De novo assembly and phasing of a Korean human genome.
Advances in genome assembly and phasing provide an opportunity to investigate the diploid architecture of the human genome and reveal the full range of structural variation across population groups. Here we report the de novo assembly and haplotype phasing of the Korean individual AK1 (ref. 1) using single-molecule real-time sequencing, next-generation mapping, microfluidics-based linked reads, and bacterial artificial chromosome (BAC) sequencing approaches. Single-molecule sequencing coupled with next-generation mapping generated a highly contiguous assembly, with a contig N50 size of 17.9 Mb and a scaffold N50 size of 44.8 Mb, resolving 8 chromosomal arms into single scaffolds. The de novo assembly, along with local assemblies and spanning long reads, closes 105 and extends into 72 out of 190 euchromatic gaps in the reference genome, adding 1.03 Mb of previously intractable sequence. High concordance between the assembly and paired-end sequences from 62,758 BAC clones provides strong support for the robustness of the assembly. We identify 18,210 structural variants by direct comparison of the assembly with the human reference, identifying thousands of breakpoints that, to our knowledge, have not been reported before. Many of the insertions are reflected in the transcriptome and are shared across the Asian population. We performed haplotype phasing of the assembly with short reads, long reads and linked reads from whole-genome sequencing and with short reads from 31,719 BAC clones, thereby achieving phased blocks with an N50 size of 11.6 Mb. Haplotigs assembled from single-molecule real-time reads assigned to haplotypes on phased blocks covered 89% of genes. The haplotigs accurately characterized the hypervariable major histocompatability complex region as well as demonstrating allele configuration in clinically relevant genes such as CYP2D6. This work presents the most contiguous diploid human genome assembly so far, with extensive investigation of unreported and Asian-specific structural variants, and high-quality haplotyping of clinically relevant alleles for precision medicine.


Telecare for patients with type 1 diabetes and inadequate glycemic control: a randomized controlled trial and meta-analysis.
To determine the efficacy of telecare (modem transmission of glucometer data and clinician feedback) to support intensive insulin therapy in patients with type 1 diabetes and inadequate glycemic control. Thirty-one patients with type 1 diabetes on intensive insulin therapy and with HbA1c >7.8% were randomized to telecare (glucometer transmission with feedback) or control (glucometer transmission without feedback) for 6 months. The primary end point was 6-month HbA1c. To place our findings in context, we pooled HbA1c change from baseline reported in randomized trials of telecare identified in a systematic review of the literature. Compared with the control group, telecare patients had a significantly lower 6-month HbA1c (8.2 vs. 7.8%, P = 0.03, after accounting for HbA1c at baseline) and a nonsignificant fourfold greater chance of achieving 6-month HbA1c < or =7% (29 vs. 7%; risk difference 21.9%, 95% CI -4.7 to 50.5). Nurses spent 50 more min/patient giving feedback on the phone with telecare patients than with control patients. Meta-analysis of seven randomized trials of adult patients with type 1 diabetes found a 0.4% difference (95% CI 0-0.8) in HbA1c mean change from baseline between the telecare and control groups. Telecare is associated with small effects on glycemic control in patients with type 1 diabetes on intensive insulin therapy but with inadequate glycemic control.


Rapid pulse shaping with homodyne detection for measuring nonlinear optical signals.
We have designed a common-mode interferometric acousto-optic pulse shaper that is capable of shaping individual pulses differently from a mode-locked laser. The design enables the measurement of weak nonlinear optical signals such as two-photon absorption and self-phase modulation at megahertz rates. The experimental apparatus incorporates homodyne detection as a means of resolving the phase of the detected signals. The fast data acquisition rate and the ability to perform measurements in scattering media make this experimental apparatus amenable to imaging applications analogous to measurements of two-photon fluorescence using a mode-locked laser.


Extinction dynamics of a discrete population in an oasis.
Understanding the conditions ensuring the persistence of a population is an issue of primary importance in population biology. The first theoretical approach to the problem dates back to the 1950s with the Kierstead, Slobodkin, and Skellam (KiSS) model, namely a continuous reaction-diffusion equation for a population growing on a patch of finite size L surrounded by a deadly environment with infinite mortality, i.e., an oasis in a desert. The main outcome of the model is that only patches above a critical size allow for population persistence. Here we introduce an individual-based analog of the KiSS model to investigate the effects of discreteness and demographic stochasticity. In particular, we study the average time to extinction both above and below the critical patch size of the continuous model and investigate the quasistationary distribution of the number of individuals for patch sizes above the critical threshold.


Magnesium as a neuroprotectant in cardiac surgery: a randomized clinical trial.
We sought to evaluate magnesium as a neuroprotectant in patients undergoing cardiac surgery with cardiopulmonary bypass. From February 2002 to September 2003, 350 patients undergoing elective coronary artery bypass grafting, valve surgery, or both were enrolled in a randomized, blinded, placebo-controlled trial to receive either magnesium sulfate to increase plasma levels 1(1/2) to 2 times normal during cardiopulmonary bypass (n = 174) or no intervention (n = 176). Neurologic function, neuropsychologic function, and depression were assessed preoperatively, at 24 and 96 hours after extubation (neurologic) and at 3 months (neuropsychologic, depression). Neurologic scores were analyzed using ordinal longitudinal methods, and neuropsychologic and depression inventory data were summarized by principal component analysis, followed by linear regression analysis using component scores as response variables. Seven (2%) patients had a postoperative stroke, 2 (1%) in the magnesium and 5 (3%) in the placebo group (P = .4). Neurologic score was worse postoperatively in both groups (P < .0001); however, magnesium group patients performed better than placebo group patients (P = .0001), who had prolonged declines in short-term memory and reemergence of primitive reflexes. Three-month neuropsychologic performance and depression inventory score were generally better than preoperatively, with few differences between groups (P > .6); however, older age (P = .0006), previous stroke (P = .003), and lower education level (P = .0007) were associated with worse performance. Magnesium administration is safe and improves short-term postoperative neurologic function after cardiac surgery, particularly in preserving short-term memory and cortical control over brainstem functions. However, by 3 months, other factors and not administration of magnesium influence neuropsychologic and depression inventory performance.


Does Primary Hip Arthroscopy Result in Improved Clinical Outcomes?: 2-Year Clinical Follow-up on a Mixed Group of 738 Consecutive Primary Hip Arthroscopies Performed at a High-Volume Referral Center.
Hip arthroscopy has gained increasing popularity over the past decade. The need to develop metrics to evaluate success and complications in primary hip arthroscopy is an important goal. To evaluate 2-year patient-related outcome (PRO) scores and patient satisfaction scores for a single surgeon at a high-volume referral center for all primary hip arthroscopy procedures performed. Case series; Level of evidence, 4. During the study period between April 2008 and October 2011, data were collected on all patients who underwent primary hip arthroscopy. All patients were assessed pre- and postoperatively with 4 PRO measures: the modified Harris Hip Score (mHHS), Non-Arthritic Hip Score (NAHS), Hip Outcome Score-Activities of Daily Living (HOS-ADL), and Hip Outcome Score-Sport-Specific Subscale (HOS-SSS). Pain was estimated on the visual analog scale (VAS), and satisfaction was measured on a scale from 0 to 10. The number of patients who underwent revision arthroscopy, total hip arthroplasty (THA), or a resurfacing procedure during the study period was also reported. A total of 595 patients were included in the study. The score improvement from preoperative to 2-year follow-up was 61.29 to 82.02 for mHHS, 62.79 to 83.05 for HOS-ADL, 40.96 to 70.07 for HOS-SSS, 57.97 to 80.41 for NAHS, and 5.86 to 2.97 for VAS. All scores were statistically significantly different (P < .0001). Overall patient satisfaction was 7.86 ± 2.3 (range, 1-10). Forty-seven (7.7%) patients underwent revision hip arthroscopy, and 54 (9.1%) patients underwent either THA or the hip resurfacing procedure during the study period. The multivariate regression analysis showed that increased age at time of surgery was a significant risk factor for conversion to THA, revision arthroscopy, and change in NAHS <10 points. Acute injury, acetabuloplasty, iliopsoas release, and patient sex were significant for 2 of these 3 types of failure. Primary hip arthroscopy for all procedures performed in aggregate had excellent clinical outcomes and patient satisfaction scores at short-term follow-up in this study. More studies must be conducted to determine the definition of a successful outcome. There was a 6.1% minor complication rate, which was consistent with previous studies. Patients should be counseled regarding the potential progression of degenerative change leading to arthroplasty as well as the potential for revision surgery.


Self-reported benefits and risks of yoga in individuals with bipolar disorder.
Although hatha yoga has frequently been recommended for patients with bipolar disorder (BD) and there is preliminary evidence that it alleviates depression, there are no published data on the benefits-and potential risks-of yoga for patients with BD. Thus, the goal of this study was to assess the risks and benefits of yoga in individuals with BD. We recruited self-identified yoga practitioners with BD (N=109) to complete an Internet survey that included measures of demographic and clinical information and open-ended questions about yoga practice and the impact of yoga. 86 respondents provided sufficient information for analysis, 70 of whom met positive screening criteria for a lifetime history of mania or hypomania. The most common styles of yoga preferred were hatha and vinyasa. When asked what impact yoga had on their life, participants responded most commonly with positive emotional effects, particularly reduced anxiety, positive cognitive effects (e.g., acceptance, focus, or "a break from my thoughts"), or positive physical effects (e.g., weight loss, increased energy). Some respondents considered yoga to be significantly life changing. The most common negative effect of yoga was physical injury or pain. Five respondents gave examples of specific instances or a yoga practice that they believed increased agitation or manic symptoms; five respondents gave examples of times that yoga increased depression or lethargy. Many individuals who self-identify as having BD believe that yoga has benefits for mental health. However, yoga is not without potential risks. It is possible that yoga could serve as a useful adjunctive treatment for BD.


A survey of the perspectives of specialist palliative care providers in the UK of inpatient respite.
One of the major reasons for admission of patients to hospital in late stage disease is the inability of carers to continue to provide care at home. Specialist palliative care services have typically admitted patients for acute symptom control, terminal care and respite care to benefit them and their carers. This paper reports the results of a cross-sectional survey of inpatient respite care provision provided by specialist palliative care services and hospices in the UK. A structured questionnaire was mailed to 242 clinical services managers listed in the Hospice Information Directory in 2003. A 69% response rate was achieved. The questionnaire explored the nature of respite services, their purpose, organization, delivery and examined definitions used. The analysis indicated that 80% of the sample provided inpatient respite care. Most inpatient respite admissions were planned, of fixed duration (7-14 days) and were intended to benefit patients and carers. There was some evidence that respite provision was regarded as a lower priority than admissions for symptom control and terminal care, and that patients' needs were prioritized over those of carers. Only 10% of services conducted regular, routine audit, with very few seeking the views of service users. Findings suggest that carers' needs and wishes are not prioritized by specialist palliative care services offering inpatient respite, which may mean that they find it difficult to maintain their caregiving roles over longer disease trajectories or in the face of overwhelming demands.


