Tympanostomy Tubes or Medical Management for Recurrent Acute Otitis Media.

BACKGROUND: Official recommendations differ regarding tympanostomy-tube placement for children with recurrent acute otitis media. METHODS: We randomly assigned children 6 to 35 months of age who had had at least three episodes of acute otitis media within 6 months, or at least four episodes within 12 months with at least one episode within the preceding 6 months, to either undergo tympanostomy-tube placement or receive medical management involving episodic antimicrobial treatment. The primary outcome was the mean number of episodes of acute otitis media per child-year (rate) during a 2-year period. RESULTS: In our main, intention-to-treat analysis, the rate (±SE) of episodes of acute otitis media per child-year during a 2-year period was 1.48±0.08 in the tympanostomy-tube group and 1.56±0.08 in the medical-management group (P = 0.66). Because 10% of the children in the tympanostomy-tube group did not undergo tympanostomy-tube placement and 16% of the children in the medical-management group underwent tympanostomy-tube placement at parental request, we conducted a per-protocol analysis, which gave corresponding episode rates of 1.47±0.08 and 1.72±0.11, respectively. Among secondary outcomes in the main analysis, results were mixed. Favoring tympanostomy-tube placement were the time to a first episode of acute otitis media, various episode-related clinical findings, and the percentage of children meeting specified criteria for treatment failure. Favoring medical management was children's cumulative number of days with otorrhea. Outcomes that did not show substantial differences included the frequency distribution of episodes of acute otitis media, the percentage of episodes considered to be severe, and antimicrobial resistance among respiratory isolates. Trial-related adverse events were limited to those included among the secondary outcomes of the trial. CONCLUSIONS: Among children 6 to 35 months of age with recurrent acute otitis media, the rate of episodes of acute otitis media during a 2-year period was not significantly lower with tympanostomy-tube placement than with medical management. (Funded by the National Institute on Deafness and Other Communication Disorders and others; ClinicalTrials.gov number, NCT02567825.).

Levothyroxine for a high-normal TSH in unexplained infertility.

OBJECTIVE: Unexplained infertility affects nearly one-third of infertile couples. Women with unexplained infertility are more likely to have a high-normal thyroid-stimulating hormone level (TSH: 2.5-5 mIU/L) compared to women with severe male factor infertility. Practice guidelines vary on whether treatment should be initiated for TSH levels >2.5 mIU/L in women attempting conception because the effects of treating a high-normal TSH level with levothyroxine are not known. We evaluated conception and live birth rates in women with unexplained infertility and high-normal TSH levels. DESIGN, PATIENTS AND MEASUREMENTS: Retrospective study including 96 women evaluated for unexplained infertility at a large academic medical centre between 1 January 2000 and 30 June 2017 with high-normal TSH (TSH: 2.5-5 mIU/L and within the normal range of the assay) who were prescribed (n = 31) or not prescribed (n = 65) levothyroxine. Conception and live birth rates were assessed. RESULTS: The conception rate in the levothyroxine group was 100% compared to 90% in the untreated group (p = .086 unadjusted; p < .05 adjusted for age; p = .370 adjusted for TSH; p = .287 adjusted for age and TSH). The live birth rate was lower in the levothyroxine group (63%) compared to the untreated group (84%) (p = .05 unadjusted; p = .094 adjusted for age; p = .035 adjusted for TSH; p = .057 adjusted for age and TSH). CONCLUSIONS: Women with unexplained infertility and high-normal TSH levels treated with levothyroxine had a higher rate of conception but lower live birth rate compared to untreated women, with the limitation of a small sample size. These findings assert the need for prospective, randomized studies to determine whether treatment with levothyroxine in women with unexplained infertility and high-normal TSH is beneficial.

Identifying Children Likely to Benefit From Antibiotics for Acute Sinusitis: A Randomized Clinical Trial.

