Type 1 VWD classification revisited: novel insights from combined analysis of the LoVIC and WiN studies.

ABSTRACT: There is significant ongoing debate regarding type 1 von Willebrand disease (VWD) defintion. Previous guidelines recommended patients with von Willebrand factor (VWF) levels <30 IU/dL be diagnosed type 1 VWD, whereas patients with significant bleeding and VWF levels from 30 to 50 IU/dL be diagnosed with low VWF. To elucidate the relationship between type 1 VWD and low VWF in the context of age-induced increases in VWF levels, we combined data sets from 2 national cohort studies: 162 patients with low VWF from the Low VWF in Ireland Cohort (LoVIC) and 403 patients with type 1 VWD from the Willebrand in The Netherlands (WiN) studies. In 47% of type 1 VWD participants, VWF levels remained <30 IU/dL despite increasing age. Conversely, VWF levels increased to the low VWF range (30-50 IU/dL) in 30% and normalized (>50 IU/dL) in 23% of type 1 VWD cases. Crucially, absolute VWF antigen (VWF:Ag) levels and increase of VWF:Ag per year overlapped between low VWF and normalized type 1 VWD participants. Moreover, multiple regression analysis demonstrated that VWF:Ag levels in low VWF and normalized type 1 VWD patients would not have been different had they been diagnosed at the same age (ß = 0.00; 95% confidence interval, -0.03 to 0.04). Consistently, no difference was found in the prevalence of VWF sequence variants; factor VIII activity/VWF:Ag or VWF propeptide/VWF:Ag ratios; or desmopressin responses between low VWF and normalized type 1 VWD patients. In conclusion, our findings demonstrate that low VWF does not constitute a discrete clinical or pathological entity. Rather, it is part of an age-dependent type 1 VWD evolving phenotype. Collectively, these data have important implications for future VWD classification criteria.

Shaping leaves through TALE homeodomain transcription factors.

The first TALE homeodomain transcription factor gene to be described in plants was maize knotted1 (kn1). Dominant mutations in kn1 disrupt leaf development, with abnormal knots of tissue forming in the leaf blade. kn1 was found to be expressed in the shoot meristem but not in a peripheral region that gives rise to leaves. Furthermore, KN1 and closely related proteins were excluded from initiating and developing leaves. These findings were a prelude to a large body of work wherein TALE homeodomain proteins have been identified as vital regulators of meristem homeostasis and organ development in plants. KN1 homologues are widely represented across land plant taxa. Thus, studying the regulation and mechanistic action of this gene class has allowed investigations into the evolution of diverse plant morphologies. This review will focus on the function of TALE homeodomain transcription factors in leaf development in eudicots. Here, we discuss how TALE homeodomain proteins contribute to a spectrum of leaf forms, from the simple leaves of Arabidopsis thaliana to the compound leaves of Cardamine hirsuta and species beyond the Brassicaceae.

Vaccine-induced immune thrombotic thrombocytopenia (VITT) - a novel clinico-pathological entity with heterogeneous clinical presentations.

Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a novel entity that emerged in March 2021 following reports of unusual thrombosis after ChAdOx1 nCoV-19, (AstraZeneca) vaccination. Following the recognition of this syndrome, multiple consensus guidelines have been released to risk stratify patients presenting with possible symptoms after ChAdOx1 nCoV-19 vaccination. All guidelines rapidly identify VITT in patients with the complete triad of thrombocytopenia, thrombosis and elevated D-dimers after ChAdOx1 nCoV-19 vaccination. However, with earlier recognition of the associated symptoms, the clinical manifestations are likely to be more heterogeneous and represent an evolving spectrum of disease. In this setting, current guidelines may lack the sensitivity to detect early cases of VITT and risk missed or delayed diagnoses. The broad clinical phenotype and challenges associated with diagnosis of VITT are highlighted in our present case series of four patients with confirmed VITT. Dependent on the guidance used, each patient could have been classified as a low probability of VITT at presentation. The present study highlights the issues associated with the recognition of VITT, the limitations of current guidance and the need for heightened clinical vigilance as our understanding of the pathophysiology of this novel condition evolves.

Increased galactose expression and enhanced clearance in patients with low von Willebrand factor.

