Nonparametric analysis of delayed treatment effects using single-crossing constraints.

Clinical trials involving novel immuno-oncology therapies frequently exhibit survival profiles which violate the proportional hazards assumption due to a delay in treatment effect, and, in such settings, the survival curves in the two treatment arms may have a crossing before the two curves eventually separate. To flexibly model such scenarios, we describe a nonparametric approach for estimating the treatment arm-specific survival functions which constrains these two survival functions to cross at most once without making any additional assumptions about how the survival curves are related. A main advantage of our approach is that it provides an estimate of a crossing time if such a crossing exists, and, moreover, our method generates interpretable measures of treatment benefit including crossing-conditional survival probabilities and crossing-conditional estimates of restricted residual mean life. Our estimates of these measures may be used together with efficacy measures from a primary analysis to provide further insight into differences in survival across treatment arms. We demonstrate the use and effectiveness of our approach with a large simulation study and an analysis of reconstructed outcomes from a recent combination therapy trial.

Fangji Fuling Decoction Alleviates Sepsis by Blocking MAPK14/FOXO3A Signaling Pathway / 中国结合医学杂志

OBJECTIVE@#To examine the therapeutic effect of Fangji Fuling Decoction (FFD) on sepsis through network pharmacological analysis combined with in vitro and in vivo experiments.@*METHODS@#A sepsis mouse model was constructed through intraperitoneal injection of 20 mg/kg lipopolysaccharide (LPS). RAW264.7 cells were stimulated by 250 ng/mL LPS to establish an in vitro cell model. Network pharmacology analysis identified the key molecular pathway associated with FFD in sepsis. Through ectopic expression and depletion experiments, the effect of FFD on multiple organ damage in septic mice, as well as on cell proliferation and apoptosis in relation to the mitogen-activated protein kinase 14/Forkhead Box O 3A (MAPK14/FOXO3A) signaling pathway, was analyzed.@*RESULTS@#FFD reduced organ damage and inflammation in LPS-induced septic mice and suppressed LPS-induced macrophage apoptosis and inflammation in vitro (P<0.05). Network pharmacology analysis showed that FFD could regulate the MAPK14/FOXO signaling pathway during sepsis. As confirmed by in vitro cell experiments, FFD inhibited the MAPK14 signaling pathway or FOXO3A expression to relieve LPS-induced macrophage apoptosis and inflammation (P<0.05). Furthermore, FFD inhibited the MAPK14/FOXO3A signaling pathway to inhibit LPS-induced macrophage apoptosis in the lung tissue of septic mice (P<0.05).@*CONCLUSION@#FFD could ameliorate the LPS-induced inflammatory response in septic mice by inhibiting the MAPK14/FOXO3A signaling pathway.

Efficacy and safety of autologous platelet-rich plasma for diabetic foot ulcers: a systematic review and meta-analysis.

OBJECTIVE: To investigate the efficacy and safety of autologous platelet-rich plasma (au-PRP) for diabetic foot ulcer (DFU) treatment. METHOD: We conducted database searches (MEDLINE, EMBASE, evidence-based medicine reviews: CENTRAL, PubMed, and Web of Science) and reference mining for randomised controlled trials from inception to 23 January 2022. Results were scrutinised, data were extracted and research quality was investigated by two independent authors. Primary outcome was the proportion of complete ulcer healing. Secondary outcomes included both the mean time to complete healing and the incidence of adverse events. Statistical analyses were performed in RevMan 5.4 (Cochrane, UK). Kaplan-Meier curves for time to complete healing were pooled in R software (version 4.1.2) (R Foundation, Austria). RESULTS: Of the 231 records identified, 17 studies with a total of 1303 participants (649 randomised to the au-PRP group and 654 to a standard of care (SOC) group) met the eligibility criteria and were included in our study. Compared with SOC, au-PRP appeared to promote the complete healing rate (odds ratio (OR): 2.11; 95% Confidence Interval: 1.55-2.86). Au-PRP also appeared to significantly shorten complete healing time (mean duration: -19.04 days; 95%CI: -20.46--17.61]). There was no significant difference on adverse events. Results were robust on sensitivity analyses. CONCLUSION: Based on the findings of this review and meta-analysis, Au-PRP is an effective and safe adjuvant therapy for DFUs.

Efficacy and anti-inflammatory analysis of glucocorticoid, antihistamine and leukotriene receptor antagonist in the treatment of allergic rhinitis.

