bluuebunny/crossref_metadata_2025 huggingface dataset:
Effectiveness and safety of reactive focal mass drug administration (rfMDA) using dihydroartemisinin–piperaquine to reduce malaria transmission in the very low-endemic setting of Eswatini: a pragmatic cluster randomised controlled trial
Authors: Vilakati Sibonakaliso , Mngadi Nontokozo , Benjamin-Chung Jade , Dlamini Nomcebo , Dufour Mi-Suk Kang , Whittemore Brooke , Bhangu Khayelihle , Prach Lisa M , Baltzell Kimberly , Nhlabathi Nomcebo , Malambe Calisile , Dlamini Bongani , Helb Danica , Greenhouse Bryan , Maphalala Gugu , Pindolia Deepa , Kalungero Muhindo , Tesfa Getahun , Gosling Roly , Ntshalintshali Nyasatu , Kunene Simon , Hsiang Michelle S
Published: June 2021

Introduction

To reduce malaria transmission in very low-endemic settings, screening and treatment near index cases (reactive case detection (RACD)), is widely practised, but the rapid diagnostic tests (RDTs) used miss low-density infections. Reactive focal mass drug administration (rfMDA) may be safe and more effective.

Methods

We conducted a pragmatic cluster randomised controlled trial in Eswatini, a very low-endemic setting. 77 clusters were randomised to rfMDA using dihydroartemisin–piperaquine (DP) or RACD involving RDTs and artemether–lumefantrine. Interventions were delivered by the local programme. An intention-to-treat analysis was used to compare cluster-level cumulative confirmed malaria incidence among clusters with cases. Secondary outcomes included safety and adherence.

Results

From September 2015 to August 2017, 222 index cases from 47 clusters triggered 46 RACD events and 64 rfMDA events. RACD and rfMDA were delivered to 1455 and 1776 individuals, respectively. Index case coverage was 69.5% and 62.4% for RACD and rfMDA, respectively. Adherence to DP was 98.7%. No serious adverse events occurred. For rfMDA versus RACD, cumulative incidences (per 1000 person-years) of all malaria were 2.11 (95% CI 1.73 to 2.59) and 1.97 (95% CI 1.57 to 2.47), respectively; and of locally acquired malaria, they were 1.29 (95% CI 1.00 to 1.67) and 0.97 (95% CI 0.71 to 1.34), respectively. Adjusting for imbalance in baseline incidence, incidence rate ratio for rfMDA versus RACD was 0.93 (95% CI 0.54 to 1.62) for all malaria and 0.84 (95% CI 0.42 to 1.66) for locally acquired malaria. Similar results were obtained in a per-protocol analysis that excluded clusters with <80% index case coverage.

Conclusion

In a very low-endemic, real-world setting, rfMDA using DP was safe, but did not lower incidence compared with RACD, potentially due to insufficient coverage and/or power. To assess impact of interventions in very low-endemic settings, improved coverage, complementary interventions and adaptive ring trial designs may be needed.

Trial registration number

NCT02315690.
COVID-19 distribution in Bogotá, Colombia: effect of poverty during the first 2 months of pandemic
Authors: Moreno-Montoya Jose , Ballesteros Silvia Marcela , Idrovo Alvaro Javier
Published: June 2021

Background

The current SARS-CoV-2 pandemic has especially affected individuals living in conglomerate settings having poverty as common characteristic. However, evidence of the association between COVID-19 severity and social determinants is still scarce, particularly, for Latin American countries. The objective was to assess the effect of socioeconomic deprivation in the clinical severity of COVID-19 infection among different localities of Bogotá, Colombia.

Methods

Secondary analyses using data of SARS-CoV-2 infected cases in Bogotá from 6 March 2020 to 19 April 2020 were carried out. Direct and indirect indicators of deprivation at area level and individual demographic characteristics (age, sex and type of case) were included in the analyses.

Findings

1684 COVID-19 cases were included in the study. There were 217 (12.9%; 95% CI 11.3 to 14.5) serious cases, of which 32.6% (95% CI 26.4 to 38.8) cases were deceased. In the multilevel logistic regression, age, sex (female), type of case (different of imported case), number of serious cases recorded the previous day and multidimensional poverty were associated with serious cases (median OR: 1.72, 95% CI 1.56 to 1.87).

Interpretation

This paper explored the association between COVID-19 severity and social determinants. Expressions of poverty were associated with more severe cases during first 2 months of pandemic. It is a clear syndemic for the joint presentation of COVID-19 and other comorbidities among more serious cases.
Characteristics of those most vulnerable to employment changes during the COVID-19 pandemic: a nationally representative cross-sectional study in Wales
Authors: Gray Benjamin J , Kyle Richard G , Song Jiao , Davies Alisha R
Published: June 2021

Background

The public health response to the SARS-CoV-2 (COVID-19) pandemic has had a detrimental impact on employment and there are concerns the impact may be greatest among the most vulnerable. We examined the characteristics of those who experienced changes in employment status during the early months of the pandemic.

Methods

Data were collected from a cross-sectional, nationally representative household survey of the working age population (18–64 years) in Wales in May/June 2020 (n=1379). We looked at changes in employment and being placed on furlough since February 2020 across demographics, contract type, job skill level, health status and household factors. χ2or Fisher’s exact test and multinomial logistic regression models examined associations between demographics, subgroups and employment outcomes.

