Autism-associated mutations in ProSAP2/Shank3 impair synaptic transmission and neurexin-neuroligin-mediated transsynaptic signaling.
Mutations in several postsynaptic proteins have recently been implicated in the molecular pathogenesis of autism and autism spectrum disorders (ASDs), including Neuroligins, Neurexins, and members of the ProSAP/Shank family, thereby suggesting that these genetic forms of autism may share common synaptic mechanisms. Initial studies of ASD-associated mutations in ProSAP2/Shank3 support a role for this protein in glutamate receptor function and spine morphology, but these synaptic phenotypes are not universally penetrant, indicating that other core facets of ProSAP2/Shank3 function must underlie synaptic deficits in patients with ASDs. In the present study, we have examined whether the ability of ProSAP2/Shank3 to interact with the cytoplasmic tail of Neuroligins functions to coordinate pre/postsynaptic signaling through the Neurexin-Neuroligin signaling complex in hippocampal neurons of Rattus norvegicus. Indeed, we find that synaptic levels of ProSAP2/Shank3 regulate AMPA and NMDA receptor-mediated synaptic transmission and induce widespread changes in the levels of presynaptic and postsynaptic proteins via Neurexin-Neuroligin transsynaptic signaling. ASD-associated mutations in ProSAP2/Shank3 disrupt not only postsynaptic AMPA and NMDA receptor signaling but also interfere with the ability of ProSAP2/Shank3 to signal across the synapse to alter presynaptic structure and function. These data indicate that ASD-associated mutations in a subset of synaptic proteins may target core cellular pathways that coordinate the functional matching and maturation of excitatory synapses in the CNS.


NSAIDs modulate CDKN2A, TP53, and DNA content risk for progression to esophageal adenocarcinoma.
Somatic genetic CDKN2A, TP53, and DNA content abnormalities are common in many human cancers and their precursors, including esophageal adenocarcinoma (EA) and Barrett's esophagus (BE), conditions for which aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) have been proposed as possible chemopreventive agents; however, little is known about the ability of a biomarker panel to predict progression to cancer nor how NSAID use may modulate progression. We aimed to evaluate somatic genetic abnormalities with NSAIDs as predictors of EA in a prospective cohort study of patients with BE. Esophageal biopsies from 243 patients with BE were evaluated at baseline for TP53 and CDKN2A (p16) alterations, tetraploidy, and aneuploidy using sequencing; loss of heterozygosity (LOH); methylation-specific PCR; and flow cytometry. At 10 y, all abnormalities, except CDKN2A mutation and methylation, contributed to EA risk significantly by univariate analysis, ranging from 17p LOH (relative risk [RR] = 10.6; 95% confidence interval [CI] 5.2-21.3, p < 0.001) to 9p LOH (RR = 2.6; 95% CI 1.1-6.0, p = 0.03). A panel of abnormalities including 17p LOH, DNA content tetraploidy and aneuploidy, and 9p LOH was the best predictor of EA (RR = 38.7; 95% CI 10.8-138.5, p < 0.001). Patients with no baseline abnormality had a 12% 10-y cumulative EA incidence, whereas patients with 17p LOH, DNA content abnormalities, and 9p LOH had at least a 79.1% 10-y EA incidence. In patients with zero, one, two, or three baseline panel abnormalities, there was a significant trend toward EA risk reduction among NSAID users compared to nonusers (p = 0.01). The strongest protective effect was seen in participants with multiple genetic abnormalities, with NSAID nonusers having an observed 10-y EA risk of 79%, compared to 30% for NSAID users (p < 0.001). A combination of 17p LOH, 9p LOH, and DNA content abnormalities provided better EA risk prediction than any single TP53, CDKN2A, or DNA content lesion alone. NSAIDs are associated with reduced EA risk, especially in patients with multiple high-risk molecular abnormalities.


Stressful life events, depression and demoralization as risk factors for acute coronary heart disease.
While the effect of psychological stress and depression on the course of heart disease is commonly recognized, the relationship between recent life events, major depression, depressive symptomatology and the onset of acute coronary heart disease (CHD) has been less considered. The aim of this study was to investigate the presence of stressful life events, major and minor depression, recurrent depression and demoralization in the year preceding the occurrence of a first acute myocardial infarction (AMI) and/or a first episode of instable angina and to compare stressful life events, also related with mood disorders, in patients and healthy controls. 97 consecutive patients with a first episode of CHD (91 with AMI and 6 with instable angina) and 97 healthy subjects matched for sociodemographic variables were included. All patients were interviewed with Paykel's Interview for Recent Life Events, a semistructured interview for determining the psychiatric diagnosis of mood disorders (DSM-IV), a semistructured interview for demoralization (DCPR). Patients were assessed while on remission from the acute phase. The time period considered was the year preceding the first episode of CHD and the year before the interview for controls. Patients with acute CHD reported significantly more life events than control subjects (p < 0.001). All categories of events (except entrance events) were significantly more frequent. 30% of patients were identified as suffering from a major depressive disorder; 9% of patients were suffering from minor depression, 20% from demoralization. Even though there was an overlap between major depression and demoralization (12%), 17% of patients with major depression were not classified as demoralized and 7% of patients with demoralization did not satisfy the criteria for major depression. Independently of mood disorders, patients had a higher (p < 0.001) mean number of life events than controls. With regard to life events, the same significant difference (p < 0.001) compared to controls applied to patients with and without mood disorders. Our findings emphasize, by means of reliable methodology, the relationship between life events and AMI. These data, together with those regarding traditional cardiac risk factors, may have clinical and prognostic implications to be verified in longitudinal studies.


CD8 independence and specificity of cytotoxic T lymphocytes restricted by HLA-Aw68.1.
The crystal structure of the HLA-Aw68.1 antigen binding site revealed a negatively charged pocket centred on aspartic acid 74 (Garrett et al. 1989). Access to this '74 pocket' is blocked in HLA-Aw68.2 and HLA-Aw69 by two substitutions at positions 97 and 116. This key feature suggests that the Aw68.1-peptide-specific interactions may involve salt bridges between oppositely charged residues. In this paper, the influenza epitope recognized by virus-specific HLA-Aw68.1-restricted cytotoxic T lymphocytes (CTL) has been defined in vitro with a synthetic peptide corresponding to residues 89-101 of the nucleoprotein (NP). Amino acid substitutions of the peptide NP 89-101 showed that the arginine at position 99 is an anchor point of the peptide within the Aw68.1 antigen binding site. Consistent with this we find that neither HLA-Aw68.2 nor HLA-Aw69 positive cells can present peptide NP 89-101 to Aw68.1-restricted CTL. Our results therefore suggest a model in which presentation of NP 89-101 by HLA-Aw68.1 is dependent upon interaction of the positively charged arginine residue at position 99 of the peptide, with the negatively charged aspartic acid in the '74 pocket' of HLA-Aw68.1. We also show that influenza-virus-specific HLA-Aw68.1-restricted CTL are CD8 independent. This result is consistent with the low affinity of HLA-Aw68.1 for CD8 (Salter et al. 1989) and reveals a unique example of CD8-independent priming of CTL by natural infection with a common pathogen in humans.


Associations Between Longitudinal Trajectories of Cognitive and Social Activities and Brain Health in Old Age.
Prior neuroimaging studies have found that late-life participation in cognitive (eg, reading) and social (eg, visiting friends and family) leisure activities are associated with magnetic resonance imaging (MRI) markers of the aging brain, but little is known about the neural and cognitive correlates of changes in leisure activities during the life span. To examine trajectories of cognitive and social activities from midlife to late life and evaluate whether these trajectories are associated with brain structure, functional connectivity, and cognition. This prospective cohort included participants enrolled in the Whitehall II study and its MRI substudy based in the UK. Participants provided information on their leisure activities at 5 times during calendar years 1997 to 1999, 2002 to 2004, 2006, 2007 to 2009, and 2011 to 2013 and underwent MRI and cognitive battery testing from January 1, 2012, to December 31, 2016. Data analysis was performed from October 7, 2017, to July 15, 2019. Growth curve models and latent class growth analysis were used to identify longitudinal trajectories of cognitive and social activities. Multiple linear regression was used to evaluate associations between activity trajectories and gray matter, white matter microstructure, functional connectivity, and cognition. A total of 574 individuals (468 [81.5%] men; mean [SD] age, 69.9 [4.9] years; median Montreal Cognitive Assessment score, 28 [interquartile range, 26-28]) were included in the present analysis. During a mean (SD) of 15 (4.2) years, cognitive and social activity levels increased during midlife before reaching a plateau in late life. Both baseline (global cognition: unstandardized β [SE], 0.955 [0.285], uncorrected P = .001; executive function: β [SE], 1.831 [0.499], uncorrected P < .001; memory: β [SE], 1.394 [0.550], uncorrected P = .01; processing speed: β [SE], 1.514 [0.528], uncorrected P = .004) and change (global cognition: β [SE], -1.382 [0.492], uncorrected P = .005, executive function: β [SE], -2.219 [0.865], uncorrected P = .01; memory: β [SE], -2.355 [0.948], uncorrected P = .01) in cognitive activities were associated with multiple domains of cognition as well as global gray matter volume (β [SE], -0.910 [0.388], uncorrected P = .02). Baseline (β [SE], 1.695 [0.525], uncorrected P = .001) and change (β [SE], 2.542 [1.026], uncorrected P = .01) in social activities were associated only with executive function, in addition to voxelwise measures of functional connectivity that involved sensorimotor (quadratic change in social activities: number of voxels, 306; P = 0.01) and temporoparietal (linear change in social activities: number of voxels, 16; P = .02) networks. Otherwise, no voxelwise associations were found with gray matter, white matter, or resting-state functional connectivity. False discovery rate corrections for multiple comparisons suggested that the association between cognitive activity levels and executive function was robust (β [SE], 1.831 [0.499], false discovery rate P < .001). The findings suggest that a life course approach may delineate the association between leisure activities and cognitive and brain health and that interventions aimed at improving and maintaining cognitive engagement may be valuable for the cognitive health of community-dwelling older adults.


