Clinical Study on the Eradication of Helicobacter pylori by Vonoprazan Combined with Amoxicillin for 10-Day Dual Therapy.

Vonoprazan holds significant research promise for Helicobacter pylori eradication, with the goal of determining the most effective drug regimen. In this study, H. pylori patients (426) were enrolled and randomized into 3 groups: an EA14 group (20 mg of esomeprazole qid and 1000 mg of amoxicillin tid for 14 days), a VA14 group (20 mg of vonoprazan bid and 750 mg of amoxicillin qid for 14 days), and a VA10 group (20 mg of vonoprazan bid and 1000 mg of amoxicillin tid for 10 days). Key outcomes encompassed the H. pylori eradication rate, patient adverse effects, and compliance. In the EA14, VA14, and VA10 groups, H. pylori eradication rates were 89.4%, 90.1%, and 88.7% in intention-to-treat analysis, and 94.2%, 94.4%, and 94.6% in per-protocol analysis, respectively. Adverse events incidences were 14.8%, 12.7%, and 5.6%, while compliance rates were 88.7%, 90.9%, and 95.8%, respectively. Notably, the VA10 regimen demonstrated comparable H. pylori eradication rates, adverse effect incidences, and compliance levels to the EA14 and VA14 regimens.

Early extracorporeal CPR for refractory out-of-hospital cardiac arrest - A pre-planned per-protocol analysis of the INCEPTION-trial.

BACKGROUND: Evidence for extracorporeal cardiopulmonary resuscitation (CPR) in refractory out-of-hospital cardiac arrest (OHCA) remains inconclusive. Recently, the INCEPTION-trial, comparing extracorporeal with conventional CPR, found no statistically significant difference in neurologically favorable survival. Since protocol deviations were anticipated, a pre-specified per-protocol analysis was foreseen. METHODS: The per-protocol analysis of the INCEPTION trial excluded patients not meeting inclusion or exclusion criteria, amongst which time-to-cannulation of >60 minutes, and achieving a return of spontaneous circulation before hospital arrival. Crossovers were excluded as well. The primary outcome (30-day survival in a neurologically favorable condition; cerebral performance category [CPC] 1-2) was primarily analyzed under a frequentist statistical framework. In addition, Bayesian analysis under a minimally informative prior was performed. RESULTS: Eighty-one patients were included in the per-protocol analysis (extracorporeal CPR n = 33, conventional CPR n = 48). Thirty-day survival with CPC1-2 was 15% in the extracorporeal CPR group versus 9% in the conventional CPR group (adjusted OR 1.9; 95% CI 0.4-9.3; p-value 0.393). Bayesian analysis showed an 84% posterior probability of any ECPR benefit and a 61% posterior probability of a 5% absolute risk reduction for the primary outcome. CONCLUSION: A pre-planned, pre-specified per-protocol analysis of the INCEPTION-trial, found a higher survival with favorable neurological in patients undergoing ECPR versus CCPR for refractory shockable OHCA. This difference did not reach statistical significance, but results should be interpreted with care, in the light of the small remaining sample size.

Common misunderstandings of evidence-based medicine.

Currently, most evidence assessments in guidelines or health technology assessments (HTAs) rely on the assumption that a randomized controlled trial (RCT) is always the best source of evidence. However, if the outcome in a control group is certain, e.g. death within a short time with an almost 100% chance, or if an event can only occur in the treatment group, there is no need for a randomized control group; the evidence cannot be improved by a control group, nor by an RCT design. If a cause-effect relationship is certain ("primary or direct evidence"), a therapeutic effect can be diluted in the population of an RCT by cross-over, etc. This can lead to serious misinterpretations of the effect. While experts such as the GRADE group or Cochrane institutes recommend using all available evidence, the leading approach in many guidelines and HTAs is assessing "the best available trials", i.e. RCTs. But since RCTs only deliver probabilities of cause-effect relationships, it is not appropriate to demand RCTs for certain effects. A control group can only diminish the net value of a treatment since the outcome in the control group is subtracted from the outcome in the treatment group. Therefore, under identical circumstances, an RCT will always show lower effect rates compared to a single arm study of the same quality, for desired as well as for adverse effects. Considering these inconsistencies in evidence-based medicine interpretation, the evidence pyramid with RCTs at the top is not always a reliable indicator for the best quality of evidence.

