Background and Purpose- The FOCUS trial (Fluoxetine or Control Under Supervision) showed that fluoxetine did not improve modified Rankin Scale scores (mRS) but increased the risk of fractures. We ...aimed to describe the fractures, their impact on mRS and factors associated with fracture risk. Methods- A United Kingdom, multicenter, parallel-group, randomized, placebo-controlled trial. Patients ≥18 years with a clinical stroke and persisting deficit assessed 2 to 15 days after onset were eligible. Consenting patients were allocated fluoxetine 20 mg or matching placebo for 6 months. The primary outcome was the mRS at 6 months and secondary outcomes included fractures. Results- Sixty-five of 3127 (2.1%) patients had 67 fractures within 6 months of randomization; 43 assigned fluoxetine and 22 placebo. Fifty-nine (90.8%) had fallen and 26 (40%) had fractured their neck of femur. The effect of fluoxetine on mRS (common odds ratio =0.951) was not significantly altered by excluding fracture patients (common odds ratio =0.961). Cox proportional hazards modeling showed that only age >70 year (hazard ratio =1.97; 95% CI, 1.13-3.45;
=0.017), female sex (hazard ratio =2.13; 95% CI, 1.29-3.51;
=0.003), and fluoxetine (hazard ratio =2.00; 95% CI, 1.20-3.34;
=0.008) were independently associated with fractures. Conclusions- Most fractures resulted from falls. Although many fractures were serious, and likely to impair patients' function, the increased fracture risk did not explain the lack of observed effect of fluoxetine on mRS. Only increasing age, female sex, and fluoxetine were independent predictors of fractures. Clinical Trial Registration- URL: http://www.controlled-trials.com. Unique identifier: ISRCTN83290762.
Mutations in the retinitis pigmentosa protein gene RP2 account for up to 15% of X-linked retinitis pigmentosa. RP2 is a novel protein of unknown function, which is targeted to the plasma membrane by ...dual N-terminal acyl-modification. Dual-acylated proteins are targeted to lipid rafts, and some are subject to polarized sorting. Therefore we investigated the organization of RP2 on the plasma membrane. Endogenous RP2 protein was predominantly localized at the plasma membrane, and exogenously expressed green-fluorescent-protein-tagged protein was also targeted to the membrane in a wide range of cultured cells. High levels of endogenous RP2 protein were present in HeLa cells and in the retinal pigment epithelium-derived cell line ARPE19. A significant proportion of RP2 in cultured neuroblastoma cells was associated with detergent-resistant membranes (DRMs), but much less than other dually acylated proteins (e.g. Lyn and Fyn). In contrast, the RP2-interacting protein Arl3 (ADP-ribosylation factor-like 3) was not found to be associated with DRMs. The association of RP2 with DRMs was cholesterol-dependent. In polarized epithelial cells in culture and in vivo, RP2 was present in both the apical and basolateral domains of the plasma membrane. These data show that RP2 is not specific to either domain, unlike some other dually acylated proteins. Interestingly, the level of RP2 protein increased in the epithelial cell line Caco-2 with differentiation and polarization. These data show that RP2 is present on the membrane of all cell types examined both in vitro and in vivo, and that RP2 associates with lipid rafts, suggesting a potential role for the protein in signal transduction.
There are no randomized controlled trials of statin therapy in patients with severe bronchiectasis who are chronically infected with Pseudomonas aeruginosa.
Thirty-two patients chronically infected ...with P aeruginosa were recruited in this double-blind cross-over randomized controlled trial. Sixteen patients were recruited in each arm, were given atorvastatin 80 mg or placebo for 3 months followed by a washout period for 6 weeks, and then crossed over and administered the alternative therapy for 3 months.
Twenty-seven patients completed the study. Atorvastatin did not significantly improve the primary end point of cough as measured by the Leicester Cough Questionnaire (mean difference, 1.92; 95% CI for difference, –0.57-4.41; P = .12). However, atorvastatin treatment resulted in an improved St. Georges Respiratory Questionnaire (–5.62 points; P = .016) and reduced serum levels of CXCL8 (P = .04), tumor necrosis factor (P = .01), and intercellular adhesion molecule 1 (P = .04). There was a trend toward improvement in serum C-reactive protein and serum neutrophil counts (P = .07 and P = .06, respectively). We demonstrated in vitro that atorvastatin 10 μM reduced formyl-methionyl-leucyl phenylalanine-induced upregulation of CD11b expression and changes in calcium flux, reflecting an ability to decrease neutrophil activation.
