Precursors to social and communication difficulties in infants at-risk for autism: gaze following and attentional engagement.
Whilst joint attention (JA) impairments in autism have been widely studied, little is known about the early development of gaze following, a precursor to establishing JA. We employed eye-tracking to record gaze following longitudinally in infants with and without a family history of autism spectrum disorder (ASD) at 7 and 13 months. No group difference was found between at-risk and low-risk infants in gaze following behaviour at either age. However, despite following gaze successfully at 13 months, at-risk infants with later emerging socio-communication difficulties (both those with ASD and atypical development at 36 months of age) allocated less attention to the congruent object compared to typically developing at-risk siblings and low-risk controls. The findings suggest that the subtle emergence of difficulties in JA in infancy may be related to ASD and other atypical outcomes.


C5-Morpholinomethylation of N1-sulfonylcytosines by a one-pot microwave assisted Mannich reaction.
A fast and efficient route for the introduction of a methylene bridged-amine (morpholinomethyl) functionality in the C5 position of the sulfonylated cytosine nucleobase has been developed. First, novel N1-sulfonylcytosine derivatives 3-6 were prepared by the condensation of silylated cytosine with selected sulfonyl chlorides. They were subsequently transformed to 5-morpholinomethyl-N1-sulfonylcytosine derivatives (8, 12-15) using microwave irradiation. As a result of cytosine ring opening in N1-tosylcytosine, depending on the reaction conditions, peculiar tosyl-urea derivative 9 has been isolated, which provided additional insight into the reaction pathway. The influence of the C5-substituent on the antiproliferative activity has been evaluated by performing the MTT test on U251, MCF-7 and MOLT-4 tumor cell-lines.


A prospective study of the relationship between adverse life events and trauma in adults with mild to moderate intellectual disabilities.
Research has demonstrated a relationship between the experience of life events and psychopathology in people with intellectual disabilities (ID), however few studies have established causal links and to date no prospective studies have utilised a measure of trauma that has been developed specifically for this population group. This 6-month prospective study examined longitudinal relationships between adverse life events and trauma in 99 adults with mild to moderate ID. Life events during the previous 6 months were significantly predictive of levels of trauma as measured by the self-report Lancaster and Northgate trauma scales (LANTS), and the informant LANTS behavioural changes, frequency and severity sub-scales. This prospective causal relationship was demonstrated while controlling for any prior life events or pre-existing trauma, though the relationship was not moderated by social support. Evidence of a causal relationship between adverse life events and trauma symptoms is important for treatment planning and funding allocation.


Population trends in the 10-year incidence and prevalence of diabetic retinopathy in the UK: a cohort study in the Clinical Practice Research Datalink 2004-2014.
To describe trends in the incidence and prevalence of diabetic retinopathy (DR) in the UK by diabetes type, age, sex, ethnicity, deprivation, region and calendar year. Cohort study using the Clinical Practice Research Datalink (CPRD). UK primary care. 7.7 million patients ≥12 contributing to the CPRD from 2004 to 2014. Age-standardised prevalence and incidence of diabetes, DR and severe DR (requiring photocoagulation) by calendar year and population subgroup. Relative risk of developing DR and severe DR by population subgroup. The prevalence of DR was 48.4% in the population type 1 diabetes mellitus (T1DM) (14 846/30 657) and 28.3% (95 807/338 390) in the population with type 2 diabetes mellitus (T2DM). Prevalence of DR remained stable in people with T2DM and decreased in people with T1DM. Screening for DR increased over time for patients with T2DM and remained static for patients with T1DM Incidence of DR increased in parallel with the incidence of T2DM in both diabetic populations. Among patients with T2DM, relative risk of DR varied significantly by region, was increased for older age groups and in men compared with women, with risk of severe DR increased in South Asian groups and more deprived groups. Relative risk of DR for patients with T1DM varied by age and region, but not by gender, ethnic group or deprivation. This is the largest study to date examining the burden of DR in the UK. Regional disparities in incidence may relate to differences in screening delivery and disease ascertainment. Evidence that deprivation and ethnicity are associated with a higher risk of severe DR highlights a significant potential health inequality. Findings from this study will have implications for professionals working in the diabetes and sight loss sectors, particularly to inform approaches for diagnosis of retinopathy and campaigning to better tackle the disease for at risk groups.


Barrel cortex function.
Neocortex, the neuronal structure at the base of the remarkable cognitive skills of mammals, is a layered sheet of neuronal tissue composed of juxtaposed and interconnected columns. A cortical column is considered the basic module of cortical processing present in all cortical areas. It is believed to contain a characteristic microcircuit composed of a few thousand neurons. The high degree of cortical segmentation into vertical columns and horizontal layers is a boon for scientific investigation because it eases the systematic dissection and functional analysis of intrinsic as well as extrinsic connections of the column. In this review we will argue that in order to understand neocortical function one needs to combine a microscopic view, elucidating the workings of the local columnar microcircuits, with a macroscopic view, which keeps track of the linkage of distant cortical modules in different behavioral contexts. We will exemplify this strategy using the model system of vibrissal touch in mice and rats. On the macroscopic level vibrissal touch is an important sense for the subterranean rodents and has been honed by evolution to serve an array of distinct behaviors. Importantly, the vibrissae are moved actively to touch - requiring intricate sensorimotor interactions. Vibrissal touch, therefore, offers ample opportunities to relate different behavioral contexts to specific interactions of distant columns. On the microscopic level, the cortical modules in primary somatosensory cortex process touch inputs at highest magnification and discreteness - each whisker is represented by its own so-called barrel column. The cellular composition, intrinsic connectivity and functional aspects of the barrel column have been studied in great detail. Building on the versatility of genetic tools available in rodents, new, highly selective and flexible cellular and molecular tools to monitor and manipulate neuronal activity have been devised. Researchers have started to combine these with advanced and highly precise behavioral methods, on par with the precision known from monkey preparations. Therefore, the vibrissal touch model system is exquisitely positioned to combine the microscopic with the macroscopic view and promises to be instrumental in our understanding of neocortical function.


N-Glycosylation Patterns Correlate with Hepatocellular Carcinoma Genetic Subtypes.
Hepatocellular carcinoma (HCC) is the second leading cause of cancer deaths globally, and the incidence rate in the United States is increasing. Studies have identified inter- and intratumor heterogeneity as histologic and/or molecular subtypes/variants associated with response to certain molecular targeted therapies. Spatial HCC tissue profiling of N-linked glycosylation by matrix-assisted laser desorption ionization imaging mass spectrometry (MALDI-IMS) may serve as a new method to evaluate the tumor heterogeneity. Previous work has identified significant changes in the N-linked glycosylation of HCC tumors but has not accounted for the heterogeneous genetic and molecular nature of HCC. To determine the correlation between HCC-specific N-glycosylation changes and genetic/molecular tumor features, we profiled HCC tissue samples with MALDI-IMS and correlated the spatial N-glycosylation with a widely used HCC molecular classification (Hoshida subtypes). MALDI-IMS data displayed trends that could approximately distinguish between subtypes, with subtype 1 demonstrating significantly dysregulated N-glycosylation versus adjacent nontumor tissue. Although there were no individual N-glycan structures that could identify specific subtypes, trends emerged regarding the correlation of branched glycan expression to HCC as a whole and fucosylated glycan expression to subtype 1 tumors specifically. IMPLICATIONS: Correlating N-glycosylation to specific subtypes offers the specific detection of subtypes of HCC, which could both enhance early HCC sensitivity and guide targeted clinical therapies.


Reduced incidence of Prevotella and other fermenters in intestinal microflora of autistic children.
High proportions of autistic children suffer from gastrointestinal (GI) disorders, implying a link between autism and abnormalities in gut microbial functions. Increasing evidence from recent high-throughput sequencing analyses indicates that disturbances in composition and diversity of gut microbiome are associated with various disease conditions. However, microbiome-level studies on autism are limited and mostly focused on pathogenic bacteria. Therefore, here we aimed to define systemic changes in gut microbiome associated with autism and autism-related GI problems. We recruited 20 neurotypical and 20 autistic children accompanied by a survey of both autistic severity and GI symptoms. By pyrosequencing the V2/V3 regions in bacterial 16S rDNA from fecal DNA samples, we compared gut microbiomes of GI symptom-free neurotypical children with those of autistic children mostly presenting GI symptoms. Unexpectedly, the presence of autistic symptoms, rather than the severity of GI symptoms, was associated with less diverse gut microbiomes. Further, rigorous statistical tests with multiple testing corrections showed significantly lower abundances of the genera Prevotella, Coprococcus, and unclassified Veillonellaceae in autistic samples. These are intriguingly versatile carbohydrate-degrading and/or fermenting bacteria, suggesting a potential influence of unusual diet patterns observed in autistic children. However, multivariate analyses showed that autism-related changes in both overall diversity and individual genus abundances were correlated with the presence of autistic symptoms but not with their diet patterns. Taken together, autism and accompanying GI symptoms were characterized by distinct and less diverse gut microbial compositions with lower levels of Prevotella, Coprococcus, and unclassified Veillonellaceae.


