Clinico-epidemiological profile of burn patients admitted in a tertiary care hospital in coastal South India.
Every year a substantial proportion of deaths in India occur due to burn injuries. Prolonged morbidity as well as temporary and permanent disability due to burns results in a heavy economic loss. The etiological factors of burn injuries vary considerably in different communities and regions and hence the need for detailed epidemiological studies to understand the problem status in different regions. This study was aimed to study the sociodemographic profile of burn patients and to evaluate the causes, manner, and place of occurrence of burns injuries along with its outcome. A registry-based retrospective study was conducted at a tertiary care hospital in coastal South India, and the medical records of all the patients admitted to the burns centre during the year 2009 were reviewed. The data were analyzed using SPSS version 11.5. A total of 101 burn patients were admitted during the study period. The burn patients were aged between 4 months and 80 years with a mean age of 32.11 (± 3.46) years. The overall male to female ratio was 0.83:1. Majority of the patients were Hindus and were married. Flame burns were the most common etiology for sustaining burns (82.2%). Most of the burn injuries were sustained at home (n = 81, 80.2%), and the manner was designated as accidental in 79.2% of the cases. The TBSA involvement in burns ranged from 5 to 100% and the mean TBSA was found to be 45.8 ± 24.7%. A higher TBSA involvement is associated with an increased risk of mortality and this association between TBSA and mortality was found to be statistically significant (P < .05). Mortality rate in our study was 40.9%. Septicemia (n = 24, 63.2%) was the most common cause of death followed by shock (n = 12, 31.6%). Higher mortality is found to be associated with female sex, suicides, and flame burns. This study identifies the epidemiological and clinical features associated with burn injuries in coastal South India. Majority of the burn victims in our study were married females of younger age group. Although the manner of sustaining burns was mostly accidental, females were proportionately more commonly the victims of suicides and homicides than males. Injuries and deaths due to burns are preventable, provided a community-specific preventive program is implemented with a strong educational component.


Effects of social networks on interventions to change conservation behavior.
Social networks are critical to the success of behavioral interventions in conservation because network processes such as information flows and social influence can enable behavior change to spread beyond a targeted group. We investigated these mechanisms in the context of a social marketing campaign to promote a wildlife poisoning hotline in Cambodia. With questionnaire surveys we measured a social network and knowledge and constructs from the theory of planned behavior at 3 points over 6 months. The intervention initially targeted ∼11% (of 365) of the village, but after 6 months ∼40% of the population was knowledgeable about the campaign. The likelihood of being knowledgeable nearly doubled with each additional knowledgeable household member. In the short term, there was also a modest, but widespread improvement in proconservation behavioral intentions, but this did not persist after 6 months. Estimates from stochastic actor-oriented models suggested that the influences of social peers, rather than knowledge, were driving changes in intention and contributed to the failure to change behavioral intention in the long term, despite lasting changes in attitudes and perceived norms. Our results point to the importance of accounting for the interaction between networks and behavior when designing conservation interventions.


Risks for opioid abuse and dependence among recipients of chronic opioid therapy: results from the TROUP study.
To estimate the prevalence of and risk factors for opioid abuse/dependence in long-term users of opioids for chronic pain, including risk factors for opioid abuse/dependence that can potentially be modified to decrease the likelihood of opioid abuse/dependence, and non-modifiable risk factors for opioid abuse/dependence that may be useful for risk stratification when considering prescribing opioids. We used claims data from two disparate populations, one national, commercially insured population (HealthCore) and one state-based, publicly insured (Arkansas Medicaid). Among users of chronic opioid therapy, we regressed claims-based diagnoses of opioid abuse/dependence on patient characteristics, including physical health, mental health and substance abuse diagnoses, sociodemographic factors, and pharmacological risk factors. Among users of chronic opioid therapy, 3% of both the HealthCore and Arkansas Medicaid samples had a claims-based opioid abuse/dependence diagnosis. There was a strong inverse relationship between age and a diagnosis of opioid abuse/dependence. Mental health and substance use disorders were associated with an increased risk of opioid abuse/dependence. Effects of substance use disorders were especially strong, although mental health disorders were more common. Concerning opioid exposure; lower days supply, lower average doses, and use of Schedule III-IV opioids only, were all associated with lower likelihood of a diagnosis of opioid abuse/dependence. Opioid abuse and dependence are diagnosed in a small minority of patients receiving chronic opioid therapy, but this may under-estimate actual misuse. Characteristics of the patients and of the opioid therapy itself are associated with the risk of abuse and dependence.


Ankle/hindfoot arthrodesis in rheumatoid arthritis improves kinematics and kinetics of the knee and hip: a prospective gait analysis study.
To evaluate the effects of ankle/hindfoot arthrodesis in rheumatoid arthritis (RA) patients on gait pattern of the knee and hip. In this prospective follow-up study, 14 RA patients scheduled for ankle/hindfoot arthrodesis (talo-calcaneal, talo-navicular, calcaneo-cuboid and/or talo-crural joints) and 14 age- and sex-matched healthy controls were included. Three-dimensional gait analyses of joint angles, moments and work were performed at the index operation and after 13 months of follow-up. Each patient underwent clinical assessments of pain while walking, overall evaluation of disease activity, Health Related Quality of Life Questionnaire (EQ-5D), activity limitations, maximum walking distance, difficulty with walking surface and gait abnormality. For comparisons of pre- vs post-operative conditions, Wilcoxon's matched pairs test and Friedman ANOVA by rank test were used. At follow-up after ankle/hindfoot fusion surgery, RA patients demonstrated a statistically significant improvement in mean range of joint motions, moments and work in the overlying joints such as the knee and hip. Moreover, there was significantly less pain, disease activity, activity limitation, difficulty with walking surface and gait abnormality. EQ-5D and maximum walking distance were also significantly improved at follow-up. Our results demonstrate that ankle/hindfoot arthrodesis in RA is an effective intervention to reduce pain and to improve Health Related Quality of Life and functional ability. Moreover, the overlying leg joints experience an improvement in joint motion, muscle-generated joint moments and work during walking. Three-dimensional gait analysis may assist future investigations of the effects of orthopaedic surgery on functional mobility in RA to prevent irreversible disablement.


Analysis of the discriminative inhibition of mammalian digestive lipases by 3-phenyl substituted 1,3,4-oxadiazol-2(3H)-ones.
We report here the reactivity and selectivity of three 5-Methoxy-N-3-Phenyl substituted-1,3,4-Oxadiazol-2(3H)-ones (MPOX, as well as meta and para-PhenoxyPhenyl derivatives, i.e.MmPPOX and MpPPOX) with respect to the inhibition of mammalian digestive lipases: dog gastric lipase (DGL), human (HPL) and porcine (PPL) pancreatic lipases, human (HPLRP2) and guinea pig (GPLRP2) pancreatic lipase-related proteins 2, human pancreatic carboxyl ester hydrolase (hCEH), and porcine pancreatic extracts (PPE). All three oxadiazolones displayed similar inhibitory activities on DGL, PLRP2s and hCEH than the FDA-approved anti-obesity drug Orlistat towards the same enzymes. These compounds appeared however to be discriminative of HPL (poorly inhibited) and PPL (fully inhibited). The inhibitory activities obtained experimentally in vitro were further rationalized using in silico molecular docking. In the case of DGL, we demonstrated that the phenoxy group plays a key role in specific molecular interactions within the lipase's active site. The absence of this group in the case of MPOX, as well as its connectivity to the neighbouring aromatic ring in the case of MmPPOX and MpPPOX, strongly impacts the inhibitory efficiency of these oxadiazolones and leads to a significant gain in selectivity towards the lipases tested. The powerful inhibition of PPL, DGL, PLRP2s, hCEH and to a lesser extend HPL, suggests that oxadiazolone derivatives could also provide useful leads for the development of novel and more discriminative inhibitors of digestive lipases. These inhibitors could be used for a better understanding of individual lipase function as well as for drug development aiming at the regulation of the whole gastrointestinal lipolysis process.


Distractor inhibition is more effective at a central than at a peripheral location.
The "distractor eccentricity effect" refers to the finding of reduced interference from an incompatible distractor at a central relative to a peripheral location (Chen, 2008). The present study examines the mechanism that underlies the distractor eccentricity effect, and relates it to the inattentional blindness explored by Mack and Rock (1998), which was also more marked at a foveal than at a parafoveal location. The results suggest that these two visual phenomena may reflect the same underlying mechanism--a gradient of increasing attentional suppression from the periphery to the center.


An exploration of compassion focused therapy following acquired brain injury.
People with acquired brain injuries (ABI) frequently experience psychological difficulties such as anxiety and depression, which may be underpinned and maintained by high self-criticism and shame alongside an inability to self-soothe. Compassionate focused therapy (CFT) was developed to address shame and self-criticism and foster the ability to self-soothe. This is a naturalistic evaluation with the aim of assessing the feasibility, safety, and potential value of CFT for ABI patients with emotional difficulties receiving neuropsychological rehabilitation. This study employed a mixed methods design combining self-report measures and qualitative interviews. Twelve patients received a combination of CFT group and individual intervention. Self-report measures of self-criticism, self-reassurance, and symptoms of anxiety and depression were collected pre and post programme and analysed using Wilcoxon signed rank test (N=12; five female, seven males). Follow-up data were analysed in the same manner (N=9). Interviews were conducted with six patients and analysed using interpretative phenomenological analysis. CFT was associated with significant reductions in measures of self-criticism, anxiety, and depression and an increase in the ability to reassure the self. No adverse effects were reported. Three superordinate themes emerged from the interviews: psychological difficulties; developing trust and finding safeness; and a new approach. This study suggests that CFT is well accepted in ABI survivors within the context of neuropsychological rehabilitation. Furthermore, the results indicate that further research into CFT for psychological problems after ABI is needed and that there may be key aspects, which are specific to CFT intervention, which could reduce psychological difficulties after ABI. CFT appears to be a feasible intervention for psychological problems after ABI. CFT was associated with a reduction in symptoms of anxiety and depression and associated self-criticism, as well as enhanced self-reassurance for ABI survivors. These ABI survivors reported that CFT provided them with tools to manage continued psychological difficulties.


