Secreted IgD Amplifies Humoral T Helper 2 Cell Responses by Binding Basophils via Galectin-9 and CD44.

B cells thwart antigenic aggressions by releasing immunoglobulin M (IgM), IgG, IgA, and IgE, which deploy well-understood effector functions. In contrast, the role of secreted IgD remains mysterious. We found that some B cells generated IgD-secreting plasma cells following early exposure to external soluble antigens such as food proteins. Secreted IgD targeted basophils by interacting with the CD44-binding protein galectin-9. When engaged by antigen, basophil-bound IgD increased basophil secretion of interleukin-4 (IL-4), IL-5, and IL-13, which facilitated the generation of T follicular helper type 2 cells expressing IL-4. These germinal center T cells enhanced IgG1 and IgE but not IgG2a and IgG2b responses to the antigen initially recognized by basophil-bound IgD. In addition, IgD ligation by antigen attenuated allergic basophil degranulation induced by IgE co-ligation. Thus, IgD may link B cells with basophils to optimize humoral T helper type 2-mediated immunity against common environmental soluble antigens.

A comprehensive MRI investigation to identify potential biomarkers of Osgood Schlatter disease in adolescents: A cross sectional study comparing Osgood Schlatter disease with controls.

BACKGROUND: Osgood-Schlatter disease (OSD) is the most common knee pain complaint among adolescents playing sports. Despite this, there remains controversy over the pathophysiology and whether specific anatomical characteristics are associated with OSD. PURPOSE: This study aimed to systematically and comprehensively characterize adolescents with OSD using magnetic resonance imaging (MRI) compared to pain-free controls, including both tissue abnormalities that may be associated with OSD, as well as anatomical characteristics. A secondary objective was to identify potential imaging biomarkers associated with pain. STUDY DESIGN: Cross-sectional study. METHODS: Adolescents with OSD and controls were recruited from 2020 to 2022. Following a clinical exam, demographics, pain, sports participation, and Tanner stage were collected. Knee MRI was conducted on the participants' most symptomatic knee (OSD) or the dominant leg (controls). RESULTS: Sixty-seven adolescents (46 with OSD and 30 controls) were included. 80% of participants with OSD had at least one tissue alteration compared to 54% of controls. Compared to controls, OSD had 36.3 (95%CI 4.5 to 289.7) higher odds of bony oedema at the tibial tuberosity, and 32.7 (95%CI 4.1 to 260.6) and 5.3 (95%CI 0.6 to 46.2) higher odds of bony oedema at the  tibial epiphysis and metaphysis respectively. Participants with OSD also had higher odds of fluid/oedema at the patellar tendon (12.3 95%CI 3.3 to 46.6), and superficial infrapatellar bursitis (7.2).  Participants with OSD had a more proximal tendon attachment (mean tibial attachment portion difference, -0.05, 95% CI: -0.1 to 0.0, p = 0.02), tendon thickness (proximal mean difference, -0.09, 95% CI: -0.4 to 0.2, p = 0.04; distal mean difference, -0.6, 95% CI: -0.9 to -0.2, p = 0.01). Those with bony/tendon oedema had 1.8 points (95% CI: 0.3 to 3.2) higher pain on palpation than those without (t = -2.5, df = 26.6, p = 0.019), but there was no difference between these groups in a functional single leg pain provocation. CONCLUSION: Adolescents with OSD present with tissue and structural abnormalities on MRI that differed from age-matched controls. The majority had findings in the patellar tendon and bone, which often co-occurred. However, a small proportion of OSD also presents without alterations. It appears these findings may be associated with clinical OSD-related pain on palpation of the tibial tuberosity. CLINICAL RELEVANCE: Our highlight the pathophysiology on imaging, which has implications for understanding the mechanism and treatment of OSD.

Where have all the pediatric anesthesiology fellows gone in the USA? Anesthesiology fellowship trends.

