Targeting myeloid chemotaxis to reverse prostate cancer therapy resistance.

Inflammation is a hallmark of cancer1. In patients with cancer, peripheral blood myeloid expansion, indicated by a high neutrophil-to-lymphocyte ratio, associates with shorter survival and treatment resistance across malignancies and therapeutic modalities2-5. Whether myeloid inflammation drives progression of prostate cancer in humans remain unclear. Here we show that inhibition of myeloid chemotaxis can reduce tumour-elicited myeloid inflammation and reverse therapy resistance in a subset of patients with metastatic castration-resistant prostate cancer (CRPC). We show that a higher blood neutrophil-to-lymphocyte ratio reflects tumour myeloid infiltration and tumour expression of senescence-associated mRNA species, including those that encode myeloid-chemoattracting CXCR2 ligands. To determine whether myeloid cells fuel resistance to androgen receptor signalling inhibitors, and whether inhibiting CXCR2 to block myeloid chemotaxis reverses this, we conducted an investigator-initiated, proof-of-concept clinical trial of a CXCR2 inhibitor (AZD5069) plus enzalutamide in patients with metastatic CRPC that is resistant to androgen receptor signalling inhibitors. This combination was well tolerated without dose-limiting toxicity and it decreased circulating neutrophil levels, reduced intratumour CD11b+HLA-DRloCD15+CD14- myeloid cell infiltration and imparted durable clinical benefit with biochemical and radiological responses in a subset of patients with metastatic CRPC. This study provides clinical evidence that senescence-associated myeloid inflammation can fuel metastatic CRPC progression and resistance to androgen receptor blockade. Targeting myeloid chemotaxis merits broader evaluation in other cancers.

Measuring The Harms Caused by Illicit Drugs. A New Methodology for Estimating Drug Harm Index.

BACKGROUND: Substance use carries a wide range of negative consequences, impacting both the individual using the substances and others. In recent years, there have been multiple efforts to assess the harm caused by drugs and to rank them, with each taking a distinctive approach to the matter. Objectives: This study seeks to introduce a new model for assessing the harm index and ranking of drugs. Methods: This prospective study involved the evaluation of 277 male drug users, assessing substance use harm on four separate occasions throughout the span of 1 year. Various aspects of harm were quantified through the utilization of the Duke Health Profile (DUKE) and the Addiction Severity Index (ASI) questionnaire. The pharmaceutical properties of each drug were incorporated into the study. The relationship between the combined variables in a mixed statistical model was determined at a significance level of .05 using the Rsoftware. This procedure facilitated the establishment of models and the definition of harm index ranges for each substance. Result: The results indicated that heroin had the highest harm index at 71.2 (95% CI69.6-72.8), while pure methadone scored the lowest at 36.5 (95% CI31.7-41.7), along with methadone combined with methamphetamine, which scored 35 (95% CI33-37.1). Conclusion: The variables utilized in this study can help estimate the approximate harm index range for both traditional and novel substances. Furthermore, the harm model designed in this study has the capability to predict the extent of harm to a drug user.

Association of obesity with mortality and clinical outcomes in children and adolescents with transplantation: A systematic review and meta-analysis.

