The role of chest X-ray in the diagnosis of neonatal respiratory distress syndrome: a systematic review concerning low-resource birth scenarios.

BACKGROUND: Access to diagnostic tools like chest radiography (CXR) is challenging in resource-limited areas. Despite reduced reliance on CXR due to the need for quick clinical decisions, its usage remains prevalent in the approach to neonatal respiratory distress syndrome (NRDS). OBJECTIVES: To assess CXR's role in diagnosing and grading NRDS severity compared to current clinical features and laboratory standards. METHODS: A review of studies with NRDS diagnostic criteria was conducted across six databases (MEDLINE, EMBASE, BVS, Scopus-Elsevier, Web of Science, Cochrane) up to 3 March 2023. Independent reviewers selected studies, with discrepancies resolved by a senior reviewer. Data were organised into descriptive tables to highlight the use of CXR and clinical indicators of NRDS. RESULTS: Out of 1,686 studies screened, 23 were selected, involving a total of 2,245 newborns. All selected studies used CXR to diagnose NRDS, and 21 (91%) applied it to assess disease severity. While seven reports (30%) indicated that CXR is irreplaceable by other diagnostic tools for NRDS diagnosis, 10 studies (43%) found that alternative methods surpassed CXR in several respects, such as severity assessment, monitoring progress, predicting the need for surfactant therapy, foreseeing Continuous Positive Airway Pressure failure, anticipating intubation requirements, and aiding in differential diagnosis. CONCLUSION: CXR remains an important diagnostic tool for NRDS. Despite its continued use in scientific reports, the findings suggest that the study's outcomes may not fully reflect the current global clinical practices, especially in low-resource settings where the early NRDS approach remains a challenge for neonatal survival.Trial registration: PROSPERO number CRD42022336480.

Main findings: Access to diagnostic tools like chest radiography is challenging in resource-limited areas, yet its usage persists in the management of neonatal respiratory distress syndrome despite a decreased dependency due to the imperative for swift clinical decisions.Added knowledge: Despite its continued significance in scientific literature, the usage of chest radiography as a diagnostic tool for neonatal respiratory distress syndrome may not entirely reflect current global clinical practices, particularly in low-resource settings where early management of neonatal respiratory distress syndrome poses a challenge for neonatal survival.Global health impact for policy and action: The results underscore the necessity of guidelines for the utilisation of chest radiography to minimise unnecessary ionising radiation exposure while ensuring timely access to critical clinical information for appropriate newborn care.

Scale up of implementation of a multidimensional intervention to enhance hypertension and diabetes care at the primary care setting: A protocol for a cluster-randomized study in Brazil.

BACKGROUND: Hypertension and diabetes mellitus (DM) are highly prevalent in low and middle-income countries (LMICs), and the proportion of patients with uncontrolled diseases is higher than in high-income countries. Innovative strategies are required to surpass barriers of low sources, distance and quality of health care. Our aim is to assess the uptake and effectiveness of the implementation of an integrated multidimensional strategy in the primary care setting, for the management of people with hypertension and diabetes mellitus in Brazil. METHODS: This scale up implementation study called Control of Hypertension and diAbetes in MINas Gerais (CHArMING) Project has mixed-methods, and comprehends 4 steps: (1) needs assessment, including a standardized structured questionnaire and focus groups with health care practitioners; (2) baseline period, 3 months before the implementation of the intervention; (3) cluster randomized controlled trial (RCT) with a 12-months follow-up period; and (4) a qualitative study after the end of follow-up. The cluster RCT will randomize 35 centers to intervention (n = 18) or usual care (n = 17). Patients ≥18 years old, with diagnosis of hypertension and/or DM, of 5 Brazilian cities in a resource-constrained area will be enrolled. The intervention consists of a multifaceted strategy, with a multidisciplinary approach, including telehealth tools (decision support systems, short message service, telediagnosis), continued education with an approach to issues related to the care of people with hypertension and diabetes in primary care, including pharmacological and non-pharmacological treatment and behavioral change. The project has actions focused on professionals and patients. CONCLUSIONS: This study consists of a multidimensional strategy with multidisciplinary approach using digital health to improve the control of hypertension and/or DM in the primary health care setting. We expect to provide the basis for implementing an innovative management program for hypertension and DM in Brazil, aiming to reduce the present and future burden of these diseases in Brazil and other LMICs. CLINICAL TRIAL IDENTIFIER: This study was registered in ClinicalTrials.gov. (NCT05660928).

Usability of Telehealth Systems for Noncommunicable Diseases in Primary Care From the COVID-19 Pandemic Onward: Systematic Review.