BACKGROUND: Recent consternation over the number of unfilled Pediatric Anesthesiology fellowship positions in the United States compelled us to assess the change in the ratio of Pediatric Anesthesiology fellows to the number of graduating anesthesiology residents over the 14-year period between 2008 and 2022. We also sought to report the total ratio of anesthesiology fellows to graduating residents and trends in the annual number of fellowship applicants relative to the number of Accreditation Council for Graduate Medical Education (ACGME)-accredited anesthesiology fellowship positions by specialty. METHODS: We used publicly available resources, including ACGME Data Resource Books, National Resident Matching Program (NRMP) data, San Francisco (SF) Match data, and American Board of Medical Specialties (ABMS) data, to determine the ratio of anesthesiology fellows to graduating anesthesiology residents and to compare the number of fellowship applicants to fellowship positions for Adult Cardiothoracic Anesthesiology, Critical Care Anesthesiology, Obstetric Anesthesiology, Pain Medicine and Pediatric Anesthesiology. RESULTS: Since 2008, the ratio of ACGME-accredited anesthesiology fellows to graduating residents increased from 0.36 in 2008 (2007 residency graduates) to 0.59 in 2022 (2021 residency graduates) and the ratio of Pediatric Anesthesiology fellows to graduating residents remained relatively stable from 0.10 to 0.11. The number of unmatched positions in Pediatric Anesthesiology increased from 17 in 2017 to 86 in 2023, and all ACGME-accredited fellowships had more positions available than applicants in 2023. CONCLUSION: In the USA, while the ratio of Pediatric Anesthesiology fellowship graduates to anesthesiology residency graduates remained relatively constant from 2008 to 2022, this is likely a lagging indicator that has not yet accounted for the recent decrease in fellowship applicants. These findings refute prior estimates for a surplus in Pediatric Anesthesia supply in the USA and have significant implications for the future.

Addressing the workforce crisis in (rural) social care: A scoping review.

BACKGROUND: This scoping review identifies strategies potentially addressing the 'workforce crisis' in rural social care. The increasing global demand for social care has been coupled with widely recognised challenges in recruiting and retaining sufficient staff to provide this care. While the social care workforce crisis is a global phenomenon, it is particularly acute in rural areas. METHODS: The review identified 75 papers which (i) had been published since 2017, (ii) were peer reviewed, (iii) concerned social care, (iv) were relevant to rural settings, (v) referenced workforce shortages, and (vi) made recommendations for ways to address those shortages. Thematic synthesis was used to derive three analytical themes with a combined 17 sub-themes applying to recommended strategies and evidence supporting those strategies. RESULTS: The most common strategies for addressing social care workforce shortages were to improve recruitment and retention ('recruit and retain') processes without materially changing the workforce composition or service models. Further strategies involved 'revitalising' the social care workforce through redeploying existing staff or identifying new sources of labour. A small number of strategies involved 're-thinking' social care service models more fundamentally. Very few papers specifically considered how these strategies might apply to rural contexts, and evidence for the effectiveness of strategies was sparse. CONCLUSION: The review identifies a significant gap in the literature in relation to workforce innovation and placed-based studies in rural social care systems. It is unlikely that the social care workforce crisis can be addressed through continuing attempts to recruit and retain workers within existing service models.

Anesthesia and Developing Brains: Unanswered Questions and Proposed Paths Forward.

Anesthetic agents disrupt neurodevelopment in animal models, but evidence in humans is mixed. The morphologic and behavioral changes observed across many species predicted that deficits should be seen in humans, but identifying a phenotype of injury in children has been challenging. It is increasingly clear that in children, a brief or single early anesthetic exposure is not associated with deficits in a range of neurodevelopmental outcomes including broad measures of intelligence. Deficits in other domains including behavior, however, are more consistently reported in humans and also reflect findings from nonhuman primates. The possibility that behavioral deficits are a phenotype, as well as the entire concept of anesthetic neurotoxicity in children, remains a source of intense debate. The purpose of this report is to describe consensus and disagreement among experts, summarize preclinical and clinical evidence, suggest pathways for future clinical research, and compare studies of anesthetic agents to other suspected neurotoxins.

Integrated Assessment of Viral Transcription, Antigen Presentation, and CD8+ T Cell Function Reveals Multiple Limitations of Class I-Selective Histone Deacetylase Inhibitors during HIV-1 Latency Reversal.

