Full pulpotomy has been proposed as an alternative to root canal treatment in teeth with signs and symptoms indicative of irreversible pulpitis (IRP), but the evidence is limited, relying on ...underpowered studies with a high risk of bias. The aim of this study is to conduct a prospective meta-analysis (PMA) of individual participant data of a series of individual randomised trials to provide robust evidence on the clinical and cost-effectiveness of pulpotomy compared with root canal treatment.
Individual participant data will be obtained from a series of randomised trials designed and conducted by a consortium of multi-national investigators with an interest in vital pulp treatment. These individualised trials will be conducted using a specified protocol, defined outcomes, and outcome measures. Ten parallel-group randomised trials currently being conducted in 10 countries will provide data from more than 500 participants. The primary outcome is a composite measure defined as (1) the absence of pain indicative of IRP, (2) the absence of signs and symptoms indicative of acute or chronic apical periodontitis, and (3) the absence of radiographic evidence of failure including radiolucency or resorption. Individual participant data will be obtained, assessed, and checked for quality by two independent reviewers prior to the PMA. Pooled estimates on treatment effects will be generated using a 2-stage meta-analysis approach. The first stage involves a standard regression analysis in each trial to produce aggregate data on treatment effect estimates followed by an inverse variance weighted meta-analysis to combine these aggregate data and produce summary statistics and forest plots. Cost-effectiveness analysis based on the composite outcome will be undertaken as a process evaluation to evaluate treatment fidelity and acceptability by patients and dentists.
The research question and trial protocol were developed and approved by investigators in all 10 sites. All sites use shared resources including study protocols, data collection forms, participant information leaflets, and consent forms in order to improve flow, consistency, and reproducibility. Each site obtained its own Institutional Review Board approval, and trials were registered in appropriate open access platforms. Patient recruitment has started in most sites, as of July 2023.
PMA offers a rigorous, flexible, and efficient methodology to answer this important research question and provide results with improved generalisability and external validity compared with traditional trials and retrospective meta-analyses. The results of this study will have implications for both the delivery of clinical practice and structured clinical guidelines' development.
PROSPERO CRD42023446809. Registered on 08 February 2023.
The few genetically informative studies to examine post-traumatic stress disorder (PTSD) and alcohol dependence (AD), all of which are based on a male veteran sample, suggest that the co-morbidity ...between PTSD and AD may be attributable in part to overlapping genetic influences, but this issue has yet to be addressed in females.MethodData were derived from an all-female twin sample (n=3768) ranging in age from 18 to 29 years. A trivariate genetic model that included trauma exposure as a separate phenotype was fitted to estimate genetic and environmental contributions to PTSD and the degree to which they overlap with those that contribute to AD, after accounting for potential confounding effects of heritable influences on trauma exposure.
Additive genetic influences (A) accounted for 72% of the variance in PTSD; individual-specific environmental (E) factors accounted for the remainder. An AE model also provided the best fit for AD, for which heritability was estimated to be 71%. The genetic correlation between PTSD and AD was 0.54.
The heritability estimate for PTSD in our sample is higher than estimates reported in earlier studies based almost exclusively on an all-male sample in which combat exposure was the precipitating traumatic event. However, our findings are consistent with the absence of evidence for shared environmental influences on PTSD and, most importantly, the substantial overlap in genetic influences on PTSD and AD reported in these investigations. Additional research addressing potential distinctions by gender in the relative contributions of genetic and environmental influences on PTSD is merited.
Different ambrosia beetle species can coexist in tree trunks, where their immature stages feed upon symbiotic fungi. Although most ambrosia beetles are not primary pests and their fungal symbionts ...are not pathogenic to the host tree, exceptional situations exist. Notably, Xyleborus glabratus carries a phytopathogenic symbiont, Raffaelea lauricola, which causes laurel wilt, a lethal disease of some Lauraceae species. Both X. glabratus and R. lauricola are natives of Asia that recently invaded much of the coastal plain of the southeastern USA. This study examined ambrosia beetles that breed in susceptible trees in Florida (USA), including avocado (Persea americana), redbay (P. borbonia) and swampbay (P. palustris). Raffaelea lauricola was recovered from six of eight ambrosia beetle species that emerged from laurel wilt‐affected swampbay trees, in addition to X. glabratus. Controlled infestations with cohorts of the six species other than X. glabratus revealed that each could transmit the pathogen to healthy redbay trees and two could transmit the pathogen to healthy avocado trees; laurel wilt developed in five and one of the respective beetle × host interactions. These results indicate flexibility in the lateral transfer of a non‐native ambrosial fungus to other ambrosia beetles, and for the first time documents the transmission of a laterally transferred phytopathogenic symbiont by new ambrosia beetle species. Additional work is needed to determine whether, or to what extent, the new beetle × R. lauricola combinations play a role in spreading laurel wilt.