BACKGROUND: During the COVID-19 pandemic, telehealth was expanded without the opportunity to extensively evaluate the adopted technology's usability. OBJECTIVE: We aimed to synthesize evidence on health professionals' perceptions regarding the usability of telehealth systems in the primary care of individuals with noncommunicable diseases (NCDs; hypertension and diabetes) from the COVID-19 pandemic onward. METHODS: A systematic review was performed of clinical trials, prospective cohort studies, retrospective observational studies, and studies that used qualitative data collection and analysis methods published in English, Spanish, and Portuguese from March 2020 onward. The databases queried were MEDLINE, Embase, BIREME, IEEE Xplore, BVS, Google Scholar, and grey literature. Studies involving health professionals who used telehealth systems in primary care and managed patients with NCDs from the COVID-19 pandemic onward were considered eligible. Titles, abstracts, and full texts were reviewed. Data were extracted to provide a narrative qualitative evidence synthesis of the included articles. The risk of bias and methodological quality of the included studies were analyzed. The primary outcome was the usability of telehealth systems, while the secondary outcomes were satisfaction and the contexts in which the telehealth system was used. RESULTS: We included 11 of 417 retrieved studies, which had data from 248 health care professionals. These health care professionals were mostly doctors and nurses with prior experience in telehealth in high- and middle-income countries. Overall, 9 studies (82%) were qualitative studies and 2 (18%) were quasiexperimental or multisite trial studies. Moreover, 7 studies (64%) addressed diabetes, 1 (9%) addressed diabetes and hypertension, and 3 (27%) addressed chronic diseases. Most studies used a survey to assess usability. With a moderate confidence level, we concluded that health professionals considered the usability of telehealth systems to be good and felt comfortable and satisfied. Patients felt satisfied using telehealth. The most important predictor for using digital health technologies was ease of use. The main barriers were technological challenges, connectivity issues, low computer literacy, inability to perform complete physical examination, and lack of training. Although the usability of telehealth systems was considered good, there is a need for research that investigates factors that may influence the perceptions of telehealth usability, such as differences between private and public services; differences in the level of experience of professionals, including professional experience and experience with digital tools; and differences in gender, age groups, occupations, and settings. CONCLUSIONS: The COVID-19 pandemic has generated incredible demand for virtual care. Professionals' favorable perceptions of the usability of telehealth indicate that it can facilitate access to quality care. Although there are still challenges to telehealth, more than infrastructure challenges, the most reported challenges were related to empowering people for digital health. TRIAL REGISTRATION: PROSPERO International Prospective Register of Systematic Reviews CRD42021296887; https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=296887. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.21801/ppcrj.2022.82.6.

A hyperinflammation clinical risk tool, HI5-NEWS2, stratifies hospitalised COVID-19 patients to associate risk of death and effect of early dexamethasone in an observational cohort.

BACKGROUND: The success of early dexamethasone therapy for hospitalised COVID-19 cases in treatment of Sars-CoV-2 infection may predominantly reflect its anti-inflammatory action against a hyperinflammation (HI) response. It is likely that there is substantial heterogeneity in HI responses in COVID-19. METHODS: Blood CRP, ferritin, neutrophil, lymphocyte and platelet counts were scored to assess HI (HI5) and combined with a validated measure of generalised medical deterioration (NEWS2) before day 2. Our primary outcome was 28 day mortality from early treatment with dexamethasone stratified by HI5-NEWS2 status. FINDINGS: Of 1265 patients, high risk of HI (high HI5-NEWS2) (n = 367, 29.0%) conferred a strikingly increased mortality (36.0% vs 7.8%; Age adjusted hazard ratio (aHR) 5.9; 95% CI 3.6-9.8, p<0.001) compared to the low risk group (n = 455, 36.0%). An intermediate risk group (n = 443, 35.0%) also showed significantly higher mortality than the low risk group (17.6% vs 7.8%), aHR 2.2, p = 0.005). Early dexamethasone treatment conferred a 50.0% reduction in mortality in the high risk group (36.0% to 18.0%, aHR 0.56, p = 0.007). The intermediate risk group showed a trend to reduction in mortality (17.8% to 10.3%, aHR 0.82, p = 0.46) which was not observed in the low risk group (7.8% to 9.2%, aHR 1.4, p = 0.31). INTERPRETATION: Higher HI5-NEWS2 scores measured at COVID-19 diagnosis, strongly associate with increased mortality at 28 days. Significant reduction in mortality with early dexamethasone treatment was only observed in the high risk group. Therefore, the HI5-NEWS2 score could be utilised to stratify randomised clinical trials to test whether intensified anti-inflammatory therapy would further benefit high risk patients and whether alternative approaches would benefit low risk groups. Considering its recognised morbidity, we suggest that early dexamethasone should not be routinely prescribed for HI5-NEWS2 low risk individuals with COVID-19 and clinicians should cautiously assess the risk benefit of this intervention in all cases.

Assessment of Skin Maturity by LED Light at Birth and Its Association With Lung Maturity: Clinical Trial Secondary Outcomes.

