Prolonged respiratory failure responds to conventional therapy in isolated homocysteine remethylation defects

Isolated remethylation defects are rare inherited diseases caused by a defective remethylation of homocysteine to methionine, preventing various essential methylation reactions to occur. Patients present with a systemic phenotype, which can especially affect the central and peripheral nervous systems leading to epileptic encephalopathy, developmental delay and peripheral neuropathy. Respiratory failure has been described in some cases, caused by both central and peripheral neurological involvement. In published cases, the genetic diagnosis and initiation of appropriate therapy were rapidly performed following respiratory failure and led to a rapid recovery of respiratory insufficiency within days. Here, we present two infantile-onset cases of isolated remethylation defects, cobalamine (Cbl)G and methylenetetrahydrofolate reductase (MTHFR) deficiencies, which were diagnosed after several months of respiratory failure. Disease modifying therapy based on hydroxocobalamin and betaine was initiated and shows a progressive improvement and enabled weaning off respiratory support after 21 and 17 months in CblG and MTHFR patients respectively. We show that prolonged respiratory failure responds to conventional therapy in isolated remethylation defects, but can require a sustained period of time before observing a full response to therapy

Characterizing the Interplay Between Autism Spectrum Disorder and Comorbid Medical Conditions: An Integrative Review

Co-occurring medical disorders and associated physiological abnormalities in individuals with autism spectrum disorder (ASD) may provide insight into causal pathways or underlying biological mechanisms. Here, we review medical conditions that have been repeatedly highlighted as sharing the strongest associations with ASD—epilepsy, sleep, as well as gastrointestinal and immune functioning. We describe within each condition their prevalence, associations with behavior, and evidence for successful treatment. We additionally discuss research aiming to uncover potential aetiological mechanisms. We then consider the potential interaction between each group of conditions and ASD and, based on the available evidence, propose a model that integrates these medical comorbidities in relation to potential shared aetiological mechanisms. Future research should aim to systematically examine the interactions between these physiological systems, rather than considering these in isolation, using robust and sensitive biomarkers across an individual's development. A consideration of the overlap between medical conditions and ASD may aid in defining biological subtypes within ASD and in the development of specific targeted interventions

TightRight : augmenting screwdrivers to reduce bone stripping rates and optimise tightness when inserting non-locking screws

Objectives Non-locking screws remain one of the most commonly used orthopaedic implants, however they are often poorly inserted. Exceeding the stripping torque for a screw hole reduces pullout strength. The aims of this study were firstly to quantify stripping rates and screw tightness for surgeons and secondly to assess how these change when using a screwdriver that indicates when optimum tightness is reached. Methods At the AO Davos Courses 2018 (Davos, Switzerland), 302 orthopaedic surgeons tightened 20 screws in two phases: Phase 1 - screws tightened to the surgeon’s perception of optimum tightness. Phase 2 - using an augmented screwdriver that indicated, by audibly alarming and vibrating, when a predetermined optimum tightness was reached (defined as 70% of the maximum stripping torque). Within each phase, 10 partially inserted 3.5 mm non-locking cortical screws were tightened through a 3.5 mm plate into 4 mm thick artificial bone analogue of 0.32 g/cm3. The stopping torque for each screw was recorded and compared to the stripping torque; if the stopping torque greatly exceeded the stripping torque, tightness values >100% were possible. A confidence value in each screw’s purchase was recorded, 1-10. Following tests of normality, Student t-tests were performed to compare different phases and insertion confidences. Results For phases 1 and 2 respectively, stripping rates were 58 ± 32% and 15 ± 25% (p<0.0001) and the tightness for all screws was 190% ± 255% (n=3020) and 87 ± 49% (n=3020) (p<0.0001). Considering only unstripped insertions, tightness was 81 ± 12% (n=1242) and 71 ± 12% (n=2579) respectively. In phase 1, confidence was 7 ± 2 (out of 10) for screws found to have not unstripped and 6 ± 2 for stripped insertions (p=0.441), and 7 ± 2 and 7 ± 2 (p=0.216) in phase 2 respectively. Conclusion With an unaugmented screwdriver (Phase 1), stripping rates were high, though varied greatly amongst surgeons. Using an augmented screwdriver (Phase 2) greatly improved insertion, with optimum tightness being achieving alongside a significantly reduced rate of bone stripping. Further work incorporating these techniques into surgical education and clinical practice are recommended

