Pulmonary epithelial barrier and immunological functions at birth and in early life - key determinants of the development of asthma? A description of the protocol for the Breathing Together study

Acknowledgements The authors are indebted to the participants and parents who have already been recruited. We also acknowledge the enthusiasm and endeavour of the research nurse team which includes: Stephen Main, Margaret Connon, Catherine Beveridge, Julie Baggott, Kay Riding, Ellie McCamie, Maria Larsson, Lynda Melvin, Mumtaz Idris, Tara Murray, Nicky Tongue, Nicolene Plaatjies, Sheila Mortimer, Sally Spedding, Susy Grevatt, Victoria Welch, Morag Zelisko, Jillian Doherty, Jane Martin, Emma Macleod and Cilla Snape. We are also delighted to be working alongside the following colleagues in laboratories: Marie Craigon, Marie McWilliam, Maria Zarconi, Judit Barabas, Lindsay Broadbent, Ceyda Oksel and Sheerien Manzoor. Grant information The study is supported by the Wellcome Trust [108818]; and the PHA HSC R&D Division, Northern Ireland.Peer reviewedPublisher PD

The effects of exercise on pain, fatigue, insomnia, and health perceptions in patients with operable advanced stage rectal cancer prior to surgery: a pilot trial

Background: Promoting quality of life (QoL) is a key priority in cancer care. We investigated the hypothesis that, in comparison to usual care, exercise post-neoadjuvant chemoradiation therapy/prior to surgical resection will reduce pain, fatigue, and insomnia, and will improve physical and mental health perceptions in patients with locally advanced stage rectal cancer. Methods: In this non-randomized controlled pilot trial, patients in the supervised exercise group (EG; Mage = 64 years; 64% male) and in the control group (CG; Mage = 72 years; 69% male) completed the European Organization for Research and Treatment of Cancer core Quality of Life questionnaire and the RAND 36-Item Health Survey three times: pre-neoadjuvant chemoradiation therapy (Time 1; nEC = 24; nCG = 11), post-neoadjuvant chemoradiation therapy/pre-exercise intervention (Time 2; nEC = 23; nCG = 10), and post-exercise intervention (Time 3; nEC = 22; nCG = 10). The 6-week exercise intervention was delivered in hospital and comprised of interval aerobic training. Patients trained in pairs three times per week for 30 to 40 minutes. Data were analyzed by Mann-Whitney tests and by Wilcoxon matched-pairs signed rank tests. Results: No significant between-group differences in change were found for any of the outcomes. In both groups, fatigue levels decreased and physical health perceptions increased from pre- to post-exercise intervention. Pain levels also decreased from pre- to post-exercise intervention, albeit not significantly. Conclusions: The findings from this study can be used to guide a more definitive trial as they provide preliminary evidence regarding the potential effects of pre-operative exercise on self-reported pain, fatigue, insomnia, and health perceptions in patients with locally advanced rectal cancer. Trial registration: This study has been registered with clinicaltrials.gov (NCT01325909; March 29, 2011)

The Use of Preoperative Prophylactic Systemic Antibiotics for the Prevention of Endopthalmitis in Open Globe Injuries:A Meta-Analysis

Topic:This study reports the effect of systemic prophylactic antibiotics (and their route) on the risk of endophthalmitis after open globe injury. Clinical relevance:Endophthalmitis is a major complication of open globe injury, it can lead to rapid sight loss in the affected eye. The administration of systemic antibiotic prophylaxis is common practice in some health care systems, although there is no consensus on their use. PubMed, CENTRAL, Web of Science, CINAHL and Embase were searched. This was completed 6th July 2021 and updated 10th Dec 2022. We included randomised and non-randomised prospective studies which reported the rate of post-open globe injury endophthalmitis, when systemic pre-operative antibiotic prophylaxis (via the oral or intravenous route) was given. The Cochrane Risk of Bias tool and ROBINS-I tool were used for assessing the risk of bias. Where meta-analysis was performed results were reported as odds ratio. PROSPERO registration: CRD42021271271. Three studies were included. One prospective observational study compared outcomes of patients who had received systemic or no systemic pre-operative antibiotics. The endophthalmitis rates reported were 3.75% and 4.91% in the systemic and no systemic pre-operative antibiotics groups, a non-significant difference (p = 0.68). Two randomised controlled trials were included (1,555 patients). The rates of endophthalmitis were 17 events in 751 patients (2.26%) and 17 events in 804 patients (2.11%) in the oral antibiotics and intravenous (+/- oral) antibiotics groups, respectively. Meta-analysis demonstrated no significant differences between groups (OR 1.07 [95% confidence interval 0.54 – 2.12]). The incidences of endophthalmitis after open globe injury were low with and without systemic antibiotic prophylaxis, although high risk cases were excluded in the included studies. When antibiotic prophylaxis is considered, there is moderate evidence that oral antibiotic administration is non-inferior to intravenous