We demonstrated that atorvastatin reduced systemic inflammation and improved quality of life in patients with bronchiectasis who were infected with P aeruginosa. These effects may be due to an ability of atorvastatin to modulate neutrophil activation.
ClinicalTrials.gov; No.: NCT01299194; URL: www.clinicaltrials.gov
Abstract
Background
Three large trials of fluoxetine for stroke recovery (FOCUS (fluoxetine or control under supervision), AFFINITY (the Assessment oF FluoxetINe In sTroke recovery) and EFFECTS ...(Efficacy oF Fluoxetine—a randomisEd Controlled Trial in Stroke)) have been collaboratively designed with the same basic protocol to facilitate an individual patient data analysis (IPDM). The statistical analysis plan for the three individual trials has already been reported in
Trials
, including a brief description of the IPDM. In this protocol, we describe in detail how we will perform the IPDM.
Methods/design
Data from EFFECTS and AFFINITY will be transferred securely to the FOCUS statistician, who will perform a one-stage IPDM and a two-stage IPDM. For the one-stage IPDM, data will be combined into a single data set and the same analyses performed as described for the individual trials. For the two-stage IPDM, the results for the three individual trials will be combined using fixed effects meta-analyses.
The primary and secondary outcome domains for the IPDM are the same as for individual trials. We will also perform analyses according to several subgroups including country of recruitment, ethnicity and trial. We will also explore the effects of fluoxetine on our primary and secondary outcomes in subgroups defined by combinations of characteristics.
We also describe additional research questions that will be addressed using the combined data set, and published subsequently, including predictors of important post-stroke problems such as seizures, low mood and bone fractures.
Discussion
An IPDM of our three large trials of fluoxetine for stroke recovery will allow us to provide the most precise estimates of any risks and benefits of fluoxetine vs placebo, to detect reliably a smaller overall effect size than those detectable by the individual trials, to better determine the effects of fluoxetine vs placebo in subgroups of patients and outcomes and to broaden the generalisability of the results. Also, we may identify differences in treatment effects between studies.
Trial registration
FOCUS: ISRCTN
ISRCTN83290762
. Registered on 23 May 2012. EudraCT
2011-005616-29
. Registered on 3 February 2012.
AFFINITY: Australian New Zealand Clinical Trials Registry
ACTRN12611000774921
. Registered on 22 July 2011.
EFFECTS: ISRCTN
ISRCTN13020412
. Registered on 19 December 2014. ClinicalTrials.gov
NCT02683213
. Registered on 2 February 2016. EudraCT
2011-006130-16
. Registered on 8 August 2014.
Unstable ankle fractures are routinely managed operatively. However, because of soft tissue and implant-related complications, recent literature has reported on the nonoperative management of ...well-reduced medial malleolus fractures after fibular stabilization, but with limited evidence supporting the routine application.
To assess the superiority of internal fixation of well-reduced (displacement ≤2 mm) medial malleolus fractures compared with nonfixation after fibular stabilization.
This superiority, pragmatic, parallel, prospective randomized clinical trial was conducted from October 1, 2017, to August 31, 2021. A total of 154 adult participants (≥16 years) with a closed, unstable bimalleolar or trimalleolar ankle fracture requiring surgery at an academic major trauma center in the UK were assessed. Exclusion criteria included injuries with no medial-sided fracture, open fractures, neurovascular injury, and the inability to comply with follow-up. Data analysis was performed in July 2022 and confirmed in September 2023.
Once the lateral (and where appropriate, posterior) malleolus had been fixed and satisfactory intraoperative reduction of the medial malleolus fracture was confirmed by the operating surgeon, participants were randomly allocated to fixation (n = 78) or nonfixation (n = 76) of the medial malleolus.
Olerud-Molander Ankle Score (OMAS) 1 year after randomization (range, 0-100 points, with 0 indicating worst possible outcome and 100 indicating best possible outcome).