Results

Of our respondents, 91.0% remained in the same job in May/June 2020 as they were in February 2020, 5.7% were now in a new job and 3.3% experienced unemployment. In addition, 24% of our respondents reported being placed on furlough. Non-permanent contract types, individuals who reported low mental well-being and household financial difficulties were all significant factors in experiencing unemployment. Being placed on ‘furlough’ was more likely in younger (18–29 years) and older (60–64 years) workers, those in lower skilled jobs and from households with less financial security.

Conclusion

A number of vulnerable population groups were observed to experience detrimental employment outcomes during the initial stage of the COVID-19 pandemic. Targeted support is needed to mitigate against both the direct impacts on employment, and indirect impacts on financial insecurity and health.
Prevalence of hepatitis B immunity and infection in home self-sampling HIV service users
Authors: Roche Rachel , Simmons Ruth , Logan Louise , Ledesma Juan , Sabin Caroline , Ijaz Samreen , Mandal Sema
Published: June 2021

Objectives

Although hepatitis B virus (HBV) vaccination for high-risk groups including gay, bisexual and other men who have sex with men (MSM) is recommended in the UK, data on HBV immunisation coverage are limited. This study aimed to understand the prevalence of HBV infection, susceptibility and immunity due to immunisation among a high-risk population of MSM and heterosexuals who are less likely to attend sexual health services.

Methods

Residual HIV-negative serology samples archived from a national HIV self-sampling service in 2016 were tested for HBV markers using an unlinked anonymous approach. Prevalence of HBV infection, evidence of immunisation and susceptibility were calculated and stratified by individuals’ characteristics. Multinomial logistic regression was used to estimate relative risk ratios (RRRs) associated with covariates.

Results

Of 2172 samples tested, 1497 (68.9%) were from MSM and 657 (30.2%) were from heterosexuals. Susceptibility to HBV infection was 66.1% among MSM and 77.0% among heterosexuals. Only 29.9% of MSM and 17.4% of heterosexuals had serological evidence of immunisation. Current infection was 1.1% in heterosexuals and 0.2% in MSM. Adjusted analysis showed evidence of immunisation was lower among heterosexuals (RRR 0.66, 95% CI 0.50 to 0.86) and those with no previous HIV test (RRR 0.41, 95% CI 0.31 to 0.54), and higher in those of other white or other ethnicity.

Conclusions

Among MSM and heterosexual users of a self-sampling HIV service, evidence of immunisation to HBV infection was low and susceptibility to infection was comparatively high, suggesting suboptimal delivery of HBV immunisation in sexual health services.
California’s tobacco 21 minimum sales age law and adolescents’ tobacco and nicotine use: differential associations among racial and ethnic groups
Authors: Grube Joel W , Lipperman-Kreda Sharon , García-Ramírez Grisel , Paschall Mallie J , Abadi Melissa H
Published: June 2021

Objective

A California, USA, law raised the minimum tobacco sales age to 21 (T21) on 9 June 2016. We investigated whether T21 was associated with reductions adolescents’ use of tobacco cigarettes, smokeless tobacco and electronic cigarettes and whether these associations differed across racial and ethnic groups.

Methods

Secondary analyses of data from 2 956 054 7th, 9th and 11th grade students who participated in the California Healthy Kids Survey from 2010–11 to 2017–2018.

Results

Multilevel mixed effects logistic regression analyses showed that T21 was associated with reduced prevalence of lifetime smokeless tobacco and e-cigarette use and past month smokeless tobacco use in the overall student population. T21 was associated with increases in prevalence of past month e-cigarette use. Moderation analyses indicated differences by racial and ethnic groups. Notably, T21 was associated with reductions in lifetime and past 30-day use of all tobacco and nicotine products among Latinx youth. The findings were more mixed for other racial and ethnic groups. Slopes analyses indicated that T21 was associated with accelerated downward trends for 30-day cigarette and smokeless use; moderated trends for lifetime cigarette smoking such that downward slopes became less steep; and reversed downward trends for e-cigarette use. Changes in slopes varied across racial and ethnic groups.

Conclusions

Our findings highlight the importance of understanding the complex associations that T21 and other tobacco control policies have with the use of different tobacco and nicotine products among racial and ethnic groups. Future research should investigate mechanisms underlying these differences to inform tobacco control efforts.
Flavour chemicals, synthetic coolants and pulegone in popular mint-flavoured and menthol-flavoured e-cigarettes
Authors: Omaiye Esther E , Luo Wentai , McWhirter Kevin J , Pankow James F , Talbot Prue
Published: June 2021

Background

The Food and Drug Administration (FDA) has recently banned flavours from pod-style electronic cigarettes (e-cigarettes), except for menthol and tobacco. JUUL customers have quickly discovered that flavoured disposable e-cigarettes from other manufacturers, such as Puff, are readily available. Our goal was to compare flavour chemicals, synthetic coolants and pulegone in mint-flavoured/menthol-flavoured e-cigarettes from JUUL and Puff, evaluate the cytotoxicity of the coolants and perform a cancer risk assessment for pulegone, which is present in both JUUL pods and disposable Puff products.

Methods

Identification and quantification of chemicals were performed using gas chromatography/mass spectrometry. Cytotoxicity of the coolants was evaluated with BEAS-2B cells using the MTT 3-(4,5-dimethylthiazol-2-yl)−2,5-diphenyltetrazolium bromide assay. The cancer risk of pulegone was calculated using the margin of exposure (MOE).

