Adjuvant treatment strategies in ovarian stimulation for poor responders undergoing IVF: a systematic review and network meta-analysis.

BACKGROUND: Despite great advances in assisted reproductive technology, poor ovarian response (POR) is still considered as one of the most challenging tasks in reproductive medicine. OBJECTIVE AND RATIONALE: The aim of this systemic review is to evaluate the role of different adjuvant treatment strategies on the probability of pregnancy achievement in poor responders undergoing IVF. Randomized controlled trials (RCTs) comparing 10 adjuvant treatments [testosterone, dehydroepiandrosterone (DHEA), letrozole, recombinant LH, recombinant hCG, oestradiol, clomiphene citrate, progesterone, growth hormone (GH) and coenzyme Q10 (CoQ10)] were included. SEARCH METHODS: Relevant studies published in the English language were comprehensively selected using PubMed, Embase and the Cochrane Central Register of Controlled Trials (CENTRAL) until 11 July 2018. We included studies that investigated various adjuvant agents, including androgen and androgen-modulating agents, oestrogen, progesterone, clomiphene citrate, GH and CoQ10, during IVF treatment and reported subsequent pregnancy outcomes. The administration of GnRH analogs and gonadotrophins without adjuvant treatment was set as the control. We measured study quality based on the methodology and categories listed in the Cochrane Collaboration Handbook. This review protocol was registered with PROSPERO (CRD42018086217). OUTCOMES: Of the 1124 studies initially identified, 46 trials reporting on 6312 women were included in this systematic review, while 19 trials defining POR using the Bologna criteria reporting 2677 women were included in the network meta-analysis. Compared with controls, DHEA and CoQ10 treatments resulted in a significantly higher chance of clinical pregnancy [odds ratio (OR) 2.46, 95% CI 1.16 to 5.23; 2.22, 1.08-4.58, respectively]. With regard to the number of retrieved oocytes, HCG, oestradiol and GH treatments had the highest number of oocytes retrieved [weighted mean difference (WMD) 2.08, 0.72 to 3.44; 2.02, 0.23 to 3.81; 1.72, 0.98 to 2.46, compared with controls, respectively]. With regard to the number of embryos transferred, testosterone and GH treatment led to the highest number of embryos transferred (WMD 0.72, 0.11 to 1.33; 0.67, 0.43 to 0.92; compared with controls, respectively). Moreover, GH resulted in the highest oestradiol level on the HCG day (WMD 797.63, 466.45 to 1128.81, compared with controls). Clomiphene citrate, letrozole and GH groups used the lowest dosages of gonadotrophins for ovarian stimulation (WMD 1760.00, -2890.55 to -629.45; -1110.17, -1753.37 to -466.96; -875.91, -1433.29 to -282.52; compared with controls, respectively). CoQ10 led to the lowest global cancelation rate (OR 0.33, 0.15 to 0.74, compared with controls). WIDER IMPLICATIONS: For patients with POR, controlled ovarian stimulation protocols using adjuvant treatment with DHEA, CoQ10 and GH showed better clinical outcomes in terms of achieving pregnancy, and a lower dosage of gonadotrophin required for ovulation induction. Furthermore, high-level RCT studies using uniform standards for POR need to be incorporated into future meta-analyses.

Systematic review of controlled clinical studies using umbilical cord blood for regenerative therapy: Identifying barriers to assessing efficacy.

