Assessing author willingness to enter study information into structured data templates as part of the manuscript submission process: A pilot study.

Background: Environmental health and other researchers can benefit from automated or semi-automated summaries of data within published studies as summarizing study methods and results is time and resource intensive. Automated summaries can be designed to identify and extract details of interest pertaining to the study design, population, testing agent/intervention, or outcome (etc.). Much of the data reported across existing publications lack unified structure, standardization and machine-readable formats or may be presented in complex tables which serve as barriers that impede the development of automated data extraction methodologies.As full automation of data extraction seems unlikely soon, encouraging investigators to submit structured summaries of methods and results in standardized formats with meta-data tagging of content may be of value during the publication process. This would produce machine-readable content to facilitate automated data extraction, establish sharable data repositories, help make research data FAIR, and could improve reporting quality. Objectives: A pilot study was conducted to assess the feasibility of asking participants to summarize study methods and results using a structured, web-based data extraction model as a potential workflow that could be implemented during the manuscript submission process. Methods: Eight participants entered study details and data into the Health Assessment Workplace Collaborative (HAWC). Participants were surveyed after the extraction exercise to ascertain 1) whether this extraction exercise will impact their conducting and reporting of future research, 2) the ease of data extraction, including which fields were easiest and relatively more problematic to extract and 3) the amount of time taken to perform data extractions and other related tasks. Investigators then presented participants the potential benefits of providing structured data in the format they were extracting. After this, participants were surveyed about 1) their willingness to provide structured data during the publication process and 2) whether they felt the potential application of structured data entry approaches and their implementation during the journal submission process should continue to be further explored. Conclusions: Routine provision of structured data that summarizes key information from research studies could reduce the amount of effort required for reusing that data in the future, such as in systematic reviews or agency scientific assessments. Our pilot study suggests that directly asking authors to provide that data, via structured templates, may be a viable approach to achieving this: participants were willing to do so, and the overall process was not prohibitively arduous. We also found some support for the hypothesis that use of study templates may have halo benefits in improving the conduct and completeness of reporting of future research. While limitations in the generalizability of our findings mean that the conditions of success of templates cannot be assumed, further research into how such templates might be designed and implemented does seem to have enough chance of success that it ought to be undertaken.

OX40 and 4-1BB delineate distinct immune profiles in sarcoma.

Systemic relapse after radiotherapy and surgery is the major cause of disease-related mortality in sarcoma patients. Combining radiotherapy and immunotherapy is under investigation as a means to improve response rates. However, the immune contexture of sarcoma is understudied. Here, we use a retrospective cohort of sarcoma patients, treated with neoadjuvant radiotherapy, and TCGA data. We explore therapeutic targets of relevance to sarcoma, using genomics and multispectral immunohistochemistry to provide insights into the tumor immune microenvironment across sarcoma subtypes. Differential gene expression between radioresponsive myxoid liposarcoma (MLPS) and more radioresistant undifferentiated pleomorphic sarcoma (UPS) indicated UPS contained higher transcript levels of a number of immunotherapy targets (CD73/NT5E, CD39/ENTPD1, CD25/IL2RA, and 4-1BB/TNFRSF9). We focused on 4-1BB/TNFRSF9 and other costimulatory molecules. In TCGA data, 4-1BB correlated to an inflamed and exhausted phenotype. OX40/TNFRSF4 and 4-1BB/TNFRSF9 were highly expressed in sarcoma subtypes versus other cancers. Despite OX40 and 4-1BB being described as Treg markers, we identified that they delineate distinct tumor immune profiles. This was true for sarcoma and other cancers. While only a limited number of samples could be analyzed, spatial analysis of OX40 expression identified two diverse phenotypes of OX40+ Tregs, one associated with and one independent of tertiary lymphoid structures (TLSs). Patient stratification is of intense interest for immunotherapies. We provide data supporting the viewpoint that a cohort of sarcoma patients, appropriately selected, are promising candidates for immunotherapies. Spatial profiling of OX40+ Tregs, in relation to TLSs, could be an additional metric to improve future patient stratification.

Is There a Benefit of Combining Immunotherapy and Radiotherapy in Bladder Cancer?

