Tetraether archaeal lipids promote long-term survival in extreme conditions.

The sole unifying feature of the incredibly diverse Archaea is their isoprenoid-based ether-linked lipid membranes. Unique lipid membrane composition, including an abundance of membrane-spanning tetraether lipids, impart resistance to extreme conditions. Many questions remain, however, regarding the synthesis and modification of tetraether lipids and how dynamic changes to archaeal lipid membrane composition support hyperthermophily. Tetraether membranes, termed glycerol dibiphytanyl glycerol tetraethers (GDGTs), are generated by tetraether synthase (Tes) by joining the tails of two bilayer lipids known as archaeol. GDGTs are often further specialized through the addition of cyclopentane rings by GDGT ring synthase (Grs). A positive correlation between relative GDGT abundance and entry into stationary phase growth has been observed, but the physiological impact of inhibiting GDGT synthesis has not previously been reported. Here, we demonstrate that the model hyperthermophile Thermococcus kodakarensis remains viable when Tes (TK2145) or Grs (TK0167) are deleted, permitting phenotypic and lipid analyses at different temperatures. The absence of cyclopentane rings in GDGTs does not impact growth in T. kodakarensis, but an overabundance of rings due to ectopic Grs expression is highly fitness negative at supra-optimal temperatures. In contrast, deletion of Tes resulted in the loss of all GDGTs, cyclization of archaeol, and loss of viability upon transition to the stationary phase in this model archaea. These results demonstrate the critical roles of highly specialized, dynamic, isoprenoid-based lipid membranes for archaeal survival at high temperatures.

Contribution of mutant HSC clones to immature and mature cells in MDS and CMML, and variations with AZA therapy.

Myelodysplastic neoplasms (MDSs) and chronic myelomonocytic leukemia (CMML) are clonal disorders driven by progressively acquired somatic mutations in hematopoietic stem cells (HSCs). Hypomethylating agents (HMAs) can modify the clinical course of MDS and CMML. Clinical improvement does not require eradication of mutated cells and may be related to improved differentiation capacity of mutated HSCs. However, in patients with established disease it is unclear whether (1) HSCs with multiple mutations progress through differentiation with comparable frequency to their less mutated counterparts or (2) improvements in peripheral blood counts following HMA therapy are driven by residual wild-type HSCs or by clones with particular combinations of mutations. To address these questions, the somatic mutations of individual stem cells, progenitors (common myeloid progenitors, granulocyte monocyte progenitors, and megakaryocyte erythroid progenitors), and matched circulating hematopoietic cells (monocytes, neutrophils, and naïve B cells) in MDS and CMML were characterized via high-throughput single-cell genotyping, followed by bulk analysis in immature and mature cells before and after AZA treatment. The mutational burden was similar throughout differentiation, with even the most mutated stem and progenitor clones maintaining their capacity to differentiate to mature cell types in vivo. Increased contributions from productive mutant progenitors appear to underlie improved hematopoiesis in MDS following HMA therapy.

Microvascular obstruction identifies a subgroup of patients who benefit from stem cell therapy following ST-elevation myocardial infarction.

BACKGROUND: Microvascular obstruction (MVO) is associated with greater infarct size, adverse left-ventricular (LV) remodeling and reduced ejection fraction following ST-elevation myocardial infarction (STEMI). We hypothesized that patients with MVO may constitute a subgroup of patients that would benefit from intracoronary stem cell delivery with bone marrow mononuclear cells (BMCs) given previous findings that BMCs tended to improve LV function only in patients with significant LV dysfunction. METHODS AND RESULTS: We analyzed the cardiac MRIs of 356 patients (303 M, 53 F) with anterior STEMIs who received autologous BMCs or placebo / control as part of 4 randomized clinical trials that included the Cardiovascular Cell Therapy Research Network (CCTRN) TIME trial and its pilot, the multicenter French BONAMI trial and SWISS-AMI trials. A total of 327 patients had paired imaging data at 1 year. All patients received 100 to 150 million intracoronary autologous BMCs or placebo / control 3 to 7 days following primary PCI and stenting. LV function, volumes, infarct size and MVO were assessed prior to infusion of BMCs and 1 year later. Patients with MVO (n = 210) had reduced LVEF and much greater infarct size and LV volumes compared to patients without MVO (n = 146) (P < .01). At 12 months, patients with MVO who received BMCs had significantly greater recovery of LVEF compared to those patients with MVO who received placebo (absolute difference = 2.7%; P < .05). Similarly, left-ventricular end-diastolic (LVEDVI) and end-systolic volume indices (LVESVI) demonstrated significantly less adverse remodeling in patients with MVO who received BMCs compared to placebo. In contrast, no improvement in LVEF or LV volumes was observed in those patients without MVO who received BMCs compared to placebo. CONCLUSIONS: The presence of MVO on cardiac MRI following STEMI identifies a subgroup of patients who benefit from intracoronary stem cell therapy.