BACKGROUND: There are many adverse reactions in the treatment of allergic rhinitis (AR) mainly with conventional drugs. Leukotriene receptor antagonists, glucocorticoids and nasal antihistamines can all be used as first-line drugs for AR, but the clinical effects of the three drugs are not clear. AIM: To examine the impact of glucocorticoids, antihistamines, and leukotriene receptor antagonists on individuals diagnosed with AR, specifically focusing on their influence on serum inflammatory indexes. METHODS: The present retrospective study focused on the clinical data of 80 patients diagnosed and treated for AR at our hospital between May 2019 and May 2021. The participants were categorized into the control group and the observation group. The control group received leukotriene receptor antagonists, while the observation group was administered glucocorticoids and antihistamines. Conducted an observation and comparison of the symptoms, physical sign scores, adverse reactions, and effects on serum inflammatory indexes in two distinct groups of patients, both before and after treatment. RESULTS: Subsequent to treatment, the nasal itching score, sneeze score, runny nose score, nasal congestion score, and physical signs score exhibited notable discrepancies (P < 0.05), with the observation group demonstrating superior outcomes compared to the control group (P < 0.05). The interleukin (IL)-6, IL-10, tumor necrosis factor-alpha, Soluble Intercellular Adhesion Molecule-1, Leukotriene D4 after treatment were significantly different and the observation group It is better than the control group, which is statistically significant (P < 0.05). Following the intervention, the incidence of adverse reactions in the observation group, including symptoms such as nasal dryness, discomfort in the throat, bitter taste in the mouth, and minor erosion of the nasal mucosa, was found to be 7.5%. This rate was significantly lower compared to the control group, which reported an incidence of 27.5%. The difference between the two groups was statistically significant (P < 0.05). CONCLUSION: Glucocorticoids and antihistamines have obvious therapeutic effects, reduce serum inflammatory index levels, relieve symptoms and signs of patients, and promote patients' recovery, which can provide a reference for clinical treatment of AR.

Disease Control with Upadacitinib in Patients with Psoriatic Arthritis: A Post Hoc Analysis of the Randomized, Placebo-Controlled SELECT-PsA 1 and 2 Phase 3 Trials.

INTRODUCTION: Low disease activity (LDA)/remission is the target of treatment in patients with psoriatic arthritis (PsA). We assessed the proportions of patients with PsA receiving upadacitinib who achieved LDA/remission over 1 year. METHODS: This was a post hoc analysis of the double-blind, placebo-controlled SELECT-PsA 1 (also adalimumab-controlled) and SELECT-PsA 2 trials. Treatment targets assessed included LDA/remission defined by Disease Activity in Psoriatic Arthritis (≤ 14/ ≤ 4) and Psoriatic Arthritis Disease Activity Scores (≤ 3.2/ ≤ 1.9), as well as minimal disease activity (MDA)/very low disease activity (VLDA) states (5/7 and 7/7 components, respectively, of MDA criteria). Targets were assessed at 24 and 56 weeks. For binary outcomes, non-responder imputation was used for missing data. Data from patients receiving upadacitinib 30 mg was not included in the analysis. RESULTS: Overall, 1386 patients were analyzed. Disease control (i.e., LDA/MDA) was achieved at 24 weeks in upadacitinib 15 mg-treated patients across both studies: LDA/MDA was achieved by 25-48% of patients receiving upadacitinib 15 mg versus 2-16% of patients receiving placebo, and remission/VLDA rates were 7-14% with upadacitinib 15 mg versus 0-4% with placebo. The proportions of patients achieving treatment targets were numerically similar to upadacitinib 15 mg and adalimumab. All responses were sustained at 56 weeks. CONCLUSIONS: Remission and LDA are feasible targets with upadacitinib treatment in patients with PsA. TRIAL REGISTRATION: ClinicalTrial.gov identifiers NCT03104400 (SELECT-PsA 1) and NCT03104374 (SELECT-PsA 2).

Psoriatic arthritis is a disease that causes inflammation of the skin and joints. Doctors measure how bad a patient's disease is by measuring signs and symptoms of the disease, and using these to make a "score." The aim of treatment is to reduce the score to low levels (known as "low disease activity") or very low levels ("remission"). This study looked at results from two clinical trials that compared upadacitinib, a medicine used to treat psoriatic arthritis, with no medicine (placebo) to see how many patients had low disease activity or were in remission after 1 year of treatment. The results showed that more patients who were taking upadacitinib had low disease activity or were in remission after the first 6 months of treatment compared with those who took placebo. This difference between upadacitinib and placebo could still be seen after 1 year of treatment. These results show that treatment with upadacitinib is effective enough for some patients with psoriatic arthritis to achieve low disease activity or remission and to stay at this level, even after more than 1 year of treatment.

