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Study Design. This study retrospectively analyzes prospectively collected data. Objective. Here we aim to develop predictive models for 3-month medical and surgical readmission after elective lumbar surgery, based on a multi-institutional, national spine registry. Summary of Background Data. Unplanned readmissions place considerable stress on payers, hospitals, and patients. Medicare data reveals a 30-day readmission rate of 7.8% for lumbar-decompressions and 13.0% for lumbar-fusions, and hospitals are now being penalized for excessive 30-day readmission rates by virtue of the Hospital Readmissions Reduction Program. Methods. The Quality and Outcomes Database (QOD) was queried for patients undergoing elective lumbar surgery for degenerative diseases. The QOD prospectively captures 3-month readmissions through electronic medical record (EMR) review and self-reported outcome questionnaires. Distinct multivariable logistic regression models were fitted for surgery-related and medical readmissions adjusting for patient and surgery-specific variables. Results. Of the total 33,674 patients included in this study 2079 (6.15%) reported at least one readmission during the 90-day postoperative period. The odds of medical readmission were significantly higher for older patients, males versus females, African Americans versus Caucasion, those with higher American Society of Anesthesiologists (ASA) grade, diabetes, coronary artery disease, higher numbers of involved levels, anterior only or anterior–posterior versus posterior approach; also, for patients who were unemployed compared with employed patients and those with high baseline Oswestry Disability Index (ODI). The odds of surgery-related readmission were significantly greater for patients with a higher body mass index (BMI), a higher ASA grade, female versus male, and African Americans versus Caucasians; also, for patients with severe depression, more involved spinal levels, anterior-only surgical approaches and higher baseline ODI scores. Conclusion. In this study we present internally validated predictive models for medical and surgical readmission after elective lumbar spine surgery. These findings set the stage for targeted interventions with a potential to reduce unnecessary readmissions, and also suggest that medical and surgical readmissions be treated as distinct clinical events. Level of Evidence: 3

BackgroundEfforts to promote the cessation of harmful alcohol use are hindered by the affective and physiological components of alcohol withdrawal (AW), which can include life‐threatening seizures. Although previous studies ofAWand relapse have highlighted the detrimental role of stress, little is known about genetic risk factors.MethodsWe conducted a genome‐wide association study ofAWsymptom count in uniformly assessed subjects with histories of seriousAW, followed by additional genotyping in independentAWsubjects.ResultsThe top association signal forAWseverity was in sortilin family neurotrophin receptor geneSORCS2on chromosome 4 (European American meta‐analysisn = 1,478,p = 4.3 × 10−9). There were no genome‐wide significant findings in African Americans (n = 1,231). Bioinformatic analyses were conducted using publicly available high‐throughput transcriptomic and epigenomic data sets, showing that in humansSORCS2is most highly expressed in the nervous system. The identifiedSORCS2risk haplotype is predicted to disrupt a stress hormone‐modulated regulatory element that has tissue‐specific activity in human hippocampus. We used human neural lineage cells to demonstrate in vitro a causal relationship between stress hormone levels andSORCS2expression, and show thatSORCS2levels in culture are increased upon ethanol exposure and withdrawal.ConclusionsTaken together, these findings indicate that the pathophysiology of withdrawal may involve the effects of stress hormones on neurotrophic factor signaling. Further investigation of these pathways could produce new approaches to managing the aversive consequences of abrupt alcohol cessation.

AbstractBACKGROUNDDroplet digital PCR (ddPCR) is an emerging technology for quantitative cell-free DNA oncology applications. However, assay performance criteria must be established in a standardized manner to harness this potential. We reasoned that standard protocols used in clinical chemistry assay validation should be able to fill this need.METHODSWe validated KRAS, EGFR, and BRAF quantitative ddPCR assays based on the Clinical Laboratory Improvement Act regulations for laboratory-developed tests in clinical chemistry and the matching Clinical and Laboratory Standards Institute guidelines. This included evaluation of limit of the blank (LOB), limit of detection (LOD), limit of quantification (LOQ), intraassay and interassay imprecision, analytical range, dilution linearity, accuracy (including comparison with orthogonal platforms), reference range study, interference, and stability studies.RESULTSFor the ddPCR assays, the LOB was 4 mutant copies, LODs were 12 to 22 copies, and LOQs were 35 to 64 copies. The upper limit of the dynamic range was 30000 copies, and dilutions were linear down to the LOQs with good accuracy of spike recovery of Horizon reference material. Method comparisons with next-generation sequencing and an alternative ddPCR platform showed complete qualitative agreement and quantitative concordance, with slopes of 0.73 to 0.97 and R2s of 0.83 to 0.99. No substantial interferences were discovered. Wild-type copy numbers in plasma ranged from 462 to 6169/mL in healthy individuals.CONCLUSIONSStandard clinical chemistry assay validation protocols can be applied to quantitative ddPCR assays. This should facilitate comparison of the performance of different assays and allow establishment of minimal significant change thresholds in monitoring applications.