Importance: The large overlap between symptoms of acute sinusitis and viral upper respiratory tract infection suggests that certain subgroups of children being diagnosed with acute sinusitis, and subsequently treated with antibiotics, derive little benefit from antibiotic use. Objective: To assess if antibiotic therapy could be appropriately withheld in prespecified subgroups. Design, Setting, and Participants: Randomized clinical trial including 515 children aged 2 to 11 years diagnosed with acute sinusitis based on clinical criteria. The trial was conducted between February 2016 and April 2022 at primary care offices affiliated with 6 US institutions and was designed to evaluate whether symptom burden differed in subgroups defined by nasopharyngeal Streptococcus pneumoniae, Haemophilus influenzae, or Moraxella catarrhalis on bacterial culture and by the presence of colored nasal discharge. Interventions: Oral amoxicillin (90 mg/kg/d) and clavulanate (6.4 mg/kg/d) (n = 254) or placebo (n = 256) for 10 days. Main Outcomes and Measures: The primary outcome was symptom burden based on daily symptom scores on a validated scale (range, 0-40) during the 10 days after diagnosis. Secondary outcomes included treatment failure, adverse events including clinically significant diarrhea, and resource use by families. Results: Most of the 510 included children were aged 2 to 5 years (64%), male (54%), White (52%), and not Hispanic (89%). The mean symptom scores were significantly lower in children in the amoxicillin and clavulanate group (9.04 [95% CI, 8.71 to 9.37]) compared with those in the placebo group (10.60 [95% CI, 10.27 to 10.93]) (between-group difference, -1.69 [95% CI, -2.07 to -1.31]). The length of time to symptom resolution was significantly lower for children in the antibiotic group (7.0 days) than in the placebo group (9.0 days) (P = .003). Children without nasopharyngeal pathogens detected did not benefit from antibiotic treatment as much as those with pathogens detected; the between-group difference in mean symptom scores was -0.88 (95% CI, -1.63 to -0.12) in those without pathogens detected compared with -1.95 (95% CI, -2.40 to -1.51) in those with pathogens detected. Efficacy did not differ significantly according to whether colored nasal discharge was present (the between-group difference was -1.62 [95% CI, -2.09 to -1.16] for colored nasal discharge vs -1.70 [95% CI, -2.38 to -1.03] for clear nasal discharge; P = .52 for the interaction between treatment group and the presence of colored nasal discharge). Conclusions: In children with acute sinusitis, antibiotic treatment had minimal benefit for those without nasopharyngeal bacterial pathogens on presentation, and its effects did not depend on the color of nasal discharge. Testing for specific bacteria on presentation may represent a strategy to reduce antibiotic use in this condition. Trial Registration: ClinicalTrials.gov Identifier: NCT02554383.

Construction of full-length infectious cDNA clones of two Korean isolates of turnip mosaic virus breaking resistance in Brassica napus.

In this work, two new turnip mosaic virus (TuMV) strains (Canola-12 and Canola-14) overcoming resistance in canola (Brassica napus) were isolated from a B. napus sample that showed typical TuMV-like symptoms and was collected in the city of Gimcheon, South Korea, in 2020. The complete genome sequence was determined and an infectious clone was made for each isolate. Phylogenetic analysis indicated that the strains isolated from canola belonged to the World-B group. Both infectious clones, which used 35S and T7 promoters to drive expression, induced systemic symptoms in Nicotiana benthamiana and B. napus. To our knowledge, this is the first report of TuMV infecting B. napus in South Korea.

Useful Serum Pepsinogen Levels for Detecting Ongoing Helicobacter pylori Infection in Asymptomatic Subjects: A Cross-Sectional Study Based on 13C-urea Breath Test Findings.