Results

Menthol was the dominant flavour chemical (>1 mg/mL) in all products from both manufacturers. Minor flavour chemicals (<1 mg/mL) differed in the JUUL and Puff fluids and may produce flavour accents. The concentrations of WS-3 and WS-23 were higher in Puff than in JUUL. WS-23 was cytotoxic in the MTT assay at concentrations 90 times lower than concentrations in Puff fluids. The risk of cancer (MOE<10 000) was greater for mint than for menthol products and greater for Puff than for JUUL.

Conclusions

Switching from flavoured JUUL to Puff e-cigarettes may expose users to increased harm due to the higher levels of WS-23 and pulegone in Puff products. Cancer risk may be reduced in e-cigarettes by using pure menthol rather than mint oils to produce minty-flavoured e-cigarette products.
Own-price and cross-price elasticities of demand for cigarettes and waterpipe tobacco in three Eastern Mediterranean countries: a volumetric choice experiment
Authors: Chalak Ali , Nakkash Rima , Abu-Rmeileh Niveen M E , Khader Yousef S , Jawad Mohammed , Mostafa Aya , Abla Ruba , Louviere Jordan , Salloum Ramzi G
Published: June 2021

Background

Waterpipe tobacco smoking rates in the Eastern Mediterranean region are among the highest worldwide, yet little evidence exists on its economics. Estimates of demand elasticities for tobacco products are largely limited to cigarettes. This study aimed to estimate own-price and cross-price elasticities of demand for cigarettes and waterpipe tobacco products in Lebanon, Jordan and Palestine.

Methods

A volumetric choice experiment was conducted using nationally representative household surveys. The choice experiment elicited respondents’ stated purchases of eight cigarette and waterpipe tobacco product varieties by hypothetically varying prices. Data were analysed using zero-inflated Poisson models that yielded demand elasticity estimates of cigarette and waterpipe tobacco consumption.

Results

The study included 1680 participants in Lebanon (50% female), 1925 in Jordan (44.6% female) and 1679 in Palestine (50% female). We found the demand for premium cigarettes to be price elastic (range, −1.0 to −1.2) across all three countries, whereas the demand for discount cigarettes was less elastic than premium cigarettes in Lebanon (−0.6) and Jordan (−0.7) and more elastic in Palestine (−1.2). The demand for premium waterpipe tobacco was highly elastic in Lebanon (−1.9), moderately elastic in Jordan (−0.6) and inelastic in Palestine (0.2). The cross-price elasticity between cigarettes and waterpipe tobacco was near zero, suggesting that the two products are not considered to be close substitutes by consumers.

Conclusions

These results serve as a strong evidence base for developing and implementing fiscal policies for tobacco control in the Eastern Mediterranean region that address cigarettes and waterpipe tobacco products.
A revised coastal sensitivity index for Canada’s marine coasts calculated using nonparametric statistics
Authors: Hatcher S.V. , Manson G.K.
Published: June 2021

A coastal sensitivity index (CSI) is a measure of the sensitivity of a coastline to its physical environment, which provides information useful for coastal management. Traditionally, a CSI is calculated as the mathematical aggregation of coastal sensitivity indicators, which may include factors such as coastal material, relief, and wave energy. The indicators differ depending on study area, but generally are assigned a score ranging from one to five in order of increasing sensitivity. These scores are then aggregated using either the square root of the product mean (the “classic” method) or the geometric mean. Both of these methods are limited by mathematical assumptions, lack of comparability, and the need for empirical validation. In this study, we applied an alternative nonparametric method of calculation, known as μ-statistics, to Canada's marine coasts to provide an improved measure of coastal sensitivity. μ-statistics, which offer a mathematically sound method of aggregating ordinal indicators, have a number of theoretical advantages over the classic and geometric mean methods. In practice, when applied to Canada’s marine coasts, we find that the μ-statistics method (1) compresses the mid-range variability in the resulting sensitivity index, (2) accentuates positive and negative distribution tails, and (3) minimizes propagated errors by 190% and 50%, respectively, compared with the classic and geometric mean methods. Additionally, the μ-statistics method has a theoretical foundation that relieves the necessity to empirically validate the aggregating assumptions and relies only on the assumptions inherent in the scoring method. μ-statistics thus provide a new, rigourous method for the calculation of coastal sensitivity indices when the underlying variables have ordinal scores.
Fine-scale behavior of red snapper (Lutjanus campechanus) around bait: approach distances, bait plume dynamics, and effective fishing area
Authors: Bacheler Nathan M. , Runde Brendan J. , Shertzer Kyle W. , Buckel Jeffrey A. , Rudershausen Paul J.
Published: July 2021

The behavior of fish around bait is poorly understood despite it being important for the fish catching process and estimating relative abundance. We used a fine-scale acoustic positioning system to quantify the movements of 26 red snapper (Lutjanus campechanus) around 120 bait deployments in 2019 at a natural reef site (∼37-m deep) in North Carolina, USA. There were 39 instances of tagged red snapper approaching bait during four baiting days, some of which approached due to apparent sensory cues (28%), while most approached incidentally (72%). Tagged red snapper approached bait from initial distances of 1 to 1147 m (median = 27 m; mean = 86 m), and took 0–77 min (mean = 22 min) to approach. Fish were more likely to approach bait if they were located close to, and down-current of, the bait at deployment. Our estimated effective fishing area of 2290 m2 (within which >50% of red snapper responded to bait) could be used along with video counts and other information to estimate densities of red snapper.
Temperature-dependent mixing behavior of Pb–Sb alloys in liquid state
Authors: Bhandari Indra Bahadur , Panthi Narayan , Koirala Ishwar
Published: June 2021