Clinical use of umbilical cord blood (UCB) for novel indications in regenerative therapy continues to rise, however, whether new indications are proven is less clear. An updated systematic search of the literature, focusing only on controlled clinical studies, is needed to properly assess potential efficacy. After updating our systematic search to April 1, 2018 (PROSPERO protocol CRD42016040157), a total of 16 studies were identified that addressed the treatment of cerebral palsy (four studies), type 1 diabetes (three studies), and nine other novel potential indications where only a single controlled study was identified. In the four controlled studies of patients with cerebral palsy, three used allogeneic cells and reported greater improvement in motor-related scores at 1, 3 and 6 months compared with controls. The results were mixed for other scores at other time points, including additional measures of mental and motor function. One study of autologous UCB treatment reported an improvement in motor function scores at 12 months compared with controls. In the three controlled studies of type 1 diabetes, two studies used autologous cells whereas one used allogeneic cord blood cells to "educate" autologous lymphocytes. Taken together, there was no clear difference in HbA1c levels or daily insulin requirements between treated patients and controls. For the nine published reports with a single controlled study, eight used allogeneic UCB cells and seven infused mesenchymal stromal cells derived from UCB. All but one study reported benefit. Many other published reports that lack a control group were not included in our analysis. More controlled studies are needed that use similar approaches regarding cell source and outcome measures at similar time points. Pooled estimates of results from multiple studies will be essential as published studies remain modest in size. Patients should continue to be enrolled in clinical trials because there are no novel potential indications remain unproven.

Fractures in Adults After Weight Loss from Bariatric Surgery and Weight Management Programs for Obesity: Systematic Review and Meta-analysis.

BACKGROUND: Weight loss interventions for obesity, such as bariatric surgery, are associated with reductions in bone mineral density and may increase the risk of fractures. We undertook a systematic review and meta-analysis of bariatric surgery and lifestyle weight management programs (WMPs) with fracture outcomes. METHODS: We searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials from 1966 to 2018, and our trial registry of WMP randomized controlled trials (RCTs). We included RCTs, non-randomized trials, and observational studies of bariatric surgery, and RCTs of WMPs. Studies had follow-up ≥ 12 months, mean group body mass index ≥ 30 kg/m2. The primary outcome measure was incidence of any type of fracture in participants, and the secondary outcome was weight change. We used random effects meta-analysis for trial data. RESULTS: Fifteen studies were included. Three small trials provided short-term evidence of the association between bariatric surgery and participants with any fracture (365 participants; RR 0.82; 95% CI 0.29 to 2.35). Four out of six observational studies of bariatric surgery demonstrated significantly increased fracture risk. Six RCTs of WMPs with 6214 participants, the longest follow-up 11.3 years, showed no clear effect on any type of fracture (RR 1.04; 95% CI 0.91 to 1.18), although authors of the largest RCT reported an increased risk of frailty fracture by their definition (RR 1.40; 95% CI 1.04 to 1.90). CONCLUSION: Bariatric surgery appears to increase the risk of any fracture; however, longer-term trial data are needed. The effect of lifestyle WMPs on the risk of any fracture is currently unclear.

Ensayos clínicos publicados en el Boletín Médico del Hospital Infantil de México: un análisis crítico / Clinical trials published in the Boletín Médico del Hospital Infantil de México: a critical analysis

Resumen Introducción: El ensayo clínico es la manera más rigurosa de conducir los experimentos en seres humanos. Desde su introducción en investigación biomédica se han implementado cambios en el modo de establecer las bases para el diagnóstico, pronóstico y la terapéutica en la práctica clínica. Se han realizado estudios para identificar los ensayos clínicos publicados en diferentes áreas médicas, pero hasta el momento ninguno había identificado los ensayos clínicos publicados en el Boletín Médico del Hospital Infantil de México (BMHIM). El objetivo de este trabajo fue identificar y describir los ensayos clínicos controlados (ECC) publicados en el BMHIM. Métodos: Se realizó búsqueda manual y sistemática en cada uno de los números y volúmenes del BMHIM de 1968 a 2016. Se registraron los ECC para obtener sus principales características. Adicionalmente, se evaluó su calidad metodológica mediante la herramienta de riesgo de sesgo. Los resultados se presentan de forma descriptiva, gráfica y temporal. Resultados: Se revisaron 73 números con 363 volúmenes, analizando 4925 artículos. La proporción de ECC identificados en el BMHIM fue del 1% (67/4925). En general, los ensayos clínicos se realizaron en el contexto nacional, en el tercer nivel de atención, con un tamaño de muestra reducido, y las intervenciones farmacológicas fueron las más utilizadas. La calidad metodológica de los estudios fue baja, con alto riesgo de sesgo. Conclusiones: Los ensayos clínicos representan el 1% de todos los artículos de investigación originales publicados en el BMHIM. Aún existen áreas de investigación pediátrica, las cuales requieren del desarrollo de ECC para mejorar la práctica clínica, así como para elevar la calidad de la investigación.

