Mutations within a putative cysteine loop of the transmembrane protein of an attenuated immunodeficiency-inducing feline leukemia virus variant inhibit envelope protein processing.
A replication-defective feline leukemia virus molecular clone, 61B, has been shown to cause immunodeficiency in cats and cytopathicity in T cells after a long latency period when coinfected with a minimally pathogenic helper virus (J. Overbaugh, E. A. Hoover, J. I. Mullins, D. P. W. Burns, L. Rudensey, S. L. Quackenbush, V. Stallard, and P. R. Donahue, Virology 188:558-569, 1992). The long-latency phenotype of 61B has been mapped to four mutations in the extracellular domain of the envelope transmembrane protein, and we report here that these mutations cause a defect in envelope protein processing. Immunoprecipitation analyses demonstrated that the 61B gp85 envelope precursor was produced but that further processing to generate the surface protein (SU/gp70) and the transmembrane protein (TM/p15E) did not occur. The 61B precursor was not expressed on the cell surface and appeared to be retained in the endoplasmic reticulum or Golgi apparatus. Two of the four 61B-specific amino acid changes are located within a putative cysteine loop in a region of TM that is conserved among retroviruses. Introduction of these two amino acid changes into a replication-competent highly cytopathic virus resulted in the production of noninfectious virus that exhibited an envelope-protein-processing defect. This analysis suggests that mutations in a conserved region within a putative cysteine loop affect retroviral envelope protein maturation and viral infectivity.


Ease of use versus clinical effectiveness of restorative materials.
"Ease of use," as applied to dental materials and techniques, means different things to different people. Factors that may contribute to ease of use include a minimum number of application stages, easy application and shaping ability, quickness of use, lack of stick, and moisture sensitivity. Ease of use may also imply that a material or technique does not cause stress for the dentist and patient, is cost effective, is easy to learn, and should provide the operators with a sense of satisfaction with their work. Similarly, "clinical effectiveness" of the treatments prescribed for patients is not always capable of being accurately defined. Suggested factors that may contribute to clinical effectiveness include a lack of patient complaints with respect to longevity and/or cost, no secondary caries, and preservation of the remaining tooth structure during functional loading. Ease of use and clinical effectiveness are not necessarily related, but they must be combined for a technique to be successful. The achievement of this demands a partnership between clinicians, manufacturers, and patients.


Inhibitors of the lipoxygenase arachidonic acid pathway impair glycocholate efflux in isolated rat hepatocytes.
Lipoxygenase arachidonic acid metabolites mediate secretory processes in several tissues, but their possible involvement in liver transport functions is still unknown. This study evaluated the influence of the lipoxygenase inhibitor nordihydroguayaretic acid (NDGA), the cyclooxygenase inhibitor indomethacin (INDO), and the dual cyclo and lipoxygenase inhibitors 3-amino-1-[m-(trifluoromethyl)-phenyl]-2-pyrazoline (BW 755c) and eicosatetraynoic acid (ETYA) on the handling of glycocholic acid (GC) by isolated rat hepatocytes. No drug modified cell viability or oxygen consumption in hepatocytes. In 30-min incubations with 50 microM GC the initial rate of GC uptake (V0) in control hepatocytes was 1.15 +/- 0.09 nmol.mg protein-1.min-1. The cellular GC content remained constant from 10 to 30 min (steady-state phase), the 30-min value being 6.63 +/- 0.35 nmol.mg protein-1. NDGA (10-50 microM), BW 755c (25-200 microM) and ETYA (5-100 microM), prevented the steady-state phase occurring, thus determining a progressive accumulation of GC in cells with time. As compared to controls, 50 microM NDGA (+37%, p less than 0.01), 200 microM BW 755c (+39%, p less than 0.01) and 5 microM ETYA (+19%, p less than 0.05) induced the highest increases in the amount of GC in cells at 30 min, in all cases V0 being unchanged. Concentrations of BW 755c and ETYA above those indicated also decreased V0. Both V0 and the amount of cellular GC in the steady-state phase were proportionally decreased by high INDO concentrations (25-100 microM) which did not modify the morphology of the uptake curve. Since experiments with dual and lipoxygenase inhibitors suggested an impairment of GC efflux, the initial rate of GC efflux (V0ef) was measured in hepatocytes preloaded with 50 microM GC and transferred to a GC-free medium. In controls, V0ef was 1.12 +/- 0.12 nmol.mg protein-1.min-1. BW 755c (200 microM) and NDGA (50 microM) reduced V0ef by 45 and 38%, respectively. The kinetic analysis of the effect of 200 microM BW 755c on the efflux process using hepatocytes preloaded with GC from 5 to 200 microM disclosed a non-competitive inhibition. Vmax was reduced from 1.37 +/- 0.15 to 0.89 +/- 0.10 (p less than 0.01), whereas Km was unchanged (3.79 +/- 0.33 vs. 4.25 +/- 0.54, N.S.). In summary, inhibitors of the lipoxygenase arachidonic acid pathway impaired the efflux of GC from isolated rat hepatocytes. The hypothesis is raised that oxidized metabolites of arachidonic acid may participate on the secretion of bile salts in these cells.


Management of depressive symptoms in schizophrenia.
Although depressive symptoms are a frequently occurring phenomenon in schizophrenia, effective treatments remain an area of clinical need. To assess the benefit of short-term treatment with the atypical antipsychotic asenapine versus placebo on depressive symptoms in patients with acute schizophrenia in an exacerbated state. Data were pooled from intent-to-treat (ITT) populations of three 6-week, randomized controlled studies with fixed doses of asenapine (ASE; n=427), olanzapine (OLA; n=82), risperidone (RIS; n=54), haloperidol (HAL; n=97), or placebo (PLA; n=254). Change from baseline Calgary Depression Scale for Schizophrenia (CDSS) total score and individual item scores were assessed at Day 21 and Day 42 in the total patient population (n=914), and in patients presenting with a CDSS total score of .6 at baseline (n=248). Mixed model repeated measures (MMRM) analyses were performed on patient data. The observed change from baseline in CDSS total score was significantly larger with ASE.compared to PLA.at both Day 21 (p<0.05) and Day 42 (p<0.01) for the total patient population group, and at Day 21 (p<0.05) in patients with baseline CDSS total score .6. For both populations, there was a significant change from baseline in the CDSS depression item score with ASE.compared to PLA.at Day 21 (p<0.01, all patient population; p<0.05, patients with baseline CDSS .6), and at Day 42 (p<0.01) in the all patient population. Statistically significant changes from baseline, in favor of ASE versus PLA, were also observed in other individual CDSS item scores including hopelessness (p<0.05, Day 21, patients with baseline CDSS .6), self-depreciation (p<0.05, Day 42, all patient population), guilty ideas of reference (p<0.01, Day 42, all patient population), pathological guilt (p<0.01, Day 21, all patient population; p<0.05, Day 21 and Day 42, patients with baseline CDSS score .6), and observed depression (p<0.05, Day 21, all patient population). ASE significantly improved a range of depressive symptoms in people with an acute exacerbation of schizophrenia, as measured by the CDSS. ASE may represent a beneficial treatment option for the management of depressive symptoms in patients with schizophrenia.


Varying susceptibility of different low density lipoproteins to oxidative modification.
The oxidative modification of low density lipoprotein (LDL) may provide a crucial link between plasma LDL and the atherosclerotic lesion. The studies presented herein define time-dependent modifications of LDL constituents caused by CuSO4-catalyzed oxidation. Measurement of the cholesterol content of oxidized LDL by the cholesterol esterase-oxidase assay was found to be inaccurate. The enzymatic assay detected oxysterols as well as cholesterol and thus substantially overestimated the actual cholesterol content. Alteration of electrophoretic mobility and conversion of sterols into oxysterols increased in a parallel, time-dependent manner. Lipid peroxidation, judged by the thiobarbituric acid-reacting substances assay, increased early to maximal values but was not linearly related to either electrophoretic mobility or to oxysterol formation. Neither electrophoretic mobility nor oxysterol formation varied much between repeated oxidative modifications of any given LDL preparation but varied markedly among LDLs from different normolipidemic individuals, suggesting that LDL particles contain some factor conferring susceptibility or resistance to oxidation. Indeed, LDL preparations from different individuals have varying susceptibilities to oxidative modification as evidenced by the three indexes used. The major oxysterol generated was 7-ketocholesterol. Macrophage modification of LDL also resulted in the generation of oxysterols. Thus, measurement of oxysterols may afford an additional index of the oxidative modification of LDL. Since incubation of macrophages with oxidized LDL but not native LDL resulted in the accumulation of oxysterols, this could account for some of the toxic and metabolic effects of oxidized LDL on cells.


Demographic patterns of a widespread long-lived tree are associated with rainfall and disturbances along rainfall gradients in SE Australia.
Predicting species distributions with changing climate has often relied on climatic variables, but increasingly there is recognition that disturbance regimes should also be included in distribution models. We examined how changes in rainfall and disturbances along climatic gradients determined demographic patterns in a widespread and long-lived tree species, Callitris glaucophylla in SE Australia. We examined recruitment since 1950 in relation to annual (200-600 mm) and seasonal (summer, uniform, winter) rainfall gradients, edaphic factors (topography), and disturbance regimes (vertebrate grazing [tenure and species], fire). A switch from recruitment success to failure occurred at 405 mm mean annual rainfall, coincident with a change in grazing regime. Recruitment was lowest on farms with rabbits below 405 mm rainfall (mean = 0-0.89 cohorts) and highest on less-disturbed tenures with no rabbits above 405 mm rainfall (mean = 3.25 cohorts). Moderate levels of recruitment occurred where farms had no rabbits or less disturbed tenures had rabbits above and below 405 mm rainfall (mean = 1.71-1.77 cohorts). These results show that low annual rainfall and high levels of introduced grazing has led to aging, contracting populations, while higher annual rainfall with low levels of grazing has led to younger, expanding populations. This study demonstrates how demographic patterns vary with rainfall and spatial variations in disturbances, which are linked in complex ways to climatic gradients. Predicting changes in tree distribution with climate change requires knowledge of how rainfall and key disturbances (tenure, vertebrate grazing) will shift along climatic gradients.


