Tuberculin skin-test reactions are unaffected by the severity of hyperendemic intestinal helminth infections and co-infections.
The tuberculin skin test (TST) quantifies cell-mediated immunity to tuberculosis antigens. Helminths suppress cell-mediated immunity, so we studied the effect of helminth infection and deworming on the TST in a randomized, double-blind, placebo-controlled study in an indigenous Amazon community (N = 195). Stool microscopy diagnosed helminths in 98% and co-infection with multiple species in 24% of study subjects. The TST was positive (> or = 10 mm) for 49%, and responses increased with age (P < 0.001), Bacille Calmette Guerin (BCG) vaccination (P = 0.01), and tuberculosis contact (P = 0.05). TST results had no association with helminth-egg concentrations, species, or co-infections (all P > 0.1). One month after deworming with albendazole (three daily 400-mg doses), helminths were reduced, but 63% remained infected with helminths. Albendazole did not cause a change in TST size (P = 0.8) or positivity (P = 0.9) relative to placebo. Thus, TST reactions were unaffected by albendazole therapy that partially cured intestinal helminth infections, and TST interpretation was unaffected by high-burden helminth infections and co-infection with multiple helminth species.


The cell adhesion molecule Fasciclin2 regulates brush border length and organization in Drosophila renal tubules.
Multicellular organisms rely on cell adhesion molecules to coordinate cell-cell interactions, and to provide navigational cues during tissue formation. In Drosophila, Fasciclin 2 (Fas2) has been intensively studied due to its role in nervous system development and maintenance; yet, Fas2 is most abundantly expressed in the adult renal (Malpighian) tubule rather than in neuronal tissues. The role Fas2 serves in this epithelium is unknown. Here we show that Fas2 is essential to brush border maintenance in renal tubules of Drosophila. Fas2 is dynamically expressed during tubule morphogenesis, localizing to the brush border whenever the tissue is transport competent. Genetic manipulations of Fas2 expression levels impact on both microvilli length and organization, which in turn dramatically affect stimulated rates of fluid secretion by the tissue. Consequently, we demonstrate a radically different role for this well-known cell adhesion molecule, and propose that Fas2-mediated intermicrovillar homophilic adhesion complexes help stabilize the brush border.


Compact, flexible and versatile photonic differentiator using silicon Mach-Zehnder interferometers.
We propose and experimentally demonstrate the flexibility and versatility of photonic differentiators using a silicon-based Mach-Zehnder Interferometer (MZI) structure. Two differentiation schemes are investigated. In the first scheme, we demonstrate high-order photonic field differentiators using on-chip cascaded MZIs, including first-, second-, and third-order differentiators. For single Gaussian optical pulse injection, the average deviations of all differentiators are less than 6.5%. In the second scheme, we demonstrate multifunctional differentiators, including intensity differentiator and field differentiator, using an on-chip single MZI structure. These different differentiator forms rely on the relative shift between the probe wavelength and the MZI resonant notch. Our schemes show the advantages of compact footprint, flexible functions and versatile differentiation forms. For example, high order field differentiators can be used to generate complex temporal waveforms, such as high order Hermite-Gaussian waveforms. And intensity differentiators are useful for ultra-wideband pulse generation.


Evaluating Clinical Outcomes of an Advanced Practice Provider-Led Newborn Circumcision Clinic.
To determine the safety and efficacy of advanced practice provider (APP)-performed newborn circumcisions (NBCs), we reviewed outcomes of NBCs performed by pediatric urologists and APPs. We hypothesize comparable clinical outcomes between the groups. All urology performed NBCs during a 5-year period were reviewed, including time surrounding implementation of the APP-led clinic. Return to emergency department (ED) rates, return to operating room (OR) rates, and intraprocedure bleeding requiring intervention were reviewed. Fisher exact and Mann-Whitney testing were utilized. There were no statistically significant differences in rates of intraprocedure bleeding, return to ED in 30days, return to OR for revision or other related penile surgery, or the overall number of patients with complications between the groups. Thirteen patients had complications in the APP cohort, compared to 8 in the urologist cohort. There was a difference in age and weight, with urologists performing NBCs on older and heavier patients. There was no difference in clinical outcomes between children over and under 10 pounds (4.5 kg). There was a significant difference in the need for revision circumcision when comparing children older vs younger than 30days (1.9% vs 0%, P = 0.034). An APP-led NBC clinic is both safe and feasible. The widely used age and weight cutoffs for NBC need to be further evaluated, as there was no significant difference in clinical outcomes. This practice design provides pediatric urologists more time to focus on the most complex patients, both in the clinic and OR.


Transient life-threatening cerebral edema in a patient with systemic lupus erythematosus.
Central nervous system symptoms occur in a substantial portion of patients with systemic lupus erythematosus. However, coma is a rare presentation and is usually secondary to complications such as subarachnoid hemorrhage, seizure, or ischemia. Here, we present a 49-year-old woman with lupus erythematosus and a history of recurrent aseptic meningitis and mild subarachnoid hemorrhage who presented with altered mental status and lethargy that progressed rapidly over hours to the herniation syndrome of coma, extensor posturing, and unilateral pupillary dilation. Spinal fluid showed massive protein elevation (>1600), and head computed tomography revealed global cerebral edema. The clinical and radiologic findings rapidly reversed with intravenous corticosteroids and mannitol within 24 hours, and her mental status improved to baseline. Her course was complicated by 2 episodes of recurrent encephalopathy when corticosteroids were tapered; these resolved after resuming high dosing. Because of ongoing pancytopenia, chemotherapy immunosuppression was delayed, and instead she received intravenous immunoglobulin with improvement in the pancytopenia. She remained cognitively intact during subsequent corticosteroid tapering. Rapid development of coma in lupus patients may be due to a primary process of the disease impacting blood brain barrier integrity. Although rare, this potentially fatal complication may be reversible with acute corticosteroid administration.


Significance of serum and peritoneal fluid lactate dehydrogenase levels in ovarian cancer.
We investigated prospectively whether the detection of serum lactate dehydrogenase (LDH) and/or peritoneal fluid LDH levels may serve as a reliable biochemical marker in discriminating ovarian carcinoma from benign ovarian tumors. In this series, postoperatively 20 of 50 patients had a diagnosis of ovarian cancer while the remaining 30 patients had benign ovarian tumor. No significant difference in peritoneal fluid LDH levels was observed between patients with ovarian cancer and benign ovarian tumor (p > 0.05). Serum LDH levels in ovarian cancer patients were significantly higher than those in patients with benign ovarian tumor (p < 0.05). Statistically significant differences were not observed in LDH levels of different histological types of ovarian cancer and different stages of the disease. Serum LDH levels presented diagnostic accuracy with high specificity and may have a potential use as a biochemical marker.


Application of fluoroimmunoassay to cerebrospinal fluid immunoglobulin G and albumin.
Special solid-phase fluoroimmunoasssay protocols were used to measure the amount of immunoglobulin G (IgG) and albumin in 1,511 samples of cerebrospinal fluid. The fluoroimmunoassay is an inhibition test conducted on the surface of a plastic probe, whose fluorescence is inversely related to the concentration of spinal fluid IgG or albumin. A microcomputer interfaced with the fluorometer calculates the sample IgG or albumin from a calibration curve based on standard cerebrospinal fluid values. The test and interpretation take less than 90 min. Correlation coefficients for over 100 cerebrospinal fluid samples tested by both fluoroimmunoassay and radial immunodiffusion were: IgG, 0.90 (slope, 1.04); albumin, 0.95 (slope, 0.99). The within-run precision (coefficient of variation) was: IgG, 4.4%; albumin, 6.3%. Run-to-run precision on a midrange sample was: IgG, 7.7%, albumin, 11.7%. These findings establish the simplicity, speed, and precision of the modified fluoroimmunoassay system for specific cerebrospinal fluid proteins.


The association between genetic variants in SORL1 and Alzheimer disease in an urban, multiethnic, community-based cohort.
To investigate the association between Alzheimer disease (AD) and variant alleles in SORL1 using a series of single nucleotide polymorphisms (SNPs) in an urban, multiethnic, community-based population. We used a nested case-control analysis in a population-based, prospective study of aging and dementia in Medicare recipients, 65 years and older. Northern Manhattan, NY. There were 296 patients with probable AD and 428 healthy, elderly controls. The participants were African American (34%), Caribbean Hispanic (51%), or non-Hispanic white (15%). We genotyped all 29 SNPs in SORL1 that were examined in the earlier report. We assessed allelic association with AD using standard case-control methods, which included apolipoprotein E genotype as a covariate. Several individual SNPs and SNP haplotypes were significantly associated with AD in this prospectively collected community-based cohort, confirming the previously reported positive association of SORL1 with AD. Single nucleotide polymorphism 12, near the 5' region, was associated with AD in African American and Hispanic individuals. Two SNPs in the 3' region were also associated with AD in African American (SNP 26) and non-Hispanic white (SNP 20) individuals. A single haplotype in the 3' region was associated with AD in Hispanic individuals. However, several different haplotypes were associated with AD in African American and white individuals, including the TTC haplotypes at SNPs 23 through 25 (P = .035), which was significantly associated with AD in the North European white individuals in our previous report. This study confirms the association between genetic variants in SORL1 and AD. While the associations observed in these data sets overlap with those previously reported, the finding of novel SNP and haplotype associations suggests that there may be extensive allelic heterogeneity in SORL1. Broad regions of the SORL1 gene will therefore need to be scrutinized for functional pathogenic variants.


