The distillation method: A novel approach for analyzing randomized trials when exposure to the intervention is diluted.

OBJECTIVE: To introduce a novel analytical approach for randomized controlled trials that are underpowered because of low participant enrollment or engagement. DATA SOURCES: Reanalysis of data for 805 patients randomized as part of a pilot complex care intervention in 2015-2016 in a large delivery system. In the pilot randomized trial, only 64.6% of patients assigned to the intervention group participated. STUDY DESIGN: A case study and simulation. The "Distillation Method" capitalizes on the frequently observed correlation between the probability of subjects' participation or engagement in the intervention and the magnitude of benefit they experience. The novel method involves three stages: first, it uses baseline covariates to generate predicted probabilities of participation. Next, these are used to produce nested subsamples of the randomized intervention and control groups that are more concentrated with subjects who were likely to participate/engage. Finally, for the outcomes of interest, standard statistical methods are used to re-evaluate intervention effectiveness in these concentrated subsets. DATA EXTRACTION METHODS: We assembled secondary data on patients who were randomized to the pilot intervention for one year prior to randomization and two follow-up years. Data included program enrollment status, membership data, demographics, utilization, costs, and clinical data. PRINCIPAL FINDINGS: Using baseline covariates only, Generalized Boosted Regression Models predicting program enrollment performed well (AUC 0.884). We then distilled the full randomized sample to increasing levels of concentration and reanalyzed program outcomes. We found statistically significant differences in outpatient utilization and emergency department utilization (both follow-up years), and in total costs (follow-up year two only) at select levels of population concentration. CONCLUSIONS: By offering an internally valid analytic framework, the Distillation Method can increase the power to detect effects by redefining the estimand to subpopulations with higher enrollment probabilities and stronger average treatment effects while maintaining the original randomization.

The natural history of large abdominal aortic aneurysms in patients without timely repair.

OBJECTIVE: Contemporary data on the natural history of large abdominal aortic aneurysms (AAAs) in patients undergoing delayed or no repair are lacking. In this study, we examine the impact of large AAA size on the incidence of rupture and mortality. METHODS: From a prospectively maintained aneurysm surveillance registry, patients with an unrepaired, large AAA (≥5.5 cm in men and ≥5.0 cm in women) at baseline (ie, index imaging) or who progressed to a large size from 2003 to 2017 were included, with follow-up through March 2020. Outcomes of interest obtained by manual chart review included rupture (confirmed by imaging/autopsy), probable rupture (timing/findings consistent with rupture without more likely cause of death), repair, reasons for either no or delayed (>1 year after diagnosis of large AAA) repair and total mortality. Cumulative incidence of rupture was calculated using a nonparametric cumulative incidence function, accounting for the competing events of death and aneurysm repair and was stratified by patient sex. RESULTS: Of the 3248 eligible patients (mean age, 83.6 ± 9.1 years; 71.2% male; 78.1% white; and 32.0% current smokers), 1423 (43.8%) had large AAAs at index imaging, and 1825 progressed to large AAAs during the follow-up period, with a mean time to qualifying size of 4.3 ± 3.4 years. In total, 2215 (68%) patients underwent repair, of which 332 were delayed >1 year; 1033 (32%) did not undergo repair. The most common reasons for delayed repair were discrepancy in AAA measurement between surgeon and radiologist (34%) and comorbidity (20%), whereas the most common reasons for no repair were patient preference (48%) and comorbidity (30%). Among patients with delayed repair (mean time to repair, 2.6 ± 1.8 years), nine (2.7%) developed symptomatic aneurysms, and an additional 11 (3.3%) ruptured. Of patients with no repair, 94 (9.1%) ruptured. The 3-year cumulative incidence of rupture was 3.4% for initial AAA size 5.0 to 5.4 cm (women only), 2.2% for 5.5 to 6.0 cm, 6.0% for 6.1 to 7.0 cm, and 18.4% for >7.0 cm. Women with AAA size 6.1 to 7.0 cm had a 3-year cumulative incidence of rupture of 12.8% (95% confidence interval, 7.5%-19.6%) compared with 4.5% (95% confidence interval, 3.0%-6.5%) in men (P = .002). CONCLUSIONS: In this large cohort of AAA registry patients over 17 years, annual rupture rates for large AAAs were lower than previously reported, with possible increased risk in women. Further analyses are ongoing to identify those at increased risk for aneurysm rupture and may provide targeted surveillance regimens and improve patient counseling.

Facial Gunshot Wound: Mandibular Fracture With Internal Fixation and a Pectoralis Myocutaneous Flap Coverage.

