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Severe obesity is a complex, chronic disease affecting nearly 9% of adolescents in the U.S. Although the current mainstay of treatment is lifestyle therapy, pediatric clinical practice guidelines recommend the addition of adjunct anti-obesity medication (AOM), such as phentermine and topiramate. However, guidance regarding when adjunct AOM should be started and how AOM should be used is unclear. Furthermore, an inherent limitation of current treatment guidelines is their "one-size-fits-all" approach, which does not account for the heterogeneous nature of obesity and high degree of patient variability in response to all interventions. This paper describes the study design and methods of a sequential multiple assignment randomized trial (SMART), "SMART Use of Medications for the Treatment of Adolescent Severe Obesity." The trial will examine 1) when to start AOM (specifically phentermine) in adolescents who are not responding to lifestyle therapy and 2) how to modify AOM when there is a sub-optimal response to the initial pharmacological intervention (specifically, for phentermine non-responders, is it better to add topiramate to phentermine or switch to topiramate monotherapy). Critically, participant characteristics that may differentially affect response to treatment will be assessed and evaluated as potential moderators of intervention efficacy. Data from this study will be used to inform the development of an adaptive intervention for the treatment of adolescent severe obesity that includes empirically-derived decision rules regarding when and how to use AOM. Future research will test this adaptive intervention against standard "one-size-fits-all" treatments. [ABSTRACT FROM AUTHOR]

Background An elevated body mass index (>30 kg/m2) has been a relative contraindication for living kidney donation; however, such donors have become more common. Given the association between obesity and development of diabetes, hypertension, and end-stage renal disease, there is concern about the long-term health of obese donors. Methods Donor and recipient demographics, intraoperative parameters, complications, and short- and long-term outcomes were compared between contemporaneous donors—obese donors (body mass index ≥30 kg/m2) versus nonobese donors (body mass index <30 kg/m2). Results Between the years 1975 and 2014, we performed 3,752 donor nephrectomies; 656 (17.5%) were obese donors. On univariate analysis, obese donors were more likely to be older (P <.01) and African American (P <.01) and were less likely to be a smoker at the time of donation (P =.01). Estimated glomerular filtration rate at donation was higher in obese donors (115 ± 36 mL/min/1.73m2) versus nonobese donors (97 ± 22 mL/min/1.73m2; P <.001). There was no difference between groups in intraoperative and postoperative complications; but intraoperative time was longer for obese donors (adjusted P <.001). Adjusted postoperative length of stay (LOS) was longer (adjusted P =.01), but after adjustment for donation year, incision type, age, sex, and race, there were no differences in short-term (<30 days) and long-term (>30 days) readmissions. Estimated glomerular filtration rate and rates of end-stage renal disease were not significantly different between donor groups >20 years after donation (P =.71). However, long-term development of diabetes mellitus (adjusted hazard ratio (HR) 3.14; P <.001) and hypertension (adjusted hazard ratio (HR) 1.75; P <.001) was greater among obese donors and both occurred earlier (diabetes mellitus: 12 vs 18 years postnephrectomy; hypertension: 11 vs 15 years). Conclusion Obese donors develop diabetes mellitus and hypertension more frequently and earlier than nonobese donors after donation, raising concerns about increased rates of end-stage renal disease. [ABSTRACT FROM AUTHOR]

Executive dysfunction occurs early and is prevalent in Alzheimer's disease (AD). This study tested the ability of different measures for identifying changes in executive function and the effect of 6-months of aerobic exercise on executive function in older adults with mild to moderate AD, using a single-group, repeated-measures design (n = 28, age 78.1 ± 8.37). Factor analysis and linear mixed-effects model analyses showed that individually the Exit Interview-25 (EXIT-25), Behavioral Dyscontrol Scale (BDS), and Golden Stroop test were the preferred instruments for measuring changes in executive function in the sample. The COWAT and TMT had substantial floor effects limiting their ability to identify changes in executive function. A single latent factor was sufficient to describe the heterogeneity of executive function. Over 6 months, aerobic exercise maintained executive function (effect size = −0.11, −0.24, −0.27, and −0.21 for the EXIT-25, BDS, Stroop, and latent factor, respectively). Decline in the latent factor (effect size = −0.21, p = 0.06) was minimal and comparable to that in global cognition (effect size = − 0.20, p = 0.34). Aerobic exercise may be effective on maintaining executive function in AD. [ABSTRACT FROM AUTHOR]

