Evaluating the cost implications of integrating SARS-CoV-2 genome sequencing for infection prevention and control investigation of nosocomial transmission within hospitals.

BACKGROUND: The COG-UK hospital-onset COVID-19 infection (HOCI) trial evaluated the impact of SARS-CoV-2 whole-genome sequencing (WGS) on acute infection, prevention, and control (IPC) investigation of nosocomial transmission within hospitals. AIM: To estimate the cost implications of using the information from the sequencing reporting tool (SRT), used to determine likelihood of nosocomial infection in IPC practice. METHODS: A micro-costing approach for SARS-CoV-2 WGS was conducted. Data on IPC management resource use and costs were collected from interviews with IPC teams from 14 participating sites and used to assign cost estimates for IPC activities as collected in the trial. Activities included IPC-specific actions following a suspicion of healthcare-associated infection (HAI) or outbreak, as well as changes to practice following the return of data via SRT. FINDINGS: The mean per-sample costs of SARS-CoV-2 sequencing were estimated at £77.10 for rapid and £66.94 for longer turnaround phases. Over the three-month interventional phases, the total management costs of IPC-defined HAIs and outbreak events across the sites were estimated at £225,070 and £416,447, respectively. The main cost drivers were bed-days lost due to ward closures because of outbreaks, followed by outbreak meetings and bed-days lost due to cohorting contacts. Actioning SRTs, the cost of HAIs increased by £5,178 due to unidentified cases and the cost of outbreaks decreased by £11,246 as SRTs excluded hospital outbreaks. CONCLUSION: Although SARS-CoV-2 WGS adds to the total IPC management cost, additional information provided could balance out the additional cost, depending on identified design improvements and effective deployment.

Management of a large outbreak of COVID-19 at a British Army training centre: lessons for the future.

INTRODUCTION: The COVID-19 pandemic has posed major challenges for infection control within training centres, both civilian and military. Here we present a narrative review of an outbreak that occurred at the Royal Military Academy Sandhurst (RMAS) in January-March 2021, in the context of the circulating, highly transmissible SARS-CoV-2 variant B.1.1.7. METHODS: Testing for SARS-CoV-2 was performed using a combination of reverse transcriptase PCR and Lateral Flow Devices (LFDs). Testing and isolation procedures were conducted in line with a pre-established symptom stratification system. Genomic sequencing was performed on 10 sample isolates. RESULTS: By the end of the outbreak, 185 cases (153 Officer Cadets, 32 permanent staff) had contracted confirmed COVID-19. This represented 15% of the total RMAS population. This resulted in 0 deaths and 0 hospitalisations, but due to necessary isolation procedures did represent an estimated 12 959 person-days of lost training. 9 of 10 (90%) of sequenced isolates had a reportable lineage. All of those reported were found to be the Alpha lineage B.1.1.7. CONCLUSIONS: We discuss the key lessons learnt from the after-action review by the Incident Management Team. These include the importance of multidisciplinary working, the utility of sync matrices to monitor outbreaks in real time, issues around Officer Cadets reporting symptoms, timing of high-risk training activities, infrastructure and use of LFDs. COVID-19 represents a vital learning opportunity to minimise the impact of potential future pandemics, which may produce considerably higher morbidity and mortality in military populations.

Nosocomial or not? A combined epidemiological and genomic investigation to understand hospital-acquired COVID-19 infection on an elderly care ward.

