Maternal and neonatal complications in pregnancies with and without pre-gestational diabetes mellitus.

OBJECTIVES: To compare pregnancy complications in pregnancies with and without pre-gestational diabetes mellitus (DM) managed in a multidisciplinary high-risk diabetes antenatal clinic. METHODS: This screening cohort study was undertaken at a large maternity unit in the United Kingdom between January 2010 and December 2022. We included singleton pregnancies that booked at our unit at 11-13 weeks' gestation. Univariate and multivariate logistic regression analysis was carried out to determine risks of complications in pregnancies with type 1 and type 2 DM after adjusting for maternal and pregnancy characteristics. Effect sizes were expressed as absolute risks (AR) and odds ratio (OR) (95 % confidence intervals [CI]). RESULTS: The study population included 53,649 singleton pregnancies, including 509 (1.0 %) with pre-existing DM and 49,122 (99.0 %) without diabetes. Multivariate logistic regression analysis demonstrated that there was a significant contribution from pre-existing DM in prediction of adverse outcomes, including antenatal complications such as fetal defects, stillbirth, preterm delivery, polyhydramnios, preeclampsia and delivery of large for gestational age (LGA) neonates; intrapartum complications such as caesarean delivery (CS) and post-partum haemorrhage; and neonatal complications including admission to neonatal intensive care unit, hypoglycaemia, jaundice and hypoxic ischaemic encephalopathy (HIE). In particular, there was a 5-fold increased risk of stillbirth and HIE. CONCLUSIONS: The maternal and neonatal complications in pregnancies with pre-existing DM are significantly increased compared to those without DM despite a decade of intensive multidisciplinary antenatal care. Further research is required to investigate strategies and interventions to prevent morbidity and mortality in pregnancies with pre-gestational DM.

A blended future? A cross-sectional study demonstrating the impacts of the COVID-19 pandemic on student experiences of well-being, teaching and learning.

INTRODUCTION: The COVID-19 pandemic necessitated emergency changes to teaching, learning and assessment across higher education. Healthcare courses were particularly affected because of their interdependence with overstretched health services. We used this unprecedented situation to provide insight into how students react to unexpected crises and how institutions can most effectively support them. MATERIALS AND METHODS: This cohort study explored students' experiences of the pandemic across programmes and stages from five schools (medicine, dentistry, biomedical sciences, psychology and health professions) in a health faculty in a UK university. We carried out an inductive thematic analysis on the data collected. RESULTS: Many students reported fluctuating emotions and struggled to adapt to home working. Students' changes in motivation and coping strategies varied, many found structure, recreation and social interaction important. Opinions on how well online learning worked relative to face-to-face diverged across programmes. CONCLUSION: A one-size-fits-all blended learning response is unlikely to be appropriate. Our study shows students across one faculty, within one institution, responded diversely to an emergency affecting them all. Educators need to be flexible and dynamic in delivering curricula and supporting students responding to an unexpected crisis during their higher education.

Improved transplant survival and long-term disease outcome in children with MHC class II deficiency.

MHC class II deficiency is a rare, but life-threatening, primary combined immunodeficiency. Hematopoietic cell transplantation (HCT) remains the only curative treatment for this condition, but transplant survival in the previously published result was poor. We analyzed the outcome of 25 patients with MHC class II deficiency undergoing first HCT at Great North Children's Hospital between 1995 and 2018. Median age at diagnosis was 6.5 months (birth to 7.5 years). Median age at transplant was 21.4 months (0.1-7.8 years). Donors were matched family donors (MFDs; n = 6), unrelated donors (UDs; n = 12), and haploidentical donors (HIDs; n = 7). Peripheral blood stem cells were the stem cell source in 68% of patients. Conditioning was treosulfanbased in 84% of patients; 84% received alemtuzumab (n = 14) or anti-thymocyte globulin (n = 8) as serotherapy. With a 2.9-year median follow-up, OS improved from 33% (46-68%) for HCT before 2008 (n = 6) to 94% (66-99%) for HCT after 2008 (n = 19; P = .003). For HCT after 2008, OS according to donor was 100% for MFDs and UDs and 85% for HIDs (P = .40). None had grade III-IV acute or chronic graft-versus-host disease. Latest median donor myeloid and lymphocyte chimerism were 100% (range, 0-100) and 100% (range, 64-100), respectively. Latest CD4+ T-lymphocyte number was significantly lower in transplant survivors (n = 14) compared with posttransplant disease controls (P = .01). All survivors were off immunoglobulin replacement and had protective vaccine responses to tetanus and Haemophilus influenzae. None had any significant infection or autoimmunity. Changing transplant strategy in Great North Children's Hospital has significantly improved outcomes for MHC class II deficiency.