tcplfit2: an R-language general purpose concentration-response modeling package.

SUMMARY: Many applications of chemical screening are performed in concentration or dose-response mode, and it is necessary to extract appropriate parameters, including whether the chemical/assay pair is active and if so, what are concentrations where activity is seen. Typically, multiple mathematical models or curve shapes are tested against the data to assess the best fit. There are several commercial programs used for this purpose as well as open-source libraries. A widely used system for managing high-throughput screening (HTS) concentration-response data is tcpl (ToxCast Pipeline). The current implementation of tcpl has the concentration-response modeling code tightly integrated with the data management and databasing aspects of HTS data processing. Tcplfit2 is a stand-alone version of the curve-fitting and hitcalling core of tcpl that has been extended to include a large number of standard curve classes and to use benchmark dose modeling. This package will be useful for HTS concentration-response data such as high-throughput whole genome transcriptomics. AVAILABILITY AND IMPLEMENTATION: tcplfit2 is written in R and is available from CRAN.

The characteristics of SARS-CoV-2-positive children in Australian hospitals: a PREDICT network study.

OBJECTIVES: To examine the clinical characteristics and short term outcomes for children with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections who presented to Australian hospitals during 2020 and 2021. DESIGN, SETTING: Retrospective case review study in nineteen hospitals of the Paediatric Research in Emergency Departments International Collaborative (PREDICT) network from all Australian states and territories, including seven major paediatric tertiary centres and eight Victorian hospitals. PARTICIPANTS: SARS-CoV-2-positive people under 18 years of age who attended emergency departments or were admitted to hospital during 1 February 2020 - 31 December 2021. MAIN OUTCOME MEASURES: Epidemiological and clinical characteristics, by hospital care type (emergency department [ED] or inpatient care). RESULTS: A total of 1193 SARS-CoV-2-positive children and adolescents (527 girls, 44%) attended the participating hospitals (107 in 2020, 1086 in 2021). Their median age was 3.8 years (interquartile range [IQR], 0.8-11.4 years); 63 were Aboriginal or Torres Strait Islander people (5%). Other medical conditions were recorded for 293 children (25%), including asthma (86, 7%) and premature birth (68, 6%). Medical interventions were not required during 795 of 1181 ED presentations (67%); children were discharged directly home in 764 cases (65%) and admitted to hospital in 282 (24%; sixteen to intensive care units). The 384 admissions to hospital (including 102 direct admissions) of 341 children (25 infants under one month of age) included 23 to intensive care (6%); the median length of stay was three days (IQR, 1-9 days). Medical interventions were not required during 261 admissions (68%); 44 children received respiratory support (11%) and 21 COVID-19-specific treatments, including antiviral and biologic agents (5%). Being under three months of age (v one year to less than six years: odds ratio [OR], 2.6; 95% confidence interval [CI], 1.7-4.0) and pre-existing medical conditions (OR, 2.5; 95% CI, 1.9-3.2) were the major predictors of hospital admission. Two children died, including one without a known pre-existing medical condition. CONCLUSION: During 2020 and 2021, most SARS-CoV-2-positive children and adolescents who presented to participating hospitals could be managed as outpatients. Outcomes were generally good, including for those admitted to hospital.

Factors associated with higher risk of small-for-gestational-age infants in women treated for gestational diabetes.