Health effects of wind turbines on humans in residential settings: Results of a scoping review.
As the global number of wind turbines has increased steadily in recent years, as has the number of studies about putative health effects in residential settings, it is the review purpose to give an overview of the characteristics and methodologies of the scientific literature around the topic in order to identify research gaps and to derive implications for research and practice. Additionally, study findings from higher-quality observational studies as well as results that seem to be of interest for the scientific and political debate are presented. The scoping review was conducted following systematic review methods. Comprehensive literature searches were carried out in several databases, and with extensive hand searches. All review steps were carried out in parallel by two reviewers or by one reviewer and in duplicate checked by another reviewer. The following important methodological criteria were investigated: Reporting, ethical aspects, generalization, selection bias, information bias, confounder bias. Findings from observational studies without a selection bias, information bias, and confounder bias are presented. 84 articles, that varied significantly in methods and outcomes assessed, met the inclusion criteria. Multiple cross-sectional studies reported that wind turbine noise is associated with noise annoyance, which is moderated by several variables such as noise sensitivity, attitude towards wind turbines, or economic benefit. Wind turbine noise is not associated with stress effects and biophysiological variables of sleep. Results on the impact of wind turbine noise on sleep disburbance, quality of life, and mental health problems differed among cross-sectional studies. There were few studies that addressed the potential impact of turbine noise on clinically apparent health outcomes. There were also few studies on visual risk factors or infrasound exposure. No literature was identified regarding low-frequency noise, electromagnetic radiation, and ice throw. There is an extensive and diverse body of evidence around health impacts of wind turbines in residential settings, that increased sharply since 2010, showing particularly noise consequences concerning increased noise annoyance with its complex pathways; no relationship between wind turbine noise and stress effects and biophysiological variables of sleep; and heterogeneous findings concerning sleep disturbance, quality of life, as well as mental health problems. Research gaps concern the complex pathways of annoyance, the examination of clinically apparent health outcomes in comparison with non-exposed residents, an objective investigation of visual wind turbine features, the interaction between all wind turbine exposures, and epidemiological observational studies on field low-frequency and infrasound from wind turbines. Future research needs thorough high-quality and prospective study designs.


Dissociation between rate of hepatic lipoprotein secretion and hepatocyte microtubule content.
The fact that colchicines inhibits hepatic secretion of very low density lipoprotein (VLDL) particles has been interpreted to mean that microtubules are involved in hepatic VLDL secretion. To further define this relationship, we have attempted to see if changes in hepatic VLDL secretion are associated with changes in hepatocyte microtubule or tubulin content. Accordingly, hepatic secretion of VLDL was increased in rats, and the hepatocyte content of both microtubules (using quantitative morphometric methods) and tubulin (using a time-decay colchicine binding assay) was determined. In acute experiments, VLDL secretion was increased by perfusion of isolated rat livers for 2 h with varying concentrations of free fatty acids (FFA). Results indicate that hepatic VLDL triglyceride (TG) secretion at perfusate FFA levels of 0.7 muEq/ml is threefold greater (P < 0.01) than when livers are perfused without added FFA. However, no differences are observed in the content of microtubules in these livers: specifically, microtubules occupy 0.029 percent of hepatocyte cytoplasm in livers perfused without FFA and 0.030 percent of cytoplasm in livers perfused with FFA. In chronic experiments, rats were fed for 1 wk with either standard rat chow or a hyperlipidemic (sucrose/lard) diet. With the experimental diet, plasma triglyceride levels increase threefold over controls, and liver VLDL-TG production, as determined by [(3)H]glycerol turnover studies, is 55 percent greater (P < 0.01) than controls. However, microtubules occupy 0.027 percent of the cytoplasm of hepatocyte cytoplasm whether rats are on standard or hyperlipidemic diets. Furthermore, the tubulin content of isolated hepatocytes does change, and represents 1 percent of hepatocyte soluble protein, irrespective of diet. These results suggest that increases in hepatic VLDL secretion can occur without any demonstrable change in hepatocyte assembled microtubule or tubulin content, and raise questions as to the role played by microtubules in hepatic VLDL secretion.


Challenges to DNA replication in hypoxic conditions.
The term hypoxia refers to any condition where insufficient oxygen is available and therefore encompasses a range of actual oxygen concentrations. The regions of tumours adjacent to necrotic areas are at almost anoxic levels and are known to be extremely therapy resistant (radiobiological hypoxia). The biological response to radiobiological hypoxia includes the rapid accumulation of replication stress and subsequent DNA damage response, including both ATR- and ATM-mediated signalling, despite the absence of detectable DNA damage. The causes and consequences of hypoxia-induced replication stress will be discussed.


Ultranarrow-bandwidth atomic filter with Raman light amplification.
A Raman-amplified atomic filter is demonstrated experimentally. With a coupling light detuned from the D2 line of 85Rb, a weak signal light can be amplified by a factor of 55, and the bandwidth of the filter's transmission spectrum is narrowed to approximately 60 MHz. Moreover, the transmission wavelength is adjustable by changing the coupling-light frequency. Compared with a conventional dispersive atomic filter, this Raman-amplified atomic filter could be more efficient to suppress background noise in free-space quantum-key distribution or a laser-communication system.


Predictors and dynamics of postpartum relapses in women with multiple sclerosis.
Several studies have shown that pregnancy reduces multiple sclerosis (MS) relapses, which increase in the early postpartum period. Postpartum relapse risk has been predicted by pre-pregnancy disease activity in some studies. To re-examine effect of pregnancy on relapses using the large international MSBase Registry, examining predictors of early postpartum relapse. An observational case-control study was performed including pregnancies post-MS onset. Annualised relapse rate (ARR) and median Expanded Disability Status Scale (EDSS) scores were compared for the 24 months pre-conception, pregnancy and 24 months postpartum periods. Clustered logistic regression was used to investigate predictors of early postpartum relapses. The study included 893 pregnancies in 674 females with MS. ARR (standard error) pre-pregnancy was 0.32 (0.02), which fell to 0.13 (0.03) in the third trimester and rose to 0.61 (0.06) in the first three months postpartum. Median EDSS remained unchanged. Pre-conception ARR and disease-modifying treatment (DMT) predicted early postpartum relapse in a multivariable model. Results confirm a favourable effect on relapses as pregnancy proceeds, and an early postpartum peak. Pre-conception DMT exposure and low ARR were independently protective against postpartum relapse. This novel finding could provide clinicians with a strategy to minimise postpartum relapse risk in women with MS planning pregnancy.


Homocysteine induced cardiovascular events: a consequence of long term anabolic-androgenic steroid (AAS) abuse.
The long term effects (>20 years) of anabolic-androgenic steroid (AAS) use on plasma concentrations of homocysteine (HCY), folate, testosterone, sex hormone binding globulin (SHBG), free androgen index, urea, creatinine, haematocrit (HCT), vitamin B12, and urinary testosterone/epitestosterone (T/E) ratio, were examined in a cohort of self-prescribing bodybuilders. Subjects (n = 40) were divided into four distinct groups: (1) AAS users still using AAS (SU; n = 10); (2) AAS users abstinent from AAS administration for 3 months (SA; n = 10); (3) non-drug using bodybuilding controls (BC; n = 10); and (4) sedentary male controls (SC; n = 10). HCY levels were significantly higher in SU compared with BC and SC (p<0.01), and with SA (p<0.05). Fat free mass was significantly higher in both groups of AAS users (p<0.01). Daily energy intake (kJ) and daily protein intake (g/day) were significantly higher in SU and SA (p<0.05) compared with BC and SC, but were unlikely to be responsible for the observed HCY increases. HCT concentrations were significantly higher in the SU group (p<0.01). A significant linear inverse relationship was observed in the SU group between SHBG and HCY (r = -0.828, p<0.01), indicating a possible influence of the sex hormones in determining HCY levels. With mounting evidence linking AAS to adverse effects on some clotting factors, the significantly higher levels of HCY and HCT observed in the SU group suggest long term AAS users have increased risk of future thromboembolic events.


Isolation and Characterization of Halotolerant Soil Fungi from the Great Salt Plains of Oklahoma.
The Great Salt Plains (GSP) of Oklahoma is an inland terrestrial hypersaline environment where saturated brines leave evaporite crusts of NaCl. The current report examines the fungal community, complementing earlier reports on the bacterial and archaeal communities. Twenty-five fungal isolates from GSP soils were obtained on medium containing 10% NaCl and characterized. Based on 18S rRNA gene sequence analysis, all of the isolates fall within the Ascomycetes, with a predominance of Trichocomaceae, represented by Aspergillus, Eurotium, and Penicillium species. Representatives of Anthrinium, Cladosporium, Debaryomyces, Fusarium, and Ulocladium also were isolated. Overall the isolates were widely halotolerant, with best growth observed at lower salinities and no halophilism. The fungal genera observed were all cosmopolitan, without strong specialization. Taken together, these results support the conclusion that hypersaline environments do not have a characteristic community, in contrast to what was observed at the GSP for bacteria and archaea.


Does a trauma course improve resident performance on the trauma domain of the OITE?
Lecture-based courses are common in orthopaedic surgery; however, their effectiveness in improving medical knowledge has not been widely assessed. The Orthopaedic Trauma Association conducts a resident trauma course that occurs four to six weeks prior to the Orthopaedic In-Training Examination (OITE). The purposes of this study were to determine whether residents who had taken this course performed better on the trauma domain of the OITE and to compare the effect of the course with the effect of a focused rotation in orthopaedic trauma. The percentile scores on the trauma domain of the OITE for forty-seven residents in postgraduate year (PGY) 2 were reviewed. Twenty-nine residents who took a trauma course within six weeks before the OITE were compared with eighteen residents who took the course after the OITE. As a secondary analysis, the effect of a trauma rotation for the same PGY-2 residents before and after the OITE was also assessed. Baseline orthopaedic knowledge was assessed with use of the overall OITE percentage scores. The trauma domain scores were not significantly better among the residents who took the course (mean and standard deviation, 62.2 ± 9.9) compared with those who had not taken it (mean, 59.2 ± 6.2) (p = 0.2). A significant difference (p = 0.04) was found for a trauma rotation, with the residents who had a trauma rotation scoring better (mean, 64.5 ± 6.8) than the residents who had not (mean, 58.8 ± 8.9). The subgroup of residents who had both a course and a trauma rotation before the test scored significantly better (p = 0.01) than the subgroup that had neither of these experiences before the test (mean, 65.6 ± 8.0 and 56.9 ± 6.4, respectively). An orthopaedic trauma course alone does not enhance an orthopaedic resident's trauma medical knowledge as assessed on a standardized test. However, a trauma rotation before, and in particular the combination of both a course and a trauma rotation, can improve trauma test scores.