All-optical switching in Sagnac loop mirror containing an ytterbium-doped fiber and fiber Bragg grating.
A configuration of all-optical switching based on a Signac loop mirror that incorporates an ytterbium-doped fiber and uniform fiber Bragg grating (FBG) is proposed in this paper. It is found that the transmission spectrum of this structure is the narrow splitting of the reflection spectrum of the FBG. The shift of this ultranarrow transmission spectrum is very sensitive to the intensity of the pump power. Thus, the threshold switching power can be greatly reduced by shifting such narrow transmission spectrum. Compared with the single FBG, the threshold switching power of this configuration is reduced by 4 orders of magnitude. In addition, the results indicate that this optical switching has a high extinction ratio of 20 dB and a ultrafast response time of 3 ns. The operation regime and switching performance under the cross-phase modulation cases are also investigated.


Addition of 18F-FDG PET/CT to clinical assessment predicts overall survival in HNSCC: a retrospective analysis with follow-up for 12 years.
(18)F-FDG PET/CT is used in the follow-up of patients with head and neck squamous cell cancer (HNSCC). However, its impact on clinical decision making and patient outcome is not fully established. The objective of this study was to determine the prognostic value of (18)F-FDG PET/CT for overall survival (OS) of HNSCC patients when performed in addition to clinical assessment between 4 and 24 mo after treatment. This was a retrospective study at a single tertiary center. The institutional review board approved this study, and the requirement to obtain informed consent was waived. The study included 134 biopsy-proven HNSCC patients with 227 follow-up PET/CT scans. The primary outcome measure was OS. Median follow-up was 40 mo (range, 7-145 mo). Survival is presented as Kaplan-Meier plots with Mantel-Cox log-rank test. The multivariate Cox model included clinical covariates. Of the 227 PET/CT scans, 41 (18%) were positive for tumor and 186 (82%) were negative for tumor. PET/CT identified recurrence in 5% (9/194) of scans performed without prior clinical concern and ruled out tumor in 51.5% (17/33) of scans performed to evaluate clinical suspicion or uncertainty of recurrence. The median survival of PET-positive and -negative groups from the date of the scan was 20 and 30.5 mo, respectively (P < 0.0001). There was a significant difference in OS from the scan date between patients who had a positive PET/CT result for tumor and those who had a negative result (log-rank, P < 0.0001), with a hazard ratio of 29.74. Human papillomavirus status (P = 0.001) and PET/CT result (P = 0.04) were the only factors significantly associated with OS, adjusted for all other covariates. (18)F-FDG PET/CT performed between 4 and 24 mo after treatment adds value to clinical assessment at the time of the study, especially when there is clinical suspicion or uncertainty, and can serve as a prognostic marker of OS in HNSCC.


Natural T Cell-mediated Protection against Seasonal and Pandemic Influenza. Results of the Flu Watch Cohort Study.
A high proportion of influenza infections are asymptomatic. Animal and human challenge studies and observational studies suggest T cells protect against disease among those infected, but the impact of T-cell immunity at the population level is unknown. To investigate whether naturally preexisting T-cell responses targeting highly conserved internal influenza proteins could provide cross-protective immunity against pandemic and seasonal influenza. We quantified influenza A(H3N2) virus-specific T cells in a population cohort during seasonal and pandemic periods between 2006 and 2010. Follow-up included paired serology, symptom reporting, and polymerase chain reaction (PCR) investigation of symptomatic cases. A total of 1,414 unvaccinated individuals had baseline T-cell measurements (1,703 participant observation sets). T-cell responses to A(H3N2) virus nucleoprotein (NP) dominated and strongly cross-reacted with A(H1N1)pdm09 NP (P < 0.001) in participants lacking antibody to A(H1N1)pdm09. Comparison of paired preseason and post-season sera (1,431 sets) showed 205 (14%) had evidence of infection based on fourfold influenza antibody titer rises. The presence of NP-specific T cells before exposure to virus correlated with less symptomatic, PCR-positive influenza A (overall adjusted odds ratio, 0.27; 95% confidence interval, 0.11-0.68; P = 0.005, during pandemic [P = 0.047] and seasonal [P = 0.049] periods). Protection was independent of baseline antibodies. Influenza-specific T-cell responses were detected in 43%, indicating a substantial population impact. Naturally occurring cross-protective T-cell immunity protects against symptomatic PCR-confirmed disease in those with evidence of infection and helps to explain why many infections do not cause symptoms. Vaccines stimulating T cells may provide important cross-protective immunity.


Cumulative occupational lumbar load and lumbar disc disease--results of a German multi-center case-control study (EPILIFT).
The to date evidence for a dose-response relationship between physical workload and the development of lumbar disc diseases is limited. We therefore investigated the possible etiologic relevance of cumulative occupational lumbar load to lumbar disc diseases in a multi-center case-control study. In four study regions in Germany (Frankfurt/Main, Freiburg, Halle/Saale, Regensburg), patients seeking medical care for pain associated with clinically and radiologically verified lumbar disc herniation (286 males, 278 females) or symptomatic lumbar disc narrowing (145 males, 206 females) were prospectively recruited. Population control subjects (453 males and 448 females) were drawn from the regional population registers. Cases and control subjects were between 25 and 70 years of age. In a structured personal interview, a complete occupational history was elicited to identify subjects with certain minimum workloads. On the basis of job task-specific supplementary surveys performed by technical experts, the situational lumbar load represented by the compressive force at the lumbosacral disc was determined via biomechanical model calculations for any working situation with object handling and load-intensive postures during the total working life. For this analysis, all manual handling of objects of about 5 kilograms or more and postures with trunk inclination of 20 degrees or more are included in the calculation of cumulative lumbar load. Confounder selection was based on biologic plausibility and on the change-in-estimate criterion. Odds ratios (OR) and 95% confidence intervals (CI) were calculated separately for men and women using unconditional logistic regression analysis, adjusted for age, region, and unemployment as major life event (in males) or psychosocial strain at work (in females), respectively. To further elucidate the contribution of past physical workload to the development of lumbar disc diseases, we performed lag-time analyses. We found a positive dose-response relationship between cumulative occupational lumbar load and lumbar disc herniation as well as lumbar disc narrowing among men and women. Even past lumbar load seems to contribute to the risk of lumbar disc disease. According to our study, cumulative physical workload is related to lumbar disc diseases among men and women.


Evidence-based recommendations for genetic diagnosis of familial Mediterranean fever.
Familial Mediterranean fever (FMF) is a disease of early onset which can lead to significant morbidity. In 2012, Single Hub and Access point for pediatric Rheumatology in Europe (SHARE) was launched with the aim of optimising and disseminating diagnostic and management regimens for children and young adults with rheumatic diseases. The objective was to establish recommendations for FMF focusing on provision of diagnostic tools for inexperienced clinicians particularly regarding interpretation of MEFV mutations. Evidence-based recommendations were developed using the European League against Rheumatism standard operating procedure. An expert committee of paediatric rheumatologists defined search terms for the systematic literature review. Two independent experts scored articles for validity and level of evidence. Recommendations derived from the literature were evaluated by an online survey and statements with less than 80% agreement were reformulated. Subsequently, all recommendations were discussed at a consensus meeting using the nominal group technique and were accepted if more than 80% agreement was reached. The literature search yielded 3386 articles, of which 25 were considered relevant and scored for validity and level of evidence. In total, 17 articles were scored valid and used to formulate the recommendations. Eight recommendations were accepted with 100% agreement after the consensus meeting. Topics covered were clinical versus genetic diagnosis of FMF, genotype-phenotype correlation, genotype-age at onset correlation, silent carriers and risk of amyloid A (AA) amyloidosis, and role of the specialist in FMF diagnosis. The SHARE initiative provides recommendations for diagnosing FMF aimed at facilitating improved and uniform care throughout Europe.


Prophylactic Antibiotic Regimens In Tumor Surgery (PARITY): a multi-center randomized controlled study comparing alternative antibiotic regimens in patients undergoing tumor resections with endoprosthetic replacements-a statistical analysis plan.
Limb salvage with endoprosthetic reconstruction is the current standard practice for the surgical management of lower extremity bone tumors in skeletally mature patients and typically includes tumor resection followed by the functional limb reconstruction with modular metallic and polyethylene endoprosthetic implants. However, owing to the complexity and length of these procedures, as well as the immunocompromised nature of patients treated with chemotherapy, the risk of surgical site infection (SSI) is high. The primary research objective of the Prophylactic Antibiotic Regimens In Tumor Surgery (PARITY) trial is to assess whether a 5-day regimen of post-operative antibiotics decreases the risk of SSI at 1 year post-operatively compared to a 1-day regimen. This article describes the statistical analysis plan for the PARITY trial. The PARITY trial is an ongoing multi-center, blinded parallel two-arm randomized controlled trial (RCT) of 600 participants who have been diagnosed with a primary bone tumor, a soft tissue sarcoma that has invaded the bone or oligometastatic bone disease of the femur or tibia that requires surgical resection and endoprosthetic reconstruction. This article describes the overall analysis principles, including how participants will be included in each analysis, the presentation of results, adjustments for covariates, the primary and secondary outcomes, and their respective analyses. Additionally, we will present the planned sensitivity and sub-group analyses. Our prior work has demonstrated (1) high rates of SSI after the treatment of lower extremity tumors by surgical excision and endoprosthetic reconstruction, (2) highly varied opinion and practice among orthopedic oncologists with respect to prophylactic antibiotic regimens, (3) an absence of applicable RCT evidence, (4) extensive support from international investigators to participate in a RCT, and (5) the feasibility of conducting a definitive RCT to evaluate a 5-day regimen of post-operative antibiotics in comparison with a 1-day regimen. ClinicalTrials.gov NCT01479283 . Registered on 24 November 2011.


