Soluble ACE2 correlates with severe COVID-19 and can impair antibody responses.

Identifying immune modulators that impact neutralizing antibody responses against severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) is of great relevance. We postulated that high serum concentrations of soluble angiotensin-converting enzyme 2 (sACE2) might mask the spike and interfere with antibody maturation toward the SARS-CoV-2-receptor-binding motif (RBM). We tested 717 longitudinal samples from 295 COVID-19 patients and showed a 2- to 10-fold increase of enzymatically active sACE2 (a-sACE2), with up to 1 µg/mL total sACE2 in moderate and severe patients. Fifty percent of COVID-19 sera inhibited ACE2 activity, in contrast to 1.3% of healthy donors and 4% of non-COVID-19 pneumonia patients. A mild inverse correlation of a-sACE2 with RBM-directed serum antibodies was observed. In silico, we show that sACE2 concentrations measured in COVID-19 sera can disrupt germinal center formation and inhibit timely production of high-affinity antibodies. We suggest that sACE2 is a biomarker for COVID-19 and that soluble receptors may contribute to immune suppression informing vaccine design.

History of the National Cancer Registry of Panama.

Background: The National Cancer Registry of Panama (NCRP) was established in 1974. In 1984, histological confirmation became mandatory. The now pathology-based registry has evolved and has been a population-based cancer registry (PBCR) since 2012 with cancer-specific Web-based reporting software. Herein, we characterize the main features in its development that may help readers understand its evolution and improvements that are needed to be in line with international standards. Methods: We describe the major components of the NCRP using its structure, processes, and a results framework for 3 major periods since its inception: 1974-1999, 2000-2011, and 2012 to present. Results: The NCRP has always been linked to the Ministry of Health of Panama. Until the end of its second period, it operated as a pathology-based registry and all staff worked part time. Currently, the NCRP is based on passive reporting through a Web-based system set up for both public and private health institutions, covering 77% of the existing health-care institutions in the nation. The number of cases with unknown age were less than 10 per year and primary tumors with unknown origin were at most 3%. The proportion of death certificate only (DCO) cases decreased 5% in 18 years. Men are more likely to have DCO than women (odds ratio, 1.53; 95% CI, 1.48-1.58). Discussion: The NCRP has evolved, achieving significant improvements and progress over the years. Yet, much remains to be done. To provide internationally comparable, valid, and timely cancer incidence data, the NCRP should continue to improve its quality and coverage and provide continuous staff training on cancer registry procedures.

Causal analysis of plasma IL-8 on carotid intima media thickness, a measure of subclinical atherosclerosis.

BACKGROUND: We investigated the causality of IL-8 on carotid intima-media thickness (c-IMT), a measure of sub-clinical atherosclerosis. METHODS: The IMPROVE is a multicenter European study (n = 3,711). The association of plasma IL-8 with c-IMT (mm) was estimated by quantile regression. Genotyping was performed using the Illumina CardioMetabo and Immuno chips. Replication was attempted in three independent studies and a meta-analysis was performed using a random model. RESULTS: In IMPROVE, each unit increase in plasma IL-8 was associated with an increase in median c-IMT measures (all p<0·03) in multivariable analyses. Linear regression identified rs117518778 and rs8057084 as associated with IL-8 levels and with measures of c-IMT. The two SNPs were combined in an IL-8-increasing genetic risk that showed causality of IL-8 on c-IMT in IMPROVE and in the UK Biobank (n = 22,179). The effect of IL-8 on c-IMT measures was confirmed in PIVUS (n = 1,016) and MDCCC (n = 6,103). The association of rs8057084 with c-IMT was confirmed in PIVUS and UK Biobank with a pooled estimate effect (ß) of -0·006 with 95%CI (-0·008- -0·003). CONCLUSION: Our results indicate that genetic variants associated with plasma IL-8 also associate with c-IMT. However, we cannot infer causality of this association, as these variants lie outside of the IL8 locus.

Description of the National Mortality Register of Panama.