Compaction bone-grafting in prosthetic shoulder arthroplasty.
Compaction bone-grafting has been suggested as a means of improving the stability of the humeral component in shoulder arthroplasty, but the clinical and radiographic results of the procedure have not been reported in the literature, to our knowledge. To address this deficit, we report on a series of shoulder arthroplasties performed with compaction bone-grafting to secure humeral component fixation. These prostheses were implanted in shoulders demonstrating a suboptimal interference fit of the humeral component. Fifty-eight shoulders in fifty-three patients were treated with prosthetic shoulder arthroplasty that included compaction bone-grafting. Clinical assessments were performed at regular intervals with use of visual analog scales for pain, shoulder comfort and function, and overall quality of life, and with use of patient self-assessments including the American Shoulder and Elbow Surgeons Score and the validated Simple Shoulder Test. A detailed radiographic analysis was performed by three raters to determine whether radiolucent lines were present immediately postoperatively and at a later follow-up interval. The humeral tilt angle was determined by measuring the angle between the humeral axis and the component. Subsidence was also evaluated. The mean of the raters' measurements was used in the analysis. The mean duration of follow-up was sixty-nine months (range, twenty-six to 148 months). No loose stems were observed, and no humeral component was revised. At the time of follow-up, there was significant improvement in the Simple Shoulder Test scores and all visual analog scores (p < 0.0001 in each instance). Thirty-four stems had no radiolucent line at the time of follow-up, and the mean maximum thickness of the lucent lines was 0.21 mm in the entire group of fifty-eight shoulders. Most lucent lines occurred near the distal stem tip. The mean tilt of the valgus and varus humeral components was 2.2 degrees and 2.6 degrees , respectively, on the immediate postoperative radiographs. No humeral component shifted from varus to valgus or vice versa. The duration of follow-up was not correlated with the maximum thickness of the humeral component lucency, and the presence or absence of a prosthetic glenoid was also unrelated to the maximum thickness of the lucency. Compaction bone-grafting in shoulder arthroplasty can yield stable and durable fixation of the humeral component, as seen clinically and radiographically, without use of cement. Our findings provide evidence that compaction bone-grafting in shoulder arthroplasty is an option to ensure intermediate-term fixation (at a mean of five years) of humeral components that have a suboptimal fit.


Arrayed CRISPR Screening Identifies Novel Targets That Enhance the Productive Delivery of mRNA by MC3-Based Lipid Nanoparticles.
Modified messenger RNAs (mRNAs) hold great potential as therapeutics by using the body's own processes for protein production. However, a key challenge is efficient delivery of therapeutic mRNA to the cell cytosol and productive protein translation. Lipid nanoparticles (LNPs) are the most clinically advanced system for nucleic acid delivery; however, a relatively narrow therapeutic index makes them unsuitable for many therapeutic applications. A key obstacle to the development of more potent LNPs is a limited mechanistic understanding of the interaction of LNPs with cells. To address this gap, we performed an arrayed CRISPR screen to identify novel pathways important for the functional delivery of MC3 lipid-based LNP encapsulated mRNA (LNP-mRNA). Here, we have developed and validated a robust, high-throughput screening-friendly phenotypic assay to identify novel targets that modulate productive LNP-mRNA delivery. We screened the druggable genome (7795 genes) and validated 44 genes that either increased (37 genes) or inhibited (14 genes) the productive delivery of LNP-mRNA. Many of these genes clustered into families involved with host cell transcription, protein ubiquitination, and intracellular trafficking. We show that both UDP-glucose ceramide glucosyltransferase and V-type proton ATPase can significantly modulate the productive delivery of LNP-mRNA, increasing and decreasing, respectively, with both genetic perturbation and by small-molecule inhibition. Taken together, these findings shed new light into the molecular machinery regulating the delivery of LNPs into cells and improve our mechanistic understanding of the cellular processes modulating the interaction of LNPs with cells.


[Regulatory peptides and psychomotor development in infants].
Regulatory peptides (RP) are an important homeostatic factor. The maternal organism and placenta are substantial sources of RP for fetus during the prenatal period. Not only endogenous, but also exogenous RP play an important role during early postnatal period. In this study, the concentration of exogenous RP (casomorphins-7) and the activity of peptidases (enkephalinases) in the serum of breastfed and bottle-fed infants were estimated. Possible interrelation between these two parameters and the psychomotor development (PMD) of infants were evaluated. Using specially developed RIA, the investigators estimated the presence of human and bovine casomorphins immunoreactivity (CMir) in the serum of breastfed and bottle-fed infants. A distinct correlation of CMir with PMD was demonstrated. The activity of RP-degrading serum enzymes also correlated with PMD level. The role of endo- and exogenous peptides in normal PMD process and in the pathogenesis of early child autism is discussed in the article.


Breakpoints around the HOXD cluster result in various limb malformations.
Characterisation of disease associated balanced chromosome rearrangements is a promising starting point in the search for candidate genes and regulatory elements. We have identified and investigated three patients with limb abnormalities and breakpoints involving chromosome 2q31. Patient 1 with severe brachydactyly and syndactyly, mental retardation, hypoplasia of the cerebellum, scoliosis, and ectopic anus, carries a balanced t(2;10)(q31.1;q26.3) translocation. Patient 2, with translocation t(2;10)(q31.1;q23.33), has aplasia of the ulna, shortening of the radius, finger anomalies, and scoliosis. Patient 3 carries a pericentric inversion of chromosome 2, inv(2)(p15q31). Her phenotype is characterised by bilateral aplasia of the fibula and the radius, bilateral hypoplasia of the ulna, unossified carpal bones, and hypoplasia and dislocation of both tibiae. By fluorescence in situ hybridisation, we have mapped the breakpoints to intervals of approximately 170 kb or less. None of the three 2q31 breakpoints, which all mapped close to the HOXD cluster, disrupted any known genes. Hoxd gene expression in the mouse is regulated by cis-acting DNA elements acting over distances of several hundred kilobases. Moreover, Hoxd genes play an established role in bone development. It is therefore very likely that the three rearrangements disturb normal HOXD gene regulation by position effects.


First-time traumatic patellar dislocation: a systematic review.
Acute patellar dislocations can result in patellar instability, pain, recurrent dislocations, decreased level of sporting activity, and patellofemoral arthritis. The initial management of a first-time traumatic patellar dislocation is controversial with no evidence-based consensus to guide decision making. Most first-time traumatic patellar dislocations have been traditionally treated nonoperatively; however, there has been a recent trend in initial surgical management. We performed a systematic review of Level I-IV studies to make evidence-based medicine recommendations on how a clinician should approach the diagnosis and treatment of a first-time traumatic dislocation. More specifically we answer the primary question of when initial treatment should consist of operative versus closed management. Based on the review of 70 articles looking at study design, mean followup, subjective and validated outcome measures, redislocation rates, and long-term symptoms, we recommend initial nonoperative management of a first-time traumatic dislocation except in several specific circumstances. These include the presence of an osteochondral fracture, substantial disruption of the medial patellar stabilizers, a laterally subluxated patella with normal alignment of the contralateral knee, or a second dislocation, or in patients not improving with appropriate rehabilitation.


Cytochrome P450 in neurological disease.
Advances in a multitude of disciplines support an emerging role for cytochrome P450 enzymes and their metabolic substrates and end-products in the pathogenesis and treatment of central nervous system disorders, including acute cerebrovascular injury, such as stroke, chronic neurodegenerative disease, such as Alzheimer's and Parkinson's disease, as well as epilepsy, multiple sclerosis and psychiatric disorders, including anxiety and depression. The neural tissue contains its own unique set of P450 genes that are regulated in a manner that is distinct from their molecular regulation in peripheral tissue. Furthermore, brain P450s catalyze the formation of important brain signaling molecules, such as neurosteroids and eicosanoids, and metabolize substrates as diverse as vitamins A and D, cholesterol, bile acids, as well as centrally acting drugs, anesthetics and environmental neurotoxins. These unique characteristics allow this family of proteins and their metabolites to perform such vital functions in brain as neurotrophic support, neuroprotection, control of cerebral blood flow, temperature control, neuropeptide release, maintenance of brain cholesterol homoeostasis, elimination of retinoids from CNS, regulation of neurotransmitter levels and other functions important in brain physiology, development and disease.


Disruption of adolescents' circadian clock: The vicious circle of media use, exposure to light at night, sleep loss and risk behaviors.
Although sleep is a key element in adolescent development, teens are spending increasing amounts of time online with health risks related to excessive use of electronic media (computers, smartphones, tablets, consoles…) negatively associated with daytime functioning and sleep outcomes. Adolescent sleep becomes irregular, shortened and delayed in relation with later sleep onset and early waking time due to early school starting times on weekdays which results in rhythm desynchronization and sleep loss. In addition, exposure of adolescents to the numerous electronic devices prior to bedtime has become a great concern because LEDs emit much more blue light than white incandescent bulbs and compact fluorescent bulbs and have therefore a greater impact on the biological clock. A large number of adolescents move to evening chronotype and experience a misalignment between biological and social rhythms which, added to sleep loss, results in e.g. fatigue, daytime sleepiness, behavioral problems and poor academic achievement. This paper on adolescent circadian disruption will review the sensitivity of adolescents to light including LEDs with the effects on the circadian system, the crosstalk between the clock and the pineal gland, the role of melatonin, and the behavior of some adolescents(media use, alcohol consumption, binge drinking, smoking habits, stimulant use…). Lastly, some practical recommendations and perspectives are put forward. The permanent social jet lag resulting in clock misalignment experienced by a number of adolescents should be considered as a matter of public health.


