of samples diluted with BSS for all time points. The addition of 0.001% PF68 did not, however, affect rAAV physical titer, or REP1 protein expression and biological activity. Hence we observed that neither the genomic titer nor the biological activity of a rAAV2-REP1-containing solution was affected following passage through the surgical device when PF68 was present as a surfactant and this was maintained over a period up to 10 h.


Morphogenesis of the vulva and the vulval-uterine connection.
The C. elegans hermaphrodite vulva is an established model system to study mechanisms of cell fate specification and tissue morphogenesis. The adult vulva is a tubular shaped organ composed of seven concentric toroids that arise from selective fusion between differentiated vulval progeny. The dorsal end of the vulval tubule is connected to the uterus via a multinucleate syncytium utse (uterine-seam) cell. The vulval tubule and utse are formed as a result of changes in morphogenetic processes such as cell polarity, adhesion, and invagination. A number of genes controlling these processes are conserved all the way up to human and function in similar developmental contexts. This makes it possible to extend the findings to other metazoan systems. Gene expression studies in the vulval and uterine cells have revealed the presence of regulatory networks specifying distinct cell fates. Thus, these two cell types serve as a good system to understand how gene networks confer unique cell identities both experimentally and computationally. This chapter focuses on morphogenetic processes during the formation of the vulva and its connection to uterus.


A Dynamic Multi-Tissue Flux Balance Model Captures Carbon and Nitrogen Metabolism and Optimal Resource Partitioning During Arabidopsis Growth.
Plant metabolism is highly adapted in response to its surrounding for acquiring limiting resources. In this study, a dynamic flux balance modeling framework with a multi-tissue (leaf and root) diel genome-scale metabolic model of Arabidopsis thaliana was developed and applied to investigate the reprogramming of plant metabolism through multiple growth stages under different nutrient availability. The framework allowed the modeling of optimal partitioning of resources and biomass in leaf and root over diel phases. A qualitative flux map of carbon and nitrogen metabolism was identified which was consistent across growth phases under both nitrogen rich and limiting conditions. Results from the model simulations suggested distinct metabolic roles in nitrogen metabolism played by enzymes with different cofactor specificities. Moreover, the dynamic model was used to predict the effect of physiological or environmental perturbation on the growth of Arabidopsis leaves and roots.


Dismantling the Justice Silos: avoiding the pitfalls and reaping the benefits of information-sharing between forensic science, medicine and law.
Forensic science is increasingly relied on by police and the courts to exonerate the innocent and to establish links to crime. With this increased reliance the potential for unjust outcomes increases, especially in serious matters for two reasons. The more serious the matter, the more likely that evidence mishandling can lead to wrongful imprisonment, and the more likely the personnel involved will be multi-disciplinary (police, medicine, law, forensic science), and multi-organisational (Health, Justice, private legal/medical, police). The importance of identifying effective multi-organisational interactions was highlighted in the recent wrongful imprisonment of an Australian male for a sexual assault he did not commit. One factor that led to this unjust outcome was the justice silo effect: where forensic practitioners from different agencies operate in isolation (rarely communicating or sharing information/knowledge). In this paper we discuss findings from the Interfaces Project designed to assess the extent of the justice silos within Australia. We interviewed 103 police, forensic scientists, lawyers, judges, coroners, pathologists and forensic physicians Australian-wide. Five main themes were identified in the data: the silo effect was only partial and in each jurisdiction some form of inter-agency communication was actively occurring; inter-agency meetings were more common in homicide than sexual assault cases; forensic physicians were semi-invisible; there had been considerable momentum over the past ten years for practice improvement groups, and; practitioners gain more benefits than pitfalls from inter-agency information-sharing. Based on these findings, five recommendations are made for improving practice.


Intrinsic properties and reflex compensation in reinnervated triceps surae muscles of the cat: effect of activation level.
The manner in which activation levels influence intrinsic muscular properties and contributions of the stretch reflex were studied in homogeneous soleus (SOL) and heterogeneous gastrocnemius (G) muscles in the decerebrate cat. Intrinsic mechanical properties were represented by the initial stiffness of the muscle, measured prior to reflex action, and by the tendency of the muscle to yield during stretch in the absence of the stretch reflex. Stiffness regulation by the stretch reflex was evaluated by measuring the extent to which reflex action reduces yielding and the extent to which stiffness depends on background force. Intrinsic mechanical properties were measured in muscles deprived of effective autogenic reflexes using the method of muscular reinnervation. Reinnervated muscles were recruited to force levels comparable to those achieved during natural locomotion. As force declined during crossed-extension reflexes in reinnervated and intact muscles, initial stiffness declined according to similar convex trajectories. The data did not support the hypothesis that, for a given force level, initial stiffness is greatest in populations of predominantly type I motor units. Incremental stiffness (Deltaf/Deltal) of both G and SOL increased in the presence of the stretch reflex. Yielding of SOL (ratio of incremental to initial stiffness) substantially decreased in the presence of the stretch reflex over the full range of forces. In reflexive G, yielding significantly decreased for low to intermediate forces, whereas at higher forces, yielding was similar irrespective of the presence or absence of the stretch reflex. The stretch reflex regulates stiffness in both homogeneous and heterogeneous muscles.


Hypoimmunogenic derivatives of induced pluripotent stem cells evade immune rejection in fully immunocompetent allogeneic recipients.
Autologous induced pluripotent stem cells (iPSCs) constitute an unlimited cell source for patient-specific cell-based organ repair strategies. However, their generation and subsequent differentiation into specific cells or tissues entail cell line-specific manufacturing challenges and form a lengthy process that precludes acute treatment modalities. These shortcomings could be overcome by using prefabricated allogeneic cell or tissue products, but the vigorous immune response against histo-incompatible cells has prevented the successful implementation of this approach. Here we show that both mouse and human iPSCs lose their immunogenicity when major histocompatibility complex (MHC) class I and II genes are inactivated and CD47 is over-expressed. These hypoimmunogenic iPSCs retain their pluripotent stem cell potential and differentiation capacity. Endothelial cells, smooth muscle cells, and cardiomyocytes derived from hypoimmunogenic mouse or human iPSCs reliably evade immune rejection in fully MHC-mismatched allogeneic recipients and survive long-term without the use of immunosuppression. These findings suggest that hypoimmunogenic cell grafts can be engineered for universal transplantation.


Interpretable Almost-Exact Matching for Causal Inference.
Matching methods are heavily used in the social and health sciences due to their interpretability. We aim to create the highest possible quality of treatment-control matches for categorical data in the potential outcomes framework. The method proposed in this work aims to match units on a weighted Hamming distance, taking into account the relative importance of the covariates; the algorithm aims to match units on as many relevant variables as possible. To do this, the algorithm creates a hierarchy of covariate combinations on which to match (similar to downward closure), in the process solving an optimization problem for each unit in order to construct the optimal matches. The algorithm uses a single dynamic program to solve all of the units' optimization problems simultaneously. Notable advantages of our method over existing matching procedures are its high-quality interpretable matches, versatility in handling different data distributions that may have irrelevant variables, and ability to handle missing data by matching on as many available covariates as possible.


Second-line therapy for gemcitabine-pretreated advanced or metastatic pancreatic cancer.
To investigate second-line chemotherapy in gemcitabine-pretreated patients with advanced or metastatic pancreatic cancer [(frequency, response, outcome, course of carbohydrate antigen 19-9 (CA 19-9)]. This retrospective study included all patients with advanced or metastatic pancreatic cancer (adenocarcinoma or carcinoma) treated with second-line chemotherapy in our center between 2000 and 2008. All patients received first-line chemotherapy with gemcitabine, and prior surgery or radiotherapy was permitted. We analyzed each chemotherapy protocol for second-line treatment, the number of cycles and the type of combination used. The primary endpoint was overall survival. Secondary endpoints included progression-free survival, response rate, grade 3-4 toxicity, dosage modifications and CA 19-9 course. A total of eighty patients (38%) underwent a second-line therapy among 206 patients who had initially received first-line treatment with a gemcitabine-based regimen. Median number of cycles was 4 (range: 1-12) and the median duration of treatment was 2.6 mo (range: 0.3-7.4). The overall disease control rate was 40.0%. The median overall survival and progression-free survival from the start of second-line therapy were 5.8 (95% CI: 4.1-6.6) and 3.4 mo (95% CI: 2.4-4.2), respectively. Toxicity was generally acceptable. Median overall survival of patients with a CA 19-9 level declining by more than 20% was 10.3 mo (95% CI: 4.5-11.6) vs 5.2 mo (95% CI: 4.0-6.4) for others (P = 0.008). A large proportion of patients could benefit from second-line therapy, and CA 19-9 allows efficient treatment monitoring both in first and second-line chemotherapy.


