bluuebunny/crossref_metadata_2025 huggingface dataset:
Association between triglycerides, known risk SNVs and conserved rare variation in SLC25A40 in a multi-ancestry cohort
Authors: Rosenthal Elisabeth A. , Crosslin David R. , Gordon Adam S. , Carrell David S. , Stanaway Ian B. , Larson Eric B. , Grafton Jane , Wei Wei-Qi , Denny Joshua C. , Feng Qi-Ping , Shah Amy S. , Sturm Amy C. , Ritchie Marylyn D. , Pacheco Jennifer A. , Hakonarson Hakon , Rasmussen-Torvik Laura J. , Connolly John J. , Fan Xiao , Safarova Maya , Kullo Iftikhar J. , Jarvik Gail P.
Published: January 2021

Background

Elevated triglycerides (TG) are associated with, and may be causal for, cardiovascular disease (CVD), and co-morbidities such as type II diabetes and metabolic syndrome. Pathogenic variants in APOA5 and APOC3 as well as risk SNVs in other genes [APOE (rs429358, rs7412), APOA1/C3/A4/A5 gene cluster (rs964184), INSR (rs7248104), CETP (rs7205804), GCKR (rs1260326)] have been shown to affect TG levels. Knowledge of genetic causes for elevated TG may lead to early intervention and targeted treatment for CVD. We previously identified linkage and association of a rare, highly conserved missense variant in SLC25A40, rs762174003, with hypertriglyceridemia (HTG) in a single large family, and replicated this association with rare, highly conserved missense variants in a European American and African American sample.

Methods

Here, we analyzed a longitudinal mixed-ancestry cohort (European, African and Asian ancestry, N = 8966) from the Electronic Medical Record and Genomics (eMERGE) Network. We tested associations between median TG and the genes of interest, using linear regression, adjusting for sex, median age, median BMI, and the first two principal components of ancestry.

Results

We replicated the association between TG and APOC3, APOA5, and risk variation at APOE, APOA1/C3/A4/A5 gene cluster, and GCKR. We failed to replicate the association between rare, highly conserved variation at SLC25A40 and TG, as well as for risk variation at INSR and CETP.

Conclusions

Analysis using data from electronic health records presents challenges that need to be overcome. Although large amounts of genotype data is becoming increasingly accessible, usable phenotype data can be challenging to obtain. We were able to replicate known, strong associations, but were unable to replicate moderate associations due to the limited sample size and missing drug information.
Heterologous expression of Phanerochaete chrysosporium cellobiose dehydrogenase in Trichoderma reesei
Authors: Wohlschlager Lena , Csarman Florian , Chang Hucheng , Fitz Elisabeth , Seiboth Bernhard , Ludwig Roland
Published: January 2021

Background

Cellobiose dehydrogenase from Phanerochaete chrysosporium (PcCDH) is a key enzyme in lignocellulose depolymerization, biosensors and biofuel cells. For these applications, it should retain important molecular and catalytic properties when recombinantly expressed. While homologous expression is time-consuming and the prokaryote Escherichia coli is not suitable for expression of the two-domain flavocytochrome, the yeast Pichia pastoris is hyperglycosylating the enzyme. Fungal expression hosts like Aspergillus niger and Trichoderma reesei were successfully used to express CDH from the ascomycete Corynascus thermophilus. This study describes the expression of basidiomycetes PcCDH in T. reesei (PcCDHTr) and the detailed comparison of its molecular, catalytic and electrochemical properties in comparison with PcCDH expressed by P. chrysosporium and P. pastoris (PcCDHPp).

Results

PcCDHTr was recombinantly produced with a yield of 600 U L−1 after 4 days, which is fast compared to the secretion of the enzyme by P. chrysosporium. PcCDHTr and PcCDH were purified to homogeneity by two chromatographic steps. Both enzymes were comparatively characterized in terms of molecular and catalytic properties. The pH optima for electron acceptors are identical for PcCDHTr and PcCDH. The determined FAD cofactor occupancy of 70% for PcCDHTr is higher than for other recombinantly produced CDHs and its catalytic constants are in good accordance with those of PcCDH. Mass spectrometry showed high mannose-type N-glycans on PcCDH, but only single N-acetyl-d-glucosamine additions at the six potential N-glycosylation sites of PcCDHTr, which indicates the presence of an endo-N-acetyl-β-d-glucosaminidase in the supernatant.

Conclusions

Heterologous production of PcCDHTr is faster and the yield higher than secretion by P. chrysosporium. It also does not need a cellulose-based medium that impedes efficient production and purification of CDH by binding to the polysaccharide. The obtained high uniformity of PcCDHTr glycoforms will be very useful to investigate electron transfer characteristics in biosensors and biofuel cells, which are depending on the spatial restrictions inflicted by high-mannose N-glycan trees. The determined catalytic and electrochemical properties of PcCDHTr are very similar to those of PcCDH and the FAD cofactor occupancy is good, which advocates T. reesei as expression host for engineered PcCDH for biosensors and biofuel cells.
Circular RNA hsa_circ_0061395 accelerates hepatocellular carcinoma progression via regulation of the miR-877-5p/PIK3R3 axis
Authors: Yu Yanhui , Bian Lijuan , Liu Renfei , Wang Yitong , Xiao Xia
Published: January 2021

Background

Circular RNA hsa_circ_0061395 (circ_0061395) has been reported to accelerate the advancement of hepatocellular carcinoma (HCC). However, the regulatory mechanism by which circ_0061395 modulates the progression of HCC is unclear.

