Power analysis for stratified cluster randomisation trials with cluster size being the stratifying factor

Stratified cluster randomisation trial design is widely employed in biomedical research and cluster size has been frequently used as the stratifying factor.Conventional sample size calculation methods have assumed the cluster sizes to be constant within each stratum,which is rarely true in practice.Ignoring the random variability in cluster size leads to underestimated sample sizes and underpowered clinical trials.In this study,we proposed to directly incorporate the variability in cluster size(represented by coefficient of variability)into sample size calculation.This approach provides closed-form sample size formulas,and is flexible to accommodate arbitrary randomisation ratio and varying numbers of clusters across strata.Simulation study shows that the proposed approach achieves desired power and type I error over a wide spectrum of design configurations,including different distributions of cluster sizes.An application example is presented.

Progress in the Application of Mendelian Randomization Analysis in Allergic Rhinitis

Allergic rhinitis (AR) is a non-infectious chronic inflammatory disease of the nasal mucosa mediated mainly by immunoglobulin E (IgE) in atopic individuals after exposure to allergens, with the typical symptoms of paroxysmal sneezing, watery runny nose, itchy nose and nasal congestion. Mendelian randomization (MR), an innovative epidemiological approach that uses common genetic variants as instrumental variables for exposure, thus enabling prediction of their causal relationship with outcomes, has been widely used in recent years in studies related to AR. This paper provides a review of the method and its progress in the field of allergic rhinitis research.

Systematic review of randomised controlled trials:Probiotics for functional constipation

AIM:To systematically evaluate and update evidence on the efficacy and safety of probiotic supplementation for the treatment of constipation. METHODS:The MEDLINE,EMBASE,CINAHL,and Cochrane Library databases were searched in May 2009 for randomised controlled trials(RCTs)performed in paediatric or adult populations related to the study aim. RESULTS:We included five RCTs with a total of 377 subjects(194 in the experimental group and 183 in the control group).The participants were adults (three RCTs,n=266)and children(two RCTs,n= 111)with constipation.In adults,data suggests a favourable effect of treatment with Bifidobacterium lactis DN-173 010,Lactobacillus casei Shirota,and Escherichia coli Nissle 1917 on defecation frequency and stool consistency.In children,L.casei rhamnosusLcr35,but not L.rhamnosus GG,showed a beneficial effect. CONCLUSION:Until more data are available,we believe the use of probiotics for the treatment of constipation condition should be considered investigational.

Early postoperative feeding in resectional gastrointestinal surgical cancer patients

Malnutrition is present in the majority of patients presenting for surgical management of gastrointestinal malignancies,due to the effects of the tumour and preoperative anti-neoplastic treatments.The traditional practice of fasting patients until the resumption of bowel function threatens to further contribute to the malnutrition experienced by these patients.Furthermore,the rationale behind this traditional practice has been rendered obsolete through developments in anaesthetic agents and changes to postoperative analgesia practices.Conversely,there is a growing body of literature that consistently demonstrates that providing oral or tube feeding proximal to the anastomosis within 24 h postoperatively,is not only safe,but might be associated with significant benefits to the postoperative course.Early post operative feeding should therefore be adopted as a standard of care in oncology patients undergoing gastrointestinal resections.

Volar locking distal radius plates show better short-term results than other treatment options: A prospective randomised controlled trial

AIM To compare the outcomes of displaced distal radius fractures treated with volar locking plates and with immediate postoperative mobilisation with the outcomes of these fractures treated with modalities that necessitate 6 wk wrist immobilisation.METHODS A prospective, randomised controlled single-centre trial was conducted with 56 patients who had a displaced radius fracture were randomised to treatment either with a volar locking plate(n = 29), or another treatment modality(n = 27; cast immobilisation with or without wires or external fixator). Outcomes were measured at 12 wk. Functional outcome scores measured were the Patient-Rated Wrist Evaluation(PRWE) Score; Disabilities of the Arm, Shoulder and Hand and activities of daily living(ADLs). Clinical outcomes were wrist range of motion and grip strength. Radiographic parameters were volar inclination and ulnar variance.RESULTS Patients in the volar locking plate group had significantly better PRWE scores, ADL scores, grip strength and range of extension at three months compared with the control group. All radiological parameters were significantly better in the volar locking plate group at 3 mo. CONCLUSION The present study suggests that volar locking plates produced significantly better functional and clinical outcomes at 3 mo compared with other treatment modalities. Anatomical reduction was significantly more likely to be preserved in the plating group. Level of evidence: Ⅱ.