Analyzing longitudinal binary data in clinical studies.

In clinical studies, it is common to have binary outcomes collected over time as repeated measures. This manuscript reviews and evaluates two popular classes of statistical methods for analyzing binary response data with repeated measures: likelihood-based Generalized Linear Mixed Model (GLMM), and semiparametric Generalized Estimating Equation (GEE). Recommendations for choice of analysis model and points to consider for implementation in clinical studies in the presence of missing data are provided based on a comprehensive literature review, as well as, a simulation study evaluating the performance of both GLMM and GEE under scenarios representative of typical clinical trial settings. Under Missing at Random (MAR) assumption, GLMM is preferred over GEE, and the SAS PROC GLIMMIX marginal model is recommended for implementing GLMM in analyzing clinical trial data. When there is an underlying continuous variable used to define the binary response, and the missing proportion is high and/or unbalanced between treatment groups, a two-step approach combining Multiple Imputation (MI) and GEE (MI-GEE) is recommended.

Effect of upadacitinib on reducing pain in patients with active psoriatic arthritis or ankylosing spondylitis: post hoc analysis of three randomised clinical trials.

OBJECTIVE: Evaluate the effect of upadacitinib on pain outcomes in patients with active psoriatic arthritis (PsA) or ankylosing spondylitis (AS) across 3 randomised trials (SELECT-PsA 1 and 2 for PsA; SELECT-AXIS 1 for AS). METHODS: Patients were randomised to upadacitinib 15 mg once daily or placebo (all 3 studies), or adalimumab 40 mg every other week (SELECT-PsA 1 only). Pain outcomes included proportion of patients achieving ≥30%, ≥50% and ≥70% reduction from baseline in patient global assessment of pain and other end points. RESULTS: A higher proportion of patients receiving upadacitinib versus placebo achieved ≥30%, ≥50% and ≥70% reduction in pain end points as early as week 2; these improvements with upadacitinib were generally sustained or increased through year 1 (PsA 1/2 studies: 64%/48%, 58%/42% and 38%/22%, respectively; SELECT-AXIS 1 study: 76%, 72% and 54%). Results were similar with adalimumab in PsA 1 (59%, 49% and 32%). Patients who switched from placebo to upadacitinib 15 mg were able to reach a similar level of improvement as the continuous upadacitinib groups by year 1 (PsA 1/2 studies: 46%-60%, 35%-49% and 15%-34%; AS study: 83%, 72% and 46%). Results were similar with other pain end points. CONCLUSION: Rapid and sustained improvements in pain outcomes across several end points were consistently shown with upadacitinib over 1 year in patients with active PsA or AS who had either inadequate response to prior non-biologic or biologic disease-modifying antirheumatic drugs (PsA studies) or were biologic-naïve with inadequate response to non-steroidal anti-inflammatory drugs (AS study).

Upadacitinib as monotherapy and in combination with non-biologic disease-modifying antirheumatic drugs for psoriatic arthritis.

OBJECTIVE: To assess the efficacy and safety of upadacitinib (UPA), an oral Janus kinase inhibitor, as monotherapy or in combination with non-biologic DMARDs (nbDMARDs) in patients with PsA. METHODS: Pooled data were analysed from patients with prior inadequate response or intolerance to one or more nbDMARD (SELECT-PsA 1) or one or more biologic DMARD (SELECT-PsA 2) who received placebo, UPA 15 mg once daily (QD) or UPA 30 mg QD as monotherapy or in combination with two or fewer nbDMARDs for 24 weeks. Efficacy outcomes included achievement of ACR responses, Psoriasis Area and Severity Index responses, minimal disease activity and change from baseline and clinically meaningful improvement in the HAQ Disability Index. Adverse events (AEs) were summarized. RESULTS: A total of 1916 patients were included; 574 (30%) received monotherapy and 1342 (70%) received combination therapy. Placebo-subtracted treatment effects for a 20% improvement in ACR criteria at week 12 were 33.7% (95% CI 24.4, 43.1) and 34.0% (95% CI 27.9, 40.1) for UPA 15 mg QD monotherapy and combination therapy, respectively, and 45.7% (95% CI 36.9, 54.5) and 39.6% (95% CI 33.7, 45.5) for UPA 30 mg QD monotherapy and combination therapy, respectively. Treatment effects for other outcomes were consistent between monotherapy and combination therapy. AE frequency was generally similar for UPA monotherapy and combination therapy, although hepatic disorders and creatine phosphokinase elevation were more common with combination therapy vs monotherapy. CONCLUSION: The efficacy and safety of UPA were generally consistent when administered as monotherapy or in combination with nbDMARDs through 24 weeks, supporting the use of UPA with or without nbDMARDs in PsA. TRIAL REGISTRATION: ClinicalTrials.gov (https://clinicaltrials.gov): SELECT-PsA 1 (NCT03104400), SELECT-PsA 2 (NCT03104374).

