Citations

AbstractBackgroundColony‐stimulating factor‐1 receptor (CSF1R)‐related leukoencephalopathy is a rapidly progressive neurodegenerative disease for which there is currently no cure. Hematopoietic stem cell transplantation (HSCT) has been proposed as a disease‐modifying treatment.ObjectiveThe objective of this study was to determine the effect of HSCT on disease progression.MethodsWe collected all available clinical data from a cohort of 7 patients with CSF1R‐related leukoencephalopathy who underwent HSCT at our institutions. Clinical data included detailed neurological examination by a board‐certified neurologist, serial cognitive screens, formal neuropsychological evaluations, and serial brain magnetic resonance imaging (MRI).ResultsOur patients had an average disease duration of 27.6 months at the time of transplant, and we have 87 months of total posttransplant follow‐up time (median, 11; range, 2–27). One patient died in the periprocedural period. The remaining patients showed a variable response to treatment, with 6 of 7 patients trending toward stabilization on motor examination, cognitive scores, and/or MRI abnormalities, especially with white matter lesion burden.ConclusionsThis is the largest series of patients with CSF1R‐related leukoencephalopathy receiving HSCT. We conclude that HSCT can stabilize the disease in some patients. Variability in patient responsiveness suggests that measures of disease heterogeneity and severity need to be considered when evaluating a patient's candidacy for transplant. HSCT appears to be the first disease‐modifying therapy for CSF1R‐related leukoencephalopathy. This milestone may serve as a foothold toward better understanding the disease's pathomechanism, thus providing new opportunities for better disease‐specific therapies. © 2021 International Parkinson and Movement Disorder Society

Abstract Background: Use of menopausal hormone therapy (MHT) is associated with increased risk for breast cancer. However, the relevant mechanisms and its interaction with genetic variants are not fully understood. Methods: We conducted a genome-wide interaction analysis between MHT use and genetic variants for breast cancer risk in 27,585 cases and 34,785 controls from 26 observational studies. All women were post-menopausal and of European ancestry. Multivariable logistic regression models were used to test for multiplicative interactions between genetic variants and current MHT use. We considered interaction p-values<5x10-8 as genome-wide significant, and p-values<1x10-5 as suggestive. Linkage disequilibrium (LD)-based clumping was performed to identify independent candidate variants.Results: None of the 9.7 million genetic variants tested for interactions with MHT use reached genome-wide significance. Only 213 variants, representing 18 independent loci, had p-values<1x105. The strongest evidence was found for rs4674019 (p-value=2.27x10-7), which showed genome-wide significant interaction (p-value=3.8x10-8) with current MHT use when analysis was restricted to population-based studies only. Limiting the analyses to combined estrogen-progesterone MHT use only or to estrogen receptor (ER) positive cases did not identify any genome-wide significant evidence of interactions. Conclusions: In this large genome-wide SNP-MHT interaction study of breast cancer, we found no strong support for common genetic variants modifying the effect of MHT on breast cancer risk. These results suggest that common genetic variation has limited impact on the observed MHT–breast cancer risk association.

Background Analysis of current and past reimbursement patterns for federally funded programs is crucial to develop sustainable future payment models. Methods The Centers for Medicare and Medicaid Services Physician Fee Schedule was used to evaluate 26 common ophthalmic plastic and reconstructive surgery (OPRS) procedures. From 2010 to 2019, compound annual growth rate, total percent change, and annual percent change were calculated using inflation-adjusted reimbursement rates. Centers for Medicare and Medicaid Services’ Physician/Supplier Procedure Summary was used to assess the surgical volume of the 26 procedures in ophthalmology and plastic surgery services. Results From 2010 to 2019, total billed surgical procedures in OPRS decreased by 57.0%, affecting both ophthalmologists (−54.3%) and plastic surgeons (−80.1%). Over the study period, inflation-adjusted reimbursement rates decreased by 5.6%. Compound annual growth rate was −0.66%, and annual percent change was −0.62%. From 2010 to 2013, reimbursement rates increased by 1.8% each year. In contrast, from 2013 to 2019, reimbursement rates decreased by 1.7% each year (P < 0.0001). Conclusions From 2010 to 2019, Medicare utilization has substantially declined for OPRS procedures. Inflation-adjusted Medicare reimbursement rates have decreased for the majority of common procedures since 2013. Surgeons and policymakers need to be aware of these trends to ensure future availability of subspecialty surgical services.