The nature and role of periosteum in bone and cartilage regeneration.
This study was undertaken to determine whether periosteum from different bone sources in a donor results in the same formation of bone and cartilage. In this case, periosteum obtained from the cranium and mandible (examples of tissue supporting intramembranous ossification) and the radius and ilium (examples of tissues supporting endochondral ossification) of individual calves was used to produce tissue-engineered constructs that were implanted in nude mice and then retrieved after 10 and 20 weeks. Specimens were compared in terms of their osteogenic and chondrogenic potential by radiography, histology, and gene expression levels. By 10 weeks of implantation and more so by 20 weeks, constructs with cranial periosteum had developed to the greatest extent, followed in order by ilium, radius, and mandible periosteum. All constructs, particularly with cranial tissue although minimally with mandibular periosteum, had mineralized by 10 weeks on radiography and stained for proteoglycans with safranin-O red (cranial tissue most intensely and mandibular tissue least intensely). Gene expression of type I collagen, type II collagen, runx2, and bone sialoprotein (BSP) was detectable on QRT-PCR for all specimens at 10 and 20 weeks. By 20 weeks, the relative gene levels were: type I collagen, ilium >> radial ≥ cranial ≥ mandibular; type II collagen, radial > ilium > cranial ≥ mandibular; runx2, cranial >>> radial > mandibular ≥ ilium; and BSP, ilium ≥ radial > cranial > mandibular. These data demonstrate that the osteogenic and chondrogenic capacity of the various constructs is not identical and depends on the periosteal source regardless of intramembranous or endochondral ossification. Based on these results, cranial and mandibular periosteal tissues appear to enhance bone formation most and least prominently, respectively. The appropriate periosteal choice for bone and cartilage tissue engineering and regeneration should be a function of its immediate application as well as other factors besides growth rate.


Epithelial tethering of MUC5AC-rich mucus impairs mucociliary transport in asthma.
The development of pathologic mucus, which is not readily cleared from the airways, is an important contributor to the morbidity and mortality associated with asthma. It is not clear how the major airway mucins MUC5AC and MUC5B are organized within the mucus gel or how this gel contributes to airway obstruction in asthma. Here, we demonstrated that mucus plugs from individuals with fatal asthma are heterogeneous gels with distinct MUC5AC- and MUC5B-containing domains. Stimulation of cultured human bronchial epithelial cells with IL-13, a key mediator in asthma, induced the formation of heterogeneous mucus gels and dramatically impaired mucociliary transport. Impaired transport was not associated with defects in ciliary function but instead was related to tethering of MUC5AC-containing mucus gel domains to mucus-producing cells in the epithelium. Replacement of tethered mucus with untethered mucus restored mucociliary transport. Together, our results indicate that tethering of MUC5AC-containing domains to the epithelium causes mucostasis and likely represents a major cause of mucus plugging in asthma.


Similarity and diversity of the tumor microenvironment in multiple metastases: critical implications for overall and progression-free survival of high-grade serous ovarian cancer.
The tumor microenvironment is pivotal in influencing cancer progression and metastasis. Different cells co-exist with high spatial diversity within a patient, yet their combinatorial effects are poorly understood. We investigate the similarity of the tumor microenvironment of 192 local metastatic lesions in 61 ovarian cancer patients. An ecologically inspired measure of microenvironmental diversity derived from multiple metastasis sites is correlated with clinicopathological characteristics and prognostic outcome. We demonstrate a high accuracy of our automated analysis across multiple sites. A low level of similarity in microenvironmental composition is observed between ovary tumor and corresponding local metastases (stromal ratio r = 0.30, lymphocyte ratio r = 0.37). We identify a new measure of microenvironmental diversity derived from Shannon entropy that is highly predictive of poor overall (p = 0.002, HR = 3.18, 95% CI = 1.51-6.68) and progression-free survival (p = 0.0036, HR = 2.83, 95% CI = 1.41-5.7), independent of and stronger than clinical variables, subtype stratifications based on single cell types alone and number of sites. Although stromal influence in ovary tumors is known to have significant clinical implications, our findings reveal an even stronger impact orchestrated by diverse cell types. Quantitative histology-based measures can further enable objective selection of patients who are in urgent need of new therapeutic strategies such as combinatorial treatments targeting heterogeneous tumor microenvironment.


Molecular and structural basis of olfactory sensory neuron axon coalescence by Kirrel receptors.
Projections from sensory neurons of olfactory systems coalesce into glomeruli in the brain. The Kirrel receptors are believed to homodimerize via their ectodomains and help separate sensory neuron axons into Kirrel2- or Kirrel3-expressing glomeruli. Here, we present the crystal structures of homodimeric Kirrel receptors and show that the closely related Kirrel2 and Kirrel3 have evolved specific sets of polar and hydrophobic interactions, respectively, disallowing heterodimerization while preserving homodimerization, likely resulting in proper segregation and coalescence of Kirrel-expressing axons into glomeruli. We show that the dimerization interface at the N-terminal immunoglobulin (IG) domains is necessary and sufficient to create homodimers and fail to find evidence for a secondary interaction site in Kirrel ectodomains. Furthermore, we show that abolishing dimerization of Kirrel3 in vivo leads to improper formation of glomeruli in the mouse accessory olfactory bulb as observed in Kirrel3-/- animals. Our results provide evidence for Kirrel3 homodimerization controlling axonal coalescence.


Pyrazinamide inhibits trans-translation in Mycobacterium tuberculosis.
Pyrazinamide (PZA) is a first-line tuberculosis drug that plays a unique role in shortening the duration of tuberculosis chemotherapy. PZA is hydrolyzed intracellularly to pyrazinoic acid (POA) by pyrazinamidase (PZase, encoded by pncA), an enzyme frequently lost in PZA-resistant strains, but the target of POA in Mycobacterium tuberculosis has remained elusive. Here, we identify a previously unknown target of POA as the ribosomal protein S1 (RpsA), a vital protein involved in protein translation and the ribosome-sparing process of trans-translation. Three PZA-resistant clinical isolates without pncA mutation harbored RpsA mutations. RpsA overexpression conferred increased PZA resistance, and we confirmed that POA bound to RpsA (but not a clinically identified ΔAla mutant) and subsequently inhibited trans-translation rather than canonical translation. Trans-translation is essential for freeing scarce ribosomes in nonreplicating organisms, and its inhibition may explain the ability of PZA to eradicate persisting organisms.


Challenges in early diagnosis of primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma: a case series of four patients.
Primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma (AECTCL) is a rare and aggressive lymphoma characterised by ulcerated lesions and a poor prognosis. To present a case series of four previously misdiagnosed AECTCL patients and discuss the importance of early diagnosis. All patients in this study were identified from the database of the Dermatology Department of the Medical School of Bezmialem Vakif University, based on clinical and histopathological diagnosis of AECTCL between 2010 and 2018. AECTCL cases may mimic many benign dermatoses and accurate diagnosis may be delayed. Because of its poor prognosis, early diagnosis of AECTCL may be helpful in improving the likelihood of patient survival, but further study is needed to address the challenges in diagnosing this rare and aggressive lymphoma.


Validation of a deep-learning-based retinal biomarker (Reti-CVD) in the prediction of cardiovascular disease: data from UK Biobank.
Currently in the United Kingdom, cardiovascular disease (CVD) risk assessment is based on the QRISK3 score, in which 10% 10-year CVD risk indicates clinical intervention. However, this benchmark has limited efficacy in clinical practice and the need for a more simple, non-invasive risk stratification tool is necessary. Retinal photography is becoming increasingly acceptable as a non-invasive imaging tool for CVD. Previously, we developed a novel CVD risk stratification system based on retinal photographs predicting future CVD risk. This study aims to further validate our biomarker, Reti-CVD, (1) to detect risk group of ≥ 10% in 10-year CVD risk and (2) enhance risk assessment in individuals with QRISK3 of 7.5-10% (termed as borderline-QRISK3 group) using the UK Biobank. Reti-CVD scores were calculated and stratified into three risk groups based on optimized cut-off values from the UK Biobank. We used Cox proportional-hazards models to evaluate the ability of Reti-CVD to predict CVD events in the general population. C-statistics was used to assess the prognostic value of adding Reti-CVD to QRISK3 in borderline-QRISK3 group and three vulnerable subgroups. Among 48,260 participants with no history of CVD, 6.3% had CVD events during the 11-year follow-up. Reti-CVD was associated with an increased risk of CVD (adjusted hazard ratio [HR] 1.41; 95% confidence interval [CI], 1.30-1.52) with a 13.1% (95% CI, 11.7-14.6%) 10-year CVD risk in Reti-CVD-high-risk group. The 10-year CVD risk of the borderline-QRISK3 group was greater than 10% in Reti-CVD-high-risk group (11.5% in non-statin cohort [n = 45,473], 11.5% in stage 1 hypertension cohort [n = 11,966], and 14.2% in middle-aged cohort [n = 38,941]). C statistics increased by 0.014 (0.010-0.017) in non-statin cohort, 0.013 (0.007-0.019) in stage 1 hypertension cohort, and 0.023 (0.018-0.029) in middle-aged cohort for CVD event prediction after adding Reti-CVD to QRISK3. Reti-CVD has the potential to identify individuals with ≥ 10% 10-year CVD risk who are likely to benefit from earlier preventative CVD interventions. For borderline-QRISK3 individuals with 10-year CVD risk between 7.5 and 10%, Reti-CVD could be used as a risk enhancer tool to help improve discernment accuracy, especially in adult groups that may be pre-disposed to CVD.


