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Background: The first nationwide lockdown due to the COVID-19 pandemic was implemented in Vietnam from April 1 to 15, 2020. Nevertheless, there has been limited information on the impact of COVID-19 on the psychological health of the public., Objective: This study aimed to estimate the prevalence of psychological issues and identify the factors associated with the psychological impact of COVID-19 during the first nationwide lockdown among the general population in Vietnam., Methods: We employed a cross-sectional study design with convenience sampling. A self-administered, online survey was used to collect data and assess psychological distress, depression, anxiety, and stress of participants from April 10 to 15, 2020. The Impact of Event Scale-Revised (IES-R) and the Depression, Anxiety, and Stress Scale-21 (DASS-21) were utilized to assess psychological distress, depression, anxiety, and stress of participants during social distancing due to COVID-19. Associations across factors were explored using regression analysis., Results: A total of 1385 respondents completed the survey. Of this, 35.9% (n=497) experienced psychological distress, as well as depression (n=325, 23.5%), anxiety (n=195, 14.1%), and stress (n=309, 22.3%). Respondents who evaluated their physical health as average had a higher IES-R score (beta coefficient [B]=9.16, 95% CI 6.43 to 11.89), as well as higher depression (B=5.85, 95% CI 4.49 to 7.21), anxiety (B=3.64, 95% CI 2.64 to 4.63), and stress (B=5.19, 95% CI 3.83 to 6.56) scores for DASS-21 than those who rated their health as good or very good. Those who self-reported their health as bad or very bad experienced more severe depression (B=9.57, 95% CI 4.54 to 14.59), anxiety (B=7.24, 95% CI 3.55 to 10.9), and stress (B=10.60, 95% CI 5.56 to 15.65). Unemployment was more likely to be associated with depression (B=3.34, 95% CI 1.68 to 5.01) and stress (B=2.34, 95% CI 0.84 to 3.85). Regarding worries about COVID-19, more than half (n=755, 54.5%) expressed concern for their children aged <18 years, which increased their IES-R score (B=7.81, 95% CI 4.98 to 10.64) and DASS-21 stress score (B=1.75, 95% CI 0.27 to 3.24). The majority of respondents (n=1335, 96.4%) were confident about their doctor's expertise in terms of COVID-19 diagnosis and treatment, which was positively associated with less distress caused by the outbreak (B=-7.84, 95% CI -14.58 to -1.11)., Conclusions: The findings highlight the effect of COVID-19 on mental health during the nationwide lockdown among the general population in Vietnam. The study provides useful evidence for policy decision makers to develop and implement interventions to mitigate these impacts., (©Khanh Ngoc Cong Duong, Tien Nguyen Le Bao, Phuong Thi Lan Nguyen, Thanh Vo Van, Toi Phung Lam, Anh Pham Gia, Luerat Anuratpanich, Bay Vo Van. Originally published in JMIR Formative Research (http://formative.jmir.org), 15.12.2020.)

Over the past decade, there have been many attempts to engineer systems capable of delivering oxygen to overcome the effects of both systemic and local hypoxia that occurs as a result of traumatic injury, cell transplantation, or tumor growth, among many others. Despite progress in this field, which has led to a new class of oxygen-generating biomaterials, most reported techniques lack the tunability necessary for independent control over the oxygen flux (volume per unit time) and the duration of delivery, both of which are key parameters for overcoming tissue hypoxia of varying etiologies. Here, we show that these critical parameters can be effectively manipulated using hyperbarically-loaded polymeric microcapsules (PMC). PMCs are micron-sized particles with hollow cores and polymeric shells. We show that oxygen delivery through PMCs is dependent on its permeability through the polymeric shell, the shell thickness, and the pressure gradient across the shell. We also demonstrate that incorporating an intermediate oil layer between the polymeric shell and the gas core prevents rapid outgassing by effectively lowering the resultant pressure gradient across the polymeric membrane following depressurization., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Natural disasters can affect mental health and result in symptoms of depression, anxiety, and post-traumatic stress disorder (PTSD). Playback Theatre (PT) is a form of improvisation where actors play-back personal stories told by audience members. Whether PT can be therapeutic in post-disaster settings is not known., Method: We used a series of PT performances and studied levels of depression, anxiety, and PTSD symptoms in a sample of 13 people affected by Hurricane Harvey that happened in Houston, TX, August 2017. Brain imaging, specifically resting state functional connectivity of the amygdala was also studied before and after the PT performances., Results: Both anxiety ( p  = .001, Cohen's d = -1.25) and PTSD ( p  = .002, Cohen's d = -1.0) symptoms significantly decreased after a series of 4 PT performances from January 2019 - February 2019. Depression reduction was not significant. We performed resting state functional connectivity (RSFC) MRI before and after the series of performances. We used the right and left amygdala as seeds for RSFC analysis and found that the connectivity between the left amygdala and the bilateral supramarginal gyri was increased after PT. The bilateral supramarginal connectivity with the default mode and the saliency networks increased too, which correlated with reduction in anxiety scores., Conclusions: PT may offer a form of intervention for anxiety caused by disasters. An increase in left amygdala/supramarginal gyri connectivity may be the underlying mechanism., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2020.)

