A modified two temperature molecular dynamics (2T-MD) model for cascades.

Two-Temperature molecular dynamics (2T-MD) is a common approach for describing how electrons contribute to the evolution of a damage cascade by addressing their role in the redistribution of energy in the system. However, inaccuracies in 2T-MD's treatment of the high-energy particles have limited its utilisation. Here, we propose a reformulation of the traditional 2T-MD scheme to overcome this limitation by addressing the spurious double-interaction of high-energy atoms with electrons. We conduct a series of radiation damage cascades for 30, 50, and 100 keV primary knock-on atoms in increasingly large cubic W cells. In the simulations, we employ our modified 2T-MD scheme along with other treatments of electron-phonon coupling to explore their impact on the cascade evolution and the number of remnant defects. The results suggest that with the proposed modification, 2T-MD simulations account for the temperature time evolution during the ballistic phase and remove arbitrary choices, thus providing a better description of the underlying physics of the damage process.

Pilot study of a community pharmacist led program to treat hepatitis C virus among people who inject drugs.

Background: People who inject drugs (PWID) are a key population for treatment with direct-acting antiviral medications (DAAs) to eliminate hepatitis C virus (HCV). We developed a Pharmacist, Physician, and Patient Navigator Collaborative Care Model (PPP-CCM) for delivery of HCV treatment; this study describes clinical outcomes related to HCV treatment (initial evaluation, treatment initiation, completion, and cure), as well as patient satisfaction. Methods: We conducted a single-arm prospective pilot study of adult PWID living with HCV. Participants completed baseline and six-month follow-up surveys, and treatment and outcomes were abstracted from electronic health records. Primary outcome was linkage to pharmacist for HCV evaluation; secondary outcomes included DAA initiation, completion, and cure, as well as patient-reported satisfaction. Results: Of the 40 PWID enrolled, mean age was 43.6 years, 12 (30 %) were female, 20 (50 %) were non-white, and 15 (38 %) were unhoused. Thirty-eight (95 %) were successfully linked to the pharmacist for initial evaluation. Of those, 21/38 (55 %) initiated DAAs, and 16/21 (76 %) completed treatment. Among those completing treatment who had viral load data to document whether they achieved "sustained virologic response", i.e. cure, 10/11 (91 %) were found to be cured. There was high satisfaction with 100 % responding "agree or strongly agree" that they had a positive experience with the pharmacist. Conclusion: Nearly all participants in this pilot were successfully linked to the pharmacist for evaluation, and more than half were started on DAAs; results provide preliminary evidence of feasibility of pharmacist-led models of HCV treatment for PWID. Clinicaltrialsgov registration number: NCT04698629.

An investigation into the factor structure of the Health of the Nation Outcome Scales for People with Learning Disabilities.

BACKGROUND: The Health of the Nation Outcome Scales for People with Learning Disabilities (HoNOS-LD) is one of the most used outcome measures in learning disability services in the United Kingdom. There is relatively little known of the psychometric properties of the scales. METHOD: A data set of HoNOS-LD scales from 571 people with learning disabilities was randomly split into two halves. Exploratory Mokken analysis was applied to the first dataset, and confirmatory scale factor analysis was applied to the second dataset to test the fit of scale structures. RESULTS: Two-factor and three-factor solutions were explored in the Mokken analysis, with the three-factor option having somewhat better characteristics. One-factor, three-factor and seven-factor solutions were explored using confirmatory factor analysis; a three-factor solution with items 8, 16, 17 and 18 used separately offers the best characteristics. CONCLUSIONS: The HoNOS-LD is best conceptualised as consisting of three scales, accounting for 14 items that can be labelled as 'Cognitive and Physical Functioning', 'Behaviour and Mood Disturbances' and 'Functional Difficulties'.

Daily patterns in parasite processes: diel variation in fish louse transcriptomes.