Glycan determinants on von Willebrand factor (VWF) play critical roles in regulating its susceptibility to proteolysis and clearance. Abnormal glycosylation has been shown to cause von Willebrand disease (VWD) in a number of different mouse models. However, because of the significant technical challenges associated with accurate assessment of VWF glycan composition, the importance of carbohydrates in human VWD pathogenesis remains largely unexplored. To address this, we developed a novel lectin-binding panel to enable human VWF glycan characterization. This methodology was then used to study glycan expression in a cohort of 110 patients with low VWF compared with O blood group-matched healthy controls. Interestingly, significant interindividual heterogeneity in VWF glycan expression was seen in the healthy control population. This variation included terminal sialylation and ABO(H) blood group expression on VWF. Importantly, we also observed evidence of aberrant glycosylation in a subgroup of patients with low VWF. In particular, terminal α(2-6)-linked sialylation was reduced in patients with low VWF, with a secondary increase in galactose (Gal) exposure. Furthermore, an inverse correlation between Gal exposure and estimated VWF half-life was observed in those patients with enhanced VWF clearance. Together, these findings support the hypothesis that loss of terminal sialylation contributes to the pathophysiology underpinning low VWF in at least a subgroup of patients by promoting enhanced clearance. In addition, alterations in VWF carbohydrate expression are likely to contribute to quantitative and qualitative variations in VWF levels in the normal population. This trial was registered at www.clinicaltrials.gov as #NCT03167320.

SAW homeodomain transcription factors regulate initiation of leaf margin serrations.

Plant leaves are the main photosynthetic organ of plants and they occur in an array of different shapes. Leaf shape is determined by morphogenesis whereby patterning of the leaf margin can result in interspaced leaf serrations, lobes, or leaflets, depending on the species, developmental stage, and in some instances the environment. In Arabidopsis, mutations in the homeodomain transcription factors SAW1 and SAW2 result in more prominent leaf margin serrations. Here we show that serrations appear precociously in the saw1 saw2 mutant. The pattern of auxin maxima, and of PIN1 and CUC2 expression, which form a feedback loop that drives serration outgrowth, is altered in saw1 saw2 and correlates with precocious serration initiation. SAW1 is not expressed in the outer epidermal cell layer where PIN1 convergence points generate auxin maxima. Instead, SAW1 is expressed on the adaxial side of the leaf and expression in this domain is sufficient for function. We suggest that SAW1 and SAW2 repress serration initiation and outgrowth by promoting the transition to a determinate fate in the leaf margin.

Real-world outcomes with recombinant factor IX Fc fusion protein (rFIXFc) prophylaxis: Longitudinal follow-up in a national adult cohort.

INTRODUCTION: In 2017, all people with severe haemophilia B (PWSHB) in Ireland switched from standard half-life (SHL) recombinant FIX (rFIX) to rFIX Fc fusion protein (rFIXFc) prophylaxis. AIMS: To evaluate prophylaxis regimens, bleeding rates and factor usage for two years of rFIXFc prophylaxis in a real-world setting. METHODS: Data collected retrospectively from electronic diaries and medical records of PWSHB for a two-year period on rFIXFc prophylaxis were compared with paired baseline data on SHL rFIX treatment. RESULTS: 28 PWSHB (≥18 years) were enrolled, and at switchover 79% were receiving prophylaxis and 21% episodic treatment with SHL rFIX. At 24 months following switchover, all remained on rFIXFc prophylaxis with reduced infusion frequency; median dose per infusion once weekly (55 IU/kg, 20/28), every 10 days (63 IU/kg, 2/28) or every 14 days (98 IU/kg, 6/28). Median annualised bleed rate improved significantly on rFIXFc prophylaxis (2.0 versus 3.3 on SHL FIX) (p = 0.01). Median FIX trough level with once-weekly infusions was 0.09 IU/ml (0.06-0.14 IU/ml). Management of bleeding episodes was similar with rFIXFc and SHL rFIX; one infusion was sufficient to treat 74% and 77% of bleeds, respectively, with similar total median treatment per bleeding episode. Factor consumption reduced by 28% with rFIXFc prophylaxis (57 IU/kg/week, range 40-86 IU/kg/week) compared with SHL rFIX (79 IU/kg/week, range 44-210 IU/kg/week) (p = 0.002). CONCLUSION: This study provides important insights into real-world experience of switching to rFIXFc prophylaxis in an adult population, demonstrating high rates of prophylaxis, with reduced infusion frequency, bleeding and FIX consumption.

