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Purpose: To assess whether the poor prognosis of triple-negative breast cancer (TNBC) necessitates a more aggressive surgical approach. Methods: We examined the association of: breast-conserving surgery (BCS); BCS plus radiotherapy; mastectomy; and mastectomy plus radiotherapy with overall and breast cancer-specific survival of stage I–III TNBC patients aged 66 years and older. We used unweighted and inverse probability of treatment weighted Cox proportional hazards regression and the Fine and Gray sub-distribution model. Results: Among 4333 women, individuals who were selected for BCS, mastectomy or mastectomy plus radiotherapy had lower adjusted overall and breast cancer-specific survival compared with women who had BCS plus radiotherapy. Conclusion: In this population-based study, women with TNBC treated with BCS plus radiotherapy have a better prognosis than those treated with BCS, mastectomy or mastectomy plus radiotherapy. Given the poor prognosis of TNBC and selection bias inherent in observational studies, these findings should be confirmed in further studies such as randomized clinical trials.

Purpose This study aims to develop and test feasibility of a colorectal cancer (CRC) education video appropriate for Somali immigrants. Design One-group pretest–posttest design. Setting Minneapolis, MN. Sample Thirty-one Somali men (mean age = 60.6; SD = 13.0). Intervention A CRC education video was developed in the Somali language with Somali community partners. Participants were invited to a workshop and watched the video. Measures Levels of understanding about CRC and screening were assessed before vs after the video. Analysis Binomial tests were conducted to examine changes in level of understanding. Results Analysis on pre–post, within-person changes in understanding about cancer, and CRC screening showed that proportions with a positive change in understanding risks of cancer (80%) and benefits of CRC screening (90%) were significantly higher than expected if the video had no effect (50%; P = .012, P < .001, respectively). Ninety-three percent of participants agreed that the video contained useful information. Conclusion These results provide evidence of usefulness of culturally tailored videos to facilitate CRC screening in the Somali community. Results of this study were limited by a small sample size and lack of a control group.

BACKGROUND Total pancreatectomy with islet autotransplantation (TPIAT) involves pancreatectomy, splenectomy, and reinjection of the patient's pancreatic islets into the portal vein. This process triggers a local inflammatory reaction and increase in portal pressure, threatening islet survival and potentially causing portal vein thrombosis. Recent research has highlighted a high frequency of extreme thrombocytosis (platelets ≥1000 × 109/L) after TPIAT, but its cause and association with thrombotic risk remain unclear. METHODS This retrospective single-site study of a contemporary cohort of 409 pediatric and adult patients analyzed the frequency of thrombocytosis, risk factors for thrombosis, and antiplatelet and anticoagulation strategies. RESULTS Of 409 patients, 67% developed extreme thrombocytosis, peaking around postoperative day 16. Extreme thrombocytosis was significantly associated with infused islet volumes. Thromboembolic events occurred in 12.2% of patients, with portal vein thromboses occurring significantly earlier than peripheral thromboses. Portal vein thromboses were associated with infused islet volumes and portal pressures but not platelet counts or other measures. Most thromboembolic events (82.7%) occurred before the postoperative day of maximum platelet count. Only 4 of 27 (14.8%) of portal vein thromboses occurred at platelet counts ≥500 × 109/L. Perioperative heparin was given to all patients. Treatment of reactive thrombocytosis using aspirin in adults and hydroxyurea in children was not associated with significantly decreased thromboembolic risk. CONCLUSIONS These results suggest that post-TPIAT thrombocytosis and portal vein thromboses may be linked to the islet infusion inflammation, not directly to each other, and further reducing this inflammation may reduce thrombosis and thrombocytosis frequencies simultaneously.

Cancer screening is an important approach to reducing disease burden. The rate of colorectal cancer (CRC) screening among immigrants in the U.S. is very low. Our study's aim was to examine correlates of experience with, and intention to, receive CRC screening among East African men who were up-to-date (UTD) with CRC screening (n = 64, mean age 65) and those who had never been screened or were overdue for one (NOD; n = 47, mean age 60), compared on demographic characteristics, attitudes toward cancer, psychosocial stress, and health behaviors. UTD men had significantly less emotional concerns about cancer screening and experienced significantly greater distress and lower resiliency than NOD men. However, these results were attenuated after controlling for demographic confounders. Perceived risk, trust in the medical system, and PTSD symptoms were significantly associated with an intention to undertake CRC screening in the next 12 months. These results should be used to guide efforts toward increasing CRC screening rates among immigrant communities.

Meta-analysis is commonly used to compare two treatments. Network meta-analysis (NMA) is a powerful extension for comparing and contrasting multiple treatments simultaneously in a systematic review of multiple clinical trials. Although the practical utility of meta-analysis is apparent, it is not always straightforward to implement, especially for those interested in a Bayesian approach. This paper demonstrates that the recently-developed SAS procedure BGLIMM provides an intuitive and computationally efficient means for conducting Bayesian meta-analysis in SAS, using a worked example of a smoking cessation NMA data set. BGLIMM gives practitioners an effective and simple way to implement Bayesian meta-analysis (pairwise and network, either contrast-based or arm-based) without requiring significant background in coding or statistical modeling. Those familiar with generalized linear mixed models, and especially the SAS procedure GLIMMIX, will find this tutorial a useful introduction to Bayesian meta-analysis in SAS.