Introduction: The National Mortality Register (NMR) of Panama is a key element in demographic analysis and in acquiring an updated picture of population health in Panama. The main objectives of this study are to characterize the NMR and to enumerate its strengths and weaknesses. Methods: We describe the history, processes, and structure of the Vital Statistics Section of the National Institute of Statistics and Census (the curator of the NMR database). In addition, we discuss publication punctuality, underregistration of the data, the proportion of registered deaths certified by medical doctors, and the top 5 causes of death according to the 80 groups of the International Classification of Diseases, Tenth Revision. We also examine works derived from the register's data, from the first publication on its website (2002) until 2019. Results: The NMR procedures were described. The web reports of the NMR were performed with a delay of between 1 to 2 years. The underregistration of deaths in 2002-2019 was 14.7%, and the national yearly proportion of deaths certified by medical doctors was always above 90%. Hard-to-reach areas had higher underregistration proportions and fewer deaths certified by medical doctors. Information extracted from the NMR supports several national and international reports, geographic information systems, and studies. The most common causes of death between 2002 and 2019 were noncommunicable diseases. Conclusions: The NMR is a robust official information system. However, hard-to-reach areas require improvement in terms of the NMR. The NMR is used for publishing official reports, writing studies, and updating reports on the current health status of Panama in a timely fashion following international guidelines.

The bias from heaping on risk estimation: effect of age at diagnosis of hypertension on risk of subsequent cardiovascular comorbidities.

PURPOSE: To investigate (1) the bias in effect estimation due to heaping or digit preference, (2) the association between age at hypertension diagnosis and risk of cardiovascular comorbidities, and (3) the influence of heaping on risk estimates. METHODS: We performed a simulation study with various scenarios, binary outcome, and normal or lognormal distributed covariables. We calculated mean logistic coefficients under the original and heaped data and their relative deviation. The association of age at hypertension diagnosis and risk of ≥1 cardiovascular comorbidity was investigated using logistic regression among 50,858 participants in the NAKO Gesundheitsstudie (German National Cohort) who reported such diagnosis. We assessed the proportion of heaped observations and to what extent heaping may have influenced risk estimates. RESULTS: Based on the simulation study and assuming 50% of observations in the variable of interest to be heaped, relative bias was <6%. In NAKO, a 5-year younger age at hypertension diagnosis was associated with a 15% increased risk of having ≥1 cardiovascular comorbidity. Observed heaping in age at hypertension diagnosis was 12.6%, and bias of the risk estimate was 0.14%. CONCLUSIONS: Bias in effect estimation due to heaping is low in most common scenarios. Younger age at hypertension diagnosis is associated with a higher risk of cardiovascular comorbidities.

Prevalence of central obesity according to different definitions in normal weight adults of two cross-sectional studies in Panama.

Background: Central Obesity (CO) might arise among individuals with normal body mass index (BMI). We aim to estimate the prevalence of Normal Weight CO (NWCO), using different definitions, and to compare its association with cardiometabolic risk factors in the adult population of Panama. Methods: Data from two population-based studies conducted in Panama in 2010 and 2019 were used. Using standard definitions, normal weight was defined as a BMI between 18·5 and 24·9 while CO was defined as a Waist-to-Height Ratio (WHtR) ≥ 0·5 in both sexes or a Waist Circumference (WC) ≥ 90, ≥94, or ≥102 cm for men, and 80 or 88 cm for women. Unconditional logistic regression models were used to estimate the association between each CO definition and dyslipidemia, high blood pressure (HBP), diabetes, and clusters of cardiovascular risk factors. Findings: Recent CO prevalence ranged between 3·9% (WC ≥ 102 cm for men and WC ≥ 88 cm for women) and 43·9% (WHtR ≥ 0·5) among individuals classify as normal weigh according to the BMI. Different cardiovascular risk factors were present in this normal weight population but among men the threshold of WC ≥ 102 cm screened less than 1·0%. Interpretation: NWCO was associated with cardiovascular risk factors, particularly with elevated concentration of triglycerides. CO evaluation at the primary health care level may be a useful technique to identify normal weight people with metabolically obese characteristics. Funding: Gorgas Memorial Institute for Health studies via Ministry of Economy and Finance of Panama and Inter-American Development Bank.

Baseline characteristics, survival and direct costs associated to treatment of gastric cancer patients at the National Oncology Institute of Panama from 2012 to 2015: a hospital-based observational study.