Single centre, real-world experience of perioperative rFIXFc use in adult patients with haemophilia B undergoing major and minor surgery.

INTRODUCTION: Recombinant factor IX fusion protein concentrate (rFIXFc) is increasingly used for prophylaxis in people with haemophilia B (PWHB), but experience in the perioperative setting is limited. AIMS: To evaluate real-world perioperative factor usage, bleeding and complications in PWHB (≥18 years) who received rFIXFc for surgical haemostasis and to describe the treatment regimens used. METHODS: Single centre, retrospective review of all PWHB who underwent a major or minor surgical procedure between June 2017 and July 2020 and received rFIXFc perioperatively for maintenance of surgical haemostasis. RESULTS: A total of 56 PWHB (45 male and 11 female), including people with mild (n = 32), moderate (n = 4) and severe (n = 20) haemophilia B, underwent 11 major and 131 minor procedures with rFIXFc for surgical haemostasis. Haemostasis was rated as excellent (9/11) or good (2/11) in all major procedures. Median total rFIXFc consumption for orthopaedic surgeries was 972 IU/kg (range 812-1031 IU/kg) and for other major (non-orthopaedic) surgeries was 323 IU/kg (range 167-760 IU/kg). The median number of perioperative rFIXFc infusions was 19 (range 17-26) for orthopaedic surgery and 7 (range 5-17) for other major surgeries. The number of infusions in the postoperative period was determined by procedure and patient factors. Complications included bowel ileus and wound infection. Most minor procedures were managed with single infusion of rFIXFc, with no bleeding complications in 95% of minor procedures. There were no thromboembolic events or inhibitor formation. CONCLUSION: This unique data provides real-world evidence that rFIXFc is safe and effective in achieving haemostasis in PWHB undergoing surgery.

COVID19 coagulopathy in Caucasian patients.

Although the pathophysiology underlying severe COVID19 remains poorly understood, accumulating data suggest that a lung-centric coagulopathy may play an important role. Elevated D-dimer levels which correlated inversely with overall survival were recently reported in Chinese cohort studies. Critically however, ethnicity has major effects on thrombotic risk, with a 3-4-fold lower risk in Chinese compared to Caucasians and a significantly higher risk in African-Americans. In this study, we investigated COVID19 coagulopathy in Caucasian patients. Our findings confirm that severe COVID19 infection is associated with a significant coagulopathy that correlates with disease severity. Importantly however, Caucasian COVID19 patients on low molecular weight heparin thromboprophylaxis rarely develop overt disseminated intravascular coagulation (DIC). In rare COVID19 cases where DIC does develop, it tends to be restricted to late-stage disease. Collectively, these data suggest that the diffuse bilateral pulmonary inflammation observed in COVID19 is associated with a novel pulmonary-specific vasculopathy termed pulmonary intravascular coagulopathy (PIC) as distinct to DIC. Given that thrombotic risk is significantly impacted by race, coupled with the accumulating evidence that coagulopathy is important in COVID19 pathogenesis, our findings raise the intriguing possibility that pulmonary vasculopathy may contribute to the unexplained differences that are beginning to emerge highlighting racial susceptibility to COVID19 mortality.

Novel insights into the clinical phenotype and pathophysiology underlying low VWF levels.