Fasting plasma glucose cutoff for diagnosis of diabetes in a Japanese population.
We examined the relationship between fasting plasma glucose (FPG) and 2-h post-load glucose (PG) levels, and the optimal FPG cutoff level to correspond to a 2-h PG of 11.1 mmol/liter, the gold standard diagnostic criterion, in a general Japanese population. Cross-sectional study populations of 2421 subjects in 1988 and 2698 subjects in 2002, aged 40-79 yr and without antidiabetic medication, were tested with an oral glucose tolerance test. The relationship between FPG and 2-h PG was investigated by various regression models and a receiver operating characteristic curve. The best-fit model for the relationship between FPG and 2-h PG was a quadratic regression model. The FPG cutoff levels corresponding to the 2-h PG of 11.1 mmol/liter by this model were 6.2 mmol/liter in 1988 and 6.3 mmol/liter in 2002. In the combined populations, the FPG cutoff point was 6.3 mmol/liter; the sensitivity and specificity of this cutoff point for detecting a 2-h PG of 11.1 mmol/liter were 75.2 and 88.6%, respectively. The receiver operating characteristic curve analysis confirmed that the corresponding FPG point was 6.2 mmol/liter in both the 1988 and 2002 populations. In a stratified analysis, the FPG cutoff level increased with increasing body mass index levels; however, even in subjects with body mass index more than or equal to 30 kg/m2, the FPG cutoff level was lower than 7.0 mmol/liter. Our findings suggest that the FPG cutoff level corresponding to the 2-h PG of 11.1 mmol/liter in the general Japanese population is lower than the current diagnostic criterion.


The role of geography and ecological opportunity in the diversification of day geckos (Phelsuma).
We examine the effects of ecological opportunity and geographic area on rates of species accumulation and morphological evolution following archipelago colonization in day geckos (genus Phelsuma) in the Indian Ocean. Using a newly generated molecular phylogeny for the genus, we present evidence that these geckos likely originated on Madagascar, whereas colonization of three archipelagos in the Indian Ocean, the Seychelles, Mascarene, and Comoros Islands has produced three independent monophyletic radiations. We find that rates of species accumulation are not elevated following colonization but are roughly equivalent on all three isolated archipelagos and on the larger island of Madagascar. However, rates of species accumulation have slowed through time on Madagascar. Rates of morphological evolution are higher in both the Mascarene and Seychelles archipelagos compared to rates on Madagascar. This negative relationship between rate of morphological evolution and island area suggests that ecological opportunity is an important factor in diversification of day gecko species.


Racial Discrimination, Sexual Partner Race/Ethnicity, and Depressive Symptoms Among Black Sexual Minority Men.
Although racial sexual exclusivity among Black gay, bisexual, and other sexual minority men (SMM) is frequently framed as a cause of HIV inequities, little research has examined how these sexual relationships may be driven by and protective against racism. This study examined associations between general racial discrimination, Black sexual exclusivity, sexual racial discrimination, and depressive symptoms among Black SMM. We conducted analyses on cross-sectional self-report data from 312 cisgender Black SMM in the U.S. Deep South who participated in the MARI study. Measures included general racial and sexual identity discrimination, race/ethnicity of sexual partners, sexual racial discrimination, and depressive symptoms. We estimated a moderated-mediation model with associations from discrimination to Black sexual exclusivity, moderated by discrimination target, from Black sexual exclusivity to sexual racial discrimination, and from sexual racial discrimination to depressive symptoms. We tested an indirect effect from racial discrimination to depressive symptoms to examine whether Black sexual exclusivity functioned as an intervening variable in the associations between racial discrimination and depressive symptoms. Results indicated that participants who experienced racial discrimination were more likely to exclusively have sex with Black men. Men with higher Black sexual exclusivity were less likely to experience sexual racial discrimination and, in turn, reported lower depressive symptoms. The indirect pathway from racial discrimination to depressive symptoms through Black sexual exclusivity and sexual racial discrimination was significant. Our results suggest that one of the drivers of sexual exclusivity among Black SMM may be that it helps to protect against the caustic psychological effects of racial discrimination.


Genomic and proteomic analysis of the Alkali-Tolerance Response (AlTR) in Listeria monocytogenes 10403S.
Information regarding the Alkali-Tolerance Response (AlTR) in Listeria monocytogenes is very limited. Treatment of alkali-adapted cells with the protein synthesis inhibitor chloramphenicol has revealed that the AlTR is at least partially protein-dependent. In order to gain a more comprehensive perspective on the physiology and regulation of the AlTR, we compared differential gene expression and protein content of cells adapted at pH 9.5 and un-adapted cells (pH 7.0) using complementary DNA (cDNA) microarray and two-dimensional (2D) gel electrophoresis, (combined with mass spectrometry) respectively. In this study, L. monocytogenes was shown to exhibit a significant AlTR following a 1-h exposure to mild alkali (pH 9.5), which is capable of protecting cells from subsequent lethal alkali stress (pH 12.0). Adaptive intracellular gene expression involved genes that are associated with virulence, the general stress response, cell division, and changes in cell wall structure and included many genes with unknown functions. The observed variability between results of cDNA arrays and 2D gel electrophoresis may be accounted for by posttranslational modifications. Interestingly, several alkali induced genes/proteins can provide a cross protective overlap to other types of stresses. Alkali pH provides therefore L. monocytogenes with nonspecific multiple-stress resistance that may be vital for survival in the human gastrointestinal tract as well as within food processing systems where alkali conditions prevail. This study showed strong evidence that the AlTR in L. monocytogenes functions as to minimize excess alkalisation and energy expenditures while mobilizing available carbon sources.


Will This Hemodynamically Unstable Patient Respond to a Bolus of Intravenous Fluids?
Fluid overload occurring as a consequence of overly aggressive fluid resuscitation may adversely affect outcome in hemodynamically unstable critically ill patients. Therefore, following the initial fluid resuscitation, it is important to identify which patients will benefit from further fluid administration. To identify predictors of fluid responsiveness in hemodynamically unstable patients with signs of inadequate organ perfusion. Search of MEDLINE and EMBASE (1966 to June 2016) and reference lists from retrieved articles, previous reviews, and physical examination textbooks for studies that evaluated the diagnostic accuracy of tests to predict fluid responsiveness in hemodynamically unstable adult patients who were defined as having refractory hypotension, signs of organ hypoperfusion, or both. Fluid responsiveness was defined as an increase in cardiac output following intravenous fluid administration. Two authors independently abstracted data (sensitivity, specificity, and likelihood ratios [LRs]) and assessed methodological quality. A bivariate mixed-effects binary regression model was used to pool the sensitivities, specificities, and LRs across studies. A total of 50 studies (N = 2260 patients) were analyzed. In all studies, indices were measured before assessment of fluid responsiveness. The mean prevalence of fluid responsiveness was 50% (95% CI, 42%-56%). Findings on physical examination were not predictive of fluid responsiveness with LRs and 95% CIs for each finding crossing 1.0. A low central venous pressure (CVP) (mean threshold <8 mm Hg) was associated with fluid responsiveness (positive LR, 2.6 [95% CI, 1.4-4.6]; pooled specificity, 76%), but a CVP greater than the threshold made fluid responsiveness less likely (negative LR, 0.50 [95% CI, 0.39-0.65]; pooled sensitivity, 62%). Respiratory variation in vena cava diameter measured by ultrasound (distensibility index >15%) predicted fluid responsiveness in a subgroup of patients without spontaneous respiratory efforts (positive LR, 5.3 [95% CI, 1.1-27]; pooled specificity, 85%). Patients with less vena cava distensibility were not as likely to be fluid responsive (negative LR, 0.27 [95% CI, 0.08-0.87]; pooled sensitivity, 77%). Augmentation of cardiac output or related parameters following passive leg raising predicted fluid responsiveness (positive LR, 11 [95% CI, 7.6-17]; pooled specificity, 92%). Conversely, the lack of an increase in cardiac output with passive leg raising identified patients unlikely to be fluid responsive (negative LR, 0.13 [95% CI, 0.07-0.22]; pooled sensitivity, 88%). Passive leg raising followed by measurement of cardiac output or related parameters may be the most useful test for predicting fluid responsiveness in hemodynamically unstable adults. The usefulness of respiratory variation in the vena cava requires confirmatory studies.


Effects of cadmium on the glial architecture in lizard brain.
The glial cells are positioned to be the first cells of the brain parenchyma to face molecules crossing the blood-brain barrier with a relevant neuroprotective role from cytotoxic action of heavy metals on the nervous system. Cadmium is a highly toxic metal and its levels in the environment are increasing due to industrial activities. This element can pass the blood-brain barrier and have neurotoxic activity. For this reason we have studied the effects of cadmium on the glial architecture in the lizard Podarcis siculus, a significant bioindicator of chemical exposure due to its persistence in a variety of habitats. The study was performed on two groups of lizards. The first group of P. siculus was exposed to an acute treatment by a single i.p. injection (2 mg/kg-BW) of CdCl2 and sacrificed after 2, 7 and 16 days. The second one was used as control. The histology of the brain was studied by Hematoxylin/Eosin and Cresyl/Violet stains while the glial structures were analyzed by immunodetection of the glial fibrillary acidic protein (GFAP), the most widely accepted marker for astroglial cells. Evident morphological alterations of the brain were observed at 7 and 16 days from the injection, when we revealed also a decrease of the GFAP-immunopositive structures in particular in the rhombencephalic ventricle, telencephalon and optic tectum. These results show that in the lizards an acute exposure to cadmium provokes morphological cellular alterations in the brain but also a decrement of the expression of GFAP marker with possible consequent damage of glial cells functions.


Double nuclear magnetic resonance observation of electron exchange between ferri- and ferrocytochrome c.
Cyanide-inhibited electron exchange between ferri- and ferrocytochrome c molecules has been observed by nuclear magnetic resonance. Irradiation of a partially reduced protein solution at resonance frequencies arising from protons of the oxidized state results in a decrease in the absorption due to the corresponding protons of the reduced state. The experiment quantitates the hyperfine shifts observed in this system and can be used to identify hitherto unassignable resonances. Analysis of the shifts suggests that an aromatic side chain ring lies near the edge of the heme ring.