LPA Variants Are Associated With Residual Cardiovascular Risk in Patients Receiving Statins.
Coronary heart disease (CHD) is a leading cause of death globally. Although therapy with statins decreases circulating levels of low-density lipoprotein cholesterol and the incidence of CHD, additional events occur despite statin therapy in some individuals. The genetic determinants of this residual cardiovascular risk remain unknown. We performed a 2-stage genome-wide association study of CHD events during statin therapy. We first identified 3099 cases who experienced CHD events (defined as acute myocardial infarction or the need for coronary revascularization) during statin therapy and 7681 controls without CHD events during comparable intensity and duration of statin therapy from 4 sites in the Electronic Medical Records and Genomics Network. We then sought replication of candidate variants in another 160 cases and 1112 controls from a fifth Electronic Medical Records and Genomics site, which joined the network after the initial genome-wide association study. Finally, we performed a phenome-wide association study for other traits linked to the most significant locus. The meta-analysis identified 7 single nucleotide polymorphisms at a genome-wide level of significance within the LPA/PLG locus associated with CHD events on statin treatment. The most significant association was for an intronic single nucleotide polymorphism within LPA/PLG (rs10455872; minor allele frequency, 0.069; odds ratio, 1.58; 95% confidence interval, 1.35-1.86; P=2.6×10-10). In the replication cohort, rs10455872 was also associated with CHD events (odds ratio, 1.71; 95% confidence interval, 1.14-2.57; P=0.009). The association of this single nucleotide polymorphism with CHD events was independent of statin-induced change in low-density lipoprotein cholesterol (odds ratio, 1.62; 95% confidence interval, 1.17-2.24; P=0.004) and persisted in individuals with low-density lipoprotein cholesterol ≤70 mg/dL (odds ratio, 2.43; 95% confidence interval, 1.18-4.75; P=0.015). A phenome-wide association study supported the effect of this region on coronary heart disease and did not identify noncardiovascular phenotypes. Genetic variations at the LPA locus are associated with CHD events during statin therapy independently of the extent of low-density lipoprotein cholesterol lowering. This finding provides support for exploring strategies targeting circulating concentrations of lipoprotein(a) to reduce CHD events in patients receiving statins.


Absence of gender differences in clinical outcomes in patients with cardiogenic shock complicating acute myocardial infarction. A report from the SHOCK Trial Registry.
The aim of this study was to assess the impact of gender on clinical course and in-hospital mortality in patients with cardiogenic shock (CS) complicating acute myocardial infarction (AMI). Previous studies have demonstrated higher mortality for women compared with men with ST elevation myocardial infarctions and higher rates of CS after AMI. The influence of gender and its interaction with various treatment strategies on clinical outcomes once CS develops is unclear. Using the SHould we emergently revascularize Occluded Coronaries for cardiogenic shocK? (SHOCK) Registry database of 1,190 patients with suspected CS in the setting of AMI, we examined shock etiologies by gender. Among the 884 patients with predominant left ventricular (LV) failure, we compared the patient demographics, angiographic and hemodynamic findings, treatment approaches as well as the clinical outcomes of women versus men. This study had a 97% power to detect a 10% absolute difference in mortality by gender. Left ventricular failure was the most frequent cause of CS for both gender groups. Women in the SHOCK Registry had a significantly higher incidence of mechanical complications including ventricular septal rupture and acute severe mitral regurgitation. Among patients with predominant LV failure, women were, on average, 4.6 years older, had a higher incidence of hypertension, diabetes and a lower cardiac index. The overall mortality rate for the entire cohort was high (61%). After adjustment for differences in patient demographics and treatment approaches, there was no significant difference in in-hospital mortality between the two gender groups (odds ratio = 1.03, 95% confidence interval of 0.73 to 1.43, p = 0.88). Mortality was also similar for women and men who were selected for revascularization (44% vs. 38%, p = 0.244). Women with CS complicating AMI had more frequent adverse clinical characteristics and mechanical complications. Women derived the same benefit as men from revascularization, and gender was not independently associated with in-hospital mortality in the SHOCK Registry.


A meta-synthesis of behavioral outcomes from telemedicine clinical trials for type 2 diabetes and the Clinical User-Experience Evaluation (CUE).
A worldwide demographic shift is in progress and the aged population proportion is projected to more than double across the next four decades. Our current healthcare models may not be adequate to handle this shift in demography, which may have serious consequences for the ageing population who are more prone to chronic diseases. One proposed remediation is to provide in-home assisted healthcare with technology-intervened approaches. Telemedicine, telehealth, e-health are paradigms found in scientific literature that provide clinical treatment through a technology intervention. In evidence-based medical science, these technology interventions are evaluated through clinical trials, which are targeted to measure improvements in medical conditions and the treatment's cost effectiveness. However, effectiveness of a technology also depends on the interaction pattern between the technology and its' users, especially the patients. This paper presents (1) a meta-synthesis of clinical trials for technology-intervened treatments of type 2 diabetes and (2) the Clinical User-Experience Evaluation (CUE). CUE is a recommendation for future telemedicine clinical trials that focuses on the patient as the user from Human-Computer Interaction (HCI) perspective and was developed as part of this research. The clinical trials reviewed were interpreted from a technology perspective and the non-medical or non-biological improvements of the users (patients) rather than the medical outcome. Results show that technology-intervened treatments provide positive behavior changes among patients and are potentially highly beneficial for chronic illness management such as type 2 diabetes. The results from the CUE method show how it complements clinical trials to capture patients' interaction with a technology.


Neuroscience of apathy and anhedonia: a transdiagnostic approach.
Apathy and anhedonia are common syndromes of motivation that are associated with a wide range of brain disorders and have no established therapies. Research using animal models suggests that a useful framework for understanding motivated behaviour lies in effort-based decision making for reward. The neurobiological mechanisms underpinning such decisions have now begun to be determined in individuals with apathy or anhedonia, providing an important foundation for developing new treatments. The findings suggest that there might be some shared mechanisms between both syndromes. A transdiagnostic approach that cuts across traditional disease boundaries provides a potentially useful means for understanding these conditions.


Impact of medical and nonmedical factors on physician decision making for HIV/AIDS antiretroviral treatment.
To examine influences of medical factors (e.g., viral load) and nonmedical factors (e.g., patient characteristics) on treatment decisions for highly active antiretroviral therapy (HAART), we sent a survey to a random sample of 995 infectious disease physicians who treat patients with HIV/AIDS in the United States in August, 1998. The response rate was 53%. Respondents were asked to report their current practices with respect to antiretroviral treatment and the extent to which each of three medical and 17 nonmedical factors would influence them for or against prescribing HAART to a hypothetical HIV-positive patient. Most reported initiating HAART with findings of low CD4+ cell counts and high viral loads, and weighing CD4+ cell counts, viral load, and opportunistic infection heavily in their decisions to prescribe HAART. Patients' prior history of poor adherence was weighed very much against initiating HAART. Patient homelessness, heavy alcohol use, injection drug use, and prior psychiatric hospitalization were cited by most physicians as weighing against HAART initiation. Thus, most physicians in this sample follow guidelines for the use of HAART, and nonmedical factors related to patients' life situations are weighed as heavily as disease severity in treatment decisions. As HIV increasingly becomes a disease associated with economic disadvantage and other social health problems, it will be essential to develop interventions and care support systems to enable patients experiencing these problems to benefit from HIV treatment advances.


Association of depression and diabetes complications: a meta-analysis.
The objective of this study was to examine the strength and consistency of the relationship between depression and diabetes complications in studies of type 1 and type 2 adult patients with diabetes. MEDLINE and PsycINFO databases were searched for articles examining depression and diabetes complications in type 1 and type 2 diabetes samples published between 1975 and 1999. Meta-analytic procedures were used. Studies were reviewed for diabetes type, sample size, statistical tests, and measures of diabetes complications and depression. Significance values, weighted effect sizes r, 95% confidence intervals (CI), and tests of homogeneity of variance were calculated for the overall sample (k = 27) and for subsets of interest. A total of 27 studies (total combined N = 5374) met the inclusion criteria. A significant association was found between depression and complications of diabetes (p < .00001, z = 5.94). A moderate and significant weighted effect size (r = 0.25; 95% CI: 0.22-0.28) was calculated for all studies reporting sufficient data (k = 22). Depression was significantly associated with a variety of diabetes complications (diabetic retinopathy, nephropathy, neuropathy, macrovascular complications, and sexual dysfunction). Effect sizes were in the small to moderate range (r = 0.17 to 0.32). These findings demonstrate a significant and consistent association of diabetes complications and depressive symptoms. Prospective, longitudinal studies are needed to identify the pathways that mediate this association.


Dual catalytic enantioselective desymmetrization of allene-tethered cyclohexanones.
The construction of enantioenriched azabicyclo[3.3.1]nonan-6-one heterocycles via an enantioselective desymmetrization of allene-linked cyclohexanones, enabled through a dual catalytic system, that provides synchronous activation of the cyclohexanone with a chiral prolinamide and the allene with a copper(i) co-catalyst to deliver the stereodefined bicyclic core, is described. Successful application to oxygen analogues was also achieved, thereby providing a new enantioselective synthetic entry to architecturally complex bicyclic ethereal frameworks. The mechanistic pathway and the origin of enantio- and diastereoselectivities has been uncovered using density functional theory (DFT) calculations.


Prevalence and predictors of persistent pelvic girdle pain 12 years postpartum.
Pelvic girdle pain (PGP) is not always a self-limiting condition. Women with more pronounced persistent PGP (PPGP) report poorer health status compared to women with less pronounced symptoms. The knowledge concerning the long-term consequences of PPGP is limited, thus more knowledge in this area is needed. The overall aim was to study the prevalence and predictors of PPGP 12 years after delivery. This is a long-term follow-up study based on a previous cohort study that commenced in 2002. New questionnaire data 12 years postpartum were collected in 2014 and early 2015. The questionnaire was distributed to a total of 624 women from the initial cohort. In total, 295 women (47.3%) responded to the questionnaire where 40.3% (n = 119) reported pain to a various degree and 59% (n = 174) reported no pain. Increased duration and/or persistency of pain, self-rated health, sciatica, neck and/or thoracic spinal pain, sick leave the past 12 months, treatment sought, and prescription and/or non-prescription drugs used were all associated with an statistically significant increase in the odds of reporting pain 12 years postpartum. Widespread pain was common and median expectation of improvement score was 5 on an 11-point numeric scale (interquartile range 2-7.50). More than one of five women (21.8%) reporting pain stated that they had been on sick leave the past 12 months and nearly 11% had been granted disability pension due to PPGP. No statistically significant differences were found between respondents and non-respondents regarding most background variables. This study is unique as it is one of few long-term follow-up studies following women with PPGP of more than 11 years. The results show that spontaneous recovery with no recurrences is an unlikely scenario for a subgroup of women with PPGP. Persistency and/or duration of pain symptoms as well as widespread pain appear to be the strongest predictors of poor long-term outcome. Moreover, widespread pain is commonly associated with PPGP and may thus contribute to long-term sick leave and disability pension. A screening tool needs to be developed for the identification of women at risk of developing PPGP to enable early intervention.


