Citations

Abstract Objectives The association of bipolar disorder with early and excessive cardiovascular disease was identified over a century ago. Nonetheless, the vascular‐bipolar link remains underrecognized, particularly with regard to how this link can contribute to our understanding of pathogenesis and treatment. Methods An international group of experts completed a selective review of the literature, distilling core themes, identifying limitations and gaps in the literature, and highlighting future directions to bridge these gaps. Results The association between bipolar disorder and vascular disease is large in magnitude, consistent across studies, and independent of confounding variables where assessed. The vascular‐bipolar link is multifactorial and is difficult to study given the latency between the onset of bipolar disorder, often in adolescence or early adulthood, and subsequent vascular disease, which usually occurs decades later. As a result, studies have often focused on risk factors for vascular disease or intermediate phenotypes, such as structural and functional vascular imaging measures. There is interest in identifying the most relevant mediators of this relationship, including lifestyle (eg, smoking, diet, exercise), medications, and systemic biological mediators (eg, inflammation). Nonetheless, there is a paucity of treatment studies that deliberately engage these mediators, and thus far no treatment studies have focused on engaging vascular imaging targets. Conclusions Further research focused on the vascular‐bipolar link holds promise for gleaning insights regarding the underlying causes of bipolar disorder, identifying novel treatment approaches, and mitigating disparities in cardiovascular outcomes for people with bipolar disorder.

Background Past research in population health trends has shown that injuries form a substantial burden of population health loss. Regular updates to injury burden assessments are critical. We report Global Burden of Disease (GBD) 2017 Study estimates on morbidity and mortality for all injuries. Methods We reviewed results for injuries from the GBD 2017 study. GBD 2017 measured injury-specific mortality and years of life lost (YLLs) using the Cause of Death Ensemble model. To measure non-fatal injuries, GBD 2017 modelled injury-specific incidence and converted this to prevalence and years lived with disability (YLDs). YLLs and YLDs were summed to calculate disability-adjusted life years (DALYs). Findings In 1990, there were 4 260 493 (4 085 700 to 4 396 138) injury deaths, which increased to 4 484 722 (4 332 010 to 4 585 554) deaths in 2017, while age-standardised mortality decreased from 1079 (1073 to 1086) to 738 (730 to 745) per 100 000. In 1990, there were 354 064 302 (95% uncertainty interval: 338 174 876 to 371 610 802) new cases of injury globally, which increased to 520 710 288 (493 430 247 to 547 988 635) new cases in 2017. During this time, age-standardised incidence decreased non-significantly from 6824 (6534 to 7147) to 6763 (6412 to 7118) per 100 000. Between 1990 and 2017, age-standardised DALYs decreased from 4947 (4655 to 5233) per 100 000 to 3267 (3058 to 3505). Interpretation Injuries are an important cause of health loss globally, though mortality has declined between 1990 and 2017. Future research in injury burden should focus on prevention in high-burden populations, improving data collection and ensuring access to medical care.

Autophagy is a homeostatic process for the elimination of damaged, unnecessary proteins or organelles within cells. Our overarching hypothesis is that autophagy contributes to neuromuscular dysfunction, specifically increased NMTF seen with aging. Understanding the mechanisms regulating autophagy flux is essential to discovering therapeutic agents which may mitigate the effects of neuromuscular dysfunction across conditions including old age. In recent studies, we found that in 18 month old mice autophagy in the cervical spinal cord is accelerated and neuromuscular transmission failure (NMTF) in diaphragm muscle‐phrenic nerve preparations is increased. Neurotrophin activity, specifically brain‐derived neurotrophic factor (BDNF) signaling through its high affinity receptor tropomyosin‐related kinase receptor subtype B (TrkB) decreases NMTF. Thus, we predict BDNF/TrkB signaling suppresses autophagy in phrenic motor neurons located in the cervical spinal cord. We hypothesize that inhibiting TrkB kinase activity accelerates autophagy in phrenic motor neurons. TrkB F616A mice at 18 months of age were randomized to receive 1 week treatment with vehicle (n=4) or 1NMPP1 (TrkB kinase inhibitor; n=6). Additionally, 18 month old wild type C57BL/6 mice (n=2) were studied. Whole cervical spinal cord (CSC) was harvested for measurements of autophagy marker protein expression analyzed by Western blotting. Data for the vehicle‐treated TrkB F616A and wild type mice was combined given lack of differences for any measurement. p62, a marker associated with the initiation of autophagy, was significantly decreased in the 1NMPP1‐treated group compared to vehicle‐treated or wild type mice. LC3, a protein marking the autophagosome membrane elongation phase, was not significantly changed across groups indicating that LC3‐tagged autophagosomes proceed to lysosomal degradation and do not accumulate. These results support our hypothesis that inhibiting BDNF/TrkB signaling accelerates autophagy flux in the CSC and reveal trophic effects of BDNF/TrkB signaling in the neuromuscular system. Accelerated autophagy may underlie age‐related neuromuscular dysfunction in a BDNF/TrkB signaling dependent manner. Support or Funding Information Support: NIH R01 AG057052

