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Exploratory cost-effectiveness model of electromagnetic navigation bronchoscopy (ENB) compared with CT-guided biopsy (TTNA) for diagnosis of malignant indeterminate peripheral pulmonary nodules.
No full textINTRODUCTION
Lung cancer is accountable for 35 000 deaths annually, and prognosis is improved when the cancer is diagnosed early. CT-guided biopsy (transthoracic needle aspiration, TTNA) and electromagnetic navigation bronchoscopy (ENB) can be used to investigate indeterminate pulmonary nodules if the patient is unfit for surgery. However, there is a paucity of clinical and health economic evidence that directly compares ENB with TTNA in this population group. This cost-effectiveness study aimed to explore potential scenarios whereby ENB may be considered cost-effective when compared with TTNA.
METHODS
A cohort decision analytic model was developed using a UK National Health Service perspective. ENB was assumed to have equal sensitivity to TTNA at 82%. Lifetime costs and quality-adjusted life-year (QALY) gain were calculated to estimate the net monetary benefit at a £20 000 per QALY threshold. Sensitivity analyses were used to explore scenarios where ENB could be considered a cost-effective intervention.
RESULTS
Under the assumption that ENB has equal efficacy to TTNA, ENB was found to be dominant (less costly and more effective) when compared with TTNA, due to having a reduced risk and cost of adverse events. This conclusion was most sensitive to changes in the cost of intervention, estimates of effectiveness and adverse event rates.
DISCUSSION
ENB is expected to be cost-effective when the likelihood of an accurate diagnosis is equal to (or better than) TTNA, which may occur in certain subgroups of patients in whom TTNA is unlikely to accurately diagnose malignancy or when an experienced practitioner achieves a high accuracy with ENB
Hypothermic oxygenated perfusion protects from mitochondrial injury before liver transplantation.
No full textBACKGROUND
Mitochondrial succinate accumulation has been suggested as key event for ischemia reperfusion injury in mice. No specific data are however available on behavior of liver mitochondria during ex situ machine perfusion in clinical transplant models.
METHODS
We investigated mitochondrial metabolism of isolated perfused rat livers before transplantation. Livers were exposed to warm and cold ischemia to simulate donation after circulatory death (DCD) and organ transport. Subsequently, livers were perfused with oxygenated Belzer-MPS for 1h, at hypothermic or normothermic conditions. Various experiments were performed with supplemented succinate and/or mitochondrial inhibitors. The perfusate, liver tissues, and isolated mitochondria were analyzed by mass-spectroscopy and fluorimetry. Additionally, rat DCD livers were transplanted after 1h hypothermic or normothermic oxygenated perfusion. In parallel, perfusate samples were analysed during HOPE-treatment of human DCD livers before transplantation.
FINDINGS
Succinate exposure during rat liver perfusion triggered a dose-dependent release of mitochondrial Flavin-Mononucleotide (FMN) and NADH in perfusates under normothermic conditions. In contrast, perfusate FMN was 3-8 fold lower under hypothermic conditions, suggesting less mitochondrial injury during cold re-oxygenation compared to normothermic conditions. HOPE-treatment induced a mitochondrial reprogramming with uploading of the nucleotide pool and effective succinate metabolism. This resulted in a clear superiority after liver transplantation compared to normothermic perfusion. Finally, the degree of mitochondrial injury during HOPE of human DCD livers, quantified by perfusate FMN and NADH, was predictive for liver function.
INTERPRETATION
Mitochondrial injury determines outcome of transplanted rodent and human livers. Hypothermic oxygenated perfusion improves mitochondrial function, and allows viability assessment of liver grafts before implantation.
FUNDING
detailed information can be found in Acknowledgments
Developing specific reporting guidelines for diagnostic accuracy studies assessing AI interventions: The STARD-AI Steering Group.
No full textHartmann's procedure versus Intersphincteric APE (HiP Study):A Multicentre Prospective Cohort Study.
No full textINTRODUCTION
In patients with low rectal cancer, it is occasionally necessary to avoid a low colo-anal anastomosis due to patient frailty or poor function. In such situations there are two alternative approaches: Hartmann's procedure [HP] or intersphincteric APE [IAPE]. There are little data to guide surgeons as to which of these two procedures is the safest. The aim of this study was to determine the surgical complication rates associated with each procedure.
METHODS
This was a multicentre, non-randomised prospective cohort study of patients undergoing either HP or IAPE. The primary objective was to determine surgical complication rates. Secondary objectives included length of stay, time to adjuvant therapy and quality of life at 90 days.