Upper extremity interaction with a helicopter side airbag: injury criteria for dynamic hyperextension of the female elbow joint.
This paper describes a three part analysis to characterize the interaction between the female upper extremity and a helicopter cockpit side airbag system and to develop dynamic hyperextension injury criteria for the female elbow joint. Part I involved a series of 10 experiments with an original Army Black Hawk helicopter side airbag. A 5(th) percentile female Hybrid III instrumented upper extremity was used to demonstrate side airbag upper extremity loading. Two out of the 10 tests resulted in high elbow bending moments of 128 Nm and 144 Nm. Part II included dynamic hyperextension tests on 24 female cadaver elbow joints. The energy source was a drop tower utilizing a three-point bending configuration to apply elbow bending moments matching the previously conducted side airbag tests. Post-test necropsy showed that 16 of the 24 elbow joint tests resulted in injuries. Injury severity ranged from minor cartilage damage to more moderate joint dislocations and severe transverse fractures of the distal humerus. Peak elbow bending moments ranged from 42.4 Nm to 146.3 Nm. Peak bending moment proved to be a significant indicator of any elbow injury (p = 0.02) as well as elbow joint dislocation (p = 0.01). Logistic regression analyses were used to develop single and multiple variate injury risk functions. Using peak moment data for the entire test population, a 50% risk of obtaining any elbow injury was found at 56 Nm while a 50% risk of sustaining an elbow joint dislocation was found at 93 Nm for the female population. These results indicate that the peak elbow bending moments achieved in Part I are associated with a greater than 90% risk for elbow injury. Subsequently, the airbag was re-designed in an effort to mitigate this as well as the other upper extremity injury risks. Part III assessed the redesigned side airbag module to ensure injury risks had been reduced prior to implementing the new system. To facilitate this, 12 redesigned side airbag deployments were conducted using the same procedures as Part I. Results indicate that the re-designed side airbag has effectively mitigated elbow injury risks induced by the original side airbag design. It is anticipated that this study will provide researchers with additional injury criteria for assessing upper extremity injury risk caused by both military and automotive side airbag deployments.


Revealing the principal attributes of protein adsorption on block copolymer surfaces with direct experimental evidence at the single protein level.
Understanding protein adsorption onto polymer surfaces is of great importance in designing biomaterials, improving bioanalytical devices, and controlling biofouling, to name a few examples. Although steady research efforts have been advancing this field, our knowledge of this ubiquitous and complex phenomenon is still limited. In this study, we elucidate competitive protein adsorption behaviors sequentially occurring onto nanoscale block copolymer (BCP) surfaces via combined experimental and computer simulation approaches. The model systems chosen for our investigation are immunoglobulin G and fibrinogen introduced in different orders into the self-assembled nanodomains of poly(styrene)-block-poly(methylmethacrylate). We unambiguously reveal the adsorption, desorption, and replacement events of the same protein molecules via single protein tracking with atomic force microscopy. We then ascertain adsorption-related behaviors such as lateral mobility and self-association of proteins. We provide the much-needed, direct experimental proof of sequential adsorption events at the biomolecular level, which was virtually nonexistent before. We determine key protein adsorption pathways and dominant tendencies of sequential protein adsorption. We also reveal preadsorbed surface-associated behaviors in sequential adsorption, distinct from situations involving initially empty surfaces. We perform Monte-Carlo simulations to further substantiate our experimental outcomes. Our endeavors in this study may facilitate a well-guided mechanistic understanding of protein-polymer interactions by providing definite experimental evidence of competitive, sequential adsorption at the nanoscale. Increasingly, biomaterial and biomedical applications rely on systems of multicomponent proteins and chemically intricate, nanoscale polymer surfaces. Hence, our findings can also be beneficial for the development of next-generation nanobiomaterials and nanobiosensors exploiting self-assembled BCP nanodomain surfaces.


OncoRep: an n-of-1 reporting tool to support genome-guided treatment for breast cancer patients using RNA-sequencing.
Breast cancer comprises multiple tumor entities associated with different biological features and clinical behaviors, making individualized medicine a powerful tool to bring the right drug to the right patient. Next generation sequencing of RNA (RNA-Seq) is a suitable method to detect targets for individualized treatment. Challenges that arise are i) preprocessing and analyzing RNA-Seq data in the n-of-1 setting, ii) extracting clinically relevant and actionable targets from complex data, iii) integrating drug databases, and iv) reporting results to clinicians in a timely and understandable manner. To address these challenges, we present OncoRep, an RNA-Seq based n-of-1 reporting tool for breast cancer patients. It reports molecular classification, altered genes and pathways, gene fusions, clinically actionable mutations and drug recommendations. It visualizes the data in an approachable html-based interactive report and a PDF clinical report, providing the clinician and tumor board with a tool to guide the treatment decision making process. OncoRep is free and open-source ( https://bitbucket.org/sulab/oncorep/ ), thereby offering a platform for future development and innovation by the community.


Multiple, large granulomas in a patient with extensive intestinal tuberculosis.
A 42-year-old patient presented with low-grade fever, pain of the right iliac fossa, constipation and tendency to vomit. Clinical examination revealed abdominal wall rigidity and rebound tenderness of the right iliac fossa. The patient was operated immediately because of an acute abdomen and the probable diagnosis of ruptured appendicitis. In laparotomy, terminal ileum, ileocaecal valve and the entire ascending colon, up to the right colic flexure, were occupied and distorted by multiple, large masses. In addition, many enlarged lymph nodes were scattered in the mesentery and the mesocolon. A right hemicolectomy was performed. Pathological examination of biopsy specimens revealed findings compatible with tuberculosis. The patient was started on empirical anti-tuberculosis treatment with a four-drug regimen. He was discharged 10 days later with marked improvement. Six months after surgery, the patient remains in very good condition without any symptoms.


Weighted pedigree-based statistics for testing the association of rare variants.
With the advent of next-generation sequencing (NGS) technologies, researchers are now generating a deluge of data on high dimensional genomic variations, whose analysis is likely to reveal rare variants involved in the complex etiology of disease. Standing in the way of such discoveries, however, is the fact that statistics for rare variants are currently designed for use with population-based data. In this paper, we introduce a pedigree-based statistic specifically designed to test for rare variants in family-based data. The additional power of pedigree-based statistics stems from the fact that while rare variants related to diseases or traits of interest occur only infrequently in populations, in families with multiple affected individuals, such variants are enriched. Note that while the proposed statistic can be applied with and without statistical weighting, our simulations show that its power increases when weighting (WSS and VT) are applied. Our working hypothesis was that, since rare variants are concentrated in families with multiple affected individuals, pedigree-based statistics should detect rare variants more powerfully than population-based statistics. To evaluate how well our new pedigree-based statistics perform in association studies, we develop a general framework for sequence-based association studies capable of handling data from pedigrees of various types and also from unrelated individuals. In short, we developed a procedure for transforming population-based statistics into tests for family-based associations. Furthermore, we modify two existing tests, the weighted sum-square test and the variable-threshold test, and apply both to our family-based collapsing methods. We demonstrate that the new family-based tests are more powerful than corresponding population-based test and they generate a reasonable type I error rate.To demonstrate feasibility, we apply the newly developed tests to a pedigree-based GWAS data set from the Framingham Heart Study (FHS). FHS-GWAS data contain approximately 5000 uncommon variants with frequencies less than 0.05. Potential association findings in these data demonstrate the feasibility of the software PB-STAR (note, PB-STAR is now freely available to the public). Our tests show that when analyzing for rare variants, a pedigree-based design is more powerful than a population-based case-control design. We further demonstrate that a pedigree-based statistic's power to detect rare variants increases in direct relation to the proportion of affected individuals within the pedigree.


Protein structure networks provide insight into active site flexibility in esterase/lipases from the carnivorous plant Drosera capensis.
In plants, esterase/lipases perform transesterification reactions, playing an important role in the synthesis of useful molecules, such as those comprising the waxy coatings of leaf surfaces. Plant genomes and transcriptomes have provided a wealth of data about expression patterns and the circumstances under which these enzymes are upregulated, e.g. pathogen defense and response to drought; however, predicting their functional characteristics from genomic or transcriptome data is challenging due to weak sequence conservation among the diverse members of this group. Although functional sequence blocks mediating enzyme activity have been identified, progress to date has been hampered by the paucity of information on the structural relationships among these regions and how they affect substrate specificity. Here we present methodology for predicting overall protein flexibility and active site flexibility based on molecular modeling and analysis of protein structure networks (PSNs). We define two new types of specialized PSNs: sequence region networks (SRNs) and active site networks (ASNs), which provide parsimonious representations of molecular structure in reference to known features of interest. Our approach, intended as an aid to target selection for poorly characterized enzyme classes, is demonstrated for 26 previously uncharacterized esterase/lipases from the genome of the carnivorous plant Drosera capensis and validated using a case/control design. Analysis of the network relationships among functional blocks and among the chemical moieties making up the catalytic triad reveals potentially functionally significant differences that are not apparent from sequence analysis alone.