Critical clinical questions remain unanswered regarding diagnosis and management of patients with low von Willebrand factor (VWF) levels (30-50 IU/dL). To address these questions, the Low VWF Ireland Cohort (LoVIC) study investigated 126 patients registered with low VWF levels. Despite marginally reduced plasma VWF levels, International Society of Thrombosis and Haemostasis Bleeding Assessment Tool (ISTH BAT) confirmed significant bleeding phenotypes in the majority of LoVIC patients. Importantly, bleeding tendency did not correlate with plasma VWF levels within the 30 to 50 IU/dL range. Furthermore, bleeding phenotypes could not be explained by concurrent hemostatic defects. Plasma factor VIII to VWF antigen (VWF:Ag) ratios were significantly increased in LoVIC patients compared with controls (P < .0001). In contrast, VWF propeptide to VWF:Ag ratios >3 were observed in only 6% of the LoVIC cohort. Furthermore, platelet-VWF collagen binding activity levels were both significantly reduced compared with controls (P < .05). In response to 1-desamino-8-D-arginine vasopressin (DDAVP), peak VWF:Ag levels exceeded 100 IU/dL in 88% of patients and was sustained >100 IU/dL after 4 hours in 72% of subjects. In conclusion, our novel data suggest that low VWF levels can be associated with significant bleeding and are predominantly due to reductions in VWF synthesis and/or constitutive secretion. Although enhanced VWF clearance may contribute to the pathophysiology in some individuals, the absolute reduction in VWF plasma half-life is usually mild and not sufficient to significantly impact upon the duration of DDAVP-induced VWF response. This trial was registered at www.clinicaltrials.gov as #NCT03167320.

Missed at first Glanz: Glanzmann thrombasthenia initially misdiagnosed as Von Willebrand Disease.

Glanzmann thrombasthenia (GT) is an autosomal recessive bleeding disorder caused by a defect in platelet integrin αIIbß3. Given the rarity of the condition (1/1,000,000), assessment and diagnosis should be undertaken in a specialist centre. We report the case of a 34 year old woman with severe menorrhagia and a childhood diagnosis from another centre of Von Willebrand Disease. She had an extensive bleeding history, with epistaxis, menorrhagia and postoperative bleeding requiring multiple previous transfusions. Repeat haemostatic workup in our centre revealed normal Von Willebrand levels but abnormal platelet aggregation consistent with Glanzmann thrombasthenia. Antibody screening detected both anti-HLA and anti-αIIbß3 antibodies, complicating subsequent haemostatic management. This case highlights the importance of diagnostic accuracy, the potential negative sequelae of misdiagnosis and subsequent therapeutic interventions.

Precision health: Advancing symptom and self-management science.

BACKGROUND: Precision health considers individual lifestyle, genetics, behaviors, and environment context and facilitates interventions aimed at helping individuals achieve well-being and optimal health. PURPOSE: To present the Nursing Science Precision Health (NSPH) Model and describe the integration of precision health concepts within the domains of symptom and self-management science as reflected in the National Institute of Nursing Research P30 Centers of Excellence and P20 Exploratory Centers. METHODS: Center members developed the NSPH Model and the manuscript based on presentations and discussions at the annual NINR Center Directors Meeting and in follow-up telephone meetings. DISCUSSION: The NSPH Model comprises four precision components (measurement; characterization of phenotype including lifestyle and environment; characterization of genotype and other biomarkers; and intervention target discovery, design, and delivery) that are underpinned by an information and data science infrastructure. CONCLUSION: Nurse scientist leadership is necessary to realize the vision of precision health as reflected in the NSPH Model.

Do longer root hairs improve phosphorus uptake? Testing the hypothesis with transgenic Brachypodium distachyon lines overexpressing endogenous RSL genes.

Mutants without root hairs show reduced inorganic orthophosphate (Pi) uptake and compromised growth on soils when Pi availability is restricted. What is less clear is whether root hairs that are longer than wild-type provide an additional benefit to phosphorus (P) nutrition. This was tested using transgenic Brachypodium lines with longer root hairs. The lines were transformed with the endogenous BdRSL2 and BdRSL3 genes using either a constitutive promoter or a root hair-specific promoter. Plants were grown for 32 d in soil amended with various Pi concentrations. Plant biomass and P uptake were measured and genotypes were compared on the basis of critical Pi values and P uptake per unit root length. Ectopic expression of RSL2 and RSL3 increased root hair length three-fold but decreased plant biomass. Constitutive expression of BdRSL2, but not expression of BdRSL3, consistently improved P nutrition as measured by lowering the critical Pi values and increasing Pi uptake per unit root length. Increasing root hair length through breeding or biotechnology can improve P uptake efficiency if the pleotropic effects on plant biomass are avoided. Long root hairs, alone, appear to be insufficient to improve Pi uptake and need to be combined with other traits to benefit P nutrition.

Compliance with telephone triage advice among adults aged 45 years and older: an Australian data linkage study.