BACKGROUND: Clinicians face barriers when assessing lung maturity at birth due to global inequalities. Still, strategies for testing based solely on gestational age to predict the likelihood of respiratory distress syndrome (RDS) do not offer a comprehensive approach to addressing the challenge of uncertain outcomes. We hypothesize that a noninvasive assessment of skin maturity may indicate lung maturity. OBJECTIVE: This study aimed to assess the association between a newborn's skin maturity and RDS occurrence. METHODS: We conducted a case-control nested in a prospective cohort study, a secondary endpoint of a multicenter clinical trial. The study was carried out in 5 Brazilian urban reference centers for highly complex perinatal care. Of 781 newborns from the cohort study, 640 were selected for the case-control analysis. Newborns with RDS formed the case group and newborns without RDS were the controls. All newborns with other diseases exhibiting respiratory manifestations were excluded. Skin maturity was assessed from the newborn's skin over the sole by an optical device that acquired a reflection signal through an LED sensor. The device, previously validated, measured and recorded skin reflectance. Clinical data related to respiratory outcomes were gathered from medical records during the 72-hour follow-up of the newborn, or until discharge or death, whichever occurred first. The main outcome measure was the association between skin reflectance and RDS using univariate and multivariate binary logistic regression. Additionally, we assessed the connection between skin reflectance and factors such as neonatal intensive care unit (NICU) admission and the need for ventilatory support. RESULTS: Out of 604 newborns, 470 (73.4%) were from the RDS group and 170 (26.6%) were from the control group. According to comparisons between the groups, newborns with RDS had a younger gestational age (31.6 vs 39.1 weeks, P<.001) and birth weight (1491 vs 3121 grams, P<.001) than controls. Skin reflectance was associated with RDS (odds ratio [OR] 0.982, 95% CI 0.979-0.985, R2=0.632, P<.001). This relationship remained significant when adjusted by the cofactors antenatal corticosteroid and birth weight (OR 0.994, 95% CI 0.990-0.998, R2=0.843, P<.001). Secondary outcomes also showed differences in skin reflectance. The mean difference was 0.219 (95% CI 0.200-0.238) between newborns that required ventilatory support versus those that did not and 0.223 (95% CI 0.205-0.241) between newborns that required NICU admission versus those that did not. Skin reflectance was associated with ventilatory support (OR 0.996, 95% CI 0.992-0.999, R2=0.814, P=.01) and with NICU admission (OR 0.994, 95% CI 0.990-0.998, R2=0.867, P=.004). CONCLUSIONS: Our findings present a potential marker of lung immaturity at birth using the indirect method of skin assessment. Using the RDS clinical condition and a medical device, this study demonstrated the synchrony between lung and skin maturity. TRIAL REGISTRATION: Registro Brasileiro de Ensaios Clínicos (ReBEC) RBR-3f5bm5; https://tinyurl.com/9fb7zrdb. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.1136/bmjopen-2018-027442.

Persistently normal blood tests in patients taking methotrexate for RA or azathioprine for IBD: a retrospective cohort study.

BACKGROUND: Disease-modifying anti-rheumatic drugs (DMARDs), including methotrexate and azathioprine, are commonly used to treat rheumatoid arthritis (RA) and inflammatory bowel disease (IBD). Blood-test safety monitoring is mainly undertaken in primary care. Normal blood results are common. AIM: To determine the frequency and associations of persistently normal blood tests in patients with RA prescribed methotrexate, and patients with IBD prescribed azathioprine. DESIGN AND SETTING: Two-year retrospective study of a cohort taken from an electronic pseudonymised primary care/laboratory database covering >1.4 million patients across Hampshire, UK. METHOD: Patients with RA and IBD, and associated methotrexate and azathioprine prescriptions, respectively, were identified. Tests and test thresholds recommended by the National Institute for Health and Care Excellence were applied. Persistent normality was defined as no abnormalities of any tests nor alanine aminotransferase (ALT), white blood count (WBC), neutrophils, and estimated glomerular filtration rate (eGFR) individually. Logistic regression was used to identify associations with test normality. RESULTS: Of 702 265 adults, 7102 had RA and 8597 had IBD. In total, 3001 (42.3%) patients with RA were prescribed methotrexate and 1162 (13.5%) patients with IBD were prescribed azathioprine; persistently normal tests occurred in 1585 (52.8%) and 657 (56.5%) of the populations, respectively. In patients with RA on methotrexate, 585 (19.5%) had eGFR, 219 (7.3%) ALT, 217 (7.2%) WBC, and 202 (6.7%) neutrophil abnormalities. In patients with IBD on azathioprine, 138 (11.9%) had WBC, 88 (7.6%) eGFR, 72 (6.2%) ALT, and 65 (5.6%) neutrophil abnormalities. Those least likely to have persistent test normality were older and/or had comorbidities. CONCLUSION: Persistent test normality is common when monitoring these DMARDs, with few hepatic or haematological abnormalities. More stratified monitoring approaches should be explored.

Immune responses against SARS-CoV-2 variants after two and three doses of vaccine in B-cell malignancies: UK PROSECO study.

Patients with hematological malignancies are at increased risk of severe COVID-19 outcomes due to compromised immune responses, but the insights of these studies have been compromised due to intrinsic limitations in study design. Here we present the PROSECO prospective observational study ( NCT04858568 ) on 457 patients with lymphoma that received two or three COVID-19 vaccine doses. We show undetectable humoral responses following two vaccine doses in 52% of patients undergoing active anticancer treatment. Moreover, 60% of patients on anti-CD20 therapy had undetectable antibodies following full vaccination within 12 months of receiving their anticancer therapy. However, 70% of individuals with indolent B-cell lymphoma displayed improved antibody responses following booster vaccination. Notably, 63% of all patients displayed antigen-specific T-cell responses, which increased after a third dose irrespective of their cancer treatment status. Our results emphasize the urgency of careful monitoring of COVID-19-specific immune responses to guide vaccination schemes in these vulnerable populations.