Immune checkpoint inhibitors have transformed the management of patients with metastatic urothelial cancer, by leading to long-term response and prolongation of survival in a subset of patients. Unfortunately, only one in five patients with metastatic urothelial cancer responds to anti-programmed death ligand-1 ([AQ1]anti-PD-1) monotherapy. Preclinical and early clinical evidence indicates that radiotherapy not only acts locally, but also exerts systemic anti-tumour effects by modulating the immune system. It is hypothesised that combining checkpoint inhibitors with radiotherapy might enhance an anti-tumour immune response and increase response rates. So far, a handful of early phase clinical trials have been performed seeking to answer this question in urothelial cancer patients. The current review summarises the available preclinical and clinical evidence on radiotherapy/immunotherapy combinations in locally advanced and metastatic bladder cancer and suggests future avenues worthy of exploration.

KIF5A and the contribution of susceptibility genotypes as a predictive biomarker for multiple sclerosis.

There is increasing interest in the development of multiple sclerosis (MS) biomarkers that reflect central nervous system tissue injury to determine prognosis. We aimed to assess the prognostic value of kinesin superfamily motor protein KIF5A in MS by measuring levels of KIF5A in cerebrospinal fluid (CSF) combined with analysis of single nucleotide polymorphisms (SNPs; rs12368653 and rs703842) located within a MS susceptibility gene locus at chromosome 12q13-14 region. Enzyme-linked immunosorbent assay was used to measure KIF5A in CSF obtained from two independent biobanks comprising non-inflammatory neurological disease controls (NINDC), clinically isolated syndrome (CIS) and MS cases. CSF KIF5A expression was significantly elevated in progressive MS cases compared with NINDCs, CIS and relapsing-remitting MS (RRMS). In addition, levels of KIF5A positively correlated with change in MS disease severity scores (EDSS, MSSS and ARMSSS), in RRMS patients who had documented disease progression at 2-year clinical follow-up. Copies of adenine risk alleles (AG/AA; rs12368653 and rs703842) corresponded with a higher proportion of individuals in relapse at the time of lumbar puncture (LP), higher use of disease-modifying therapies post LP and shorter MS duration. Our study suggests that CSF KIF5A has potential as a predictive biomarker in MS and further studies into the potential prognostic value of analysing MS susceptibility SNPs should be considered.

The possible use of precision tinted lenses to improve social cognition in children with autism spectrum disorders.

A masked randomised control design compared the effectiveness of precision ophthalmic tints in improving the recognition of emotion in Autism Spectrum Disorders (ASD). Fourteen children aged 10-14 with ASD and 14 control children matched on verbal and non-verbal IQ, wore spectacles with coloured lenses to complete two tasks that involved the observation of coloured video sequences in which social interactions were depicted. On one occasion (randomly first or second) the coloured lenses provided light of a colour that the child had one month previously selected as optimal for the clarity of text. On the other occasion the lenses differed in CIE UCS chromaticity by 0.077. Performance in the ASD group was superior in both social interaction tasks with the lenses that provided the optimal colour of light.

Glucocorticoid and inflammatory reactivity to a repeated physiological stressor in insomnia disorder.

Despite known associations of insomnia disorder with alterations in cytokine and glucocorticoid (GC) production, neither the sensitivity of immune cells to a GC signal nor the reactivity of the hypothalamus-pituitary-adrenal (HPA) axis and inflammatory system to stress, or adaptation of these systems to repeated stress have been assessed in patients with insomnia. To investigate potential dysregulation in stress reactivity and adaptation to repeated exposure, a physiological stressor (the cold pressor test; CPT) was repeatedly administered to N = 20 participants with insomnia disorder (based on DSM-V, 18 females, age 30 ±â€¯2.5 years) and N = 20 sex-matched healthy controls following an at-home actigraphy and in-laboratory PSG. HPA and inflammatory markers (serum cortisol, plasma interleukin [IL]-6) were measured at baseline/resting levels and following each of the three CPTs. In addition, sensitivity of monocytes to the synthetic GC dexamethasone was assessed in-vitro at baseline levels in order to examine the cortisol-IL-6 interplay at the cell level. Compared to healthy controls, individuals with insomnia disorder exhibited shorter sleep duration as assessed by actigraphy and PSG (p ≤ 0.05). HPA, but not inflammatory reactivity to the repeated CPT challenge was greater in insomnia disorder (p ≤ 0.05 for group effect), due to greater cortisol responses to the initial CPT (p ≤ 0.05). There were no between-group differences in the ability of the HPA to adapt to stress repetition nor in basal/resting levels of cortisol, IL-6, and GC sensitivity. These findings suggest that insomnia disorder potentiates HPA axis reactivity to initial/novel stressors, which may constitute a pathway underlying adverse health consequences in the long term.

Emerging clinical experience with vaccines against group B meningococcal disease.