Background: Population-based interventions aimed at reducing cardiovascular disease (CVD) hold significant potential and will be increasingly relied upon as the model for health care changes in the United States.Methods: The Heart of New Ulm Project is a population-based project with health care, community, and workplace interventions addressing multiple levels of the social-ecological model designed to reduce modifiable CVD risk factors in rural New Ulm, MN. The community is served by one health system, enabling the use of electronic health record data for surveillance. Electronic health record data were extracted at baseline (2008-2009) and 2 follow-up periods (2010-2011, 2012-2013) for residents aged 40 to 79 years. Generalized estimating equations were used to fit longitudinal models of the risk factors.Results: Of 7,855 residents in the target population, 80% had electronic health record data for each period. The prevalence of at goal (blood pressure [BP] <140/90 mm Hg) and (low-density lipoprotein cholesterol [LDL-C] <130 mg/dL) increased from 79.3% to 86.4% and 68.9% to 71.1%, respectively, from baseline to 5 years, with the largest reductions in BP and LDL-C seen in individuals not at goal at baseline. Blood pressure and lipid-lowering medication use increased from 41.8% to 44.0% and 25.3% to 29.1%, respectively. The proportion at goal for glucose increased from 46.9% to 48.2%. The prevalence body mass index <30 kg/m(2) (55%) did not change, whereas the proportion at-goal for high-density lipoprotein decreased from 63.8% to 58%, and smoking showed an increase from 11.3% to 13.6%.Conclusion: In a community participating in a multifaceted, population-based project aimed at reducing modifiable CVD risk factors, significant improvements in BP, LDL-C, and glucose were observed for 5 years, and body mass index remained stable in a state where obesity was increasing. [ABSTRACT FROM AUTHOR]

Primary care is a frequent source of pain treatment and opioid prescribing. The objective of the Prescribing Interventions for Chronic Pain using the Electronic health record (PRINCE) study is to assess the effects of two behavioral economics-informed interventions embedded within the electronic health record (EHR) on guideline-concordant pain treatment and opioid prescribing decisions in primary care settings. Setting : The setting for this study is 43 primary care clinics in Minnesota. Design: The PRINCE study uses a cluster-randomized 2 × 2 factorial design to test the effects of two interventions. An adaptive design allows for the possibility of secondary randomization to test if interventions can be titrated while maintaining efficacy. Interventions: One intervention alters the "choice architecture" within the EHR to nudge clinicians toward non-opioid treatments for opioid-naïve patients and toward tapering for patients currently receiving a "high risk" opioid. The other intervention integrates the prescription drug monitoring program (PDMP) directly within the EHR. Outcome : The primary outcome for opioid-naïve patients is whether an opioid is prescribed in a primary care visit without a non-opioid alternative pain treatment. The primary outcome for current opioid-using patients is whether opioid prescriptions were tapered with a documented rationale. The PRINCE study will provide real-world evidence on two approaches to improving pain treatment in primary care using the EHR. The adaptive study design strikes a balance between establishing intervention efficacy and testing whether efficacy varies with intervention intensity. [ABSTRACT FROM AUTHOR]

Objective Severe, late functional tricuspid regurgitation is characterized by annulus dilation, right ventricular enlargement, and papillary muscle displacement with leaflet tethering. However, the early stages of mild tricuspid regurgitation and its progression are poorly understood. This study examined structural heart changes in mild, early tricuspid regurgitation. Methods Sequential patients undergoing cardiac computed tomography and transthoracic echocardiography with tricuspid regurgitation were identified and evaluated. The tricuspid annulus area and chamber volumes were measured by computed tomography angiography and categorized by tricuspid regurgitation severity. Results Patients (n = 622) were divided into 3 groups by tricuspid regurgitation severity: no/trace (n = 386), mild (n = 178), and moderate/severe tricuspid regurgitation (n = 58). Annulus area was highly dependent on and proportional to regurgitation severity and correlated with both right/left atrial enlargement. Annulus area most strongly correlated with right and left atrial volume, and the annulus shape changed from elliptical to circular in moderate/severe tricuspid regurgitation. Mild tricuspid regurgitation was associated with less right/left atrial enlargement than significant tricuspid regurgitation, normal right ventricular size, and annular dilation. Significant tricuspid regurgitation was associated with annular dilation, circularization, and right ventricular enlargement. Mild and significant tricuspid regurgitation were differentiated by annulus area and indexed right ventricular volume. Conclusions Tricuspid annular dilation and right/left atrial enlargement comprise early events in mild functional tricuspid regurgitation. Atrial enlargement occurs before right ventricular dilation, which occurs late, when tricuspid regurgitation is severe. Atrial volume and tricuspid annular dilation are early and sensitive indicators of tricuspid regurgitation significance. [ABSTRACT FROM AUTHOR]

