Abstract Objective Shang's recently published meta-analysis on homeopathic remedies ( Lancet ) based its main conclusion on a subset of eight larger trials out of 21 high quality trials (out of 110 ...included trials). We performed a sensitivity analysis on various other meaningful trial subsets of all high quality trials. Study Design Subsets were defined according to sample size, type of homeopathy, type of publication, and treated disease/condition. For each subset, we estimated the overall odds ratios (ORs) from random effect meta-analyses. Results All trials were highly heterogeneous ( I2 = 62.2%). Homeopathy had a significant effect beyond placebo (OR = 0.76; 95% CI: 0.59–0.99; p = 0.039). When the set of analyzed trials was successively restricted to larger patient numbers, the ORs varied moderately (median: 0.82, range: 0.71–1.02) and the P -values increased steadily (median: 0.16, range: 0.03–0.93), including Shang's results for the eight largest trials (OR = 0.88, CI: 0.66–1.18; P = 0.41). Shang's negative results were mainly influenced by one single trial on preventing muscle soreness in 400 long-distance runners. Conclusions The meta-analysis results change sensitively to the chosen threshold defining large sample sizes. Because of the high heterogeneity between the trials, Shang's results and conclusions are less definite than had been presented.
Long-term data on mortality after first-ever stroke in adults aged 18 through 50 years are scarce and usually restricted to ischemic stroke. Moreover, expected mortality not related to first-ever ...stroke is not taken in account. OBJECTIVES To investigate long-term mortality and cause of death after acute stroke in adults aged 18 through 50 years and to compare this with nationwide age- and sex-matched mortality rates.
The Follow -Up of Transient Ischemic Attack and Stroke Patients and Unelucidated Risk Factor Evaluation (FUTURE) study, a prospective cohort study of prognosis after transient ischemic attack (TIA), ischemic stroke, or hemorrhagic stroke in adults aged 18 through 50 years admitted to Radboud University Nijmegen Medical Centre, the Netherlands, between January 1, 1980, and November 1, 2010. The survival status of 959 consecutive patients with a first-ever TIA (n = 262), ischemic stroke (n = 606), or intracerebral hemorrhage (n = 91) was assessed as of November 1, 2012. Mean follow-up duration was 11.1 (SD, 8.7) years (median, 8.3 interquartile range, 4.0-17.4). Observed mortality was compared with the expected mortality, derived from mortality rates in the general population with similar age, sex, and calendar-year characteristics.
Cumulative 20-year mortality among 30-day survivors of stroke.
At the end of follow-up, 192 patients (20.0%) had died. Among 30-day survivors, cumulative 20-year risk of death was 24.9% (95% CI, 16.0%-33.7%) for TIA, 26.8% (95% CI, 21.9%-31.8%) for ischemic stroke, and 13.7% (95% CI, 3.6%-23.9%) for intracerebral hemorrhage. Observed mortality was increased compared with expected mortality (standardized mortality ratio SMR, 2.6 95% CI, 1.8-3.7 for TIA, 3.9 95% CI, 3.2-4.7 for ischemic stroke, and 3.9 95% CI, 1.9-7.2 for intracerebral hemorrhage, respectively). For ischemic stroke, cumulative 20-year mortality among 30-day survivors was higher in men than in women (33.7% 95% CI, 26.1%-41.3% vs 19.8% 95% CI, 13.8%-25.9%). The SMR was 4.3 (95% CI, 3.2-5.6) for women and 3.6 (95% CI, 2.8-4.6) for men. For all etiologic subtypes of ischemic stroke, observed mortality exceeded expected mortality.
Among adults aged 18 through 50 years, 20-year mortality following acute stroke was relatively high compared with expected mortality. These findings may warrant further research evaluating secondary prevention strategies in these patients.