OBJECTIVES: Comprehensive epidemiological and economic studies of gastric cancer (GC) in Panama are limited. This study aims to evaluate the association between socioeconomic and clinical variables with survival, describe the survival outcomes according to clinical stage and estimate the direct costs associated to GC care in a Panamanian population with GC. DESIGN AND SETTING: A retrospective observational study was conducted at the leading public institution for cancer treatment in Panama. PARTICIPANTS: Data were obtained from 611 records of patients diagnosed with gastric adenocarcinoma (codes C16.0-C16.9 of the International Classification of Diseases 10th revision), identified between 1 January 2012 and 31 December 2015. METHODS: Cox proportional hazards models were used to calculate HRs with 95% CI to examine associations between the variables and survival. Kaplan-Meier curves were used to assess overall and stage-specific survival. Direct costs (based on 2015 US$) were calculated per patient using standard costs provided by the institution for hospital admission (occupied bed-days), radiotherapy, surgery and chemotherapy, yielding total and overall mean costs (OMC). A comparison of OMC between groups (sex, social security status, clinical stage) was performed applying the bootstrap method with a t-test of unequal variances. RESULTS: An increased risk of dying was observed for patients without social security coverage (HR: 2.02; 95% CI 1.16 to 3.53), overlapping tumours (HR: 1.50; 95% CI 1.02 to 2.22), poorly differentiated tumours (HR: 2.27; 95% CI 1.22 to 4.22) and stage IV disease (HR: 5.54; 95% CI 3.38 to 9.08) (adjusted models). Overall 1-year survival rate was 41%. The estimated OMC of GC care per patient was 4259 US$. No statistically significant differences were found in OMC between groups. CONCLUSIONS: Socioeconomic disparities influence GC outcomes and healthcare utilisation. Policies addressing healthcare disparities related to GC are needed, as well as in-depth studies evaluating barriers of access to GC-related services.

Analysis of the role of interleukin 6 receptor haplotypes in the regulation of circulating levels of inflammatory biomarkers and risk of coronary heart disease.

Variants at the interleukin 6 receptor (IL6R) gene regulate inflammation and are associated with risk of coronary heart disease (CHD). The aim of the present study was to investigate the effects of IL6R haplotypes on circulating levels of inflammatory biomarkers and risk of CHD. We performed a discovery analysis in SHEEP, a myocardial infarction (MI) case control study (n = 2,774) and replicated our results in two large, independent European populations, PROCARDIS, a CHD case control study (n = 7,998), and IMPROVE (n = 3,711) a prospective cardiovascular cohort study. Two major haplotype blocks (rs12083537A/G and rs4075015A/T--block 1; and rs8192282G/A, rs4553185T/C, rs8192284A/C, rs4240872T/C and rs7514452T/C--block 2) were identified in the IL6R gene. IL6R haplotype associations with C-reactive protein (CRP), fibrinogen, IL6, soluble IL6R (sIL6R), IL6, IL8 and TNF-α in SHEEP, CRP and fibrinogen in PROCARDIS and CRP in IMPROVE as well as association with risk of MI and CHD, were analyzed by THESIAS. Haplotypes in block 1 were associated neither with circulating inflammatory biomarkers nor with the MI/CHD risk. Haplotypes in block 2 were associated with circulating levels of CRP, in all three study populations, with fibrinogen in SHEEP and PROCARDIS, with IL8 and sIL6Rin SHEEP and with a modest, non significant, increase (7%) in MI/CHD risk in the three populations studied. Our results indicate that IL6R haplotypes regulate the circulating levels of inflammatory biomarkers. Lack of association with the risk of CHD may be explained by the combined effect of SNPs with opposite effect on the CHD risk, the sample size as well as by structural changes affecting sIL6R stability in the circulation.

Association of interleukin 8 with myocardial infarction: results from the Stockholm Heart Epidemiology Program.

BACKGROUND: Interleukin 8 (IL8) has been contradictorily associated with the risk of myocardial infarction (MI). AIM: To investigate the association of IL8 serum levels with the risk of MI and the association of the IL8 (IL8) and IL8 receptors (CXCR1 and CXCR2) genetic variants with IL8 levels and MI risk in a large case control study, the Stockholm Heart Epidemiology Program. METHODS AND RESULTS: IL8 levels (pg/mL) were divided into quartiles and the MI risk was calculated by logistic regression and expressed as odds ratio (OR) and 95% CI. Two IL8 SNPs (rs4073A/T, rs2227306C/T) and three SNPs tagging CXCR1 and CXCR2 (rs4674258C/T, rs1008563C/T, rs6723449T/C) were analyzed for association with IL8 levels and with MI risk. Multivariate adjusted ORs for MI risk by IL8 levels in the highest quartiles indicated reduced point estimates in both women (OR 0.37; 95% CI 0.2-0.8) and men when compared to the lowest quartile. In female cases, IL8 levels decreased progressively in the six months after MI (p=0.03). IL8, CXCR1 and CXCR2 genetic variants were not associated with IL8 levels. In men, the T allele at the IL8 SNP rs4073 was associated with a slight increase in the MI risk under an additive and a recessive model of inheritance. CONCLUSIONS: IL8 serum levels were associated with a reduced occurrence of MI among women, whereas IL8 was associated with a slightly increased risk among men, possibly through different mechanisms. These data suggest that the biological effects of IL8 on MI risk may vary over time and warrant further cohort studies with repetitive IL8 measurements.