BACKGROUND /AIMS: The serum pepsinogen (PG) assay is used to screen subjects at high risk for gastric cancer. Currently, there are few studies on the PG levels for the detection of Helicobacter pylori infection. This study aimed to determine the PG assay findings for detecting ongoing infection. METHODS: Asymptomatic subjects who underwent a 13C-urea breath test (13C-UBT) on the day of gastroscopy and serum assay for cancer screening were included. Subjects with a recent intake of acid suppressants or antibiotics, gastrectomy, or renal failure were excluded. H. pylori infection was defined as a positive 13C-UBT result. RESULTS: Among the 500 included subjects, 167 (33.4%) had current infection. The serum PG II levels of > 12.95 ng/mL (area under the curve [AUC] = 0.930, sensitivity 86.5%, specificity 90.7%) and PG I/II ratios of < 4.35 (AUC = 0.875, sensitivity 86.8%, specificity 79.6%) were related to infection. The PG I/II ratios were inversely correlated with age (r = -0.160, p = 0.039). The cutoff values of PG I/II ratios were lower in older subjects aged ≥ 50 years (< 4.05; AUC = 0.875, sensitivity 80.7%, specificity 88.2%) than in younger subjects aged < 50 years (< 4.35; AUC = 0.873, sensitivity 77.4%, specificity 88.9%). CONCLUSIONS: Serum PG II levels > 12.95 ng/mL and PG I/II ratios < 4.35 suggest ongoing infection in asymptomatic subjects; therefore, H. pylori confirmation tests (i.e., 13C-UBT) should be considered under these conditions. Stricter criteria are required in older subjects aged ≥ 50 years (PG I/II ratio < 4.05) to detect ongoing infection than younger subjects.

Clinical Significance of the Neutrophil-Lymphocyte Ratio as an Early Predictive Marker for Adverse Outcomes in Patients with Acute Cholangitis.

Background and objectives: Acute cholangitis can be life-threatening if not recognized early. We investigated the predictive value of the neutrophil-lymphocyte ratio (NLR) in acute cholangitis. Materials and Methods: We retrospectively evaluated 206 patients with acute cholangitis who underwent biliary drainage. The severity of acute cholangitis was graded according to the Tokyo 2018 guideline. Patients were dichotomized according to the acute cholangitis severity (mild/moderate vs. severe), the presence of shock requiring a vasopressor/inotrope, and blood culture positivity. The baseline NLR, white blood cell (WBC) count, and C-reactive protein (CRP) levels were compared between groups. Results: The severity of acute cholangitis was graded as mild, moderate, or severe in 71 (34.5%), 107 (51.9%), and 28 (13.6%) patients, respectively. Ten patients (4.8%) developed shock. Positive blood culture (n = 50) was observed more frequently in severe acute cholangitis (67.9% vs. 17.4%, p < 0.001). The NLR was significantly higher in patients with severe cholangitis, shock, and positive blood culture. The area under the curve (AUC) for the NLR, WBC, and CRP for severe acute cholangitis was 0.87, 0.73, and 0.74, respectively. The AUC for the NLR, WBC, and CRP for shock was 0.81, 0.64, and 0.67, respectively. The AUC for the NLR, WBC, and CRP for positive blood culture was 0.76, 0.64, and 0.61, respectively; the NLR had greater power to predict disease severity, shock, and positive blood culture. The optimal cut-off value of the baseline NLR for the prediction of severe acute cholangitis, shock, and positive blood culture was 15.24 (sensitivity, 85%; specificity, 79%), 15.54 (sensitivity, 80%; specificity, 73%), and 12.35 (sensitivity, 72%; specificity, 70%), respectively. The sequential NLR values from admission to 2 days after admission were significantly higher in patients with severe cholangitis and shock. Conclusions: An elevated NLR correlates with severe acute cholangitis, shock, and positive blood culture. Serial NLR can track the clinical course of acute cholangitis.

Cause-specific quantile regression on inactivity time.

In time-to-event analysis, the traditional summary measures have been based on the hazard function, survival function, quantile event time, restricted mean event time, and residual lifetime. Under competing risks, furthermore, typical summary measures have been the cause-specific hazard function and cumulative incidence function. Recently inactivity time has recaptured attention in the literature, being interpreted as life lost. In this paper, we further interpret it as quality of life reduced and time period after transition to a drug, and propose a quantile regression model to associate the inactivity time with potential predictors under competing risks. We define the proper cumulative distribution function of the inactivity time distribution for each specific event type among those subjects who experience the same type of events during a follow-up period. A score function-type estimating equation is developed and asymptotic properties of the regression coefficient estimators are derived by assuming that competing events are censored at their occurrence times as in the cause-specific hazard analysis. The proposed approach reduces to a regular quantile regression on the inactivity time without competing risks when all types of competing events are collapsed into the same type. Due to difficulty in estimating the improper probability density function of the cause-specific inactivity distribution to evaluate the variance of the quantiles, a computationally efficient perturbation method is adopted to infer the regression coefficients. Simulation results show that our proposed method works well under the assumed finite sample settings. The proposed method is illustrated with a real dataset from a breast cancer study.