Disposition of ethimizol, a nootropic drug, in rats and mice.
The pharmacokinetics of ethimizol, a nootropic drug, were studied in rats and mice using [2-14C]-4,5-di(methylcarbamoyl)-1-ethyl-imidazole. Autoradiography in mice injected iv showed a rapid and homogeneous distribution of the label into the tissues, brain included, and its excretion by the urinary pathway. The determination of ethimizol in plasma, organs, and excreta was based on combined extraction and the TLC procedure. In rats, the elimination half-life of ethimizol after iv administration of 10 mg/kg was 25 min, and its distribution volume was 1.4 liters/kg. The tissue/plasma concentration ratio for organs investigated was 1 immediately after iv administration, with a subsequent gradual increase. Based on this, saturable tissue binding of ethimizol in the liver, kidney, and brain was suggested. The drug was almost completely absorbed after administration, yet its systemic availability was only 32%. The brain uptake index of ethimizol was 101% as compared to 3H2O. Ethimizol was eliminated by metabolism. The labeled metabolites were predominantly excreted in the urine.


Differential cell death programmes induced by silver dressings in vitro.
In past decades the gold standard for topical burn treatment was the use of silver sulfadiazine. Due to toxicity caused by the silver, the cream base itself, or a combination of both negatively influencing the wound healing process, the healthcare industry searched for alternatives. In recent years, various dressings containing silver have become available to wound professionals. Although these have been reported to be a significant improvement, the dressings still show residual cytotoxicity. Given the ongoing debate about whether and how these dressings influence cell survival, this article endeavours to clarify some of the mystique surrounding the subject. Various commercially available silver-type dressings were analysed in vitro and attention was paid to the cell death stage induced by these dressings on different cell lines. The results show that within 2 hours, for all dressings tested, cells undergo cell death and further analysis suggests that the death stage induced is dependent on the cell line and type of dressing investigated. Further, the antimicrobial activity of all dressings was analysed. The silver dressings tested have potent antimicrobial activity. Our results showed, however, that silver dressings induce rapid cell death of cells involved in wound healing. We therefore recommend the use of silver dressings only on critically contaminated wounds rather than use on a de facto basis.


Intentional resection of the diaphragm during cytoreductive laparoscopic radical nephrectomy.
Laparoscopic radical nephrectomy is being performed more commonly. To our knowledge intentional resection of the diaphragm during laparoscopic radical nephrectomy for large renal tumors has not yet been described. We detail the laparoscopic management of diaphragmatic resection. From March 1996 to February 2001, 36 patients underwent cytoreductive laparoscopic radical nephrectomy at our institution in preparation for systemic immunotherapy. Charts and operative tapes were reviewed and cases were identified in which diaphragmatic resection was performed for locally invasive tumors. In 3 patients a portion of the diaphragm was dissected via laparoscopy during debulking nephrectomy. All patients had renal cell carcinoma with documented metastatic disease. The diaphragm was repaired laparoscopically using intracorporeal suturing techniques in 2 of the 3 patients and a chest tube was placed in all 3. Transient systolic hypotension and hypercarbia in 1 case resolved with manual ventilation. The chest tube was removed on postoperative days 2 to 4. There were no complications and no ipsilateral pleural metastasis was identified at an average of 6 weeks (range 2 to 23) of followup. A portion of the diaphragm may be intentionally resected during laparoscopic radical nephrectomy. This maneuver may be successfully managed without conversion to an open procedure. In cases of a large diaphragmatic defect or the potential for coagulopathy postoperatively a chest tube should be inserted. Potential invasion of the diaphragm by large tumors should not be considered a contraindication to cytoreductive laparoscopic radical nephrectomy.


Fallopian tube choriocarcinoma presenting as ovarian tumour: a case report.
Choriocarcinoma of the fallopian tube is a rare form of gestational trophoblastic disease. It can be gestational or non gestational choriocarcinoma, based on the origin. Fallopian tube choriocarcinoma has been reported commonly after ectopic pregnancy. Choriocarcinomas are germ cell tumours formed by trophoblastic elements. A 26-year-old lady presented with pain and mass abdomen of 15 days duration. Clinical examination revealed a ovarian tumour with elevated beta HCG. The working diagnosis was ovarian choriocarcinoma. Patient was also found to be having pulmonary artery hypertension due to the metastasis to lungs. Staging laparotomy was done. Histopathology revealed it to be metastatic gestational choriocarcinoma of fallopian tube with vascular emboli. The stage was stage III and WHO scoring of 15. She received Etoposide, Methotrexate, Actinomicin, Cyclophosphamide and Oncovin therapy. Following treatment there was a significant drop in the beta HCG. Patient tolerated the chemotherapy well. This is a rare presentation of choriocarcinoma with good prognosis.


Highly volatile alkaline earth metal fluoroalkoxides.
The synthetic strategies, structural comparison, and thermal gravimetric analyses for a novel family of alkaline earth metal perfluoro-tert-butoxides (PFTB) are presented. The isolated complexes follow the general formula, [Ae(PFTB)(2)(d)(x)]; (1a, Ae = Mg, d = THF, x = 2; 1b, Ae = Ca, d = THF, x = 4; 1c, Ae = Sr, d = THF, x = 4; 1d, Ae = Ba, d = THF, x = 4; 2a, Ae = Mg, d = DME, x = 1; 2b, Ae = Ca, d = DME, x = 2; 2c, Ae = Sr, d = DME, x = 2; 2d, Ae = Ba, d = DME, x = 3; 3a, Ae = Mg, d = diglyme, x = 1; 3b, Ae = Ca, d = diglyme, x = 2; 3c, Ae = Sr, d = diglyme, x = 2; 3d, Ae = Ba, d = diglyme, x = 2; THF = tetrahydrofuran, DME = 1,2-dimethoxyethane) where the crystallographically characterized compounds display either a cis or trans conformations in octahedral or pseudo-octahedral environments. Alkane elimination (Mg), direct metalation via ammonia activation (Ca, Sr, Ba), and transamination (Ca, Sr, Ba) methods yielded the target compounds in moderate to good yields. Structural studies of select compounds showed all compounds to be monomeric with varying degrees of co-ligand coordination, possibly explaining some of the observed physical properties. Thermal gravimetric analyses of the compounds shows sublimation at low temperatures, associated with minimal residue, making this family of fluoroalkoxides promising candidates for metal organic chemical vapor deposition (MOCVD).


Label-free free-solution nanoaperture optical tweezers for single molecule protein studies.
Nanoaperture optical tweezers are emerging as useful label-free, free-solution tools for the detection and identification of biological molecules and their interactions at the single molecule level. Nanoaperture optical tweezers provide a low-cost, scalable, straight-forward, high-speed and highly sensitive (SNR ∼ 33) platform to observe real-time dynamics and to quantify binding kinetics of protein-small molecule interactions without the need to use tethers or labeling. Such nanoaperture-based optical tweezers, which are 1000 times more efficient than conventional optical tweezers, have been used to trap and isolate single DNA molecules and to study proteins like p53, which has been claimed to be in mutant form for 75% of human cancers. More recently, nanoaperture optical tweezers have been used to probe the low-frequency (in the single digit wavenumber range) Raman active modes of single nanoparticles and proteins. Here we review recent developments in the field of nanoaperture optical tweezers and how they have been applied to protein-antibody interactions, protein-small molecule interactions including single molecule binding kinetics, and protein-DNA interactions. In addition, recent works on the integration of nanoaperture optical tweezers at the tip of optical fiber and in microfluidic environments are presented.


Emotional Awareness: A Transdiagnostic Predictor of Depression and Anxiety for Children and Adolescents.
Research increasingly suggests that low emotional awareness may be associated with symptoms of depression and anxiety among children and adolescents. However, because most studies have been cross-sectional, it has remained unclear whether low emotional awareness predicts subsequent internalizing symptoms. The current study used longitudinal data to examine the role of emotional awareness as a transdiagnostic predictor of subsequent symptoms of depression and anxiety. Participants were 204 youth (86 boys and 118 girls) ages 7-16 who completed self-report measures of emotional awareness, depressive symptoms, and anxiety symptoms at baseline, as well as measures of depression and anxiety symptoms every 3 months for a year. Results from hierarchical mixed effects modeling indicated that low baseline emotional awareness predicted both depressive and anxiety symptoms across a 1-year period. These findings suggest that emotional awareness may constitute a transdiagnostic factor, predicting symptoms of both depression and anxiety, and that emotional awareness training may be a beneficial component of treatment and prevention programs for youth depression and anxiety.


Radiation effects and oxygen vacancies in silicates.
Proton and electron irradiation of silicates, minerals, and rocks produces a paramagnetic defect whose resonance spectrum is identical to that of the singly charged oxygen vacancy in silica glass and alpha-quartz. It is suggested that this defect is characteristic of all structures containing SiO(4) tetrahedra. Cracks, fracturing, and electric discharges have been observed after irradiation in planes determined by the particle ranges. These processes may contribute to the erosion materials.


Family reports of dying patients' distress: the adaptation of a research tool to assess global symptom distress in the last week of life.
Understanding dying patients' symptom distress is an important component of efforts to improve care at the end of life. It can, however, be problematic to conduct research with dying patients. Family members can serve as sources of information about decedents' last days of life. In order to assess family reports of decedents' global symptom distress in the last week of life, we adapted the Memorial Symptom Assessment Scale Global Distress Index (MSAS-GDI), a brief measure of patient global symptom distress, for use in a retrospective study of family reports about end-of-life care. It was administered to a sample of 103 family members to assess the psychometric properties of the instrument in bereaved family members. The Family MSAS-GDI consists of questions about 11 psychological and physical symptoms commonly experienced by dying patients. The majority of family members were able to respond to the scale items. The mean Family MSAS-GDI score was 1.14 (SD = 0.87) with a range of 0 to 3.73. The scale demonstrated good internal consistency (alpha = 0.82). The average item-total correlation was r = 0.49 and the average inter-item correlation was r= 0.30, suggesting items were moderately correlated with the overall total scale and with each other. The Family MSAS-GDI could prove to be a useful tool in assessing and tracking global symptom distress in dying patients.


