Evaluation of the Effects of Aedes Vector Indices and Climatic Factors on Dengue Incidence in Gampaha District, Sri Lanka

Constant monitoring of Aedes vector indices such as Aedes mosquito abundance and ovitrap data is important for the control of dengue epidemics. Therefore, the current study attempted to evaluate the effect of larval and climatic factors on the incidence of dengue outbreaks in the Gampaha district. Based on the distribution of previously reported dengue cases, 34 households in Narangodapaluwa PHI area, Ragama, Sri Lanka, were selected randomly, and entomological surveillance was done fortnightly using adult mosquito catches and larval surveillance techniques for a period of two years. Further, weekly ovitrap surveillance was conducted for one year, by maintaining four ovitraps in a single house, two indoors and two outdoors at ground and at a height of 1.5–2 m. Based on the findings, larval indices, namely, Breteau index (BI), House index (HI), and Container index (CI), were calculated, along with the Ovitrap index (OI). The study area was positive for Ae. albopictus with an adult capturing range of 1~15/34 households. BI initially remained 0.05), 95% level of confidence. The OI varied from 56.9% to 94.7% during the study period of 12 months, indicating two peaks at the monsoons. Statistics of one-way ANOVA revealed a significant difference in the monthly OI during the study period (p≤0.001) with two peaks representing the monsoonal rainfall patterns. Pearson's correlation analysis revealed that the association between dengue cases and larval indices (BI, CI, HI, and OI) and meteorological parameters was not significant (p

http://bit.ly/2Tmijju

Nexplanon Subdermal Implant: Assessment of Sexual Profile, Metabolism, and Bleeding in a Cohort of Italian Women

Objectives. To evaluate the impact on metabolism, bleeding, and sexual function of Nexplanon, a subdermal implant. Study Design. We recruited women (n=101) receiving the Nexplanon implant at two university centers in Italy between 2011 and 2016 into this prospective, observational, multicenter research trial. Participants completed the Interview for Ratings of Sexual Function (IRSF) and the Female Sexual Function Index (FSFI) questionnaires before and 3 and 6 months after the implant was inserted. In addition, all blood parameters were assessed at these visits. All women were given a menstrual diary card and a pictorial blood assessment chart to record daily any vaginal bleeding. Results. The studied metabolic parameters remained in the normal range, showing no alarming modifications: minimal statistical reductions (in aspartate aminotransferase, alanine aminotransferase, total cholesterol, triglycerides, and activated partial thromboplastin time) and increases (in glucose and prothrombin activity) were observed. Changes in IRSF score over 6 months showed a significant increase in pleasure, personal initiative, orgasm, intensity of orgasm, and satisfaction, and a significant decrease in anxiety and discomfort. Mean Body Mass Index decreased, and the weekly frequency of sexual intercourse increased. Conclusions. Nexplanon showed not only a lower metabolic and bleeding impact, but also important positive effects on sexual function. It expands the range of possibilities for women, 38 and couples, in the modern concepts of sexual and reproductive wellbeing.

http://bit.ly/2BcnHhQ

Mutations in the microtubule-associated protein MAP11 (C7orf43) cause microcephaly in humans and zebrafish

Abstract

Microtubule associated protein 11 (MAP11, previously termed C7orf43) encodes a highly conserved protein whose function is unknown. Through genome-wide linkage analysis combined with whole exome sequencing, we demonstrate that human autosomal recessive primary microcephaly is caused by a truncating mutation in MAP11. Moreover, homozygous MAP11-orthologue CRISPR/Cas9 knock-out zebrafish presented with microcephaly and decreased neuronal proliferation, recapitulating the human phenotype. We demonstrate that MAP11 is ubiquitously transcribed with high levels in brain and cerebellum. Immunofluorescence and co-immunoprecipitation studies in SH-SY5Y cells showed that MAP11 associates with mitotic spindles, co-localizing and physically associating with α-tubulin during mitosis. MAP11 expression precedes α-tubulin in gap formation of cell abscission at the midbody and is co-localized with PLK1, a key regulator of cytokinesis, at the edges of microtubule extensions of daughter cells post cytokinesis abscission, implicating a role in mitotic spindle dynamics and in regulation of cell abscission during cytokinesis. Finally, lentiviral-mediated silencing of MAP11 diminished SH-SY5Y cell viability, reducing proliferation rather than affecting apoptosis. Thus, MAP11 encodes a microtubule-associated protein that plays a role in spindle dynamics and cell division, in which mutations cause microcephaly in humans and zebrafish.

http://bit.ly/2G0uAqW

Early neurophysiological biomarkers and spinal cord pathology in inherited prion disease

Abstract

A common presentation of inherited prion disease is Gerstmann-Sträussler-Scheinker syndrome, typically presenting with gait ataxia and painful dysaesthesiae in the legs evolving over 2–5 years. The most frequent molecular genetic diagnosis is a P102L mutation of the prion protein gene (PRNP). There is no explanation for why this clinical syndrome is so distinct from Creutzfeldt-Jakob disease, and biomarkers of the early stages of disease have not been developed. Here we aimed, first, at determining if quantitative neurophysiological assessments could predict clinical diagnosis or disability and monitor progression and, second, to determine the neuropathological basis of the initial clinical and neurophysiological findings. We investigated subjects known to carry the P102L mutation in the longitudinal observational UK National Prion Monitoring Cohort study, with serial assessments of clinical features, peripheral nerve conduction, H and F components, threshold tracking and histamine flare and itch response and neuropathological examination in some of those who died. Twenty-three subjects were studied over a period of up to 12 years, including 65 neurophysiological assessments at the same department. Six were symptomatic throughout and six became symptomatic during the study. Neurophysiological abnormalities were restricted to the lower limbs. In symptomatic patients around the time of, or shortly after, symptom onset the H-reflex was lost. Lower limb thermal thresholds were at floor/ceiling in some at presentation, in others thresholds progressively deteriorated. Itch sensation to histamine injection was lost in most symptomatic patients. In six patients with initial assessments in the asymptomatic stage of the disease, a progressive deterioration in the ability to detect warm temperatures in the feet was observed prior to clinical diagnosis and the onset of disability. All of these six patients developed objective abnormalities of either warm or cold sensation prior to the onset of significant symptoms or clinical diagnosis. Autopsy examination in five patients (including two not followed clinically) showed prion protein in the substantia gelatinosa, spinothalamic tracts, posterior columns and nuclei and in the neuropil surrounding anterior horn cells. In conclusion, sensory symptoms and loss of reflexes in Gerstmann-Sträussler-Scheinker syndrome can be explained by neuropathological changes in the spinal cord. We conclude that the sensory symptoms and loss of lower limb reflexes in Gerstmann-Sträussler-Scheinker syndrome is due to pathology in the caudal spinal cord. Neuro-physiological measures become abnormal around the time of symptom onset, prior to diagnosis, and may be of value for improved early diagnosis and for recruitment and monitoring of progression in clinical trials.

http://bit.ly/2G0uwaG

Brain white matter damage and its association with neuronal synchrony during sleep

Abstract

The restorative function of sleep partly relies on its ability to deeply synchronize cerebral networks to create large slow oscillations observable with EEG. However, whether a brain can properly synchronize and produce a restorative sleep when it undergoes massive and widespread white matter damage is unknown. Here, we answer this question by testing 23 patients with various levels of white matter damage secondary to moderate to severe traumatic brain injuries (ages 18–56; 17 males, six females, 11–39 months post-injury) and compared them to 27 healthy subjects of similar age and sex. We used MRI and diffusion tensor imaging metrics (e.g. fractional anisotropy as well as mean, axial and radial diffusivities) to characterize voxel-wise white matter damage. We measured the following slow wave characteristics for all slow waves detected in N2 and N3 sleep stages: peak-to-peak amplitude, negative-to-positive slope, negative and positive phase durations, oscillation frequency, and slow wave density. Correlation analyses were performed in traumatic brain injury and control participants separately, with age as a covariate. Contrary to our hypotheses, we found that greater white matter damage mainly over the frontal and temporal brain regions was strongly correlated with a pattern of higher neuronal synchrony characterized by slow waves of larger amplitudes and steeper negative-to-positive slopes during non-rapid eye movement sleep. The same pattern of associations with white matter damage was also observed with markers of high homeostatic sleep pressure. More specifically, higher white matter damage was associated with higher slow-wave activity power, as well as with more severe complaints of cognitive fatigue. These associations between white matter damage and sleep were found only in our traumatic brain injured participants, with no such correlation in controls. Our results suggest that, contrary to previous observations in healthy controls, white matter damage does not prevent the expected high cerebral synchrony during sleep. Moreover, our observations challenge the current line of hypotheses that white matter microstructure deterioration reduces cerebral synchrony during sleep. Our results showed that the relationship between white matter and the brain's ability to synchronize during sleep is neither linear nor simple.

http://bit.ly/2G0uuQ6

Fumarates target the metabolic-epigenetic interplay of brain-homing T cells in multiple sclerosis

Abstract

Cell-permeable formulations of metabolites, such as fumaric acid esters, have been used as highly effective immunomodulators in patients with multiple sclerosis and yet their mechanism of action remains elusive. Since fumaric acid esters are metabolites, and cell metabolism is highly intertwined with the epigenetic regulation of gene expression, we investigated whether this metabolic-epigenetic interplay could be leveraged for therapeutic purposes. To this end we recruited 47 treatment-naïve and 35 fumaric acid ester-treated patients with multiple sclerosis, as well as 16 glatiramer acetate-treated patients as a non-metabolite treatment control. Here we identify a significant immunomodulatory effect of fumaric acid esters on the expression of the brain-homing chemokine receptor CCR6 in CD4 and CD8 T cells of patients with multiple sclerosis, which include T helper-17 and T cytotoxic-17 cells. We report differences in DNA methylation of CD4 T cells isolated from untreated and treated patients with multiple sclerosis, using the Illumina EPIC 850K BeadChip. We first demonstrate that Krebs cycle intermediates, such as fumaric acid esters, have a significantly higher impact on epigenome-wide DNA methylation changes in CD4 T cells compared to amino-acid polymers such as glatiramer acetate. We then define a fumaric acid ester treatment-specific hypermethylation effect on microRNA MIR-21, which is critical for the differentiation of T helper-17 cells. This hypermethylation effect was attributed to the subpopulation of T helper-17 cells using a decomposition analysis and was further validated in an independent prospective cohort of seven patients before and after treatment with fumaric acid esters. In vitro treatment of CD4 and CD8 T cells with fumaric acid esters supported a direct and dose-dependent effect on DNA methylation at the MIR-21 promoter. Finally, the upregulation of miR-21 transcripts and CCR6 expression was inhibited if CD4 or CD8 T cells stimulated under T helper-17 or T cytotoxic-17 polarizing conditions were treated with fumaric acid esters in vitro. These data collectively define a direct link between fumaric acid ester treatment and hypermethylation of the MIR-21 locus in both CD4 and CD8 T cells and suggest that the immunomodulatory effect of fumaric acid esters in multiple sclerosis is at least in part due to the epigenetic regulation of the brain-homing CCR6+ CD4 and CD8 T cells.