Background: Prostate cancer (PC) is the most frequently diagnosed cancer in North American men. Pathologists are in critical need of accurate biomarkers to characterize PC, particularly to confirm the presence of intraductal carcinoma of the prostate (IDC-P), an aggressive histopathological variant for which therapeutic options are now available. Our aim was to identify IDC-P with Raman micro-spectroscopy (RμS) and machine learning technology following a protocol suitable for routine clinical histopathology laboratories., Methods and Findings: We used RμS to differentiate IDC-P from PC, as well as PC and IDC-P from benign tissue on formalin-fixed paraffin-embedded first-line radical prostatectomy specimens (embedded in tissue microarrays [TMAs]) from 483 patients treated in 3 Canadian institutions between 1993 and 2013. The main measures were the presence or absence of IDC-P and of PC, regardless of the clinical outcomes. The median age at radical prostatectomy was 62 years. Most of the specimens from the first cohort (Centre hospitalier de l'Université de Montréal) were of Gleason score 3 + 3 = 6 (51%) while most of the specimens from the 2 other cohorts (University Health Network and Centre hospitalier universitaire de Québec-Université Laval) were of Gleason score 3 + 4 = 7 (51% and 52%, respectively). Most of the 483 patients were pT2 stage (44%-69%), and pT3a (22%-49%) was more frequent than pT3b (9%-12%). To investigate the prostate tissue of each patient, 2 consecutive sections of each TMA block were cut. The first section was transferred onto a glass slide to perform immunohistochemistry with H&E counterstaining for cell identification. The second section was placed on an aluminum slide, dewaxed, and then used to acquire an average of 7 Raman spectra per specimen (between 4 and 24 Raman spectra, 4 acquisitions/TMA core). Raman spectra of each cell type were then analyzed to retrieve tissue-specific molecular information and to generate classification models using machine learning technology. Models were trained and cross-validated using data from 1 institution. Accuracy, sensitivity, and specificity were 87% ± 5%, 86% ± 6%, and 89% ± 8%, respectively, to differentiate PC from benign tissue, and 95% ± 2%, 96% ± 4%, and 94% ± 2%, respectively, to differentiate IDC-P from PC. The trained models were then tested on Raman spectra from 2 independent institutions, reaching accuracies, sensitivities, and specificities of 84% and 86%, 84% and 87%, and 81% and 82%, respectively, to diagnose PC, and of 85% and 91%, 85% and 88%, and 86% and 93%, respectively, for the identification of IDC-P. IDC-P could further be differentiated from high-grade prostatic intraepithelial neoplasia (HGPIN), a pre-malignant intraductal proliferation that can be mistaken as IDC-P, with accuracies, sensitivities, and specificities > 95% in both training and testing cohorts. As we used stringent criteria to diagnose IDC-P, the main limitation of our study is the exclusion of borderline, difficult-to-classify lesions from our datasets., Conclusions: In this study, we developed classification models for the analysis of RμS data to differentiate IDC-P, PC, and benign tissue, including HGPIN. RμS could be a next-generation histopathological technique used to reinforce the identification of high-risk PC patients and lead to more precise diagnosis of IDC-P., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: F.D. holds a fellowship co-sponsored by Mitacs and ODS Medical. ODS Medical is a medical device company. A.B. reports grant from Astellas Pharma Canada, Merck and IMV, personal fees from Merck, outside the submitted work; In addition, A.B. has an issued patent on MAGE antigen binding proteins with GSK biologicals.

Background: Linking human genetics and brain imaging data is extremely challenging, among other reasons because both fields suffer from multiple comparison problems., New Method: ProcessGeneLists (PGL) links genetics and human brain imaging by using genes associated with a disease and calculating a normalized mRNA expression average of those genes in each brain region. Brain regions in which those genes are most co-expressed become regions of interest (ROIs) to perform brain imaging in participants with and without the disease, decreasing multiple comparisons. Once a region is identified as "imaging-relevant", the genes most responsible for that ROI being highlighted can be genotyped in the imaged sample. This allows to re-analyze imaging data under the light of likely relevant genetics, to study possible brain imaging/gene variant interactions., Results: As proof-of-concept, we created two lists of genes expressed in the habenula and the striatum, to verified that PGL would highlight those regions. Next, we used a list of genes likely important in alcohol abuse from the literature, which identified several brain regions previously associated with alcohol abuse such as the striatum, habenula, and hippocampus., Comparison With Existing Methods: To our knowledge there is no current method to obtain brain regions of interest from genetics data., Conclusions: Genetics typically asks "which genes are associated with a disease?" while human brain imaging typically asks "which brain regions are associated with a disease?" PGL asks "which genes, via modulation within specific brain regions, are found to be associated with a disease?"., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020. Published by Elsevier B.V.)

The disassembly of apoptotic cells into small membrane-bound vesicles termed apoptotic bodies (ApoBDs) is a hallmark of apoptosis; however, the functional significance of this process is not well defined. We recently discovered a new membrane protrusion (termed beaded apoptopodia) generated by apoptotic monocytes which fragments to release an abundance of ApoBDs. To investigate the function of apoptotic monocyte disassembly, we used influenza A virus (IAV) infection as a proof-of-concept model, as IAV commonly infects monocytes in physiological settings. We show that ApoBDs generated from IAV-infected monocytes contained IAV mRNA, protein and virions and consequently, could facilitate viral propagation in vitro and in vivo, and induce a robust antiviral immune response. We also identified an antipsychotic, Haloperidol, as an unexpected inhibitor of monocyte cell disassembly which could impair ApoBD-mediated viral propagation under in vitro conditions. Together, this study reveals a previously unrecognised function of apoptotic monocyte disassembly in the pathogenesis of IAV infections.