Dual Targeting of ERBB2/ERBB3 for the Treatment of SLC3A2-NRG1-Mediated Lung Cancer.
We characterized the SLC3A2-NRG1 fusion gene in non-small cell lung cancer (NSCLC) and established an effective therapy for patients with SLC3A2-NRG1 fusion-positive cancer. The SLC3A2-NRG1 fusion product was composed of the SLC3A2 transmembrane domain and the EGF-like domain of the neuregulin 1 (NRG1) protein. The NRG1 family is classified as a ligand of the ERBB family. We identified ERBB3 and ERBB4 in the ERBB family as binding partners of the SLC3A2-NRG1 fusion protein via ligand and receptor binding assays. We confirmed that SLC3A2-NRG1 increased formation of a heterocomplex of ERBB3 with ERBB2. Activation of the ERBB2-ERBB3 heterocomplex by SLC3A2-NRG1 increased colony formation and tumor growth through PI3K-AKT and MAP kinase. The specific siRNAs for ERBB2 and ERBB3, pertuzumab, lumretuzumab, and afatinib all decreased ERBB2-ERBB3 heterocomplex formation, phosphorylation of each protein, and their downstream signaling. In addition, single treatment with pertuzumab, lumretuzumab, or afatinib decreased tumor volume and weight, whereas combination treatment with these drugs and taxol enhanced generation of cleaved caspase 3, PARP, and TUNEL-positive cells compared with each single treatment. Thus, the SLC3A2-NRG1 fusion gene plays an important role in lung cancer cell proliferation and tumor growth by promoting generation of the ERBB2-ERBB3 heterocomplex, its phosphorylation, and activation of the PI3K/ERK/mTOR signaling pathway. Inhibition of either ERBB2 or ERBB3 alone did not completely shut down downstream signaling of ERBB2 and ERBB3; however, inhibition of both ERBB2 and ERBB3 blocked downstream signaling activated by SLC3A2-NRG1 fusion. ERBB2 and ERBB3 might be promising targets for treatment of SLC3A2-NRG1-positive tumors. Mol Cancer Ther; 17(9); 2024-33. ©2018 AACR.


The importance of leadership in preventing healthcare-associated infection: results of a multisite qualitative study.
Healthcare-associated infection (HAI) is costly and causes substantial morbidity. We sought to understand why some hospitals were engaged in HAI prevention activities while others were not. Because preliminary data indicated that hospital leadership played an important role, we sought better to understand which behaviors are exhibited by leaders who are successful at implementing HAI prevention practices in US hospitals. We report phases 2 and 3 of a 3-phase study. In phase 2, 14 purposefully sampled US hospitals were selected from among the 72% of 700 invited hospitals whose lead infection preventionist had completed a quantitative survey on HAI prevention during phase 1. Qualitative data were collected during 38 semistructured phone interviews with key personnel at the 14 hospitals. During phase 3, we conducted 48 interviews during 6 in-person site visits to identify recurrent and unifying themes that characterize behaviors of successful leaders. We found that successful leaders (1) cultivated a culture of clinical excellence and effectively communicated it to staff; (2) focused on overcoming barriers and dealt directly with resistant staff or process issues that impeded prevention of HAI; (3) inspired their employees; and (4) thought strategically while acting locally, which involved politicking before crucial committee votes, leveraging personal prestige to move initiatives forward, and forming partnerships across disciplines. Hospital epidemiologists and infection preventionists often played more important leadership roles in their hospital's patient safety activities than did senior executives. Leadership plays an important role in infection prevention activities. The behaviors of successful leaders could be adopted by others who seek to prevent HAI.


Epidemiology of life events: life events and psychiatric disorders in the Sesto Fiorentino study.
Although life events have been consistently reported as precipitating factors for most psychiatric disorders, there is no comprehensive investigation of the relationship between severe life events and psychiatric disorders in the general population. This is a community-based study of psychiatric disorders among a cohort representative of adults in an Italian town. A total of 2,363 subjects out of 2,500 selected to be representative of the population living in Sesto Fiorentino, central Italy, were interviewed by their own general practitioner using the Mini International Neuropsychiatric Interview. Of the 613 subjects, 609 who resulted positive for any psychiatric disorders and 123 out of a random sample of 130 negatives were re-interviewed by the psychiatrists using the Florence Psychiatric Interview. The Florence Psychiatric Interview was used to explore each distinct psychiatric episode. Life events were recorded in detail by a specific interview. During the year prior to the onset of the first psychiatric disorder, 35.8% of cases suffered from at least a severe event, compared with 12.2% of non-cases during a comparable period (OR = 4.0, 95% CI = 2.3-7.1). The excess of life events occurred for almost all the diagnostic categories. The same results were reproduced even when only the 'independent' life events were considered. The distribution of the events through the 12 months taken into account showed an even distribution of events among non-cases, whereas there was a clear accumulation in the last 3 months prior to the onset of the pathology in the cases. Life stress is one of the main precipitating factors of psychopathology.


Pulmonary resection in the treatment of patients with pulmonary multidrug-resistant tuberculosis in Taiwan.
Chronic Disease Control Bureau, Department of Health, Taiwan. To evaluate the role of pulmonary resection in the treatment of pulmonary tuberculosis resistant to isoniazid and rifampin (MDR-TB). In a retrospective cohort study, 27 MDR-TB patients who underwent pulmonary resection between December 1990 and March 1999 were reviewed. Individually-tailored treatment regimens were selected at a once-weekly staff conference following review of the patient's case history and drug susceptibility results. Surgery was performed for selected patients, essentially those: 1) whose medical treatment had failed, or for whom treatment failure seemed highly likely, or for whom post-treatment relapse seemed likely, 2) with predominantly localised disease, 3) with adequate cardiopulmonary reserve, and 4) whose treatment regimen had been composed of at least two effective drugs to diminish the mycobacterial burden. There was no surgical mortality apart from one peri-operative death (4%). Three patients (11%) developed complications, and 24 (92%) patients demonstrated sputum conversion and/or remained negative after surgery. Twenty-three patients have already completed treatment, and during a mean of 42 +/- 18 follow-up months (range 15-80 months), one patient relapsed. This patient was disease-free after another course of treatment. For selected patients, pulmonary resection may improve the outcome of pulmonary MDR-TB.


Can Emergency Medical Services Utilization Rates Be Used to Measure the Success of An Alcohol Amnesty Policy?
Medical Amnesty/Good Samaritan (MAGS) policies, which eliminate legal charges when students call 9-1-1 for excessive drinking, have been implemented with the goal of reducing barriers to accessing Emergency Medical Services (EMS). This study investigated the impact of MAGS policy implementation on EMS calls on campus and if that EMS call volume could be used to measure policy success. The aim of this study was to compare the prevalence of alcohol-related EMS calls before and after MAGS implementation at a single large public university campus. Methods: A retrospective review of all 9-1-1 calls to on-campus locations was conducted using patient care records (PCRs) from a collegiate EMS agency responding exclusively to on-campus 9-1-1 calls. Calls were excluded if the PCR was marked "incomplete", were outside the 2015 CBEMS response zone boundaries, or if patient age was <15 or >25 years old to ensure analysis was targeting the on-campus student population. The incidence of alcohol-related 9-1-1 calls was compared between one academic year (AY) prior to (pre-MAGS, AY2015) and two years after MAGS implementation (post-MAGS, AY2016/17). An alcohol-related 9-1-1 call was defined as an EMS provider primary or secondary impression of "Alcohol, Alcohol Intoxication, or Alcohol Ingestion" or a call in which the patient explicitly admitted to alcohol use. Relative risk (RR) with 95% confidence intervals (CI) were used to describe the results. Results: Over the three-year study period, the collegiate EMS agency responded to 2440 calls of which 1283 met inclusion criteria. 58 calls were excluded for being incomplete, 227 were outside the original boundaries and 872 were outside the defined age range. Of those calls, 351 were pre-MAGS and 932 were post-MAGS. Of the total 9-1-1 calls, 127 (36.2%) were related to alcohol pre-MAGS and 327 (35.1%) were related to alcohol post-MAGS policy implementation. The relative risk of a 9-1-1 call being made for alcohol-related issues after MAGS implementation was RR = 0.97 (95% CI 0.83-1.14; P = 0.713). Conclusion: Implementation of a MAGS policy was not associated with a significant change in the number of alcohol-related EMS responses. It is unclear if these results reflect ineffective policy implementation or a general reduction in on-campus alcohol consumption. However, using EMS call volume as a marker for policy success and quality improvement offers an innovative tool through which EMS agencies can provide valuable feedback to other system stakeholders.


Dorsal Forebrain-Specific Deficiency of Reelin-Dab1 Signal Causes Behavioral Abnormalities Related to Psychiatric Disorders.
Reelin-Dab1 signaling is involved in brain development and neuronal functions. The abnormalities in the signaling through either reduction of Reelin and Dab1 gene expressions or the genomic mutations in the brain have been reported to be associated with psychiatric disorders. However, it has not been clear if the deficiency in Reelin-Dab1 signaling is responsible for symptoms of the disorders. Here, to examine the function of Reelin-Dab1 signaling in the forebrain, we generated dorsal forebrain-specific Dab1 conditional knockout mouse (Dab1 cKO) and performed a behavioral test battery on the Dab1 cKO mice. Although conventional Dab1 null mutant mice exhibit cerebellar atrophy and cerebellar ataxia, the Dab1 cKO mice had normal cerebellum and showed no motor dysfunction. Dab1 cKO mice exhibited behavioral abnormalities, including hyperactivity, decreased anxiety-like behavior, and impairment of working memory, which are reminiscent of symptoms observed in patients with psychiatric disorders such as schizophrenia and bipolar disorder. These results suggest that deficiency of Reelin-Dab1 signal in the dorsal forebrain is involved in the pathogenesis of some symptoms of human psychiatric disorders.


Intestinal steroidogenesis controls PPARγ expression in the colon and is impaired during ulcerative colitis.
Immune tolerance breakdown during UC involves the peroxisome proliferator-activated receptor-γ (PPARγ), a key factor in mucosal homoeostasis and the therapeutic target of 5-aminosalycilates, which expression is impaired during UC. Here we assess the impact of glucocorticoids (GCs) on PPARγ expression, focusing especially on extra-adrenal cortisol production by colonic epithelial cells (CECs). Activation of PPARγ in the colon was evaluated using transgenic mice for the luciferase gene under PPAR control (peroxisome proliferator response element-luciferase mice). Protein and mRNA expression of PPARγ were evaluated with colon fragments and purified CEC from mice. Cortisol production and steroidogenic factor expression were quantified in human CEC of patients with UC and those of controls. Gene expression knockdown by short hairpin RNA in Caco-2 cells was used for functional studies. GCs were able to raise luciferase activity in peroxisome proliferator response element-luciferase mice. In the mice colons and Caco-2 cells, PPARγ expression was increased either with GCs or with an inducer of steroidogenesis and then decreased after treatment with a steroidogenesis inhibitor. Cortisol production and steroidogenic factor expression, such as liver receptor homologue-1 (LRH-1), were decreased in CEC isolated from patients with UC, directly correlating with PPARγ impairment. Experiments on Caco-2 cells lacking LRH-1 expression confirmed that LRH-1 controls PPARγ expression by regulating GC synthesis in CEC. These results demonstrate cortisol control of PPARγ expression in CEC, highlighting cortisol production deficiency in colonocytes as a key molecular event in the pathophysiology of UC.