Clinical trials investigating histone deacetylase inhibitors (HDACi) to reverse HIV-1 latency aim to expose reservoirs in antiretroviral (ARV)-treated individuals to clearance by immune effectors, yet have not driven measurable reductions in the frequencies of infected cells. We therefore investigated the effects of the class I-selective HDACi nanatinostat and romidepsin on various blocks to latency reversal and elimination, including viral splicing, antigen presentation, and CD8+ T cell function. In ex vivo CD4+ T cells from ARV-suppressed individuals, both HDACi significantly induced viral transcription, but not splicing nor supernatant HIV-1 RNA. In an HIV-1 latency model using autologous CD8+ T cell clones as biosensors of antigen presentation, neither HDACi-treated CD4+ T cell condition induced clone degranulation. Both HDACi also impaired the function of primary CD8+ T cells in viral inhibition assays, with nanatinostat causing less impairment. These findings suggest that spliced or cell-free HIV-1 RNAs are more indicative of antigen expression than unspliced HIV-RNAs and may help to explain the limited abilities of HDACi to generate CD8+ T cell targets in vivoIMPORTANCE Antiretroviral (ARV) drug regimens suppress HIV-1 replication but are unable to cure infection. This leaves people living with HIV-1 burdened by a lifelong commitment to expensive daily medication. Furthermore, it has become clear that ARV therapy does not fully restore health, leaving individuals at elevated risk for cardiovascular disease, certain types of cancers, and neurocognitive disorders, as well as leaving them exposed to stigma. Efforts are therefore under way to develop therapies capable of curing infection. A key focus of these efforts has been on a class of drugs called histone deacetylase inhibitors (HDACi), which have the potential of exposing hidden reservoirs of HIV-1 to elimination by the immune system. Unfortunately, clinical trial results with HDACi have thus far been disappointing. In the current study, we integrate a number of experimental approaches to build a model that provides insights into the limited activity of HDACi in clinical trials and offers direction for future approaches.

A computational framework for finding parameter sets associated with chaotic dynamics.

Many biological ecosystems exhibit chaotic behavior, demonstrated either analytically using parameter choices in an associated dynamical systems model or empirically through analysis of experimental data. In this paper, we use existing software tools (COPASI, R) to explore dynamical systems and uncover regions with positive Lyapunov exponents where thus chaos exists. We evaluate the ability of the software's optimization algorithms to find these positive values with several dynamical systems used to model biological populations. The algorithms have been able to identify parameter sets which lead to positive Lyapunov exponents, even when those exponents lie in regions with small support. For one of the examined systems, we observed that positive Lyapunov exponents were not uncovered when executing a search over the parameter space with small spacings between values of the independent variables.

Early Signals of Vaccine-driven Perturbation Seen in Pneumococcal Carriage Population Genomic Data.

BACKGROUND: Pneumococcal conjugate vaccines (PCVs) have reduced pneumococcal diseases globally. Pneumococcal genomic surveys elucidate PCV effects on population structure but are rarely conducted in low-income settings despite the high disease burden. METHODS: We undertook whole-genome sequencing (WGS) of 660 pneumococcal isolates collected through surveys from healthy carriers 2 years from 13-valent PCV (PCV13) introduction and 1 year after rollout in northern Malawi. We investigated changes in population structure, within-lineage serotype dynamics, serotype diversity, and frequency of antibiotic resistance (ABR) and accessory genes. RESULTS: In children <5 years of age, frequency and diversity of vaccine serotypes (VTs) decreased significantly post-PCV, but no significant changes occurred in persons ≥5 years of age. Clearance of VT serotypes was consistent across different genetic backgrounds (lineages). There was an increase of nonvaccine serotypes (NVTs)-namely 7C, 15B/C, and 23A-in children <5 years of age, but 28F increased in both age groups. While carriage rates have been recently shown to remain stable post-PCV due to replacement serotypes, there was no change in diversity of NVTs. Additionally, frequency of intermediate-penicillin-resistant lineages decreased post-PCV. Although frequency of ABR genes remained stable, other accessory genes, especially those associated with mobile genetic element and bacteriocins, showed changes in frequency post-PCV. CONCLUSIONS: We demonstrate evidence of significant population restructuring post-PCV driven by decreasing frequency of vaccine serotypes and increasing frequency of few NVTs mainly in children under 5. Continued surveillance with WGS remains crucial to fully understand dynamics of the residual VTs and replacement NVT serotypes post-PCV.

A mosaic tetracycline resistance gene tet(S/M) detected in an MDR pneumococcal CC230 lineage that underwent capsular switching in South Africa.

