CD193 (CCR3) expression by B cells correlates with reduced IgE production in paediatric schistosomiasis.

We demonstrate that CD193, the eotaxin receptor, is highly expressed on circulating B cells in paediatric schistosomiasis mansoni. CD193 plays a role in directing granulocytes into sites of allergic-like inflammation in the mucosa, but little is known about its functional significance on human B cells. We sought to characterize CD193 expression and its relationship with S. mansoni infection. We found that CD193+ B cells increased with the intensity of schistosome infection. In addition, a significant negative association was observed between CD193 expression by B cells and IgE production. Decreased IgE levels are generally associated with susceptibility to re-infection. B cell stimulation with eotaxin-1 increased CD193 levels whereas IL-4 led to a reduction. This was supported by plasma levels of eotaxin-1 correlating with CD193 levels on B cells and other cells. In contrast, CD193 expression was induced on naive B cells with a combination of IL-10 and schistosome antigens. Whereas T cells had a modest increase in CD193 expression, only B cell CD193 appeared functionally chemotactic to eotaxin-1. Thus, CD193+ B cells, which co-express CXCR5, may be enroute to sites with allergic-like inflammation, such as gastrointestinal follicles, or even to Th2 granulomas, which develop around parasite eggs. Overall, our results suggest that schistosome infection may promote CD193 expression and suppress IgE via IL-10 and other undefined mechanisms related to B cell trafficking. This study adds to our understanding of why young children may have poor immunity. Nonetheless, praziquantel treatment was shown to reduce percentages of circulating CD193+ B cells lending hope for future vaccine efforts.

Development and verification of the signal to noise ratio for a layer of turbulence in a multi-layer atmosphere.

Wide-field image correction in systems that look through the atmosphere generally requires a tomographic reconstruction of the turbulence volume to compensate for anisoplanatism. The reconstruction is conditioned by estimating the turbulence volume as a profile of thin homogeneous layers. We present the signal to noise ratio (SNR) of a layer, which quantifies how difficult a single layer of homogeneous turbulence is to detect with wavefront slope measurements. The signal is the sum of wavefront tip and tilt variances at the signal layer, and the noise is the sum of wavefront tip and tilt auto-correlations given the aperture shape and projected aperture separations at all non-signal layers. An analytic expression for layer SNR is found for Kolmogorov and von Kármán turbulence models, then verified with a Monte Carlo simulation. We show that the Kolmogorov layer SNR is a function of only layer Fried length, the spatio-angular sampling of the system, and normalized aperture separation at the layer. In addition to these parameters, the von Kármán layer SNR also depends on aperture size, and layer inner and outer scales. Due to the infinite outer scale, layers of Kolmogorov turbulence tend to have lower SNR than von Kármán layers. We conclude that the layer SNR is a statistically valid performance metric to be used when designing, simulating, operating, and quantifying the performance of any system that measures properties of layers of turbulence in the atmosphere from slope data.

Building biosecurity for synthetic biology.

The fast-paced field of synthetic biology is fundamentally changing the global biosecurity framework. Current biosecurity regulations and strategies are based on previous governance paradigms for pathogen-oriented security, recombinant DNA research, and broader concerns related to genetically modified organisms (GMOs). Many scholarly discussions and biosecurity practitioners are therefore concerned that synthetic biology outpaces established biosafety and biosecurity measures to prevent deliberate and malicious or inadvertent and accidental misuse of synthetic biology's processes or products. This commentary proposes three strategies to improve biosecurity: Security must be treated as an investment in the future applicability of the technology; social scientists and policy makers should be engaged early in technology development and forecasting; and coordination among global stakeholders is necessary to ensure acceptable levels of risk.

Machine learning classification of disrotatory IRC and conrotatory non-IRC trajectory motion for cyclopropyl radical ring opening.