Postoperative Chylothorax of Unclear Etiology in a Patient with Right-sided Subclavian Central Venous Catheter Placement.
A young male underwent decompressive craniotomy for an intracerebral bleed. A right-sided subclavian central venous catheter was placed in the operating room after induction of anesthesia. Postoperatively, he was shifted to Intensive Care Unit (ICU) for mechanical ventilation due to low Glasgow coma scale. He had an episode of severe agitation and straining on the tracheal tube in the evening same day. On the 2nd postoperative day in ICU, his airway pressures were high, and chest X-ray revealed massive pleural effusion on right side. Under ultrasound guidance, 1400 milky white fluid was aspirated. It was sent for analysis (triglycerides) that confirmed chyle and hence, chylothorax was made as diagnosis. A duplex scan was done which ruled out thrombosis in subclavian vein. The catheter had normal pressure tracing with free aspiration of blood from all ports. Enteral feeding was continued as it is a controversial matter in the literature and he was monitored clinically and radiologically.


[The effect of natural selection on the allelic frequency of gliadin-coding loci and their associations in an artificially created hybrid population of winter wheat].
Hybrid population with heterogeneity for five gliadin-coding loci was created by crossing of five winter common wheat cultivars (Belozerskaya 47, Ilyichevka, Kyyanka, Mironovskaya 808, Polesskaya 70) by the complete scheme. Frequencies of alleles at these loci and their associations were analyzed after two, four and ten years of resowing. The ratio of alleles at the studied loci was changed as reproduction occurred. Gli 1A5 allele displayed stable tendency to frequency increasing, Gli 1D1--a little tendency and Gli 6A3--very essential tendency. The share of Gli 6D2 allele increased only after ten years of population reproduction. Combination of alleles at two, three, and five loci was not accidental. The most common regularity was predominance of the frequency of allelic associations characteristic of the parents (except for Ilyichevka) over new combinations. Possible causes of this phenomenon are discussed.


Colonisation of Irish patients with chronic obstructive pulmonary disease by Streptococcus pneumoniae and analysis of the pneumococcal vaccine coverage: a non-interventional, observational, prospective cohort study.
To characterise the pattern of colonisation and serotypes of Streptococcus pneumoniae among patients with chronic obstructive pulmonary disease (COPD) who currently receive the 23-valent pneumococcal polysaccharide vaccine (PPV-23) according to vaccination status, use of antibiotics and steroids. To investigate the prevalence of PPV-23 and 13-valent pneumococcal conjugate vaccine (PCV-13) serotypes within the study cohort. A non-interventional, observational, prospective cohort study with a 12 -month follow-up period inclusive of quarterly study visits. Beaumont Hospital and The Royal College of Surgeons in Ireland Clinical Research Centre, Dublin, Ireland. Patients with an established diagnosis of COPD attending a tertiary medical centre. Colonisation rate of S. pneumoniae in patients with COPD and characterisation of serotypes of S. pneumoniae with correlation to currently available pneumococcal vaccines. Sputum and oropharyngeal swab samples were collected for the isolation of S. pneumoniae. Seasonality of colonisation of S. pneumoniae and its relationship with the incidence of exacerbations of COPD. S. pneumoniae was detected in 16 of 417 samples, a colonisation incident rate of 3.8% and in 11 of 133 (8%) patients at least once during the study. The majority of S. pneumoniae isolates were identified in spring and were non-vaccine serotypes for either the PPV-23 or PCV-13 (63%). The colonisation incident rate of S. pneumoniae fluctuated over the four seasons with a peak of 6.6% in spring and the lowest rate of 2.2% occurring during winter. Antibiotic use was highest during periods of low colonisation. There is seasonal variation in S. pneumoniae colonisation among patients with COPD which may reflect antibiotic use in autumn and winter. The predominance of non-vaccine types suggests that PCV-13 may have limited impact among patients with COPD in Ireland who currently receive PPV-23. NCT02535546; post-results.


The molecular mechanism of bacterial lipoprotein modification--how, when and why?
Posttranslational modification of proteins by lipidation is a common process in biological systems. Lipids provide protein stability, interaction with other membrane components, and in some cases, due to reversibility of the process, a mechanism for regulating protein localization and function. Bacterial lipoproteins possess fatty acids at their amino-termini that are derived from phospholipids, and this lipid moiety anchors the proteins into the membrane. These lipids, as is the case for lipopolysaccharides and lipoteichoic acids, play an important role in signaling of the innate immune system through the interaction with Toll-like receptors. Over the past three years, tremendous progress has been made in understanding the mechanism by which lipoproteins become lipidated. Advanced methodology in mass spectrometry, proteomics and genome-wide analyses allowed precise characterization of lipoprotein modifications and the identification of the enzymes catalyzing the reactions in diverse bacterial species. This review will highlight new findings on bacterial lipoprotein modification with focus on the reaction mechanisms and the role of lipoproteins in cell envelope homeostasis.


Relationship between body mass index and quantitative 24-hour urine chemistries in patients with nephrolithiasis.
To examine the relationship between body mass index and 24-hour urine constituents in a population of stone-forming patients. A total of 880 patients who presented to a metabolic stone clinic for initial evaluation were analyzed. Patients were stratified by gender and divided into quartiles of body mass index. Associations between body mass index (BMI) and urine parameters were explored using bivariate and multivariate linear regression. On bivariate analysis, increasing body mass index was associated with a significant increase in sodium, calcium, citrate, uric acid, magnesium, calcium oxalate, uric acid, and a decrease in pH in men. In women, it was associated with a significant increase in sodium, uric acid, oxalate, uric acid, and decreasing pH. On multivariate analysis, BMI was associated only with increases in sodium and calcium oxalate and decrease in pH in men. In women, multivariate analysis demonstrated positive association between BMI and urine sodium, creatinine, and phosphate and a negative relationship with urine citrate and sulfate. Increasing body mass index was related to several risk factors for urinary stone disease in this study, including increasing urine sodium and decreasing pH in men and increasing urine uric acid, sodium, and decreasing urine citrate in women. Just as general recommendations for patients with nephrolithiasis include high voided volumes, low dietary sodium, and low animal protein intake, perhaps weight reduction should be included as part of the counseling of stone-formers to optimize 24-hour urine parameters.


Accreditation and quality assurance for Radiation Therapy Oncology Group: Multicenter clinical trials using Stereotactic Body Radiation Therapy in lung cancer.
Starting in 2002, the Radiation Therapy Oncology Group in North America began the process of developing multicenter prospective trials in lung cancer using Stereotactic Body Radiation Therapy (SBRT). Much of the work was based on the prospective single institution trials from Indiana University that had been presented and published. In late 2004, RTOG 0236 using SBRT for medically inoperable patients with clinical stage I non-small cell lung cancer (NSCLC) was activated for accrual. Prior to activation, representatives from the Lung, Image-Guided Therapy, Physics, and Radiobiology Committees met on regular occasions to design the multicenter study and quality assurance measures. SBRT is not a black box, and the essence of the therapy had to be distilled via guidelines. Issues related to patient selection, method of dosimetry construction, equipment requirements, motion assessments and control, site accreditation, data exchange, and follow-up policies were worked out by compromise and consensus. RTOG 0236 has nearly completed its accrual. The Lung Committee has initiated the development of several other trials, each building on the last, to investigate the therapy in central tumors, in combinations with systemic therapy, in operable patients, and in lung metastases patients. The guidelines developed for RTOG 0236 will be refined to take advantage of more modern innovations including heterogeneity corrections and intensity modulation when appropriate. The development of RTOG 0618 using SBRT in operable patients with early stage NSCLC is a testament to both the enthusiasm from already published works and prospective multicenter clinical testing using SBRT techniques.


Executive Functions and Social Cognition in Juveniles Who Have Sexually Offended.
Although neuropsychological assessments provide valuable information for those working in forensic mental health, few neuropsychological studies concern persons who sexually offend, particularly juveniles who have sexually offended (JSO). It has been suggested that, contrary to current theories, executive function in JSO, as a group, is no more impaired than it is in juvenile delinquents in general. However, JSO with child victims seem to be more impulsive than JSO whose victims are peers or adults. To verify this potentially important (and unexpected) finding, a sample of adolescent males (N = 134; 15.6 ± 1.5 years old) that included JSO, general delinquents, and underprivileged nondelinquents was assessed using a battery of behavioral and psychological tests that focus on impulsivity. No difference was found between groups regarding higher order executive functions as measured with the Wisconsin Card Sorting Task but JSO with child victims were found to be the most impulsive subgroup as evidenced with the Iowa Gambling Task, the Stop-Signal Reaction Task, and the Impulsive scale of the Social Problem Solving Inventory. They also had the highest number of prescriptions for attention deficit hyperactivity disorder (ADHD) medication. These results, which contradict hypotheses derived from assessment of adult sex offenders, illustrate an important difference between the cognitive profiles of adult and juvenile males who sexually offended. They also confirm that JSO whose victims are children appear to be more impulsive.


Peanut sensitisation and allergy: influence of early life exposure to peanuts.
The aim of the present systematic review was to evaluate the influence of early life exposure (maternal and childhood) to peanuts and the subsequent development of sensitisation or allergy to peanuts during childhood. Studies were identified using electronic databases and bibliography searches. Studies that assessed the impact of non-avoidance compared with avoidance or reduced quantities of peanuts or peanut products on either sensitisation or allergy to peanuts, or both outcomes, were eligible. Six human studies were identified: two randomised controlled trials, two case-control studies and two cross-sectional studies. In addition, published animal and mechanistic studies, relevant to the question of whether early life exposure to peanuts affects the subsequent development of peanut sensitisation, were reviewed narratively. Overall, the evidence reviewed was heterogeneous, and was limited in quality, for example, through lack of adjustment for potentially confounding factors. The nature of the evidence has therefore hindered the development of definitive conclusions. The systematic review of human studies and narrative expert-led reviews of animal studies do not provide clear evidence to suggest that either maternal exposure, or early or delayed introduction of peanuts in the diets of children, has an impact upon subsequent development of sensitisation or allergy to peanuts. Results from some animal studies (and limited evidence from human subjects) suggest that the dose of peanuts is an important mediator of peanut sensitisation and tolerance; low doses tend to lead to sensitisation and higher doses tend to lead to tolerance.