We have extended a computational model used to research the thermodynamic properties of binary liquid alloys to study chemical short-range order parameters and diffusion coefficients. Numerous simulations have also been employed for surface properties such as surface concentration and surface tension. The propensities for phase separation of the Pb–Sb alloy were also observed with a temperature rise. The structural and thermodynamic properties of the alloys were measured using the same interaction parameters that are suitable for the free energy of mixing and mixing enthalpy. The interaction parameters are discovered to be temperature-dependent but concentration-independent. Our results indicate that the liquid alloy Pb–Sb has a weakly interacting composition. According to the surface property review, the element Sb having a higher surface concentration than its bulk concentration segregates over the surface of the alloy.
Balancing Straight-line Programs
Authors: Ganardi Moses , Jeż Artur , Lohrey Markus
Published: June 2021

We show that a context-free grammar of size

that produces a single string

of length

(such a grammar is also called a string straight-line program) can be transformed in linear time into a context-free grammar for

of size

, whose unique derivation tree has depth

. This solves an open problem in the area of grammar-based compression, improves many results in this area, and greatly simplifies many existing constructions. Similar results are shown for two formalisms for grammar-based tree compression: top dags and forest straight-line programs. These balancing results can be all deduced from a single meta-theorem stating that the depth of an algebraic circuit over an algebra with a certain finite base property can be reduced to

with the cost of a constant multiplicative size increase. Here,

refers to the size of the unfolding (or unravelling) of the circuit. In particular, this results applies to standard arithmetic circuits over (noncommutative) semirings.
Modeling and Simulation: A Study on Predicting the Outbreak of COVID-19 in Saudi Arabia
Authors: Msmali Ahmed , Zico Mutum , Mechai Idir , Ahmadini Abdullah
Published: June 2021

The novel coronavirus disease (COVID-19) has resulted in an ongoing pandemic affecting the health system and economy of more than 200 countries worldwide. Mathematical models are used to predict the biological and epidemiological tendencies of an epidemic and to develop methods for controlling it. In this work, we use a mathematical model perspective to study the role of behavior change in slowing the spread of COVID-19 in Saudi Arabia. The real-time updated data from March 2, 2020, to January 8, 2021, were collected from the Saudi Ministry of Health, aiming to provide dynamic behaviors of the epidemic in Saudi Arabia. During this period, 363,692 people were infected, resulting in 6293 deaths, with a mortality rate of 1.73%. There was a weak positive relationship between the spread of infection and mortality

R

2

=
0.459

. We used the susceptible-exposed-infection-recovered (SEIR) model, a logistic growth model, with a special focus on the exposed, infected, and recovered individuals to simulate the final phase of the outbreak. The results indicate that social distancing, hygienic conditions, and travel limitations are crucial measures to prevent further spread of the epidemic.
Systematic Elucidation of the Mechanism of Sappan Lignum in the Treatment of Diabetic Peripheral Neuropathy Based on Network Pharmacology
Authors: Kang Xiaomin , Jin De , Zhang Yuqing , Zhou Rongrong , Zhang Yuehong , Lian Fengmei
Published: June 2021

Background. Diabetic peripheral neuropathy (DPN) is one of the most common chronic complications of diabetes, which seriously affects the physical and mental health of patients. Sappan Lignum (SL) is effective in treating DPN. Previous reports have shown that SL has a clear hypoglycemic and anti-inflammatory effect. However, the study of SL in the treatment of DPN is still limited and rare. Objective. To investigate the mechanism of SL in the treatment of DPN based on network pharmacology. Methods. The active ingredients of SL were screened by related databases. The compound targets were collected by the target prediction platforms. The DPN-related targets were gathered through disease databases. The intersection targets were obtained by uploading the compound targets and disease targets to Venny 2.1.0, and a compound-target network was constructed by Cytoscape3.7.2. The protein-protein interaction (PPI) relationships were obtained by the STRING11.0 database. Genome Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed using the DAVID6.8 database. Molecular docking of key compounds and core targets was performed by DockThor. Results. A total of 29 compounds and 51 intersection targets with potential therapeutic effects on DPN were obtained. The compound-target network construction resulted in four key compounds: protostemonine, 3-deoxysappanchalcone, 7,3′,4′-trihydroxy-3-benzyl-2H-chromene, and o-12′-methylergocornine. PPI network analysis yielded 10 core targets: AKT1, MAPK3, CXCL8, TNF, OPRM1, MTOR, STAT3, MAPK8, SIRT1, and HSP90AA1. KEGG analysis resulted in 82 signaling pathways (

P
<
0.05

), including insulin resistance, HIF-1 signaling pathway, and type II diabetes. The docking results indicated that the main active compounds could stably bind to core targets. Conclusion. SL had the mechanism of multiple ingredients, multiple targets, and multiple pathways in the treatment of DPN. This study provided a scientific basis for further research on the treatment of DPN with SL and its extracts.
Computational Analysis for Rainfall Characterization and Drought Vulnerability in Peninsular India
Authors: Akhtar M. P. , Faroque Firoz Alam , Roy L. B. , Rizwanullah Mohd. , Didwania Mukesh
Published: June 2021