Flow-through anterolateral thigh perforator flap or medial sural artery perforator flap in repair of Gustilo Ⅲ C wound of foot / 中华显微外科杂志

Objective:To investigate the therapeutic effect of Flow-through anterolateral thigh perforator flap (ALTPF) or medial sural artery perforator flap (MSAPF) in repair of Gustilo III C wound of foot.Methods:From July 2015 to June 2021, 8 patients with Gustilo III C wound of foot were treated in the Department of Foot and Ankle Surgery of Wuxi No.9 People’s Hospital. The patients were 7 males and 1 female, aged 25-62 years old, and (45.88±12.96) years old in average. Flow-through ALTPF or Flow-through MSAPF were used to repair the defect according to the size of the wound and the length and diameter of the defect vascular. Among the patients, 6 were repaired with free Flow-through ALTPF, and 2 with free Flow-through MSAPF. The size of flap was 9 cm×5 cm-22 cm×8 cm with (115.00±46.16) cm 2 in average, and the vascular bridging was 6-12 cm in length, with (8.75±2.50) cm in average. All patients received outpatient follow-up. The appearance of the flap, blood supply of affected limb, healing of fracture and dislocation and the recovery of limb function were recorded. Maryland score was used to evaluate functional recovery. Results:The flaps survived uneventfully in all 8 patients, and the wounds in donor site healed primarily. All patients were followed-up for 6-22 months with (12.25±5.39 ) months in average. At the last follow-up, all the flaps had satisfactory contour in soft texture and blood supply without occlusion in the bridging vessels. The fractures and dislocation were healed, and the appearance and function of the foot recovered satisfactorily. The Maryland score showed excellent in 3 patients, good in 4 patients and fair in 1 patient.Conclusion:Flow-through ALTPF or MSAPF can selectively used to reconstruct the Gustilo III C wound of foot in one stage. The functional recovery of the affected limb was satisfactory and the clinical effect was good.

Epidemiological trends for human schistosomiasis prevalence in Hubei Province from 2004 to 2018 based on Joinpoint regression analysis / 中国血吸虫病防治杂志

Objective To analyze the trends of human schistosomiasis prevalence in Hubei Province from 2004 to 2018, so as to provide the evidence for formulating the schistosomiasis elimination strategy in the province. Methods All data pertaining to human schistosomiasis prevalence in Hubei Province were collected from 2004 to 2018, and the trends for changes in seroprevalence, egg-positive rate and prevalence of human Schistosoma japonicum infection were analyzed using a Joinpoint regression model. Results Both of the numbers of residents seropositive and egg-positive for S. japonicum infections appeared a tendency towards a decline in Hubei Province from 2004 to 2018, and the prevalence of human S. japonicum infections reduced from 6.85% in 2004 to 0 in 2018. Joinpoint regression analysis showed that the prevalence of human S. japonicum infections appeared an overall tendency towards a reduction in Hubei Province from 2004 to 2018 [average annual percent change (AAPC) = −24.1%, P < 0.01], and the trends for the reduction were both significant during the period from 2004 to 2006 [annual percent change (APC) = −35.1%, P < 0.01] and from 2006 to 2018 (APC = −22.1%, P < 0.01). The prevalence of human S. japonicum infections appeared a tendency towards a decline in islet (AAPC = −25.1%, P < 0.01), inner embankment (AAPC = −26.4%, P < 0.01) and hilly subtypes of schistosomiasis-endemic areas (AAPC = −32.5%, P < 0.01) of Hubei Province from 2004 to 2018, and the prevalence all appeared a tendency towards a decline during the infection control stage (from 2004 to 2008), the transmission control stage (from 2009 to 2013) and the transmission interruption stage (from 2014 to 2018) (AAPC = −28.0%, −24.4% and −63.8%, all P values < 0.01). The seroprevalence of human S. japonicum infections appeared an overall tendency towards a decline in Hubei Province from 2004 to 2018 (AAPC = −14.5%, P < 0.01), and the trends for the reduction were both significant during the period from 2004 to 2012 (APC = −8.4%, P < 0.01) and from 2012 to 2018 (APC = −22.1%, P < 0.01). In addition, the egg-positive rate of human S. japonicum infections appeared an overall tendency towards a decline in Hubei Province from 2004 to 2018 (AAPC = −30.6%, P < 0.05), and the trend for the reduction was significant during the period from 2007 to 2014 (APC = −15.5%, P < 0.01). Conclusions The prevalence of human schistosomiasis appeared a tendency towards a decline in Hubei Province from 2004 to 2018, and the islet and inner embankment subtypes of endemic areas are a high priority for schistosomiasis control during the stage moving towards elimination in Hubei Province.