Abstract Vitamin D is an essential nutrient for bone health and may influence the risks of respiratory illness, adverse pregnancy outcomes, and chronic diseases of adulthood. Because many countries have a relatively low supply of foods rich in vitamin D and inadequate exposure to natural ultraviolet B (UVB) radiation from sunlight, an important proportion of the global population is at risk of vitamin D deficiency. There is general agreement that the minimum serum/plasma 25‐hydroxyvitamin D concentration (25(OH)D) that protects against vitamin D deficiency–related bone disease is approximately 30 nmol/L; therefore, this threshold is suitable to define vitamin D deficiency in population surveys. However, efforts to assess the vitamin D status of populations in low‐ and middle‐income countries have been hampered by limited availability of population‐representative 25(OH)D data, particularly among population subgroups most vulnerable to the skeletal and potential extraskeletal consequences of low vitamin D status, namely exclusively breastfed infants, children, adolescents, pregnant and lactating women, and the elderly. In the absence of 25(OH)D data, identification of communities that would benefit from public health interventions to improve vitamin D status may require proxy indicators of the population risk of vitamin D deficiency, such as the prevalence of rickets or metrics of usual UVB exposure. If a high prevalence of vitamin D deficiency is identified (>20% prevalence of 25(OH)D < 30 nmol/L) or the risk for vitamin D deficiency is determined to be high based on proxy indicators (e.g., prevalence of rickets >1%), food fortification and/or targeted vitamin D supplementation policies can be implemented to reduce the burden of vitamin D deficiency–related conditions in vulnerable populations.

Background Aortic syndromes (ASs), including aortic dissection, intramural hematoma, and penetrating aortic ulcer, carry significant acute and long-term morbidity and mortality. However, the contemporary incidence and outcomes of AS are unknown. Methods and Results We used the Rochester Epidemiology Project record linkage system to identify all Olmsted County, MN, residents with AS (1995–2015). Diagnostic imaging, medical records, and death certificates were reviewed to confirm the diagnosis and AS subtype. Age- and sex-adjusted incidence rates were estimated using annual county-level census data. Survival for patients with AS was compared with age- and sex-matched controls using Cox regression to adjust for comorbid conditions. We identified 133 patients with AS (77, aortic dissection; 21, intramural hematoma; and 35, penetrating aortic ulcer). Average age was 71.8 years (SD=14.1), and 57% were men. The age- and sex-adjusted incidence was 7.7 per 100 000 person-years, was higher for men than women (10.2 versus 5.7 per 100 000 person-years), and increased with age. Among subtypes, the incidence of aortic dissection was highest (4.4 per 100 000 person-years), whereas the incidence of penetrating aortic ulcer and intramural hematoma was lower (2.1 and 1.2 per 100 000 person-years). Overall, the incidence of AS was stable over time ( P trend=0.33), although the incidence of penetrating aortic ulcer seemed to increase from 0.6 to 2.6 per 100 000 person-years ( P =0.008) with variability over the study interval. Patients with AS had more than twice the mortality rate at 5, 10, and 20 years when compared with population-based controls (5-, 10-, and 20-year mortality 39%, 57%, and 91% versus 18%, 41%, and 66%; overall adjusted mortality hazards ratio=2.1; P <0.001). Survival was lower than expected up to 90 days after AS diagnosis and did not differ significantly by subtype or by 5-year strata of diagnosis. Conclusions Overall, the incidence of aortic dissection and intramural hematoma has remained stable since 1995, despite the decline noted for other cardiovascular disease. AS confers increased early and long-term mortality that has not changed. These data highlight the need to improve long-term care to impact the prognosis of this patient group.