This paper analyzes the historical rainfall characterization and drought conditions in two major southern states of India, namely, Tamil Nadu and Karnataka, through estimation of meteorological drought indices, namely, drought index (DI), Palmer drought index (PDI), and standardized precipitation index (SPI). Monthly and yearly rainfall data, including temperature, have been considered for 110 years. Deficient rainfall conditions have been identified and compared using annual rainfall classification thresholds. Annual rainfall variability and trend have been estimated using Mann–Kendall test and Sen’s slope test. Comparative study on results implies that drought characterization using SPI may amply facilitate the standardization of threshold classification for severity and frequency. Based on threshold classification, it is found that Tamil Nadu witnessed on an average 11 years of moderate drought, 4.36 years of severe drought, and 1.32 years of extreme drought conditions with standard deviations of 4.28, 1.87, and 1.63 years, respectively, during the study period, whereas Karnataka witnessed on an average 9.74 years of moderate drought, 3.91 years of severe drought, and 2.30 years of extreme drought conditions with standard deviations of 4.54, 2.04, and 2.21 years, respectively, during the study period. According to the analysis, drought vulnerability in Tamil Nadu was higher than in Karnataka, based on the number of dry and wet years in terms of SPI threshold values and area covered over 110 years. Karnataka was more susceptible in terms of severity. When compared with other indices, analysis based on drought indices indicates that a single variable-based estimation using SPI is easy to assess and may be significant and definitive in terms of decision making for prioritizing drought mitigation measures in the study area in case of inadequate available data for multiple variable-based drought analysis.
Effects of Side Load Chains of a Combine Harvester on Unbalanced Dynamic Vibrations of Its Threshing Drum
Authors: Zhiwu Yu , Yaoming Li , Xinzhong Wang , Zhong Tang , Lu Jiahui
Published: June 2021

In order to study the influence of the side drive on the balance state of the threshing drum, this paper used the side eccentric load chain drive as the power on the threshing drum dynamic balance test bench. By analyzing the influence of different radial phases, different axial distances, and spiral combinations of the threshing drum on the counterweight, this paper studies the law of the effect of side partial load chain drive on the dynamic balance of the threshing drum and finds that the side chain drive has obvious influence on the unbalance phase of the threshing drum and the change of the axial distance of unbalance has little effect on the equilibrium state of the threshing drum. And from this, a vibration balance method based on the equivalent unbalance of the chain drive is proposed, which can predict and calculate the unbalance of the threshing drum. The unbalance of the threshing drum predicted by this method is smaller than the actual measured unbalance. The maximum error is 32.64% and the minimum error is 4.6%. In the two tests, the predicted unbalance is 1.24 mm/s in amplitude and 270 degrees in phase and amplitude 1.4 mm/s and phase 120 degrees, respectively. The measured unbalance is amplitude 1.587 mm/s and phases 286 degrees. The error between prediction and actual measurement is less than 32.64%, and the unbalance amplitudes that can be reduced by one-time dynamic balance are 0.856 mm/s and 0.674 mm/s, respectively. The research results in this paper provide an effective method for the balance state of the multidrum side chain transmission.
New Perspectives on Classical Meanness of Some Ladder Graphs
Authors: Alanazi A. M. , Muhiuddin G. , Kannan A. R. , Govindan V.
Published: June 2021

In this study, we investigate a new kind of mean labeling of graph. The ladder graph plays an important role in the area of communication networks, coding theory, and transportation engineering. Also, we found interesting new results corresponding to classical mean labeling for some ladder-related graphs and corona of ladder graphs with suitable examples.
Mieloma múltiple. Experiencia de 9 años en el Hospital Naval Almirante Nef
Authors: Cortés Saavedra Magdalena , Figueroa Carolina , Varela Roxana , Valdivia-Cortés Karla , Barría Katherine , Salvo Carla
Published: July 2021

Introducción: el mieloma múltiple (MM) continúa siendo una enfermedad incurable sin embargo el trasplante autólogo de médula ósea (TAH) y las drogas antineoplásicas han permitido mejorar la sobrevida global (SG) de los pacientes.  Materiales y métodos: estudio de cohorte retrospectivo de 50 pacientes con diagnóstico de MM en el hospital Naval Almirante Nef, desde 2005 a 2013. Los pacientes se dividieron en dos cohortes, según la eligibilidad a trasplante, y analizados acordes a la primera línea de tratamiento y la sobrevida global (SG) hasta abril de 2019. Resultados: mediana de edad 73 años (47-88 años), SG 49 meses, y 50% en etapa-II del IIS. La SG de los 39 no candidatos a TAH fue 46 meses; con un mayor número de respuestas completas y sobrevida, con el esquema melfalán-prednisona-talidomida. La SG de los 11 candidatos a TAH fue 66 meses, siendo el esquema bortezomib-ciclofosfamida-dexametasona el que concentró un mayor número de respuestas completas libres de progresión. Se trasplantó el 45% de los candidatos, con una mediana de sobrevida de 79 meses versus a los 51 meses de aquellos no trasplantados. Tres casos de neuropatía asociada a talidomida y uno a bortezomib. La SG a los seis meses y a los cinco años de todos los pacientes fue 86% y 44%, respectivamente. Conclusión: la incorporación de nuevos fármacos permitió obtener mejores resultados de sobrevida lo que se condice con estudios nacionales e internacionales.
Abstract 1360: Exposure-response safety analysis of avelumab in patients with locally advanced or metastatic urothelial carcinoma
Authors: Li Jerry , Bello Carlo , Khandelwal Akash , Vugmeyster Yulia , Nickens Dana , Lin Swan
Published: July 2021

BACKGROUND: Avelumab is a human IgG1 monoclonal antibody targeting PD-L1 that is approved in the US for second-line locally advanced or metastatic urothelial carcinoma (UC) and first-line maintenance (1LM) treatment of patients with UC that has not progressed with first-line platinum-containing chemotherapy. The current analysis was conducted to evaluate the relationships between avelumab exposure and the probability of experiencing adverse events in 1LM-UC patients.