Efficacy of vagus nerve stimulation for drug-resistant epilepsy in children age six and younger.

OBJECTIVES: The objective of the study were to examine the safety and efficacy of vagus nerve stimulation (VNS) for reducing seizure frequency and antiepileptic drugs (AEDs) in children younger than six years and to examine long-term VNS efficacy for children who receive the device at ages 1-3 and at ages 4-6. METHODS: We conducted a 10-year retrospective analysis of VNS implantations at UPMC Children's Hospital of Pittsburgh. Relevant data were collected within 12 months of VNS implantation and at six months, one, two, and four years after VNS implantation. RESULTS: This analysis included 99 patients ages 0-3 (n = 40) and 4-6 (n = 59) at first VNS implantation. Eighty-six patients followed up for ≥4 years. There were no significant differences between age at VNS implant (0-3 vs. 4-6) and seizure etiology or most seizure semiologies. Patients took an average of 3.01 ±â€¯1.29 AEDs prior to VNS and 3.84 ±â€¯1.68 AEDs at their latest follow-up. The overall response to VNS therapy (≥50% seizure reduction) at one year, two years, and four years after VNS implantation was 55%, 60%, and 52%, respectively. At two years, 59% of 0- to 3-year-old patients responded to VNS and 52% of 4- to 6-year-old patients responded to VNS. The overall major complication rate was 5.6%, consistent with VNS use for older age groups. SIGNIFICANCE: This study demonstrates the safety and efficacy of VNS for children with drug-resistant epilepsy (DRE) younger than six. One, two, and four years after VNS implantation, 55%, 60%, and 52% of these patients, respectively, achieved ≥50% reduction in seizure frequency. The safety of VNS is also comparable with older, better studied, age groups. Based on these data, VNS therapy should be considered for children younger than six.

Identifying Predictors of Recommendations for and Participation in Multimodal Nonpharmacological Treatments for Chronic Pain Using Patient-Reported Outcomes and Electronic Medical Records.

OBJECTIVE: High-quality chronic pain care emphasizes multimodal treatments that include medication and nonpharmacological treatments. But it is not clear which patients will participate in nonpharmacological treatments, such as physical therapy or mental health care, and previous research has shown conflicting evidence. METHODS: We used the Patient Outcomes Repository for Treatment (PORT) registry, which combines patient-reported outcomes data with electronic medical records. In this retrospective observational study, we performed two separate multinomial regression analyses with feature selection to identify PORT variables that were predictive of 1) recommendation of a nonpharmacological treatment by the provider and 2) patient participation in nonpharmacological treatments. Two hundred thirty-six patients were recommended (REC) or not recommended (NO REC) a nonpharmacological treatment, and all REC patients were classified as participating (YES) or not participating (NO) in the recommendations. RESULTS: Female gender and a diagnosis of Z79 "Opioid drug therapy" were significant positive and negative predictors of nonpharmacological treatment recommendations, respectively. Schedule II opioid use at initial presentation and recommendations for rehabilitation therapy were significant predictors of nonparticipation. CONCLUSIONS: Patients using opioids are less likely to be recommended nonpharmacological treatments as part of multimodal chronic pain care and are less likely to participate in nonpharmacological treatments once recommended. Males are also less likely to be recommended nonpharmacological treatments. Patients referred for rehabilitation therapies are less likely to comply with those recommendations. We have identified patients in vulnerable subgroups who may require additional resources and/or encouragement to comply with multimodal chronic pain treatment recommendations.

Comparative Effectiveness of Embedded Mental Health Services in Pain Management Clinics vs Standard Care.