BACKGROUND: Previously, management of gestational diabetes (GDM) has focused largely on glycaemic control, with a view to reduce the occurrence of large-for-gestational-age (LGA) infants. However, tight glycaemic control in GDM is associated with a higher incidence of small-for-gestational-age (SGA) infants, which has been linked to higher rates of adverse outcomes. AIM: The aim was to characterise risk factors associated with having an SGA infant in women being treated for GDM. METHODS: This was a retrospective observational cohort study of 308 women with GDM. Women were split into groups based on their infant's size at delivery (SGA, appropriate-for-gestational-age (AGA) or LGA). Literature review and expert opinion helped to determine several predictors of women with GDM delivering an SGA infant, and statistical analysis was used to produce odds ratios (OR) for these predictors. RESULTS: The sample included primiparous women with a mean pre-pregnancy body mass index (BMI) of 25.72 (standard deviation: 5.75). Metabolic risk factors associated with delivering an SGA infant included a lower pre-pregnancy BMI (adjusted OR 1.13, P = 0.04, 95% confidence interval (CI): 1.01-1.26), a lower fasting blood glucose level (BGL) (adjusted OR: 3.21, P = 0.01, 95% CI: 1.30-7.93) and growth that was high risk for SGA at baseline ultrasound scan (USS) (adjusted OR: 7.43, P < 0.001, 95% CI: 2.93-18.79). CONCLUSIONS: The combined clinical picture of lower pre-pregnancy BMI, fasting BGL and baseline USS growth measurements may indicate a need for less aggressive glucose management in women with GDM to prevent SGA infants.

Increasing myocardial edema is associated with greater microvascular obstruction in ST-segment elevation myocardial infarction.

Microvascular obstruction (MVO) frequently develops after ST-elevation myocardial infarction (STEMI) and is associated with increased mortality and adverse left ventricular remodeling. We hypothesized that increased extravascular compressive forces in the myocardium that arise from the development of myocardial edema because of ischemia-reperfusion injury would contribute to the development of MVO. We measured MVO, infarct size, and left ventricular mass in patients with STEMI (n = 385) using cardiac MRI 2 to 3 days following successful percutaneous coronary intervention and stenting. MVO was found in 57% of patients with STEMI. The average infarct size was 45 ± 29 g. Patients with MVO had significantly greater infarct size and reduced left ventricular (LV) function (P < 0.01) compared with patients without MVO. Patients with MVO had significantly greater LV mass than patients without MVO and there was a linear increase in MVO with increasing LV mass (P < 0.001). Myocardial edema by T2-weighted imaging increased with increasing LV mass and patients with MVO had significantly greater myocardial edema than patients without MVO (P < 0.01). Patients with MVO had significantly greater left ventricular end-diastolic pressure (LVEDP) than patients without MVO (P < 0.05). In a cohort of patients with STEMI who underwent primary percutaneous intervention, we observed that MVO increased linearly with increasing LV mass and was associated with increased myocardial edema and higher LVEDP. These observations support the concept that extravascular compressive forces in the left ventricle may increase with increasing ischemic injury and contribute to the development of MVO.NEW & NOTEWORTHY Patients with STEMI (n = 385) had cardiac MRIs 2 to 3 days following reperfusion with primary PCI to determine the relationship between myocardial edema, LV mass, and MVO. We observed that MVO increased linearly with LV mass and that myocardial edema measured by T2-imaging also increased linearly with LV mass. Patients with MVO had greater edema and LVEDP than subjects without MVO. These findings suggest that myocardial edema which arises from ischemia-reperfusion injury may result in extravascular compression of the microcirculation manifested as MVO on cardiac MRI.

An Observational Study of Paediatric Preoperative Transfusion Practice in a Resource-Limited Setting.

