Citations

Background: Multimorbidity is common in atrial fibrillation (AF); however, the impact of the number and type of comorbid conditions on death and hospitalizations is uncertain. Methods: The prevalence of 17 chronic conditions was obtained in 1430 patients with incident AF from 2000-2010 from Olmsted County, MN. Chronic conditions were ascertained electronically prior to AF and were classified into 3 groups: cardiovascular (CV), other physical, and mental. All hospitalizations and deaths were obtained through 12/31/2014. Associations of the number and type of condition and each individual condition with hospitalizations and death were determined using Andersen-Gill and Cox regression, respectively. Results: Among the 1430 patients with AF (median age 76 years, 48.6% men), the mean (SD) number of chronic conditions was 4.7 (2.7). A total of 4496 hospitalizations and 812 deaths occurred over a mean (SD) follow-up of 5.4 (4.1) years. An increase in the number of conditions of each type was associated with increased risks of death and hospitalizations (Table). Mental conditions (which included depression, anxiety, dementia, schizophrenia, and substance abuse) exhibited the strongest association with death, whereas other physical conditions exhibited the strongest association with hospitalizations. Individual predictors of death included heart failure (HF), hypertension, chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD), depression, dementia, and substance abuse. Predictors of hospitalizations included HF, coronary artery disease, diabetes, COPD, CKD, arthritis, osteoporosis, and substance abuse. Conclusions: Patients with AF have many comorbid conditions which are associated with death and hospitalizations. Although conditions of each type were associated with outcomes, mental conditions exhibited strongest association with death. These data highlight the importance of management of not only CV comorbidities but other physical and mental comorbidities in patients with AF.

Background: The superficial femoral artery and medial thigh region has been an underused donor site for perforator flaps. This study evaluated perforasomes of the superficial femoral artery and its principal branches to review the clinical applications for locoregional reconstruction. Methods: Twenty-six fresh cadaveric lower extremities were dissected. Perforator size and anatomical course from the superficial femoral artery, descending genicular artery, and saphenous artery branch were documented. Perforators were selectively injected with iodinated contrast to assess vascular territories using computed tomography. A retrospective chart review was conducted on consecutive patients (2014 to 2015). Results: One hundred thirty perforators were mapped in the medial thigh region. Eleven extended medial thigh perforator flaps and 15 hemicircumferential flaps were harvested. The mean distance from the joint line was 16.7 ± 7.3 cm. Perforators arose from the superficial femoral artery (62 percent), saphenous artery branch (23 percent), and descending genicular artery (15 percent). Superficial femoral artery perforators were located around the mid and proximal thigh region (p < 0.001). The median perforasome surface area was 244 cm2, representing 36 percent in hemithigh flaps with preferential filling in the anteromedial region. Proximal perforasomes were the smallest. Perforasome areas based on vessel origin were comparable; however, saphenous artery perforators had a broader perforasome compared with descending genicular (p = 0.01) and superficial femoral artery perforators (p = 0.04). Six clinical case examples were presented for knee, thigh, and lower leg reconstruction. Conclusions: The superficial femoral artery or its branches can provide nontraditional reconstructive perforator flap options in regional reconstruction. They can be simple to harvest using a free-style approach, do not require preoperative imaging, offer a one-stage reconstructive method with low morbidity, and obviate the need for microsurgery or muscle flaps.

The tyrosine kinase inhibitor sorafenib improves hepatopulmonary syndrome (HPS) in an experimental model. However, the efficacy and adverse effect profile in patients with HPS are unknown. We aimed to determine the effect of sorafenib on the alveolar‐arterial oxygen gradient (AaPO2) at 3 months in patients with HPS. We performed a randomized, double‐blind, placebo‐controlled parallel trial of sorafenib in patients with HPS at 7 centers. A total of 28 patients with HPS were randomized to sorafenib 400 mg by mouth daily or a matching placebo in a 1:1 ratio. We found no statistically significant difference in the median change in AaPO2 from baseline to 12 weeks between the patients allocated to sorafenib (4.5 mm Hg; IQR, –3.8 to 7.0 mm Hg) and those allocated to placebo (–2.4 mm Hg; IQR, –4.8 to 8.2 mm Hg; P = 0.70). There was also no difference between the groups in terms of degree of intrapulmonary shunting by contrast echocardiography. Sorafenib significantly reduced circulating levels of angiogenic markers, including vascular endothelial growth factor receptors (P < 0.01) and TIE2‐expressing M2 monocytes (P = 0.03), but it reduced the mental component scores of the Short Form 36 (P = 0.04), indicating a worse quality of life. In conclusion, sorafenib did not change the AaPO2 or other disease markers at 3 months in patients with HPS. Alternative antiangiogenic therapies or treatments targeting other pathways should be investigated.