OBJECTIVE: Embedded behavioral medicine services are a common component of multidisciplinary chronic pain treatment programs. However, few studies have studied whether these services are associated with improved treatment outcomes. METHODS: Using a retrospective, matched, two-cohort study design, we examined patient-reported outcomes (PROs), including Patient-Reported Outcomes Measurement Information System pain, mental health, and physical function measures, collected at every clinic visit in every patient. Changes from baseline through 12 months were compared in those receiving embedded Behavioral Medicine in addition to usual care to a Standard Care group seen in the same pain practice and weighted via propensity scoring. RESULTS: At baseline, Behavioral Medicine patients had worse scores on most pain, mental health, and physical health measures and were more likely to be female, a member of a racial minority, and have lower socioeconomic status. Regardless of having a worse clinical pain syndrome at baseline, at follow-up both Behavioral Medicine (N = 451) and Standard Care patients (N = 8,383) showed significant and comparable improvements in pain intensity, physical function, depression, and sleep disturbance. Behavioral Medicine patients showed significantly greater improvements in their global impressions of change than the Standard Care patients. CONCLUSIONS: Despite worse pain and physical and psychological functioning at baseline, Behavioral Medicine patients showed improvements comparable to patients not receiving these services. Further, Behavioral Medicine patients report higher global impressions of change, indicating that embedded mental health services appear to have the additive value of amplifying the benefits of multimodal pain care.

Frailty modelling approaches for semi-competing risks data.

In the semi-competing risks situation where only a terminal event censors a non-terminal event, observed event times can be correlated. Recently, frailty models with an arbitrary baseline hazard have been studied for the analysis of such semi-competing risks data. However, their maximum likelihood estimator can be substantially biased in the finite samples. In this paper, we propose effective modifications to reduce such bias using the hierarchical likelihood. We also investigate the relationship between marginal and hierarchical likelihood approaches. Simulation results are provided to validate performance of the proposed method. The proposed method is illustrated through analysis of semi-competing risks data from a breast cancer study.

Use of letrozole after aromatase inhibitor-based therapy in postmenopausal breast cancer (NRG Oncology/NSABP B-42): a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: The optimal duration of extended therapy with aromatase inhibitors in patients with postmenopausal breast cancer is unknown. In the NSABP B-42 study, we aimed to determine whether extended letrozole treatment improves disease-free survival after 5 years of aromatase inhibitor-based therapy in women with postmenopausal breast cancer. METHODS: This randomised, double-blind, placebo-controlled, phase 3 trial was done in 158 centres in the USA, Canada, and Ireland. Postmenopausal women with stage I-IIIA hormone receptor-positive breast cancer, who were disease-free after about 5 years of treatment with an aromatase inhibitor or tamoxifen followed by an aromatase inhibitor, were randomly assigned (1:1) to receive 5 years of letrozole (2·5 mg orally per day) or placebo. Randomisation was stratified by pathological node status, previous tamoxifen use, and lowest bone mineral density T score in the lumbosacral spine, total hip, or femoral neck. The primary endpoint was disease-free survival, defined as time from randomisation to breast cancer recurrence, second primary malignancy, or death, and was analysed by intention to treat. To adjust for previous interim analyses, the two-sided statistical significance level for disease-free survival was set at 0·0418. This study is registered with ClinicalTrials.gov, number NCT00382070, is active, and is no longer enrolling patients. FINDINGS: Between Sept 28, 2006, and Jan 6, 2010, 3966 patients were randomly assigned to receive letrozole (n=1983) or placebo (n=1983). Follow-up information was available for 3903 patients for the analyses of disease-free survival. Median follow-up was 6·9 years (IQR 6·1-7·5). Letrozole treatment did not significantly improve disease-free survival (339 disease-free survival events were reported in the placebo group and 292 disease-free survival events were reported in the letrozole group; hazard ratio 0·85, 95% CI 0·73-0·999; p=0·048). 7-year disease-free survival estimate was 81·3% (95% CI 79·3-83·1) in the placebo group and 84·7% (82·9-86·4) in the letrozole group. The most common grade 3 adverse events were arthralgia (47 [2%] of 1933 patients in the placebo group vs 50 [3%] of 1941 patients in the letrozole group) and back pain (44 [2%] vs 38 [2%]). The most common grade 4 adverse event in the placebo group was thromboembolic event (eight [<1%]) and the most common grade 4 adverse events in the letrozole group were urinary tract infection, hypokalaemia, and left ventricular systolic dysfunction (four [<1%] each). INTERPRETATION: After 5 years of aromatase inhibitor-based therapy, 5 years of letrozole therapy did not significantly prolong disease-free survival compared with placebo. Careful assessment of potential risks and benefits is required before recommending extended letrozole therapy to patients with early-stage breast cancer. FUNDING: National Cancer Institute, Korea Health Technology R&D Project, Novartis.