Reliability of vascularized fibula in maintaining arthrodesis following extra-articular wide excisions of malignant musculoskeletal tumors.
To evaluate the reliability of vascularized fibula transfer in maintaining arthrodesis following wide excision of malignant tumors located at the metaphyseal ends of long bones. Fourteen patients underwent wide extra-articular excisions followed by arthrodesis with vascularized fibula and its variants at the Department of Orthopedic Surgery and Traumatology, University of Hacettepe Medical School, Ankara, Turkey, in the period from 1996 to 2003. There were 9 males and 5 females. Their mean age was 28 years (ranging 12-52 years). The mean follow-up time was 68 months (range 28-110 months). The most common diagnosis was malignant giant cell tumor (6), followed by Ewing's sarcoma (3), hemangioendothelioma (2), osteosarcoma (2) and chondrosarcoma (1). Three tumors were located at the distal end of the radius, 4 at the proximal humerus, 3 at the distal femur, one at the proximal tibia, one in distal tibia, one in distal humerus and one in proximal ulna. We used fibula as a vascularized graft in 4 patients; fibula osteoseptocutaneous flap in 4 cases; bilateral vascularized fibulae in 3; fibula with autoclaved autograft in 4 and free osteoseptocutaneous fibula in conjunction with a structural allograft and a circular external fixator in one patient. In 4 cases, implant failure developed and revision was required in 3. One case had local infection around the distal interlocking screw. In one case, clawing of first and second toes were developed at the donor side. Two patients with metastatic Ewing's sarcoma had metastatic disease. We achieved union within 9 months in 12 cases. In 2 cases with implant failure, bony consolidations were maintained at 11th and 13th months. Vascularized fibula transfer is reliable to achieve arthrodesis following extra-articular excision of malignant tumors from the metaphyseal ends.


Hyperoxia decreases muscle glycogenolysis, lactate production, and lactate efflux during steady-state exercise.
The aim of this study was to determine whether the decreased muscle and blood lactate during exercise with hyperoxia (60% inspired O2) vs. room air is due to decreased muscle glycogenolysis, leading to decreased pyruvate and lactate production and efflux. We measured pyruvate oxidation via PDH, muscle pyruvate and lactate accumulation, and lactate and pyruvate efflux to estimate total pyruvate and lactate production during exercise. We hypothesized that 60% O2 would decrease muscle glycogenolysis, resulting in decreased pyruvate and lactate contents, leading to decreased muscle pyruvate and lactate release with no change in PDH activity. Seven active male subjects cycled for 40 min at 70% VO2 peak on two occasions when breathing 21 or 60% O2. Arterial and femoral venous blood samples and blood flow measurements were obtained throughout exercise, and muscle biopsies were taken at rest and after 10, 20, and 40 min of exercise. Hyperoxia had no effect on leg O2 delivery, O2 uptake, or RQ during exercise. Muscle glycogenolysis was reduced by 16% with hyperoxia (267 +/- 19 vs. 317 +/- 21 mmol/kg dry wt), translating into a significant, 15% reduction in total pyruvate production over the 40-min exercise period. Decreased pyruvate production during hyperoxia had no effect on PDH activity (pyruvate oxidation) but significantly decreased lactate accumulation (60%: 22.6 +/- 6.4 vs. 21%: 31.3 +/- 8.7 mmol/kg dry wt), lactate efflux, and total lactate production over 40 min of cycling. Decreased glycogenolysis in hyperoxia was related to an approximately 44% lower epinephrine concentration and an attenuated accumulation of potent phosphorylase activators ADPf and AMPf during exercise. Greater phosphorylation potential during hyperoxia was related to a significantly diminished rate of PCr utilization. The tighter metabolic match between pyruvate production and oxidation resulted in a decrease in total lactate production and efflux over 40 min of exercise during hyperoxia.


Bayesian adaptive designs for multi-arm trials: an orthopaedic case study.
Bayesian adaptive designs can be more efficient than traditional methods for multi-arm randomised controlled trials. The aim of this work was to demonstrate how Bayesian adaptive designs can be constructed for multi-arm phase III clinical trials and assess potential benefits that these designs offer. We constructed several alternative Bayesian adaptive designs for the Collaborative Ankle Support Trial (CAST), which was a randomised controlled trial that compared four treatments for severe ankle sprain. These designs incorporated response adaptive randomisation (RAR), arm dropping, and early stopping for efficacy or futility. We studied the operating characteristics of the Bayesian designs via simulation. We then virtually re-executed the trial by implementing the Bayesian adaptive designs using patient data sampled from the CAST study to demonstrate the practical applicability of the designs. We constructed five Bayesian adaptive designs, each of which had high power and recruited fewer patients on average than the original designs target sample size. The virtual executions showed that most of the Bayesian designs would have led to trials that declared superiority of one of the interventions over the control. Bayesian adaptive designs with RAR or arm dropping were more likely to allocate patients to better performing arms at each interim analysis. Similar estimates and conclusions were obtained from the Bayesian adaptive designs as from the original trial. Using CAST as an example, this case study shows how Bayesian adaptive designs can be constructed for phase III multi-arm trials using clinically relevant decision criteria. These designs demonstrated that they can potentially generate earlier results and allocate more patients to better performing arms. We recommend the wider use of Bayesian adaptive approaches in phase III clinical trials. CAST study registration ISRCTN, ISRCTN37807450. Retrospectively registered on 25 April 2003.


A Schiff base connectivity switch in sensory rhodopsin signaling.
Sensory rhodopsin I (SRI) in Halobacterium salinarum acts as a receptor for single-quantum attractant and two-quantum repellent phototaxis, transmitting light stimuli via its bound transducer HtrI. Signal-inverting mutations in the SRI-HtrI complex reverse the single-quantum response from attractant to repellent. Fast intramolecular charge movements reported here reveal that the unphotolyzed SRI-HtrI complex exists in two conformational states, which differ by their connection of the retinylidene Schiff base in the SRI photoactive site to inner or outer half-channels. In single-quantum photochemical reactions, the conformer with the Schiff base connected to the cytoplasmic (CP) half-channel generates an attractant signal, whereas the conformer with the Schiff base connected to the extracellular (EC) half-channel generates a repellent signal. In the wild-type complex the conformer equilibrium is poised strongly in favor of that with CP-accessible Schiff base. Signal-inverting mutations shift the equilibrium in favor of the EC-accessible Schiff base form, and suppressor mutations shift the equilibrium back toward the CP-accessible Schiff base form, restoring the wild-type phenotype. Our data show that the sign of the behavioral response directly correlates with the state of the connectivity switch, not with the direction of proton movements or changes in acceptor pK(a). These findings identify a shared fundamental process in the mechanisms of transport and signaling by the rhodopsin family. Furthermore, the effects of mutations in the HtrI subunit of the complex on SRI Schiff base connectivity indicate that the two proteins are tightly coupled to form a single unit that undergoes a concerted conformational transition.


Multibeam bathymetry data from the Kane Gap and south-eastern part of the Canary Basin (Eastern tropical Atlantic).
We present a multibeam bathymetry dataset from eastern part of the Canary Basin and from the Kane Gap located north and south of the Cape Verde Islands, respectively. Special attention was paid to the deep-water Kane Gap between Sierra Leone Rise and Guinea Plateau. The Kane Gap is the only possible gateway that allows the exchange of Antarctic Bottom Water between the Sierra Leone and Gambia Basins. Bathymetry surveys were carried out during the 44th cruise of the Research Vessel (R/V) "Akademik Nikolaj Strakhov" in October 2019. The data were collected using the system RESON SeaBat 7150 (12.5 kHz) and processed using QINSy software. The multibeam bathymetry data are presented in tabular format (ASCII (*.txt)) and as digital elevation models in ESRI ASCII grid (*.asc) and GeoTIFF raster (*.tif) formats with a resolution of 100 m. The dataset is available with the article.


Oral human papillomavirus in men having sex with men: risk-factors and sampling.
Human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma is becoming more common. We examined prevalence and risk factors for oral HPV among men who have sex with men (MSM) and compared sampling and transport methods. In 2010, 500 MSM (249 HIV-positive) attending Melbourne Sexual Health Centre answered a questionnaire, swabbed their mouth and throat and collected a gargled oral rinse sample. Half the oral rinse was transported absorbed in a tampon (to enable postage). HPV was detected by polymerase chain reaction, and genotyped by Roche Linear Array®. Men with HPV 16 or 18 were retested after six months. Any HPV genotype was detected in 19% (95% confidence intervals (CI) 15-25%) of HIV-infected men and 7% (95% CI 4-11%) of HIV-negative men (p<0.001), and HPV 16 was detected in 4.4% (95% CI 2-8%) of HIV-infected men and 0.8% (0.1-2.8%) of HIV-negative men. Oral HPV was associated with: current smoking (adjusted odds ratio (aOR) 2.2 (95%CI: 1.2-3.9)), time since tooth-brushing (aOR per hour 0.87, 95%CI: 0.8-0.96) and number of lifetime tongue-kissing partners aOR 3.2 95%CI: (1.2-8.4) for 26-100 partners and 4.9 95%CI: (1.9-12.5) for>100 partners. Lifetime oral-penile sex partner numbers were significantly associated in a separate model: aOR 2.8(1.2-6.3) for 26-100 partners and 3.2(1.4-7.2) for>100 partners. HPV 16 and 18 persisted in 10 of 12 men after a median six months. Sensitivities of sampling methods compared to all methods combined were: oral rinse 97%, tampon-absorbed oral rinse 69%, swab 32%. Oral HPV was associated with HIV infection, smoking, recent tooth-brushing, and more lifetime tongue-kissing and oral sex partners. The liquid oral rinse sample was more sensitive than a tampon-absorbed oral rinse or a self-collected swab.