Facial penetrating gunshot wounds (GSWs) are seen in an assault, suicide, and accidental injury. They often carry high mortality given the important anatomical structures located within the neck. The foundations of maxillofacial GSWs are rooted in data from military combat, specifically the last world war. This type of injury is complex for reconstructive surgery due to significant soft tissue and bone loss. Management of maxillofacial GSWs is often challenging and has trended from serial debridement, immediate reconstruction, local tissue flaps, and distant free flap transfers depending on bullet trajectory and wound intricacy. We present a case of a 51-year-old male with a 22-caliber GSW to the left side of his face. Hemodynamics were stable on arrival and history included alcohol use. A left mandibular wound measured approximately 8 cm in diameter with exposed bone. A small 0.5-1 cm wound was also present inferiorly. A maxillofacial CT scan was utilized, showing a left mandibular body fracture. The patient underwent exploration and debridement on the same day of injury. Open reduction with internal fixation of the left mandible fracture and Synthes 2.5 mm locking plate was done. Additionally, a left pectoralis major myocutaneous muscle flap was performed two days later. Regional pectoralis flap reconstruction of facial firearm injury is scarcely acknowledged in the literature. Due to the location of the wound, the functionality of the jaw can be maintained in addition to ample blood supply by performing mandibular fixation and pectoralis major myocutaneous flap.

Validation of natural language processing to determine the presence and size of abdominal aortic aneurysms in a large integrated health system.

OBJECTIVE: Previous studies of the natural history of abdominal aortic aneurysms (AAAs) have been limited by small cohort sizes or heterogeneous analyses of pooled data. By quickly and efficiently extracting imaging data from the health records, natural language processing (NLP) has the potential to substantially improve how we study and care for patients with AAAs. The aim of the present study was to test the ability of an NLP tool to accurately identify the presence or absence of AAAs and detect the maximal abdominal aortic diameter in a large dataset of imaging study reports. METHODS: Relevant imaging study reports (n = 230,660) from 2003 to 2017 were obtained for 32,778 patients followed up in a prospective aneurysm surveillance registry within a large, diverse, integrated healthcare system. A commercially available NLP algorithm was used to assess the presence of AAAs, confirm the absence of AAAs, and extract the maximal diameter of the abdominal aorta, if stated. A blinded expert manual review of 18,000 randomly selected imaging reports was used as the reference standard. The positive predictive value (PPV or precision), sensitivity (recall), and the kappa statistics were calculated. RESULTS: Of the randomly selected 18,000 studies that underwent expert manual review, 48.7% were positive for AAAs. In confirming the presence of an AAA, the interrater reliability of the NLP compared with the expert review showed a kappa value of 0.84 (95% confidence interval [CI], 0.83-0.85), with a PPV of 95% and sensitivity of 88.5%. The NLP algorithm showed similar results for confirming the absence of an AAA, with a kappa of 0.79 (95% CI, 0.799-0.80), PPV of 77.7%, and sensitivity of 91.9%. The kappa, PPV, and sensitivity of the NLP for correctly identifying the maximal aortic diameter was 0.88 (95% CI, 0.87-0.89), 88.8%, and 88.2% respectively. CONCLUSIONS: The use of NLP software can accurately analyze large volumes of radiology report data to detect AAA disease and assemble a contemporary aortic diameter-based cohort of patients for longitudinal analysis to guide surveillance, medical management, and operative decision making. It can also potentially be used to identify from the electronic medical records pre- and postoperative AAA patients "lost to follow-up," leverage human resources engaged in the ongoing surveillance of patients with AAAs, and facilitate the construction and implementation of AAA screening programs.

BAM15-mediated mitochondrial uncoupling protects against obesity and improves glycemic control.

Obesity is a leading cause of preventable death worldwide. Despite this, current strategies for the treatment of obesity remain ineffective at achieving long-term weight control. This is due, in part, to difficulties in identifying tolerable and efficacious small molecules or biologics capable of regulating systemic nutrient homeostasis. Here, we demonstrate that BAM15, a mitochondrially targeted small molecule protonophore, stimulates energy expenditure and glucose and lipid metabolism to protect against diet-induced obesity. Exposure to BAM15 in vitro enhanced mitochondrial respiratory kinetics, improved insulin action, and stimulated nutrient uptake by sustained activation of AMPK. C57BL/6J mice treated with BAM15 were resistant to weight gain. Furthermore, BAM15-treated mice exhibited improved body composition and glycemic control independent of weight loss, effects attributable to drug targeting of lipid-rich tissues. We provide the first phenotypic characterization and demonstration of pre-clinical efficacy for BAM15 as a pharmacological approach for the treatment of obesity and related diseases.