BACKGROUND: Paediatric anaemia is highly prevalent in low-middle-income countries and can negatively impact postoperative outcomes. Currently, there are no guidelines for the management of paediatric preoperative anaemia. To ensure optimal care in resource-limited settings: balancing the risks of anaemia and using resources such as blood transfusion, we first need to understand current practices. To address this, a joint UK-Bangladesh team conducted an observational study at a paediatric surgical centre in Bangladesh. METHODS: A total of 464 patients ≤16 years who underwent elective and emergency surgery were categorised into major (351/464), moderate (92/464) and minor (21/464) surgery groups according to anticipated blood loss. Preoperative anaemia testing and transfusion was assessed retrospectively through patient notes. RESULTS: Median age was 4 years and 73% were male. 32.5% (151/464) patients had preoperative blood testing for anaemia. 17.5% (81/464) children were transfused preoperatively. Of those children transfused, 40.7% (33/81) underwent transfusion solely based on visible signs of anaemia on clinical examination. Seventy-five percentage (36/48) of children who underwent transfusion after blood testing had haemoglobin ≥80 g/L. Major surgery category had the highest proportion of children who were transfused and tested for anaemia. CONCLUSION: A liberal transfusion approach is evident here. Discussion with local clinicians revealed that this was due to limitations in obtaining timely blood results and reduction in laboratory costs incurred by families when clinical suspicion of anaemia was high. Further research is needed to analyse the potential of using bedside haemoglobin testers in conjunction with patient blood management strategies to limit blood transfusions and its associated risks.

Probiotics for preventing gestational diabetes.

BACKGROUND: Gestational diabetes mellitus (GDM) is associated with a range of adverse pregnancy outcomes for mother and infant. The prevention of GDM using lifestyle interventions has proven difficult. The gut microbiome (the composite of bacteria present in the intestines) influences host inflammatory pathways, glucose and lipid metabolism and, in other settings, alteration of the gut microbiome has been shown to impact on these host responses. Probiotics are one way of altering the gut microbiome but little is known about their use in influencing the metabolic environment of pregnancy. This is an update of a review last published in 2014. OBJECTIVES: To systematically assess the effects of probiotic supplements used either alone or in combination with pharmacological and non-pharmacological interventions on the prevention of GDM. SEARCH METHODS: We searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (20 March 2020), and reference lists of retrieved studies. SELECTION CRITERIA: Randomised and cluster-randomised trials comparing the use of probiotic supplementation with either placebo or diet for the prevention of the development of GDM. Cluster-randomised trials were eligible for inclusion but none were identified. Quasi-randomised and cross-over design studies were not eligible for inclusion in this review. Studies presented only as abstracts with no subsequent full report of study results were only included if study authors confirmed that data in the abstract came from the final analysis. Otherwise, the abstract was left awaiting classification. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed study eligibility, extracted data and assessed risk of bias of included studies. Data were checked for accuracy. MAIN RESULTS: In this update, we included seven trials with 1647 participants. Two studies were in overweight and obese women, two in obese women and three did not exclude women based on their weight. All included studies compared probiotics with placebo. The included studies were at low risk of bias overall except for one study that had an unclear risk of bias. We excluded two studies, eight studies were ongoing and three studies are awaiting classification. Six included studies with 1440 participants evaluated the risk of GDM. It is uncertain if probiotics have any effect on the risk of GDM compared to placebo (mean risk ratio (RR) 0.80, 95% confidence interval (CI) 0.54 to 1.20; 6 studies, 1440 women; low-certainty evidence). The evidence was low certainty due to substantial heterogeneity and wide CIs that included both appreciable benefit and appreciable harm. Probiotics increase the risk of pre-eclampsia compared to placebo (RR 1.85, 95% CI 1.04 to 3.29; 4 studies, 955 women; high-certainty evidence) and may increase the risk of hypertensive disorders of pregnancy (RR 1.39, 95% CI 0.96 to 2.01, 4 studies, 955 women), although the CIs for hypertensive disorders of pregnancy also indicated probiotics may have no effect. There were few differences between groups for other primary outcomes. Probiotics make little to no difference in the risk of caesarean section (RR 1.00, 95% CI 0.86 to 1.17; 6 studies, 1520 women; high-certainty evidence), and probably make little to no difference in maternal weight gain during pregnancy (MD 0.30 kg, 95% CI -0.67 to 1.26; 4 studies, 853 women; moderate-certainty evidence). Probiotics probably make little to no difference in the incidence of large-for-gestational age infants (RR 0.99, 95% CI 0.72 to 1.36; 4 studies, 919 infants; moderate-certainty evidence) and may make little to no difference in neonatal adiposity (2 studies, 320 infants; data not pooled; low-certainty evidence). One study reported adiposity as fat mass (MD -0.04 kg, 95% CI -0.12 to 0.04), and one study reported adiposity as percentage fat (MD -0.10%, 95% CI -1.19 to 0.99). We do not know the effect of probiotics on perinatal mortality (RR 0.33, 95% CI 0.01 to 8.02; 3 studies, 709 infants; low-certainty evidence), a composite measure of neonatal morbidity (RR 0.69, 95% CI 0.36 to 1.35; 2 studies, 623 infants; low-certainty evidence), or neonatal hypoglycaemia (mean RR 1.15, 95% CI 0.69 to 1.92; 2 studies, 586 infants; low-certainty evidence). No included studies reported on perineal trauma, postnatal depression, maternal and infant development of diabetes or neurosensory disability. AUTHORS' CONCLUSIONS: Low-certainty evidence from six trials has not clearly identified the effect of probiotics on the risk of GDM. However, high-certainty evidence suggests there is an increased risk of pre-eclampsia with probiotic administration. There were no other clear differences between probiotics and placebo among the other primary outcomes. The certainty of evidence for this review's primary outcomes ranged from low to high, with downgrading due to concerns about substantial heterogeneity between studies, wide CIs and low event rates. Given the risk of harm and little observed benefit, we urge caution in using probiotics during pregnancy. The apparent effect of probiotics on pre-eclampsia warrants particular consideration. Eight studies are currently ongoing, and we suggest that these studies take particular care in follow-up and examination of the effect on pre-eclampsia and hypertensive disorders of pregnancy. In addition, the underlying potential physiology of the relationship between probiotics and pre-eclampsia risk should be considered.