Abstract Fluorescence in situ hybridization (FISH) is an effective alternative for the analysis of cytogenetic abnormalities of low proliferative entities such as Waldenström macroglobulinemia (WM) but, to date, no studies have been carried out to explore the potential impact of molecular cytogenetics on disease evolution. Deletion of the long arm of chromosome 6 (6q-) is the most frequent cytogenetic abnormality in WM. In this study we have analyzed the incidence of this aberration (using both conventional cytogenetics and FISH analysis) in 102 WM patients, and we have correlated it with disease characteristics. Deletion of 6q21 was detected in 6% of patients by conventional cytogenetics, while FISH studies increased this incidence up to 39%. Moreover, in those patients analyzed by cIgM-FISH, the incidence of 6q- was higher (54%). Interestingly, 6q- patients displayed features associated with adverse prognosis (higher levels of ESR, CRP and beta-2 microglobulin), and a greater tendency to display anemia and hypoalbuminemia. Other differentiating variables without reaching statistical significance were a tendency of displaying a higher bone marrow lymphoplasmacytoid infiltration and the amount of monoclonal component in 6q- patients (table). In addition, patients with 6q- displayed shorter survival from time of diagnose (log-rank; p=0.09). In summary, our results show that 6q deletion in WM patients is currently the most frequently found cytogenetic abnormality. Patients with this deletion also shows a trend towards an aggressive disease and poorer outcome in WM. Further studies should focus on possible tumor suppressor genes in the minimal area of deletion at 6q and to determine their role in disease progression. table del6q present del6q absent p-value n 40 (39%) 62 (61%) β2M ≥4mg/dL 48% 16% 0.005 CRP ≥3.5 mg/dL 47% 11% 0.006 Albumin <4mg/dL 86% 55% 0.006 ESR ≥100 mm/h 73% 44% 0.02 Hb <11 g/dL 63% 40% 0.02 serum IgM >20 g/L 86% 73% 0.10 BM infiltration >40% 44% 31% 0.20