The Risk of Sympathetic Ophthalmia Associated with Open-Globe Injury Management Strategies:A Meta-analysis

Topic: Sympathetic ophthalmia (SO) is a sight-threatening granulomatous panuveitis caused by a sensitizing event. Primary enucleation or primary evisceration, versus primary repair, as a risk management strategy after open-globe injury (OGI) remains controversial.Clinical Relevance: This systematic review was conducted to report the incidence of SO after primary repair compared with that of after primary enucleation or primary evisceration. This enabled the reporting of an estimated number needed to treat.Methods: Five journal databases were searched. This review was registered with International Prospective Register of Systematic Reviews (identifier, CRD42021262616). Searches were carried out on June 29, 2021, and were updated on December 10, 2022. Prospective or retrospective studies that reported outcomes (including SO or lack of SO) in a patient population who underwent either primary repair and primary enucleation or primary evisceration were included. A systematic review and meta-analysis were carried out in accordance with Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Random effects modelling was used to estimate pooled SO rates and absolute risk reduction (ARR).Results: Eight studies reporting SO as an outcome were included in total. The included studies contained 7500 patients and 7635 OGIs. In total, 7620 OGIs met the criteria for inclusion in this analysis; SO developed in 21 patients with OGI. When all included studies were pooled, the estimated SO rate was 0.12% (95% confidence interval [CI], 0.00%–0.25%) after OGI. Of 779 patients who underwent primary enucleation or primary evisceration, no SO cases were reported, resulting in a pooled SO estimate of 0.05% (95% CI, 0.00%–0.21%). For primary repair, the pooled estimate of SO rate was 0.15% (95% CI, 0.00%–0.33%). The ARR using a random effects model was −0.0010 (in favour of eye removal; 95% CI, −0.0031 [in favor of eye removal] to 0.0011 [in favor of primary repair]). Grading of Recommendations, Assessment, Development, and Evaluations analysis highlighted a low certainty of evidence because the included studies were observational, and a risk of bias resulted from missing data.Discussion: Based on the available data, no evidence exists that primary enucleation or primary evisceration reduce the risk of secondary SO.Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article

Identification of Mammalian Protein Quality Control Factors by High-Throughput Cellular Imaging

Protein Quality Control (PQC) pathways are essential to maintain the equilibrium between protein folding and the clearance of misfolded proteins. In order to discover novel human PQC factors, we developed a high-content, high-throughput cell-based assay to assess PQC activity. The assay is based on a fluorescently tagged, temperature sensitive PQC substrate and measures its degradation relative to a temperature insensitive internal control. In a targeted screen of 1591 siRNA genes involved in the Ubiquitin-Proteasome System (UPS) we identified 25 of the 33 genes encoding for 26S proteasome subunits and discovered several novel PQC factors. An unbiased genome-wide siRNA screen revealed the protein translation machinery, and in particular the EIF3 translation initiation complex, as a novel key modulator of misfolded protein stability. These results represent a comprehensive unbiased survey of human PQC components and establish an experimental tool for the discovery of genes that are required for the degradation of misfolded proteins under conditions of proteotoxic stress

Measurement of flavor asymmetry of light-quark sea in the proton with Drell-Yan dimuon production in p+pp+p and p+dp+d collisions at 120 GeV

Evidence for a flavor asymmetry between the $\bar u$ and $\bar d$ quark distributions in the proton has been found in deep-inelastic scattering and Drell-Yan experiments. The pronounced dependence of this flavor asymmetry on $x$ (fraction of nucleon momentum carried by partons) observed in the Fermilab E866 Drell-Yan experiment suggested a drop of the $\bar d\left(x\right) / \bar u\left(x\right)$ ratio in the $x > 0.15$ region. We report results from the SeaQuest Fermilab E906 experiment with improved statistical precision for $\bar d\left(x\right) / \bar u\left(x\right)$ in the large $x$ region up to $x=0.45$ using the 120 GeV proton beam. Two different methods for extracting the Drell-Yan cross section ratios, $\sigma^{pd} /2 \sigma^{pp}$, from the SeaQuest data give consistent results. The $\bar{d}\left(x\right) / \bar{u}\left(x\right)$ ratios and the $\bar d\left(x\right) - \bar u\left(x\right)$ differences are deduced from these cross section ratios for $0.13 < x < 0.45$. The SeaQuest and E866/NuSea $\bar{d}\left(x\right) / \bar{u}\left(x\right)$ ratios are in good agreement for the $x\lesssim 0.25$ region. The new SeaQuest data, however, show that $\bar d\left(x\right)$ continues to be greater than $\bar u\left(x\right)$ up to the highest $x$ value ($x = 0.45$). The new results on $\bar{d}\left(x\right) / \bar{u}\left(x\right)$ and $\bar{d}\left(x\right) - \bar{u}\left(x\right)$ are compared with various parton distribution functions and theoretical calculations