Safety and efficacy of veliparib plus carboplatin/paclitaxel in patients with HER2-negative metastatic or locally advanced breast cancer: subgroup analyses by germline BRCA1/2 mutations and hormone receptor status from the phase-3 BROCADE3 trial.

PURPOSE: To evaluate efficacy and safety of veliparib combined with carboplatin/paclitaxel in patients with advanced human epidermal growth factor receptor 2 (HER2)-negative, germline BRCA (gBRCA)-associated breast cancer defined by hormone receptor (HR) and gBRCA1/2 mutation status. PATIENTS AND METHODS: In this phase-3, double-blind, placebo-controlled trial, patients (N = 509) with advanced HER2-negative breast cancer and gBRCA1/2 mutations were randomized 2:1 to receive veliparib plus carboplatin/paclitaxel or placebo plus carboplatin/paclitaxel. Patients who discontinued chemotherapy prior to disease progression continued receiving blinded veliparib/placebo monotherapy. The primary endpoint was investigator-assessed progression-free survival (PFS). Subgroup analyses of PFS stratified by HR and gBRCA1/2 mutation status were prespecified. RESULTS: In the intention-to-treat population, there were similar proportions of patients with gBRCA1 versus gBRCA2 mutations (51% vs 49%) and HR+ disease versus triple-negative breast cancer (TNBC) (52% vs 48%). Median PFS was longer in the veliparib arm compared with the placebo arm for all subgroups (HR+: 13.0 vs 12.5 months, hazard ratio (95% confidence interval (CI)): 0.69 (0.52, 0.93), p = 0.013; TNBC: 16.6 vs 14.1 months, hazard ratio (95% CI): 0.72 (0.52, 1.00), p = 0.052; gBRCA1: 14.2 vs 12.6 months, hazard ratio (95% CI): 0.75 (0.55, 1.03), p = 0.073; gBRCA2: 14.6 vs 12.6 months, hazard ratio (95% CI): 0.69 (0.50, 0.95); p = 0.021). Benefit was durable, with improved PFS rates at 2 years (HR+, 27.5% vs 15.3%; TNBC, 40.4% vs 25.0%) and 3 years (HR+, 17.5% vs 8.6%; TNBC, 35.3% vs 13.0%) in all subgroups. gBRCA status (BRCA1 vs BRCA2) did not substantially affect the carboplatin/paclitaxel ± veliparib toxicity profile. CONCLUSION: Veliparib plus carboplatin/paclitaxel resulted in durable benefit in subgroups defined by HR status or by gBRCA1 versus gBRCA2 mutation. Overall, addition of veliparib to carboplatin/paclitaxel was tolerable, and there were no clinically meaningful differences in adverse events between the gBRCA1 versus gBRCA2 and HR+ versus TNBC subgroups. TRIAL REGISTRATION: NCT02163694, https://clinicaltrials.gov/ct2/show/NCT02163694.