Vagotomy impairs pentagastrin-induced relaxation of canine gastric fundus.
In eight dogs, a separated, vagally innervated pouch was made from the gastric fundus. Electrodes were implanted on the pouch, and an antral gastric fistula was created through which gastric juice was drained externally during all tests. After recovery, the fasted, conscious dogs received intravenous infusions of 154 mM NaCl to which randomly selected doses of pentagastrin were intermittently added while intraluminal pressure and electric activity of the distended pouch were recorded. Transthoracic vagotomy was then performed, and the dogs were restudied. Before vagotomy, pentagastrin decreased the amplitude of the phasic changes in intraluminal pressure and of the bursts of spiking potentials of the pouch. The D50 for inhibition of mean intrapouch pressure was 4.2 ng/kg per min. After vagotomy, pentagastrin still decreased intrapouch pressure and inhibited fundal spikes, but larger doses were required to produce equivalent decreases in pressure. The D50 was 41.4 ng/kg per min after vagotomy. Our conclusion is that pentagastrin-induced relaxation of the canine gastric fundus is impaired, but not abolished, by vagotomy.


Modulators of sensitivity and resistance to inhibition of PI3K identified in a pharmacogenomic screen of the NCI-60 human tumor cell line collection.
The phosphoinositide 3-kinase (PI3K) signaling pathway is significantly altered in a wide variety of human cancers, driving cancer cell growth and survival. Consequently, a large number of PI3K inhibitors are now in clinical development. To begin to improve the selection of patients for treatment with PI3K inhibitors and to identify de novo determinants of patient response, we sought to identify and characterize candidate genomic and phosphoproteomic biomarkers predictive of response to the selective PI3K inhibitor, GDC-0941, using the NCI-60 human tumor cell line collection. In this study, sixty diverse tumor cell lines were exposed to GDC-0941 and classified by GI(50) value as sensitive or resistant. The most sensitive and resistant cell lines were analyzed for their baseline levels of gene expression and phosphorylation of key signaling nodes. Phosphorylation or activation status of both the PI3K-Akt signaling axis and PARP were correlated with in vitro response to GDC-0941. A gene expression signature associated with in vitro sensitivity to GDC-0941 was also identified. Furthermore, in vitro siRNA-mediated silencing of two genes in this signature, OGT and DDN, validated their role in modulating sensitivity to GDC-0941 in numerous cell lines and begins to provide biological insights into their role as chemosensitizers. These candidate biomarkers will offer useful tools to begin a more thorough understanding of determinants of patient response to PI3K inhibitors and merit exploration in human cancer patients treated with PI3K inhibitors.


The convergence of maturational change and structural covariance in human cortical networks.
Large-scale covariance of cortical thickness or volume in distributed brain regions has been consistently reported by human neuroimaging studies. The mechanism of this population covariance of regional cortical anatomy has been hypothetically related to synchronized maturational changes in anatomically connected neuronal populations. Brain regions that grow together, i.e., increase or decrease in volume at the same rate over the course of years in the same individual, are thus expected to demonstrate strong structural covariance or anatomical connectivity across individuals. To test this prediction, we used a structural MRI dataset on healthy young people (N = 108; aged 9-22 years at enrollment), comprising 3-6 longitudinal scans on each participant over 6-12 years of follow-up. At each of 360 regional nodes, and for each participant, we estimated the following: (1) the cortical thickness in the median scan and (2) the linear rate of change in cortical thickness over years of serial scanning. We constructed structural and maturational association matrices and networks from these measurements. Both structural and maturational networks shared similar global and nodal topological properties, as well as mesoscopic features including a modular community structure, a relatively small number of highly connected hub regions, and a bias toward short distance connections. Using resting-state functional magnetic resonance imaging data on a subset of the sample (N = 32), we also demonstrated that functional connectivity and network organization was somewhat predictable by structural/maturational networks but demonstrated a stronger bias toward short distance connections and greater topological segregation. Brain structural covariance networks are likely to reflect synchronized developmental change in distributed cortical regions.


Castel Gandolfo workshop: an introduction to the impact of climate change, the economic crisis, and the increase in the food prices on malnutrition.
The global food supply system is facing serious new challenges from economic and related crises and climate change, which directly affect the nutritional well-being of the poor by reducing their access to nutritious food. To cope, vulnerable populations prioritize consumption of calorie-rich but nutrient-poor food. Consequently, dietary quality and eventually quantity decline, increasing micronutrient malnutrition (or hidden hunger) and exacerbating preexisting vulnerabilities that lead to poorer health, lower incomes, and reduced physical and intellectual capabilities. This article introduces the series of papers in this supplement, which explore the relationships between crises and their cumulative impacts among vulnerable populations, particularly through hidden hunger.


Bone mineral density and turnover in non-corticosteroid treated African American children with juvenile rheumatoid arthritis.
To determine bone mineral content (BMC), bone mineral density (BMD), Z scores, and markers of bone turnover in African American children with juvenile rheumatoid arthritis (JRA). Eight children with JRA with no prior exposure to corticosteroids were evaluated. Lumbar spine (L1-L4) and total body and total hip BMC and BMD were determined using dual x-ray absorptiometry (DXA), and Z scores (BMD) were calculated. Serum samples of markers of bone turnover including pyridinoline (PYR), N-terminal propeptide of type I procollagen (P1NP), osteocalcin (OC), and bone-specific alkaline phosphatase (BSAP) were measured. The mean Z score (BMD) at the lumbar spine (L1-L4) in patients with JRA was -1.2+/-0.8. Z scores for total body and total hip were within 1 standard deviation of normal compared with healthy historical controls matched for age, sex, and race. BMD was normal for chronological age (defined as Z score >or= 2.0) in African American children with JRA who had not previously been treated with corticosteroids. Further studies are needed on the effects of JRA on skeletal health in African American children.


Micrometer-scale oxygen delivery rearranges cells and prevents necrosis in tumor tissue in vitro.
Oxygen availability plays a critical role in cancer progression and is correlated with poor prognosis. Despite this connection, the independent effects of oxygen gradients on tumor tissues have not been measured. To address this, we developed an oxygen delivery device that uses microelectrodes to generate oxygen directly underneath three-dimensional tumor cylindroids composed of colon carcinoma cells. The extent of cell death was measured using fluorescence staining. Supplying oxygen for 60 h eliminated the necrotic region typically found in the center of cylindroids despite the continued presence of other nutrient gradients. A mathematical model of cylindroid growth showed that the rate of cell death was more sensitive to oxygen than the growth rate. After oxygenation, a ring of dead cells was observed at the outside edge of cylindroids, and dead cells were observed moving outward from cylindroid centers. This movement suggests that dead cells were pushed by viable cells migrating in response to oxygen gradients, a mechanism that may connect transient oxygen gradients to metastasis formation. These measurements show that oxygen gradients are a primary factor governing cell viability and rearrange cells in tumors.


Investigating the Role of the Photorespiratory Pathway in Non-photosynthetic Tissues.
Whilst photorespiration represents one of the dominant pathway fluxes in photosynthetic tissues there are hints from publically available gene expression data such as that housed in the bioarray resource (BAR; www.bar.utoronto.ca) that several of the constituent enzymes are present in roots and other heterotrophic tissues. Here we describe a protocol based on modification of the gaseous environment surrounding individual tissues of mutant and wild type Arabidopsis and evaluation of the consequences. This method could additionally easily be used for larger plants.


Optical imaging of the whole-body to cellular biodistribution of clinical-stage PEG-b-pHPMA-based core-crosslinked polymeric micelles.
Core-crosslinked polymeric micelles (CCPM) based on PEG-b-pHPMA-lactate are clinically evaluated for the treatment of cancer. We macroscopically and microscopically investigated the biodistribution and target site accumulation of CCPM. To this end, fluorophore-labeled CCPM were intravenously injected in mice bearing 4T1 triple-negative breast cancer (TNBC) tumors, and their localization at the whole-body, tissue and cellular level was analyzed using multimodal and multiscale optical imaging. At the organism level, we performed non-invasive 3D micro-computed tomography-fluorescence tomography (μCT-FLT) and 2D fluorescence reflectance imaging (FRI). At the tissue and cellular level, we performed extensive immunohistochemistry, focusing primarily on cancer, endothelial and phagocytic immune cells. The CCPM achieved highly efficient tumor targeting in the 4T1 TNBC mouse model (18.6 %ID/g), with values twice as high as those in liver and spleen (9.1 and 8.9 %ID/g, respectively). Microscopic analysis of tissue slices revealed that at 48 h post injection, 67% of intratumoral CCPM were localized extracellularly. Phenotypic analyses on the remaining 33% of intracellularly accumulated CCPM showed that predominantly F4/80+ phagocytes had taken up the nanocarrier formulation. Similar uptake patterns were observed for liver and spleen. The propensity of CCPM to primarily accumulate in the extracellular space in tumors suggests that the anticancer efficacy of the formulation mainly results from sustained release of the chemotherapeutic payload in the tumor microenvironment. In addition, their high uptake by phagocytic immune cells encourages potential use for immunomodulatory anticancer therapy. Altogether, the beneficial biodistribution, efficient tumor targeting and prominent engagement of PEG-b-pHPMA-lactate-based CCPM with key cell populations underline the clinical versatility of this clinical-stage nanocarrier formulation.