OBJECTIVES: We reported tet(S/M) in Streptococcus pneumoniae and investigated its temporal spread in relation to nationwide clinical interventions. METHODS: We whole-genome sequenced 12 254 pneumococcal isolates from 29 countries on an Illumina HiSeq sequencer. Serotype, multilocus ST and antibiotic resistance were inferred from genomes. An SNP tree was built using Gubbins. Temporal spread was reconstructed using a birth-death model. RESULTS: We identified tet(S/M) in 131 pneumococcal isolates and none carried other known tet genes. Tetracycline susceptibility testing results were available for 121 tet(S/M)-positive isolates and all were resistant. A majority (74%) of tet(S/M)-positive isolates were from South Africa and caused invasive diseases among young children (59% HIV positive, where HIV status was available). All but two tet(S/M)-positive isolates belonged to clonal complex (CC) 230. A global phylogeny of CC230 (n=389) revealed that tet(S/M)-positive isolates formed a sublineage predicted to exhibit resistance to penicillin, co-trimoxazole, erythromycin and tetracycline. The birth-death model detected an unrecognized outbreak of this sublineage in South Africa between 2000 and 2004 with expected secondary infections (effective reproductive number, R) of ∼2.5. R declined to ∼1.0 in 2005 and <1.0 in 2012. The declining epidemic could be related to improved access to ART in 2004 and introduction of pneumococcal conjugate vaccine (PCV) in 2009. Capsular switching from vaccine serotype 14 to non-vaccine serotype 23A was observed within the sublineage. CONCLUSIONS: The prevalence of tet(S/M) in pneumococci was low and its dissemination was due to an unrecognized outbreak of CC230 in South Africa. Capsular switching in this MDR sublineage highlighted its potential to continue to cause disease in the post-PCV13 era.

Landscapes of care and despair for rural youth - a qualitative study in the northern Swedish 'periphery'.

BACKGROUND: This study emerges as a response to the lack of youth perspectives when it comes to discussions about access to and experiences of health and social services in rural areas. It subsequently contributes to the literature by positioning young people at the centre of this debate, and by taking a more holistic approach to the topic than is typically the case. Specifically, based on the idea that a good life in proper health for young people may be contingent on notions of care that are bounded up in multi-layered social and spatial environments, the aim of this study was to explore what characterises 'landscapes of care' for rural youth. METHODS: In this qualitative study, the participants included young people and professionals residing in five diverse areas across the northern Swedish 'peripheral' inland. Individual interviews (16 in total) and focus group discussions (26 in total) were conducted with 63 youth aged 14-27 years and with 44 professionals operating across sectors such as health centres, school health, integration units, youth clinics and youth clubs. Following an emergent design and using thematic analysis, we developed one main theme, 'landscapes of care and despair', comprising the two themes: '(dis)connectedness' and 'extended support or troubling gaps'. RESULTS: The findings illustrate how various health-promoting and potentially harmful aspects acting at structural, organisational and interpersonal levels contributed to dynamic landscapes characterised simultaneously by care and despair. In particular, our study shows how rural youths' feelings of belongingness to people and places coupled with opportunities to participate in society and access practical and emotional support appear to facilitate their care within rural settings. However, although the results indicate that some in the diverse group of rural youth were cared for and about, a negative picture was painted in parallel. These aspects of despair included youths' senses of exclusion and marginalisation, degrading attitudes towards them and their problems, as well as recurrent gaps in the provision and practices of care. CONCLUSIONS: To gain a more comprehensive understanding about the health of rural youth, this study highlights the benefits investigating 'care-ful' and 'uncaring' aspects bounded up in dynamic and multi-layered landscapes.

Analysis of 1478 Cases of Hypospadias Repair: The Incidence of Requiring Repeated Anesthetic Exposure as Well as Exploration of the Involvement of Trainees on Case Duration.

BACKGROUND: Recently, there has been significant focus on the effects of anesthesia on the developing brain. Concern is heightened in children <3 years of age requiring lengthy and/or multiple anesthetics. Hypospadias correction is common in otherwise healthy children and may require both lengthy and repeated anesthetics. At academic centers, many of these cases are performed with the assistance of anesthesia and surgical trainees. We sought to identify both the incidence of these children undergoing additional anesthetics before age 3 as well as to understand the effect of trainees on duration of surgery and anesthesia and thus anesthetic exposure (AE), specifically focusing on those cases >3 hours. METHODS: We analyzed all cases of hypospadias repair from December 2011 through December 2018 at Texas Children's Hospital. In all, 1326 patients undergoing isolated hypospadias repair were analyzed for anesthesia time, surgical time, provider types involved, AE, caudal block, and additional AE related/unrelated to hypospadias. RESULTS: For the primary aim, a total of 1573 anesthetics were performed in children <3 years of age, including 1241 hypospadias repairs of which 1104 (89%) were completed with <3 hours of AE. For patients with <3 hours of AE, 86.1% had a single surgical intervention for hypospadias. Of patients <3 years of age, 17.3% required additional nonrelated surgeries. There was no difference in anesthesia time in cases performed solely by anesthesia attendings versus those performed with trainees/assistance (16.8 vs 16.8 minutes; P = .98). With regard to surgery, cases performed with surgical trainees were of longer duration than those performed solely by surgical attendings (83.5 vs 98.3 minutes; P < .001). Performance of surgery solely by attending surgeon resulted in a reduced total AE in minimal alveolar concentration (MAC) hours when compared to procedures done with trainees (1.92 vs 2.18; P < .001). Finally, comparison of patients undergoing initial correction of hypospadias with subsequent revisions revealed a longer time (117.7 vs 132.2 minutes; P < .001) and AE during the primary stage. CONCLUSIONS: The majority of children with hypospadias were repaired within a single AE. In general, most children did not require repeated AE before age 3. While presence of nonattending surgeons was associated with an increase in AE, this might at least partially be due to differences in case complexity. Moreover, the increase is likely not clinically significant. While it is critical to maintain a training environment, attempts to minimize AE are crucial. This information facilitates parental consent, particularly with regard to anesthesia duration and the need for additional anesthetics in hypospadias and nonhypospadias surgeries.

