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Williams–Beuren syndrome (WBS) is a developmental disorder with characteristic physical, cognitive and behavioural traits caused by a microdeletion of ∼1.5 Mb on chromosome 7q11.23. In total, 24 genes have been described within the deleted region to date. We have isolated and characterised a novel human gene, GTF2IRD2 , mapping to the WBS critical region thought to harbour genes important for the cognitive aspects of the disorder. GTF2IRD2 is the third member of the novel TFII-I family of genes clustered on 7q11.23. The GTF2IRD2 protein contains two putative helix-loop-helix regions (I-repeats) and an unusual C-terminal CHARLIE8 transposon-like domain, thought to have arisen as a consequence of the random insertion of a transposable element generating a functional fusion gene. The retention of a number of conserved transposase-associated motifs within the protein suggests that the CHARLIE8-like region may still have some degree of transposase functionality that could influence the stability of the region in a mechanism similar to that proposed for Charcot–Marie–Tooth neuropathy type 1A. GTF2IRD2 is highly conserved in mammals and the mouse ortholgue ( Gtf2ird2 ) has also been isolated and maps to the syntenic WBS region on mouse chromosome 5G. Deletion mapping studies using somatic cell hybrids show that some WBS patients are hemizygous for this gene, suggesting that it could play a role in the pathogenesis of the disorder.

The past two decades have seen expansion of childhood vaccination programmes in low-income and middle-income countries (LMICs). We quantify the health impact of these programmes by estimating the deaths and disability-adjusted life-years (DALYs) averted by vaccination against ten pathogens in 98 LMICs between 2000 and 2030. 16 independent research groups provided model-based disease burden estimates under a range of vaccination coverage scenarios for ten pathogens: hepatitis B virus, Haemophilus influenzae type B, human papillomavirus, Japanese encephalitis, measles, Neisseria meningitidis serogroup A, Streptococcus pneumoniae, rotavirus, rubella, and yellow fever. Using standardised demographic data and vaccine coverage, the impact of vaccination programmes was determined by comparing model estimates from a no-vaccination counterfactual scenario with those from a reported and projected vaccination scenario. We present deaths and DALYs averted between 2000 and 2030 by calendar year and by annual birth cohort. We estimate that vaccination of the ten selected pathogens will have averted 69 million (95% credible interval 52–88) deaths between 2000 and 2030, of which 37 million (30–48) were averted between 2000 and 2019. From 2000 to 2019, this represents a 45% (36–58) reduction in deaths compared with the counterfactual scenario of no vaccination. Most of this impact is concentrated in a reduction in mortality among children younger than 5 years (57% reduction [52–66]), most notably from measles. Over the lifetime of birth cohorts born between 2000 and 2030, we predict that 120 million (93–150) deaths will be averted by vaccination, of which 58 million (39–76) are due to measles vaccination and 38 million (25–52) are due to hepatitis B vaccination. We estimate that increases in vaccine coverage and introductions of additional vaccines will result in a 72% (59–81) reduction in lifetime mortality in the 2019 birth cohort. Increases in vaccine coverage and the introduction of new vaccines into LMICs have had a major impact in reducing mortality. These public health gains are predicted to increase in coming decades if progress in increasing coverage is sustained. Gavi, the Vaccine Alliance and the Bill & Melinda Gates Foundation.