Predicting Pulmonary Function From the Analysis of Voice: A Machine Learning Approach.

INTRODUCTION: To self-monitor asthma symptoms, existing methods (e.g. peak flow metre, smart spirometer) require special equipment and are not always used by the patients. Voice recording has the potential to generate surrogate measures of lung function and this study aims to apply machine learning approaches to predict lung function and severity of abnormal lung function from recorded voice for asthma patients. METHODS: A threshold-based mechanism was designed to separate speech and breathing from 323 recordings. Features extracted from these were combined with biological factors to predict lung function. Three predictive models were developed using Random Forest (RF), Support Vector Machine (SVM), and linear regression algorithms: (a) regression models to predict lung function, (b) multi-class classification models to predict severity of lung function abnormality, and (c) binary classification models to predict lung function abnormality. Training and test samples were separated (70%:30%, using balanced portioning), features were normalised, 10-fold cross-validation was used and model performances were evaluated on the test samples. RESULTS: The RF-based regression model performed better with the lowest root mean square error of 10·86. To predict severity of lung function impairment, the SVM-based model performed best in multi-class classification (accuracy = 73.20%), whereas the RF-based model performed best in binary classification models for predicting abnormal lung function (accuracy = 85%). CONCLUSION: Our machine learning approaches can predict lung function, from recorded voice files, better than published approaches. This technique could be used to develop future telehealth solutions including smartphone-based applications which have potential to aid decision making and self-monitoring in asthma.

Pandemic-Related Impairment in the Monitoring of Patients With Hypertension and Diabetes and the Development of a Digital Solution for the Community Health Worker: Quasiexperimental and Implementation Study.

BACKGROUND: The restrictions imposed by the COVID-19 pandemic reduced health service access by patients with chronic diseases. The discontinuity of care is a cause of great concern, mainly in vulnerable regions. OBJECTIVE: This study aimed to assess the impact of the COVID-19 pandemic on people with hypertension and diabetes mellitus (DM) regarding the frequency of consultations and whether their disease was kept under control. The study also aimed to develop and implement a digital solution to improve monitoring at home. METHODS: This is a multimethodological study. A quasiexperimental evaluation assessed the impact of the pandemic on the frequency of consultations and control of patients with hypertension and DM in 34 primary health care centers in 10 municipalities. Then, an implementation study developed an app with a decision support system (DSS) for community health workers (CHWs) to identify and address at-risk patients with uncontrolled hypertension or DM. An expert panel assessment evaluated feasibility, usability, and utility of the software. RESULTS: Of 5070 patients, 4810 (94.87%) had hypertension, 1371 (27.04%) had DM, and 1111 (21.91%) had both diseases. There was a significant reduction in the weekly number of consultations (107, IQR 60.0-153.0 before vs 20.0, IQR 7.0-29.0 after social restriction; P<.001). Only 15.23% (772/5070) of all patients returned for a consultation during the pandemic. Individuals with hypertension had lower systolic (120.0, IQR 120.0-140.0 mm Hg) and diastolic (80.0, IQR 80.0-80.0 mm Hg) blood pressure than those who did not return (130.0, IQR 120.0-140.0 mm Hg and 80.0, IQR 80.0-90.0 mm Hg, respectively; P<.001). Also, those who returned had a higher proportion of controlled hypertension (64.3% vs 52.8%). For DM, there were no differences in glycohemoglobin levels. Concerning the DSS, the experts agreed that the CHWs can easily incorporate it into their routines and the app can identify patients at risk and improve treatment. CONCLUSIONS: The COVID-19 pandemic caused a significant drop in the number of consultations for patients with hypertension and DM in primary care. A DSS for CHW has proved to be feasible, useful, and easily incorporated into their routines.

Biomarker identification using dynamic time warping analysis: a longitudinal cohort study of patients with COVID-19 in a UK tertiary hospital.

OBJECTIVES: COVID-19 is a heterogeneous disease, and many reports have described variations in demographic, biochemical and clinical features at presentation influencing overall hospital mortality. However, there is little information regarding longitudinal changes in laboratory prognostic variables in relation to disease progression in hospitalised patients with COVID-19. DESIGN AND SETTING: This retrospective observational report describes disease progression from symptom onset, to admission to hospital, clinical response and discharge/death among patients with COVID-19 at a tertiary centre in South East England. PARTICIPANTS: Six hundred and fifty-one patients treated for SARS-CoV-2 between March and September 2020 were included in this analysis. Ethical approval was obtained from the HRA Specific Review Board (REC 20/HRA/2986) for waiver of informed consent. RESULTS: The majority of patients presented within 1 week of symptom onset. The lowest risk patients had low mortality (1/45, 2%), and most were discharged within 1 week after admission (30/45, 67%). The highest risk patients, as determined by the 4C mortality score predictor, had high mortality (27/29, 93%), with most dying within 1 week after admission (22/29, 76%). Consistent with previous reports, most patients presented with high levels of C reactive protein (CRP) (67% of patients >50 mg/L), D-dimer (98%>upper limit of normal (ULN)), ferritin (65%>ULN), lactate dehydrogenase (90%>ULN) and low lymphocyte counts (81%

Wave comparisons of clinical characteristics and outcomes of COVID-19 admissions - Exploring the impact of treatment and strain dynamics.