Patient and provider perspectives on eHealth interventions in Canada and Australia: a scoping review.

INTRODUCTION: Despite the promises of universal health care in most developed countries, health inequities remain prevalent within and between rural and remote communities. Remote health technologies are often promoted as solutions to increase health system efficiency, to enhance quality of care, and to decrease gaps in access to care for rural and remote communities. However, there is mixed evidence for these interventions, particularly related to how they are received and perceived by health providers and by patients. Health technologies do not always adequately meet the needs of patients or providers. To examine this, a broad-based scoping review was conducted to provide an overview of patient and provider perspectives of eHealth initiatives in rural communities. The unique objective of this review was to prioritize the voices of patients and providers in discussing the disparities between health interventions and needs of people in rural communities. eHealth initiatives were reviewed for rural communities of Australia and Canada, two countries that have similar geographies and comparable health systems at the local level. METHODS: Searches were performed in PubMed, Scopus, and Web of Science with results limited from 2000 to 2018. Keywords included combinations of 'eHealth', 'telehealth', 'telemedicine', 'electronic health', and 'rural/remote'. Individual patient and provider perspectives on health care were identified, followed by qualitative thematic coding based on the type of intervention, the feedback provided, the affected population, geographic location, and category of individual providing their perspective. Quotes from patients and providers are used to illustrate the identified benefits and disadvantages of eHealth technologies. RESULTS: Based on reviewed literature, 90.1% of articles reported that eHealth interventions were largely positive. Articles noted decreased travel time (18%), time/cost saving (15.1%), and increased access to services (13.9%) as primary benefits to eHealth. The most prevalent disadvantages of eHealth were technological issues (24.5%), lack of face-to-face contact (18.6%), limited training (10.8%), and resource disparities (10.8%). These results show where existing eHealth interventions could improve and can inform policymakers and providers in designing new interventions. Importantly, benefits to eHealth extend beyond geographic access. Patients reported ancillary benefits to eHealth that include reduced anxiety, disruption on family life, and improved recovery time. Providers reported closer connections to colleagues, improved support for complex care, and greater eLearning opportunity. Barriers to eHealth are recognized by patient and providers alike to be largely systemic, where lack of rural high-speed internet and unreliability of installed technologies were significant. CONCLUSION: Regional and national governments are seen as the key players in addressing these technical barriers. This scoping review diverges from many reviews of eHealth with the use of first-person perspectives. It is hoped that this focus will highlight the importance of patient voices in evaluating important healthcare interventions such as eHealth and associated technologies.

Genomic analysis of Klebsiella pneumoniae isolates from Malawi reveals acquisition of multiple ESBL determinants across diverse lineages.

OBJECTIVES: ESBL-producing Klebsiella pneumoniae (KPN) pose a major threat to human health globally. We carried out a WGS study to understand the genetic background of ESBL-producing KPN in Malawi and place them in the context of other global isolates. METHODS: We sequenced genomes of 72 invasive and carriage KPN isolates collected from patients admitted to Queen Elizabeth Central Hospital, Blantyre, Malawi. We performed phylogenetic and population structure analyses on these and previously published genomes from Kenya (n = 66) and from outside sub-Saharan Africa (n = 67). We screened for presence of antimicrobial resistance (AMR) genetic determinants and carried out association analyses by genomic sequence cluster, AMR phenotype and time. RESULTS: Malawian isolates fit within the global population structure of KPN, clustering into the major lineages of KpI, KpII and KpIII. KpI isolates from Malawi were more related to those from Kenya, with both collections exhibiting more clonality than isolates from the rest of the world. We identified multiple ESBL genes, including blaCTX-M-15, several blaSHV, blaTEM-63 and blaOXA-10, and other AMR genes, across diverse lineages of the KPN isolates from Malawi. No carbapenem resistance genes were detected; however, we detected IncFII and IncFIB plasmids that were similar to the carbapenem resistance-associated plasmid pNDM-mar. CONCLUSIONS: There are multiple ESBL genes across diverse KPN lineages in Malawi and plasmids in circulation that are capable of carrying carbapenem resistance. Unless appropriate interventions are rapidly put in place, these may lead to a high burden of locally untreatable infection in vulnerable populations.