Development and Modification of an Outcome Measure to Follow Symptoms of Children with Sinusitis.

OBJECTIVE: To develop a parent-reported Pediatric Rhinosinusitis Symptom Scale (PRSS) that could be used to monitor symptoms of young children with acute sinusitis in response to therapy. STUDY DESIGN: We developed an 8-item symptom severity scale and evaluated its internal reliability, construct validity, and responsiveness in children 2-12 years of age with acute sinusitis. Parents of 258 children with acute sinusitis completed the PRSS at the time of diagnosis, as a diary at home, and at the follow-up visit at days 10-12. Based on psychometric results and additional parent feedback, we revised the scale. We evaluated the revised version in 185 children with acute sinusitis. RESULTS: Correlations between the scale and reference measures on the day of enrollment were in the expected direction and of the expected magnitude. PRSS scores at the time of presentation correlated with radiographic findings (P < .001), functional status (P < .001), and parental assessment of overall symptom severity (P < .001). Responsiveness (standardized response mean) and test-retest reliability of the revised scale were good (2.17 and 0.75, respectively). CONCLUSIONS: We have developed an outcome measure to track the symptoms of acute sinusitis. Data presented here support the use of the PRSS as a measure of change in symptom burden in clinical trials of children with acute sinusitis.

21-Gene Recurrence Score for prognosis and prediction of taxane benefit after adjuvant chemotherapy plus endocrine therapy: results from NSABP B-28/NRG Oncology.

BACKGROUND: The 21-gene recurrence score (RS) predicts outcome and benefit from adjuvant chemotherapy benefit in breast cancer patients treated with adjuvant endocrine therapy. In the NSABP B-28 study, we evaluated the 21-gene RS for its prognostic impact and its ability to predict benefit from paclitaxel (P) in node-positive, estrogen receptor-positive (ER+) breast cancer patients treated with adjuvant chemotherapy plus tamoxifen. METHODS: The B-28 trial compared doxorubicin/cyclophosphamide (AC) with AC followed by P in 3060 patients. Tamoxifen for 5 years was also given to patients > 50 years and those < 50 years with ER+ and/or progesterone receptor-positive (PR+) tumors. The present study includes 1065 ER-positive, tamoxifen-treated patients with RS assessment. Median follow-up time was 11.2 years. RESULTS: In univariate analyses, RS was a significant predictor of outcome. In multivariate analyses, RS remained a significant independent predictor of outcome beyond clinico-pathologic factors, age, and type of surgery (p < 0.001). In the study population (n = 1065), the disease-free survival (DFS) hazard ratio (HR) with adding P to AC was 0.87 (95% CI 0.72-1.05; p = 0.14). RS was not a significant predictor of P benefit: for DFS, HRs for adding P to AC in RS low, intermediate, and high subgroups were 1.01 (95% CI 0.69-1.47; p = 0.99), 0.84 (95% CI 0.62-1.14; p = 0.26), and 0.81 (95% CI 0.60-1.10; p = 0.21), respectively (interaction p = 0.64). Similar findings were observed for the other study endpoints. CONCLUSIONS: RS maintains significant prognostic impact in ER-positive, node-positive patients treated with adjuvant chemotherapy plus tamoxifen. However, RS did not significantly predict benefit from adding paclitaxel to AC chemotherapy. (Trial Registration: PDQ: NSABP-B-28).