Abstract Rationale Improved therapeutic options are needed for patients with treatment-refractory nontuberculous mycobacterial lung disease caused by Mycobacterium avium complex (MAC). Objectives To evaluate the efficacy and safety of daily amikacin liposome inhalation suspension (ALIS) added to standard guideline-based therapy (GBT) in patients with refractory MAC lung disease. Methods Adults with amikacin-susceptible MAC lung disease and MAC-positive sputum cultures despite at least 6 months of stable GBT were randomly assigned (2:1) to receive ALIS with GBT (ALIS + GBT) or GBT alone. Once-daily ALIS was supplied in single-use vials delivering 590 mg amikacin to the nebulizer. The primary endpoint was culture conversion, defined as three consecutive monthly MAC-negative sputum cultures by Month 6. Measurements and Main Results Enrolled patients (ALIS + GBT, n = 224; GBT-alone, n = 112) were a mean 64.7 years old and 69.3% female. Most had underlying bronchiectasis (62.5%), chronic obstructive pulmonary disease (14.3%), or both (11.9%). Culture conversion was achieved by 65 of 224 patients (29.0%) with ALIS + GBT and 10 of 112 (8.9%) with GBT alone (odds ratio, 4.22; 95% confidence interval, 2.08–8.57; P &lt; 0.001). Patients in the ALIS + GBT arm versus GBT alone were more likely to achieve conversion (hazard ratio, 3.90; 95% confidence interval, 2.00–7.60). Respiratory adverse events (primarily dysphonia, cough, and dyspnea) were reported in 87.4% of patients receiving ALIS + GBT and 50.0% receiving GBT alone; serious treatment-emergent adverse events occurred in 20.2% and 17.9% of patients, respectively. Conclusions Addition of ALIS to GBT for treatment-refractory MAC lung disease achieved significantly greater culture conversion by Month 6 than GBT alone, with comparable rates of serious adverse events. Clinical trial registered with www.clinicaltrials.gov (NCT02344004).

BackgroundPreoperative prediction of tumor recurrence is important in the management of patients with hepatocellular carcinoma (HCC).PurposeTo investigate whether tumor stiffness derived by magnetic resonance elastography (MRE) could predict early recurrence of HCC after hepatic resection.Study TypeRetrospective.PopulationIn all, 99 patients with pathologically confirmed HCCs after surgical resection.Field Strength/Sequence3.0T; preoperative MRE with 60‐Hz mechanical vibrations using an active acoustic driver.AssessmentRegions of interest (ROIs) were manually drawn in the tumors to measure mean tumor stiffness. Surgical specimens were reviewed for histological grade, capsule, vascular invasion, and surgical margins. The early recurrence of HCC was defined as that occurring within 2 years after resection.Statistical TestsCox proportional hazard models were used to evaluate risk factors associated with the time to early recurrence.ResultsHCCs with recurrence had higher tumor stiffness, higher rate of advanced T stage, vascular invasion, lower rate of capsule formation, larger tumor size, higher aspartate aminotransferase (AST), and hepatitis B virus (HBV)‐DNA level and aspartate aminotransferase / alanine aminotransferase ratio (P = 0.031, 0.007, 0.01, <0.001, 0.015, 0.034, 0.01, and 0.014, respectively) than HCCs without recurrence. Vascular invasion (hazard ratio [HR] = 2.922; 95% confidence interval [CI]: [1.079, 7.914], P = 0.035) and mean tumor stiffness (HR = 1.163; 95% CI: [1.055, 1.282], P = 0.002) were risk factors associated with early recurrence. Each 1‐kPa increase in tumor stiffness was associated with a 16.3% increase in the risk for tumor recurrence.Data ConclusionThe mean stiffness of HCCs may be a useful, noninvasive, quantitative biomarker for the prediction of early HCC recurrence after hepatic resection.Level of Evidence: 4Technical Efficacy: Stage 5J. Magn. Reson. Imaging 2019;49:719–730.