RESULTS
179 patients were recruited between April 2016 and June 2019; approximately two thirds of patients underwent HP and one third IAPE. The overall complication rate was high in both groups: 54% [HP], 52% [IAPE]. Surgery specific complication rates were also high, but not significantly different: 43% [HP], 48% [IAPE]. The pelvic abscess rate in HP was 11% and was significantly higher in patients with a palpable staple line (15% vs 2%). There was a higher incidence of serious medical complications following IAPE[16% vs 5%], along with a reduction in 90-day QoL scores.
CONCLUSIONS
This is the largest prospective study comparingHP and IAPE in patients undergoing rectal cancer surgery where primary anastomosis is not deemed appropriate. With similar complication rates, these data support the ongoing use of either HP or IAPE in this patient group
A Timely Oral Option: Single Agent Vinorelbine in Desmoid Tumours.
No full textINTRODUCTION
Desmoid tumours (DT) are rare collagen-forming tumours which can exhibit locally aggressive patterns of behaviour. The aim of this study was to evaluate the efficacy and safety of treatment of DT with single agent oral vinorelbine.
METHODS
A retrospective review of patients treated with vinorelbine 90mg orally on Days 1, 8 and 15 of a 28-day cycle from January 2004-July 2019 was performed. Response was assessed using Response Evaluation Criteria in Solid Tumours version 1.1. Descriptive statistics were employed.
RESULTS
29 patients were included. Response rate was 20.7% (6/29) and clinical benefit rate (response by RECIST 1.1 and/or clinical symptom improvement) was 65.5% (19/29).. No patient experienced grade 3 or above toxicity. Common toxicities were grade 1-2 nausea (14/26, 48.3%), fatigue (9/26, 31.0%) and diarrhoea (4/26, 13.8%).
CONCLUSION
Single agent oral vinorelbine is an effective, safe and well tolerated treatment for DT. It represents a new oral alternative for management of DT
SARS-CoV-2 seroprevalence and asymptomatic viral carriage in healthcare workers: a cross-sectional study.
No full textOBJECTIVE
To determine the rates of asymptomatic viral carriage and seroprevalence of SARS-CoV-2 antibodies in healthcare workers.
DESIGN
A cross-sectional study of asymptomatic healthcare workers undertaken on 24/25 April 2020.
SETTING
University Hospitals Birmingham NHS Foundation Trust (UHBFT), UK.
PARTICIPANTS
545 asymptomatic healthcare workers were recruited while at work. Participants were invited to participate via the UHBFT social media. Exclusion criteria included current symptoms consistent with COVID-19. No potential participants were excluded.
INTERVENTION
Participants volunteered a nasopharyngeal swab and a venous blood sample that were tested for SARS-CoV-2 RNA and anti-SARS-CoV-2 spike glycoprotein antibodies, respectively. Results were interpreted in the context of prior illnesses and the hospital departments in which participants worked.
MAIN OUTCOME MEASURE
Proportion of participants demonstrating infection and positive SARS-CoV-2 serology.
RESULTS
The point prevalence of SARS-CoV-2 viral carriage was 2.4% (n=13/545). The overall seroprevalence of SARS-CoV-2 antibodies was 24.4% (n=126/516). Participants who reported prior symptomatic illness had higher seroprevalence (37.5% vs 17.1%, χ=21.1034, p<0.0001) and quantitatively greater antibody responses than those who had remained asymptomatic. Seroprevalence was greatest among those working in housekeeping (34.5%), acute medicine (33.3%) and general internal medicine (30.3%), with lower rates observed in participants working in intensive care (14.8%). BAME (Black, Asian and minority ethnic) ethnicity was associated with a significantly increased risk of seropositivity (OR: 1.92, 95% CI 1.14 to 3.23, p=0.01). Working on the intensive care unit was associated with a significantly lower risk of seropositivity compared with working in other areas of the hospital (OR: 0.28, 95% CI 0.09 to 0.78, p=0.02).
CONCLUSIONS AND RELEVANCE
We identify differences in the occupational risk of exposure to SARS-CoV-2 between hospital departments and confirm asymptomatic seroconversion occurs in healthcare workers. Further investigation of these observations is required to inform future infection control and occupational health practices
Composite type-2 biomarker strategy versus a symptom-risk-based algorithm to adjust corticosteroid dose in patients with severe asthma: a multicentre, single-blind, parallel group, randomised controlled trial.