Parasites, similar to all other organisms, time themselves to environmental cues using a molecular clock to generate and maintain rhythms. Chronotherapeutic (timed treatment) techniques based on such rhythms offer great potential for improving control of chronic, problematic parasites. Fish lice are a key disease threat in aquaculture, with current control insufficient. Assessing the rhythmicity of fish lice transcriptomes offers not only insight into the viability of chronotherapy, but the opportunity to identify new drug targets. Here, for the first known time in any crustacean parasite, diel changes in gene transcription are examined, revealing that approximately half of the Argulus foliaceus annotated transcriptome displays significant daily rhythmicity. We identified rhythmically transcribed putative clock genes including core clock/cycle and period/timeless pairs, alongside rhythms in feeding-associated genes and processes involving immune response, as well as fish louse drug targets. A substantial number of gene pathways showed peak transcription in hours immediately preceding onset of light, potentially in anticipation of peak host anti-parasite responses or in preparation for increased feeding activity. Genes related to immune haemocyte activity and chitin development were more highly transcribed 4 h post light onset, although inflammatory gene transcription was highest during dark periods. Our study provides an important resource for application of chronotherapy in fish lice; timed application could increase efficacy and/or reduce dose requirement, improving the current landscape of drug resistance and fish health while reducing the economic cost of infection.

Cross-sectional characteristics of pediatric-onset discoid lupus erythematosus: Results of a multicenter, retrospective cohort study.

BACKGROUND: The incidence of systemic lupus in children with discoid lupus is unknown. OBJECTIVE: This study assessed the baseline characteristics of patients with pediatric discoid lupus erythematosus (pDLE). METHODS: Medical records at 17 sites were reviewed for pediatric dermatology and rheumatology patients with discoid lupus erythematosus. The inclusion criteria were clinical and/or histopathologic diagnosis of discoid lupus erythematosus with an age at onset of <18 years. Baseline data were collected at the first documented visit. Outcomes included diagnosis of systemic lupus erythematosus (SLE) at the baseline visit using the 1997 American College of Rheumatology (primary) and the 2012 Systemic Lupus International Collaborating Clinics (secondary) criteria. RESULTS: Of the >1500 charts reviewed, 438 patients met the inclusion criteria. The cohort was predominantly female (72%) and racially/ethnically diverse. A diagnosis of SLE at the baseline visit (pDLE + SLE) was rendered in 162 (37%) patients using the American College of Rheumatology and in 181 (41%) patients using the Systemic Lupus International Collaborating Clinics criteria. Patients with pDLE + SLE were older at the time of rash onset (median, 12.9 vs 8.9 years; P < .001), with shorter time from discoid lupus erythematosus onset to diagnosis, compared with patients with pDLE-only (median, 2 vs 7 months; P < .001). Patients with pDLE + SLE were more likely to be female (P = .004), with generalized discoid lupus erythematosus and clinically aggressive disease, including end-organ involvement, positive serologies, and higher- titer levels of antinuclear antibodies (P < .001). LIMITATIONS: Retrospective study. CONCLUSION: A diagnosis of discoid lupus erythematosus in adolescence should prompt thorough screening for SLE.

A partially randomised trial of pretomanid, moxifloxacin and pyrazinamide for pulmonary TB.

BACKGROUND: Treatment for TB is lengthy and toxic, and new regimens are needed.METHODS: Participants with pulmonary drug-susceptible TB (DS-TB) were randomised to receive: 200 mg pretomanid (Pa, PMD) daily, 400 mg moxifloxacin (M) and 1500 mg pyrazinamide (Z) for 6 months (6Pa200MZ) or 4 months (4Pa200MZ); 100 mg pretomanid daily for 4 months in the same combination (4Pa100MZ); or standard DS-TB treatment for 6 months. The primary outcome was treatment failure or relapse at 12 months post-randomisation. The non-inferiority margin for between-group differences was 12.0%. Recruitment was paused following three deaths and not resumed.RESULTS: Respectively 4/47 (8.5%), 11/57 (19.3%), 14/52 (26.9%) and 1/53 (1.9%) DS-TB outcomes were unfavourable in patients on 6Pa200MZ, 4Pa200MZ, 4Pa100MZ and controls. There was a 6.6% (95% CI -2.2% to 15.4%) difference per protocol and 9.9% (95%CI -4.1% to 23.9%) modified intention-to-treat difference in unfavourable responses between the control and 6Pa200MZ arms. Grade 3+ adverse events affected 68/203 (33.5%) receiving experimental regimens, and 19/68 (27.9%) on control. Ten of 203 (4.9%) participants on experimental arms and 2/68 (2.9%) controls died.CONCLUSION: PaMZ regimens did not achieve non-inferiority in this under-powered trial. An ongoing evaluation of PMD remains a priority.