Acute effects of firefighting on cardiac performance.
This study examined standard echocardiographic measures of cardiac size and performance in response to a 3-h firefighting training exercise. Forty experienced male personnel completed a standardized 3 h live firefighting exercise. Before and after the firefighting activities, participants were weighed, height, heart rate, blood pressure and blood samples were obtained, and echocardiographic measurements were made. Firefighting produced significant decreases in left ventricular diastolic dimension, stroke volume, fractional shortening, and mitral E velocity, tachycardia, a rise in core temperature, and a reduction in calculated plasma volume. On tissue Doppler imaging, there were no changes in systolic contractile function, but a decreased lateral wall diastolic velocity was observed. These findings show that 3 h of live firefighting produced cardiac changes consistent with cardiac fatigue, coupled with a decrease in systemic arterial compliance. These data show that live firefighting produces significant cardiovascular changes and future work is needed to evaluate if these changes are related to the increase in cardiovascular risk during live firefighting.


A human monoclonal antibody prevents malaria infection by targeting a new site of vulnerability on the parasite.
Development of a highly effective vaccine or antibodies for the prevention and ultimately elimination of malaria is urgently needed. Here we report the isolation of a number of human monoclonal antibodies directed against the Plasmodium falciparum (Pf) circumsporozoite protein (PfCSP) from several subjects immunized with an attenuated Pf whole-sporozoite (SPZ) vaccine (Sanaria PfSPZ Vaccine). Passive transfer of one of these antibodies, monoclonal antibody CIS43, conferred high-level, sterile protection in two different mouse models of malaria infection. The affinity and stoichiometry of CIS43 binding to PfCSP indicate that there are two sequential multivalent binding events encompassing the repeat domain. The first binding event is to a unique 'junctional' epitope positioned between the N terminus and the central repeat domain of PfCSP. Moreover, CIS43 prevented proteolytic cleavage of PfCSP on PfSPZ. Analysis of crystal structures of the CIS43 antigen-binding fragment in complex with the junctional epitope determined the molecular interactions of binding, revealed the epitope's conformational flexibility and defined Asn-Pro-Asn (NPN) as the structural repeat motif. The demonstration that CIS43 is highly effective for passive prevention of malaria has potential application for use in travelers, military personnel and elimination campaigns and identifies a new and conserved site of vulnerability on PfCSP for next-generation rational vaccine design.


Pulmonary vascular and ventricular dysfunction in the susceptible patient (2015 Grover Conference series).
Pulmonary blood vessel structure and tone are maintained by a complex interplay between endogenous vasoactive factors and oxygen-sensing intermediaries. Under physiological conditions, these signaling networks function as an adaptive interface between the pulmonary circulation and environmental or acquired perturbations to preserve oxygenation and maintain systemic delivery of oxygen-rich hemoglobin. Chronic exposure to hypoxia, however, triggers a range of pathogenetic mechanisms that include hypoxia-inducible factor 1α (HIF-1α)-dependent upregulation of the vasoconstrictor peptide endothelin 1 in pulmonary endothelial cells. In pulmonary arterial smooth muscle cells, chronic hypoxia induces HIF-1α-mediated upregulation of canonical transient receptor potential proteins, as well as increased Rho kinase-Ca2+ signaling and pulmonary arteriole synthesis of the profibrotic hormone aldosterone. Collectively, these mechanisms contribute to a contractile or hypertrophic pulmonary vascular phenotype. Genetically inherited disorders in hemoglobin structure are also an important etiology of abnormal pulmonary vasoreactivity. In sickle cell anemia, for example, consumption of the vasodilator and antimitogenic molecule nitric oxide by cell-free hemoglobin is an important mechanism underpinning pulmonary hypertension. Contemporary genomic and transcriptomic analytic methods have also allowed for the discovery of novel risk factors relevant to sickle cell disease, including GALNT13 gene variants. In this report, we review cutting-edge observations characterizing these and other pathobiological mechanisms that contribute to pulmonary vascular and right ventricular vulnerability.


In vitro and in vivo experiments on electrochemotherapy for bladder cancer.
Electrochemotherapy is widely performed to treat solid tumors but experience with bladder cancer is limited. We investigated mitomycin C and cisplatin administered with electrochemotherapy for bladder cancer in vitro and in vivo. The human bladder cancer cell line SW780 was used. Cells were treated with electroporation, drug alone or electroporation plus increasing concentrations of drug (mitomycin C 0.001 to 2,000 μM or cisplatin 1.56 to 300 μM). Electrochemotherapy parameters were 8 pulses of 1.2 kV/cm for 99 microseconds at 1 Hz. We investigated survival and apoptosis, the latter evaluated by caspase activity. NMRI-Fox1nu nude mice were inoculated subcutaneously and randomized to 1) electrochemotherapy plus NaCl, 2) NaCl alone, 3) electrochemotherapy plus drug or 4) drug alone (mitomycin C 5 mM or cisplatin 250 μM). Tumors were measured 3 times per week. A similar experiment was done to assess necrosis by histology at days 2 and 6. In vitro mitomycin C cytotoxicity and caspase activity was unaffected by electrochemotherapy (p = 0.9057 and 0.53, respectively). However, electrochemotherapy with cisplatin caused 6.6-fold increased cytotoxicity and higher caspase activity (p <0.0001 and <0.001, respectively). In vivo electrochemotherapy plus mitomycin C resulted in tumor volume reduction (p <0.0005). The survival rate in mice that received electrochemotherapy plus mitomycin C and mitomycin C alone was greater than in controls (p = 0.0004). The tumor response rate was 100% for electrochemotherapy plus mitomycin C, 53% for mitomycin C alone, 14% for electrochemotherapy plus NaCl and 0% for NaCl alone. In vivo electrochemotherapy plus cisplatin was associated with slower tumor growth over other combinations as well as significantly higher survival (p = 0.0005 and 0.0003, respectively). The tumor response rate was 47% for electrochemotherapy plus cisplatin, 0% for cisplatin alone, 0% for electrochemotherapy plus NaCl and 8% for NaCl alone In vivo electrochemotherapy with mitomycin C or cisplatin was more effective than chemotherapy alone in a bladder cancer tumor model, opening new perspectives in bladder cancer therapy.


Gambling as a search for justice: examining the role of personal relative deprivation in gambling urges and gambling behavior.
The present article explores the hypothesis that gambling might serve a justice-seeking function for some people, as gambling might offer a means to pursuing desirable outcomes that people feel they deserve but might be unable or unwilling to attain through conventional means. In Study 1, across two separate samples, self-reports of personal relative deprivation predict problem gambling and gambling urges over and above relevant control variables. In Study 2, the authors manipulate personal relative deprivation by informing participants that they have either less or more discretionary income than "similar others." They then give participants $20 and the opportunity to gamble. The results show that a greater percentage of participants who are "relatively deprived" (vs. "not relatively deprived") opt to gamble. Two manipulation validation studies demonstrate that the "relatively deprived" participants are preoccupied with justice during a modified Stroop task and feel resentful. Implications for understanding why people gamble are discussed.


Autism Spectrum Disorder: Primary Care Principles.
Autism spectrum disorder is characterized by difficulty with social communication and restricted, repetitive patterns of behavior, interest, or activities. The Diagnostic and Statistical Manual of Mental Disorders, 5th ed., created an umbrella diagnosis that includes several previously separate conditions: autistic disorder, Asperger syndrome, childhood disintegrative disorder, and pervasive developmental disorder not otherwise specified. There is insufficient evidence to recommend screening for autism spectrum disorder in children 18 to 30 months of age in whom the disorder is not suspected; however, there is a growing body of evidence that early intensive behavioral intervention based on applied behavior analysis improves cognitive ability, language, and adaptive skills. Therefore, early identification of autism spectrum disorder is important, and experts recommend the use of a validated screening tool at 18- and 24-month well-child visits. Medications can be used as adjunctive treatment for maladaptive behaviors and comorbid psychiatric conditions, but there is no single medical therapy that is effective for all symptoms of autism spectrum disorder. Prognosis is heavily affected by the severity of diagnosis and the presence of intellectual disability. Children with optimal outcomes receive earlier, more intensive behavioral interventions and less pharmacologic treatment.