Augmented screwdrivers can increase the performance of orthopaedic surgeons compared with use of normal screwdrivers

Orthopaedic screws insertion can be trivialised as a simple procedure, however it is frequently performed poorly. Limited work exists defining how well surgeons insert screws or whether augmented screwdrivers can aid surgeons to reduce stripping rates and optimise tightness. We aimed to establish the performance of surgeons inserting screws and whether this be improved with screwdriver augmentation. 302 orthopaedic surgeons tightened 10 non-locking screws to what they determined to be optimum tightness into artificial bone sheets. The confidence in the screw purchase was given (1–10). A further 10 screws were tightened, using an augmented screwdriver that indicated when a predetermined optimum tightness was reached. The tightness for unstripped insertions under normal conditions and with the augmented screwdriver were 81% (95% CI 79–82%)(n = 1275) and 70% (95% CI 69–72%)(n = 2577) (p < 0.001). The stripping rates were 58% (95% CI 54–61%) and 15% (95% CI 12–17%) respectively (p < 0.001). The confidences when using the normal and augmented screwdrivers respectively were 7.2 and 7.1 in unstripped insertions and 6.2 and 6.5 in stripped insertions. Performance improved with an augmented screwdriver, both in reduced stripping rates and greater accuracy in detecting stripping. Augmenting screwdrivers to indicate optimum tightness offer potentially enormous clinical benefits by improving screw fixation

Ablation of prion protein in wild type human amyloid precursor protein (APP) transgenic mice does not alter the proteolysis of APP, levels of amyloid-β or pathologic phenotype

The cellular prion protein (PrPC) has been proposed to play an important role in the pathogenesis of Alzheimer's disease. In cellular models PrPC inhibited the action of the β-secretase BACE1 on wild type amyloid precursor protein resulting in a reduction in amyloid-β (Aβ) peptides. Here we have assessed the effect of genetic ablation of PrPC in transgenic mice expressing human wild type amyloid precursor protein (line I5). Deletion of PrPC had no effect on the α- and β-secretase proteolysis of the amyloid precursor protein (APP) nor on the amount of Aβ38, Aβ40 or Aβ42 in the brains of the mice. In addition, ablation of PrPC did not alter Aβ deposition or histopathology phenotype in this transgenic model. Thus using this transgenic model we could not provide evidence to support the hypothesis that PrPC regulates Aβ production

Respiratory virus type to guide predictive enrichment approaches in the management of the first episode of bronchiolitis: A systematic review

It has become clear that severe bronchiolitis is a heterogeneous disease; even so, current bronchiolitis management guidelines rely on the one-size-fits-all approach regarding achieving both short-term and chronic outcomes. It has been speculated that the use of molecular markers could guide more effective pharmacological management and achieve the prevention of chronic respiratory sequelae. Existing data suggest that asthma-like treatment (systemic corticosteroids and beta2-agonists) in infants with rhinovirus-induced bronchiolitis is associated with improved short-term and chronic outcomes, but robust data is still lacking. We performed a systematic search of PubMed, Embase, Web of Science, and the Cochrane’s Library to identify eligible randomized controlled trials to determine the efficacy of a personalized, virus-dependent application of systemic corticosteroids in children with severe bronchiolitis. Twelve studies with heterogeneous methodology were included. The analysis of the available results comparing the respiratory syncytial virus (RSV)-positive and RSV-negative children did not reveal significant differences in the associatons between systemic corticosteroid use in acute episode and duration of hospitalization (short-term outcome). However, this systematic review identified a trend of the positive association between the use of systematic corticosteroids and duration of hospitalization in RSV-negative infants hospitalized with the first episode of bronchiolitis (two studies). This evidence is not conclusive. Taken together, we suggest the design for future studies to assess the respiratory virus type in guiding predictive enrichment approaches in infants presenting with the first episode of bronchiolitis. </p

Genomic Informed Breeding Strategies for Strawberry Yield and Fruit Quality Traits