BACKGROUND: COVID-19 has the potential to cause outbreaks in hospitals. Given the comorbid and elderly cohort of patients hospitalized, hospital-acquired COVID-19 infection is often fatal. Pathogen genome sequencing is becoming increasingly important in infection prevention and control (IPC). AIM: To inform the understanding of in-hospital SARS-CoV-2 transmission in order to improve IPC practices and to inform the future development of virological testing for IPC. METHODS: Patients detected COVID-19 positive by polymerase chain reaction on Ward A in April and May 2020 were included with contact tracing to identify other potential cases. Genome sequencing was undertaken for a subgroup of cases. Epidemiological, genomic, and cluster analyses were performed to describe the epidemiology and to identify factors contributing to the outbreak. FINDINGS: Fourteen cases were identified on Ward A. Contact tracing identified 16 further patient cases; in addition, eight healthcare workers (HCWs) were identified as being COVID-19 positive through a round of asymptomatic testing. Genome sequencing of 16 of these cases identified viral genomes differing by two single nucleotide polymorphisms or fewer, with further cluster analysis identifying two groups of infection (a five-person group and a six-person group). CONCLUSION: Despite the temporal relationship of cases, genome sequencing identified that not all cases shared transmission events. However, 11 samples were found to be closely related and these likely represented in-hospital transmission. This included three HCWs, thereby confirming transmission between patients and HCWs.

Implementation of a fetal ultrasound telemedicine service: women's views and family costs.

BACKGROUND: The complexity of fetal medicine (FM) referrals that can be managed within obstetric units is dependent on the availability of specialist ultrasound expertise. Telemedicine can effectively transfer real-time ultrasound images via video-conferencing. We report the successful introduction of a fetal ultrasound telemedicine service linking a specialist fetal medicine (FM) centre and a remote obstetric unit. METHODS: Over a four-year period from October 2015, all women referred for FM consultation from the obstetric unit were seen via telemedicine, excluding cases where invasive testing, intrauterine therapy or cardiac anomalies were anticipated. The outcomes measured included the indication for FM referral; scan duration and image and sound quality during the consultation. Women's perceptions of the telemedicine consultation and estimated costs to attend the FM centre were measured by a structured questionnaire completed following the first telemedicine appointment during the Phase 1 of the project. RESULTS: Overall, 297 women had a telemedicine consultation during Phase 1 (pilot and evaluation) and Phase 2 (embedding and adoption) of the project, which covered a 4 year period 34 women completed questionnaires during the Phase 1 of the study. Travel to the telemedicine consultation took a median (range) time of 20 min (4150), in comparison to an estimated journey of 230 min (120,450) to the FM centre. On average, women would have spent approximately £28 to travel to the FM centre per visit. The overall costs for the woman and her partner/ friend to attend the FM centre was estimated to be £439. Women were generally satisfied with the service and valued the opportunity to have a FM consultation locally. CONCLUSIONS: We have demonstrated that a fetal ultrasound telemedicine service can be successfully introduced to provide FM ultrasound of sufficient quality to allow fetal diagnosis and specialist consultation with parents. Furthermore, the service is acceptable to parents, has shown a reduction in family costs and journey times.

Characterization of pulmonary immune responses to hyperoxia by high-dimensional mass cytometry analyses.

Prolonged exposure to hyperoxia has deleterious effects on the lung, provoking both inflammation and alveolar injury. The elements of hyperoxic injury, which result in high rates of lethality in experimental models, are thought to include multicellular immune responses. To characterize these alterations in immune cell populations, we performed time-of-flight mass cytometry (CyTOF) analysis of CD45-expressing immune cells in whole lung parenchyma and the bronchoalveolar space of mice, exposed to 48 hours of hyperoxia together with normoxic controls. At the tested time point, hyperoxia exposure resulted in decreased abundance of immunoregulatory populations (regulatory B cells, myeloid regulatory cells) in lung parenchyma and markedly decreased proliferation rates of myeloid regulatory cells, monocytes and alveolar macrophages. Additionally, hyperoxia caused a shift in the phenotype of alveolar macrophages, increasing proportion of cells with elevated CD68, CD44, CD11c, PD-L1, and CD205 expression levels. These changes occurred in the absence of histologically evident alveolar damage and abundance of neutrophils in the parenchyma or alveolar space did not change at these time points. Collectively, these findings demonstrate that pulmonary response to hyperoxia involves marked changes in specific subsets of myeloid and lymphoid populations. These findings have important implications for therapeutic targeting in acute lung injury.

Obstetric anal sphincter injuries before and after the introduction of the Episcissors-60: A multi-centre time series analysis.