Clinical utility of probiotics in inflammatory bowel disease.
Many patients with inflammatory bowel disease (IBD) use probiotics to manage this intestinal condition. Despite widespread use of these natural therapies by patients, health care providers may be unfamiliar with probiotics as a treatment modality. This review describes the rationale for use of probiotics in IBD, the history behind current research directions, and recent controlled clinical studies in which efficacy of probiotics has been explored in patients with IBD. Emphasis is placed upon critical analysis of study designs for investigations that used lactic acid-producing bacteria or Saccharomyces boulardii in management of Crohn's disease or ulcerative colitis. While there is suggestion of benefit when patients with ulcerative colitis use bacterial therapies and when patients with Crohn's disease use S boulardii, small sample sizes and methodological flaws in study designs necessitate that additional investigations be conducted before probiotics can be routinely recommended in clinical practice.


Respiratory gas exchange ratio and prediction of aerobic power.
The Issekutz procedure for the prediction of maximum oxygen intake from the respiratory exchange ratio (R) has been evaluated on a diverse group of 308 subjects, including "whites" and Eskimos, men and women ranging in age from 16 to 65 yr. When applied to young white men performing 12 min of progressive step or treadmill exercise, the prediction procedure has a coefficient of variation of less than 10%, without systematic error. Unfortunately, the standard equation lacks generality, and erroneous predictions can arise from a change of test protocol, the use of a different exercise modality, or application to older subjects. If a brief exercise format is used, low R values may be reported during an early phase of relative hypoventilation. At a given metabolic loading, bicycle ergometry yields a higher respiratory minute volume than other modes of exercise. A heavy loading of one muscle group seems responsible, and the results is a high R value in submaximum effort. Aging is associated with a lowering of maximum blood lactate levels and thus maximum figures for R.


[Anxiety disorders in nursing homes: a literature review of prevalence, course and risk indicators].
Psychiatric disorders such as dementia and depression are highly prevalent in nursing homes. The prevalence of anxiety disorders is less clear. Prevalence, course and risk-indicators of anxiety disorders among nursing home residents were examined, based on a review of the literature. Medline and PsychINFO searches were conducted for 1966-2002. Twelve studies were considered relevant. These differed substantially with respect to study-population, diagnostic instruments and diagnostic criteria that were used and the specific anxiety disorders investigated. The prevalence of anxiety disorders ranged from 0-20%. Only in one study the course of anxiety disorders was investigated. About 60% of the nursing home residents recovered in one year. The most important risk-indicators for anxiety disorders identified were: female sex, depression, lack of social support, poor physical health and functional and cognitive impairments. Generalization of these results to the Dutch nursing home population is restricted by the substantial heterogeneity of the studies. Further studies are required to provide reliable estimates of prevalence, course and risk-indicators of anxiety disorders among nursing home residents using appropriate diagnostic instruments and adjusted diagnostic criteria. This will enhance detection and improve treatment of anxiety disorders among nursing home residents.


Effects of direct brain stimulation depend on seizure dynamics.
Brain stimulation is currently used as an experimental treatment for patients with medically refractory epilepsy. However, the results of such stimulation are still less than optimal. A major factor is the lack of understanding of the mechanisms of applied stimuli. Herein we review evidence on the effects of stimulation in models of epileptic seizures. We show that the effects of stimulation during epileptic seizures can differ from those observed under normal conditions. Several studies suggest a potentially greater beneficial therapeutic effect of strong depolarizing and overactivating stimulations than hyperpolarizing ones in the treatment of seizures. The potential relevance of these results to other therapeutic stimulation protocols is discussed.


CCAT2, a novel long non-coding RNA in breast cancer: expression study and clinical correlations.
The clinical outcome of BC patients receiving the same treatment is known to vary considerably and thus, there is a compelling need to identify novel biomarkers that can select the patients that would benefit most from a given therapy and can predict the clinical outcome. The aim of this study was to determine the prognostic value of CCAT2, a novel long ncRNA recently characterized by our group and overlapping SNP rs6983267, in BC patients. We first evaluated by RT-qPCR and ISH the expression of CCAT2 in normal breast tissue and BC tissue and further analyzed CCAT2 expression in an independent set of 997 primary BC with regard to clinical, histological, pathological and other biological factors. Also, we explored the possibility of CCAT2 adding to the prognostic value of multivariate models that already included the traditional prognostic factors. Finally, we identified in in vitro models the impact of CCAT2 expression and SNP rs6983267 genotype on cell migration and chemoresistance. Our results revealed that although overexpressed in BCs in two out of three sets of patients, and having the highest expression in lymph node negative (LNN) disease, CCAT2 expression levels are informative solely for a subgroup of BC patients, namely for patients with LNP disease that have received adjuvant CMF chemotherapy. For this subgroup high levels of CCAT2 suggest the patients will not benefit from CMF containing adjuvant chemotherapy (shorter MFS and OS). Additionally, we found that CCAT2 upregulates cell migration and downregulates chemosensitivity to 5'FU in a rs6983267-independent manner.


Cryptorchidism: a prospective study of 7500 consecutive male births, 1984-8. John Radcliffe Hospital Cryptorchidism Study Group.
A total of 7441 boys were examined for cryptorchidism at birth and, if present, again at 3 months of age. After excluding boys with severe congenital malformations noted at birth, the cryptorchidism rates at 3 months in babies weighing less than 2000 g, 2000-2499 g, and greater than or equal to 2500 g were 7.7%, 2.5%, and 1.41% respectively. The overall rate was 1.55%. The cryptorchidism rate at birth had increased by 35.1% and at 3 months by 92.7%, over Scorer's rates in the 1950s. Part of these increases may be attributable to differences in neonatal mortality, but the increases in babies weighing 2500 g or more of 50.2% at birth and 77.4% at 3 months are unlikely to be overestimates. At birth 1.92% of boys had bilateral cryptorchidism and 3.0% unilateral cryptorchidism. Boys with cryptorchidism at 3 months were more likely to have hypospadias, a small scrotum, and poor scrotal rugation compared with boys having normally descended testes at birth. Factors predicting descent by 3 months in babies cryptorchid at birth are birth weight, laterality and scrotal size, babies with low birth weight, bilateral cryptorchidism, and normal scrotal size being more likely to have normally descended testes by 3 months. Descent by 3 months was more likely the lower the testis along the normal pathway of descent. The orchidopexy rate at an average age of 3 years was 1.24%. This is substantially lower than in other series and lower than our estimated rate of 2.9% using Hospital In-Patient Enquiry data for England and Wales.


Industrial Application of Artificially Induced Diploid Strains of Torulaspora delbrueckii.
Diploid strains of Torulaspora delbrueckii were tested for industrial application. Because the cell volume of the diploid strain was three times as large as that of the parental haploid strain, collection and subsequent dehydration to make compressed yeast cakes were greatly improved with the diploid YL3. The time required for dehydration of the diploid strain was shortened to 1/2.5 that of the parent strain under conventional conditions. Moreover, for the diploid cells frequent filter changes for dehydration were not required, which was the case with parental cells. Fermentation activity and tolerance to freeze-thawing in dough were succesfully inherited by the diploid strains. The diploid YL3 showed nearly the same activity as the diploid F31 in bread making. However, the endurance period of yeast cakes when stored at 30 degrees C without softening to lead to liquefaction was much longer in YL3 (199 h) than in F31 (132 h). This superiority was ascribed to the fact that YL3 was induced through direct diploidization and had no genetic defect on chromosomes because the wild-type strain was employed as the parent, whereas F31 was obtained through protoplast fusion from two auxotrophic mutants and carried at least two mutagenized genes that were masked by heterolallelism.


Comparative risk of oral ulcerations among antipsychotics users - population-based retrospective cohort study.
The study aimed to evaluate the comparative risk of oral ulcerations among antipsychotic medications. We analyzed the National Health Insurance Research Database of Taiwan and included patients newly initiated with a single antipsychotic agent including haloperidol, sulpiride, olanzapine, quetiapine, risperidone, or amisulpride during 2002 to 2010. The outcome of interest was oral ulceration, defined by the presence diagnoses of stomatitis and mucositis, aphthous-like ulceration and oral burns, or dispensing of stomatological corticosteroids included triamcinolone, dexamethasone, hydrocortisone, and prednisolone. We conducted Cox proportional hazards regression to compare the risks of oral ulceration among antipsychotics. The rate of oral ulcerations was highest in the amisulpride group (217.7 per 1000 person-year), followed by quetiapine (193.9 per 1000 person-year), olanzapine (161.9 per 1000 person-year), sulpiride (147.1 per 1000 person-year), risperidone (115.6 per 1000 person-year), haloperidol (107.5 per 1000 person-year) and aripiprazole (49.8 per 1000 person-year). Compared with haloperidol users, the adjusted hazard ratio (AHR) was 1.40 (95% CI, 1.12-1.73) in olanzapine, 1.48 (95% CI, 1.30-1.69) in quetiapine, 1.27 (95% CI, 1.19-1.44) in sulpiride, 1.68 (95% CI, 0.97-2.59) in amisulpride, 1.02 (95% CI, 0.83-1.45) in risperidone, and 0.41 (95% CI, 0.24-0.72) in aripiprazole users by Cox regression model. Olanzapine, quetiapine, and sulpiride posed a higher risk, while aripiprazole posed a lower risk of oral ulcerations compared with haloperidol in subjects with newly initiated antipsychotic therapy. Risperidone and amisulpride tended to have higher risk of oral ulcerations, but this was not statistically significant.


Inhibition of dihydropyridine metabolism in rat and human liver microsomes by flavonoids found in grapefruit juice.
The effects of naringenin, quercetin and kaempferol, flavonoids found in grapefruit as glycosides, on the metabolism of nifedipine and the enantiomers of felodipine were studied in microsomes from rat and human liver. Flavonoid concentrations of 10, 50 and 100 mumol/l were added to rat liver microsomes. The metabolism of nifedipine, (R)- and (S)-felodipine was inhibited to a similar extent, and the inhibition was dependent on the chemical structure and the concentration of flavonoid. Naringenin had lower inhibitory potency than quercetin and kaempferol. These flavonoids exhibited the same order of inhibitory potency in human liver microsomes. No inhibition of naringenin was found, however, until higher concentrations, 300 and 500 mumol/l, were added. A likely mechanism is inhibition of cytochrome P-450 IIIA4, the isoenzyme that catalyzes the oxidation of the dihydropyridine ring to form the corresponding pharmacologically inactive pyridine metabolite. This is a predominant metabolic step that determines the extent of first-pass extraction of dihydropyridines. Grapefruit juice has been shown recently to increase the p.o. bioavailability of the dihydropyridine calcium antagonists nifedipine and felodipine. The interaction may be explained by an inhibition of the first-pass metabolism by flavonoids in grapefruit juice. Furthermore, the results indicate that the rat may be used for in vivo studies of interactions between flavonoids and dihydropyridines or other drugs that are metabolized by cytochrome P-450 IIIA4.