OBJECTIVE Gastrointestinal bleeding (GIB) is an uncommon complication after abdominal surgery. Given the unique risks in the total pancreatectomy with islet autotransplant (TPIAT) population, we aimed to describe this population's incidence of postoperative GIB. METHODS Prospectively collected data on patients who underwent a TPIAT from 2001 to 2018 at the University of Minnesota were reviewed for postoperative GIB. Each GIB patient was matched to a control patient and compared for medical, medication, and social history and for clinical outcomes. RESULTS Sixty-eight patients developed a GIB (12.4%) at median time after surgery of 17 months. Etiologies included the following: anastomotic ulcer (35%), Clostridium difficile (4%), gastric or duodenal ulcers (9%), esophagitis/gastritis (10%), hemorrhoids (3%), inflammatory bowel disease (4%), Mallory-Weiss tears (1%), and unknown (29%). During diagnostic workup, 87% had an endoscopic procedure and 3% underwent imaging. Seven patients required an operation (10%), 1 required an open embolization (1%), and 13 required endoscopic treatments (19%). Patients with a GIB were more likely to die (15% vs 5%, P = 0.055). CONCLUSIONS Twelve percent of patients developed a GIB after TPIAT. One third of those had an undefined etiology despite endoscopy. The need for intervention was high (30%).

INTRODUCTION/AIMS Clinical trials addressing treatments for Duchenne muscular dystrophy (DMD) require reliable and valid measurement of muscle contractile function across all disease severity levels. In this work we aimed to evaluate a protocol combining voluntary and evoked contractions to measure strength and excitability of wrist extensor muscles for safety, feasibility, reliability, and discriminant validity between males with DMD and controls. METHODS Wrist extensor muscle strength and excitability were assessed in males with DMD (N = 10; mean ± standard deviation: 15.4 ± 5.9 years of age), using the Brooke Upper Extremity Rating Scale (scored 1-6), and age-matched healthy male controls (N = 15; 15.5 ± 5.0 years of age). Torque and electromyographic (EMG) measurements were analyzed under maximum voluntary and stimulated conditions at two visits. RESULTS A protocol of multiple maximal voluntary contractions (MVCs) and evoked twitch contractions was feasible and safe, with 96% of the participants completing the protocol and having a less than 7% strength decrement on either measure for both DMD patients and controls (P ≥ .074). Reliability was excellent for voluntary and evoked measurements of torque and EMG (intraclass correlation coefficient [ICC] over 0.90 and over 0.85 within and between visits, respectively). Torque, EMG, and timing of twitch-onset measurements discriminated between DMD and controls (P

Network meta-analysis (NMA) is a powerful tool to compare multiple treatments directly and indirectly by combining and contrasting multiple independent clinical trials. Because many NMAs collect only a few eligible randomized controlled trials (RCTs), there is an urgent need to synthesize different sources of information, e.g., from both RCTs and single-arm trials. However, single-arm trials and RCTs may have different populations and quality, so that assuming they are exchangeable may be inappropriate. This article presents a novel method using a commensurate prior on variance (CPV) to borrow variance (rather than mean) information from single-arm trials in an arm-based (AB) Bayesian NMA. We illustrate the advantages of this CPV method by reanalyzing an NMA of immune checkpoint inhibitors in cancer patients. Comprehensive simulations investigate the impact on statistical inference of including single-arm trials. The simulation results show that the CPV method provides efficient and robust estimation even when the two sources of information are moderately inconsistent.

In total pancreatectomy with islet auto-transplantation, successful diabetes outcomes are limited by islet loss from the instant blood mediated inflammatory response. We hypothesized that blockade of the inflammatory response with either etanercept or alpha-1-antitrypsin would improve islet function and insulin independence.We randomized 43 participants to receive A1AT (90 mg/kg x 6 doses, n = 13), or etanercept (50 mg then 25 mg x 5 doses, n = 14), or standard care (n = 16), aiming to reduce detrimental effects of innate inflammation on early islet survival. Islet graft function was assessed using mixed meal tolerance testing, intravenous glucose tolerance testing, glucose-potentiated arginine-induced insulin secretion studies, HbA1c, and insulin dose 3 months and 1 year post-TPIAT.We observed the most robust acute insulin response (AIRglu) and acute C-peptide response to glucose (ACRglu) at 3 months after TPIAT in the etanercept-treated group (p ≤ 0.02), but no differences in other efficacy measures. The groups did not differ overall at 1 year but when adjusted by sex, there was a trend towards a sex-specific treatment effect in females (AIRglu p = 0.05, ACRglu p = 0.06), with insulin secretion measures highest in A1AT-treated females.Our randomized trial supports a potential role for etanercept in optimizing early islet engraftment but it is unclear whether this benefit is sustained. Further studies are needed to evaluate possible sex-specific responses to either treatment.This study was performed under an Investigational New Drug Application (IND #119828) from the Food and Drug Administration and was registered on clinicaltrials.gov (NCT#02713997).

Total pancreatectomy with islet autotransplantation is performed to treat chronic pancreatitis in children. Successful islet isolation must address the challenges of severe pancreatic fibrosis and young donor age. We have progressively introduced modifications to optimize enzymatic and mechanical dissociation of the pancreas during islet isolation. We evaluated 2 islet isolation metrics in 138 children-digest islet equivalents per gram pancreas tissue (IEQ/g) and digest IEQ per kilogram body weight (IEQ/kg), using multiple regression to adjust for key disease and patient features. Islet yield at digest had an average 4569 (standard deviation 2949) islet equivalent (IEQ)/g and 4946 (4009) IEQ/kg, with 59.1% embedded in exocrine tissue. Cases with very low yield (