Achieved systolic blood pressure and cardiovascular outcomes in 60-80-year-old patients: the Strategy of Blood Pressure Intervention in the Elderly Hypertensive Patients (STEP) trial.

AIMS: Intensive systolic blood pressure (SBP) lowering has been increasingly used; however, data is missing on patients who had target-achieved (TA). This study aims to show the cardiovascular effect of maintaining SBP at intensive levels. METHODS: The Strategy of Blood Pressure Intervention in Elderly Hypertensive Patients (STEP) trial was a multicentre, randomized, controlled trial which enrolled 8511 young-older (60-80 years) hypertensive patients without prior stroke to compare the cardiovascular prognosis of the intensive treatment (SBP target, 110 to <130 mmHg) vs. the standard treatment (130 to <150 mmHg). This secondary analysis assessed data in patients who achieved a mean SBP within target values. The association of mean achieved SBP and cardiovascular events was examined using a cubic spline function. RESULTS: In total, 3053 patients (72.0%) in the intensive-treatment group and 3427 (80.3%) in the standard-treatment group had an SBP target achieved, with mean follow-up SBP values of 124.2 mmHg and 137.4 mmHg, respectively. Throughout the median 3.38-year follow-up, the cardiovascular risk was significantly lower in the TA intensive-treatment group than in the TA standard-treatment group [adjusted hazard ratio (HR) 0.61, 95% confidence interval (CI) 0.46-0.80; P < 0.001]. In the intensive-treatment group, patients failing to achieve SBP targets presented higher cardiovascular risk than those TA patients (HR 2.04, 95% CI 1.44-2.88; P < 0.001). A J-shaped relationship was observed between the mean achieved SBP and risk of cardiovascular events, with the lowest risk at an SBP of 126.9 mmHg. CONCLUSIONS: Maintaining SBP at <130 mmHg offers additional cardiovascular benefits among young-older patients with hypertension. REGISTRATION: ClinicalTrials.gov: NCT03015311.

This present study is a secondary analysis that investigated the association between mean achieved BP in the two treatment groups (SBP target, 110 to <130 vs. 130 to <150 mmHg) and their cardiovascular outcomes in the STEP study (60­80-year-old patients with hypertension).Patients achieving a target in the intensive-treatment group have better cardiovascular outcome than patients achieving a target in the standard treatment arm, supporting the cardiovascular benefits of maintaining SBP <130 mmHg.J-shaped relationships were observed between mean achieved SBP and cardiovascular outcomes (with the nadir around 130 mmHg), but not for stroke.

Exercise volume load in women with breast cancer: Study protocol for the ABRACE randomized clinical trial.

Background: An increased number of breast cancer patients are challenged by acute and persistent treatment side effects. Oncology guidelines have been establishing physical exercise to counteract several treatment-related toxicities throughout cancer care. However, evidence regarding the optimal dose-response, feasibility, and the minimal resistance exercise volume and/or intensity remains unclear. The ABRACE Study will assess the impact of different resistance training volumes (i.e., single or multiple sets) combined with aerobic exercise on physical and psychological outcomes of breast cancer patients undergoing primary treatment. Methods: This study is a randomized, controlled, three-armed parallel trial. A total of 84 participants, aged ≥18 years, with breast cancer stages I-III, initiating adjuvant or neoadjuvant chemotherapy (≤50% of sessions completed) will be randomized to multiple sets resistance training plus aerobic training group, single set resistance training plus aerobic training group or control group. Neuromuscular and cancer-related fatigue (primary outcomes), muscle strength, muscle thickness, muscle quality by echo intensity, body composition, cardiorespiratory capacity, functional performance, upper-body endurance and quality of life will be measured before and after the 12-week intervention. Our analysis will follow the intention-to-treat approach and per-protocol criteria, with additional sub-group analysis. Discussion: Findings support prescribing exercise during chemotherapy for breast cancer and elucidate the potential role of different resistance training volumes as a management strategy for physical and psychological impairments in women with early-stage breast cancer. Our main hypothesis is for superiority in physical and psychological outcomes for both training groups compared to the control group, with no difference between single or multiple sets groups. Trial registration: Clinical trials NCT03314168.