UCC118 supplementation reduces exercise-induced gastrointestinal permeability and remodels the gut microbiome in healthy humans.

Dysregulation of gut microbiota and intestinal barrier function has emerged as potential mechanisms underlying digestive diseases, yet targeted therapies are lacking The purpose of this investigation was to assess the efficacy of UCC118, a characterized probiotic strain, on exercise-induced GI permeability in healthy humans. In a randomized, double-blind, placebo-controlled crossover study, seven healthy adults received 4 weeks of daily UCC118 or placebo supplementation. GI hyperpermeability was induced by strenuous treadmill running performed before and after each supplementation period. While running, participants ingested 5 g of lactulose, rhamnose, and sucrose. Urine was collected before, immediately after, and every hour for 5 h after exercise to assess GI permeability. Metagenomic sequencing was performed on fecal homogenates collected prior to exercise to identify changes in microbial diversity and taxon abundances. Inflammatory biomarkers were assessed from blood and fecal homogenates collected prior to and immediately following the cessation of exercise. Exercise significantly induced intestinal permeability of lactulose, rhamnose, and sucrose (P < 0.001). UCC118 significantly reduced sucrose (Δ = -0.38 ± 0.13 vs. 1.69 ± 0.79; P < 0.05) recovery, with no substantial change in lactulose (Δ = -0.07 ± 0.23 vs. 0.35 ± 0.15; P = 0.16) or rhamnose (Δ = -0.06 ± 0.22 vs. 0.48 ± 0.28; P = 0.22). Taxonomic sequencing revealed 99 differentially regulated bacteria spanning 6 taxonomic ranks (P < 0.05) after UCC118 supplementation. No differences in plasma IL-6 or fecal zonulin were observed after UCC118 supplementation. The results described herein provide proof of principle that 4 weeks of UCC118 supplementation attenuated exercise-induced intestinal hyperpermeability. Further research is warranted to investigate the as-yet-to-be defined molecular processes of intestinal hyperpermeability and the effects of probiotic supplementation.

Association Between Annual Surgeon Total Thyroidectomy Volume and Transient and Permanent Complications.

IMPORTANCE: Although the association between annual surgeon total thyroidectomy volume and clinical outcomes is well established, published methods typically group surgeons into volume categories. The volume-outcomes association is likely continuous, but little is known about the point at which the annual surgeon procedure volumes begin to be associated with a decrease in complication rates. OBJECTIVE: To model the volume-outcomes association as a continuous function and identify the point at which increasing surgeon volume begins yielding better outcomes. DESIGN, SETTING, AND PARTICIPANTS: A retrospective cohort study was conducted in 2018 to 2019 on 10 546 patients from 2 Kaiser Permanente regions (Northern and Southern California), who underwent total thyroidectomy from January 1, 2008, through December 31, 2015, and were followed up through December 31, 2017. The association between annual surgeon procedure volume and outcomes was modeled with analyses that accounted for an association of unknown form and surgeon-specific effects, after adjusting for sociodemographics, prior-year utilization, and multiple comorbidities. Data were analyzed from October 2018 to April 2019. EXPOSURE: Total thyroidectomy. MAIN OUTCOMES AND MEASURES: Presence or absence of transient and permanent hypoparathyroidism and vocal cord paralysis (VCP) in relation to surgeon volume of total thyroidectomies. RESULTS: Of 10 546 patients in this study, 8500 (81.0%) were male and 4877 (46.2%) aged 45 to 64 years. Surgeons with annual volumes of 1 to 9 total thyroidectomies operated on 2912 patients (27.7%), those with an annual volume of 10 to 19 operated on 3404 (32.6%), and those with an annual volume of 20 or more operated on the remaining 4232 (40.6%). During 2008-2015, a mean of 53.5 (range, 46-198) thyroidectomies were performed each year by surgeons with an annual volume of 40 or more procedures. A generalized additive model showed that the occurrence rates of VCP and hypoparathyroidism began to decrease at annual surgeon procedure volumes of 18.2 (95% CI, 15.0-21.5) and 18.1 (95% CI, 13.8-21.3) procedures per year, respectively. The model revealed a subsequent increase in complication rates for transient VCP. With the use of a refined model, statistically significant decreases were noted in the occurrence rates of complications as annual surgeon volumes increased. Among all 10 546 patients who underwent total thyroidectomy, 632 (6.0%) experienced transient hypoparathyroidism and 170 (1.6%) experienced permanent hypoparathyroidism, whereas 440 (4.2%) experienced transient VCP and 182 (1.7%) experienced permanent VCP. Absolute decreases in complication rates when all surgeons had modeled minimum annual procedure volumes greater than 40 were low, ranging from 0.6% for permanent VCP and hypoparathyroidism to 1.5% for transient hypoparathyroidism. CONCLUSIONS AND RELEVANCE: In this study, occurrence rates of transient and permanent hypoparathyroidism and VCP appeared to decrease as the annual surgeon procedure volume increased, but the absolute decrease may be modest if the affected health system already has low complication rates. Shifting patients to higher-volume surgeons to realize these reductions may be of variable attractiveness in systems with low baseline complication rates.