Abstract Background: Controlled clinical trials (CCT) are the study design with the highest accuracy and evidence level. From its introduction in biomedical research, changes have been implemented in the way of establishing the basis for diagnosis, prognosis and treatment in clinical practice. Studies to identify published CCTs regarding different medical fields have been carried out. To date, none of them has identified the clinical trials that have been published in the Boletín Médico del Hospital Infantil de México (BMHIM). The aim of this study was to identify and describe the controlled clinical trials published in the BMHIM. Methods: A manual and systematic search was performed in each of the volumes of the BMHIM from 1968 to 2016. CCTs were recorded to obtain their main characteristics. Additionally, their methodological quality was assessed through the "risk of bias" tool. Results are presented in a descriptive, graphic and time-based manner. Results: In total, 73 issues with 363 volumes were reviewed, and 4925 articles were analyzed. The proportion of CCTs identified in the BMHIM was 1% (67/4925). In general, clinical trials were performed in the national context and in the third-level of medical care. CCTs also presented reduced sample sizes; pharmacological interventions were the most frequent. The methodological quality of the studies was low with a high risk of bias. Conclusions: Clinical trials represented 1% of all the original research articles published in the BMHIM. There are still pediatric research fields that require CCTs to be developed in order to improve clinical practice, as well as to increase the quality of the research.

Controlled multi-arm platform design using predictive probability.

The process of screening agents one-at-a-time under the current clinical trials system suffers from several deficiencies that could be addressed in order to extend financial and patient resources. In this article, we introduce a statistical framework for designing and conducting randomized multi-arm screening platforms with binary endpoints using Bayesian modeling. In essence, the proposed platform design consolidates inter-study control arms, enables investigators to assign more new patients to novel therapies, and accommodates mid-trial modifications to the study arms that allow both dropping poorly performing agents as well as incorporating new candidate agents. When compared to sequentially conducted randomized two-arm trials, screening platform designs have the potential to yield considerable reductions in cost, alleviate the bottleneck between phase I and II, eliminate bias stemming from inter-trial heterogeneity, and control for multiplicity over a sequence of a priori planned studies. When screening five experimental agents, our results suggest that platform designs have the potential to reduce the mean total sample size by as much as 40% and boost the mean overall response rate by as much as 15%. We explain how to design and conduct platform designs to achieve the aforementioned aims and preserve desirable frequentist properties for the treatment comparisons. In addition, we demonstrate how to conduct a platform design using look-up tables that can be generated in advance of the study. The gains in efficiency facilitated by platform design could prove to be consequential in oncologic settings, wherein trials often lack a proper control, and drug development suffers from low enrollment, long inter-trial latency periods, and an unacceptably high rate of failure in phase III.

Estimation in multi-arm two-stage trials with treatment selection and time-to-event endpoint.

We consider estimation of treatment effects in two-stage adaptive multi-arm trials with a common control. The best treatment is selected at interim, and the primary endpoint is modeled via a Cox proportional hazards model. The maximum partial-likelihood estimator of the log hazard ratio of the selected treatment will overestimate the true treatment effect in this case. Several methods for reducing the selection bias have been proposed for normal endpoints, including an iterative method based on the estimated conditional selection biases and a shrinkage approach based on empirical Bayes theory. We adapt these methods to time-to-event data and compare the bias and mean squared error of all methods in an extensive simulation study and apply the proposed methods to reconstructed data from the FOCUS trial. We find that all methods tend to overcorrect the bias, and only the shrinkage methods can reduce the mean squared error. © 2017 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd.

Effect of dipeptidyl peptidase-4 inhibitors on circulating tumor necrosis factor-α concentrations: A systematic review and meta-analysis of controlled trials.