Where is your shoulder? Neural correlates of localizing others' body parts.
Neuropsychological studies, based on pointing to body parts paradigms, suggest that left posterior parietal lobe is involved in the visual processing of other persons' bodies. In addition, some patients have been found with mild deficit when dealing with abstract human representations but marked impairment with realistically represented bodies, suggesting that this processing could be modulated by the abstraction level of the body to be analyzed. These issues were examined in the present fMRI experiment, designed to evaluate the effects of visually processing human bodies of different abstraction levels on brain activity. The human specificity of the studied processes was assessed using whole-body representations of humans and of dogs, while the effects of the abstraction level of the representation were assessed using drawings, photographs, and videos. To assess the effect of species and stimulus complexity on BOLD signal, we performed a two-way ANOVA with factors species (human versus animal) and stimulus complexity (drawings, photographs and videos). When pointing to body parts irrespective of the stimulus complexity, we observed a positive effect of humans upon animals in the left angular gyrus (BA 39), as suggested by lesion studies. This effect was also present in midline cortical structures including mesial prefrontal, anterior cingulate and precuneal regions. When pointing to body parts irrespective of the species to be processed, we observed a positive effect of videos upon photographs and drawings in the right superior parietal lobule (BA 7), and bilaterally in the superior temporal sulcus, the supramarginal gyrus (BA 40) and the lateral extrastriate visual cortex (including the "extrastriate body area"). Taken together, these data suggest that, in comparison with other mammalians, the visual processing of other humans' bodies is associated with left angular gyrus activity, but also with midline structures commonly implicated in self-reference. They also suggest a role of the lateral extrastriate cortex in the processing of dynamic and biologically relevant body representations.


Improving outcomes for ill and injured children in emergency departments: protocol for a program in pediatric emergency medicine and knowledge translation science.
Approximately one-quarter of all Canadian children will seek emergency care in any given year, with the two most common medical problems affecting children in the emergency department (ED) being acute respiratory illness and injury. Treatment for some medical conditions in the ED remains controversial due to a lack of strong supporting evidence. The purpose of this paper is to describe a multi-centre team grant in pediatric emergency medicine (PEM) that has been recently funded by the Canadian Institutes of Health Research (CIHR). This program of research integrates clinical research (in the areas of acute respiratory illness and injury) and knowledge translation (KT). This initiative includes seven distinct projects that address the objective to generate new evidence for clinical care and KT in the pediatric ED. Five of the seven research projects in this team grant make significant contributions to knowledge development in KT science, and these contributions are the focus of this paper. The research designs employed in this program include: cross-sectional surveys, randomized controlled trials (RCTs), quasi-experimental designs with interrupted time-series analysis and staggered implementation strategies, and qualitative designs. This team grant provides unique opportunities for making important KT methodological developments, with a particular focus on developing a better theoretical understanding of the causal mechanisms and effect modifiers of different KT interventions.


Oats do not induce systemic or mucosal autoantibody response in children with coeliac disease.
A gluten-free diet omitting wheat, rye, and barley is the only effective treatment for coeliac disease. The necessity of excluding oats from the diet has remained controversial. We studied the toxicity of oats in children with coeliac disease during a 2-year follow-up by investigating jejunal transglutaminase 2 (TG2)-targeted IgA-class autoantibody deposits, a potentially more sensitive disease marker than serum antibodies or conventional histology. Twenty-three coeliac children in remission were randomized to undergo oat or gluten challenge with wheat, rye, barley, and oats. When jejunal histological relapse was evident after gluten challenge, patients excluded wheat, rye, and barley but continued with oats. Mucosal morphology and TG2-targeted autoantibody deposits were studied in jejunal biopsies taken at baseline and after 6 and 24 months. Furthermore, serum IgA-class TG2 antibodies were measured. At baseline, serum TG2 antibodies were negative in all 23 patients, but 7 of them had minor mucosal deposits. In the oats group, there was no significant change in the intensity of the deposits within 2 years. In contrast, during the gluten challenge, the intensity of the deposits clearly increased and decreased again when wheat, rye, and barley were excluded but consumption of oats was continued; this was in line with serum autoantibodies. The intensity of the mucosal deposits correlated well with both villous morphology and serum autoantibody levels. Consumption of oats does not induce TG2 autoantibody production at mucosal level in children with coeliac disease. Measurement of small-intestinal mucosal autoantibody deposits is suitable for monitoring treatment in coeliac patients.


Population structure and dispersal of the coral-excavating sponge Cliona delitrix.
Some excavating sponges of the genus Cliona compete with live reef corals, often killing and bioeroding entire colonies. Important aspects affecting distribution of these species, such as dispersal capability and population structure, remain largely unknown. Thus, the aim of this study was to determine levels of genetic connectivity and dispersal of Cliona delitrix across the Greater Caribbean (Caribbean Sea, Bahamas and Florida), to understand current patterns and possible future trends in their distribution and effects on coral reefs. Using ten species-specific microsatellite markers, we found high levels of genetic differentiation between six genetically distinct populations: one in the Atlantic (Florida-Bahamas), one specific to Florida and four in the South Caribbean Sea. In Florida, two independent breeding populations are likely separated by depth. Gene flow and ecological dispersal occur among other populations in the Florida reef tract, and between some Florida locations and the Bahamas. Similarly, gene flow occurs between populations in the South Caribbean Sea, but appears restricted between the Caribbean Sea and the Atlantic (Florida-Bahamas). Dispersal of C. delitrix was farther than expected for a marine sponge and favoured in areas where currents are strong enough to transport sponge eggs or larvae over longer distances. Our results support the influence of ocean current patterns on genetic connectivity, and constitute a baseline to monitor future C. delitrix trends under climate change.


Exploring Plasmodium falciparum Var Gene Expression to Assess Host Selection Pressure on Parasites During Infancy.
In sub-Saharan Africa, children below 5 years bear the greatest burden of severe malaria because they lack naturally acquired immunity that develops following repeated exposure to infections by Plasmodium falciparum. Antibodies to the surface of P. falciparum infected erythrocytes (IE) play an important role in this immunity. In children under the age of 6 months, relative protection from severe malaria is observed and this is thought to be partly due to trans-placental acquired protective maternal antibodies. However, the protective effect of maternal antibodies has not been fully established, especially the role of antibodies to variant surface antigens (VSA) expressed on IE. Here, we assessed the immune pressure on parasites infecting infants using markers associated with the acquisition of naturally acquired immunity to surface antigens. We hypothesized that, if maternal antibodies to VSA imposed a selection pressure on parasites, then the expression of a relatively conserved subset of var genes called group A var genes in infants should change with waning maternal antibodies. To test this, we compared their expression in parasites from children between 0 and 12 months and above 12 months of age. The transcript quantity and the proportional expression of group A var subgroup, including those containing domain cassette 13, were positively associated with age during the first year of life, which contrasts with above 12 months. This was accompanied by a decline in infected erythrocyte surface antibodies and an increase in parasitemia during this period. The observed increase in group A var gene expression with age in the first year of life, when the maternal antibodies are waning and before acquisition of naturally acquired antibodies with repeated exposure, is consistent with the idea that maternally acquired antibodies impose a selection pressure on parasites that infect infants and may play a role in protecting these infants against severe malaria.


Economic burden of cardiovascular diseases in the enlarged European Union.
Cardiovascular disease (CVD), together with its main components, coronary heart disease (CHD), and cerebrovascular diseases, is the main source of morbidity and mortality in the European Union (EU), but to date, there has not been any systematic cost-of-illness study to assess the economic impact of CVD in the EU. CVD-related expenditure was estimated using aggregate data on morbidity, mortality, and healthcare resource use. Healthcare costs were estimated from expenditure on primary, outpatient, emergency, and inpatient care, as well as medications. Costs of unpaid care and lost earnings due to morbidity and premature death were included in the study. CVD was estimated to cost the EU Euro 169 billion annually, with healthcare accounting for 62% of costs. Productivity losses and informal care represented 21% and 17% of costs, respectively. CHD represented 27% and cerebrovascular diseases 20% of overall CVD costs. CVD is a leading public health problem. Our study is the first to assess the economic burden of CVD across the EU, and our results should help policy makers evaluate policy impact and prioritize research expenditures. However, because of data unavailability, our study has important limitations, which highlight the need for more accurate and comparable CVD-specific information.


Effect of antenatal peer support on breastfeeding initiation: a systematic review.
Our objective was to examine the effect of antenatal peer support on rates of breastfeeding initiation. We performed a systematic review of randomized controlled trials, quasi-randomized trials and cohort studies with concurrent controls. We searched the Cochrane Library, MEDLINE, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), the National Research Register and the British Nursing Index from inception or from 1980 to 2009. We carried out study selection, data abstraction and quality assessment independently and in duplicate. We defined high-quality studies as those that minimized the risk of at least three of the following types of bias: selection, performance, measurement and attrition bias. We calculated risk ratios (RRs) and 95% confidence intervals (CIs) for individual studies and undertook separate meta-analyses for high-quality trials of universal peer support and targeted peer support. We did not include low-quality studies. We selected 11 studies, which involved 5445 women in total. Seven of these studies (involving 4416 women in total) evaluated universal peer support, and four studies (involving 1029 women in total) targeted antenatal peer support. In the three high-quality studies of universal peer support, all involving low-income women, the relative risk for not initiating breastfeeding was 0.96 (95% CI 0.76-1.22). In the three high-quality studies of antenatal peer support that targeted women considering breastfeeding, the relative risk for not initiating breastfeeding was 0.64 (95% CI 0.41-0.99). Universal antenatal peer support does not appear to improve rates of breastfeeding initiation, but targeted antenatal peer support may be beneficial. This effect may be related to context, however, so any new peer-support program should undergo concurrent high-quality evaluation.


Directional dominance on stature and cognition in diverse human populations.
Homozygosity has long been associated with rare, often devastating, Mendelian disorders, and Darwin was one of the first to recognize that inbreeding reduces evolutionary fitness. However, the effect of the more distant parental relatedness that is common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power. Here we use runs of homozygosity to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts, and find statistically significant associations between summed runs of homozygosity and four complex traits: height, forced expiratory lung volume in one second, general cognitive ability and educational attainment (P < 1 × 10(-300), 2.1 × 10(-6), 2.5 × 10(-10) and 1.8 × 10(-10), respectively). In each case, increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months' less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing evidence that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been.