BACKGROUND AND AIMS: Many patients undergoing total pancreatectomy with islet autotransplant (TPIAT) for severe, refractory chronic pancreatitis or recurrent acute pancreatitis have a history of endoscopic retrograde cholangiopancreatography (ERCP). Using data from the multicenter POST (Prospective Observational Study of TPIAT) cohort, we aimed to determine clinical characteristics associated with ERCP and the effect of ERCP on islet yield. METHODS: Using data from 230 participants (11 centers), demographics, pancreatitis history, and imaging features were tested for association with ERCP procedures. Logistic and linear regression were used to assess association of islet yield measures with having any pre-operative ERCPs and with the number of ERCPs, adjusting for confounders. RESULTS: 175 (76%) underwent ERCPs [median number of ERCPs (IQR) 2 (1–4)]. ERCP was more common in those with obstructed pancreatic duct (p=0.0009), pancreas divisum (p=0.0009), prior pancreatic surgery (p=0.005), and longer disease duration (p=0.004). A greater number of ERCPs was associated with disease duration (p

Immune correlates of protection against clinical malaria are difficult to ascertain in low-transmission areas because of the limited number of malaria cases. We collected blood samples from 5,753 individuals in a Kenyan highland area, ascertained malaria incidence in this population over the next 6 years, and then compared antibody responses to 11 Plasmodium falciparum vaccine candidate antigens in individuals who did versus did not develop clinical malaria in a nested case-control study (154 cases and 462 controls). Individuals were matched by age and village. Antigens tested included circumsporozoite protein (CSP), liver-stage antigen (LSA)-1, apical membrane antigen-1 FVO and 3D7 strains, erythrocyte-binding antigen-175, erythrocyte-binding protein-2, merozoite surface protein (MSP)-1 FVO and 3D7 strains, MSP-3, and glutamate-rich protein (GLURP) N-terminal non-repetitive (R0) and C-terminal repetitive (R2) regions. After adjustment for potential confounding factors, the presence of antibodies to LSA-1, GLURP-R2, or GLURP-R0 was associated with decreased odds of developing clinical malaria (odds ratio [OR], [95% CI] 0.56 [0.36-0.89], 0.56 [0.36-0.87], and 0.77 [0.43-1.02], respectively). Levels of antibodies to LSA-1, GLURP-R2, and CSP were associated with decreased odds of developing clinical malaria (OR [95% CI]; 0.61 [0.41-0.89], 0.60 [0.43-0.84], and 0.49 [0.24-0.99], for every 10-fold increase in antibody levels, respectively). The presence of antibodies to CSP, GLURP-R0, GLURP-R2, and LSA-1 combined best-predicted protection from clinical malaria. Antibodies to CSP, GLURP-R0, GLURP-R2, and LSA-1 are associated with protection against clinical malaria in a low-transmission setting. Vaccines containing these antigens should be evaluated in low malaria transmission areas.

Childhood cancer survivors who receive a hematopoietic cell transplantation (HCT) are at increased risk for follicle-stimulating hormone (FSH) abnormalities, which may have a substantial negative impact on vascular function. The purpose of this study was to examine the association of vascular function with FSH in HCT recipients, non-HCT recipients and healthy controls. The study included childhood cancer survivors who were HCT recipients (n=24) and non-HCT recipients (n=308), and a control group of healthy siblings (n=211) all aged between 9 and 18 years. Vascular measures of carotid artery structure and function (compliance and distensibility), brachial artery flow-mediated dilation and endothelial-independent dilation were measured using ultrasound imaging. A fasting blood sample was collected to measure hormone levels. FSH was significantly higher in HCT recipients compared with non-HCT recipients and healthy controls (P

Noncompliance with assigned treatments is a common challenge in analyzing and interpreting randomized clinical trials (RCTs). One way to handle noncompliance is to estimate the complier-average causal effect (CACE), the intervention’s efficacy in the subpopulation that complies with assigned treatment. In a two-step meta-analysis, one could first estimate CACE for each study, then combine them to estimate the population-averaged CACE. However, when some trials do not report noncompliance data, the two-step meta-analysis can be less efficient and potentially biased by excluding these trials. This paper proposes a flexible Bayesian hierarchical CACE framework to simultaneously account for heterogeneous and incomplete noncompliance data in a meta-analysis of RCTs. The models are motivated by and used for a meta-analysis estimating the CACE of epidural analgesia on cesarean section, in which only 10 of 27 trials reported complete noncompliance data. The new analysis includes all 27 studies and the results present new insights on the causal effect after accounting for noncompliance. Compared to the estimated risk difference of 0.8% (95% CI: −0.3%, 1.9%) given by the two-step intention-to-treat meta-analysis, the estimated CACE is 4.1% (95% CrI: −0.3%, 10.5%). We also report simulation studies to evaluate the performance of the proposed method.

BACKGROUND: The Igls criteria assess islet function after islet allotransplant, based on C-peptide, insulin use, hemoglobin A1c, and severe hypoglycemia. However, these criteria as currently defined cannot be applied to total pancreatectomy islet autotransplant (TPIAT) patients. METHODS: We tested modified criteria for assessing islet function in a large cohort TPIAT patients (n=379). Metabolic outcomes were assessed. We assigned Auto-Igls class to each patient as able and evaluated the utility, validity, and perioperative risk factors of Auto-Igls at 1 year post-IAT. We tested the association of Auto-Igls with independent measures of islet graft function, specifically continuous glucose monitoring (CGM) data or acute C-peptide response to glucose (ACRglu) from intravenous glucose tolerance tests. RESULTS: An Auto-Igls class was assigned to 264 patients (69%). Among patients who could not be classified, most were missing exact insulin dose. Seventy-three percent of TPIAT recipients were classified as optimal or good at 1 year. The only significant predictor of Auto-Igls class was islet mass transplanted (p