Is the frequent sonographic anechoic area distally in metacarpophalangeal joints a sign of arthritis?
In clinical practice, ultrasonography (US) often reveals, in the dorsal scan, a small anechoic area distally in both inflamed and clinically non-inflamed metacarpophalangeal joints. This "distal anechogenicity in the metacarpophalangeal joint" (DAEM) might thus be scored false positively as arthritis. We aimed to investigate whether the DAEM is a sign of arthritis. We evaluated the prevalence of DAEMs in 24 non-arthritic subjects. We then compared the dimensions of the DAEM in 10 non-arthritic subjects with a DAEM and 7 consecutive rheumatoid arthritis (RA) outpatients, using 2-D and 3-D ultrasound. Furthermore, we dissected two fresh-frozen postmortem hand specimens after US. A DAEM was observed in the metacarpophalangeal 2 (MCP2) joints of 54% of the 24 non-selected non-arthritic individuals; in none of those did the joint exhibit a power Doppler signal. A DAEM was observed in 86% of the 7 RA patients. Dimensions of DAEMs did not statistically significantly differ between these groups. At 3-D imaging and dissection, the DAEM was found to be an extension of the metacarpophalangeal joint capsule. In conclusion, DAEMs occur frequently and are not a sign of arthritis, but are distal joint recesses. This should be taken into account when using current sensitive ultrasonographic scoring systems grading arthritis.


Factors associated with chronic opioid use after cervical spine surgery for degenerative conditions.
Opioids are commonly prescribed after surgery for painful spinal conditions, yet little is known about postoperative opioid use. The relationship between chronic opioid use and patient-reported outcomes and satisfaction with surgery is also unclear. The purpose of this study was to evaluate factors associated with opioid use 1 year after elective cervical spine surgery for degenerative conditions causing radiculopathy and myelopathy. The authors hypothesized that patients with preoperative opioid use would be more likely to report postoperative opioid use at 1 year, and that postoperative opioid use would be associated with patient-reported outcomes and dissatisfaction with surgery. The authors performed a retrospective study of a prospective cohort of adult patients who underwent elective cervical spine surgery for degenerative changes causing radiculopathy or myelopathy. Patients were prospectively and consecutively enrolled from a single academic center after the decision for surgery had been made. Postoperative in-hospital pain management was conducted using a standardized protocol. The primary outcome was any opioid use 1 year after surgery. Secondary outcomes were the Neck Disability Index (NDI); 36-Item Short-Form Health Survey (SF-36) physical function (PF), bodily pain (BP), and mental component summary (MCS) scores; the modified Japanese Orthopaedic Association (mJOA) score among myelopathy patients; and patient expectations surveys. Patients with and without preoperative opioid use were compared using the chi-square and Student t-tests, and multiple logistic regression was used to study the associations between patient and surgical characteristics and postoperative opioid use 1 year after surgery. Two hundred eleven patients were prospectively and consecutively enrolled, of whom 39 were lost to follow-up for the primary outcome; 43.6% reported preoperative opioid use. Preoperative NDI and SF-36 PF and BP scores were significantly worse in the preoperative opioid cohort. More than 94% of both cohorts rated expectations of pain relief as extremely or somewhat important. At 1 year after surgery, 50.7% of the preoperative-opioid-use cohort reported ongoing opioid use, and 17.5% of patients in the no-preoperative-opioid-use cohort reported ongoing opioid use. Despite this, both cohorts reported similar improvements in NDI as well as SF-36 PF, BP, and MCS scores. More than 70% of both cohorts also reported being extremely or somewhat satisfied with pain relief after surgery. Predictors of 1-year opioid use included preoperative opioid use, duration of symptoms for more than 9 months before surgery, tobacco use, and higher comorbidity index. One year after elective cervical spine surgery, patients with preoperative opioid use were significantly more likely to report ongoing opioid use. However, patients in both groups reported similar improvements in patient-reported outcomes and satisfaction with pain relief. Interventions targeted at decreasing opioid use may need to focus on patient factors such as preoperative opioid use or duration of symptoms before surgery.


A novel peptide modulates alpha7 nicotinic receptor responses: implications for a possible trophic-toxic mechanism within the brain.
The alpha7 nicotinic acetylcholine receptor (nAChR) plays a key role in neural development and neurodegeneration. Here, we identify a novel, modulatory receptor ligand, a 14-amino acid peptide (AEFHRWSSYMVHWK) derived from the C-terminus of acetylcholinesterase (AChE). In three different in vitro preparations, this 'AChE-peptide' is bioactive in a ligand-specific and concentration-dependent manner. First, it modulates acutely the effect of acetylcholine (ACh) on Xenopus oocytes transfected with human alpha7, but not alpha4/beta2, nAChR. The action persists when intracellular calcium is chelated with BAPTA or when calcium is substituted with barium ions. This observation suggests that intracellular Ca(2+) signals do not mediate the interaction between the peptide and nAChR, but rather that the interaction is direct: however, the intervention of other mediators cannot be excluded. Secondly, in recordings from the CA1 region in guinea-pig hippocampal slices, AChE-peptide modulates synaptic plasticity in a alpha-bungarotoxin (alpha-BgTx)-sensitive manner. Thirdly, in organotypic cultures of rat hippocampus, long-term exposure to peptide attenuates neurite outgrowth: this chronic, functional effect is selectively blocked by the alpha7 nAChR antagonists, alpha-BgTx and methyllycaconitine, but not by the alpha4/beta2-preferring blocker dihydro-beta-ethroidine. A scrambled peptide variant, and the analogous peptide from butyrylcholinesterase, are ineffective in all three paradigms. The consequences of this novel modulation of the alpha7 nAChR may be activation of a trophic-toxic axis, of relevance to neurodegeneration.


Role of skin immune cells on the host susceptibility to mosquito-borne viruses.
Due to climate change and the propagation of competent arthropods worldwide, arboviruses have become pathogens of major medical importance. Early transmission to vertebrates is initiated by skin puncture and deposition of virus together with arthropod saliva in the epidermis and dermis. Saliva components have the capacity to modulate skin cell responses by enhancing and/or counteracting initial replication and establishment of systemic viral infection. Here, we review the nature of the cells targeted by arboviruses at the skin level and discuss the type of cellular responses elicited by these pathogens in light of the immunomodulatory properties of arthropod vector-derived salivary factors injected at the inoculation site. Understanding cutaneous arbovirus-host interactions may provide new clues for the design of future therapeutics.


The insula of Reil revisited: multiarchitectonic organization in macaque monkeys.
The insula of Reil represents a large cortical territory buried in the depth of the lateral sulcus and subdivided into 3 major cytoarchitectonic domains: agranular, dysgranular, and granular. The present study aimed at reinvestigating the architectonic organization of the monkey's insula using multiple immunohistochemical stainings (parvalbumin, PV; nonphosphorylated neurofilament protein, with SMI-32; acetylcholinesterase, AChE) in addition to Nissl and myelin. According to changes in density and laminar distributions of the neurochemical markers, several zones were defined and related to 8 cytoarchitectonic subdivisions (Ia1-Ia2/Id1-Id3/Ig1-Ig2/G). Comparison of the different patterns of staining on unfolded maps of the insula revealed: 1) parallel ventral to dorsal gradients of increasing myelin, PV- and AChE-containing fibers in middle layers, and of SMI-32 pyramidal neurons in supragranular layers, with merging of dorsal and ventral high-density bands in posterior insula, 2) definition of an insula "proper" restricted to two-thirds of the "morphological" insula (as bounded by the limiting sulcus) and characterized most notably by lower PV, and 3) the insula proper is bordered along its dorsal, posterodorsal, and posteroventral margin by a strip of cortex extending beyond the limits of the morphological insula and continuous architectonically with frontoparietal and temporal opercular areas related to gustatory, somatosensory, and auditory modalities.