Methods

The morphology and size of exosomes were analyzed by transmission electron microscope (TEM) and nanoparticle-tracking analysis (NTA). Protein levels were detected by western blotting. Expression levels of circ_0061395, microRNA (miR)-877-5p, and phosphoinositide-3-kinase regulatory subunit 3 (PIK3R3) mRNA were assessed by quantitative real time polymerase chain reaction (qRT-PCR). The proliferation, invasion, migration, cell cycle progression, and apoptosis were analyzed by cell counting kit-8 (CCK-8), plate clone, transwell, or flow cytometry assays. The targeting relationship between circ_0061395 or PIK3R3 and miR-877-5p was verified using the dual-luciferase reporter and/or RNA immunoprecipitation (RIP) assays. Xenograft assay was performed to confirm the biological function of circ_0061395 in HCC.

Results

Circ_0061395 was upregulated in HCC tissues, serum, cells, and serum-derived exosomes. Circ_0061395 silencing decreased tumor growth in vivo, and induced cell cycle arrest, apoptosis, repressed proliferation, invasion, and migration of HCC cells in vitro. MiR-877-5p was downregulated while PIK3R3 was upregulated in HCC. Circ_0061395 regulated PIK3R3 expression via competitively binding to miR-877-5p. MiR-877-5p inhibitor overturned circ_0061395 knockdown-mediated influence on malignant behaviors of HCC cells. PIK3R3 overexpression reversed the suppressive influence of miR-877-5p mimic on malignant behaviors of HCC cells.

Conclusion

Circ_0061395 facilitated HCC progression via regulating the miR-877-5p/PIK3R3 axis, providing a new perspective on the advancement of HCC.
RETRACTED ARTICLE: LncRNA PCAT6 regulates the progression of pituitary adenomas by regulating the miR-139-3p/BRD4 axis
Authors: Zhao Peng , Cheng Jianhua , Li Bin , Nie Ding , Wang Hongyun , Li Chuzhong , Gui Songbai , Zhang Yazhuo
Published: January 2021

Background

Dysregulated lncRNA PCAT6 was discovered in many cancers excluding pituitary adenomas (PA). Therefore, we explored the role of PCAT6 in PA in this research.

Methods

Abnormally expressed miRNAs were analyzed by bioinformatics and RT-qPCR. The target and regulator of miR-139-3p were determined by bioinformatics, dual-luciferase reporter assay, or RIP. The correlation among PCAT6, miR-139-3p, and BRD4 was further analyzed. The viability, apoptosis, cell cycle distribution of PA cells, as well as their ability to invade, migrate, and proliferate, were tested after transfection through CCK-8, flow cytometry, transwell, wound healing, and colony formation assays. After construction of transplanted-tumor model in nude mice, cell apoptosis in the tumor was detected by TUNEL. The expressions of PCAT6, BRD4, miR-139-3p, and apoptosis-related factors in PA tissues, cells, or tumor tissues were detected by RT-qPCR, Western blot, or IHC.

Results

PCAT6 and BRD4 were high-expressed but miR-139-3p was low-expressed in PA. Both the 3′-untranslated regions of PCAT6 and BRD4 mRNAs were demonstrated to contain a potential binding site for miR-139-3p. PCAT6 was positively correlated to BRD4, and miR-139-3p was negatively correlated to PCAT6 and BRD4. MiR-139-3p mimic, shPCAT6 and siBRD4 inhibited the viability, migration, invasion, and proliferation of PA cells while inducing apoptosis. MiR-139-3p mimic and shPCAT6 inhibited the cell cycle progression of PA cells, decreased the weight and volume of the xenotransplanted tumor, and reduced the levels of Bcl-2 and BRD4 while enhancing the levels of Bax, miR-139-3p, and Cleaved caspase-3. MiR-139-3p inhibitor caused the opposite effect of miR-139-3p mimic and further reversed the effect of shPCAT6 on on PA cells.

Conclusion

PCAT6 regulated the progression of PA via modulating the miR-139-3p/BRD4 axis, which might provide a novel biomarker for the prevention, diagnosis, and treatment of PA.
PPP2R2B downregulation is associated with immune evasion and predicts poor clinical outcomes in triple-negative breast cancer
Authors: Li Zheng , Li Yaming , Wang Xiaolong , Yang Qifeng
Published: January 2021

Background

Although immune checkpoint blockade has emerged as a novel promising strategy for triple-negative breast cancer (TNBC), many patients fail response or acquire resistance to current agents. Consequently, our focus need to shift toward alternative inhibitory targets, predictor for responsiveness, and immune suppressive mechanisms.

Methods

In this study, we performed systematic bioinformatics analyses to identify PPP2R2B as a robust tumor suppressor in TNBC. Meanwhile, breast cancer progression cell line model was applied in our research. Quantitative real-time PCR assay (Q-PCR) was carried out to assess the role of PPP2R2B in the onset and progression of breast cancer. Furthermore, we validated the effect of PPP2R2B on immune activity via in vitro experiments based on macrophages. To further decipher the roles of PPP2R2B in TNBC, we investigated the transcriptome level, genomic profiles, and its clinical prognostic value.