METHODS: Avelumab exposures following 10-mg/kg every-2-weeks (Q2W) dosing in 1LM-UC patients were derived from post hoc parameter estimates from a population pharmacokinetic model. Safety endpoints included grade ≥3 treatment-emergent adverse events (TEAEs), any-grade infusion-related reactions (IRRs), and any-grade immune-related adverse events (irAEs). For each safety endpoint, avelumab exposures were assessed by univariate screen followed by a full model including influence of all potential covariates and a final model that retained statistically significant covariates (α=0.01) after backwards elimination. Safety analyses were performed with R version 3.5.0 by binomial logistic regression.

RESULTS: A total of 344 1LM-UC patients treated with avelumab were included in the analyses. Of these patients, 163 (47%), 101 (29%), and 74 (21.5%) experienced grade ≥3 TEAE, any-grade IRR, and any-grade irAE, respectively. Avelumab exposure did not demonstrate statistically significant relationships with grade ≥3 TEAE or any-grade irAE. Any-grade IRR demonstrated a potentially confounded inverse relationship with avelumab exposure (p=0.009), a trend also seen in patients with advanced renal cell carcinoma. In all models, immunogenicity and PD-L1 status were tested as covariates but were not predictors for any safety endpoint.

CONCLUSIONS: The exposure range associated with avelumab 10-mg/kg Q2W dosing demonstrated no clinically meaningful relationships with any of the safety endpoints. Given the similarity in avelumab exposures between the flat 800-mg Q2W and weight-based 10-mg/kg dosing, the findings of this analysis support the use of the flat-dosing regimen for 1LM-UC patients.

Citation Format: Jerry Li, Carlo Bello, Akash Khandelwal, Yulia Vugmeyster, Dana Nickens, Swan Lin. Exposure-response safety analysis of avelumab in patients with locally advanced or metastatic urothelial carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1360.
Abstract 1568: A2aR inhibition enhances the antitumor activity of CTLA4 blockade in mouse Pten-deficient prostate cancer
Authors: De Velasco Marco A. , Kura Yurie , Sako Noriko , Ando Naomi , Sakai Kazuko , Schuller Alwin , Fujita Kazutoshi , Nozawa Masahiro , Yoshimura Kazuhiro , Nishio Kazuto , Uemura Hirotsugu
Published: July 2021

Extracellular adenosine impairs immune function in tumors and limits the efficacy of anti-CTAL4 immune checkpoint blockade. We previously showed that adenosine 2A receptor (A2aR) blockade with AZD4635 moderately inhibited tumor growth, in part by improving antigen presentation and cytotoxic T cell (CTL) activity in mouse Pten-deficient prostate cancer. Here, we continue to investigate the antitumor activity of AZD4635 and its effects when combined with CTLA4 blockade (aCTLA4) in preclinical models of Pten-deficient prostate cancer. Prostate tumors from Pten conditional knockout (KO) mice treated with aCTLA4 for five days had increased expression levels of adenosinergic genes. Furthermore, gene expression, flow cytometric and IHC analyses showed increased T regulatory cell differentiation and accumulation that was offset with the addition of AZD4635. Moreover, expression levels of genes associated with Th 1 cell differentiation and T cell-mediated cytotoxicity were increased in AZD4635/aCTLA4 treated tumors. Adding AZD4635 to a four-week regimen of aCTLA4 therapy improved the antitumor response by two-fold in an early-stage intervention model of Pten-deficient prostate cancer. Androgen deprivation (AD) has the potential to promote T cell infiltration in prostate tumors and using the AZD4635/aCTLA4 treatment combination as neoadjuvant therapy to AD via surgical castration led to a greater antitumor response. The antitumor activity of this treatment combination was further examined and confirmed in a subcutaneous syngeneic genome-derived allograft model using tumor-bearing conditional Pten-deficient knockout mice grafted with Pten-deficient CRPC tumor fragments. In a Pten/Trp53 conditional double knockout (DKO) mouse model of advanced prostate cancer, the AZD4635/aCTLA4 treatment combination did not improve overall survival rates. However, when AZD4635/aCTLA4 was used as neoadjuvant therapy to AR inhibition with the anti-androgen apalutamide, it improved median survival time from 21 days in monotherapy treated mice to 34 days in AZD4635/aCTLA4 treated mice. These results provide preclinical evidence to support the rational combination of A2AR blockade with AZD4635 and aCTLA4 immune checkpoint inhibition for PTEN-deficient prostate cancer.