The outcome predicted value of enhanced MRI for prolapsed or sequestrated lumbar disc herniation / 中华骨科杂志

Objective:To analyze the predictive value of enhanced MRI in the outcome of prolapsed and sequestrated lumbar disc herniation through a retrospective analysis.Methods:A retrospective analysis of the data of 64 patients with prolapsed and sequestrated lumbar disc herniation from January 2015 to December 2018, including 38 males and 26 females; age 35.72±12.44 years (range, 22-64 years) ; 43 cases of prolapsed type, 21 cases of sequestrated type. Conservative treatment was the first choice for all patients, in case of surgical indications during the treatment, percutaneous endoscopic lumbar discectomy or fenestration discectomy will be performed. Enhanced MRI was performed at the first and last inspections, the volume of the protrusion, the thickness of rim enhancement (Tr), and the extent of rim enhancement (Er) were measured and calculated at the same time. According to the ring around the protrusion, the size of the rim-enhancement area was divided into type I-III; then compared the relationship between the rim-enhancement signal differentiation and the resorption rate of protrusions, and the correlation between Tr, Er values and the resorption rate of protrusions during the initial inspection.Results:Among the 64 patients, 42 patients completed conservative treatment, and 22 received surgical treatment. According to the rim-enhancement signal differentiation, 23 cases were treated conservatively for type I, 3 cases were treated by surgery; 16 cases were treated for type II conservatively, 7 cases were treated by surgery; 3 cases were treated for type III conservatively, and 12 cases were treated by surgery. All patients were followed up for 12 to 34 months. Among 42 conservatively treated patients, The volume of the protrusion before treatment was 2 645.67±690.86 mm 3, and the volume of the protrusion after treatment was 842.76±573.35 mm 3. The volume of protrusions before and after treatment was statistical significance ( t=11.897, P<0.001), Tr was 1.38±0.83 mm, and Er was 73.08%±34.39%, the resorption rate of protrusions was 65.10%±24.50%, and 39 cases (92.86%, 39/42) reached the standard for protrusion resorption (resorption rate ≥30%); 23 cases of type I , the resorption rate was 76.54%±18.62%; 16 cases of type II had an resorption rate of 56.81%±21.44%; 3 cases of type III had an resorption rate of 21.58%±12.19%. The resorption rate of type III were compared by single factor analysis of variance, and the difference was statistically significant ( F=12.885, P<0.001); 32 cases of both type I and II (82.05%, 32/39) had significant resorption (resorption rate ≥50%), and no case of type Ⅲ had significant resorption, comparing with type I and II, the difference was statistically significant ( P=0.010); Tr was positively correlated with resorption rate ( r=0.569, P<0.001), Er was positively correlated with resorption rate ( r=0.677, P<0.001). Conclusion:Under close clinical observation, parts of the prolapsed or sequestrated lumbar disc herniations can be conservatively treated, and the herniated disc can be resorption in many people and the clinical symptoms were alleviated. Rim-enhancement signal differentiation by enhanced MR has a better predictive value for the outcome of the herniation, type I is more prone to resorption, preferred conservative treatment, type Ⅲ is not easy to resorption, preferred surgery treatment, and the higher thickness of rim enhancement, the greater extend the rim-enhancement, the more prone to resorption phenomenon.

Deep Neural Networks for Survival Analysis Using Pseudo Values.

There has been increasing interest in modelling survival data using deep learning methods in medical research. Current approaches have focused on designing special cost functions to handle censored survival data. We propose a very different method with two simple steps. In the first step, we transform each subject's survival time into a series of jackknife pseudo conditional survival probabilities and then use these pseudo probabilities as a quantitative response variable in the deep neural network model. By using the pseudo values, we reduce a complex survival analysis to a standard regression problem, which greatly simplifies the neural network construction. Our two-step approach is simple, yet very flexible in making risk predictions for survival data, which is very appealing from the practice point of view. The source code is freely available at http://github.com/lilizhaoUM/DNNSurv.

Bayesian credible subgroup identification for treatment effectiveness in time-to-event data.

Due to differential treatment responses of patients to pharmacotherapy, drug development and practice in medicine are concerned with personalized medicine, which includes identifying subgroups of population that exhibit differential treatment effect. For time-to-event data, available methods only focus on detecting and testing treatment-by-covariate interactions and may not consider multiplicity. In this work, we introduce the Bayesian credible subgroups approach for time-to-event endpoints. It provides two bounding subgroups for the true benefiting subgroup: one which is likely to be contained by the benefiting subgroup and one which is likely to contain the benefiting subgroup. A personalized treatment effect is estimated by two common measures of survival time: the hazard ratio and restricted mean survival time. We apply the method to identify benefiting subgroups in a case study of prostate carcinoma patients and a simulated large clinical dataset.

Two-level approaches to missing data in longitudinal trials with daily patient-reported outcomes.