Traffic Through the Trans-Golgi Network and the Endosomal System Requires Collaboration Between Exomer and Clathrin Adaptors in Fission Yeast.
Despite its biological and medical relevance, traffic from the Golgi to the plasma membrane (PM) is one of the least understood steps of secretion. Exomer is a protein complex that mediates the trafficking of certain cargoes from the trans-Golgi network/early endosomes to the PM in budding yeast. Here, we show that in Schizosaccharomyces pombe the Cfr1 and Bch1 proteins constitute the simplest form of an exomer. Cfr1 co-immunoprecipitates with Assembly Polypeptide adaptor 1 (AP-1), AP-2, and Golgi-localized, gamma-adaptin ear domain homology, ARF-binding (GGA) subunits, and cfr1+ interacts genetically with AP-1 and GGA genes. Exomer-defective cells exhibit multiple mild defects, including alterations in the morphology of Golgi stacks and the distribution of the synaptobrevin-like Syb1 protein, carboxypeptidase missorting, and stress sensitivity. S. pombe apm1Δ cells exhibit a defect in trafficking through the early endosomes that is severely aggravated in the absence of exomer. apm1Δ cfr1Δ cells exhibit a dramatic disorganization of intracellular compartments, including massive accumulation of electron-dense tubulovesicular structures. While the trans-Golgi network/early endosomes are severely disorganized in the apm1Δ cfr1Δ strain, gga21Δ gga22Δ cfr1Δ cells exhibit a significant disturbance of the prevacuolar/vacuolar compartments. Our findings show that exomer collaborates with clathrin adaptors in trafficking through diverse cellular compartments, and that this collaboration is important to maintain their integrity. These results indicate that the effect of eliminating exomer is more pervasive than that described to date, and suggest that exomer complexes might participate in diverse steps of vesicle transport in other organisms.


Broadly distributed T cell reactivity, with no immunodominant loci, to the pre-erythrocytic antigen thrombospondin-related adhesive protein of Plasmodium falciparum in West Africans.
Protective immunity to malaria has been achieved in human volunteers utilizing the pre-erythrocytic Plasmodium falciparum antigen, the circumsporozoite protein (CS). However, T cell reactivity to CS is focused on several highly polymorphic T cell epitope regions, potentially limiting the efficacy of any vaccine to specific malaria strains. Another important pre-erythrocytic malaria antigen, the thrombospondin-related adhesive protein (TRAP), can induce protection in animal models of malaria, but knowledge of human T cell responses is limited to the identification of CD8 T cell epitopes, with no CD4 epitopes identified to date. This comprehensive study assessed reactivity to overlapping peptides spanning almost the whole of P. falciparum TRAP (PfTRAP), as well as peptides selected on the basis of HLA class II-binding motifs. A total of 50 naturally exposed Gambian adults were assessed to define 26 T cell epitopes in PfTRAP capable of inducing rapid IFN-gamma or IL-4 production, as assessed by enzyme-linked immunospot assays. In contrast to the CS protein, this reactivity was broadly distributed along the length of TRAP. Moreover, of the 26 epitopes identified, 10 were found to be conserved in West Africa.


Antihypertensive drug therapy prevents cerebral microvascular abnormalities in hypertensive rats.
Studies were performed on anesthetized 16-18 week old normotensive Wistar-Kyoto rats, spontaneously hypertensive rats, and Goldblatt two-kidney one clip renal hypertensive rats, treated from age 4-5 weeks with an oral antihypertensive regimen consisting of hydralazine, reserpine, and chlorothiazide. Measurements of flow and intravascular pressure in the cerebral microvasculature were made via a constantly suffused open cranial window using video microscopy. A significant upward shift was seen in the pressure range for cerebral blood flow autoregulation in both groups of untreated hypertensive animals. Following treatment, the autoregulatory range in both hypertensive models was restored to a level nearly identical to control. The prevention of this shift in treated animals was due primarily to the prevention of structural microvascular adaptations that occur in untreated hypertensive animals. By preventing elevations in microvascular pressure, treatment may have eliminated the major stimulus for development of hypertrophy in resistance vessels. However, a persistent increment of arteriolar wall mass in treated spontaneously hypertensive rats may represent a hyperplastic response not influenced by treatment. Likewise, a persistent constriction of the smallest arterioles in treated renal hypertensive rats may represent a differential sensitivity of microvessels to circulating vasoactive agents. It appears that treatment initiated in the prehypertensive state, or before significant sustained hypertension has occurred, can markedly reduce the cerebrovascular morbidity associated with two different forms of hypertension.


Developing a New Definition and Assessing New Clinical Criteria for Septic Shock: For the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3).
Septic shock currently refers to a state of acute circulatory failure associated with infection. Emerging biological insights and reported variation in epidemiology challenge the validity of this definition. To develop a new definition and clinical criteria for identifying septic shock in adults. The Society of Critical Care Medicine and the European Society of Intensive Care Medicine convened a task force (19 participants) to revise current sepsis/septic shock definitions. Three sets of studies were conducted: (1) a systematic review and meta-analysis of observational studies in adults published between January 1, 1992, and December 25, 2015, to determine clinical criteria currently reported to identify septic shock and inform the Delphi process; (2) a Delphi study among the task force comprising 3 surveys and discussions of results from the systematic review, surveys, and cohort studies to achieve consensus on a new septic shock definition and clinical criteria; and (3) cohort studies to test variables identified by the Delphi process using Surviving Sepsis Campaign (SSC) (2005-2010; n = 28,150), University of Pittsburgh Medical Center (UPMC) (2010-2012; n = 1,309,025), and Kaiser Permanente Northern California (KPNC) (2009-2013; n = 1,847,165) electronic health record (EHR) data sets. Evidence for and agreement on septic shock definitions and criteria. The systematic review identified 44 studies reporting septic shock outcomes (total of 166,479 patients) from a total of 92 sepsis epidemiology studies reporting different cutoffs and combinations for blood pressure (BP), fluid resuscitation, vasopressors, serum lactate level, and base deficit to identify septic shock. The septic shock-associated crude mortality was 46.5% (95% CI, 42.7%-50.3%), with significant between-study statistical heterogeneity (I2 = 99.5%; τ2 = 182.5; P < .001). The Delphi process identified hypotension, serum lactate level, and vasopressor therapy as variables to test using cohort studies. Based on these 3 variables alone or in combination, 6 patient groups were generated. Examination of the SSC database demonstrated that the patient group requiring vasopressors to maintain mean BP 65 mm Hg or greater and having a serum lactate level greater than 2 mmol/L (18 mg/dL) after fluid resuscitation had a significantly higher mortality (42.3% [95% CI, 41.2%-43.3%]) in risk-adjusted comparisons with the other 5 groups derived using either serum lactate level greater than 2 mmol/L alone or combinations of hypotension, vasopressors, and serum lactate level 2 mmol/L or lower. These findings were validated in the UPMC and KPNC data sets. Based on a consensus process using results from a systematic review, surveys, and cohort studies, septic shock is defined as a subset of sepsis in which underlying circulatory, cellular, and metabolic abnormalities are associated with a greater risk of mortality than sepsis alone. Adult patients with septic shock can be identified using the clinical criteria of hypotension requiring vasopressor therapy to maintain mean BP 65 mm Hg or greater and having a serum lactate level greater than 2 mmol/L after adequate fluid resuscitation.


The effect of vitamin D and magnesium supplementation on the mental health status of attention-deficit hyperactive children: a randomized controlled trial.
Attention-Deficit / Hyperactivity Disorder (ADHD) is a neurodevelopmental disorder, characterized by varying severity in attention deficit and hyperactivity. Studies have shown deficiencies in the serum level of magnesium and vitamin D in people with ADHD. The aim of this study is to determine the effect of vitamin D and magnesium supplementation on mental health in children with ADHD. We conducted a randomized, double blind, placebo-controlled clinical trial of 66 children with ADHD. Participants were randomly allocated to receive both vitamin D (50,000 IU/week) plus magnesium (6 mg/kg/day) supplements (n = 33) or placebos (n = 33) for 8-weeks. Strengths and difficulties questionnaire was used to evaluate children's mental health at baseline and the end of the study. After eight weeks of intervention, the serum levels of 25-hydroxy-vitamin D3 and magnesium increased significantly in the intervention group compared with the control group. Also, children receiving vitamin D plus magnesium showed a significant reduction in emotional problems (p = 0.001), conduct problems (p = 0.002), peer problems (p = 0.001), prosocial score (p = 0.007), total difficulties (p = 0.001), externalizing score (p = 0.001), and internalizing score (p = 0.001) compared with children treated with the placebo. Vitamin D (50,000 IU/week) and magnesium (6 mg/kg/day) co-supplementation for a duration of 8-weeks could improve the behavioral function and mental health of children with ADHD. However, further well-designed studies with a larger sample size are needed. IRCT2016030326886N1 .


Epratuzumab with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy in patients with previously untreated diffuse large B-cell lymphoma.
Approximately 60% of patients with diffuse large B-cell non-Hodgkin lymphoma (DLBCL) are curable with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemoimmunotherapy. Epratuzumab (E) is an unlabeled anti-CD22 monoclonal antibody with efficacy in relapsed DLBCL. This phase 2 trial tested the safety and efficacy of combining E with R-CHOP (ER-CHOP) in untreated DLBCL. A secondary aim was to assess the efficacy of interim positron emission tomography (PET) to predict outcome in DLBCL. Standard R-CHOP with the addition of E 360 mg/m(2) intravenously was administered for 6 cycles. A total of 107 patients were enrolled in the study. Toxicity was similar to standard R-CHOP. Overall response rate in the 81 eligible patients was 96% (74% CR/CRu) by computed tomography scan and 88% by PET. By intention to treat analysis, at a median follow-up of 43 months, the event-free survival (EFS) and overall survival (OS) at 3 years in all 107 patients were 70% and 80%, respectively. Interim PET was not associated with EFS or OS. Comparison with a cohort of 215 patients who were treated with R-CHOP showed an improved EFS in the ER-CHOP patients. ER-CHOP is well tolerated and results appear promising as a combination therapy. This study was registered at www.clinicaltrials.gov as #NCT00301821.


Are diagnostic peritoneal lavage or focused abdominal sonography for trauma safe screening investigations for hemodynamically stable patients after blunt abdominal trauma? A review of the literature.
Assessment of patients in the emergency department who sustain blunt abdominal trauma represents a significant diagnostic challenge. Computed tomography (CT) is increasingly used as the principal investigation for these patients. A sensitive screening test could safely reduce the use of CT. To appraise the evidence supporting the use of diagnostic peritoneal lavage and focused abdominal sonography for trauma as screening tests in the emergency department to reduce the use of CT in the initial assessment of patients sustaining blunt abdominal trauma. A search of high-quality evidence resources was performed, followed by a hand search of the bibliographies of all relevant articles. Altogether, 55 articles were found during the initial search, of which 23 were relevant. An additional 11 were found by hand searching. Six relevant original research articles were found. Screening diagnostic peritoneal lavage and selective CT is a safe diagnostic strategy for the investigation of blunt abdominal trauma. Further research is needed to determine the role of focused abdominal sonography for trauma scanning in diagnostic protocols.