Modeling Water Quality in Watersheds: From Here to the Next Generation.

In this synthesis, we assess present research and anticipate future development needs in modeling water quality in watersheds. We first discuss areas of potential improvement in the representation of freshwater systems pertaining to water quality, including representation of environmental interfaces, in-stream water quality and process interactions, soil health and land management, and (peri-)urban areas. In addition, we provide insights into the contemporary challenges in the practices of watershed water quality modeling, including quality control of monitoring data, model parameterization and calibration, uncertainty management, scale mismatches, and provisioning of modeling tools. Finally, we make three recommendations to provide a path forward for improving watershed water quality modeling science, infrastructure, and practices. These include building stronger collaborations between experimentalists and modelers, bridging gaps between modelers and stakeholders, and cultivating and applying procedural knowledge to better govern and support water quality modeling processes within organizations.

When do pictures reduce false memory?

An important discovery in false-memory research is Israel and Schacter's (Psychonomic Bulletin & Review, 4, 577-581, 1997) finding that presenting pictures at study relative to words alone reduces false memory in the DRM paradigm, a result that has been replicated many times. The standard interpretation is that memory for visual processing of the pictures can be used to reject the critical distractors, which were not explicitly present at study. Beginning from the empirical observation that the pictures used by Israel and Schacter are not consistently labelled with the DRM word they are supposed to represent, we present a series of four studies designed to determine if it is the presentation of pictures or the mismatch between the pictures and the words that reduces false memory. The results across the four experiments demonstrate that picture presentation at study is neither necessary nor sufficient to reduce false memory in the DRM and the categorical associate paradigms. However, we discuss other studies in which picture processing clearly is responsible for reduction of false alarms and note that these studies use study materials and memory tests that are different from the DRM and categorical associate paradigms in that critical lures are externally provided rather than generated. We speculate that the effectiveness of memory for visual processing for reducing false memory may depend on the source of the false memory, but this remains for future research.

Practice-based differences in paediatric discoid lupus erythematosus.

BACKGROUND: Children with discoid lupus erythematosus (DLE) are at risk for disfigurement and progression to systemic lupus erythematosus (SLE). Consensus is lacking regarding optimal care for children with DLE. OBJECTIVES: The aim of this study was to compare practice patterns among paediatric dermatologists/rheumatologists treating paediatric DLE. METHODS: An online survey was sent to 292 paediatric rheumatologists in the Childhood Arthritis and Rheumatology Research Alliance and 200 paediatric dermatologists in the Pediatric Dermatology Research Alliance. Consensus was defined as ≥ 70% agreement. RESULTS: Survey response rates were 38% (76 of 200) for dermatology and 21% (60 of 292) for rheumatology. Both specialties agreed that screening labs should include complete blood counts with differential, urinalysis, complement levels, erythrocyte sedimentation rate, antinuclear antibody and other autoantibodies, hepatic function and renal function/electrolytes. Both specialties agreed that arthritis or nephritis should prompt intensified evaluation for SLE. No other patient features achieved consensus as disease-modifying risk factors. Hydroxychloroquine was agreed upon as first-line systemic therapy, but consensus was lacking for second- or third-line treatment. CONCLUSIONS: We found few areas of consensus and significant practice differences between paediatric dermatologists and rheumatologists treating DLE. Knowledge gaps include risk factors for SLE, optimal screening and treatment of refractory skin disease.