OBJECTIVES: Dexamethasone has now been incorporated into the standard of care for COVID-19 hospital patients. However, larger intensive care unit studies have failed to show discernible improvements in mortality in the recent wave. We aimed to investigate the impacts of these factors on disease outcomes in a UK hospital study. METHODS: This retrospective observational study reports patient characteristics, interventions and outcomes in COVID-19 patients from a UK teaching hospital; cohort 1, pre 16th June-2020 (pre-dexamethasone); cohort 2, 17th June to 30th November-2020 (post-dexamethasone, pre-VOC 202,012/01 as dominant strain); cohort 3, 1st December-2020 to 3rd March-2021 (during establishment of VOC202012/01 as the dominant strain). RESULTS: Dexamethasone treatment was more common in cohorts 2 and 3 (42.7% and 51.6%) compared with cohort 1 (2.5%). After adjusting for risk, odds of death within 28 days were 2-fold lower in cohort 2 vs 1 (OR:0.47,[0.27,0.79],p = 0.006). Mortality was higher cohort 3 vs 2 (20% vs 14%); but not significantly different to cohort 1 (OR: 0.86,[0.64, 1.15],p = 0.308). CONCLUSIONS: The real world finding of lower mortality following dexamethasone supports the published trial evidence and highlights ongoing need for research with introduction of new treatments and ongoing concern over new COVID-19 variants.

Secondary haemophagocytic lymphohistiocytosis in hospitalised COVID-19 patients as indicated by a modified HScore is infrequent and high scores do not associate with increased mortality.

A significant proportion of COVID-19 patients show evidence of hyperinflammation (HI), of which secondary haemophagocytic lymphohistiocytosis (sHLH) is the most severe manifestation and diagnosed with HScore. Using a COVID-relevant modification of the HScore (%HScore), we set out to determine the prevalence of sHLH in 567 COVID-19 inpatient cases.The overall incidence of individuals with an 80% probability of sHLH in our COVID-19 cohort was 1.59% on admission and only rose to 4.05% if calculated at any time during admission. This small cohort as defined by %HScore showed no excess mortality compared with the whole cohort. Overall, %HScores were lower in older patients (p<0.0001) and did not reliably predict outcome at any cut-off value (AUROC 0.533, p=0.211, odds ratio 0.99).Our study demonstrates that a modified version (%HScore) of the conventional sHLH scoring system (HScore) does not enable risk stratification in people hospitalised with COVID. We propose further work is needed to develop novel approaches to predict HI and improve trial stratification for HI directed therapy in people with COVID-19.

Evaluation and improvement of the National Early Warning Score (NEWS2) for COVID-19: a multi-hospital study.

BACKGROUND: The National Early Warning Score (NEWS2) is currently recommended in the UK for the risk stratification of COVID-19 patients, but little is known about its ability to detect severe cases. We aimed to evaluate NEWS2 for the prediction of severe COVID-19 outcome and identify and validate a set of blood and physiological parameters routinely collected at hospital admission to improve upon the use of NEWS2 alone for medium-term risk stratification. METHODS: Training cohorts comprised 1276 patients admitted to King's College Hospital National Health Service (NHS) Foundation Trust with COVID-19 disease from 1 March to 30 April 2020. External validation cohorts included 6237 patients from five UK NHS Trusts (Guy's and St Thomas' Hospitals, University Hospitals Southampton, University Hospitals Bristol and Weston NHS Foundation Trust, University College London Hospitals, University Hospitals Birmingham), one hospital in Norway (Oslo University Hospital), and two hospitals in Wuhan, China (Wuhan Sixth Hospital and Taikang Tongji Hospital). The outcome was severe COVID-19 disease (transfer to intensive care unit (ICU) or death) at 14 days after hospital admission. Age, physiological measures, blood biomarkers, sex, ethnicity, and comorbidities (hypertension, diabetes, cardiovascular, respiratory and kidney diseases) measured at hospital admission were considered in the models. RESULTS: A baseline model of 'NEWS2 + age' had poor-to-moderate discrimination for severe COVID-19 infection at 14 days (area under receiver operating characteristic curve (AUC) in training cohort = 0.700, 95% confidence interval (CI) 0.680, 0.722; Brier score = 0.192, 95% CI 0.186, 0.197). A supplemented model adding eight routinely collected blood and physiological parameters (supplemental oxygen flow rate, urea, age, oxygen saturation, C-reactive protein, estimated glomerular filtration rate, neutrophil count, neutrophil/lymphocyte ratio) improved discrimination (AUC = 0.735; 95% CI 0.715, 0.757), and these improvements were replicated across seven UK and non-UK sites. However, there was evidence of miscalibration with the model tending to underestimate risks in most sites. CONCLUSIONS: NEWS2 score had poor-to-moderate discrimination for medium-term COVID-19 outcome which raises questions about its use as a screening tool at hospital admission. Risk stratification was improved by including readily available blood and physiological parameters measured at hospital admission, but there was evidence of miscalibration in external sites. This highlights the need for a better understanding of the use of early warning scores for COVID.