Intrapartum tests for group B streptococcus: accuracy and acceptability of screening.
To assess the accuracy and acceptability of polymerase chain reaction (PCR) and optical immunoassay (OIA) tests for the detection of maternal group B streptococcus (GBS) colonisation during labour, comparing their performance with the current UK policy of risk factor-based screening. Diagnostic test accuracy study. Fourteen hundred women in labour at two large UK maternity units provided vaginal and rectal swabs for testing. The PCR and OIA index tests were compared with the reference standard of selective enriched culture, assessed blind to index tests. Factors influencing neonatal GBS colonisation were assessed using multiple logistic regression, adjusting for antibiotic use. The acceptability of testing to participants was evaluated through a structured questionnaire administered after delivery. The sensitivity and specificity of PCR, OIA and risk factor-based screening. Maternal GBS colonisation was 21% (19-24%) by combined vaginal and rectal swab enriched culture. PCR test of either vaginal or rectal swabs was more sensitive (84% [79-88%] versus 72% [65-77%]) and specific (87% [85-89%] versus 57% [53-60%]) than OIA (P < 0.001), and far more sensitive (84 versus 30% [25-35%]) and specific (87 versus 80% [77-82%]) than risk factor-based screening (P < 0.001). Maternal antibiotics (odds ratio, 0.22 [0.07-0.62]; P = 0.004) and a positive PCR test (odds ratio, 29.4 [15.8-54.8]; P < 0.001) were strongly related to neonatal GBS colonisation, whereas risk factors were not (odds ratio, 1.44 [0.80-2.62]; P = 0.2). Intrapartum PCR screening is a more accurate predictor of maternal and neonatal GBS colonisation than is OIA or risk factor-based screening, and is acceptable to women.


Evaluation of a model of violence risk assessment among forensic psychiatric patients.
This study tested the interrater reliability and criterion-related validity of structured violence risk judgments made by using one application of the structured professional judgment model of violence risk assessment, the HCR-20 violence risk assessment scheme, which assesses 20 key risk factors in three domains: historical, clinical, and risk management. The HCR-20 was completed for a sample of 100 forensic psychiatric patients who had been found not guilty by reason of a mental disorder and were subsequently released to the community. Violence in the community was determined from multiple file-based sources. Interrater reliability of structured final risk judgments of low, moderate, or high violence risk made on the basis of the structured professional judgment model was acceptable (weighted kappa=.61). Structured final risk judgments were significantly predictive of postrelease community violence, yielding moderate to large effect sizes. Event history analyses showed that final risk judgments made with the structured professional judgment model added incremental validity to the HCR-20 used in an actuarial (numerical) sense. The findings support the structured professional judgment model of risk assessment as well as the HCR-20 specifically and suggest that clinical judgment, if made within a structured context, can contribute in meaningful ways to the assessment of violence risk.


Variation in sorbitol accumulation and polyol-pathway activity in cultured human proximal tubule cells.
The polyol pathway is present in tissues of several organs where its activation may participate in the development of diabetic complications. We measured the accumulation of polyol-pathway intermediates in HPT cells isolated from 21 different human kidneys from nondiabetic individuals. When exposed to 27.5 mM glucose in the growth media, cells isolated from approximately 75% of individuals (accumulators) accumulated sorbitol within 1-4 days, whereas 25% (nonaccumulators) accumulated only negligible amounts, even when the period of exposure was extended to 2 wk. Surprisingly, measurement of the activities of the polyol-pathway enzymes showed no difference in the levels of either AR or SDH between accumulators and nonaccumulators, even when the conversion of galactose to galactitol was used to measure AR activity in intact cells independently of SDH. Measurement of sorbitol in the growth media indicated that nonaccumulators were not releasing sorbitol into the growth media. Fructose levels in the conditioned growth media were 4 times higher in the sorbitol-accumulating cells. Together, these results indicate that the tendency of cells from an individual to accumulate significant amounts of sorbitol may reflect the cells' ability to metabolize sorbitol in steps subsequent to the polyol pathway.


Understanding the anomalous electrophoresis of bent DNA molecules: a reptation model.
In polyacrylamide gel electrophoresis, the retardation of DNA molecules containing regions of intrinsic curvature can be explained by a novel reptation model that includes the elastic free energy of the DNA chain. Computer simulations based on this model give results that reproduce the dependence of anomalous mobility on gel concentration, which is quantified by new experimental data on the mobilities of circularly permuted isomers of kinetoplast DNA fragments. Fitting of the data required allowing for the elasticity of the gel.


A combined community- and facility-based approach to improve pregnancy outcomes in low-resource settings: a Global Network cluster randomized trial.
Fetal and neonatal mortality rates in low-income countries are at least 10-fold greater than in high-income countries. These differences have been related to poor access to and poor quality of obstetric and neonatal care. This trial tested the hypothesis that teams of health care providers, administrators and local residents can address the problem of limited access to quality obstetric and neonatal care and lead to a reduction in perinatal mortality in intervention compared to control locations. In seven geographic areas in five low-income and one middle-income country, most with high perinatal mortality rates and substantial numbers of home deliveries, we performed a cluster randomized non-masked trial of a package of interventions that included community mobilization focusing on birth planning and hospital transport, community birth attendant training in problem recognition, and facility staff training in the management of obstetric and neonatal emergencies. The primary outcome was perinatal mortality at ≥28 weeks gestation or birth weight ≥1000 g. Despite extensive effort in all sites in each of the three intervention areas, no differences emerged in the primary or any secondary outcome between the intervention and control clusters. In both groups, the mean perinatal mortality was 40.1/1,000 births (P = 0.9996). Neither were there differences between the two groups in outcomes in the last six months of the project, in the year following intervention cessation, nor in the clusters that best implemented the intervention. This cluster randomized comprehensive, large-scale, multi-sector intervention did not result in detectable impact on the proposed outcomes. While this does not negate the importance of these interventions, we expect that achieving improvement in pregnancy outcomes in these settings will require substantially more obstetric and neonatal care infrastructure than was available at the sites during this trial, and without them provider training and community mobilization will not be sufficient. Our results highlight the critical importance of evaluating outcomes in randomized trials, as interventions that should be effective may not be. ClinicalTrials.gov NCT01073488.


Coryneform bacteria associated with canine otitis externa.
This study aims to investigate the occurrence of coryneform bacteria in canine otitis externa. A combined case series and case-control study was carried out to improve the current knowledge on frequency and clinical significance of coryneform bacteria in samples from canine otitis externa. A total of 16 cases of otitis externa with involvement of coryneform bacteria were recorded at two referral veterinary hospitals in Denmark and the US, respectively. Coryneform bacteria were identified by partial 16S rRNA gene sequencing. Corynebacterium auriscanis was the most common coryneform species (10 cases). Small colony variants of this species were also observed. Other coryneform isolates were identified as Corynebacterium amycolatum (3 cases), Corynebacterium freneyi (2 cases) and an Arcanobacterium-like species (1 case). The coryneform bacteria were in all cases isolated together with other bacteria, mainly Staphylococcus pseudintermedius alone (n=5) or in combination with Malassezia pachydermatis (n=5). Some coryneform isolates displayed resistance to fusidic acid or enrofloxacin, two antimicrobial agents commonly used for the treatment of otitis externa in dogs. The frequency of isolation of coryneform bacteria was 16% among 55 cases of canine otitis externa examined at the Danish hospital during 2007. In contrast, detectable levels of coryneform bacteria were not demonstrated in samples from the acustic meatus of 35 dogs with apparently healthy ears, attending the hospital during the same year. On basis of the current knowledge, these coryneform bacteria should be regarded as potential secondary pathogens able to proliferate in the environment of an inflamed ear canal.


Effects of Dairy Consumption on Body Composition and Bone Properties in Youth: A Systematic Review.
Background: According to previous reviews, there is no clear evidence on the effects of dairy consumption on body composition and bone properties in pediatric populations. There is a need for further assessment of existing findings and the methodologic quality of studies before summarizing the evidence. Objective: The aim of the study was to assess the quality, methodologies, and substantive findings of randomized controlled trials (RCTs) that examined the effects of dairy consumption on body size, body composition, and bone properties in children and adolescents. Methods: After searching PubMed and Google Scholar up to December 2016, 15 RCTs were retained and included in this systematic review for further analysis. The quality of the included studies was assessed via the Jadad scale; detailed methodologic and statistical characteristics were evaluated, and the main findings were summarized. Results: The effects of dairy consumption were found to be significant for bone structure and nonsignificant for body size and composition. Eight of the 11 RCTs that assessed bone found significant effects (P < 0.05) for bone mineral content and bone mineral density (BMD), with an average 8% increase in BMD after 16 mo of dairy consumption. Conversely, significant effects (P < 0.05) were found only in 2 of the 14 RCTs that focused on body size (i.e., height and weight) and in only 1 of the 11 RCTs that focused on body composition (i.e., lean mass). Conclusions: The systematic consumption of dairy products may benefit bone structure and development, but it does not appear to affect body composition or body size in children and adolescents. On the basis of the Jadad scale, the methodologic quality of the 15 RCTs was rated as good overall. However, there were methodologic disparities and limitations that may have led to nonsignificant results, particularly for body size and composition. Future RCTs designed to address these limitations are warranted.