OBJECTIVE: To investigate the impact of the Episcissors-60 on obstetric anal sphincter injury (OASI) rates. STUDY DESIGN: Observational multi-centre time series analysis at four maternity units in the North-East of England. The main outcome measures were obstetric anal sphincter injury rates and delivery blood loss. RESULTS: Data were analysed for women who had a vaginal birth of a singleton pregnancy before (11,192) and after (8064) the introduction of the Episcissors-60. There were 2115 episiotomies before and 1498 after the introduction of the Episcissors-60, of which 1311 (87.5%) were undertaken with the Episcissors-60, 114 (7.6%) with other scissors and the scissors used were not stated in 73 (4.8%) women. There was no significant association between the introduction of Episcissors-60 and the performance of an episiotomy (χ2 = 0.006, p  = 0.94). Episiotomy was associated with a significant reduction in OASI rates (1.9% Vs 2.8%, odds ratio = 0.67 [0.51 - 0.86]; p =  0.001). There was no significant association between the introduction of the Episcissors-60 and the occurrence of OASIs in all women (χ2 = 0.6, p =  0.46) or in women who had an episiotomy (χ2 = 0.20, p = 0.71). In women who had an episiotomy, the mean estimated delivery blood loss was 550.3 ±â€¯8.2 ml before and 598.8 ±â€¯10.9 ml after the introduction of the Episcissors-60 (p <  0.001). CONCLUSION: Introduction of the Episcissors-60 was not associated with a change in OASI or episiotomy rates but may be associated with a small increase in delivery blood loss.

Quantification of spiral artery remodelling using an Adobe Photoshop-based technique.

Uterine spiral arteries undergo remodelling in normal pregnancy, with replacement of the musculoelastic arterial media by fibrinoid containing extravillous trophoblast cells. Deficient spiral artery remodelling is associated with several adverse pregnancy outcomes. Although there are distinct components of spiral artery remodelling, assessment is subjective and often based on an overall impression of morphology. We aimed to develop a quantitative approach for assessment of uterine spiral artery remodelling. Placental bed biopsies were immunostained using smooth muscle markers, digital images of spiral arteries were captured and Adobe Photoshop was used to analyse positive immunostaining. The method was then used to investigate variation in the same vessel at different levels within a paraffin block, and the effect of parity, pre-eclampsia or miscarriage on vascular smooth muscle cell content. Results were also compared with a more subjective morphology-based assessment system. There was good intra- and interobserver agreement and the method correlated well with the more subjective assessment system. There was an overall reduction in vascular smooth muscle, as detected by caldesmon 1 (h-caldesmon) immunopositivity, with increasing gestational age from 8 weeks to term. A previous pregnancy did not affect the amount of spiral artery smooth muscle. Comparison of pre-eclampsia and late miscarriage samples with controls of the appropriate gestational age demonstrated increased medial smooth muscle in pathological samples. This technique provides a simple, rapid, reproducible and inexpensive approach to quantitative assessment of spiral artery remodelling in normal and pathological human pregnancy, a process which although fundamental for successful pregnancy, is still incompletely understood.

Uterine spiral artery muscle dedifferentiation.