Fingolimod versus interferon beta/glatiramer acetate after natalizumab suspension in multiple sclerosis.
The comparative effectiveness of fingolimod versus interferon beta/glatiramer acetate was assessed in a multicentre, observational, prospectively acquired cohort study including 613 patients with relapsing multiple sclerosis discontinuing natalizumab in the Italian iMedWeb registry. First, after natalizumab suspension, the relapse risk during the untreated wash-out period and during the course of switch therapies was estimated through Poisson regression analyses in separated models. During the wash-out period an increased risk of relapses was found in patients with a higher number of relapses before natalizumab treatment (incidence rate ratio = 1.31, P = 0.0014) and in patients discontinuing natalizumab due to lack of efficacy (incidence rate ratio = 2.33, P = 0.0288), patient's choice (incidence rate ratio = 2.18, P = 0.0064) and adverse events (incidence rate ratio = 2.09, P = 0.0084). The strongest independent factors influencing the relapse risk after the start of switch therapies were a wash-out duration longer than 3 months (incidence rate ratio = 1.78, P < 0.0001), the number of relapses experienced during and before natalizumab treatment (incidence rate ratio = 1.61, P < 0.0001; incidence rate ratio = 1.13, P = 0.0118, respectively) and the presence of comorbidities (incidence rate ratio = 1.4, P = 0.0097). Switching to fingolimod was associated with a 64% reduction of the adjusted-risk for relapse in comparison with switching to interferon beta/glatiramer acetate (incidence rate ratio = 0.36, P < 0.0001). Secondly, patients who switched to fingolimod or to interferon beta/glatiramer acetate were propensity score-matched on a 1-to-1 basis at the switching date. In the propensity score-matched sample a Poisson model showed a significant lower incidence of relapses in patients treated with fingolimod in comparison with those treated with interferon beta/glatiramer acetate (incidence rate ratio = 0.52, P = 0.0003) during a 12-month follow-up. The cumulative probability of a first relapse after the treatment switch was significantly lower in patients receiving fingolimod than in those receiving interferon beta/glatiramer acetate (P = 0.028). The robustness of this result was also confirmed by sensitivity analyses in subgroups with different wash-out durations (less or more than 3 months). Time to 3-month confirmed disability progression was not significantly different between the two groups (Hazard ratio = 0.58; P = 0.1931). Our results indicate a superiority of fingolimod in comparison to interferon beta/glatiramer acetate in controlling disease reactivation after natalizumab discontinuation in the real life setting.


Mitochondrial ion channels in cardiac function and dysfunction.
The study of mitochondrial physiology continues to provide new and surprising insights into how this organelle participates in the integration of cellular activities, far beyond the traditional view of the mitochondrion in energy transduction. Emerging evidence indicates that mitochondria are a centre of organization of numerous signalling pathways and are a cellular target that undergoes vast modification during both the acute and chronic phases of disease development and ageing. In this context, it is also important to understand the spatial and temporal organization of mitochondrial function and how this might influence the cell's response to stress. Here, we present evidence supporting the hypothesis that mitochondria from heart cells act as a network of coupled oscillators, capable of producing frequency- and/or amplitude-encoded reactive oxygen species (ROS) signals under physiological conditions. This intrinsic property of the mitochondria can lead to a mitochondrial 'critical' state, i.e. an emergent macroscopic response manifested as complete collapse or synchronized oscillation in the mitochondrial network under stress. The large amplitude depolarizations of deltapsi(m) and bursts of ROS have widespread effects on all subsystems of the cell including energy-sensitive ion channels in the plasma membrane, producing an effect that scales to cause organ level electrical and contractile dysfunction. Mitochondrial ion channels appear to play a key role in the mechanism of this non-linear network phenomenon and hence are an important target for potential therapeutic intervention.


Distribution of ghrelin-producing cells in stomach and the effects of ghrelin administration in the house musk shrew (Suncus murinus).
To investigate the distribution of ghrelin, an important appetite regulatory factor related to obesity, in the stomach of Suncus murinus, and attempted to elucidate the ghrelin-mediated regulatory effect in this animal. The stomachs of Suncus murinus were divided into 5 sections, cardia, fundus, greater curvature, lesser curvature, and pylorus, for investigating the ghrelin-producing cells by immunohistochemistry and Western blotting. Then Suncus murinus were randomized into two groups with ghrelin intraperitoneal injection (ghrelin-ip group) and saline intraperitoneal injection (control group), respectively. The effects of food intake and body weight were measured, and furthermore, the distribution of ghrelin in stomach was also investigated by immunohistochemistry and Western blotting. The immunolocalization and protein levels of ghrelin differed significantly in different regions of the stomach of Suncus murinus. Furthermore, ghrelin administration did not change the rate of food intake, but resulted in an increase in body weight compared with the control group. In this study, we elucidated the distribution of ghrelin-producing cells in the stomach of Suncus murinus in detail for the first time. Ghrelin intraperitoneal administration was found to induce an increase in body weight without changing food intake in this species. Our study implied ghrelin showed a different regulatory function in Suncus murinus from other species. It is considered that ghrelin may be associated with obesity-resistance phenomenon in Suncus murinus.


High-throughput proteomics using antibody microarrays: an update.
Antibody-based microarrays are a rapidly emerging technology that has advanced from the first proof-of-concept studies to demanding serum protein profiling applications during recent years, displaying great promise within disease proteomics. Miniaturized micro- and nanoarrays can be fabricated with an almost infinite number of antibodies carrying the desired specificities. While consuming only minute amounts of reagents, multiplexed and ultrasensitive assays can be performed targeting high- as well as low-abundance analytes in complex nonfractionated proteomes. The microarray images generated can then be converted into protein expression profiles or protein atlases, revealing a detailed composition of the sample. The technology will provide unique opportunities for fields such as disease diagnostics, biomarker discovery, patient stratification, predicting disease recurrence and drug target discovery. This review describes an update of high-throughput proteomics, using antibody-based microarrays, focusing on key technological advances and novel applications that have emerged over the last 3 years.


Thrombotic microangiopathy associated with synthetic cannabinoid receptor agonists.
Marijuana is one of the most commonly used recreational drugs in the United States. As marijuana is illegal in the majority of countries, the use of readily available and unregulated synthetic cannabinoids (SCBs) has increased. Little is known about the potential adverse effects of SCBs especially in regards to their nephrotoxicity. Case reports of acute kidney injury (AKI) from acute tubular injury secondary to their use have been reported. However, the exact pathology, mechanism, and extent of renal injury remain unknown. We report the first case of biopsy proven thrombotic microangiopathy (TMA) associated with SCBs resulting in AKI. The patient suffered significant morbidity with loss of renal function eventually requiring renal replacement therapy.


The specific content of core beliefs and schema in adolescent girls high and low in eating disorder symptoms.
The specific content of core beliefs and schema in adolescent girls high and low in eating disorder symptoms was investigated using the Eating Disorder Belief Questionnaire (EDBQ)-negative self-beliefs sub-scale and Young Schema Questionnaire (YSQ). Girls with high Eating Attitude Test (EAT) scores had higher scores on both measures (using total and sub-scale scores) than girls with low EAT scores. However, all scores were related to eating disorder as well as depressive symptoms. Analysis of individual items on the EDBQ and YSQ found that scores on all EDBQ, but not all YSQ items, differed between the two groups, with higher scores in the high EAT group. However, a number of individual items (on both measures) in the high EAT group, as well as in the low EAT group, were related specifically to eating disorder symptoms and not also to depressive symptoms.


Comparison of the binding of 3-fluoromethyl-7-sulfonyl-1,2,3,4-tetrahydroisoquinolines with their isosteric sulfonamides to the active site of phenylethanolamine N-methyltransferase.
3-Fluoromethyl-7-(N-substituted aminosulfonyl)-1,2,3,4-tetrahydroisoquinolines (14, 16, and 18-22) are highly potent and selective inhibitors of phenylethanolamine N-methyltransferase (PNMT). Molecular modeling studies with 3-fluoromethyl-7-(N-alkyl aminosulfonyl)-1,2,3,4-tetrahydroisoquinolines, such as 16, suggested that the sulfonamide -NH- could form a hydrogen bond with the side chain of Lys57. However, SAR studies and analysis of the crystal structure of human PNMT (hPNMT) in complex with 7 indicated that the sulfonamide oxygens, and not the sulfonamide -NH-, formed favorable interactions with the enzyme. Thus, we hypothesized that replacement of the sulfonamide -NH- with a methylene group could result in compounds that would retain potency at PNMT and that would have increased lipophilicity, thus increasing the likelihood they will cross the blood brain barrier. A series of 3-fluoromethyl-7-sulfonyl-1,2,3,4-tetrahydroisoquinolines (23-30) were synthesized and evaluated for their PNMT inhibitory potency and affinity for the alpha2-adrenoceptor. A comparison of these compounds with their isosteric sulfonamides (14, 16, and 18-22) showed that the sulfones were more lipophilic but less potent than their corresponding sulfonamides. Sulfone 24 (hPNMT Ki = 1.3 microM) is the most potent compound in this series and is quite selective for PNMT versus the alpha2-adrenoceptor, but 24 is less potent than the corresponding sulfonamide, 16 (hPNMT Ki = 0.13 microM). We also report the crystal structure of hPNMT in complex with sulfonamide 15, from which a potential hydrogen bond acceptor within the hPNMT active site has been identified, the main chain carbonyl oxygen of Asn39. The interaction of this residue with the sulfonamide -NH- is likely responsible for much of the enhanced inhibitory potency of the sulfonamides versus the sulfones.


New insights into structural determinants of prion protein folding and stability.
Prions are the etiological agent of fatal neurodegenerative diseases called prion diseases or transmissible spongiform encephalopathies. These maladies can be sporadic, genetic or infectious disorders. Prions are due to post-translational modifications of the cellular prion protein leading to the formation of a β-sheet enriched conformer with altered biochemical properties. The molecular events causing prion formation in sporadic prion diseases are still elusive. Recently, we published a research elucidating the contribution of major structural determinants and environmental factors in prion protein folding and stability. Our study highlighted the crucial role of octarepeats in stabilizing prion protein; the presence of a highly enthalpically stable intermediate state in prion-susceptible species; and the role of disulfide bridge in preserving native fold thus avoiding the misfolding to a β-sheet enriched isoform. Taking advantage from these findings, in this work we present new insights into structural determinants of prion protein folding and stability.


