The evolution into personalized therapies in pancreatic ductal adenocarcinoma: challenges and opportunities

Introduction: Pancreatic ductal adenocarcinoma (PDAC) is projected to be the second leading cause of cancer related mortality in the United States in 2030, with a 5-year overall survival of less than 10% despite decades of extensive research. Pancreatic cancer is marked by the accumulation of complex molecular changes, complex tumor-stroma interaction, and an immunosuppressive tumor microenvironment. PDAC has proven to be resistant to many cytotoxic, targeted and immunologic treatment approaches.

Areas covered: In this paper, we review the major areas of research in PDAC, with highlights on the challenges and areas of opportunity for personalized treatment approaches.

Expert commentary: The focus of research in pancreatic cancer has moved away from developing conventional cytotoxic combinations. The marked advances in understanding the molecular biology of this disease especially in the areas of the microenvironment, metabolism, and DNA repair have opened new opportunities for developing novel treatment strategies. Improved understanding of molecular abnormalities allows the development of personalized treatment approaches.     

Trend and causes of adult mortality in Kersa health and demographic surveillance system (Kersa HDSS), eastern Ethiopia: verbal autopsy method

Background

The health problems of adults have been neglected in many developing countries, yet many studies in these countries show high rates of premature mortality in adults. Measuring adult mortality and its cause through verbal autopsy (VA) methods is becoming an important process for mortality estimates and is a good indicator of the overall mortality rates in resource-limited settings. The objective of this analysis is to describe the levels, distribution, and trends of adult mortality over time (2008-2013) and causes of adult deaths using VA in Kersa Health and Demographic Surveillance System (Kersa HDSS).

Methods

Kersa HDSS is a demographic and health surveillance and research center established in 2007 in the eastern part of Ethiopia. This is a community-based longitudinal study where VA methods were used to assign probable cause of death. Two or three physicians independently assigned cause of death based on the completed VA forms in accordance with the World Health Organization’s International Classification of Diseases. In this analysis, the VA data considered were of all deaths of adults age 15 years and above, over a period of six years (2008–2013). The mortality fractions were determined and the causes of death analyzed. Analysis was done using STATA and graphs were designed using Microsoft Excel.

Results

A total of 1535 adult deaths occurred in the surveillance site during the study period and VA was completed for all these deaths. In general, the adult mortality rate over the six-year period was 8.5 per 1000 adult population, higher for males (9.6) and rural residents (8.6) than females (7.5) and urban residents (8.2). There is a general decrease in the mortality rates over the study period from 9.4 in 2008–2009 to 8.1 in 2012–2013. Out of the total deaths, about one-third (32.4%) occurred due to infectious and parasitic causes, and the second leading cause of death was diseases of circulatory system (11.4%), followed by gastrointestinal disorders (9.2%). Tuberculosis (TB) showed an increasing trend over the years and has been the leading cause of death in 2012 and 2013 for all adult age categories (15–49, 50–64, and 65 years and over). Chronic liver disease (CLD) was indicated as leading cause of death among adults in the age group 15–49 years.

Conclusion

The increasing TB-related mortality in the study years as well as the relative high mortality due to CLD among adults of age 15–49 years should be further investigated and triangulated with health service data to understand the root cause of death.

     

National disability-adjusted life years (DALYs) for 257 diseases and injuries in Ethiopia, 1990–2015: findings from the global burden of disease study 2015

Background

Disability-adjusted life years (DALYs) provide a summary measure of health and can be a critical input to guide health systems, investments, and priority-setting in Ethiopia. We aimed to determine the leading causes of premature mortality and disability using DALYs and describe the relative burden of disease and injuries in Ethiopia.

Methods

We used results from the Global Burden of Diseases, Injuries, and Risk Factors Study 2015 (GBD 2015) for non-fatal disease burden, cause-specific mortality, and all-cause mortality to derive age-standardized DALYs by sex for Ethiopia for each year. We calculated DALYs by summing years of life lost due to premature mortality (YLLs) and years lived with disability (YLDs) for each age group and sex. Causes of death by age, sex, and year were measured mainly using Causes of Death Ensemble modeling. To estimate YLDs, a Bayesian meta-regression method was used. We reported DALY rates per 100,000 for communicable, maternal, neonatal, and nutritional (CMNN) disorders, non-communicable diseases, and injuries, with 95% uncertainty intervals (UI) for Ethiopia.