Electronic health record use, intensity of hospital care, and patient outcomes.
Previous studies have suggested that weekend hospital care is inferior to weekday care and that this difference may be related to diminished care intensity. The purpose of this study was to determine whether a metric for measuring intensity of hospital care based on use of the electronic health record was associated with patient-level outcomes. We performed a cohort study of hospitalizations at an academic medical center. Intensity of care was defined as the hourly number of provider accessions of the electronic health record, termed "electronic health record interactions." Hospitalizations were categorized on the basis of the mean difference in electronic health record interactions between the first Friday and the first Saturday of hospitalization. We used regression models to determine the association of these categories with patient outcomes after adjusting for covariates. Electronic health record interactions decreased from Friday to Saturday in 77% of the 9051 hospitalizations included in the study. Compared with hospitalizations with no change in Friday to Saturday electronic health record interactions, the relative lengths of stay for hospitalizations with a small, moderate, and large decrease in electronic health record interactions were 1.05 (95% confidence interval [CI], 1.00-1.10), 1.11 (95% CI, 1.05-1.17), and 1.25 (95% CI, 1.15-1.35), respectively. Although a large decrease in electronic health record interactions was associated with in-hospital mortality, these findings were not significant after risk adjustment (odds ratio 1.74, 95% CI, 0.93-3.25). Intensity of inpatient care, measured by electronic health record interactions, significantly diminished from Friday to Saturday, and this decrease was associated with length of stay. Hospitals should consider monitoring and correcting temporal fluctuations in care intensity.


Placental morphology in two sympatric Andean lizards of the genus Liolaemus (Reptilia: Liolaemidae).
Viviparity is a remarkable feature in squamate sauropsids and it has evolved multiple times in parallel with the formation of a placenta. One example of this repeated evolution of viviparity and placentation occurs in the species-rich South American genus Liolaemus with at least six independent origins of viviparity. However, evolutionary studies of placentation in this genus are limited by a lack of data on placental morphology. The aim of this study is to describe and compare the microanatomy and vessel diameter (Dv, a function of blood flow) of the placenta using scanning electron microscopy (SEM) and confocal laser scanning microscopy (cLSM) in two sympatric Andean viviparous but highly divergent species, Liolaemus robustus and Liolaemus walkeri. We found interspecific differences in cell types in the chorion, allantois, and omphalopleure that may be explained by divergent phylogenetic history. Time elapsed since divergence may also explain the pronounced interspecific differences in vessel diameter, and within each species, there are strong differences in Dv between tissue locations. Both species show features to improve gas exchange in the chorioallantoic placenta including absence of eggshell, large Dv in the allantois (L. robustus) or embryonic side of the uterus (L. walkeri), and when present, microvillous cells in the allantois (L. walkeri). Both species also show features that suggest transfer of nutrients or water in the omphaloplacenta, including an almost complete reduction of the eggshell, secretive material (L. robustus), or vesicles (L. walkeri) on cell surface uterus, and when present specialized cells in the omphalopleure (L. walkeri). No statistical differences in Dv were found among stages 32-39 in each species, suggesting that a different mechanism, other than enhanced blood flow, might satisfy the increased oxygen demand of the developing embryos in the hypoxic environments of the high Andes.


Lord-Wingersky Algorithm Version 2.0 for Hierarchical Item Factor Models with Applications in Test Scoring, Scale Alignment, and Model Fit Testing.
Lord and Wingersky's (Appl Psychol Meas 8:453-461, 1984) recursive algorithm for creating summed score based likelihoods and posteriors has a proven track record in unidimensional item response theory (IRT) applications. Extending the recursive algorithm to handle multidimensionality is relatively simple, especially with fixed quadrature because the recursions can be defined on a grid formed by direct products of quadrature points. However, the increase in computational burden remains exponential in the number of dimensions, making the implementation of the recursive algorithm cumbersome for truly high-dimensional models. In this paper, a dimension reduction method that is specific to the Lord-Wingersky recursions is developed. This method can take advantage of the restrictions implied by hierarchical item factor models, e.g., the bifactor model, the testlet model, or the two-tier model, such that a version of the Lord-Wingersky recursive algorithm can operate on a dramatically reduced set of quadrature points. For instance, in a bifactor model, the dimension of integration is always equal to 2, regardless of the number of factors. The new algorithm not only provides an effective mechanism to produce summed score to IRT scaled score translation tables properly adjusted for residual dependence, but leads to new applications in test scoring, linking, and model fit checking as well. Simulated and empirical examples are used to illustrate the new applications.


How virus induces a rapid or slow onset insulin-dependent diabetes mellitus in a transgenic model.
We developed two distinct transgenic mouse models in which virus induced insulin-dependent (type 1) diabetes mellitus (IDDM). In one of these lines, the unique viral transgene was expressed in the islets of Langerhans and also in the thymus, but in the other line, expression was only in the islets. Insertion and expression of the viral (self) gene, per se, did not lead to IDDM, (incidence < 5%). By contrast, induction of an anti-self (anti-viral) CD8+ CTL response to the same virus later in life caused IDDM (incidence < 90%) in both transgenic lines, although the kinetics and requirements for CD4 help, the affinity and avidity of CD8+ CTL differed in each line. Mice not expressing the viral (self) gene in the thymus developed IDDM 10-14 days after infection. CD4+ T cells played no detectable role, since their depletion failed to alter either the kinetics or incidence of IDDM. By contrast, mice that expressed the viral gene in the thymus required significantly more time to develop IDDM. Their anti-self (viral) CD8+ CTL were of lower affinity and avidity than CD8+ CTL generated by nontransgenic controls. Disease was dependent on T cell help, since deletion of CD4+ cells completely circumvented the IDDM.


Geographic differences in gastric cancer incidence can be explained by differences between Helicobacter pylori strains.
Certain populations with high incidences of Helicobacter pylori infection, such as those in East Asian countries, have high incidences of gastric cancer, while other highly infected populations, such as those in Africa and South Asia, do not. The various rates of gastric cancer associated with different geographic areas can be explained, at least in part, by the differences in the genotypes of H. pylori cagA and vacA. Populations expressing a high incidence of gastric cancer are mostly identical with regions where East Asian type CagA is predominant. In contrast, incidence of gastric cancer is low in Africa, South Asia, and Europe, where strains typically possess Western type CagA. Within East Asia, strains from northern parts, where the incidence of gastric cancer is high, predominantly possess the vacA m1 genotype, whereas the m2 genotype is predominant in southern parts where the gastric cancer incidence is low.


Serum protein profiles to identify head and neck cancer.
New and more consistent biomarkers of head and neck squamous cell carcinoma (HNSCC) are needed to improve early detection of disease and to monitor successful patient management. The purpose of this study was to determine whether a new proteomic technology could correctly identify protein expression profiles for cancer in patient serum samples. Surface-enhanced laser desorption/ionization-time of flight-mass spectrometry ProteinChip system was used to screen for differentially expressed proteins in serum from 99 patients with HNSCC and 102 normal controls. Protein peak clustering and classification analyses of the surface-enhanced laser desorption/ionization spectral data were performed using the Biomarker Wizard and Biomarker Patterns software (version 3.0), respectively (Ciphergen Biosystems, Fremont, CA). Several proteins, with masses ranging from 2778 to 20800 Da, were differentially expressed between HNSCC and the healthy controls. The serum protein expression profiles were used to develop and train a classification and regression tree algorithm, which reliably achieved a sensitivity of 83.3% and a specificity of 100% in discriminating HNSCC from normal controls. We propose that this technique has potential for the development of a screening test for the detection of HNSCC.


Concurrent cetuximab and radiotherapy after docetaxel-cisplatin induction chemotherapy in stage III NSCLC: satellite--a phase II study from the Swedish Lung Cancer Study Group.
Several attempts to increase the locoregional control in locally advanced lung cancer including concurrent chemotherapy, accelerated fractionation and dose escalation have been made during the last years. As the EGFR directed antibody cetuximab has shown activity concurrent with radiotherapy in squamous cell carcinoma of the head and neck, as well as in stage IV NSCLC combined with chemotherapy, we wanted to investigate radiotherapy with concurrent cetuximab in locally advanced NSCLC, a tumour type often over expressing the EGF-receptor. Between February 2006 and August 2007 75 patients in stage III NSCLC with good performance status (PS 0 or 1) and adequate lung function (FEV1>1.0) were enrolled in this phase II study at eight institutions. Treatment consisted of 2 cycles of induction chemotherapy, docetaxel 75 mg/m² and cisplatin 75 mg/m² with 3 weeks interval. An initial dose of cetuximab 400 mg/m² was given before start of 3D-CRT to 68 Gy with 2 Gy per fraction in 7 weeks concurrent with weekly cetuximab 250 mg/m². TOXICITY was scored weekly during radiotherapy (CTC 3.0), and after treatment the patients were followed every third month with CT-scans, toxicity scoring and QLQ. Seventy-one patients were eligible for analysis as four were incorrectly enrolled. adenocarcinoma 49%, squamous cell carcinoma 39% and other NSCLC 12%. The majority had PS 0 (62.5%), median age 62.2 (42-81), 50% were women and 37% had a pre-treatment weight loss>5%. esophagitis grade 1-2: 72%; grade 3: 1.4%. Hypersensitivity reactions grade 3-4: 5.6%. Febrile neutropenia grade 3-4: 15.4%. Skin reactions grade 1-2: 74%; grade 3: 4.2%. Diarrhoea grade 1-2: 38%; grade 3: 11.3%. Pneumonitis grade 1-2: 26.8%; grade 3: 4.2%; grade 5: 1.4%. The median follow-up was 39 months for patients alive and the median survival was 17 months with a 1-, 2- and 3-year OS of 66%, 37% and 29% respectively. Until now local or regional failure has occurred in 20 patients and 22 patients have developed distant metastases. Weight loss, PS and stage were predictive for survival in univariate as well as in multivariate analysis. Induction chemotherapy followed by concurrent cetuximab and RT to 68 Gy is clearly feasible with promising survival. TOXICITY, e.g. pneumonitis and esophagitis is low compared to most schedules with concurrent chemotherapy. This treatment strategy should be evaluated in a randomised manner vs. concurrent chemoradiotherapy to find out if it is a valid treatment option.