The epidemiology of depression in metropolitan China.
Previous surveys on depression in China focused on prevalence estimates without providing a detailed epidemiological profile. Face-to-face household interviews were conducted with a multi-stage household probability sample of 2633 adults (age > or = 18 years) in Beijing and 2568 in Shanghai between November 2001 and February 2002. The World Health Organization Composite International Diagnostic Interview (CIDI) was used to assess major depressive episode (MDE) according to Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV criteria. The lifetime prevalence and 1-year prevalence estimates of DSM-IV/CIDI MDE were 3.6% [95% confidence interval (CI) 2.8-4.4%] and 1.8% (95% CI 1.2-2.4%) respectively. No significant gender difference was found in these estimates. Respondents born in 1967 or later were at elevated lifetime risk compared with respondents born in earlier cohorts. The mean age of onset was 30.3 years. Among those reporting 1-year MDE, 15.7, 51.8, 25.3 and 6.4% reported mild, moderate, severe and very severe symptoms respectively; 4.8, 2.6 and 3.2% reported suicidal ideation, plans, and recent attempts in the same year respectively. Respondents with 1-year MDE reported a mean of 27.5 days out of role owing to their depression in the year before interview. Significant co-morbidity was found between MDE and other mental disorders [odds ratio (OR) 22.0] and chronic physical disorders (OR 3.2). Only 22.7% of respondents with 1-year MDE sought treatment. The low prevalence and insignificant gender difference, but not patterns of onset, course, co-morbidity, and impairment, distinguish the epidemiological profile of MDE in metropolitan China from those in other countries.


Optoacoustic imaging identifies ovarian cancer using a microenvironment targeted theranostic wormhole mesoporous silica nanoparticle.
At the intersection of the newly emerging fields of optoacoustic imaging and theranostic nanomedicine, promising clinical progress can be made in dismal prognosis of ovarian cancer. An acidic pH targeted wormhole mesoporous silica nanoparticle (V7-RUBY) was developed to serve as a novel tumor specific theranostic nanoparticle detectable using multispectral optoacoustic tomographic (MSOT) imaging. We report the synthesis of a small, < 40 nm, biocompatible asymmetric wormhole pore mesoporous silica core particle that has both large loading capacity and favorable release kinetics combined with tumor-specific targeting and gatekeeping. V7-RUBY exploits the acidic tumor microenvironment for tumor-specific targeting and tumor-specific release. In vitro, treatment with V7-RUBY containing either paclitaxel or carboplatin resulted in increased cell death at pH 6.6 in comparison to drug alone (p < 0.0001). In orthotopic ovarian xenograft mouse models, V7-RUBY containing IR780 was specifically detected within the tumor 7X and 4X higher than the liver and >10X higher than in the kidney using both multispectral optoacoustic tomography (MSOT) imaging with secondary confirmation using near infrared fluorescence imaging (p < 0.0004). The V7-RUBY system carrying a cargo of either contrast agent or an anti-neoplastic drug has the potential to become a theranostic nanoparticle which can improve both diagnosis and treatment of ovarian cancer.


Understanding human fetal pancreas development using subpopulation sorting, RNA sequencing and single-cell profiling.
To decipher the populations of cells present in the human fetal pancreas and their lineage relationships, we developed strategies to isolate pancreatic progenitors, endocrine progenitors and endocrine cells. Transcriptome analysis of the individual populations revealed a large degree of conservation among vertebrates in the drivers of gene expression changes that occur at different steps of differentiation, although notably, sometimes, different members of the same gene family are expressed. The transcriptome analysis establishes a resource to identify novel genes and pathways involved in human pancreas development. Single-cell profiling further captured intermediate stages of differentiation and enabled us to decipher the sequence of transcriptional events occurring during human endocrine differentiation. Furthermore, we evaluate how well individual pancreatic cells derived in vitro from human pluripotent stem cells mirror the natural process occurring in human fetuses. This comparison uncovers a few differences at the progenitor steps, a convergence at the steps of endocrine induction, and the current inability to fully resolve endocrine cell subtypes in vitro.


Efficacy of Stroke Volume Variation, Cardiac Output and Cardiac Index as Predictors of Fluid Responsiveness using Minimally Invasive Vigileo Device in Intracranial Surgeries.
Functional hemodynamic monitoring using dynamic parameters such as stroke volume variations (SVVs) based on pulse contour analysis is considered more accurate than central venous pressure and mean arterial pressure (MAP) in predicting fluid responsiveness. New device, i.e., Vigileo system, allows automatic and continuous monitoring of cardiac output (CO) based on pulse contour analysis and respiratory stroke volume. The study aims to test the above hypothesis using graded volume loading step (VLS) to assess the accuracy of SVV as a predictor of fluid responsiveness in patients undergoing intracranial surgery. After taking ethical committee approval and informed consent, 60 patients aged between 18 and 55 years belonging to the American Society of Anesthesiologists physical status Class I and II, of either sex, scheduled for brain surgery were included in the study. In this study, 5 min after intubation, with stable hemodynamics, patients received volume loading in successive steps (VLS) of 200 ml of lactated Ringer's solution until the stroke volume increased to <10%. Blood pressure (BP), heart rate (HR), stroke volume (SV), and SVV were measured before and after each VLS. Optimal preload augmentation required by each patient was measured by the number of VLS after which an increase in SV was <10%. There was a significant decrease in the baseline BP and SV in responsive and nonresponsive groups for the first VLS, but there is no change in HR statistically. There was a significant change in SV after first VLS. Receiver operating characteristic analysis showed a larger area under the curve of 0.758 for SVV compared to other measured variables. The median number of VLS administered were 2 per patient equating to a mean ± SD requirement of 368 ± 176 ml of crystalloid per patient as the optimal preoperative infusion volume. SVV is a better predictor of preload responsiveness measured with third-generation Vigileo device when compared to BP and HR.


Disinfection by-product formation and mitigation strategies in point-of-use chlorination with sodium dichloroisocyanurate in Tanzania.
Almost a billion persons lack access to improved drinking water, and diarrheal diseases cause an estimated 1.87 million deaths per year. Sodium dichloroisocyanurate (NaDCC) tablets are widely recommended for household water treatment to reduce diarrhea. Because NaDCC is directly added to untreated water sources, concerns have been raised about the potential health impact of disinfection by-products. This study investigated trihalomethane (THM) production in water from six sources used for drinking (0.6-888.5 nephelometric turbidity units) near Arusha, Tanzania. No sample collected at 1, 8, and 24 hours after NaDCC addition exceeded the World Health Organization guideline values for either individual or total THMs. Ceramic filtration, sand filtration, cloth filtration, and settling and decanting were not effective mitigation strategies to reduce THM formation. Chlorine residual and THM formation were not significantly different in NaDCC and sodium hypochlorite treatment. Household chlorination of turbid and non-turbid waters did not create THM concentrations that exceeded health risk guidelines.


Primary spinal hydatid disease.
Primary spinal hydatid disease is rare. Spinal hydatid disease should be considered in the differential diagnosis of spinal cord compression syndrome in endemic countries and evaluated with imaging and serology. Our case was a 34- year-old man. The patient presented with progressive back pain for 8 months and lower extremity weakness for 3 months. Neurological examination was suggestive of upper motor neuron type of paraperesis. Magnetic resonance images of the thoracal region showed an intradural multicystic lesion. The mass was explored with T 10-11 laminectomy. It had displaced the cord to the right side. The fluid was clear and did not contain pus. The lesion was easily dissected from the cord and was resected totally. The pathological diagnosis was hydatid disease.


The synergy of permeable pavements and geothermal heat pumps for stormwater treatment and reuse.
The use of permeable pavement systems with integrated geothermal heat pumps for the treatment and recycling of urban runoff is novel and timely. This study assesses the efficiency of the combined technology for controlled indoor and uncontrolled outdoor experimental rigs. Water quality parameters such as biochemical oxygen demand, nutrients, total viable heterotrophic bacteria and total coliforms were tested before and after treatment in both rigs. The water borne bacterial community genomic deoxyribonucleic acid (DNA) was analyzed by polymerase chain reaction (PCR) amplification followed by denaturing gradient gel electrophoresis (DGGE) and was further confirmed by DNA sequencing techniques. Despite the relatively high temperatures in the indirectly heated sub-base of the pavement, potentially pathogenic organisms such as Salmonella spp., Escherichia coli, faecal Streptococci and Legionella were not detected. Moreover, mean removal rates of 99% for biochemical oxygen demand, 97% for ammonia-nitrogen and 95% for orthophosphate-phosphates were recorded. This research also supports decision-makers in assessing public health risks based on qualitative molecular microbiological data associated with the recycling of treated urban runoff.


Phase II trial of subcutaneous anti-CD52 monoclonal antibody alemtuzumab (Campath-1H) as first-line treatment for patients with B-cell chronic lymphocytic leukemia (B-CLL).
This phase II study determined the efficacy and safety of alemtuzumab, a humanized anti-CD52 monoclonal antibody, delivered subcutaneously as first-line therapy, over a prolonged treatment period of 18 weeks in 41 patients with symptomatic B-cell chronic lymphocytic leukemia (B-CLL). Injections were administered subcutaneously 3 times per week, from week 2 to 3 onward. An overall response rate (OR) of 87% (95% CI, 76%-98%; complete remission [CR], 19%; partial remission [PR], 68%) was achieved in 38 evaluable patients (81% of intent-to-treat population). CLL cells were cleared from blood in 95% patients in a median time of 21 days. CR or nodular PR in the bone marrow was achieved in 66% of the patients and most patients achieved this after 18 weeks of treatment. An 87% OR (29% CR) was achieved in the lymph nodes. The median time to treatment failure has not yet been reached (18+ months; range, 8-44+ months). Transient injection site skin reactions were seen in 90% of patients. Rigor, rash, nausea, dyspnea, and hypotension were rare or absent. Transient grade IV neutropenia developed in 21% of the patients. Infections were rare, but 10% patients developed cytomegalovirus (CMV) reactivation. These patients rapidly responded to intravenous ganciclovir. One patient, allergic to cotrimoxazole prophylaxis, developed Pneumocystis carinii pneumonia. Alemtuzumab is highly effective as first-line treatment in patients with B-CLL. Prolonged treatment is important for maximal bone marrow response. Subcutaneous administration induced very few "first-dose" flulike symptoms and may reduce health care costs in comparison with the intravenous infusions.