The global pandemic of coronavirus disease 2019 (COVID-19) has placed a huge strain on UK hospitals. Early studies suggest that patients can deteriorate quickly after admission to hospital. The aim ...of this study was to model changes in vital signs for patients hospitalised with COVID-19.
This was a retrospective observational study of adult patients with COVID-19 admitted to one acute hospital trust in the UK (CV) and a cohort of patients admitted to the same hospital between 2013-2017 with viral pneumonia (VI). The primary outcome was the start of continuous positive airway pressure/non-invasive positive pressure ventilation, ICU admission or death in hospital. We used non-linear mixed-effects models to compare changes in vital sign observations prior to the primary outcome. Using observations and FiO2 measured at discharge in the VI cohort as the model of normality, we also combined individual vital signs into a single novelty score.
There were 497 cases of COVID-19, of whom 373 had been discharged from hospital. 135 (36.2%) of patients experienced the primary outcome, of whom 99 died in hospital. In-hospital mortality was over 4-times higher in the CV than the VI cohort (26.5% vs 6%). For those patients who experienced the primary outcome, CV patients became increasingly hypoxaemic, with a median estimated FiO2 (0.75) higher than that of the VI cohort (estimated FiO2 of 0.35). Prior to the primary outcome, blood pressure remained within normal range, and there was only a small rise in heart rate. The novelty score showed that patients with COVID-19 deteriorated more rapidly that patients with viral pneumonia.
Patients with COVID-19 who deteriorate in hospital experience rapidly-worsening respiratory failure, with low SpO2 and high FiO2, but only minor abnormalities in other vital signs. This has potential implications for the ability of early warning scores to identify deteriorating patients.
The relativistic jets created by some active galactic nuclei are important agents of AGN feedback. In spite of this, our understanding of what produces these jets is still incomplete. X-ray ...observations, which can probe the processes operating in the central regions in the immediate vicinity of the supermassive black hole, the presumed jet launching point, are potentially particularly valuable in illuminating the jet formation process. Here, we present the hard X-ray NuSTAR observations of the radio-loud quasar 4C 74.26 in a joint analysis with quasi-simultaneous, soft X-ray Swift observations. Our spectral analysis reveals a high-energy cutoff of keV and confirms the presence of ionized reflection in the source. From the average spectrum we detect that the accretion disk is mildly recessed, with an inner radius of Rin = 4-180 Rg. However, no significant evolution of the inner radius is seen during the three months covered by our NuSTAR campaign. This lack of variation could mean that the jet formation in this radio-loud quasar differs from what is observed in broad-line radio galaxies.
Late recognition of patient deterioration in hospital is associated with worse outcomes, including higher mortality. Despite the widespread introduction of early warning score (EWS) systems and ...electronic health records, deterioration still goes unrecognized.
To develop and externally validate a Hospital- wide Alerting via Electronic Noticeboard (HAVEN) system to identify hospitalized patients at risk of reversible deterioration.
This was a retrospective cohort study of patients 16 years of age or above admitted to four UK hospitals. The primary outcome was cardiac arrest or unplanned admission to the ICU. We used patient data (vital signs, laboratory tests, comorbidities, and frailty) from one hospital to train a machine-learning model (gradient boosting trees). We internally and externally validated the model and compared its performance with existing scoring systems (including the National EWS, laboratory-based acute physiology score, and electronic cardiac arrest risk triage score).
We developed the HAVEN model using 230,415 patient admissions to a single hospital. We validated HAVEN on 266,295 admissions to four hospitals. HAVEN showed substantially higher discrimination (c-statistic, 0.901 95% confidence interval, 0.898-0.903) for the primary outcome within 24 hours of each measurement than other published scoring systems (which range from 0.700 0.696-0.704 to 0.863 0.860-0.865). With a precision of 10%, HAVEN was able to identify 42% of cardiac arrests or unplanned ICU admissions with a lead time of up to 48 hours in advance, compared with 22% by the next best system.
The HAVEN machine-learning algorithm for early identification of in-hospital deterioration significantly outperforms other published scores such as the National EWS.