Results

In TNBC tissues, PPP2R2B expression was significantly downregulated compared to normal breast tissues. Kaplan‐Meier survival analysis revealed that patients with low PPP2R2B expression had shorter survival time than those with high PPP2R2B expression. Q-PCR analysis suggested that PPP2R2B downregulation could play a key role in breast-cancer initiation and progression. Additionally, our findings showed that PPP2R2B was positively related with CD8 T cells, CD4 Th1 helper cells, and M1 macrophages, but negatively related with M2 macrophages. Subsequent results identified that PPP2R2B was strongly related with immune inhibitor genes (GZMA, PRF1, and IFNG), which could improve T lymphocytes antitumor function and restrict immune evasion. Meanwhile, T cell receptor signaling pathway and antigen processing and presentation signaling pathway were significantly suppressed in low PPP2R2B expression group. Afterwards, distinct subgroups based on PPP2R2B expression exhibited several unique features in somatic mutations, copy numbers alterations, extent of copy number burden, and promoter methylation level.

Conclusion

Our results indicated that PPP2R2B could serve as a promising biomarker for TNBC, and help predict immunotherapeutic response and guide personalized strategies in TNBC treatment.
XPF expression and its relationship with the risk and prognosis of colorectal cancer
Authors: Hu Huixin , Jing Jingjing , Lu Xiaodong , Yuan Yuan , Xing Chengzhong
Published: January 2021

Background

XPF (xeroderma pigmentosum complementation group F) is a key factor contributing to DNA damage excision of nucleotide excision repair pathway. The relationship between XPF expression and the risk and prognosis of colorectal cancer (CRC) is unclear.

Methods

In this experiment, a total of 824 cases of colorectal tissue were collected. XPF protein expression was detected by immunohistochemical staining. We conducted a Mann–Whitney U test in order to explore the differential expression of XPF between CRC and non-cancer controls, and the correlation between XPF expression and CRC clinicopathological parameters. Univariate and multivariate Cox regression analyses were conducted to investigate the relationship between XPF expression and CRC prognosis. The Java based software GSEA as well as STRING, David, GO, KEGG were used to explore the function and regulation network of XPF.

Results

The results demonstrated that the XPF expression in CRC was significantly up-regulated compared with non-tumor controls (P < 0.001) and adenoma tissue (P < 0.001). XPF protein was increased in the dynamic sequence of anal diseases to adenoma tissue to CRC. Expression of XPF was related to tumor location (P = 0.005) and tumor growth pattern (P = 0.009). The results of prognosis analysis suggested that in patients with stage T1-T2, XPF low expression may be significantly associated with better overall survival (HR = 7.978, 95% CI 1.208–52.673, P = 0.031). XPF and its interacting genes played a vital role in different processes of nucleotide excision repair pathway. XPF expression was related with Ubiquitin like protein specific protease activity.

Conclusions

XPF might be a promising biomarker for CRC risk, and also showed potential as a prognostic predictor in CRC patients.
Transition of radical, preventive and presumptive treatment regimens for malaria in China: a systematic review
Authors: Xu Jian-Wei , Lee Rogan , Li Xiao-Hong , Liu Hui
Published: January 2021

Background

Globally, malaria is still a major public health challenge. Drug-based treatment is the primary intervention in malaria control and elimination. However, optimal use of mass or targeted treatments remains unclear. A variety of radical, preventive and presumptive treatment regimens have been administrated in China and a systematic review was conducted to evaluate effectiveness, and discuss experiences, limitations, and lessons learnt in relation to the use of these regimens.

Methods

The search for information includes both paper documents, such as books, malaria control annals and guidelines for malaria prevention and treatment, as well as three computer-based databases in Chinese (CNKI, WanFangdata and Xueshu.baidu) and two databases in English (PubMed and Google Scholar), to identify original articles and reports associated with drug administration for malaria in China.

Results

Starting from hyperendemicity to elimination of malaria in China, a large number of radical, preventive and presumptive treatment regimens had been tried. Those effective regimens were scaled up for malaria control and elimination programmes in China. Between 1949 and 1959, presumptive treatment with available anti-malarial drugs was given to people with enlarged spleens and those who had symptoms suggestive of malaria within the last 6 months. Between 1960 and 1999, mass drug administration (MDA) was given for preventive and radical treatment. Between 2000 and 2009, the approach was more targeted, and drugs were administed only to prevent malaria infection in those at high risk of exposure and those who needed radical treatment for suspected malaria. Presumptive therapy was only given to febrile patients. From 2010, the malaria programme changed into elimination phase, radical treatment changed to target individuals with confirmed either Plasmodium vivax or Plasmodium ovale within the last year. Preventive treatment was given to those who will travel to other endemic countries. Presumptive treatment was normally not given during this elimination phase. All cases of suspected were confirmed by either microscopy or rapid diagnosis tests for malaria antigens before drugs were administered. The engagement of the broader community ensured high coverage of these drug-based interventions, and the directly-observed therapy improved patient safety during drug administration.

Conclusion

A large number of radical, preventive and presumptive treatment regimens for malaria had been tried in China with reported success, but the impact of drug-based interventions has been difficult to quantify because they are just a part of an integrated malaria control strategy. The historical experiences of China suggest that intervention trials should be done by the local health facilities with community involvement, and a local decision is made according to their own trial results.
Pharmacokinetic profile of amodiaquine and its active metabolite desethylamodiaquine in Ghanaian patients with uncomplicated falciparum malaria
Authors: Anyorigiya Thomas A. , Castel Sandra , Mauff Katya , Atuguba Frank , Ogutu Bernhards , Oduro Abraham , Dosoo David , Asante Kwaku-Poku , Owusu-Agyei Seth , Dodoo Alexander , Hodgson Abraham , Binka Fred , Workman Lesley J. , Allen Elizabeth N. , Denti Paolo , Wiesner Lubbe , Barnes Karen I.
Published: January 2021

Background

Accurate measurement of anti-malarial drug concentrations in therapeutic efficacy studies is essential to distinguish between inadequate drug exposure and anti-malarial drug resistance, and to inform optimal anti-malarial dosing in key target population groups.