http://bit.ly/2GczQa7

Brain on fire

The Inflamed Mind, the title of this book, says it all. Inflammation, a response of the innate immune system to injury, does not stay local, at the site of injury, but propagates and influences brain functions. And this influence can lead to depression as we learn from the subtitle.

http://bit.ly/2FZaKwa

Overt social interaction and resting state in young adult males with autism: core and contextual neural features

Abstract

Conversation is an important and ubiquitous social behaviour. Individuals with autism spectrum disorder (autism) without intellectual disability often have normal structural language abilities but deficits in social aspects of communication like pragmatics, prosody, and eye contact. Previous studies of resting state activity suggest that intrinsic connections among neural circuits involved with social processing are disrupted in autism, but to date no neuroimaging study has examined neural activity during the most commonplace yet challenging social task: spontaneous conversation. Here we used functional MRI to scan autistic males (n = 19) without intellectual disability and age- and IQ-matched typically developing control subjects (n = 20) while they engaged in a total of 193 face-to-face interactions. Participants completed two kinds of tasks: conversation, which had high social demand, and repetition, which had low social demand. Autistic individuals showed abnormally increased task-driven interregional temporal correlation relative to controls, especially among social processing regions and during high social demand. Furthermore, these increased correlations were associated with parent ratings of participants' social impairments. These results were then compared with previously-acquired resting state data (56 autism, 62 control subjects). While some interregional correlation levels varied by task or rest context, others were strikingly similar across both task and rest, namely increased correlation among the thalamus, dorsal and ventral striatum, somatomotor, temporal and prefrontal cortex in the autistic individuals, relative to the control groups. These results suggest a basic distinction. Autistic cortico-cortical interactions vary by context, tending to increase relative to controls during task and decrease during test. In contrast, striato- and thalamocortical relationships with socially engaged brain regions are increased in both task and rest, and may be core to the condition of autism.

http://bit.ly/2GejwFJ

Astrocyte adenosine deaminase loss increases motor neuron toxicity in amyotrophic lateral sclerosis

Abstract

As clinical evidence supports a negative impact of dysfunctional energy metabolism on the disease progression in amyotrophic lateral sclerosis, it is vital to understand how the energy metabolic pathways are altered and whether they can be restored to slow disease progression. Possible approaches include increasing or rerouting catabolism of alternative fuel sources to supplement the glycolytic and mitochondrial pathways such as glycogen, ketone bodies and nucleosides. To analyse the basis of the catabolic defect in amyotrophic lateral sclerosis we used a novel phenotypic metabolic array. We profiled fibroblasts and induced neuronal progenitor-derived human induced astrocytes from C9orf72 amyotrophic lateral sclerosis patients compared to normal controls, measuring the rates of production of reduced nicotinamide adenine dinucleotides from 91 potential energy substrates. This approach shows for the first time that C9orf72 human induced astrocytes and fibroblasts have an adenosine to inosine deamination defect caused by reduction of adenosine deaminase, which is also observed in induced astrocytes from sporadic patients. Patient-derived induced astrocyte lines were more susceptible to adenosine-induced toxicity, which could be mimicked by inhibiting adenosine deaminase in control lines. Furthermore, adenosine deaminase inhibition in control induced astrocytes led to increased motor neuron toxicity in co-cultures, similar to the levels observed with patient derived induced astrocytes. Bypassing metabolically the adenosine deaminase defect by inosine supplementation was beneficial bioenergetically in vitro, increasing glycolytic energy output and leading to an increase in motor neuron survival in co-cultures with induced astrocytes. Inosine supplementation, in combination with modulation of the level of adenosine deaminase may represent a beneficial therapeutic approach to evaluate in patients with amyotrophic lateral sclerosis.

http://bit.ly/2G9Q43A

Fatty liver disease and the risk of erosive oesophagitis in the Korean population: a cross-sectional study

Objectives

To investigate an association between fatty liver disease (FLD) and erosive oesophagitis.

Design and setting

This was a cross-sectional study of subjects selected from examinees who underwent health check-up, including oesophagogastroduodenoscopy in one hospital between 2004 and 2011. Erosive oesophagitis was classified according to the Los Angeles classification and FLD was diagnosed with ultrasonography. The anthropometric and laboratory data of the subjects were analysed using ² test and multivariate logistic regression. Additionally, we have analysed our data with two-stage least square estimation using the Baltagi-Chang one-way model to clarify unobserved confounding variable.

Primary outcome measure

The effect of FLD on erosive oesophagitis.

Results

Among the 14 723 eligible subjects, 4232 (28.7%) subjects diagnosed with FLD were classified into the fatty liver group and 10 491 (71.3%) subjects without FLD were classified into the non-fatty liver group. The incidence rate of erosive oesophagitis was significantly higher in the fatty liver group than in the non-fatty liver group (10.4%vs6.1%, p<0.0001). The multivariate analysis revealed that the fatty liver group was significantly associated with erosive oesophagitis (OR 1.19, 95% CI 1.03 to 1.37, p=0.016).

Conclusion

FLD diagnosed by ultrasonography is an independent risk factor of erosive oesophagitis. It suggests that FLD-related metabolic abnormality may be associated with erosive oesophagitis.

http://bit.ly/2Tovfp0

Trends in HIV prevalence and risk behaviours among men who have sex with men from 2013 to 2017 in Nanjing, China: a consecutive cross-sectional survey

Objective

To examine the trends of HIV prevalence, risk behaviours and HIV testing among men who have sex with men (MSM) in Nanjing.

Design

Five consecutive cross-sectional surveys.

Setting

Nanjing, China.

Primary and secondary outcome measures

HIV and syphilis prevalence, HIV testing rate and factors associated with HIV infection; demographic characteristics and behaviours.

Results

649, 669, 577, 633, 503 MSM were recruited from 2013 to 2017. HIV prevalence was 9.9%, 12.3%, 12.5%, 9.8% and 10.1%, respectively. Syphilis prevalence decreased with a range from 10.6% to 5.6%. Risk behaviours like unprotected anal intercourse (UAI) and unprotected virginal sex in the past 6 months decreased, but multiple sex partners and ever used rush popper rose significantly. MSM tested for HIV in the previous year remained stable from 57.0% to 64.1% (P=0.633). Multivariate analysis showed that tested for HIV in the past year was protective factor against HIV infection. MSM who had UAI in the past 6 months, sex role as receptive and dual, diagnosed with sexually transmitted diseases (STDs) in the past year and currently syphilis infected were risk factors for HIV infection.

Conclusions

We observed stable high HIV prevalence, a steady HIV testing rate, decreasing syphilis prevalence and UAI among MSM in Nanjing. However, rush popper use rose dramatically. The HIV preventive strategies for MSM including condom promotion, HIV testing expansion and reduction of rush popper use, STDs screening and standardised treatment should be strengthened.

http://bit.ly/2B6esQv

Protocol for a multicentre randomised controlled parallel-group trial to compare the effectiveness of remotely delivered cognitive-behavioural and graded exercise interventions with usual care alone to lessen the impact of fatigue in inflammatory rheumatic diseases (LIFT)

Introduction

Fatigue remains pervasive, disabling and challenging to manage across all inflammatory rheumatic diseases (IRDs). Non-pharmacological interventions, specifically cognitive-behavioural approaches (CBAs) and graded exercise programmes designed to support and increase exercise, are valuable treatments which help patients with IRD to manage their fatigue. Yet, healthcare systems have encountered substantial barriers to the implementation of these therapeutic options. Lessening the Impact of Fatigue in Inflammatory Rheumatic Diseases: a Randomised Trial (LIFT) is designed to give insights into the effectiveness of a remotely delivered standardised intervention for a range of patients with IRD. It will also enable the exploration of putative moderating factors which may allow for the future triage of patients and to investigate the precise mediators of treatment effect in IRD-related fatigue.

Methods and analysis

LIFT is a pragmatic, multicentre, three-arm randomised, controlled trial, which will test whether adapted CBA and personalised exercise programme interventions can individually reduce the impact and severity of fatigue. This will be conducted with up to 375 eligible patients diagnosed with IRD and interventions will be delivered by rheumatology healthcare professionals, using the telephone or internet-based audio/video calls.

Ethics approval and dissemination

Ethical approval has been granted by Wales REC 7 (17/WA/0065). Results of this study will be disseminated through presentation at scientific conferences and in scientific journal. A lay summary of the results will be sent to participants.

Trial registration number

NCT03248518; Pre-results.

http://bit.ly/2TopHdY

Intervention to reduce benzodiazepine prescriptions in primary care, study protocol of a hybrid type 1 cluster randomised controlled trial: the BENZORED study

Introduction

Benzodiazepines (BZDs) are mainly used to treat anxiety and sleep disorders, and are often prescribed for long durations, even though prescription guidelines recommend short-term use due to the risk of dependence, cognitive impairment, and falls and fractures. Education of general practitioners (GPs) regarding the prescription of BZDs may reduce the overuse and of these drugs.

The aims of this study are to analyse the effectiveness of an intervention targeted to GPs to reduce BZD prescription and evaluate the implementation process.

Methods and analysis

The healthcare centres in three regions of Spain (Balearic Islands, Catalonia and Community of Valencia) will be randomly allocated to receive a multifactorial intervention or usual care (control). GPs in the intervention group will receive a 2-hour workshop about best-practice regarding BZD prescription and BZD deprescribing, monthly feedback about their BZD prescribing practices and access to a support web page. Outcome measures for each GP are the defined daily dosage per 1000 inhabitants per day and the proportion of long-term BZD users at 12 months. Data will be collected from the electronic prescription database of the public health system, and will be subjected to intention-to-treat analysis. Implementation will be evaluated by mixed methods following the five domains of the Consolidated Framework For Implementation Research.

Ethics and dissemination

This study was approved by the Balearic Islands Ethical Committee of Clinical Research (IB3065/15), l'IDIAP Jordi Gol Ethical Committee of Clinical Research (PI 15/0148) and Valencia Primary Care Ethical Committee of Clinical Research (P16/024). The results will be submitted for publication in peer-reviewed journals.

Trial registration number

ISRCTN28272199.

http://bit.ly/2Bd3Gbb

Endovenous ablation and surgery in great saphenous vein reflux: a systematic review and network meta-analysis of randomised controlled trials protocol

Introduction

Endovenous ablations are the new standard procedures for treatment of great saphenous vein reflux including endovenous laser ablation (EVLA), radio frequency ablation (RFA), endovenous steam ablation (EVSA), mechanochemical ablation (MOCA), cyanoacrylate injection and ultrasound-guided foam sclerotherapy (UGFS). EVLA and RFA have demonstrated similar anatomical success for short-term outcome, but results are controversial for longer term (≥5 years). Additional evidences from randomised controlled trials have been published. This study is, therefore, conducted to, directly and indirectly, compare outcomes among all procedures stratifying by short-term and long-term follow-up.