Chen et al. (2022) recently proposed a set of estimating equations that incorporate data from secondary endpoints to improve precision in parameter estimates related to a primary endpoint. We were motivated to translate their methodology to the context of randomized controlled trials to gain precision in treatment effect estimation using data from secondary endpoints. Our results suggest that this estimator cannot gain efficiency in this context because of random treatment assignment, especially when there is a treatment effect on secondary endpoints, and that further methodological work in this area is needed. [ABSTRACT FROM AUTHOR]

• 582 oropharyngeal cancer patients under radiation treatment were analyzed. • We aim to predict post-treatment aspiration or gastronomy tube dependence. • Tumor spread patterns to head and neck lymph nodes were identified. • Patients were clustered based on their unique lymph node spread patterns. • Patient clustered were significantly correlated with dysphagia 6 months post treatment. • Lymph node spread patterns are an effective prognostic indicator of late toxicity. To determine whether patient similarity in terms of head and neck cancer spread through lymph nodes correlates significantly with radiation-associated toxicity. 582 head and neck cancer patients received radiotherapy for oropharyngeal cancer (OPC) and had non-metastatic affected lymph nodes in the head and neck. Affected lymph nodes were segmented from pretreatment contrast-enhanced tomography scans and categorized according to consensus guidelines. Similar patients were clustered into 4 groups according to a graph-based representation of disease spread through affected lymph nodes. Correlation between dysphagia-associated symptoms and patient groups was calculated. Out of 582 patients, 26% (152) experienced toxicity during a follow up evaluation 6 months after completion of radiotherapy treatment. Patient groups identified by our approach were significantly correlated with dysphagia, feeding tube, and aspiration toxicity (p <.0005). Our results suggest that structural geometry-aware characterization of affected lymph nodes can be used to better predict radiation-associated dysphagia at time of diagnosis, and better inform treatment guidelines. Our work successfully stratified a patient cohort into similar groups using a structural geometry, graph-encoding of affected lymph nodes in oropharyngeal cancer patients, that were predictive of late radiation-associated dysphagia and toxicity. [ABSTRACT FROM AUTHOR]

• 200 H&N cancer patients under radiation treatment were analyzed. • We aim to predict post-treatment dysphagia. • Patient similarity was defined in terms of tumor location with respect to organs at risk. • Tumor location and predicted doses were used to stratify the cohort into 4 groups. • Patient groups were significantly correlated with dysphagia 6 months post treatment. Using a 200 Head and Neck cancer (HNC) patient cohort, we employ patient similarity based on tumor location, volume, and proximity to organs at risk to predict radiation-associated dysphagia (RAD) in a new patient receiving intensity modulated radiation therapy (IMRT). All patients were treated using curative-intent IMRT. Anatomical features were extracted from contrast-enhanced tomography scans acquired pre-treatment. Patient similarity was computed using a topological similarity measure, which allowed for the prediction of normal tissues' mean doses. We performed feature selection and clustering, and used the resulting groups of patients to forecast RAD. We used Logistic Regression (LG) cross-validation to assess the potential toxicity risk of these groupings. Out of 200 patients, 34 patients were recorded as having RAD. Patient clusters were significantly correlated with RAD (p <.0001). The area under the receiver-operator curve (AUC) using pre-established, baseline features gave a predictive accuracy of 0.79, while the addition of our cluster labels improved accuracy to 0.84. Our results show that spatial information available pre-treatment can be used to robustly identify groups of RAD high-risk patients. We identify feature sets that considerably improve toxicity risk prediction beyond what is possible using baseline features. Our results also suggest that similarity-based predicted mean doses to organs can be used as valid predictors of risk to organs. [ABSTRACT FROM AUTHOR]