Functionally Overlapping Variants Control Tuberculosis Susceptibility in Collaborative Cross Mice.
Host genetics plays an important role in determining the outcome of Mycobacterium tuberculosis infection. We previously found that Collaborative Cross (CC) mouse strains differ in their susceptibility to M. tuberculosis and that the CC042/GeniUnc (CC042) strain suffered from a rapidly progressive disease and failed to produce the protective cytokine gamma interferon (IFN-γ) in the lung. Here, we used parallel genetic and immunological approaches to investigate the basis of CC042 mouse susceptibility. Using a population derived from a CC001/Unc (CC001) × CC042 intercross, we mapped four quantitative trait loci (QTL) underlying tuberculosis immunophenotypes (Tip1 to Tip4). These included QTL that were associated with bacterial burden, IFN-γ production following infection, and an IFN-γ-independent mechanism of bacterial control. Further immunological characterization revealed that CC042 animals recruited relatively few antigen-specific T cells to the lung and that these T cells failed to express the integrin alpha L (αL; i.e., CD11a), which contributes to T cell activation and migration. These defects could be explained by a CC042 private variant in the Itgal gene, which encodes CD11a and is found within the Tip2 interval. This 15-bp deletion leads to aberrant mRNA splicing and is predicted to result in a truncated protein product. The ItgalCC042 genotype was associated with all measured disease traits, indicating that this variant is a major determinant of susceptibility in CC042 mice. The combined effect of functionally distinct Tip variants likely explains the profound susceptibility of CC042 mice and highlights the multigenic nature of tuberculosis control in the Collaborative Cross.IMPORTANCE The variable outcome of Mycobacterium tuberculosis infection observed in natural populations is difficult to model in genetically homogeneous small-animal models. The newly developed Collaborative Cross (CC) represents a reproducible panel of genetically diverse mice that display a broad range of phenotypic responses to infection. We explored the genetic basis of this variation, focusing on a CC line that is highly susceptible to M. tuberculosis infection. This study identified multiple quantitative trait loci associated with bacterial control and cytokine production, including one that is caused by a novel loss-of-function mutation in the Itgal gene, which is necessary for T cell recruitment to the infected lung. These studies verify the multigenic control of mycobacterial disease in the CC panel, identify genetic loci controlling diverse aspects of pathogenesis, and highlight the utility of the CC resource.


Broad-Spectrum Antiviral Effect of Cannabidiol Against Enveloped and Nonenveloped Viruses.
Introduction: Cannabidiol (CBD), the main non-psychoactive cannabinoid of the Cannabis sativa plant, is a powerful antioxidant compound that in recent years has increased interest due to causes effects in a wide range of biological functions. Zika virus (ZIKV) is a virus transmitted mainly by the Aedes aegypti mosquitoes, which causes neurological diseases, such as microcephaly and Guillain-Barre syndrome. Although the frequency of viral outbreaks has increased recently, no vaccinations or particular chemotherapeutic treatments are available for ZIKV infection. Objectives: The major aim of this study was to explore the in vitro antiviral activity of CBD against ZIKV, expanding also to other dissimilar viruses. Materials and Methods: Cell cultures were infected with enveloped and nonenveloped viruses and treated with non-cytotoxic concentrations of CBD and then, viral titers were determined. Additionally, the mechanism of action of the compound during ZIKV in vitro infections was studied. To study the possible immunomodulatory role of CBD, infected and uninfected Huh-7 cells were exposed to 10 μM CBD during 48 h and levels of interleukins 6 and 8 and interferon-beta (IFN-β) expression levels were measured. On the other hand, the effect of CBD on cellular membranes was studied. For this, an immunofluorescence assay was performed, in which cell membranes were labeled with wheat germ agglutinin. Finally, intracellular cholesterol levels were measured. Results: CBD exhibited a potent antiviral activity against all the tested viruses in different cell lines with half maximal effective concentration values (CE50) ranging from 0.87 to 8.55 μM. Regarding the immunomodulatory effect of CBD during ZIKV in vitro infections, CBD-treated cells exhibited significantly IFN-β increased levels, meanwhile, interleukins 6 and 8 were not induced. Furthermore, it was determined that CBD affects cellular membranes due to the higher fluorescence intensity that was observed in CBD-treated cells and lowers intracellular cholesterol levels, thus affecting the multiplication of ZIKV and other viruses. Conclusions: It was demonstrated that CBD inhibits structurally dissimilar viruses, suggesting that this phytochemical has broad-spectrum antiviral effect, representing a valuable alternative in emergency situations during viral outbreaks, like the one caused by severe acute respiratory syndrome coronavirus 2 in 2020.


Why do oVEMPs become larger when you look up? Explaining the effect of gaze elevation on the ocular vestibular evoked myogenic potential.
The ocular vestibular evoked myogenic potential (oVEMP) is a vestibular reflex recorded from the inferior oblique (IO) muscles, which increases in amplitude during eye elevation. We investigated whether this effect of gaze elevation could be explained by movement of the IO closer to the recording electrode. We compared oVEMPs recorded with different gaze elevations to those recorded with constant gaze position but electrodes placed at increasing distance from the eyes. oVEMPs were recorded in ten healthy subjects using bursts of skull vibration. oVEMP amplitude decreased more with decreasing gaze elevation (9 μV from 24° up to neutral) than with increasing electrode distance (2.7 μV from baseline to 6.4 mm; P<0.005). The oVEMP recorded with gaze 24° down had delayed latency (by 4.5 ms). The effect of gaze elevation on the oVEMP cannot be explained by changes in position of the muscle alone and is likely mainly due to increased tonic contraction of the IO muscle in up-gaze. The oVEMP recorded in down-gaze (when the IO is inactivated, but the IR activated) likely originates in the adjacent IR muscle. Our results suggest that oVEMP amplitudes in extraocular muscles scale in response to changing tonic muscle activity.


Non-polarized distribution of synaptotagmin IV in neurons: evidence that synaptotagmin IV is not a synaptic vesicle protein.
Synaptotagmin IV (Syt IV) expression is regulated by neuronal development and by depolarization in the brain and in neuronal cell cultures. In cultures, immunocytochemical analysis has shown that Syt IV is localized at the Golgi and at the tips of growing neurites, but little was known about associations between Syt IV and vesicles or organelles [J. Neurochem. 74 (2000) 518]. In this study we performed an electron microscopic (EM) analysis of developing mouse neocortex to determine the exact localization of Syt IV in native mouse tissues. In neurons of layer II/III, Syt IV was found to be localized in the dendrites and axons, and at the Golgi in the cell body. Some Syt IV signals were clearly associated with vesicles and/or organelles, but EM and cell fractionation studies showed no Syt IV signals at synaptic vesicles. Detection of fluorescence protein-tagged Syt IV (Syt IV-EGFP) in hippocampal neurons also showed the presence of Syt IV-EGFP vesicles or organelles in the axons and dendrites. These results suggest that Syt IV regulates non-polarized membrane trafficking in neurons, which may be involved in synaptic plasticity or neuronal development.


Effects of intervertebral distraction screw fixation of the lumbosacral joint on the adjacent lumbar segments in Beagles.
To investigate the effects of intervertebral distraction screw (IDS) fixation of the lumbosacral joint (LSJ) on the intervertebral foraminal area (IFA) and intervertebral stabilization of the LSJ and adjacent lumbar segments in dogs. 7 healthy Beagles. Dorsal laminectomy was performed at the LSJ in each dog to expose the intervertebral disk. The IDS was then inserted into the L7-S1 disk. Computed tomography was performed before and after laminectomy and after IDS insertion (intact, laminectomy, and IDS conditions, respectively) to measure the intervertebral range of motion (ROM) and intervertebral distance (ID) at L7-S1, L6-7, and L5-6 with the LSJ in a flexed and extended position. The intervertebral foramina stenosis rate was calculated from the intervertebral foramina area in entrance, middle, and exit zones. Results were compared among conditions. The ROM at L7-S1 after IDS insertion was lower than that observed before and after laminectomy; no other differences were identified among conditions. With the LSJ in the flexed position, the ID at L7-S1 was larger after IDS insertion than before and after laminectomy; no other differences in ID were identified. In all evaluated zones, the stenosis rate was lower after IDS insertion than before and after laminectomy. No differences in ROM, ID, and stenosis rate were identified among conditions at L6-7 or L5-6. Results suggested that IDS fixation of the LSJ restricted lumbosacral ROM and prevented decreases in lumbosacral ID and IFA in healthy dogs. There were no changes at L6-7 and L5-6.


Antibiotic prophylaxis for preventing surgical-site infection in plastic surgery: an evidence-based consensus conference statement from the American Association of Plastic Surgeons.
There is a growing concern for microbial resistance as a result of overuse of antibiotics. Although guidelines have focused on the use of antibiotics for surgery in general, few have addressed plastic surgery specifically. The objective of this expert consensus conference was to evaluate the evidence for efficacy and safety of antibiotic prophylaxis in plastic surgical procedures. THE AUTHORS: searched for existing high-quality systematic reviews for antibiotic prophylaxis in the literature from the MEDLINE, Cochrane Library, and Embase databases. All synonyms for antibiotics were combined with terms for relevant plastic surgery procedures. The searches were not limited by language, and included all study designs. In addition, supplemental hand searches were performed of bibliographies of relevant articles, and extensive "related articles." Meta-analyses were performed and reviewed by experts selected by the American Association of Plastic Surgeons to reach consensus recommendations. Database searches identified 4300 articles, from which 2042 full-text articles were identified for eligibility. De novo meta-analyses were performed for each plastic surgical category. In total, 67 studies met the inclusion criteria, including nine for breast surgery, 17 for head and neck surgery, 10 for orthognathic surgery, seven for rhinoplasty/septoplasty, 19 for hand surgery, five for skin surgery, and two for abdominoplasty. Systemic antibiotic prophylaxis is recommended for clean breast surgery and for contaminated surgery of the hand or the head and neck. It is not recommended to reduce infection in clean surgical cases of the hand, skin, head and neck, or abdominoplasty.