The issue of lymphadenectomy during laparoscopic gastrectomy for gastric carcinoma

Surgical resection remains the mainstay of treatment for gastric cancer.Laparoscopic assisted gastrectomy has failed to gain universal acceptance as an alternative to the open approach for a number of reasons,one of which includes the issue of oncological radicality in terms of lymph node dissection.Nodal status,which is one of the most crucial and independent predictors of patient survival,therefore has been examined both in single institutional trials and also in randomised controlled trials especially on early gastric cancer.The issue of oncological adequacy for laparoscopic lymph node harvesting for advanced gastric cancer remains a contentious issue because of the unique challenges it poses in terms of complexity,safety and time,and also the lack of randomised controlled trials in this area.It is thus imperative that good quality multicentre randomised controlled trials are designed to investigate the benef its of extended lymphadenectomy in the setting of laparoscopic surgery,especially for advanced gastric cancer and its impact on both short and long term survival.

Multicenter randomised controlled trial comparing the high definition white light endoscopy and the bright narrow band imaging for colon polyps

AIM To compare high definition white light endoscopy and bright narrow band imaging for colon polyps' detection rates. METHODS Patients were randomised to high definition white light endoscopy(HD-WLE) or the bright narrow band imaging(b NBI) during withdrawal of the colonoscope. Polyps identified in either mode were characterised using b NBI with dual focus(b NBI-DF) according to the Sano's classification. The primary outcome was to compare adenoma detection rates(ADRs) between the two arms. The secondary outcome was to assess the negative predictive value(NPV) in differentiating adenomas from hyperplastic polyps for diminutive rectosigmoid lesions.RESULTS A total of 1006 patients were randomised to HD-WLE(n = 511) or b NBI(n = 495). The mean of adenoma per patient was 1.62 and 1.84, respectively. The ADRs in b NBI and HD-WLE group were 37.4% and 39.3%, respectively. When adjusted for withdrawal time(OR = 1.19, 95%CI: 1.15-1.24, P < 0.001), the use of b NBI was associated with a reduced ADR(OR = 0.69, 95%CI: 0.52-0.92). Nine hundred and thirty three polyps(86%) in both arms were predicted with high confidence. The sensitivity(Sn), specificity(Sp), positive predictive value and NPV in differentiating adenomatous from non-adenomatous polyps of all sizes were 95.9%, 87.2%, 94.0% and 91.1% respectively. The NPV in differentiating an adenoma from hyperplastic polyp using b NBI-DF for diminutive rectal polyps was 91.0%.CONCLUSION ADRs did not differ between b NBI and HD-WLE, however HD-WLE had higher ADR after adjustment of withdrawal time. b NBI surpassed the PIVI threshold for diminutive polyps.

Adjunctive Peony-Glycyrrhiza decoction for antipsychotic-induced hyperprolactinaemia:a meta-analysis of randomised controlled trials