Quasiclassical trajectory analysis is now a standard tool to analyze non-minimum energy pathway motion of organic reactions. However, due to the large amount of information associated with trajectories, quantitative analysis of the dynamic origin of reaction selectivity is complex. For the electrocyclic ring opening of cyclopropyl radical, more than 4000 trajectories were run showing that allyl radicals are formed through a mixture of disrotatory intrinsic reaction coordinate (IRC) motion as well as conrotatory non-IRC motion. Geometric, vibrational mode, and atomic velocity transition-state features from these trajectories were used for supervised machine learning analysis with classification algorithms. Accuracy >80% with a random forest model enabled quantitative and qualitative assessment of transition-state trajectory features controlling disrotatory IRC versus conrotatory non-IRC motion. This analysis revealed that there are two key vibrational modes where their directional combination provides prediction of IRC versus non-IRC motion.

Machine Learning Analysis of Direct Dynamics Trajectory Outcomes for Thermal Deazetization of 2,3-Diazabicyclo[2.2.1]hept-2-ene.

Experimentally, the thermal gas-phase deazetization of 2,3-diazabicyclo[2.2.1]hept-2-ene (1) results in the loss of N2 and the formation of bicyclo products 3 (exo) and 4 (endo) in a nonstatistical ratio, with preference for the exo product. Here, we report unrestricted M06-2X quasiclassical trajectories initialized from the concerted N2 ejection transition state that were able to replicate the experimental preference to form 3. We found that the 3:4 ratio results from the relative amounts of very fast (ballistic) exotype trajectories versus trajectories that lead to the 1,3-diradical intermediate 2. These quasiclassical trajectories provided a set of transition-state vibrational, velocity, momenta, and geometric features for the machine learning analysis. A selection of popular supervised classification algorithms (e.g., random forest) provided poor prediction of trajectory outcomes based on only transition-state vibrational quanta and energy features. However, these machine learning models provided more accurate predictions using atomic velocities and atomic positions, attaining ∼70% accuracy using initial conditions and between 85 and 95% accuracy at later reaction time steps. This increased accuracy allowed the feature importance analysis to reveal that, at the later-time analysis, the methylene bridge out-of-plane bending is correlated with trajectory outcomes for the formation of either the exo product or toward the diradical intermediate. Possible reasons for the struggle of machine learning algorithms to classify trajectories based on transition-state features is the heavily overlapping feature values, the finite but very large possible vibrational mode combinations, and the possibility of chaos as trajectories propagate. We examined this chaos by comparing a set of nearly identical trajectories that differed by only a very small scaling of the kinetic energies resulting from the transition-state reaction coordinate.

Phospholamban cardiomyopathy: a Canadian perspective on a unique population.

INTRODUCTION: Phospholamban cardiomyopathy is an inherited cardiomyopathy, characterised by a defect in regulation of the sarcoplasmic reticulum Ca2+ pump, often presenting with malignant arrhythmias and progressive cardiac dysfunction occurring at a young age. METHODS: Phospholamban R14del mutation carriers and family members were identified from inherited arrhythmia clinics at 13 sites across Canada. Cardiac investigations, including electrocardiograms, Holter monitoring (premature ventricular complexes, PVCs), and imaging results were summarised. RESULTS: Fifty patients (10 families) were identified (median age 30 years, range 3-71, 46% female). Mutation carriers were more likely to be older, have low-voltage QRS, T­wave inversion, frequent PVCs, and cardiac dysfunction, compared to unaffected relatives. Increasing age, low-voltage QRS, T­wave inversion, late potentials, and frequent PVCs were predictors of cardiac dysfunction (p < 0.05 for all). Older carriers (age ≥45 years) were more likely to have disease manifestations than were their younger counterparts, with disease onset occurring at an older age in Canadian patients and their Dutch counterparts. DISCUSSION: Among Canadian patients with phospholamban cardiomyopathy, clinical manifestations resembled those of their Dutch counterparts, with increasing age a major predictor of disease manifestation. Older mutation carriers were more likely to have electrical and structural abnormalities, and may represent variable expressivity, age-dependent penetrance, or genetic heterogeneity among Canadian patients.

Dark-adapted red flash ERGs in healthy adults.