Abstract MM has a median age at presentation of 65–68 years, rarely occurring in pts before age 40. Here, we present clinical, laboratory and survival data in the largest ever-analyzed cohort of young pts compared with pts aged ≥ 40 years. 259 pts aged < 40 and 8,296 aged ≥ 40 years were enrolled. These 8.555 pts were part of the cohort analyzed for the ISS staging project. Previously untreated pts entered into randomized trials with standard (SDT) or high dose treatment (HDT). Clinical data were available for all pts, 526 pts had karyotypic analysis and 454 pts testing for Del 13 testing by FISH. The Chi-Square test was used to identify significant prognostic factors. A maximum likelihood model was used to estimate relative excess risk (RER) for younger versus older pts treated with SDT or HDT. Observed survival was adjusted by life expectancy depending on age, gender, and nationality. Young pts had significantly lower ISS stage I than older pts (stage I; 39% vs. 28%, stage II: 28 vs. 39%, stage III 33% vs. 33%, p<. 001, p<001, p=0.863, respectively) due primarily to a lower prevalence of high ß2m levels and low albumin levels in the younger age group. Paradoxically, the younger pts more frequently presented with higher M-component levels and Durie Salmon stage III (65% vs. 54%, p<0.001). Prevalence of other important prognostic parameters like Hb, platelet count, creatinine, calcium, CRP, LDH and bone marrow PC infiltration was similar in both groups. Younger pts had more frequently good ECOG performance status (PS) (0–2), (87% vs. 81%, p<0.01). Karyotypic abnormalities and Del 13 were similarly distributed between both cohorts. Median OS was significantly longer in young pts (median: 4.8 years vs. 3.7 years; hazard ratio (HR): 1.46; 95%, CI (1.27, 1.68); p=<0.001). Better outcome in the younger cohort was seen in all three ISS stages, independent of gender. Median OS survival was significantly longer after SDT in the young cohort (median: 49 months (mos) vs. 39 mos; HR 1.49; CI (1.27, 1.75); p<0.001). Median survival: 86 mos in young and 68 mos in older pts on HDT; this did not translate into a statistical difference (HR 1.8; CI (0.81,1.44); p=0.6). Risk estimates in a maximum likelihood analysis revealed that, apart from ISS Stage, young age followed by female sex was statistical significant for a good outcome for pts treated with SDT (Age RER: 1.43, CI (1.20, 1.70), p<0.001; Sex RER: 1.07, CI (1.02, 1.14); p < 0.013). For pts treated with HDT, only ISS Stage was found to be a risk factor, but not age or gender. Conclusions: Patients < 40 have better prognosis and survival than older patients. The most important features of young patients are low SßM, normal S. Alb, and good performance status.

Abstract The objective of this study was to investigate the underlying molecular alteration in multiple myeloma at the protein level in order to identify regulators of pathogenesis, discover novel targets of therapy, and compare genetic and proteomic alterations. We employed antibody protein microarrays (BD Clonetech, CA) to measure changes in the patterns of protein expression between MM and normal plasma cells. The antibody array is a new technique enabling protein differences to be assayed directly by hybridizing fluorescently labeled protein mixtures from cell extracts onto glass slides spotted with 512 different monoclonal antibodies. CD138+purified plasma cells were obtained from cryopreserved bone marrow samples of 12 newly diagnosed patients with MM. The labeling index was high (1% cutoff) in 7 samples and low in the other 5. Control plasma cells were obtained from 9 pooled CD138+ purified normal donor bone marrow plasma cells. Interphase FISH analysis for 17p deletion, 13q deletion, and t(11:14) were performed. To assess differential expression, the mean of the ratios of Cy5/Cy3 for each sample were analyzed using the Clontech software to calculate an internally normalized ratio. The normalized data were analyzed by the Genespring software. Unsupervised clustering identified 4 groups of MM. Changes of protein expression ≥2 fold in 70% of the samples as compared to control were identified. There were 6 proteins differentially expressed between all MM samples and control cells including proteins in the ras signaling pathway (KSR-1), the ubiquitin pathway (Ubc-H6), cyclin-dependent kinases (CDK4), cytokines (IL-6), DNA toposisomerase II, and the rho-interacting serine-threonine kinase CRIK. Proteins differentially expressed in MM groups 1 and 2 compared to normal control included cell cycle regulators (cul-2, MCM6, PCNA, TGFb1), kinases (p70S6K, PKC), and chromatin regulators (Ran, AKAP450, Rad50). Protiens differentially expressed in MM group 3 included cell cycle regulators (CDK2, CLK1, MENA), apoptosis regulators (XIAP, caspase 4, perforin) kinases (IKKa and RAC1 in the Wnt signaling pathway) and P53 regulators, while proteins identified in MM group 4 included NFkB/ubiquitin proteins (IKKa and Ubch6), cell cycle regulators (c-myc, CDK4), p53 pathway proteins (53bp2), ras-signaling proteins (KSR1), and the kinase CRIK. There were no differences in protein expression between the high and low labeling index groups. 13q was identified in 5 (42%), 17 p in 1(8%) and t(11:14) in 1(8%) patients. 80% of the 13 q deletion cases clustered in MM group 1 and 2 patients. Cyclin D-1 was upregulated in 5 (42%) patients including the patient with (11:14) translocation. This is the first proteomic study of patients with MM. The results are consistent with previously identified genetic alterations in MM indicating that this novel technique could be used in identifying molecular changes in MM. It identifies novel proteins dysregulated in MM that differ between the 4 MM groups. These results may be used in the future to individualize therapy based on the proteins dysregulated in each group. For example, IKK inhibitors may be useful in group 3 MM patients, while mTOR inhibitors (upstream of p70S6K) could be used in groups 1 and 2 patients. Future correlations with gene expression arrays and prognosis in a larger cohort of patients is warranted.