Objective When total pancreatectomy with islet autotransplantation (TPIAT) is performed for chronic pancreatitis, the pancreas and most of the duodenum are removed, with Roux-en-Y reconstruction of the gastrointestinal tract. Enteroendocrine cells in the intestines and pancreas secrete hormones coordinating digestion and motility, but anatomic reconstruction alters transit of nutrients to these cells. We hypothesized that TPIAT leads to changes in enteroendocrine hormones. Methods Glucagon-like peptide 1 (GLP-1), peptide YY (PYY), and pancreatic polypeptide (PP) were measured from mixed-meal tolerance tests of 34 clinical trial participants before and 18 months after TPIAT. Area under the curve of GLP-1 and PYY-stimulated responses were calculated by trapezoidal method, and the PP response was measured as the stimulated max minus baseline (ΔPP). Results Area under the curve of GLP-1 and PYY increased significantly after TPIAT (GLP-1 average +553.1 pg/mL per minute, P = 0.004; PYY average +4647.9 pg/mL per minute, P = 0.02). ΔPP trended toward lower after TPIAT (average, -52.2 pg/mL, P = 0.06). Conclusions In this novel study of enteroendocrine hormones in TPIAT patients, stimulated levels of GLP-1 and PYY were significantly higher after versus before TPIAT. ΔPP was lower after TPIAT, but not significantly. These hormone changes have potential clinical implications that warrant further research.

Bayesian analyses with the arm-based (AB) network meta-analysis (NMA) model require researchers to specify a prior distribution for the covariance matrix of the treatment-specific event rates in a transformed scale, for example, the treatment-specific log-odds when a logit transformation is used. The commonly used conjugate prior for the covariance matrix, the inverse-Wishart (IW) distribution, has several limitations. For example, although the IW distribution is often described as noninformative or weakly informative, it may in fact provide strong information when some variance components are small (eg, when the standard deviation of study-specific log-odds of a treatment is smaller than 1/2), as is common in NMAs with binary outcomes. In addition, the IW prior generally leads to underestimation of correlations between treatment-specific log-odds, which are critical for borrowing strength across treatment arms to estimate treatment effects efficiently and to reduce potential bias. Alternatively, several separation strategies (ie, separate priors on variances and correlations) can be considered. To study the IW prior's impact on NMA results and compare it with separation strategies, we did simulation studies under different missing-treatment mechanisms. A separation strategy with appropriate priors for the correlation matrix and variances performs better than the IW prior, and should be recommended as the default vague prior in the AB NMA approach. Finally, we reanalyzed three case studies and illustrated the importance, when performing AB-NMA, of sensitivity analyses with different prior specifications on variances.

Social scientists have frequently sought to understand the distinct effects of age, period, and cohort, but disaggregation of the three dimensions is difficult because cohort = period − age. We argue that this technical difficulty reflects a disconnection between how the cohort effect is conceptualized and how it is modeled in the traditional age-period-cohort framework. We propose a new method, called the age-period-cohort-interaction (APC-I) model, that is qualitatively different from previous methods in that it represents Ryder’s theoretical account about the conditions under which cohort differentiation may arise. This APC-I model does not require problematic statistical assumptions and the interpretation is straightforward. It quantifies inter-cohort deviations from the age and period main effects and also permits hypothesis testing about intra-cohort life-course dynamics. We demonstrate how this new model can be used to examine age, period, and cohort patterns in women’s labor force participation.

As an extension of pairwise meta-analysis of two treatments, network meta-analysis has recently attracted many researchers in evidence-based medicine because it simultaneously synthesizes both direct and indirect evidence from multiple treatments and thus facilitates better decision making. The Bayesian hierarchical model is a popular method to implement network meta-analysis, and it is generally considered more powerful than conventional pairwise meta-analysis, leading to more precise effect estimates with narrower credible intervals. However, the improvement of effect estimates produced by Bayesian network meta-analysis has never been studied theoretically. This article shows that such improvement depends highly on evidence cycles in the treatment network. When all treatment comparisons are assumed to have different heterogeneity variances, a network meta-analysis produces posterior distributions identical to separate pairwise meta-analyses for treatment comparisons that are not contained in any evidence cycles. However, this equivalence does not hold under the commonly-used assumption of a common heterogeneity variance for all comparisons. Simulations and a case study are used to illustrate the equivalence of the Bayesian network and pairwise meta-analyses in certain networks.

BACKGROUND Patients with head and neck cancer (HNC) treated with radiation therapy (RT) are at risk for jaw osteoradionecrosis (ORN), which is largely characterized by the presence of exposed necrotic bone. This report describes the incidence and clinical course of and risk factors for exposed intraoral bone in the multicenter Observational Study of Dental Outcomes in Head and Neck Cancer Patients (OraRad) cohort. METHODS Participants were evaluated before RT and at 6, 12, 18, and 24 months after RT. Exposed bone was characterized by location, sequestrum formation, and other associated features. The radiation dose to the affected area was determined, and the history of treatment for exposed bone was recorded. RESULTS The study enrolled 572 participants; 35 (6.1%) were diagnosed with incident exposed bone at 6 (47% of reports), 12 (24%), 18 (20%), and 24 months (8%), with 60% being sequestrum and with 7 cases (20%) persisting for >6 months. The average maximum RT dose to the affected area of exposed bone was 5456 cGy (SD, 1768 cGy); the most frequent associated primary RT sites were the oropharynx (42.9%) and oral cavity (31.4%), and 76% of episodes occurred in the mandible. The diagnosis of ORN was confirmed in 18 participants for an incidence rate of 3.1% (18 of 572). Risk factors included pre-RT extractions (P = .008), a higher RT dose (P = .039), and tobacco use (P = .048). CONCLUSIONS The 2-year incidence of exposed bone in the OraRad cohort was 6.1%; the incidence of confirmed ORN was 3.1%. Exposed bone after RT for HNC is relatively uncommon and, in most cases, is a short-term complication, not a recurring or persistent one.

