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Reduction in length of stay of patients admitted to a regional burn centre during COVID-19 pandemic.
No full textTreating age-related multimorbidity: the drug discovery challenge.
No full textPatients with multimorbidities have shorter life expectancy and their clinical management is more complex and expensive for healthcare systems currently focused on treating single diseases. Given that age is the major risk factor for multimorbidity, the challenge of treating these patients will only increase in coming years. Here, we review the case for targeting the core processes that drive the ageing phenotype as a novel pharmaceutical approach to multimorbidity. There is growing evidence that targeting ageing mechanisms can reduce or delay age-related diseases in animal models, and the first reports of clinical trials are now appearing. Although these trials currently focus on repurposed drugs, we propose several novel targets that would more specifically target ageing processes and thereby reduce multimorbidity and polypharmacy in future generations
Renewed KIDS SAVE LIVES campaign to further increase awareness and fight sudden cardiac death in the era of Covid-19.
No full textPushing the limits in DCD donor selection: optimizing graft rehabilitation with ex vivo machine perfusion.
No full textBACKGROUND
The use of liver grafts from donors after circulatory death (DCD) is associated with an increased risk of developing severe transplant-related complications. However, a balanced evaluation of risks calculated on both donor's and recipient's specific medical history, may reduce the incidence of post-operative complications avoiding a futile transplant.
METHODS
We report a case wherein we transplanted a patient with hepatocellular carcinoma (HCC) outside Milan criteria using a borderline DCD graft. The decision to accept the offered DCD liver was difficult given the extent of injury from severe abdominal trauma, initial blood tests (AST 1782 U/I, ALT 1803 U/I, CPK 12931 mg/dl on procurement day) and technical complexity of Normothermic Regional Perfusion (NRP) due to the amputation of the left lower limb and multiple pelvic fractures. Liver biopsy showed 0% of macro-steatosis and 30% necrosis. We applied our standardized protocol of sequential NRP during graft procurement followed by D-HOPE machine perfusion prior implantation.
RESULTS
The graft underwent 130 minutes of cold storage and 192 minutes of D-HOPE machine perfusion before being transplanted and total ischemia time was of 261 minutes. After eleven months, the patient is in good general conditions, no signs of HCC recurrence, AFP 2,7 ng/ml.
CONCLUSIONS
The evaluation of the donor should always be based on both pre- and intra-procurement data, taking into-account lactate and transaminase trend during ECMO, liver perfusion and macroscopic appearance of the organ. The use of this grafts may result in a curative chance for patients that demonstrated a favorable HCC biology by pushing the limits of both organ and recipient selection
How to determine if a treatment works for some people but not for others?: Testing for sub-group effects.
No full textQuantitative IFN-γ Release Assay and Tuberculin Skin Test Results to Predict Incident Tuberculosis. A Prospective Cohort Study.
No full textDevelopment of diagnostic tools with improved predictive value for tuberculosis (TB) is a global research priority. We evaluated whether implementing higher diagnostic thresholds than currently recommended for QuantiFERON Gold-in-Tube (QFT-GIT), T-SPOT.TB, and the tuberculin skin test (TST) might improve prediction of incident TB. Follow-up of a UK cohort of 9,610 adult TB contacts and recent migrants was extended by relinkage to national TB surveillance records (median follow-up 4.7 yr). Incidence rates and rate ratios, sensitivities, specificities, and predictive values for incident TB were calculated according to ordinal strata for quantitative results of QFT-GIT, T-SPOT.TB, and TST (with adjustment for prior bacillus Calmette-Guérin [BCG] vaccination). For all tests, incidence rates and rate ratios increased with the magnitude of the test result ( < 0.0001). Over 3 years' follow-up, there was a modest increase in positive predictive value with the higher thresholds (3.0% for QFT-GIT ≥0.35 IU/ml vs. 3.6% for ≥4.00 IU/ml; 3.4% for T-SPOT.TB ≥5 spots vs. 5.0% for ≥50 spots; and 3.1% for BCG-adjusted TST ≥5 mm vs. 4.3% for ≥15 mm). As thresholds increased, sensitivity to detect incident TB waned for all tests (61.0% for QFT-GIT ≥0.35 IU/ml vs. 23.2% for ≥4.00 IU/ml; 65.4% for T-SPOT.TB ≥5 spots vs. 27.2% for ≥50 spots; 69.7% for BCG-adjusted TST ≥5 mm vs. 28.1% for ≥15 mm). Implementation of higher thresholds for QFT-GIT, T-SPOT.TB, and TST modestly increases positive predictive value for incident TB, but markedly reduces sensitivity. Novel biomarkers or validated multivariable risk algorithms are required to improve prediction of incident TB
Three-dimensional versus two-dimensional imaging during laparoscopic cholecystectomy: a systematic review and meta-analysis of randomised controlled trials.
No full textOBJECTIVES
To evaluate the comparative outcomes of three-dimensional (3D) versus two-dimensional (2D) imaging during laparoscopic cholecystectomy.