Methods and analysis

Medline and Scopus will be searched from 2000 to September 2018 with predefined search strategy. Interventions of interest are open surgery (ie, saphenofemoral or high ligation (HL) with stripping) and endovenous ablations (ie, EVLA, RFA, EVSA, MOCA, cyanoacrylate injection and UGFS). The primary outcome is anatomical success. Two independent reviewers will select studies, extract data and assess risk of bias. Disagreement will be adjudicated by the third party. Outcomes will be directly pooled if there are at least three studies in that comparison. A fixed-effect model will be used unless heterogeneity is present, in which case a random-effect model will be applied. Sources of heterogeneity will be explored using meta-regression analysis, and sub-group analysis will be done accordingly. Publication bias will be assessed using Egger's test and funnel plot. A network meta-analysis will be applied to indirect compare all interventions including RFA, EVLA, EVLA with HL, UGFS, UGFS with HL and HL with stripping. Probability of being best intervention will be estimated and ranked. Inconsistency assumption will be checked using a design-by-treatment interaction model.

Ethics and dissemination

Ethical approval is not required for systematic review and network meta-analysis. The study will be published in a peer-reviewed journal.

PROSPERO registration number

CRD42018096794.

http://bit.ly/2Tph0QD

Demographic and clinical characteristics of hospitalised unintentional poisoning in Aboriginal and non-Aboriginal preschool children in New South Wales, Australia: a population data linkage study

Objectives

To investigate differences in demographic and clinical characteristics of Aboriginal and non-Aboriginal children aged 0–4 years hospitalised for unintentional poisoning in New South Wales (NSW), Australia.

Design and setting

Retrospective whole-of-population cohort analysis of linked hospital and mortality data for 2000–2014.

Participants

All children (Aboriginal and non-Aboriginal) under the age of 5 years who were born in a hospital in NSW from 2000 to 2009.

Outcomes

The primary outcome was hospitalisation for unintentional poisoning. Logistic regression was used to estimate odds of poisoning hospitalisation for Aboriginal and non-Aboriginal children. Poisoning agents and clinical outcomes were compared by Aboriginality.

Results

The cohort included 767 119 children, including 28 528 (3.7%) Aboriginal children. Aboriginal children had approximately three times higher rates of hospitalised poisoning (1.34%) compared with non-Aboriginal children (0.41%). Poisoning incidence peaked at 2–3 years of age. Male sex, socioeconomic disadvantage and geographical remoteness were associated with higher odds of poisoning hospitalisation for Aboriginal and non-Aboriginal children, but associations with disadvantage and remoteness were statistically significant only for non-Aboriginal children. Most (83%) poisonings were caused by pharmaceutical agents. Few Aboriginal and non-Aboriginal children had repeat admissions for poisoning; most had a length of stay of 1 day or less. Only 8% of poisoning admissions involved contact with a social worker.

Conclusion

Commonly used medications in the general population contribute to poisonings among both Aboriginal and non-Aboriginal preschool-aged children. This study highlights a need to develop culturally safe poisoning prevention strategies and policies.

http://bit.ly/2B8NoQw

Economic impact of potentially inappropriate prescribing and related adverse events in older people: a cost-utility analysis using Markov models

Objectives

To determine the economic impact of three drugs commonly involved in potentially inappropriate prescribing (PIP) in adults aged ≥65 years, including their adverse effects (AEs): long-term use of non-steroidal anti-inflammatory drugs (NSAIDs), benzodiazepines and proton pump inhibitors (PPIs) at maximal dose; to assess cost-effectiveness of potential interventions to reduce PIP of each drug.

Design

Cost-utility analysis. We developed Markov models incorporating the AEs of each PIP, populated with published estimates of probabilities, health system costs (in 2014 euro) and utilities.

Participants

A hypothetical cohort of 65 year olds analysed over 35 1-year cycles with discounting at 5% per year.

Outcome measures

Incremental cost, quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios with 95% credible intervals (CIs, generated in probabilistic sensitivity analysis) between each PIP and an appropriate alternative strategy. Models were then used to evaluate the cost-effectiveness of potential interventions to reduce PIP for each of the three drug classes.

Results

All three PIP drugs and their AEs are associated with greater cost and fewer QALYs compared with alternatives. The largest reduction in QALYs and incremental cost was for benzodiazepines compared with no sedative medication (3470, 95% CI 2434 to 5001; –0.07 QALYs, 95% CI –0.089 to –0.047), followed by NSAIDs relative to paracetamol (806, 95% CI 415 and 1346; –0.07 QALYs, 95% CI –0.131 to –0.026), and maximal dose PPIs compared with maintenance dose PPIs (989, 95% CI -69 and 2127; –0.01 QALYs, 95% CI –0.029 to 0.003). For interventions to reduce PIP, at a willingness-to-pay of 45 000 per QALY, targeting NSAIDs would be cost-effective up to the highest intervention cost per person of 1971. For benzodiazepine and PPI interventions, the equivalent cost was 1480 and 831, respectively.

Conclusions

Long-term benzodiazepine and NSAID prescribing are associated with significantly increased costs and reduced QALYs. Targeting inappropriate NSAID prescribing appears to be the most cost-effective PIP intervention.

http://bit.ly/2TtbfSl

Inequalities in healthcare resources and outcomes threatening sustainable health development in Ethiopia: panel data analysis

Objective

To measure inequalities in the distributions of selected healthcare resources and outcomes in Ethiopia from 2000 to 2015.

Design

A panel data analysis was performed to measure inequalities in distribution of healthcare workforce, infrastructure, outcomes and finance, using secondary data.

Setting

The study was conducted across 11 regions in Ethiopia.

Participants

Regional population and selected healthcare workforce.

Outcomes measured

Aggregate Theil and Gini indices, changes in inequalities and elasticity of healthcare resources.

Results

Despite marked inequality reductions over a 16 year period, the Theil and Gini indices for the healthcare resources distributions remained high. Among the healthcare workforce distributions, the Gini index (GI) was lowest for nurses plus midwives (GI=0.428, 95% CI 0.393 to 0.463) and highest for specialist doctors (SPDs) (GI=0.704, 95% CI 0.652 to 0.756). Inter-region inequality was the highest for SPDs (95.0%) and the lowest for health officers (53.8%). The GIs for hospital beds, hospitals and health centres (HCs) were 0.592(95% CI 0.563 to 0.621), 0.460(95% CI 0.404 to 0.517) and 0.409(95% CI 0.380 to 0.439), respectively. The interaction term was highest for HC distributions (47.7%). Outpatient department visit per capita (GI=0.349, 95% CI 0.321 to 0.377) and fully immunised children (GI=0.307, 95% CI 0.269 to 0.345) showed inequalities; inequality in the under 5 years of age mortality rate increased overtime (P=0.048). Overall, GI for government health expenditure (GHE) was 0.596(95% CI 0.544 to 0.648), and the estimated relative GHE share of the healthcare workforce and infrastructure distributions were 46.5% and 53.5%, respectively. The marginal changes in the healthcare resources distributions were towards the advantaged populations.

Conclusion

This study revealed high inequalities in healthcare resources in favour of the advantaged populations which can hinder equal access to healthcare and the achievements of healthcare outcomes. The government should strengthen monitoring mechanisms to address inequalities based on the national healthcare standards.

http://bit.ly/2B8NkjK

Internet delivery of intensive speech and language therapy for children with cerebral palsy: a pilot randomised controlled trial

Objectives

To test the feasibility of recruitment, retention, outcome measures and internet delivery of dysarthria therapy for young people with cerebral palsy in a randomised controlled trial.

Design

Mixed methods. Single blind pilot randomised controlled trial, with control offered Skype therapy at end of study. Qualitative study of the acceptability of therapy delivery via Skype.

Setting

Nine speech and language therapy departments in northern England recruited participants to the study. Skype therapy was provided in a university setting.

Participants

Twenty-two children (14 M, 8 F) with dysarthria and cerebral palsy (mean age 8.8 years (SD 3.2)) agreed to take part. Participants were randomised to dysarthria therapy via Skype (n=11) or treatment as usual (n=11).

Interventions

Children received either usual speech therapy from their local therapist for 6 weeks or dysarthria therapy via Skype from a research therapist. Usual therapy sessions varied in frequency, duration and content. Skype dysarthria therapy focused on breath control and phonation to produce clear speech at a steady rate, and comprised three 40 min sessions per week for 6 weeks.

Primary and secondary outcome measures

Feasibility and acceptability of the trial design, intervention and outcome measures.

Results

Departments recruited two to three participants. All participants agreed to random allocation. None withdrew from the study. Recordings of children's speech were made at all time points and rated by listeners. Families allocated to Skype dysarthria therapy judged internet delivery of the therapy to be acceptable. All families reported that the study design was acceptable. Treatment integrity checks suggested that the phrases practised in one therapy exercise should be reduced in length.

Conclusions

A delayed treatment design, in which dysarthria therapy is offered at the end of the study to families allocated to treatment as usual, is acceptable. A randomised controlled trial of internet delivered dysarthria therapy is feasible.

http://bit.ly/2TpufkC

Determinants of imbalanced sex ratio at birth in Nepal: evidence from secondary analysis of a large hospital-based study and nationally-representative survey data

Objectives

To quantify sex ratios at births (SRBs) in hospital deliveries in Nepal, and understand the socio-demographic correlates of skewed SRB. Skewed SRBs in hospitals could be explained by sex selective abortion, and/or by decision to have a son delivered in a hospital—increased in -utero investments for male fetus. We use data on ultrasound use to quantify links between prenatal knowledge of sex, parity and skewed SRBs.

Design

Secondary analysis of: (1) de-identified data from a randomizedrandomised controlled trial, and (2) 2011 Nepal Demographic and Health Survey (NDHS).

Setting

Nepal.

Participants

(1) 75 428 women who gave birth in study hospitals, (2) NDHS: 12 674 women aged 15–49 years.

Outcome measures

SRB, and conditional SRB of a second child given first born male or female were calculated.

Results

Using data from 75 428 women who gave birth in six tertiary hospitals in Nepal between September 2015 and March 2017, we report skewed SRBs in these hospitals, with some hospitals registering deliveries of 121 male births per 100 female births. We find that a nationally representative survey (2011 NDHS) reveals no difference in the number of hospital delivery of male and female babies. Additionally, we find that: (1) estimated SRB of second-order births conditional on the first being a girl is significantly higher than the biological SRB in our study and (2) multiparous women are more likely to have prenatal knowledge of the sex of their fetus and to have male births than primiparous women with the differences increasing with increasing levels of education.

Conclusions

Our analysis supports sex-selective abortion as the dominant cause of skewed SRBs in study hospitals. Comprehensive national policies that not only plan and enforce regulations against gender-biased abortions and, but also ameliorate the marginalizedmarginalised status of women in Nepal are urgently required to change this alarming manifestation of son preference.

Trial registration number

NCT02718222.

http://bit.ly/2BewnV5

Short email with attachment versus long email without attachment when contacting authors to request unpublished data for a systematic review: a nested randomised trial

Objective

Systematic reviews often rely on the acquisition of unpublished analyses or data. We carried out a nested randomised trial comparing two different approaches for contacting authors to request additional data for a systematic review.