Changed gene expression in subjects with schizophrenia and low cortical muscarinic M1 receptors predicts disrupted upstream pathways interacting with that receptor.

We tested the hypothesis that, compared with subjects with no history of psychiatric illness (controls), changes in gene expression in the dorsolateral prefrontal cortex from two subgroups of subjects with schizophrenia, one with a marked deficit in muscarinic M1 receptors (muscarinic receptor-deficit schizophrenia (MRDS)), would identify different biochemical pathways that would be affected by their aetiologies. Hence, we measured levels of cortical (Brodmann area 9) mRNA in 15 MRDS subjects, 15 subjects with schizophrenia but without a deficit in muscarinic M1 receptors (non-MRDS) and 15 controls using Affymetrix Exon 1.0 ST arrays. Levels of mRNA for 65 genes were significantly different in the cortex of subjects with MRDS and predicted changes in pathways involved in cellular movement and cell-to-cell signalling. Levels of mRNA for 45 genes were significantly different in non-MRDS and predicted changes in pathways involved in cellular growth and proliferation as well as cellular function and maintenance. Changes in gene expression also predicted effects on pathways involved in amino acid metabolism, molecular transport and small-molecule biochemistry in both MRDS and non-MRDS. Overall, our data argue a prominent role for glial function in MRDS and neurodevelopment in non-MRDS. Finally, the interactions of gene with altered levels of mRNA in the cortex of subjects with MRDS suggest many of their affects will be upstream of the muscarinic M1 receptor. Our study gives new insight into the molecular pathways affected in the cortex of subjects with MRDS and supports the notion that studying subgroups within the syndrome of schizophrenia is worthwhile.

Observed and calculated cerebral critical closing pressure are highly correlated in preterm infants.

BACKGROUND: Cerebrovascular critical closing pressure (CrCP) is the arterial blood pressure (ABP) at which cerebral blood flow ceases. Preterm ABP is low and close to CrCP. The diastolic closing margin (diastolic ABP minus CrCP) has been associated with intraventricular hemorrhage in preterm infants. CrCP is estimated from middle cerebral artery cerebral blood flow velocity (CBFV) and ABP waveforms. However, these estimations have not been validated due to a lack of gold standard. Direct observation of the CrCP in preterm infants with hypotension is an opportunity to validate synchronously estimated CrCP. METHODS: ABP and CBFV tracings were obtained from 24 extremely low birth weight infants. Recordings where diastolic CBFV was zero were identified. The gold standard CrCP was delineated using piecewise regression of ABP and CBFV values paired by rank ordering and then estimated using a published formula. The measured and estimated values were compared using linear regression and Bland-Altman analysis. RESULTS: Linear regression showed a high degree of correlation between measured and calculated CrCP (r2 = 0.93). CONCLUSIONS: This is the first study to validate a calculated CrCP by comparing it to direct measurements of CrCP from preterm infants when ABP is lower than CrCP.

First clinical experiences with a high field 1.5 T MR linac.

Purpose: A 1.5 T MR Linac (MRL) has recently become available. MRL treatment workflows (WF) include online plan adaptation based on daily MR images (MRI). This study reports initial clinical experiences after five months of use in terms of patient compliance, cases, WF timings, and dosimetric accuracy. Method and materials: Two different WF were used dependent on the clinical situation of the day; Adapt To Position WF (ATP) where the reference plan position is adjusted rigidly to match the position of the targets and the OARs, and Adapt To Shape WF (ATS), where a new plan is created to match the anatomy of the day, using deformable image registration. Both WFs included three 3D MRI scans for plan adaptation, verification before beam on, and validation during IMRT delivery. Patient compliance and WF timings were recorded. Accuracy in dose delivery was assessed using a cylindrical diode phantom. Results: Nineteen patients have completed their treatment receiving a total of 176 fractions. Cases vary from prostate treatments (60Gy/20F) to SBRT treatments of lymph nodes (45 Gy/3F) and castration by ovarian irradiation (15 Gy/3F). The median session time (patient in to patient out) for 127 ATPs was 26 (21-78) min, four fractions lasted more than 45 min due to additional plan adaptation. For the 49 ATSs a median time of 12 (1-24) min was used for contouring resulting in a total median session time of 42 (29-91) min. Three SBRT fractions lasted more than an hour. The time on the MRL couch was well tolerated by the patients. The median gamma pass rate (2 mm,2% global max) for the adapted plans was 99.2 (93.4-100)%, showing good agreement between planned and delivered dose. Conclusion: MRL treatments, including daily MRIs, plan adaptation, and accurate dose delivery, are possible within a clinically acceptable timeframe and well tolerated by the patients.