Methotrexate reduces the complications of endophthalmitis resulting from intravitreal injection compared with dexamethasone in a rabbit model.
The incidence of infectious endophthalmitis associated with intravitreal injection (IVI) of steroid has been reported to be as high as 0.87%. This study was designed to investigate whether the antimicrobial activity of intravitreal methotrexate (MTX) alters the incidence or course of bacterial endophthalmitis associated with IVI in a rabbit model. A rabbit model of endophthalmitis induced by Staphylococcus epidermidis (S) was established. Six groups of rabbits had IVI of sterile balanced salt solution (BSS), MTX (400 microg), dexamethasone (Dex, 200 microg), S, S and MTX (S-MTX), or S and dexamethasone (S-Dex). On days 0, 1, 3, 6, 10, and 14, total intraocular inflammation was measured in each animal. Vitritis was graded by the degree of vitreal haze. An intravitreal tap was performed on two animals from groups S, S-Dex, and S-MTX. A histopathologic study was performed on day 14. No endophthalmitis was observed in the control groups BSS, MTX, and Dex. Group S-Dex had the highest and group S-MTX had the least total ocular inflammation and vitritis scores from days 3 to 14. The difference in total inflammation and vitritis among groups S, S-Dex, and S-MTX is significant (P = 0.046 and P = 0.001, respectively). Live bacteria were isolated only from groups S and S-Dex. Pathology revealed severe ocular destruction in groups S and S-Dex and intact structures in group S-MTX. MTX appears to reduce the risk of development of bacterial endophthalmitis and ocular destruction associated with IVI compared with Dex. IVI of MTX may be a safer alternative than steroid injection in treating noninfectious uveitis.


Genetic Polymorphism, Telomere Biology and Non-Small Lung Cancer Risk.
Recent genome-wide association studies (GWAS) have identified a number of chromosomal regions associated with the risk of lung cancer. Of these regions, single-nucleotide polymorphisms (SNPs), especially rs2736100 located in the telomerase reverse transcriptase (TERT) gene show unique and significant association with non-small cell lung cancer (NSCLC) in a few subpopulations including women, nonsmokers, East Asians and those with adenocarcinoma. Recent studies have also linked rs2736100 with a longer telomere length and lung cancer risk. In this review, we seek to summarize the relationship between these factors and to further link the underlying telomere biology to lung cancer etiology. We conclude that genetic alleles combined with environmental (e.g., less-smoking) and physiological factors (gender and age) that confer longer telomere length are strong risk factors for NSCLC. This linkage may be particularly relevant in lung adenocarcinoma driven by epidermal growth factor receptor (EGFR) mutations, as these mutations have also been strongly linked to female gender, less-smoking history, adenocarcinoma histology and East Asian ethnicity. By establishing this connection, a strong argument is made for further investigating of the involvement of these entities during the tumorigenesis of NSCLC.


Effects of oxygen on pyruvate formate-lyase in situ and sugar metabolism of Streptococcus mutans and Streptococcus sanguis.
The strictly anaerobic metabolism of sugar in strains of Streptococcus mutans and Streptococcus sanguis was studied because deep layers of dental plaque are strictly anaerobic. Galactose-grown cells of these streptococcal strains had higher pyruvate formate-lyase activity than did glucose-grown cells. Among these strains, two strains of S. mutans had a significantly higher pyruvate formate-lyase activity than did the others. This enzyme is extremely sensitive to oxygen, and even in situ the enzyme was inactivated by exposure of the cells to air. Lactate was less than 50% of the total end product of the strictly anaerobic incubation of the galactose-grown cells of S. mutans with excess glucose, and a significant amount of formate, acetate, and ethanol was produced through the catalysis of pyruvate formate-lyase. But the cells exclusively produced lactate when exposed to air for 2 min before the anaerobic incubation. The metabolism of sorbitol by S. mutans was seriously impaired by the exposure of the cells to oxygen, and the metabolic rate was reduced to less than 1/20 of that found under strictly anaerobic conditions because of the inactivation of pyruvate formate-lyase. S. sanguis produced a smaller amount of the volatile products from glucose than did S. mutans because of the low level of pyruvate formate-lyase. However, the pyruvate formate-lyase in situ in S. sanguis was less sensitive to oxygen than was that in S. mutans. Because of this low sensitivity, S. sanguis metabolized glucose more rapidly under aerobic conditions, whereas the rates of the aerobic and anaerobic metabolism of glucose by S. mutans were similar, which suggests that S. mutans rather than S. sanguis can sustain the rapid sugar metabolism in the deep layers of dental plaque.


Bioresorbable Vascular Scaffolds in a Real-World Patient Population-Results From a Mid-Term Angiographic Follow-Up.
We aimed to investigate the safety and efficacy of bioresorbable vascular scaffolds (BVS) in daily use in a real-world patient population. Between March 2013 and September 2014, 224 patients (233 lesions) were treated with BVS at a tertiary care center. Patients underwent follow-up coronary angiography 3-6 months after implantation. Clinical presentations were stable angina in 101 patients (45.1%), unstable angina in 47 (21.0%), NSTEMI in 38 (17.0%), and STEMI in 38 (17.0%) patients. Twenty-two patients (27 lesions) had chronic total occlusion (CTO). Procedural success was achieved in all patients. Two patients died in the follow-up period due to BVS thrombosis (0.9%). In-hospital death occurred in further 3 patients (1.3%) due to other causes not related to the BVS implantation. Total BVS thrombosis was 3.1% (7 patients) and there was only 1 case of relevant restenosis on angiographic follow-up. The overall incidence of major adverse cardiac events was 11 (4.9%). Mid-term follow-up after implantation of BVS suggests a satisfactory safety profile and low restenosis rate in routine daily practice involving a large range of complex lesions.


Cellular and molecular biology of the liver.
Recently, several lines of investigation focused on basic mechanisms governing cellular and molecular aspects of liver biology have intersected at the study of the hepatic stem cell. Despite years of study, the very question of the existence of the hepatic stem cell has yet to be unequivocally established. A second field of investigation into the cellular and molecular aspects of liver biology is aimed at liver-directed gene therapy in which several new vehicles have been devised to mediate gene transfer. Gene therapy is no longer thought of in the limited framework of a means to correct inherited disorders; it is now expanding into new therapeutic applications. A third major area of investigation includes studies of mechanisms that regulate membrane protein traffic necessary to maintain the integrity of differentiated liver cell function. In this review, some of the most recent advances and applications in these three areas are highlighted, and, where appropriate, points of interaction and potential therapeutic importance are emphasized.


Genomic and SNP analyses demonstrate a distant separation of the hospital and community-associated clades of Enterococcus faecium.
Recent studies have pointed to the existence of two subpopulations of Enterococcus faecium, one containing primarily commensal/community-associated (CA) strains and one that contains most clinical or hospital-associated (HA) strains, including those classified by multi-locus sequence typing (MLST) as belonging to the CC17 group. The HA subpopulation more frequently has IS16, pathogenicity island(s), and plasmids or genes associated with antibiotic resistance, colonization, and/or virulence. Supporting the two clades concept, we previously found a 3-10% difference between four genes from HA-clade strains vs. CA-clade strains, including 5% difference between pbp5-R of ampicillin-resistant, HA strains and pbp5-S of ampicillin-sensitive, CA strains. To further investigate the core genome of these subpopulations, we studied 100 genes from 21 E. faecium genome sequences; our analyses of concatenated sequences, SNPs, and individual genes all identified two distinct groups. With the concatenated sequence, HA-clade strains differed by 0-1% from one another while CA clade strains differed from each other by 0-1.1%, with 3.5-4.2% difference between the two clades. While many strains had a few genes that grouped in one clade with most of their genes in the other clade, one strain had 28% of its genes in the CA clade and 72% in the HA clade, consistent with the predicted role of recombination in the evolution of E. faecium. Using estimates for Escherichia coli, molecular clock calculations using sSNP analysis indicate that these two clades may have diverged ≥1 million years ago or, using the higher mutation rate for Bacillus anthracis, ∼300,000 years ago. These data confirm the existence of two clades of E. faecium and show that the differences between the HA and CA clades occur at the core genomic level and long preceded the modern antibiotic era.