Contrary to trends in most other diseases, the average age of ischaemic stroke onset is decreasing, owing to a rise in the incidence of stroke among 'young' individuals (under 50 years of age). This ...Review provides a critical overview of the risk factors and aetiology of young ischaemic stroke and addresses its long-term prognosis, including cardiovascular risk, functional outcome and psychosocial consequences. We highlight the diminishing role of 'rare' risk factors in the pathophysiology of young stroke in light of the rising prevalence of 'traditional' vascular risk factors in younger age groups. Long-term prognosis is of particular interest to young patients, because of their long life expectancy and major responsibilities during a demanding phase of life. The prognosis of young stroke is not as favourable as previously thought, with respect either to mortality or cardiovascular disease or to psychosocial consequences. Therefore, secondary stroke prevention is probably a life-long endeavour in most young stroke survivors. Due to under-representation of young patients in past trials, new randomized trials focusing on this age group are needed to confirm the benefits of long-term secondary preventive medication. The high prevalence of poor functional outcome and psychosocial problems warrants further study to optimize treatment and rehabilitation for these young patients.
The prevalence of metabolic syndrome in COPD patients and its impact on patient related outcomes has been little studied. We evaluated the prevalence of metabolic syndrome and clinical and functional ...characteristics in patients with COPD and healthy subjects.
228 COPD patients and 156 healthy subjects were included. Metabolic syndrome was defined using criteria of the IDF. In all patients spirometry, body composition, functional exercise performance, and mood and health status were assessed. Groups were stratified for BMI and gender.
Metabolic syndrome was present in 57% of the COPD patients and 40% of the healthy subjects. After stratification for BMI, presence of metabolic syndrome in patients with a BMI ≥25 kg/m2 was higher than in healthy peers. Patients with metabolic syndrome and a BMI <25 kg/m2 had higher BMI, fat free mass index and bone mineral density, and a lower 6MWD than the BMI matched patients without metabolic syndrome. Spirometry, maximal ergometry, mood and health status, and blood gases were not different between those groups. In COPD patients with metabolic syndrome self-reported co-morbidities and medication use were higher than in those without.
Metabolic syndrome is more prevalent in overweight or obese COPD patients than in BMI matched healthy subjects. Metabolic syndrome did not additionally impact patients' functional outcomes, but did impact the prevalence of co-morbidities.
Aims
The most commonly mutated gene in vulvar squamous cell carcinoma (VSCC) is TP53 and its prognostic value, particularly in HPV‐independent VSCC, is uncertain. In other tumours, p53 ...immunohistochemistry (IHC) is an excellent surrogate marker for TP53 mutations. In order to study this in VSCC, we assigned six p53 IHC patterns into two final classes: ‘wild‐type’ or ‘mutant’. We determined the performance and interobserver variability of this pattern‐based p53 IHC approach.
Methods and results
Two experienced gynaecological pathologists scored the predefined p53 IHC patterns of 59 VSCC, independently and blinded for molecular data. Agreement was calculated by Cohen's kappa. All disagreements regarding p53 IHC patterns were resolved by a consensus meeting. After DNA isolation, the presence of pathogenic TP53 variants was determined by next‐generation sequencing (NGS). Sensitivity, specificity and accuracy of p53 IHC as a surrogate marker for TP53 mutation status were calculated. Initial p53 IHC pattern interpretation showed substantial agreement between both observers (k = 0.71, P < 0.001). After consensus, 18 cases (30.5%) were assigned a final p53 IHC class as TP53 wild‐type and 41 cases (69.5%) as mutant. The accuracy between the p53 IHC class and TP53 mutation status, after the consensus meeting, was 96.6%. Moreover, the sensitivity and specificity were high 95.3% 95% confidence interval (CI) = 82.9–99.1% and 100% (95% CI = 75.9–100%).
Conclusions
Pattern‐based p53 IHC classification is highly reproducible among experienced gynaecological pathologists and accurately reflects TP53 mutations in VSCC. This approach to p53 IHC interpretation offers guidance and provides necessary clarity for resolving the proposed prognostic relevance of final p53 IHC class within HPV‐independent VSCC.