Vaccination is one of the most effective public health interventions. We investigate the impact of vaccination activities for type b, hepatitis B, human papillomavirus, Japanese encephalitis, measles, serogroup A, rotavirus, rubella, , and yellow fever over the years 2000-2030 across 112 countries. Twenty-one mathematical models estimated disease burden using standardised demographic and immunisation data. Impact was attributed to the year of vaccination through vaccine-activity-stratified impact ratios. We estimate 97 (95%CrI[80, 120]) million deaths would be averted due to vaccination activities over 2000-2030, with 50 (95%CrI[41, 62]) million deaths averted by activities between 2000 and 2019. For children under-5 born between 2000 and 2030, we estimate 52 (95%CrI[41, 69]) million more deaths would occur over their lifetimes without vaccination against these diseases. This study represents the largest assessment of vaccine impact before COVID-19-related disruptions and provides motivation for sustaining and improving global vaccination coverage in the future. VIMC is jointly funded by Gavi, the Vaccine Alliance, and the Bill and Melinda Gates Foundation (BMGF) (BMGF grant number: OPP1157270 / INV-009125). Funding from Gavi is channelled via VIMC to the Consortium's modelling groups (VIMC-funded institutions represented in this paper: Imperial College London, London School of Hygiene and Tropical Medicine, Oxford University Clinical Research Unit, Public Health England, Johns Hopkins University, The Pennsylvania State University, Center for Disease Analysis Foundation, Kaiser Permanente Washington, University of Cambridge, University of Notre Dame, Harvard University, Conservatoire National des Arts et Métiers, Emory University, National University of Singapore). Funding from BMGF was used for salaries of the Consortium secretariat (authors represented here: TBH, MJ, XL, SE-L, JT, KW, NMF, KAMG); and channelled via VIMC for travel and subsistence costs of all Consortium members (all authors). We also acknowledge funding from the UK Medical Research Council and Department for International Development, which supported aspects of VIMC's work (MRC grant number: MR/R015600/1).JHH acknowledges funding from National Science Foundation Graduate Research Fellowship; Richard and Peggy Notebaert Premier Fellowship from the University of Notre Dame. BAL acknowledges funding from NIH/NIGMS (grant number R01 GM124280) and NIH/NIAID (grant number R01 AI112970). The Lives Saved Tool (LiST) receives funding support from the Bill and Melinda Gates Foundation.This paper was compiled by all coauthors, including two coauthors from Gavi. Other funders had no role in study design, data collection, data analysis, data interpretation, or writing of the report. All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication.

IntroductionPatients with Ebola virus disease (EVD) frequently suffer from haemodynamic instability and shock, leading to multiple organ failure and death. Clinical assessment of circulatory status is extremely challenging in these patients, hampered by the need for physicians to wear restrictive personal protective equipment, and adverse environmental factors within the EVD treatment unit (EVDTU). No EVDTUs currently use invasive cardiac output monitoring. Transthoracic echocardiography (TTE) can be used to assess haemodynamic status in critical care resuscitation. Additionally, the incidence of pericardial effusion in Ebola virus disease (EVD) is unknown. We describe the use of focused TTE (fTTE) in a military EVDTU in Sierra Leone.MethodsBaseline fTTE was performed early during the admission of all patients presenting with confirmed EVD and haemodynamic instability. Studies were performed by either a consultant cardiologist or intensivist. The median duration of EVD was 6 days prior to initial fTTE (range 3–7). In some cases, serial studies were performed during admission. Data were collected on haemodynamics, TTE view availability, LV function, presence of pericardial effusion, IVC dimensions and variability with respiration. Where central venous catheter (CVC) insertion was performed, fTTE was used to check placement by visualisation of the CVC tip, and modified views were used to exclude pneuomothorax, as no radiology facility exists within the EVDTU.ResultsDuring the first 4 weeks of operation, 8 patients with Ebola virus disease and haemodynamic instability underwent fTTE examination.TTE windows available were as follows: parasternal long axis 60%, parasternal short axis 60%, apical 4 chamber 90%, subcostal 100%. IVC imaging was possible in 80% of cases.All hearts examined were structurally normal. LV function was normal in all cases (EF >55%). Small pericardial effusions (mean 0.58 cm,) were found in 3 cases (37.5%).In 3 cases, hypovolaemia was so profound that LV systolic cavity obliteration was noted. The mean maximal IVC diameter in studies performed during inital resuscitation was 1.73 (±0.05) cm, compared with 2.10 (±0.18) in a partially resuscitated cohort.In 90% of studies, fTTE findings supported continued intravascular volume expansion. In one case, fTTE values suggested that further filing was not required, resulting in a change in management strategy.In studies following CVC placement (n = 9) the tip of the device was visualised in all cases, and lung imaging confirmed no cases of pneumothorax.ConclusionsThis study demonstrates, for the first time in a deployed military Ebola virus disease treatment unit, that fTTE can assist with assessment of volume status during the resuscitation phase. In addition, the incidence of pericardial effusion appears to be low.