Sedation and the Food and Drug Administration Warning: What a Pediatric Gastroenterologist, Hepatologist, and Pancreatologist Should Know.

Pediatric gastroenterologists recommend and perform a range of procedures requiring sedation and anesthesia in young children. A recent warning from the US Food and Drug Administration (FDA) states that "repeated or lengthy use of general anesthetics and sedation drugs during surgeries or procedures in children younger than 3 years or in pregnant women during their third trimester may affect the development of children's brains." 1 As it relates to time, the FDA warning details risks of "procedures lasting longer than 3 hours or if multiple procedures are required." Pediatric gastroenterologists and related specialists should be aware of the warning and its relevance to their patients.

Results of a phase 1 multicentre investigation of dexmedetomidine bolus and infusion in corrective infant cardiac surgery.

BACKGROUND: Dexmedetomidine (DEX) is increasingly used intraoperatively in infants undergoing cardiac surgery. This phase 1 multicentre study sought to: (i) determine the safety of DEX for cardiac surgery with cardiopulmonary bypass; (ii) determine the pharmacokinetics (PK) of DEX; (iii) create a PK model and dosing for steady-state DEX plasma levels; and (iv) validate the PK model and dosing. METHODS: We included 122 neonates and infants (0-180 days) with D-transposition of the great arteries, ventricular septal defect, or tetralogy of Fallot. Dose escalation was used to generate NONMEM® PK modelling, and then validation was performed to achieve low (200-300 pg ml-1), medium (400-500 pg ml-1), and high (600-700 pg ml-1) DEX plasma concentrations. RESULTS: Five of 122 subjects had adverse safety outcomes (4.1%; 95% confidence interval [CI], 1.8-9.2%). Two had junctional rhythm, two had second-/third-degree atrioventricular block, and one had hypotension. Clearance (CL) immediately postoperative and CL on CPB were reduced by approximately 50% and 95%, respectively, compared with pre-CPB CL. DEX clearance after CPB was 1240 ml min-1 70 kg-1. Age at 50% maximum clearance was approximately 2 days, and that at 90% maximum clearance was 18 days. Overall, 96.1% of measured DEX concentrations fell within the 5th-95th percentile prediction intervals in the PK model validation. Dosing strategies are recommended for steady-state DEX plasma levels ranging from 200 to 1000 pg ml-1. CONCLUSIONS: When used with a careful dosing strategy, DEX results in low incidence and severity of adverse safety events in infants undergoing cardiac surgery with cardiopulmonary bypass. This validated PK model should assist clinicians in selecting appropriate dosing. The results of this phase 1 trial provide preliminary data for a phase 3 trial of DEX neuroprotection. CLINICAL TRIALS REGISTRATION: NCT01915277.

Mental toughness in surgeons: Is there room for improvement?

Background: Mental toughness is crucial to high-level performance in stressful situations. However, there is no formal evaluation or training in mental toughness in surgery. Our objective was to examine differences in mental toughness between staff and resident surgeons, and whether there is an interest in improving this attribute. Methods: We distributed a survey containing the Mental Toughness Index (domains of self-belief, attention regulation, emotion regulation, success mindset, context knowledge, buoyancy, optimism and adversity capacity) among general surgery residents and staff at 3 Canadian academic institutions. Responses were recorded on a 7-point Likert scale. Participants were also asked about techniques they used to help them perform under pressure and interest in further developing mental toughness. Results: Eighty-three of 193 surgeons participated: 56/105 (52.8%) residents and 27/87 (31.0%) staff. The average age was 29 (standard deviation 5) years and 42 (standard deviation 8) years, respectively. Residents scored significantly lower than staff in all mental toughness domains. Men scored significantly higher than women in attention regulation and emotion regulation. Age, staff experience and resident postgraduate year were not significantly associated with mental toughness scores. Twenty residents (36%) and 17 staff (63%) reported using specific techniques to deal with stressful situations; 49 (88%) and 15 (56%), respectively, were interested in further developing mental toughness. Conclusion: Staff surgeons scored significantly higher than residents in all mental toughness domains measured. Both groups expressed a desire to improve mental toughness. There are many techniques to improve mental toughness, and further research is needed to assess their effectiveness in surgical training.