A novel atlas-based segmentation approach based on the combination of multiple registrations is presented. Multiple atlases are registered to a target image. To obtain a segmentation of the target, ...labels of the atlas images are propagated to it. The propagated labels are combined by spatially varying decision fusion weights. These weights are derived from local assessment of the registration success. Furthermore, an atlas selection procedure is proposed that is equivalent to sequential forward selection from statistical pattern recognition theory. The proposed method is compared to three existing atlas-based segmentation approaches, namely (1) single atlas-based segmentation, (2) average-shape atlas-based segmentation, and (3) multi-atlas-based segmentation with averaging as decision fusion. These methods were tested on the segmentation of the heart and the aorta in computed tomography scans of the thorax. The results show that the proposed method outperforms other methods and yields results very close to those of an independent human observer. Moreover, the additional atlas selection step led to a faster segmentation at a comparable performance.
Cerebral small‐vessel disease (cSVD) is a common cause of stroke, functional decline, vascular cognitive impairment, and dementia. Pathological processes in the brain's microcirculation are tightly ...interwoven with pathology in the brain parenchyma, and this interaction has been conceptualized as the neurovascular unit (NVU). Despite intensive research efforts to decipher the NVU's structure and function to date, molecular mechanisms underlying cSVD remain poorly understood, which hampers the development of cSVD‐specific therapies. Important steps forward in understanding the disease mechanisms underlying cSVD have been made using genetic approaches in studies of both monogenic and sporadic SVD. We provide an overview of the NVU's structure and function, the implications for cSVD, and the underlying molecular mechanisms of dysfunction that have emerged from recent genetic studies of both monogenic and sporadic diseases of the small cerebral vasculature.
A common cause of stroke is cerebral small‐vessel disease (cSVD), which results from pathological processes in the neurovascular unit (NVU). The review provides an overview of the structure and function of the NVU, the implications for cSVD, and the underlying molecular mechanisms of NVU dysfunction in cSVD that have emerged from recent genetic studies.
Background
Patients with a pathological complete response (pCR) after neoadjuvant chemoradiotherapy (nCRT) for oesophageal cancer may benefit from non‐surgical management. The aim of this study was ...to determine the diagnostic performance of visual response assessment of the primary tumour after nCRT on T2‐weighted (T2W) and diffusion‐weighted (DW) MRI.
Methods
Patients with locally advanced oesophageal cancer who underwent T2W‐ and DW‐MRI (1·5 T) before and after nCRT in two hospitals, between July 2013 and September 2017, were included in this prospective study. Three radiologists evaluated T2W images retrospectively using a five‐point score for the assessment of residual tumour in a blinded manner and immediately rescored after adding DW‐MRI. Histopathology of the resection specimen was used as the reference standard; ypT0 represented a pCR. Sensitivity, specificity, area under the receiver operating characteristic (ROC) curve (AUC) and interobserver agreement were calculated.
Results
Twelve of 51 patients (24 per cent) had a pCR. The sensitivity and specificity of T2W‐MRI for detection of residual tumour ranged from 90 to 100 and 8 to 25 per cent respectively. Respective values for T2W + DW‐MRI were 90–97 and 42–50 per cent. AUCs for the three readers were 0·65, 0·66 and 0·68 on T2W‐MRI, and 0·71, 0·70 and 0·70 on T2W + DW‐MRI (P = 0·441, P = 0·611 and P = 0·828 for readers 1, 2 and 3 respectively). The κ value for interobserver agreement improved from 0·24–0·55 on T2W‐MRI to 0·55–0·71 with DW‐MRI.
Conclusion
Preoperative assessment of residual tumour on MRI after nCRT for oesophageal cancer is feasible with high sensitivity, reflecting a low chance of missing residual tumour. However, the specificity was low; this results in overstaging of complete responders as having residual tumour and, consequently, overtreatment.