For the first time, native proteorhodopsins of the marine dinoflagellate Oxyrrhis marina were isolated. Total cell membrane fractions were minced in a bead beater and solubilized with the detergent Triton X-100. Subsequent sucrose density gradient centrifugation resulted in three or four red-colored bands. Nonsolubilized, but still red colored, membranes sedimented at the bottom. For each of these bands, absorbance maxima were registered at approximately 514-516 nm with shoulders toward shorter wavelengths (470-490 nm). Sodium dodecyl sulfate-polyacrylamide gel electrophoresis revealed that the uppermost band represented free retinal chromophore, as it contained no protein. The other bands were almost pure proteorhodopsin fractions as the banding patterns showed one major protein of 25 kDa. Tryptic, in-gel digestion of the 25 kDa proteins and of faint protein bands above and below 25 kDa was followed by mass spectrometry, confirming these protein bands to consist, nearly exclusively, proteorhodopsins. Only single peptides of few other proteins were detected. In total, at least seven predicted proteorhodopsin protein sequences were experimentally verified., (© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Introduction: Aminoglycosides are a well-known clinically relevant antibiotic family used to treat bacterial infections in humans and animals and can produce toxic side effects. Aminoglycoside-induced hearing loss (HL) has been shown to have a genetic susceptibility. Mitochondrial DNA mutations have been implicated in inherited and acquired hearing impairment., Objective: Literature review of genetic mutations associated with aminoglycoside-induced ototoxicity., Methods: PubMed was accessed from 1993 to 2017 using the search terms "aminoglycoside, genetic, ototoxicity, hearing loss". Exclusion criteria consisted of a literature in a language other than English, uncompleted or ongoing studies, literature with non-hearing related diseases, literature on ototoxicity due to cisplatin/carboplatin based chemotherapy, literature on ototoxicity from loop diuretics, animal studies, literature studying oto-protective agents, and literature without documented aminoglycoside exposure., Results: 108 articles were originally identified, and 25 articles were included in our review. Mitochondrial 12S rRNA mutations were identified in all 25 studies in a total of 220 patients. Eight studies identified A1555G mutation as primary genetic factor underlying HL in cases of aminoglycoside-induced ototoxicity. The next most common mutation identified was C1494T., Discussion: Mitochondrial 12s rRNA mutation A1555G was present in American, Chinese, Arab-Israeli, Spanish and Mongolian ethnicities. All mutations leading to aminoglycoside ototoxicity were mitochondrial mutations., Conclusions: Consideration of preexisting genetic defects may be valuable in treatments involving aminoglycosides. In particular populations such as those of Chinese origin, clinicians should continue to consider the increased susceptibility to aminoglycosides., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Changes in salinity are known to alter the morphology of protists, and we hypothesized that these changes subsequently alter also the predatory behavior of the dinoflagellate Oxyrrhis marina. Oxyrrhis was grown in media of 33, 25, 20, and 10% of the regular salinity of f/2 medium (31-32‰). In all cases, the cells discharged trichocysts and swelled. Cell surfaces and volumes increased with decreasing salinity, such that cell surface area at least doubled at 10% and the cell volume increased approximately fourfold. After 1 h, the cells started to regain their regular shape, which was almost completed after 24 h. Oxyrrhis immediately regained its regular shape when culture medium was added 5-10 min after the osmotic stress. When incubated with Pyramimonas grossii as prey, those short-term stressed cells showed no significant different prey uptake in comparison to non-stressed cells. In contrast, 24 h after the addition of prey, short-term stressed Oxyrrhis cells had, with weak statistical significance, more Pyramimonas cells engulfed than non-stressed cells. These results indicated that (1) trichocysts were most likely not involved in prey capture and (2) salinity-stressed Oxyrrhis either enhanced its capability to capture more prey, or its digestion apparatus was hampered., (Copyright © 2019 Elsevier GmbH. All rights reserved.)

Purpose: Age-related aortic changes are related to adverse cardiac remodeling and reduced cardiac function. Here, we aim to assess the correlations between aortic arch width (AAW) and left ventricular (LV) remodeling and LV function as well as coronary artery calcification (CAC)., Materials and Methods: This retrospective study included 194 patients (ages, 67±12 y) who underwent both coronary computed tomography angiography and echocardiography. The AAW is defined as the longest width between the ascending and descending aorta on a transaxial noncontrast coronary computed tomography angiography image at the level of the pulmonary artery bifurcation. Left ventricular mass, relative wall thickness ratio, left ventricular ejection fraction, left atrial volume, and early mitral inflow velocity to mitral annular early diastolic velocity ratio (E/e') were evaluated by echocardiography. CAC was assessed by Agatston score. The relationships between AAW and echocardiography parameters were assessed, and adjusted for demographic data and cardiovascular disease risk factors by multivariate linear regression analysis., Results: AAW (mean±SD, 11.6±1.4 cm) was positively correlated with left ventricular mass (r=0.28, P<0.0001), left atrial volume (r=0.28, P<0.0001), and E/e' (r=0.21, P<0.01). These correlations remained significant after adjustment for demographic data and cardiovascular disease risk factors. There was no correlation between AAW and left ventricular ejection fraction or relative wall thickness. There was a significant difference of AAW between the groups with Agatston score <100 and those with Agatston score ≥100, and this difference persisted after adjustment for all covariates (P<0.01)., Conclusion: Greater AAW was significantly associated with LV remodeling and impaired function as well as advanced CAC.