As treatment of HIV has improved, people living with HIV (PLWH) have experienced a decreased risk of AIDS and AIDS-defining cancers (non-Hodgkin’s lymphoma, Kaposi sarcoma, and cervical cancer), but the risk of Kaposi sarcoma in PLWH is still elevated about 500-fold compared with the general population in the United States. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for AIDS-Related Kaposi Sarcoma provide diagnosis, treatment, and surveillance recommendations for PLWH who develop limited cutaneous Kaposi sarcoma and for those with advanced cutaneous, oral, visceral, or nodal disease.

It has been challenging to produce ex vivo models of the inclusion pathologies that are hallmark pathologies of many neurodegenerative diseases. Using three-dimensional mouse brain slice cultures (BSCs), we have developed a paradigm that rapidly and robustly recapitulates mature neurofibrillary inclusion and Lewy body formation found in Alzheimer’s and Parkinson’s disease, respectively. This was achieved by transducing the BSCs with recombinant adeno-associated viruses (rAAVs) that express α-synuclein or variants of tau. Notably, the tauopathy BSC model enables screening of small molecule therapeutics and tracking of neurodegeneration. More generally, the rAAV BSC “toolkit” enables efficient transduction and transgene expression from neurons, microglia, astrocytes, and oligodendrocytes, alone or in combination, with transgene expression lasting for many months. These rAAV-based BSC models provide a cost-effective and facile alternative to in vivo studies, and in the future can become a widely adopted methodology to explore physiological and pathological mechanisms related to brain function and dysfunction.

How dipeptide repeats cause pathology A repeat expansion in the chromosome 9 open reading frame 72 ( C9orf72 ) gene is the most common known cause of two neurodegenerative diseases: frontotemporal dementia and amyotrophic lateral sclerosis. This expansion leads to the abnormal production of proteins of repeating dipeptides, but their contribution to disease pathogenesis remains unclear. Zhang et al. engineered a mouse model to study the consequences of one of these dipeptides—prolinearginine dipeptide repeat protein, poly(PR)—in the brain. They found that poly(PR) caused neuron loss as well as motor and memory impairments. These detrimental effects resulted from poly(PR)-induced perturbation of heterochromatin function, a tightly packed form of DNA that represses gene expression. Science , this issue p. eaav2606

ABSTRACTObjectives:The aim of the present study was to investigate the natural history of chronic pancreatitis (CP); patients in the North American Pancreatitis Study2 (NAPS2, adults) and INternational Study group of Pediatric Pancreatitis: In search for a cuRE (INSPPIRE, pediatric) were compared.Methods:Demographics, risk factors, disease duration, management and outcomes of 224 children and 1063 adults were compared using appropriate statistical tests for categorical and continuous variables.Results:Alcohol was a risk in 53% of adults and 1% of children (P < 0.0001); tobacco in 50% of adults and 7% of children (P < 0.0001). Obstructive factors were more common in children (29% vs 19% in adults, P = 0.001). Genetic risk factors were found more often in children. Exocrine pancreatic insufficiency was similar (children 26% vs adult 33%, P = 0.107). Diabetes was more common in adults than children (36% vs 4% respectively, P < 0.0001). Median emergency room visits, hospitalizations, and missed days of work/school were similar across the cohorts. As a secondary analysis, NAPS2 subjects with childhood onset (NAPS2‐CO) were compared with INSPPIRE subjects. These 2 cohorts were more similar than the total INSPPIRE and NAPS2 cohorts, including for genetic risk factors. The only risk factor significantly more common in the NAPS2‐CO cohort compared with the INSPPIRE cohort was alcohol (9% NAPS2‐CO vs 1% INSPPIRE cohorts, P = 0.011).Conclusions:Despite disparity in age of onset, children and adults with CP exhibit similarity in demographics, CP treatment, and pain. Differences between groups in radiographic findings and diabetes prevalence may be related to differences in risk factors associated with disease and length of time of CP.