Background Hyperprolactinaemia is a common adverse effect of antipsychotics （APs）. The results of Peony-Glycyrrhiza decoction （PGD） as a potentially useful adjunctivetreatment for hyperprolactinaemia are inconsistent.Aim This meta-analysis of randomised controlled trials （RCTs） examined the effcacy and safety of adjunctive PGDtherapy for AP-induced hyperprolactinaemia.Methods English （PubMed, Embase, Cochrane Library, PsycINFO） and Chinese （Chinese National Knowledge Infrastructure, Wanfang Data） databases were systematicallysearched up to 10 June 2018. The inclusion criteria were based on PICOS-Participants： adult patients with schizophrenia; Intervention： PGD plus APs; Comparison： APs plus placebo or AP monotherapy; Outcomes： effcacy and safety; Study design： RCTs. The weighted mean difference （WMD） and risk ratio （RR） along with their 95% CIs were calculated using Review Manager （RevMan） V.5.3 software.Results Five RCTs （n=450） were included and analysed. Two RCTs （n=140） were double-blind and four RCTs （n=409） reported ‘random’ assignment with specifc description. The PGD group showed a signifcantly lower serum prolactin level at endpoint than the control group （n=380, WMD： ？32.69 ng/mL （95% CI -41.66 to 23.72）, p〈0.00001, I2=97%）. Similarly, the superiority of PGD over the control groups was also found in the improvement of hyperprolactinaemia-related symptoms. No difference was found in the improvement of psychiatric symptoms assessed by the Positive and Negative Syndrome Scale （n=403, WMD： -0.62 （95% CI -2.38 to 1.15）, p=0.49, I^2=0%）. There were similar rates of all-cause discontinuation （n=330, RR 0.93 （95% CI 0.63 to 1.37）, p=0.71, I^2=0%） and adverse drug reactions between the two groups. According to the Grading of Recommendations Assessment, Development and Evaluation approach, the level of evidence of primary and secondary outcomes ranged from ‘very low’ （14.3%）, ‘low’ （42.8%）, ‘moderate’ （14.3%）, to ‘high’ （28.6%）.Conclusions Current evidence supports the adjunctive use of PGD to suppress elevated prolactin and improve prolactin-induced symptoms without signifcant adverse events in adult patients with AP-induced hyperprolactinaemia. High-quality RCTs with longer duration are needed to confrm these fndings.

Difficulties in Recruitment for a Randomised Controlled Trial of Lifestyle Intervention for Type 2 Diabetes: Implications for Diabetes Management

Objective: To report our experience of attempting a randomised controlled trial of an intensive lifestyle intervention for early type 2 diabetes delivered in a residential setting. Methods: We established a trial requiring 84 participants (46 standard care and 38 intervention) to detect a 1% difference in HbA1c between intervention and control groups at 12 months, allowing for attrition. Ethics approval was obtained from Monash University. Results: The study was abandoned after five months of consistent promotion due to recruitment failure (four subjects recruited). Conclusion: It appears to be difficult for patients with diabetes to commit to a live-in period of education regarding lifestyle modification as a means of treating the illness. We recommend better education of patients and their doctors about the potential health benefits of lifestyle change to manage type 2 diabetes, and further research into novel methods of delivering lifestyle advice which are both effective and sustainable.

Biodegradable stent or balloon dilatation for benign oesophageal stricture: Pilot randomised controlled trial

AIM: To undertake a randomised pilot study comparing biodegradable stents and endoscopic dilatation in patients with strictures.

Use of fibrates in the metabolic syndrome:A review

The use of fibrates in the treatment of dyslipidaemia has changed significantly over recent years.Their role appeared clear at the start of this century.The Helsinki Heart Study and Veterans Affairs High-Density Cholesterol Intervention Trial suggested significant benefit,especially in patients with atherogenic dyslipidaemia.However,this clarity disintegrated following the negative outcomes reported by the Bezafibrate Infarction Prevention,Fenofibrate Intervention and Event Lowering in Diabetes and Action to Control Cardiovascular Risk in Diabetes randomised controlled trials.In this review we discuss these and other relevant trials and consider patient subgroups such as those with the metabolic syndrome and those needing treatment to prevent the microvascular complications associated with diabetes in whom fibrates may be useful.We also discuss observations from our group that may provide some explanation for the varying outcomes reported in large trials.The actions of fibrates in patients who are also on statins are interesting and appear to differ from those in patients not on statins.Understanding this is key as statins are the primary lipid lowering agents and likely to occupy that position for the foreseeable future.We also present other features of fibrate treatment we have observed in our clinical practice;changes in creatinine,liver function tests and the paradoxical high density lipoprotein reduction.Our purpose is to provide enough data for the reader to make objective decisions in their own clinical practice regarding fibrate use.