Participants

Participants were authors of published reports of prevention or treatment trials in stroke in which there was central adjudication of events. A primary and secondary research active author were selected as contacts for each trial.

Interventions

Authors were randomised to be sent either a short email with a protocol of the systematic review attached ('Short') or a longer email that contained detailed information and without the protocol attached ('Long'). A maximum of two emails were sent to each author to obtain a response. The unit of analysis was trial, accounting for clustering by author.

Primary and secondary outcome measures

The primary outcome was whether a response was received from authors. Secondary outcomes included time to response, number of reminders needed before a response was received and whether authors agreed to collaborate.

Results

88 trials with 76 primary authors were identified in the systematic review, and of these, 36 authors were randomised to Short (trials=45) and 40 to Long (trials=43). Responses were received for 69 trials. There was no evidence of a difference in response rate between trial arms (Short vs Long, OR 1.10, 95% CI 0.36 to 3.33). There was no evidence of a difference in time to response between trial arms (Short vs Long, HR 0.91, 95% CI 0.55 to 1.51). In total, 27% of authors responded within a day and 22% of authors never responded.

Conclusions

There was no evidence to suggest that email format had an impact on the number of responses received when acquiring data for a systematic review involving stroke trials or the time taken to receive these responses.

http://bit.ly/2Tm7XA7

Protocol of a scoping review assessing injury rates and their determinants among healthcare workers in western countries

Introduction

Healthcare workers (HCWs) are exposed to various risk factors and risky behaviours that may seriously affect their health and ability to work. The aim of this protocol is to detail the steps to follow in order to carry out a scoping review to assess the prevalence/incidence of injuries among HCWs.

Methods and analysis

The study will be carried out in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses-Protocols guidelines. Studies will be selected according to the following criteria: P (HCWs), E (exposure to injuries), C (different types of exposure and different categories of HCWs) and O (prevalence/incidence and determinants of injuries). A time filter has been set (literature between 2000 and 2018) to enable updated, direct comparison between the findings and the epidemiological data available at national and local 'Istituto Nazionale per l'Assicurazione contro gli Infortuni sul Lavoro' (National Institute for Insurance Against Accidents at Work) centres in Italy. No language restriction will be applied.

Ethics and dissemination

Formal ethical approval is not required; primary data will not be collected, as they have already been published. The results will be disseminated through peer-reviewed publication(s), conference presentation(s) and the press.

http://bit.ly/2Bb5C40

Barriers to HIV care among Francophone African, Caribbean and Black immigrant people living with HIV in Canada: a protocol for a scoping systematic review

Introduction

Language is a social determinant of health. Addressing social determinants of health is paramount to successful progression along the HIV-care continuum. Canada is a bilingual country with French and English as official languages. There are few studies to date that have focused on the impact of being a French-speaking linguistic minority on the HIV-care continuum. The primary objective of this scoping, systematic review of literature is to evaluate existing gaps in access to HIV- care among French-speaking people living with HIV in Canada. Our primary outcome is healthcare services availability and access for French- speaking people living with HIV.

Methods and analyses

Our scoping, systematic review will draw on a systematic search of published literature, both quantitative and qualitative studies published on French-speaking individuals' healthcare and HIV status in Canada, with particular emphasis on the province of Ontario. We will conduct our search in MEDLINE, the Excerpta Medica Database, the Cumulative Index to Nursing and Allied Health Literature, Web of Science, EBSCO and Google Scholar for work published between 1990 and 2018. Identified articles will be screened in duplicate and full-text articles of relevant studies will be retrieved. Data will also be extracted by two researchers working independently. Any discrepancies that arise will be resolved by consensus or by consulting a third author. Our findings will be reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

Ethics and dissemination

Our proposed research will not be conducted with human participants. We will only use secondary published data and therefore ethics approval is not required. Our findings will be disseminated as peer reviewed manuscripts at conferences and student rounds, and could be of interest to government health agencies and local HIV/AIDS service organisations.

http://bit.ly/2Tm90Qp

Sinensetin induces apoptosis and autophagy in the treatment of human T-cell lymphoma

The present study was carried out to explore the effect of sinensetin in human T-cell lymphoma Jurkat cells and to reveal the underlying molecular mechanisms. We found that sinensetin significantly impeded Jurkat cell proliferation in a dose-dependent and time-dependent manner. Additionally, sinensetin treatment triggered apoptosis and autophagy in Jurkat cells. The apoptosis induction was related to a loss of mitochondrial membrane potential and to increased caspase-3/-8/-9 and poly(ADP-ribose) polymerase (PARP) cleavage. Sinensetin also induced autophagy, as evidenced by the formation of acidic vacuoles, the upregulation of LC3-II and beclin-1, and the downregulation of p62. In addition, the inhibition of autophagy by 3-methyladenine significantly enhanced the apoptosis rate and improved the sensitivity of the Jurkat cells to sinensetin. Moreover, sinensetin induced cell death, apoptosis, and autophagy through the activation of the reactive oxygen species/ c-Jun N-terminal kinase signaling pathway and the inhibition of the Akt/mTOR signaling pathways. In summary, our results revealed that sinensetin induced apoptosis and autophagy in human T-cell lymphoma Jurkat cells by activating reactive oxygen species/ c-Jun N-terminal kinase and blocking the Akt/mTOR signaling pathways. Thus, sinensetin might be a potential candidate in the development of antitumor drugs targeting T-cell leukemia. Correspondence to Chi-Chien Lin, PhD, Institute of Biomedical Science, National Chung-Hsing University, 145 Xingda Road, South District, Taichung City 402, Taiwan, Republic of China Tel: +886 422 851 175; fax: +886 422 853 469; e-mail: lincc@dragon.nchu.edu.tw Received October 24, 2018 Accepted January 14, 2019 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

http://bit.ly/2G3Hcxx

An astonishing case of liver-only metastatic colorectal cancer cured by FOLFOXIRI alone

The array of tools currently available and the aim of treatment make choosing the best therapeutic strategy in metastatic colorectal cancer (CRC) an increasing challenge worldwide. We present the case of a 53-year-old man with metachronous metastases (liver-only metastatic disease) treated with FOLFOXIRI as first-line treatment. In March 2010, a colonoscopy carried out for persistent constipation revealed a neoplastic stenosing mass. After a month, the patient underwent a low anterior rectal resection with colorectal anastomosis; no metastases were found on the computed tomography scan. Histology confirmed adenocarcinoma (pT3N0M0; stage IIA). No adjuvant treatment was given because of the absence of negative prognostic and molecular factors in stage II. After 6 months of follow-up, a computed tomography scan and 18F-FDG PET showed five focal hepatic lesions. We decided to start a FOLFOXIRI regimen aimed at conversion. The patient had a complete clinical and radiological response to chemotherapy after eight cycles. After 7 years, the patient is currently without any evidence of recurrence or progression of the disease. Few literature reports suggest that chemotherapy alone can cure patients with CRC liver metastases. Although regimens including oxaliplatin have never been reported as potential healing tools, the FOLFOXIRI chemotherapeutic schedule (oxaliplatin, irinotecan, and 5-fluorouracil) showed a high response rate in mCRC and can even cure the metastatic disease in sporadic cases. Correspondence to Giovanni Brandi, MD, PhD, Department of Experimental, Diagnostic and Specialty Medicine, S. Orsola-Malpighi University Hospital, via Massarenti 9, 40138 Bologna, Italy Tel: +39 512 143 838; fax: +39 516 363 815; e-mail: giovanni.brandi@unibo.it Received October 10, 2018 Accepted January 18, 2019 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

http://bit.ly/2GcmryQ

Sleep Abnormalities in Multiple Sclerosis

Abstract

Purpose of review

This review summarizes the most well-documented sleep disorders seen in patients with multiple sclerosis (MS), with a special focus on the impact on quality of life.

Recent findings

Sleep abnormalities in patients with MS are a multifactorial and relatively complex issue affecting approximately 60% of the patients while the pathophysiology of these symptoms is not fully understood. Circadian rhythm disorders and increased levels of pro-inflammatory cytokines have been recognized as potential players in affecting sleep homeostasis in MS patients. Medication-related side effects such as in immunotherapy and other factors such as lesion load can contribute to the disruption of normal sleep patterns.

Summary

Most frequently encountered sleep disorders are insomnia, sleep-related movement disorders, sleep-related breathing disorders, and circadian rhythm disorders affecting both adults and paediatric MS populations. Aetiology still remains unknown with treatment options focusing on behavioural cognitive therapy and lifestyle modification including improvement in sleep hygiene as well as melatonin supplementation. Given MS prevalence is still rising affecting millions of people, more personalized medicine applications should possibly form the key approach for improving patients' quality of life and quality years.

http://bit.ly/2HEVKFq

Experts Question Recent Pharma Acquisitions [News in Brief]

Deals may not yield much benefit for patients or shareholders.

http://bit.ly/2MLM3nu

Death at 10 Years Similar With Bilateral-, Single-Artery CABG

WEDNESDAY, Jan. 30, 2019 -- There is no difference in the rate of death from any cause at 10 years for patients undergoing coronary artery bypass grafting (CABG) with bilateral or single internal-thoracic-artery grafting, according to a study...

http://bit.ly/2GhVGJt

Expanded Recall Announced for Ibuprofen Oral Suspension Drops

WEDNESDAY, Jan. 30, 2019 -- An expanded recall of ibuprofen oral suspension drops that may contain higher-than-specified levels of ibuprofen that could harm infants' kidneys has been announced by Tris Pharma, Inc. The original recall last November...

http://bit.ly/2FZZQGt

FDA Receives an 'F' in Tobacco Prevention Report Card

WEDNESDAY, Jan. 30, 2019 -- The U.S. Food and Drug Administration was given an "F" in a new American Lung Association report card evaluating tobacco prevention programs. The FDA is failing to protect youth from electronic cigarettes, which can lead...

http://bit.ly/2GdM6Y0

Infective Endocarditis Related to Injection Drug Use Rising

WEDNESDAY, Jan. 30, 2019 -- The risk for infective endocarditis related to injection drug use increased from 2006 to 2015, according to a study published online Jan. 28 in CMAJ, the journal of the Canadian Medical Association. Matthew A. Weir, M.D.,...

http://bit.ly/2FZAZCI

Aerobic Exercise Tied to Better Cognition at All Ages

WEDNESDAY, Jan. 30, 2019 -- Aerobic exercise contributes to brain health in individuals as young as 20 years, according to a study published online Jan. 30 in Neurology. Yaakov Stern, Ph.D., from Columbia University in New York City, and colleagues...

http://bit.ly/2Gcxkkf

What is the contribution of physician associates in hospital care in England? A mixed methods, multiple case study

Objectives

To investigate the deployment of physician associates (PAs); the factors supporting and inhibiting their employment and their contribution and impact on patients' experience and outcomes and the organisation of services.

Design

Mixed methods within a case study design, using interviews, observations, work diaries and documentary analysis.

Setting

Six acute care hospitals in three regions of England in 2016–2017.

