Citations

Abstract Background Stenotrophomonas maltophilia is a gram-negative, opportunistic infection that is usually hospital-acquired and associated with high morbidity and mortality. The reported increase in S. maltophilia infections is presumed to be due to an increase in the population at risk. Methods We retrospectively reviewed 10-year data for S. maltophilia bacteremia in hospitalized adults at our institution to determine the population at risk, sources of infection, common complications, antimicrobial susceptibility profiles, and clinical outcome trends over the past decade. Results Among the 98 patients analyzed, the most common source of infection was catheter-related (62, 63.3%). Most isolates (61, 65%) were resistant to ceftazidime; fewer were resistant to trimethoprim-sulfamethoxazole (TMP-SMX; 2, 2.1%) and levofloxacin (22, 23.4%). All-cause in-hospital mortality was 29.6% (29 patients). The highest mortality, 53.8%, was observed in pulmonary sources of bacteremia. Conclusions Although TMP-SMX continues to have reliable activity in our cohort, we noted resistance to TMP-SMX in patients with recent TMP-SMX exposure, including a case with developing resistance to TMP-SMX while on therapy.

Background The epidemiological transition of non-communicable diseases replacing infectious diseases as the main contributors to disease burden has been well documented in global health literature. Less focus, however, has been given to the relationship between sociodemographic changes and injury. The aim of this study was to examine the association between disability-adjusted life years (DALYs) from injury for 195 countries and territories at different levels along the development spectrum between 1990 and 2017 based on the Global Burden of Disease (GBD) 2017 estimates. Methods Injury mortality was estimated using the GBD mortality database, corrections for garbage coding and CODEm—the cause of death ensemble modelling tool. Morbidity estimation was based on surveys and inpatient and outpatient data sets for 30 cause-of-injury with 47 nature-of-injury categories each. The Socio-demographic Index (SDI) is a composite indicator that includes lagged income per capita, average educational attainment over age 15 years and total fertility rate. Results For many causes of injury, age-standardised DALY rates declined with increasing SDI, although road injury, interpersonal violence and self-harm did not follow this pattern. Particularly for self-harm opposing patterns were observed in regions with similar SDI levels. For road injuries, this effect was less pronounced. Conclusions The overall global pattern is that of declining injury burden with increasing SDI. However, not all injuries follow this pattern, which suggests multiple underlying mechanisms influencing injury DALYs. There is a need for a detailed understanding of these patterns to help to inform national and global efforts to address injury-related health outcomes across the development spectrum.

Abstract Background: Lung cancer kills more people than any other cancer in the United States. In addition to environmental factors, lung cancer has genetic risk factors as well, though the genetic etiology is still not well understood. We have performed whole exome sequencing on 262 individuals from 28 extended families with a family history of lung cancer. Methods: Parametric genetic linkage analysis was performed on these samples using two distinct analyses—the lung cancer only (LCO) analysis, where only patients with lung cancer were coded as affected, and the all aggregated cancers (AAC) analysis, where other cancers seen in the pedigree were coded as affected. Results: The AAC analysis yielded a genome-wide significant result at rs61943670 in POLR3B at 12q23.3. POLR3B has been implicated somatically in lung cancer, but this germline finding is novel and is a significant expression quantitative trait locus in lung tissue. Interesting genome-wide suggestive haplotypes were also found within individual families, particularly near SSPO at 7p36.1 in one family and a large linked haplotype spanning 4q21.3-28.3 in a different family. The 4q haplotype contains potential causal rare variants in DSPP at 4q22.1 and PTPN13 at 4q21.3. Conclusions: Regions on 12q, 7p, and 4q are linked to increased cancer risk in highly aggregated lung cancer families, 12q across families and 7p and 4q within a single family. POLR3B, SSPO, DSPP, and PTPN13 are currently the best candidate genes. Impact: Functional work on these genes is planned for future studies and if confirmed would lead to potential biomarkers for risk in cancer.