Antiviral activity and mechanism of action of calanolide A against the human immunodeficiency virus type-1.
Calanolide A, recently discovered in extracts from the tropical rainforest tree, Calophyllum lanigerum, is a novel inhibitor of the human immunodeficiency virus (HIV) type 1. The compound is essentially inactive against strains of the less common HIV type 2. The present study focused on the further characterization of the selective antiviral activity and mechanism of action of calanolide A. The compound inhibited a wide variety of laboratory strains of HIV type 1, with EC50 values ranging from 0.10 to 0.17 microM. The compound similarly inhibited promonocytotropic and lymphocytotropic isolates from patients in various stages of HIV disease, as well as drug-resistant strains. Viral life-cycle studies indicated that calanolide A acted early in the infection process, similar to the known HIV reverse transcriptase (RT) inhibitor 2', 3'-dideoxycytidine. In enzyme inhibition assays, calanolide A potently and selectively inhibited recombinant HIV type 1 RT but not cellular DNA polymerases or HIV type 2 RT within the concentration range tested. Serial passage of the virus in host cells exposed to increasing concentrations of calanolide A yielded a calanolide A resistant virus strain. RT from the resistant virus was not inhibited by calanolide A but retained sensitivity to other nonnucleoside as well as nucleoside RT inhibitors, including 3'-azido-2',3'-dideoxythymidine triphosphate and nevirapine. The study substantially supports the conclusion that calanolide A represents a novel subclass of nonnucleoside RT inhibitor which merits consideration for anti-HIV drug development.


Positron emission tomography imaging of mu- and delta-opioid receptor binding in alcohol-dependent and healthy control subjects.
The endogenous opioid system plays a significant role in alcohol dependence. The goal of the current study was to investigate regional brain mu-opioid receptor (MOR) and delta-opioid receptor (DOR) availability in recently abstinent alcohol-dependent and age-matched healthy control men and women with positron emission tomography (PET) imaging. Alcohol-dependent subjects completed an inpatient protocol, which included medically supervised withdrawal and PET imaging on day 5 of abstinence. Control subjects completed PET imaging following an overnight stay. PET scans with the MOR-selective ligand [(11)C]carfentanil (CFN) were completed in 25 alcohol-dependent and 30 control subjects. Most of these same subjects (20 alcohol-dependent subjects and 18 controls) also completed PET scans with the DOR-selective ligand [(11)C]methylnaltrindole (MeNTL). Volumes of interest and statistical parametric mapping analyses indicated that alcohol-dependent subjects had significantly higher [(11)C]CFN binding potential (BP(ND) ) than healthy controls in multiple brain regions including the ventral striatum when adjusting for age, gender, and smoking status. There was an inverse relationship between [(11)C]CFN BP(ND) and craving in several brain regions in alcohol-dependent subjects. Groups did not differ in [(11)C]MeNTL BP(ND) ; however, [(11)C]MeNTL BP(ND) in caudate was positively correlated with recent alcohol drinking in alcohol-dependent subjects. Our observation of higher [(11)C]CFN BP(ND) in alcohol-dependent subjects can result from up-regulation of MOR and/or reduction in endogenous opioid peptides following long-term alcohol consumption, dependence, and/or withdrawal. Alternatively, the higher [(11)C]CFN BP(ND) in alcohol-dependent subjects may be an etiological difference that predisposed these individuals to alcohol dependence or may have developed as a result of increased exposure to childhood adversity, stress, and other environmental factors known to increase MOR. Although the direction of group differences in [(11)C]MeNTL BP(ND) was similar in many brain regions, differences did not achieve statistical significance, perhaps as a result of our limited sample size. Additional research is needed to further clarify these relationships. The finding that alcohol-dependent subjects had higher [(11)C]CFN BP(ND) is consistent with a prominent role of the MOR in alcohol dependence.


Roles of TRP14, a thioredoxin-related protein in tumor necrosis factor-alpha signaling pathways.
The possible roles of a 14-kDa human thioredoxin (Trx)-related protein (TRP14) in TNF-alpha signaling were studied in comparison with those of Trx1 by RNA interference in HeLa cells. Depletion of TRP14 augmented the TNF-alpha-induced phosphorylation and degradation of I kappa B alpha as well as the consequent activation of NF-kappa B to a greater extent than did Trx1 depletion. Deficiency of TRP14 or Trx1 enhanced TNF-alpha-induced activation of caspases and subsequent apoptosis by a similar extent. The TNF-alpha-induced activation of c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinases (MAPKs), however, was promoted by depletion of TRP14 but not by that of Trx1. Unlike Trx1, TRP14 neither associated with nor inhibited the kinase activity of apoptosis signal-regulating kinase-1 (ASK1), an upstream activator of JNK and p38. In combination with the results in the accompanying paper that TRP14 did not reduce the known substrates of Trx1, these results suggest that TRP14 modulates TNF-alpha signaling pathways, provably by interacting with proteins distinct from the targets of Trx1. In an effort to identify target proteins of TRP14, a mutant of TRP14, in which the active site cysteine (Cys(46)) was substituted with serine, was shown to form a disulfide-linked complex with LC8 cytoplasmic dynein light chain. The complex was detected in HeLa cells treated with H(2)O(2) or TNF-alpha but not in untreated cells, suggesting that LC8 cytoplasmic dynein light chain is a possible substrate of TRP14.


The crystal structure of human protein farnesyltransferase reveals the basis for inhibition by CaaX tetrapeptides and their mimetics.
Protein farnesyltransferase (FTase) catalyzes the attachment of a farnesyl lipid group to the cysteine residue located in the C-terminal tetrapeptide of many essential signal transduction proteins, including members of the Ras superfamily. Farnesylation is essential both for normal functioning of these proteins, and for the transforming activity of oncogenic mutants. Consequently FTase is an important target for anti-cancer therapeutics. Several FTase inhibitors are currently undergoing clinical trials for cancer treatment. Here, we present the crystal structure of human FTase, as well as ternary complexes with the TKCVFM hexapeptide substrate, CVFM non-substrate tetrapeptide, and L-739,750 peptidomimetic with either farnesyl diphosphate (FPP), or a nonreactive analogue. These structures reveal the structural mechanism of FTase inhibition. Some CaaX tetrapeptide inhibitors are not farnesylated, and are more effective inhibitors than farnesylated CaaX tetrapeptides. CVFM and L-739,750 are not farnesylated, because these inhibitors bind in a conformation that is distinct from the TKCVFM hexapeptide substrate. This non-substrate binding mode is stabilized by an ion pair between the peptide N terminus and the alpha-phosphate of the FPP substrate. Conformational mapping calculations reveal the basis for the sequence specificity in the third position of the CaaX motif that determines whether a tetrapeptide is a substrate or non-substrate. The presence of beta-branched amino acids in this position prevents formation of the non-substrate conformation; all other aliphatic amino acids in this position are predicted to form the non-substrate conformation, provided their N terminus is available to bind to the FPP alpha-phosphate. These results may facilitate further development of FTase inhibitors.


Structure of human ADP-ribosyl-acceptor hydrolase 3 bound to ADP-ribose reveals a conformational switch that enables specific substrate recognition.
ADP-ribosyl-acceptor hydrolase 3 (ARH3) plays important roles in regulation of poly(ADP-ribosyl)ation, a reversible post-translational modification, and in maintenance of genomic integrity. ARH3 degrades poly(ADP-ribose) to protect cells from poly(ADP-ribose)-dependent cell death, reverses serine mono(ADP-ribosyl)ation, and hydrolyzes O-acetyl-ADP-ribose, a product of Sirtuin-catalyzed histone deacetylation. ARH3 preferentially hydrolyzes O-linkages attached to the anomeric C1″ of ADP-ribose; however, how ARH3 specifically recognizes and cleaves structurally diverse substrates remains unknown. Here, structures of full-length human ARH3 bound to ADP-ribose and Mg2+, coupled with computational modeling, reveal a dramatic conformational switch from closed to open states that enables specific substrate recognition. The glutamate flap, which blocks substrate entrance to Mg2+ in the unliganded closed state, is ejected from the active site when substrate is bound. This closed-to-open transition significantly widens the substrate-binding channel and precisely positions the scissile 1″-O-linkage for cleavage while securing tightly 2″- and 3″-hydroxyls of ADP-ribose. Our collective data uncover an unprecedented structural plasticity of ARH3 that supports its specificity for the 1″-O-linkage in substrates and Mg2+-dependent catalysis.