Participants

43 PAs, 77 other health professionals, 28 managers, 28 patients and relatives.

Results

A key influencing factor supporting the employment of PAs in all settings was a shortage of doctors. PAs were found to be acceptable, appropriate and safe members of the medical/surgical teams by the majority of doctors, managers and nurses. They were mainly deployed to undertake inpatient ward work in the medical/surgical team during core weekday hours. They were reported to positively contribute to: continuity within their medical/surgical team, patient experience and flow, inducting new junior doctors, supporting the medical/surgical teams' workload, which released doctors for more complex patients and their training. The lack of regulation and attendant lack of authority to prescribe was seen as a problem in many but not all specialties. The contribution of PAs to productivity and patient outcomes was not quantifiable separately from other members of the team and wider service organisation. Patients and relatives described PAs positively but most did not understand who and what a PA was, often mistaking them for doctors.

Conclusions

This study offers new insights concerning the deployment and contribution of PAs in medical and surgical specialties in English hospitals. PAs provided a flexible addition to the secondary care workforce without drawing from existing professions. Their utility in the hospital setting is unlikely to be completely realised without the appropriate level of regulation and authority to prescribe medicines and order ionising radiation within their scope of practice.

http://bit.ly/2DLoPuS

Sterol synthesis is essential for viability in the planctomycete bacterium Gemmata obscuriglobus

Abstract

Oxidosqualene cyclases (OSCs) are remarkable enzymes that catalyze the production of the first sterol, lanosterol, in sterol biosynthetic pathways. These reactions are present in a limited number of bacterial species unlike eukaryotic species where sterol synthesis is ubiquitous. The biological role(s) of OSCs, and the sterols produced by the different sterol biosynthetic pathways in bacteria, are not clearly understood. Here, we show that inhibition of the G. obscuriglobus OSC enzyme resulted in the inability of cells to form colonies on solid medium and resulted in cell death within 24 hours of inactivation for planktonic cells. The inclusion of lanosterol in cell culture medium was able to rescue the cell lethality associated with the OSC inhibitors. We purified active, recombinant bacterial OSC to high levels (> 3 mg L⁻¹ of culture) and demonstrated that the purified enzyme is active and inhibited by common OSC inhibitors. Comparable inhibitor concentrations were used in in vivo lethality experiments and in vitro enzymatic assays. Together, these results show that OSC, and the sterols produced by this enzyme, are essential for G. obscuriglobus viability.

http://bit.ly/2BaHY7u

Application of lactic acid bacteria in green biorefineries

Abstract

Lactic acid bacteria (LAB) have extensive industrial applications as producers of lactic acid, as probiotics, as biocontrol agents and as biopreservatives. LAB play a large role in food fermentation and in silage processes where crops such as grass, legumes, cereals or corn are fermented into high-moisture feed that is storable and can be used to feed cattle, sheep or other ruminants. LAB also have great applications within green biorefineries, with simultaneous production of protein-rich feed for monogastric animals, silage or feed pellets for ruminants and production of lactic acid or specific amino acids. In green biorefineries, fresh or ensiled wet biomass is mechanically fractionated into green juice and solid residues (press cake) where the plant juice for example can be used for production of lactic acid using LAB. In a process named 'ENLAC', recovery of protein and chlorophyll from silage by simultaneous lactic acid fermentation and enzyme hydrolysis has been developed. Furthermore, a process for protein recovery was recently developed by applying a specific LAB starter culture to green juice from freshly harvested crops. This paper focuses on reviewing LAB for their applications within biorefining of 'green' crops such as clover, alfalfa, grasses and other green plant materials.

http://bit.ly/2TmPHXp

Endoscopic stricturotomy versus ileocolonic resection in the treatment of ileocolonic anastomotic strictures in Crohn’s disease

Endoscopic stricturotomy is a novel technique in the treatment of anastomotic strictures in Crohn's disease (CD). The aim of this study was to compare the outcome of patients with ileocolonic anastomotic stricture treated with endoscopic stricturotomy (ESt) versus ileocolonic resection (ICR).

http://bit.ly/2BaKA5E

Painful anal lump

http://bit.ly/2TmPC63

A rare cause of bowel obstruction post laparoscopic totally extraperitoneal inguinal hernia repair

http://bit.ly/2BdKgTE

Variant metatarsal morphology causing metatarsal deformation in postaxial polydactyly

http://bit.ly/2TmPxzh

Increasing rate of para‐oesophageal hiatus hernia surgical repair within Australia

Operations claimed under MBS item number 31468 (para‐oesophageal hiatus hernia, repair of, with complete reduction of hernia, resection of sac and repair of hiatus, with or without fundoplication) have significantly increased in Australia since January 2001. Reasons for this rise are likely multifactorial, and may indicate: increasing para‐oesophageal hiatus hernia incidence; increased diagnosis and investigation; or increased surgical capability to manage the issue laparoscopically with reduced peri‐operative morbidity.

Background

Symptomatic para‐oesophageal hiatus (PEH) hernias are treated by surgical intervention, and are associated with older age (>50 years) and higher body mass index (>25 kg/m²). Both risk factors are increasing within the Australian population. Given these trends, this study aimed to determine if the rate of PEH repair is increasing within Australia.

Methods

The study used publically available Medicare Benefits Scheme service data for operations claimed under the item number 31468 (PEH hernia, repair of, with complete reduction of hernia, resection of sac and repair of hiatus, with or without fundoplication) between 1 January 2001 and 31 December 2016. Directly age‐standardized rates per 100 000 population were calculated using the 2001 Australian standard population and compared using Poisson regression models.

Results

Repair of PEH significantly increased (P < 0.0001) in Australia during this period, with the average number of services increasing by 14.6% per annum. Average rates of repair increased significantly (P < 0.001) with increasing age up to 75 years after which they significantly reduced (P < 0.001) in each successive age group. Western Australia had the greatest increase in annual claims and Northern Territory had the least, but the state‐specific average claim rate over the whole period was highest in Queensland and lowest in Northern Territory.

Conclusion

Operations claimed under Medicare Benefits Scheme item number 31468 have significantly increased in Australia since January 2001. Reasons for this rise are likely multifactorial, and may indicate increasing PEH incidence, increased diagnosis and investigation or increased surgical capability to manage the issue laparoscopically with reduced peri‐operative morbidity.

http://bit.ly/2Bc34SW

Renal trauma: a 3‐year audit from a Gold Coast trauma centre

Renal trauma trends from a Gold Coast trauma centre, including mechanisms of injury, American Association for the Surgery of Trauma (AAST) grades of injury, associated injuries, management and complications. Unique mechanisms in the authors' institution included Australian Rules Football‐ and Surf‐related renal trauma. Outcomes supported that the majority of haemodynamically stable high‐grade renal trauma can be successfully managed conservatively.

Background

Limited data Exists ? on the Australian epidemiology of renal trauma, with very few studies published in the literature. The authors aim to detail the trends of renal trauma in the coastal city of the Gold Coast.

Methods

Retrospective data collection yielded 81 patients who sustained renal trauma from our 3‐year period. Data included information on demographics, mechanism, American Association for the Surgery of Trauma (AAST) grade, presence of haematuria, associated injuries, management, and complications.

Results

Male patients accounted for 83% (n = 67) of cases, and the average age of all injuries was 36 years. Low‐grade AAST Grade I–III injuries comprised of 76% (n = 62) of injuries, AAST Grade IV contributed to 20% (n = 16) and 4% (n = 3) of injuries were AAST Grade V. The most common mechanism of injury was road accidents accounting for 35% (n = 28) followed by fall‐related injuries (26%, n = 21). Other mechanisms included sport‐related (13.5%, n = 11), non‐motorized bicycle injuries (8.5%, n = 7), alleged assault (8.5%, n = 7), pedestrian injuries (5%, n = 4) and horse‐related injuries (2%, n = 2). Ninety‐six percent (n = 78) of kidney injuries were managed conservatively. Of the patients requiring intervention, all were AAST Grade V kidney injuries.

Conclusion

Males accounted for the majority of renal trauma cases, similar to the 3:1 ratio of male‐to‐female injuries found in other studies. In line with other studies, renal trauma reviewed on the Gold Coast also revealed road trauma as the leading cause, closely followed by falls. The majority of high‐grade renal trauma was managed conservatively.

http://bit.ly/2TkBkCM

FDA Approves First Generic Advair Diskus

January 30, 2019 -- The U.S. Food and Drug Administration today approved the first generic of Advair Diskus (fluticasone propionate and salmeterol inhalation powder) for the twice-daily treatment of asthma in patients aged four years and older and...

http://bit.ly/2FYXFmj

Ectoine-Containing Inhalation Solution versus Saline Inhalation Solution in the Treatment of Acute Bronchitis and Acute Respiratory Infections: A Prospective, Controlled, Observational Study

Purpose. This study investigated an inhalation solution containing ectoine, a bacterial-derived extremolyte, for the treatment of acute bronchitis and acute respiratory infections in comparison with saline inhalation solution. Methods. This prospective, controlled, observational study comprised an inclusion visit (day 1), a final visit (day 7), and a follow-up questionnaire (day 17). The treatment itself was administered from day 1 to day 7. The Bronchitis Severity Score, patients' general health, general effectiveness of the treatment, tolerability, and adverse events were compared between two groups. Results. In total, 135 patients were recruited; 79 patients received ectoine inhalation solution and 56 saline inhalation solution. After treatment, symptom scores decreased significantly in both groups (P

http://bit.ly/2sXq9o8

Reply to Letter to the Editor regarding the Houston Consensus conference on testing for H. pylori infection in the United States

http://bit.ly/2MF7MgR

Reply to Methodological issues on prediction of hepatocellular carcinoma after sustained virological responses

http://bit.ly/2sXPWfU

A rare cause of pneumatosis intestinalis

http://bit.ly/2MHH5rM

Annular Pancreas

http://bit.ly/2sXpWkQ

Localized Gastrointestinal Amyloidosis Manifesting as an Isolated Colonic Ulcer: A Rare Cause of Hematochezia

http://bit.ly/2MEqFAi

Primary large anorectal melanoma presenting as intermittent rectal bleeding and mimicking a hemorrhoid

http://bit.ly/2sVYvYw

Target and whirl signs: volvulus of intussuscepted colon in an infant

http://bit.ly/2MHqeFv

Biliary ascariasis – an unusual case of obstructive jaundice

http://bit.ly/2sWiBlm

Sigmoid gallstone ileus

http://bit.ly/2MHqaFL

A conceptual approach to understanding treatment response in eosinophilic esophagitis

While the diagnosis and initial treatment of eosinophilic esophagitis (EoE) are becoming more standardized, there are still major gaps in knowledge related to measuring treatment response. One such question centers on how to measure treatment response and what treatment end-points should be. This impacts not only patient care and engagement in decision-making, but also the field of drug development. In addition, studies so far have use a myriad of treatment end-points including over a dozen histology end-point criteria.