Sulfate content and specific glycosaminoglycan backbone of perlecan are critical for perlecan's enhancement of islet amyloid polypeptide (amylin) fibril formation.
Islet amyloidosis is characterized by the deposition and accumulation of amylin in pancreatic beta-cells and is observed in 90% of patients with type 2 diabetes. Previous studies have also revealed the presence of the specific heparan sulfate proteoglycan, perlecan, colocalized to islet amyloid deposits, similar to perlecan's known involvement with other amyloid proteins. In the present study, perlecan purified from the Engelbreth-Holm-Swarm (EHS) tumor was used to define perlecan's interactions with amylin (i.e., islet amyloid polypeptide) and its effects on amylin fibril formation. Using a solid phase-binding immunoassay, human amylin, but not rat amylin, bound immobilized EHS perlecan with a single dissociation constant (Kd) = 2.75 x 10(-6) mol/l. The binding of human amylin to perlecan was similarly observed using perlecan heparan sulfate glycosaminoglycans (GAGs), and was completely abolished by 10 micromol/l heparin. Using thioflavin T fluorometry, Congo red staining, and electron microscopy methodology, intact perlecan was found to enhance amylin fibril formation in a dosage-dependent manner, with the majority of these effects attributed to the heparan sulfate GAG chains of perlecan. Other sulfated GAGs and related macromolecules were also effective in the enhancement of amylin fibril formation in the order of heparin > heparan sulfate > chondroitin-4-sulfate = dermatan sulfate = dextran sulfate > pentosan polysulfate, implicating the importance of the specific GAG/carbohydrate backbone. The sulfate content of heparin/heparan sulfate was also important for the enhancement of amylin fibril formation in the order of heparin > N-desulfated N-acetylated heparin > completely desulfated N-sulfated heparin > completely desulfated N-acetylated heparin. These studies suggest that the enhancement effects of perlecan on amylin fibril formation are mediated primarily by both specific GAG chain backbone and GAG sulfate content, and implicate perlecan as an important macromolecule that is likely involved in the pathogenesis of islet amyloidosis.


Patient-Centered Decision Support: Formative Usability Evaluation of Integrated Clinical Decision Support With a Patient Decision Aid for Minor Head Injury in the Emergency Department.
The Canadian Computed Tomography (CT) Head Rule, a clinical decision rule designed to safely reduce imaging in minor head injury, has been rigorously validated and implemented, and yet expected decreases in CT were unsuccessful. Recent work has identified empathic care as a key component in decreasing CT overuse. Health information technology can hinder the clinician-patient relationship. Patient-centered decision tools to support the clinician-patient relationship are needed to promote evidence-based decisions. Our objective is to formatively evaluate an electronic tool that not only helps clinicians at the bedside to determine the need for CT use based on the Canadian CT Head Rule but also promotes evidence-based conversations between patients and clinicians regarding patient-specific risk and patients' specific concerns. User-centered design with practice-based and participatory decision aid development was used to design, develop, and evaluate patient-centered decision support regarding CT use in minor head injury in the emergency department. User experience and user interface (UX/UI) development involved successive iterations with incremental refinement in 4 phases: (1) initial prototype development, (2) usability assessment, (3) field testing, and (4) beta testing. This qualitative approach involved input from patients, emergency care clinicians, health services researchers, designers, and clinical informaticists at every stage. The Concussion or Brain Bleed app is the product of 16 successive iterative revisions in accordance with UX/UI industry design standards. This useful and usable final product integrates clinical decision support with a patient decision aid. It promotes shared use by emergency clinicians and patients at the point of care within the emergency department context. This tablet computer app facilitates evidence-based conversations regarding CT in minor head injury. It is adaptable to individual clinician practice styles. The resultant tool includes a patient injury evaluator based on the Canadian CT Head Rule and provides patient specific risks using pictographs with natural frequencies and cues for discussion about patient concerns. This tool was designed to align evidence-based practices about CT in minor head injury patients. It establishes trust, empowers active participation, and addresses patient concerns and uncertainty about their condition. We hypothesize that, when implemented, the Concussion or Brain Bleed app will support-not hinder-the clinician-patient relationship, safely reduce CT use, and improve the patient experience of care.


Support systems for poor readers: empirical data from six EU member states.
This study surveyed and compared support systems for poor readers in six member states of the European Union (EU). The goal was to identify features of effective support systems. A large-scale questionnaire survey was conducted among mainstream teachers (n = 4,210) and remedial teachers (n = 2,395). Results indicate that the six support systems differed substantially, with effective support systems showing high performance on all variables measured. More specifically, effective support systems were characterized by (a) high levels of both teacher and student support and (b) frequent interactions between teachers and remedial teachers as well as between remedial teachers and diagnosticians. The high prevalence of poor reading ability in the current EU member states demonstrates that educational reforms are critically needed. The results of this study provide concrete starting points for improving support systems for poor readers.


Tear MMP-9 levels as a marker of ocular surface inflammation in conjunctivochalasis.
To evaluate the efficacy of surgical treatment for conjunctivochalasis by monitoring matrix metalloproteinase (MMP)-9 levels in the tears of patients with conjunctivochalasis before and after surgery and their correlation with clinical signs and symptoms. Twelve eyes of patients with symptomatic conjunctivochalasis were included in this study as well as five eyes of healthy volunteers. Ocular surface inflammation was measured in terms of the concentration of pro-MMP-9 in tears, by enzyme-linked immunosorbent assay and zymography. Tear analysis was performed before and 1 month after surgery. The surgical technique consisted of the excision of redundant tissue and the use of organic glue for wound closure. The concentration of pro-MMP-9 was significantly higher in the conjunctivochalasis eyes than in the healthy controls (223.4 ± 74.53 ng/mL vs. 20.32 ± 5.21 ng/mL; P < 0.001). Tear pro-MMP-9 levels decreased significantly after conjunctival resection in patients with conjunctivochalasis without dry eye compared with patients with conjunctivochalasis and dry eye associated. Zymographic analysis indicated that MMP-9 is present in its active form only in conjunctivochalasis tears. After a follow-up of 4.9 ± 1.3 weeks, all operated eyes were found to have recovered a smooth and stable conjunctival surface, epithelial defects had improved, and epiphora had been resolved in 89% of cases. Our results indicate that inflammation is likely to play a relevant role in the pathogenesis of conjunctivochalasis. Appropriate surgery decreases inflammatory activity, leading to symptom improvement, and tear analysis may facilitate the treatment of the ocular surface.


3,5-Dicaffeoylquinic acid protects H9C2 cells against oxidative stress-induced apoptosis via activation of the PI3K/Akt signaling pathway.
Oxidative stress-induced apoptosis plays an important role in the development of heart failure. 3,5-Dicaffeoylquinic acid (3,5-diCQA), a phenolic compound, has shown protective effects against oxidative stress in many diseases. The objective of this study was to investigate the anti-apoptosis potential of 3,5-diCQA in cardiomyocyte cells under oxidative stress and explore its underlying mechanisms. A model of tert-butyl hydroperoxide (TBHP)-induced apoptosis in a cardiomyocyte cell line (H9C2) was established. Cell viabilities on cell lines were determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium (MTT) assay. The apoptosis was measured by hoechst33342 and propidium iodide (PI) fluorescent staining. PI (in red) stained the regions of cell apoptosis; Hoechet33342 (in blue) stained the nuclei. The Western blot was used to determine the expressions of related proteins such as p-PI3K: phosphorylated phosphatidylinositol-3-kinase (p-PI3K), phosphorylated Serine and Threonine kinase AKT (p-AKT), p-PTEN, Bcl-2, Bax, and caspase-3. Afterward, a PI3K inhibitor, LY294002, was applied to confirm the influence of the PI3K/Akt pathway on TBHP-treated cells of 3,5-diCQA. Then, H9C2 cells were pre-incubated with 3,5-diCQA alone to determine if the expression of activated PI3K/Akt signaling was mediated by 3,5-diCQA in H9C2 cells. The results showed that TBHP resulted in an increase in cardiomyocyte apoptosis, whereas 3,5-diCQA treatment protected cells from TBHP-induced apoptosis in a dose-dependent manner. Moreover, 3,5-diCQA decreased expressions of Bax and caspase-3 but increased the phosphorylation levels of PI3K and Akt in TBHP-treated cells, which are the key molecules mediating cell survival, whereas phosphatase and tensin homologue deleted on chromosome 10 (PTEN) phosphorylation was unchanged. Importantly, pre-incubation with a PI3K inhibitor (LY294002) partly abolished the anti-apoptosis effects of 3,5-diCQA. Further, 3,5-diCQA enhanced the phosphorylation levels of PI3K and Akt in H9C2 cells directly, while LY294002 attenuated the effects of 3,5-diCQA on PI3K and Akt. This study suggested that 3,5-diCQA rescued myocardium from apoptosis by increasing the activation of the PI3K/Akt signaling pathway.


Mosquitoes associated with ditch-plugged and control tidal salt marshes on the Delmarva Peninsula.
A study was conducted during the summer of 2009 (from July to September) to characterize mosquito communities among different habitats in five historically ditched tidal salt marshes and three adjacent wooded areas in the E.A. Vaughn Wetland Management Area on the Maryland Delmarva Peninsula, USA. Study marshes are characteristic of Atlantic coastal salt marshes that had undergone grid ditching from the 1930s to 1950s. In the autumn of 2008 (October and November) ditches were plugged near their outlets in two ('experimental') marshes with the aim to restore their natural tidal hydrology. The three other marshes were not plugged. Marshes were sampled from July to September in 2009 by using standard dip count method. A total of 2,457 mosquito larvae representing six species were collected on 15.4% (86/557) of all sample occasions and 399 adults representing four mosquito species were collected from landing counts. Aedes sollicitans, Anopheles bradleyi and Culex salinarius were the most common species collected in larval habitats, and Ae. sollicitans was the most common adult collected. Wooded habitats had more total mosquitoes, were also more frequently occupied by mosquitoes and had higher densities of mosquitoes than marsh habitats. Almost all larvae collected from marshes were from one experimental and one control site. The majority of larvae at the control site were Ae. sollicitans in marsh pannes while Cx. salinarius, An. bradleyi, Ae. cantator, and Ae. sollicitans were collected in high numbers from ditches at the experimental site. We found a difference in the proportion of marsh pannes occupied by Ae. sollicitans but not total mosquitoes sampled 4-5 days after spring tide events than on other occasions. Salinity measures of 42 larval habitats showed lower median salinity in mosquito-occupied habitats (11.5 ppt) than unoccupied habitats (20.1 ppt), and in habitats in wooded areas followed by ditches and pannes in marsh areas. The results of this study suggest that wooded areas adjacent to salt marshes may be a substantial source of biting adult mosquitoes usually associated with salt marsh habitats and that ditch plugging may alter the productivity of mosquitoes on some marshes. We recommend future studies consider mosquito productivity from habitats surrounding salt marshes, and if assessments of marsh alterations are a goal, compare multiple experimental and control areas before and after treatments to determine if alterations have a consistent impact on regional mosquito production.