Neuromuscular dysfunction is common in old age. A hallmark of aging is the aggregation of damaged cytoplasmic structures, especially in post‐mitotic cells like motor neurons. Autophagy flux may be impaired as a result of deficits in the formation of double membrane autophagosomes, the fusion of autophagosomes with lysosomes, or lysosome‐based degradation. Our overarching hypothesis is that autophagy contributes to neuromuscular dysfunction in old age, and that this effect occurs in motor neurons. We evaluated changes in expression levels of core autophagy proteins necessary for the initiation (Beclin1) and elongation (LC3‐I, LC3‐II, ATG7 and ATG5‐ATG12 complex) phases of autophagsome formation, as well as lysosome degradation (assessed by p62 clearance), in adult male and female C57BL/6 mice at 6, 18, and 24 months of age (reflecting 100%, 90% and 75% survival, respectively). Protein expression was analyzed by Western blotting in the cervical spinal cord segments C2–C6. Expression of p62 was reduced in the cervical spinal cord of adult mice at 18 months compared to 24 months, suggesting increased clearance and autophagy flux at 18 months of age. There was no evidence of an effect of age on the expression of the other autophagy markers. In separate animals, immunohistochemical (IHC) analyses of the C2‐C6 segments was used to determine the relative expression of LC3 and p62 in gray and white matter regions. Across all age groups, LC3 and p62 immunoreactivity was evident in the gray matter with minimal expression in the white matter. The ratio of both LC3 and p62 in motor neurons vs. gray matter was compared using a mixed linear model with animal as a random effect. No effect of sex was evident. Increased expression of both LC3 and p62 was evident in choline acetyl transferase (ChAT)‐positive motor neurons (~2–3 fold) compared to the remainder of the gray matter. There was evidence of a difference in relative LC3 and p62 expression in motor neurons across age (F 349,2 =12.5, p<0.001), with a significant increase by 24 months of age (p<0.005). Taken together, these findings suggest that 1) there is an aging effect on autophagy markers in the cervical spinal cord of mice; 2) an increase in autophagy by 18 months of age reflects an increase in autophagosome clearance (reduced p62 expression) not restricted to motor neurons; and, 3) increased motor neuron expression of both LC3 and p62 by 24 months of age reflect autophagsome accumulation and autophagy impairment in motor neurons. These findings are also is in accordance with previous reports suggesting a period of vulnerability between 18 and 24 months of age in mice, where autophagy may play a role in the development of age‐related neuromuscular dysfunction. Support or Funding Information Supported by NIH R01 AG057052.

Summary Objectives: To identify the different ethical issues that should be considered in participatory health through social media from different stakeholder perspectives (i.e., patients/service users, health professionals, health information technology (If) professionals, and policy makers) in any healthcare context. Methods: We implemented a two-round survey composed of open ended questions in the first round, aggregated into a list of ethical issues rated for importance by participants in the second round, to generate a ranked list of possible ethical issues in participatory health based on healthcare professionals’ and policy makers’ opinions on both their own point of view and their beliefs for other stakeholders’ perspectives. Results: Twenty-six individuals responded in the first round of the survey. Multiple ethical issues were identified for each perspective. Data privacy, data security, and digital literacy were common themes in all perspectives. Thirty-three individuals completed the second round of the survey. Data privacy and data security were ranked among the three most important ethical issues in all perspectives. Quality assurance was the most important issue from the healthcare professionals’ perspective and the second most important issue from the patients’ perspective. Data privacy was the most important consideration for patients/service users. Digital literacy was ranked as the fourth most important issue, except for policy makers’ perspective. Conclusions: Different stakeholders’ opinions fairly agreed that there are common ethical issues that should be considered across the four groups (patients, healthcare professionals, health IT professionals, policy makers) such as data privacy, security, and quality assurance.