Minimally invasive synthetic suburethral sling operations for stress urinary incontinence in women.
Stress urinary incontinence (SUI) is a common condition affecting up to 30% of women. Minimally invasive synthetic suburethral sling operations are among the latest forms of procedures introduced to treat SUI. To assess the effects of minimally invasive synthetic suburethral sling operations for treatment of SUI, urodynamic stress incontinence (USI) or mixed urinary incontinence (MUI) in women. We searched the Cochrane Incontinence Group Specialised Register (searched 20 March 2008), MEDLINE (January 1950 to April 2008), EMBASE (January 1988 to April 2008), CINAHL (January 1982 to April 2008), AMED (January 1985 to April 2008), the UK National Research Register, ClinicalTrials.gov, and reference lists of relevant articles. Randomised or quasi-randomised controlled trials amongst women with SUI, USI or symptoms of stress or mixed urinary incontinence, in which at least one trial arm involved a minimally invasive synthetic suburethral sling operations. Two review authors assessed the methodological quality of potentially eligible studies and independently extracted data from the included trials. Sixty two trials involving 7101 women were included. The quality of evidence was moderate for most trials. Minimally invasive synthetic suburethral sling operations appeared to be as effective as traditional suburethral slings ( trials, n = 599, Risk Ratio (RR) 1.03, 95% Confidence Interval (CI) 0.94 to 1.13) but with shorter operating time and less post-operative voiding dysfunction and de novo urgency symptoms.Minimally invasive synthetic suburethral sling operations appeared to be as effective as open retropubic colposuspension (subjective cure rate at 12 months RR 0.96, 95% CI 0.90 to 1.03; at 5 years RR 0.91, 95% CI 0.74 to 1.12) with fewer perioperative complications, less postoperative voiding dysfunction, shorter operative time and hospital stay but significantly more bladder perforations (6% versus 1%, RR 4.24, 95% CI 1.71 to 10.52).There was conflicting evidence about the effectiveness of minimally invasive synthetic suburethral sling operations compared to laparoscopic colposuspension in the short term (objective cure, RR 1.15, 95% CI 1.06 to 1.24; subjective cure RR 1.11, 95% CI 0.99 to 1.24). Minimally invasive synthetic suburethral sling operations had significantly less de novo urgency and urgency incontinence, shorter operating time, hospital stay and time to return to daily activities.A retropubic bottom-to-top route was more effective than top-to-bottom route (RR 1.10, 95% CI 1.01 to 1.20; RR 1.06, 95% CI 1.01 to 1.11) and incurred significantly less voiding dysfunction, bladder perforations and tape erosions.Monofilament tapes had significantly higher objective cure rates (RR 1.15, 95% CI 1.02 to 1.30) compared to multifilament tapes and fewer tape erosions (1.3% versus 6% RR 0.25, 95% CI 0.06 to 1.00).The obturator route was less favourable than the retropubic route in objective cure (84% versus 88%; RR 0.96, 95% CI 0.93 to 0.99; 17 trials, n = 2434), although there was no difference in subjective cure rates. However, there was less voiding dysfunction, blood loss, bladder perforation (0.3% versus 5.5%, RR 0.14, 95% CI 0.07 to 0.26) and shorter operating time with the obturator route. The current evidence base suggests that minimally invasive synthetic suburethral sling operations are as effective as traditional suburethral slings, open retropubic colposuspension and laparoscopic colposuspension in the short term but with less postoperative complications. Women were less likely to be continent after operations performed via the obturator (rather than retropubic) route, but they had fewer complications. Most of the trials had short term follow up and the quality of the evidence was variable.


Metabolic effects of the nocturnal rise in cortisol on carbohydrate metabolism in normal humans.
Glucocorticoid concentrations vary throughout the day. To determine whether an increase in cortisol similar to that present during sleep is of physiologic significance in humans, we studied the disposition of a mixed meal when the nocturnal rise in cortisol was mimicked or prevented using metyrapone plus either a variable or constant hydrocortisone infusion. When glucose concentrations were matched with a glucose infusion, hepatic glucose release (2.6 +/- 0.2 vs. 1.5 +/- 0.4 nmol/kg per 6 h) was higher (P < 0.05) while glucose disappearance (5.9 +/- 0.3 vs. 7.3 +/- 0.9 mmol/kg per 6 h) and forearm arteriovenous glucose difference (64 +/- 24 vs. 231 +/- 62 mmol/dl per 6 h) were lower (P < 0.05) during the variable than basal infusion. The greater hepatic response during the variable cortisol infusion was mediated (at least in part) by inhibition of insulin and stimulation of glucagon secretion as reflected by lower (P < 0.05) C-peptide (0.29 +/- 0.01 vs. 0.38 +/- 0.04 mmol/liter per 6 h) and higher (P < 0.05) glucagon (42.7 +/- 2.0 vs. 39.3 +/- 1.8 ng/ml per 6 h) concentrations. In contrast, the decreased rates of glucose uptake appeared to result from a state of "physiologic" insulin resistance. The variable cortisol infusion also increased (P < 0.05) postprandial palmitate appearance as well as palmitate, beta-hydroxybutyrate, and alanine concentrations, suggesting stimulation of lipolysis, ketogenesis, and proteolysis. We conclude that the circadian variation in cortisol concentration is of physiologic significance in normal humans.


Experimental Protocol to Determine the Chloride Threshold Value for Corrosion in Samples Taken from Reinforced Concrete Structures.
The aging of reinforced concrete infrastructure in developed countries imposes an urgent need for methods to reliably assess the condition of these structures. Corrosion of the embedded reinforcing steel is the most frequent cause for degradation. While it is well known that the ability of a structure to withstand corrosion depends strongly on factors such as the materials used or the age, it is common practice to rely on threshold values stipulated in standards or textbooks. These threshold values for corrosion initiation (Ccrit) are independent of the actual properties of a certain structure, which clearly limits the accuracy of condition assessments and service life predictions. The practice of using tabulated values can be traced to the lack of reliable methods to determine Ccrit on-site and in the laboratory. Here, an experimental protocol to determine Ccrit for individual engineering structures or structural members is presented. A number of reinforced concrete samples are taken from structures and laboratory corrosion testing is performed. The main advantage of this method is that it ensures real conditions concerning parameters that are well known to greatly influence Ccrit, such as the steel-concrete interface, which cannot be representatively mimicked in laboratory-produced samples. At the same time, the accelerated corrosion test in the laboratory permits the reliable determination of Ccrit prior to corrosion initiation on the tested structure; this is a major advantage over all common condition assessment methods that only permit estimating the conditions for corrosion after initiation, i.e., when the structure is already damaged. The protocol yields the statistical distribution of Ccrit for the tested structure. This serves as a basis for probabilistic prediction models for the remaining time to corrosion, which is needed for maintenance planning. This method can potentially be used in material testing of civil infrastructures, similar to established methods used for mechanical testing.


Social meanings and understandings in patient-nurse interaction in the community practice setting: a grounded theory study.
The patient-nurse relationship is a traditional concern of healthcare research. However, patient-nurse interaction is under examined from a social perspective. Current research focuses mostly on specific contexts of care delivery and experience related to medical condition or illness, or to nurses' speciality. Consequentially, this paper is about the social meanings and understandings at play within situated patient-nurse interaction in the community practice setting in a transforming healthcare service. Grounded theory methodology was used and the research process was characterised by principles of theoretical sensitivity and constant comparative analysis. The field of study was four health centres in the community. The participants were patients and nurses representative of those attending or working in the health centres and meeting there by scheduled appointment. Data collection methods were observations, informal interviews and semi-structured interviews. Key properties of 'Being a good patient, being a good nurse', 'Institutional experiences' and 'Expectations about healthcare' were associated with the construction of a category entitled 'Experience'. Those key properties captured that in an evolving healthcare environment individuals continually re-constructed their reality of being a patient or nurse as they endeavoured to perform appropriately; articulation of past and present healthcare experiences was important in that process. Modus operandi in role as patient was influenced by past experiences in healthcare and by those in non-healthcare institutions in terms of engagement and involvement (or not) in interaction. Patients' expectations about interaction in healthcare included some uncertainly as they strived to make sense of the changing roles and expertise of nurses and, differentiating between the roles and expertise of nurses and doctors. The importance of social meanings and understandings in patient-nurse interaction is not fully apparent to nurses, but important in the patient experience. Seeking understanding from a social perspective makes a contribution to enhancing knowledge about patient-nurse interaction with subsequent impact on practice, in particular the development of the patient-nurse relationship. The implications are that the meanings and understandings patients and nurses generate from experiences beyond and within their situated interaction are pivotal to the development of their relationship in the transforming community healthcare environment.


Growth Hormone Research Society perspective on the development of long-acting growth hormone preparations.
The Growth Hormone (GH) Research Society (GRS) convened a workshop to address important issues regarding trial design, efficacy, and safety of long-acting growth hormone preparations (LAGH). A closed meeting of 55 international scientists with expertise in GH, including pediatric and adult endocrinologists, basic scientists, regulatory scientists, and participants from the pharmaceutical industry. Current literature was reviewed for gaps in knowledge. Expert opinion was used to suggest studies required to address potential safety and efficacy issues. Following plenary presentations summarizing the literature, breakout groups discussed questions framed by the planning committee. Attendees reconvened after each breakout session to share group reports. A writing team compiled the breakout session reports into a draft document that was discussed and revised in an open forum on the concluding day. This was edited further and then circulated to attendees from academic institutions for review after the meeting. Participants from pharmaceutical companies did not participate in the planning, writing, or in the discussions and text revision on the final day of the workshop. Scientists from industry and regulatory agencies reviewed the manuscript to identify any factual errors. LAGH compounds may represent an advance over daily GH injections because of increased convenience and differing phamacodynamic properties, providing the potential for improved adherence and outcomes. Better methods to assess adherence must be developed and validated. Long-term surveillance registries that include assessment of efficacy, cost-benefit, disease burden, quality of life, and safety are essential for understanding the impact of sustained exposure to LAGH preparations.


Reversal of threatening blindness after initiation of eculizumab in Purtscher-like retinopathy secondary to atypical hemolytic uremic syndrome.
Purtscher-like retinopathy, a rare manifestation of systemic thrombotic microangiopathy, is a potentially visually debilitating condition with no effective proven treatment. Distinct pathogenic pathways have been proposed as etiological factors. We revisit the etiology of Purtscher-like retinopathy based on the rapid response and profound visual improvement after initiation of systemic intravenous eculizumab, an inhibitor of the complement cascade, in a patient with Purtscher-like retinopathy secondary to familial atypical hemolytic uremic syndrome (aHUS) due to a mutation in complement factor H. We hypothesize that the efficacy of eculizumab in this patient provides evidence for pathogenic events in the retina similar to those encountered in the renal microvasculature of aHUS patients, namely complement-mediated thromboembolization as a result of activation of the complement cascade in endothelial cells with release of tissue factor and development and amplification of a procoagulant state. To the best of our knowledge, this is the first report in the literature of eculizumab as an effective therapeutic strategy in Purtscher-like retinopathy.


Isolated acetabular liner exchange.
During the past two decades, most total hip arthroplasties were performed with metal or ceramic heads on conventional polyethylene, an articulation associated with wear and limited life expectancy. Wear is associated with acetabular osteolysis. Isolated liner exchange has become a common surgical intervention when the acetabular component remains well-fixed. The purpose of isolated liner exchange is to prevent loosening of the components secondary to osteolysis and catastrophic mechanical failure caused by bearing wear-through. Treatment options for polyethylene wear include observation (in the asymptomatic hip), liner exchange, and more extensive revision procedures. Patients frequently present with asymptomatic but substantial polyethylene wear with or without associated osteolysis, the treatment of which is controversial. Other areas of debate include complete acetabular component removal to allow bone grafting and placement of an improved bearing surface, reuse of modular mechanisms, cementation into well-fixed shells, and whether to use periacetabular bone grafting.