Modeling Signal Propagation Mechanisms and Ligand-Based Conformational Dynamics of the Hsp90 Molecular Chaperone Full-Length Dimer

Hsp90 is a molecular chaperone essential for protein folding and activation in normal homeostasis and stress response. ATP binding and hydrolysis facilitate Hsp90 conformational changes required for client activation. Hsp90 plays an important role in disease states, particularly in cancer, where chaperoning of the mutated and overexpressed oncoproteins is important for function. Recent studies have illuminated mechanisms related to the chaperone function. However, an atomic resolution view of Hsp90 conformational dynamics, determined by the presence of different binding partners, is critical to define communication pathways between remote residues in different domains intimately affecting the chaperone cycle. Here, we present a computational analysis of signal propagation and long-range communication pathways in Hsp90. We carried out molecular dynamics simulations of the full-length Hsp90 dimer, combined with essential dynamics, correlation analysis, and a signal propagation model. All-atom MD simulations with timescales of 70 ns have been performed for complexes with the natural substrates ATP and ADP and for the unliganded dimer. We elucidate the mechanisms of signal propagation and determine “hot spots” involved in interdomain communication pathways from the nucleotide-binding site to the C-terminal domain interface. A comprehensive computational analysis of the Hsp90 communication pathways and dynamics at atomic resolution has revealed the role of the nucleotide in effecting conformational changes, elucidating the mechanisms of signal propagation. Functionally important residues and secondary structure elements emerge as effective mediators of communication between the nucleotide-binding site and the C-terminal interface. Furthermore, we show that specific interdomain signal propagation pathways may be activated as a function of the ligand. Our results support a “conformational selection model” of the Hsp90 mechanism, whereby the protein may exist in a dynamic equilibrium between different conformational states available on the energy landscape and binding of a specific partner can bias the equilibrium toward functionally relevant complexes

Comparative Linkage Meta-Analysis Reveals Regionally-Distinct, Disparate Genetic Architectures: Application to Bipolar Disorder and Schizophrenia

New high-throughput, population-based methods and next-generation sequencing capabilities hold great promise in the quest for common and rare variant discovery and in the search for ”missing heritability.” However, the optimal analytic strategies for approaching such data are still actively debated, representing the latest rate-limiting step in genetic progress. Since it is likely a majority of common variants of modest effect have been identified through the application of tagSNP-based microarray platforms (i.e., GWAS), alternative approaches robust to detection of low-frequency (1–5% MAF) and rare (<1%) variants are of great importance. Of direct relevance, we have available an accumulated wealth of linkage data collected through traditional genetic methods over several decades, the full value of which has not been exhausted. To that end, we compare results from two different linkage meta-analysis methods—GSMA and MSP—applied to the same set of 13 bipolar disorder and 16 schizophrenia GWLS datasets. Interestingly, we find that the two methods implicate distinct, largely non-overlapping, genomic regions. Furthermore, based on the statistical methods themselves and our contextualization of these results within the larger genetic literatures, our findings suggest, for each disorder, distinct genetic architectures may reside within disparate genomic regions. Thus, comparative linkage meta-analysis (CLMA) may be used to optimize low-frequency and rare variant discovery in the modern genomic era

Treatment of bipolar disorder: a complex treatment for a multi-faceted disorder

Background: Manic-depression or bipolar disorder (BD) is a multi-faceted illness with an inevitably complex treatment. Methods: This article summarizes the current status of our knowledge and practice of its treatment. Results: It is widely accepted that lithium is moderately useful during all phases of bipolar illness and it might possess a specific effectiveness on suicidal prevention. Both first and second generation antipsychotics are widely used and the FDA has approved olanzapine, risperidone, quetiapine, ziprasidone and aripiprazole for the treatment of acute mania. These could also be useful in the treatment of bipolar depression, but only limited data exists so far to support the use of quetiapine monotherapy or the olanzapine-fluoxetine combination. Some, but not all, anticonvulsants possess a broad spectrum of effectiveness, including mixed dysphoric and rapid-cycling forms. Lamotrigine may be effective in the treatment of depression but not mania. Antidepressant use is controversial. Guidelines suggest their cautious use in combination with an antimanic agent, because they are supposed to induce switching to mania or hypomania, mixed episodes and rapid cycling. Conclusion: The first-line psychosocial intervention in BD is psychoeducation, followed by cognitive-behavioral therapy. Other treatment options include Electroconvulsive therapy and transcranial magnetic stimulation. There is a gap between the evidence base, which comes mostly from monotherapy trials, and clinical practice, where complex treatment regimens are the rule