The MACADAM database: a MetAboliC pAthways DAtabase for Microbial taxonomic groups for mining potential metabolic capacities of archaeal and bacterial taxonomic groups.
Progress in genome sequencing and bioinformatics opens up new possibilities, including that of correlating genome annotations with functional information such as metabolic pathways. Thanks to the development of functional annotation databases, scientists are able to link genome annotations with functional annotations. We present MetAboliC pAthways DAtabase for Microbial taxonomic groups (MACADAM) here, a user-friendly database that makes it possible to find presence/absence/completeness statistics for metabolic pathways at a given microbial taxonomic position. For each prokaryotic 'RefSeq complete genome', MACADAM builds a pathway genome database (PGDB) using Pathway Tools software based on MetaCyc data that includes metabolic pathways as well as associated metabolites, reactions and enzymes. To ensure the highest quality of the genome functional annotation data, MACADAM also contains MicroCyc, a manually curated collection of PGDBs; Functional Annotation of Prokaryotic Taxa (FAPROTAX), a manually curated functional annotation database; and the IJSEM phenotypic database. The MACADAM database contains 13 509 PGDBs (13 195 bacterial and 314 archaeal), 1260 unique metabolic pathways, completed with 82 functional annotations from FAPROTAX and 16 from the IJSEM phenotypic database. MACADAM contains a total of 7921 metabolites, 592 enzymatic reactions, 2134 EC numbers and 7440 enzymes. MACADAM can be queried at any rank of the NCBI taxonomy (from phyla to species). It provides the possibility to explore functional information completed with metabolites, enzymes, enzymatic reactions and EC numbers. MACADAM returns a tabulated file containing a list of pathways with two scores (pathway score and pathway frequency score) that are present in the queried taxa. The file also contains the names of the organisms in which the pathways are found and the metabolic hierarchy associated with the pathways. Finally, MACADAM can be downloaded as a single file and queried with SQLite or python command lines or explored through a web interface.


Topographical risk factor analysis of new neurological deficits following precentral gyrus resection.
Precentral gyrus resections (PGRs) have been regarded as excessively hazardous interventions because of the risk of postoperative major neurological complications. To evaluate the neurological deterioration that follows PGRs and to assess the topographical risk factors associated with these morbidities. We reviewed 33 consecutive patients who experienced pharmacologically intractable epilepsy and underwent PGR with intraoperative cortical stimulation and mapping while under awake anesthesia. The etiological diagnoses were brain neoplasm in 26 patients (78.8%), cortical lesion in 4 (12.1%), and no lesion in 3 (9.1%). The mean follow-up period was 62.6 months (range, 12-146 months). All topographical analyses of the resected quadrant area were performed based on postoperative magnetic resonance images. After PGR, 22 patients (66.7%) experienced neurological worsening, including 5 permanent deficits (15.2%) and 17 transient deficits (51.5%). Permanent deficits included 2 instances of weakness, 1 dysarthria, 1 dysesthesia, and 1 fine-movement disturbance of the hand. While the neurological risk for anterior lower quadrant PGR was 20.0% (1/5), the risk for posterior upper quadrant PGR was 100.0% (10/10). The anterior upper and posterior lower quadrant PGR caused neurological deteriorations in 60.0% (6/10) and 62.5% (5/8) of the patients, respectively. In a multivariate analysis, PGR of the posterior and upper quadrant sections were significant risk factors for post-PGR neurological deteriorations (P = .022 and 0.030, respectively). The posterior upper quadrant of the precentral gyrus was vulnerable to post-resective neurological impairment.


Antibiotic treatment of infections caused by carbapenem-resistant Gram-negative bacilli: an international ESCMID cross-sectional survey among infectious diseases specialists practicing in large hospitals.
To explore contemporary antibiotic management of infections caused by carbapenem-resistant Gram-negative bacteria in hospitals. Cross-sectional, internet-based questionnaire survey. We contacted representatives of all hospitals with more than 800 acute-care hospital beds in France, Greece, Israel, Italy, Kosovo, Slovenia, Spain and selected hospitals in the USA. We asked respondents to describe the most common actual practice at their hospital regarding management of carbapenem-resistant Enterobacteriaceae, Acinetobacter baumannii and Pseudomonas aeruginosa through close-ended questions. Between January and June 2017, 115 of 141 eligible hospitals participated (overall response rate 81.6%, country-specific rates 66.7%-100%). Most were tertiary-care (99/114, 86.8%), university-affiliated (110/115, 89.1%) hospitals and most representatives were infectious disease specialists (99/115, 86.1%). Combination therapy was prescribed in 114/115 (99.1%) hospitals at least occasionally. Respondents were more likely to consider combination therapy when treating bacteraemia, pneumonia and central nervous system infections and for Enterobacteriaceae, P. aeruginosa and A. baumannii similarly. Combination of a polymyxin with a carbapenem was used in most cases, whereas combinations of a polymyxin with tigecycline, an aminoglycoside, fosfomycin or rifampicin were also common. Monotherapy was used for treatment of complicated urinary tract infections, usually with an aminoglycoside or a polymyxin. The intended goal of combination therapy was to improve the effectiveness of the treatment and to prevent development of resistance. In general, respondents shared the misconception that combination therapy is supported by strong scientific evidence. Combination therapy was the preferred treatment strategy for infections caused by carbapenem-resistant Gram-negative bacteria among hospital representatives, even though high-quality evidence for carbapenem-based combination therapy is lacking.


Epilepsy-related long-term amnesia: anatomical perspectives.
There are few clues as to the neural basis of selective long-term amnesia. We report group and single-case data to shed light on this issue. In a group study of patients with transient epileptic amnesia, there were no significant correlations between volumetric measures of the hippocampus and indices of accelerated long-term forgetting or longer-term autobiographical memory loss. Post-mortem investigations in a patient with temporal lobe epilepsy who showed accelerated long-term forgetting, together with a degree of autobiographical memory loss, yielded evidence of neuronal loss and gliosis in regions of both the right and the left hippocampus. Neuronal loss and gliosis were more evident in anterior than posterior hippocampus. These results indicate that the unusual forms of long-term forgetting seen in some patients with temporal lobe epilepsy have no gross anatomical correlate. The findings leave open the possibilities that subtle structural damage or subtle functional disturbance, perhaps in the form of subclinical epileptiform activity, underly epilepsy-related long-term amnesia.


Inhibition of microvesiculation sensitizes prostate cancer cells to chemotherapy and reduces docetaxel dose required to limit tumor growth in vivo.
Microvesicles shed from cells carry constituents of the cell cytoplasm, including, of importance in multidrug resistance to cancer chemotherapy, drugs that the tumor cell attempts to efflux. To see whether such drugs could be used at lower concentrations with the same efficacy, it was first shown that microvesiculation of prostate cancer (PCa) cells, PC3, could be inhibited pharmacologically with calpeptin (calpain inhibitor) and by siRNA (CAPNS1). In cells treated with docetaxel (DTX), this inhibition resulted in a third-fold increase in intracellular concentrations of DTX. As a result, 20-fold lower concentrations of DTX (5 nM) could be used, in the presence of calpeptin (20 μM) inducing the same degree of apoptosis after 48 h in PC3 cells, as 100 nM of DTX alone. Inhibition of microvesiculation similarly improved combination chemotherapy (DTX and methotrexate). In a mouse xenograft model of PCa, DTX (0.1 mg/kg) together with calpeptin (10 mg/kg), administered i.p., significantly reduced tumor volumes compared to DTX alone (0.1 mg/kg) and brought about the same reductions in tumor growth as 10 mg/kg of DTX alone. As well as further reducing vascularization, it also increased apoptosis and reduced proliferation of PC3 cells in tumor xenografts.


The vitamin D sterol-vitamin D receptor ensemble model offers unique insights into both genomic and rapid-response signaling.
Steroid hormones serve as chemical messengers in a wide number of species and target tissues by transmitting signals that result in both genomic and nongenomic responses. Genomic responses are mediated by the formation of a ligand-receptor complex with its cognate steroid hormone nuclear receptor (NR). Nongenomic responses can be mediated at the plasma membrane by a membrane-localized NR. The focus of this Review is on the structural attributes and molecular mechanisms underlying vitamin D sterol (VDS)-vitamin D receptor (VDR) selective and stereospecific regulation of nongenomic and genomic signaling. The VDS-VDR conformational ensemble model describes how VDSs can selectively initiate or block either nongenomic or genomic biological responses by interacting with two VDR ligand-binding pockets, one kinetically favored by 1alpha,25(OH)(2)D(3) (1,25D) and the other thermodynamically favored. We describe the variables that affect the three major elements of the model: the conformational flexibility of the unliganded (apo) protein, the flexibility of the VDS, and the physicochemical selectivity of the VDR genomic pocket (VDR-GP) and alternative pocket (VDR-AP). We also discuss how these three factors collectively provide a rational explanation for the complexities of VDS regulation of cell biology and highlight the current limitations of the model.


Deriving literature-based benchmarks for surgical complications in high-income countries: a protocol for a systematic review and meta-analysis.
To improve surgical safety, health systems must identify preventable adverse outcomes and measure changes in these outcomes in response to quality improvement initiatives. This requires understanding of the scope and limitations of available population-level data. To derive literature-based summary estimates of benchmarks of care, we will systematically review and meta-analyse rates of postoperative complications associated with several common and/or high-risk operations performed in five high-income countries (HICs). An electronic search of PubMed, Embase, Web of Science, Cochrane Central, the NHS Economic Evaluations Database and Health Technology Assessment database will be performed to identify studies reviewing national surgical complication rates between 2000 and 2016. Two reviewers will screen titles and abstracts and full texts of potentially relevant studies to determine eligibility for inclusion in the systematic review. We will include English-language publications using data from health databases in the USA, Canada, the UK, Australia and New Zealand. We will include studies of patients who underwent hip or knee arthoplasty, appendectomy, cholecystectomy, oesophagectomy, abdominal aortic aneurysm repair, aortic valve replacement or coronary artery bypass graft. Outcomes will include mortality, length of hospital stay, pulmonary embolism, pneumonia, sepsis or septic shock, reoperation, surgical site infection, wound dehiscence/disruption, blood transfusion, bile duct injury, stroke and myocardial infarction. We will calculate summary estimates of cumulative incidence, incidence rate, prevalence and occurrence rate of complications using DerSimonian and Laird random effects models. Heterogeneity in these estimates will be examined using subgroup analyses and meta-regression. We will correlate findings within contemporary clinical databases. This study of secondary data does not require ethics approval. It will be presented internationally and published in the peer-reviewed literature. Results will inform a future quality improvement tool and provide benchmarks of surgical complication rates within HICs. International Prospective Register of Systematic Reviews (PROSPERO). Registration number CRD42016037519.