Wearable sensor-based rehabilitation exercise assessment for knee osteoarthritis.
Since the knee joint bears the full weight load of the human body and the highest pressure loads while providing flexible movement, it is the body part most vulnerable and susceptible to osteoarthritis. In exercise therapy, the early rehabilitation stages last for approximately six weeks, during which the patient works with the physical therapist several times each week. The patient is afterwards given instructions for continuing rehabilitation exercise by him/herself at home. This study develops a rehabilitation exercise assessment mechanism using three wearable sensors mounted on the chest, thigh and shank of the working leg in order to enable the patients with knee osteoarthritis to manage their own rehabilitation progress. In this work, time-domain, frequency-domain features and angle information of the motion sensor signals are used to classify the exercise type and identify whether their postures are proper or not. Three types of rehabilitation exercise commonly prescribed to knee osteoarthritis patients are: Short-Arc Exercise, Straight Leg Raise, and Quadriceps Strengthening Mini-squats. After ten subjects performed the three kinds of rehabilitation activities, three validation techniques including 10-fold cross-validation, within subject cross validation, and leave-one-subject cross validation are utilized to confirm the proposed mechanism. The overall recognition accuracy for exercise type classification is 97.29% and for exercise posture identification it is 88.26%. The experimental results demonstrate the feasibility of the proposed mechanism which can help patients perform rehabilitation movements and progress effectively. Moreover, the proposed mechanism is able to detect multiple errors at once, fulfilling the requirements for rehabilitation assessment.


Clinical characteristics of liver failure from a systemic cause: A report from an advanced critical care center.
Background/Purpose. In Japan, acute liver failure (ALF) has generally been described using the diagnostic term, "fulminant hepatitis", because of the fact that most cases of ALF has been thought to occur in association with hepatitis mainly due to a hepatitis virus infection. New diagnostic criteria for ALF, including ALF other than fulminant hepatitis, were established in 2011. We therefore examined the prognostic factors of patients with liver failure from a systemic cause, including warfarin users. Sixty-six patients with ALF that were diagnosed according to the Japanese diagnostic criteria for ALF between 2009 and 2013 were divided into a survivor group and a non-survivor group. The data regarding demography, liver tests, coagulation tests, Sequential Organ Failure Assessment (SOFA) scores, and the use of oral warfarin or aspirin were compared between the two groups. The SOFA score was significantly higher in the non-survivor group (p = 0.025). The proportion of oral warfarin users was significantly higher in the survivor group (p = 0.013) (58.1% vs. 26.1%). A multivariate logistic regression analysis showed the SOFA score (odds ratio: 0.851, 95% confidence interval (CI): 0.728-0.995, p = 0.043) and warfarin use (odds ratio: 3.261, 95% CI: 1.028-10.347, p = 0.045) to be significant factors that were negatively and positively associated with the prognosis, respectively. In this study, among the patients with ALF other than fulminant hepatitis, those with a high SOFA score on admission exhibited a poor prognosis. In addition, oral warfarin use prior to disease onset was found to be a factor which indicated a good prognosis.


Innovation and Integrity in Intervention Research: Conceptual Issues, Methodology, and Knowledge Translation.
In this article, we introduce the special issue entitled Innovation and Integrity in Intervention Science. Its focus is on essential problems and prospects for intervention research examining two related topics, i.e., methodological issues and research integrity, and challenges in the transfer of research knowledge into practice and policy. The main aims are to identify how to advance methodology in order to improve research quality, examine scientific integrity in the field of intervention science, and discuss future steps to enhance the transfer of knowledge about evidence-based intervention principles into sustained practice, routine activities, and policy decisions. Themes of the special issue are twofold. The first includes questions about research methodology in intervention science, both in terms of research design and methods, as well as data analyses and the reporting of findings. Second, the issue tackles questions surrounding the types of knowledge translation frameworks that might be beneficial to mobilize the transfer of research-based knowledge into practice and public policies. The issue argues that innovations in methodology and thoughtful approaches to knowledge translation can enable transparency, quality, and sustainability of intervention research.


17 β-estradiol rapidly increases ATP-sensitive potassium channel activity in gonadotropin-releasing hormone neurons [corrected] via a protein kinase signaling pathway.
17Beta-estradiol (E2) both inhibits and excites GnRH neurons via presynaptic as well as postsynaptic mechanisms. Although it has been demonstrated that E2 can alter the excitability of GnRH neurons via direct actions, the intracellular signaling cascades mediating these actions are not well understood. Previously we have shown that the activity of one of the critical ion channels needed for maintaining GnRH neurons in a hyperpolarized state, the ATP-sensitive potassium channel (K(ATP)) channel, is augmented by E2 in ovariectomized females. However, the mRNA expression of the K(ATP) channel subunits Kir6.2 and SUR1 are unchanged with in vivo E2 treatment. Therefore, to elucidate the cellular signaling mechanism(s) modulating the channel activity, we did whole-cell patch-clamp recording of enhanced green fluorescent protein-GnRH neurons from ovariectomized female mice to study the acute effects of E2. E2 dose-dependently (EC(50) = 0.6 nM) enhanced the diazoxide (channel opener)-activated K(ATP) channel currents by 1.2- to 2.0-fold, which was antagonized by ICI 182,780. E2-BSA was equally as effective as E2, whereas 17 alpha-estradiol [corrected] had no effect. The protein kinase A (PKA) activator forskolin mimicked the effects of E2, whereas the PKA inhibitor H89 and the protein kinase C (PKC) inhibitor bisindolylmaleimide I blocked the effects of E2. Similar to E2, STX, a membrane estrogen receptor (ER) agonist that does not bind to ERalpha or ERbeta, also potentiated the diazoxide-induced K(ATP) channel current by 1.5-fold. Therefore, E2 can potentiate K(ATP) channel activity in GnRH neurons through a membrane ER-activated PKC-PKA signaling pathway.


Surveillance of perchlorate in ground water, surface water and bottled water in Kerala, India.
Perchlorate is an emerging water contaminant that disrupts normal functioning of human thyroid gland and poses serious threat to health, especially for pregnant women, fetus and children. High level of perchlorate contamination in fresh water sources at places nearby ammonium perchlorate (rocket fuel) handled in bulk is reported in this study. Of 160 ground water samples analyzed from 27 locations in the State Kerala, 58 % had perchlorate above detection limit (2 μg/L) and the highest concentration observed was 7270 μg/L at Ernakulam district, this value is ~480 times higher than USEPA drinking water equivalent level (15 μg/L). Perchlorate was detected in all surface water samples analyzed (n = 10) and the highest value observed was 355 μg/L in Periyar river (a major river in the State). The bottled drinking water (n = 5) tested were free of perchlorate. The present study underlines the need for frequent screening of water sources for perchlorate contamination around places the chemical is handled in bulk. It will help to avoid human exposure to high levels of perchlorate.


Patient and Clinician Perspectives on Electronic Patient-Reported Outcome Measures in the Management of Advanced CKD: A Qualitative Study.
Chronic kidney disease (CKD) can substantially affect patients' health-related quality of life. Electronic patient-reported outcome measures (ePROMs) may capture symptoms and health-related quality of life and assist in the management of CKD. This study explored patient and clinician views on the use of a renal ePROM system. Qualitative study. 12 patients with stage 4 or 5 CKD (non-dialysis dependent); 22 clinicians (6 CKD community nurses, 1 clinical psychologist, 10 nephrologists, 3 specialist registrars, and 2 renal surgeons) in the United Kingdom. Semi-structured interviews and focus group discussion during which patients received paper versions of the Kidney Disease Quality of Life-36 and the Integrated Patient Outcome Scale-Renal to exemplify the type of content that could be included in an ePROM. Thematic analysis of interview transcripts. 4 themes were identified: (1) general opinions of PROMs, (2) potential benefits and applications of an ePROM system, (3) practical considerations for the implementation of ePROMs, and (4) concerns, barriers, and facilitators. Patients were willing to complete ePROMs on a regular basis as part of their care despite clinician concerns about patient burden. Patients assessed the questionnaires favorably. Clinicians suggested that the extent of adoption of renal ePROM systems in routine clinical settings should be based on evidence of significant impact on patient outcomes. Clinicians were concerned that an ePROM system may raise patient expectations to unrealistic levels and expose clinicians to the risk for litigation. Patients and clinicians identified potential benefits and highlighted issues and concerns that need to be addressed to ensure the successful implementation of the renal ePROM system. Transferability of the findings may be limited because only English-speaking participants were recruited to the study. A renal ePROM system may play a supportive role in the routine clinical management of patients with advanced CKD if the concerns of clinicians and patients can be sufficiently addressed.


Reliability and validity of the AGREE instrument used by physical therapists in assessment of clinical practice guidelines.
The AGREE instrument has been validated for evaluating Clinical Practice Guidelines (CPG) pertaining to medical care. This study evaluated the reliability and validity of physical therapists using the AGREE to assess quality of CPGs relevant to physical therapy practice. A total of 69 physical therapists participated and were classified as generalists, specialist or researchers. Pairs of appraisers within each category evaluated independently, a set of 6 CPG selected at random from a pool of 55 CPGs. Reliability between pairs of appraisers indicated low to high reliability depending on the domain and number of appraisers (0.17-0.81 for single appraiser; 0.30-0.96 when score averaged across a pair of appraisers). The highest reliability was achieved for Rigour of Development, which exceeded ICC> 0.79, if scores from pairs of appraisers were pooled. Adding more than 3 appraisers did not consistently improve reliability. Appraiser type did not determine reliability scores. End-users, including study participants and a separate sample of 102 physical therapy students, found the AGREE useful to guide critical appraisal. The construct validity of the AGREE was supported in that expected differences on Rigour of Development domains were observed between expert panels versus those with no/uncertain expertise (differences of 10-21% p = 0.09-0.001). Factor analysis with varimax rotation, produced a 4-factor solution that was similar, although not in exact agreement with the AGREE Domains. Validity was also supported by the correlation observed (Kendall-tao = 0.69) between Overall Assessment and the Rigour of Development domain. These findings suggest that the AGREE instrument is reliable and valid when used by physiotherapists to assess the quality of CPG pertaining to physical therapy health services.