BACKGROUND Childhood cancer survivors who received a hematopoietic cell transplantation (HCT) are at increased risk for follicle-stimulating hormone (FSH) abnormalities, which may have a significant negative impact on bone health and body composition. This study's purpose was to examine FSH and body composition in HCT recipients, non-HCT recipients and healthy controls. METHODS The study included HCT recipients (n = 24), non-HCT recipients (n = 309), and a control group of healthy siblings (n = 211) all aged 9-18 years. A fasting blood sample was collected to measure FSH. All participants underwent a dual X-ray absorptiometry scan to assess total and regional percent fat, lean mass (LM), fat mass (FM), bone mineral content (BMC), bone mineral density (BMD), and visceral adipose tissue (VAT) mass. RESULTS FSH was significantly higher in HCT recipients compared to non-HCT recipients and healthy controls. HCT recipients had significantly lower total body weight, total LM, arm and leg LM, BMC and BMD compared to non-HCT recipients and healthy controls (p

Background/objectives The effect of total pancreatectomy with islet autotransplantation (TPIAT) on bone mineral density (BMD) in patients with CP is unknown. We aimed to assess bone health in patients with CP after TPIAT. Methods We measured BMD, BMD Z-score, and bone mineral content (BMC) for total body, lumbar spine, right and left hip in 78 patients before and after TPIAT using dual-energy X-ray absorptiometry (DXA, n = 78 pre-TPIAT, n = 65 paired pre- and 12 months post-TPIAT, n = 33 paired 12 and 18 months post-TPIAT), and tested for association with clinical history including age, smoking status, and medications using paired and two-sample t-tests, linear regression, and Fisher's exact test. Laboratory measures related to bone health were also assessed. Results In the patients with pre-TPIAT DXA, 12% had low BMD (Z-score ≤ −2). BMD, BMD Z-score, and BMC all decreased from pre-to 12 months post-TPIAT. BMD declined by 1.7%–4.1% with the greatest change at the hips. Adjusted for change in lean and fat body mass, DXA changes remained significant for total body and hip. Serum carboxy-terminal collagen crosslinks telopeptide and alkaline phosphatase increased at 12 months post-TPIAT, suggesting possible increased bone remodeling. BMD, BMD Z-score, and BMC did not change between 12 months and 18 months in any of the four regions (p > 0.6). Conclusions TPIAT is associated with decreases in BMD in the body, lumbar, and hip regions of patients with CP in the first year after TPIAT but these appear to stabilize between 12 and 18 months after TPIAT.

Objectives Smoking and alcohol use are risk factors for acute and chronic pancreatitis, and their role on anxiety, depression, and opioid use in patients who undergo total pancreatectomy and islet autotransplantation (TPIAT) is unknown. Methods We included adults enrolled in the Prospective Observational Study of TPIAT (POST). Measured variables included smoking (never, former, current) and alcohol abuse or dependency history (yes vs no). Using univariable and multivariable analyses, we investigated the association of smoking and alcohol dependency history with anxiety and depression, opioid use, and postsurgical outcomes. Results Of 195 adults studied, 25 were current smokers and 77 former smokers, whereas 18 had a history of alcohol dependency (of whom 10 were current smokers). A diagnosis of anxiety was associated with current smoking (P = 0.005), and depression was associated with history of alcohol abuse/dependency (P = 0.0001). However, active symptoms of anxiety and depression at the time of TPIAT were not associated with smoking or alcohol status. Opioid use in the past 14 days was associated with being a former smoker (P = 0.005). Conclusions Active smoking and alcohol abuse history were associated with a diagnosis of anxiety and depression, respectively; however, at the time of TPIAT, symptom scores suggested that they were being addressed.

Eccentric contractions (ECCs) induce force loss in several skeletal muscles of dystrophin-deficient mice (mdx), with the exception of the soleus (Sol). The eccentric force : isometric force (ECC : ISO), expression level of utrophin, fiber type distribution, and sarcoendoplasmic reticulum calcium ATPase expression are factors that differ between muscles and may contribute to the sensitivity of mdx skeletal muscle to ECC. Here, we confirm that the Sol of mdx mice loses only 13% force compared to 87% in the extensor digitorum longus (EDL) following 10 ECC of isolated muscles. The Sol has a greater proportion of fibers expressing Type I myosin heavy chain (MHC) and expresses 2.3-fold more utrophin compared to the EDL. To examine the effect of ECC : ISO, we show that the mdx Sol is insensitive to ECC at ECC : ISO up to 230 ± 15%. We show that the peroneus longus (PL) muscle presents with similar ECC : ISO compared to the EDL, intermediate force loss (68%) following 10 ECC, and intermediate fiber type distribution and utrophin expression relative to EDL and Sol. The combined absence of utrophin and dystrophin in mdx/utrophin-/- mice rendered the Sol only partially susceptible to ECC and exacerbated force loss in the EDL and PL. Most interestingly, the expression levels of cytoplasmic β- and γ-actins correlate inversely with a given muscle's sensitivity to ECC; EDL

Morris and Ebey reported the following curiosity. “The unweighted sample mean is examined as an estimator of the population mean in a first-order autoregressive model. It is demonstrated that the p...