Methods

A sensitive and selective LC–MS/MS method was developed and validated for the simultaneous determination of amodiaquine and its active metabolite, desethylamodiaquine, and used to describe their pharmacokinetic parameters in Ghanaian patients with uncomplicated falciparum malaria treated with the fixed-dose combination, artesunate-amodiaquine.

Results

The day-28 genotype-adjusted adequate clinical and parasitological response rate in 308 patients studied was > 97% by both intention-to-treat and per-protocol analysis. After excluding 64 patients with quantifiable amodiaquine concentrations pre-treatment and 17 with too few quantifiable concentrations, the pharmacokinetic analysis included 227 patients (9 infants, 127 aged 1–4 years, 91 aged ≥ 5 years). Increased median day-3 amodiaquine concentrations were associated with a lower risk of treatment failure [HR 0.87 (95% CI 0.78–0.98), p = 0.021]. Amodiaquine exposure (median AUC0-∞) was significantly higher in infants (4201 ng h/mL) and children aged 1–5 years (1994 ng h/mL) compared to older children and adults (875 ng h/mL, p = 0.001), even though infants received a lower mg/kg amodiaquine dose (median 25.3 versus 33.8 mg/kg in older patients). Desethylamodiaquine AUC0-∞ was not significantly associated with age. No significant safety concerns were identified.

Conclusions

Efficacy of artesunate-amodiaquine at currently recommended dosage regimens was high across all age groups. Reassuringly, amodiaquine and desethylamodiaquine exposure was not reduced in underweight-for-age young children or those with high parasitaemia, two of the most vulnerable target populations. A larger pharmacokinetic study with close monitoring of safety, including full blood counts and liver function tests, is needed to confirm the higher amodiaquine exposure in infants, understand any safety implications and assess whether dose optimization in this vulnerable, understudied population is needed.
Community demand for comprehensive primary health care from malaria volunteers in South-East Myanmar: a qualitative study
Authors: Win Han Oo  , Hoban Elizabeth , Gold Lisa , Kyu Kyu Than  , Thazin La  , Aung Thi  , Fowkes Freya J. I.
Published: January 2021

Background

Malaria volunteers have contributed significantly to malaria control achieving a reduction of annual parasite incidence to pre-elimination levels in several townships across Myanmar. However, the volunteers’ role is changing as Myanmar transitions from a malaria control to elimination programme and towards the goal of universal health coverage. The aim of the study is to explore the perspectives of community leaders, members and malaria volunteers in South-East Myanmar on community-delivered models to inform an optimal design that targets malaria elimination in the context of primary health care in Myanmar.

Methods

Qualitative methods including focus group discussions (FGDs) with community members and current or ex-malaria volunteers, and participatory workshops with community leaders were conducted. All data collection tools were pilot tested with similar participants. The FGDs were stratified into male and female participants in consideration of diverse gender roles among the ethnic groups of Myanmar. Data saturation was the key cut-off point to cease recruitment of participants. Inductive thematic analysis was used.

Results

Community members were willing to be tested for malaria because they were concerned about the consequences of malaria although they were aware that malaria prevalence is low in their villages. Malaria volunteers were the main service providers for malaria and other infectious diseases in the community. Apart from malaria, the community identified common health problems such as the flu (fever, sneezing and coughing), diarrhoea, skin infections and tuberculosis as priority diseases in this order. Incorporating preventive, and whenever possible curative, services for those diseases into the current malaria volunteer model was recommended.

Discussion and conclusion

There was a gap between the communities’ expectations of health services and the health services currently being delivered by volunteers in the community that highlights the need for reassessment and reform of the volunteer model in the changing context. An evidence-based, community preferred, pragmatic community-delivered integrated model should be constructed based on the context of malaria elimination and progressing towards universal health coverage in Myanmar.
Novel endoscopic optical diagnostic technologies in medical trial research: recent advancements and future prospects
Authors: He Zhongyu , Wang Peng , Ye Xuesong
Published: January 2021

Novel endoscopic biophotonic diagnostic technologies have the potential to non-invasively detect the interior of a hollow organ or cavity of the human body with subcellular resolution or to obtain biochemical information about tissue in real time. With the capability to visualize or analyze the diagnostic target in vivo, these techniques gradually developed as potential candidates to challenge histopathology which remains the gold standard for diagnosis. Consequently, many innovative endoscopic diagnostic techniques have succeeded in detection, characterization, and confirmation: the three critical steps for routine endoscopic diagnosis. In this review, we mainly summarize researches on emerging endoscopic optical diagnostic techniques, with emphasis on recent advances. We also introduce the fundamental principles and the development of those techniques and compare their characteristics. Especially, we shed light on the merit of novel endoscopic imaging technologies in medical research. For example, hyperspectral imaging and Raman spectroscopy provide direct molecular information, while optical coherence tomography and multi-photo endomicroscopy offer a more extensive detection range and excellent spatial–temporal resolution. Furthermore, we summarize the unexplored application fields of these endoscopic optical techniques in major hospital departments for biomedical researchers. Finally, we provide a brief overview of the future perspectives, as well as bottlenecks of those endoscopic optical diagnostic technologies. We believe all these efforts will enrich the diagnostic toolbox for endoscopists, enhance diagnostic efficiency, and reduce the rate of missed diagnosis and misdiagnosis.
Reducing regional health inequality: a sub-national distributional cost-effectiveness analysis of community-based treatment of childhood pneumonia in Ethiopia
Authors: Olsen Maria , Norheim Ole F. , Memirie Solomon Tessema
Published: January 2021