• Retrospective analysis of 695 HPV+ oropharyngeal cancer patients. • Risk prediction using machine learning to predict toxicity and survival. • Pre-treatment anatomical information improves standard (AJCC-8) risk prediction. • Machine-learning derived patient stratifications improve outcome prediction. Evaluate the effectiveness of machine learning tools that incorporate spatial information such as disease location and lymph node metastatic patterns-of-spread, for prediction of survival and toxicity in HPV+ oropharyngeal cancer (OPC). 675 HPV+ OPC patients that were treated at MD Anderson Cancer Center between 2005 and 2013 with curative intent IMRT were retrospectively collected under IRB approval. Risk stratifications incorporating patient radiometric data and lymph node metastasis patterns via an anatomically-adjacent representation with hierarchical clustering were identified. These clusterings were combined into a 3-level patient stratification and included along with other known clinical features in a Cox model for predicting survival outcomes, and logistic regression for toxicity, using independent subsets for training and validation. Four groups were identified and combined into a 3-level stratification. The inclusion of patient stratifications in predictive models for 5-yr Overall survival (OS), 5-year recurrence free survival, (RFS) and Radiation-associated dysphagia (RAD) consistently improved model performance measured using the area under the curve (AUC). Test set AUC improvements over models with clinical covariates, was 9 % for predicting OS, and 18 % for predicting RFS, and 7 % for predicting RAD. For models with both clinical and AJCC covariates, AUC improvement was 7 %, 9 %, and 2 % for OS, RFS, and RAD, respectively. Including data-driven patient stratifications considerably improve prognosis for survival and toxicity outcomes over the performance achieved by clinical staging and clinical covariates alone. These stratifications generalize well to across cohorts, and sufficient information for reproducing these clusters is included. [ABSTRACT FROM AUTHOR]

Background: Post-transplant malignancy (PTM) remains a concern among pediatric kidney transplant (PKT) recipients.Study Design: Between 1963 and 2015, 884 pediatric (age 0 to 17 years old) patients received 1,055 PKTs at our institution. Cox proportional hazards models were constructed to identify risk factors for PTM after PKT with time-to-first-PTM as a primary outcome. Secondly, the hazard of death or graft loss was calculated in patients who developed PTM.Results: Median patient survival was 33 years (interquartile range [IQR] 18.7 to 47 years); 260 patients died during the study period and 47 had been diagnosed with PTM. There were 235 PTMs that occurred in 136 (15.4%) recipients at a median age of 29 years (IQR 17.8 to 37 years). The percentages of patients with PTM were 13% at 20 years post-PKT and 26% at 30 years post-PKT. Of PTM patients who died, 63.8% died of PTM. Among those who developed PTM, there was a higher hazard of death or graft loss (hazard ratio [HR] 1.62; 95% CI 1.11 to 2.38). In multivariable proportional hazards models, factors associated with PTM were increasing age at PKT (adjusted HR [AHR] 3.14; 95% CI 1.80 to 5.48 for 14 to 17 year-olds compared with children less than 3 years), having a living unrelated donor (LURD; AHR 3.25; 95% CI 1.27 to 8.35 compared with a living related donor), or implanting an Epstein-Barr virus (EBV)-positive allograft in an EBV-negative recipient (AHR 5.66; 95% CI 1.11 to 29.0). Compared with the general population, the cancer rate for PKT recipients was 6 times higher (126 vs 21 per 100,000 person-years).Conclusions: Pediatric kidney transplant recipients are at increased risk of PTM, which adversely affects survival. Children receiving transplants at an older age, from a LURD, or who receive an EBV-positive organ, should be monitored closely for the development of PTM. [ABSTRACT FROM AUTHOR]

An individualized treatment rule (ITR) formalizes personalized medicine by assigning treatment as a function of patients' clinical information, which contrasts with a static treatment rule that assigns everyone the same treatment. ITR identification has become a common aim in randomized clinical trials but sample size considerations for this aim are lacking. One approach is to select a sample size that will reliably identify an ITR with a performance close to the theoretical optimal rule. However, this approach could still lead to identifying ITRs that perform worse than the optimal static rule, particularly in the absence of substantial effect heterogeneity. This limitation motivates sample size considerations aimed at reliable identification of a beneficial ITR, which outperforms the optimal static rule, and analysis methods that identify the estimated optimal static rule when there is substantial uncertainty about whether an ITR will improve outcomes. To address these limitations, we propose a sample size approach based on the probability of identifying a beneficial ITR and introduce an approach for selecting the LASSO penalty parameter such that in the absence of treatment effect heterogeneity the estimated optimal static rule is identified with high probability. We apply these approaches to the PLUTO trial aimed at developing methods to assist with smoking cessation. [ABSTRACT FROM AUTHOR]

College student alcohol use and associated negative consequences are clear public health problems with consequences including damage to self, others, and institutions. This paper describes the protocol of a research study designed to answer a number of important questions in the development of an adaptive preventive intervention (API) to reduce high-risk drinking among first-year college students. The API is designed to educate students and to motivate heavy-drinking college students to engage in existing resources to support reducing high-risk alcohol use, by leveraging technology-based intervention modalities. The primary outcome is a reduction in binge drinking, with secondary outcomes of reducing negative alcohol-related consequences and increasing health services utilization. Adaptive preventive interventions have the potential to reduce the acute and long-term negative health consequences of young adult alcohol use. [ABSTRACT FROM AUTHOR]