BACKGROUND: Middle-aged and older patients are prominent users of telephone triage services for timely access to health information and appropriate referrals. Non-compliance with advice to seek appropriate care could potentially lead to poorer health outcomes among those patients. It is imperative to assess the extent to which middle-aged and older patients follow triage advice and how this varies according to their socio-demographic, lifestyle and health characteristics as well as features of the call. METHODS: Records of calls to the Australian healthdirect helpline (July 2008-December 2011) were linked to baseline questionnaire data from the 45 and Up Study (participants age ≥ 45 years), records of emergency department (ED) presentations, hospital admissions, and medical consultation claims. Outcomes of the call included compliance with the advice "Attend ED immediately"; "See a doctor (immediately, within 4 hours, or within 24 hours)"; "Self-care"; and self-referral to ED or hospital within 24 h when given a self-care or low-urgency care advice. Multivariable logistic regression was used to investigate associations between call outcomes and patient and call characteristics. RESULTS: This study included 8406 adults (age ≥ 45 years) who were subjects of 11,088 calls to the healthdirect helpline. Rates of compliance with the advices "Attend ED immediately", "See a doctor" and "Self-care" were 68.6%, 64.6% and 77.5% respectively, while self-referral to ED within 24 h followed 7.0% of calls. Compliance with the advice "Attend ED immediately" was higher among patients who had three or more positive lifestyle behaviours, called after-hours, or stated that their original intention was to attend ED, while it was lower among those who lived in rural and remote areas or reported high or very high levels of psychological distress. Compliance with the advice "See a doctor" was higher in patients who were aged ≥65 years, worked full-time, or lived in socio-economically advantaged areas, when another person made the call on the patient's behalf, and when the original intention was to seek care from an ED or a doctor. It was lower among patients in rural and remote areas and those taking five medications or more. Patients aged ≥65 years were less likely to comply with the advice "Self-care". The rates of self-referral to ED within 24 h were greater in patients from disadvantaged areas, among calls made after-hours or by another person, and when the original intention was to attend ED. Patients who were given a self-care or low-urgency care advice, whose calls concerned bleeding, cardiac, gastrointestinal, head and facial injury symptoms, were more likely to self-refer to ED. CONCLUSIONS: Compliance with telephone triage advice among middle-age and older patients varied substantially according to both patient- and call-related factors. Knowledge about the patients who are less likely to comply with telephone triage advice, and about characteristics of calls that may influence compliance, will assist in refining patient triage protocols and referral pathways, training staff and tailoring service design and delivery to achieve optimal patient compliance.

The quality, safety and governance of telephone triage and advice services - an overview of evidence from systematic reviews.

BACKGROUND: Telephone triage and advice services (TTAS) are increasingly being implemented around the world. These services allow people to speak to a nurse or general practitioner over the telephone and receive assessment and healthcare advice. There is an existing body of research on the topic of TTAS, however the diffuseness of the evidence base makes it difficult to identify key lessons that are consistent across the literature. Systematic reviews represent the highest level of evidence synthesis. We aimed to undertake an overview of such reviews to determine the scope, consistency and generalisability of findings in relation to the governance, safety and quality of TTAS. METHODS: We searched PubMed, MEDLINE, EMBASE, CINAHL, Web of Science and the Cochrane Library for English language systematic reviews focused on key governance, quality and safety findings related to telephone based triage and advice services, published since 1990. The search was undertaken by three researchers who reached consensus on all included systematic reviews. An appraisal of the methodological quality of the systematic reviews was independently undertaken by two researchers using A Measurement Tool to Assess Systematic Reviews. RESULTS: Ten systematic reviews from a potential 291 results were selected for inclusion. TTAS was examined either alone, or as part of a primary care service model or intervention designed to improve primary care. Evidence of TTAS performance was reported across nine key indicators - access, appropriateness, compliance, patient satisfaction, cost, safety, health service utilisation, physician workload and clinical outcomes. Patient satisfaction with TTAS was generally high and there is some consistency of evidence of the ability of TTAS to reduce clinical workload. Measures of the safety of TTAS tended to show that there is no major difference between TTAS and traditional care. CONCLUSIONS: Taken as a whole, current evidence does not provide definitive answers to questions about the quality of care provided, access and equity of the service, its costs and outcomes. The available evidence also suggests that there are many interactional factors (e.g., relationship with other health service providers) which can impact on measures of performance, and also affect the external validity of the research findings.