Evaluation of the reliability and validity of the Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) in paediatric cutaneous lupus among paediatric dermatologists and rheumatologists.

BACKGROUND: The Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) is a reliable outcome measure for cutaneous lupus erythematosus (CLE) in adults used in clinical trials. However, it has not been validated in children, limiting clinical trials for paediatric CLE. OBJECTIVES: This study aimed to validate the CLASI in paediatrics. METHODS: Eleven paediatric patients with CLE, six dermatologists and six rheumatologists participated. The physicians were trained to use the CLASI and Physician's Global Assessment (PGA), and individually rated all patients using both tools. Each physician reassessed two randomly selected patients. Within each physician group, the intraclass correlation coefficient (ICC) was calculated to assess the reliability of each measure. RESULTS: CLASI activity scores demonstrated excellent inter- and intrarater reliability (ICC > 0·90), while the PGA activity scores had good inter-rater reliability (ICC 0·73-0·77) among both specialties. PGA activity scores showed excellent (ICC 0·89) and good intrarater reliability (ICC 0·76) for dermatologists and rheumatologists, respectively. Limitations of this study include the small sample size of patients and potential recall bias during the physician rerating session. CONCLUSIONS: CLASI activity measurement showed excellent inter- and intrarater reliability in paediatric CLE and superiority over the PGA. These results demonstrate that the CLASI is a reliable and valid outcome instrument for paediatric CLE.

Gender differences in tuberculosis treatment outcomes: a post hoc analysis of the REMoxTB study.

BACKGROUND: In the REMoxTB study of 4-month treatment-shortening regimens containing moxifloxacin compared to the standard 6-month regimen for tuberculosis, the proportion of unfavourable outcomes for women was similar in all study arms, but men had more frequent unfavourable outcomes (bacteriologically or clinically defined failure or relapse within 18 months after randomisation) on the shortened moxifloxacin-containing regimens. The reason for this gender disparity in treatment outcome is poorly understood. METHODS: The gender differences in baseline variables were calculated, as was time to smear and culture conversion and Kaplan-Meier plots were constructed. In post hoc exploratory analyses, multivariable logistic regression modelling and an observed case analysis were used to explore factors associated with both gender and unfavourable treatment outcome. RESULTS: The per-protocol population included 472/1548 (30%) women. Women were younger and had lower rates of cavitation, smoking and weight (all p < 0.05) and higher prevalence of HIV (10% vs 6%, p = 0.001). They received higher doses (mg/kg) than men of rifampicin, isoniazid, pyrazinamide and moxifloxacin (p ≤ 0.005). There was no difference in baseline smear grading or mycobacterial growth indicator tube (MGIT) time to positivity. Women converted to negative cultures more quickly than men on Lowenstein-Jensen (HR 1.14, p = 0.008) and MGIT media (HR 1.19, p < 0.001). In men, the presence of cavitation, positive HIV status, higher age, lower BMI and 'ever smoked' were independently associated with unfavourable treatment outcome. In women, only 'ever smoked' was independently associated with unfavourable treatment outcome. Only for cavitation was there a gender difference in treatment outcomes by regimen; their outcome in the 4-month arms was significantly poorer compared to the 6-month treatment arm (p < 0.001). Women, with or without cavities, and men without cavities had a similar outcome on all treatment arms (p = 0.218, 0.224 and 0.689 respectively). For all other covariate subgroups, there were no differences in treatment effects for men or women. CONCLUSIONS: Gender differences in TB treatment responses for the shorter regimens in the REMoxTB study may be explained by poor outcomes in men with cavitation on the moxifloxacin-containing regimens. We observed that women with cavities, or without, on the 4-month moxifloxacin regimens had similar outcomes to all patients on the standard 6-month treatment. The biological reasons for this difference are poorly understood and require further exploration.