Verification of the association between cognitive decline and olfactory dysfunction using a DEmentia screening kit in subjects with Alzheimer's dementia, mild cognitive impairment, and normal cognitive function (DESK study): A multicenter, open-label, interventional study.

Background and purpose: Olfactory dysfunction may be an early symptom of degenerative neurological disorders such as mild cognitive impairment (MCI), which may progress to cognitive decline and Alzheimer's disease (AD). We investigated the relationship between cognitive decline and olfactory dysfunction in healthy controls and patients with MCI or AD using the DEmentia Screening Kit (DESK), an olfactory identification assessment tool designed for Japanese populations. Methods: In this multicenter, open-label, interventional study conducted from 16 September 2020 to 30 April 2021, participants underwent olfactory tests using the DESK tool. This included 10 odorants at two concentrations (weak/strong) including toothpaste, butter, and India ink. Results: Among 223 participants, 100, 61, and 62 were healthy controls, MCI patients, and AD patients (mean ages, 57.4, 72.8, and 76.3 years; total DESK olfaction scores, 18.4, 14.7, and 7.4), respectively. Significant differences in total olfaction scores were observed between groups (healthy controls vs MCI, healthy controls vs AD, and MCI vs AD). Significant between-group total score differences were shown for olfaction scores with both the 10 strong and 10 weak odorant varieties. Conclusion: The DESK tool may discriminate between healthy individuals and those with MCI or AD, facilitating early screening for cognitive decline among Japanese patients, although the effect of age on DESK olfaction scores has not been fully explored.

Intent-to-Treat (ITT) vs Completer or Per-Protocol Analysis in Randomized Controlled Trials.

In randomized controlled trials, randomization creates groups that are reasonably well balanced on all baseline variables, whether measured, unmeasured, or unknown. Postbaseline events disturb this balance, resulting in postrandomization biases. Drop-out is one such event. There are two main methods for data analysis when there are dropouts. One method is to analyze data from only those who complete the study (completer analysis), or only those who complete the study and also comply with all its key elements (per-protocol analysis, a special type of completer analysis). The other method is to analyze the data from all randomized patients, regardless of dropout (intent-to-treat [ITT] analysis), or all randomized patients who meet an additional criterion, such as taking at least one dose of study drug (modified ITT [mITT] analysis, a special type of ITT analysis). Completer analyses present results in the ideal situation in which patients take medications as advised. ITT analyses present results related to real-world practice, where patients may be irregular with dosing or stop taking medications. The advantages and disadvantages of each type of analysis are discussed. The handling of missing data in ITT and mITT analysis is also briefly discussed.

Impact of a community-policing initiative promoting substance use disorder treatment over criminal charges on arrest recidivism.

BACKGROUND: Overdose deaths, addiction, and drug-related crime have increased in the United States over the past decade. Treatment improves outcomes, including reducing crime, but few individuals with addiction receive treatment. Here, we determine whether the Madison Addiction Recovery Initiative (MARI), a community policing program implemented by the City of Madison (Wisconsin) Police Department (MPD) that diverts adults who committed a non-violent, drug use-related crime from criminal prosecution to addiction treatment, reduces the risk of recidivism (i.e., an arrest) in the 6-month period following the index crime. METHODS: Observational data were collected by the MPD for 12 months before through 6 months after an index crime from participants in the MARI program (n = 263) who referred to MARI between September 1, 2017 and August 31, 2020 and a Historical Comparison group (n = 52) who committed a comparable crime between September 1, 2015 and August 31, 2016. Average effects were estimated using intention-to-treat (ITT), a per-protocol, and a complier average causal effects (CACE) analyses, adjusted for covariates. RESULTS: ITT analysis did not show that MARI assignment lowered adjusted odds of 6-month recidivism (aOR = 0.59 [0.32, 1.12], p = 0.11). Per-protocol analysis showed that completing MARI lowered the adjusted odds of 6-month recidivism (aOR = 0.23 [0.10, 0.52], p < 0.001). CACE analysis indicated that assignment to MARI among individuals who would complete the MARI program if assigned to the program lowered the adjusted odds of 6-month recidivism (aOR = 0.85 [0.80, 0.90], p < 0.001). CONCLUSIONS: Diverting adults who committed a non-violent, drug use-related crime from criminal prosecution to addiction treatment may reduce 6-month recidivism.