STUDY QUESTION: Is vascular smooth muscle cell (VSMC) dedifferentiation a feature of uterine spiral artery (SpA) remodelling in early human pregnancy? SUMMARY ANSWER: Remodelling of human uterine SpAs is associated with dedifferentiation of VSMCs and can be induced in vitro by uterine natural killer (uNK) cells and extravillous trophoblast cells (EVTs). WHAT IS KNOWN ALREADY: Uterine SpAs undergo profound morphological changes in normal pregnancy with replacement of the musculoelastic arterial wall structure by fibrinoid containing EVTs. The fate of VSMCs in SpA remodelling is unknown; in guinea pig uterine artery VSMCs dedifferentiate, remain in the vessel wall and differentiate after parturition to restore the arterial wall. There is increasing evidence that uNK cells play a role in SpA remodelling. We hypothesized that SpA remodelling in human pregnancy is associated with VSMC dedifferentiation, initiated by uNK cell-derived growth factors. STUDY DESIGN, SIZE, DURATION: Formalin fixed, paraffin embedded placental bed biopsies were immunostained for angiogenic growth factor (AGF) receptors and markers of VSMC differentiation. An in vitro model of SpA remodelling using chorionic plate arteries (CPAs) was used to test the effect of different cell types and AGFs on VSMC differentiation. PARTICIPANTS/MATERIALS, SETTING, METHODS: Placental bed biopsies were immunostained for vascular endothelial growth factor receptors 1-3 (VEGF-R1, VEGF-R2, VEGF-R3), transforming growth factor beta 1 receptors I and II (TGF-ßRI, TGF-ßRII), interferon gamma receptors 1 and 2 (IFN-γR1, IFN-γR2), Tie2, α-smooth muscle actin (α-SMA), H-caldesmon (H-Cal), myosin heavy chain (MyHC), osteopontin and smoothelin. Staining intensity was assessed using a modified quickscore. Expression by VSMCs of the AGF receptors was confirmed by laser capture microdissection and real-time RT-PCR of non-remodelled SpAs, after laser removal of the endothelium. As an in vitro model, VSMC differentiation was assessed in CPAs by immunohistochemistry after culture in uNK cell-conditioned medium (CM), EVT-CM, uNK cell/EVT co-culture CM, Ang-1, Ang-2, IFN-γ, VEGF-A and VEGF-C, and after blocking of both Ang-1 and Ang-2 in uNK-CM. MAIN RESULTS AND THE ROLE OF CHANCE: SpA VSMC expression of Tie-2 (P = 0.0007), VEGF-R2 (P = 0.005) and osteopontin (P = 0.0001) increased in partially remodelled SpAs compared with non-remodelled SpAs, while expression of contractile VSMC markers was reduced (α-SMA P < 0.0001, H-Cal P = 0.03, MyHC P = 0.03, smoothelin P = 0.0001). In the in vitro CPA model, supernatants from purified uNK cell (H-Cal P < 0.0001, MyHC P = 0.03, α-SMA P = 0.02, osteopontin P = 0.03), EVT (H-Cal P = 0.0006, MyHC P = 0.02, osteopontin P = 0.01) and uNK cell/EVT co-cultures (H-Cal P = 0.001, MyHC P = 0.05, osteopontin P = 0.02) at 12-14 weeks, but not 8-10 weeks, gestational age induced reduced expression of contractile VSMC markers and increased osteopontin expression. Addition of exogenous (10 ng/ml) Ang-1 (P = 0.006) or Ang-2 (P = 0.009) also reduced H-Cal expression in the CPA model. Inhibition of Ang-1 (P = 0.0004) or Ang-2 (P = 0.004) in uNK cell supernatants blocked the ability of uNK cell supernatants to reduce H-Cal expression. LIMITATIONS, REASONS FOR CAUTION: This is an in vitro study and the role of uNK cells, Ang-1 and Ang-2 in SpA remodelling in vivo has not yet been shown. WIDER IMPLICATIONS OF THE FINDINGS: VSMC dedifferentiation is a feature of early SpA remodelling and uNK cells and EVT play key roles in this process by secretion of Ang-1 and Ang-2. This is one of the first studies to suggest a direct role for Ang-1 and Ang-2 in VSMC biology. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by a grant from British Biotechnology and Biosciences Research Council (BB/E016790/1). The authors have no competing interests to declare.

Views, experience and adherence among pregnant women with gestational diabetes participating in a weight loss study (WELLBABE).