OBJECTIVE: Dipeptidyl peptidase-4 (DPP-4) inhibitors improve glycemic control in patients with type 2 diabetes mellitus. There are also reports of an effect of these drugs in reducing inflammation through inhibition of tumor necrosis factor-α (TNF-α) that is an important mediator for several inflammatory processes. The present systematic review and meta-analysis were performed to evaluate the effect of DPP-4 inhibitors on circulating TNF-α levels in T2DM patients. METHODS: A systematic review and a meta-analysis were undertaken on all controlled trials of DPP-4 inhibitors that included measurement of TNF-α. The search included PubMed-Medline, Scopus, ISI Web of Knowledge and Google Scholar databases. Quantitative data synthesis was performed using a random-effects model, with standardized mean difference (SMD) and 95% confidence interval (CI) as summary statistics. Meta-regression and leave-one-out sensitivity analysis were performed to assess the modifiers of treatment response. RESULTS: Eight eligible articles (6 with sitagliptin and 2 with vildagliptin) comprising 9 treatment arms were selected for this meta-analysis. Meta-analysis suggested a significant reduction of circulating TNF-α concentrations following treatment with DPP-4 inhibitors (SMD: -1.84, 95% CI: -2.88, -0.80, p=0.001). The effect size was robust in the sensitivity analysis and not mainly driven by a single study. A subgroup analysis did not suggest any significant difference between the TNF-α-lowering activity of sitagliptin (SMD: -1.49, 95% CI: -2.89, -0.10) and vildagliptin (SMD: -2.80, 95% CI: -4.98, -0.61) (p=0.326). CONCLUSION: This meta-analysis of the 8 available controlled trials showed that DPP-4 inhibition in patients with type 2 diabetes mellitus was associated with significant reductions in plasma TNF-α levels with no apparent difference between sitagliptin and vildagliptin.

Effectiveness of mild ovarian stimulation versus GnRH agonist protocol in women undergoing assisted reproductive technology: a meta-analysis.

OBJECTIVE: our meta-analysis was conducted to evaluate the effectiveness of the mild ovulation induction protocol using CC/gonadotropin/GnRH antagonist compared to the conventional GnRH agonist protocol in women undergoing ART. METHOD: Six electronic databases were searched from their date of establishment until August 2016. Outcomes in our analysis were calculated in terms of relative risk (RR) and weighted mean differences (WMD) and standard mean differences (SMD) with 95% confidence intervals (CI) using random effect models or fixed effect models. RESULTS: Six prospective controlled clinical trials with 1543 women comparing the clinical impacts of the two protocols were included. The synthesized results suggested a significant reduction in the quantity of gonadotropins (SMD: -1.96, 95% CI: -2.28 to 1.64, I2 = 78.5%), the incidence of OHSS (RR: 0.16, 95% CI 0.03-0.86, I2 = 0%) and an increase in the cycle cancelation rate (RR: 1.46, 95% CI 1.05-2.03, I2 = 89.4%). While no evidence of statistically significant differences between the groups existed in the other clinical outcomes. CONCLUSION: This study suggested that the probable benefits of the mild protocol, including its less costs and safer process without reducing the overall IVF treatment success rates, seemed to make it a better treatment option. Larger sample prospective trials evaluating live birth, clinical pregnancy, OHSS, multiple pregnancy incidence and so on were desired to establish.

The effects of spiritual interventions in patients with cancer: a meta-analysis.

PURPOSE/OBJECTIVES: To evaluate the effects of a spiritual intervention in patients with cancer. DATA SOURCES: Databases searched included both international electronic databases (MEDLINE® via PubMed, Cochrane Library CENTRAL, EMBASE, and CINAHL®) as well as Korean electronic databases (KMBASE, KOREAMED, RISS, KISS, and NANET) through December 2013. DATA SYNTHESIS: A meta-analysis was conducted of 15 studies involving 14 controlled trials (7 randomized and 7 nonrandomized) with 889 patients with cancer. Spiritual interventions were compared with a usual care control group or other psychosocial interventions. The weighted average effect size across studies was -0.48 (p = 0.006, I2 = 65%) for spiritual well-being, -0.58 (p = 0.02, I2 = 70%) for meaning of life, -0.87 (p = 0.02, I2 = 87%) for anxiety, and -0.62 (p = 0.001, I2 = 73%) for depression. CONCLUSIONS: The findings showed that spiritual interventions had significant but moderate effects on spiritual well-being, meaning of life, and depression. However, the evidence remains weak because of the mixed study design and substantial heterogeneity. IMPLICATIONS FOR NURSING: Oncology nurses increasingly recognize the significance of the spiritual domain of care. The current study indicates that facilitating spiritual awareness and needs may be a worthwhile nursing intervention for patients with cancer.