Abstract Aims As health systems around the world increasingly look to measure and improve the value of care that they provide to patients, being able to measure the outcomes that matter most to patients is vital. To support the shift towards value-based health care in atrial fibrillation (AF), the International Consortium for Health Outcomes Measurement (ICHOM) assembled an international Working Group (WG) of 30 volunteers, including health professionals and patient representatives to develop a standardized minimum set of outcomes for benchmarking care delivery in clinical settings. Methods and results Using an online-modified Delphi process, outcomes important to patients and health professionals were selected and categorized into (i) long-term consequences of disease outcomes, (ii) complications of treatment outcomes, and (iii) patient-reported outcomes. The WG identified demographic and clinical variables for use as case-mix risk adjusters. These included baseline demographics, comorbidities, cognitive function, date of diagnosis, disease duration, medications prescribed and AF procedures, as well as smoking, body mass index (BMI), alcohol intake, and physical activity. Where appropriate, and for ease of implementation, standardization of outcomes and case-mix variables was achieved using ICD codes. The standard set underwent an open review process in which over 80% of patients surveyed agreed with the outcomes captured by the standard set. Conclusion Implementation of these consensus recommendations could help institutions to monitor, compare and improve the quality and delivery of chronic AF care. Their consistent definition and collection, using ICD codes where applicable, could also broaden the implementation of more patient-centric clinical outcomes research in AF.

Here, we provide a first comparative study of the therapeutic potential of allogeneic mesenchymal stem cells derived from bone marrow (BM-MSCs), adipose tissue (AD-MSCs), and dental pulp (DP-MSCs) embedded in fibrin matrix, in small (rat) and large (pig) spinal cord injury (SCI) models during subacute period of spinal contusion. Results of behavioral, electrophysiological, and histological assessment as well as immunohistochemistry and real-time polymerase chain reaction analysis suggest that application of AD-MSCs combined with a fibrin matrix within the subacute period in rats (2 weeks after injury), provides significantly higher post-traumatic regeneration compared to a similar application of BM-MSCs or DP-MSCs. Within the rat model, use of AD-MSCs resulted in a marked change in: (1) restoration of locomotor activity and conduction along spinal axons; (2) reduction of post-traumatic cavitation and enhancing tissue retention; and (3) modulation of microglial and astroglial activation. The effect of an autologous application of AD-MSCs during the subacute period after spinal contusion was also confirmed in pigs (6 weeks after injury). Effects included: (1) partial restoration of the somatosensory spinal pathways; (2) reduction of post-traumatic cavitation and enhancing tissue retention; and (3) modulation of astroglial activation in dorsal root entry zone. However, pigs only partially replicated the findings observed in rats. Together, these results indicate application of AD-MSCs embedded in fibrin matrix at the site of SCI during the subacute period can facilitate regeneration of nervous tissue in rats and pigs. These results, for the first time, provide robust support for the use of AD-MSC to treat subacute SCI.

Objective Since comorbidities such as autoimmune diseases may be associated with rheumatoid arthritis (RA) risk, we hypothesized that a family history of these other conditions might also predict RA. Therefore, we aimed to determine the association between family history of 79 comorbidities and RA. Methods This case–control study identified 821 cases of RA in the Mayo Clinic Biobank (positive predictive value 95%) and matched 3 controls to each case based on age, sex, recruitment year, and location. Patients self reported family history and characteristics (adjusted). Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs) for RA risk according to the presence of family history for each comorbidity, adjusted for body mass index, race, and smoking. Results Family history of several conditions was associated with developing RA, including rheumatic autoimmune diseases (OR adj 1.89 [95% CI 1.41–2.52]), pulmonary fibrosis (OR adj 2.12 [95% CI 1.16–3.80]), inflammatory bowel disease (OR adj 1.45 [95% CI 1.05–1.98]), hyper/hypothyroidism (OR adj 1.34 [95% CI 1.10–1.63]), and obstructive sleep apnea (OR adj 1.28 [95% CI 1.05–1.55]). Parkinson’s disease and type 2 diabetes mellitus were associated with a statistically decreased risk of RA that did not reach the prespecified significance threshold of P < 0.01 (OR adj 0.70 [95% CI 0.49–0.98] and OR adj 0.81 [95% CI 0.67–0.97], respectively). Analyses among 143 cases of incident RA were similar and also suggested an association with a family history of autism (OR 10.5 [95% CI 2.51–71.3]). Conclusion Family history of several autoimmune and nonautoimmune comorbidities was associated with increased risk of RA, providing an opportunity to identify novel populations at risk for RA.