Among 154 randomized participants (mean SD age, 56.5 16.7 years; 119 77% female), 144 (94%) completed the trial. At 1 year, the median OMAS was 80.0 (IQR, 60.0-90.0) in the fixation group compared with 72.5 (IQR, 55.0-90.0) in the nonfixation group (P = .17). Complication rates were comparable. Significantly more patients in the nonfixation group developed a radiographic nonunion (20% vs 0%; P < .001), with 8 of 13 clinically asymptomatic; 1 patient required surgical reintervention for this. Fracture type and reduction quality appeared to influence fracture union and patient outcome.
In this randomized clinical trial comparing internal fixation of well-reduced medial malleolus fractures with nonfixation, after fibular stabilization, fixation was not superior according to the primary outcome. However, 1 in 5 patients developed a radiographic nonunion after nonfixation, and although the reintervention rate to manage this was low, the future implications are unknown. These results support selective nonfixation of anatomically reduced medial malleolar fractures after fibular stabilization.
ClinicalTrials.gov Identifier: NCT03362229.
ObjectiveTo establish the likely accuracy of pH testing to identify gastric aspirates at different pH cut-offs to confirm nasogastric tube placement.MethodsThis prospective observational study ...included a convenience sample of adult patients who had two (one fresh and one frozen) gastric and oesophageal samples taken during gastroscopy or two bronchial and saliva samples taken during bronchoscopy. The degree of observer agreement for the pH of fresh and frozen samples was indicted by kappa (k) statistics. The sensitivities and specificities at pH ≤5.5 and the area under the receiver operating characteristics (ROC) curve at different pH cut-offs were calculated to identify gastric and non-gastric aspirates.ResultsNinety-seven patients had a gastroscopy, 106 a bronchoscopy. There was complete agreement between observers in 57/92 (62%) of the paired fresh and frozen gastric samples (k=0.496, 95% CI 0.364 to 0.627). The sensitivity of a pH ≤5.5 to correctly identify gastric samples was 68% (95% CI 57 to 77) and the specificity was 79% (95% CI 74 to 84). The overall accuracy to correctly classify samples was between 76% and 77%, regardless of whether patients were taking antacids or not. The area under the ROC curve at different pH cut-offs was 0.74.ConclusionThe diagnostic accuracy of pH ≤5.5 to differentiate gastric from non-gastric samples was low, regardless of whether patients were taking antacids or not. Due to the limited accuracy of the pH sticks and the operators’ ability to differentiate colorimetric results, there is an urgent need to identify more accurate and safer methods to confirm correct placement of nasogastric tubes.
Variceal band ligation (VBL) can reduce the rate of the first variceal by 45-52% compared with beta-blockers (BBs). We performed an updated meta-analysis of nine randomized controlled trials ...published as full papers, comparing VBL with BB for primary prevention.
Relative risk (RR) was computed using a random effects model. Sensitivity analysis was performed using a fixed effects model. Publication bias was also assessed using funnel plots and the rank correlation test.
In total, 734 patients were studied (356, VBL; 378, BB). The pooled RR favoured VBL for first variceal bleed 0.63; 95% confidence interval (CI), 0.43-0.92 with number needed to treat being 13 (95% CI, 7-33), and for adverse events resulting in treatment withdrawal (0.24; 95% CI, 0.12-0.47) with the corresponding number needed to treat being 10 (95% CI, 6-25). Banding-related bleeding occurred in six patients (fatal in two). No difference was seen in bleeding-related deaths (RR, 0.71; 95% CI, 0.38-1.32), or overall mortality (RR, 1.09; 95% CI, 0.86-1.38). No significant heterogeneity or publication bias was present, and outcomes remained robust after sensitivity analyses.
VBL was superior to BB in preventing the first variceal bleed, with fewer adverse events resulting in treatment discontinuation. Careful attention to technique and patient selection are important to minimize iatrogenic complications with VBL. VBL has a role in patients with poor drug compliance, or tolerance, and in those who bleed on BB therapy.
The diagnosis of stroke or TIA in the emergency department is difficult, though important for early treatment. Circulating biomarkers might improve upon clinical assessment at admission.