Variability among electronic cigarettes in the pressure drop, airflow rate, and aerosol production.
This study investigated the performance of electronic cigarettes (e-cigarettes), compared different models within a brand, compared identical copies of the same model within a brand, and examined performance using different protocols. Airflow rate required to generate aerosol, pressure drop across e-cigarettes, and aerosol density were examined using three different protocols. First 10 puff protocol: The airflow rate required to produce aerosol and aerosol density varied among brands, while pressure drop varied among brands and between the same model within a brand. Total air hole area correlated with pressure drop for some brands. Smoke-out protocol: E-cigarettes within a brand generally performed similarly when puffed to exhaustion; however, there was considerable variation between brands in pressure drop, airflow rate required to produce aerosol, and the total number of puffs produced. With this protocol, aerosol density varied significantly between puffs and gradually declined. CONSECUTIVE TRIAL PROTOCOL: Two copies of one model were subjected to 11 puffs in three consecutive trials with breaks between trials. One copy performed similarly in each trial, while the second copy of the same model produced little aerosol during the third trial. The different performance properties of the two units were attributed to the atomizers. There was significant variability between and within brands in the airflow rate required to produce aerosol, pressure drop, length of time cartridges lasted, and production of aerosol. Variation in performance properties within brands suggests a need for better quality control during e-cigarette manufacture.


Complete Genome Sequence of blaCTX-M-27-Encoding Escherichia coli Strain H105 of Sequence Type 131 Lineage C1/H30R.
Escherichia coli sequence type 131 (ST131) is the most frequent antimicrobial-resistant lineage of E. coli, propagating extended-spectrum β-lactamases (ESBL) worldwide. Recently, an alarming rate of increase in isolates of the sublineage C1/H30R-blaCTX-M-27 of ST131 in geographically distant countries was reported. Here, we present the complete genome sequence of the ST131 sublineage C1/H30R E. coli isolate harboring blaCTX-M-27 from Germany.


The virtue of multiculturalism: personal transformation, character, and openness to the other.
The social, intellectual, and moral movement known as multiculturalism has been enormously influential in psychology. Its ability to reshape psychology has been due to its ethical force, which derives from the attractiveness of its aims of inclusion, social justice, and mutual respect. The cultivation of cultural competence, presented as a developmental process of acquiring self-awareness, cultural knowledge, and skills, is an important emphasis in the multicultural literature. The authors place the cultural competence literature in dialogue with virtue ethics (a contemporary ethical theory derived from Aristotle) to develop a rich and illuminating way for psychologists to understand and embody the personal self-examination, commitment, and transformation required for learning and practicing in a culturally competent manner. According to virtue ethics, multiculturalism can be seen as the pursuit of worthwhile goals that require personal strengths or virtues, knowledge, consistent actions, proper motivation, and practical wisdom. The authors term the virtue of multiculturalism openness to the other and conclude by describing how attention to cultural matters also transforms virtue ethics in important and necessary ways.


Voluntary control of a phantom limb.
Voluntary actions are often accompanied by a conscious experience of intention. The content of this experience, and its neural basis, remain controversial. On one view, the mind just retrospectively ascribes intentions to explain the occurrence of actions that lack obvious triggering stimuli. Here, we use EEG frequency analysis of sensorimotor rhythms to investigate brain activity when a participant (CL, co-author of this paper) with congenital absence of the left hand and arm, prepared and made a voluntary action with the right or the phantom "left hand". CL reported the moment she experienced the intention to press a key. This timepoint was then used as a marker for aligning and averaging EEG. In a second condition, CL was asked to prepare the action on all trials, but then, on some trials, to cancel the action at the last moment. For the right hand, we observed a typical reduction in beta-band spectral power prior to movement, followed by beta rebound after movement. When CL prepared but then cancelled a movement, we found a characteristic EEG pattern reported previously, namely a left frontal increase in spectral power close to the time of the perceived intention to move. Interestingly, the same neural signatures of positive and inhibitory volition were also present when CL prepared and inhibited movements with her phantom left hand. These EEG signals were all similar to those reported previously in a group of 14 healthy volunteers. Our results suggest that conscious intention may depend on preparatory brain activity, and not on making, or ever having made, the corresponding physical body movement. Accounts that reduce conscious volition to mere retrospective confabulation cannot easily explain our participant's neurophenomenology of action and inhibition. In contrast, the results are consistent with the view that specific neural events prior to movement may generate conscious experiences of positive and negative volition.


Treatment with isotretinoin inhibits lipofuscin accumulation in a mouse model of recessive Stargardt's macular degeneration.
Recessive Stargardt's macular degeneration is an inherited blinding disease of children caused by mutations in the ABCR gene. The primary pathologic defect in Stargardt's disease is accumulation of toxic lipofuscin pigments such as N-retinylidene-N-retinylethanolamine (A2E) in cells of the retinal pigment epithelium. This accumulation appears to be responsible for the photoreceptor death and severe visual loss in Stargardt's patients. Here, we tested a therapeutic strategy to inhibit lipofuscin accumulation in a mouse model of recessive Stargardt's disease. Isotretinoin (Accutane) has been shown to slow the synthesis of 11-cis-retinaldehyde and regeneration of rhodopsin by inhibiting 11-cis-retinol dehydrogenase in the visual cycle. Light activation of rhodopsin results in its release of all-trans-retinaldehyde, which constitutes the first reactant in A2E biosynthesis. Accordingly, we tested the effects of isotretinoin on lipofuscin accumulation in abcr(-/-) knockout mice. Isotretinoin blocked the formation of A2E biochemically and the accumulation of lipofuscin pigments by electron microscopy. We observed no significant visual loss in treated abcr(-/-) mice by electroretinography. Isotretinoin also blocked the slower, age-dependent accumulation of lipofuscin in wild-type mice. These results corroborate the proposed mechanism of A2E biogenesis. Further, they suggest that treatment with isotretinoin may inhibit lipofuscin accumulation and thus delay the onset of visual loss in Stargardt's patients. Finally, the results suggest that isotretinoin may be an effective treatment for other forms of retinal or macular degeneration associated with lipofuscin accumulation.


Lumbar supports for prevention and treatment of low back pain.
Lumbar supports are used in the treatment of low back pain patients to make the impairment and disability vanish or decrease. Lumbar supports are also used to prevent the onset of low back pain (primary prevention) or to prevent recurrences of a low back pain episode (secondary prevention). The objective of this systematic review was to assess the effects of lumbar supports for prevention and treatment of non-specific low back pain. We searched the Medline, Cinahl and Current Contents databases and the Cochrane Controlled Trials Register up to September 1999, and the Embase database up to September 1998. We also screened references given in relevant reviews and identified controlled trials, and used Science Citation Index to identify additional controlled trials. Controlled clinical trials that reported on any type of lumbar supports as preventive or therapeutic intervention for non-specific low back pain were included. One reviewer extracted data from the trials considering characteristics of the study population, characteristics of the interventions and the final results for each outcome measure. The reviewer compared these findings to data regarding the same characteristics of the same studies published already in other reviews. The methodological quality was independently assessed by two reviewers. Because it was not possible to perform a quantitative analysis, a qualitative meta-analysis was performed in which the strength of evidence on the effectiveness of lumbar supports was classified as being strong, moderate, limited or conflicting, and no evidence. Five randomized and two nonrandomized controlled preventive trials and six randomized therapeutic trials were included in our review. Overall the methodological quality of the studies included in our review was rather low. Only four of the thirteen studies scored positive on 50% or more of the the internal validity items. There was moderate evidence that for primary prevention lumbar supports are not more effective than other types of treatment or no intervention. No evidence was found on the effectiveness of lumbar supports for secondary prevention. The systematic review of therapeutic trials showed that there is limited evidence that lumbar supports are more effective than no treatment, while it is still unclear if lumbar supports are more effective than other interventions for treatment of low back pain. There is still a need for high quality randomised trials on the effectiveness of lumbar supports. One of the most essential issues to tackle in these future trials seems to be the realisation of an adequate compliance.


Catatonia. A prospective clinical study.
We studied 55 patients admitted during 14 months to two inpatient psychiatric units of a municipal hospital who exhibited one or more of the catatonic signs of mutism, stereotypy, posturing, catalepsy, automatic obedience, negativism, echolalia/echopraxia, or stupor. Only four of the 55 patients satisfied our research criteria for schizophrenia, whereas over two thirds had diagnosable affective disorders, usually mania. The eight catatonic motor signs were nonspecific and homogeneously distributed among the various research diagnostic groups, with the number and type of individual signs unrelated to short-term treatment outcome. A favorable treatment response was shown for the entire catatonic sample, with two thirds markedly improved or in remission at the time of discharge. These findings are consistent with those of other investigators of the catatonic syndrome for the past 100 years.


Endocranial features of Australopithecus africanus revealed by 2- and 3-D computed tomography.
The earliest hominid from South Africa, Australopithecus africanus, is known from only six specimens in which accurate assessment of endocranial capacity and cranial venous outflow pattern can be obtained. This places a severe limit on a number of hypotheses concerning early hominid evolution, particularly those involving brain-body size relationships and adaptations of the circulatory system to evolving upright posture. Advances in high-resolution two- and three-dimensional computed tomography (CT) now allow the inclusion of another important specimen to this list, MLD 37/38 from Makapansgat. A new computer imaging technique is described that "reconstructs" the missing portions of the endocranial cavity in order to determine endocranial capacity. In addition, CT evaluation allows assessment of cranial venous outflow pattern even in cases where the endocranial cavity is completely filled with stone matrix. Results show that endocranial capacity in this specimen is less than originally proposed and also support the view that gracile and robust australopithecines evolved different cranial venous outflow patterns in response to upright postures.