Abstract Philadelphia-negative Myeloproliferative Neoplasms (MPN), including Polycythemia Vera (PV), Essential Thrombocythemia (ET), Myelofibrosis (Primary [PMF] and secondary to PV and ET [PPV-, PET-MF] and unclassified MPN (U-MPN), are associated with an increased risk of venous thrombosis in unusual sites, such as splanchnic vessels (SVT). SVT can lead to complications such as portal hypertension, esophageal and gastric varices, ascites,hepatic failure and biliopathy. According to a meta-analysis MPN is the underlying cause of portal vein thrombosis (PVT) in 31.5% and Budd Chiari syndrome (BCS) in 40.9% of cases (Smalberg, 2012); a more in-depth analysis of clinical characteristics and evolution of MPN-associated SVT has been hampered by heterogeneity of cohorts comprising small number of cases. We conducted a retrospective multicenter study in patients (pts) with SVT associated with WHO2008-diagnosed MPN, with the aim to describe patient characteristics, disease course and prognostic factors with potential implications for clinical practice. Data were collected from 16 international hematologic centers in the framework of the Italian AGIMM and the IWG-MRT groups. We collected 519 cases of pts with PVT, splenic or mesenteric vein thrombosis (75.1%) and BCS (24.9%) associated with MPN. We used as comparator a cohort of 1686 controls (Ctr) represented by MPN without (w/o) SVT: 741 ET (43.9%), 684 PV (39.7%), 261 PMF (15.5%). Frequency of MPN associated with SVT was 37.8% ET (n=196), 36.8% PV (n=191), 15.4% MF (n=80), 10% U-MPN (n=52). Median follow-up was 89.9 months (mo) (range 0.5-430). For SVT vs Ctr group females were 54.5% vs 44.4% in PV (P=0.001), 68.4 vs 63.5% (p=0.13) in ET, 63.7% vs 29.1% in PMF (p<0.0001); median age at MPN diagnosis (dg) was 43.5 yr (range 12-90) vs 60.6 yr (range 12-93) (p<0.0001). Age at SVT dg was 44 yr (range 15-85). In 240 cases (46.7%) MPN and SVT dg were coincident, in 121 (23.6%) SVT occurred before MPN dg (median 26 mo, range 4-307) and in 153 (29.8%) during MPN follow up (median 68 mo, range 4-362). JAK2V617F mutation was found in 94% PV vs 94% in Ctr, 84% vs 61% ET (p<0.0001), 88.1% vs 68% PMF (p=0.006) and in 93% U-MPN. Erythropoietin-independent colonies (EEC) were evaluated in 111 SVT pts and found in 80 (72%), accounting for 38/48 PV (79%), 31/44 ET (70.5%), 9/12 PMF (75%) and 2/7 U-MPN (28.6%). At dg, SVT PV pts had lower hemoglobin levels than Ctr: median was 17.4 g/dL vs 18.5 g/dL (p<0.0001) in male, 16.9 g/dL vs 17.7 g/dL (p=0.0006) in female. A co-existing thrombophilic status was found in 38.5% SVT vs 11.8% of Ctr (p<0.0001). Recurrent SVT occurred in 12.2% of pts with a rate of 1.6% person/year (CI 1.2-2.1); risk of venous thrombosis other than SVT was increased in SVT group vs Ctr (p=0.02), with no difference for arterial thrombosis. Hemorrhage was more frequent in SVT group (32%) vs Ctr (7.2%)(p<0.0001), mainly related to esophageal varices, which were present in 66.9% of SVT pts. There was no difference in evolution to MF and acute leukemia (AL) for PV and ET pts with and w/o SVT, while risk of AL was lower in MF with SVT (p<0.00001). Overall survival was shorter in ET pts with SVT vs Ctr (p<0.0001). In PMF survival was better in SVT group (p<0.00001) and was associated with a higher proportion of SVT pts in lowest risk categories: IPSS low 65%, intermediate-1 20%, intermediate-2 10% and high 5% compared with 15%, 34%, 25% and 26% in Ctr group. At last FU, 79/519 pts (15.2%) had died; causes of death were evolution to AL (15.4%), other cancers (13.8%), disease progression without AL (10.8%), SVT (10.8%), hepatic failure and venous thrombosis other than SVT (7.7% each), heart failure and arterial thrombosis (6.2% each), hemorrhage (5.5%), renal failure and infection (4.6% each). Therapy after SVT included anticoagulation in 77%, antiaggregant in 21.2% and combination in 1.8%; 70% received cytotoxic drugs; 12.4% were treated with transjugular porto-systemic shunt. Beta blocker therapy was used in 48.5% of pts and correlated with improved survival (p=0.041) MPN associated with SVT correlated with younger age and female sex and might antedate the clinical phenotype in a quarter of the patients. MPN-associated SVT equally affected PV and ET, was more likely to occur in the presence of JAK2V617F or underlying thrombophilia and predicted recurrent venous but not arterial thrombosis. The apparent association of SVT with better or worse prognosis in PMF and ET, respectively, requires further investigation. Disclosures No relevant conflicts of interest to declare.