The prevention of paediatric bacterial meningitis and septicaemia has recently entered a new era with the availability of two vaccines against capsular group B meningococcus (MenB). Both of these vaccines are based on sub-capsular proteins of the meningococcus, an approach that overcomes the challenges set by the poorly immunogenic MenB polysaccharide capsule but adds complexity to predicting and measuring the impact of their use. This review describes the development and use of MenB vaccines to date, from the use of outer membrane vesicle (OMV) vaccines in MenB outbreaks around the world, to emerging evidence on the effectiveness of the newly available vaccines. While recent data from the United Kingdom supports the potential for protein-based vaccines to provide direct protection against MenB disease in immunised children, further research is required to understand the breadth and duration of this protection. A more detailed understanding of the impact of immunisation with these vaccines on nasopharyngeal carriage of the meningococcus is also required, to inform both their potential to induce herd immunity and to preferentially select for carriage of strains not susceptible to vaccine-induced antibodies. Although a full understanding of the potential impact of these vaccines will only be possible with this additional information, the availability of new tools to prevent the devastating effect of invasive MenB disease is a significant breakthrough in the fight against childhood sepsis and meningitis.

Chromaticity separation and the alpha response.

Chromatic gratings can be uncomfortable to view and can evoke a large haemodynamic response. Both the discomfort and the amplitude of the haemodynamic response increase monotonically with the perceptual difference in the colour of the component bars of the grating, as registered by the separation in their chromaticity in the CIE 1976 UCS diagram. Individuals with photosensitive epilepsy exhibit epileptiform EEG activity in response to flickering light of alternate colours. The probability of the epileptiform response again increases monotonically with the separation of the colours in the CIE UCS diagram. We investigated whether alpha power, which is known to reflect the excitation of large populations of neurons, is similarly affected by the separation in chromaticity. Chromatic square-wave gratings with bars that differed in CIE UCS chromaticity were presented, together with a central fixation cross. In 18 non-clinical participants, alpha responses were recorded over the visual cortex (O1, Oz, O2, PO3, POz, PO4, P1, P2) and compared to responses in prefrontal cortex (F1, F2). Gratings comprised bars of two alternate colours that either had a small difference in chromaticity (mean CIE UCS separation of 0.03), a medium difference (mean separation of 0.19), or a large difference (mean separation of 0.43). The colour pairs had chromaticities that lay on the red-green, red-blue, or blue-green borders of the screen gamut. Regardless of the hue, the larger the separation in chromaticity, the greater the alpha desynchronization and the lower the alpha power (p = 0.004), but only in posterior electrodes (p < 0.001). Together this indicates that differences in colour evoke a cortical excitation that increases monotonically with the colour difference. In this respect the alpha response resembles the haemodynamic response.

Axonal motor protein KIF5A and associated cargo deficits in multiple sclerosis lesional and normal-appearing white matter.

AIMS: Understanding the causes of axonal pathology remains a key goal in the pursuit of new therapies to target disease progression in multiple sclerosis (MS). Anterograde axonal transport of many proteins vital for axonal viability is mediated by the motor protein KIF5A, which has been linked to several neurological diseases. This study aimed to investigate the expression of KIF5A protein and its associated cargoes: amyloid precursor protein (APP) and neurofilament (NF) in post mortem MS and control white matter (WM) and to determine if KIF5A expression is influenced by the presence of MS risk single nucleotide polymorphisms (SNPs) identified in the region of the KIF5A gene. METHODS: Using immunoblotting assays we analysed the expression of KIF5A, APP and NF phospho-isoforms in 23 MS cases and 12 controls. RESULTS: We found a significant reduction in KIF5A and associated cargoes in MS WM and an inverse correlation between KIF5A and APP/NF protein levels. Furthermore, homozygous carriers of MS risk gene SNPs show significantly lower levels of KIF5A protein compared to MS patients with no copies of the risk SNPs. CONCLUSIONS: We conclude that reduced expression of axonal motor KIF5A may have important implications in determining axonal transport deficits and ongoing neurodegeneration in MS.

Neurosarcoidosis: a clinical approach to diagnosis and management.