Failure to address potential bias in non-randomised controlled clinical trials may cause lack of evidence on patient-reported outcomes: a method study.

OBJECTIVES: We conducted a workup of a previously published systematic review and aimed to analyse why most of the identified non-randomised controlled clinical trials with patient-reported outcomes did not match a set of basic quality criteria. SETTING: There were no limits on the level of care and the geographical location. PARTICIPANTS: The review evaluated permanent interstitial low-dose rate brachytherapy in patients with localised prostate cancer and compared that intervention with alternative procedures such as external beam radiotherapy, radical prostatectomy and no primary therapy. PRIMARY OUTCOME MEASURE: Fulfilment of basic inclusion criteria according to a Participants, Interventions, Comparisons, Outcomes (PICO) framework and accomplishment of requirements to contain superimposed risk of bias. RESULTS: We found that 21 of 50 excluded non-randomised controlled trials did not meet the PICO inclusion criteria. The remaining 29 studies showed a lack in the quality of reporting. The resulting flaws included attrition bias due to loss of follow-up, lack of reporting baseline data, potential confounding due to unadjusted data and lack of statistical comparison between groups. CONCLUSIONS: With respect to the reporting of patient-reported outcomes, active efforts are required to improve the quality of reporting in non-randomised controlled trials concerning permanent interstitial low-dose rate brachytherapy in patients with localised prostate cancer.

[Cost-effectiveness of buccal midazolam in the treatment of prolonged convulsive seizures in the outpatient setting in Spain]. / Coste-efectividad de una solucion bucal de midazolam en el tratamiento de las crisis convulsivas prolongadas en el entorno ambulatorio en España.

INTRODUCTION: To be able to treat prolonged epileptic crises practical, safe and effective rescue medication is needed. Today, the standard treatment in community healthcare is rectal diazepam. The introduction of a buccal solution of midazolam opens up a new perspective in their treatment. AIMS: To evaluate the cost-effectiveness of buccal midazolam with respect to rectal diazepam for children diagnosed with epilepsy who present prolonged convulsive seizures in the community setting in Spain. MATERIALS AND METHODS: The study produces a model of its cost-effectiveness from the perspective of the Spanish National Health System (SNS), with the outcomes presented in terms of cost-quality adjusted life years. Data were collected from different sources, including estimations regarding the clinical effectiveness from a clinical trial, from a Delphi panel in Spain and from a national survey carried out on parents of children with epilepsy in order to determine the current practices. RESULTS: Treatment with buccal midazolam produces a saving in costs in comparison to rectal diazepam. The amount saved by the Spanish SNS comes to 5,484 euros per patient per year. Treatment with buccal midazolam offers an improved health-related quality of life. This, together with the savings in costs, means that there is a dominance of buccal midazolam over rectal diazepam in all the settings that have been examined. CONCLUSIONS: The results obtained with the model show that buccal midazolam is more cost-effective than rectal diazepam due to a reduction in the need to call out ambulances and for stays in hospital, as well as an improved health-related quality of life.