Background: We evaluated the potential of diffusion-weighted MRI (DW-MRI) and 18 F-FDG-PET for the early prediction of a triple negative breast cancer (TNBC) response to cisplatin., Methods: Cisplatin-treated TNBC tumor-bearing mice were categorized as responders or non-responders based on the tumor growth rate. DW-MRI and 18 F-FDG-PET were performed before and after treatment (day 0 and days 3 and 7, respectively). The average apparent diffusion coefficient value (ADC mean ), the highest standardized uptake value (SUV max ), and the metabolic tumor volume (MTV) were measured. The ratios of each parameter relative to day 0 were calculated [ΔADC mean (day 3) and (day 7), ΔSUV max (day 3) and (day 7), and ΔMTV (day 3) and (day 7), respectively]. Overall survival rates were compared based on the thresholds determined by these parameters., Results: Both the day 3 and day 7 ratios of ADC mean and MTV showed significant differences between the responder and non-responder groups, whereas the ratios of SUV max did not. Mice with ΔADC mean (day 3) exceeding the threshold showed a longer overall survival rate. Mice with ΔSUV max (day 7), ΔMTV (day 3), and ΔMTV (day 7) below the respective thresholds showed a longer overall survival rate., Conclusions: The ratios of ADC mean , SUV max , and MTV have the potential to predict the therapeutic response and to screen non-responders in the ultra-early phase following cisplatin treatment in patients with TNBC.

In this work, we report the anticancer properties of a series of 11 chemically synthesized alkylaminophenols against human osteosarcoma U2OS tumor cell line. Several assays including cytotoxicity, inhibitor kinetic study, cell migration, Annexin-V/PI double staining, reactive oxygen species (ROS) and caspase 3/7 assays were conducted on this cell line. Cytotoxic 2-((3,4-dihydroquinolin-1(2H)-yl)(p-tolyl)methyl)phenol was determined to have an IC 50 value of 36.6μM against U2OS cells and it also inhibits the cell growth in time-dependent manner. The potent activity of lead compound against the growth of multiple cell lines, U2OS, MG-65 and HEK-293T, confirms the osteosarcoma cell specific inhibition. Further studies indicated that such compound is an inhibitor of metastatic property of tumor cells and inducing apoptosis agent. The ability of increasing ROS and inducing caspases 3 and 7 further confirm the contribution of programmed cell death in U2OS and HEK-293T cells. Additionally, four compounds based on the 2-(indolin-1-yl(aryl)methyl)-4-nitrophenol core were also identified to be cytotoxic with IC 50 values in the 66-88μM range. This work further demonstrates the anticancer properties of phenol derivatives, adding one more entry to the collection of promising chemotherapeutic agents for cancer treatment., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objective: To analyse patterns of knowledge, comprehension, attitudes and practices regarding the traffic light label placed on processed food packages to inform Ecuadorian consumers about levels of added fat, sugar and salt., Design: Twenty-one focus group discussions organized by age group, sex and place of residence. Interviews with representatives of companies that manufacture or market processed foods. Analysis of regulations and structured observations of processed food labels., Setting: Cities and towns in Ecuador's coastal, highland and eastern lowland regions., Subjects: One hundred and seventy-eight participants in twenty-one focus group discussions and nine key informants., Results: Focus group participants knew about the traffic light label and understood the information it conveys, but not all changed their attitudes and practices related to the purchase and consumption of processed foods. Children, adolescents and adult males reported using the information infrequently; adolescents interested in health and adult women used the label the most to select products. Representatives of companies that manufacture or market processed foods generally opposed the policy, stating that the information is misleading. Nevertheless, some companies have reduced levels of added fat, sugar or salt in their products., Conclusions: The traffic light label is an effective tool for conveying complex information. Its potential contribution to reduce consumption of products with high levels of fat, sugar and salt could be enhanced by promoting healthy diets among consumers who have not changed purchasing and consumption behaviour, by placing the label on front panels and by monitoring the production and marketing of processed foods.

Objectives: To determine the correlation between the spot albumin-to-creatinine (ACR) ratio and protein-to-creatinine ratio (PCR) in pregnancy and if either test is predictive of adverse pregnancy outcome., Study Design: Prospective consecutive cohort study in a single tertiary centre examining 181 patients undergoing proteinuria screening after 20weeks of pregnancy. A spot PCR and ACR was performed on the first void of the day. Comparison was with linear and logistic regression and ROC curve. Optimal values for the ACR were obtained and compared to a PCR value of 30mg/mmol with respect to adverse pregnancy outcomes., Main Outcome Measures: Birth weight <10th centile, preterm birth <32 and <37weeks, placental abruption, caesarean section, induction of labour, fetal death in utero or neonatal death, Apgar score <5 at 1min and/or 5min, pulmonary oedema, sustained blood pressure >170/110mmHg, magnesium infusion or labetalol infusion during labour., Results: 254 tests were performed. The ACR and PCR were highly correlated (r=0.95, p<0.001) and the area under ROC curve was 0.98. An ACR of 13.4mg/mmol corresponded to a PCR of 30mg/mmol. Neither was more predictive of adverse pregnancy outcome nor was the level of proteinuria., Conclusions: The ACR is not inferior to nor does it perform better than the PCR in screening for proteinuria in pregnancy. Clinicians should use the test with which they are more familiar and may wish to assess local laboratory costs and methods in their selection., (Copyright © 2015 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)