Sarcoidosis is a rare but important cause of neurological morbidity, and neurological symptoms often herald the diagnosis. Our understanding of neurosarcoidosis has evolved from early descriptions of a uveoparotid fever to include presentations involving every part of the neural axis. The diagnosis should be suspected in patients with sarcoidosis who develop new neurological symptoms, those presenting with syndromes highly suggestive of neurosarcoidosis, or neuro-inflammatory disease where more common causes have been excluded. Investigation should look for evidence of neuro-inflammation, best achieved by contrast-enhanced brain magnetic resonance imaging and cerebrospinal fluid analysis. Evidence of sarcoidosis outside the nervous system should be sought in search of tissue for biopsy. Skin lesions should be identified and biopsies taken. Chest radiography including high-resolution computed tomography is often informative. In difficult cases, fluorodeoxyglucose positron emission tomography and gallium-67 imaging may identify subclinical disease and a target for biopsy. Symptomatic patients should be treated with corticosteroids, and if clinically indicated other immunosuppressants such as hydroxychloroquine, azathioprine, cyclophosphamide or methotrexate should be added. Anti-tumour necrosis factor alpha therapies may be considered in refractory disease but caution should be exercised as there is evidence to suggest they may unmask disease.

Female gender and diabetes mellitus increase the risk of recurrence after laparoscopic incisional hernia repair.

BACKGROUND: Laparoscopic hernia repair is used widely for the repair of incisional hernias. Few case studies have focussed on purely 'incisional' hernias. This multicentre series represents a collaborative effort and employed statistical analyses to provide insight into the factors predisposing to recurrence of incisional hernia after laparoscopic repair. A specific hypothesis (ie, laterality of hernias as well as proximity to the xyphoid process and pubic symphysis predisposes to recurrence) was also tested. METHODS: This was a retrospective study of all laparoscopic incisional hernias undertaken in six centres from 1 January 2004 to 31 December 2010. It comprised a comprehensive review of case notes and a follow-up using a structured telephone questionnaire. Patient demographics, previous medical/surgical history, surgical procedure, postoperative recovery, and perceived effect on quality of life were recorded. Repairs undertaken for primary ventral hernias were excluded. A logistic regression analysis was then fitted with recurrence as the primary outcome. RESULTS: A total of 186 cases (91 females) were identified. Median follow-up was 42 months. Telephone interviews were answered by 115/186 (62%) of subjects. Logistic regression analyses suggested that only female sex (odds ratio (OR) 3.53; 95% confidence interval (CI) 1.39-8.97) and diabetes mellitus (3.54; 1-12.56) significantly increased the risk of recurrence. Position of the defect had no statistical effect. CONCLUSIONS: These data suggest an increased risk of recurrence after laparoscopic incisional hernia repair in females and subjects with diabetes mellitus. These data will help inform surgeons and patients when considering laparoscopic management of incisional hernias. We recommend a centrally hosted, prospectively maintained national/international database to carry out additional research.

Cortical excitability and the shape of the haemodynamic response.

Individual differences in the temporal dynamics of the haemodynamic response can reflect cortical excitation and can reveal underlying cortical physiology. Here, we show differences in the shape of the haemodynamic response that are dependent on stimulus parameters. Two sets of visual stimuli were used varying in parameters that are known to manipulate the haemodynamic response in the visual cortex. We measured the oxyhaemoglobin response using near infrared spectroscopy. The first set of stimuli comprised chromatic square-wave gratings that varied with respect to the separation in the CIE UCS chromaticities of the alternating bars. The gratings with large separations in chromaticity evoked an oxyhaemoglobin response with greater amplitude, consistent with greater activation of the visual cortex. The second set of stimuli comprised horizontal achromatic gratings that (1) were static, (2) drifted at a constant velocity towards fixation, or (3) reversed direction every half spatial cycle to create a vertical vibrating motion. Although the three types of grating had a similar effect on the amplitude of the oxyhaemoglobin response, the moving gratings (2 and 3) evoked a steeper decrease in oxyhaemoglobin concentration after stimulus-offset. The steeper slope appears to reflect the post-stimulus undershoot and the slope may provide a correlate of cortical excitability when the amplitude of the haemodynamic response has saturated.

Reduced axonal motor protein expression in non-lesional grey matter in multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) is a neurological disease characterised by central nervous system inflammation, demyelination, axonal degeneration and neuronal injury. Preventing neuronal and axon damage is of paramount importance in attempts to prevent disease progression. Intact axonal transport mechanisms are crucial to axonal integrity and evidence suggests these mechanisms are disrupted in MS. Anterograde axonal transport is mediated to a large extent through the kinesin superfamily proteins. Recently, certain kinesin superfamily proteins (KIF5A, KIF1B and KIF21B) were implicated in MS pathology. OBJECTIVES: To investigate the expression of KIF5A, KIF21B and KIF1B in MS and control post-mortem grey matter. METHODS: Using both quantitative real-time polymerase chain reaction (PCR) and Immunodot-blots assays, we analysed the expression of kinesin superfamily proteins in 27 MS cases and 13 control cases not linked to neurological disease. RESULTS: We have shown significant reductions in KIF5A, KIF21B and KIF1B messenger ribonucleic acid (mRNA) expression and also KIF5A protein expression in MS grey matter, as compared to control grey matter. CONCLUSION: We have shown significant reductions in mRNA and protein levels of axonal motor proteins in the grey matter of MS cases, which may have important implications for the pathogenesis of neuronal/axonal injury in the disease.