Medication-related calls received by a national telenursing triage and advice service in Australia: a retrospective cohort study.

BACKGROUND: Telenursing triage and advice services are increasingly being used to deliver health advice. Medication-related queries are common, however little research has explored the medication-related calls made to these services. The aim of this study was to examine the profile of medication-related calls to a national telenursing triage and advice service and the medications involved. METHODS: This was a retrospective cohort study of medication-related calls received by Australia's national helpline (healthdirect helpline) in 2014, which provides free advice from registered nurses. We examined the volume of medication-related calls over time, user profiles for patients and callers, and call characteristics and we also investigated medications involved in the calls by their generic names and therapeutic classes. RESULTS: Of 675,774 calls, 3.8% (n = 25,744) were medication-related, which was the largest category of calls. The average call length was 10 min. Over half of callers (55.4%) were advised to deliver self-care. Of 7,459 calls where the callers reported they did not know what to do prior to calling, 56.8% were advised to self-care and 3.5% were transferred to the Poisons Information Centre immediately. Of 1,277 calls where callers reported that they had originally intended to call an ambulance or attend an emergency department (ED), none were advised to do so. Advice most frequently requested was about analgesics and antipyretics, followed by non-steroidal anti-inflammatory agents. CONCLUSION: The telenursing triage and advice helpline offered quick and easily accessible advice, and provided reassurance to patients and callers with medication-related queries. The service also potentially diverted some patients from attending an ED unnecessarily.

District health manager and mid-level provider perceptions of practice environments in acute obstetric settings in Tanzania: a mixed-method study.

BACKGROUND: In sub-Saharan Africa, the capacity of human resources for health (HRH) managers to create positive practice environments that enable motivated, productive, and high-performing HRH is weak. We implemented a unique approach to examining HRH management practices by comparing perspectives offered by mid-level providers (MLPs) of emergency obstetric care (EmOC) in Tanzania to those presented by local health authorities, known as council health management teams (CHMTs). METHODS: This study was guided by the basic strategic human resources management (SHRM) component model. A convergent mixed-method design was utilized to assess qualitative and quantitative data from the Health Systems Strengthening for Equity: The Power and Potential of Mid-Level Providers project. Survey data was obtained from 837 mid-level providers, 83 of whom participated in a critical incident interview whose aim was to elicit negative events in the practice environment that induced intention to leave their job. HRH management practices were assessed quantitatively in 48 districts with 37 members of CHMTs participating in semi-structured interviews. RESULTS: The eight human resources management practices enumerated in the basic SHRM component model were implemented unevenly. On the one hand, members of CHMTs and mid-level providers agreed that there were severe shortages of health workers, deficient salaries, and an overwhelming workload. On the other hand, members of CHMTs and mid-level providers differed in their perspectives on rewards and allocation of opportunities for in-service training. Although written standards of performance and supervision requirements were available in most districts, they did not reflect actual duties. Members of CHMTs reported high levels of autonomy in key HRH management practices, but mid-level providers disputed the degree to which the real situation on the ground was factored into job-related decision-making by CHMTs. CONCLUSIONS: The incongruence in perspectives offered by members of CHMTs and mid-level providers points to deficient HRH management practices, which contribute to poor practice environments in acute obstetric settings in Tanzania. Our findings indicate that members of CHMTs require additional support to adequately fulfill their HRH management role. Further research conducted in low-income countries is necessary to determine the appropriate package of interventions required to strengthen the capacity of members of CHMTs.

Association Between a Single General Anesthesia Exposure Before Age 36 Months and Neurocognitive Outcomes in Later Childhood.