http://bit.ly/2sXpH9q

A pancreatic lymphoepithelial cyst with floating-balls

http://bit.ly/2MF7GWx

Successful endoscopic removal of a large pancreatic stone in a patient after pancreaticoduodenectomy

http://bit.ly/2sXpCTa

The voltage signals of microbial fuel cell based sensors positively correlated with methane emission flux in paddy fields of China

Abstract

Previous studies showed that exoelectrogenic bacteria in paddy soil could suppress methanogens and methanogenesis after they were enriched by application of Fe³⁺ or running microbial fuel cells (MFCs). However, it is unknown the relationship between exoelectrogenic bacteria and methanogens without the enrichment process. Our study was conducted in three rice paddy fields in China and over three seasons. We explored novel MFC based sensors to in situ detect voltage signals that were generated from paddy soil within ten minutes. The voltage and methane emission flux were determined as an indicator of the exoelectrogenic activity and methanogenic activity, respectively. The abundance of exoelectrogenic bacteria were assessed by quantifying five exoelectrogenic bacterial-associated genera including Geobacter, Shewanella, Anaeromyxobacter, Desulfovibrio and Clostridium while the methanogens were studied by quantifying and sequencing the mcrA gene. The results showed that the abundance of exoelectrogenic bacteria and the voltage signals were positively correlated to the abundance of mcrA gene and methane emission flux, respectively. Moreover, non-metric dimensional scaling reveals that the abundance of Geobacter, Desulfovibrio and Clostridium significantly correlated with that of Methanomassiliicoccus, Methanoregula and Methanolinea. The present study suggests that the voltage signals might act as a novel indicator of methane emission flux in paddy fields.

http://bit.ly/2MHbKWd

The Fe(II)-oxidizing Zetaproteobacteria: Historical, ecological, and genomic perspectives

Abstract

The Zetaproteobacteria are a class of bacteria typically associated with marine Fe(II)-oxidizing environments. First discovered in the hydrothermal vents at Loihi Seamount, Hawaii, they have become model organisms for marine microbial Fe(II) oxidation. In addition to deep sea and shallow hydrothermal vents, Zetaproteobacteria are found in coastal sediments, other marine subsurface environments, steel corrosion biofilms, and saline terrestrial springs. Isolates from a range of environments all grow by autotrophic Fe(II) oxidation. Their success lies partly in their microaerophily, which enables them to compete with abiotic Fe(II) oxidation at Fe(II)-rich oxic/anoxic transition zones. To determine the known diversity of the Zetaproteobacteria, we have used 16S rRNA gene sequences to define 59 operational taxonomic units (OTUs), at 97% similarity. While some Zetaproteobacteria taxa appear to be cosmopolitan, others are enriched by specific habitats. OTU networks show that certain Zetaproteobacteria co-exist, sharing compatible niches. These niches may correspond with adaptations to O₂, H₂, and nitrate availability, based on genomic analyses of metabolic potential. Also, a putative Fe(II) oxidation gene has been found in diverse Zetaproteobacteria taxa, suggesting that the Zetaproteobacteria evolved as Fe(II) oxidation specialists. In all, studies suggest that Zetaproteobacteria are widespread, and therefore may have a broad influence on marine and saline terrestrial Fe cycling.

http://bit.ly/2sWmTcL

Acute-on-chronic breathlessness: recognition and response

Lovell et al are to be commended for their description of the widespread effects of breathlessness within the construct 'total breathlessness'.(1) Despite the large body of evidence on the experience of people living with chronic breathlessness, clinicians still struggle with its recognition and assessment. Even when recognised, the symptom is undertreated (2) and is experienced by people over many years (3-5) and is associated with repeated unplanned presentations to health services.(6)

http://bit.ly/2HHEpLM

Isolated Teres Minor Injury in a Dragon Boat Racer

No abstract available

http://bit.ly/2SbbRP1

Using In Vitro and In-cell SHAPE to Investigate Small Molecule Induced Pre-mRNA Structural Changes

Detailed protocols for both in vitro and in-cell selective 2'-hydroxyl acylation analyzed by primer extension (SHAPE) experiments to determine the secondary structure of pre-mRNA sequences of interest in the presence of an RNA-targeting small molecule are presented in this article.

http://bit.ly/2FXezSl

Measuring the Shape and Size of Activated Sludge Particles Immobilized in Agar with an Open Source Software Pipeline

The size and shape of particles in activated sludge are important parameters that are measured using varying methods. Inaccuracies arise from non-representative sampling, suboptimal images, and subjective analysis parameters. To minimize these errors and ease measurement, we present a protocol specifying every step, including an open source software pipeline.

http://bit.ly/2G95HIy

Detection of Endotoxin in Nano-formulations Using Limulus Amoebocyte Lysate (LAL) Assays

Detection of endotoxins in engineered nanomaterials represents one of the grand challenges in the field of nanomedicine. Here, we present a case study that describes the framework composed of three different LAL formats to estimate potential endotoxin contamination in nanoparticles.

http://bit.ly/2FXezBP

ACTN2 mutations cause “Multiple structured Core Disease” (MsCD)

Abstract

The identification of genes implicated in myopathies is essential for diagnosis and for revealing novel therapeutic targets. Here we characterize a novel subclass of congenital myopathy at the morphological, molecular, and functional level. Through exome sequencing, we identified de novo ACTN2 mutations, a missense and a deletion, in two unrelated patients presenting with progressive early-onset muscle weakness and respiratory involvement. Morphological and ultrastructural analyses of muscle biopsies revealed a distinctive pattern with the presence of muscle fibers containing small structured cores and jagged Z-lines. Deeper analysis of the missense mutation revealed mutant alpha-actinin-2 properly localized to the Z-line in differentiating myotubes and its level was not altered in muscle biopsy. Modelling of the disease in zebrafish and mice by exogenous expression of mutated alpha-actinin-2 recapitulated the abnormal muscle function and structure seen in the patients. Motor deficits were noted in zebrafish, and muscle force was impaired in isolated muscles from AAV-transduced mice. In both models, sarcomeric disorganization was evident, while expression of wild-type alpha-actinin-2 did not result in muscle anomalies. The murine muscles injected with mutant ACTN2 displayed cores and Z-line defects. Dominant ACTN2 mutations were previously associated with cardiomyopathies, and our data demonstrate that specific mutations in the well-known Z-line regulator alpha-actinin-2 can cause a skeletal muscle disorder.

http://bit.ly/2CSTc0F

Data Show No Evidence that Teens’ Social Media Use Predicts Depression Over Time

Longitudinal data from adolescents and young adults show no evidence that social media use predicts later depressive symptoms, according to research published in Clinical Psychological Science, a journal of the Association for Psychological Science. However, the findings do show that relatively higher depressive symptoms predicted later social media use among adolescent girls.

This research stands in contrast with recent claims that adolescents' use of social media may lead to depression, claims based primarily on studies that examined associations between average social media use and average well-being measured at a single point in time.

"You have to follow the same people over time in order to draw the conclusion that social media use predicts greater depressive symptoms," says lead author Taylor Heffer of Brock University. "By using two large longitudinal samples, we were able to empirically test that assumption."

Beginning in 2017, Heffer and coauthors surveyed 6th, 7th, and 8th graders in Ontario, Canada once a year for two years. The researchers also conducted annual surveys of undergraduate participants, beginning in their first year of university over a span of 6 years.

To measure depressive symptoms, the researchers used the Center for Epidemiological Studies Depression Scale for the young adults and an age-appropriate version of the same scale for the adolescents. All participants answered two questions about their average daily hours spent on social media – one measuring weekday use and the other measuring weekend use. The participants also answered questions about other screen time, such as watching TV, and non-screen activities including doing homework and exercising.

Heffer and colleagues analyzed the data separately for each age group and gender.

The results showed that social media use did not predict later depressive symptoms among adolescents or college undergraduates. Rather, greater depressive symptoms predicted more social media use over time, but only among adolescent girls.

"This finding contrasts with the idea that people who use a lot of social media become more depressed over time. Instead, adolescent girls who are feeling down may turn to social media to try and make themselves feel better," says Heffer.

Overall, the research suggests that the fear surrounding social media use and its impact on mental health may be premature.

"When parents read media headlines such as 'Facebook Depression,' there is an inherent assumption that social media use leads to depression. Policymakers also have recently been debating ways to tackle the effects of social media use on mental health," says Heffer.

Evaluating whether fears about the impacts of social media have merit requires prospective longitudinal studies that allow researchers to examine whether it is social media use that predicts depressive symptoms (rather than the other way around), while controlling for other potential influences. As Heffer and colleagues note, individual differences in personality, motivation, and current well-being are likely to play a critical role in the relationship between media use and future well-being.

"There may be different groups of people who use social media for different reasons," Heffer explains. "For example, there may be a group of people who use social media to make social comparisons or turn to it when they are feeling down, while another group of people may use it for more positive reasons, such as keeping in contact with friends."

Examining the role that these differences play will help clarify the ways in which social media interacts with mental health, with implications for parents, policymakers, and healthcare professionals alike.

Coauthors on the research include Marie Good of Redeemer University College and Owen Daly, Elliott MacDonnell, and Teena Willoughby, all of Brock University.

T. Willoughby received funding for this study from Social Sciences and Humanities Research Council of Canada and Canadian Institutes of Health Research.

http://bit.ly/2Ruhvr0

Patient Attitude Tied to Physical Therapy Outcomes

WEDNESDAY, Jan. 30, 2019 -- Patient expectation and pain self-efficacy are associated with clinical outcomes among patients undergoing physical therapy for shoulder pain, according to a study published online Jan. 24 in the British Journal of Sports...

http://bit.ly/2S3jlo4

ASA: Flu-Like Illness Linked to Increased Risk for Stroke

WEDNESDAY, Jan. 30, 2019 -- Influenza-like illness (ILI) is associated with an increased risk for ischemic stroke and cervical artery dissection (CeAD), according to two studies presented at the American Stroke Association International Stroke...

http://bit.ly/2RXcUTi

More Severe Injuries Sustained at Jump Parks Versus Home Trampolines

WEDNESDAY, Jan. 30, 2019 -- The proportion of fractures/dislocations, lower-extremity fractures, fractures in adults, and surgical interventions is higher for injuries associated with jump parks versus home trampolines, according to a study...

http://bit.ly/2CPqEF6

Avoiding Full-Blown Diabetes Cuts Cardiovascular Risk

WEDNESDAY, Jan. 30, 2019 -- Midlife increases in fasting glucose (FG) with conversion to diabetes are associated with higher cardiovascular disease (CVD) risk, according to research published online Jan. 7 in Diabetes Care. Michael P. Bancks, Ph.D.,...

http://bit.ly/2RXcTic

Thymectomy + PDN Beneficial for Non-Thymomatous Myasthenia Gravis

WEDNESDAY, Jan. 30, 2019 -- For patients with non-thymomatous myasthenia gravis, thymectomy plus prednisone confers benefits versus prednisone alone at five years, according to a study published online Jan. 25 in The Lancet Neurology. Gil I. Wolfe,...