Research Evaluation Alongside Clinical Treatment in COVID-19 (REACT COVID-19): an observational and biobanking study.

INTRODUCTION: The COVID-19 pandemic caused by SARS-CoV-2 places immense worldwide demand on healthcare services. Earlier identification of patients at risk of severe disease may allow intervention with experimental targeted treatments, mitigating the course of their disease and reducing critical care service demand. METHODS AND ANALYSIS: This prospective observational study of patients tested or treated for SARS-CoV-2, who are under the care of the tertiary University Hospital Southampton NHS Foundation Trust (UHSFT), captured data from admission to discharge; data collection commenced on 7 March 2020. Core demographic and clinical information, as well as results of disease-defining characteristics, was captured and recorded electronically from hospital clinical record systems at the point of testing. Manual data were collected and recorded by the clinical research team for assessments which are not part of the structured electronic healthcare record, for example, symptom onset date. Thereafter, participant records were continuously updated during hospital stay and their follow-up period. Participants aged >16 years were given the opportunity to provide consent for excess clinical sample storage with optional further biological sampling. These anonymised samples were linked to the clinical data in the Real-time Analytics for Clinical Trials platform and were stored within a biorepository at UHSFT. ETHICS AND DISSEMINATION: Ethical approval was obtained from the HRA Specific Review Board (REC 20/HRA/2986) for waiver of informed consent for the database-only cohort; the procedures conform with the Declaration of Helsinki. The study design, protocol and patient-facing documentation for the biobanking arm of the study have been approved by North West Research Ethics Committee (REC 17/NW/0632) as an amendment to the National Institute for Health Research Southampton Clinical Research Facility-managed Southampton Research Biorepository. This study will be published as peer-reviewed articles and presented at conferences, presentations and workshops.

Nebulised surfactant for the treatment of severe COVID-19 in adults (COV-Surf): A structured summary of a study protocol for a randomized controlled trial.