AIMS: To investigate the views and experience of pregnant women newly diagnosed with gestational diabetes mellitus participating in a 1200 kcal/day diet to achieve moderate weight loss (the WELLBABE study), and to explore barriers to and facilitators of adherence. METHODS: Twelve participants engaged in semi-structured interviews after completion of the 4-week diet. An interview schedule was devised using open-ended questions guided by the Theoretical Domains Framework. Transcript responses were analysed thematically. RESULTS: Participants were anxious about their diagnosis of gestational diabetes, but concerns related to dieting in pregnancy were allayed by reassurance from the research team. Participants expected health benefits, improved knowledge and support from enrolling on the study. The participants' primary motivator to diet adherence was their baby's wellbeing. Other facilitatory factors included improving their own health and reducing any future risk of diabetes. Trying to provide reliable results and receiving extra care also facilitated adherence. Partners, friends and family were an important source of social support and no barrier caused by concern about weight loss in pregnancy was encountered. Observed and experienced physical changes and feedback from the research team positively reinforced adherence. The main barrier was that learning new skills was initially time-consuming. CONCLUSIONS: Weight loss was acceptable to women with gestational diabetes provided with clear information about likely benefit. A randomized controlled trial of this intervention is now required, employing clear information and feedback of glycaemic benefit to facilitate efficacy.

Anatomical subgroup analysis of the MERIDIAN cohort: failed commissuration.

OBJECTIVE: To assess the contribution of fetal magnetic resonance imaging (MRI) in fetuses of the MERIDIAN cohort diagnosed with either agenesis or hypogenesis of the corpus callosum (referred to collectively as failed commissuration) on antenatal ultrasound. METHODS: This was a subgroup analysis of the MERIDIAN study of fetuses with failed commissuration (with or without ventriculomegaly) diagnosed on ultrasound in women who had MRI assessment within 2 weeks of ultrasound and for whom outcome reference data were available. The diagnostic accuracy of ultrasound and MRI was studied, as well as indicators of diagnostic confidence and effects on prognosis/clinical management. Appropriate diagnostic confidence was assessed by the score-based weighted average method, which combines diagnostic accuracy with diagnostic confidence data. RESULTS: In the MERIDIAN cohort, 79 fetuses were diagnosed with failed commissuration on ultrasound (55 with agenesis and 24 with hypogenesis of the corpus callosum). The diagnostic accuracy for detecting failed commissuration was 34.2% for ultrasound and 94.9% for MRI (difference, 60.7% (95% CI, 47.6-73.9%), P < 0.0001). The diagnostic accuracy for detecting hypogenesis of the corpus callosum as a discrete entity was 8.3% for ultrasound and 87.5% for MRI, and for detecting agenesis of the corpus callosum as a distinct entity was 40.0% for ultrasound and 92.7% for MRI. There was a statistically significant improvement in 'appropriate' diagnostic confidence when using MRI as assessed by the score-based weighted average method (P < 0.0001). Prognostic information given to the women changed in 36/79 (45.6%) cases after MRI and its overall effect on clinical management was 'significant', 'major' or 'decisive' in 35/79 cases (44.3%). CONCLUSIONS: Our data suggest that any woman whose fetus has failed commissuration as the only intracranial finding detected on ultrasound should have MRI examination for further evaluation. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Anatomical subgroup analysis of the MERIDIAN cohort: posterior fossa abnormalities.