Treatment of NAFLD with intermittent calorie restriction or low-carb high-fat diet - a randomised controlled trial.

BACKGROUND & AIMS: The first-line treatment for non-alcoholic fatty liver disease (NAFLD) is weight reduction. Several diets have been proposed, with various effects specifically on liver steatosis. This trial compared the effects of intermittent calorie restriction (the 5:2 diet) and a low-carb high-fat diet (LCHF) on reduction of hepatic steatosis. METHODS: We conducted an open-label randomised controlled trial that included 74 patients with NAFLD randomised in a 1:1:1 ratio to 12 weeks' treatment with either a LCHF or 5:2 diet, or general lifestyle advice from a hepatologist (standard of care; SoC). The primary outcome was reduction of hepatic steatosis as measured by magnetic resonance spectroscopy. Secondary outcomes included transient elastography, insulin resistance, blood lipids, and anthropometrics. RESULTS: The LCHF and 5:2 diets were both superior to SoC treatment in reducing steatosis (absolute reduction: LCHF: -7.2% [95% CI = -9.3 to -5.1], 5:2: -6.1% [95% CI = -8.1 to -4.2], SoC: -3.6% [95% CI = -5.8 to -1.5]) and body weight (LCHF: -7.3 kg [95% CI = -9.6 to -5.0]; 5:2: -7.4 kg [95% CI = -8.7 to -6.0]; SoC: -2.5 kg [95% CI =-3.5 to -1.5]. There was no difference between 5:2 and LCHF (p = 0.41 for steatosis and 0.78 for weight). Liver stiffness improved in the 5:2 and SoC but not in the LCHF group. The 5:2 diet was associated with reduced LDL levels and was tolerated to a higher degree than LCHF. CONCLUSIONS: The LCHF and 5:2 diets were more effective in reducing steatosis and body weight in patients with NAFLD than SoC, suggesting dietary advice can be tailored to meet individual preferences. LAY SUMMARY: For a person with obesity who suffers from fatty liver, weight loss through diet can be an effective treatment to improve the condition of the liver. Many popular diets that are recommended for weight reduction, such as high-fat diets and diets based on intermittent fasting, have not had their effects on the liver directly evaluated. This study shows that both a low-carb high-fat and the 5:2 diet are effective in treating fatty liver caused by obesity. CLINICAL TRIALS REGISTRATION: This study is registered at Clinicaltrials.gov (NCT03118310).

Adjuvant chemotherapy is superior to chemoradiation after D2 surgery for gastric cancer in the per-protocol analysis of the randomized CRITICS trial.

BACKGROUND: The Intergroup 0116 and the MAGIC trials changed clinical practice for resectable gastric cancer in the Western world. In these trials, overall survival improved with post-operative chemoradiotherapy (CRT) and perioperative chemotherapy (CT). Intention-to-treat analysis in the CRITICS trial of post-operative CT or post-operative CRT did not show a survival difference. The current study reports on the per-protocol (PP) analysis of the CRITICS trial. PATIENTS AND METHODS: The CRITICS trial was a randomized, controlled trial in which 788 patients with stage Ib-Iva resectable gastric or esophagogastric adenocarcinoma were included. Before start of preoperative CT, patients from the Netherlands, Sweden and Denmark were randomly assigned to receive post-operative CT or CRT. For the current analysis, only patients who started their allocated post-operative treatment were included. Since it is uncertain that the two treatment arms are balanced in such PP analysis, adjusted proportional hazards regression analysis and inverse probability weighted analysis were used to minimize the risk of selection bias and to estimate and compare overall and event-free survival. RESULTS: Of the 788 patients, 478 started post-operative treatment according to protocol, 233 (59%) patients in the CT group and 245 (62%) patients in the CRT group. Patient and tumor characteristics between the groups before start of the post-operative treatment were not different. After a median follow-up of 6.7 years since the start of post-operative treatment, the 5-year overall survival was 57.9% (95% confidence interval: 51.4% to 64.3%) in the CT group versus 45.5% (95% confidence interval: 39.2% to 51.8%) in the CRT group (adjusted hazard ratio CRT versus CT: 1.62 (1.24-2.12), P = 0.0004). Inverse probability weighted analysis resulted in similar hazard ratios. CONCLUSION: After adjustment for all known confounding factors, the PP analysis of patients who started the allocated post-operative treatment in the CRITICS trial showed that the CT group had a significantly better 5-year overall survival than the CRT group (NCT00407186).