Importance: Effective patient-physician communication is essential for optimal health care. Recent introduction of online patient portals to access test results are changing the communication landscape, but regulatory guidelines for the online release of biopsy results vary from state to state., Objectives: To assess patient preferences for receiving skin biopsy results to rule out melanoma and to compare those preferences to current physicians' practices for notification., Design, Setting, and Participants: English-speaking individuals 18 years or older were recruited consecutively from melanoma clinics at 3 academic tertiary referral medical centers: University of California, San Francisco, University of Pennsylvania, and Duke University. Patients were surveyed from July 1, 2012, through July 31, 2013. A second survey of physicians at these institutions was conducted to assess physician notification practices., Results: A total of 301 of 305 patients agreed to participate (98.7 response rate). Most of the patients (67.1%) preferred to speak directly with their physician by telephone to receive their skin biopsy results, followed by a distant second choice (19.5%) of being notified in person at a clinic visit. Voice message or online patient portal were each the preferred method of communication for 5.1% of patients. The most important consideration for patients was a communication modality that provided test results in the most rapid manner; 51.7% wanted a method that was rapid, and 7.8% preferred a method that was not only speedy but also allowed them an opportunity to ask questions. A total of 59.5% of the study participants would choose the same communication method regardless of the biopsy results, but 40.5% preferred a different mode of notification if their biopsy results revealed a malignant tumor. Younger and more highly educated patients favored the online portal. Of 84 physicians surveyed, 47 responded (56% response rate). Physicians' overall preferred method of contacting patients aligned with patient preference for speaking by telephone (56.5%). However, for benign results, 31.2% of physicians chose to speak by telephone, whereas patients preferred voicemail (32.1%). There was physician uncertainty as to guidelines regarding communication of test results., Conclusions and Relevance: Patient preference has shifted from face-to-face visit to discussion over the telephone because of a desire for rapid notification. Experience with online portal delivery of results favorably inclined patients toward that modality. We recommend that patients be queried regarding their notification preference on the biopsy consent form.

Thyroid hormone levels are implicated in mood disorders in the adult human but the mechanisms remain unclear partly because, in rodent models, more attention has been paid to the consequences of perinatal hypo and hyperthyroidism. Thyroid hormones act via the thyroid hormone receptor (TR) α and β isoforms, both of which are expressed in the limbic system. TR's modulate gene expression via both unliganded and liganded actions. Though the thyroid hormone receptor (TR) knockouts and a transgenic TRα1 knock-in mouse have provided us valuable insight into behavioral phenotypes such as anxiety and depression, it is not clear if this is because of the loss of unliganded actions or liganded actions of the receptor or due to locomotor deficits. We used a hypothyroid mouse model and supplementation with tri-iodothyronine (T3) or thyroxine (T4) to investigate the consequences of dysthyroid hormone levels on behaviors that denote anxiety. Our data from the open field and the light-dark transition tests suggest that adult onset hypothyroidism in male mice produces a mild anxiogenic effect that is possibly due to unliganded receptor actions. T3 or T4 supplementation reverses this phenotype and euthyroid animals show anxiety that is intermediate between the hypothyroid and thyroid hormone supplemented groups. In addition, T3 but not T4 supplemented animals have lower spine density in the CA1 region of the hippocampus and in the central amygdala suggesting that T3-mediated rescue of the hypothyroid state might be due to lower neuronal excitability in the limbic circuit., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Recent genome-wide association studies (GWAS) have identified multiple genetic risk factors for psoriasis, but data on their association with age of onset have been marginally explored. The goal of this study was to evaluate known risk alleles of psoriasis for association with age of psoriasis onset in three well-defined case-only cohorts totaling 1,498 psoriasis patients. We selected 39 genetic variants from psoriasis GWAS and tested these variants for association with age of psoriasis onset in a meta-analysis. We found that rs10484554 and rs12191877 near HLA-C and rs17716942 near IFIH1 were associated with age of psoriasis onset with false discovery rate < 0.05. The association between rs17716942 and age of onset was not replicated in a fourth independent cohort of 489 patients (P = 0.94). The imputed HLA-C∗06:02 allele demonstrated a much stronger association with age of psoriasis onset than rs10484554 and rs12191877. We conclude that despite the discovery of numerous psoriasis risk alleles, HLA-C∗06:02 still plays the most important role in determining the age of onset of psoriasis. Larger studies are needed to evaluate the contribution of other risk alleles, including IFIH1, to age of psoriasis onset.

Psoriasis is a chronic, auto-inflammatory disease affecting millions of individuals worldwide. In addition to classic cutaneous manifestations, the condition is linked to significant co-morbidities including cardiovascular disease, metabolic syndrome, melanoma and non-melanoma skin cancer, and psychiatric disease. Therefore, more aggressive treatment and multi-disciplinary care is critical. Measures of disease burden (quantified by anatomic location, body surface area (BSA) of involvement, and impact on daily life) assist in determining the severity of disease and have been integral in objective assessment of treatment regimens and new drug therapies. Biologic agents have entered the clinical armamentarium as treatment options for patients with moderate-to-severe psoriasis who have failed traditional systemic therapies. Three of the four FDA-approved biologic agents for psoriasis suppress TNF-α mediated pathways, which are essential for granuloma formation and maintenance, key components of host defenses against intracellular pathogens. Subsequently, the increased use of these agents is accompanied by increased reporting of granulomatous infectious diseases such as tuberculosis, histoplasmosis, nocardia, and nontuberculous mycobacteria. Report of any unusual infection is therefore vitally important in the care of this immune suppressed patient population.

We report the discovery of nontoxic fungicide fenarimol (1) as an inhibitor of Trypanosoma cruzi ( T. cruzi ), the causative agent of Chagas disease, and the results of structure-activity investigations leading to potent analogues with low nM IC(50)s in a T. cruzi whole cell in vitro assay. Lead compounds suppressed blood parasitemia to virtually undetectable levels after once daily oral dosing in mouse models of T. cruzi infection. Compounds are chemically tractable, allowing rapid optimization of target biological activity and drug characteristics. Chemical and biological studies undertaken in the development of the fenarimol series toward the goal of delivering a new drug candidate for Chagas disease are reported.