Background

Increasing the coverage of community-based treatment of childhood pneumonia (CCM) is part of the strategy to improve child survival, increase life-expectancy at birth and promote equity in Ethiopia. However, full coverage of CCM has not been reached in any regions of the country. There are no sub-national cost-effectiveness analyses available to inform decision makers on the most equitable scale up strategy.

Objectives

Our first objective is to estimate the sub-national cost-effectiveness and the interindividual inequality impacts of scaling up CCM coverages to 90% in each region. Our second objective is to explore the costs, health effects, and geographical inequality impacts associated with three scale-up scenarios promoting different policy-aims: maximizing health, reducing geographical inequalities, and achieving 90% universal coverage.

Methods

We used Markov modelling to estimate the sub-national cost-effectiveness of CCM in each region. All data were collected through literature review and adjusted to the region-specific proportions of the rural population. Health effects were modeled as life years gained and under-five deaths averted. Interindividual and geographical inequality impacts were measured by the GINI index applied to health. In scenario analysis we explored three different scale-up strategies: 1) maximizing health by prioritizing the regions where the intervention was the most cost-effective, 2) reducing geographical inequalities by prioritizing the regions with high baseline under-five mortality rate (U5MR), and 3) universal upscaling to 90% coverage in all the regions.

Results

The regional incremental-cost effectiveness ratio (ICER) of scaling up the intervention coverage varied from 26 USD per life year gained in Addis to 199 USD per life year gained in the Southern Nations, Nationalities, and Peoples’ region. Universal upscaling of CCM in all regions would cost about 1.3 billion USD and prevent about 90,000 under-five deaths. This is less than 15,000 USD per life saved and translates to an increase in life expectancy at birth of 1.6 years across Ethiopia. In scenario analysis, we found that prioritizing regions with high U5MR is effective in reducing geographical inequalities, although at the cost of fewer lives saved as compared to the health maximizing strategy.

Conclusions

Our model results illustrate a trade-off between maximizing health and reducing health inequalities, two common policy-aims in low-income settings.
Infant mortality inequities for Māori in New Zealand: a tale of three policies
Authors: Rutter Christopher , Walker Simon
Published: January 2021

Background

The history of infant mortality inequities among Māori in New Zealand provides a remarkable case study for understanding the shortcomings of policy which fails to consider the differential risks associated with disadvantaged groups. Specifically, the failure of the initial 1991 reform in addressing Māori infant health, followed by the relative success of post-1994 policy, demonstrate that disadvantaged populations carry differential social risks which require adjusting policy accordingly. Literature on these policies show that differential risks may include disparities in representation, access to resources, socioeconomic status, and racism. The consideration of differential risks is important in analyzing the underlying causes of inequities and social policy deficiencies.

Aim

To describe and illustrate the need for policy addressing inequities to consider the differential risks associated with disadvantaged groups through an analysis of New Zealand’s Māori infant mortality policy progression.

Methods

The article is a commentary on a series of policies aimed at reducing infant mortality in New Zealand. It analyses three policies and how their differences are linked to the corresponding trends in equity between Māori and non-Māori populations.

Findings

The progression of Māori infant mortality policy clearly demonstrates that equitable social policy must be culturally sensitive and inclusive towards disadvantaged groups, as well as willing to adapt to changing circumstances and shortcomings of current policy. Prior to 1994, health policy which did not account for the differential risks of Māori populations caused inequities in infant mortality to increase, despite infant mortality decreasing on a national level. After policy was adjusted to account for Māori-specific risks in 1994, infant mortality inequities significantly declined. A comprehensive analysis of these policies shows that the consideration of differential risks is highly related to a decrease in corresponding inequities.

Conclusions

As New Zealand, and other countries facing inequities such as the United States and Australia, move forward in constructing policy, they would do well to consider the lessons of how New Zealand policy changed the frequency of infant mortality in Māori populations. The study shows that the consideration of differential risks associated with disadvantaged groups is necessary for policy to successfully address inequities.
Willingness to pay for private health insurance among workers with mandatory social health insurance in Mongolia
Authors: Batbold Ochirbat , Pu Christy
Published: January 2021

Background

High out-of-pocket health expenditure is a common problem in developing countries. The employed population, rather than the general population, can be considered the main contributor to healthcare financing in many developing countries. We investigated the feasibility of a parallel private health insurance package for the working population in Ulaanbaatar as a means toward universal health coverage in Mongolia.

Methods

This cross-sectional study used a purposive sampling method to collect primary data from workers in public and primary sectors in Ulaanbaatar. Willingness to pay (WTP) was evaluated using a contingent valuation method and a double-bounded dichotomous choice elicitation questionnaire. A final sample of 1657 workers was analyzed. Perceptions of current social health insurance were evaluated. To analyze WTP, we performed a 2-part model and computed the full marginal effects using both intensive and extensive margins. Disparities in WTP stratified by industry and gender were analyzed.