Prediction of sudden cardiac death in Japanese heart failure patients: international validation of the Seattle Proportional Risk Model.
Heart failure (HF) is associated with an increased risk of sudden cardiac death (SCD). This study sought to demonstrate the incidence of SCD within a multicentre Japanese registry of HF patients hospitalized for acute decompensation, and externally validate the Seattle Proportional Risk Model (SPRM). We consecutively registered 2240 acute HF patients from academic institutions in Tokyo, Japan. The discrimination and calibration of the SPRM were assessed by the c-statistic, Hosmer-Lemeshow statistic, and visual plotting among non-survivors. Patient-level SPRM predictions and implantable cardioverter-defibrillator (ICD) benefit [ICD estimated hazard ratio (HR), derived from the Cox proportional hazards model in the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT)] was calculated. During the 2-year follow-up, 356 deaths (15.9%) occurred, which included 76 adjudicated SCDs (3.4%) and 280 non-SCDs (12.5%). The SPRM showed acceptable discrimination [c-index = 0.63; 95% confidence interval (CI) 0.56-0.70], similar to that of original SPRM-derivation cohort. The calibration plot showed reasonable conformance. Among HF patients with reduced ejection fraction (EF; < 40%), SPRM showed improved discrimination compared with the ICD eligibility criteria (e.g. New York Heart Association functional Class II-III with EF ≤ 35%): c-index = 0.53 (95% CI 0.42-0.63) vs. 0.65 (95% CI 0.55-0.75) for SPRM. Finally, in the subgroup of 246 patients with both EF ≤ 35% and SPRM-predicted risk of ≥ 42.0% (SCD-HeFT defined ICD benefit threshold), mean ICD estimated HR was 0.70 (30% reduction of all-cause mortality by ICD). The cumulative incidence of SCD was 3.4% in Japanese HF registry. The SPRM performed reasonably well in Japanese patients and may aid in improving SCD prediction.


Parity and hypertension.
Among the many physiological factors which have been hypothesized as associated with elevated blood pressure levels and increased incidence of hypertension, the possible effect of pregnancy in the production of these conditions has proven to be among the more elusive to quantitate and evaluate. At the same time, the possible association is among the more interesting from an epidemiological standpoint, not only because of the importance of the primal question of whether or not pregnancy is a factor in the etiology of hypertension, but also because of the component parts represented by those pregnancies complicated by preeclampsia. Age is considered by many observers to be an important factor in the production of residual hypertension, and the statistical association of age with increased blood pressure levels is probably the most pronounced and easily demonstrated phenomenon observable in any study population. A moderate decline in average diastolic blood pressure among the general population after age 55 is an exception to this, and is less frequently evaluated. Body measurements, race, and several other variables may be cited as also being correlated with blood pressure levels, however, their effect is much less significant than that observable for age.


Late reposition of a lateral luxated maxillary incisor with an immature apex.
Here we describe an unusual trauma case. A recently erupted permanent upper-right incisor sustained a lateral luxation when a 5-year-old girl on a playground climbing net dropped off, catching the right upper incisor in the net. The tooth was laterally luxated in vestibular direction, and no other signs of injury occurred. A dental practitioner could not reposition the bony locked tooth. Four days later, the girl came to our clinic, and we performed an incomplete repositioning of the tooth and made a flexible splint. Controls were made at 1, 6, and 12 weeks and at 6, 12, 18, and 24 months later. The 24-month follow-up clinical examination revealed the patient to be asymptomatic and the tooth to be completely functional, and the recall radiograph showed further apical root growth. The implications of a late incomplete reposition of laterally luxated permanent teeth with immature apices are discussed.


Comparison of a Traditional and Novel Evoked Compound Action Potentials Recording Approach and Evoked Auditory Brainstem Responses in Pediatric Cochlear Implants Users.
Electrically evoked compound action potentials (eCAP) recordings are widely used in functional evaluation and fitting of cochlear implants (CI) in clinics. We compared the results from two eCAP recording approaches (StandardART and FineGrain, MED-EL, Austria). The FineGrain method is more advanced than the Auditory Nerve Response Telemetry (StandardART) method in terms of the stimulation and algorithm for the eCAP threshold detection. To understand the benefits of these alterations, we compared the two methods on a larger scale in pediatric CI users alongside evoked auditory brainstem responses (eABR). We collected the eCAP recordings obtained with both methods from a population of pediatric subjects with CI, either intra- or post-operatively. The eABR recordings were only collected post-operatively. For comparability reasons, we used the same stimulation rate and similar amplitude levels for all three approaches. Our results demonstrate that, although the success rates are similar, the FineGrain method outperforms traditional StandardART in terms of robustness and measurement duration. The eCAP recordings in general outperform the eABR in terms of speed. We conclude that the eCAP recordings are the method of choice for measuring the auditory neural activity, and FineGrain outperforms StandardART. From the three investigated approaches, we conclude that FineGrain performed best and should be the first-choice method in pediatric patients.


Mining complex genotypic features for predicting HIV-1 drug resistance.
Human immunodeficiency virus type 1 (HIV-1) evolves in human body, and its exposure to a drug often causes mutations that enhance the resistance against the drug. To design an effective pharmacotherapy for an individual patient, it is important to accurately predict the drug resistance based on genotype data. Notably, the resistance is not just the simple sum of the effects of all mutations. Structural biological studies suggest that the association of mutations is crucial: even if mutations A or B alone do not affect the resistance, a significant change might happen when the two mutations occur together. Linear regression methods cannot take the associations into account, while decision tree methods can reveal only limited associations. Kernel methods and neural networks implicitly use all possible associations for prediction, but cannot select salient associations explicitly. Our method, itemset boosting, performs linear regression in the complete space of power sets of mutations. It implements a forward feature selection procedure where, in each iteration, one mutation combination is found by an efficient branch-and-bound search. This method uses all possible combinations, and salient associations are explicitly shown. In experiments, our method worked particularly well for predicting the resistance of nucleotide reverse transcriptase inhibitors (NRTIs). Furthermore, it successfully recovered many mutation associations known in biological literature. http://www.kyb.mpg.de/bs/people/hiroto/iboost/. Supplementary data are available at Bioinformatics online.


Treatment of cancer pain.
In patients with active cancer, the management of chronic pain is an essential element in a comprehensive strategy for palliative care. This strategy emphasises multidimensional assessment and the coordinated use of treatments that together mitigate suffering and provide support to the patient and family. This review describes this framework, an approach to pain assessment, and widely accepted techniques to optimise the safety and effectiveness of opioid drugs and other treatments. The advances of recent decades suggest a future that includes increased evidence-based targeting of specific analgesic interventions within an individualised plan of care that is appropriate throughout the course of illness.


Critical incident monitoring in paediatric and adult critical care: from reporting to improved patient outcomes?
Critical incident reporting alone does not necessarily improve patient safety or even patient outcomes. Substantial improvement has been made by focusing on the further two steps of critical incident monitoring, that is, the analysis of critical incidents and implementation of system changes. The system approach to patient safety had an impact on the view about the patient's role in safety. This review aims to analyse recent advances in the technique of reporting, the analysis of reported incidents, and the implementation of actual system improvements. It also explores how families should be approached about safety issues. It is essential to make as many critical incidents as possible known to the intensive care team. Several factors have been shown to increase the reporting rate: anonymity, regular feedback about the errors reported, and the existence of a safety climate. Risk scoring of critical incident reports and root cause analysis may help in the analysis of incidents. Research suggests that patients can be successfully involved in safety. A persisting high number of reported incidents is anticipated and regarded as continuing good safety culture. However, only the implementation of system changes, based on incident reports, and also involving the expertise of patients and their families, has the potential to improve patient outcome. Hard outcome criteria, such as standardized mortality ratio, have not yet been shown to improve as a result of critical incident monitoring.


Lack of association between smoking and DNA fragmentation in the spermatozoa of normal men.
Male factor infertility patients can have anomalies in their sperm nuclei, displaying high levels of loosely packaged chromatin and damaged DNA. The primary objectives of this study were to compare the extent of DNA fragmentation in the spermatozoa of healthy light and heavy smokers versus non-smokers, and to investigate its correlation with concentrations of the smoking markers cotinine and cadmium. A secondary objective was to compare the concentrations of blood cadmium and serum cotinine with corresponding concentrations in seminal plasma. Ninety-seven healthy male volunteers were divided into three groups: non-smokers, light and heavy smokers. There was no difference between the three groups with respect to age, number of ejaculations per week, serum testosterone concentration, and parameters of semen analysis. The percentages of DNA fragmentation in spermatozoa were not statistically different in the heavy smokers (12.11%), light smokers (11.66%) and non-smokers (20.41%). Serum and seminal plasma concentrations of cotinine were significantly higher in heavy smokers compared with the other groups (P < 0.0001). Median values for blood cadmium concentration were higher in heavy smokers (4.50 microg/l) than in light smokers (0.20 microg/l) and non-smokers (0.20 microg/l) (P < 0.001). Cadmium concentration in seminal plasma was significantly higher in heavy smokers (0.20 microg/l) than in light smokers (0.10 microg/l) and non-smokers (0. 10 microg/l) (P < 0.05). In summary, our results indicate no association between smoking and DNA fragmentation in the spermatozoa of healthy men.


Effect of emulsifiers and their liquid crystalline structures in emulsions on dermal and transdermal delivery of hydroquinone, salicylic acid and octadecenedioic acid.
This study investigated the effect of emulsifiers and their liquid crystalline structures on the dermal and transdermal delivery of hydroquinone (HQ), salicylic acid (SA) and octadecenedioic acid (DIOIC). Emulsions containing liquid crystalline phases were compared with an emulsion without liquid crystals. Skin permeation experiments were performed using Franz-type diffusion cells and human abdominal skin dermatomed to a thickness of 400 mum. The results indicate that emulsifiers arranging in liquid crystalline structures in the water phase of the emulsion enhanced the skin penetration of the active ingredients with the exception of SA. SA showed a different pattern of percutaneous absorption, and no difference in dermal and transdermal delivery was observed between the emulsions with and without liquid crystalline phases. The increase in skin penetration of HQ and DIOIC could be attributed to an increased partitioning of the actives into the skin. It was hypothesized that the interaction between the different emulsifiers and active ingredients in the formulations varied and, therefore, the solubilization capacities of the various emulsifiers and their association structures.