Citation Format: Marco A. De Velasco, Yurie Kura, Noriko Sako, Naomi Ando, Kazuko Sakai, Alwin Schuller, Kazutoshi Fujita, Masahiro Nozawa, Kazuhiro Yoshimura, Kazuto Nishio, Hirotsugu Uemura. A2aR inhibition enhances the antitumor activity of CTLA4 blockade in mouse Pten-deficient prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1568.
Abstract 1861: Advancing bispecific antibody discovery using common light chain immunoglobulin humanized mouse
Authors: Hui Li , Lu Hui , Zhang Yabo , Huang Shuwen , Zhang Ping , Zhao Huizhen , Chang Ruifang , Yang Bing , Zhang Fengqian , Yang Wendong , Yang Fang , Yang Hao , Yao Jiawei , Chen Lei , Lin Qingcong
Published: July 2021

The common challenges of bispecific therapeutic antibody discovery are immunogenicity and chain mispairing issues. Biocytogen's RenLiteTM immunoglobulin humanized mouse is designed not only to overcome these two issues, but also to provide a full human heavy chain repertoire diversity. RenLiteTM mouse carries full human heavy chain VDJ loci and a fixed common human light chain VJ gene. The derived antibodies share the same light chain with different heavy chain variable domain. This technology dramatically simplifies the following heavy and light chain pairing process. Antibodies generated by RenLiteTM mice underwent natural selection, differentiation, and affinity maturation in vivo utilizing a human heavy chain repertoire, the potential of immunogenicity is minimized. RenLiteTM mice show robust immune response comparable to wild type mice and RenLiteTM mice derived antibodies have high binding affinity at subnanomolar range. RenLiteTM antibodies also showed strong in vivo efficacy against tumor growth in xenograft mouse models. In summary, RenLiteTM mouse is a powerful tool for advancing current bispecific or multispecific antibody discovery.

Citation Format: Li Hui, Hui Lu, Yabo Zhang, Shuwen Huang, Ping Zhang, Huizhen Zhao, Ruifang Chang, Bing Yang, Fengqian Zhang, Wendong Yang, Fang Yang, Hao Yang, Jiawei Yao, Lei Chen, Qingcong Lin. Advancing bispecific antibody discovery using common light chain immunoglobulin humanized mouse [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1861.
Abstract 2886: The mechanistic effect of DHA on FABP7 associated membrane lipid order & nanodomain distribution in glioblastoma migration
Authors: Xu Xia , Wang Yixiong , Choi Wonshik , Godbout Roseline
Published: July 2021

Glioblastoma (GBM) is the most common primary brain malignancy. Brain fatty acid binding protein (B-FABP, FABP7) promotes glioblastoma (GBM) migration and correlates to dismal prognosis in GBM patients. Long chain polyunsaturated fatty acids (PUFAs) such as docosahexaenoic acid (DHA) and arachidonic acid (AA) are abundant in brain cell membranes. DHA and AA are preferred ligands of FABP7, with DHA having the stronger affinity for FABP7. Previous studies have shown that DHA inhibits GBM migration in an FABP7-dependent manner. In the current study, we have demonstrated that DHA dramatically altered membrane FABP7 nanoscale distribution pattern, which resulting from plasma membrane lipid ordered domain disruption in GBM cells and neurosphere cultures. We used quantitative membrane order assay to show that FABP7-expressing cells has increased membrane lipid order which is tightly correlated with higher GBM migration property. Using stimulated emission depletion (STED) microscopy, we observed lipid ordered domain was associated with FABP7 nanoscale domain formation. Interestingly, super-resolution microscopy quantitative image analysis revealed that FABP7 membrane nanodomains distribution was dramatically altered upon DHA treatment, which is associated with DHA inhibitory effect on membrane lipid order. Furthermore, STED microscopy has also revealed that reduced FABP7 nanodomain formation in slow migrating GBM cells are similar as FABP7-expressing GBM cells upon DHA treatment. Therefore, we hypothesize that these alterations are likely to be the mechanism of FABP7-mediated DHA inhibitory role in GBM migration.

Citation Format: Xia Xu, Yixiong Wang, Wonshik Choi, Roseline Godbout. The mechanistic effect of DHA on FABP7 associated membrane lipid order & nanodomain distribution in glioblastoma migration [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2886.
Abstract 3094: Estrogen receptor β agonist depletes ovarian cancer stem cells via repressing epithelial to mesenchymal transition
Authors: Banerjee Ananya , Cai Shurui , Li Na , Lavudi Kousalya , Pal Tejinder , Bai Xuetao , Wang Qi-En
Published: July 2021

Ovarian cancer is considered a hormone sensitive tumor. A healthy ovary expresses both Estrogen Receptors alpha (ERα) and beta (ERβ). However, although expression of ERα fairly remains constant, the expression of ERβ gradually decreases as the cells undergo malignant transformation and furthers with the progression of cancer. ERα is thought to promote expression of genes associated with cell survival and proliferation enhancing tumor growth. In contrast, the ability of ERβ to suppress orthotropic ovarian xenograft development supported the role of ERβ as a ‘tumor suppressor' in EOC tumorigenesis. Thus, use of ERβ agonists might prove to be therapeutically beneficial in ovarian cancer. Our studies reveal that activation of ERβ by using a newly developed ERβ agonist, WT-IV-012, is able to suppress the subpopulation of ovarian cancer stem cells. Mechanistically, WT-IV-012 inhibits epithelial to mesenchymal transition (EMT)-mediated CSC expansion, probably by downregulating ERα, which is a key regulator in the maintenance of stemness of CSCs. Taken together, our data indicate that suppressed expression of ERβ is critical to maintaining stemness of ovarian cancer stem cells, in turn, contributing to cancer relapse and chemoresistance. ERβ agonist would be able to limit the CSC subpopulation and prevent tumor relapse and metastasis.