TITLE: Coste-efectividad de una solucion bucal de midazolam en el tratamiento de las crisis convulsivas prolongadas en el entorno ambulatorio en España.Introduccion. El tratamiento de las crisis epilepticas prolongadas requiere disponer de una medicacion de rescate comoda, segura y efectiva. Actualmente, el tratamiento estandar en la comunidad es el diacepam rectal. La introduccion de una solucion bucal de midazolam abre una perspectiva nueva en el tratamiento. Objetivo. Evaluar el coste-efectividad del midazolam bucal respecto al diacepam rectal para los niños con un diagnostico de epilepsia que presentan crisis convulsivas prolongadas en la comunidad en España. Materiales y metodos. Modelo coste-efectividad desde la perspectiva del Sistema Nacional de Salud (SNS) español, con resultados presentados en terminos de costes y años de vida ajustados por calidad. Los datos se obtuvieron de varias fuentes, incluidas las estimaciones de efectividad clinica de un ensayo clinico, de un panel Delphi en España y de una encuesta nacional a padres de niños con epilepsia para determinar las practicas actuales. Resultados. El tratamiento con midazolam bucal produce un ahorro de costes en comparacion con el diacepam rectal. El ahorro para el SNS español es de 5.484 euros por paciente al año. El tratamiento con midazolam bucal ofrece una mejora en la calidad de vida relacionada con la salud. Esto, unido al ahorro de costes, hace que el midazolam bucal sea dominante frente al diacepam rectal en todos los escenarios examinados. Conclusion. Los resultados del modelo muestran que el midazolam bucal es mas coste-efectivo que el diacepam rectal debido a una reduccion en la necesidad de llamadas a la ambulancia y estancias en el hospital, asi como a una mejora en la calidad de vida relacionada con la salud.

Model-based estimates of long-term persistence of induced HPV antibodies: a flexible subject-specific approach.

In infectious diseases, it is important to predict the long-term persistence of vaccine-induced antibodies and to estimate the time points where the individual titers are below the threshold value for protection. This article focuses on HPV-16/18, and uses a so-called fractional-polynomial model to this effect, derived in a data-driven fashion. Initially, model selection was done from among the second- and first-order fractional polynomials on the one hand and from the linear mixed model on the other. According to a functional selection procedure, the first-order fractional polynomial was selected. Apart from the fractional polynomial model, we also fitted a power-law model, which is a special case of the fractional polynomial model. Both models were compared using Akaike's information criterion. Over the observation period, the fractional polynomials fitted the data better than the power-law model; this, of course, does not imply that it fits best over the long run, and hence, caution ought to be used when prediction is of interest. Therefore, we point out that the persistence of the anti-HPV responses induced by these vaccines can only be ascertained empirically by long-term follow-up analysis.

Coil embolization versus clipping for ruptured intracranial aneurysms: a meta-analysis of prospective controlled published studies.

BACKGROUND AND PURPOSE: Coil embolization is an alternative to clipping for intracranial aneurysms. However, controversy exists regarding the best therapeutic strategy in patients with ruptured aneurysms, and there is great center- and country-related variability in the rates of clipping versus coiling. We performed a meta-analysis of prospective controlled trials of clipping versus coil embolization for ruptured aneurysms. MATERIALS AND METHODS: We performed a search of the English literature for published prospective controlled trials comparing surgical clipping with endovascular coil embolization for ruptured intracranial aneurysms. Data were abstracted from the identified references. Outcomes of interest were the proportion of patients with a poor outcome at 1 year and episodes of rebleeding from the index treated aneurysm after the allocated treatment. RESULTS: There were 3 prospective controlled trials eligible for inclusion. These studies enrolled 2723 patients. Meta-analysis of these studies showed that the rate of poor outcome at 1 year was significantly lower in patients allocated to coil embolization (risk ratio, 0.75; 95% confidence interval, 0.65-0.87). This relative effect is consistent with an absolute risk reduction of 7.8% and a number needed to treat of 13. The effect on mortality was not statistically different across the 2 treatments. Rebleeding rates within the first month were higher in patients allocated to endovascular coil embolization. CONCLUSIONS: On the basis of the analysis of the 3 high-quality prospective controlled trials available, there is strong evidence to indicate that endovascular coil embolization is associated with better outcomes compared with surgical clipping in patients amenable to either therapeutic strategy.

Laparoscopy for rectal cancer reduces short-term mortality and morbidity: results of a systematic review and meta-analysis.