Hydrogen bonding, solvent exchange, and coupled proton and electron transfer in the oxidation and reduction of redox-active tyrosine Y(Z) in Mn-depleted core complexes of photosystem II.
The redox-active tyrosines, Y(Z) and Y(D), of Photosystem II are oxidized by P680+ to the neutral tyrosyl radical. This oxidation thus involves the transfer of the phenolic proton as well as an electron. It has recently been proposed that tyrosine Y(Z) might replace the lost proton by abstraction of a hydrogen atom or a proton from a water molecule bound to the manganese cluster, thereby increasing the driving force for water oxidation. To compare and contrast with the intact system, we examine here, in a simplified Mn-depleted PSII core complex, isolated from a site-directed mutant of Synechocystis PCC 6803 lacking Y(D), the role of proton transfer in the oxidation and reduction of Y(Z). We show how the oxidation and reduction rates for Y(Z), the deuterium isotope effect on these rates, and the Y(Z)* - Y(Z) difference spectra all depend on pH (from 5.5 to 9.5). This simplified system allows examination of electron-transfer processes over a broader range of pH than is possible with the intact system and with more tractable rates. The kinetic isotope effect for the oxidation of P680+ by Y(Z) is maximal at pH 7.0 (3.64). It decreases to lower pH as charge recombination, which shows no deuterium isotope, starts to become competitive with Y(Z) oxidation. To higher pH, Y(Z) becomes increasingly deprotonated to form the tyrosinate, the oxidation of which at pH 9.5 becomes extremely rapid (1260 ms(-1)) and no longer limited by proton transfer. These observations point to a mechanism for the oxidation of Y(Z) in which the tyrosinate is the species from which the electron occurs even at lower pH. The kinetics of oxidation of Y(Z) show elements of rate limitation by both proton and electron transfer, with the former dominating at low pH and the latter at high pH. The proton-transfer limitation of Y(Z) oxidation at low pH is best explained by a gated mechanism in which Y(Z) and the acceptor of the phenolic proton need to form an electron/proton-transfer competent complex in competition with other hydrogen-bonding interactions that each have with neighboring residues. In contrast, the reduction of Y(Z)* appears not to be limited by proton transfer between pH 5.5 and 9.5. We also compare, in Mn-depleted Synechocystis PSII core complexes, Y(Z) and Y(D) with respect to solvent accessibility by detection of the deuterium isotope effect for Y(Z) oxidation and by 2H ESEEM measurement of hydrogen-bond exchange. Upon incubation of H2O-prepared PSII core complexes in D2O, the phenolic proton of Y(Z) is exchanged for a deuterium in less than 2 min as opposed to a t(1/2) of about 9 h for Y(D). In addition, we show that Y(D)* is coordinated by two hydrogen bonds. Y(Z)* shows more disordered hydrogen bonding, reflecting inhomogeneity at the site. With 2H ESEEM modulation comparable to that of Y(D)*, Y(Z)* would appear to be coordinated by two hydrogen bonds in a significant fraction of the centers.


Productivity of malaria vectors from different habitat types in the western Kenya highlands.
Mosquito Larval Source Management (LSM) could be a valuable additional tool for integrated malaria vector control especially in areas with focal transmission like the highlands of western Kenya if it were not for the need to target all potential habitats at frequent intervals. The ability to determine the productivity of malaria vectors from identified habitats might be used to target LSM only at productive ones. Each aquatic habitat within three highland sites in western Kenya was classified as natural swamp, cultivated swamp, river fringe, puddle, open drain or burrow pit. Three habitats of each type were selected in each site in order to study the weekly productivity of adult malaria vectors from February to May 2009 using a sweep-net and their habitat characteristics recorded. All surveyed habitat types produced adult malaria vectors. Mean adult productivity of Anopheles gambiae sensu lato in puddles (1.8/m(2)) was 11-900 times higher than in the other habitat types. However, puddles were the most unstable habitats having water at 43% of all sampling occasions and accounted for 5% of all habitats mapped in the study areas whereas open drains accounted for 72%. Densities of anopheline late instars larvae significantly increased with the presence of a biofilm but decreased with increasing surface area or when water was flowing. Taking stability and frequency of the habitat into account, puddles were still the most productive habitat types for malaria vectors but closely followed by open drains. Even though productivity of An. gambiae s.l. was greatest in small and unstable habitats, estimation of their overall productivity in an area needs to consider the more stable habitats over time and their surface extension. Therefore, targeting only the highly productive habitats is unlikely to provide sufficient reduction in malaria vector densities.


Tacrine treatment at high dose suppresses the recognition memory in juvenile and adult mice with attention to hepatotoxicity.
It is well established that cholinergic over-stimulation can interfere with memory processes. The aim of this study was to evaluate the effect of tacrine, an acetylcholinesterase inhibitor, on recognition memory as well as the associated hepatotoxicity in juvenile (20-day-old) and adult (100-day-old) ICR male mice. Recognition memory was assessed by open-field test and step-through task without footshocks for three sessions between 08:00 and 13:00, with a 24-hr retention interval. Tacrine (10 or 40 μmol/kg) or vehicle was administered (s.c.) 20 min. prior to the first session. During the acquisition session, tacrine suppressed the open-field behaviours, including locomotor activity, rearing, grooming and defecation (by 77-100%) in mice of both ages. During the recall (observable in both ages) and re-recall (observable in juvenile mice) session, the locomotor activity and rearing number were significantly increased, indicative of impairment in recognition memory, in mice treated with tacrine 40 μmol/kg. During the training trial, tacrine decreased the step-through number in mice of both ages. In contrast, during the retention and re-retention trials, the step-through number was increased (by 92% and 93%, respectively), indicative of impairment in step-through memory, in juvenile but not adult mice treated with tacrine 40 μmol/kg. Tacrine 40 μmol/kg elevated the serum alanine aminotransferase (ALT) activity (by 135%) in juvenile mice, but reduced the ALT activity (by 42%) in adult mice. The results indicated that 20-day-old mice seemed to be more sensitive than 100-day-old mice to tacrine-induced impairment in recognition memory and the associated liver damage.


TOM9.2 Is a Calmodulin-Binding Protein Critical for TOM Complex Assembly but Not for Mitochondrial Protein Import in Arabidopsis thaliana.
The translocon on the outer membrane of mitochondria (TOM) facilitates the import of nuclear-encoded proteins. The principal machinery of mitochondrial protein transport seems conserved in eukaryotes; however, divergence in the composition and structure of TOM components has been observed between mammals, yeast, and plants. TOM9, the plant homolog of yeast Tom22, is significantly smaller due to a truncation in the cytosolic receptor domain, and its precise function is not understood. Here we provide evidence showing that TOM9.2 from Arabidopsis thaliana is involved in the formation of mature TOM complex, most likely by influencing the assembly of the pore-forming subunit TOM40. Dexamethasone-induced RNAi gene silencing of TOM9.2 results in a severe reduction in the mature TOM complex, and the assembly of newly imported TOM40 into the complex is impaired. Nevertheless, mutant plants are fully viable and no obvious downstream effects of the loss of TOM complex, i.e., on mitochondrial import capacity, were observed. Furthermore, we found that TOM9.2 can bind calmodulin (CaM) in vitro and that CaM impairs the assembly of TOM complex in the isolated wild-type mitochondria, suggesting a regulatory role of TOM9.2 and a possible integration of TOM assembly into the cellular calcium signaling network.


Inhibition of development of exoerythrocytic forms of malaria parasites by gamma-interferon.
A specific DNA probe was used to study the effect of recombinant rat, mouse, and human gamma-interferon (gamma-IFN) on the course of sporozoite-induced malaria infections. In mice and rats infected with sporozoites of Plasmodium berghei, mouse and rat gamma-IFN's strongly inhibited the development of the exoerythrocytic forms in the liver liver cells of the hosts, but not the development of the erythrocytic stages. The degree of inhibition of the exoerythrocytic forms was proportional to the dose of gamma-IFN administered, but was independent of the number of sporozoites used for challenge. A 30 percent reduction in the development of exoerythrocytic forms in rat liver was achieved when 150 units (about 15 nanograms of protein) of rat gamma-IFN were injected a few hours before sporozoite challenge; the reduction was 90 percent or more with higher doses of gamma-IFN. The effect was less pronounced if the gamma-IFN was administered 18 hours before or a few hours after challenge. Human gamma-IFN also diminished the parasitemia in chimpanzees infected with sporozoites of the human malaria parasite Plasmodium vivax. The target of gamma-IFN activity may be the infected hepatocytes themselves, as shown by in vitro experiments in which small doses of the human lymphokine inhibited the development of exoerythrocytic forms of Plasmodium berghei in a human hepatoma cell line. These results suggest that immunologically induced interferon may be involved in controlling malaria infection under natural conditions.


Erection quality scale: initial scale development and validation.
The Erection Quality Scale (EQS) is a new, self-report measure for assessing the quality of penile erections. It is intended to complement existing diagnostic and outcome measures (eg, International Index of Erectile Function, Sexual Encounter Profile) in both clinical practice and outcomes research in erectile dysfunction (ED). The initial phases of development and psychometric validation of the EQS are described. Specifically, qualitative research in patients and healthy men was used to generate relevant constructs. On the basis of the findings from these phases, and recommendations from an expert panel, seven constructs were selected for inclusion. Multiple items with different formats were drafted to measure each of the key constructs. An iterative process of cognitive testing, item revision, and item reduction was used to identify the 15 most appropriate items and their optimal response scales. This version of the scale was tested in a 200-subject discriminant validity study designed to gather data for a psychometric evaluation. Participants were classified into ED-untreated, ED-treated, and healthy control groups to evaluate the discriminant validity of the measure in men with different levels of erectile function. The study results supported a robust single-factor structure, indicating that the EQS provides an overall index of erection quality. An intraclass correlation coefficient of 0.85 denotes adequate test-retest reliability. Furthermore, the EQS correlated well with existing measures and differentiated patients from the three ED classifications, a preliminary indication of discriminant validity. The findings presented provide evidence of the scale's potential utility for measuring erection quality in future studies.