Design-to-fabricate: maker hardware requires maker software.
As a result of consumer-level 3D printers' increasing availability and affordability, the audience for 3D-design tools has grown considerably. However, current tools are ill-suited for these users. They have steep learning curves and don't take into account that the end goal is a physical object, not a digital model. A new class of "maker"-level design tools is needed to accompany this new commodity hardware. However, recent examples of such tools achieve accessibility primarily by constraining functionality. In contrast, the meshmixer project is building tools that provide accessibility and expressive power by leveraging recent computer graphics research in geometry processing. The project members have had positive experiences with several 3D-design-to-print workshops and are exploring several design-to-fabricate problems. This article is part of a special issue on 3D printing.


Synchronous Telehealth Yoga and Cognitive Processing Group Therapies for Women Veterans with Posttraumatic Stress Disorder: A Multisite Randomized Controlled Trial Adapted for COVID-19.
Background: Providing care over telehealth grew slowly until the COVID-19 pandemic. Since the onset of the COVID-19 pandemic, providing mental health care was readily adapted to virtual means; however, clinical trial research is nascent in adapting methods and procedures to the virtual world. Methods: We present protocol modifications to pivot a multisite randomized controlled trial study, conducted at Southeastern and Pacific Northwestern Veterans Affairs Health Care Systems, from being conducted in-person to virtually, following the onset of the COVID-19 pandemic. We measured outcomes of posttraumatic stress disorder (PTSD) symptoms and psychophysiological markers of stress among female Veterans with PTSD secondary to military sexual trauma. We collected qualitative data about provider and participant experiences with telehealth. Results: Across sites, 200 participants were consented (48 virtually), 132 were randomized (28 to virtual groups), and 117 completed data collection and treatment (69 completed all or some data collection or treatment virtually). Conclusions: The pivots made for this study were in response to the COVID-19 pandemic and offer innovative procedures leveraging technology and contributing to the broader landscape of conducting research virtually. Clinical Trials Number: NCT02640690.


Functional significance of Wnt inhibitory factor-1 gene in kidney cancer.
Wnt inhibitory factor-1 (WIF-1) has been identified as one of the secreted antagonists that bind Wnt protein. WIF-1 has been described as a tumor suppressor in various types of cancer. However, the molecular function of WIF-1 gene has never been examined in human renal cell carcinoma (RCC). Therefore, we hypothesized that WIF-1 functions as a tumor suppressor gene and overexpression of this gene may induce apoptosis and inhibit tumor growth in RCC cells. Immunohistochemistry and real-time reverse transcription-PCR revealed that WIF-1 was significantly downregulated in RCC samples and RCC cell lines, respectively. Bisulfite sequencing of the WIF-1 promoter region in RCC cell lines showed it to be densely methylated, whereas there was no methylation of WIF-1 promoter in normal kidney. Significant inhibition of cell growth and colony formation in WIF-1-transfected cells compared with controls were observed. WIF-1 transfection significantly induced apoptosis and suppressed in vivo tumor growth. Also, Wnt signaling activity and beta-catenin expression were reduced by WIF-1 transfection. In conclusion, this is the first report documenting that the WIF-1 is downregulated by promoter methylation and functions as a tumor suppressor gene by inducing apoptosis in RCC cells.


Titanium dioxide nanoparticles induce DNA damage and genetic instability in vivo in mice.
Titanium dioxide (TiO(2)) nanoparticles are manufactured worldwide in large quantities for use in a wide range of applications including pigment and cosmetic manufacturing. Although TiO(2) is chemically inert, TiO(2) nanoparticles can cause negative health effects, such as respiratory tract cancer in rats. However, the mechanisms involved in TiO(2)-induced genotoxicity and carcinogenicity have not been clearly defined and are poorly studied in vivo. The present study investigates TiO(2) nanoparticles-induced genotoxicity, oxidative DNA damage, and inflammation in a mice model. We treated wild-type mice with TiO(2) nanoparticles in drinking water and determined the extent of DNA damage using the comet assay, the micronuclei assay, and the gamma-H2AX immunostaining assay and by measuring 8-hydroxy-2'-deoxyguanosine levels and, as a genetic instability endpoint, DNA deletions. We also determined mRNA levels of inflammatory cytokines in the peripheral blood. Our results show that TiO(2) nanoparticles induced 8-hydroxy-2'-deoxyguanosine, gamma-H2AX foci, micronuclei, and DNA deletions. The formation of gamma-H2AX foci, indicative of DNA double-strand breaks, was the most sensitive parameter. Inflammation was also present as characterized by a moderate inflammatory response. Together, these results describe the first comprehensive study of TiO(2) nanoparticles-induced genotoxicity in vivo in mice possibly caused by a secondary genotoxic mechanism associated with inflammation and/or oxidative stress. Given the growing use of TiO(2) nanoparticles, these findings raise concern about potential health hazards associated with TiO(2) nanoparticles exposure.


Building a competitive insurance system: Switzerland's strategy for managed-care healthcare.
This paper applies the five standard criteria for assessing the performance of an economy to one of its sectors, namely, the provision of health care. They are (1) matching of consumer preferences, (2) technical efficiency, (3) adaptive capacity, (4) dynamic efficiency, and (5) a distribution of income that provides incentives for producers to attain criteria (1) through (4). Being insurance-based, the Swiss healthcare system comprises three contractual relationships that can be judged in the light of these criteria. First, the relationship between consumers and health insurers satisfies criterion (1) to a high degree, not least thanks to the managed-care (MC) options that were introduced with the new law on health insurance (effective 1996). However, it fails with regard to (2) because cost reductions achieved by MC cannot be passed on to consumers but to a very limited degree. The relationship between health insurers and service providers, by way of contrast, does not fully satisfy any of the five criteria, mainly because health insurers continue to operate under an any-willing-provider clause for conventional fee-for-service care. This makes it difficult for them to find MC providers. Finally, the relationship between consumers and healthcare providers match consumer preferences well (criterion 1) but do not result in an income distribution in the healthcare sector that is conducive to the attainment of criteria (2) through (4). The total score for the Swiss healthcare system amounts to 13 points out of a maximum of 30, to which the relationship between insurers and providers contributes only 3 points. Therefore, performance could be improved by granting health insurers freedom to contract not only with domestic but also foreign healthcare providers offering a favorable benefit cost ratio.


Isometric handgrip exercise training attenuates blood pressure in prehypertensive subjects at 30% maximum voluntary contraction.
Prehypertension highlights a category of subjects who are at high risk of developing hypertension. This study assessed the blood pressure attenuating effect of isometric handgrip exercise in the management of prehypertension. A total of 400 prehypertensive subject with a mean age of 40 ± 10 years and recently diagnosed as prehypertension were recruited for the study. They were randomly distributed into exercise and control groups (n = 200). The control group was placed on lifestyle modification only, while the exercise group performed a 24 consecutive days isometric hand grip exercise training at 30% maximum voluntary contraction (MVC) for 2 min each day in combination with lifestyle modification protocol. The results show a statistically significant reduction in systolic blood pressure (SBP) and diastolic blood pressure (DBP). The exercise group had a mean reduction of 7.48 ± 0.06 and 6.41 ± 1.01 mmHg of the SBP and DBP, respectively. It was further observed that both the SBP and DBP and pulse rate significantly increased acutely within 5 min post exercise at 30% MVC with a mean value of 8.60 ± 0.20 mmHg, 7.33 ± 0.03 mmHg, and 8.24 ± 0.20 beats/min of the SBP and DBP and pulse rate, respectively. However, this increase returned to pre-exercise value within 10 min post exercises to a mean value of -0.68 + 1.64 mmHg, 1.48 ± 1.02 mmHg, and 3.00 ± 0.11 beats/min, respectively. This study has shown that isometric handgrip exercise is effective in the attenuation of blood pressure in prehypertensive subjects especially when combined with the routinely recommended lifestyle modifications. However, caution should be taken when recommending it because of acute increase in blood pressure.


Association between waste management and cancer in companion animals.
Increased cancer rates have been documented in people residing in areas around Naples characterized by illegal dumping and incineration of waste. Risk of cancer in dogs and cats is associated with waste management. Four hundred and fifty-three dogs and cats with cancer and 1,554 cancer-free animals. Hospital-based case-control study in Naples (low danger) and nearby cities having a history of illegal waste dumping (high danger). Odds ratio (OR) between high- and low-danger areas was calculated for all tumors and various malignancies in dogs and cats. An increased risk for cancer development was identified in dogs but not in cats residing in high-danger areas (OR: 1.55; 95% confidence interval: 1.18-2.03; P < .01). A 2.39-fold increased risk of lymphoma (P < .01) accounted for the greater tumor frequency in dogs residing in high-danger areas. The risk of mast cell tumor and mammary cancer did not differ in dogs residing in high- or low-danger areas. Waste emission from illegal dumping sites increases cancer risk in dogs residing in high-danger areas. An increased prevalence of lymphoma has been previously recognized in humans living close to illegal waste dumps. Thus, epidemiological studies of spontaneous tumors in dogs might suggest a role for environmental factors in canine and human carcinogenesis and can predict health hazards for humans.


Occupant Interactions and Effectiveness of Natural Ventilation Strategies in Contemporary New Housing in Scotland, UK.
The need to reduce carbon emissions and fuel poverty has led to increased building envelope air tightness, intended to reduce uncontrolled ventilation heat losses. Ventilation strategies in dwellings still allow the use of trickle ventilators in window frames for background ventilation. The extent to which this results in "healthy" Indoor Air Quality (IAQ) in recently constructed dwellings was a concern of regulators in Scotland. This paper describes research to explore this. First a review of literature was conducted, then data on occupant interactions with ventilation provisions (windows, doors, trickle vents) gathered through an interview-based survey of 200 recently constructed dwellings, and measurements made on a sample of 40 of these. The main measured parameter discussed here is CO2 concentration. It was concluded after the literature review that 1000 ppm absolute was a reasonable threshold to use for "adequate" ventilation. The occupant survey found that there was very little occupant interaction with the trickle ventilators e.g., in bedrooms 63% were always closed, 28% always open, and in only 9% of cases occupants intervened to make occasional adjustments. In the measured dwellings average bedroom CO2 levels of 1520 ppm during occupied (night time) hours were observed. Where windows were open the average bedroom CO2 levels were 972 ppm. With windows closed, the combination of "trickle ventilators open plus doors open" gave an average of 1021 ppm. "Trickle ventilators open" gave an average of 1571 ppm. All other combinations gave averages of 1550 to 2000 ppm. Ventilation rates and air change rates were estimated from measured CO2 levels, for all dwellings calculated ventilation rate was less than 8 L/s/p, in 42% of cases calculated air change rate was less than 0.5 ach. It was concluded that trickle ventilation as installed and used is ineffective in meeting desired ventilation rates, evidenced by high CO2 levels reported across the sampled dwellings. Potential implications of the results are discussed.