In longitudinal clinical trials with daily patient-reported outcomes, the analysis endpoints are often defined as the averaged daily diary outcomes in a treatment cycle (such as a month or a week). Conventional methods often deal with missing data at the cycle level by imputing the average, and the cycle average is treated as missing if the number of days with available outcomes in the treatment cycle is less than a certain number. This was the method used for a case study of a phase 3 clinical trial evaluating a treatment for insomnia with daily patient-reported outcomes. Such methods may introduce bias. Motivated by this, we propose methods to impute missing daily outcomes in this paper. Specifically, we define a two-level missing pattern for clinical trials with daily patient-reported outcomes, and propose two-level methods to impute missing data at daily base. Other than the standard methods by multiple imputations, we derive analytic formulas for the proposed two-level methods to reduce computational intensity and improve the estimates of variances. The proposed two-level methods provide more powerful approaches to estimate the treatment difference compared to the conventional cycle-level methods, which are evaluated by theoretical development and simulation studies. In addition, the methods are applied to the motivating phase 3 trial evaluating a treatment for insomnia with daily patient-reported outcomes.

A 5 year follow-up study on non-surgical treatment of ruptured lumbar disc herniation / 中国骨伤

OBJECTIVE@#To investigate the short-term and mid-term efficacy with non-surgical treatment and to predict the long-term outcomes of ruptured lumbar disc herniation.@*METHODS@#From February 2011 to February 2014, 75 patients with single-segment ruptured lumbar disc herniation treated by non-surgical therapy were selected for prospective study. There were 53 males and 22 females, aged from 18 to 58 (35.62±9.96) years old. The course of disease was from 5 days to 6 months, with an average of (46.45±40.66) days. The lesions were located at L in 4 cases, at L in 29 cases, at LS in 42 cases. Radiation pain in 46 cases on the left and 29 cases on the right. The JOA score, straight leg raising test angle and finger-to-ground distance were assessed pretreatment and at 3 months, 6 months, 1 year, 2 years and 5 years after treatment. The improvement rate of JOA at the final follow up (5 years after treatment) was calculated and the curative effect according to JOA score was evaluated;the volume change of protrusion before treatment and at the final follow-up (5 years after treatment) was analyzed, the volume absorption rate of protrusion was calculated and the absorption of protrusion was observed;the relationship between the improvement rate of JOA and the absorption rate of protrusion were analyzed.@*RESULTS@#Seventy one patients were finally followed up at 5 years after non surgical treatment. The JOA score, straight leg raising test angle and finger to ground distance at 3 months, 6 months, 1 year, 2 years and 5 years after treatment were significantly improved (0.05). There was significant differencein other time points (<0.05). The results of the straight leg raising test angle and the finger-to-ground distance were similar to the JOA scores. The improvement rate of JOA score was (62.69± 2.47)% at the final follow-up. According to JOA score, the results were excellent in 26 cases, good in 26 cases, fair in 14 cases, poor in 5 cases, and the excellent and good rate was 73.24%. The volume of protrusion decreased from (1 981.73±588.72) mm to (1 011.82±395.47) mm3, the total absorption rate was (45.65±2.83)%, the protrusion was obviously absorbed in 24 cases, partially absorbed in 26 cases, not absorbed in 19 cases, and increased in 2 cases. It was found that there was a positive correlation between improvement rate of JOA scores and protrusion absorption rate at 5 years after non surgical treatment (r= 0.679, <0.001).@*CONCLUSION@#Non-surgical treatment of ruptured lumbar disc herniation can achieve good results, clear the characteristics of the ruptured lumbar disc herniation and prognosis, and some patients have "reabsorption" phenomenon.

Curcuma wenyujin Y. H. Chen et C. Ling n-Butyl Alcohol Extract Inhibits AGS Cell Helicobacter pylori Promoted Invasiveness by Down-Regulating Caudal Type Homeobox Transcription Factor and Claudin-2 Expression / 中国结合医学杂志