The effect of dynamic intermittent hypoxic conditioning on arterial oxygen saturation.
Increases in arterial oxygen saturation (SaO2) in response to intermittent hypoxic exposure (IHE) are well established. However, IHE protocols have historically involved static hypoxic environments. The effect of a dynamic hypoxic environment on SaO2 is not known. The purpose of this study was to examine the effect of dynamic IHE conditioning on SaO2 using the Cyclical Variable Altitude Conditioning Unit. Thirteen trained participants (9 males, age 30.1 +/- 9.2 years; 4 females, age 30.3 +/- 8.9 years) residing at or near sea level were exposed to a 7-week IHE conditioning protocol (mean total exposure time = 30.8 hours). Participants were exposed to a constantly varying series of hypobaric pressures simulating altitudes from sea level to 6858 m (22 500 feet) in progressive conditioning tiers, creating a dynamic hypoxic environment. SaO2 was evaluated using pulse oximetry (SpO2) 4 times: at 2740, 3360, and 4570 m, prior to and following the first 3 weeks of IHE, and at 4570, 5490, and 6400 m at the start and end of the final 4 weeks. SpO2 improved 3.5%, 3.8%, and 4.1% at 2470, 3360, and 4570 m, respectively (P < .05), and 3.3%, 3.4%, and 5.9% at 4570, 5490, and 6400 m, respectively (P < .05). At 4570 m, SpO2 increased from 81.7% +/- 6.5% to 89.1% +/- 3.2% over the entire 7-week conditioning period. The dynamic intermittent hypoxic conditioning protocol used in the present study resulted in an acclimation response, such that SpO2 was significantly increased at all altitudes tested, with shorter exposure times than generally reported.


Do Patients Thought to Lack Consciousness Retain the Capacity for Internal as Well as External Awareness?
It is well established that some patients, who are deemed to have disorders of consciousness, remain entirely behaviorally non-responsive and are diagnosed as being in a vegetative state, yet can nevertheless demonstrate covert awareness of their external environment by modulating their brain activity, a phenomenon known as cognitive-motor dissociation. However, the extent to which these patients retain internal awareness remains unknown. To investigate the potential for internal and external awareness in patients with chronic disorders of consciousness (DoC), we asked whether the pattern of juxtaposition between the functional time-courses of the default mode (DMN) and fronto-parietal networks, shown in healthy individuals to mediate the naturally occurring dominance switching between internal and external aspects of consciousness, was present in these patients. We used a highly engaging movie by Alfred Hitchcock to drive the recruitment of the fronto-parietal networks, including the dorsal attention (DAN) and executive control (ECN) networks, and their maximal juxtaposition to the DMN in response to the complex stimulus, relative to rest and a scrambled, meaningless movie baseline condition. We tested a control group of healthy participants (N = 13/12) and two groups of patients with disorders of consciousness, one comprised of patients who demonstrated independent, neuroimaging-based evidence of covert external awareness (N = 8), and the other of those who did not (N = 8). Similarly to the healthy controls, only the group of patients with overt and, critically, covert external awareness showed significantly heightened differentiation between the DMN and the DAN in response to movie viewing relative to their resting state time-courses, which was driven by the movie's narrative. This result suggested the presence of functional integrity in the DMN and fronto-parietal networks and their relationship to one another in patients with covert external awareness. Similar to the effect in healthy controls, these networks became more strongly juxtaposed to one another in response to movie viewing relative to the baseline conditions, suggesting the potential for internal and external awareness during complex stimulus processing. Furthermore, our results suggest that naturalistic paradigms can dissociate between groups of DoC patients with and without covert awareness based on the functional integrity of brain networks.


A dermal model for spray painters. Part I: subjective exposure modelling of spray paint deposition.
The discriminative power of existing dermal exposure models is limited. Most models only allow occupational hygienists to rank workers between and within workplaces according to broad bands of dermal exposure. No allowance is made for the work practices of different individuals. In this study a process-based, structured approach has been used to estimate dermal exposure from overspray generated by a spray painting process. Factors for spray technique, object shape and workers' individual work practices involved in the processes of droplet formation and deposition were incorporated into the model. The model was applied to predict dermal exposure of airless spray painters and the results were compared with exposure data. The predicted levels of exposure showed reasonable rank correlation with the measured exposure, although the model tended to over-predict the actual level of exposure. It was concluded that a structured, process-based approach has the potential to produce reliable estimates of dermal exposure. The reliability of exposure models of this type should be explored further and the relationship between the determinants of exposure should be validated by additional field studies.


CVIT expert consensus document on primary percutaneous coronary intervention (PCI) for acute myocardial infarction (AMI) in 2018.
While primary percutaneous coronary intervention (PCI) has significantly contributed to improve the mortality in patients with ST segment elevation myocardial infarction even in cardiogenic shock, primary PCI is a standard of care in most of Japanese institutions. Whereas there are high numbers of available facilities providing primary PCI in Japan, there are no clear guidelines focusing on procedural aspect of the standardized care. Whilst updated guidelines for the management of acute myocardial infarction were recently published by European Society of Cardiology, the following major changes are indicated; (1) radial access and drug-eluting stent over bare metal stent were recommended as Class I indication, and (2) complete revascularization before hospital discharge (either immediate or staged) is now considered as Class IIa recommendation. Although the primary PCI is consistently recommended in recent and previous guidelines, the device lag from Europe, the frequent usage of coronary imaging modalities in Japan, and the difference in available medical therapy or mechanical support may prevent direct application of European guidelines to Japanese population. The Task Force on Primary Percutaneous Coronary Intervention of the Japanese Association of Cardiovascular Intervention and Therapeutics (CVIT) has now proposed the expert consensus document for the management of acute myocardial infarction focusing on procedural aspect of primary PCI.


Report From the International Society of Urological Pathology (ISUP) Consultation Conference on Molecular Pathology of Urogenital Cancers: IV: Current and Future Utilization of Molecular-Genetic Tests for Testicular Germ Cell Tumors.
The International Society of Urological Pathology (ISUP) organized a Consultation Conference in March 2019 dealing with applications of molecular pathology in Urogenital Pathology, including testicular tumors (with a focus on germ cell tumors [GCTs]), preceded by a survey among its members to get insight into current practices in testicular germ cell tumor (TGCT) diagnostics and adoption of the ISUP immunohistochemical guidelines published in 2014. On the basis of the premeeting survey, the most commonly used immunomarker panel includes OCT3/4, placental alkaline phosphate, D2-40, SALL4, CD117, and CD30 for GCTs and the documentation of germ cell neoplasia in situ (GCNIS). Molecular testing, specifically 12p copy gain, is informative to distinguish non-GCNIS versus GCNIS related GCTs, and establishing germ cell origin of tumors both in the context of primary and metastatic lesions. Other molecular methodologies currently available but not widely utilized for TGCTs include genome-wide and targeted approaches for specific genetic anomalies, P53 mutations, genomic MDM2 amplification, and detection of the p53 inactivating miR-371a-3p. The latter also holds promise as a serum marker for malignant TGCTs. This manuscript provides an update on the classification of TGCTs, and describes the current and future role of molecular-genetic testing. The following recommendations are made: (1) Presence of GCNIS should be documented in all cases along with extent of spermatogenesis; (2) Immunohistochemical staining is optional in the following scenarios: identification of GCNIS, distinguishing embryonal carcinoma from seminoma, confirming presence of yolk sac tumor and/or choriocarcinoma, and differentiating spermatocytic tumor from potential mimics; (3) Detection of gain of the short arm of chromosome 12 is diagnostic to differentiate between non-GCNIS versus GCNIS related GCTs and supportive to the germ cell origin of both primary and metastatic tumors.


Post-transcriptional regulation of long noncoding RNAs in cancer.
It is a great surprise that the genomes of mammals and other eukaryotes harbor many thousands of long noncoding RNAs (lncRNAs). Although these long noncoding transcripts were once considered to be simply transcriptional noise or cloning artifacts, multiple studies have suggested that lncRNAs are emerging as new players in diverse human diseases, especially in cancer, and that the molecular mechanisms of lncRNAs need to be elucidated. More recently, evidence has begun to accumulate describing the complex post-transcriptional regulation in which lncRNAs are involved. It was reported that lncRNAs can be implicated in degradation, translation, pre-messenger RNA (mRNA) splicing, and protein activities and even as microRNAs (miRNAs) sponges in both a sequence-dependent and sequence-independent manner. In this review, we present an updated vision of lncRNAs and summarize the mechanism of post-transcriptional regulation by lncRNAs, providing new insight into the functional cellular roles that they may play in human diseases, with a particular focus on cancers.


Effect of the shell material and confinement type on the conversion efficiency of core/shell quantum dot nanocrystal solar cells.
In this study, the effects of the shell material and confinement type on the conversion efficiency of core/shell quantum dot nanocrystal (QDNC) solar cells have been investigated in detail. For this purpose, the conventional, i.e. original, detailed balance model, developed by Shockley and Queisser to calculate an upper limit for the conversion efficiency of silicon p-n junction solar cells, is modified in a simple and effective way to calculate the conversion efficiency of core/shell QDNC solar cells. Since the existing model relies on the gap energy ([Formula: see text]) of the solar cell, it does not make an estimation about the effect of QDNC materials on the efficiency of the solar cells, and gives the same efficiency values for several QDNC solar cells with the same [Formula: see text]. The proposed modification, however, estimates a conversion efficiency in relation to the material properties and also the confinement type of the QDNCs. The results of the modified model show that, in contrast to the original one, the conversion efficiencies of different QDNC solar cells, even if they have the same [Formula: see text], become different depending upon the confinement type and shell material of the core/shell QDNCs, and this is crucial in the design and fabrication of the new generation solar cells to predict the confinement type and also appropriate QDNC materials for better efficiency.


