Hierarchical Clustering Applied to Chronic Pain Drawings Identifies Undiagnosed Fibromyalgia: Implications for Busy Clinical Practice.

Currently-used assessments for fibromyalgia require clinicians to suspect a fibromyalgia diagnosis, a process susceptible to unintentional bias. Automated assessments of standard patient-reported outcomes (PROs) could be used to prompt formal assessments, potentially reducing bias. We sought to determine whether hierarchical clustering of patient-reported pain distribution on digital body map drawings predicted fibromyalgia diagnosis. Using an observational cohort from the University of Pittsburgh's Patient Outcomes Repository for Treatment registry, which contains PROs and electronic medical record data from 21,423 patients (March 17, 2016-June 25, 2019) presenting to pain management clinics, we tested the hypothesis that hierarchical clustering subgroup was associated with fibromyalgia diagnosis, as determined by ICD-10 code. Logistic regression revealed a significant relationship between the body map cluster subgroup and fibromyalgia diagnosis. The cluster subgroup with the most body areas selected was the most likely to receive a diagnosis of fibromyalgia when controlling for age, gender, anxiety, and depression. Despite this, more than two-thirds of patients in this cluster lacked a clinical fibromyalgia diagnosis. In an exploratory analysis to better understand this apparent underdiagnosis, we developed and applied proxies of fibromyalgia diagnostic criteria. We found that proxy diagnoses were more common than ICD-10 diagnoses, which may be due to less frequent clinical fibromyalgia diagnosis in men. Overall, we find evidence of fibromyalgia underdiagnosis, likely due to gender bias. Coupling PROs that take seconds to complete, such as a digital pain body map, with machine learning is a promising strategy to reduce bias in fibromyalgia diagnosis and improve patient outcomes. PERSPECTIVE: This investigation applies hierarchical clustering to patient-reported, digital pain body maps, finding an association between body map responses and clinical fibromyalgia diagnosis. Rapid, computer-assisted interpretation of pain body maps would be clinically useful in prompting more detailed assessments for fibromyalgia, potentially reducing gender bias.

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.

Mediation Analysis using Semi-parametric Shape-Restricted Regression with Applications.

Often linear regression is used to perform mediation analysis. However, in many instances, the underlying relationships may not be linear, as in the case of placentalfetal hormones and fetal development. Although, the exact functional form of the relationship may be unknown, one may hypothesize the general shape of the relationship. For these reasons, we develop a novel shape-restricted inference-based methodology for conducting mediation analysis. This work is motivated by an application in fetal endocrinology where researchers are interested in understanding the effects of pesticide application on birth weight, with human chorionic gonadotropin (hCG) as the mediator. We assume a practically plausible set of nonlinear effects of hCG on the birth weight and a linear relationship between pesticide exposure and hCG, with both exposure-outcome and exposure-mediator models being linear in the confounding factors. Using the proposed methodology on a population-level prenatal screening program data, with hCG as the mediator, we discovered that, while the natural direct effects suggest a positive association between pesticide application and birth weight, the natural indirect effects were negative.

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.

Ten-year update: NRG Oncology/National Surgical Adjuvant Breast and Bowel Project B-42 randomized trial: extended letrozole therapy in early-stage breast cancer.

BACKGROUND: The National Surgical Adjuvant Breast and Bowel Project B-42 trial evaluated extended letrozole therapy (ELT) in postmenopausal breast cancer patients who were disease free after 5 years of aromatase inhibitor (AI)-based therapy. Seven-year results demonstrated a nonstatistically significant trend in disease-free survival (DFS) in favor of ELT. We present 10-year outcome results. METHODS: In this double-blind, phase III trial, patients with stage I-IIIA hormone receptor-positive breast cancer, disease free after 5 years of an AI or tamoxifen followed by an AI, were randomly assigned to 5 years of letrozole or placebo. Primary endpoint was DFS, defined as time from random assignment to breast cancer recurrence, second primary malignancy, or death. All statistical tests are 2-sided. RESULTS: Between September 2006 and January 2010, 3966 patients were randomly assigned (letrozole: 1983; placebo: 1983). Median follow-up time for 3923 patients included in efficacy analyses was 10.3 years. There was statistically significant improvement in DFS in favor of letrozole compared with placebo (hazard ratio [HR] = 0.85, 95% confidence interval [CI] = 0.74 to 0.96; P = .01; 10-year DFS: placebo = 72.6%, letrozole = 75.9%, absolute difference = 3.3%). There was no difference in the effect of letrozole on overall survival (HR = 0.97, 95% CI = 0.82 to 1.15; P = .74). Letrozole statistically significantly reduced breast cancer-free interval events (HR = 0.75, 95% CI = 0.62 to 0.91; P = .003; absolute difference in cumulative incidence = 2.7%) and distant recurrences (HR = 0.72, 95% CI = 0.55 to 0.92; P = .01; absolute difference = 1.8%). The rates of osteoporotic fractures and arterial thrombotic events did not differ between treatment groups. CONCLUSIONS: The beneficial effect of ELT on DFS persisted at 10 years. Letrozole also improved breast cancer-free interval and distant recurrences without improving overall survival. Careful assessment of potential risks and benefits is necessary for selecting appropriate candidates for ELT.