Biogeochemical impacts of sewage effluents in predominantly rural river catchments: Are point source inputs distinct to background diffuse pollution?

Discharge of treated sewage effluent to rivers can degrade aquatic ecosystem quality, interacting with multiple stressors in the wider catchment. In predominantly rural catchments, the river reach influence of point source effluents is unknown relative to complex background pressures. We examined water column, sediment and biofilm biogeochemical water quality parameters along river transects (200 m upstream to 1 km downstream) during summer at five wastewater treatment works (WWTW) in Scotland. Treated sewage effluent (subset, n = 3) pollutant concentrations varied between sites. Downstream concentration profiles of water and sediment biogeochemical parameters showed complex spatial changes. A hypothesised point source signature of elevated concentrations of pollution immediately downstream of WWTW then a decaying pollution 'plume' did not commonly occur. Instead, elevated soluble reactive phosphorus (SRP), ammonium and coliforms (maximum 0.23 mgP/l, 0.33 mgN/l and >2 × 106 MPN/100 ml) occurred immediately downstream of two WWTW, whereas some downstream pollutant concentrations decreased. Microbial substrate respiration responses only differed 1 km downstream. Significantly greater concentrations of sediment metal occurred >500 m downstream, likely due to the redeposition of historic contaminated sediments. Significantly lowered chlorophyll-a downstream of one WWTW coincided with elevated metals, despite water SRP and sediment P increases. Overall, stress caused to microbes and algae by effluent contaminants outweighed the subsidy effect of WWTW nutrients. We observed variable effluent flows to the rivers limited localised pollution downstream of WWTW and overall influence of arable land cover on river water quality. Together, this challenges views of consistently discharging point sources impacting low dilution sensitive rivers in summer contrasting with 'diffuse' sources. Thus, river water column and benthic compartments are altered at varying scales by point source effluents in combination with rural catchment pollution sources, both discrete (e.g. farmyards and septic tanks) and diffuse.

Midwives' experiences of cultural competency training and providing perinatal care for migrant women a mixed methods study: Operational Refugee and Migrant Maternal Approach (ORAMMA) project.

BACKGROUND: The number of international migrants continues to increase worldwide. Depending on their country of origin and migration experience, migrants may be at greater risk of maternal and neonatal morbidity and mortality. Having compassionate and culturally competent healthcare providers is essential to optimise perinatal care. The "Operational Refugee and Migrant Maternal Approach" (ORAMMA) project developed cultural competence training for health professionals to aid with providing perinatal care for migrant women. This presents an evaluation of ORAMMA training and explores midwives' experiences of the training and providing care within the ORAMMA project. METHODS: Cultural competence was assessed before and after midwives (n = 35) received ORAMMA compassionate and culturally sensitive maternity care training in three different European countries. Semi-structured interviews (n = 12) explored midwives' experiences of the training and of caring for migrant women within the ORAMMA project. RESULTS: A significant improvement of the median score pre to post-test was observed for midwives' knowledge (17 to 20, p < 0.001), skills (5 to 6, p = 0.002) and self-perceived cultural competence (27 to 29, p = 0.010). Exploration of midwives' experiences of the training revealed themes of "appropriate and applicable", "made a difference" and "training gaps" and data from ORAMMA project experiences identified three further themes; "supportive care", "working alongside peer supporters" and "challenges faced". CONCLUSIONS: The training improved midwives' knowledge and self-perceived cultural competence in three European countries with differing contexts and workforce provision. A positive experience of ORAMMA care model was expressed by midwives, however clearer expectations of peer supporters' roles and more time within appointments to assess the psychosocial needs of migrant women were desired. Future large-scale research is required to assess the long-term impact of the ORAMMA model and training on practice and clinical perinatal outcomes.