Traumatic rupture of the aorta in the rare setting of the aberrant right subclavian artery (ARSA) requires special consideration to prevent the occurrence of a devastating posterior cerebral circulation stroke. We present three cases managed by using an endovascular approach, with a discussion of important preoperative and operative issues. Three patients involved in motor vehicle collisions with multiple injuries were managed at two institutions. Computed tomography revealed transection of the aorta with incidental ARSA. All three cases were managed with a different approach. One patient did not undergo a preoperative bypass because imaging confirmed an adequate landing zone distal to the origin of the left subclavian artery. Two patients received preoperative right carotid-to-subclavian bypass for anticipated endograft coverage of both subclavian arteries to preserve single vertebral arterial flow. In one patient, an endovascular occlusion device was deployed in the ARSA before aortic endograft deployment. In the other, ARSA occlusion was performed 4 days later for a persistent type II endoleak. The patient who underwent bypass and preoperative ARSA occlusion suffered a fatal posterior circulation stroke shortly after surgery. The other two patients had no procedural complications and have not required any reinterventions at follow-up after 2 and 5 years. One patient is still undergoing rehabilitation after 5 years of follow-up for traumatic brain injury unrelated to the endograft repair. Although the incidence of ARSA is very low, preoperative imaging and assessment of cerebral blood flow are critical to prevent a perioperative stroke. Revascularization, if required to achieve a secure proximal landing zone, must be performed before endograft deployment. Bilateral subclavian revascularization is indicated if anomalies of the cerebral circulation are present., (Copyright © 2011 Annals of Vascular Surgery Inc. Published by Elsevier Inc. All rights reserved.)

Ozonide OZ439 is a synthetic peroxide antimalarial drug candidate designed to provide a single-dose oral cure in humans. OZ439 has successfully completed Phase I clinical trials, where it was shown to be safe at doses up to 1,600 mg and is currently undergoing Phase IIa trials in malaria patients. Herein, we describe the discovery of OZ439 and the exceptional antimalarial and pharmacokinetic properties that led to its selection as a clinical drug development candidate. In vitro, OZ439 is fast-acting against all asexual erythrocytic Plasmodium falciparum stages with IC(50) values comparable to those for the clinically used artemisinin derivatives. Unlike all other synthetic peroxides and semisynthetic artemisinin derivatives, OZ439 completely cures Plasmodium berghei-infected mice with a single oral dose of 20 mg/kg and exhibits prophylactic activity superior to that of the benchmark chemoprophylactic agent, mefloquine. Compared with other peroxide-containing antimalarial agents, such as the artemisinin derivatives and the first-generation ozonide OZ277, OZ439 exhibits a substantial increase in the pharmacokinetic half-life and blood concentration versus time profile in three preclinical species. The outstanding efficacy and prolonged blood concentrations of OZ439 are the result of a design strategy that stabilizes the intrinsically unstable pharmacophoric peroxide bond, thereby reducing clearance yet maintaining the necessary Fe(II)-reactivity to elicit parasite death.

Background: There is an urgent need to develop new, safe and effective treatments for human African trypanosomiasis (HAT) because current drugs have extremely poor safety profiles and are difficult to administer. Here we report the discovery of 2,4-diaminopyrimidines, exemplified by 4-[4-amino-5-(2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidine-1-carboxylic acid phenylamide (SCYX-5070), as potent inhibitors of Trypanosoma brucei and the related trypanosomatid protozoans Leishmania spp., Methodology/principal Findings: In this work we show that loss of T. brucei viability following SCYX-5070 exposure was dependent on compound concentration and incubation time. Pulse incubation of T. brucei with SCYX-5070 demonstrates that a short period of exposure (10-12 hrs) is required to produce irreversible effects on survival or commit the parasites to death. SCYX-5070 cured an acute trypanosomiasis infection in mice without exhibiting signs of compound related acute or chronic toxicity. To identify the molecular target(s) responsible for the mechanism of action of 2,4-diaminopyrimidines against trypanosomatid protozoa, a representative analogue was immobilized on a solid matrix (sepharose) and used to isolate target proteins from parasite extracts. Mitogen-activated protein kinases (MAPKs) and cdc2-related kinases (CRKs) were identified as the major proteins specifically bound to the immobilized compound, suggesting their participation in the pharmacological effects of 2,4-diaminopyrimidines against trypanosomatid protozoan parasites., Conclusions/significance: Results show that 2,4-diaminopyrimidines have a good in vitro and in vivo pharmacological profile against trypanosomatid protozoans and that MAPKs and CRKs are potential molecular targets of these compounds. The 2,4-diminipyrimidines may serve as suitable leads for the development of novel treatments for HAT.

Phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2) is the most recently identified phosphoinositide, and its functions have yet to be fully elucidated. Recently, members of our muscle group have shown that PI(3,5)P2 plays an important role in skeletal muscle function by altering Ca(2+) homeostasis. Therefore, we hypothesized that PI(3,5)P2 may also modulate cardiac muscle contractility by altering intracellular Ca(2+) ([Ca(2+)](i)) in cardiac myocytes. We first confirmed that PI(3,5)P2 was present and increased by insulin treatment of cardiomyocytes via immunohistochemistry. To examine the acute effects of PI(3,5)P2 treatment, electrically paced left ventricular muscle strips were incubated with PI(3,5)P2. Treatment with PI(3,5)P2 increased the magnitude of isometric force, the rate of force development, and the area associated with the contractile waveforms. These enhanced contractile responses were also observed in MIP/Mtmr14(-/-) mouse hearts, which we found to have elevated levels of PI(3,5)P2. In cardiac myocytes loaded with fura-2, PI(3,5)P2 produced a robust elevation in [Ca(2+)](i). The PI(3,5)P2-induced elevation of [Ca(2+)](i) was not present in conditions free of extracellular Ca(2+) and was completely blocked by ryanodine. We investigated whether the phosphoinositide acted directly with the Ca(2+) release channels of the sarcoplasmic reticulum (ryanodine receptors; RyR2). PI(3,5)P2 increased [(3)H]ryanodine binding and increased the open probability (P(o)) of single RyR2 channels reconstituted in lipid bilayers. This strongly suggests that the phosphoinositide binds directly to the RyR2 channel. Thus, we provide inaugural evidence that PI(3,5)P2 is a powerful activator of sarcoplasmic reticulum Ca(2+) release and thereby modulates cardiac contractility.