This study examined the effects of hematopoietic cell transplantation (HCT) and associated preparative regimens on vascular structure and function. Measures of carotid artery stiffness and brachial artery endothelial-dependent dilation were obtained in patients who had survived ≥ 2 years after HCT for hematologic malignancy and were diagnosed at ≤21 years. HCT survivors (n = 108) were examined: 66 received total body irradiation (TBI) alone or with a low-dose cranial radiation boost (TBI±LD-CRT), 19 received TBI plus high-dose cranial radiation (TBI+HD-CRT), and 23 received a chemotherapy-only preparative regimen (CHEMO). Siblings (n = 83) were invited to participate as control subjects. Although endothelial-dependent dilation did not differ between siblings and HCT survivors, carotid cross-sectional compliance, cross-sectional distensibility, diameter compliance, and diameter distensibility were greater in siblings than HCT survivors. Comparing the HCT preparative regimens, carotid cross-sectional compliance, cross-sectional distensibility, diameter compliance, diameter distensibility, and incremental elastic modulus were significantly lower in the TBI+HD-CRT group compared with siblings or with TBI±LD-CRT and CHEMO treatment groups. Cross-sectional distensibility and diameter compliance were significantly lower in the TBI±LD-CRT group compared with siblings. TBI±LD-CRT and CHEMO groups did not differ from each other in these vascular measures. HCT preparative regimens containing TBI+HD-CRT resulted in greater arterial decrements, indicating increased risk for cardiovascular disease.

To elucidate long-term sequelae of radiation therapy (RT) in head and neck cancer (HNC) patients, a multicenter, prospective study, Clinical Registry of Dental Outcomes in Head and Neck Cancer Patients (OraRad), was established with tooth failure as its primary outcome. We report tooth failure and associated risk factors.Demographics and cancer and dental disease characteristics were documented in 572 HNC patients at baseline and 6, 12, 18, and 24 months after RT. Eligible patients were aged 18 or older, diagnosed with HNC, and receiving RT to treat HNC. Tooth failure during follow-up was defined as losing a tooth or having a tooth deemed hopeless. Analyses of time to first tooth-failure event and number of teeth that failed used Kaplan-Meier estimators, Cox regression, and generalized linear models.At 2 years, the estimated fraction of tooth failure was 17.8% (95% confidence interval, 14.3%-21.3%). The number of teeth that failed was higher for those with fewer teeth at baseline (P.0001), greater reduction in salivary flow rate (P = .013), and noncompliance with daily oral hygiene (P = .03). Patients with dental caries at baseline had a higher risk of tooth failure with decreased salivary flow. Patients who were oral-hygiene noncompliant at baseline but compliant at all follow-up visits had the fewest teeth that failed; greatest tooth failure occurred in participants who were noncompliant at baseline and follow-up.Despite pre-RT dental management, substantial tooth failure occurs within 2 years after RT for HNC. Identified factors may help to predict or reduce risk of post-RT tooth failure.

Background Methadone treatment of opioid use disorder in HIV-infected individuals is complicated by drug-drug interactions. Genetic and other cofactors further contribute to interindividual variability in methadone pharmacokinetics. We used population pharmacokinetics to estimate the effect of drug-drug interactions, genetics, and other cofactors on methadone pharmacokinetics in a methadone maintained population in Vietnam. Methods Plasma R- and S-methadone levels were measured in 309 methadone maintained individuals just before and 2−5 h following methadone dosing. A linear one-compartment population pharmacokinetic model with first-order conditional estimation with interaction was used to evaluate methadone clearance (CL/F) and volume of distribution (V/F). The influence of covariates on parameter estimates was evaluated using stepwise covariate modeling. Covariates included HIV status, antiretroviral use (efavirenz or nevirapine), weight, BMI, age, methadone dose, and 8 single nucleotide polymorphisms in across the CYP2B6, ABCB1, and NR1I3 genes. Results Taking either efavirenz or nevirapine increased R-methadone CL/F 220%. Nevirapine and efavirenz increased S-methadone CL/F by 404% and 273%, respectively. Variants in NR1I3 increased R- and S-methadone CL/F by approximately 20% only in patients taking efavirenz. Different alleles in ABCB1 rs2032582 either increased or decreased R-methadone CL/F by 10%. The CYP 2B6*4 variant decreased S-methadone CL/F by 18%. HIV-infection increased R- and S-methadone CL/F and V/F by 24%–39%. Conclusions The HIV antiretrovirals nevirapine and efavirenz significantly increase methadone clearance. Variants inNR1I3 increased the effect of efavirenz on methadone clearance. Other variants affecting methadone CL/F were also confirmed. To our knowledge, this is the first report of HIV itself affecting methadone pharmacokinetics.

Objective: Compare effectiveness of two differently formatted training programs in educating night-time postural care implementers. Design: Mixed-methods parallel-group double-blind design with random assignment. Setting: United States academic institution. Participants: Thirty-eight adult caregivers/providers of children with cerebral palsy. Interventions: Both 2-hour online programs included content on night-time postural care evidence, risk-factor monitoring, sleep-system types, positioning methods, and assessments. Group A used interactive videos, Group B summary information with web-links. Main Measures: We measured self-perceived competence via questionnaires (baseline, post-training, post-simulation) containing 4-point rating-scales of knowledge, ability, and confidence and measured positioning ability via a simulation observation instrument comprising 16 positioning-task ratings with space for describing performance. We recorded participant actions/statements using fieldnotes. Results: Thirty-eight completed training (19 per group). Group A (vs B) showed significantly greater self-perceived competence changes post-training (0.46 points (SE 0.17), P = 0.008). Thirty-seven positioned a standardized “client,” with groups not differing significantly on total tasks completed correctly ( F(1, 92.32) = 1.91, P = 0.17) averaging 11.85 (SE 0.83) and 12.60 (SE 0.84) of 16 tasks correct. Group A’s post-positioning/simulation self-ratings were significantly associated with actual ability ( r = 0.53, P = 0.019). In both groups ⩾47% of caregivers incorrectly completed the tasks of placing head and neck in neutral and snugging up all [positioning] parts. Conclusion: The sleep care positioning training program (interactive video-based format) is effective in building caregivers’ self-perceived competence for night-time postural care. While the lesson was well-received by caregivers and considered a “match [to their] learning style,” the lesson did not lead to greater improvement in actual ability to position the “client” compared to control training.