Omega-3 fatty acid supplementation for cystic fibrosis.

BACKGROUND: Studies suggest that a diet rich in omega-3 essential fatty acids may have beneficial anti-inflammatory effects for chronic conditions such as cystic fibrosis. This is an updated version of a previously published review. OBJECTIVES: To determine whether there is evidence that omega-3 polyunsaturated fatty acid supplementation reduces morbidity and mortality and to identify any adverse events associated with supplementation. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. Date of last search: 01 April 2020. We also searched online study registries and contacted authors. Date of last search: 12 February 2020. SELECTION CRITERIA: Randomised controlled trials in people with cystic fibrosis comparing omega-3 fatty acid supplements with placebo. DATA COLLECTION AND ANALYSIS: Two authors independently selected studies for inclusion, extracted data and assessed the risk of bias of the studies. The quality of the evidence was assessed using GRADE. MAIN RESULTS: The searches identified 23 studies; five studies with 106 participants (children and adults) were included; duration of studies and interventions differed. Two studies compared omega-3 fatty acids to olive oil for six weeks; one study compared omega-3 fatty acids and omega-6 fatty acids to control capsules (customised fatty acid blends) for three months; one study compared a liquid dietary supplement containing omega-3 fatty acids to one without for six months; and one study compared omega-3 fatty acids to a placebo for 12 months. Three studies had a low risk of bias for randomisation, but the risk was unclear in the remaining two studies; all studies had an unclear risk of bias for allocation concealment. Three of the studies adequately blinded participants; the risk of bias for selective reporting was high in one study and unclear for four studies. Two studies reported the number of respiratory exacerbations. At three months, one study (43 participants) reported no change in antibiotic usage. At 12 months the second study (15 participants) reported a reduction in the number of pulmonary exacerbations and cumulative antibiotic days in the supplement group compared to the previous year (no data for the control group); very low-quality evidence means we are unsure whether supplementation has any effect on this outcome. With regards to adverse events, one six-week study (12 participants) reported no difference in diarrhoea between omega-3 or placebo capsules; the very low-quality evidence means we are unsure if supplementation has any effect on this outcome. Additionally, one study reported an increase in steatorrhoea requiring participants to increase their daily dose of pancreatic enzymes, but three studies had already increased pancreatic enzyme dose at study begin so as to reduce the incidence of steatorrhoea. One study (43 participants) reported stomach pains at three months (treatment or control group not specified). One six-week study (19 participants) reported three asthma exacerbations leading to exclusion of participants since corticosteroid treatment could affect affect essential fatty acid metabolism. Four studies reported lung function. One six-week study (19 participants) reported an increase in forced expiratory volume in one second (FEV1) (L) and forced vital capacity (FVC) (L), but the very low-quality evidence means we are unsure if supplementation has any effect on lung function. The remaining studies did not report any difference in lung function at three months (unit of measurement not specified) or at six months and one year (FEV1 % predicted and FVC % predicted). No deaths were reported in any of the five studies. Four studies reported clinical variables. One study reported an increase in Schwachman score and weight alongside a reduction in sputum volume with supplementation compared to placebo at three months (data not analysable). However, three studies reported no differences in either weight at six weeks, in body mass index (BMI) standard deviation (SD) score at six months (very low-quality evidence) or BMI Z score at 12 months. Three studies reported biochemical markers of fatty acid status. One study showed an increase from baseline in both EPA and DHA content of serum phospholipids in the omega-3 group compared to placebo at three months and also a significant decrease in n-6/n-3 ratio in the supplement group compared to placebo; since the quality of the evidence is very low we are not certain that these changes are due to supplementation. One six-month cross-over study showed a higher EPA content of the neutrophil membrane in the supplement group compared to the placebo group, but, no difference in DHA membrane concentration. Furthermore, the leukotriene B4 to leukotriene B5 ratio was lower at six months in the omega-3 group compared to placebo. A one-year study reported a greater increase in the essential fatty acid profile and a decrease in AA levels in the treatment arm compared to placebo. AUTHORS' CONCLUSIONS: This review found that regular omega-3 supplements may provide some limited benefits for people with cystic fibrosis with relatively few adverse effects: however, the quality of the evidence across all outcomes was very low. The current evidence is insufficient to draw firm conclusions or recommend routine use of these supplements in people with cystic fibrosis. A large, long-term, multicentre, randomised controlled study is needed to determine any significant therapeutic effect and to assess the influence of disease severity, dosage and duration of treatment. Future researchers should note the need for additional pancreatic enzymes when providing omega-3 supplementation or olive oil placebo capsules. More research is required to determine the exact dose of pancreatic enzyme required.