Citation Format: Ananya Banerjee, Shurui Cai, Na Li, Kousalya Lavudi, Tejinder Pal, Xuetao Bai, Qi-En Wang. Estrogen receptor β agonist depletes ovarian cancer stem cells via repressing epithelial to mesenchymal transition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3094.
Abstract 882: Associations of genetically predicted blood protein biomarkers with pancreatic ductal adenocarcinoma risk: A study using comprehensive protein genetic prediction models
Authors: Ghoneim Dalia , Zhu Jingjing , Ha Jihwan , Surendran Praveen , Yao Qizhi Cathy , Liu Tao , Fahle Sarah , Butterworth Adam , Wu Chong , Wu Lang
Published: July 2021

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with few known risk factors and biomarkers. Identification of biomarkers is critical for understanding the pathogenesis of this deadly cancer and identifying high-risk individuals for close surveillance. Several blood protein biomarkers have been linked to PDAC in previous studies, but these studies have assessed only a limited number of protein biomarkers usually in small set(s) of samples. To identify novel circulating protein biomarkers of PDAC, we studied 8,275 cases and 6,723 controls of European descent from the Pancreatic Cancer Cohort Consortium and the Pancreatic Cancer Case-Control Consortium.

Leveraging genome and plasma proteome data of 2,841 healthy European descendants included in the INTERVAL study, we established models using four methods (best linear unbiased predictor, elastic net, LASSO, and top1) to predict protein levels based on genetic variants. For each protein, of the four sets of models developed, the model showing the highest prediction performance (R2) was retained. We selected 2,164 built protein models with a prediction performance (R2) of >0.01 for association analyses with PDAC risk.

We observed associations between predicted concentrations of 14 proteins and PDAC risk at a false discovery rate of < 0.05, including those of eight proteins that showed a significant association after Bonferroni correction (2.31 × 10-5). These include Histo-blood group ABO system transferase encoded by ABO, which has been previously implicated as a potential target gene of PDAC risk variant identified in GWAS. Besides eight proteins that were previously reported in our earlier study using protein quantitative trait loci as instruments, we identified six novel proteins which have not been identified in previous studies. Six of the identified proteins showed positive associations and eight showed inverse associations (P-values from 2.62 × 10-4 to 5.71 × 10-21).

In conclusion, we identified 14 protein biomarker candidates for PDAC risk, which if validated in future studies, may contribute to the etiological understanding of PDAC development.

Citation Format: Dalia Ghoneim, Jingjing Zhu, Jihwan Ha, Praveen Surendran, Qizhi Cathy Yao, Tao Liu, Sarah Fahle, Adam Butterworth, Chong Wu, Lang Wu. Associations of genetically predicted blood protein biomarkers with pancreatic ductal adenocarcinoma risk: A study using comprehensive protein genetic prediction models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 882.
Abstract 104: Barriers and Facilitators to Integrating Breast and Cervical Cancer Screening Programs in Outpatient Clinics in Western Kenya
Authors: Diala Prisca , Randa Magdalene , Odhiambo Jackline , Ganda Gregory , Cohen Craig , Mungo Chemtai
Published: July 2021

Purpose: Nearly 50% of Kenyan women with breast cancer present with advanced disease – owing partially to limited patient awareness of the importance of breast cancer screening and financial limitations of screening in low- and middle-income countries. With increasing access to nurse-led cervical cancer screening in government clinics in Kenya, we investigated provider-perceived barriers and facilitators to integrating breast cancer screening into ongoing cervical cancer screening programs in Kisumu County, Kenya.

Methods: Providers offering cervical cancer screening within Ministry of Health Clinics in Kisumu County were recruited to participate in a two-phase, sequential, mixed methods study. Providers' knowledge of breast cancer screening guidelines was assessed with a questionnaire based on the 2018 Kenya National Cancer Guidelines. Providers with significant cervical and breast cancer screening experience were invited to complete a 1-on-1 interview to discuss barriers and facilitators to integration.

Results: Sixty-nine nurses and clinical officers from 20 randomly selected facilities participated in the survey. Providers all agreed that breast cancer screening was very important. While 93% said they routinely offered clinical breast examinations, only 22% of these providers screened at least 8 of their last 10 patients. Forty-four percent correctly identified 4 or more of 5 signs and symptoms of breast cancer and 45% correctly identified the recommended screening frequency for women aged 40-55 years. While providers showed enthusiasm for integration, several barriers were identified and grouped into four themes: 1) fragmentation of services; 2) staffing shortage and inadequate on-job training; 3) limited space and referral system challenges; 4) limited patient awareness on need for cancer screening.

Conclusion: Addressing providers' concerns by providing routine on-job clinical training, strengthening the diagnostic and treatment referral pathway, and increasing patient education are some of the first steps in facilitating integration of breast and cervical cancer screening services in primary care clinics in Kenya.

Citation Format: Prisca Diala, Magdalene Randa, Jackline Odhiambo, Gregory Ganda, Craig Cohen, Chemtai Mungo. Barriers and Facilitators to Integrating Breast and Cervical Cancer Screening Programs in Outpatient Clinics in Western Kenya [abstract]. In: Proceedings of the 9th Annual Symposium on Global Cancer Research; Global Cancer Research and Control: Looking Back and Charting a Path Forward; 2021 Mar 10-11. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2021;30(7 Suppl):Abstract nr 104.