METHODS
We conducted a systematic search of electronic information sources and bibliographic reference lists and applied a combination of free text and controlled vocabulary search adapted to thesaurus headings, search operators and limits. Procedure time, Calot's triangle dissection time, gallbladder removal time, gallbladder perforation, intraoperative bleeding, postoperative complications, conversion to open and intraoperative errors were the evaluated outcome parameters.
RESULTS
We identified 6 randomised controlled trials (RCT) reporting a total of 577 patients who underwent laparoscopic cholecystectomy using 3D (n = 282) or 2D (n = 295) imaging. The 3D imaging was associated with significantly shorter procedure time (MD - 4.23, 95% CI - 8.14 to - 0.32, p = 0.03), Calot's triangle dissection time (MD - 4.19, 95% CI - 6.52 to - 1.86, p = 0.0004) and significantly lower risk of gallbladder perforation (RR 0.50, 95% CI 0.28-0.88, p = 0.02) compared to the 2D approach. No significant difference was found in gallbladder removal time (MD - 0.79, 95% CI - 2.24 to 0.66, p = 0.28), intraoperative bleeding (RR 1.14, 95% CI 0.68-1.90, p = 0.61), postoperative complications (RD - 0.01, 95% CI - 0.06 to 0.05, p = 0.85), conversion to open (RD 0.00, 95% CI - 0.02 to 0.03, p = 0.70) or intraoperative errors (RR 0.96, 95% CI 0.79-1.17, p = 0.70) between the two groups.
CONCLUSIONS
Although our findings suggest that the use of 3D imaging during laparoscopic cholecystectomy may be associated with significantly shorter procedure time, Calot's triangle dissection time and gallbladder injury compared to the 2D imaging, the differences seem to be clinically insignificant. Moreover, both approaches carry s similar risk of postoperative morbidities. The impact of the surgeon's level of experience and difficulty of the procedure on the outcomes of each imaging modality remains unknown
Signs and symptoms to determine if a patient presenting in primary care or hospital outpatient settings has COVID-19 disease.
No full textBACKGROUND
Some people with SARS-CoV-2 infection remain asymptomatic, whilst in others the infection can cause mild to moderate COVID-19 disease and COVID-19 pneumonia, leading some patients to require intensive care support and, in some cases, to death, especially in older adults. Symptoms such as fever or cough, and signs such as oxygen saturation or lung auscultation findings, are the first and most readily available diagnostic information. Such information could be used to either rule out COVID-19 disease, or select patients for further diagnostic testing.
OBJECTIVES
To assess the diagnostic accuracy of signs and symptoms to determine if a person presenting in primary care or to hospital outpatient settings, such as the emergency department or dedicated COVID-19 clinics, has COVID-19 disease or COVID-19 pneumonia.
SEARCH METHODS
On 27 April 2020, we undertook electronic searches in the Cochrane COVID-19 Study Register and the University of Bern living search database, which is updated daily with published articles from PubMed and Embase and with preprints from medRxiv and bioRxiv. In addition, we checked repositories of COVID-19 publications. We did not apply any language restrictions.
SELECTION CRITERIA
Studies were eligible if they included patients with suspected COVID-19 disease, or if they recruited known cases with COVID-19 disease and controls without COVID-19. Studies were eligible when they recruited patients presenting to primary care or hospital outpatient settings. Studies including patients who contracted SARS-CoV-2 infection while admitted to hospital were not eligible. The minimum eligible sample size of studies was 10 participants. All signs and symptoms were eligible for this review, including individual signs and symptoms or combinations. We accepted a range of reference standards including reverse transcription polymerase chain reaction (RT-PCR), clinical expertise, imaging, serology tests and World Health Organization (WHO) or other definitions of COVID-19.
DATA COLLECTION AND ANALYSIS
Pairs of review authors independently selected all studies, at both title and abstract stage and full-text stage. They resolved any disagreements by discussion with a third review author. Two review authors independently extracted data and resolved disagreements by discussion with a third review author. Two review authors independently assessed risk of bias using the QUADAS-2 checklist. Analyses were descriptive, presenting sensitivity and specificity in paired forest plots, in ROC (receiver operating characteristic) space and in dumbbell plots. We did not attempt meta-analysis due to the small number of studies, heterogeneity across studies and the high risk of bias.