BACKGROUND: Although definitive long-term results are not yet available, the global safety of laparoscopic surgery for rectal cancer treatment remains controversial. We evaluated differences in the safety of laparoscopic rectal resection versus open surgery for cancer. METHODS: A systematic review from 2000 to 2011 was performed searching the Medline and Embase databases (prospero registration CRD42012002406). We included randomized and prospective controlled clinical studies comparing laparoscopic and open resection for rectal cancer. Primary end points were 30-day mortality and overall morbidity. Then a meta-analysis was conducted by a fixed-effect model, performing a sensitivity analysis by a random-effect model. Relative risk (RR) was used as an indicator of treatment effect; a RR of less than 1.0 was in favor of laparoscopy. Publication bias was assessed by funnel plot and heterogeneity by the I (2) test and subgroup analysis on surgical and medical complications. RESULTS: Twenty-three studies, representing 4,539 patients, met the inclusion criteria; eight were randomized for a total of 1,746 patients. Mortality was observed in 1.0 % of patients in the laparoscopic group and in 2.4 % of patients in the open group. The overall RR was 0.46 (95 % confidence interval 0.21-0.99, p = 0.048). The raw incidence of overall complications was lower in the laparoscopic group (31.8 %) compared to the open group (35.4 %). The overall RR was 0.83 (95 % confidence interval 0.76-0.91, p < 0.001). CONCLUSIONS: On the basis of evidence of both randomized and prospective controlled series, mortality and morbidity RR, including subgroup analysis, were significantly lower after laparoscopic compared to open surgery.

Accurate mean comparisons for paired samples with missing data: an application to a smoking-cessation trial.

In this paper, we consider mean comparisons for paired samples in which a certain portion of the observations are missing. This type of data commonly arises in medical researches where the outcomes are assessed at two time points after the application of treatments. New methods for statistical inference are proposed by making finiteness correction based on asymptotic expansions of some intuitive statistics. The comparison methods naturally extend to the two-group case after some suitable manipulations. Simulation study is carried out to demonstrate the numerical accuracy of the proposed methods. Data from a smoking-cessation trial are used to illustrate the application of the methods.

Comparing the effectiveness of infertility treatments by numbers needed to treat (NNT).

To compare the clinical efficiency of different modes of treatment of infertile couples and to estimate the possible benefit of nutraceutical food supplementation (NFS), the numbers needed to treat (NNT) was calculated in 4143 infertile couples based on controlled trials in recent literature and personal data. The NNT expresses the number of individuals who need to be treated to obtain one complementary pregnancy. In female infertility, the NNT of mild or moderate endometriosis was 8.4, and in anti-estrogens treatment of anovulation, it was 5.9. In tamoxifen treatment of idiopathic oligozoospermia, NNT was 3.9, and in antioxidant supplementation, it was 7.8. Treatment of varicocele yielded NNT of 6.3 and 6.8 after 1 year in multi- or single-centre trials, respectively, and NFS lowered the NNT after 3 months to 2.6. Adding NFS to the male partner increased the ongoing pregnancy rate by IVF with NNT of 8.3, and adding NFS to both partners reduced the NNT to 4.0. Although these results were obtained in heterogeneous trials and populations, it is suggested that the NNT should be useful for comparing the effectiveness of different modes of treatment of the infertile couple, and that complementary nutraceutical food supplementation may be beneficial.

Integrated safety analysis: short- and long-term safety profiles of etanercept in patients with psoriasis.