Prognostic Value of HIV-1 RNA on CD4 Trajectories and Disease Progression Among Antiretroviral-Naive HIV-Infected Adults in Botswana: A Joint Modeling Analysis.
Although HIV-1 RNA levels are measured at the time of initial diagnosis, the results are not used for the clinical follow-up of the patients. This study evaluates the prognostic value of the baseline HIV-1 RNA levels (above or below 10,000 copies/ml) on rate of disease progression, among antiretroviral therapy (ART)-naive patients in Botswana. A prospective cohort of 436 HIV-infected ART-naive adults with baseline CD4 > 400 cells/mm(3) were followed quarterly for 5 years in an urban clinic in Botswana. Baseline HIV-1 RNA levels and longitudinal CD4(+) T-cell count data were analyzed, using mixed-effects regression jointly modeled with the times to a composite endpoint defined by AIDS-defining clinical conditions or death. During 1,547 person-years (PYs) follow-up time, 106 individuals became eligible for ART initiation (incidence rate: 0.07 PYs) and 6 participants died of AIDS-related illness. There were 203 (47%) individuals with baseline HIV-1 RNA <10,000 copies/ml and 233 (53%) individuals with baseline RNA >10,000 copies/ml. The slope of the predicted CD4 trajectory for individuals with baseline HIV-1 RNA >10,000 copies/ml is 30% steeper than that for those with baseline RNA <10,000. The hazard of reaching the composite endpoint for the individuals with baseline HIV-1 RNA >10,000 copies/ml was 2.3 (95% confidence interval: 1.5-3.0) times higher than that for those with baseline HIV-1 RNA <10,000 copies/ml. CD4 decline in individuals with HIV-1 RNA >10,000 copies/ml is much faster than that in those with RNA <10,000. The elevated HIV-1 RNA can be used as a marker to identify individuals at risk of faster disease progression.


Interactions of dietary fat intake and the hepatic lipase -480C-->T polymorphism in determining hepatic lipase activity: the Hoorn Study.
Gene-nutrient interactions affecting hepatic lipase (HL) activity may contribute to the interindividual variability of the cardiovascular disease risk associated with dietary fat intake. We determined the associations of dietary fat intake with postheparin HL activity and the possible modifying effect of the HL -480C-->T polymorphism on these associations. Subjects were recruited from participants in the 2000-2001 follow-up examination of the Hoorn Study. HL activity was determined in postheparin plasma in a sample of 211 men and 218 women aged 60-87 y. Information about dietary intake of the participants was obtained with a validated food-frequency questionnaire. Linear regression was performed, adjusted for age. Total dietary fat was positively associated with HL activity (standardized beta: 0.11; 95% CI: 0.02, 0.21), and this association was also seen for saturated fat (0.10; 0.01, 0.20) and monounsaturated fatty acid (0.10; 0.01, 0.19). We observed a significant interaction of the HL polymorphism with the relation between total fat intake and HL activity. The association of total fat with HL activity was stronger in subjects with CT (0.27; 0.11, 0.43) and TT (0.39; -0.22, 1.00) genotypes than in subjects with the CC genotype (0.06; -0.06, 0.18; P for interaction < 0.10). The interaction remained statistically significant in models that included age, sex, carbohydrate and protein intakes, and insulin or body mass index. Higher intakes of total and saturated fat were positively associated with higher HL activity. In addition, the observed association of total fat with HL activity was modified by the HL-480C-->T polymorphism, after adjustment for age, sex, carbohydrate and protein intakes, and insulin or body mass index.


Detection of EGFR gene mutations using the wash fluid of CT-guided biopsy needle in NSCLC patients.
In this study, we examined whether epidermal growth factor receptor (EGFR) mutations were detectable using a polymerase chain reaction-based assay and wash fluid of computed tomography (CT)-guided lung biopsy needles. DNA was extracted from wash fluid of CT-guided biopsy needles of 53 lung tumors (as diagnosed according to the results of the CT-guided biopsies). EGFR mutations, specifically exon19 deletions and exon21 L858R mutations, were examined using a mutant-enriched polymerase chain reaction assay. We also examined the presence of EGFR mutations in 26 surgically resected tumor specimens and compared the results with those obtained for the corresponding wash fluid samples. The amount of DNA obtained for the wash fluid of the CT-guided biopsy needles ranged from 35 to 2360 ng. There were no significant differences in the amount of extracted DNA according to the tumor characteristics, including tumor size and the percentage of ground glass opacity. Thirty-four of the 53 lung tumor samples were histologically diagnosed as non-small cell lung cancer (NSCLC). Exon19 deletions and exon21 L858R mutations in EGFR were detected in 4 (12%) and 13 (38%) of 34 NSCLC cases, respectively. No EGFR mutations were found in the non-NSCLC cases. The EGFR mutation status in the wash fluid samples was consistent with those obtained for all 26 corresponding surgical specimens. Our results indicate that EGFR mutations can be detected using wash fluid of CT-guided biopsy needles. In this manner, the DNA genotype can be determined even in extremely small clinical specimens using highly sensitive assays.


Simulated forward and backward self motion, based on realistic parameters, causes motion induced blindness.
Motion Induced Blindness (MIB) is a well-established visual phenomenon whereby highly salient targets disappear when viewed against a moving background mask. No research has yet explored whether contracting and expanding optic flow can also trigger target disappearance. We explored MIB using mask speeds corresponding to driving at 35, 50, 65 and 80 km/h in simulated forward (expansion) and backward (contraction) motion as well as 2-D radial movement, random, and static mask motion types. Participants (n = 18) viewed MIB targets against masks with different movement types, speed, and target locations. To understand the relationship between saccades, pupil response and perceptual disappearance, we ran two additional eye-tracking experiments (n = 19). Target disappearance increased significantly with faster mask speeds and upper visual field target presentation. Simulated optic flow and 2-D radial movement caused comparable disappearance, and all moving masks caused significantly more disappearance than a static mask. Saccades could not entirely account for differences between conditions, suggesting that self-motion optic flow does cause MIB in an artificial setting. Pupil analyses implied that MIB disappearance induced by optic flow is not subjectively salient, potentially explaining why MIB is not noticed during driving. Potential implications of MIB for driving safety and Head-Up-Display (HUD) technologies are discussed.


The dual frontier: Patented inventions and prior scientific advance.
The extent to which scientific advances support marketplace inventions is largely unknown. We study 4.8 million U.S. patents and 32 million research articles to determine the minimum citation distance between patented inventions and prior scientific advances. We find that most cited research articles (80%) link forward to a future patent. Similarly, most patents (61%) link backward to a prior research article. Linked papers and patents typically stand 2 to 4 degrees distant from the other domain. Yet, advances directly along the patent-paper boundary are notably more impactful within their own domains. The distance metric further provides a typology of the fields, institutions, and individuals involved in science-to-technology linkages. Overall, the findings are consistent with theories that emphasize substantial and fruitful connections between patenting and prior scientific inquiry.


Effect of caffeinated and decaffeinated coffee on serum uric acid and uric acid clearance, a randomised within-subject experimental study.
The effect of coffee on serum uric acid (SUA) has shown conflicting results. This study was to determine the effects of caffeinated coffee (CC) and decaffeinated coffee (DC) on SUA, serum xanthine oxidase activity (sXOA) and urine uric acid clearance (UAC). This was a prospective randomised within-subject experimental study design of 51 healthy male participants. Each study period consisted of 3 periods, including a control, an intervention, and washout period for 1, 3 and 1 week, respectively. During the intervention period, the participants received 2, 4 or 6 gram/day of coffee, either CC or DC. For DC groups, SUA significantly decreased by 6.5 (±1.1) mg/dL to 6.2 (±1.1) mg/dL during the intervention period (p=0.014). sXOA significantly increased by 0.05 (±0.07) nmol/min/mL to 0.20 (±0.38) nmol/min/mL during the intervention period (p=0.010) of CC. For UAC, there was no significant change with CC or DC. In hyperuricaemic participants, SUA significantly decreased by 7.7 (±0.7) mg/dL to 7.2 (±0.7) mg/dL during the intervention period (p=0.028) of DC. For non-hyperuricaemic, CC significantly increased SUA by 5.9 (±0.7) mg/dL to 6.2 (±0.9) mg/dL during the intervention period (p=0.008) and significantly decreased SUA to 6.0 (±0.8) mg/dL (p=0.049) during the withdrawal period. A significant increase of sXOA according with SUA in CC groups from 0.05 (±0.07) nmol/min/mL to 0.25 (±0.44) nmol/min/mL during the intervention period (p=0.040) was presented in non-hyperuricaemic participants. DC had a significant decrease of SUA during the intervention period. However, in non-HUS participants, SUA significantly increased in CC.


Silver Anniversary: 25 Editions of the IMIA Yearbook.
To provide an editorial introduction into the special 25th anniversary edition of the IMIA Yearbook of Medical Informatics with discussion of the significance of the Yearbook, past and current editorial teams, and a look into the future. A brief overview of the 2016 anniversary edition of the Yearbook allows for a discussion of the significance and value of the Yearbook to the Biomedical Informatics community as well as a review of changes in Yearbook team and format over time. The IMIA Yearbook celebrates its 25th edition bearing witness to the quality of the IMIA brand, the Yearbook content, as well as to the dedication of and the inordinate amount of labor from the authors and editors of the Yearbook. Editorial teams are to be applauded for their hard work and for their foresight in steering the Yearbook from a paperback to an open access online publication. The special edition provides reviews of past editorials with the knowledge of today. The IMIA Yearbook celebrates a remarkable milestone providing a testament to the maturity of the Biomedical Informatics field. Informaticians across the world are encouraged to thank past editorial teams and celebrate with IMIA.