Intention to treat and per protocol analysis in clinical trials.

In clinical epidemiology, experimental studies usually take the form of randomized controlled clinical trials (RCTs). The data analysis of an RCT can be performed by using two complementary strategies, that is according to the intention to treat (ITT) principle and the per protocol (PP) analysis. By using the ITT approach, investigators aim to assess the effect of assigning a drug whereas by adopting the PP analysis, researchers investigate the effect of receiving the assigned treatment, as specified in the protocol. Both ITT and PP analyses are essentially valid but they have different scopes and interpretations dependent on the context.

Development of an algorithm using ultrasonography-assisted peripheral intravenous catheter placement for reducing catheter failure.

Up to 50% peripheral intravenous catheters (PIVs) are removed prematurely because of failures. Catheter failure (CF) leads to replacement and is a great concern for patients and medical staff. It is known that visualization of catheters and vessels with ultrasonography (US) during placement prevents CF. However, US is not a common technique for general nurses. In order to standardize US-assisted PIV placement techniques, an algorithm is needed. This study aimed to develop an algorithm using US-assisted PIV placement to reduce CF rate. Furthermore, to evaluate the effectiveness of the algorithm, CF rates were compared before and after intervention. A pretest-posttest study was performed. The intervention was PIV placement by 23 nurses undergoing training sessions for the algorithm. Intention to treat, per protocol analyses were applied. Logistic regression analysis was used for factor analysis. The CF rate in the pre-intervention group 35.2% (19/54) did not significantly differ from post-intervention group 33.6% (48/143) (p = 0.831), yet significantly differ from complete algorithm-use group 8.7% (2/23; p = 0.017). In factor analysis, compliance to the algorithm was significantly correlated with CF (p = 0.032). The compliance rate was low 16.1% (23/143). Algorithm compliance reduced CF by confirming appropriate catheter tip position from the insertion to the securement phase. This algorithm effectively reduced CF, however, the compliance rate was unacceptable. In order to increase the compliance rate, modified algorithm and new visualizing technology is required.

[Eradication Rates of 10-day Sequential Therapy for Helicobacter pylori: Results of an 8-year Prospective Study Conducted at a Tertiary Korean Hospital].

BACKGROUND/AIMS: The Helicobacter pylori (H. pylori) eradication rate of standard triple therapy is unsatisfactory in Korea, and sequential therapy (SQT) has been suggested to be a practical first-line alternative regimen. The aim of this prospective study was to document changes in annual eradication rates of SQT. METHODS: A total of 983 H. pylori-positive subjects were enrolled from 2010 to 2018 and their data were subjected to intention-to-treat (ITT) and per-protocol (PP) analysis. All subjects received 10-day sequential therapy consisting of 40 mg esomeprazole and 1 g amoxicillin b.i.d for 5 days followed by 40 mg esomeprazole b.i.d, 500 mg clarithromycin b.i.d and 500 mg metronidazole t.i.d for 5 days. The 13C-urea breath test, rapid urease test (CLO test®), and histology were used to confirm eradication. Compliance and side effects were also investigated. RESULTS: ITT and PP eradication rates of SQT were 69.9% (687 of 983) and 87.1% (657 of 754), respectively. The annual eradication rate of ITT remained consistent over the 8-year study period (p for trend=0.167), whereas PP analysis showed the eradication rate increased (p for trend=0.042). The overall adverse event rate for SQT was 41.7% (410 subjects). CONCLUSIONS: Despite high antibiotic resistance rates in Korea, the eradication rate of SQT did not decrease over the 8-year study period.