Utility of ethological analysis to overcome locomotor confounds in elevated maze models of anxiety.
The elevated plus-maze is a commonly used model to identify putative anxiolytic and anxiogenic drugs. However, the validity of elevated plus-maze and other recently developed variants such as the elevated zero-maze has recently been questioned on the grounds that both the reference anxiolytic drug chlordiazepoxide and the psychostimulant d-amphetamine increase open arm exploration and stimulate locomotor activity. These findings suggest that measures of "anxiety" in the elevated maze cannot be adequately dissociated from simple changes in locomotor activity, which may confound the interpretation of results obtained using these models. A variety of approaches to assess drug effects on locomotor activity in the elevated maze have been suggested, including the use of total and closed arm entries, as well as supplementary tests such as exploration of the holeboard apparatus. However, all these approaches utilise the measurement of exploration in a novel environment, and as such, could potentially be influenced by either changes in anxiety or locomotor activity. Recently, it has been shown that ethological measures of "risk assessment", such as stretched-attend postures and head-dipping, are sensitive indicators of drug-effects in the elevated maze. The present study assessed the utility of ethological analysis in dissociating locomotor activity from "anxiety" by comparing the effects of d-amphetamine to those of chlordiazepoxide in the rat elevated zero-maze. The results showed that both chlordiazepoxide and d-amphetamine increase the amount of time spent in the open arms and reduce "risk assessment" without increasing line crossing or rearing. These results confirm that under certain test conditions, psychostimulants are capable of producing "false-positives" in elevated maze models, and that both traditional methods and the ethological measures used in this study fail to unequivocally dissociate drug effects on anxiety from effects on locomotor activity. Further studies using other species and different classes of psychostimulants are warranted to determine the generality of these findings.


Increased prevalence of abnormal Papanicolaou smears in urban adolescents.
To determine the secular trend in the prevalence of cervical dysplasia as evidenced by abnormal Papanicolaou smear results in sexually active adolescents. Descriptive case series. Outpatient department of an urban public hospital. All sexually active adolescents with Papanicolaou smear results recorded during 2 periods: January 1, 1982, through December 31, 1983 (n = 577), and January 1, 1992, through December 31, 1993 (n = 871). Age, ethnicity, patient care location in which the Papanicolaou smear preparation was performed, and Papanicolaou smear results were obtained for each patient. For patients with more than 1 Papanicolaou smear result during the specified period, only the first result was included in this study. Papanicolaou smear results were classified according to the Bethesda system as within normal limits, benign cellular change, atypical squamous cells of undetermined significance, lowgrade squamous intraepithelial lesion, or high-grade squamous intraepithelial lesion. Any Papanicolaou smear classified as atypical squamous cells of undetermined significance or low- or high-grade squamous intraepithelial lesion was defined as abnormal. The prevalence of abnormal Papanicolaou smear results was 2.8% in 1982 through 1983 vs 11.7% in 1992 through 1993; prevalence odds ratio was 4.7 (95% confidence interval, 2.7-8.3). The higher rate of abnormal Papanicolaou smear results in 1992 through 1993 persisted after controlling for age, patient care location, and ethnicity in a logistic regression model (adjusted prevalence odds ratio, 5.0; 95% confidence interval, 2.8-8.9). The prevalence of benign cellular change was 8.7% in 1982 through 1983 vs 20.1% in 1992 through 1993; prevalence odds ratio was 2.7 (95% confidence interval, 1.9-3.8). The prevalence of abnormal Papanicolaou smear results has significantly increased in the last decade in sexually active adolescents seen at a city hospital clinic. The results of this study emphasize the importance of routine Papanicolaou smear screening for all sexually active female adolescents.


The impact of psychiatric disorders on employment: results from a national survey (NESARC).
In this study we examine the longitudinal effects of psychiatric and substance use disorders on employment, in an employed population. The sample included respondents to the National epidemiologic survey on alcohol related conditions (NESARC) who were employed at Wave 1 (N=22,407). Bivariate and multivariable analyses were conducted examining the associations between 12-month and new onset 12-month psychiatric diagnoses at Wave 1 and employment status at Wave 2. Past year and new onset 12-month depression, 12-month bipolar, new onset 12-month drug abuse, and 12-month and new onset 12-month drug dependence were associated with a decreased odds of being employed at Wave 2. This study suggests that it would be beneficial for employers to support their employees in participating in mental health treatment. Additionally, understanding how psychiatric disorders influence employment over the life course might inform the development of preemptive interventions to treat mental health symptoms.


Pancreatic injuries in children.
Pancreatic injuries over an 11-year period were reviewed. Pedestrian motor vehicle accidents accounted for 45% of the injuries. Diagnosis was made clinically and on raised serial serum amylase levels. Eighty per cent of the patients were managed conservatively. Two patients required emergency surgery for pancreatic trauma. There were no deaths. It is concluded that a conservative approach is successful in most paediatric patients with pancreatic trauma.


Use of reconstruction rings for the management of acetabular bone loss during revision hip surgery.
Aseptic loosening remains the leading cause of failure after total hip replacement. Extensive bone loss and acetabular bone stock deficiency are frequently encountered. Simple autografting techniques are often not possible, and copious amounts of allograft may be required to reconstruct the defect. The mechanically stable environment that is a prerequisite for successful graft incorporation cannot be achieved with routine acetabular fixation techniques alone. A reconstruction ring that is secured to the surrounding pelvis provides a more rigid construct. Several types of reconstruction rings are available for the management of acetabular bone loss during revision hip surgery. Early results suggest that these devices may prove to be a useful alternative for treatment of a difficult problem.


Genomic assessment of invasion dynamics of SARS-CoV-2 Omicron BA.1.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) now arise in the context of heterogeneous human connectivity and population immunity. Through a large-scale phylodynamic analysis of 115,622 Omicron BA.1 genomes, we identified >6,000 introductions of the antigenically distinct VOC into England and analyzed their local transmission and dispersal history. We find that six of the eight largest English Omicron lineages were already transmitting when Omicron was first reported in southern Africa (22 November 2021). Multiple datasets show that importation of Omicron continued despite subsequent restrictions on travel from southern Africa as a result of export from well-connected secondary locations. Initiation and dispersal of Omicron transmission lineages in England was a two-stage process that can be explained by models of the country's human geography and hierarchical travel network. Our results enable a comparison of the processes that drive the invasion of Omicron and other VOCs across multiple spatial scales.


Pharmacometabonomics and personalized medicine.
Pharmacometabonomics is a new branch of science, first described in 2006 and defined as 'the prediction of the effects of a drug on the basis of a mathematical model of pre-dose metabolite profiles'. Pharmacometabonomics has been used to predict drug metabolism, pharmacokinetics (PK), drug safety and drug efficacy in both animals and humans and is complementary to both pharmacogenomics (PGx) and pharmacoproteomics. A literature review using the search terms pharmacometabonomics, pharmacometabolomics, pharmaco-metabonomics, pharmaco-metabolomics and the singular form of all those terms was conducted in October 2012 using PubMed and Web of Science. The review was updated until mid April 2013. Since the original description of pharmacometabonomics in 2006, 21 original publications and eight reviews have emerged, covering a broad range of applications from the prediction of PK to the prediction of drug metabolism, efficacy and safety in humans and animals. Pharmacometabonomics promises to be an important new approach to the delivery of personalized medicine to improve both drug efficacy and safety for patients in the future. Pharmacometabonomics is particularly powerful as it is sensitive to both genetic and environmental factors such as diet, drug intake and most importantly, a person's microbiome. PGx is now over 50 years old and although it has not achieved as much as some hoped, it is starting to have important applications in personalized medicine. We predict that pharmacometabonomics will be equally important in the next few decades and will be both valuable in its own right and complementary to pharmacoproteomics and PGx.


Spatial hearing and speech intelligibility in bilateral cochlear implant users.
The abilities to localize sounds and segregate speech from interfering sounds in a complex auditory environment were studied in a group of adults who use bilateral cochlear implants. The first aim of the study was to investigate the change in speech intelligibility under bilateral and unilateral listening modes as a function of bilateral experience during the first 6 mo of activation. The second aim was to look at whether localization and speech intelligibility in the presence of interfering speech are correlated and if the relationship is specific to the bilateral listening mode. The third aim was to examine whether sound lateralization (right versus left) emerges before sound localization within a hemifield. Participants were 17 native English speaking adults with postlingual deafness. All subjects received the Nucleus 24 Contour implant in both ears, either during the same surgery or during two separate surgeries that were no more than 1 mo apart. Both devices for each subject were activated at the same time, regardless of surgical approach. Speech intelligibility was measured at 3 and 6 mo after activation. Target speech was presented at 0 degrees in front. Testing was conducted in quiet and in the presence of four-talker babble. The babble was located on the right, on the left, or in front (colocated with the target). Sound localization abilities were measured at the 3 mo interval. All testing was conducted under three listening modes: left ear alone, right ear alone, or bilateral. On the speech-in-babble task, benefit of listening with two ears compared with one was greater when going from 3 to 6 mo of experience. This was evident when the target speech and interfering speech were spatially separated, but not when they were presented from the same location. At 3 mo postactivation of bilateral hearing, 82% of subjects demonstrated bilateral benefit when right/left discrimination was evaluated. In contrast, 47% of subjects showed a bilateral benefit when sound localization was evaluated, suggesting that directional hearing might emerge in a two-step process beginning with discrimination and converging on more fine-grained localization. The bilateral speech intelligibility scores were positively correlated with sound localization abilities, so that listeners who were better able to hear speech in babble were generally better able to identify source locations. During the early stages of bilateral hearing through cochlear implants in postlingually deafened adults, there is an early emergence of spatial hearing skills. Although nearly all subjects can discriminate source locations to the right versus left, less than half are able to perform the more difficult task of identifying source locations in a multispeaker array. Benefits for speech intelligibility with one versus two implants improve with time, in particular when spatial cues are used to segregate speech and competing noise. Localization and speech-in-noise abilities in this group of patients are somewhat correlated.