Treatment of locally advanced oesophageal cancer consists of neoadjuvant chemoradiotherapy (nCRT) followed by surgery. In 25–30 per cent of these patients, the resection specimen shows a pathological complete response. This study shows that preoperative response assessment after nCRT performed visually on (diffusion‐weighted) MRI has promising overall diagnostic performance. To further increase the accuracy of response assessment, larger studies are needed, ideally using a multimodal approach combining (diffusion‐weighted) MRI with endoscopy/endoscopic ultrasonography and fluorodeoxyglucose PET/CT. T2W, T2‐weighted; DW, diffusion weighted.
Not there yet
Objective
Long‐term data on recurrent vascular events after young stroke are limited. Our objective was to examine the long‐term risk of recurrent vascular events after young stroke.
Methods
We ...prospectively included 724 consecutive patients with a first‐ever transient ischemic attack (TIA), ischemic stroke, or intracerebral hemorrhage (ICH), aged 18 to 50 years, admitted to our hospital between January 1, 1980 and November 1, 2010. Outcomes were (1) stroke; (2) myocardial infarction or cardiac or peripheral arterial revascularization procedures; or (3) composite event of these, whichever occurred first.
Results
After a mean follow‐up of 9.1 years (standard deviation = 8.2, range = 0–31.0), 142 patients (19.6%) had at least 1 recurrent vascular event. Cumulative 20‐year risk of stroke was 17.3% (95% confidence interval CI = 9.5–25.1) after TIA, 19.4% (95% CI = 14.6–24.3) after ischemic stroke, and 9.8% (95% CI = 1.0–18.7) after ICH. Cumulative 20‐year risk of any vascular event was 27.7% (95% CI = 18.5–37.0) after TIA and 32.8% (95% CI = 26.7–38.9) after ischemic stroke. Age and male sex were associated with other arterial events, but not with stroke. Among TOAST (Trial of Org 10172 in Acute Stroke Treatment) subtypes, adjusted for age, sex, and decennium of inclusion, atherothrombotic stroke, cardioembolic stroke, and lacunar stroke were associated with recurrent stroke (hazard ratio HR = 2.72, 95% CI = 1.34–5.52; HR = 2.49, 95% CI = 1.23–5.07; and HR = 2.92, 95% CI = 1.45–5.88, respectively).
Interpretation
Patients with young stroke remain at substantial risk of recurrent vascular events for decades, suggesting that the underlying disease that caused stroke at a young age continues to put these patients at a high risk for vascular disease throughout their lives. Ann Neurol 2013;74:592–601
Chronic obstructive pulmonary disease (COPD) is associated with systemic inflammation and oxidative stress. These conditions may lead to the formation of advanced glycation end-products (AGEs). In ...this study we investigated in 88 COPD patients and 55 control subjects (80% ex-smokers) the association of the plasma protein-bound AGEs N(ε)-(carboxymethyl)lysine (CML), pentosidine, N(ε)-(carboxyethyl)lysine (CEL), and AGE accumulation in skin by skin autofluorescence (AFR), with lung function. Mean ± sd plasma CML was decreased (COPD 61.6 ± 15.6 nmol · mmol(-1) lysine, never-smokers 80.7 ± 19.8 nmol · mmol(-1) lysine and ex-smokers 82.9 ± 19.3 nmol · mmol(-1) lysine) and CEL (COPD 39.1 ± 10.9 nmol · mmol(-1) lysine, never-smokers 30.4 ± 5.0 nmol · mmol(-1) lysine and ex-smokers 27.7 ± 6.4 nmol · mmol(-1) lysine) and AFR (COPD 3.33 ± 0.67 arbitrary units (AU), never-smokers 2.24 ± 0.45 AU and ex-smokers 2.31 ± 0.47 AU) were increased in COPD patients compared to controls. Disease state was inversely associated with CML, and linearly associated with CEL and AFR. Performing regression analyses in the total group, CEL and AFR showed a negative association and CML a positive association with lung function, even after correction for potential confounders. In conclusion, CEL and AFR were negatively and CML was positively associated with disease state. In the total group only the AGEs showed an association with forced expiratory volume in 1 s. Our data suggest that AGEs are involved in the pathophysiology of COPD, although their exact role remains to be determined.
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