Reduced-Concentration Clavulanate for Young Children with Acute Otitis Media.

Amoxicillin-clavulanate (A/C) is currently the most effective oral antimicrobial in treating children with acute otitis media (AOM), but the standard dosage of 90 mg amoxicillin/6.4 mg clavulanate/kg of body weight/day commonly causes diarrhea. We examined whether an A/C formulation containing lower concentrations of clavulanate would result in less diarrhea while maintaining plasma levels of amoxicillin and clavulanate adequate to eradicate middle-ear pathogens and to achieve clinical success. We conducted an open-label study in children with AOM who were 6 to 23 months of age. In phase 1, we treated 40 children with a reduced-clavulanate A/C formulation providing 90 mg amoxicillin/3.2 mg clavulanate/kg/day for 10 days. In phase 2, we treated 72 children with the same formulation at a dosage of 80 mg amoxicillin/2.85 mg clavulanate/kg/day for 10 days. We compared the rates of protocol-defined diarrhea (PDD), diaper dermatitis, and AOM clinical response in these children with rates we had reported in children who received the standard A/C regimen, and we obtained plasma levels of amoxicillin and clavulanate at various time points. Outcomes in phase 1 children and in children who had received the standard regimen did not differ significantly. Rates of PDD in children receiving phase 2 and standard regimens were 17% and 26%, respectively (P = 0.10). The corresponding rates of diaper dermatitis were 21% and 33% (P = 0.04) and of AOM treatment failure were 12% and 16% (P = 0.44). Symptomatic responses did not differ significantly between regimens; both gave clavulanate levels sufficient to inhibit ß-lactamase activity. In young children with AOM, clavulanate dosages lower than those currently used may be associated with fewer side effects without reducing clinical efficacy. (This study has been registered at ClinicalTrials.gov under registration no. NCT02630992.).

Nonparametric inference on quantile lost lifespan.

In this article, the existing concept of reversed percentile residual life, or percentile inactivity time, is recast to show that it can be used for routine analysis of time-to-event data under right censoring to summarize "life lost," which poses several advantages over the existing methods for survival analysis. An estimating equation approach is adopted to avoid estimation of the probability density function of the underlying time-to-event distribution to estimate the variance of the quantile estimator. Additionally a K-sample test statistic is proposed to test the ratio of the quantile lost lifespans. Simulation studies are performed to assess finite properties of the proposed K-sample statistic in terms of coverage probability and power. The proposed method is illustrated with a real data example from a breast cancer study.

Hierarchical likelihood inference on clustered competing risks data.

The frailty model, an extension of the proportional hazards model, is often used to model clustered survival data. However, some extension of the ordinary frailty model is required when there exist competing risks within a cluster. Under competing risks, the underlying processes affecting the events of interest and competing events could be different but correlated. In this paper, the hierarchical likelihood method is proposed to infer the cause-specific hazard frailty model for clustered competing risks data. The hierarchical likelihood incorporates fixed effects as well as random effects into an extended likelihood function, so that the method does not require intensive numerical methods to find the marginal distribution. Simulation studies are performed to assess the behavior of the estimators for the regression coefficients and the correlation structure among the bivariate frailty distribution for competing events. The proposed method is illustrated with a breast cancer dataset.

Low-Fidelity Haptic Simulation Versus Mental Imagery Training for Epidural Anesthesia Technical Achievement in Novice Anesthesiology Residents: A Randomized Comparative Study.