Competitiveness measurement system in the advertising sector.
In this paper a new approach to find indicators that can be used to measure companies' competitiveness and performance in an efficient and reliable way is presented. The aim is to assist managers of companies within a specific industrial sector by providing information about their relative position in the market so as to define better action plans that may improve the company's performance. The approach combines the use of the Analytic Network Process, a multicriteria decision method, with the Balanced Scorecard. It allows the definition of a number of competitiveness indicators based on the performance and setting of the advertising sector. In this way it is possible to obtain a Competitiveness Index that allows a company to know its relative position with respect to other companies in the sector, and establish a ranking of the companies ordered by their competitiveness level. A case study in the advertising industry of Venezuela is provided. Results show that improvement plans for the agencies analyzed should promote creativity, innovation and the use of new technologies, as a particular form of innovation. These factors were considered to be the most relevant indicators in the advertising sector. The participating experts agreed that the methodology is useful and an improvement over current competitiveness assessment methods.


The Lys-Asp-Tyr Triad within the Mite Allergen Der p 1 Propeptide Is a Critical Structural Element for the pH-Dependent Initiation of the Protease Maturation.
The major house dust mite allergen, Der p 1, is a papain-like cysteine protease expressed as an inactive precursor, proDer p 1, carrying an N-terminal propeptide with a unique structure. The maturation of the zymogen into an enzymatically-active form of Der p 1 is a multistep autocatalytic process initiated under acidic conditions through conformational changes of the propeptide, leading to the loss of its inhibitory ability and its subsequent gradual cleavage. The aims of this study were to characterize the residues present in the Der p 1 propeptide involved in the initiation of the zymogen maturation process, but also to assess the impact of acidic pH on the propeptide structure, the activity of Der p 1 and the fate of the propeptide. Using various complementary enzymatic and structural approaches, we demonstrated that a structural triad K17p-D51p-Y19p within the N-terminal domain of the propeptide is essential for its stabilization and the sensing of pH changes. Particularly, the protonation of D51p under acidic conditions unfolds the propeptide through disruption of the K17p-D51p salt bridge, reduces its inhibition capacity and unmasks the buried residues K17p and Y19p constituting the first maturation cleavage site of the zymogen. Our results also evidenced that this triad acts in a cooperative manner with other propeptide pH-responsive elements, including residues E56p and E80p, to promote the propeptide unfolding and/or to facilitate its proteolysis. Furthermore, we showed that acidic conditions modify Der p 1 proteolytic specificity and confirmed that the formation of the first intermediate represents the limiting step of the in vitro Der p 1 maturation process. Altogether, our results provide new insights into the early events of the mechanism of proDer p 1 maturation and identify a unique structural triad acting as a stabilizing and a pH-sensing regulatory element.


Tenascin-C inhibits extracellular matrix-dependent gene expression in mammary epithelial cells. Localization of active regions using recombinant tenascin fragments.
The physiological role of tenascin in vivo has remained obscure. Although tenascin is regulated in a stage and tissue-dependent manner, knock-out mice appear normal. When tenascin expression was examined in the normal adult mouse mammary gland, little or none was present during lactation, when epithelial cells actively synthesize and secrete milk proteins in an extracellular matrix/lactogenic hormone-dependent manner. In contrast, tenascin was prominently expressed during involution, a stage characterized by the degradation of the extracellular matrix and the subsequent loss of milk production. Studies with mammary cell lines indicated that tenascin expression was high on plastic, but was suppressed in the presence of the laminin-rich, Engelbreth-Holm-Swarm (EHS) tumour biomatrix. When exogenous tenascin was added together with EHS to mammary epithelial cells, beta-casein protein synthesis and steady-state mRNA levels were inhibited in a concentration-dependent manner. Moreover, this inhibition by tenascin could be segregated from its effects on cell morphology. Using two beta-casein promoter constructs attached to the chloramphenicol acetyltransferase reporter gene we showed that tenascin selectively suppressed extracellular matrix/prolactin-dependent transcription of the beta-casein gene in three-dimensional cultures. Finally, we mapped the active regions within the fibronectin type III repeat region of the tenascin molecule that are capable of inhibiting beta-casein protein synthesis. Our data are consistent with a model where both the loss of a laminin-rich basement membrane by extracellular matrix-degrading enzymes and the induction of tenascin contribute to the loss of tissue-specific gene expression and thus the involuting process.


Remotely tunable microfluidic platform driven by nanomaterial-mediated on-demand photothermal pumping.
The requirement of on-demand microfluidic pumps and instrument-free readout methods remains a major challenge for the development of microfluidics. Herein, a new type of microfluidic platform, an on-demand photothermal microfluidic pumping platform, has been developed using an on-chip nanomaterial-mediated photothermal effect as novel and remotely tunable microfluidic driving force. The photothermal microfluidic pumping performance can be adjusted remotely by tuning the irradiation parameters, without changing on-chip parameters or replacing enzymes or other reagents. In contrast to graphene oxide, Prussian blue nanoparticles with higher photothermal conversion efficiency were used as the model photothermal agent to demonstrate the proof of concept. The on-chip pumping distance is linearly correlated with both the irradiation time and the nanomaterial concentration. The applications of photothermal microfluidic pumping have been demonstrated in multiplexed on-chip transport of substances, such as gold nanoparticles, and visual quantitative bar-chart detection of cancer biomarkers without using specialized instruments. Upon contact-free irradiation using a laser pointer, a strong on-chip nanomaterial-mediated photothermal effect can serve as a robust and remotely tunable microfluidic pump in a PMMA/PDMS hybrid bar-chart chip to drive ink bars in a visual quantitative readout fashion. This is the first report on a photothermal microfluidic pumping platform, which has great potential for various microfluidic applications.


Mental models accurately predict emotion transitions.
Successful social interactions depend on people's ability to predict others' future actions and emotions. People possess many mechanisms for perceiving others' current emotional states, but how might they use this information to predict others' future states? We hypothesized that people might capitalize on an overlooked aspect of affective experience: current emotions predict future emotions. By attending to regularities in emotion transitions, perceivers might develop accurate mental models of others' emotional dynamics. People could then use these mental models of emotion transitions to predict others' future emotions from currently observable emotions. To test this hypothesis, studies 1-3 used data from three extant experience-sampling datasets to establish the actual rates of emotional transitions. We then collected three parallel datasets in which participants rated the transition likelihoods between the same set of emotions. Participants' ratings of emotion transitions predicted others' experienced transitional likelihoods with high accuracy. Study 4 demonstrated that four conceptual dimensions of mental state representation-valence, social impact, rationality, and human mind-inform participants' mental models. Study 5 used 2 million emotion reports on the Experience Project to replicate both of these findings: again people reported accurate models of emotion transitions, and these models were informed by the same four conceptual dimensions. Importantly, neither these conceptual dimensions nor holistic similarity could fully explain participants' accuracy, suggesting that their mental models contain accurate information about emotion dynamics above and beyond what might be predicted by static emotion knowledge alone.


Silicone breast phantoms for elastographic imaging evaluation.
Breast cancer is a major public health issue for women, and early detection significantly increases survival rate. Currently, there is increased research interest in elastographic soft-tissue imaging techniques based on the correlation between pathology and mechanical stiffness. Anthropomorphic breast phantoms are critical for ex vivo validation of emerging elastographic technologies. This research develops heterogeneous breast phantoms for use in testing elastographic imaging modalities. Mechanical property estimation of eight different elastomers is performed to determine storage moduli (E') and damping ratios (ζ) using a dynamic mechanical analyzer. Dynamic compression testing was carried out isothermally at room temperature over a range of 4-50 Hz. Silicone compositions with physiologically realistic storage modulus were chosen for mimicking skin adipose, cancerous tumors, and pectoral muscles and 13 anthropomorphic breast phantoms were constructed for ex vivo trials of digital image elastotomography (DIET) breast cancer screening system. A simpler fabrication was used to assess the possibility of multiple tumor detection using magnetic resonance elastography (MRE). Silicone materials with ranges of storage moduli (E') from 2 to 570 kPa and damping ratios (ζ) from 0.03 to 0.56 were identified. The resulting phantoms were tested in two different elastographic breast cancer diagnostic modalities. A significant contrast was successfully identified between healthy tissues and cancerous tumors both in MRE and DIET. The phantoms presented promise aid to researchers in elastographic imaging modalities for breast cancer detection and provide a foundation for silicone based phantom materials for mimicking soft tissues of other human organs.


Boronic Acid-Functionalized Two-Dimensional MoS2 at Biointerfaces.
While noncovalent interactions at two-dimensional nanobiointerfaces are extensively investigated, less knowledge about covalent interactions at this interface is available. In this work, boronic acid-functionalized 2D MoS2 was synthesized and its covalent multivalent interactions with bacteria and nematodes were investigated. Polymerization of glycidol by freshly exfoliated MoS2 and condensation of 2,5-thiophenediylbisboronic acid on the produced platform resulted in boronic acid-functionalized 2D MoS2. The destructive interactions between 2D MoS2 and bacteria as well as nematodes were significantly amplified by boronic acid functional groups. Because of the high antibacterial and antinematodal activities of boronic acid-functionalized 2D MoS2, its therapeutic efficacy for diabetic wound healing was investigated. The infected diabetic wounds were completely healed 10 days after treatment with boronic acid-functionalized 2D MoS2, and a normal structure for recovered tissues including different layers of skin, collagen, and blood vessels was detected.


SPR phase detection for measuring the thickness of thin metal films.
In this paper, a novel method to determine the thickness of thin metal film is put forward which uses Surface Plasmon Resonance (SPR) phase detection method. The relations between the metal film thickness and the phases of the transverse magnetic (TM) and transverse electric (TE) polarization of the reflected light are shown in the simulation results. By recording the interference patterns which contain the information of the phase differences in the experiments, the values of thickness are calculated. Both of the theoretical analysis and experimental results indicate that the approach presented is feasible and reliable. Thus, it is possible to use the method of phase detection to determine the thickness of thin metal films within 100nm in SPR prism couplers directly with nanometer resolution.