Obesity might be associated with mortality and clinical outcomes following transplantation; however, the direction of this relationship has not been well-recognized in youth. The aim of this systematic review and meta-analysis was to investigate the association of obesity with post-transplant mortality and clinical outcomes in children and adolescents. Following a systematic search of observational studies published by December 2018 in PubMed, Scopus, Embase, and Cochrane library, 15 articles with total sample size of 50,498 patients were included in the meta-analysis. The main outcome was mortality and secondary outcomes included acute graft versus host disease (GVHD), acute rejection, and overall graft loss. The pooled data analyses showed significantly higher odds of long term mortality (OR 1.30, 95% CI 1.15-1.48, P < 0.001, I2 = 50.3%), short term mortality (OR 1.79, 95% CI 1.19-2.70, P = 0.005, I2 = 59.6%), and acute GVHD (OR 2.13, 95% CI 1.5-3.02, P < 0.001, I2 = 1.7%) in children with obesity. There were no significant differences between patients with and without obesity in terms of acute rejection (OR 1.07, 95% CI 0.98-1.16, P = 0.132, I2 = 7.5%) or overall graft loss (OR 1.04, 95% CI 0.84-1.28, P = 0.740, I2 = 51.6%). This systematic review and meta-analysis has stated higher post-transplant risk of short and long term mortality and higher risk of acute GVHD in children with obesity compared to those without obesity. Future clinical trials are required to investigate the effect of pre-transplant weight management on post-transplant outcomes to provide insights into the clinical application of these findings. This may in turn lead to establish guidelines for the management of childhood obesity in transplantations.

The quality of care index for low back pain: a systematic analysis of the global burden of disease study 1990-2017.

BACKGROUND: . Low back pain is one of the major causes of morbidity worldwide. Studies on low back pain quality of care are limited. This study aimed to evaluate the quality of care of low back pain worldwide and compare gender, age, and socioeconomic groups. METHODS: . This study used GBD data from 1990 to 2017 from the Institute for Health Metrics and Evaluation (IHME) website. Extracted data included low back pain incidence, prevalence, disability-adjusted life years (DALYs), and years lived with disability (YLDs). DALYs to prevalence ratio and prevalence to incidence ratio were calculated and used in the principal component analysis (PCA) to make a proxy of the quality-of-care index (QCI). Age groups, genders, and countries with different socioeconomic statuses regarding low back pain care quality from 1990 to 2017 were compared. RESULTS: The proxy of QCI showed a slight decrease from 36.44 in 1990 to 35.20 in 2017. High- and upper-middle-income countries showed a decrease in the quality of care from 43.17 to 41.57 and from 36.37 to 36.00, respectively, from 1990 to 2017. On the other hand, low and low-middle-income countries improved, from a proxy of QCI of 20.99 to 27.89 and 27.74 to 29.36, respectively. CONCLUSION: . Despite improvements in the quality of care for low back pain in low and lower-middle-income countries between 1990 and 2017, there is still a large gap between these countries and higher-income countries. Continued steps must be taken to reduce healthcare barriers in these countries.

Investigating the safety and efficacy of hematopoietic and mesenchymal stem cell transplantation for treatment of T1DM: a systematic review and meta-analysis.

BACKGROUND: Stem cell transplantation (SCT) has paved the way for treatment of autoimmune diseases. SCT has been investigated in type 1 diabetes mellitus (T1DM) as an autoimmune-based disorder, but previous studies have not presented a comprehensive view of its effect on treatment of T1DM. METHODOLOGY: After registration of the present systematic review and meta-analysis in the PROSPERO, a search was done according to the Cochrane guidelines for evaluation of clinical trials to find eligible clinical trials that investigated the effect of SCT on T1DM (based on ADA® diagnostic criteria) from PubMed, Web of science, Scopus, etc, as well as registries of clinical trials from January 1, 2000, to September 31, 2019. A search strategy was designed using MeSH and EM-tree terms. Primary outcome included the changes in the insulin total daily dose (TDD) (U/kg) level, and secondary outcomes included the changes in the HbA1c, c-peptide, and adjusted HbA1c levels. The Q Cochrane test and I2 statistic were performed to assess the heterogeneity and its severity in primary clinical trials. The Cochrane ROB was used to determine risk of bias, and Cochrane Handbook for Systematic Reviews of Interventions was used in the full text papers. The meta-analysis was accomplished in the STATA software, and the results were shown on their forest plots. Confounders were evaluated by the meta-regression test. RESULTS: A total of 9452 studies were electronically screened, and 35 papers were included for data extraction. The results of this review study showed that 173 (26.5%) diabetic patients experienced insulin-free period (from 1 to 80 months), and 445 (68%) showed reduction in TDD of insulin after the SCT. Combination of hematopoietic stem cell (HSC) with mesenchymal stem cell (MSC) transplantation were significantly associated with improvement of the TDD (SMD: - 0.586, 95% CI: - 1.204/- 0.509, I2: 0%), HbA1c (SMD: - 0.736, 95% CI: - 1.107/- 0.365, I2: 0%), adjusted HbA1c (SMD: - 2.041, 95% CI: - 2.648/- 1.434, I2: 38.4%), and c-peptide (SMD: 1.917, 95% CI: 0.192/3.641, I2: 92.5%) on month 3 of follow-up, while its association had a growing trend from 3 to 12 months after the transplantation. Considering severe adverse events, HSC transplantation accompanied with conditioning could not be suggested as a safe treatment. CONCLUSION: Most of the clinical trials of SCT in T1DM were single arm. Although meta-analysis illustrated the SCT is associated with T1DM improvement, well-designed randomized clinical trials are needed to clarify its efficacy. RECOMMENDATION: Based on the results of this meta-analysis, the MSC and its combination with HSC could be considered as "Safe Cell" for SCT in T1DM. Furthermore, to evaluate the SCT efficacy, calculation of insulin TDD (U/kg/day), AUC of c-peptide, and adjusted HbA1c are highly recommended.