BACKGROUND: There are many teaching methods for epidural anesthesia skill acquisition. Previous work suggests that there is no difference in skill acquisition whether novice learners engage in low-fidelity (LF) versus high-fidelity haptic simulation for epidural anesthesia. No study, however, has compared the effect of LF haptic simulation for epidural anesthesia versus mental imagery (MI) training in which no physical practice is attempted. We tested the hypothesis that MI training is superior to LF haptic simulation training for epidural anesthesia skill acquisition. METHODS: Twenty Post-Graduate Year 2 (PGY-2) anesthesiology residents were tested at the beginning of the training year. After a didactic lecture on epidural anesthesia, they were randomized into 2 groups. Group LF had LF simulation training for epidural anesthesia using a previously described banana simulation technique. Group MI had guided, scripted MI training in which they initially were oriented to the epidural kit components and epidural anesthesia was described stepwise in detail, followed by individual mental rehearsal; no physical practice was undertaken. Each resident then individually performed epidural anesthesia on a partial-human task trainer on 3 consecutive occasions under the direct observation of skilled evaluators who were blinded to group assignment. Technical achievement was assessed with the use of a modified validated skills checklist. Scores (0-21) and duration to task completion (minutes) were recorded. A linear mixed-effects model analysis was performed to determine the differences in scores and duration between groups and over time. RESULTS: There was no statistical difference between the 2 groups for scores and duration to task completion. Both groups showed similarly significant increases (P = 0.0015) in scores over time (estimated mean score [SE]: group MI, 15.9 [0.55] to 17.4 [0.55] to 18.6 [0.55]; group LF, 16.2 [0.55] to 17.7 [0.55] to 18.9 [0.55]). Time to complete the procedure decreased similarly and significantly (P = 0.032) for both groups after the first attempt (estimated mean time [SE]: group MI, 16.0 [1.04] minutes to 13.7 [1.04] minutes to 13.3 [1.04] minutes; group LF: 15.8 [1.04] minutes to 13.4 [1.04] minutes to 13.1 [1.04] minutes). CONCLUSIONS: MI is not different from LF simulation training for epidural anesthesia skill acquisition. Education in epidural anesthesia with structured didactics and continual MI training may suffice to prepare novice learners before an attempt on human subjects.

An isoform of C/EBPß, LIP, regulates expression of the chemokine receptor CXCR4 and modulates breast cancer cell migration.

Metastasis is the primary cause of death in cancer patients. CXCR4/CXCL12 chemokine axis provides directional cues for breast cancer cells to metastasize to specific organs. Despite their potential clinical importance, how CXCR4 expression in breast cancer cells is regulated at the molecular level is not well understood. We identified an isoform of C/EBPß, liver-enriched inhibitory protein (LIP), as a previously unrecognized transcriptional regulator of CXCR4 in breast cancer cells. LIP up-regulated the transcription of CXCR4 through direct interaction with the CXCR4 promoter. The increase in CXCR4 mRNA was paralleled by an increased cell surface expression of the CXCR4, which in turn promoted CXCR4-mediated breast cancer cell migration. A significant positive correlation between LIP and CXCR4 expression was observed in stage III and IV human breast carcinoma specimens. Neuregulin 1 (or NRG1, hereafter referred to as heregulin) increased CXCR4 expression in breast cancer cells, and this coincided with increased LIP binding on the CXCR4 promoter. These findings may have important implications for understanding the molecular basis of CXCR4-mediated breast cancer cell metastasis and could potentially allow us to develop novel strategies to reduce morbidity and mortality in patients with metastatic breast cancer.

Variable selection in subdistribution hazard frailty models with competing risks data.

The proportional subdistribution hazards model (i.e. Fine-Gray model) has been widely used for analyzing univariate competing risks data. Recently, this model has been extended to clustered competing risks data via frailty. To the best of our knowledge, however, there has been no literature on variable selection method for such competing risks frailty models. In this paper, we propose a simple but unified procedure via a penalized h-likelihood (HL) for variable selection of fixed effects in a general class of subdistribution hazard frailty models, in which random effects may be shared or correlated. We consider three penalty functions, least absolute shrinkage and selection operator (LASSO), smoothly clipped absolute deviation (SCAD) and HL, in our variable selection procedure. We show that the proposed method can be easily implemented using a slight modification to existing h-likelihood estimation approaches. Numerical studies demonstrate that the proposed procedure using the HL penalty performs well, providing a higher probability of choosing the true model than LASSO and SCAD methods without losing prediction accuracy. The usefulness of the new method is illustrated using two actual datasets from multi-center clinical trials.