The cost of infection: Argulus foliaceus and its impact on the swimming performance of the three-spined stickleback (Gasterosteus aculeatus).

For fish, there can be multiple consequences of parasitic infections, including the physical impacts on swimming and the pathological costs of infection. This study used the three-spined stickleback (Gasterosteus aculeatus) and the ectoparasitic fish louse, Argulus foliaceus, to assess both physical (including form drag and mass) and pathological effects of infection. Both sustained (prolonged swimming within an open channel flume) and burst (C-start) swimming performance were measured on individual fish before (trials 1-2) and after infection (trials 3-5). Experimental infection occurred shortly before the third trial, when the physical impacts of infection could be separated from any subsequent pathology as transmission of adult parasites causes instantaneous drag effects prior to observable pathology. Despite the relatively large size of the parasite and corresponding increase in hydrodynamic drag for the host, there were no observable physical effects of infection on either sustained or burst host swimming. By contrast, parasite-induced pathology is the most probable explanation for reduced swimming performance across both tests. All sticklebacks displayed a preference for flow refugia, swimming in low-velocity regions of the flume, and this preference increased with both flow rate and infection time. This study suggests that even with large, physically demanding parasites their induced pathology is of greater concern than direct physical impact.

Spinal dural arteriovenous fistula: delay to radiological diagnosis and sources of radiological error.

AIM: To highlight the magnetic resonance imaging (MRI) signs associated with spinal dural arteriovenous fistula (SDAVF) through categorisation of sources of radiological error and investigation of the delay to radiological diagnosis. MATERIAL AND METHODS: This was a retrospective, observational study of cases referred to a neuroscience centre over 11 years. All patients who underwent spinal digital subtraction angiography (DSA) with a subsequent diagnosis of SDAVF were identified. Prior imaging was reviewed and compared with the formal reports issued. RESULTS: Thirty-seven patients with SDAVF were initially imaged in seven institutions. Radiological abnormalities including intradural vessels (37/37, 100%), cord T2 signal change (34/37, 91.9%), and cord expansion (26/37, 70.2%) were present on prior MRI. These signs were not recognised in 22/37 (59.5%), 7/34 (20.5%), and 15/26 (57.7%) of cases, respectively. Increased T2 signal in the cord was the most commonly identified sign (27/34; 79.4%), but prompted either no diagnosis (7/34; 20.5%) or differential diagnoses including ischaemic, inflammatory, or neoplastic aetiologies or a syrinx in 11/34 (32.4%). An appropriate diagnosis was made on initial MRI in 15 patients (40.5%). The time from initial imaging to diagnosis was significantly delayed for those patients who did not have an arteriovenous vascular aetiology included in the initial differential diagnosis (281 (423.3) days versus 22 (15.7) days, p=0.03). CONCLUSION: SDAVF have imaging features that are frequently missed or misinterpreted. This results in a significant delay to definitive diagnosis and therefore treatment.

Ethical Challenges Inherent in the Evaluation of an American Indian/Alaskan Native Circles of Care Project.

This article provides first-person accounts of ethical issues inherent in an evaluation of the Native American Indian Center of Central Ohio (NAICCO) Circles of Care project. Circles of Care is a three-year, infrastructure development program funded through the Substance Abuse and Mental Health Services Administration (SAMHSA) which is part of the federal Department of Health and Human Services (DHHS). The grant program is for American Indian and Alaskan Native (AI/AN) tribes and urban Indian communities and includes a strong emphasis on community engagement and community ownership. The Native American Indian Center of Central Ohio received a Circles of Care grant in the fifth cohort of the program. The first author (Project Evaluator) presents views that typically represent a western approach to evaluation, while the second author (Project Director) presents a Native perspective. Ethical issues are defined as well as the authors' efforts to address these concerns.

Elevated preoperative von Willebrand factor is associated with perioperative thrombosis in infants and neonates with congenital heart disease.