Global, regional, and national burden and quality of care index of endocarditis: the global burden of disease study 1990-2019.

AIMS: Endocarditis accounts for significant morbidity and mortality. Timely diagnosis and prompt treatment are of paramount importance for optimal patient outcome. However, only few studies have assessed quality of care (QoC) in endocarditis. We aimed to describe QoC and changes in epidemiological features of endocarditis from 1990 to 2019. METHODS AND RESULTS: Using primary indices of mortality, incidence, years of life lost, years lived with disability, and disability-adjusted life year, obtained from the Global Burden of Disease Study 2019, we calculated four secondary measures. Principal component analysis was performed to calculate QoC index (QCI), scored on a scale of 0-100 with higher values indicating better QoC, for different locations, age groups, and genders from 1990 to 2019. The all-ages incidence rate of endocarditis was estimated to increase significantly from 1990 to 2019, while mortality rate did not change. The age-standardized QCI was 73.6% globally, with higher values in high-income countries than in low-income countries. High-income North America (82.0%) and Asia Pacific (81.1%) had the highest QCI, whereas Eastern Europe (43.3%) had the lowest. Globally, the 30-49 and 95+ age groups had the highest (91.3%) and the lowest (71.7%) QCI, respectively. In most countries, particularly those with lower socio-demographic index, women had better QCI. CONCLUSION: This is the first global assessment of QCI, shedding light on the current trends and highlighting the necessity of improving the endocarditis QoC, mainly by timely case detection, adherence to antibiotic prophylaxis guidelines, utilizing targeted antibiotics and advanced treatments, in the African region and resolving gender inequality in selected countries.

A global, regional, and national survey on burden and Quality of Care Index (QCI) of bladder cancer: The global burden of disease study 1990-2019.

INTRODUCTION: Bladder cancer (BCa) is the second most common genitourinary cancer and among the leading causes of cancer-related deaths. We aimed to assess BCa quality of care (QOC) utilizing a novel multi-variable quality of care index (QCI). MATERIALS AND METHODS: Data were retrieved from the Global Burden of Disease 1990-2019 database. QCI scores were calculated using four indices of prevalence-to-incidence ratio, Disability-Adjusted Life Years-to-prevalence ratio, mortality-to-incidence ratio, and Years of Life Lost-to-Years Lived with Disability ratio. We used principal component analysis to allocate 0-100 QCI scores based on region, age groups, year, and gender. RESULTS: Global burden of BCa is on the rise with 524,305 (95% UI 475,952-569,434) new BCa cases and 228,735 (95% UI 210743-243193) deaths in 2019, but age-standardized incidence and mortality rates did not increase. Global age-standardized QCI improved from 75.7% in 1990 to 80.9% in 2019. The European and African regions had the highest and lowest age-standardized QCI of 89.7% and 37.6%, respectively. Higher Socio-demographic index (SDI) quintiles had better QCI scores, ranging from 90.1% in high SDI to 30.2% in low SDI countries in 2019; however, 5-year QCI improvements from 2014 to 2019 were 0.0 for high and 4.7 for low SDI countries. CONCLUSION: The global QCI increased in the last 30 years, but the gender disparities remained relatively unchanged despite substantial improvements in several regions. Higher SDI quintiles had superior QOC and less gender- and age-based inequalities compared to lower SDI countries. We encourage countries to implement the learned lessons and improve their QOC shortcomings.