Expression of CD24, a Stem Cell Marker, in Pancreatic and Small Intestinal Neuroendocrine Tumors.
CD24 has been considered a normal and cancer stem cell marker. Potential intestinal stem cells weakly express CD24. In the pancreas, CD24 is a possible cancer stem cell marker for ductal adenocarcinoma. Expression of CD24 in intestinal and pancreatic neuroendocrine tumors (NETs) was examined. Immunohistochemistry was performed on benign duodenum, ileum mucosa, and pancreas, as well as primary duodenal, primary and metastatic ileal, and pancreatic NETs. Scattered CD24-positive cells were noted in the duodenal and ileal crypts, most of which showed a strong subnuclear labeling pattern. Similar expression was observed in 41 (95%) of 43 primary ileal NETs but in only four (15%) of 26 duodenal NETs (P < .01). In addition, metastatic ileal NETs retained CD24 expression. Pancreatic islets did not express CD24, and only rare cells had subnuclear labeling of CD24 in the pancreatic ducts. Unlike ileal NETs, only five (5%) of 92 pancreatic NETs expressed CD24 in the subnuclear compartment (P < .01). All five NETs showed a unique morphology with prominent stromal fibrosis. CD24 expression was frequent in primary and metastatic midgut NETs but rare in pancreatic and duodenal NETs. Expression of CD24 in ileal NETs may have future diagnostic and therapeutic implications.


How Do Households Respond to Unreliable Water Supplies? A Systematic Review.
Although the Millennium Development Goal (MDG) target for drinking water was met, in many developing countries water supplies are unreliable. This paper reviews how households in developing countries cope with unreliable water supplies, including coping costs, the distribution of coping costs across socio-economic groups, and effectiveness of coping strategies in meeting household water needs. Structured searches were conducted in peer-reviewed and grey literature in electronic databases and search engines, and 28 studies were selected for review, out of 1643 potentially relevant references. Studies were included if they reported on strategies to cope with unreliable household water supplies and were based on empirical research in developing countries. Common coping strategies include drilling wells, storing water, and collecting water from alternative sources. The choice of coping strategies is influenced by income, level of education, land tenure and extent of unreliability. The findings of this review highlight that low-income households bear a disproportionate coping burden, as they often engage in coping strategies such as collecting water from alternative sources, which is labour and time-intensive, and yields smaller quantities of water. Such alternative sources may be of lower water quality, and pose health risks. In the absence of dramatic improvements in the reliability of water supplies, a point of critical avenue of enquiry should be what coping strategies are effective and can be readily adopted by low income households.


Under Diffusion Control: from Structuring Matter to Directional Motion.
Self-organization in synthetic chemical systems is quickly developing into a powerful strategy for designing new functional materials. As self-organization requires the system to exist far from thermodynamic equilibrium, chemists have begun to go beyond the classical equilibrium self-assembly that is often applied in bottom-up supramolecular synthesis, and to learn about the surprising and unpredicted emergent properties of chemical systems that are characterized by a higher level of complexity and extended reactivity networks. The present review focuses on self-organization in reaction-diffusion systems. Selected examples show how the emergence of complex morphogenesis is feasible in synthetic systems leading to hierarchically and nanostructured matter. Starting from well-investigated oscillating reactions, recent developments extend diffusion-limited reactivity to supramolecular systems. The concept of dynamic instability is introduced and illustrated as an additional tool for the design of smart materials and actuators, with emphasis on the realization of motion even at the macroscopic scale. The formation of spatio-temporal patterns along diffusive chemical gradients is exploited as the main channel to realize symmetry breaking and therefore anisotropic and directional mechanical transformations. Finally, the interaction between external perturbations and chemical gradients is explored to give mechanistic insights in the design of materials responsive to external stimuli.


Identification of Borrelia burgdorferi sensu lato, Anaplasma and Ehrlichia species, and spotted fever group Rickettsiae in ticks from Southeastern Europe.
Prevalence data for tick-borne pathogens are used to assess the risk for human health. In this study the presence and identity of Borrelia burgdorferi sensu lato, Ehrlichia, Anaplasma, and Rickettsia species in Bulgarian Ixodes ricinus ticks and in non- Ixodes ticks from Turkey and Albania was determined by polymerase chain reaction (PCR) and reverse line blot hybridization. In the adult Bulgarian ticks, the prevalence of Borrelia burgdorferi sensu lato infection was approximately 40%, while Borrelia afzelii was the predominant species, representing more than half of all Borrelia-positive ticks. Ehrlichia and Anaplasma species were detected in 35% of the adult Ixodes ricinus ticks and in 10% of the nymphs. Sequence analysis of PCR products reacting with the Anaplasma phagocytophila probe revealed a 16S rRNA gene identical to that of the Anaplasma phagocytophila prototype strain. Ehrlichia and Anaplasma species were found in approximately 7% of the non- Ixodes ticks. Sequence analysis of some of these samples revealed the presence of Anaplasma ovis, Ehrlichia canis, and a species closely resembling Ehrlichia chaffeensis. About half of all adult ticks examined and approximately 20% of all nymphs were infected with Rickettsia species. In Ixodes ricinus ticks, Rickettsia helvetica and a Rickettsia species designated as IRS3 were found in high prevalence. Rickettsia conorii was found in virtually all non- Ixodes tick species from Albania and Turkey. The results of this study show that many tick-borne diseases are most probably endemic in the Balkan area. Furthermore, the results suggest that there is a considerable chance for simultaneous transmission of tick-borne pathogens to human beings.


The simplest Diels-Alder reactions are not endo-selective.
There is a widespread perception that the high level of endo selectivity witnessed in many Diels-Alder reactions is an intrinsic feature of the transformation. In contrast to expectations based upon this existing belief, the first experimental Diels-Alder reactions of a novel, deuterium-labeled 1,3-butadiene with commonly used mono-substituted alkenic dienophiles (acrolein, methyl vinyl ketone, acrylic acid, methyl acrylate, acrylamide and acrylonitrile) reveal kinetic endo : exo ratios close to 1 : 1. Maleonitrile, butenolide, α-methylene γ-butyrolactone, and N-methylmaleimide behave differently, as does methyl vinyl ketone under Lewis acid catalysis. CBS-QB3 calculations incorporating solvent and temperature parameters give endo : exo product ratios that are in near quantitative agreement with these and earlier experimental findings. This work challenges the preconception of innate endo-selectivity by providing the first experimental evidence that the simplest Diels-Alder reactions are not endo-selective. Trends in behaviour are traced to steric and electronic effects in Diels-Alder transition structures, giving new insights into these fundamental processes.


Pharmacy-based management for depression in adults.
It is common for peoples not to take antidepressant medication as prescribed, with around 50% of people likely to prematurely discontinue taking their medication after six months. Community pharmacists may be well placed to have a role in antidepressant management because of their unique pharmacotherapeutic knowledge and ease of access for people. Pharmacists are in an ideal position to offer proactive interventions to people with depression or depressive symptoms. However, the effectiveness and acceptability of existing pharmacist-based interventions is not yet well understood. The degree to which a pharmacy-based management approach might be beneficial, acceptable to people, and effective as part of the overall management for those with depression is, to date, unclear. A systematic review of randomised controlled trials (RCTs) will help answer these questions and add important knowledge to the currently sparse evidence base. To examine the effects of pharmacy-based management interventions compared with active control (e.g. patient information materials or any other active intervention delivered by someone other than the pharmacist or the pharmacy team), waiting list, or treatment as usual (e.g. standard pharmacist advice or antidepressant education, signposting to support available in primary care services, brief medication counselling, and/or (self-)monitoring of medication adherence offered by a healthcare professional outside the pharmacy team) at improving depression outcomes in adults. We searched the Cochrane Common Mental Disorders Controlled Trials Register (CCMD-CTR) to June 2016; the Cochrane Library (Issue 11, 2018); and Ovid MEDLINE, Embase, and PsycINFO to December 2018. We searched theses and dissertation databases and international trial registers for unpublished/ongoing trials. We applied no restrictions on date, language, or publication status to the searches. SELECTION CRITERIA: We included all RCTs and cluster-RCTs where a pharmacy-based intervention was compared with treatment as usual, waiting list, or an alternative intervention in the management of depression in adults over 16 years of age. Eligible studies had to report at least one of the following outcomes at any time point: depression symptom change, acceptability of the intervention, diagnosis of depression, non-adherence to medication, frequency of primary care appointments, quality of life, social functioning, or adverse events. DATA COLLECTION AND ANALYSIS: Two authors independently, and in duplicate, conducted all stages of study selection, data extraction, and quality assessment (including GRADE). We discussed disagreements within the team until we reached consensus. Where data did not allow meta-analyses, we synthesised results narratively. MAIN RESULTS: Twelve studies (2215 participants) met the inclusion criteria and compared pharmacy-based management with treatment as usual. Two studies (291 participants) also included an active control (both used patient information leaflets providing information about the prescribed antidepressant). Neither of these studies reported depression symptom change. A narrative synthesis of results on acceptability of the intervention was inconclusive, with one study reporting better acceptability of pharmacy-based management and the other better acceptability of the active control. One study reported that participants in the pharmacy-based management group had better medication adherence than the control participants. One study reported adverse events with no difference between groups. The studies reported no other outcomes. Meta-analyses comparing pharmacy-based management with treatment as usual showed no evidence of a difference in the effect of the intervention on depression symptom change (dichotomous data; improvement in symptoms yes/no: risk ratio (RR), 0.95, 95% confidence interval (CI) 0.86 to 1.05; 4 RCTs, 475 participants; moderate-quality evidence; continuous data: standard mean difference (SMD) -0.04, 95% CI -0.19 to 0.10; 5 RCTs, 718 participants; high-certainty evidence), or acceptability of the intervention (RR 1.09, 95% CI 0.81 to 1.45; 12 RCTs, 2072 participants; moderate-certainty evidence). The risk of non-adherence was reduced in participants receiving pharmacy-based management (RR 0.73, 95% CI 0.61 to 0.87; 6 RCTs, 911 participants; high-certainty evidence). We were unable to meta-analyse data on diagnosis of depression, frequency of primary care appointments, quality of life, or social functioning. We found no evidence of a difference between pharmacy-based management for depression in adults compared with treatment as usual in facilitating depression symptom change. Based on numbers of participants leaving the trials early, there may be no difference in acceptability between pharmacy-based management and controls. However, there was uncertainty due to the low-certainty evidence.