Essentials Perioperative thrombosis is a major cause of morbidity and mortality in congenital heart disease. Neonates and infants undergoing repair of congenital heart lesions were prospectively followed. Elevated von Willebrand factor (VWF) to ADAMTS-13 activity ratios typified the postoperative period. Thrombosis was associated with preoperative VWF activity and cryoprecipitate transfusion SUMMARY: Background The surgical repair of congenital heart malformations is frequently complicated by perioperative thrombosis of unclear etiology. An imbalance between von Willebrand factor (VWF) and ADAMTS-13 is an emerging variable in thrombosis. Objectives To describe perioperative changes to VWF, ADAMTS-13 and NETosis, and evaluate clinical and biochemical associations with postoperative thrombosis. Methods Neonates and infants undergoing palliation or definitive surgical repair of congenital heart malformations were recruited (n = 133). Preoperative and postoperative plasma levels of VWF, ADAMTS-13 and markers of NETosis were determined. Patients were followed for up to 30 days for the occurrence of thrombosis. Univariate and multivariate logistic regression analyses were conducted to identify variables associated with thrombosis. Results We identified significant postoperative increases in VWF activity, VWF level, DNA-histone complexes and cell-free DNA with an overall decrease in ADAMTS-13 activity. Patients experiencing postoperative thrombotic events (9%) were characterized by surgery performed at a lower intraoperative temperature, higher preoperative lactic acid levels, and higher preoperative VWF activity and level. A multivariate logistic regression model identified preoperative VWF activity (odds ratio (OR) 8.39 per IU mL-1 , 95% confidence interval [CI] 1.73-40.55) and transfusion of cryoprecipitate (OR 1.10 per mL kg-1 , 95% CI 1.03-1.17) as being associated with thrombosis. Conclusions Pediatric patients undergoing surgical repair of congenital heart malformations are exposed to high levels of VWF with diminished or minimal change to ADAMTS-13 in the immediate postoperative period. Elevated preoperative VWF activity is associated with postoperative thrombosis in pediatric congenital heart disease.

Differences in Blood Pressure in Infants After General Anesthesia Compared to Awake Regional Anesthesia (GAS Study-A Prospective Randomized Trial).

BACKGROUND: The General Anesthesia compared to Spinal anesthesia (GAS) study is a prospective randomized, controlled, multisite, trial designed to assess the influence of general anesthesia (GA) on neurodevelopment at 5 years of age. A secondary aim obtained from the blood pressure data of the GAS trial is to compare rates of intraoperative hypotension after anesthesia and to identify risk factors for intraoperative hypotension. METHODS: A total of 722 infants ≤60 weeks postmenstrual age undergoing inguinal herniorrhaphy were randomized to either bupivacaine regional anesthesia (RA) or sevoflurane GA. Exclusion criteria included risk factors for adverse neurodevelopmental outcome and infants born at <26 weeks of gestation. Moderate hypotension was defined as mean arterial pressure measurement of <35 mm Hg. Any hypotension was defined as mean arterial pressure of <45 mm Hg. Epochs were defined as 5-minute measurement periods. The primary outcome was any measured hypotension <35 mm Hg from start of anesthesia to leaving the operating room. This analysis is reported primarily as intention to treat (ITT) and secondarily as per protocol. RESULTS: The relative risk of GA compared with RA predicting any measured hypotension of <35 mm Hg from the start of anesthesia to leaving the operating room was 2.8 (confidence interval [CI], 2.0-4.1; P < .001) by ITT analysis and 4.5 (CI, 2.7-7.4, P < .001) as per protocol analysis. In the GA group, 87% and 49%, and in the RA group, 41% and 16%, exhibited any or moderate hypotension by ITT, respectively. In multivariable modeling, group assignment (GA versus RA), weight at the time of surgery, and minimal intraoperative temperature were risk factors for hypotension. Interventions for hypotension occurred more commonly in the GA group compared with the RA group (relative risk, 2.8, 95% CI, 1.7-4.4 by ITT). CONCLUSIONS: RA reduces the incidence of hypotension and the chance of intervention to treat it compared with sevoflurane anesthesia in young infants undergoing inguinal hernia repair.