Women's perspectives on antenatal breast expression: a cross-sectional survey.

BACKGROUND: The practice of antenatal breast expression (ABE) has been proposed as a strategy to promote successful breastfeeding. Although there has been some focus on the evaluation of the effects of ABE in promotion of breastfeeding, little or no evidence exists on women's experiences of ABE or opinions on ABE, particularly amongst overweight or obese women. METHODS: This study aimed to explore women's knowledge, practices and opinions of ABE, and any differences within the overweight and obese subgroups. A cross-sectional survey was undertaken using an online questionnaire distributed by a maternity user group representative via social media. Quantitative data were analysed using Chi-square and Fisher's exact tests in SPSS. Simple thematic analysis was used for the qualitative data. RESULTS: A total of 688 responses were analysed; the sample represented a group of breastfeeding mothers, of whom 64.5% had heard of ABE, 8.2% had been advised to do ABE, and 14.2% had undertaken ABE. Of the women who had been advised to do ABE, 67.9% had complied. Most participants (58.6%) were unsure if ABE was a good idea; however 80.9% would consider doing ABE if it was found to be helpful to prepare for breastfeeding. Women in the overweight or obese subgroups were significantly more likely to have heard of ABE (p < 0.001), and positive opinion of ABE also increased with higher BMI groups. The qualitative data demonstrated participants felt ABE may be beneficial when mother or baby have medical problems, and in preparation for breastfeeding, but highlighted their concerns that it may interfere with nature and be harmful, and that they wanted more information and knowledge about ABE. CONCLUSIONS: Amongst women who have breastfed, many have heard of ABE, compliance with advice to undertake ABE is relatively high, and ABE is considered an acceptable practice. Further investigation into the benefits and safety of ABE is warranted, to address the needs of childbearing women for evidence-based information about this practice. If the evidence base is established, overweight and obese pregnant women could be an important target group for this intervention.

Discrimination against childbearing Romani women in maternity care in Europe: a mixed-methods systematic review.

BACKGROUND: Freedom from discrimination is one of the key principles in a human rights-based approach to maternal and newborn health. OBJECTIVE: To review the published evidence on discrimination against Romani women in maternity care in Europe, and on interventions to address this. SEARCH STRATEGY: A systematic search of eight electronic databases was undertaken in 2015 using the terms "Roma" and "maternity care". A broad search for grey literature included the websites of relevant agencies. DATA EXTRACTION AND SYNTHESIS: Standardised data extraction tables were utilised, quality was formally assessed and a line of argument synthesis was developed and tested against the data from the grey literature. RESULTS: Nine hundred papers were identified; three qualitative studies and seven sources of grey literature met the review criteria. These revealed that many Romani women encounter barriers to accessing maternity care. Even when they are able to access care, they can experience discriminatory mistreatment on the basis of their ethnicity, economic status, place of residence or language. The grey literature revealed some health professionals held underlying negative beliefs about Romani women. There were no published research studies examining the effectiveness of interventions to address discrimination against Romani women and their infants in Europe. The Roma Health Mediation Programme is a promising intervention identified in the grey literature. CONCLUSIONS: There is evidence of discrimination against Romani women in maternity care in Europe. Interventions to address discrimination against childbearing Romani women and underlying health provider prejudice are urgently needed, alongside analysis of factors predicting the success or failure of such initiatives.

Omega-3 fatty acids for cystic fibrosis.