Results

Only < 40% of the participants were satisfied with the current mandatory social health insurance in Mongolia. Low quality of service was a major source of dissatisfaction. The predicted WTP for the parallel private health insurance for men and women was Mongolian Tugrik (₮)16,369 (p < 0.001) and ₮16,661 (p < 0.001), respectively, accounting for approximately 2.4% of the median or 1.7% of the average salary in the country. The highest predicted WTP was found for workers from the education industry (₮22,675, SE = 3346). Income and past or current medical expenditures were significantly associated with WTP.

Conclusion

To reduce out-of-pocket health expenditure among the working population in Ulaanbaatar, Mongolia, supplementary parallel health insurance is feasible given the predicted WTP. However, given high variations among different industries and sectors, different incentives may be required for participation.
Addressing cancer prevention and control in Armenia: tobacco control and mHealth as key strategies
Authors: Berg Carla J. , Harutyunyan Arusyak , Paichadze Nino , Hyder Adnan A. , Petrosyan Varduhi
Published: January 2021

This paper focuses on the particular challenges in cancer prevention and control (CPC) in low- and middle-income countries (LMICs). In particular, this paper extrapolates challenges and opportunities in Armenia, which has the 2nd highest rate of cancer-related deaths in the world, the 11th highest smoking prevalence among men globally, and an evolving health system infrastructure for non-communicable disease (NCD) prevention and control, including CPC. Despite significant progress in enhancing research capacity in Armenia over the past decade, additional efforts are needed, particularly in CPC-related research. Key opportunities are to advance tobacco control and utilization of mHealth. Public health training programs remain insufficient in the area of CPC, and in-country research expertise regarding CPC and related areas (e.g., tobacco control, mHealth, policy) is limited, particularly given the need to address the diverse and complex determinants of onset, prevention, and management of cancer. Moreover, critical gaps in research dissemination and knowledge translation from evidence to policy and practice continue to exist. Thus, public health infrastructure must be enhanced, in-country CPC leaders across various relevant disciplines must be further developed and supported, and medical and public health training must more fully integrate CPC and research dissemination and translation to inform policy and practice.
Achieving equitable uptake of handwashing and sanitation by addressing both supply and demand-based constraints: findings from a randomized controlled trial in rural Bangladesh
Authors: Parvez Sarker Masud , Rahman Musarrat Jabeen , Azad Rashidul , Rahman Mahbubur , Unicomb Leanne , Ashraf Sania , Mondol Momenul Haque , Jahan Farjana , Winch Peter J. , Luby Stephen P.
Published: January 2021

Background

Supply driven programs that are not closely connected to community demand and demand-driven programs that fail to ensure supply both risk worsening inequity. Understanding patterns of uptake of behaviors among the poorest under ideal experimental conditions, such as those of an efficacy trial, can help identify strategies that could be strengthened in routine programmatic conditions for more equitable uptake. WASH Benefits Bangladesh was a randomized controlled efficacy trial that provided free-of cost WASH hardware along with behavior change promotion. The current paper aimed to determine the impact of the removal of supply and demand constraints on the uptake of handwashing and sanitation behaviors across wealth and education levels.

Methods

The current analysis selected 4 indicators from the WASH Benefits trial— presence of water and soap in household handwashing stations, observed mother’s hand cleanliness, observed visible feces on latrine slab or floor and reported last child defecation in potty or toilet. A baseline assessment was conducted immediately after enrolment and endline assessment was conducted approximately 2 years later. We compared change in uptake of these indicators including wealth quintiles (Q) between intervention and control groups from baseline to endline.

Results

For hand cleanliness, the poorest mothers improved more [Q1 difference in difference, DID: 16% (7, 25%)] than the wealthiest mothers [Q5 DID: 7% (− 4, 17%)]. The poorest households had largest improvements for observed presence of water and soap in handwashing station [Q1 DID: 82% (75, 90%)] compared to the wealthiest households [Q5 DID: 39% (30, 50%)]. Similarly, poorer household demonstrated greater reductions in visible feces on latrine slab or floor [Q1DID, − 25% (− 35, − 15) Q2: − 34% (− 44, − 23%)] than the wealthiest household [Q5 DID: − 1% (− 11, 8%). For reported last child defecation in potty or toilet, the poorest mothers showed greater improvement [Q1–4 DID: 50–54% (44, 60%)] than the wealthier mothers [Q5 DID: 39% (31, 46%).

Conclusion

By simultaneously addressing supply and demand-constraints among the poorest, we observed substantial overall improvements in equity. Within scaled-up programs, a separate targeted strategy that relaxes constraints for the poorest can improve the equity of a program.

Trial registration

WASH Benefits Bangladesh: ClinicalTrials.gov, identifier: NCT01590095. Date of registration: April 30, 2012 ‘Retrospectively registered’.
Prognostic effect of increased left ventricular wall thickness in severe aortic stenosis
Authors: Park Kyungil , Park Tae-Ho , Jo Yoon-Seong , Cho Young-Rak , Park Jong-Sung , Kim Moo-Hyun , Kim Young-Dae
Published: January 2021

Background

It is unclear whether increased left ventricular (LV) thickness is associated with worse clinical outcomes in severe aortic stenosis (AS). The aim of this study was to determine the effect of increased LV wall thickness (LVWT) on major clinical outcomes in patients with severe AS.