OBJECTIVES: SARS-Cov-2 virus preferentially binds to the Angiotensin Converting Enzyme 2 (ACE2) on alveolar epithelial type II cells, initiating an inflammatory response and tissue damage which may impair surfactant synthesis contributing to alveolar collapse, worsening hypoxia and leading to respiratory failure. The objective of this study is to evaluate the feasibility, safety and efficacy of nebulised surfactant in COVID-19 adult patients requiring mechanical ventilation for respiratory failure. TRIAL DESIGN: This study is a dose-escalating randomized open-label clinical trial of 20 COVID-19 patients. PARTICIPANTS: This study is conducted in two centres: University Hospital Southampton and University College London Hospitals. Eligible participants are aged ≥18, hospitalised with COVID-19 (confirmed by PCR), who require endotracheal intubation and are enrolled within 24 hours of mechanical ventilation. For patients unable to consent, assent is obtained from a personal legal representative (PerLR) or professional legal representative (ProfLR) prior to enrolment. The following are exclusion criteria: imminent expected death within 24 hours; specific contraindications to surfactant administration (e.g. known allergy, pneumothorax, pulmonary hemorrhage); known or suspected pregnancy; stage 4 chronic kidney disease or requiring dialysis (i.e., eGFR < 30); liver failure (Child-Pugh Class C); anticipated transfer to another hospital, which is not a study site, within 72 hours; current or recent (within 1 month) participation in another study that, in the opinion of the investigator, would prevent enrollment for safety reasons; and declined consent or assent. INTERVENTION AND COMPARATOR: Intervention: The study is based on an investigational drug/device combination product. The surfactant product is Bovactant (Alveofact®), a natural animal derived (bovine) lung surfactant formulated as a lyophilized powder in 108 mg vials and reconstituted to 45 mg/mL in buffer supplied in a prefilled syringe. It is isolated by lung lavage and, by weight, is a mixture of: phospholipid (75% phosphatidylcholine, 13% phosphatidylglycerol, 3% phosphatidylethanolamine, 1% phosphatidylinositol and 1% sphingomyelin), 5% cholesterol, 1% lipid-soluble surfactant-associated proteins (SP-B and SP-C), very low levels of free fatty acid, lyso-phosphatidylcholine, water and 0.3% calcium. The Drug Delivery Device is the AeroFact-COVID™ nebulizer, an investigational device based on the Aerogen® Solo vibrating mesh nebulizer. The timing and escalation dosing plans for the surfactant are as follows. Cohort 1: Three patients will receive 10 vials (1080 mg) each of surfactant at dosing times of 0 hours, 8 hours and 24 hours. 2 controls with no placebo intervention. Cohort 2: Three patients will receive 10 vials (1080 mg) of surfactant at dosing times of 0 hours and 8 hours, and 30 vials (3240 mg) at a dosing time of 24 hours. 2 controls with no placebo intervention. Cohort 3: Three patients will receive 10 vials (1080 mg) of surfactant at a dosing time of 0 hours, and 30 vials (3240 mg) at dosing times of 8 hours and 24 hours. 2 controls with no placebo intervention. Cohort 4: Three patients will receive 30 (3240 mg) vials each of surfactant at dosing times of 0 hours, 8 hours and 24 hours. 2 controls. 2 controls with no placebo intervention. The trial steering committee, advised by the data monitoring committee, will review trial progression and dose escalation/maintenance/reduction after each cohort is completed (48-hour primary outcome timepoint reached) based on available feasibility, adverse event, safety and efficacy data. The trial will not be discontinued on the basis of lack of efficacy. The trial may be stopped early on the basis of safety or feasibility concerns. Comparator: No placebo intervention. All participants will receive usual standard of care in accordance with the local policies for mechanically ventilated patients and all other treatments will be left to the discretion of the attending physician. MAIN OUTCOMES: The co-primary outcome is the improvement in oxygenation (PaO2/FiO2 ratio) and pulmonary ventilation (Ventilation Index (VI), where VI = [RR x (PIP - PEEP) × PaCO2]/1000) at 48 hours after study initiation. The secondary outcomes include frequency and severity of adverse events (AEs), Adverse Device Effects (ADEs), Serious Adverse Events (SAEs) and Serious Adverse Device Events (SADEs), change in pulmonary compliance, change in positive end-expiratory pressure (PEEP) requirement of ventilatory support at 24 and 48 hours after study initiation, clinical improvement defined by time to one improvement point on the ordinal scale described in the WHO master protocol (2020) recorded while hospitalised, days of mechanical ventilation, mechanical ventilator free days (VFD) at day 21, length of intensive care unit stay, number of days hospitalised and mortality at day 28. Exploratory end points will include quantification of SARS-CoV-2 viral load from tracheal aspirates using PCR, surfactant dynamics (synthesis and turnover) and function (surface tension reduction) from deep tracheal aspirate samples (DTAS), surfactant phospholipid concentrations in plasma and DTAS, inflammatory markers (cellular and cytokine) in plasma and DTAS, and blood oxidative stress markers. RANDOMISATION: After informed assent, patients fulfilling inclusion criteria will be randomised to 3:2 for the treatment and control arms using an internet-based block randomization service (ALEA tool for clinical trials, FormsVision BV) in combination with electronic data collection. Randomisation will be done by the recruiting centre with a unique subject identifier specific to that centre. BLINDING (MASKING): This is an open-labelled unblinded study. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): The total sample size is 20 COVID-19 mechanically ventilated patients (12 intervention; 8 control). TRIAL STATUS: Current protocol version is V2 dated 5th of June 2020. The recruitment is currently ongoing and started on the 14th of October 2020. The anticipated study completion date is November 2021. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04362059 (Registered 24 April 2020), EUDAMED number: CIV-GB-20-06-033328, EudraCT number: 2020-001886-35 (Registered 11 May 2020) FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).

The allocation of USdollar;105 billion in global funding from G20 countries for infectious disease research between 2000 and 2017: a content analysis of investments.

BACKGROUND: Each year, billions of US$ are spent globally on infectious disease research and development. However, there is little systematic tracking of global research and development. We present research on investments into infectious diseases research from funders in the G20 countries across an 18-year time period spanning 2000-17, comparing amounts invested for different conditions and considering the global burden of disease to identify potential areas of relative underfunding. METHODS: The study examined research awards made between 2000 and 2017 for infectious disease research from G20-based public and philanthropic funders. We searched research databases using a range of keywords, and open access data were extracted from funder websites. Awards were categorised by type of science, specialty, and disease or pathogen. Data collected included study title, abstract, award amount, funder, and year. We used descriptive statistics and Spearman's correlation coefficient to investigate the association between research investment and disease burden, using Global Burden of Disease 2017 study data. FINDINGS: The final 2000-17 dataset included 94 074 awards for infectious disease research, with a sum investment of $104·9 billion (annual range 4·1 billion to 8·4 billion) and a median award size of $257 176 (IQR 62 562-770 661). Pre-clinical research received $61·1 billion (58·2%) across 70 337 (74·8%) awards and public health research received $29·5 billion (28·1%) from 19 197 (20·4%) awards. HIV/AIDS received $42·1 billion (40·1%), tuberculosis received $7·0 billion (6·7%), malaria received $5·6 billion (5·3%), and pneumonia received $3·5 billion (3·3%). Funding for Ebola virus ($1·2 billion), Zika virus ($0·3 billion), influenza ($4·4 billion), and coronavirus ($0·5 billion) was typically highest soon after a high-profile outbreak. There was a general increase in year-on-year investment in infectious disease research between 2000 and 2006, with a decline between 2007 and 2017. Funders based in the USA provided $81·6 billion (77·8%). Based on funding per 2017 disability-adjusted life years (DALYs), HIV/AIDS received the greatest relative investment ($772 per DALY), compared with tuberculosis ($156 per DALY), malaria ($125 per DALY), and pneumonia ($33 per DALY). Syphilis and scabies received the least relative investment (both $9 per DALY). We observed weak positive correlation (r=0·30) between investment and 2017 disease burden. INTERPRETATION: HIV research received the highest amount of investment relative to DALY burden. Scabies and syphilis received the lowest relative funding. Investments for high-threat pathogens (eg, Ebola virus and coronavirus) were often reactive and followed outbreaks. We found little evidence that funding is proactively guided by global burden or pandemic risk. Our findings show how research investments are allocated and how this relates to disease burden and diseases with pandemic potential. FUNDING: Bill & Melinda Gates Foundation.