Results

Non-communicable diseases caused 23,118.1 (95% UI, 17,124.4–30,579.6), CMNN disorders resulted in 20,200.7 (95% UI, 16,532.2–24,917.9), and injuries caused 3781 (95% UI, 2642.9–5500.6) age-standardized DALYs per 100,000 in Ethiopia in 2015. Lower respiratory infections, diarrheal diseases, and tuberculosis were the top three leading causes of DALYs in 2015, accounting for 2998 (95% UI, 2173.7–4029), 2592.5 (95% UI, 1850.7–3495.1), and 2562.9 (95% UI, 1466.1–4220.7) DALYs per 100,000, respectively. Ischemic heart disease and cerebrovascular disease were the fourth and fifth leading causes of age-standardized DALYs, with rates of 2535.7 (95% UI, 1603.7–3843.2) and 2159.9 (95% UI, 1369.7–3216.3) per 100,000, respectively. The following causes showed a reduction of 60% or more over the last 25 years: lower respiratory infections, diarrheal diseases, tuberculosis, neonatal encephalopathy, preterm birth complications, meningitis, malaria, protein-energy malnutrition, iron-deficiency anemia, measles, war and legal intervention, and maternal hemorrhage.

Conclusions

Ethiopia has been successful in reducing age-standardized DALYs related to most communicable, maternal, neonatal, and nutritional deficiency diseases in the last 25 years, causing a major ranking shift to types of non-communicable disease. Lower respiratory infections, diarrheal disease, and tuberculosis continue to be leading causes of premature death, despite major declines in burden. Non-communicable diseases also showed reductions as premature mortality declined; however, disability outcomes for these causes did not show declines. Recently developed non-communicable disease strategies may need to be amended to focus on cardiovascular diseases, cancer, diabetes, and major depressive disorders. Increasing trends of disabilities due to neonatal encephalopathy, preterm birth complications, and neonatal disorders should be emphasized in the national newborn survival strategy. Generating quality data should be a priority through the development of new initiatives such as vital events registration, surveillance programs, and surveys to address gaps in data. Measuring disease burden at subnational regional state levels and identifying variations with urban and rural population health should be conducted to support health policy in Ethiopia.

     

Severe Acute Malnutrition among Unoperated Ethiopian Children with Congenital Heart Disease: A Wake-up Call to Reverse the Situation,A Retrospective Cross-Sectional Study

BackgroundChildren with Congenital Heart Disease (CHD) are at increased risk for severe acute malnutrition (SAM). We aimed to determine the magnitude and determinants of SAM among children with CHD in a tertiary hospital.MethodsRetrospective cross-sectional study was conducted among children with CHD between 2016 and 2019. Clinical and anthropometric data were retrieved from medical records. Anthropometric assessment was done by using WHO standard growth curves. Data analysis was done using Statistical Package for Social Sciences V22. Statistical significance was set at p-value <0.05, and multivariable logistic regression was used to determine predictors.ResultsThere were 2400 pediatric admissions during the study period, CHD accounted for 6.5%(156) of admissions. For review, 141 records were eligible. The gender distribution was comparable, males 51.1% (72). Infants (<12 months) and older children (≥12 months) accounted for 57.4% (81) and 42.6% (60) of study subjects, respectively. SAM was documented in 51.8% (73) of the study subjects, [95% CI: 44.7–60.2]. Infants had higher odds of SAM compared to children aged ≥12 months[adjusted odds ratio (AOR)= 4.48, 95%CI:2.07–9.70]. Anemic children had higher odds for SAM[AOR =3.76, 95% CI:1.54–9.18]. Children without acyanotic CHD with heart failure(HF) were 58% less likely to develop SAM[AOR= 0.42, 95% CI:0.19–0.96].ConclusionThe burden of SAM among children with CHD is high. Younger age, anemia and acyanotic CHD with HF predicted SAM. Screening for anemia and targeted anthropometric assessment are recommended for early SAM detection.     