Characteristics and in-hospital outcomes of patients requiring aeromedical retrieval for pregnancy, compared to non-retrieved metropolitan cohorts.

BACKGROUND: Limited access to obstetrics and gynaecology (O&G) services in rural and remote Australia is believed to contribute to suboptimal birth outcomes. AIMS: To describe the characteristics of pregnancy aeromedical transfers, in-hospital outcomes, and patient access to O&G services, as compared to whole of Australia data. MATERIALS AND METHODS: We conducted a cohort study of women who required aeromedical retrieval for pregnancy-related issues between the 1 January 2015 and 31 December 2017. RESULTS: Hospital outcome data were collected on 2171 (65.2%) mothers and 2438 (100.0%) babies. The leading retrieval reason was threatened preterm labour and delivery (n = 883; 40.7%). Most patients were retrieved from rural and remote areas (n = 2224; 93.0%). Retrieved patients were significantly younger (28.0 vs 30.0 years, 95% CI 27.7-28.3), more likely to be overweight or obese (52.2% vs 45.1%, 95% CI 47.5-56.9) and to have smoked during their pregnancy (14.0% vs 9.9%, 95% CI 12.5-15.5) compared to Australian pregnant women overall. Over one-third of transferred women gave birth by Caesarean section (n = 812; 37.4%); the median gestational age at birth was 33.0 (95% CI 32.7-33.3) weeks. Early gestation is associated with low birth weights (median = 2579.5 g; 95% CI 2536.1-2622.9), neonatal resuscitation (35.4%, 95% CI 33.5-37.3), and special care nursery admission (41.2%, 95% CI 39.3-43.2). There were 42 (1.7%, 95% CI 1.2-2.2) stillbirths, which was significantly higher than seen Australia-wide (n = 6441; 0.7%). CONCLUSION: This study found that pregnant women retrieved by the Royal Flying Doctor Service were younger, with higher rates of obesity and smoking.

Light-level geolocator analyses: A user's guide.