Establishment of a healthy human range for the whole blood 'OX40' assay for the detection of antigen-specific CD4+ T cells by flow cytometry.
Background: Clinical investigation of antigen-specific T cells in potentially immunodeficient patients is an important and often challenging aspect of patient diagnostic work up. Methods for detection of microbial exposure to the T cell compartment exist but are laborious and time consuming. Recently, a whole blood technique involving flow cytometry and detection of CD25 and OX40 (CD134) expression on the surface of activated CD4+ T cells was shown to be accurate and concordant when compared with more traditional methods of antigen-specific T cell detection. Methods: Whole heparinised blood was collected from healthy donors and set up using the 'OX40' assay to detect antigen specific CD4+ T cell responses to Varicella Zoster Virus (VZV), Epstein-Barr Virus (EBV), Cytomegalovirus (CMV), Candida albicans and Streptococcus pneumoniae. Results: The 'OX40' assay technique was clinically validated for routine use in an NHS clinical immunology laboratory by analysis of incubation length (40-50 hours), sample transport time (up to 24 hours at room temperature), concordance with serology testing, proliferation and IFN-γ production. In addition, 63 healthy controls (age range 21-78) were tested for responses to generate a healthy control reference range. Conclusions: The OX40 assay, as presented in this report, represents an economical, rapid, robust whole blood technique to detect antigen-specific T cells which is suitable for clinical immunology diagnostic laboratory use. © 2013 Clinical Cytometry Society.


Role of cannabinoid receptor type 1 desensitization in greater tetrahydrocannabinol impairment of memory in adolescent rats.
Adolescence is a well defined developmental period during which marijuana use is common. However, little is known about the response to marijuana in adolescents compared with adults. We have shown previously that adolescent rats are more impaired than adults by Δ(9)-tetrahydrocannabinol (THC), the main psychoactive compound in marijuana, in a spatial learning task, but the mechanism responsible for this differential impairment is not understood. We determined the role of THC tolerance and cannabinoid receptor type 1 (CB1) regulation in THC-induced spatial learning impairment in adolescent and adult rats. We measured the development of tolerance to THC-induced learning impairment in adolescent (postnatal days 30-35) and adult (postnatal days 70-75) rats. We pretreated them for 5 days with 10 mg/kg THC, and then evaluated the effects of vehicle or THC treatment on learning during training in the Morris water maze. We also determined CB1 number and functional coupling in the hippocampus of adolescents and adults. Finally, we measured the time course of hippocampal CB1 desensitization in adolescents and adults during treatment with 10 mg/kg THC or vehicle. Our results indicate that adults, but not adolescents, become tolerant to the effects of THC during water maze training after 5 days of pretreatment. CB1s in adolescent hippocampus are less functionally coupled to G proteins and desensitize more slowly in response to THC treatment than those of adults. THC may impair learning in adolescents more than in adults because of delayed activation of cellular homeostatic adaptive mechanisms underlying cannabinoid tolerance in the hippocampus.


A single and rapid calcium wave at egg activation in Drosophila.
Activation is an essential process that accompanies fertilisation in all animals and heralds major cellular changes, most notably, resumption of the cell cycle. While activation involves wave-like oscillations in intracellular Ca(2+) concentration in mammals, ascidians and polychaete worms and a single Ca(2+) peak in fish and frogs, in insects, such as Drosophila, to date, it has not been shown what changes in intracellular Ca(2+) levels occur. Here, we utilise ratiometric imaging of Ca(2+) indicator dyes and genetically encoded Ca(2+) indicator proteins to identify and characterise a single, rapid, transient wave of Ca(2+) in the Drosophila egg at activation. Using genetic tools, physical manipulation and pharmacological treatments we demonstrate that the propagation of the Ca(2+) wave requires an intact actin cytoskeleton and an increase in intracellular Ca(2+) can be uncoupled from egg swelling, but not from progression of the cell cycle. We further show that mechanical pressure alone is not sufficient to initiate a Ca(2+) wave. We also find that processing bodies, sites of mRNA decay and translational regulation, become dispersed following the Ca(2+) transient. Based on this data we propose the following model for egg activation in Drosophila: exposure to lateral oviduct fluid initiates an increase in intracellular Ca(2+) at the egg posterior via osmotic swelling, possibly through mechano-sensitive Ca(2+) channels; a single Ca(2+) wave then propagates in an actin dependent manner; this Ca(2+) wave co-ordinates key developmental events including resumption of the cell cycle and initiation of translation of mRNAs such as bicoid.


Effects of valence and arousal on written word recognition: time course and ERP correlates.
Models of affect assume a two-dimensional framework, composed of emotional valence and arousal. Although neuroimaging evidence supports a neuro-functional distinction of their effects during single word processing, electrophysiological studies have not yet compared the effects of arousal within the same category of valence (positive and negative). Here we investigate effects of arousal and valence on written lexical decision. Amplitude differences between emotion and neutral words were seen in the early posterior negativity (EPN), the late positive complex and in a sustained slow positivity. In addition, trends towards interactive effects of valence and arousal were observed in the EPN, showing larger amplitude for positive, high-arousal and negative, low-arousal words. The results provide initial evidence for interactions between arousal and valence during processing of positive words and highlight the importance of both variables in studies of emotional stimulus processing.


Psychological autopsy study comparing suicide decedents, suicide ideators, and propensity score matched controls: results from the study to assess risk and resilience in service members (Army STARRS).
The suicide rate has increased significantly among US Army soldiers over the past decade. Here we report the first results from a large psychological autopsy study using two control groups designed to reveal risk factors for suicide death among soldiers beyond known sociodemographic factors and the presence of suicide ideation. Informants were next-of-kin and Army supervisors for: 135 suicide cases, 137 control soldiers propensity-score-matched on known sociodemographic risk factors for suicide and Army history variables, and 118 control soldiers who reported suicide ideation in the past year. Results revealed that most (79.3%) soldiers who died by suicide have a prior mental disorder; mental disorders in the prior 30-days were especially strong risk factors for suicide death. Approximately half of suicide decedents tell someone that they are considering suicide. Virtually all of the risk factors identified in this study differed between suicide cases and propensity-score-matched controls, but did not significantly differ between suicide cases and suicide ideators. The most striking difference between suicides and ideators was the presence in the former of an internalizing disorder (especially depression) and multi-morbidity (i.e. 3+ disorders) in the past 30 days. Most soldiers who die by suicide have identifiable mental disorders shortly before their death and tell others about their suicidal thinking, suggesting that there are opportunities for prevention and intervention. However, few risk factors distinguish between suicide ideators and decedents, pointing to an important direction for future research.


Survival of polished compared with precoated roughened cemented femoral components. A prospective, randomized study.
The optimal surface finish for cemented femoral components remains controversial. The purpose of this randomized clinical trial was to compare the survival of two femoral components with similar geometry but substantially different surface finishes. During a five-year period, 201 patients (219 hips) were prospectively randomized to be treated with a total hip arthroplasty with either a polished (Ra, 0.18 to 0.3 microm) or a precoated roughened (Ra, 1.8 to 2.3 microm) cemented femoral component with similar geometry. There were no significant differences between the patient groups in terms of age, sex, weight, preoperative diagnosis, component size, or cement grade. So-called third-generation cementing techniques were used. One hundred and thirteen polished components and 106 precoated roughened components were followed for a mean of 5.3 years. Complete clinical and radiographic data were available for 134 hips at a minimum of five years (mean, 6.1 years; range, five to ten years) postoperatively. In the entire cohort of 219 hips, there was no significant difference (log rank p = 0.66) in survival, with the end point defined as component removal for any reason or definite radiographic loosening, between the precoated components (96.2%; 95% confidence interval, 90.9% to 100%) and the polished components (97.1%; 95% confidence interval, 93.8% to 100%). There was a periprosthetic fracture in three hips with a polished component. Two precoated roughened components were revised because of loosening, and two polished components were revised: one because of loosening and one because of a nonunion of a periprosthetic fracture. There was no significant difference between the groups with regard to the Harris hip scores or the clinical results. There was also no significant difference with regard to the presence or number of bone-cement radiolucent lines. Kaplan-Meier survival analysis showed no significant differences between two types of cemented femoral components with similar geometry but substantially different surface finishes at seven years. In the patient population selected for treatment with a cemented femoral component, the surface finish may not be a crucial factor affecting component survival at a minimum of five years, provided that good cement technique is used.


Variations of telencephalic development that paved the way for neocortical evolution.
Charles Darwin stated, "community in embryonic structure reveals community of descent". Thus, to understand how the neocortex emerged during mammalian evolution we need to understand the evolution of the development of the pallium, the source of the neocortex. In this article, we review the variations in the development of the pallium that enabled the production of the six-layered neocortex. We propose that an accumulation of subtle modifications from very early brain development accounted for the diversification of vertebrate pallia and the origin of the neocortex. Initially, faint differences of expression of secretable morphogens promote a wide variety in the proportions and organization of sectors of the early pallium in different vertebrates. It prompted different sectors to host varied progenitors and distinct germinative zones. These cells and germinative compartments generate diverse neuronal populations that migrate and mix with each other through radial and tangential migrations in a taxon-specific fashion. Together, these early variations had a profound influence on neurogenetic gradients, lamination, positioning, and connectivity. Gene expression, hodology, and physiological properties of pallial neurons are important features to suggest homologies, but the origin of cells and their developmental trajectory are fundamental to understand evolutionary changes. Our review compares the development of the homologous pallial sectors in sauropsids and mammals, with a particular focus on cell lineage, in search of the key changes that led to the appearance of the mammalian neocortex.