Randomised controlled trial comparing modified Sano's and narrow band imaging international colorectal endoscopic classifications for colorectal lesions

AIM To assess the utility of modified Sano′s(MS) vs thenarrow band imaging international colorectal endoscopic(NICE) classification in differentiating colorectal polyps.METHODS Patients undergoing colonoscopy between 2013 and 2015 were enrolled in this trial.Based on the MS or the NICE classifications,patients were randomised for real-time endoscopic diagnosis.This was followed by biopsies,endoscopic or surgical resection.The endoscopic diagnosis was then compared to the final(blinded) histopathology.The primary endpoint was the sensitivity(Sn),specificity(Sp),positive predictive value(PPV) and negative predictive value(NPV) of differentiating neoplastic and non-neoplastic polyps(MSⅡ/Ⅱo/Ⅲa/Ⅲb vs I or NICE 1 vs 2/3).The secondary endpoints were "endoscopic resectability"(MSⅡ/Ⅱo/Ⅲa vs Ⅰ/Ⅲb or NICE 2 vs 1/3),NPV for diminutive distal adenomas and prediction of post-polypectomy surveillance intervals.RESULTS A total of 348 patients were evaluated.The Sn,Sp,PPV and NPV in differentiating neoplastic polyps from non-neoplastic polyps were,98.9%,85.7%,98.2% and 90.9% for MS;and 99.1%,57.7%,95.4% and 88.2% for NICE,respectively.The area under the receiver operating characteristic curve(AUC) for MS was 0.92(95%CI:0.86-0.98);and AUC for NICE was 0.78(95%CI:0.69,0.88).The Sn,Sp,PPV and NPV in predicting "endoscopic resectability" were 98.9%,86.1%,97.8% and 92.5% for MS;and 98.6%,66.7%,94.7% and 88.9% for NICE,respectively.The AUC for MS was 0.92(95%CI:0.87-0.98);and the AUC for NICE was 0.83(95%CI:0.75-0.90).The AUC values were statistically different for both comparisons(P = 0.0165 and P = 0.0420,respectively).The accuracy for diagnosis of sessile serrated adenoma/polyp(SSA/P) with high confidence utilizing MS classification was 93.2%.The differentiation of SSA/P from other lesions achieved Sp,Sn,PPV and NPV of 87.2%,91.5%,89.6% and 98.6%,respectively.The NPV for predicting adenomas in diminutive rectosigmoid polyps(n = 150) was 96.6% and 95% with MS and NICE respectively.The calculated accuracy of post-polypectomy surveillance for MS group was 98.2%(167 out of 170) and for NICE group was 92.1%(139 out of 151).CONCLUSION The MS classification outperformed the NICE classification in differentiating neoplastic polyps and predicting endoscopic resectability.Both classifications met ASGE PIVI thresholds.

Effects of Ginkgo Biloba Special Extract EGb 761^(█) in Very Mild Cognitive Impairment(vMCI)

Objective: To assess effects of EGb 761? on cognition and quality of life in subjects with very mild cognitive impair-ment. Methods: We randomized 300 subjects aged 45 to 65 with cognitive complaints and low functioning (more than one standard deviation below appropriate norm) in at least one cognitive test to double-blind treatment with once daily 240 mg EGb 761? or placebo for 12 weeks. Results: The exploratory intention-to-treat analysis showed significant im-provement (p < 0.025, one-sided) beyond practice effects for EGb 761? in a measure of attention (Vienna Test System - Work Performance Series) and trends in favour of EGb 761? in measures of memory (Wechsler Memory Scale III - Faces I, Appointments Test – delayed recall), and perceived physical health (SF36 - factor score Physical Health). Cognitive effects were more pronounced and more consistent (p < 0.025 in 4 of 5 tests) in subjects with lower memory function at baseline. Specifically, practice effects in the more demanding tests were attenuated or absent in these sub-jects. Conclusion: Ginkgo biloba extract EGb 761? improved cognitive functioning and aspects of quality of life in sub-jects with very mild cognitive impairment.

Acupuncture of different stimulation for the treatment of neck type cervical spondylosis:a randomised controlled trial