Preoperative Vision and Surgeon Volume as Predictors of Visual Outcomes after Cataract Surgery.

PURPOSE: To evaluate the relationship between preoperative vision and surgeon volume with visual outcomes after cataract surgery. DESIGN: Retrospective cohort study. PARTICIPANTS: Patients aged ≥18 years old enrolled in the Kaiser Permanente Southern California Health Plan who underwent cataract surgery by nontrainee surgeons. METHODS: Patients who underwent cataract surgery between January 1, 2013 and December 31, 2015, were included. A multivariate analysis using Generalized Additive Mixed Models was performed to determine the relationship between surgeon volume and postoperative visual acuity after controlling for patient age, preoperative visual acuity, history of diabetes, and history of diabetic retinopathy. Modeling was done for the relationship between preoperative vision and visual outcomes while controlling for surgeon volume, patient age, history of diabetes, and history of diabetic retinopathy. MAIN OUTCOME MEASURE: Absolute letter change and percentage of patients to achieve ≥5 Early Treatment Diabetic Retinopathy Study (ETDRS) letter gain postoperatively. RESULTS: There were 103 920 cataract surgeries performed by 136 surgeons included in this analysis. Patients whose surgeons performed <91.0 surgeries/year (95% confidence interval [CI], 61.1-139; P < 0.05) gained fewer letters postoperatively than the overall average, whereas those whose surgeons performed >91 but <227 surgeries/year (95% CI, 169-∞; P < 0.05) gained more letters than average. Although statistically significant, the difference between the lowest and highest performing surgeons was approximately 1.25 letters. Surgeons who performed <110 surgeries/year (95% CI, 81.7-149; P < 0.05) had fewer patients who gained ≥5 letters. Surgeons who performed >110 but <293 surgeries/year (95% CI, 232-∞; P < 0.05) were approximately 15% more likely to have patients who gained ≥5 letters. Patients with preoperative vision <74.7 letters (95% CI, 74.7-74.8; P < 0.05) and <75.8 letters (95% CI, 75.8-75.9; P < 0.05) gained more letters and were more likely to gain ≥5 letters postoperatively, respectively. CONCLUSIONS: Patients whose vision is approximately 20/32 or worse are more likely to have significant visual gains after cataract surgery. Although statistically significant differences exist in postoperative vision based on surgeon volume, these do not appear to be clinically meaningful. Overall, visual outcomes are functionally comparable across a wide range of surgeon volumes.

Synthesis and structures of Pb3O2(CH3COO)2·0.5H2O and Pb2O(HCOO)2: two corrosion products revisited.

Reactions of carboxylic acids with lead play an important role in the atmospheric corrosion of lead and lead-tin alloys. This is of particular concern for the preservation of lead-based cultural objects, including historic lead-tin alloy organ pipes. Two initial corrosion products, Pb(3)O(2)(CH(3)COO)(2)·0.5H(2)O (1) and Pb(2)O(HCOO)(2) (2), had been identified through powder diffraction fingerprints in the Powder Diffraction File, but their structures had never been determined. We have crystallized both compounds using hydrothermal solution conditions, and structures were determined using laboratory and synchrotron single-crystal X-ray diffraction data. Compound 1 crystallizes in P1, and 2 in Cccm. These compounds may be viewed as inorganic-organic networks containing single and double chains of edge-sharing Pb(4)O tetrahedra and have structural similarities to inorganic basic lead compounds. Bond valence sum analysis has been applied to the hemidirected lead coordination environments in each compound. Atmospheric exposure experiments contribute to understanding of the potential for conversion of these short-term corrosion products to hydrocerussite, Pb(3)(CO(3))(2)(OH)(2), previously identified as a long-term corrosion product on lead-rich objects. Each compound was also characterized by elemental analysis, thermogravimetric analysis and differential scanning calorimetry (TGA-DSC), and Raman spectroscopy.