Contexte: La force mentale est indispensable à un rendement de haut niveau en situation de stress. Par contre, il n'existe pas de méthode d'évaluation formelle ni de formation pour promouvoir la force mentale en chirurgie. Notre objectif était de comparer la force mentale des chirurgiens en poste à celle des résidents, et de vérifier si l'amélioration de cette compétence suscite l'intérêt. Méthodes: Nous avons distribué un questionnaire sur les divers domaines qui constituent l'indice de force mentale (confiance en soi, régulation de l'attention et des émotions, attitude gagnante, connaissances du contexte, dynamisme, optimisme et résistance à l'adversité) aux résidents et aux chirurgiens en poste en chirurgie générale dans 3 établissements universitaires canadiens. Les réponses étaient consignées sur une échelle de Likert en 7 points. Les participants ont aussi été interrogés sur les techniques qu'ils utilisent pour mieux composer avec la pression et sur leur intérêt pour l'acquisition d'une plus grande force mentale. Résultats: Quatre-vingt-trois chirurgiens sur 193 ont participé : 56/105 (52,8 %) résidents et 27/87 (31,0 %) chirurgiens en poste. L'âge moyen était de 29 ans (écarttype 5) et de 42 ans (écart-type 8), respectivement. Les résidents ont obtenu un score significativement moindre que les chirurgiens en poste pour tous les domaines constitutifs de la force mentale. Les hommes ont obtenu des scores significativement plus élevés que les femmes pour la régulation de l'attention et des émotions. L'âge, l'expérience des chirurgiens en poste et l'année de formation postdoctorale des résidents n'ont pas été significativement associés aux scores de force mentale. Vingt résidents (36 %) et 17 chirurgiens en poste (63 %) ont indiqué utiliser des techniques spécifiques pour affronter les situations stressantes; 49 (88 %) et 15 (56 %), respectivement, se sont montrés intéressés à acquérir davantage de force mentale. Conclusion: Les chirurgiens en poste ont obtenu des scores significativement plus élevés que les résidents pour tous les domaines de la force mentale mesurés. Les 2 groupes ont exprimé un intérêt pour l'amélioration de leur force mentale. Il existe plusieurs techniques à cet effet et il faudra approfondir la recherche pour en évaluer l'efficacité chez les chirurgiens en formation.

Global Distribution of Invasive Serotype 35D Streptococcus pneumoniae Isolates following Introduction of 13-Valent Pneumococcal Conjugate Vaccine.

A newly recognized pneumococcal serotype, 35D, which differs from the 35B polysaccharide in structure and serology by not binding to factor serum 35a, was recently reported. The genetic basis for this distinctive serology is due to the presence of an inactivating mutation in wciG, which encodes an O-acetyltransferase responsible for O-acetylation of a galactofuranose. Here, we assessed the genomic data of a worldwide pneumococcal collection to identify serotype 35D isolates and understand their geographical distribution, genetic background, and invasiveness potential. Of 21,980 pneumococcal isolates, 444 were originally typed as serotype 35B by PneumoCaT. Analysis of the wciG gene revealed 23 isolates from carriage (n = 4) and disease (n = 19) with partial or complete loss-of-function mutations, including mutations resulting in premature stop codons (n = 22) and an in-frame mutation (n = 1). These were selected for further analysis. The putative 35D isolates were geographically widespread, and 65.2% (15/23) of them was recovered after the introduction of pneumococcal conjugate vaccine 13 (PCV13). Compared with serotype 35B isolates, putative serotype 35D isolates have higher invasive disease potentials based on odds ratios (OR) (11.58; 95% confidence interval[CI], 1.42 to 94.19 versus 0.61; 95% CI, 0.40 to 0.92) and a higher prevalence of macrolide resistance mediated by mefA (26.1% versus 7.6%; P = 0.009). Using the Quellung reaction, 50% (10/20) of viable isolates were identified as serotype 35D, 25% (5/20) as serotype 35B, and 25% (5/20) as a mixture of 35B/35D. The discrepancy between phenotype and genotype requires further investigation. These findings illustrated a global distribution of an invasive serotype, 35D, among young children post-PCV13 introduction and underlined the invasive potential conferred by the loss of O-acetylation in the pneumococcal capsule.