Perceptions and Experiences of Integrated Service Delivery Among Women Living with HIV Attending Reproductive Health Services in Kenya: A Mixed Methods Study.
This is one of the few studies that explores preferences of and experiences with integrated sexual and reproductive health (SRH)-HIV care among users of mainstream family planning and postnatal care services who are women living with HIV (WLWH). This paper reports on the quantitative data from 179 clients attending public sector clinics and from 30 qualitative in-depth interviews with WLHIV in Kenya. Quantitative data show that integration is happening for the vast majority of these clients at their last HIV visit. However, qualitative data show that very often the care received by WLWH is fragmented as providers do not offer multiple same-day appointments for FP and ARV refills. Our study has shown factors that could either prevent or enable receipt of integrated SRH and HIV care for WLWH. To address these factors, management systems need to be able to support providers to make flexible decisions and facilitate better coordination and communication across clinics within facilities.


Medial unicompartmental knee arthroplasty in the ACL-deficient knee.
Symptomatic osteoarthritis (OA) of the knee develops often in association with anterior cruciate ligament (ACL) deficiency. Two distinct pathologies should be recognised while considering treatment options in patients with end-stage medial compartment OA and ACL deficiency. Patients with primary ACL deficiency (usually traumatic ACL rupture) can develop secondary OA (typically presenting with symptoms of instability and pain) and these patients are typically young and active. Patients with primary end stage medial compartment OA can develop secondary ACL deficiency (usually degenerate ACL rupture) and these patients tend to be older. Treatment options in either of these patient groups include arthroscopic debridement, reconstruction of the ACL, high tibial osteotomy (HTO) with or without ACL reconstruction, unicompartmental knee arthroplasty (UKA) and total knee arthroplasty (TKA). General opinion is that a functionally intact ACL is a fundamental prerequisite to perform a UKA. This is because previous reports showed higher failure rates when ACL was deficient, probably secondary to wear and tibial loosening. Nevertheless in some cases of ACL deficiency with end-stage medial compartment OA, UKA has been performed in isolation and recent papers confirm good short- to mid-term outcome without increased risk of implant failure. Shorter hospital stay, fewer blood transfusions, faster recovery and significantly lower risk of developing major complications like death, myocardial infarction, stroke, deep vein thrombosis (as compared to TKA) make the UKA an attractive option, especially in the older patients. On the other hand, younger patients with higher functional demands are likely to benefit from a simultaneous or staged ACL reconstruction in addition to UKA to regain knee stability. These procedures tend to be technically demanding. The main aim of this review was to provide a synopsis of the existing literature and outline an evidence-based treatment algorithm.


Direct control of shoot meristem activity by a cytokinin-activating enzyme.
The growth of plants depends on continuous function of the meristems. Shoot meristems are responsible for all the post-embryonic aerial organs, such as leaves, stems and flowers. It has been assumed that the phytohormone cytokinin has a positive role in shoot meristem function. A severe reduction in the size of meristems in a mutant that is defective in all of its cytokinin receptors has provided compelling evidence that cytokinin is required for meristem activity. Here, we report a novel regulation of meristem activity, which is executed by the meristem-specific activation of cytokinins. The LONELY GUY (LOG) gene of rice is required to maintain meristem activity and its loss of function causes premature termination of the shoot meristem. LOG encodes a novel cytokinin-activating enzyme that works in the final step of bioactive cytokinin synthesis. Revising the long-held idea of multistep reactions, LOG directly converts inactive cytokinin nucleotides to the free-base forms, which are biologically active, by its cytokinin-specific phosphoribohydrolase activity. LOG messenger RNA is specifically localized in shoot meristem tips, indicating the activation of cytokinins in a specific developmental domain. We propose the fine-tuning of concentrations and the spatial distribution of bioactive cytokinins by a cytokinin-activating enzyme as a mechanism that regulates meristem activity.


Functional analysis of RNA structures present at the 3' extremity of the murine norovirus genome: the variable polypyrimidine tract plays a role in viral virulence.
Interactions of host cell factors with RNA sequences and structures in the genomes of positive-strand RNA viruses play various roles in the life cycles of these viruses. Our understanding of the functional RNA elements present in norovirus genomes to date has been limited largely to in vitro analysis. However, we recently used reverse genetics to identify evolutionarily conserved RNA structures and sequences required for norovirus replication. We have now undertaken a more detailed analysis of RNA structures present at the 3' extremity of the murine norovirus (MNV) genome. Biochemical data indicate the presence of three stable stem-loops, including two in the untranslated region, and a single-stranded polypyrimidine tract [p(Y)] of variable length between MNV isolates, within the terminal stem-loop structure. The well-characterized host cell pyrimidine binding proteins PTB and PCBP bound the 3'-untranslated region via an interaction with this variable sequence. Viruses lacking the p(Y) tract were viable both in cell culture and upon mouse infection, demonstrating that this interaction was not essential for virus replication. However, competition analysis with wild-type MNV in cell culture indicated that the loss of the p(Y) tract was associated with a fitness cost. Furthermore, a p(Y)-deleted mutant showed a reduction in virulence in the STAT1(-/-) mouse model, highlighting the role of RNA structures in norovirus pathogenesis. This work highlights how, like with other positive-strand RNA viruses, RNA structures present at the termini of the norovirus genome play important roles in virus replication and virulence.


Cingulate gyrus epilepsy: semiology, invasive EEG, and surgical approaches.
The semiology of cingulate gyrus epilepsy is varied and may involve the paracentral area, the adjacent limbic system, and/or the orbitofrontal gyrus. Invasive electroencephalography (iEEG) recording is usually required for patients with deeply located epileptogenic foci. This paper reports on the authors' experiences in the diagnosis and surgical treatment of patients with focal epilepsy originating in the cingulate gyrus. Eighteen patients (median age 24 years, range 5-53 years) with a mean seizure history of 23 years (range 2-32 years) were analyzed retrospectively. The results of presurgical evaluation, surgical strategy, and postoperative pathology are reported, as well as follow-up concerning functional morbidity and seizures (median follow-up 7 years, range 2-12 years). Patients with cingulate gyrus epilepsy presented with a variety of semiologies and scalp EEG patterns. Prior to ictal onset, 11 (61%) of the patients presented with aura. Initial ictal symptoms included limb posturing in 12 (67%), vocalization in 5, and hypermotor movement in 4. In most patients (n = 16, 89%), ictal EEG presented as widespread patterns with bilateral hemispheric origin, as well as muscle artifacts obscuring the onset of EEG during the ictal period in 11 patients. Among the 18 patients who underwent resection, the pathology revealed mild malformation of cortical development in 2, focal cortical dysplasia (FCD) Ib in 4, FCD IIa in 4, FCD IIb in 4, astrocytoma in 1, ganglioglioma in 1, and gliosis in 2. The seizure outcome after surgery was satisfactory: Engel class IA in 12 patients, IIB in 3, IIIA in 1, IIIB in 1, and IVB in 1 at the 2-year follow-up. In this study, the authors exploited the improved access to the cingulate epileptogenic network made possible by the use of 3D electrodes implanted using stereoelectroencephalography methodology. Under iEEG recording and intraoperative neuromonitoring, epilepsy surgery on lesions in the cingulate gyrus can result in good outcomes in terms of seizure recurrence and the incidence of postoperative permanent deficits.


The MO15 gene encodes the catalytic subunit of a protein kinase that activates cdc2 and other cyclin-dependent kinases (CDKs) through phosphorylation of Thr161 and its homologues.
Phosphorylation of Thr161, a residue conserved in all members of the cdc2 family, has been reported to be absolutely required for the catalytic activity of cdc2, the major regulator of eukaryotic cell cycle. In the present work, we have purified from starfish oocytes a kinase that specifically activates cdc2 in a cyclin-dependent manner through phosphorylation of its Thr161 residue. Our most highly purified preparation contained only two major proteins of apparent M(r) 37 and 40 kDa (p37 and p40), which could not be separated from each other without loss of activity. The purified kinase was found to phosphorylate not only cdc2, but also cdk2 and a divergent cdc2-like protein from Caenorhabditis, in chimeric complexes including both mitotic and G1/S cyclins. Extensive microsequencing of p40 did not reveal any convincing homology with any known protein. In contrast, p37 is the starfish homologue of the M015 gene product, a kinase previously cloned by homology probing from a Xenopus cDNA library. As expected, immunodepletion of the MO15 protein depleted Xenopus egg extracts of CAK (cdk-activating kinase) activity, which was recovered in immunoprecipitates. Taken together, the above results demonstrate that MO15 is a gene conserved throughout evolution (at least from echinoderms to vertebrates) that encodes the catalytic subunit of a protein kinase that activates cdc2-cdks complexes through phosphorylation of Thr161 (or its homologues).


Quality Measures to Reduce Opioid Use After Common Soft Tissue Hand and Wrist Procedures.
To develop quality measures that are clinically important, feasible, usable, and scientifically acceptable for reducing opioid use after soft tissue procedures of the hand and wrist, and which can be used to evaluate quality in hand surgery. A consortium of 9 fellowship-trained hand/upper-limb surgeons with expertise in quality measure development used the RAND Corporation/University of California Los Angeles Delphi Appropriateness method to evaluate the validity of 2 quality measures for reducing opioid use, based on 4 quality indicators (clinical importance, feasibility, usability, and scientific acceptability). Panelists rated each measure on a scale of 1 (definitely not important/feasible/usable/supported) to 9 (definitely important/feasible/usable/supported) in 2 voting rounds with an intervening face-to-face discussion. Agreement was assessed using predetermined criteria. A measure was considered a valid quality measure if it received a median score of 7 or higher for all 4 indicators with no more than 2 panelists rating outside the range of 7 to 9. Panelists achieved agreement on the 4 quality indicators for measuring the proportion of patients undergoing carpal tunnel release, trigger finger release, first dorsal compartment release, or ganglion cyst excision who received structured counseling on opioid use. Panelists also achieved agreement on the 4 quality indicators for measuring the proportion of patients without recent opioid use who did not fill an opioid prescription within 30 days after these procedures. Both candidate quality measures were considered valid. Using a validated consensus-building approach, we developed process and outcome quality measures for reducing opioid use after soft tissue hand surgery that were demonstrated to be valid according to 4 quality indicators. In the era of value-based health care, hand surgeons are assuming increasing responsibility in the prevention of excess opioid prescribing. Quality measures for reducing opioid overprescription can help promote the delivery of evidence-based, high-quality care in hand surgery.