OBJECTIVE: To assess the diagnostic and clinical contribution of fetal magnetic resonance imaging (MRI) in fetuses of the MERIDIAN cohort diagnosed with abnormalities of the posterior fossa as the only intracranial abnormality recognized on antenatal ultrasound. METHODS: This was a subgroup analysis of the MERIDIAN study of fetuses with abnormalities of the posterior fossa (with or without ventriculomegaly) diagnosed on antenatal ultrasound in women who had MRI within 2 weeks of ultrasound and for whom outcome reference data were available. The diagnostic accuracy of ultrasound and MRI is reported, as well as indicators of diagnostic confidence and effects on prognosis and clinical management. Appropriate diagnostic confidence was assessed by the score-based weighted average method, which combines diagnostic accuracy with diagnostic confidence data. RESULTS: Abnormalities confined to the posterior fossa according to ultrasound were found in 81 fetuses (67 with parenchymal and 14 with cerebrospinal fluid-containing lesions). The overall diagnostic accuracy for detecting an isolated posterior fossa abnormality was 65.4% for ultrasound and 87.7% for MRI (difference, 22.3% (95% CI, 14.0-30.5%); P < 0.0001). There was an improvement in 'appropriate' diagnostic confidence, as assessed by the score-based weighted average method (P < 0.0001), and a three-fold reduction in 'high confidence but incorrect diagnosis' was achieved using MRI. Prognostic information given to the women changed after MRI in 44% of cases, and the overall effect of MRI on clinical management was considered to be 'significant', 'major' or 'decisive' in 35% of cases. CONCLUSIONS: Our data suggest that any woman whose fetus has a posterior fossa abnormality as the only intracranial finding on ultrasound should have MRI for further evaluation. This is on the basis of improved diagnostic accuracy and confidence, which impacts substantially on the prognostic information given to women as well as their clinical management. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Anatomical subgroup analysis of the MERIDIAN cohort: ventriculomegaly.

OBJECTIVE: To assess the contribution of fetal magnetic resonance imaging (MRI) in fetuses of the MERIDIAN cohort diagnosed with ventriculomegaly (VM) as the only abnormal intracranial finding on antenatal ultrasound. METHODS: This was a subgroup analysis of the MERIDIAN study of fetuses with only VM diagnosed on ultrasound in women who had a subsequent MRI examination within 2 weeks and for whom outcome reference data were available. The diagnostic accuracy of ultrasound and MRI was reported in relation to the severity of VM. The difference in measurements of trigone size on the two imaging methods and the clinical impact of adding MRI to the diagnostic pathway were also studied. RESULTS: In 306 fetuses with VM, ultrasound failed to detect 31 additional brain abnormalities, having an overall diagnostic accuracy of 89.9% for ultrasound, whilst MRI correctly detected 27 of the additional brain abnormalities, having a diagnostic accuracy of 98.7% (P < 0.0001). There were other brain abnormalities in 14/244 fetuses with mild VM on ultrasound (diagnostic accuracy, 94.3%) and MRI correctly diagnosed 12 of these (diagnostic accuracy, 99.2%; P = 0.0005). There was a close agreement between the size of trigones measured on ultrasound and on MRI, with categorical differences in only 16% of cases, showing that MRI did not systematically overestimate or underestimate trigone size. Complete prognostic data were available in 295/306 fetuses and the prognosis category changed after MRI in 69/295 (23.4%) cases. The overall effect of MRI on clinical management was considered to be 'significant', 'major' or 'decisive' in 76/295 (25.8%) cases. CONCLUSION: Our data suggest that a woman carrying a fetus with VM as the only intracranial finding on ultrasound should be offered an adjuvant investigation by MRI for further evaluation. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Infant adiposity following a randomised controlled trial of a behavioural intervention in obese pregnancy.

OBJECTIVES: Randomised controlled trials are required to address causality in the reported associations between maternal influences and offspring adiposity. The aim of this study was to determine whether an antenatal lifestyle intervention, associated with improvements in maternal diet and reduced gestational weight gain (GWG) in obese pregnant women leads to a reduction in infant adiposity and sustained improvements in maternal lifestyle behaviours at 6 months postpartum. SUBJECTS AND METHODS: We conducted a planned postnatal follow-up of a randomised controlled trial (UK Pregnancies Better Eating and Activity Trial (UPBEAT)) of a complex behavioural intervention targeting maternal diet (glycaemic load (GL) and saturated fat intake) and physical activity in 1555 obese pregnant women. The main outcome measure was infant adiposity, assessed by subscapular and triceps skinfold thicknesses. Maternal diet and physical activity, indices of the familial lifestyle environment, were assessed by questionnaire. RESULTS: A total of 698 (45.9%) infants (342 intervention and 356 standard antenatal care) were followed up at a mean age of 5.92 months. There was no difference in triceps skinfold thickness z-scores between the intervention vs standard care arms (difference -0.14 s.d., 95% confidence interval -0.38 to 0.10, P=0.246), but subscapular skinfold thickness z-score was 0.26 s.d. (-0.49 to -0.02; P=0.03) lower in the intervention arm. Maternal dietary GL (-35.34; -48.0 to -22.67; P<0.001) and saturated fat intake (-1.93% energy; -2.64 to -1.22; P<0.001) were reduced in the intervention arm at 6 months postpartum. Causal mediation analysis suggested that lower infant subscapular skinfold thickness was partially mediated by changes in antenatal maternal diet and GWG rather than postnatal diet. CONCLUSIONS: This study provides evidence from follow-up of a randomised controlled trial that a maternal behavioural intervention in obese pregnant women has the potential to reduce infant adiposity and to produce a sustained improvement in maternal diet at 6 months postpartum.