Methods and results

This study included 290 severe AS patients (mean age 69.4 ± 11.0 years; 136 females) between January 2008 and December 2018. For outcome assessment, the endpoint was defined as death from all causes, cardiovascular death, and the aortic valve replacement (AVR) surgery rate. During follow-up (48.7 ± 39.0 months), 157 patients had AVR, 43 patients died, and 28 patients died from cardiovascular causes. Patients with increased LVWT underwent AVR surgery much more than those without LVWT (60.0% vs. 39.0%, p < 0.001). Furthermore, in patients with increased LVWT, the all-cause and cardiovascular death rates were significantly lower in the AVR group than in the non-AVR group (8.8% vs. 27.3%, p < 0.001, 4.8%, vs. 21.0%, p < 0.001). Multivariate analysis revealed that increased LVWT, age, dyspnea, and AVR surgery were significantly correlated with cardiovascular death.

Conclusions

In patients with severe AS, increased LVWT was associated with a higher AVR surgery rate and an increased rate of cardiovascular death independent of other well-known prognostic variates. Thus, these findings suggest that increased LVWT might be used as a potential prognostic factor in severe AS patients.
Developing a short-form version of the HIV Disability Questionnaire (SF-HDQ) for use in clinical practice: a Rasch analysis
Authors: O’Brien Kelly K. , Dzingina Mendwas , Harding Richard , Gao Wei , Namisango Eve , Avery Lisa , Davis Aileen M.
Published: January 2021

Background

Disability is an increasingly important health-related outcome to consider as more individuals are now aging with Human Immunodeficiency Virus (HIV) and multimorbidity. The HIV Disability Questionnaire (HDQ) is a patient-reported outcome measure (PROM), developed to measure the presence, severity and episodic nature of disability among adults living with HIV. The 69-item HDQ includes six domains: physical, cognitive, mental-emotional symptoms and impairments, uncertainty and worrying about the future, difficulties with day-to-day activities, and challenges to social inclusion. Our aim was to develop a short-form version of the HIV Disability Questionnaire (SF-HDQ) to facilitate use in clinical and community-based practice among adults living with HIV.

Methods

We used Rasch analysis to inform item reduction using an existing dataset of adults living with HIV in Canada (n = 941) and Ireland (n = 96) who completed the HDQ (n = 1037). We evaluated overall model fit with Cronbach’s alpha and Person Separation Indices (PSIs) (≥ 0.70 acceptable). Individual items were evaluated for item threshold ordering, fit residuals, differential item functioning (DIF) and unidimensionality. For item threshold ordering, we examined item characteristic curves and threshold maps merging response options of items with disordered thresholds to obtain order. Items with fit residuals > 2.5 or less than − 2.5 and statistically significant after Bonferroni-adjustment were considered for removal. For DIF, we considered removing items with response patterns that varied according to country, age group (≥ 50 years versus < 50 years), and gender. Subscales were considered unidimensional if ≤ 5% of t-tests comparing possible patterns in residuals were significant.

Results

We removed 34 items, resulting in a 35-item SF-HDQ with domain structure: physical (10 items); cognitive (3 items); mental-emotional (5 items); uncertainty (5 items); difficulties with day-to-day activities (5 items) and challenges to social inclusion (7 items). Overall models’ fit: Cronbach’s alphas ranged from 0.78 (cognitive) to 0.85 (physical and mental-emotional) and PSIs from 0.69 (day-to-day activities) to 0.79 (physical and mental-emotional). Three items were rescored to achieve ordered thresholds. All domains demonstrated unidimensionality. Three items with DIF were retained because of their clinical importance.

Conclusion

The 35-item SF-HDQ offers a brief, comprehensive disability PROM for use in clinical and community-based practice with adults living with HIV.
Genomic profile of metastatic breast cancer patient-derived xenografts established using percutaneous biopsy
Authors: Kim Seongyeong , Shin Dongjin , Min Ahrum , Kim Minjung , Na Deukchae , Lee Han-Byeol , Ryu Han Suk , Yang Yaewon , Woo Go-Un , Lee Kyung-Hun , Lee Dae-Won , Kim Tae-Yong , Lee Charles , Im Seock-Ah , Kim Jong-Il
Published: January 2021

Background

Metastatic breast cancer (mBC) is a complex and life-threatening disease and although it is difficult to cure, patients can benefit from sequential anticancer treatment, including endocrine therapy, targeted therapy and cytotoxic chemotherapy. The patient-derived xenograft (PDX) model is suggested as a practical tool to predict the clinical outcome of this disease as well as to screen novel drugs. This study aimed to establish PDX models in Korean patients and analyze their genomic profiles and utility for translational research.

Methods

Percutaneous core needle biopsy or punch biopsy samples were used for xenotransplantation. Whole exome sequencing and transcriptome analysis were performed to assess the genomic and RNA expression profiles, respectively. Copy number variation and mutational burden were analyzed and compared with other metastatic breast cancer genomic results. Mutational signatures were also analyzed. The antitumor effect of an ATR inhibitor was tested in the relevant PDX model.

Results

Of the 151 cases studied, 40 (26%) PDX models were established. Notably, the take rate of all subtypes, including the hormone receptor-positive (HR +) subtype, exceeded 20%. The PDX model had genomic fidelity and copy number variation that represented the pattern of its donor sample. TP53, PIK3CA, ESR1, and GATA3 mutations were frequently found in our samples, with TP53 being the most frequently mutated, and the somatic mutations in these genes strengthened their frequency in the PDX model. The ESR1 mutation, CCND1 amplification, and the APOBEC signature were significant features in our HR + HER2- PDX model. Fulvestrant in combination with palbociclib showed a partial response to the relevant patient’s tumor harboring the ESR1 mutation, and CCND1 amplification was found in the PDX model. AZD6738, an ATR inhibitor, delayed tumor growth in a relevant PDX model.