Introduction: Cerebral small-vessel disease (SVD) is associated with increased stroke risk and poor stroke outcomes. We aimed to evaluate if chronic SVD burden is associated with poor recruitment of collaterals in large-vessel occlusive stroke. Methods: Consecutive patients with MCA±ICA occlusion presenting within 6 hours after stroke symptoms onset from 2012- 2016 were included. Primary outcome was collateral flow, which was assessed on baseline CT-angiogram (poor ≤50% filling, good >50% filling). Markers of chronic SVD on brain MRI were rated for the presence of WMH (Fazekas scale 2-3), enlarged perivascular spaces (EPVS), chronic lacunae, and any cerebral microbleeds (CMB) using the STRIVE criteria. Severity of SVD was quantified by adding the presence of each SVD feature to a maximum score of 4. Multivariable logistic regression models were performed to evaluate the relationships between SVD and poor collaterals. Results: Of the 100 patients, the mean age was 65±16, median NIHSS was 15, and 68% had SVD. Poor collaterals were observed in 46%, and those with SVD were more likely to have poor collaterals (aOR 1.9; 95%CI 1.1-3.2) than patients without SVD. Of the SVD types, poor collaterals were associated with WMH (aOR 2.9 per Fazekas increment; 95%CI 1.6-5.3) but not EPVS (aOR 1.3; 0.4-4.0), lacunae (aOR 2.1; 0.6-7.1), or CMB (aOR 2.1; 0.6-7.8). Having a greater number of different SVD markers was associated with a higher odds of poor collaterals (crude trend p<.001; adjusted p=.056). There was a dose-dependent relationship between WMH burden and poor collaterals: adjusted odds of poor collaterals were 1.5, 3.0, and 9.7 across Fazekas scores of 1-3 (trends P=.015, Table). No patient with SVD score of 4 had good collaterals. Conclusions: Chronic cerebral small-vessel disease is associated with poor recruitment of collaterals in large-vessel occlusive stroke. A prospective study to elucidate the mechanism of how SVD may impair the recruitment of collaterals is ongoing.

Introduction: Robust leptomeningeal collaterals protect brain from ischemia, yet the determinants of poor collaterals remains unclear. We aimed to identify predictors of poor collaterals in patients with large-vessel occlusive stroke. Methods: We analyzed 112 consecutive patients with middle cerebral artery ± internal carotid artery occlusion from 2012-2016 who presented within 6 hours after stroke symptoms onset. Collaterals on baseline CT-angiogram (poor collaterals ≤50% filling, good collaterals >50% filling) were reviewed blinded to clinical data. Pre-specified predictors of poor collaterals were analyzed with adjusted logistic regression models: including known predictors (age, vascular risk factors and metabolic derangements) and hypothesized predictors (low cardiac output, elevated inflammatory markers, and imaging evidence for chronic cerebral small-vessel disease and chronic steno-occlusive arterial disease). Results: The mean age was 67± 16 years, there were 48% women, 57% white, and median NIHSS was 15 (IQR 11-20). Poor collaterals at baseline were detected in 48%. Multivariable modeling identified that age (aOR 1.8 per 10 years; 95% CI 1.3-2.6; p<0.001), black race (aOR 2.1; 95% CI 1.0-4.5; p=0.043), high blood glucose level (aOR 2.4 per 100 mg/dl; 95% CI 1.1-5.1; p=0.029), and high WMH burden (aOR 6.1; 95%CI 1.8-20.4; p=0.003) were independent predictors of poor collaterals. Associations between low cardiac output, elevated inflammatory markers, intracranial atherosclerosis and poor collaterals did not reach statistical significance (Table). Conclusions: We have identified that advanced age, black race, hyperglycemia, and white matter hyperintensities are predictors of poor collaterals. Independent replication study at another institution is ongoing to further explore the hypothesized predictors.