http://bit.ly/2CPqD40

Hand Hygiene Compliance Low Among EMS Providers

WEDNESDAY, Jan. 30 2019 -- Among emergency medical service (EMS) providers, compliance with hand hygiene (HH) is low, according to a study published online Jan. 28 in the Emergency Medical Journal. Heidi Storm Vikke, Ph.D., from the University of...

http://bit.ly/2RXcRa4

Undisturbed Maternal Sleep Tied to Higher Risk for Late Stillbirth

WEDNESDAY, Jan. 30, 2019 -- Long periods of undisturbed sleep during pregnancy are associated with late stillbirth, according to a study published online Jan. 18 in Birth. Louise M. O'Brien Ph.D., from Michigan Medicine in Ann Arbor, and colleagues...

http://bit.ly/2CPqAVS

ASA: Increased Odds of Stroke, MI With E-Cigarette Use

WEDNESDAY, Jan. 30, 2019 -- Electronic cigarette use is associated with increased odds of stroke, myocardial infarction, and angina or coronary heart disease, according to a study presented at the American Stroke Association International Stroke...

http://bit.ly/2RXN9Cs

Off-Label Uses in Dermatology Often Missing From Compendia

WEDNESDAY, Jan. 30, 2019 -- The compendia used by Medicare for making coverage determinations are inadequate for dermatologic illnesses, and there is considerable discrepancy between compendia, according to a study published online Jan. 23 in JAMA...

http://bit.ly/2CZbqNU

No Asthma Benefit Seen With n3PUFA in Overweight Teens

WEDNESDAY, Jan. 30, 2019 -- Omega-3 fatty acid (n3PUFA) supplements do not appear to improve asthma control in teens and young adults who are overweight or obese, according to a study published online Jan. 25 in the Annals of the American Thoracic...

http://bit.ly/2CZbnBI

Determining 3'-Termini and Sequences of Nascent Single-Stranded Viral DNA Molecules during HIV-1 Reverse Transcription in Infected Cells

Here we present a deep sequencing approach that provides an unbiased determination of nascent 3'-termini as well as mutational profiles of single-stranded DNA molecules. The main application is the characterization of nascent retroviral complementary DNAs (cDNAs), the intermediates generated during the process of retroviral reverse transcription.

http://bit.ly/2RrYEN4

A New Straightforward Method for Lipophilicity (logP) Measurement using 19F NMR Spectroscopy

A novel and straightforward variation of the shake-flask method was developed for accurate lipophilicity measurement of fluorinated compounds by 19F NMR spectroscopy.

http://bit.ly/2WxKiP1

Gravity modulates behaviour control strategy

Abstract

Human behaviour is a trade-off between exploitation of familiar resources and exploration of new ones. In a challenging environment—such as outer space—making the correct decision is vital. On Earth, gravity is always there, and is an important reference for behaviour. Thus, altered gravitational signals may affect behaviour control strategies. Here, we investigated whether changing the body's orientation to the gravitational vector would modulate the balance between routine and novel behaviour. Participants completed a random number generation task while upright or supine. We found decreased randomness when participants were supine. In particular, the degree of equiprobability of pairs of consecutive responses was reduced in the supine orientation. Online gravitational signals may shape the balance between exploitation and exploration, in favour of more stereotyped and routine responses.

http://bit.ly/2FYYfR9

HBV infection-induced liver cirrhosis development in dual-humanised mice with human bone mesenchymal stem cell transplantation

Objective

Developing a small animal model that accurately delineates the natural history of hepatitis B virus (HBV) infection and immunopathophysiology is necessary to clarify the mechanisms of host-virus interactions and to identify intervention strategies for HBV-related liver diseases. This study aimed to develop an HBV-induced chronic hepatitis and cirrhosis mouse model through transplantation of human bone marrow mesenchymal stem cells (hBMSCs).

Design

Transplantation of hBMSCs into Fah^-/-Rag2^-/-IL-2Rc^-/- SCID (FRGS) mice with fulminant hepatic failure (FHF) induced by hamster-anti-mouse CD95 antibody JO2 generated a liver and immune cell dual-humanised (hBMSC-FRGS) mouse. The generated hBMSC-FRGS mice were subjected to assessments of sustained viremia, specific immune and inflammatory responses and liver pathophysiological injury to characterise the progression of chronic hepatitis and cirrhosis after HBV infection.

Results

The implantation of hBMSCs rescued FHF mice, as demonstrated by robust proliferation and transdifferentiation of functional human hepatocytes and multiple immune cell lineages, including B cells, T cells, natural killer cells, dendritic cells and macrophages. After HBV infection, the hBMSC-FRGS mice developed sustained viremia and specific immune and inflammatory responses and showed progression to chronic hepatitis and liver cirrhosis at a frequency of 55% after 54 weeks.

Conclusion

This new humanised mouse model recapitulates the liver cirrhosis induced by human HBV infection, thus providing research opportunities for understanding viral immune pathophysiology and testing antiviral therapies in vivo.

http://bit.ly/2TpfvlC

Nutmeg liver, fever and elevated liver enzymes in a young man

Question

A 27-year-old man was admitted to our department because of persistent symptoms of fever, dyspnoea, dry cough, elevated C reactive protein (CRP) (258 mg/L), leucocytosis (17x10⁹/L), peripheral eosinophilia (29%) and elevated liver enzymes (alanine aminotransferase (ALT) 518.2 U/L; aspartate aminotransferase (AST) 192.4 U/L; total bilirubin 1.6 mg/dL direct bilirubin 0.7 mg/dL; alkaline phosphatase 115.9 U/L and gamma glutamyl transferase (GGT) 119,4 U/L). His medical history was unremarkable except for surgery that he underwent 3 weeks ago for his left radius and ulna fracture. Since the surgery, he has been taking paracetamol and sodium metamizole. Empirical antibiotic therapy was initiated.

Chest X-ray revealed small left and large right pleural effusion. CT was performed due to elevated D-dimer, and there were no signs of pulmonary embolism. Right pleural effusion was drained, the microbiological analysis of pleural fluid was negative. Abdominal CT showed hepatomegaly with inhomogeneous mottled liver parenchyma consistent with features of 'nutmeg liver'. In addition, hepatic veins were not identified,...

http://bit.ly/2B5F0RV

HBV antiviral immunity: not all CD8 T cells are born equal

In Gut, two compelling papers1 2 provide novel insights into the complexity of HBV-specific T-cell responses through a detailed analysis of whether T-cell immunity targeting different HBV proteins in HBV-infected patients might exhibit distinct features.

CD8 T cells are a major component of antiviral immunity. Through their ability to recognise and target the cells where viral replication occurs, they can block and even terminate the spread of viral infection in the host. Their highly selective recognition is mediated by the T-cell receptor (TCR) which detects HLA-class I/viral peptide complexes on the cell surface. These protein complexes are made by short viral peptides generated by the processing of viral proteins synthesised within the infected cells (called epitopes) non-covalently associated with HLA-class I molecules. The recognition of viral peptide/HLA complexes by the specific TCR activates the CD8 T cells, which can directly lyse the virus-producing cell or secrete cytokines that...

http://bit.ly/2Tlrfph

Puncta of Neuronal Nitric Oxide Synthase (nNOS) Mediate NMDA Receptor Signaling in the Auditory Midbrain

Nitric oxide (NO) is a neurotransmitter synthesized in the brain by neuronal nitric oxide synthase (nNOS). Using immunohistochemistry and confocal imaging in the inferior colliculus (IC, auditory midbrain) of the guinea pig (Cavia porcellus, male and female), we show that nNOS occurs in two distinct cellular distributions. We confirm that, in the cortices of the IC, a subset of neurons show cytoplasmic labeling for nNOS, whereas in the central nucleus (ICc), such neurons are not present. However, we demonstrate that all neurons in the ICc do in fact express nNOS in the form of discrete puncta found at the cell membrane. Our multi-labeling studies reveal that nNOS puncta form multiprotein complexes with NMDA receptors, soluble guanylyl cyclase (sGC), and PSD95. These complexes are found apposed to glutamatergic terminals, which is indicative of synaptic function. Interestingly, these glutamatergic terminals express both vesicular glutamate transporters 1 and 2 denoting a specific source of brainstem inputs. With in vivo electrophysiological recordings of multiunit activity in the ICc, we found that local application of NMDA enhances sound-driven activity in a concentration-dependent and reversible fashion. This response is abolished by blockade of nNOS or sGC, indicating that the NMDA effect is mediated solely via the NO and cGMP signaling pathway. This discovery of a ubiquitous, but highly localized, expression of nNOS throughout the ICc and demonstration of the dramatic influence of the NMDA activated NO pathway on sound-driven neuronal activity imply a key role for NO signaling in auditory processing.

SIGNIFICANCE STATEMENT We show that neuronal nitric oxide synthase (nNOS), the enzyme that synthesizes nitric oxide (NO), occurs as puncta in apparently all neurons in the central nucleus of the inferior colliculus (ICc) in the auditory midbrain. Punctate nNOS appears at glutamatergic synapses in a complex with glutamate NMDA receptors (NMDA-Rs), soluble guanylyl cyclase (sGC, the NO receptor), and PSD95 (a protein that anchors receptors and enzymes at the postsynaptic density). We show that NMDA-R modulation of sound-driven activity in the ICc is solely mediated by activation of nNOS and sGC. The presence of nNOS throughout this sensory nucleus argues for a major role of NO in hearing. Furthermore, this punctate form of nNOS expression may exist and have gone unnoticed in other brain regions.

http://bit.ly/2BbpnIx

Fine Control of Sound Frequency Tuning and Frequency Discrimination Acuity by Synaptic Zinc Signaling in Mouse Auditory Cortex

Neurons in the auditory cortex are tuned to specific ranges of sound frequencies. Although the cellular and network mechanisms underlying neuronal sound frequency selectivity are well studied and reflect the interplay of thalamocortical and intracortical excitatory inputs and further refinement by cortical inhibition, the precise synaptic signaling mechanisms remain less understood. To gain further understanding on these mechanisms and their effects on sound-driven behavior, we used in vivo imaging as well as behavioral approaches in awake and behaving female and male mice. We discovered that synaptic zinc, a modulator of neurotransmission and responsiveness to sound, sharpened the sound frequency tuning of principal and parvalbumin-expressing neurons and widened the sound frequency tuning of somatostatin-expressing inhibitory neurons in layer 2/3 of the primary auditory cortex. In the absence of cortical synaptic zinc, mice exhibited reduced acuity for detecting changes in sound frequencies. Together, our results reveal that cell-type-specific effects of zinc contribute to cortical sound frequency tuning and enhance acuity for sound frequency discrimination.