[Pharmacokinetic study of penetration of meropenem into pleural effusion in patients with pleurisy].
Complication by secondary infection is observed in not only bacterial pleurisy but also other pleurisy, and the appropriate administration of antibacterial agents is necessary. It is very important to secure a smooth penetration of systemically administered antibacterial agents to pleural effusion in infection therapy. In this study, we investigated the pharmacokinetics of a carbapenem antibiotic, meropenem (MEPM), in blood and pleural effusion in patients with an accumulation of pleural effusion caused by pleurisy, who underwent placement of an indwelling thoracic drain and received intravenous drip administration of MEPM for pneumonia or other respiratory tract infection. The blood pharmacokinetic parameters of MEPM after an intravenous drip administration of 0.5 g MEPM in six patients were: area under the blood concentration-time curve (AUCx), 37.9 +/- 6.2 (hr.mg/L); volume of distribution (Vd), 27.3 +/- 4.4 (L); total clearance (CLtotal), 13.4 +/- 1.8 (L/hr); elimination half life (t1/2), 0.50 +/- 0.08 (hr-1); and elimination rate constant (kel), 1.42 +/- 0.22 (hr). The pharmacokinetic parameters in pleural effusion were: AUCx, 35.7 +/- 7.1 (hr.mg/L); mean retention time (MRT), 5.00 +/- 3.25 (hr); variance of retention time (VRT), 29.9 +/- 44.6 (hr2); kel, 0.34 +/- 0.27 (hr-1); and t1/2, 3.14 +/- 2.36 (hr). The penetration rate calculated from the ratio of pleural concentration to blood concentration in each patient was 46.5 +/- 26.1%, showing good penetration comparable or superior to those of other antibacterial agents previously reported. From these results, it was suggested that MEPM was rapidly penetrated to the pleural effusion and was retained for a more prolonged time in the pleural effusion than in the blood of patients with accumulated pleural effusion, and it suggested the usefulness of MEPM in antibacterial therapy for patients with pleurisy causing accumulation of pleural effusion.


Reannotation of the genome sequence of Clostridium difficile strain 630.
A regular update of genome annotations is a prerequisite step to help maintain the accuracy and relevance of the information they contain. Five years after the first publication of the complete genome sequence of Clostridium difficile strain 630, we manually reannotated each of the coding sequences (CDSs), using a high-level annotation platform. The functions of more than 500 genes annotated previously with putative functions were reannotated based on updated sequence similarities to proteins whose functions have been recently identified by experimental data from the literature. We also modified 222 CDS starts, detected 127 new CDSs and added the enzyme commission numbers, which were not supplied in the original annotation. In addition, an intensive project was undertaken to standardize the names of genes and gene products and thus harmonize as much as possible with the HAMAP project. The reannotation is stored in a relational database that will be available on the MicroScope web-based platform (https://www.genoscope.cns.fr/agc/microscope/mage/viewer.php?S_id=752&wwwpkgdb=a78e3466ad5db29aa8fe49e8812de8a7). The original submission stored in the (International Nucleotide Sequence Database Collaboration) INSDC nucleotide sequence databases was also updated.


17q23.2q23.3 de novo duplication in association with speech and language disorder, learning difficulties, incoordination, motor skill impairment, and behavioral disturbances: a case report.
Chromosomal rearrangements involving 17q23 have been described rarely. Deletions at 17q23.1q23.2 have been reported in individuals with developmental delay and growth retardation, whereas duplications at 17q23.1q23.2 appear to segregate with clubfoot. Dosage alterations in the TBX2 and TBX4 genes, located in 17q23.2, have been proposed to be responsible for the phenotypes observed in individuals with 17q23.1q23.2 deletions and duplications. In this report, we present the clinical phenotype of a child with a previously unreported de novo duplication at 17q23.2q23.3 located distal to the TBX2 and TBX4 region. We report a 7.5-year-old boy with speech and language disorder, learning difficulties, incoordination, fine motor skill impairment, infrequent seizures with abnormal EEG, and behavior disturbances (mild self-inflicted injuries, hyperactivity-inattention, and stereotyped hand movements). Chromosomal microarray revealed a 2-Mb duplication of chromosome 17q23.2q23.3. Both parents did not have the duplication indicating that this duplication is de novo in the child. The duplicated region encompasses 16 genes. It is possible that increased dosage of one or more genes in this region is responsible for the observed phenotype. The TANC2 gene is one of the genes in the duplicated region.It encodes a member of the TANC (tetratricopeptide repeat, ankyrin repeat and coiled-coil containing) family which includes TANC1 and TANC2. These proteins are highly expressed in brain and play major roles in synapsis regulation. Hence, it is suggestive that TANC2 is the likely candidate gene responsible for the observed phenotype as an increased TANC2 dosage can potentially alter synapsis, resulting in neuronal dysfunction and the neurobehavioral phenotype observed in this child with 17q23.2q23.3 duplication.


Ontogeny and the possible function of a novel epidermal growth factor-like repeat domain-containing protein, NELL2, in the rat brain.
In this study we investigated the mRNA expression of NELL2, a neural tissue-specific epidermal growth factor (EGF)-like repeat domain-containing protein, in the developing and adult rat CNS using in situ hybridization histochemistry and northern blot analysis. The possible candidates that interact with or be regulated by NELL2 were screened with a cDNA expression array in antisense (AS) NELL2 oligodeoxynucleotide (ODN)-injected rat hypothalami. NELL2 mRNA was detected as early as embryonic day 10, and was predominant in the CNS throughout the pre-natal stages. Its expression gradually increased during embryonic development and its strong expression was observed throughout the CNS until embryonic day 20. It was detected in the ventricular zone of the spinal cord, medulla and pons in 12-day-old-embryos, suggesting that NELL2 plays a role in the neurogenesis of these areas. After birth its expression gradually decreased, but high levels of expression could be observed in the tenia tecta, piriform cortex, hippocampus, dentate gyrus, cerebellar cortex, ambiguus nucleus, and inferior olivary nucleus of adult rat brains. The analysis of cDNA expression arrays revealed that the administration of AS NELL2 ODN markedly decreased the expression of several Ca2+-binding proteins and those involved in the transport and release of vesicles such as EF-hand Ca2+-binding protein p22 and rab7. This finding was confirmed by relative reverse transcription-polymerase chain reaction. The effect of NELL2 on synaptic vesicle content in median eminence (ME) nerve terminals was determined with synaptophysin levels as a marker protein in the AS NELL2 ODN-injected rat. It was significantly decreased by the AS ODN. These data suggest that NELL2 may play an important role in the development of the CNS as well as maintenance of neural functions, by regulating the intracellular machinery involving Ca2+ signaling, synaptic transport and/or release of vesicles.


Predictive value of DNA integrity analysis in idiopathic recurrent pregnancy loss following spontaneous conception.
Standard semen parameters are poor predictors of fertility potential. To date, apart from, paternal karyotyping sperm factors are not evaluated in recurrent pregnancy loss (RPL), only recent studies have emphasized the role of sperm factors in early embryonic development as sperm transcribes genes critical for early embryonic development. Sperm DNA integrity is useful diagnostic and prognostic marker and has clinical implications in idiopathic recurrent pregnancy loss (iRPL) following spontaneous conception. The aim of this study was to assess DNA integrity in cases experiencing iRPL following spontaneous conception. Semen samples from 45 patients and 20 controls were analyzed as per WHO 1999 guidelines and sperm chromatin structure assay (SCSA) was used to measure DNA fragmentation index (DFI). By applying receiver operating curve (ROC) analysis, sperm DFI of approximately 26 % was found in male partner of couples experiencing iRPL. Our data indicate that sperm from men with a history of iRPL have a higher percentage of DNA damage as compared to control group, and this can explain pregnancy loss in these patients. Men with higher DFI are infertile whereas men with lower DFI (26 %) are able to conceive but experience recurrent pregnancy loss. Thus it is important to evaluate sperm DFI in couples experiencing iRPL to understand exact aetiology of RPL and determine prognosis and management.


Charlie Gard and the weight of parental rights to seek experimental treatment.
The case of Charlie Gard, an infant with a genetic illness whose parents sought experimental treatment in the USA, brought important debates about the moral status of parents and children to the public eye. After setting out the facts of the case, this article considers some of these debates through the lens of parental rights. Parental rights are most commonly based on the promotion of a child's welfare; however, in Charlie's case, promotion of Charlie's welfare cannot explain every fact of the case. Indeed, some seem most logically to extend from intrinsic parental rights, that is, parental rights that exist independent of welfare promotion. I observe that a strong claim for intrinsic parental rights can be built on arguments for genetic propriety and children's limited personhood. Critique of these arguments suggests the scope of parental rights remains limited: property rights entail proper use; non-personhood includes only a small cohort of very young or seriously intellectually disabled children and the uniqueness of parental genetic connection is limited. Moreover, there are cogent arguments about parents' competence to make judgements, and public interest arguments against allowing access to experimental treatment. Nevertheless, while arguments based on propriety may raise concerns about the attitude involved in envisioning children as property, I conclude that these arguments do appear to offer a prima facie case for a parental right to seek experimental treatment in certain limited circumstances.


Implicit location encoding via stored representations of familiar objects: neuropsychological evidence.
We report data on the visual localisation ability of a patient with Balint's syndrome, GK. We show that, with relatively long exposures of displays, GK is better able to judge the spatial relations between separate objects (a "between-object judgement") than the spatial relations between a part and a whole object (a "within-object judgement") (Experiments 1-3). This dissociation occurred even when the same stimulus was used for both judgements, and the task instructions biased GK to parse the stimulus as either a single or as two separate objects (Experiments 2 and 6). However, when he could use a stored representation to make a within-object judgement, then performance was better than on a comparable spatial judgement of the relations between two separate objects (Experiments 4-7). The data demonstrate that stored representations of objects can support the spatial coding of parts to perceptual wholes. In the absence of stored representations, part-whole relations must be explicitly coded by attention, a process that is impaired in this patient.