The Association of Socioeconomic Status With Hypertension in 76 Low- and Middle-Income Countries.

BACKGROUND: Effective equity-focused health policy for hypertension in low- and middle-income countries (LMICs) requires an understanding of the condition's current socioeconomic gradients and how these are likely to change in the future as countries develop economically. OBJECTIVES: This cross-sectional study aimed to determine how hypertension prevalence in LMICs varies by individuals' education and household wealth, and how these socioeconomic gradients in hypertension prevalence are associated with a country's gross domestic product (GDP) per capita. METHODS: We pooled nationally representative household survey data from 76 LMICs. We disaggregated hypertension prevalence by education and household wealth quintile, and used regression analyses to adjust for age and sex. RESULTS: We included 1,211,386 participants in the analysis. Pooling across all countries, hypertension prevalence tended to be similar between education groups and household wealth quintiles. The only world region with a clear positive association of hypertension with education or household wealth quintile was Southeast Asia. Countries with a lower GDP per capita had, on average, a more positive association of hypertension with education and household wealth quintile than countries with a higher GDP per capita, especially in rural areas and among men. CONCLUSIONS: Differences in hypertension prevalence between socioeconomic groups were generally small, with even the least educated and least wealthy groups having a substantial hypertension prevalence. Our cross-sectional interaction analyses of GDP per capita with the socioeconomic gradients of hypertension suggest that hypertension may increasingly affect adults in the lowest socioeconomic groups as LMICs develop economically.

Placenta derived Mesenchymal Stem Cells transplantation in Type 1 diabetes: preliminary report of phase 1 clinical trial.

INTRODUCTION: Type 1 Diabetes Mellitus (T1DM) is an auto immune reaction against insulin secreting beta cells. Exogenous insulin administration is the only standard treatment for T1DM. However, despite tight glycemic control many patients will develop chronic life-threatening complications. Recently, stem cell transplantation has been suggested as a novel treatment for eliminating the beta cell damage and promoting their regeneration by modulating auto-immunity. To our knowledge; this is the first preliminary report of placenta derived MSCs (PLMSCs) transplantation in juvenile T1DM. METHOD: An Open label non-randomized phase 1 clinical trial was designed to evaluate the safety of PLMSCs transplantation in new onset juvenile T1DM (IRCT20171021036903N2). PLMSCs were manufactured in our clean room facility using a Xeno-free/GMP compliant protocol. The first series of patients (n = 4) received one dose of1 × 106 PLMSCs/kg intravenously. Diabetic clinical and laboratory parameters and side effects were evaluated weekly for the first month, monthly for 6 months, and then every 3 month till 1 year. RESULTS: Serious adverse events were not seen during 1 year follow-up. Partial remission and hypoglycemic attacks were happened one month after transplantation in two patients. ZnT8-Ab decreased till month 3 and then increased again in all patients. Anti Gad-Ab decreased till month 3 of follow up then increased. DISCUSSION: This preliminary report of our phase I clinical trial demonstrated the short term safety of PLMSCs transplantation in juvenile T1DM. To prove the long term safety and probable efficacy of this treatment more investigations are needed. TRIAL REGISTRATION: Iranian Registry of Clinical Trials: IRCT20171021036903N2.