IntroductionPatients with Ebola virus disease (EVD) frequently suffer from haemodynamic instability and shock, leading to multiple organ failure and death. Clinical assessment of circulatory status is extremely challenging in these patients, hampered by the need for physicians to wear restrictive personal protective equipment, and adverse environmental factors within the EVD treatment unit (EVDTU). No EVDTUs currently use invasive cardiac output monitoring. Transthoracic echocardiography (TTE) can be used to assess haemodynamic status in critical care resuscitation. Additionally, the incidence of pericardial effusion in Ebola virus disease (EVD) is unknown. We describe the use of focused TTE (fTTE) in a military EVDTU in Sierra Leone.MethodsBaseline fTTE was performed early during the admission of all patients presenting with confirmed EVD and haemodynamic instability. Studies were performed by either a consultant cardiologist or intensivist. The median duration of EVD was 6 days prior to initial fTTE (range 3-7). In some cases, serial studies were performed during admission. Data were collected on haemodynamics, TTE view availability, LV function, presence of pericardial effusion, IVC dimensions and variability with respiration. Where central venous catheter (CVC) insertion was performed, fTTE was used to check placement by visualisation of the CVC tip, and modified views were used to exclude pneuomothorax, as no radiology facility exists within the EVDTU.ResultsDuring the first 4 weeks of operation, 8 patients with Ebola virus disease and haemodynamic instability underwent fTTE examination.TTE windows available were as follows: parasternal long axis 60%, parasternal short axis 60%, apical 4 chamber 90%, subcostal 100%. IVC imaging was possible in 80% of cases.All hearts examined were structurally normal. LV function was normal in all cases (EF >55%). Small pericardial effusions (mean 0.58 cm,) were found in 3 cases (37.5%).In 3 cases, hypovolaemia was so profound that LV systolic cavity obliteration was noted. The mean maximal IVC diameter in studies performed during inital resuscitation was 1.73 ( plus or minus 0.05) cm, compared with 2.10 ( plus or minus 0.18) in a partially resuscitated cohort.In 90% of studies, fTTE findings supported continued intravascular volume expansion. In one case, fTTE values suggested that further filing was not required, resulting in a change in management strategy.In studies following CVC placement (n = 9) the tip of the device was visualised in all cases, and lung imaging confirmed no cases of pneumothorax.ConclusionsThis study demonstrates, for the first time in a deployed military Ebola virus disease treatment unit, that fTTE can assist with assessment of volume status during the resuscitation phase. In addition, the incidence of pericardial effusion appears to be low.

Identifying whether specific phenotypes are controlled by genetic elements and the exact underlying genetic components and mechanisms responsible is a common task necessary to understand biological systems, potentially leading to novel diagnoses or treatments for human diseases. Over 2000 genomic regions (QTLs) have been identified in mice and rats responsible for associated phenotypes. However, less than 1% of these have had the underlying gene(s) and mechanism that cause the phenotype identified. Therefore gene centric strategies that aid in the identification of genes and mechanisms responsible for phenotypes are required by the research community. This work aims to produce a gene centric strategy incorporating QTL, phenotype and microarray data for mouse models of particular phenotypes with text mining searches of the biomedical literature to establish literature based relationships that either explain or indicate genes and mechanisms responsible for the phenotype. The middle-out text mining strategy (MOTMS) was developed and used with data from two mouse models: 1. Tolerance to trypanosome infection (trypanotolerance) 2. A gene knockout (Gtflird2) model of Williams-Beuren Syndrome (WBS). For the trypanotolerance model MOTMS reduced candidate QTL gene search space by 97% and identified genes and a mechanism, the reverse cholesterol transport pathway, which have since been correlated with trypanosome infection survival times. Suggesting the trypanotolerant mechanism has been identified, at least in part. MOTMS outperformed similar text ming tools, such as G2D and eVOC, that prioritise candidate QTL/disease genes and can reduce search space by around 40%. MOTMS application to the WBS mouse model has identified novel genes and mechanisms implicated in WBS. One such mechanism involving mitochondria biogenesis was investigated in human WBS patients using quantitative polymerase chain reaction (QPCR). QPCR results of blood mitochondria DNA showed statistical significance at the 5% level (p = 0.01545) indicating WBS patients have reduced mitochondria levels compared to control patients. Further research is required to define this genotype to phenotype relationship.