BACKGROUND: Multiple trials demonstrate the tolerability and safety of etanercept. However, there are limited data on etanercept tolerability in large populations of patients with psoriasis or with extended therapy. OBJECTIVES: We sought to determine whether there is an increased safety risk associated with higher etanercept doses or with extended exposure in patients with psoriasis. METHODS: Integrated adverse event (AE) data from etanercept psoriasis trials were used to evaluate short-term (up to 12 weeks from controlled studies) and long-term (up to 144 weeks from uncontrolled extension studies) safety of etanercept (25 mg once weekly to 50 mg twice weekly). Long-term data were stratified by treatment regimens. Rates of noninfectious and infectious AE and standardized incidence ratios for malignancies were determined. RESULTS: In short-term analyses, rates of noninfectious and infectious AE and serious noninfectious and infectious AE were comparable between placebo and etanercept groups. In both short- and long-term analyses, there were no dose-related increases in these events. Cumulative event rates for serious infections were not significantly different across dose groups and over time. The standardized incidence ratios for malignancies excluding nonmelanoma skin cancers did not achieve statistical significance. There was no increase in overall malignancies with etanercept therapy compared with the psoriasis population. Lymphoma (n = 2 patients), demyelination (n = 2), congestive heart failure (n = 7), and opportunistic infection (n = 1) were rare. LIMITATIONS: Study limitations include the rarity of some events and the resultant broad 95% confidence intervals. CONCLUSIONS: In this integrated analysis, etanercept was well tolerated, and there were no signs of dose-related or cumulative toxicity over time.

Rationale for and methods of superiority, noninferiority, or equivalence designs in orthopaedic, controlled trials.

BACKGROUND: To provide value-based healthcare in orthopaedics, controlled trials are needed to assess the comparative effectiveness of treatments. Typically comparative trials are based on superiority testing using statistical tests that produce a p value. However, as orthopaedic treatments continue to improve, superiority becomes more difficult to show and, perhaps, less important as margins of improvement shrink to clinically irrelevant levels. Alternative methods to compare groups in controlled trials are noninferiority and equivalence. It is important to equip the reader of the orthopaedic literature with the knowledge to understand and critically evaluate the methods and findings of trials attempting to establish superiority, noninferiority, and equivalence. QUESTIONS/PURPOSES: I will discuss supplemental and alternative methods to superiority for assessment of the outcome of controlled trials in the context of diminishing returns on new therapies over old ones. METHODS: The three methods-superiority, noninferiority, and equivalence-are presented and compared, with a discussion of implied pitfalls and problems. RESULTS: Noninferiority and equivalence offer alternatives to superiority testing and allow one to judge whether a new treatment is no worse (within a margin) or substantively the same as an active control. Noninferiority testing also allows for inclusion of superiority testing in the same study without the need for adjustment of the statistical methods. CONCLUSIONS: Noninferiority and equivalence testing might prove most valuable in orthopaedic, controlled trials as they allow for comparative assessment of treatments with similar primary end points but potentially important differences in secondary outcomes, safety profiles, and cost-effectiveness.

Inguinal hernia after radical prostatectomy for prostate cancer: results from a randomized setting and a nonrandomized setting.

BACKGROUND: Observational data indicate that retropubic radical prostatectomy (RRP) for prostate cancer (PCa) may induce inguinal hernia (IH) formation. Little is known about the influence of robot-assisted radical prostatectomy (RALP) on IH risk. OBJECTIVE: To compare the incidence of IH after RRP and RALP to that of nonoperated patients with PCa and to a population control. DESIGN, SETTING, AND PARTICIPANTS: We studied two groups. All 376 men included in the Scandinavian Prostate Cancer Group Study Number 4 constitute study group 1. Patients were randomly assigned RRP or watchful waiting (WW). The 1411 consecutive patients who underwent RRP or RALP at Karolinska University Hospital constitute study group 2. Men without PCa, matched for age and residence to each study group, constitute controls. MEASUREMENTS: Postoperative IH incidence was detected through a validated questionnaire. The participation rates were 82.7% and 88.4% for study groups 1 and 2, respectively. RESULTS AND LIMITATIONS: The Kaplan-Meier cumulative occurrence of IH development after 48 mo in study group 1 was 9.3%, 2.4%, and 0.9% for the RRP, the WW, and the control groups, respectively. There were statistically significant differences between the RRP group and the WW and control groups, but not between the last two. In study group 2 the cumulative risk of IH development at 48 mo was 12.2%, 5.8%, and 2.6% for the RRP, the RALP, and the control group, respectively. There were statistically significant differences between the RRP group and the RALP and control groups, but not between the last two. CONCLUSIONS: RRP for PCa leads to an increased risk of IH development. RALP may lower the risk as compared to open surgery.