Equivalence of cisplatin and carboplatin-based chemoradiation for locally advanced squamous cell carcinoma of the head and neck: a matched-pair analysis.

BACKGROUND: Carboplatin can be substituted for cisplatin in concomitant chemoradiation (CRT) for locally advanced squamous cell carcinoma of the head and neck (LASCCHN) when the latter is contraindicated. This matched-pair study aimed to compare the efficacy and acute toxicity of carboplatin and cisplatin. METHODS: Patients treated with 2 cycles of concomitant carboplatin-based CRT were matched to patients treated with 2 cycles of cisplatin. Matching criteria included age, tumour site, stage, smoking status and use of induction chemotherapy. Radiation was delivered using conformal techniques. Data on weekly acute toxicity throughout CRT was compared using the chi-squared test for proportions. Kaplan Meier statistics described time to local relapse, distant relapse and overall survival, the log-rank test was used to compare 3-year survival outcomes. RESULTS: Sixty-five patients who received carboplatin were matched to 65 who received cisplatin. Significant differences in toxicity included increased emesis with cisplatin and more anaemia and thrombocytopenia with carboplatin. There was no significant difference in 3-year locoregional control (87% vs. 79%, p=0.54), freedom from distant metastases (88% vs. 85%, p=0.79) and overall survival (59% vs. 68%, p=0.24) between the carboplatin and cisplatin cohorts, respectively. CONCLUSIONS: When cisplatin is contraindicated, carboplatin-based CRT yields equivalent treatment outcomes in patients with LASCCHN.

Mitochondrial sirtuins--a new therapeutic target for repair and protection in multiple sclerosis.

Given the significant socioeconomic impact of progressive multiple sclerosis (MS) and the paucity of treatment options, there is an urgent need to develop new and effective therapies for this disabling condition. The relatively recent appreciation that progressive disability is largely driven by neuronal loss has focused considerable research attention on neuroprotective strategies. This has coincided with the emergence of oxidative damage as a prominent effector mechanism of axonal damage in studies of MS pathogenesis, which has opened up a new range of putative targets for neuroprotective therapy in MS. Mitochondrial sirtuins are NAD(+)-dependent protein deacetylases associated with the control of metabolism, aging, and stem cell proliferation and differentiation. Their role in inflammatory demyelinating disease has not been fully characterized, and is the subject of ongoing research. Here, we expound the rationale behind selecting mitochondrial sirtuins as a therapeutic target in demyelinating disease, and report preliminary data that warrant further investigation.

Fusion between human mesenchymal stem cells and rodent cerebellar Purkinje cells.

AIMS: we explored whether cellular fusion and heterokaryon formation between human and rodent cells in the cerebellum of mice occurs after intravenous injection of human bone marrow-derived mesenchymal stem cells (MSCs). The influence of central nervous system inflammation on this process was also assessed. In addition, we examined whether tumour necrosis factor (TNF)-alpha and interferon (IFN)-gamma, factors associated with inflammation, increase cellular fusion between human MSCs and rodent cerebellar neurons in vitro. METHODS AND RESULTS: human MSCs were intravenously injected into mice with experimental autoimmune encephalomyelitis (EAE) and control mice. After 22 days, mouse Purkinje cells expressing human Golgi Zone were found within the Purkinje cell layer of the cerebellum, indicating that fusion and heterokaryon formation had occurred. The numbers of heterokaryons in the cerebellum were markedly increased in mice with EAE compared with control mice. Rodent cerebellar neuronal cells labelled with enhanced green fluorescent proteinin vitro were co-cultured with human bone marrow-derived MSCs in the presence of TNF-alpha and/or IFN-gamma to determine their influence on fusion events. We found that fusion between MSCs and cerebellar neurons did occur in vitro and that the frequency of cellular fusion increased in the presence of TNF-alpha and/or IFN-gamma. CONCLUSIONS: we believe that this is the first paper to define fusion and heterokaryon formation between human MSCs and rodent cerebellar neurons in vivo. We have also demonstrated that fusion between these cell populations occurs in vitro. These findings indicate that MSCs may be potential therapeutic agents for cerebellar diseases, and other neuroinflammatory and neurodegenerative disorders.