Light-level geolocator tags use ambient light recordings to estimate the whereabouts of an individual over the time it carried the device. Over the past decade, these tags have emerged as an important tool and have been used extensively for tracking animal migrations, most commonly small birds. Analysing geolocator data can be daunting to new and experienced scientists alike. Over the past decades, several methods with fundamental differences in the analytical approach have been developed to cope with the various caveats and the often complicated data. Here, we explain the concepts behind the analyses of geolocator data and provide a practical guide for the common steps encompassing most analyses - annotation of twilights, calibration, estimating and refining locations, and extraction of movement patterns - describing good practices and common pitfalls for each step. We discuss criteria for deciding whether or not geolocators can answer proposed research questions, provide guidance in choosing an appropriate analysis method and introduce key features of the newest open-source analysis tools. We provide advice for how to interpret and report results, highlighting parameters that should be reported in publications and included in data archiving. Finally, we introduce a comprehensive supplementary online manual that applies the concepts to several datasets, demonstrates the use of open-source analysis tools with step-by-step instructions and code and details our recommendations for interpreting, reporting and archiving.

"A unique little microcosm": Exploring a self-sustaining community project which harnessed social action in a public space.

Government policy in England encourages communities to capacity build from within. Community psychology has explored the role of community resilience in this process. But what happens if a community appears to lack formalized resources? This article considers such a community in which a grassroots community center thrives outside the boundaries of formalized community organizations. It aimed to find out how this community mobilized, the benefits for those connected, and how the center survives. A grounded theory 'center as a living organism' was constructed from the accounts of eleven participants. Results indicate how community centers play a role in promoting individual and community level well-being and preventing distress. The importance of learning from progressive community initiatives and more partnership working between National Health Service, statutory, voluntary, and community groups is indicated. Effective engagement with and across communities to promote resilience and well-being is also a theme of the responses to recent events in England, such as the terrorist attacks and the Grenfell Tower fire.

Temporal dynamics of the HPA axis linked to exploratory behavior in a wild European songbird (Parus major).

Variation in the reactivity of the endocrine stress axis is thought to underlie aspects of persistent individual differences in behavior (i.e. animal personality). Previous studies, however, have focused largely on estimating baseline or peak levels of glucocorticoids (CORT), often in captive animals. In contrast, the temporal dynamics of the HPA axis-how quickly it turns on and off, for example-may better indicate how an individual copes with stressors. Moreover, these HPA components might be correlated, thereby representing endocrine suites. Using wild-caught great tits (Parus major) we tested birds for exploratory behavior using a standardized novel environment assay that serves as a validated proxy for personality. We then re-captured a subset of these birds (n=85) and characterized four components of HPA physiology: baseline, endogenous stress response, a dexamethasone (DEX) challenge to estimate the strength of negative feedback, and an adrenocorticotropic hormone (ACTH) challenge to estimate adrenal capacity. We predicted that these four HPA responses would be positively correlated and that less exploratory birds would have a more rapid onset of the stress response (a CORT elevation during the baseline bleed) and weaker negative feedback (higher CORT after DEX). We found support for the first two predictions but not the third. All four components were positively correlated with each other and less exploratory birds exhibited an elevation in CORT during the baseline bleed (<3min from capture). Less exploratory birds, however, did not exhibit weaker negative feedback following the DEX challenge, but did exhibit weaker adrenal capacity. Together, our findings provide partial support for the hypothesis that the temporal reactivity of the HPA axis is linked with consistent individual differences in behavior, with more cautious (slower exploring) individuals exhibiting a faster CORT response.

Exercise maintains blood-brain barrier integrity during early stages of brain metastasis formation.

Tumor cell extravasation into the brain requires passage through the blood-brain barrier, which is a highly protected microvascular environment fortified with tight junction (TJ) proteins. TJ integrity can be regulated under physiological and pathophysiological conditions. There is evidence that exercise can modulate oxidation status within the brain microvasculature and protect against tumor cell extravasation and metastasis formation. In order to study these events, mature male mice were given access to voluntary exercise on a running wheel (exercise) or access to a locked wheel (sedentary) for five weeks. The average running distance was 9.0 ± 0.2 km/day. Highly metastatic tumor cells (murine Lewis lung carcinoma) were then infused into the brain microvasculature through the internal carotid artery. Analyses were performed at early stage (48 h) and late stage (3 weeks) post tumor cell infusion. Immunohistochemical analysis revealed fewer isolated tumor cells extravasating into the brain at both 48 h and 3 weeks post surgery in exercised mice. Occludin protein levels were reduced in the sedentary tumor group, but maintained in the exercised tumor group at 48 h post tumor cell infusion. These results indicate that voluntary exercise may participate in modulating blood-brain barrier integrity thereby protecting the brain during metastatic progression.