Eradication Rates of 10-day Sequential Therapy for Helicobacter pylori: Results of an 8-year Prospective Study Conducted at a Tertiary Korean Hospital / 대한소화기학회지

BACKGROUND/AIMS: The Helicobacter pylori (H. pylori) eradication rate of standard triple therapy is unsatisfactory in Korea, and sequential therapy (SQT) has been suggested to be a practical first-line alternative regimen. The aim of this prospective study was to document changes in annual eradication rates of SQT. METHODS: A total of 983 H. pylori-positive subjects were enrolled from 2010 to 2018 and their data were subjected to intention-to-treat (ITT) and per-protocol (PP) analysis. All subjects received 10-day sequential therapy consisting of 40 mg esomeprazole and 1 g amoxicillin b.i.d for 5 days followed by 40 mg esomeprazole b.i.d, 500 mg clarithromycin b.i.d and 500 mg metronidazole t.i.d for 5 days. The 13C-urea breath test, rapid urease test (CLO test®), and histology were used to confirm eradication. Compliance and side effects were also investigated. RESULTS: ITT and PP eradication rates of SQT were 69.9% (687 of 983) and 87.1% (657 of 754), respectively. The annual eradication rate of ITT remained consistent over the 8-year study period (p for trend=0.167), whereas PP analysis showed the eradication rate increased (p for trend=0.042). The overall adverse event rate for SQT was 41.7% (410 subjects). CONCLUSIONS: Despite high antibiotic resistance rates in Korea, the eradication rate of SQT did not decrease over the 8-year study period.

Bioestatística e epidemiologia: perguntas que você sempre quis fazer, mas nunca teve coragem / Biostatistics and epidemiology: questions you always wanted to ask but never had the courage to

Dando continuidade aos artigos da série "Perguntas que você sempre quis fazer, mas nunca teve coragem", que tem como objetivo responder e sugerir referências para o melhor entendimento das principais dúvidas estatísticas levantadas por pesquisadores da área da saúde, este terceiro artigo aborda o contexto epidemiológico. Neste contexto, foram diferenciadas as principais medidas como prevalência, incidência, Odds Ratio (OR), Risco Relativo (RR), Razão de Prevalência (RP) e Hazard Ratio (HR), foi esclarecido o uso de análises por intenção de tratar e análise por protocolo, e também discutidos alguns dos termos comumente utilizados e pouco compreendidos como tipo de amostra, nível de evidência, relevância clínica e estatística, entre outros. (AU)

Continuing the series of articles "Questions you always wanted to ask but never had the courage to," which aims to answer key statistical questions raised by health researchers and suggest references for a better understanding, this third article addresses the epidemiological context. In this context, important measures such as prevalence, incidence, odds ratio (OR), relative risk (RR), prevalence ratio (PR) and hazard ratio (HR) were differentiated; the use of intention-to-treat analysis and per-protocol analysis was clarified; and some terms commonly used and poorly understood were discussed, such as type of sample, level of evidence, clinical and statistical relevance, among others. (AU)

Addition of one session with a specialist counselor did not increase efficacy of a family physician-led smoking cessation program.

Objective Higher-intensity counseling sessions increase the smoking abstinence rate. However, counselors are limited in Taiwan. This study was performed to determine whether the addition of one session with a specialist counselor increases the efficacy of a family physician-led smoking cessation program. Methods Participants opted to either visit a family physician for brief counseling and pharmacotherapy (Po) or visit a specialist counselor for an initial session followed by a family physician for brief counseling sessions with pharmacotherapy (P+). The 7-day point prevalence (PP) rate was evaluated at weeks 12 and 24. Results In total, 356 patients were enrolled. In the intention-to-treat analysis, the PP rate at week 12 was higher in the Po than P+ group, but there was no significant difference at week 24. In the per-protocol analysis, the PP rates at weeks 12 and 24 were not significantly different between the Po and P+ groups. The adjusted odds ratios also revealed no significant differences in either the intention-to-treat analysis or the per-protocol analysis between the two groups. Conclusion The addition of one session with a specialist counselor had no benefit over the provision of counseling through a family physician at either 12 or 24 weeks of follow-up.