Post-viraemic detection of bovine ephemeral fever virus by use of autogenous lymphoid tissue-derived bovine primary cell cultures.

BACKGROUND: The potential tissue replication sites and specific cell types that support in vivo virus survival beyond the acute phase of bovine ephemeral fever virus (BEFV) infection have not been fully defined in cattle. To clarify the knowledge gap, tissue specimens were tested after collection from an adult steer necropsied 1 week after acute BEF. CASE REPORT: Significant necropsy findings included fibrinoproliferative synovitis in the stifle joints and fibrin clot-laden fluid in serous body cavities. Moderate numbers of infiltrating neutrophils were demonstrated in sections of the prefemoral lymph nodes and haemal node, and lymphoid hyperplasia in the spleen, haemal node and prefemoral lymph nodes. Viral RNA was detected by qRT-PCR in fresh spleen, haemal node, prefemoral lymph node, synovial fluid and in several spleen-derived cell cultures. BEFV was isolated from autogenously derived splenic primary cell cultures 6 days after cessation of viraemia, and characteristic bullet-shaped virions were confirmed by electron microscopy of an ultrathin haemal node section. In sections of the spleen, haemal node and other tissues, immunohistochemistry demonstrated BEFV antigens that were intracellularly associated with probable histiocytic cells. CONCLUSION: BEFV has preferential tropism for bovine lymphoid tissues and the spleen and haemal node may be potential sites for post-viraemic virus replication.

The importance of mRNA structure in determining the pathogenicity of synonymous and non-synonymous mutations in haemophilia.

INTRODUCTION: Mutational analysis is commonly used to support the diagnosis and management of haemophilia. This has allowed for the generation of large mutation databases which provide unparalleled insight into genotype-phenotype relationships. Haemophilia is associated with inversions, deletions, insertions, nonsense and missense mutations. Both synonymous and non-synonymous mutations influence the base pairing of messenger RNA (mRNA), which can alter mRNA structure, cellular half-life and ribosome processivity/elongation. However, the role of mRNA structure in determining the pathogenicity of point mutations in haemophilia has not been evaluated. AIM: To evaluate mRNA thermodynamic stability and associated RNA prediction software as a means to distinguish between neutral and disease-associated mutations in haemophilia. METHODS: Five mRNA structure prediction software programs were used to assess the thermodynamic stability of mRNA fragments carrying neutral vs. disease-associated and synonymous vs. non-synonymous point mutations in F8, F9 and a third X-linked gene, DMD (dystrophin). RESULTS: In F8 and DMD, disease-associated mutations tend to occur in more structurally stable mRNA regions, represented by lower MFE (minimum free energy) levels. In comparing multiple software packages for mRNA structure prediction, a 101-151 nucleotide fragment length appears to be a feasible range for structuring future studies. CONCLUSION: mRNA thermodynamic stability is one predictive characteristic, which when combined with other RNA and protein features, may offer significant insight when screening sequencing data for novel disease-associated mutations. Our results also suggest potential utility in evaluating the mRNA thermodynamic stability profile of a gene when determining the viability of interchanging codons for biological and therapeutic applications.

Management of Helicobacter pylori infection-the Maastricht V/Florence Consensus Report.

Important progress has been made in the management of Helicobacter pylori infection and in this fifth edition of the Maastricht Consensus Report, key aspects related to the clinical role of H. pylori were re-evaluated in 2015. In the Maastricht V/Florence Consensus Conference, 43 experts from 24 countries examined new data related to H. pylori in five subdivided workshops: (1) Indications/Associations, (2) Diagnosis, (3) Treatment, (4) Prevention/Public Health, (5) H. pylori and the Gastric Microbiota. The results of the individual workshops were presented to a final consensus voting that included all participants. Recommendations are provided on the basis of the best available evidence and relevance to the management of H. pylori infection in the various clinical scenarios.