Circulating microRNAs (miRNAs) can be biomarkers for diagnosis and progression of several pathophysiological conditions. In a cohort undergoing total pancreatectomy with islet autotransplantation (TPIAT) from the multicenter Prospective Observational Study of TPIAT (POST), we investigated associations between a panel of circulating miRNAs (hsa-miR-375, hsa-miR-29b-3p, hsa-miR-148a-3p, hsa-miR-216a-5p, hsa-miR-320d, hsa-miR-200c, hsa-miR-125b, hsa-miR-7-5p, hsa-miR-221-3p, hsa-miR-122-5p) and patient, disease and islet-isolation characteristics. Plasma samples ( n = 139) were collected before TPIAT and miRNA levels were measured by RTPCR. Disease duration, prior surgery, and pre-surgical diabetes were not associated with circulating miRNAs. Levels of hsa-miR-29b-3p ( P = 0.03), hsa-miR-148a-3p ( P = 0.04) and hsa-miR-221-3p ( P = 0.01) were lower in those with genetic risk factors. Levels of hsa-miR-148a-3p ( P = 0.04) and hsa-miR-7-5p ( P = 0.04) were elevated in toxic/metabolic disease. Participants with exocrine insufficiency had lower hsa-miR-29b-3p, hsa-miR-148a-3p, hsa-miR-320d, hsa-miR-221-3p ( P < 0.01) and hsa-miR-375, hsa-miR-200c-3p, and hsa-miR-125b-5p ( P < 0.05). Four miRNAs were associated with fasting C-peptide before TPIAT (hsa-miR-29b-3p, r = 0.18; hsa-miR-148a-3p, r = 0.21; hsa-miR-320d, r = 0.19; and hsa-miR-221-3p, r = 0.21; all P < 0.05), while hsa-miR-29b-3p was inversely associated with post-isolation islet equivalents/kg and islet number/kg ( r = −0.20, P = 0.02). Also, hsa-miR-200c ( r = 0.18, P = 0.03) and hsa-miR-221-3p ( r = 0.19, P = 0.03) were associated with islet graft tissue volume. Further investigation is needed to determine the predictive potential of these miRNAs for assessing islet autotransplant outcomes.

BACKGROUND: Total pancreatectomy with islet autotransplantation (TPIAT) is a viable option for treating debilitating recurrent acute pancreatitis (RAP) and chronic pancreatitis (CP) in adults and children. No data is currently available regarding variation in approach to operation. METHODS: We evaluated surgical techniques, islet isolation and infusion approaches, and outcomes and complications, comparing children (n=84) with adults (n=195) enrolled between January 2017 and April 2020 by 11 centers in the United States in the Prospective Observational Study of TPIAT (POST), which was launched in 2017 to collect standard history and outcomes data from patients undergoing TPIAT for RAP or CP. RESULTS: Children more commonly underwent splenectomy (100% versus 91%, p=0.002), pylorus preservation (93% versus 67%; p

Noncompliance, a common problem in randomized clinical trials (RCTs), can bias estimation of the effect of treatment receipt using a standard intention-to-treat analysis. The complier average causal effect (CACE) measures the effect of an intervention in the latent subpopulation that would comply with their assigned treatment. Although several methods have been developed to estimate the CACE in analyzing a single RCT, methods for estimating the CACE in a meta-analysis of RCTs with noncompliance await further development. This article reviews the assumptions needed to estimate the CACE in a single RCT and proposes a frequentist alternative for estimating the CACE in a meta-analysis, using a generalized linear latent and mixed model with SAS software (SAS Institute, Inc.). The method accounts for between-study heterogeneity using random effects. We implement the methods and describe an illustrative example of a meta-analysis of 10 RCTs evaluating the effect of receiving epidural analgesia in labor on cesarean delivery, where noncompliance varies dramatically between studies. Simulation studies are used to evaluate the performance of the proposed method.

In epidemic-prone areas of the western highlands, the Kenya Ministry of Health conducted campaigns of indoor residual spraying (IRS) of households, followed by mass distribution of insecticide-treated bed nets (ITNs), as part of the National Malaria Strategy. We previously reported that in the highland areas of Kipsamoite and Kapsisiywa, widespread IRS coverage in 2007, after lower but substantial coverage in 2005 and 2006, contributed to possible local interruption of malaria transmission between 2007 and 2008. Indoor residual spraying campaigns in the area ended in 2010, succeeded by a mass ITN distribution campaign in 2011 and 2012 targeting universal coverage. Insecticide-treated bed net use in the area increased from 17.1% pre-campaign in 2011 to 51.7% post-campaign in 2012, but decreased to 35.8% in 2013. The ITN campaign did not reduce malaria incidence in the population as a whole (odds ratio [OR] after ITN distribution versus before, 1.29, 95% CI: 1.00-1.66, P = 0.049). However, in 2011-2013, individuals who stated that they slept under ITNs as compared with those who did not had a decrease in malaria incidence that approached statistical significance (OR 0.74, 95% CI: 0.52-1.04, P = 0.08). Mass ITN distribution after previous annual IRS campaigns was insufficient to further reduce malaria transmission in this area of low and highly seasonal transmission possibly because of low ITN use despite the mass campaign.