Burden of Atopic Dermatitis in the United States: Analysis of Healthcare Claims Data in the Commercial, Medicare, and Medi-Cal Databases.
Comparative data on the burden of atopic dermatitis (AD) in adults relative to the general population are limited. We performed a large-scale evaluation of the burden of disease among US adults with AD relative to matched non-AD controls, encompassing comorbidities, healthcare resource utilization (HCRU), and costs, using healthcare claims data. The impact of AD disease severity on these outcomes was also evaluated. Adult AD patients in the Commercial (n = 83,106), Medicare (n = 31,060), and Medi-Cal (n = 5550) databases were matched (1:1) to non-AD controls by demographic characteristics. AD patients were stratified by disease severity (higher, lower) using treatment as a surrogate measure of severity. The comorbidity burden, HCRU, and costs were evaluated during a 12-month follow-up period. In the Commercial, Medicare, and Medi-Cal populations, patients with AD had a significantly higher overall comorbidity burden (P < 0.0001), an increased risk of asthma and allergic rhinitis (both P < 0.0001), higher HCRU (P < 0.05), and higher mean total per patient costs (Commercial: US$10,461 versus US$7187; Medicare: US$16,914 versus US$13,714; Medi-Cal; US$19,462 versus US$10,408; all P < 0.0001), compared with matched non-AD controls. Higher disease severity was associated with an increased comorbidity burden (P < 0.0001), HCRU (P < 0.05), and total costs (Commercial: US$14,580 versus US$7192; Medicare: US$21,779 versus US$12,490; Medi-Cal; US$22,123 versus US$16,639; all P < 0.0001) relative to lower severity disease. In this large-scale, healthcare claims database analysis, AD patients had a significantly higher comorbidity burden, HCRU, and costs compared with matched non-AD controls. Higher disease severity was associated with an even greater comorbidity and economic burden. Sanofi and Regeneron Pharmaceuticals, Inc.


Time course of soleus muscle myosin expression during hindlimb suspension and recovery.
This study examined the time course of adult rodent soleus muscle myofibril and myosin isoform protein expression after 4, 8, 16, 28, and 56 days of hindlimb unweighting by tail suspension (S). The time course of soleus muscle recovery (R) was also examined after 28 days of hindlimb unweighting with an additional 4, 8, 16, and 28 days of unrestricted cage activity. During suspension, soleus muscle myofibril protein rapidly decreased from 34.3 +/- 3.1 (1.96SE) mg/pair in the control (C) group to 6.9 +/- 1.4 (1.96SE) mg/pair in S (t = 56 days). The calculated first-order degradation rate constant for this loss was kd = 0.17 days-1 [half time (t1/2) = 4.1 days]. The estimated slow myosin (SM) isoform content decreased from 13.4 +/- 2.0 (1.96SE) mg/pair in C to 2.1 +/- 0.2 (1.96SE) mg/pair in S (kd = 0.19 days-1, t1/2 = 3.6 days). The relative proportion of other myosin isoforms was increased at 28 and 56 days of suspension, reflecting an apparent de novo synthesis and the loss of SM. Recovery of contractile protein after 28 days of suspension was slower for both the myofibril protein and the SM isoform (kd = 0.07 days-1, t1/2 = 10 days). These data suggest that loss of weight bearing specifically affected the mechanisms of contractile protein expression reflected in soleus muscle protein degradation processes. In addition, the expression of the myosin isoforms were apparently differentially affected by the loss of weight-bearing activity.


LYMPHOPARIETAL INDEX IN ESOPHAGEAL CANCER IS STRONGER THAN TNM STAGING IN LONG-TERM SURVIVAL PROGNOSIS IN A LATIN-AMERICAN COUNTRY.
The identification of prognostic factors of esophageal cancer has allowed to predict the evolution of patients. Assess different prognostic factors of long-term survival of esophageal cancer and evaluate a new prognostic factor of long-term survival called lymphoparietal index (N+/T). Prospective study of the Universidad de Chile Clinical Hospital, between January 2004 and December 2013. Included all esophageal cancer surgeries with curative intent and cervical anastomosis. Exclusion criteria included: stage 4 cancers, R1 resections, palliative procedures and emergency surgeries. Fifty-eight patients were included, 62.1% were men, the average age was 63.3 years. A total of 48.3% were squamous, 88% were advanced cancers, the average lymph node harvest was 17.1. Post-operative surgical morbidity was 75%, with a 17.2% of reoperations and 3.4% of mortality. The average overall survival was 41.3 months, the 3-year survival was 31%. Multivariate analysis of the prognostic factors showed that significant variables were anterior mediastinal ascent (p=0.01, OR: 6.7 [1.43-31.6]), anastomotic fistula (p=0.03, OR: 0.21 [0.05-0.87]), N classification (p=0.02, OR: 3.8 [1.16-12.73]), TNM stage (p=0.04, OR: 2.8 [1.01-9.26]), and lymphoparietal index (p=0.04, RR: 3.9 [1.01-15.17]. The ROC curves of lymphoparietal index, N classification and TNM stage have areas under the curve of 0.71, 0.63 and 0.64 respectively, with significant statistical difference (p=0.01). The independent prognostic factors of long-term survival in esophageal cancer are anterior mediastinal ascent, anastomotic fistula, N classification, TNM stage and lymphoparietal index. In esophageal cancer the new lymphoparietal index is stronger than TNM stage in long-term survival prognosis.


Learning curves for Gaussian process regression: approximations and bounds.
We consider the problem of calculating learning curves (i.e., average generalization performance) of gaussian processes used for regression. On the basis of a simple expression for the generalization error, in terms of the eigenvalue decomposition of the covariance function, we derive a number of approximation schemes. We identify where these become exact and compare with existing bounds on learning curves; the new approximations, which can be used for any input space dimension, generally get substantially closer to the truth. We also study possible improvements to our approximations. Finally, we use a simple exactly solvable learning scenario to show that there are limits of principle on the quality of approximations and bounds expressible solely in terms of the eigenvalue spectrum of the covariance function.


Rapid needs assessment among Hurricane Katrina evacuees in metro-Denver.
During September 2005, 3,600 Gulf Coast evacuees arrived in metropolitan Denver, in the aftermath of Hurricane Katrina. To better meet the medical and non-medical needs of this displaced population, a rapid needs assessment was conducted among 106 evacuee households. The assessment identified a large need for prescription medications, with 60.2% of households requiring prescription medications and 38.8% of these households lacking these medications at the time of the survey. The assessment also identified self-reported symptoms consistent with altitude sickness and the region-specific need for education on the effects of Denver's mile-high altitude. Finally, the assessment identified differential needs based on race; non-Hispanic Black households were more likely than non-Hispanic White households to require employment, housing, and dental services. These findings illustrate the importance of conducting rapid needs assessments in displaced populations, to identify unique regional, cultural, and other unanticipated needs, as well as to recognize the needs of specific sub-populations.


The plant CDF family member TgMTP1 from the Ni/Zn hyperaccumulator Thlaspi goesingense acts to enhance efflux of Zn at the plasma membrane when expressed in Saccharomyces cerevisiae.
To avoid metal toxicity, organisms have evolved mechanisms including efflux of metal ions from cells and sequestration into internal cellular compartments. Members of the ubiquitous cation diffusion facilitator (CDF) family are known to play an important role in these processes. Overexpression of the plant CDF family member metal tolerance protein 1 (MTP1) from the Ni/Zn hyperaccumulator Thlaspi goesingense (TgMTP1), in the Saccharomyces cerevisiaeDelta zinc resistance conferring (zrc)1Delta cobalt transporter (cot)1 double mutant, suppressed the Zn sensitivity of this strain. T. goesingense was found to contain several allelic variants of TgMTP1, all of which confer similar resistance to Zn in Deltazrc1Deltacot1. Similarly, MTP1 from various hyperaccumulator and non-accumulator species also confer similar resistance to Zn. Deltazrc1Deltacot1 lacks the ability to accumulate Zn in the vacuole and has lower accumulation of Zn after either long- or short-term Zn exposure. Expression of TgMTP1 in Deltazrc1Deltacot1 leads to further lowering of Zn accumulation and an increase in Zn efflux from the cells. Expression of TgMTP1 in a V-type ATPase-deficient S. cerevisiae strain also confers increased Zn resistance. In vivo and in vitro immunological staining of hemagglutinin (HA)-tagged TgMTP1::HA reveals the protein to be localized in both the S. cerevisiae vacuolar and plasma membranes. Taken together, these data are consistent with MTP1 functioning to enhance plasma membrane Zn efflux, acting to confer Zn resistance independent of the vacuole in S. cerevisiae. Transient expression in Arabidopsis thaliana protoplasts also reveals that TgMTP1::green fluorescent protein (GFP) is localized at the plasma membrane, suggesting that TgMTP1 may also enhance Zn efflux in plants.


Outcomes of patients with submucosal (T1b) esophageal adenocarcinoma: a multicenter cohort study.
The treatment of submucosal (T1b) esophageal adenocarcinoma (EAC) remains in evolution, with some evidence supporting endoscopic management of low-risk lesions. Using a multicenter cohort, we evaluated outcomes of patients with T1b EAC and predictors of survival. Patients diagnosed between 2001 and 2016 with T1b EAC were identified from 3 academic medical centers in the United States. Demographic, clinical, and outcome data were collected. Outcomes studied were overall and cancer-free survival. Cox proportional hazards models were constructed to assess independent predictors of survival. One hundred forty-one patients were included, of whom 68 (48%) underwent esophagectomy and 73 (52%) were treated endoscopically. Most patients (85.8%) had high-risk histologic features. Thirty-day operative mortality was 2.9%. Median follow-up in the esophagectomy and endoscopic cohorts was 49.4 and 43.4 months, respectively. Patients treated endoscopically were older with higher comorbidity scores, with 46 (63%) achieving histologic remission. Nineteen patients (26.0%) also received chemoradiation. Five-year overall survival rates in the surgical and endoscopic cohorts were 89% and 59%, respectively, whereas 5-year cancer-free survival rates were 92% and 69%. Presence of high-risk histologic features was associated with reduced overall survival. In this large multicenter study of patients with T1b EAC, esophagectomy was associated with improved overall but not cancer-free survival. High-risk histologic features were associated with poorer survival.