BACKGROUND: Studies suggest that a diet rich in omega-3 essential fatty acids may have beneficial anti-inflammatory effects for chronic conditions such as cystic fibrosis. This is an updated version of a previously published review. OBJECTIVES: To determine whether there is evidence that omega-3 polyunsaturated fatty acid supplementation reduces morbidity and mortality and to identify any adverse events associated with supplementation. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. Authors and persons interested in the subject of the review were contacted.Date of last search: 13 August 2013. SELECTION CRITERIA: Randomised controlled trials in people with cystic fibrosis comparing omega-3 fatty acid supplements with placebo. DATA COLLECTION AND ANALYSIS: Two authors independently selected studies for inclusion, extracted data and assessed the risk of bias of the studies. MAIN RESULTS: The searches identified 15 studies; four studies with 91 participants (children and adults) were included; duration of studies ranged from six weeks to six months. Two studies were judged to be at low risk of bias based on adequate randomisation but this was unclear in the other two studies. Three of the studies adequately blinded patients, however, the risk of bias was unclear in all studies with regards to allocation concealment and selective reporting.Two studies compared omega-3 fatty acids to olive oil for six weeks. One study compared a liquid dietary supplement containing omega-3 fatty acids to one without for six months. One study compared omega-3 fatty acids and omega-6 fatty acids to a control (capsules with customised fatty acid blends) for three months. Only one short-term study (19 participants) comparing omega-3 to placebo reported a significant improvement in lung function and Shwachman score and a reduction in sputum volume in the omega-3 group. Another study (43 participants) demonstrated a significant increase in serum phospholipid essential fatty acid content and a significant drop in the n-6/n-3 fatty acid ratio following omega-3 fatty acid supplementation compared to control. The longer-term study (17 participants) demonstrated a significant increase in essential fatty acid content in neutrophil membranes and a significant decrease in the leukotriene B4 to leukotriene B5 ratio in participants taking omega-3 supplements compared to placebo. AUTHORS' CONCLUSIONS: This review found that regular omega-3 supplements may provide some benefits for people with cystic fibrosis with relatively few adverse effects, although evidence is insufficient to draw firm conclusions or recommend routine use of these supplements in people with cystic fibrosis. This review has highlighted the lack of data for many outcomes meaningful to people with or making treatment decisions about cystic fibrosis. A large, long-term, multicentre, randomised controlled study is needed to determine any significant therapeutic effect and to assess the influence of disease severity, dosage and duration of treatment. Future researchers should note the need for additional pancreatic enzymes.

Positional editing of transmembrane domains during ion channel assembly.

The integration of transmembrane (TM)-spanning regions of many channels and ion transporters is potentially compromised by the presence of polar and charged residues required for biological function. Although the two TMs of the ATP-gated ion channel subunit P2X2 each contain charged/polar amino acids, we found that each TM is efficiently membrane inserted when it is analysed in isolation, and uncovered no evidence for cooperativity between these two TMs during P2X2 integration. However, using minimal N-glycosylation distance mapping, we find that the positioning of TM2 in newly synthesized P2X2 monomers is distinct from that seen in subunits of the high-resolution structures of assembled homologous trimers. We conclude that P2X2 monomers are initially synthesised at the endoplasmic reticulum in a distinct conformation, where the extent of the TM-spanning regions is primarily defined by the thermodynamic cost of their membrane integration at the Sec61 translocon. In this model, TM2 of P2X2 subsequently undergoes a process of positional editing within the membrane that correlates with trimerisation of the monomer, a process requiring specific polar/charged residues in both TM1 and TM2. We postulate that the assembly process offsets any energetic cost of relocating TM2, and find evidence that positional editing of TM2 in the acid-sensing ion channel (ASIC1a) is even more pronounced than that observed for P2X2. Taken together, these data further underline the potential complexities involved in accurately predicting TM domains. We propose that the orchestrated repositioning of TM segments during subunit oligomerisation plays an important role in generating the functional architecture of active ion channels, and suggest that the regulation of this underappreciated biosynthetic step may provide an elegant mechanism for maintaining ER homeostasis.

Reorientation of the first signal-anchor sequence during potassium channel biogenesis at the Sec61 complex.