Change in diagnostic confidence brought about by using in utero MRI for fetal structural brain pathology: analysis of the MERIDIAN cohort.

AIM: To measure possible change in diagnostic confidence by performing in utero magnetic resonance imaging (iuMRI) studies on fetuses with brain abnormalities recognised on ultrasonography (US). MATERIALS AND METHODS: The analyses are based on the primary cohort from the prospective MERIDIAN study, which consisted of 570 fetuses with brain abnormalities detected on US, with iuMRI performed within 2 weeks of US and complete outcome reference data. The cohort was recruited between July 2011 and August 2014, and written informed consent was obtained for all participants. They all had indicators of diagnostic confidence measured on US by fetal medicine experts and iuMRI by the reporting radiologists. Three assessments were carried out using the conventional uncorrected (C2-C1%) method, the conventional (C2-C1%) with the Omary correction, and the score-based weighted average method. RESULTS: All three assessments showed statistically significant (p<0·0001) positive effects indicating that iuMRI was potentially beneficial when included in the diagnostic pathway for prenatal structural brain anomalies (in terms of diagnostic confidence). CONCLUSION: These results strongly support the routine clinical use of iuMRI as an adjunct to US when assessing fetuses with structural brain abnormalities.

Unlocking the Potential of Purinergic Signaling in Transplantation.

Purinergic signaling has been recognized as playing an important role in inflammation, angiogenesis, malignancy, diabetes and neural transmission. Activation of signaling pathways downstream from purinergic receptors may also be implicated in transplantation and related vascular injury. Following transplantation, the proinflammatory "danger signal" adenosine triphosphate (ATP) is released from damaged cells and promotes proliferation and activation of a variety of immune cells. Targeting purinergic signaling pathways may promote immunosuppression and ameliorate inflammation. Under pathophysiological conditions, nucleotide-scavenging ectonucleotidases CD39 and CD73 hydrolyze ATP, ultimately, to the anti-inflammatory mediator adenosine. Adenosine suppresses proinflammatory cytokine production and is associated with improved graft survival and decreased severity of graft-versus-host disease. Furthermore, purinergic signaling is involved both directly and indirectly in the mechanism of action of several existing immunosuppressive drugs, such as calcineurin inhibitors and mammalian target of rapamycin inhibitors. Targeting of purinergic receptor pathways, particularly in the setting of combination therapies, could become a valuable immunosuppressive strategy in transplantation. This review focuses on the role of the purinergic signaling pathway in transplantation and immunosuppression and explores possible future applications in clinical practice.

Aspirin use is associated with lower indices of liver fibrosis among adults in the United States.