Modulation of UvrD helicase activity by covalent DNA-protein cross-links.
UvrD (DNA helicase II) has been implicated in DNA replication, DNA recombination, nucleotide excision repair, and methyl-directed mismatch repair. The enzymatic function of UvrD is to translocate along a DNA strand in a 3' to 5' direction and unwind duplex DNA utilizing a DNA-dependent ATPase activity. In addition, UvrD interacts with many other proteins involved in the above processes and is hypothesized to facilitate protein turnover, thus promoting further DNA processing. Although UvrD interactions with proteins bound to DNA have significant biological implications, the effects of covalent DNA-protein cross-links on UvrD helicase activity have not been characterized. Herein, we demonstrate that UvrD-catalyzed strand separation was inhibited on a DNA strand to which a 16-kDa protein was covalently bound. Our sequestration studies suggest that the inhibition of UvrD activity is most likely due to a translocation block and not helicase sequestration on the cross-link-containing DNA substrate. In contrast, no inhibition of UvrD-catalyzed strand separation was apparent when the protein was linked to the complementary strand. The latter result is surprising given the earlier observations that the DNA in this covalent complex is severely bent ( approximately 70 degrees ), with both DNA strands making multiple contacts with the cross-linked protein. In addition, UvrD was shown to be required for replication of plasmid DNAs containing covalent DNA-protein complexes. Combined, these data suggest a critical role for UvrD in the processing of DNA-protein cross-links.


Advances in human B cell phenotypic profiling.
To advance our understanding and treatment of disease, research immunologists have been called-upon to place more centralized emphasis on impactful human studies. Such endeavors will inevitably require large-scale study execution and data management regulation ("Big Biology"), necessitating standardized and reliable metrics of immune status and function. A well-known example setting this large-scale effort in-motion is identifying correlations between eventual disease outcome and T lymphocyte phenotype in large HIV-patient cohorts using multiparameter flow cytometry. However, infection, immunodeficiency, and autoimmunity are also characterized by correlative and functional contributions of B lymphocytes, which to-date have received much less attention in the human Big Biology enterprise. Here, we review progress in human B cell phenotyping, analysis, and bioinformatics tools that constitute valuable resources for the B cell research community to effectively join in this effort.


Phosphorylation of lamin B at the nuclear membrane by activated protein kinase C.
Both bryostatin 1 and 4 beta-phorbol 12,13-dibutyrate (PBt2) activate Ca2+- and phospholipid-dependent protein kinase (protein kinase C) at the plasma membrane in HL-60 cells (Kraft, A. S., Baker, V. V., and May, W. S. (1987) Oncogene 1, 91-100). However, whereas PBt2 causes HL-60 cells to cease dividing and differentiate, bryostatin 1 antagonizes this effect and allows cells to continue proliferating. To test whether these divergent effects could be due to the differential activation of protein kinase C at the nuclear level, the phosphorylation of nuclear envelope polypeptides was evaluated in cells treated with either bryostatin 1 or PBt2. Bryostatin 1, either alone or in combination with PBt2, but not PBt2 alone, mediates rapid and specific phosphorylation of several nuclear envelope polypeptides. A major target for bryostatin-induced phosphorylation is the major nuclear envelope polypeptide lamin B (Mr = 67,000, pI 6.0). In vitro studies combining purified protein kinase C and HL-60 cell nuclear envelopes demonstrate that bryostatin activates protein kinase C to phosphorylate lamin B, whereas PBt2 does so only weakly, suggesting selective activation of this enzyme toward this substrate. Comparative phosphopeptide and phosphoamino acid analyses demonstrate that bryostatin induces phosphorylation of identical serine sites on lamin B both in whole cells and in vitro. Treatment of whole cells with bryostatin, but not PBt2, leads to specific translocation of activated protein kinase C to the nuclear envelope. Since phosphorylation of lamin B is known to be involved in nuclear lamina depolymerization at the time of mitosis, it is possible that bryostatin-activated protein kinase C activity is involved in this process. Finally, specific activation of protein kinase C at the nuclear membrane could explain, at least in part, the divergent effects of bryostatin 1 and PBt2 on HL-60 cell growth.


Optimum number of procedures required to achieve procedural skills competency in internal medicine residents.
Procedural skills training forms an essential, yet difficult to assess, component of an Internal Medicine Residency Program. We report the development of process of documentation and assessment of procedural skills training. An explanatory sequential mixed methods design was adopted where both quantitative and qualitative information was collected sequentially. A survey was conducted within the Department of Internal Medicine at The Aga Khan University Hospital, Karachi, Pakistan to determine the optimum number of procedures needed to be performed by residents at each year of residency. Respondents included both faculty and the residents in the Department. Thereafter, all responses were compiled and later scrutinized by a focus group comprising of a mix of faculty from various subspecialties and resident representatives. A total of 64 responses were obtained. A significant difference was found in eight procedural skills' status between residents and faculty, though none of these were significant after accounting for multiple consecutive testing. However, the results were reviewed and a consensus for the procedures needed was developed through a focus group. A finalized procedural list was generated to determine: (a) the minimum number of times each procedure needed to be performed by the resident before deemed competent; (b) the level of competency for each procedure for respective year of residency. We conclude that the opinion of both the residents and the faculty as key stakeholders is vital to determine the number of procedures to be performed during an Internal Medicine Residency. Documentation of procedural competency development during the training would make the system more objective and hence reproducible. A log book was designed consisting of minimum number of procedures to be performed before attaining competency.


Neurodevelopmental outcomes at 4 to 8 years of children born at 22 to 25 weeks' gestational age: a meta-analysis.
Many centers delivering infants at 22 to 25 weeks' gestation have limited data regarding their outcomes. A meta-analysis of the 4- to 8-year neurodevelopmental outcomes and exploration of the limitations of meta-analysis would aid physicians and parents to plan care for these infants. To determine the rate of moderate to severe and severe neurodevelopmental impairment by gestational age in extremely preterm survivors followed up between ages 4 and 8 years, as well as to determine whether there is a significant difference in impairment rates between the successive weeks of gestation of survivors. A peer-reviewed search strategy obtained English-language publications from MEDLINE In-Process & Other Non-Indexed Citations, MEDLINE, and EMBASE. Personal files and reference lists from identified articles were searched. Contemporary cohorts were obtained by restriction to those published after 2004. Inclusion criteria were prospective cohort studies, follow-up rate of 65% or more, use of standardized testing or classification for impairment, reporting by gestation, and meeting prespecified definitions of impairment. We excluded randomized clinical trials, highly selective cohorts, consensus statements, and reviews. Of 1771 identified records, 89 full-text publications were assessed for eligibility. Using the full text of each publication, 2 authors independently followed a 2-step procedure. First, they determined that 9 studies met inclusion criteria. Next, they extracted data using a structured data collection form. Investigators were contacted for data clarification. All extremely preterm infant survivors have a substantial likelihood of developing moderate to severe impairment. Wide confidence intervals at the lower gestations (eg, at 22 weeks, 43% [95% CI, 21%-69%]; heterogeneity I2, 0%) and high heterogeneity at the higher gestations (eg, at 25 weeks, 24% [95% CI, 17%-32%]; I2, 66%) limit the results. There was a statistically significant absolute decrease in moderate to severe impairment between each week of gestation (6.5% [95% CI, 2%-11%]). Knowledge of these data, including the limitations, should facilitate discussion during the shared decision-making process about care plans for these infants, particularly in centers without their own data. More prospective, high-quality, complete cohorts are needed.


"How Much Time Do I Have?": Communicating Prognosis in the Era of Exceptional Responders.
Prognostication is the science by which clinicians estimate a patient's expected outcome. A robust literature shows that many patients with advanced cancer have inaccurate perceptions of their prognosis, thus raising questions about whether patients are truly making informed decisions. Clinicians' ability to communicate prognostic information is further complicated today by the availability of novel, efficacious immunotherapies and genome-guided treatments. Currently, clinicians lack tools to predict which patients with advanced disease will achieve an exceptional response to these new therapies. This increased prognostic uncertainty on the part of clinicians further complicates prognostic communication with patients. Evidence also suggests that many oncologists avoid or rarely engage in prognosis-related communication and/or lack skills in this area. Although communication skills training interventions can have a positive impact on complex communication skills for some clinicians, there is no one-size-fits-all approach to improving patient-clinician communication about prognosis. Yet improving patient understanding of prognosis is critical, because patient understanding of prognosis is linked with end-of-life care outcomes. Solutions to this problem will likely require a combination of interventions beyond communication skills training programs, including enhanced use of other cancer clinicians, such as oncology nurses and social workers, increased use of palliative care specialists, and organizational support to facilitate advance care planning.


Anti-Leptospira immunoglobulin profiling in mice reveals strain specific IgG and persistent IgM responses associated with virulence and renal colonization.
Leptospira interrogans is a pathogenic spirochete responsible for leptospirosis, a neglected, zoonotic reemerging disease. Humans are sensitive hosts and may develop severe disease. Some animal species, such as rats and mice can become asymptomatic renal carriers. More than 350 leptospiral serovars have been identified, classified on the basis of the antibody response directed against the lipopolysaccharide (LPS). Similarly to whole inactivated bacteria used as human vaccines, this response is believed to confer only short-term, serogroup-specific protection. The immune response of hosts against leptospires has not been thoroughly studied, which complicates the testing of vaccine candidates. In this work, we studied the immunoglobulin (Ig) profiles in mice infected with L. interrogans over time to determine whether this humoral response confers long-term protection after homologous challenge six months post-infection. Groups of mice were injected intraperitoneally with 2×107 leptospires of one of three pathogenic serovars (Manilae, Copenhageni or Icterohaemorrhagiae), attenuated mutants or heat-killed bacteria. Leptospira-specific immunoglobulin (IgA, IgM, IgG and 4 subclasses) produced in the first weeks up to 6 months post-infection were measured by ELISA. Strikingly, we found sustained high levels of IgM in mice infected with the pathogenic Manilae and Copenhageni strains, both colonizing the kidney. In contrast, the Icterohaemorrhagiae strain did not lead to kidney colonization, even at high dose, and triggered a classical IgM response that peaked at day 8 post-infection and disappeared. The virulent Manilae and Copenhageni serovars elicited high levels and similar profiles of IgG subclasses in contrast to Icterohaemorrhagiae strains that stimulated weaker antibody responses. Inactivated heat-killed Manilae strains elicited very low responses. However, all mice pre-injected with leptospires challenged with high doses of homologous bacteria did not develop acute leptospirosis, and all antibody responses were boosted after challenge. Furthermore, we showed that 2 months post-challenge, mice pre-infected with the attenuated M895 Manilae LPS mutant or heat-killed bacterin were completely protected against renal colonization. In conclusion, we observed a sustained IgM response potentially associated with chronic leptospiral renal infection. We also demonstrated in mice different profiles of protective and cross-reactive antibodies after L. interrogans infection, depending on the serovar and virulence of strains.