The majority of the polytopic proteins that are synthesized at the ER (endoplasmic reticulum) are integrated co-translationally via the Sec61 translocon, which provides lateral access for their hydrophobic TMs (transmembrane regions) to the phospholipid bilayer. A prolonged association between TMs of the potassium channel subunit, TASK-1 [TWIK (tandem-pore weak inwardly rectifying potassium channel)-related acid-sensitive potassium channel 1], and the Sec61 complex suggests that the ER translocon co-ordinates the folding/assembly of the TMs present in the nascent chain. The N-terminus of both TASK-1 and Kcv (potassium channel protein of chlorella virus), another potassium channel subunit of viral origin, has access to the N-glycosylation machinery located in the ER lumen, indicating that the Sec61 complex can accommodate multiple arrangements/orientations of TMs within the nascent chain, both in vitro and in vivo. Hence the ER translocon can provide the ribosome-bound nascent chain with a dynamic environment in which it can explore a range of different conformations en route to its correct transmembrane topology and final native structure.

Omega-3 fatty acids for cystic fibrosis.

BACKGROUND: Studies suggest that a diet rich in omega-3 essential fatty acids may have beneficial anti-inflammatory effects for chronic conditions such as cystic fibrosis. OBJECTIVES: To determine whether there is evidence that omega-3 polyunsaturated fatty acid supplementation reduces morbidity and mortality and to identify any adverse events associated with supplementation. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. Authors and persons interested in the subject of the review were contacted.Date of last search: 08 July 2013. SELECTION CRITERIA: Randomised controlled trials in people with cystic fibrosis comparing omega-3 fatty acid supplements with placebo. DATA COLLECTION AND ANALYSIS: Two authors independently selected studies for inclusion, extracted data and assessed the risk of bias of the studies. MAIN RESULTS: The searches identified 14 studies; four studies with 91 participants were included. Two studies were judged to be at low risk of bias based on adequate randomisation but this was unclear in the other two studies. Three of the studies adequately blinded patients, however, the risk of bias was unclear in all studies with regards to allocation concealment and selective reporting.Two studies compared omega-3 fatty acids to olive oil for six weeks. One study compared a liquid dietary supplement containing omega-3 fatty acids to one without for six months. One study compared omega-3 fatty acids and omega-6 fatty acids to a control (capsules with customised fatty acid blends) for three months. Only one short-term study (19 participants) comparing omega-3 to placebo reported a significant improvement in lung function and Shwachman score and a reduction in sputum volume in the omega-3 group. Another study (43 participants) demonstrated a significant increase in serum phospholipid essential fatty acid content and a significant drop in the n-6/n-3 fatty acid ratio following omega-3 fatty acid supplementation compared to control. The longer-term study (17 participants) demonstrated a significant increase in essential fatty acid content in neutrophil membranes and a significant decrease in the leukotriene B4 to leukotriene B5 ratio in participants taking omega-3 supplements compared to placebo. AUTHORS' CONCLUSIONS: This review found that regular omega-3 supplements may provide some benefits for people with cystic fibrosis with relatively few adverse effects, although evidence is insufficient to draw firm conclusions or recommend routine use of these supplements in people with cystic fibrosis. This review has highlighted the lack of data for many outcomes meaningful to people with or making treatment decisions about cystic fibrosis. A large, long-term, multicentre, randomised controlled study is needed to determine any significant therapeutic effect and to assess the influence of disease severity, dosage and duration of treatment. Future researchers should note the need for additional pancreatic enzymes.

Exploring basic science knowledge retention within a cohort of undergraduate medical students in the United Kingdom: A longitudinal study.