AbstractAimsCardiogenic shock (CS) is a state of low cardiac output resulting in end-organ hypoperfusion. Despite high in-hospital mortality rates, little evidence exists regarding the optimal mean arterial pressure (MAP) target in CS. We therefore evaluated the relationship between achieved MAP and clinical outcomes in patients with CS.Methods and resultsWe performed a post hoc analysis of the CAPITAL DOREMI trial: a randomized, double-blind trial comparing dobutamine to milrinone in patients with CS. We divided patients into a high MAP group (average MAP ≥ 70 mmHg over the 36 h following randomization), and a low MAP group (average MAP &lt; 70 mmHg). Our primary outcome included in-hospital all-cause mortality, resuscitated cardiac arrest, need for cardiac transplantation or mechanical circulatory support, non-fatal myocardial infarction, transient ischaemic attack or stroke, or initiation of renal replacement therapy. In total, 71 (37.0%) patients achieved an average MAP &lt; 70 mmHg, and 121 (63.0%) achieved an average MAP ≥ 70 mmHg. The primary outcome occurred in 48 (67.6%) patients in the low MAP group and 51 (42.2%) patients in the high MAP group [adjusted relative risk (aRR) 0.70; 95% confidence interval (CI) 0.53–0.92; P = 0.01]. All-cause mortality occurred in 41 (57.8%) and 35 (28.9%) patients in the low and high MAP groups, respectively (aRR 0.56; 95% CI 0.40–0.79; P &lt; 0.01). There were no significant differences in any secondary outcomes between each group.ConclusionsIn patients with CS treated with inotrope therapy, low MAP is associated with worse clinical outcomes. Randomized data evaluating optimal MAP targets in CS is needed to guide medical therapy.

Abstract BackgroundCopy number variants (CNVs) are pervasive in the human genome but potential disease associations with rare CNVs have not been comprehensively assessed in large datasets. We analysed rare CNVs in genes and non-coding regions for 86,788 breast cancer cases and 76,122 controls of European ancestry with genome-wide array data.ResultsGene burden tests detected the strongest association for deletions in BRCA1 (P= 3.7E-18). Nine other genes were associated with a p-value < 0.01 including known susceptibility genes CHEK2 (P= 0.0008), ATM (P= 0.002) and BRCA2 (P= 0.008). Outside the known genes we detected associations with p-values < 0.001 for either overall or subtype-specific breast cancer at nine deletion regions and four duplication regions. Three of the deletion regions were in established common susceptibility loci.ConclusionsThis is the first genome-wide analysis of rare CNVs in a large breast cancer case-control dataset. We detected associations with exonic deletions in established breast cancer susceptibility genes. We also detected suggestive associations with non-coding CNVs in known and novel loci with large effects sizes. Larger sample sizes will be required to reach robust levels of statistical significance.

Transforming growth factor beta (TGF‐β) is an enigmatic protein with various roles in normal tissue homeostasis/development as well as the development and/or progression of cancer, wound healing, fibrotic disorders, and immune modulation, to name a few. As TGF‐β is causal to various fibroproliferative disorders featuring localized or systemic tissue/organ fibrosis as well as the activated stroma observed in numerous malignancies, characterizing the pathways and players mediating its action is fundamental. To that end, in the current study we found that (i) TGF‐β induces the expression of the immunoinhibitory molecule Programmed Death‐Ligand 1 (PD‐L1) in human and murine fibroblasts in a Smad2/3‐dependent manner; (ii) profibrotic TGF‐β signaling is dependent upon PD‐L1 expression; and (iii) following treatment with TGF‐β, human lung fibroblasts secrete PD‐L1 into extracellular vesicles (EVs) capable of inhibiting T‐cell proliferation in response to T cell receptor stimulation. These findings provide new insights and potential targets for a variety of fibrotic and/or malignant diseases. Support or Funding Information This work was supported by Public Health Service grants GM‐55816 and GM‐54200 from the National Institute of General Medical Sciences. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