Targeted human papillomavirus vaccination of men who have sex with men in the USA: a cost-effectiveness modelling analysis.
A vaccine targeting human papillomavirus (HPV) types 16 and 18, which are associated with 80% of anal cancers, is efficacious in men. High-risk populations such as men who have sex with men (MSM) might especially benefit from vaccination. I aimed to estimate the cost-effectiveness of HPV vaccination of MSM in the USA. I constructed decision-analytic models to estimate the direct health and economic outcomes of HPV vaccination (against types 6, 11, 16, and 18) for prevention of HPV-related anal cancer and genital warts. The model parameters that were varied were age at vaccination (12 years, 20 years, and 26 years), previous exposure to vaccine-targeted HPV types, and prevalence of HIV-1. I used the models to conduct sensitivity analyses, including duration of vaccine protection, vaccine cost, and burden of anal cancer and genital warts. In a scenario of HPV vaccination of MSM at 12 years of age without previous exposure to HPV, compared with no vaccination, vaccination cost US$15,290 per quality-adjusted life-year gained. In scenarios where MSM are vaccinated at 20 years or 26 years of age, after exposure to HPV infections, the cost-effectiveness ratios worsened, but were less than $50,000 per quality-adjusted life-year under most scenarios. For example, HPV vaccination of MSM at 26 years cost $37,830 per quality-adjusted life-year when previous exposure to all vaccine-targeted HPV types was assumed to be 50%. Outcomes were most sensitive to variations in anal cancer incidence, duration of vaccine protection, and HIV prevalence in MSM. HPV vaccination of MSM is likely to be a cost-effective intervention for the prevention of genital warts and anal cancer. US National Cancer Institute.


Hospital-level variation in angina and mortality at 1 year after myocardial infarction: insights from the Translational Research Investigating Underlying Disparities in Acute Myocardial Infarction Patients' Health Status (TRIUMPH) Registry.
Despite calls to expand measurement of acute myocardial infarction (AMI) outcomes to include symptom burden, little has been done to describe hospital-level variation in this patient-centered outcome, or its association with mortality. Understanding the relationship between symptoms and longer-term mortality could inform the importance of these outcomes for monitoring quality of care. Among 4316 patients with AMI treated at 24 hospitals participating in the Translational Research Investigating Underlying Disparities in Acute Myocardial Infarction Patients' Health Status (TRIUMPH) study, we assessed risk-standardized 1-year symptom burden as measured by the Seattle Angina Questionnaire Angina Frequency Score and mortality attributed to the hospital that provided AMI care. Median odds ratios were used to assess outcome variation and reflect the relative odds of an outcome for 2 patients with identical covariates at different, randomly selected, hospitals. We then evaluated the correlation between hospital-level mortality and angina. Finally, we determined the extent to which variation in mortality and angina was explained by achievement of AMI performance measures. We observed hospital variation in risk-adjusted 1-year mortality (range, 4.9%-8.6%; median odds ratio, 1.30; P=0.01) and angina (range, 17.7%-29.4%; median odds ratio, 1.34; P<0.001). At the hospital level, mortality and angina at 1 year were weakly correlated (r=0.40; 95% confidence interval, 0.00-0.68; P=0.05). Accounting for the quality of AMI care did not attenuate variation in risk-adjusted 1-year mortality or angina. Symptom burden and mortality vary at the hospital level after AMI and are only weakly correlated. These findings suggest that symptom burden should be considered a separate quality domain that is not well captured by current quality metrics.


Luminal epidermal growth factor preserves mucosal mass of small bowel in fasting rats.
1. Fasting causes atrophy of small bowel mucosa which rapidly resolves with luminal feeding. This effect of enteral nutrient may be mediated by stimulation of growth factor secretion. We therefore evaluated whether luminal administration of epidermal growth factor, a peptide hormone found in gastro-intestinal contents and trophic for small bowel mucosa, would prevent the mucosal atrophy associated with starvation. 2. Adult rats were: (i) fasted for 3 days, (ii) fasted and then refed for 1 day or (iii) fasted and then refed for 2 days. During the 2 days before study, animals in each group received infusions of epidermal growth factor (2.5 micrograms/day) or diluent alone into distal jejunum. 3. Epidermal growth factor treatment of fasted animals resulted in a tripling of mucosal ornithine decarboxylase activity (P < 0.001) and a doubling of mucosal DNA content (P < 0.001) in the jejunum, values similar to those of refed animals. Epidermal growth factor infusion in refed rats resulted in a further doubling of mucosal ornithine decarboxylase activity (P < 0.001), but no additional increase in DNA content. Effects of epidermal growth factor infusion were generally greater in jejunum than ileum. 4. In conclusion, luminal exposure to epidermal growth factor prevents starvation-induced mucosal atrophy in the small bowel, but does not enhance the mucosal growth associated with refeeding. Effects are greatest at the site of administration. Luminal epidermal growth factor is a potential mediator of the indirect effects of nutrient on mucosal growth in the small bowel. Enteral administration of epidermal growth factor holds promise for preventing atrophy and maintaining mucosal integrity in starved and post-operative patients.


Concentrations of perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) and their associations with human semen quality measurements.
A total of 256 men were studied to evaluate whether serum concentrations of perfluorooctanoate (PFOA) and perfluorooctane sulfonate (PFOS) impacted semen quality or reproductive hormones. Blood and semen were collected and analyzed for perfluorochemicals and reproductive and thyroid hormones. Semen quality was assessed using standard clinical methods. Linear and logistic modeling was performed with semen profile measurements as outcomes and PFOS and PFOA in semen and plasma as explanatory variables. Adjusting for age, abstinence, and tobacco use, there was no indication that PFOA or PFOS was significantly associated with volume, sperm concentration, percent motility, swim-up motility and concentration, and directional motility (a function of motility and modal progression). Follicle-stimulating hormone was not associated with either PFOA or PFOS. Luteinizing hormone was positively correlated with plasma PFOA and PFOS, but not semen PFOS. Important methodological concerns included the lack of multiple hormonal measurements necessary to address circadian rhythms.


Low-sensitivity urine pregnancy testing to assess medical abortion outcome: A systematic review.
The objective was to summarize data on the accuracy and acceptability of a strategy for identifying ongoing pregnancy after medical abortion treatment using a low-sensitivity pregnancy test (LSPT). We searched PubMed to identify studies that evaluated the use of a single posttreatment LSPT for detection of ongoing pregnancy after treatment with mifepristone and misoprostol. We extracted, assessed and summarized data from each study. We found 10 studies that evaluated 6 LSPTs with human chorionic gonadotropin detection thresholds of 1000, 1500 or 2000 mIU/mL. The three earliest studies compared the pregnancy test strategy to standard assessment in the same women; the sensitivity of a positive or invalid LSPT result for detecting ongoing pregnancy ranged from 67% to 100%. Three randomized trials found no significant difference in detection of ongoing pregnancy between the LSPT strategy and routine in-person follow-up. Four noncomparative studies found that of the 12 women who had ongoing pregnancies diagnosed after performing an LSPT, 8 (67%) had positive or invalid LSPT results. Across the 10 studies, 30 of the 59 total ongoing pregnancies (51%) were identified based on symptoms without a positive or invalid LSPT result. Women expressed satisfaction with the LSPT strategy. Risk of bias in the seven later studies was high. Despite their limitations, most studies showed that the LSPT strategy had moderate sensitivity for identifying ongoing pregnancy and can enable the majority of medical abortion patients to assess treatment outcome at home. However, the LSPT itself had a limited role in the detection of treatment failures in the studies. The LSPT strategy shows promise for reducing the need for in-person follow-up after medical abortion. A range of home-based options should be validated to meet the varied needs of women and abortion providers in diverse settings.


On the validity and errors of the pseudo-first-order kinetics in ligand-receptor binding.
The simple bimolecular ligand-receptor binding interaction is often linearized by assuming pseudo-first-order kinetics when one species is present in excess. Here, a phase-plane analysis allows the derivation of a new condition for the validity of pseudo-first-order kinetics that is independent of the initial receptor concentration. The validity of the derived condition is analyzed from two viewpoints. In the first, time courses of the exact and approximate solutions to the ligand-receptor rate equations are compared when all rate constants are known. The second viewpoint assesses the validity through the error induced when the approximate equation is used to estimate kinetic constants from data. Although these two interpretations of validity are often assumed to coincide, we show that they are distinct, and that large errors are possible in estimated kinetic constants, even when the linearized and exact rate equations provide nearly identical solutions.


Possible second-order nonlinear interactions of plane waves in an elastic solid.
There exist ten possible nonlinear elastic wave interactions for an isotropic solid described by three constants of the third order. All other possible interactions out of 54 combinations (triplets) of interacting and resulting waves are prohibited, because of restrictions of various kinds. The considered waves include longitudinal and two shear waves polarized in the interacting plane and orthogonal to it. The amplitudes of scattered waves have simple analytical forms, which can be used for experimental setup and design. The analytic results are verified by comparison with numerical solutions of initial equations. Amplitude coefficients for all ten interactions are computed as functions of frequency for polyvinyl chloride, together with interaction and scattering angles. The nonlinear equation of motion is put into a general vector form and can be used for any coordinate system.


Interactions among predators and plant specificity protect herbivores from top predators.
The worldwide loss of top predators from natural and agricultural systems has heightened the need to understand how important they are in controlling herbivore abundance. The effect of top predators on herbivore species is likely to depend on (1) the importance of the consumption of intermediate predators by top predators (intra-guild predation; IGP), but also on (2) plant specificity by herbivores, because specialists may defend themselves better (enemy-free space; EFS). Insectivorous birds, as top predators, are generally known to effectively control herbivorous insects, despite also consuming intermediate predators such as spiders, but how this effect varies among herbivore species in relation to the cascading effects of IGP and EFS is not known. To explore this, we excluded birds from natural fynbos vegetation in South Africa using large netted cages and recorded changes in abundance relative to control plots for 199 plant-dwelling intermediate predator and 341 herbivore morpho-species that varied in their estimated plant specificity. We found a strong negative effect of birds on the total abundance of all intermediate predators, with especially clear effects on spiders (strong IGP). In contrast with previous studies, which document a negative effect of birds on herbivores, we found an overall neutral effect of birds on herbivore abundance, but the effect varied among species: some species were negatively affected by birds, suggesting that they were mainly consumed by birds, whereas others, likely released from spiders by IGP, were positively affected. Some species were also effectively neutrally affected by birds. These tended to be more specialized to plants compared to the other species, which may imply that some plant specialists benefited from protection provided by EFS from both birds and spiders. These results suggest that the response of herbivore species to top predators may depend on cascading effects of interactions among predators and on their degree of plant specificity.