Changes in nuclear pore numbers control nuclear import and stress response of mouse hearts.

Nuclear pores are essential for nuclear-cytoplasmic transport. Whether and how cells change nuclear pores to alter nuclear transport and cellular function is unknown. Here, we show that rat heart muscle cells (cardiomyocytes) undergo a 63% decrease in nuclear pore numbers during maturation, and this changes their responses to extracellular signals. The maturation-associated decline in nuclear pore numbers is associated with lower nuclear import of signaling proteins such as mitogen-activated protein kinase (MAPK). Experimental reduction of nuclear pore numbers decreased nuclear import of signaling proteins, resulting in decreased expression of immediate-early genes. In a mouse model of high blood pressure, reduction of nuclear pore numbers improved adverse heart remodeling and reduced progression to lethal heart failure. The decrease in nuclear pore numbers in cardiomyocyte maturation and resulting functional changes demonstrate how terminally differentiated cells permanently alter their handling of information flux across the nuclear envelope and, with that, their behavior.

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.

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.

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.

Comparison of traditional and closed loop vagus nerve stimulation for treatment of pediatric drug-resistant epilepsy: A propensity-matched retrospective cohort study.

OBJECTIVE: For epilepsy patients with drug-resistant, unresectable epilepsy, vagus nerve stimulation (VNS) is an option for seizure control. Approximately 40-70% of patients will achieve ≥50% seizure reduction with VNS. New closed loop VNS models detect ictal tachycardia and responsively stimulate the vagus nerve. The effectiveness of closed loop VNS compared to traditional VNS for pediatric epilepsy is unknown. METHODS: An 11-year retrospective electronic medical record review at Children's Hospital of Pittsburgh was performed. Patients with drug-resistant epilepsy who underwent VNS implantation were included. Patients were divided into groups based on VNS model: traditional versus closed loop. Those who transitioned from traditional to closed loop VNS were excluded. Given potential for selection bias, propensity scores matching was utilized to compare traditional to closed loop VNS patients. Patients with focal versus generalized epilepsy were also separately analyzed. The primary outcome was "VNS response", defined as at least 50% seizure frequency reduction from baseline. RESULTS: A total of 320 patients were included in this sample. The percentage of matched patients (total n = 220: n = 179 traditional VNS, n = 41 closed loop VNS) who responded to VNS after one year of therapy was 43% for traditional VNS and 39% for closed loop VNS (p = 0.64). After two years of therapy, a higher proportion of closed loop VNS patients than traditional VNS patients responded to VNS among all subgroups, though no differences were statistically significant (p>0.05). Notably, for those with generalized epilepsy, 73% of closed loop patients responded to VNS compared to only 46% of traditional patients (p = 0.10). After two years of VNS therapy, patients were taking approximately the same quantity of antiseizure medications as baseline (change of +0.074 +/- 0.90 ) with no difference between VNS models (p = 0.87). SIGNIFICANCE: Among pediatric patients with drug-resistant epilepsy, closed loop VNS trends towards a higher rate of VNS response after two years of treatment, especially among generalized epilepsy patients. Neither model of VNS allows patients to reduce antiseizure medication quantity after two years.

Hierarchical clustering by patient-reported pain distribution alone identifies distinct chronic pain subgroups differing by pain intensity, quality, and clinical outcomes.

BACKGROUND: In clinical practice, the bodily distribution of chronic pain is often used in conjunction with other signs and symptoms to support a diagnosis or treatment plan. For example, the diagnosis of fibromyalgia involves tallying the areas of pain that a patient reports using a drawn body map. It remains unclear whether patterns of pain distribution independently inform aspects of the pain experience and influence patient outcomes. The objective of the current study was to evaluate the clinical relevance of patterns of pain distribution using an algorithmic approach agnostic to diagnosis or patient-reported facets of the pain experience. METHODS AND FINDINGS: A large cohort of patients (N = 21,658) completed pain body maps and a multi-dimensional pain assessment. Using hierarchical clustering of patients by body map selection alone, nine distinct subgroups emerged with different patterns of body region selection. Clinician review of cluster body maps recapitulated some clinically-relevant patterns of pain distribution, such as low back pain with radiation below the knee and widespread pain, as well as some unique patterns. Demographic and medical characteristics, pain intensity, pain impact, and neuropathic pain quality all varied significantly across cluster subgroups. Multivariate modeling demonstrated that cluster membership independently predicted pain intensity and neuropathic pain quality. In a subset of patients who completed 3-month follow-up questionnaires (N = 7,138), cluster membership independently predicted the likelihood of improvement in pain, physical function, and a positive overall impression of change related to multidisciplinary pain care. CONCLUSIONS: This study reports a novel method of grouping patients by pain distribution using an algorithmic approach. Pain distribution subgroup was significantly associated with differences in pain intensity, impact, and clinically relevant outcomes. In the future, algorithmic clustering by pain distribution may be an important facet in chronic pain biosignatures developed for the personalization of pain management.