Transforming growth factor beta (TGF‐β) plays a significant role in diverse biologic processes, including the regulation of cell growth, survival, differentiation, development, inflammation, immunity, hematopoiesis, and tissue remodeling. TGF‐β is essential for wound healing, stimulates matrix molecule deposition, and has been implicated in the pathogenesis of a variety of fibrotic disorders, including idiopathic pulmonary fibrosis, scleroderma, radiation‐induced pulmonary fibrosis, and asthma. Furthermore, activation of profibrotic TGF‐β signaling has a central role in glucose‐induced cell hypertrophy, induces glucose transporter 1, and regulates mitochondrial energetics. However, the mechanisms by which TGF‐β induces specific metabolic alterations in the fibrogenic process have not been fully defined. In this study, we demonstrate that TGF‐β stimulates type I TGF β receptor (TβRI) translocation to the mitochondria and induction of hexokinase 2 (HK2) via both Smad‐dependent and –independent pathways. Also, we showed that TbRI association with HK2 and the mitochondrial voltage‐dependent ion channel (VDAC). These findings suggest that TβRI plays a novel role in controlling mitochondrial function and regulation of glucose metabolism. Support or Funding Information This work was supported by Public Health Service grants GM‐055816 and GM‐054200 from the National Institutes of General Medical Sciences. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

Background Elective percutaneous coronary intervention (PCI) is performed to relieve symptoms of angina. Identifying patients who will benefit symptomatically after PCI would be clinically advantageous but robust predictors of symptom resolution are ill-defined. Methods Prospective indexing of baseline angina status, clinical, and procedural characteristics were collected over a 5-year period in a regional revascularization registry. At 1-year follow-up, angina resolution was assessed. We performed a stepwise selection algorithm to identify predictors of persistent angina at 1 year. Results A total of 777 patients were included in the analysis and the median follow-up was 387 days. Mean age of the cohort was 66.6 years, 23.8% were female and 23.3% had baseline Canadian Cardiovascular Society class 3 or 4 angina. Overall, 13.1% had persistent angina. The only predictor of persistent angina was the presence of a residual chronic total occlusion after PCI with odds ratio of 3.06 (95% confidence interval, 1.81–5.17). Residual stenoses 50–69%, 70–89%, and 90–99% were not associated with residual angina after PCI. Conclusion Most patients achieved symptom resolution with PCI and optimal medical therapy. A residual chronic total occlusion after PCI was associated with persistent angina. Other degrees of stenoses were not associated with persistent angina.

Introduction Despite extensive studies on the relationship between diabetes mellitus (DM) and depression, the associations of depressive symptom severity with prevalence, awareness, treatment, and control of diabetes remain unclear. We aimed to investigate changes in these outcomes of diabetes as depressive symptoms aggravate. Research design and methods We conducted a cross-sectional analysis of 14 328 participants in the 2011–2016 National Health and Nutrition Examination Survey. Participants were classified into depressive symptom groups of none, mild, moderate, moderately severe, and severe depending on their Patient Health Questionnaire-9 scores. Multivariate logistic regression analyses were conducted in three models adjusted for expanding confounders to evaluate the associations between severity of depressive symptoms and prevalence, awareness, treatment, and control of DM. Results As depressive symptom severity worsened, both prevalence and awareness of DM increased regardless of models (p value for trend <0.01 in all models for prevalence and awareness; adjusted OR (aOR) 2.14, 95% CI 1.29 to 3.56 for prevalence in the severe group, model 1; aOR 2.43, 95% CI 1.27 to 4.64 for awareness in the moderately severe group, model 1). Notwithstanding higher awareness of diabetes in the moderately severe and severe groups (84.5% and 86.2%, respectively, vs 71.3% in the none group), these groups were treated less (aOR 0.25, 95% CI 0.11 to 0.55 in the severe group, model 3) or inadequately controlled (aOR 0.51, 95% CI 0.27 to 0.98 in the moderately severe group, model 3). Conclusions The gap between patients’ higher awareness and lower treatment rate or control of diabetes among individuals with severe depressive symptoms highlights the unmet needs for postdiagnostic multidisciplinary care for patients with comorbid depression and DM.