An alamethicin channel in a lipid bilayer: molecular dynamics simulations.
We present the results of 2-ns molecular dynamics (MD) simulations of a hexameric bundle of Alm helices in a 1-palmitoyl-2-oleoylphosphatidylcholine bilayer. These simulations explore the dynamic properties of a model of a helix bundle channel in a complete phospholipid bilayer in an aqueous environment. We explore the stability and conformational dynamics of the bundle in a phospholipid bilayer. We also investigate the effect on bundle stability of the ionization state of the ring of Glu18 side chains. If all of the Glu18 side chains are ionised, the bundle is unstable; if none of the Glu18 side chains are ionized, the bundle is stable. pKA calculations suggest that either zero or one ionized Glu18 is present at neutral pH, correlating with the stable form of the helix bundle. The structural and dynamic properties of water in this model channel were examined. As in earlier in vacuo simulations (Breed et al., 1996 .Biophys. J. 70:1643-1661), the dipole moments of water molecules within the pore were aligned antiparallel to the helix dipoles. This contributes to the stability of the helix bundle.


Exploring childhood immunization uptake with First Nations mothers in north-western Ontario, Canada.
Childhood immunization is an important component of preventive health care for young children. Successful control of vaccine-preventable diseases depends on high levels of immunization coverage. Immunization statistics show that on-reserve First Nations (Native Indian) children have lower vaccination coverage than children in the general Canadian population. There has been little research, however, conducted with First Nations populations on this topic. This study explored First Nations parents' beliefs about childhood immunizations and examined factors influencing immunization uptake. This study used a qualitative descriptive design to explore the issue of childhood immunization uptake. Twenty-eight mothers from two First Nations communities in north-western Ontario, Canada, were interviewed about their perceptions of childhood immunizations and vaccine-preventable diseases. The interviews were transcribed and content analysis was used to examine the data. Data analysis revealed the following six themes: (1) the fear of disease; (2) the efficacy of immunizations; (3) the immunization experience; (4) the consequences of immunization; (5) interactions with health professionals; and (6) barriers to immunizations. Participants were motivated to seek immunizations for their children by a fear of vaccine preventable diseases. A small proportion of mothers, however, questioned the effectiveness of vaccines in preventing disease. Traumatic immunization experiences, vaccine side-effects and sequelae, negative interactions with health professionals, and barriers such as time constraints and childhood illnesses all served as deterrents to immunization. The research outcomes highlight the varied beliefs of First Nations parents about childhood immunizations and the numerous factors that both positively and negatively influence immunization uptake. Further research is needed to explore the issue of childhood immunizations in First Nations communities and to determine strategies to improve uptake.


A critical examination of the role of appreciative inquiry within an interprofessional education initiative.
Appreciative inquiry (AI) is a relatively new approach to initiating or managing organizational change that is associated with the 'positiveness' movement in psychology and its offshoot positive organizational scholarship. Rather than dwelling upon problems related to change, AI encourages individuals to adopt a positive, constructive approach to managing change. In recent years, AI has been used to initiate change across a broad range of public and private sector organizations. In this article, we report findings from a subset of 50 interviews gathered in a wider study of interprofessional education (IPE) in which AI was employed as a change agent for implementing IPE in a number of health care institutions in a North American setting. A multiple case study approach. (Yin, 2002) was employed in the wider study and semi-structured interviews were undertaken with participants both before their IPE programs and directly afterwards to obtain a detailed understanding of their expectations and experiences of IPE. Interviews were analyzed in an inductive thematic manner in order to produce key emergent themes from each of the IPE programs. A process of re-analysis provided a set of themes which offered an understanding of the role of AI within this IPE initiative. Our findings identify a strong resonance and fit for AI both among the health and social care professionals who participated in this initiative. Numerous individuals commented on the enthusiasm and energy AI engendered, while praising its ability to enhance their working lives and interprofessional relationships. Yet a number of difficulties were also reported. These focused on problems with the translation of the AI process into achievable structural level (e.g. professional, cultural) changes. Based on these findings, the article goes on to argue that the use of AI can overlook a number of structural factors, which will ultimately limit its ability to actually secure meaningful and lasting change within health care.


Association of Coffee Consumption with MRI Markers and Cognitive Function: A Population-Based Study.
Coffee is one of the most widely consumed beverages worldwide and has been of considerable interest in research on cognition and dementia. To investigate the effect of coffee on preclinical brain MRI markers of dementia and cognitive performance. In 2,914 participants from the population-based Rotterdam Study (mean age: 59.3±7.2 years, 55% females), we assessed coffee consumption, performed brain MRI, and assessed cognition at baseline. To study cognitive change, cognitive assessment was repeated after 5 years of follow-up. Coffee consumption was analyzed continuously (per cup increase) and in categories (0-1, >1-3, >3 cups/day). Using logistic and linear regression, associations of coffee consumption with lacunar infarcts and brain tissue volumes on MRI, and cognitive performance (cross-sectional and longitudinal) were investigated, adjusting for relevant confounders. We found that higher coffee consumption was associated with a lower prevalence of lacunar infarcts [odds ratio per cup increase: 0.88 (95% CI:0.79;0.98)], and smaller hippocampal volume [difference: -0.01 (95% CI:-0.02;0.00)]. Also, we found that the highest category of coffee consumption was associated with better performance on the Letter Digit Substitution Task [difference: 1.13(95% CI:0.39;1.88)], Word Fluency test [0.74(95% CI:0.04,1.45)], Stroop interference task [1.82(95% CI:0.23;3.41)], and worse performance on the 15-Word Learning test delayed recall [-0.38(95% CI:-0.74;-0.02)]. These associations were not found when cognition was analyzed longitudinally. We found complex associations between coffee consumption, brain structure, and cognition. Higher coffee consumption was cross-sectionally associated with a lower occurrence of lacunar infarcts and better executive function, but also with smaller hippocampal volume and worse memory function.


Efficacy and tolerability of pharmacotherapies for borderline personality disorder.
Borderline personality disorder is a pervasive pattern of instability of interpersonal relationships, affects and self-image, as well as marked impulsivity. Although psychotherapy is needed to attain lasting improvements in a patient's personality and overall functioning, practice guidelines state that pharmacotherapy is indicated to manage state symptoms and trait vulnerabilities. Three psychopathological dimensions are the main targets for pharmacotherapy of borderline personality disorder: affective dysregulation, impulsive-behavioural dyscontrol and cognitive-perceptual symptoms. Guidelines recommend the use of antidepressant agents and mood stabilizers for affective dysregulation and impulsive-behavioural dyscontrol, and antipsychotics for cognitive-perceptual symptoms. This review aims to report and discuss data from clinical trials, reviews and meta-analyses concerning drug efficacy and tolerability in the treatment of borderline personality disorder. Investigations that considered antidepressant agents mainly focused on SSRIs, which are recommended as first-line treatments for affective instability and impulse dyscontrol. Both open-label and randomized controlled studies have been performed, predominantly concerning the efficacy of fluoxetine and fluvoxamine. Other classes of antidepressants, such as TCAs and MAOIs, were investigated as alternative treatments for borderline personality disorder, but the risk of adverse effects and toxicity is a limitation to their use in clinical practice. Increasing amounts of data have recently been collected on the use of mood stabilizers to control mood instability and impulsivity in patients with borderline personality disorder. More substantial data were derived from controlled trials of valproate semisodium, although other drugs such as lithium, carbamazepine, oxcarbazepine and lamotrigine were tested with promising results. Several first-generation antipsychotics were studied in open-label and controlled trials, with good effects on behavioural dyscontrol and psychotic-like symptoms. Selection biases and heterogeneity of drugs and methods somewhat limited the value of these results. More recent investigations have examined atypical antipsychotics, with most of these studies being open-label trials with small sample sizes; however, a few controlled studies have been performed using olanzapine, showing improvements in impulsivity, anger and hostility. In conclusion, a large number of different drugs have been evaluated in the treatment of patients with borderline personality disorder. Initial findings are encouraging for many of these drugs. However, data need to be replicated in further controlled studies with head-to-head comparisons and long-term follow-ups. Many questions remain to be answered.


In vitro experimental models of mesothelioma revisited.
Malignant pleural mesothelioma (MPM) is a biologically unusual, highly aggressive cancer that defies current multimodality treatments. Epidemiologic data suggest that this malignancy has not abated despite increasingly strict environmental regulations on asbestos, the putative causative agent for sporadic cases. An incomplete understanding of all the factors mechanistically driving mesothelioma is largely responsible for the current lack of curative treatments. Many approaches have been employed to ascertain the step-by-step molecular events involved in mesothelioma oncogenesis including in vitro, small animal in vivo, and human experimental models; though clearly defined, druggable mechanisms still are elusive. Importantly, the foundation of the latest accepted model of tumor initiation is derived from in vitro systems. A thorough review of in vitro mesothelioma oncogenesis models may suggest further opportunities for discovery.


Severe acute respiratory syndrome and critical care medicine: the Toronto experience.
The 2003 global outbreak of severe acute respiratory syndrome (SARS) provided numerous challenges to the delivery of critical care. The Toronto critical care community has learned important lessons from SARS, which will help in preparation for future disease outbreaks. The objectives of this study were to review the epidemiology and clinical characteristics of the Toronto SARS outbreak, the challenges SARS provided to the delivery of critical care, and how we would like to be better organized for a similar challenge in the future. SARS manifests clinically as atypical pneumonia and ranges in severity from minor nonspecific symptoms to adult respiratory distress syndrome (ARDS). Approximately 20% of patients with SARS will become critically ill and require admission to the intensive care unit. ARDS develops in the majority of these patients. Mortality from ARDS in SARS is high, and outcome is associated with the presence of comorbid disease and the severity of illness at presentation. The influx of critically ill patients and the transmission of SARS to front line workers created a tremendous strain on Toronto's healthcare system. From a critical care perspective, the most important limitation in the response to SARS was the absence of a coordinated leadership and communication infrastructure. Other challenges encountered during SARS include the following: closure of intensive care unit beds and loss of staff through quarantine and illness, implementing novel infection control protocols, educating staff, conducting research to learn about SARS, system planning, and maintaining staff morale during this very difficult period. Communication and leadership strategies were key components in the critical care response to SARS. Ideally, centers should have systems in place to allow for the rapid expansion and modification of critical care services in the event of a disease outbreak. Other critical care communities should consider their crisis response strategies in advance of similar events.