PURPOSE: The x-wave of the dark-adapted (DA) ERG to a red flash reflects DA cone function. This exploratory study of healthy adults aimed to investigate changes in the DA red ERG with flash strength and during dark adaptation to optimise visualisation and therefore quantification of the x-wave. METHODS: The effect of altering red flash strength was investigated in four subjects by recording ERGs after 20 min dark adaptation to red flashes (0.2-2.0 cd s m-2) using skin electrodes and natural pupils. The effect of dark adaptation duration was investigated in 16 subjects during 20 min in the dark, by recording DA 1.5 red ERGs at 1, 2, 3, 4, 5, 10, 15 and 20 min. RESULTS: For a dark adaption period of 20 min, the x-wave was more clearly visualised to weaker (< 0.6 cd s m-2) red flash strengths: to stronger flashes it became obscured by the b-wave. For red flashes of 1.5 cd s m-2, the x-wave was most prominent in ERGs recorded after 1-5 min of dark adaptation: with longer dark adaptation, it was subsumed into the b-wave's rising edge. CONCLUSIONS: This small study suggests that x-wave visibility in healthy subjects after 20 min dark adaptation is improved by using flashes weaker than around 0.6 cd s m-2; for flash strengths of 1.5 cd s m-2, x-wave visibility is enhanced by recording after only around 5 min of dark adaptation. No evidence was found that interim red flash ERGs affect the dark-adapted state of the normal retina.

EAACI Molecular Allergology User's Guide.

The availability of allergen molecules ('components') from several protein families has advanced our understanding of immunoglobulin E (IgE)-mediated responses and enabled 'component-resolved diagnosis' (CRD). The European Academy of Allergy and Clinical Immunology (EAACI) Molecular Allergology User's Guide (MAUG) provides comprehensive information on important allergens and describes the diagnostic options using CRD. Part A of the EAACI MAUG introduces allergen molecules, families, composition of extracts, databases, and diagnostic IgE, skin, and basophil tests. Singleplex and multiplex IgE assays with components improve both sensitivity for low-abundance allergens and analytical specificity; IgE to individual allergens can yield information on clinical risks and distinguish cross-reactivity from true primary sensitization. Part B discusses the clinical and molecular aspects of IgE-mediated allergies to foods (including nuts, seeds, legumes, fruits, vegetables, cereal grains, milk, egg, meat, fish, and shellfish), inhalants (pollen, mold spores, mites, and animal dander), and Hymenoptera venom. Diagnostic algorithms and short case histories provide useful information for the clinical workup of allergic individuals targeted for CRD. Part C covers protein families containing ubiquitous, highly cross-reactive panallergens from plant (lipid transfer proteins, polcalcins, PR-10, profilins) and animal sources (lipocalins, parvalbumins, serum albumins, tropomyosins) and explains their diagnostic and clinical utility. Part D lists 100 important allergen molecules. In conclusion, IgE-mediated reactions and allergic diseases, including allergic rhinoconjunctivitis, asthma, food reactions, and insect sting reactions, are discussed from a novel molecular perspective. The EAACI MAUG documents the rapid progression of molecular allergology from basic research to its integration into clinical practice, a quantum leap in the management of allergic patients.

Effect of shorter dark adaptation on ISCEV standard DA 0.01 and DA 3 skin ERGs in healthy adults.

PURPOSE: To quantify dark-adapted (DA) skin ERG changes during 20 min of dark adaptation. METHODS: Sixteen healthy adult subjects were dark-adapted for 20 min during which ISCEV standard dim (0.01 phot cd s m(-2)) white flash ERGs were recorded at 1, 2, 3, 4, 5, 10, 15 and 20 min, and bright (3 phot cd s m(-2)) white ERGs were recorded at 2, 5, 10, 15 and 20 min without mydriasis and using skin electrodes. Amplitudes and peak times were normalised to 20 min values. RESULTS: Halving dark adaptation from 20 to 10 min had no measureable effect on the DA 3 ERG and caused a 10 % amplitude loss (range 0-23 %) only for the DA 0.01 ERG b-wave amplitude. No significant peak time changes resulted, nor increased parameter variability. CONCLUSION: Reducing dark adaptation from 20 to 10 min or even less has an effect on only DA 0.01 ERGs. Shorter dark adaptation than 20 min may not compromise the clinical utility of the ERG providing clinics adhere to the usual standards of adequate reference data.

Renegotiating hope while living with lymphoedema after cancer: a qualitative study.