Adult age differences in long-term semantic priming.
Young and older adults were first asked to decide if a list of individually presented words were "living" (e.g., "tree") or "nonliving" (e.g., "store"). This was termed the "orienting task." Next, subjects performed a pronunciation task. Semantic priming for young and older adults was indexed by determining if semantic congruence between words in the orienting task and words in the pronunciation task improved performance on the pronunciation task relative to pronounced words from semantic categories not primed in the orienting task. The present data, from two different experiments, revealed that subjects pronounced high-dominance exemplars of the "living" words primed in the orienting task faster than words not primed in the orienting task. These data indicated that semantic priming for relatively long prime-target stimulus onset asynchronies can occur, and that such priming is at least as robust for older adults as for young adults. The results are discussed in terms of four current models of semantic priming.


Clinical use of metal and plastic calipers for nutritional assessment of patients under long-term enteral feeding through endoscopic gastrostomy.
Endoscopic gastrostomy (PEG) fed patients, including those with neurologic disorders (ND) or head and neck cancer (HNC) present high malnutrition risk and speech difficulties. Teams taking care of these patients need to rely on anthropometric data. Skinfold thickness (TSF) is used to assess nutritional status, but the use of heavy, large and expensive metal calipers may become a limitation. This study aimed to compare and correlate TSF measurements using a metal caliper and a plastic caliper in PEG fed patients. Prospective observational study on adult PEG fed patients. TSF was measured using plastic Ross and Lange metal calipers. Paired measurements were compared and correlated. Fifty-one patients, 37 men (72.5%), 14 women (27.5%): 28 (54.9%) ND patients; 23 (45.1%) with HNC. In total, 94 TSF measurements were performed using both plastic and metal calipers. Significant association was found between TSF measurements with the two equipments (rs = 0.94; p < 0.001). High correlation was observed between TSF measurements using both calipers for both genders (men: rs = 0.93; p < 0.001; women: rs = 0.96; p < 0.001), age (< 65 years: rs = 0.98; p < 0.001; ≥ 65 years: rs = 0.88; p < 0.001), underlying condition (ND: rs = 0.91; p < 0.001; HNC: rs = 0.95; p < 0.001) and time of TSF evaluation (before PEG: rs = 0.95; p < 0,001; after PEG: rs = 0.92; p < 0.001). TSF measurements obtained with small, light and cheap plastic Ross caliper were equivalent to those obtained with larger, heavier and more expensive metal caliper. For everyday clinical practice, plastic calipers may be suitable for teams taking care of PEG fed patients in hospital wards, outpatient clinic and home visits.


Inverse Relationship between Hepatic Steatosis and Alanine Aminotransferase with Sex Hormone-Binding Globulin in Men.
Sex hormone-binding globulin (SHBG) is a serum glycoprotein produced predominantly in hepatocytes. As such, the synthesis of SHBG could be associated with liver function and metabolic syndrome. Alanine aminotransferase (ALT) levels could reflect hepatocellular injury and insulin resistance; however, the relationship between hepatic steatosis and ALT with SHBG has not been investigated in humans. The objective of this study was to investigate the associations between SHBG and hepatocyte damage among Korean male patients with hepatic steatosis enrolled in a health examination program. We performed a retrospective cross-sectional study with 922 participants who underwent routine health examinations. A total of 922 men with or without hepatic steatosis were divided into three groups. We analyzed the risk of lower serum SHBG levels with or without elevated serum ALT levels using odds ratios with 95% confidence intervals (CIs). A significantly increased risk of lower serum SHBG level was observed in the group with hepatic steatosis and ALT elevation (95% CI 1.591-4.681). In men with hepatic steatosis, we found that elevated serum ALT levels were associated with lower serum SHBG levels. This finding suggests that subjects with both hepatic steatosis and increased ALT should be considered to have low levels of SHBG.


Family in Rehabilitation, Empowering Carers for Improved Malnutrition Outcomes: Protocol for the FREER Pilot Study.
Interventions to improve the nutritional status of older adults and the integration of formal and family care systems are critical research areas to improve the independence and health of aging communities and are particularly relevant in the rehabilitation setting. The primary outcome aimed to determine if the FREER (Family in Rehabilitation: EmpowERing Carers for improved malnutrition outcomes) intervention in malnourished older adults during and postrehabilitation improve nutritional status, physical function, quality of life, service satisfaction, and hospital and aged care admission rates up to 3 months postdischarge, compared with usual care. Secondary outcomes evaluated include family carer burden, carer services satisfaction, and patient and carer experiences. This pilot study will also assess feasibility and intervention fidelity to inform a larger randomized controlled trial. This protocol is for a mixed-methods two-arm historically-controlled prospective pilot study intervention. The historical control group has 30 participants, and the pilot intervention group aims to recruit 30 patient-carer pairs. The FREER intervention delivers nutrition counseling during rehabilitation, 3 months of postdischarge telehealth follow-up, and provides supportive resources using a novel model of patient-centered and carer-centered nutrition care. The primary outcome is nutritional status measured by the Scored Patient-Generated Subjective Global Assessment Score. Qualitative outcomes such as experiences and perceptions of value will be measured using semistructured interviews followed by thematic analysis. The process evaluation addresses intervention fidelity and feasibility. Recruitment commenced on July 4, 2018, and is ongoing with eight patient-carer pairs recruited at the time of manuscript submission. This research will inform a larger randomized controlled trial, with potential for translation to health service policies and new models of dietetic care to support the optimization of nutritional status across a continuum of nutrition care from rehabilitation to home. Australian New Zealand Clinical Trials Registry Number (ACTRN) 12618000338268; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=374608&isReview=true (Archived by WebCite at http://www.webcitation.org/74gtZplU2). DERR1-10.2196/12647.


The Influence of Victim Vulnerability and Gender on Police Officers' Assessment of Intimate Partner Violence Risk.
This study investigated the influence of victim vulnerability factors and gender on risk assessment for intimate partner violence (IPV). 867 cases of male and female perpetrated IPV investigated by Swedish police officers using the Brief Spousal Assault Form for the Evaluation of Risk (B-SAFER) were examined. For male-to-female IPV, victim vulnerability factors were associated with summary risk judgments and risk management recommendations. For female-to-male IPV, vulnerability factors were more often omitted, and consistent associations were not found between vulnerability factors, summary risk judgments, and risk management. Results indicate that B-SAFER victim vulnerability factors can assist in assessing male-to-female IPV risk. Further research is necessary to examine the use of B-SAFER victim vulnerability factors for female-to-male IPV, as results showed victim vulnerability factors to be less relevant to officers' decision making, particularly their management recommendations. However, several variables external to the B-SAFER, such as the availability of management strategies may account for these findings.


Provision and use of maternal health services among urban poor women in Kenya: what do we know and what can we do?
In sub-Saharan Africa, the unprecedented population growth that started in the second half of the twentieth century has evolved into unparalleled urbanization and an increasing proportion of urban dwellers living in slums and shanty towns, making it imperative to pay greater attention to the health problems of the urban poor. In particular, urgent efforts need to focus on maternal health. Despite the lack of reliable trend data on maternal mortality, some investigators now believe that progress in maternal health has been very slow in sub-Saharan Africa. This study uses a unique combination of health facility- and individual-level data collected in the slums of Nairobi, Kenya to: (1) describe the provision of obstetric care in the Nairobi informal settlements; (2) describe the patterns of antenatal and delivery care, notably in terms of timing, frequency, and quality of care; and (3) draw policy implications aimed at improving maternal health among the rapidly growing urban poor populations. It shows that the study area is deprived of public health services, a finding which supports the view that low-income urban residents in developing countries face significant obstacles in accessing health care. This study also shows that despite the high prevalence of antenatal care (ANC), the proportion of women who made the recommended number of visits or who initiated the visit in the first trimester of pregnancy remains low compared to Nairobi as a whole and, more importantly, compared to rural populations. Bivariate analyses show that household wealth, education, parity, and place of residence were closely associated with frequency and timing of ANC and with place of delivery. Finally, there is a strong linkage between use of antenatal care and place of delivery. The findings of this study call for urgent attention by Kenya's Ministry of Health and local authorities to the void of quality health services in poor urban communities and the need to provide focused and sustained health education geared towards promoting use of obstetric services.


Treatment outcome of new smear positive pulmonary tuberculosis patients in Penang, Malaysia.
According to the World Health Organization's recent report, in Malaysia, tuberculosis (TB) treatment success rate for new smear positive pulmonary tuberculosis (PTB) patients is still below the global success target of 85%. In this study, we evaluated TB treatment outcome among new smear positive PTB patients, and identified the predictors of unsuccessful treatment outcome and longer duration of treatment (i.e., > 6 months). The population in this study consisted of all new smear positive PTB patients who were diagnosed at the chest clinic of Penang General Hospital between March 2010 and February 2011. During the study period, a standardized data collection form was used to obtain socio-demographic, clinical and treatment related data of the patients from their medical charts and TB notification forms (Tuberculosis Information System; TBIS). These data sources were reviewed at the time of the diagnosis of the patients and then at the subsequent follow-up visits until their final treatment outcomes were available. The treatment outcomes of the patients were reported in line with six outcome categories recommended by World Health Organization. Multiple logistic regression analysis was used to find the independent risk factors for unsuccessful treatment outcome and longer treatment duration. Data were analyzed using the PASW (Predictive Analysis SoftWare, version 19.0. Armonk, NY: IBM Corp). Among the 336 PTB patients (236 male and 100 female) notified during the study period, the treatment success rate was 67.26% (n = 226). Out of 110 patients in unsuccessful outcome category, 30 defaulted from the treatment, 59 died and 21 were transferred to other health care facilities. The mean duration of TB treatment was 8.19 (SD 1.65) months. In multiple logistic regression analysis, risk factors for unsuccessful treatment outcome were foreign nationality, male gender and being illiterate. Similarly, risk factors for mortality due to TB included high-grade sputum and presence of lung cavities at the start of treatment, being alcoholic and elderly. Likewise, concurrent diabetes, presence of lung cavities at the start of the treatment and being a smoker were the significant predictors of longer treatment duration. Our findings indicated that the treatment success rate among the new smear positive PTB patients was less than the success target set by World Health Organization. The proportion of patients in the successful outcome category may be increased by closely monitoring the treatment progress of the patients with aforementioned high risk characteristics. Similarly, more aggressive follow-up of the treatment defaulters and transferred out patients could also improve the TB treatment success rate.