Per- and polyfluoroalkyl substances and blood lipid levels in pre-diabetic adults-longitudinal analysis of the diabetes prevention program outcomes study.
Exposure to per- and polyfluoroalkyl substances (PFASs) may interfere with lipid regulation. However, most previous studies were cross-sectional with the risk of reverse causation, suggesting a need for long-term prospective studies. We examined the relationship of baseline plasma PFAS concentrations with repeated measures of blood lipids. We included 888 prediabetic adults from the Diabetes Prevention Program (DPP) and DPP Outcomes Study, who had measurements of 6 plasma PFAS concentrations at baseline (1996-1999) and repeated measures of blood lipids over 15 years of follow-up, and were initially randomized to placebo or a lifestyle intervention. We used linear regression to examine cross-sectional associations of PFAS concentrations and lipid levels at baseline, and evaluated prospective risks of hypercholesterolemia and hypertriglyceridemia using Cox proportional hazard models, and tested for effect modification by study arm. Participants (65.9% female, 57.0% White, 65.9% aged 40-59 years) had comparable PFAS concentrations [e.g., median (IQR) perfluorooctanoic acid (PFOA) 4.9 ng/mL (3.2)] with the general U.S. population in 1999-2000. We observed higher total cholesterol at baseline per doubling of PFOA (β: 6.1 mg/dL, 95% CI: 3.1, 9.04), perfluorohexane sulfonic acid (PFHxS, β: 2.2 mg/dL, 95% CI: 0.2, 4.3), and perfluorononanoic acid (PFNA, β: 2.9 mg/dL, 95% CI: 0.7, 5.0). Prospectively, baseline concentrations of several PFASs, including PFOA, PFOS, PFHxS and PFNA, predicted higher risks of incident hypercholesterolemia and hypertriglyceridemia, but only in the placebo group and not the lifestyle intervention group. For example, participants in the placebo group with PFOA concentration > median (4.9 ng/mL) were almost twice as likely (HR: 1.90, 95% CI: 1.25, 2.88) to develop hypertriglyceridemia compared to those ≤median. Findings suggest adverse effects of some PFASs on lipid profiles in prediabetic adults. However, the detrimental effect was attenuated with a lifestyle intervention.


Exposure to benevolent sexism and complementary gender stereotypes: consequences for specific and diffuse forms of system justification.
Many have suggested that complementary gender stereotypes of men as agentic (but not communal) and women as communal (but not agentic) serve to increase system justification, but direct experimental support has been lacking. The authors exposed people to specific types of gender-related beliefs and subsequently asked them to complete measures of gender-specific or diffuse system justification. In Studies 1 and 2, activating (a) communal or complementary (communal + agentic) gender stereotypes or (b) benevolent or complementary (benevolent + hostile) sexist items increased support for the status quo among women. In Study 3, activating stereotypes of men as agentic also increased system justification among men and women, but only when women's characteristics were associated with higher status. Results suggest that complementary stereotypes psychologically offset the one-sided advantage of any single group and contribute to an image of society in which everyone benefits through a balanced dispersion of benefits.


Risk of Schizophrenia and Bipolar Disorder in Patients With Multiple Sclerosis: Record-Linkage Studies.
The epidemiology of psychiatric comorbidity in multiple sclerosis (MS) remains poorly understood. We aimed to determine the risk of schizophrenia and bipolar disorder in MS patients. Retrospective cohort analyses were performed using an all-England national linked Hospital Episode Statistics (HES) dataset (1999-2016) and to determine whether schizophrenia or bipolar disorder are more commonly diagnosed subsequently in people with MS (n=128,194), and whether MS is more commonly diagnosed subsequently in people with schizophrenia (n=384,188) or bipolar disorder (n=203,592), than would be expected when compared with a reference cohort (~15 million people) after adjusting for age and other factors. Adjusted hazard ratios (aHRs) were calculated using Cox proportional hazards models. Findings were dependent on whether the index and subsequent diagnoses were selected as the primary reason for hospital admission or were taken from anywhere on the hospital record. When searching for diagnoses anywhere on the hospital record, there was a significantly elevated risk of subsequent schizophrenia (aHR 1.51, 95% confidence interval (CI) 1.40 to 1.60) and of bipolar disorder (aHR 1.14, 95% CI 1.04 to 1.24) in people with prior-recorded MS and of subsequent MS in people with prior-recorded schizophrenia (aHR 1.26, 1.15-1.37) or bipolar disorder (aHR 1.73, 1.57-1.91), but most of these associations were reduced to null when analyses were confined to diagnoses recorded as the primary reason for admission. Further research is needed to investigate the potential association between MS and schizophrenia and/or bipolar disorder as it may shed light on underlying pathophysiology and help identify potential shared risk factors.


Neural Integration in Body Perception.
The perception of other people is instrumental in guiding social interactions. For example, the appearance of the human body cues a wide range of inferences regarding sex, age, health, and personality, as well as emotional state and intentions, which influence social behavior. To date, most neuroscience research on body perception has aimed to characterize the functional contribution of segregated patches of cortex in the ventral visual stream. In light of the growing prominence of network architectures in neuroscience, the current article reviews neuroimaging studies that measure functional integration between different brain regions during body perception. The review demonstrates that body perception is not restricted to processing in the ventral visual stream but instead reflects a functional alliance between the ventral visual stream and extended neural systems associated with action perception, executive functions, and theory of mind. Overall, these findings demonstrate how body percepts are constructed through interactions in distributed brain networks and underscore that functional segregation and integration should be considered together when formulating neurocognitive theories of body perception. Insight from such an updated model of body perception generalizes to inform the organizational structure of social perception and cognition more generally and also informs disorders of body image, such as anorexia nervosa, which may rely on atypical integration of body-related information.


Learning Cellular Phenotypes through Supervision.
Image-based cell phenotyping is an important and open problem in computational pathology. The two principal challenges are: 1) making the cell cluster properties insensitive to experimental settings (like seed point and feature selection) and 2) ensuring that the phenotypes emerging are biologically relevant and support clinical reporting. To gauge robustness, we first compare the consistency of the phenotypes using self-supervised and supervised features. Through case classification, we analyse the relevance of the self-supervised and supervised feature sets with respect to the clinical diagnosis. In addition, we demonstrate how we can add model explainability through Shapley values to identify more disease relevant cellular phenotypes and measure their importance in context of the disease. Here, myeloproliferative neoplasms, a haematopoietic stem cell disorder, where one particular cell type is of diagnostic relevance is used as an exemplar. The experiments conducted on a set of bone marrow trephines demonstrate an improvement of 7.4 % in accuracy for case classification using cellular phenotypes derived from the supervised scenario.


Increased blasts mimicking acute leukemia in a patient with polysubstance abuse.
Toxic insult to the bone marrow may result in partial or complete suppression, with or without reactive changes, and probable eventual regeneration of hematopoietic elements. During the regenerative process, increased blasts may be observed. Distinguishing these changes from an acute leukemic process can be difficult. In particular, the diagnosis of hypocellular bone marrow with increased blasts, also known as hypocellular or hypoplastic acute leukemia, presents a diagnostic dilemma for pathologists. We report a case of hypocellular marrow with increased blasts in a 50-year-old man with an extensive history of alcohol and drug abuse in whom chemotherapy was deferred. Recovery of peripheral blood cell counts and reticulocytosis occurred with withdrawal of the offending agents, and he remains alive and well 1 year later.


Words matter: a qualitative investigation of which weight status terms are acceptable and motivate weight loss when used by health professionals.
Health professionals have an important role to play in the management of obesity, but may be unsure how to raise weight issues with patients. The societal stigma associated with excess weight means that weight status terms may be misunderstood, cause offence and risk upsetting patient-professional relationships. This study investigated the views of people who were overweight or obese on the acceptability of weight status terms and their potential to motivate weight loss when used by health professionals. A qualitative study comprising 34 semi-structured interviews with men and women in their mid-to-late 30s and 50s who were overweight or obese and had recently been informed of their weight status. Thematic framework analysis was conducted to allow the systematic comparison of views by age, gender and apparent motivation to lose weight. Although many people favoured 'Overweight' to describe their weight status, there were doubts about its effectiveness to motivate weight loss. Terms including 'BMI' ('Body Mass Index') or referring to the unhealthy nature of their weight were generally considered acceptable and motivational, although a number of men questioned the validity of BMI as an indicator of excess weight. Participants, particularly women, felt that health professionals should avoid using 'Fat'. Whilst response to 'Obese' was largely negative, people recognised that it could be appropriate in a health consultation. Some younger people, particularly those who appeared motivated to lose weight, felt 'Obese' could encourage weight loss, but it was also clear the term could provoke negative emotions if used insensitively. Although most people who are overweight or obese accept that it is appropriate for health professionals to discuss weight issues with patients, there is great variation in response to the terms commonly used to describe excess weight. There is no one-size-fits-all approach to discussing weight status: some men and younger people may appreciate a direct approach, whilst others need to be treated more sensitively. It is therefore important that health professionals use their knowledge and understanding to select the terms that are most likely to be acceptable, but at the same time have most potential to motivate each individual patient.


Design of microlenses with long focal depth based on the general focal length function.
A general focal length function is proposed to design microlenses with long extended focal depth and high lateral resolution. The focal performance of the designed microlenses, including the actual focal depth, the focal spot size, and the diffraction efficiency, is calculated by rigorous electromagnetic theory and the boundary-element method for several f-numbers. In contrast to conventional microlenses, the numerical results indicate that the designed microlenses can exhibit long extended focal depth and good focal performance. It is expected that the long focal length function will be widely used to design microlenses with long focal depth characteristics.