Background and purposeThe long‐term outcomes and stroke recurrence after basilar artery occlusion (BAO) are largely unknown. We aimed to assess these variables in a comparatively large series of consecutive patients.MethodsAdults with acute BAO were retrospectively identified from 1976 to 2011. Post‐discharge records were reviewed to assess for stroke recurrences, mortality and disability. Exploratory analysis of survival was carried out using Kaplan–Meier and log‐rank tests. Factors associated with survival time were determined using Cox models.ResultsA total of 86 patients (34% female, median age 72 [interquartile range (IQR), 60–79] years) with a median National Institutes of Health Stroke Scale score of 11 (IQR, 6–27) were included. Twenty‐nine patients (34%) died during the initial hospitalization. Median modified Rankin Scale (mRS) score at discharge among survivors was 4 (IQR, 2.5–5.5). At 1 and 5 years, 70% of survivors ad a mRS ≤3. Seventeen patients had recurrent strokes during the hospitalization and 12 patients had 19 recurrent strokes after discharge. The median survival time was 52 days (IQR, 6–1846). Older age per decade on admission [adjusted hazard ratios (aHR), 1.32; 95% confidence interval (CI), 1.05–1.66, P = 0.02] and a higher mRS at discharge (aHR, 4.48; 95% CI, 2.72–7.39, P < 0.0001) were associated with mortality. Patients who were not treated with any reperfusion therapy had a trend towards reduced mortality (aHR, 0.39; 95% CI, 0.14–1.08, P = 0.07).ConclusionsSurvivors from BAO had severe short‐term functional disability. Most deaths and stroke recurrences occurred within the first year following the initial event. The risk of death was higher in older and more disabled survivors. However, favorable long‐term recovery was possible.

AbstractMyeloproliferative Neoplasms (MPN) course can be complicated by thrombosis involving unusual sites as the splanchnic veins (SVT). Their management is challenging, given their composite vascular risk. We performed a retrospective, cohort study in the framework of the International Working Group for MPN Research and Treatment (IWG‐MRT), and AIRC‐Gruppo Italiano Malattie Mieloproliferative (AGIMM). A total of 518 MPN‐SVT cases were collected and compared with 1628 unselected, control MPN population, matched for disease subtype. Those with MPN‐SVT were younger (median 44 years) and enriched in females compared to controls; PV (37.1%) and ET (34.4%) were the most frequent diagnoses. JAK2V617F mutation was highly prevalent (90.2%), and 38.6% of cases had an additional hypercoagulable disorder. SVT recurrence rate was 1.6 per 100 patient‐years. Vitamin K‐antagonists (VKA) halved the incidence of recurrence (OR 0.48), unlike cytoreduction (OR 0.96), and were not associated with overall or gastrointestinal bleeding in multivariable analysis. Esophageal varices were the only independent predictor for major bleeding (OR 17.4). Among MPN‐SVT, risk of subsequent vascular events was skewed towards venous thromboses compared to controls. However, MPN‐SVT clinical course was overall benign: SVT were enriched in PMF with lower IPSS, resulting in significantly longer survival than controls; survival was not affected in PV and slightly reduced in ET. MPN‐U with SVT (n = 55) showed a particularly indolent phenotype, with no signs of disease evolution. In the to‐date largest, contemporary cohort of MPN‐SVT, VKA were confirmed effective in preventing recurrence, unlike cytoreduction, and safe; the major risk factor for bleeding was esophageal varices that therefore represent a major therapeutic target.