BACKGROUND: Clinical reasoning is reliant on students having acquired a strong foundation in the basic sciences. However, there remains uncertainty regarding whether medical students are maintaining this knowledge over the span of their degrees. Therefore, this project aimed to assess long-term retention of basic science knowledge within a cohort of students from an undergraduate medical school in the United Kingdom (UK). METHODS: This longitudinal study followed a cohort of students, from their first to final year. In their final year, participants sat a bespoke formative basic science knowledge assessment that utilised 46 single-best-answer questions. To examine for long-term attainment differences, these scores were compared with those achieved in first-year assessments. RESULTS: Of the eligible students, 40% partook in the study (n = 22). Comparing assessment scores highlighted an enhancement in overall basic science knowledge between first and final year (p < 0.01). Although most basic science domains remained unchanged between both time points, anatomy and physiology scores increased (p = 0.03 and p = 0.02, respectively), whereas biochemistry scores were the only ones to decrease (p = 0.02). DISCUSSION: This project provides insight into how well students are retaining the basic sciences during their studies. Underperforming science domains were identified, alongside pedagogical explanations for their individual shortcomings; for instance, students' perceived relevance of a domain is seen as a driver for its retention. Subsequently, a group of recommendations were derived to reinforce the most affected domains. The inclusion of more questions on the underperforming sciences, in clinically focussed assessments, is one such suggestion.

Lessons from resistance analysis in clinical trials of IV zanamivir.

Influenza infection causes substantial morbidity and mortality during seasonal epidemics and pandemics. Antivirals, including neuraminidase inhibitors, play an important role in the treatment of severely ill patients infected with influenza. Resistance is a key factor that can affect the efficacy of neuraminidase inhibitors (NAIs). It is a recommendation by regulatory authorities to monitor for resistance during the development of anti-influenza medications. An additional requirement by regulators is to examine amino acid sequences for minority species harbouring resistance substitutions. In a Phase III study of intravenous (IV) zanamivir respiratory samples were analysed for the presence of resistant quasi species using Next Generation Sequencing (NGS). In this study ten resistance substitutions, two of which were treatment emergent, were detected by NGS that otherwise would not have been detectable by Sanger sequencing. None of the substitutions were present at any other timepoints analysed. The effect these mutations have on clinical response is difficult to characterize; in fact, all patients from which these variants were isolated had a successful clinical outcome and the effect on clinical response was therefore likely minimal. Although NGS is becoming a routine method for nucleic acid sequencing and will detect substitutions previously undetected by Sanger sequencing, the value of this technique in identifying minority species with resistance substitutions that are clinically meaningful remains to be demonstrated, particularly with acute infections such as influenza.

Perspectives on Sedation Among Interdisciplinary Team Members in ICU: A Survey Study.

OBJECTIVE: To explore the interdisciplinary team members' beliefs and attitudes about sedation when caring for mechanically ventilated patients in the ICU. DESIGN: Cross-sectional survey. SETTING: A 17-bed cardiothoracic ICU at a tertiary care academic hospital in Colorado. SUBJECTS: All nurses, physicians, advanced practice providers (APPs), respiratory therapists, physical therapists (PTs), and occupational therapists (OTs) who work in the cardiothoracic ICU. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We modified a validated survey instrument to evaluate perspectives on sedation across members of the interdisciplinary ICU team. Survey responses were collected anonymously from 111 members (81% response rate). Respondents were predominantly female (70 [63%]). Most respondents across disciplines (94%) believed that their sedation practice made a difference in patients' outcomes. More nurses (48%), APPs (62%), and respiratory therapists (50%) believed that sedation could help alleviate the psychologic stress that patients experience on the ventilator than physicians (19%) and PTs/OTs (0%) (p = 0.008). The proportion of respondents who preferred to be sedated if they were mechanically ventilated themselves varied widely by discipline: respiratory therapists (88%), nurses (83%), APPs (54%), PTs/OTs (38%), and physicians (19%) (p < 0.001). In our exploratory analysis, listeners of an educational podcast had beliefs and attitudes more aligned with best evidence-based practices than nonlisteners. CONCLUSIONS: We discovered significant interdisciplinary differences in the beliefs and attitudes regarding sedation use in the ICU. Since all ICU team members are involved in managing mechanically ventilated patients in the ICU, aligning the mental models of sedation may be essential to enhance interprofessional collaboration and promote sedation best practices.

CD3+TCRαß/CD19+-Depleted Mismatched Family or Unrelated Donor Salvage Stem Cell Transplantation for Graft Dysfunction in Inborn Errors of Immunity.