Effects of diamide on cyclic nucleotide levels in rat retina.
The concentrations of guanosine 3',5' monophosphate (cyclic GMP) and adenosine 3',5' monophosphate (cyclic AMP) were measured in rat retinas incubated under control conditions and in retinas incubated with diamide, a relatively specific glutathione oxidant. Retinas incubated with either glucose or pyruvate as the substrate for 30 min in the dark contained about 50 picomoles cyclic GMP/mg protein and 7 picomoles cyclic AMP/mg protein. Light-exposed control retinas contained about 70% less cyclic GMP (14.4 picomoles/mg protein) and 20% less cyclic AMP (5.4 picomoles/mg protein). Addition of diamide to the incubation medium at concentrations between 0.1 and 1.0 mM produced a concentration-dependent decrease in the dark level of cyclic GMP, but did not affect its concentration in the light or the concentration of cyclic AMP in dark-maintained and light-exposed retinas. The major effect of diamide was to reduce the normal dark-light difference in the concentration of cyclic GMP. Oxidizing conditions thus appear to alter selectively the light-sensitive compartment of retinal cyclic GMP.


How structural and physicochemical determinants shape sequence constraints in a functional enzyme.
The need for interfacing structural biology and biophysics to molecular evolution is being increasingly recognized. One part of the big problem is to understand how physics and chemistry shape the sequence space available to functional proteins, while satisfying the needs of biology. Here we present a quantitative, structure-based analysis of a high-resolution map describing the tolerance to all substitutions in all positions of a functional enzyme, namely a TEM lactamase previously studied through deep sequencing of mutants growing in competition experiments with selection against ampicillin. Substitutions are rarely observed within 7 Å of the active site, a stringency that is relaxed slowly and extends up to 15-20 Å, with buried residues being especially sensitive. Substitution patterns in over one third of the residues can be quantitatively modeled by monotonic dependencies on amino acid descriptors and predictions of changes in folding stability. Amino acid volume and steric hindrance shape constraints on the protein core; hydrophobicity and solubility shape constraints on hydrophobic clusters underneath the surface, and on salt bridges and polar networks at the protein surface together with charge and hydrogen bonding capacity. Amino acid solubility, flexibility and conformational descriptors also provide additional constraints at many locations. These findings provide fundamental insights into the chemistry underlying protein evolution and design, by quantitating links between sequence and different protein traits, illuminating subtle and unexpected sequence-trait relationships and pinpointing what traits are sacrificed upon gain-of-function mutation.


Specific coping strategies of Africans during urbanization: comparing cardiovascular responses and perception of health data.
Specific coping mechanisms of Africans during urbanization were compared to and correlated with cardiovascular responses and perception of health data. Subjects included men (N=286) and women (N=360). The COPE questionnaire classified subjects as active (AC) or passive (PC) copers and the General Health Questionnaire measured subjective perception of health. The Finapres recorded blood pressure continuously before and during application of a handgrip test. Analyses adjusting for age, body mass index and resting cardiovascular data revealed that AC rural subjects showed predominantly cardiac responses and PC rural subjects predominantly vascular responses. All urbanized African men and women showed higher resting blood pressure, vascular responsiveness and hypertension prevalences than their rural counterparts. All rural AC subjects, especially women, and all urban PC subjects, especially men, reported a poorer perception of health. In conclusion, subjects with a PC style showed a predominantly vascular response in rural and urban areas whereas subjects with an AC style seem to shift from a predominant cardiac output response to a predominant vascular resistance response when moving from a rural to an urban area.


Progression of coronary artery calcification and thoracic aorta calcification in kidney transplant recipients.
Vascular calcification independently predicts cardiovascular disease, the major cause of death in kidney transplant recipients (KTRs). Longitudinal studies of vascular calcification in KTRs are few and small and have short follow-up. We assessed the evolution of coronary artery (CAC) and thoracic aorta calcification and their determinants in a cohort of prevalent KTRs. Longitudinal. The Agatston score of coronary arteries and thoracic aorta was measured by 16-slice spiral computed tomography in 281 KTRs. Demographic, clinical, and biochemical parameters were recorded simultaneously. The Agatston score was measured again 3.5 or more years later. Repeated analyzable computed tomographic scans were available for 197 (70%) KTRs after 4.40 ± 0.28 years; they were not available for the rest of patients because of death (n = 40), atrial fibrillation (n = 1), other arrhythmias (n = 4), refusal (n = 35), or technical problems precluding confident calcium scoring (n = 4). CAC and aorta calcification scores increased significantly (by a median of 11% and 4% per year, respectively) during follow-up. By multivariable linear regression, higher baseline CAC score, history of cardiovascular event, use of a statin, and lower 25-hydroxyvitamin D(3) level were independent determinants of CAC progression. Independent determinants of aorta calcification progression were higher baseline aorta calcification score, higher pulse pressure, use of a statin, older age, higher serum phosphate level, use of aspirin, and male sex. Significant regression of CAC or aorta calcification was not observed in this cohort. Cohort of prevalent KTRs with potential survival bias; few patients with diabetes and nonwhites, limiting the generalizability of results. In contrast to previous small short-term studies, we show that vascular calcification progression is substantial within 4 years in prevalent KTRs and is associated with several traditional and nontraditional cardiovascular risk factors, some of which are modifiable.


Biodiverse planting for carbon and biodiversity on indigenous land.
Carbon offset mechanisms have been established to mitigate climate change through changes in land management. Regulatory frameworks enable landowners and managers to generate saleable carbon credits on domestic and international markets. Identifying and managing the associated co-benefits and dis-benefits involved in the adoption of carbon offset projects is important for the projects to contribute to the broader goal of sustainable development and the provision of benefits to the local communities. So far it has been unclear how Indigenous communities can benefit from such initiatives. We provide a spatial analysis of the carbon and biodiversity potential of one offset method, planting biodiverse native vegetation, on Indigenous land across Australia. We discover significant potential for opportunities for Indigenous communities to achieve carbon sequestration and biodiversity goals through biodiverse plantings, largely in southern and eastern Australia, but the economic feasibility of these projects depend on carbon market assumptions. Our national scale cost-effectiveness analysis is critical to enable Indigenous communities to maximise the benefits available to them through participation in carbon offset schemes.


The Prevalence of Congenital Hand and Upper Extremity Anomalies Based Upon the New York Congenital Malformations Registry.
There have been few publications regarding the prevalence of congenital upper extremity anomalies and no recent reports from the United States. The purpose of this investigation was to examine the prevalence of congenital upper extremity anomalies in the total birth population of New York State over a 19-year period utilizing the New York Congenital Malformations Registry (NYCMR) database. The NYCMR includes children with at least 1 birth anomaly diagnosed by 2 years of age and listed by diagnosis code. We scrutinized these codes for specific upper extremity anomalies, including polydactyly, syndactyly, reduction defects, clubhand malformations, and syndromes with upper limb anomalies. We included children born between 1992 and 2010. There were a total of 4,883,072 live births in New York State during the study period. The overall prevalence of congenital upper extremity anomalies was 27.2 cases per 10,000 live births. Polydactyly was most common with 12,418 cases and a prevalence rate of 23.4 per 10,000 live births. The next most common anomalies included syndactyly with 627 cases affecting the hands (1498 total) and reduction defects (1111 cases). Specific syndromes were quite rare and were noted in a total of 215 live births. The prevalence of anomalies was higher in New York City compared with New York State populations at 33.0 and 21.9 per 10,000 live births, respectively. The NYCMR data demonstrate that congenital upper extremity anomalies are more common than previously reported. This is in large part due to the high prevalence of polydactyly. Although registries are imperfect, such data are helpful in monitoring prevalence rates over time, identifying potential causes or associations, and guiding health care planning and future research. Level I-diagnostic.