Automated data cleaning of paediatric anthropometric data from longitudinal electronic health records: protocol and application to a large patient cohort.

'Big data' in healthcare encompass measurements collated from multiple sources with various degrees of data quality. These data require quality control assessment to optimise quality for clinical management and for robust large-scale data analysis in healthcare research. Height and weight data represent one of the most abundantly recorded health statistics. The shift to electronic recording of anthropometric measurements in electronic healthcare records, has rapidly inflated the number of measurements. WHO guidelines inform removal of population-based extreme outliers but an absence of tools limits cleaning of longitudinal anthropometric measurements. We developed and optimised a protocol for cleaning paediatric height and weight data that incorporates outlier detection using robust linear regression methodology using a manually curated set of 6,279 patients' longitudinal measurements. The protocol was then applied to a cohort of 200,000 patient records collected from 60,000 paediatric patients attending a regional teaching hospital in South England. WHO guidelines detected biologically implausible data in <1% of records. Additional error rates of 3% and 0.2% for height and weight respectively were detected using the protocol. Inflated error rates for height measurements were largely due to small but physiologically implausible decreases in height. Lowest error rates were observed when data was measured and digitally recorded by staff routinely required to do so. The protocol successfully automates the parsing of implausible and poor quality height and weight data from a voluminous longitudinal dataset and standardises the quality assessment of data for clinical and research applications.

Pneumonia in Ghana-a need to raise the profile.

Despite the high mortality, pneumonia retains a relatively low profile among researchers, funders and policymakers. Here we reflect on the problems and priorities of pneumonia in Ghana, briefly review the evidence base and reflect upon in-person discussions between Southampton-based authors MGH and JB and academic, clinical and policy colleagues in Ghana. The discussions took place in Accra in August 2017.

Establishing the characteristics for patients with chronic Complex Regional Pain Syndrome: the value of the CRPS-UK Registry.

OBJECTIVE: The long-term prognosis of patients with Complex Regional Pain Syndrome (CRPS) is unknown with no reported prospective studies from the United Kingdom longer than 18 months. The CRPS-UK Network aims to study this by use of a Registry. The aims of this article are, to outline the CRPS-UK Registry, assess the validity of the data and to describe the characteristics of a sample of the UK CRPS population. METHODS: A web-based CRPS-UK Registry was developed and made accessible to centres experienced in diagnosing and managing patients with CRPS. Pragmatic annual follow-up questions were agreed. RESULTS: Up until July 2013, the Registry has recruited 240 patients. A blinded, validation study of 20 consecutive patients from two centres (10 each) demonstrated 95.6% completion and 99.4% accuracy of a random sample of the recorded data. These patients had chronic disease (median duration: 29 months); 72.5% were female (2.6:1), with a mean age at symptoms onset of 43 years, and were left-handed more than expected (21.8% versus 10% in the general population). Patients reported a delayed diagnosis, with the median time between symptom onset and diagnosis of 6 months. In all, 30 patients (12.5%) had multiple limb involvement and (83.3%) had a contiguous spread of CRPS. CONCLUSION: CRPS-UK Registry is a validated method for actively recruiting well-characterised patients with CRPS to provide further information on the long-term outcome.

Determination of trace metals in drinking water using solid-phase extraction disks and X-ray fluorescence spectrometry.

A convenient method is described for monitoring Cd, Ni, Cu, and Pb at trace levels in drinking water samples. These metals are preconcentrated on a chelating solid-phase extraction disk and then determined by X-ray fluorescence spectrometry. The method tolerates a wide pH range (pH 6-14) and a large amount of alkaline and alkaline earth elements. The preconcentration factor is well over 1600, assuming a 1 L water sample volume. The limits of detection for Cd, Ni, Cu, and Pb are 3.8, 0.6, 0.4, and 0.3 ng/mL, respectively. These are well below the federal maximum contaminant level values, which are 5, 100, 1300, and 15 ng/mL, respectively. The proposed method has many advantages including ease of operation, multielement capability, nondestructiveness, high sensitivity, and relative cost efficiency. The solid-phase extraction step can be conducted in the field and then the disks can be mailed to a laboratory for the analysis, eliminating the cost of transporting large volumes of water samples. Furthermore, the color of the used extraction disk provides an initial estimate of the degree of contamination for some transition metals (for example, Ni and Cu). Thus, the overall cost for analysis of metals in drinking water can be minimized by implementing the method, and small water supply companies with limited budgets will be better able to comply with the Safe Drinking Water Act.