OBJECTIVE@#To investigate the effects and possible mechanisms of action of Curcuma wenyujin Y. H. Chen et C. Ling n-Butyl alcohol extract (CWNAE) on repression of human gastric cancer (GC) AGS cell invasion induced by co-culturing with Helicobacter pylori (HP).@*METHODS@#AGS cells were cultured with HP of positive or negative cytotoxin-associated gene A (CagA) and vacuolating cytotoxin gene A (VacA) expression (CagA+/- or VacA+/-) and divided into 5 group. Group A was cultured without HP as a control, Group B with HP, Group C with HP, Group D with HP and CWNAE, and Group E with HP and CWNAE. Methylthiazolyldiphenyl-tetrazolium bromide (MTT) and tumor invasion assays, examinations of morphology and ultramicroscopic structures, quantitative real-time polymerase chain reaction and Western blots were performed to measure the effects and uncover the mechanisms behind these effects of HP and CWNAE on the epithelial-mesenchymal transition (EMT) of AGS cells.@*RESULTS@#The 10% inhibitory concentration of CWNAE against AGS cells after a 48 h incubation was 19.73±1.30 μg/mL. More AGS cells were elongated after co-culturing with HP than after culturing with HP. In tumor invasion assays, HP significantly enhanced the invasiveness of AGS cells compared to the other experimental groups (all P value <0.05), and this effect was inhibited by CWNAE. Treatment with CWNAE normalized tight junctions and reduced the number of pseudopodia of AGS cells co-cultured with HP. HP up-regulated zincfinger ebox binding homeobox 1 (ZEB1) in AGS cells after co-culturing for 24 h. Expression of caudal type homeobox transcription factor (CDX-2) and claudin-2 was significantly increased by HP (P<0.05), but not by HP.@*CONCLUSION@#HP promoted the invasiveness of AGS cells through up-regulation of ZEB1 transcription and claudin-2 and CDX-2 expression. CWNAE inhibited these effects of HP on AGS cells by down-regulating ZEB1 transcription, and CDX-2 and claudin-2 expression.

Impact of simulated microgravity on flash electroretinogram and retinal microcirculation in adult mice / 国际眼科杂志(Guoji Yanke Zazhi)

@#AIM: To observe changes in the flash electroretinogram(ERG)and retinal microcirculation in mice suspended by their tails, an animal model that simulates cephalad movement of bodily fluids under conditions of microgravity.<p>METHODS: Thirty-six adult male C57BL/6J mice(36 eyes)were randomly divided into three experimental groups and three control groups. Mice in the experimental groups were tail-suspended for 15d(Group one), tail-suspended for 30d(Group two), or tail-suspended followed by returning to normal position for 30d(Group three). Three control groups were similarly fixed with a harness but kept in the normal position for corresponding periods of 15, 30, and 60d. The mice were immediately examined using scotopic ERG(including oscillatory potentials \〖OPs\〗)and fundus fluorescein angiography(FFA)<i>in vivo</i>, and subsequently sacrificed to analyze the retinal histology(methods including immunohistochemistry and TUNEL staining)<i>in vitro</i>. Independent sample <i>t</i>-test was used for data comparison between the same time-point groups.<p>RESULTS: Following 15-days' tail-suspension, scotopic ERG showed a decline in OPs, but not in the b-wave; the second OP(O2)showed an amplitude of 197±33μV, which was about 60% of the control level(<i>t</i>=-5.938, <i>P</i><0.001). Following 30-days' tail-suspension, ERG recovered, with O2 showing an average value of 264±39μV; when compared to the corresponding control group(308±41μV), no significant difference was observed(<i>t</i>=-1.887, <i>P</i>>0.05). Morphologically, only the 15-days' tail-suspended mice showed FFA with microvascular dilation and tortuosity. Rhodopsin and cone-opsin were almost normal and no apoptotic-positive signals were detected in the retinas of the three tail-suspended groups.<p>CONCLUSION: Simulating cephalad shifting of bodily fluids as under microgravity, using short-term tail-suspension can affect rodent ERG and retinal microcirculation; however, the change is reversible with no obvious permanent injury observed in the retinas.

Building Quantitative Structure-Activity Relationship Models Using Bayesian Additive Regression Trees.

Quantitative structure-activity relationship (QSAR) is a very commonly used technique for predicting the biological activity of a molecule using information contained in the molecular descriptors. The large number of compounds and descriptors and the sparseness of descriptors pose important challenges to traditional statistical methods and machine learning (ML) algorithms (such as random forest (RF)) used in this field. Recently, Bayesian Additive Regression Trees (BART), a flexible Bayesian nonparametric regression approach, has been demonstrated to be competitive with widely used ML approaches. Instead of only focusing on accurate point estimation, BART is formulated entirely in a hierarchical Bayesian modeling framework, allowing one to also quantify uncertainties and hence to provide both point and interval estimation for a variety of quantities of interest. We studied BART as a model builder for QSAR and demonstrated that the approach tends to have predictive performance comparable to RF. More importantly, we investigated BART's natural capability to analyze truncated (or qualified) data, generate interval estimates for molecular activities as well as descriptor importance, and conduct model diagnosis, which could not be easily handled through other approaches.