Conclusions

Our PDX model was established using core needle biopsy samples from primary and metastatic tissues. Genomic profiles of the samples reflected their original tissue characteristics and could be used for the interpretation of clinical outcomes.
Amniotic fluid-derived multipotent stromal cells drive diabetic wound healing through modulation of macrophages
Authors: Subhan Bibi S. , Kwong Jennifer , Kuhn Joseph F. , Monas Arie , Sharma Sonali , Rabbani Piul S.
Published: January 2021

Background

Cutaneous wounds in patients with diabetes exhibit impaired healing due to physiological impediments and conventional care options are severely limited. Multipotent stromal cells (MSCs) have been touted as a powerful new therapy for diabetic tissue repair owing to their trophic activity and low immunogenicity. However, variations in sources and access are limiting factors for broader adaptation and study of MSC-based therapies. Amniotic fluid presents a relatively unexplored source of MSCs and one with wide availability. Here, we investigate the potential of amniotic fluid-derived multipotent stromal cells (AFMSCs) to restore molecular integrity to diabetic wounds, amend pathology and promote wound healing.

Method

We obtained third trimester amniotic fluid from term cesarean delivery and isolated and expanded MSCs in vitro. We then generated 10 mm wounds in Leprdb/db diabetic mouse skin, and splinted them open to allow for humanized wound modeling. Immediately after wounding, we applied AFMSCs topically to the sites of injuries on diabetic mice, while media application only, defined as vehicle, served as controls. Post-treatment, we compared healing time and molecular and cellular events of AFMSC-treated, vehicle-treated, untreated diabetic, and non-diabetic wounds. A priori statistical analyses measures determined significance of the data.

Result

Average time to wound closure was approximately 19 days in AFMSC-treated diabetic wounds. This was significantly lower than the vehicle-treated diabetic wounds, which required on average 27.5 days to heal (p < 0.01), and most similar to time of closure in wild type untreated wounds (an average of around 18 days). In addition, AFMSC treatment induced changes in the profiles of macrophage polarizing cytokines, resulting in a change in macrophage composition in the diabetic wound bed. We found no evidence of AFMSC engraftment or biotherapy induced immune response.

Conclusion

Treatment of diabetic wounds using amniotic fluid-derived MSCs encourages cutaneous tissue repair through affecting inflammatory cell behavior in the wound site. Since vehicle-treated diabetic wounds did not demonstrate accelerated healing, we determined that AFMSCs were therapeutic through their paracrine activities. Future studies should be aimed towards validating our observations through further examination of the paracrine potential of AFMSCs. In addition, investigations concerning safety and efficacy of this therapy in clinical trials should be pursued.
A monocentric phase I study of vemurafenib plus cobimetinib plus PEG-interferon (VEMUPLINT) in advanced melanoma patients harboring the V600BRAF mutation
Authors: Simeone Ester , Scognamiglio Giosuè , Capone Mariaelena , Giannarelli Diana , Grimaldi Antonio M. , Mallardo Domenico , Madonna Gabriele , Curvietto Marcello , Esposito Assunta , Sandomenico Fabio , Sabbatino Francesco , Bayless Nicholas L. , Warren Sarah , Ong SuFey , Botti Gerardo , Flaherty Keith T. , Ferrone Soldano , Ascierto Paolo A.
Published: January 2021

Background

Studies carried out in vitro and in a mouse model have shown that BRAF inhibitors enhance the effects of IFN-α onBRAFV600E melanoma cells through the inhibition of ERK. Therefore, the combination of vemurafenib and IFN-α in patients withBRAFV600E melanoma may provide therapeutic benefits; MEK inhibition may prevent the reactivation of the MAPK pathway induced by BRAF inhibitor resistance.

Patients and methods

In a phase I study, adult patients with advancedBRAFV600-mutated melanoma were treated with vemurafenib + PEG-IFN-α-2b or vemurafenib + cobimetinib + PEG-IFN-α-2b, to assess the safety of the combination and the upregulation of IFN-α/β receptor-1 (IFNAR1).

Results

Eight patients were treated; 59 adverse events with four serious ones (three related to study treatments) were reported. Patients with a pre-treatment IFNAR1 expression on ≤ 35% melanoma cells had a median progression-free survival of 12.0 months (range: 5.6–18.4 months) and a median overall survival of 31.0 months (range: 19.8–42.2 months), while patients with a pre-treatment IFNAR1 expression on > 35% of melanoma cells had a median progression-free survival of 4.0 months (range: 0–8.8; p = 0.03), and a median overall survival of 5 months (p = 0.02). Following treatment, responders had higher levels of growth-suppressor genes, includingGAS1andDUSP1, and genes involved in a metabolically robust immune response, includingFAP.

Conclusion

Our study supports the overall safety of the vemurafenib + PEG-IFN-α-2b + cobimetinib combination. IFNAR1 expression levels correlated with response to treatment, including survival. Vemurafenib + PEG-IFN-α-2b + cobimetinib would have difficulty finding a niche in the current treatment scenario for advanced melanoma, but we speculate that our findings may contribute to identify subjects particularly responsive to treatment.

Trial registration:The study was registered at clinicaltrials.gov (NCT01959633). Registered 10 October 2013,https://clinicaltrials.gov/ct2/show/NCT01959633