Objective:To observe the difference in clinical efficacy of acupuncture with strong and weak stimulation in treating neck type cervical spondylosis.Methods:64 patients with neck type cervical spondylosis were randomly divided into strong stimulation group and weak stimulation group,with 32 cases in each group.The acupoints selected are Jingjiaji 5-7(cervical acupoints EX-B2 C5-C7),Tianzhu(BL10)on both sides,Houxi(SI3)on both sides,Hegu(LI4)on both sides,Geshu(BL17)on both sides,and Ashi.In the strong stimulation group,deep needling with 0.25 mm×40 mm milli-needle was performed,with a mild reinforcing-reducing method.The twisting angle was 90°-180°,the frequency was 60-90 times/min,and the needles were applied for 1 min at each point.Keep the needle for 30 minutes,twisting was performed every 10 min during the retention period.Change hands once.In the weak stimulation group,shallow acupuncture with a 0.18 mm×40 mm milli-needle was performed,with a mild reinforcing-reducing method,with a twisting angle of 60°-90°,a frequency of 30-60 times/min,and acupuncture for 10 seconds at each acupoint.Keep the needle for 30 minutes,and no needle during the retention period.Patients in both groups were treated once every 1 to 2 days,3 times a week for 2 weeks,and followed up for 1 month after all treatments.The two groups of patients were compared before and after treatment and during follow-up.The McGill pain questionnaire score and the cervical spine dysfunction index score were compared to determine the clinical efficacy.Statistical analysis was performed using SPSS 22.0 statistical software.Results:1 case drop-out in the strong stimulation group and 1 case in the weak stimulation group.The total effective rate of the strong stimulation group was 90.32%,the total effective rate of the weak stimulation group was 83.87%,and the total effective rate of the strong stimulation group was higher than that of the weak stimulation group(P<0.05).The total scores of the short-form McGill pain questionnaire,the VAS score,and the cervical spine dysfunction index scores of the two groups of patients were significantly lower than those of this group before treatment,and the difference was statistically significant(P<0.05).The total scores of the short-form McGill pain questionnaire,visual analogue scale score,and cervical spine dysfunction index scores of the strong stimulation group after treatment and follow-up were significantly lower than those of the weak stimulation group(P<0.05).Conclusion:Acupuncture with strong and weak stimulation can effectively treat patients with cervical spondylosis,and deep acupuncture with filiform needles and strong stimulation have better effect.

Effects of perioperative rosuvastatin on postoperative delirium in elderly patients:A randomized,double-blind,and placebo-controlled trial

BACKGROUND Experimental evidence has indicated the benefits of statins for the treatment of postoperative delirium.Previously,clinical trials did not reach definite conclusions on the effects of statins on delirium.Some clinical trials have indicated that statins reduce postoperative delirium and improve outcomes,while some studies have reported negative results.AIM To evaluate whether perioperative rosuvastatin treatment reduces the incidence of delirium and improves clinical outcomes.METHODS This randomized,double-blind,and placebo-controlled trial was conducted in a single center in Jiangsu,China.This study enrolled patients aged greater than 60 years who received general anesthesia during elective operations and provided informed consent.A computer-generated randomization sequence(in a 1:1 ratio)was used to randomly assign patients to receive either rosuvastatin(40 mg/d)or placebo.Participants,care providers,and investigators were all masked to group assignments.The primary endpoint was the incidence of delirium,which was assessed twice daily with the Confusion Assessment Method during the first 7 postoperative days.Analyses were performed on intention-to-treat and safety populations.RESULTS Between January 1,2017 and January 1,2020,3512 patients were assessed.A total of 821 patients were randomly assigned to receive either placebo(n=411)or rosuvastatin(n=410).The incidence of postoperative delirium was significantly lower in the rosuvastatin group[23(5.6%)of 410 patients]than in the placebo group{42(13.5%)of 411 patients[odds ratios(OR)=0.522,95%confidence interval(CI):0.308-0.885;P<0.05]}.No significant difference in 30-d all-cause mortality(6.1%vs 8.7%,OR=0.67,95%CI:0.39-1.2,P=0.147)was observed between the two groups.Rosuvastatin decreased the hospitalization time(13.8±2.5 vs 14.2±2.8,P=0.03)and hospitalization expenses(9.3±2.5 vs 9.8±2.9,P=0.007).No significant differences in abnormal liver enzymes(9.0%vs 7.1%,OR=1.307,95%CI:0.787-2.169,P=0.30)or rhabdomyolysis(0.73%vs 0.24%,OR=3.020,95%CI:0.31-29.2,P=0.37)were observed between the two groups.CONCLUSION The current study suggests that perioperative rosuvastatin treatment reduces the incidence of delirium after an elective operation under general anesthesia.However,the evidence does not reveal that rosuvastatin improves clinical outcomes.The therapy is safe.Further investigation is necessary to fully understand the potential usefulness of rosuvastatin in elderly patients.