Immune correlates of protection against clinical malaria are difficult to ascertain in low-transmission areas because of the limited number of malaria cases. We collected blood samples from 5,753 individuals in a Kenyan highland area, ascertained malaria incidence in this population over the next 6 years, and then compared antibody responses to 11 Plasmodium falciparum vaccine candidate antigens in individuals who did versus did not develop clinical malaria in a nested case–control study (154 cases and 462 controls). Individuals were matched by age and village. Antigens tested included circumsporozoite protein (CSP), liver-stage antigen (LSA)-1, apical membrane antigen-1 FVO and 3D7 strains, erythrocyte-binding antigen-175, erythrocyte-binding protein-2, merozoite surface protein (MSP)-1 FVO and 3D7 strains, MSP-3, and glutamate-rich protein (GLURP) N-terminal non-repetitive (R0) and C-terminal repetitive (R2) regions. After adjustment for potential confounding factors, the presence of antibodies to LSA-1, GLURP-R2, or GLURP-R0 was associated with decreased odds of developing clinical malaria (odds ratio [OR], [95% CI] 0.56 [0.36–0.89], 0.56 [0.36–0.87], and 0.77 [0.43–1.02], respectively). Levels of antibodies to LSA-1, GLURP-R2, and CSP were associated with decreased odds of developing clinical malaria (OR [95% CI]; 0.61 [0.41–0.89], 0.60 [0.43–0.84], and 0.49 [0.24–0.99], for every 10-fold increase in antibody levels, respectively). The presence of antibodies to CSP, GLURP-R0, GLURP-R2, and LSA-1 combined best-predicted protection from clinical malaria. Antibodies to CSP, GLURP-R0, GLURP-R2, and LSA-1 are associated with protection against clinical malaria in a low-transmission setting. Vaccines containing these antigens should be evaluated in low malaria transmission areas.

Context Body composition in total pancreatectomy with islet autotransplantation (TPIAT) has never been studied. Objective Determine whether presurgical body composition is associated with islet function and insulin sensitivity after TPIAT. Methods In 88 adults undergoing TPIAT (median age 41.0 years, IQR 32.8-48.0), beta-cell function and insulin sensitivity were assessed using mixed meal tolerance test and frequent sample intravenous glucose tolerance test before surgery and 12 and 18 months afterward. Body composition was measured by dual x-ray absorptiometry. Analyses used linear and logistic regression. Results Before surgery, 8 individuals (9.1%) were underweight, 40 (45.5%) normal weight, 20 (22.7%) overweight, and 20 (22.7%) obese. Overweight/obese patients had higher area under the curve C-peptide and lower insulin sensitivity index. Baseline body weight was positively associated with first-phase insulin secretion (AIRg) at 12 months (average 38.5 [SE 17.1] mU/L/min higher per extra kg; P = 0.03) and 18 months (38.3 [18.5]; P = 0.04), while baseline lean mass was inversely associated with AIRg at 12 months (−0.05 [0.02] per extra kg; P = 0.01) and 18 months (−0.05 [0.02]; P = 0.03). Percent gynoid fat was inversely associated with disposition index at 18 months (−206.0 [97.2] per extra percent; P = 0.04). Percent body fat and percent gynoid fat were associated with glucose effectiveness index at 18 months (1.9 × 10-3 [0.9 × 10-3] per extra percent; P = 0.04 and −1.96 × 10-3 [0.8 × 10-3]; P = 0.02, respectively). Insulin independence was not significantly associated with body weight or composition. Conclusions Half of these chronic pancreatitis patients were overweight/obese; underweight was uncommon. Preoperative body weight and composition were associated with islet function but not insulin independence after TPIAT.

ObjectivesHigh-quality meta-analyses on COVID-19 are in urgent demand for evidence-based decision making. However, conventional approaches exclude double-zero-event studies (DZS) from meta-analyses. We assessed whether including such studies impacts the conclusions in a recent systematic urgent review on prevention measures for preventing person-to-person transmission of COVID-19.Study designs and settingsWe extracted data for meta-analyses containing DZS from a recent review that assessed the effects of physical distancing, face masks, and eye protection for preventing person-to-person transmission. A bivariate generalized linear mixed model was used to re-do the meta-analyses with DZS included. We compared the synthesized relative risks (RRs) of the three prevention measures, their 95% confidence intervals (CI), and significance tests (at the level of 0.05) including and excluding DZS.ResultsThe re-analyzed COVID-19 data containing DZS involved a total of 1,784 participants who were not considered in the original review. Including DZS noticeably changed the synthesized RRs and 95% CIs of several interventions. For the meta-analysis of the effect of physical distancing, the RR of COVID-19 decreased from 0.15 (95% CI, 0.03 to 0.73) to 0.07 (95% CI, 0.01 to 0.98). For several meta-analyses, the statistical significance of the synthesized RR was changed. The RR of eye protection with a physical distance of 2 m and the RR of physical distancing when using N95 respirators were no longer statistically significant after including DZS.ConclusionsDZS may contain useful information. Sensitivity analyses that include DZS in meta-analysis are recommended.

Network meta-analysis is a commonly used tool to combine direct and indirect evidence in systematic reviews of multiple treatments to improve estimation compared to traditional pairwise meta-analysis. Unlike the contrast-based network meta-analysis approach, which focuses on estimating relative effects such as odds ratios, the arm-based network meta-analysis approach can estimate absolute risks and other effects, which are arguably more informative in medicine and public health. However, the number of clinical studies involving each treatment is often small in a network meta-analysis, leading to unstable treatment-specific variance estimates in the arm-based network meta-analysis approach when using non- or weakly informative priors under an unequal variance assumption. Additional assumptions, such as equal (i.e. homogeneous) variances for all treatments, may be used to remedy this problem, but such assumptions may be inappropriately strong. This article introduces a variance shrinkage method for an arm-based network meta-analysis. Specifically, we assume different treatment variances share a common prior with unknown hyperparameters. This assumption is weaker than the homogeneous variance assumption and improves estimation by shrinking the variances in a data-dependent way. We illustrate the advantages of the variance shrinkage method by reanalyzing a network meta-analysis of organized inpatient care interventions for stroke. Finally, comprehensive simulations investigate the impact of different variance assumptions on statistical inference, and simulation results show that the variance shrinkage method provides better estimation for log odds ratios and absolute risks.