Citations

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.

PURPOSE RTOG 0617 compared standard-dose (SD; 60 Gy) versus high-dose (HD; 74 Gy) radiation with concurrent chemotherapy and determined the efficacy of cetuximab for stage III non–small-cell lung cancer (NSCLC). METHODS The study used a 2 × 2 factorial design with radiation dose as 1 factor and cetuximab as the other, with a primary end point of overall survival (OS). RESULTS Median follow-up was 5.1 years. There were 3 grade 5 adverse events (AEs) in the SD arm and 9 in the HD arm. Treatment-related grade ≥3 dysphagia and esophagitis occurred in 3.2% and 5.0% of patients in the SD arm v 12.1% and 17.4% in the HD arm, respectively ( P = .0005 and < .0001). There was no difference in pulmonary toxicity, with grade ≥3 AEs in 20.6% and 19.3%. Median OS was 28.7 v 20.3 months ( P = .0072) in the SD and HD arms, respectively, 5-year OS and progression-free survival (PFS) rates were 32.1% and 23% and 18.3% and 13% ( P = .055), respectively. Factors associated with improved OS on multivariable analysis were standard radiation dose, tumor location, institution accrual volume, esophagitis/dysphagia, planning target volume and heart V5. The use of cetuximab conferred no survival benefit at the expense of increased toxicity. The prior signal of benefit in patients with higher H scores was no longer apparent. The progression rate within 1 month of treatment completion in the SD arm was 4.6%. For comparison purposes, the resultant 2-year OS and PFS rates allowing for that dropout rate were 59.6% and 30.7%, respectively, in the SD arms. CONCLUSION A 60-Gy radiation dose with concurrent chemotherapy should remain the standard of care, with the OS rate being among the highest reported in the literature for stage III NSCLC. Cetuximab had no effect on OS. The 2-year OS rates in the control arm are similar to the PACIFIC trial.

Abstract Background We assessed glioma incidence and disparities in postglioma survival rate in the Olmsted County, Minnesota, population. Methods This population-based study assessed the incidence of pathologically confirmed primary gliomas between January 1, 1995, and December 31, 2014. Age- and sex-adjusted incidence rates per 100 000 person-years were calculated and standardized to the US white 2010 population. We compared incidence trends of glioma during our study period with previously published Olmsted County data from 1950 to 1990. We assessed postglioma survival rates among individuals with different socioeconomic status (SES), which was measured by a validated individual HOUsing-based SES index (HOUSES). Results We identified 135 incident glioma cases (93% white) with 20 pediatric (50% female) and 115 adult cases (44% female). Overall incidence rate during our study period, 5.51 per 100 000 person-years (95% CI: 4.56-6.46), showed no significant changes and was similar to that seen in 1950 to 1990, 5.5 per 100 000 person-years. The incidence of pediatric (age &lt; 20 years) glioma was 2.49 (95% CI: 1.40-3.58), whereas adult glioma incidence was 6.47 (95% CI: 5.26-7.67). Among those with grade II to IV gliomas, individuals with lower SES (&lt; median HOUSES) had significantly lower 5-year survival rates compared to those with higher SES, adjusted hazard ratio 1.61 (95% CI: 1.01-2.85). Conclusion In a well-defined North American population, long-term glioma incidence appears stable since 1950. Significant socioeconomic disparities exist for postglioma survival.

AbstractAimEosinophilic fasciitis (EF) is a rare, fibrosing disorder of skin and subcutaneous tissue. This study was undertaken to describe its clinical and laboratory features and identify prognostic factors associated with outcome.MethodsWe conducted a retrospective review of all EF patients evaluated at our institution from 1 January1997 to 30 December 2016. Kaplan‐Meier methods were used to determine treatment response rates over time. Potential associations between baseline characteristics and complete response were examined using Cox models adjusted for age and sex. Time‐dependent covariates were used to examine treatment effects.ResultsWe identified 89 EF patients, with a female‐to‐male ratio of 1:1. Clinical features included groove sign in 26 (29%), peau d'orange/dimpling in 22 (25%), inflammatory arthritis in 9 (10%) and muscle weakness in 9 (10%). Aldolase was elevated in 11/36 (31%). Complete response rate was 60% (95% confidence interval [CI]: 35‐75) at 3 years. Diagnostic delay was inversely associated with treatment response (hazards ratio: 0.84 per 1 month increase; 95% CI: 0.73‐0.98). No baseline characteristics correlated with treatment response, but a trend toward positive association of elevated aldolase, hypergammaglobulinemia and presence of hematologic disorders was noted. Methotrexate was the most commonly used immunosuppressant in 79%, hydroxychloroquine in 45%, mycophenolate mofetil in 18% and azathioprine in 8%. No single immunosuppressant agent was associated with a superior response during treatment.ConclusionsEF is characterized by relatively high response rates. Consensus diagnostic criteria, standardized management algorithms, and large prospective multi‐center cohorts are needed to develop an evidence‐directed approach to this challenging condition.