IMPORTANCE: Exposure of young animals to commonly used anesthetics causes neurotoxicity including impaired neurocognitive function and abnormal behavior. The potential neurocognitive and behavioral effects of anesthesia exposure in young children are thus important to understand. OBJECTIVE: To examine if a single anesthesia exposure in otherwise healthy young children was associated with impaired neurocognitive development and abnormal behavior in later childhood. DESIGN, SETTING, AND PARTICIPANTS: Sibling-matched cohort study conducted between May 2009 and April 2015 at 4 university-based US pediatric tertiary care hospitals. The study cohort included sibling pairs within 36 months in age and currently 8 to 15 years old. The exposed siblings were healthy at surgery/anesthesia. Neurocognitive and behavior outcomes were prospectively assessed with retrospectively documented anesthesia exposure data. EXPOSURES: A single exposure to general anesthesia during inguinal hernia surgery in the exposed sibling and no anesthesia exposure in the unexposed sibling, before age 36 months. MAIN OUTCOMES AND MEASURES: The primary outcome was global cognitive function (IQ). Secondary outcomes included domain-specific neurocognitive functions and behavior. A detailed neuropsychological battery assessed IQ and domain-specific neurocognitive functions. Parents completed validated, standardized reports of behavior. RESULTS: Among the 105 sibling pairs, the exposed siblings (mean age, 17.3 months at surgery/anesthesia; 9.5% female) and the unexposed siblings (44% female) had IQ testing at mean ages of 10.6 and 10.9 years, respectively. All exposed children received inhaled anesthetic agents, and anesthesia duration ranged from 20 to 240 minutes, with a median duration of 80 minutes. Mean IQ scores between exposed siblings (scores: full scale = 111; performance = 108; verbal = 111) and unexposed siblings (scores: full scale = 111; performance = 107; verbal = 111) were not statistically significantly different. Differences in mean IQ scores between sibling pairs were: full scale = -0.2 (95% CI, -2.6 to 2.9); performance = 0.5 (95% CI, -2.7 to 3.7); and verbal = -0.5 (95% CI, -3.2 to 2.2). No statistically significant differences in mean scores were found between sibling pairs in memory/learning, motor/processing speed, visuospatial function, attention, executive function, language, or behavior. CONCLUSIONS AND RELEVANCE: Among healthy children with a single anesthesia exposure before age 36 months, compared with healthy siblings with no anesthesia exposure, there were no statistically significant differences in IQ scores in later childhood. Further study of repeated exposure, prolonged exposure, and vulnerable subgroups is needed.

Medication-related queries received for 'after hours GP helpline' - Comparison of callers' intentions with GPs' advice.

BACKGROUND: Limited studies have explored the actual usage of the 'after hours GP helpline' (AGPH). OBJECTIVE: The objectives of the article are to describe medication-related calls to the AGPH and compare callers' original intentions versus the advice provided by the general practitioner (GP). METHODS: We performed a detailed descriptive statistical analysis of medication-related queries received by the AGPH in 2014. RESULTS: In 2014, 13,600 medication-related calls were made to the national AGPH. For 86.56% of calls, GPs advised callers to either self-care only, or self-care overnight and see their GP during business hours. Of the 1442 calls where the caller had originally intended to visit the emergency department (ED), 76.70% were advised by GPs to self-care, and only 5.48% were advised to call 000 or visit an ED. Overall, less than 2.26% of callers were directed to the ED, despite 10.60% of people originally calling with this intention. DISCUSSION: The availability of an after-hours service potentially prevented 1363 people from unnecessarily attending an ED and directed 228 people who had originally underestimated the seriousness of their condition to an ED.

Ribosomal Protein RPL27a Promotes Female Gametophyte Development in a Dose-Dependent Manner.

Ribosomal protein mutations in Arabidopsis (Arabidopsis thaliana) result in a range of specific developmental phenotypes. Why ribosomal protein mutants have specific phenotypes is not fully known, but such defects potentially result from ribosome insufficiency, ribosome heterogeneity, or extraribosomal functions of ribosomal proteins. Here, we report that ovule development is sensitive to the level of Ribosomal Protein L27a (RPL27a) and is disrupted by mutations in the two paralogs RPL27aC and RPL27aB. Mutations in RPL27aC result in high levels of female sterility, whereas mutations in RPL27aB have a significant but lesser effect on fertility. Progressive reduction in RPL27a function results in increasing sterility, indicating a dose-dependent relationship between RPL27a and female fertility. RPL27a levels in both the sporophyte and gametophyte affect female gametogenesis, with different developmental outcomes determined by the dose of RPL27a. These results demonstrate that RPL27aC and RPL27aB act redundantly and reveal a function for RPL27a in coordinating complex interactions between sporophyte and gametophyte during ovule development.