Over the last two centuries, breeders have drastically modified the fruit quality of strawberries through artificial selection. However, there remains significant variation in quality across germplasm with scope for further improvements to be made. We reported extensive phenotyping of fruit quality and yield traits in a multi-parental strawberry population to allow genomic prediction and quantitative trait nucleotide (QTN) identification, thereby enabling the description of genetic architecture to inform the efficacy of implementing advanced breeding strategies. A negative relationship (r = -0.21) between total soluble sugar content and class one yield was identified, indicating a trade-off between these two essential traits. This result highlighted an established dilemma for strawberry breeders and a need to uncouple the relationship, particularly under June-bearing, protected production systems comparable to this study. A large effect of quantitative trait nucleotide was associated with perceived acidity and pH whereas multiple loci were associated with firmness. Therefore, we recommended the implementation of both marker assisted selection (MAS) and genomic prediction to capture the observed variation respectively. Furthermore, we identified a large effect locus associated with a 10% increase in the number of class one fruit and a further 10 QTN which, when combined, are associated with a 27% increase in the number of marketable strawberries. Ultimately, our results suggested that the best method to improve strawberry yield is through selecting parental lines based upon the number of marketable fruits produced per plant. Not only were strawberry number metrics less influenced by environmental fluctuations, but they had a larger additive genetic component when compared with mass traits. As such, selecting using "number" traits should lead to faster genetic gain

Level of agreement between frequently used cardiovascular risk calculators in people living with HIV

Objectives The aim of the study was to describe agreement between the QRISK2, Framingham and Data Collection on Adverse Events of Anti‐HIV Drugs (D:A:D) cardiovascular disease (CVD) risk calculators in a large UK study of people living with HIV (PLWH). Methods PLWH enrolled in the Pharmacokinetic and Clinical Observations in People over Fifty (POPPY) study without a prior CVD event were included in this study. QRISK2, Framingham CVD and the full and reduced D:A:D CVD scores were calculated; participants were stratified into ‘low’ ( 20%) categories for each. Agreement between scores was assessed using weighted kappas and Bland–Altman plots. Results The 730 included participants were predominantly male (636; 87.1%) and of white ethnicity (645; 88.5%), with a median age of 53 [interquartile range (IQR) 49–59] years. The median calculated 10‐year CVD risk was 11.9% (IQR 6.8–18.4%), 8.9% (IQR 4.6–15.0%), 8.5% (IQR 4.8–14.6%) and 6.9% (IQR 4.1–11.1%) when using the Framingham, QRISK2, and full and reduced D:A:D scores, respectively. Agreement between the different scores was generally moderate, with the highest level of agreement being between the Framingham and QRISK2 scores (weighted kappa = 0.65) but with most other kappa coefficients in the 0.50–0.60 range. Conclusions Estimates of predicted 10‐year CVD risk obtained with commonly used CVD risk prediction tools demonstrate, in general, only moderate agreement among PLWH in the UK. While further validation with clinical endpoints is required, our findings suggest that care should be taken when interpreting any score alone

Depression, lifestyle factors and cognitive function in people living with HIV and comparable HIV-negative controls

We investigated whether differences in cognitive performance between people living with HIV (PLWH) and comparable HIV-negative people were mediated or moderated by depressive symptoms and lifestyle factors. METHODS: A cross-sectional study of 637 'older' PLWH aged ≥ 50 years, 340 'younger' PLWH aged < 50 years and 276 demographically matched HIV-negative controls aged ≥ 50 years enrolled in the Pharmacokinetic and Clinical Observations in People over Fifty (POPPY) study was performed. Cognitive function was assessed using a computerized battery (CogState). Scores were standardized into Z-scores [mean = 0; standard deviation (SD) = 1] and averaged to obtain a global Z-score. Depressive symptoms were evaluated via the Patient Health Questionnaire (PHQ-9). Differences between the three groups and the effects of depression, sociodemographic factors and lifestyle factors on cognitive performance were evaluated using median regression. All analyses accounted for age, gender, ethnicity and level of education. RESULTS: After adjustment for sociodemographic factors, older and younger PLWH had poorer overall cognitive scores than older HIV-negative controls (P < 0.001 and P = 0.006, respectively). Moderate or severe depressive symptoms were more prevalent in both older (27%; P < 0.001) and younger (21%; P < 0.001) PLWH compared with controls (8%). Depressive symptoms (P < 0.001) and use of hashish (P = 0.01) were associated with lower cognitive function; alcohol consumption (P = 0.02) was associated with better cognitive scores. After further adjustment for these factors, the difference between older PLWH and HIV-negative controls was no longer significant (P = 0.08), while that between younger PLWH and older HIV-negative controls remained significant (P = 0.01). CONCLUSIONS: Poorer cognitive performances in PLWH compared with HIV-negative individuals were, in part, mediated by the greater prevalence of depressive symptoms and recreational drug use reported by PLWH