MAIN RESULTS
We identified 16 studies including 7706 participants in total. Prevalence of COVID-19 disease varied from 5% to 38% with a median of 17%. There were no studies from primary care settings, although we did find seven studies in outpatient clinics (2172 participants), and four studies in the emergency department (1401 participants). We found data on 27 signs and symptoms, which fall into four different categories: systemic, respiratory, gastrointestinal and cardiovascular. No studies assessed combinations of different signs and symptoms and results were highly variable across studies. Most had very low sensitivity and high specificity; only six symptoms had a sensitivity of at least 50% in at least one study: cough, sore throat, fever, myalgia or arthralgia, fatigue, and headache. Of these, fever, myalgia or arthralgia, fatigue, and headache could be considered red flags (defined as having a positive likelihood ratio of at least 5) for COVID-19 as their specificity was above 90%, meaning that they substantially increase the likelihood of COVID-19 disease when present. Seven studies carried a high risk of bias for selection of participants because inclusion in the studies depended on the applicable testing and referral protocols, which included many of the signs and symptoms under study in this review. Five studies only included participants with pneumonia on imaging, suggesting that this is a highly selected population. In an additional four studies, we were unable to assess the risk for selection bias. These factors make it very difficult to determine the diagnostic properties of these signs and symptoms from the included studies. We also had concerns about the applicability of these results, since most studies included participants who were already admitted to hospital or presenting to hospital settings. This makes these findings less applicable to people presenting to primary care, who may have less severe illness and a lower prevalence of COVID-19 disease. None of the studies included any data on children, and only one focused specifically on older adults. We hope that future updates of this review will be able to provide more information about the diagnostic properties of signs and symptoms in different settings and age groups.
AUTHORS' CONCLUSIONS
The individual signs and symptoms included in this review appear to have very poor diagnostic properties, although this should be interpreted in the context of selection bias and heterogeneity between studies. Based on currently available data, neither absence nor presence of signs or symptoms are accurate enough to rule in or rule out disease. Prospective studies in an unselected population presenting to primary care or hospital outpatient settings, examining combinations of signs and symptoms to evaluate the syndromic presentation of COVID-19 disease, are urgently needed. Results from such studies could inform subsequent management decisions such as self-isolation or selecting patients for further diagnostic testing. We also need data on potentially more specific symptoms such as loss of sense of smell. Studies in older adults are especially important
Relationship of CT densitometry to lung physiological parameters and health status in alpha-1 antitrypsin deficiency: initial report of a centralised database of the NIHR rare diseases translational research collaborative.
No full textOBJECTIVES
To establish a database network for the study of alpha-1 antitrypsin deficiency (AATD) and compare the results to CT lung density as the most direct measure of emphysema.
DESIGN
A central electronic database was established to permit the upload of anonymised patient data from remote sites. Prospectively collected CT data were recorded onto disc, anonymised, analysed at the coordinating centre and compared with the clinical features of the disease.
SETTING
Tertiary referral centres with expertise in the management of AATD focused on academic Biomedical Research Units and Wellcome Clinical Research Facilities.
PARTICIPANTS
Data were collected from 187 patients over 1 year from eight UK academic sites. This included patient demographics, postbronchodilator physiology, health status and CT. Analysis was undertaken at the coordinating centre in Birmingham.
RESULTS
Patient recruitment in the 12 months reached 94% of target (set at 200) covering the whole spectrum of the disease from those with normal lung function to very severe chronic obstructive lung disease. CT scan suitable for analysis was available from 147 (79%) of the patients. CT density, analysed as the threshold for the lowest 15% of lung voxels, showed statistically significant relationships with the objective physiological parameters of lung function as determined by spirometric Global Initiative for Chronic Obstructive Lung Disease (GOLD) severity staging (p<0.001) and carbon monoxide gas transfer (p<0.01). Density also correlated with subjective measures of quality of life (p=0.02).
CONCLUSIONS
Establishment of the network for data collection and its transfer was highly successful facilitating future collaboration for the study of this rare disease and its management. CT densitometry correlated well with the objective clinical features of the disease supporting its role as the specific marker of the associated emphysema and its severity. Correlations with subjective measures of health, however, were generally weak indicating other factors play a role
The A-ring reduction of 11-ketotestosterone is efficiently catalysed by AKR1D1 and SRD5A2 but not SRD5A1.
No full textTestosterone and its 5α-reduced form, 5α-dihydrotestosterone, were previously thought to represent the only active androgens in humans. However, recent studies have shown that the potent androgen, 11-ketotestosterone, derived from the adrenal androgen precursor, 11β-hydroxyandrostenedione, may in fact serve as the primary androgen in healthy women. Yet, despite recent renewed interest in these steroids, their downstream metabolism has remained undetermined. We therefore set out to investigate the metabolism of 11-ketotestosterone by characterising the 5α- or 5β-reduction commitment step. We show that inactivation of 11-ketotestosterone is predominantly driven by AKR1D1, which efficiently catalyses the 5β-reduction of 11-ketotestosterone, committing it to a metabolic pathway that terminates in 11-ketoetiocholanolone. We demonstrate that 5α-reduction of 11-ketotestosterone is catalysed by SRD5A2, but not SRD5A1, and terminates in 11-ketoandrosterone, but is only responsible for a minority of 11-ketotestosterone inactivation. However, as 11-ketoetiocholanolone is also generated by the metabolism of the glucocorticoid cortisone, 11-ketoandrosterone should be considered a more specific urinary marker of 11-ketotestosterone production