Hope is defined as a multi-dimensional life force, a coping resource and a necessity for coping with illness. Concepts of normalcy, hope and loss are explored in this qualitative study and positioned within recent scholarship on hope in cancer survivors. The experiences of 13 participants (11 women, 2 men) in two Canadian provinces who were living with lymphoedema secondary to cancer were analysed. For these participants, hope assumed various meanings. For some, hope was seen as passive inaction, whereas hope for others was positive and action-oriented, even when faced with the uncertainty of chronic illness. Hope for the individual with lymphoedema is also juxtaposed with hope associated with cancer treatment where a desired return to normal is the object of hope and paramount to coping. However, when met with the chronic nature of lymphoedema, the hope of a return to normalcy is lost and the meaning, direction and actions of hope must be renegotiated.

An analysis of the association between prostate cancer risk loci, PSA levels, disease aggressiveness and disease-specific mortality.

BACKGROUND: Genome-wide association studies have identified multiple single-nucleotide polymorphsims (SNPs) associated with prostate cancer (PCa). Although these SNPs have been clearly associated with disease risk, their relationship with clinical outcomes is less clear. Our aim was to assess the frequency of known PCa susceptibility alleles within a single institution ascertainment and to correlate risk alleles with disease-specific outcomes. METHODS: We genotyped 1354 individuals treated for localised PCa between June 1988 and December 2007. Blood samples were prospectively collected and de-identified before being genotyped and matched to phenotypic data. We investigated associations between 61 SNPs and disease-specific end points using multivariable analysis and also determined if SNPs were associated with PSA at diagnosis. RESULTS: Seven SNPs showed associations on multivariable analysis (P<0.05), rs13385191 with both biochemical recurrence (BR) and castrate metastasis (CM), rs339331 (BR), rs1894292, rs17178655 and rs11067228 (CM), and rs11902236 and rs4857841 PCa-specific mortality. After applying a Bonferroni correction for number of SNPs (P<0.0008), the only persistent significant association was between rs17632542 (KLK3) and PSA levels at diagnosis (P=1.4 × 10(-5)). CONCLUSIONS: We confirmed that rs17632542 in KLK3 is associated with PSA at diagnosis. No significant association was seen between loci and disease-specific end points when accounting for multiple testing. This provides further evidence that known PCa risk SNPs do not predict likelihood of disease progression.

Prevalence and risk factors for allergic rhinitis in two resource-limited settings in Peru with disparate degrees of urbanization.

BACKGROUND: Allergic rhinitis is a disease with a high global disease burden, but risk factors that contribute to this condition are not well understood. OBJECTIVE: To assess the prevalence and risk factors of allergic rhinitis in two Peruvian populations with disparate degrees of urbanization. METHODS: We conducted a population-based, cross-sectional study on 1441 children aged 13-15 years at enrollment (mean age 14.9 years, 51% boys) to investigate the prevalence of allergic disease. We used a standardized, Spanish validated questionnaire to determine the prevalence of allergic rhinitis and asked about sociodemographics and family history of allergies. Children also underwent spirometry, exhaled nitric oxide, allergy skin testing to 10 common household allergens and provided a blood sample for measurement of 25OH vitamin D and total serum IgE. RESULTS: Overall prevalence of allergic rhinitis was 18% (95% CI 16% to 20%). When stratified by site, the prevalence of allergic rhinitis was 23% Lima vs. 13% in Tumbes (P < 0.001); however, this difference was no longer significant after controlling for subject-specific factors (P = 0.95). There was a strong association with other allergic diseases: 53% of children with asthma had allergic rhinitis vs. 15% in those without asthma (P < 0.001) and 42% of children with eczema vs. 17% of those without eczema (P < 0.001). Important risk factors for allergic rhinitis were parental rhinitis (adjusted OR = 3.0, 95% CI 1.9-4.7 for 1 parent and adjusted OR = 4.4, 95% CI 1.5-13.7 for 2 parents); allergic sensitization to common household aeroallergens (1.6, 1.1-2.3); being overweight (1.5, 1.0-2.3); exhaled nitric oxide ≥ 20 ppb (1.9, 1.3-2.7); and total serum IgE ≥ 95th percentile (2.4, 1.2-4.8). Population attributable risk of important factors for allergic rhinitis were 25% for high exhaled nitric oxide, 22% for allergic sensitization to common household aeroallergens, 22% for paternal rhinitis, 10% for being overweight and 7% for an elevated total serum IgE. CONCLUSION AND CLINICAL RELEVANCE: Allergic rhinitis was prevalent in both settings, and important risk factors include elevated exhaled nitric oxide, allergic sensitization to common household aeroallergens, parental rhinitis, being overweight and high total serum IgE. When considering subject-specific factors, the difference in prevalence between the urban and rural settings became non-important.