SIGNIFICANCE STATEMENT Neuronal tuning to specific features of sensory stimuli is a fundamental property of cortical sensory processing that advantageously supports behavior. Despite the established roles of synaptic thalamocortical and intracortical excitation and inhibition in cortical tuning, the precise synaptic signaling mechanisms remain unknown. Here, we investigated these mechanisms in the mouse auditory cortex. We discovered a previously unknown signaling mechanism linking synaptic zinc signaling with cell-specific cortical tuning and enhancement in sound frequency discrimination acuity. Given the abundance of synaptic zinc in all sensory cortices, this newly discovered interaction between synaptic zinc and cortical tuning can provide a general mechanism for modulating neuronal stimulus specificity and sensory-driven behavior.

http://bit.ly/2BlDdbF

Perceptual Decision-Making: Biases in Post-Error Reaction Times Explained by Attractor Network Dynamics

Perceptual decision-making is the subject of many experimental and theoretical studies. Most modeling analyses are based on statistical processes of accumulation of evidence. In contrast, very few works confront attractor network models' predictions with empirical data from continuous sequences of trials. Recently however, numerical simulations of a biophysical competitive attractor network model have shown that such a network can describe sequences of decision trials and reproduce repetition biases observed in perceptual decision experiments. Here we get more insights into such effects by considering an extension of the reduced attractor network model of Wong and Wang (2006), taking into account an inhibitory current delivered to the network once a decision has been made. We make explicit the conditions on this inhibitory input for which the network can perform a succession of trials, without being either trapped in the first reached attractor, or losing all memory of the past dynamics. We study in detail how, during a sequence of decision trials, reaction times and performance depend on nonlinear dynamics of the network, and we confront the model behavior with empirical findings on sequential effects. Here we show that, quite remarkably, the network exhibits, qualitatively and with the correct order of magnitude, post-error slowing and post-error improvement in accuracy, two subtle effects reported in behavioral experiments in the absence of any feedback about the correctness of the decision. Our work thus provides evidence that such effects result from intrinsic properties of the nonlinear neural dynamics.

SIGNIFICANCE STATEMENT Much experimental and theoretical work is being devoted to the understanding of the neural correlates of perceptual decision-making. In a typical behavioral experiment, animals or humans perform a continuous series of binary discrimination tasks. To model such experiments, we consider a biophysical decision-making attractor neural network, taking into account an inhibitory current delivered to the network once a decision is made. Here we provide evidence that the same intrinsic properties of the nonlinear network dynamics underpins various sequential effects reported in experiments. Quite remarkably, in the absence of feedback on the correctness of the decisions, the network exhibits post-error slowing (longer reaction times after error trials) and post-error improvement in accuracy (smaller error rates after error trials).

http://bit.ly/2TjddnT

Hippocampal Reactivation Extends for Several Hours Following Novel Experience

New memories are believed to be consolidated over several hours of post-task sleep. The reactivation or "replay" of hippocampal cell assemblies has been proposed to provide a key mechanism for this process. However, previous studies have indicated that such replay is restricted to the first 10–30 min of post-task sleep, suggesting that it has a limited role in memory consolidation. We performed long-duration recordings in sleeping and behaving male rats and applied methods for evaluating the reactivation of neurons in pairs as well as in larger ensembles while controlling for the continued activation of ensembles already present during pre-task sleep ("preplay"). We found that cell assemblies reactivate for up to 10 h, with a half-maximum timescale of ~6 h, in sleep following novel experience, even when corrected for preplay. We further confirmed similarly prolonged reactivation in post-task sleep of rats in other datasets that used behavior in novel environments. In contrast, we saw limited reactivation in sleep following behavior in familiar environments. Overall, our findings reconcile the duration of replay with the timescale attributed to cellular memory consolidation and provide strong support for an integral role of replay in memory.

SIGNIFICANCE STATEMENT Neurons that are active during an experience reactivate again afterward during rest and sleep. This replay of ensembles of neurons has been proposed to help strengthen memories, but it has also been reported that replay occurs only in the first 10–30 min of sleep, suggesting a circumscribed role. We performed long-duration recordings in the hippocampus of rats and found that replay persists for several hours in sleep following novel experience, far beyond the limits found in previous reports based on shorter recordings. These findings reconcile the duration of replay with the hours-long timescales attributed to memory consolidation.

http://bit.ly/2TrevO4

Sleep Deprivation Selectively Upregulates an Amygdala-Hypothalamic Circuit Involved in Food Reward

Sleep loss is associated with increased obesity risk, as demonstrated by correlations between sleep duration and change in body mass index or body fat percentage. Whereas previous studies linked this weight gain to disturbed endocrine parameters after sleep deprivation or restriction, neuroimaging studies revealed upregulated neural processing of food rewards after sleep loss in reward-processing areas such as the anterior cingulate cortex, ventral striatum, and insula. To address this ongoing debate between hormonal versus hedonic factors underlying sleep-loss-associated weight gain, we rigorously tested the association between sleep deprivation and food cue processing using high-resolution fMRI and assessment of hormones. After taking blood samples from 32 lean, healthy, human male participants, they underwent fMRI while performing a neuroeconomic, value-based decision-making task with snack food and trinket rewards following a full night of habitual sleep and a night of sleep deprivation in a repeated-measures crossover design. We found that des-acyl ghrelin concentrations were increased after sleep deprivation compared with habitual sleep. Despite similar hunger ratings due to fasting in both conditions, participants were willing to spend more money on food items only after sleep deprivation. Furthermore, fMRI data paralleled this behavioral finding, revealing a food-reward-specific upregulation of hypothalamic valuation signals and amygdala–hypothalamic coupling after a single night of sleep deprivation. Behavioral and fMRI results were not significantly correlated with changes in acyl, des-acyl, or total ghrelin concentrations. Our results suggest that increased food valuation after sleep loss might be due to hedonic rather than hormonal mechanisms.

SIGNIFICANCE STATEMENT Epidemiological studies suggest an association between overweight and reduced nocturnal sleep, but the relative contributions of hedonic and hormonal factors to overeating after sleep loss are a matter of ongoing controversy. Here, we tested the association between sleep deprivation and food cue processing in a repeated-measures crossover design using fMRI. We found that willingness to pay increased for food items only after sleep deprivation. fMRI data paralleled this behavioral finding, revealing a food-reward-specific upregulation of hypothalamic valuation signals and amygdala-hypothalamic coupling after a single night of sleep deprivation. However, there was no evidence for hormonal modulations of behavioral or fMRI findings. Our results suggest that increased food valuation after sleep loss is due to hedonic rather than hormonal mechanisms.

http://bit.ly/2TmMh75

Genetic and epigenetic analysis of the BAX and BCL2 in the placenta of pregnant women complicated by preeclampsia

Abstract

The current study examined the effects of BAX and BCL2 polymorphisms and methylation as well as mRNA expression on susceptibility to PE. After delivery, the placentas were collected from 92 women with PE, as well as 106 normotensive pregnant women. The BAX rs4645878 and BCL2 rs2279115 polymorphisms were genotyped by the PCR-RFLP method. Methylation-specific PCR (MSP) was used for analysis of promoter methylation. mRNA expression was assayed by Quantitative RT-PCR. In addition, in silico analysis was performed by bioinformatics tools. There was no relationship between PE and placental BAX rs4645878 and BCL2 rs2279115 polymorphisms. The groups were not significantly different regarding the promoter methylation of BAX gene. Nonetheless, the MM status of BCL2 promoter had a significantly higher frequency in the PE group and was associated with 2.7-fold higher risk of PE (OR = 2.7, 95% CI = 1.3–5.6; P = 0.01). The relative mRNA expression of BCL2 was decreased in the placentas of PE women (P < 0.0001). The expression of BAX gene was not significantly different between the two groups. There was no association between placental BAX rs4645878 and BCL2 rs2279115 polymorphisms and mRNA expression levels. In silico analysis indicated that BAX rs4645878 and BCL2 rs2279115 polymorphisms were located in the core recognition site of different transcription factors and these substitutions of wild allele resulted in the loss and/ or change of these binding sites and subsequently may alter BCL2 and BAX expression. This study showed that the BAX and BCL2 polymorphisms and BAX promoter methylation were not associated with PE risk. The BCL2 promoter methylation was associated with lower BCL2 expression and higher PE susceptibility.

http://bit.ly/2DLd6fT

Structural Design and Manufacturing of a Cruiser Class Solar Vehicle

In this work, several aspects related to the structural design process of a full-carbon fiber-reinforced plastic solar vehicle are detailed, focusing on the monocoque chassis, the leaf springs, and the vehicle as a whole during a crash test.

http://bit.ly/2MIg8UE

Detection of 3-Nitrotyrosine in Atmospheric Environments via a High-performance Liquid Chromatography-electrochemical Detector System

We present a method to detect 3-nitrotyrosine chemical modifications of atmospheric proteins with 6 mm-diameter rounds cut from air sampler prefilters using a high-performance liquid chromatography-electrochemical detector (HPLC-ECD).

http://bit.ly/2sROkV0

A New Beginning for Cells Tissues Organs

Cells Tissues Organs 2018;205:1–2

http://bit.ly/2FUYBrS

Input-Specific Synaptic Location and Function of the {alpha}5 GABAA Receptor Subunit in the Mouse CA1 Hippocampal Neurons

Hippocampus-dependent learning processes are coordinated via a large diversity of GABAergic inhibitory mechanisms. The α5 subunit-containing GABA_A receptor (α5-GABA_AR) is abundantly expressed in the hippocampus populating primarily the extrasynaptic domain of CA1 pyramidal cells, where it mediates tonic inhibitory conductance and may cause functional deficits in synaptic plasticity and hippocampus-dependent memory. However, little is known about synaptic expression of the α5-GABA_AR and, accordingly, its location site-specific function. We examined the cell- and synapse-specific distribution of the α5-GABA_AR in the CA1 stratum oriens/alveus (O/A) using a combination of immunohistochemistry, whole-cell patch-clamp recordings and optogenetic stimulation in hippocampal slices obtained from mice of either sex. In addition, the input-specific role of the α5-GABA_AR in spatial learning and anxiety-related behavior was studied using behavioral testing and chemogenetic manipulations. We demonstrate that α5-GABA_AR is preferentially targeted to the inhibitory synapses made by the vasoactive intestinal peptide (VIP)- and calretinin-positive terminals onto dendrites of somatostatin-expressing interneurons. In contrast, synapses made by the parvalbumin-positive inhibitory inputs to O/A interneurons showed no or little α5-GABA_AR. Inhibiting the α5-GABA_AR in control mice in vivo improved spatial learning but also induced anxiety-like behavior. Inhibiting the α5-GABA_AR in mice with inactivated CA1 VIP input could still improve spatial learning and was not associated with anxiety. Together, these data indicate that the α5-GABA_AR-mediated phasic inhibition via VIP input to interneurons plays a predominant role in the regulation of anxiety while the α5-GABA_AR tonic inhibition via this subunit may control spatial learning.

SIGNIFICANCE STATEMENT The α5-GABA_AR subunit exhibits high expression in the hippocampus, and regulates the induction of synaptic plasticity and the hippocampus-dependent mnemonic processes. In CA1 principal cells, this subunit occupies mostly extrasynaptic sites and mediates tonic inhibition. Here, we provide evidence that, in CA1 somatostatin-expressing interneurons, the α5-GABA_AR subunit is targeted to synapses formed by the VIP- and calretinin-expressing inputs, and plays a specific role in the regulation of anxiety-like behavior.

http://bit.ly/2FZEZTr