Testing the reward prediction error hypothesis with an axiomatic model.
Neuroimaging studies typically identify neural activity correlated with the predictions of highly parameterized models, like the many reward prediction error (RPE) models used to study reinforcement learning. Identified brain areas might encode RPEs or, alternatively, only have activity correlated with RPE model predictions. Here, we use an alternate axiomatic approach rooted in economic theory to formally test the entire class of RPE models on neural data. We show that measurements of human neural activity from the striatum, medial prefrontal cortex, amygdala, and posterior cingulate cortex satisfy necessary and sufficient conditions for the entire class of RPE models. However, activity measured from the anterior insula falsifies the axiomatic model, and therefore no RPE model can account for measured activity. Further analysis suggests the anterior insula might instead encode something related to the salience of an outcome. As cognitive neuroscience matures and models proliferate, formal approaches of this kind that assess entire model classes rather than specific model exemplars may take on increased significance.


Is IDH status the only factor predicting prognosis in newly diagnosed anaplastic glioma patients? Outcome evaluation and prognostic factor analysis in a single-institution large series.
Anaplastic gliomas (AGs) are an extremely heterogeneous group of primary brain tumors. More recently, new discoveries have indicated that isocitrate dehydrogenase (IDH) mutation status is the most important parameter predicting survival. The primary aim of the present analysis was to identify prognostic factors, other than IDH status, that eventually impact survival. Patients with available clinical, imaging, and molecular profile data who were amenable to resection were evaluated. The extent of resection (EOR) was defined as gross-total resection (GTR), near-total resection (NTR), subtotal resection (STR), or partial resection (PR). Residual tumor volume (RTV) was quantified. Following surgery, patients received adjuvant chemotherapy alone, radiation therapy plus concomitant and adjuvant temozolomide (TMZ), or sequential radio-chemotherapy. Clinical outcome was evaluated by neurological examination and MRI 1 month after treatment and every 4 months thereafter. Tumor progression was defined according to the Response Assessment in Neuro-Oncology (RANO) working group. Among 402 patients referred to the authors' institution for AG, 142 were included in the present analysis. Eighty-eight (62%) were male and 54 (38%) were female, with a median age of 43 years (range 19-70 years). At admission, most patients had a Karnofsky Performance Scale score of 90-100 (84.5%) and were symptomatic (93.7%). Forty-eight (33.8%) patients had newly diagnosed anaplastic oligodendrogliomas (AOs), and 94 (66.2%) had anaplastic astrocytomas (AAs). Most of them had mutant IDH tumors (67.6%) and methylated O 6-methylguanine-DNA-methyltransferase (MGMT) promoter status (71.8%). GTR was performed in more than half of the patients (56.3%). RTV was detected in 83 (58.5%) patients. Following surgery, 72 (50.7%) patients received radiotherapy with concomitant and adjuvant TMZ, 48 (33.8%) received sequential radio-chemotherapy, and 22 (15.5%) received adjuvant chemotherapy alone. The median follow-up time was 40 months (range 16-146 months). The median PFS time and the 1-, 3-, and 5-year PFS rates were 35 months (95% CI 27-76) and 78.9% ± 3.4%, 49.7% ± 4.6%, and 42.7% ± 5.4%, respectively. The median OS time and the 1-, 3-, and 5-year OS rates were 91 months (95% CI 66-95) and 90.1% ± 2.5%, 70.9% ± 4.2%, and 61.8% ± 4.9%, respectively. Prognostic factors predicting survival other than molecular profile were the EOR and the RTV (p < 0.0001). Sequential radio-chemotherapy was the more effective treatment administered. In addition to IDH status, EOR and the RTV have proved to statistically impact survival. The pivotal role of adjuvant radiotherapy has been recorded in all AG patients, regardless of tumor features.


Risk pathways for gonorrhea acquisition in sex workers: can we distinguish confounding from an exposure effect using a priori hypotheses?
The population distribution of sexually transmitted infections (STIs) varies broadly across settings. Although there have been many studies aiming to define subgroups at risk of infection that should be a target for prevention interventions by identifying risk factors, questions remain about how these risk factors interact, how their effects jointly influence the risk of acquisition, and their differential importance across populations. Theoretical frameworks describing the interrelationships among risk determinants are useful in directing both the design and analysis of research studies and interventions. In this article, we developed such a framework from a review looking at determinants of risk for STI acquisition, using gonorrhea as an index infection. We also propose an analysis strategy to interpret the associations found to be significant in uniform analyses of observational data. The framework and the hierarchical analysis strategy are of particular relevance in the understanding of risk formation and might prove useful in identifying determinants that are part of the causal pathway and therefore amenable to prevention strategies across populations.


Using the Active Movement Extent Discrimination Apparatus to Test Individual Proprioception Acuity: Implications for Test Design.
The Active Movement Extent Discrimination Apparatus (AMEDA) has been used for measuring proprioception at various joints in the body for more than two decades. The utility of this instrument for discriminating groups has been reported in terms of an area under the curve (AUC) derived from an absolute identification test. This metric has supported statistically significant group differences, but it is not clear whether the AMEDA's testing protocol is suitable for measuring individual proprioception acuity changes. This study aimed to test the reliability, variance and absolute AUC scores obtained with the AMEDA with reference to other studies that have tested absolute identification acuity in other domains and the theoretical underpinnings of the testing protocol. We re-analyzed raw data from a 2013 study involving 65 people, most of whom were tested three times over two separate sessions on the ankle AMEDA by now assessing the accuracy of individual responses and calculating the sensitivity index, d', in addition to the AUC. To assess reliability, we calculated the intraclass correlation coefficient (ICC) and standard error of measurement (SEM) for those who completed all three tests. Fewer than 50% of presented stimuli were accurately identified and relatively poor discrimination was achieved between adjacent stimuli (in only one case was the median d' value greater than 1). The ICC of AUC scores across the three tests was poor (0.47). The SEM was 0.04, while 90% of participants' AUC scores fell between 0.59 and 0.76. The variation in performance at the individual level was substantial, producing a large SEM relative to the population spread of scores. We considered potential theoretical factors that may be affecting these results and concluded that an alternative approach will be needed in order for the apparatus to be used to explore individual proprioceptive performance.


Dietary intervention among breast cancer survivors increased adherence to a Mediterranean-style, anti-inflammatory dietary pattern: the Rx for Better Breast Health Randomized Controlled Trial.
The goal of this education and culinary-based dietary intervention was to increase adherence to a Mediterranean-style, anti-inflammatory dietary pattern in breast cancer survivors (BCS) by promoting the consumption of anti-inflammatory foods, herbs, and spices. Overweight and obese, early-stage, BCS were randomized to the Intervention (n = 76) or Control (n = 77). The 6-month intervention included monthly nutrition and cooking workshops, Motivational Interviewing telephone calls, and individualized newsletters. Control participants received monthly informational brochures and no navigational services. Dietary intakes were collected via questionnaire and 3-day food records at baseline and 6 months. One hundred twenty-five BCS (n = 60 I; n = 65 C) completed post-testing (81.7%) and were included in analyses. Adherence to Mediterranean diet guidelines significantly increased in the intervention group, but not in the control group (+ 22.5% vs. + 2.7%, P < 0.001). Upon further analysis of adherence to individual dietary guidelines, the intervention group significantly improved adherence to only three guidelines: consuming ≥ 3 servings of fish or shellfish/week, reducing red meat intake to < 1 serving/day, and limiting consumption of commercial sweets and baked goods to < 3 times/week. The intervention arm increased the use of spices and herbs compared to control (+ 146.2% vs. +33.3%, P < 0.001), including significantly more frequent consumption of cinnamon, turmeric, garlic, ginger, black pepper, and rosemary. An education and culinary-based intervention in BCS successfully increased adherence to a more Mediterranean-style, anti-inflammatory dietary pattern by increasing the consumption of anti-inflammatory foods, spices, and herbs and decreasing the consumption of pro-inflammatory foods.