Hybrid Clustering Algorithms with GRASP to Construct an Initial Solution for the MVPPDP

Mobile commerce(m-commerce)contributes to increasing the popularity of electronic commerce(e-commerce),allowing anybody to sell or buy goods using a mobile device or tablet anywhere and at any time.As demand for e-commerce increases tremendously,the pressure on delivery companies increases to organise their transportation plans to achieve profits and customer satisfaction.One important planning problem in this domain is the multi-vehicle profitable pickup and delivery problem(MVPPDP),where a selected set of pickup and delivery customers need to be served within certain allowed trip time.In this paper,we proposed hybrid clustering algorithms with the greedy randomised adaptive search procedure(GRASP)to construct an initial solution for the MVPPDP.Our approaches first cluster the search space in order to reduce its dimensionality,then use GRASP to build routes for each cluster.We compared our results with state-of-the-art construction heuristics that have been used to construct initial solutions to this problem.Experimental results show that our proposed algorithms contribute to achieving excellent performance in terms of both quality of solutions and processing time.

Implementing Lagrangean Decomposition Technique to Acquire an Adequate Lower Boundon the Facility Location Problem Solution

In this work, the Lagrangean Relaxation method has been discussed to solve different sizes of capacitated facility location problem (CFLP). A good lower bound has been achieved on the solution of the CFLP considered in this paper. This lower bound has been improved by using the Volume algorithm. The methods of setting two important parameters in heuristic have been given. The approaches used to gain the lower bound have been explained. The results of this work have been compared with the known results given by Beasley.

Traditional Chinese manual acupuncture for management of obesity: A systematic review

AIM： To evaluate the effectiveness and safety ofacupuncture for the treatment of obesity by reviewing currently available randomised controlled trials.METHODS： This review followed the Cochrane Hand-book for Systematic Reviews of Interventions. Fifteen English and three Chinese databases were searched from their respective inceptions until July 2014. Key words used in the search consisted of acupuncture, needles, obesity, overweight, randomised trial and their synonyms. The risk of bias of included studies was assessed. The differences in effect size between acupuncture and control （including sham, no treatment, western medicine and dietary therapy/exercise） groups were compared using Cochrane Collaboration’s RevMan5.3 software.RESULTS： Two thousand six hundred and twenty-one records were identifed; after full-text articles assessed for eligibility, 9 of them met inclusion criteria. Majority of included studies had unclear or high risk of bias across all domains. All included studies had high or unclear risk of bias in randomisation, blinding and outcome data. Meta-analysis showed that acupuncture was more effective for reducing body weight and body mass index than no treatment group. Manual acupuncture was also superior to dietary therapy alone for decreasingbody weight. With dietary therapy as co-intervention, combined acupuncture group achieved lower body mass index than combined sham acupuncture group or dietary therapy alone group at the end of treatment period. No severe adverse events from acupuncture group were reported from all included studies.CONCLUSION： Due to the poor quality of included studies the effectiveness of acupuncture cannot be concluded. Better-designed, large-scale, randomised, sham-controlled clinical trials with long-term follow-up are needed.

Fate of meta-analyses: The case of Helicobacter pylori

AIM: To overview the current diversity of meta-analysis and the implementation of their results in international guidelines. METHODS: Relevant meta-analysis were identifiedfrom Pub Med/Medline. The topics of meta-analyses were determined. Some topics(genetics, extragastric tumors) were analysed separately. Core journals publishing meta-analyses on Helicobacter pylori were ranked. The rate of citation of meta-analysis in major guidelines was calculated. RESULTS: Between 1992 and 2014, some 356 metaanalyses were published on Pub Med. These mainly appeared in core journals, but were also found in 128 other journals. Eradicating of the infection was the most addressed topic with 134 articles. Meta-analyses were rarely used in formulating statements and recommendations in the international guidelines. In other topics- genetics, extraintestinal manifestations-meta-analyses were rather overused. CONCLUSION: The implementation of meta-analysis in current guidelines is rather rare, while other topics benefit from many studies. A more extensive use of metaanalyses in evidence-based medicine is recommended in the future, otherwise their continuous proliferation will lose reason and scientific significance.