BACKGROUND: Recent animal studies have shown that platelets directly activate hepatic stellate cells to promote liver fibrosis, whereas anti-platelet agents decrease liver fibrosis. It is unknown whether platelet inhibition by aspirin prevents liver fibrosis in humans. AIM: To examine the association between aspirin use and liver fibrosis among adults with suspected chronic liver disease. METHODS: We conducted a cross-sectional analysis using data from the National Health and Nutrition Examination Survey III. We identified 1856 individuals with suspected chronic liver disease (CLD). The degree of liver fibrosis was determined using four validated fibrosis indices and a composite index. RESULTS: The use of aspirin was associated with a significantly lower composite liver fibrosis index calculated from FIB4, APRI, Forns and NFS [0.24 standard deviation (s.d.) units lower; 95% CI -0.42 to -0.06, P = 0.009]. The association of aspirin with lower fibrosis scores was significantly larger among those with suspected CLD compared to those without (-0.23 vs. -0.03 s.d. units; P interaction = 0.05). The negative association between aspirin use and lower fibrosis index was consistent across all four fibrosis indices (P = 0.002-0.08) in individuals with chronic viral hepatitis, suspected alcoholic liver disease and NASH. In comparison, no negative associations with liver fibrosis were seen with ibuprofen in parallel analyses. CONCLUSIONS: The use of aspirin was associated with significantly lower indices of liver fibrosis among US adults with suspected chronic liver diseases. Aspirin and other anti-platelet drugs warrant further investigation for the prevention and treatment of liver fibrosis.

Role of acid sphingomyelinase bioactivity in human CD4+ T-cell activation and immune responses.

Acid sphingomyelinase (ASM), a lipid hydrolase enzyme, has the potential to modulate various cellular activation responses via the generation of ceramide and by interaction with cellular receptors. We have hypothesized that ASM modulates CD4(+) T-cell receptor activation and impacts immune responses. We first observed interactions of ASM with the intracellular domains of both CD3 and CD28. ASM further mediates T-cell proliferation after anti-CD3/CD28 antibody stimulation and alters CD4(+) T-cell activation signals by generating ceramide. We noted that various pharmacological inhibitors of ASM or knockdown of ASM using small hairpin RNA inhibit CD3/CD28-mediated CD4(+) T-cell proliferation and activation. Furthermore, such blockade of ASM bioactivity by biochemical inhibitors and/or molecular-targeted knockdown of ASM broadly abrogate T-helper cell responses. In conclusion, we detail immune, pivotal roles of ASM in adaptive immune T-cell responses, and propose that these pathways might provide novel targets for the therapy of autoimmune and inflammatory diseases.

Low-fasting triglyceride levels are associated with non-invasive markers of advanced liver fibrosis among adults in the United States.

BACKGROUND: Elevated fasting triglyceride is often associated with metabolic syndrome and non-alcoholic fatty liver disease (NAFLD), the most common form of chronic liver disease. On the other hand, as liver disease progresses, patients may develop hepatocellular dysfunction that impairs triglyceride production. AIM: To test the hypothesis that lower fasting triglyceride levels may paradoxically indicate more advanced liver disease. METHODS: A cross-sectional analysis of 11 947 adults aged 20 years or older without chronic viral hepatitis from the National Health and Nutrition Examination Survey 1999-2010 was performed to analyze the relationships between fasting triglyceride levels and five validated non-invasive indices of liver fibrosis, including Fibrosis 4 Score (FIB4), NAFLD Fibrosis Score (NFS), Ast-Platelet Ration Index, AST/ALT ratio and BARD. RESULTS: Low-fasting triglyceride levels were consistently associated with elevated liver fibrosis indices. Individuals in the lowest quintile of triglycerides (TG) had an adjusted odds ratio (OR) of 3.0 (95% CI, 1.7-5.2; P < 0.001) for advanced fibrosis estimated by FIB4 score and OR of 1.8 (95% Cl, 1.2-2.7; P = 0.009) estimated by NFS, compared to individuals in the highest quintile. This association remained highly significant when restricted to individuals with abnormal LFTs from suspected NAFLD. This inverse relationship was continuous, and more pronounced among men and whites (P interaction <0.001 and 0.008 respectively), but not modified by age or body mass index. In addition, fasting TG had a stronger, more direct association with liver fibrosis indices than did albumin or total bilirubin. CONCLUSIONS: Fasting triglyceride levels were inversely associated with liver fibrosis indicators in American adults, especially among white men. Our findings suggest that sequential lipid measurements may serve as a useful disease marker in the management of chronic liver disease patients.