Sitaxsentan may benefit patients with pulmonary arterial hypertension by blocking the vasoconstrictor effects of endothelin-A while maintaining the vasodilator/clearance functions of endothelin-B ...receptors. Patients with pulmonary arterial hypertension that was idiopathic, related to connective tissue disease or congenital heart disease, were randomized to receive placebo (n = 60), sitaxsentan 100 mg (n = 55), or sitaxsentan 300 mg (n = 63) orally once daily for 12 weeks. The primary endpoint was change in peak VO(2) at Week 12. Secondary endpoints included 6-minute walk, New York Heart Association class, VO(2) at anaerobic threshold, VE per carbon dioxide production at anaerobic threshold, hemodynamics, quality of life, and time to clinical worsening. Although the 300-mg group increased peak VO(2) compared with placebo (+3.1%, p < 0.01), none of the other endpoints derived from cardiopulmonary exercise testing were met. However, both the 100-mg dose and the 300-mg dose, compared with placebo, increased 6-minute walk distance (100 mg: +35 m, p < 0.01; 300 mg: +33 m, p < 0.01); functional class, cardiac index, and pulmonary vascular resistance also improved (p < 0.02 for each parameter at both doses). The incidence of elevated aminotransferase values (> three times normal) was 3% for the placebo group, 0% for the 100-mg group, and 10% for the 300-mg group.
RationaleIntensive care units (ICUs) admit the most severely ill patients. Once these patients are discharged from the ICU to a step-down ward, they continue to have their vital signs monitored by ...nursing staff, with Early Warning Score (EWS) systems being used to identify those at risk of deterioration.ObjectivesWe report the development and validation of an enhanced continuous scoring system for predicting adverse events, which combines vital signs measured routinely on acute care wards (as used by most EWS systems) with a risk score of a future adverse event calculated on discharge from the ICU.DesignA modified Delphi process identified candidate variables commonly available in electronic records as the basis for a ‘static’ score of the patient’s condition immediately after discharge from the ICU. L1-regularised logistic regression was used to estimate the in-hospital risk of future adverse event. We then constructed a model of physiological normality using vital sign data from the day of hospital discharge. This is combined with the static score and used continuously to quantify and update the patient’s risk of deterioration throughout their hospital stay.SettingData from two National Health Service Foundation Trusts (UK) were used to develop and (externally) validate the model.ParticipantsA total of 12 394 vital sign measurements were acquired from 273 patients after ICU discharge for the development set, and 4831 from 136 patients in the validation cohort.ResultsOutcome validation of our model yielded an area under the receiver operating characteristic curve of 0.724 for predicting ICU readmission or in-hospital death within 24 hours. It showed an improved performance with respect to other competitive risk scoring systems, including the National EWS (0.653).ConclusionsWe showed that a scoring system incorporating data from a patient’s stay in the ICU has better performance than commonly used EWS systems based on vital signs alone.Trial registration numberISRCTN32008295.
The OsII arene ethylenediamine (en) complexes (η6-biphenyl)Os(en)ClZ, Z = BPh4 (4) and BF4 (5), are inactive toward A2780 ovarian cancer cells despite 4 being isostructural with an active RuII ...analogue, 4R. Hydrolysis of 5 occurred 40 times more slowly than 4R. The aqua adduct 5A has a low pK a (6.3) compared to that of (η6-biphenyl)Ru(en)(OH2)2+ (7.7) and is therefore largely in the hydroxo form at physiological pH. The rate and extent of reaction of 5 with 9-ethylguanine were also less than those of 4R. We replaced the neutral en ligand by anionic acetylacetonate (acac). The complexes (η6-arene)Os(acac)Cl, arene = biphenyl (6), benzene (7), and p-cymene (8), adopt piano-stool structures similar to those of the RuII analogues and form weak dimers through intermolecular (arene)CH···O(acac) H-bonds. Remarkably, these OsII acac complexes undergo rapid hydrolysis to produce not only the aqua adduct, (η6-arene)Os(acac)(OH2)+, but also the hydroxo-bridged dimer, (η6-arene)Os(μ2-OH)3Os(η6-arene)+. The pK a values for the aqua adducts 6A, 7A, and 8A (7.1, 7.3, and 7.6, respectively) are lower than that for (η6-p-cymene)Ru(acac)(OH2)+ (9.4). Complex 8A rapidly forms adducts with 9-ethylguanine and adenosine, but not with cytidine or thymidine. Despite their reactivity toward nucleobases, complexes 6−8 were inactive toward A549 lung cancer cells. This is attributable to rapid hydrolysis and formation of unreactive hydroxo-bridged dimers which, surprisingly, were the only species present in aqueous solution at biologically relevant concentrations. Hence, the choice of chelating ligand in OsII (and RuII) arene complexes can have a dramatic effect on hydrolysis behavior and nucleobase binding and provides a means of tuning the reactivity and the potential for discovery of anticancer complexes.
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