Impacts of Carpobrotus edulis (L.) N.E.Br. on the germination, establishment and survival of native plants: a clue for assessing its competitive strength.
Does Carpobrotus edulis have an impact on native plants? How do C. edulis' soil residual effects affect the maintenance of native populations? What is the extent of interspecific competition in its invasion process? In order to answer those questions, we established pure and mixed cultures of native species and C. edulis on soil collected from invaded and native areas of Mediterranean coastal dunes in the Iberian Peninsula. We examined the impact of the invader on the germination, growth and survival of seeds and adult plants of two native plant species (Malcolmia littorea (L.) R.Br, and Scabiosa atropurpurea L.) growing with ramets or seeds of C. edulis. Residual effects of C. edulis on soils affected the germination process and early growth of native plants in different ways, depending on plant species and density. Interspecific competition significantly reduced the germination and early growth of native plants but this result was soil, density, timing and plant species dependent. Also, at any density of adult individuals of C. edulis, established native adult plants were not competitive. Moreover, ramets of C. edulis had a lethal effect on native plants, which died in a short period of time. Even the presence of C. edulis seedlings prevents the recruitment of native species. In conclusion, C. edulis have strong negative impacts on the germination, growth and survival of the native species M. littorea and S. atropurpurea. These impacts were highly depended on the development stages of native and invasive plants. Our findings are crucial for new strategies of biodiversity conservation in coastal habitats.


A three-year cohort study of the relationships between coping, job stress and burnout after a counselling intervention for help-seeking physicians.
Knowledge about important factors in reduction of burnout is needed, but there is a dearth of burnout intervention program studies and their effects among physicians. The present three-year follow-up study aimed to investigate the roles of coping strategies, job stress and personality traits in burnout reduction after a counselling intervention for distressed physicians. 227 physicians who attended a counselling intervention for burnout at the Resource Centre Villa Sana, Norway in 2003-2005, were followed with self-report assessments at baseline, one-year, and three-year follow-up. Main outcome measures were emotional exhaustion (one dimension of burnout), job stress, coping strategies and neuroticism. Changes in these measures were analyzed with repeated measures ANOVA. Temporal relationships between changes were examined using structural modelling with cross-lagged and synchronous panel models. 184 physicians (81%, 83 men, 101 women) completed the three-year follow-up assessment. Significantly reduced levels of emotional exhaustion, job stress, and emotion-focused coping strategies from baseline to one year after the intervention, were maintained at three-year follow-up.Panel modelling indicated that changes in emotion-focused coping (z = 4.05, p < 0.001) and job stress (z = 3.16, p < 0.01) preceded changes in emotional exhaustion from baseline to three-year follow-up. A similar pattern was found from baseline to one-year follow-up. A sequential relationship indicated that reduction in emotion-focused coping and in job stress preceded reduction in emotional exhaustion. As a consequence, coping strategies and job stress could be important foci in intervention programs that aim to reduce or prevent burnout in help-seeking physicians.


A transcript perspective on evolution.
Alternative splicing is now recognized as a major mechanism for transcriptome and proteome diversity in higher eukaryotes, yet its evolution is poorly understood. Most studies focus on the evolution of exons and introns at the gene level, while only few consider the evolution of transcripts. In this paper, we present a framework for transcript phylogenies where ancestral transcripts evolve along the gene tree by gains, losses, and mutation. We demonstrate the usefulness of our method on a set of 805 genes and two different topics. First, we improve a method for transcriptome reconstruction from ESTs (ASPic), then we study the evolution of function in transcripts. The use of transcript phylogenies allows us to double the precision of ASPic, whereas results on the functional study reveal that conserved transcripts are more likely to share protein domains than functional sites. These studies validate our framework for the study of evolution in large collections of organisms from the perspective of transcripts; for this purpose, we developed and provide a new tool, TrEvoR.


Ascorbic acid and cholesterol gallstones.
Decreased activity of cholesterol 7 alpha-hydroxylase, the rate-limiting enzyme in the catabolism of cholesterol to bile acids, is known to result in increased biliary cholesterol concentration and supersaturation of bile. Supersaturation of bile by cholesterol is a necessary condition for cholesterol gallstone formation. In guinea pigs, the hepatic concentration of ascorbic acid affects the catabolism of cholesterol: hypovitaminosis C reduces cholesterol 7 alpha-hydroxylase activity. Cholesterol gallstones are frequently found in ascorbic acid-deficient guinea pigs. Risk factors for cholesterol gallstones in humans include obesity, aging, estrogen treatment, pregnancy and diabetes. Plasma ascorbic acid levels are reduced in these groups. Vegetarian diets, which typically have high ascorbic acid contents, protect against gallstones. Since ascorbic acid effects the rate-limiting step in the catabolism of cholesterol in the guinea pig and many human risk groups for cholesterol gallstones are associated with reduced ascorbic acid levels, ascorbic acid may play a contributory role in human gallbladder disease.


Brain-derived neurotrophic factor protects neuroblastoma cells from vinblastine toxicity.
Brain-derived neurotrophic factor (BDNF) and its receptors are necessary for the survival and development of many neuronal cells. Because BDNF and TrkB are expressed in many poor-prognosis neuroblastoma (NB) tumors, we evaluated the role of BDNF in affecting sensitivity to chemotherapeutic agents. We investigated the effects of activation of the BDNF-TrkB signal transduction pathway in two NB cell lines, 15N and SY5Y. 15N cells lack the high-affinity receptor p145TrkB and express BDNF; 15N cells were used along with 15N-TrkB cells, a subline transfected with a TrkB expression vector. In cytotoxicity assays, 15N-TrkB cells were consistently 1.4-2 fold more resistant to vinblastine than 15N cells. Drug accumulation assays showed a 50% reduction in[3H]vinblastine accumulation in 15N-TrkB cells compared with control 15N cells. Addition of 30 ng/ml BDNF resulted in a reduction to 46% of control in 15N cells and a reduction to 28% of control in 15N-TrkB cells. SY5Y cells were chosen as a second model because they lack both endogenous BDNF and TrkB expression. p145TrkB expression is induced by 1 nM retinoic acid. Vinblastine accumulation was not significantly affected by 1 nM retinoic acid in SY5Y cells. Addition of 30 ng/ml BDNF decreased [3H]vinblastine accumulation to 58% of control in SY5Y cells and decreased [3H]vinblastine accumulation to 62% of control in TrkB-expressing SY5Y cells. Although an increase in BDNF expression in seen in multidrug-resistant sublines of SY5Y and BE(2)-C NB cells, the protective effect of BDNF in vinblastine toxicity may be unrelated to mdr-1, because the activity of other agents transported by P-glycoprotein was not affected. There was no increase in mdr-1 expression in 1 nM RA SY5Y cells and 15N-TrkB cells, as assessed by Northern blot analysis. In addition to the effects of BDNF on vinblastine cytotoxicity and accumulation, there was an inhibition in the ability of vinblastine to depolymerize tubulin in BDNF-treated cells. Thus, BDNF and TrkB may partially rescue NB cells from vinblastine toxicity and thereby may contribute to a more chemoresistant phenotype.


Cerebrospinal fluid neurogranin in an inducible mouse model of neurodegeneration: A translatable marker of synaptic degeneration.
Synapse impairment is thought to be an early event in Alzheimer's disease (AD); dysfunction and loss of synapses are linked to cognitive symptoms that precede neuronal loss and neurodegeneration. Neurogranin (Ng) is a somatodendritic protein that has been shown to be reduced in brain tissue but increased in the cerebrospinal fluid (CSF) of AD patients compared to age-matched controls. High levels of CSF Ng have been shown to reflect a more rapid AD progression. To gauge the translational value of Ng as a biomarker, we developed a new, highly sensitive, digital enzyme-linked immunosorbent assay (ELISA) on the Simoa platform to measure Ng in both mouse and human CSF. We investigated and confirmed that Ng levels are increased in the CSF of patients with AD compared to controls. In addition, we explored how Ng is altered in the brain and CSF of transgenic mice that display progressive neuronal loss and synaptic degeneration following the induction of p25 overexpression. In this model, we found that Ng levels increased in CSF when neurodegeneration was induced, peaking after 2 weeks, while they decreased in brain. Our data suggest that CSF Ng is a biomarker of synaptic degeneration with translational value.


Non-Steroidal Anti-Inflammatory Drug Use and Risk of Anastomotic Leakage after Anterior Resection: A Protocol-Based Study.
Non-steroidal anti-inflammatory drugs (NSAIDs) have been introduced as opioid-sparing analgesics in colorectal surgery. However, recent research has implicated these drugs as risk factors for anastomotic dehiscence. The Swedish Colorectal Cancer Registry was used to identify all patients operated with anterior resection for rectal cancer at centres that performed more than 25 abdominal operations per year, from 2007 to 2012, inclusive. The registry provided individual patient data on demographic variables and symptomatic anastomotic leakage. The patient exposure to NSAIDs was defined according to the protocol of the hospital at which the patient was operated. Logistic regression was employed to estimate ORs and 95% CIs, adjusting for confounders. The study cohort comprised 2,605 patients operated at 21 centres. In the NSAID group, 102/1,458 (7.0%) suffered an anastomotic leak, as compared to 124/1,023 (10.8%) in the non-NSAID group. With adjustment for confounding, patients treated at NSAID hospitals had a reduced risk of developing anastomotic leakage (OR 0.68; 95% CI 0.48-0.96). In this retrospective protocol-based study, NSAIDs did not increase the risk of anastomotic leakage after anterior resection for rectal cancer. The postoperative use of NSAIDs may not be detrimental, but more research is warranted.


Cancer and dementia: an exploratory study of the experience of cancer treatment in people with dementia.
Patients with comorbid cancer and dementia have poorer outcomes than those without dementia. We observe oncology teams managing patients with dementia and memory loss and explore these patients' needs and experiences of outpatient cancer services. A single site investigation of case study design to examine practices in four clinics using multi-methods of data collection: retrospective note review, observation, interviews, and recorded consultations. A framework analytic approach identifies themes within and across cases. Thirty-three clinical encounters with patients with memory loss were observed. Ten consultations were audio-recorded and 16 individuals interviewed (n = 6 patients-carer dyads, n = 1 lone patient, and n = 5 staff). Medical records were reviewed for 338 cases. Cancer referrals did not document memory health, so clinicians rely on patient/carer disclosure to identify patients with memory problems. In practice, the problem often remains hidden. Treating teams who do become aware of memory difficulties are unsure how to support patients, but marked memory loss can limit treatment options and preclude radical intent. Carers are key facilitators of successful cancer consultations and management. Their support needs are largely unrecognized. Training that educates cancer teams on how to identify and support individuals with memory problems before and during treatment and recognize the carer role may facilitate complex cancer care and help reduce inequalities of outcomes.