Malaria is a serious infectious disease caused by protozoan parasites in tropical and subtropical regions. Even inhabitants of temperate zones are exposed to the danger of malaria infection because of travel and global warming. Novel, effective, safe, and inexpensive drugs are required to treat malaria and contribute to the global goal of eradication. A search for new antimalarial agents has been performed by the synthesis of new benzo[a]phenoxazines, followed by biological evaluations. The derivative SSJ-183 (5), having a 4-aminopyridine group, showed an IC50 value against Plasmodium falciparum of 7.6 nM and a selectivity index of >7300. Cure was achieved by three oral doses of 5 at 100 mg/kg to mice infected with the Plasmodium berghei ANKA strain. The safety of 5 was supported by acute toxicity testing in mice with single doses up to 2000 mg/kg po, chromosome aberration test, in vitro as well as in vivo micronucleus tests, and phototoxicity studies in mice. Thus, 5 is a promising candidate as a new antimalarial agent.

Background: Glove powder is used as a lubricant on the inner surface of many surgical gloves to aid in donning. Although surgeons routinely wash or wipe their gloves to remove the powder, studies in patients have shown that, at the conclusion of operations in which powdered gloves have been used, the wound retains a substantial amount of residual powder granules. Furthermore, the amount of residual granules is in proportion to the number of gloves that the operating room staff wear. We determined whether glove powder in combination with Staphylococcus aureus when injected into the subcutaneous tissue of the dorsum of the rat would potentiate abscess formation., Methods: We combined methicillin-susceptible S. aureus (MSSA) in concentrations of 0, 10(2), 10(3), 10(4), and 10(5) colony forming units (cfu)/mL and starch powder in concentrations of 0, 10, 50, and 100 mg/mL and injected the inoculum into each flank of 105 Sprague-Dawley rats. Animals were euthanized 7 to 10 days after inoculation and examined for signs of abscess formation. Wounds were cultured to verify S. aureus as the causative organism., Results: No abscesses formed in our control animals (sterile inoculum). Increasing concentrations of MSSA and increasing starch powder led to more-frequent abscess formation. The presence of high concentration of starch (100 mg/mL) decreased the inoculum of bacteria needed to produce an abscess from 10(4) to 10(2) cfu/mL. The presence of starch, regardless of concentration, increased the likelihood of abscess formation in the presence of bacteria (odds ratio = 1.8, 95% confidence interval = 1.06, 2.57)., Conclusion: Surgical glove power reduces the inoculum of bacteria needed to produce an abscess and increases the likelihood of abscess formation in Sprague-Dawley rats.

Background: : Routine predictions made by surgeons or historical mean durations have only limited capacity to predict operating room (OR) time. The authors aimed to devise a prediction model using the surgeon's estimate and characteristics of the surgical team, the operation, and the patient., Methods: : Seventeen thousand four hundred twelve consecutive, elective operations from the general surgical department in an academic hospital were analyzed. The outcome was OR time, and the potential predictive factors were surgeon's estimate, number of planned procedures, number and experience of surgeons and anesthesiologists, patient's age and sex, number of previous hospital admissions, body mass index, and eight cardiovascular risk factors. Linear mixed modeling on the logarithm of the total OR time was performed., Results: : Characteristics of the operation and the team had the largest predictive performance, whereas patient characteristics had a modest but distinct effect on OR time: operations were shorter for patients older than 60 yr, and higher body mass index was associated with longer OR times. The surgeon's estimate had an independent and substantial contribution to the prediction, and the final model explained 27% of the residual variation in log (OR time). Using the prediction model instead of the surgeon's prediction based on historical averages would reduce shorter-than-predicted and longer-than-predicted OR time by 2.8 and 6.6 min per case (a relative reduction of 12 and 25%, respectively), assessed on independent validation data., Conclusions: : Detailed information on the operative session, the team, and the patient substantially improves the prediction of OR times, but the surgeon's estimate remains important. The prediction model may be used in OR scheduling.

We report the development of a gene replacement strategy for very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency. VLCAD is a mitochondrial enzyme involved in fatty acid beta-oxidation, a key step in energy production during times of fasting or stress. Deficiency of VLCAD classically presents as hepatic dysfunction, hypoglycemia, cardiomyopathy, rhabdomyolysis, and/or sudden death. While dietary therapy for VLCAD deficiency has proven beneficial in preventing some symptoms, a risk of metabolic catastrophic decompensation remains throughout life during times of increased energy demand. We designed a recombinant adeno-associated virus (AAV) expressing the human VLCAD gene (AAV8-hVLCAD). To demonstrate its in vivo activity, AAV8-hVLCAD was administered via the tail vein to VLCAD-knockout mice. A reduction in accumulated serum long-chain acylcarnitines and increased fasting tolerance judged on blood glucose concentrations were observed as of 11 days postinjections through >100 days. Western analysis of liver, skeletal muscle, and heart extracts using PEP1 anti-hVLCAD antibody revealed short-term hVLCAD expression in the liver and muscle and longer-term expression in heart. This demonstrates the ability of human VLCAD to correct the biochemical phenotype of VLCAD-deficient mice.