Multi-centre variability of ISCEV standard ERGs in two normal adults.

BACKGROUND: The reproducibility of an individual's full-field ERG between centres has not previously been investigated. METHODS: ERGs were recorded using both silver thread and skin electrodes from the same two normal adult subjects at 15 UK centres using routine, local protocols and a highly standardised, 'ISCEV-specified' protocol matching the values specified in the ISCEV standard; where the ISCEV standard allows options, a single value was chosen. RESULTS: Inter-ocular differences were small, and amplitudes were smaller for skin than silver thread electrodes. No centre produced outlying data points, and ERGs across all 15 centres were remarkably similar. Amplitude variability was less for local protocols (using LED flashes) than for the ISCEV-specified protocol using xenon flashes (22 vs. 24 %, p = 0.01), but peak time variability was less for the ISCEV-specified protocol (6.1 vs. 7.4 %, p = 0.001). Only the DA 0.01 ERG correlated with photometric variability. The bifidity of the DA 3 a-wave doubled its peak time variability compared with the DA 10 a-wave. CONCLUSIONS: Inter-centre amplitude variability was typically within clinically significant thresholds, suggesting that inter-centre variability with suitable standardisation may not add more to total variability than inter-subject variability. Variability improvements gained by the tighter specifications of the ISCEV-specified protocol were possibly more than lost due to imprecisions of xenon flashtubes. Peak time variability was far lower than amplitude variability, corresponding with acceptable variability of biochemical assays. These results represent a vindication of the existence of an ERG standard and suggest that further standardisation would lend itself to greater reproducibility of ERGs worldwide.

Resilience following spinal cord injury: a phenomenological view.

STUDY DESIGN: Qualitative research design involving semi-structured focus groups. OBJECTIVES: To increase current understanding of how persons with spinal cord injuries (SCI) define resilience and what factors contribute to their resilience or the resilience of others. SETTING: Inpatient rehabilitation program in a large urban city in the Southwestern United States. METHODS: A convenience sample of 28 participants (14 current patients; 14 former patients) participated in semi-structured focus groups led by the research investigators. RESULTS: Through a constant comparative analysis of the data, six themes emerged in participants' responses regarding what they believed contributed to their own resilience in adapting to SCI. The six themes included psychological strength, social support, perspective, adaptive coping, spirituality or faith, and serving as a role model or inspiring others. CONCLUSION: Consistent with previous research findings, individuals with SCI identified positive thinking (for example, optimism, hope and positive attitude), perseverance and determination, and social support from friends and family as important contributors to their ability to adapt in spite of experiencing traumatic events that resulted in SCI. Findings provide richness and depth to current empirical conceptualizations of resilience.

Efficacy and Safety outcomes of a novel model to assess new medical retina referrals in a high-volume medical retina virtual clinic.

BACKGROUND: Ophthalmology outpatient attendances have significantly increased recently with rising pressure from backlogs arising from the pandemic. Medical retina digital surveillance clinics for stable follow-up appointments are well established. We present a model for assessing new referrals and evaluating clinical outcomes and long-term sustainability in a complex high-volume medical retina service. METHODS: Suitable routine new patient referrals were identified from electronic referrals and referred to this new pathway. Structured history, visual acuities, and intraocular pressures were recorded, and widefield colour fundus and optical coherence tomography imaging were performed at a imaging hub for asynchronous consultant-led review. RESULTS: 1458 patients were invited to attend over four months, with a 13.2% did-not-attend (DNA) rate. Common diagnoses included stable diabetic retinopathy (19.9%), early age-related macular degeneration (6.7%), central serous retinopathy (8.8%), and retinal vein occlusion (6.3%). 7 patients (0.05%) required urgent same-day review. 61 (5.0%) required urgent face-to-face (F2F) assessment within two weeks. A total of 727 (59.0%) were either discharged or remained in the virtual pathway following their first visit. CONCLUSION: This study encourages the use of a digital model that efficiently assesses suitable newly referred medical retina patients in both complex and local eye unit settings. This decreased the need for F2F clinics and resources. Further patient satisfaction surveys for digital services are currently being evaluated to guide long-term sustainability of this model.