AbstractObjectiveTo determine the presence of racial/ethnic differences in patients with anemia and serum folate deficiency.MethodsWe performed a retrospective analysis of data from patient samples collected from January 2010 to October 2018. Reference laboratory ranges were determined by Mayo Clinic Reference Laboratories. Race and ethnicity were classified according to National Institutes of Health categories.ResultsThe analysis comprised 197 974 samples. Hemoglobin, hematocrit, and SF results were available for 173 337, 173 056, and 129 760 samples, respectively. Of the samples, 46 505 (26.8%) showed anemia, with a higher prevalence among American Indian/Alaskan Natives (AI/AN) 42.9% and African Americans (AA) 47.2% (P < .001). SF deficiency was present in 897 (0.7%), with a higher prevalence among AI/AN (9, [1.4%]) and AA (78, [1.2%]) and a lower prevalence in non‐Hispanic whites (NHW) (758, [0.7%]), Hispanics (40, [0.6%]), and Asians (8, [0.3%]). In multivariable analysis, the prevalence of anemia was higher in all non‐NHW racial/ethnic groups: AA (OR, 3.67, [95%CI: 3.47‐3.88, P < .001]), AI/AN (OR, 3.25, [95%CI: 2.71‐3.90, P < .001]), Asians (OR, 1.62, [95%CI: 1.47‐1.77, P < .001]), and Hispanics (OR, 1.41, [95%CI: 1.32‐1.50, P < .001]). SF deficiency was more common in AA (OR, 1.48, [95%CI: 1.17‐1.88, P.001]) and less common in Asians (OR, 0.35, [95%CI: 0.17‐0.70, P = .003]), compared with NHW.ConclusionsWe showed significant racial/ethnic differences in anemia and SF deficiency. Differences were observed especially among NHW, AA, and Asians. We believe that these differences may be explained by social determinants of health. More research is needed regarding the causes of these differences and their clinical implications at a population level.

Purpose To assess the correlations between United States Medical Licensing Examination (USMLE) performance, American College of Physicians Internal Medicine In-Training Examination (IM-ITE) performance, American Board of Internal Medicine Internal Medicine Certification Exam (IM-CE) performance, and other medical knowledge and demographic variables. Method The study included 9,676 postgraduate year (PGY)-1, 11,424 PGY-2, and 10,239 PGY-3 internal medicine (IM) residents from any Accreditation Council for Graduate Medical Education–accredited IM residency program who took the IM-ITE (2014 or 2015) and the IM-CE (2015–2018). USMLE scores, IM-ITE percent correct scores, and IM-CE scores were analyzed using multiple linear regression, and IM-CE pass/fail status was analyzed using multiple logistic regression, controlling for USMLE Step 1, Step 2 Clinical Knowledge, and Step 3 scores; averaged medical knowledge milestones; age at IM-ITE; gender; and medical school location (United States or Canada vs international). Results All variables were significant predictors of passing the IM-CE with IM-ITE scores having the strongest association and USMLE Step scores being the next strongest predictors. Prediction curves for the probability of passing the IM-CE based solely on IM-ITE score for each PGY show that residents must score higher on the IM-ITE with each subsequent administration to maintain the same estimated probability of passing the IM-CE. Conclusions The findings from this study should support residents and program directors in their efforts to more precisely identify and evaluate knowledge gaps for both personal learning and program improvement. While no individual USMLE Step score was as strongly predictive of IM-CE score as IM-ITE score, the combined relative contribution of all 3 USMLE Step scores was of a magnitude similar to that of IM-ITE score.