Heterogeneity of lymphatic vessels during embryogenesis is critical for organ-specific lymphatic function. Little is known about lymphatics in the developing kidney, despite their established roles in pathology of the mature organ. We performed three-dimensional imaging to characterize lymphatic vessel formation in the mammalian embryonic kidney at single-cell resolution. In mouse, we visually and quantitatively assessed the development of kidney lymphatic vessels, remodeling from a ring-like anastomosis under the nascent renal pelvis; a site of VEGF-C expression, to form a patent vascular plexus. We identified a heterogenous population of lymphatic endothelial cell clusters in mouse and human embryonic kidneys. Exogenous VEGF-C expanded the lymphatic population in explanted mouse embryonic kidneys. Finally, we characterized complex kidney lymphatic abnormalities in a genetic mouse model of polycystic kidney disease. Our study provides novel insights into the development of kidney lymphatic vasculature; a system which likely has fundamental roles in renal development, physiology and disease.

Abstract Increased pro‐inflammatory cytokine levels and proliferation of activated microglia have been found in Parkinson's disease (PD) patients and animal models of PD, suggesting that targeting of the microglial inflammatory response may result in neuroprotection in PD. Microglial proliferation is regulated by many factors, but colony stimulating factor‐1 receptor (CSF1R) has emerged as a primary factor. Using data mining techniques on existing microarray data, we found that mRNA expression of the CSF1R ligand, CSF‐1, is increased in the brain of PD patients compared to controls. In two different neurotoxic mouse models of PD, acute MPTP and sub‐chronic LPS treatment, mRNA and protein levels of CSF1R and CSF‐1 were significantly increased. Treatment with the CSF1R inhibitor GW2580 significantly attenuated MPTP‐induced CSF1R activation and Iba1‐positive cell proliferation, without a reduction of the basal Iba1‐positive population in the substantia nigra. GW2580 treatment also significantly decreased mRNA levels of pro‐inflammatory factors, without alteration of anti‐inflammatory mediators, and significantly attenuated the MPTP‐induced loss of dopamine neurons and motor behavioral deficits. Importantly, these effects were observed in the absence of overt microglial depletion, suggesting that targeting CSF1R signaling may be a viable neuroprotective strategy in PD that disrupts pro‐inflammatory signaling, but maintains the beneficial effects of microglia.

BACKGROUND: Vedolizumab (VDZ) is a gut-selective, humanized monoclonal antibody approved for moderately to severely active ulcerative colitis (UC) and Crohn’s disease (CD). Although VDZ efficacy and safety are well established, there are limited publications on longer-term (>3 years) treatment persistence. This study evaluated VDZ treatment persistence for up to 5 years in a GEMINI long-term safety (LTS) VDZ de novo cohort. METHODS: All patients in GEMINI LTS (NCT00790933) were treated with VDZ every 4 weeks. A post hoc analysis of data from patients not previously treated with VDZ before Week 0 of GEMINI LTS (de novo cohort) was conducted, with VDZ treatment persistence assessed using Kaplan-Meier survival analysis. Treatment discontinuations due to adverse events (AEs) or lack of efficacy were considered for the analysis; discontinuations due to protocol deviation, patient withdrawal, or loss to follow-up were censored. Treatment persistence analyses were further stratified by Week 12 treatment response (primary response/nonresponder), prior anti-tumor necrosis factor (anti-TNF) failure (Yes/No), type of anti-TNF failure (primary/secondary nonresponse), and concomitant therapy (corticosteroids, 5-aminosalicylates, immunomodulators, or their combinations) at baseline (Yes/No); a log-rank test assessed statistical differences between subgroups. RESULTS: The GEMINI LTS de novo cohort included 421 patients (UC 190; CD 231) with a mean disease duration of 8.7 (UC) and 10.6 (CD) years, 6.0 mean partial Mayo score (UC) and 11.1 mean Harvey-Bradshaw Index; 61% of patients with UC and 74% with CD had prior anti-TNF failure. Up to 5 years follow-up, 276 patients (66%) total discontinued VDZ: 16% with UC and 17% with CD due to AEs, and 24% with UC and 33% with CD due to lack of efficacy. Survival probabilities for VDZ treatment persistence at 54 months were 53% for UC and 41% for CD. These VDZ 54-month survival probabilities were higher in patients with VDZ treatment response at Week 12 vs without (UC, 60% vs 26%, respectively, P < 0.0001; CD, 42% vs 35%, respectively, P = 0.001) and in patients without prior anti-TNF failure vs with (UC, 63% vs 47%, respectively, P = 0.046; CD, 47% vs 42%, respectively, P = 0.016). Among patients with baseline anti-TNF failure, survival probabilities for VDZ treatment persistence at 54 months were higher in UC patients who were secondary nonresponders vs those who were primary nonresponders (65% vs 15%, respectively, P < 0.0001); this difference was not observed in CD patients (44% vs 40%, respectively, P = 0.573). There were no differences in survival probabilities of continuing VDZ at 54 months among patients with UC or CD who initiated VDZ therapy with vs without any concomitant medications. CONCLUSION(S): More than half of patients with UC and 4 of every 10 patients with CD persisted on VDZ for 54 months. Treatment persistence rates in UC and CD cohorts were significantly higher in Week 12 responders and patients without prior anti-TNF failure, whereas there were no differences in persistence rates with baseline use of concomitant medications. Vedolizumab discontinuation rates due to AEs were low. These findings from GEMINI LTS support the longer-term effectiveness and safety of VDZ in patients with moderately to severely active UC and CD.