No full textBACKGROUND
Asthma treatment guidelines recommend increasing corticosteroid dose to control symptoms and reduce exacerbations. This approach is potentially flawed because symptomatic asthma can occur without corticosteroid responsive type-2 (T2)-driven eosinophilic inflammation, and inappropriately high-dose corticosteroid treatment might have little therapeutic benefit with increased risk of side-effects. We compared a biomarker strategy to adjust corticosteroid dose using a composite score of T2 biomarkers (fractional exhaled nitric oxide [FENO], blood eosinophils, and serum periostin) with a standardised symptom-risk-based algorithm (control).
METHODS
We did a single-blind, parallel group, randomised controlled trial in adults (18-80 years of age) with severe asthma (at treatment steps 4 and 5 of the Global Initiative for Asthma) and FENO of less than 45 parts per billion at 12 specialist severe asthma centres across England, Scotland, and Northern Ireland. Patients were randomly assigned (4:1) to either the biomarker strategy group or the control group by an online electronic case-report form, in blocks of ten, stratified by asthma control and use of rescue systemic steroids in the previous year. Patients were masked to study group allocation throughout the entirety of the study. Patients attended clinic every 8 weeks, with treatment adjustment following automated treatment-group-specific algorithms: those in the biomarker strategy group received a default advisory to maintain treatment and those in the control group had their treatment adjusted according to the steps indicated by the trial algorithm. The primary outcome was the proportion of patients with corticosteroid dose reduction at week 48, in the intention-to-treat (ITT) population. Secondary outcomes were inhaled corticosteroid (ICS) dose at the end of the study; cumulative dose of ICS during the study; proportion of patients on maintenance oral corticosteroids (OCS) at study end; rate of protocol-defined severe exacerbations per patient year; time to first severe exacerbation; number of hospital admissions for asthma; changes in lung function, Asthma Control Questionnaire-7 score, Asthma Quality of Life Questionnaire score, and T2 biomarkers from baseline to week 48; and whether patients declined to progress to OCS. A secondary aim of our study was to establish the proportion of patients with severe asthma in whom T2 biomarkers remained low when corticosteroid therapy was decreased to a minimum ICS dose. This study is registered with ClinicalTrials.gov, NCT02717689 and has been completed.
FINDINGS
Patients were recruited from Jan 8, 2016, to July 12, 2018. Of 549 patients assessed, 301 patients were included in the ITT population and were randomly assigned to the biomarker strategy group (n=240) or to the control group (n=61). 28·4% of patients in the biomarker strategy group were on a lower corticosteroid dose at week 48 compared with 18·5% of patients in the control group (adjusted odds ratio [aOR] 1·71 [95% CI 0·80-3·63]; p=0·17). In the per-protocol (PP) population (n=121), a significantly greater proportion of patients were on a lower corticosteroid dose at week 48 in the biomarker strategy group (30·7% of patients) compared with the control group (5·0% of patients; aOR 11·48 [95% CI 1·35-97·83]; p=0·026). Patient choice to not follow treatment advice was the principle reason for loss to PP analysis. There was no difference in secondary outcomes between study groups and no loss of asthma control among patients in the biomarker strategy group who reduced their corticosteroid dose.
INTERPRETATION
Biomarker-based corticosteroid adjustment did not result in a greater proportion of patients reducing corticosteroid dose versus control. Understanding the reasons for patients not following treatment advice in both treatment strategies is an important area for future research. The prevalence of T2 biomarker-low severe asthma was low.
FUNDING
This study was funded, in part, by the Medical Research Council UK
Fecal microbiota transplantation in gastrointestinal and extraintestinal disorders.
No full textFecal microbiota transplantation (FMT) is the infusion of feces from a healthy donor into the gut of a recipient to treat a dysbiosis-related disease. FMT has been proven to be a safe and effective treatment for infection, but increasing evidence supports the role of FMT in other gastrointestinal and extraintestinal diseases. The aim of this review is to paint the landscape of current evidence of FMT in different fields of application (including irritable bowel syndrome, inflammatory bowel disease, liver disorders, decolonization of multidrug-resistant bacteria, metabolic disorders and neurological disorders), as well as to discuss the current regulatory scenario of FMT, and hypothesize future directions of FMT
11β-Hydroxysteroid dehydrogenase type 1 inhibition in idiopathic intracranial hypertension: a double-blind randomized controlled trial.