The Influence of Yarn and Weave Structures on Acoustic Materials and the Effect of Different Acoustic Signal Incidence Angles on Woven Fabric Absorption Possibilities

Utilizing textile-based acoustic materials can be considered basically from two points of view. First, it may be used as a sound absorbing material. Second, it may be used as a decoration that gives the surrounding area a new artistic appearance. To improve the acoustic possibilities of any woven fabric, it is necessary to study the influences of yarn characteristics and the internal structures of weave interlacement. To understand the impact of the yarn on the fabric, the samples were prepared using only polyester fiber as textured, twisted, and staple yarns. Regarding this experiment, the basic weave’s structure type, such as plain, rib, sateen, and twill, were used. Overall, 16 woven fabrics were prepared. The investigation was performed in the range of low to medium acoustic frequencies. The experiments were conducted in an anechoic chamber. Compared to other yarn types, fabrics formed from textured polyester yarn had higher sound absorption properties. Moreover, the observed results show that the different incidence angles of acoustic signals influence the measured sound absorption properties of a textile.     

Community health workers for ART in sub-Saharan Africa: learning from experience – capitalizing on new opportunities

Low-income countries with high HIV/AIDS burdens in sub-Saharan Africa must deal with severe shortages of qualified human resources for health. This situation has triggered the renewed interest in community health workers, as they may play an important role in scaling-up antiretroviral treatment for HIV/AIDS by taking over a number of tasks from the professional health workers. Currently, a wide variety of community health workers are active in many antiretroviral treatment delivery sites.     

Geostatistical Modeling of Malaria Endemicity using Serological Indicators of Exposure Collected through School Surveys

Ethiopia has a diverse ecology and geography resulting in spatial and temporal variation in malaria transmission. Evidence-based strategies are thus needed to monitor transmission intensity and target interventions. A purposive selection of dried blood spots collected during cross-sectional school-based surveys in Oromia Regional State, Ethiopia, were tested for presence of antibodies against Plasmodium falciparum and P. vivax antigens. Spatially explicit binomial models of seroprevalence were created for each species using a Bayesian framework, and used to predict seroprevalence at 5 km resolution across Oromia. School seroprevalence showed a wider prevalence range than microscopy for both P. falciparum (0–50% versus 0–12.7%) and P. vivax (0–53.7% versus 0–4.5%), respectively. The P. falciparum model incorporated environmental predictors and spatial random effects, while P. vivax seroprevalence first-order trends were not adequately explained by environmental variables, and a spatial smoothing model was developed. This is the first demonstration of serological indicators being used to detect large-scale heterogeneity in malaria transmission using samples from cross-sectional school-based surveys. The findings support the incorporation of serological indicators into periodic large-scale surveillance such as Malaria Indicator Surveys, and with particular utility for low transmission and elimination settings.     

A new photoreactive antagonist cross-links to the N-terminal domain of the gonadotropin-releasing hormone receptor

A new photoreactive gonadotropin-releasing hormone (GnRH) antagonist [Ac-(4-azidobenzoyl)-D-Lys1, D-4-Cl-Phe2, D-Trp3, D-Arg6, D-Ala10]GnRH (PAnt-1) was synthesized and shown to bind covalently to mouse and human GnRH receptors after ultraviolet irradiation. PAnt-1 exhibited high binding affinity (Ki = 3.1 +/- 0.8 nM), and high crosslinking efficiency as shown by loss of 78% of binding sites following crosslinking at saturating concentration. Crosslinking resulted in irreversible receptor blockade as shown by inhibition of GnRH-stimulated inositol phosphate production. PAnt-1 has a photoreactive group at residue 1 of the peptide, a region believed to be critical in determining antagonist versus agonist properties of GnRH analogues. The attachment site of PAnt- to the receptor was localized between residues 11 and 19 of the extracellular N-terminal domain of the receptor by peptide mapping studies using natural sequence differences between human, mouse and sheep GnRH receptors, as well as a panel of GnRH receptor constructs with a series of engineered protease cleavage sites. A disulphide bridge between Cys14 and Cys200 was cleaved during crosslinking, suggesting that Cys14 is the crosslinked residue. These results suggest that peptide GnRH antagonists bind to the receptor with the N-terminal end of the peptide positioned in a site comprising the constrained regions of the N-terminal domain and second extracellular loop in the vicinity of the Cys14-Cys200 disulphide bridge.