Background: The role of minimally invasive gastrectomy in the treatment of gastric cancer is not well defined. The aim of the current study was to compare the operative outcomes and adequacy of resection of laparoscopic gastrectomy compared to open gastrectomy for gastric cancer., Methods: The clinical course of 15 consecutive patients who underwent minimally invasive gastrectomy or esophagogastrectomy for gastric cancer were compared with that of 21 patients who underwent open gastrectomy. Main outcome measures included operative time, blood loss, length of stay, morbidity, 30-day mortality, and adequacy of lymphadenectomy and resection margins., Results: There was no conversion to laparotomy in the laparoscopic group. Intraoperative blood loss was significantly lower in the laparoscopic group (138 mL vs. 357 mL). There was no significant differences in the mean operative time (244 vs. 241 min.), transfusion rate (6% vs. 29%), median length of stay (6 vs. 7 days), morbidity (7% vs. 24%), or number of lymph nodes harvested (15 vs. 14 nodes) between the 2 groups. Resection margins were negative in all patients. There were no leaks and the 30-day mortality was 0 in both groups. Anastomotic strictures were higher in the laparoscopic patients., Conclusion: Laparoscopic gastrectomy is feasible and can be performed safely with adequate lymphadenectomy compared with open gastrectomy.

Quality of life (QoL) is an important measure of outcome after bariatric surgery. Impairment in QoL has been well documented in morbidly obese patients before undergoing bariatric surgery and has been shown to improve significantly within 3 months after the operative intervention. Improvement in QoL should be recognized as one of the benefits of bariatric surgery that can be quantified.

Context: Pancreatic schwannomas are rare neoplasms. These tumors vary in size and two thirds are partially cystic which grossly mimic pancreatic cystic lesions. Computed tomography and magnetic resonance imaging are the primary initial imaging modalities. Definitive diagnosis is typically made at the time of laparotomy following biopsy. Surgical resection is the mainstay of treatment., Case Report: A 69-year-old woman presented with abdominal pain in the epigastric and left upper quadrant. The patient had no systemic symptom and laboratory results including tumor markers were negative. A CT scan of the abdomen showed a 5 cm mass arising from the head of the pancreas. Needle biopsy revealed a mass consistent with schwannoma. At laparotomy, a large pancreatic head mass was found to encase the superior mesenteric artery, and portal vein confluence. Frozen biopsy showed schwannoma. Curative resection was deferred due to extensive vascular involvement and favorable tumor biology. A gastrojejunostomy was performed and radiation therapy was instituted post-operatively., Conclusions: Only 24 cases of pancreatic schwannoma had been previously reported. Definitive diagnosis is obtained with routine histology. Most tumors are benign and surgical resection is curative. The role of radiation therapy in the management of unresectable tumors is still unclear.

Study Objective: To evaluate the benefits obtained during the learning phase of laparoscopic nephrectomy (LN) for clinical stage cT1 and cT2 renal cancers., Patients and Methods: We retrospectively compared our first 25 cases of LN (13 right, 12 left) with 32 nephrectomies performed by Conventional Surgery (CS) (17 right, 15 left) between May 2000 and December 2001. The LN group comprised 18 men and 7 women with a mean age of 63.8 years. The CS group comprised 18 men and 14 women with a mean age of 67.7 years. Preoperative, intraoperative, postoperative and histological parameters were compared by analysis of the variance or nonparametric Mann-Whitney U test for quantitative variables and Chi-square test for qualitative data., Results: Preoperative and histological parameters, blood loss, quantity and duration of analgesics and the complication rate were similar in the two groups. Resection was complete in every case. The mean duration of radical nephrectomy was significantly shorter by CS (p < 0.001). Return of bowel sounds was more rapid (p = 0.002) and patients were discharged from hospital earlier (p = 0.004) after LN., Conclusion: Laparoscopic nephrectomy for cancer must be performed by an operator experienced in laparoscopy. During the learning phase, this procedure provided benefits in terms of return of bowel sounds and length of hospital stay, which should encourage teams performing laparoscopy to perform radical nephrectomy by laparoscopy.

RWJ-54428 (MC-02,479) is a new cephalosporin active against gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). The potency of this new cephalosporin against MRSA is related to a high affinity for penicillin-binding protein 2a (PBP 2a), as assessed in a competition assay using biotinylated ampicillin as the reporter molecule. RWJ-54428 had high activity against MRSA strains COL and 67-0 (MIC of 1 micro g/ml) and also showed affinity for PBP 2a, with a 50% inhibitory concentration (IC(50)) of 0.7 micro g/ml. RWJ-54428 also displayed excellent affinity for PBP 5 from Enterococcus hirae R40, with an IC(50) of 0.8 micro g/ml and a MIC of 0.5 micro g/ml. The affinity of RWJ-54428 for PBPs of beta-lactam-susceptible S. aureus (MSSA), enterococci (E. hirae), and Streptococcus pneumoniae showed that the good affinity of RWJ-54428 for MRSA PBP 2a and E. hirae PBP 5 does not compromise its binding to susceptible PBPs. RWJ-54428 showed stability to hydrolysis by purified type A beta-lactamase isolated from S. aureus PC1. In addition, RWJ-54428 displayed low MICs against strains of S. aureus bearing the four classes of staphylococcal beta-lactamases, including beta-lactamase hyperproducers. The frequency of isolation of resistant mutants to RWJ-54428 from MRSA strains was very low. In summary, RWJ-54428 has high affinity to multiple PBPs and is stable to beta-lactamase, properties that may explain our inability to find resistance by standard methods. These data are consistent with its excellent activity against beta-lactam-resistant gram-positive bacteria.