We recruited ...symptomatic patients with suspected stroke or TIA and drew blood soon after admission. Each patient was assessed with the Face Arm Speech Test (FAST). We measured a panel of 15 circulating inflammatory, thrombotic, cardiac, and cerebral tissue damage biomarkers. Improvement in diagnostic performance was assessed by adding biomarkers to the FAST in logistic regression models to predict a final diagnosis of stroke or TIA (verified by expert review and imaging).
405 patients had suspected stroke: 285 with TIA or stroke (230 definite or probable ischemic stroke, 40 TIA, 15 hemorrhagic stroke) and 120 with other diagnoses. Only the markers t-PA and NT-proBNP were associated positively and significantly (p < 0.01) with a diagnosis of TIA or stroke. The FAST had a sensitivity of 82% (95% CI 78-87) and specificity of 38% (95% CI 29-46) for the diagnosis of TIA or stroke. No biomarker individually improved the sensitivity or specificity of the FAST. A model containing the FAST, age, systolic blood pressure, NT-proBNP and t-PA had a better sensitivity (88%, p < 0.006) and a better specificity (48%, p = 0.04) than the FAST test alone.
No single blood marker improved the diagnostic performance of a validated clinical stroke scale. Panels of biomarkers may marginally improve diagnosis, but their practicability is uncertain, and requires further study.
From 2688 new non–muscle-invasive bladder cancer patients treated within the framework of Scotland’s novel quality performance indicator programme and followed up for 5 yr, we found that hospitals ...achieving targets for detrusor muscle sampling and single instillation of mitomycin C during and after initial transurethral resection of bladder tumour, respectively, were associated with delays in cancer recurrence and progression. These parameters should augment prognostic calculators.
Noncompliance with evidence-based interventions and guidelines contributes to significant and variable recurrence and progression in patients with non–muscle-invasive bladder cancer (NMIBC). The implementation of a quality performance indicator (QPI) programme in Scotland’s National Health Service (NHS) aimed to improve cancer outcomes and reduce nationwide variance.
To evaluate the effect of hospitals achieving benchmarks for two specific QPIs on time to recurrence and progression in NMIBC.
QPIs for bladder cancer (BC) were enforced nationally in April 2014. NHS health boards collected prospective data on all new BC patients. Prospectively recorded surveillance data were pooled from 12 collaborating centres.
QPIs of interest were (1) hospitals achieving detrusor muscle (DM) sampling target at initial transurethral resection of bladder tumour (TURBT) and (2) use of single instillation of mitomycin C after TURBT (SI-MMC).
The primary and secondary endpoints were time to recurrence and progression, respectively. Kaplan-Meier and Cox multivariable regression analyses were performed.
Between April 1, 2014 and March 31, 2017, we diagnosed 3899 patients with new BC, of which 2688 were NMIBC . With a median follow up of 60.3 mo, hospitals achieving the DM sampling target had a 5.4% lower recurrence rate at 5 yr than hospitals not achieving this target (442/1136 38.9% vs 677/1528 44.3%, 95% confidence interval CI = 1.6–9.2, p = 0.005). SI-MMC was associated with a 20.4% lower recurrence rate (634/1791 35.4% vs 469/840 55.8%, 95% CI = 16.4–24.5, p < 0.001). On Cox multivariable regression, meeting the DM target and SI-MMC were associated with significant improvement in recurrence (hazard ratio HR 0.81, 95% CI = 0.73–0.91, p = 0.0002 and HR 0.66, 95% CI = 0.59–0.74, p < 0.004, respectively) as well as progression-free survival (HR 0.62, 95% CI = 0.45–0.84, p = 0.002 and HR 0.65, 95% CI = 0.49–0.87, p = 0.004, respectively). We did not have a national multicentre pre-QPI control.
Within a national QPI programme, meeting targets for sampling DM and SI-MMC in the real world were independently associated with delays to recurrence and progression in NMIBC patients.
Following the first 3 yr of implementing a novel quality performance indicator programme in Scotland, we evaluated compliance and outcomes in non–muscle-invasive bladder cancer. In 2688 patients followed up for 5 yr, we found that achieving targets for sampling detrusor muscle and the single instillation of mitomycin C during and after transurethral resection of bladder tumour, respectively, were associated with delays in cancer recurrence and progression.
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