Acceptability of the Hall Technique to parents and children.

OBJECTIVE: To investigate the acceptability of stainless steel crowns placed by dental therapists on children's primary molars using the Hall Technique. DESIGN: Mixed methods approach, using qualitative inductive analysis and quantitative analysis. SETTING: Hawke's Bay Community Oral Health Service METHODS: One focus group was conducted and ten thirty-minute phone interviews were undertaken with parents of children who had previously had a stainless steel crown placed using the Hall Technique (over the period 1 December 2011 to 31 May 2012). An inductive approach was used to analyse the qualitative research data, and the information was arranged into several categories based on the key themes which arose. Children treated with the Hall Technique were asked immediately after treatment whether they had enjoyed their visit to the clinic that day. RESULTS: Common themes were found with regard to appearance, pain, the procedure, and general opinions on acceptability. Nearly all (90%) of the children responded positively about their visit to the clinic. CONCLUSION: There was a high degree of acceptance among both parents and children for stainless steel crown placement using the Hall Technique in this group.

Disruption of CD47-SIRPα signaling restores inflammatory function in tumor-associated myeloid-derived suppressor cells.

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous immune population with diverse immunosuppressive functions in solid tumors. Here, we explored the role of the tumor microenvironment in regulating MDSC differentiation and immunosuppressive properties via signal-regulatory protein alpha (SIRPα)/CD47 signaling. In a murine melanoma model, we observed progressive increases in monocytic MDSCs and monocyte-derived dendritic cells that exhibited potent T cell-suppressive capabilities. These adaptations could be recapitulated in vitro by exposing hematopoietic stem cells to tumor-derived factors. Engagement of CD47 with SIRPα on myeloid cells reduced their phagocytic capability, enhanced expression of immune checkpoints, increased reactive oxygen species production, and suppressed T cell proliferation. Perturbation of SIRPα signaling restored phagocytosis and antigen presentation by MDSCs, which was accompanied by renewed T cell activity and delayed tumor growth in multiple solid cancers. These data highlight that therapeutically targeting myeloid functions in combination with immune checkpoint inhibitors could enhance anti-tumor immunity.

HPV-independent cervical cancer associated with non-reducible pelvic organ prolapse: A case report.

•The presence of concomitant non-reducible prolapse and cervical cancer is rare.•Treatment of cervical cancer complicated by non-reducible prolapse must be individualized.•The role prolapse may play in the development of HPV-negative cervical cancer is unclear.

A Prospective Observational Study of Preoperative Anaemia Management Aided by Bedside Haemoglobin Testers in a Low-Resource Setting.

AIM: Paediatric-preoperative anaemia management is challenging in settings where clinical judgment is used to diagnose anaemia owing to a lack of timely, affordable preoperative haemoglobin testing. We analysed anaemia management in such a setting after the introduction of point-of-care bedside haemoglobin testers. METHOD: 1033 children who underwent surgery at a hospital in Bangladesh were included in this study. 569 underwent major surgery, and 464 underwent minor surgery and belonged to predominantly ASA category 1 or 2. RESULTS: 940/1033 children underwent preoperative anaemia testing. Average haemoglobin was 11.7 g/dL. 103/1033 children were deemed clinically anaemic. However, 285 children were found to have anaemia based on bedside testing. Sensitivity of clinical judgement was 33.68% (95 % CI 28.22%-39.49%), and the specificity was 99.08% (95 % CI 98.02%-99.66%). 63/1033 had preoperative anaemia treatment, of whom 60 underwent transfusion. Subgroup analysis of children with haemoglobin <10 g/dL (n = 124) was done to compare conservative vs liberal transfusion strategy. 43/124 of this subset was transfused. Average length of stay for those transfused was 11.7 days, and those who weren't was 9.9 days (p = 0.087). 4 patients in the transfused subgroup required post-op ICU, and only 1 patient in the conservatively managed arm required ICU (p = 0.048). CONCLUSION: This study demonstrates the positive impact of bedside haemoglobin testers as they have resulted in a significantly higher proportion of children diagnosed with anaemia at a fraction of the cost and logistics involved in laboratory testing. Further research on haemoglobin thresholds is required to understand the safety and long-term impact of restrictive transfusion in the surgical context. LEVEL OF EVIDENCE: 2c (Grading as per the Oxford Centre for Evidence Based Medicine).