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.).

NRG Oncology/NSABP B-47 menstrual history study: impact of adjuvant chemotherapy with and without trastuzumab.

The NRG Oncology/NSABP B-47 menstrual history (MH) study examined trastuzumab effects on menstrual status and associated circulating reproductive hormones. MH was evaluated by questions related to hysterectomy, oophorectomy, and reported menstrual changes. Pre/perimenopausal women were assessed at entry, 3, 6, 12, 18, 24, 30, and 36 months. Consenting women had estradiol and FSH measurement at entry, 3, 6, 12, 18, and 24 months. Logistic regression determined predictors of amenorrhea and hormone levels at 12, 24, and 36 months. Between 2/8/2011 and 2/10/2015, 3270 women with node-positive/high-risk node-negative HER2-low breast cancer were enrolled. There were 1,458 women enrolled in the MH study; 1231 consented to baseline blood samples. Trastuzumab did not contribute to a higher amenorrhea rate. Amenorrhea predictors were consistent with earlier studies; however, to our knowledge, this is the largest prospective study to include serial reproductive hormone measurements to 24 months and clinical amenorrhea reports to 36 months. These data can help to counsel patients regarding premature menopause risk.

Quantile regression on inactivity time.

The inactivity time, or lost lifespan specifically for mortality data, concerns time from occurrence of an event of interest to the current time point and has recently emerged as a new summary measure for cumulative information inherent in time-to-event data. This summary measure provides several benefits over the traditional methods, including more straightforward interpretation yet less sensitivity to heavy censoring. However, there exists no systematic modeling approach to inferring the quantile inactivity time in the literature. In this paper, we propose a semi-parametric regression method for the quantiles of the inactivity time distribution under right censoring. The consistency and asymptotic normality of the regression parameters are established. To avoid estimation of the probability density function of the inactivity time distribution under censoring, we propose a computationally efficient method for estimating the variance-covariance matrix of the regression coefficient estimates. Simulation results are presented to validate the finite sample properties of the proposed estimators and test statistics. The proposed method is illustrated with a real dataset from a clinical trial on breast cancer.

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.

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.

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.

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.

Study protocol for targeted interventions to prevent chronic low back pain in high-risk patients: A multi-site pragmatic cluster randomized controlled trial (TARGET Trial).

BACKGROUND: Low back pain (LBP) is one of the most prevalent and potentially disabling conditions for which people seek health care. Patients, providers, and payers agree that greater effort is needed to prevent acute LBP from transitioning to chronic LBP. METHODS AND STUDY DESIGN: The TARGET (Targeted Interventions to Prevent Chronic Low Back Pain in High-Risk Patients) Trial is a primary care-based, multisite, cluster randomized, pragmatic trial comparing guideline-based care (GBC) to GBC + referral to Psychologically Informed Physical Therapy (PIPT) for patients presenting with acute LBP and identified as high risk for persistent disabling symptoms. Study sites include primary care clinics within each of five geographical regions in the United States, with clinics randomized to either GBC or GBC + PIPT. Acute LBP patients at all clinics are risk stratified (high, medium, low) using the STarT Back Tool. The primary outcomes are the presence of chronic LBP and LBP-related functional disability determined by the Oswestry Disability Index at 6 months. Secondary outcomes are LBP-related processes of health care and utilization of services over 12 months, determined through electronic medical records. Study enrollment began in May 2016 and concluded in June 2018. The trial was powered to include at least 1860 high-risk patients in the randomized controlled trial cohort. A prospective observational cohort of approximately 6900 low and medium-risk acute LBP patients was enrolled concurrently. DISCUSSION: The TARGET pragmatic trial aims to establish the effectiveness of the stratified approach to acute LBP intervention targeting high-risk patients with GBC and PIPT. TRIAL REGISTRATION: ClinicalTrials.govNCT02647658 Registered Jan. 6, 2016.