A randomised controlled trial in comparing maternal and neonatal outcomes between hands-and-knees delivery position and supine position in China.

BACKGROUND: the supine position is the most frequently offered for birth delivery in China and many other countries, but the hands-and-knees position is now gaining prominence with doctors in China. This study aims to examine the differences in maternal and neonatal outcomes among low-risk women who gave birth either in the hands-and-knees position or the supine position. METHODS: a randomised controlled trial was conducted in 11 hospitals in China from May to December in 2012. In total, 1400 women were recruited and randomly allocated to either the experimental group (n=700, 446 completed the protocol) who delivered in hands-and-knees position and the control group (n=700, 440 completed the protocol) who delivered in supine position. Women who could not maintain the randomised position during the second stage of labour were allowed to withdraw from the study. The primary maternal outcome measured was rate of episiotomy. Secondary outcomes included degree of perineum laceration, rate of emergency caesarean section, rate of shoulder dystocia, and duration of labour, postpartum bleeding, neonatal Apgar score, and the rate of neonatal asphyxia. Because outcome data were only collected for women who gave birth in the randomised position, per-protocol analyses were used to compare groups. The primary outcome, episiotomy, was also compared between groups using logistic regression adjusting for maternal age，gestational age at birth, whether the woman was primiparous, the process of second stage of labour and birthweight. FINDINGS: as compared with the control group, the experimental group had lower rates of episiotomy and second-degree perineum laceration (including episiotomy), and higher rates of intact perineum and first-degree perineum laceration, with a longer duration of second stage of labour. No significant differences were found in the amount of postpartum bleeding, shoulder dystocia, neonatal asphyxia and neonatal Apgar scores at 1minute and 5minutes. Adjusted for maternal age, gestational age, parity, duration of second stage of labour and birth weight, the hands-and-knees position reduced the need for episiotomy (OR=0.024, p<0.001). CONCLUSIONS: this study provided evidence that women who could maintain the hands-and-knees position during the second stage of labour had lower rates of episiotomy and second-degree perineum laceration (including episiotomy). Both midwives and obstetricians are suggested to learn the skills to assist women with delivery in this position.

Simple Estimation of Patient-Oriented Effects From Randomized Trials: An Open and Shut CACE.

In randomized controlled trials, the intention-to-treat estimator provides an unbiased estimate of the causal effect of treatment assignment on the outcome. However, patients often want to know what the effect would be if they were to take the treatment as prescribed (the patient-oriented effect), and several researchers have suggested that the more relevant causal effect for this question is the complier average causal effect (CACE), also referred to as the local average treatment effect. Sophisticated approaches to estimating the CACE include Bayesian and frequentist methods for principal stratification, inverse-probability-of-treatment-weighted estimators, and instrumental-variable (IV) analysis. All of these approaches exploit information about adherence to assigned treatment to improve upon the intention-to-treat estimator, but they are rarely used in practice, probably because of their complexity. The IV principal stratification estimator is simple to implement but has had limited use in practice, possibly due to lack of familiarity. Here, we show that the IV principal stratification estimator is a modified per-protocol estimator that should be obtainable from any randomized controlled trial, and we provide a closed form for its robust variance (and its uncertainty). Finally, we illustrate sensitivity analyses we conducted to assess inference in light of potential violations of the exclusion restriction assumption.

Addressing missing participant outcome data in dental clinical trials.

Missing outcome data are common in clinical trials and despite a well-designed study protocol, some of the randomized participants may leave the trial early without providing any or all of the data, or may be excluded after randomization. Premature discontinuation causes loss of information, potentially resulting in attrition bias leading to problems during interpretation of trial findings. The causes of information loss in a trial, known as mechanisms of missingness, may influence the credibility of the trial results. Analysis of trials with missing outcome data should ideally be handled with intention to treat (ITT) rather than per protocol (PP) analysis. However, true ITT analysis requires appropriate assumptions and imputation of missing data. Using a worked example from a published dental study, we highlight the key issues associated with missing outcome data in clinical trials, describe the most recognized approaches to handling missing outcome data, and explain the principles of ITT and PP analysis.