Tracking national neonatal transport activity and metrics using the UK Neonatal Transport Group dataset 2012-2021: a narrative review.

There are no internationally agreed descriptors for categories of neonatal transports which facilitate comparisons between settings. To continually review and enhance neonatal transport care we need robust categories to develop benchmarks. This review aimed to report on the development and application of key measures across a national neonatal transport service. The UK Neonatal Transport Group (UK-NTG) developed a core dataset and benchmarks for transported infants and collected annual national data. Data were reported back to teams to allow benchmarking and improvements. From 2012 to 2021, the rate of UK neonatal transfers increased from 18 to 22/1000 live births despite a falling birth rate. Neonatal transfers on nitric oxide increased until 2016 before plateauing. The proportion of transport services able to provide high frequency oscillation and servo-controlled therapeutic hypothermia increased over the study period. High-flow nasal cannula oxygen use increased, becoming the most frequently used non-invasive respiratory support mode. For infants <27 weeks of gestational age, transfers for uplift of care in the first 3 days of life have fallen from 420 (2016) to 288 (2020/2021) and for lack of neonatal capacity from 24 (2016) to 2 (2020/2021). The rate of ventilated infants completing transfer with CO2 out of the benchmark range varied from 9% to 13% with marked variation between transport services' rates of hypocapnia (0-10%) and hypercapnia with acidosis (0-9%). The development of the UK-NTG dataset supports national tracking of activity and clinical trends allowing comparison of patient-focused benchmarks across teams.

Implementation and evaluation of a national quality improvement initiative in cancer surgery.

BACKGROUND: In 2017, the Canadian Partnership Against Cancer, a Canadian federally sponsored organisation, initiated a national multijurisdictional quality improvement (QI) initiative to maximise the use of synoptic data to drive cancer system improvements, known as the Evidence for Surgical Synoptic Quality Improvement Programme. The goal of our study was to evaluate the outcomes, determinants and learning of this nationally led initiative across six jurisdictions in Canada, integrating a mix of cancer surgery disease sites and clinicians. METHODS: A mixed-methods evaluation (surveys, semistructured interviews and focus groups) of this initiative was focused on the ability of each jurisdiction to use synoptic reporting data to successfully implement and sustain QI projects to beyond the completion of the initiative and the lessons learnt in the process. Resources provided to the jurisdictions included operational funding, training in QI methodology, national forums, expert coaches, and ad hoc monitoring and support. The programme emphasised foundational concepts of the QI process including data literacy, audit and feedback reports, communities of practice (CoP) and positive deviance methodology. RESULTS: 101 CoP meetings were held and 337 clinicians received feedback reports. There were 23 projects, and 22 of 23 (95%) showed improvements with 15 of 23 (65%) achieving the proposed targets. Enablers of effective data utilisation/feedback reports for QI included the need for clinicians to trust the data, have comparative data for feedback, and the engagement of both data scientists and clinicians in designing feedback reports. Enablers of sustainability of QI within each jurisdiction included QI training for clinicians, the ability to continue CoP meetings, executive and broad stakeholder engagement, and the ability to use pre-existing organisational infrastructures and processes. Barriers to continue QI work included lack of funding for core team members, lack of automated data collection processes and lack of clinician incentives (financial and other). CONCLUSION: Success and sustainability in data-driven QI in cancer surgery require skills in QI methodology, data literacy and feedback, dedicated supportive personnel and an environment that promotes the process of collective learning and shared accountability. Building these capabilities in jurisdictional teams, tailoring interventions to facility contexts and strong leadership engagement will create the capacity for continued success in QI for cancer surgery.