No full textTreatment options for idiopathic intracranial hypertension are limited. The enzyme 11β-hydroxysteroid dehydrogenase type 1 has been implicated in regulating cerebrospinal fluid secretion, and its activity is associated with alterations in intracranial pressure in idiopathic intracranial hypertension. We assessed therapeutic efficacy, safety and tolerability and investigated indicators of efficacy of the 11β-hydroxysteroid dehydrogenase type 1 inhibitor AZD4017 compared with placebo in idiopathic intracranial hypertension. A multicenter, UK, 16-week phase II randomized, double-blind, placebo-controlled trial of 12-week treatment with AZD4017 or placebo was conducted. Women aged 18-55 years with active idiopathic intracranial hypertension (>25 cmHO lumbar puncture opening pressure and active papilledema) were included. Participants received 400 mg of oral AZD4017 twice daily compared with matching placebo over 12 weeks. The outcome measures were initial efficacy, safety and tolerability. The primary clinical outcome was lumbar puncture opening pressure at 12 weeks analysed by intention-to-treat. Secondary clinical outcomes were symptoms, visual function, papilledema, headache and anthropometric measures. efficacy was evaluated in the central nervous system and systemically. A total of 31 subjects [mean age 31.2 (SD = 6.9) years and body mass index 39.2 (SD = 12.6) kg/m] were randomized to AZD4017 ( = 17) or placebo ( = 14). At 12 weeks, lumbar puncture pressure was lower in the AZD4017 group (29.7 cmHO) compared with placebo (31.3 cmHO), but the difference between groups was not statistically significant (mean difference: -2.8, 95% confidence interval: -7.1 to 1.5; =0.2). An exploratory analysis assessing mean change in lumbar puncture pressure within each group found a significant decrease in the AZD4017 group [mean change: -4.3 cmHO (SD = 5.7); =0.009] but not in the placebo group [mean change: -0.3 cmHO (SD = 5.9); =0.8]. AZD4017 was safe, with no withdrawals related to adverse effects. Nine transient drug-related adverse events were reported. One serious adverse event occurred in the placebo group (deterioration requiring shunt surgery). biomarkers of 11β-hydroxysteroid dehydrogenase type 1 activity (urinary glucocorticoid metabolites, hepatic prednisolone generation, serum and cerebrospinal fluid cortisol:cortisone ratios) demonstrated significant enzyme inhibition with the reduction in serum cortisol:cortisone ratio correlating significantly with reduction in lumbar puncture pressure ( = 0.005, = 0.70). This is the first phase II randomized controlled trial in idiopathic intracranial hypertension evaluating a novel therapeutic target. AZD4017 was safe and well tolerated and inhibited 11β-hydroxysteroid dehydrogenase type 1 activity . Reduction in serum cortisol:cortisone correlated with decreased intracranial pressure. Possible clinical benefits were noted in this small cohort. A longer, larger study would now be of interest
Ethnicity and risk of death in patients hospitalised for COVID-19 infection in the UK: an observational cohort study in an urban catchment area.
No full textBACKGROUND
Studies suggest that certain black and Asian minority ethnic groups experience poorer outcomes from COVID-19, but these studies have not provided insight into potential reasons for this. We hypothesised that outcomes would be poorer for those of South Asian ethnicity hospitalised from a confirmed SARS-CoV-2 infection, once confounding factors, health-seeking behaviours and community demographics were considered, and that this might reflect a more aggressive disease course in these patients.
METHODS
Patients with confirmed SARS-CoV-2 infection requiring admission to University Hospitals Birmingham NHS Foundation Trust (UHB) in Birmingham, UK between 10 March 2020 and 17 April 2020 were included. Standardised admission ratio (SAR) and standardised mortality ratio (SMR) were calculated using observed COVID-19 admissions/deaths and 2011 census data. Adjusted HR for mortality was estimated using Cox proportional hazard model adjusting and propensity score matching.
RESULTS
All patients admitted to UHB with COVID-19 during the study period were included (2217 in total). 58% were male, 69.5% were white and the majority (80.2%) had comorbidities. 18.5% were of South Asian ethnicity, and these patients were more likely to be younger and have no comorbidities, but twice the prevalence of diabetes than white patients. SAR and SMR suggested more admissions and deaths in South Asian patients than would be predicted and they were more likely to present with severe disease despite no delay in presentation since symptom onset. South Asian ethnicity was associated with an increased risk of death, both by Cox regression (HR 1.4, 95% CI 1.2 to 1.8), after adjusting for age, sex, deprivation and comorbidities, and by propensity score matching, matching for the same factors but categorising ethnicity into South Asian or not (HR 1.3, 95% CI 1.0 to 1.6).
CONCLUSIONS
Those of South Asian ethnicity appear at risk of worse COVID-19 outcomes. Further studies need to establish the underlying mechanistic pathways