Impaired vision in children prenatally exposed to methadone: an observational cohort study.

BACKGROUND/OBJECTIVES: To examine prevalence of failed visual assessment at 8-10 years in children born to methadone-maintained opioid dependent (MMOD) mothers and relate this to known in utero substance exposure. SUBJECTS/METHODS: Follow up of observational cohort study of methadone-exposed and comparison children matched for birthweight, gestation and postcode of residence at birth. Participants were 144 children (98 exposed, 46 comparison). Prenatal drug exposure was previously established via comprehensive maternal and neonatal toxicology. Children were invited to attend for visual assessment and casenotes were reviewed. Presence of acuity poorer than 0.2 logMAR, strabismus, nystagmus and/or impaired stereovision constituted a 'fail'. Fail rates were compared between methadone-exposed and comparison children after adjusting for known confounding variables. RESULTS: 33 children attended in person: data were also derived from casenote review for all children. After controlling for maternal reported tobacco use, methadone-exposed children were more likely to have a visual 'fail' outcome, adjusted odds ratio 2.6, 95% CI 1.1-6.2; adjusted relative risk 1.8 (95% CI 1.1-3.4). Visual 'fail' outcome rates did not differ between methadone-exposed children who had (n = 47) or had not (n = 51) received pharmacological treatment for neonatal abstinence/opioid withdrawal syndrome (NAS/NOWS); fail rate 62% vs 53% (95% CI of difference-11-27%). CONCLUSIONS: Children born to MMOD mothers are almost twice as likely as unexposed peers to have significant visual abnormalities at primary school age. Prenatal methadone exposure should be considered in the differential diagnosis of nystagmus. Findings support visual assessment prior to school entry for children with any history of prenatal opioid exposure. TRIAL REGISTRATION: The study was prospectively registered on ClinicalTrials.gov (NCT03603301), https://clinicaltrials.gov/ct2/show/NCT03603301 .

Nurses' attitudes, behaviours, and enablers of intravenous to oral switching (IVOS) of antibiotics: a mixed-methods survey of nursing staff in secondary care hospitals across the Midlands region of England.

BACKGROUND: Intravenous (IV) antibiotic use in secondary care in England is widespread. Timely appropriate intravenous to oral switch (IVOS) has the potential to deliver significant clinical and operational benefits. To date, antimicrobial stewardship (AMS) efforts around IVOS have not focused on the nursing staff who administer antibiotics, which represents a significant gap in AMS programmes. AIM: To determine the involvement of bedside nurses in acute trusts in the Midlands region of England in IVOS in their organizations and describe their views regarding how to improve IVOS. METHODS: An anonymous self-administered mixed-methods online survey was developed and distributed to nursing staff in acute trusts via antimicrobial stewardship networks between March and May 2023. Quantitative data was analysed to describe participant demographics and behaviours, whereas barriers and enablers to IVOS were explored through thematic content analysis of responses to open-ended questions. FINDINGS: A total of 545 nursing staff responded to the survey. The majority (65.3%) routinely suggested IVOS to clinicians, despite only 50.6% being aware of local IVOS policies. One-third (34.7%) did not suggest IVOS, relying on doctors, believing their patients needed IV treatment, or lacked knowledge and skills to request IVOS. Content analysis of suggestions for improving the rate of IVOS proposed three major themes (People, Process, System) and identified that education and training, improved confidence and interprofessional relationships, and prompts were important drivers. CONCLUSION: Nursing staff suggest IVOS to other clinicians, but more education and resources are needed to enable and empower them in this role.