A minority of children experience significant graft dysfunction after undergoing allogeneic hematopoietic stem cell transplantation (HSCT) for inborn errors of immunity (IEI). The optimal approach to salvage HSCT in this scenario is unclear with respect to conditioning regimen and stem cell source. This single-center retrospective case series reports the outcomes of salvage CD3+TCRαß/CD19-depleted mismatched family or unrelated donor stem cell transplantation (TCRαß-SCT) between 2013 and 2022 for graft dysfunction in 12 children with IEI. Outcomes of interest were overall survival (OS), event-free survival (EFS), graft-versus-host disease (GVHD)-free and event-free survival (GEFS), toxicities, GVHD, viremia and long-term graft function. In this retrospective audit of patients who underwent second CD3+TCRαß/CD19-depleted mismatched donor HSCT using treosulfan-based reduced-toxicity myeloablative conditioning, the median age at first HSCT was 8.76 months (range, 2.5 months to 6 years), and that at second TCRαß-SCT was 3.6 years (range, 1.2 to 11 years). The median interval between first and second HSCTs was 1.7 years (range, 3 months to 9 years). The primary diagnoses were severe combined immunodeficiency (SCID) (n = 5) and non-SCID IEI (n = 7). Indications for second HSCT were primary aplasia (n = 1), secondary autologous reconstitution (n = 6), refractory acute GVHD (aGVHD) (n = 3), and secondary leukemia (n = 1). Donors were either haploidentical parental donors (n = 10) or mismatched unrelated donors (n = 2). All patients received TCRαß/CD19-depleted peripheral blood stem cell (PBSC) grafts with a median CD34+ cell dose of 9.3 × 106/kg (range, 2.8 to 32.3 × 106/kg) and a median TCRαß+ cell dose of 4 × 104/kg (range, 1.3 to 19.2 × 104/kg). All patients engrafted, with a median time neutrophil and platelet recovery of 15 days (range, 12 to 24 days) and 12 days (range, 9 to 19 days). One patient developed secondary aplasia, and 1 had secondary autologous reconstitution; both underwent a successful third HSCT. Four (33%) had grade II aGVHD, and none had grade III-IV aGVHD. No patients had chronic GVHD (cGVHD), but 1 patient developed extensive cutaneous cGVHD after their third HSCT using PBSCs and antithymocyte globulin. Nine (75%) had at least 1episode of blood viremia with human herpesvirus 6 (n = 6; 50%), adenovirus (n = 6; 50%), Epstein-Barr virus (n = 3; 25%), or cytomegalovirus (n = 3; 25%). The median duration of follow-up was 2.3 years (range, .5 to 10 years), and the 2-year OS, EFS, and GEFS were 100% (95% confidence interval [CI], 0 to 100%), 73% (95% CI, 37% to 90%), and 73% (95% CI, 37% to 90%), respectively. TCRαß-SCT from mismatched family or unrelated donors, using a chemotherapy-only conditioning regimen, is a safe alternative donor salvage transplantation strategy for second HSCT in patients without a suitably matched donor.

The localization of the ER retrieval sequence for the calcium pump SERCA1.

A number of studies using chimeric constructs made by fusing endoplasmic/sarcoplasmic reticulum calcium pump (SERCA) sequences with those of the plasma membrane located calcium pump (PMCA) have suggested that the retention/retrieval signal responsible for maintaining SERCA in the endoplasmic reticulum (ER) is located within the N-terminus of these pumps. Because of the difficulties in identifying the presence of constructs at the plasma membrane we have used a trans-Golgi network (TGN) marker to evaluate whether chimeric proteins are retained by the ER or have lost their retention/retrieval sequences and are able to enter the wider endomembrane system and reach the TGN. In this study, attempts to locate this retention/retrieval sequence demonstrate that the retention sequences are located not in the N-terminus, as previously suggested, but in the largely transmembranous C-terminal domain of SERCA. Further attempts to identify the precise retention/retrieval motif using SERCA1/PMCA3 chimeras were unsuccessful. This may be due to the fact that introducing SERCA1 sequences into the C-terminal PMCA3 sequence and vice versa disrupts the organization of the closely packed transmembrane helices leading to retention of such constructs by the quality control mechanisms of the ER. An alternative explanation is that SERCAs have targeting motifs that are non-linear, being made up of several segments of sequence to form a patch that interacts with the retrieval machinery.