bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of nanomicelle curcumin capsules on prevention and treatment of oral mucosits in patients under chemotherapy with or without head and neck radiotherapy: a randomized clinical trial
Authors: Kia Seyed Javad , Basirat Maryam , Saedi Hamid Saeidi , Arab Seyed Ali
Published: September 2021

Background

One of the most prevalent complications of chemotherapy and radiotherapy is oral mucositis (OM) and manifests as erythema and ulceration. Curcumin is one of the components of turmeric and possesses anti-inflammatory and anti-oxidative features. Some of studies have proved the effectiveness of Curcumin in OM. This study aimed to investigate the effects of nanomicelle Curcumin on OM related chemotherapy and head and neck radiotherapy.

Methods

In this clinical trial study, 50 patients underwent chemotherapy with or without head and neck radiotherapy were divided into study and control group. The study group was received Curcumin nanomicelle capsules 80 mg twice a day and the control group took placebo two times a day for 7 weeks and the severity and pain of OM was measured.

Results

Oral mucositis severity in control group in the first (P = 0.010), fourth (P = 0.022) and seventh (P < 0.001) weeks were significantly more than the study group. Pain grade in study group was lower than control group only in the seventh week. (P = 0.001) Additionally, NRS incremental gradient in control group was more than study group. OM severity in patients who underwent only chemotherapy in the control group were significantly more than the study group in all weeks. In patients who were under chemotherapy and head and neck radiotherapy, OM in control group was significantly more intense than the study group only in the fourth and seventh weeks.

Conclusions

Nabomicelle Curcumin capsules is effective on prevention and treatment of head and neck radiotherapy and especially chemotherapy induced OM.

Trial registration

Registered 12 February 2019 at Iranian Registry of Clinical Trials (IRCT). IRCT code: IRCT20100101002950N6. https://en.irct.ir/trial/36665. GUMS ethical code: IR.Gums.Rec.1397.296.
How can we improve patients’ access to new drugs under uncertainties? : South Korea’s experience with risk sharing arrangements
Authors: Lee Boram , Bae Eun-Young , Bae SeungJin , Choi Hyun-Jin , Son Kyung-Bok , Lee Young-Sil , Jang Suhyun , Lee Tae-Jin
Published: September 2021

Background

New drugs including cancer drugs and orphan drugs are becoming increasingly more expensive. Risk sharing arrangements (RSAs) could manage the risk based on both financial impact and the health outcome of new drugs if reimbursed. To improve patients’ access to new drugs under uncertainties, many developed countries have adopted RSAs. In this study, we aimed to understand the effects of RSAs in South Korea on patients’ access.

Methods

We reviewed current status of RSA drugs in South Korea. The number of appraisals and time gap between market approval and reimbursement per RSA drug were considered to quantify improvement of patients’ access as they showed how rapidly decisions on reimbursement of RSA drugs were derived. Then, we applied a comparative analysis to determine whether the RSA drugs in South Korea were reimbursed in the UK, Italy, and Australia. Most data for this study were obtained from websites of the governmental department/agencies responsible for appraisal of drug reimbursement in each country. And literatures related to RSAs were investigated as well.

Results

The eligibility for Korean RSAs had two key components - drugs for cancer and rare diseases and not having other alternative treatments. As of the first half of 2019, there were 39 RSA drugs reimbursed in South Korea, the majority of which were financial-based schemes. Refund and expenditure cap were the representative types (89.7%). After introduction of RSAs, the time gap and number of appraisals were decreased. Based on the indications of RSA drugs, the level of drug coverage in South Korea was found lower than Italy, similar to the UK, and higher than Australia.

Conclusions

RSAs in South Korea significantly enhanced patients’ access to new drugs and led to the alleviation of patients’ out-of-pocket expenses. The drug coverage of South Korea had a level comparable to that of other countries. This study provides implications for countries that have a dual mission of containing pharmaceutical expenditure and improving access to new drugs.
Qualitative analysis of Iranian sixth five-year economic, social, and cultural development plan from universal health coverage perspective
Authors: Mahdavi Mahdi , Sajadi Haniye Sadat
Published: September 2021

Background

This research analyzed the Sixth Five-Year Economic, Social, and Cultural Development Plan of the Islamic Republic of Iran (6NPD) to shed light on how the plan addresses the Universal Health Coverage (UHC).

Methods

This research was a qualitative study. We systematically analyzed ‘Secs. 14 -Health, Insurance, Health & Women, and Family’ in the 6NPD. Through a content analysis, we converted this section into meaning units and coded them. Coding was guided through the conceptual framework ‘Six Building Blocks of Health System’ and the key principles of UHC.

Results

Six themes and twenty-one subthemes were identified. The subthemes offinancinginclude a fair and secured process of resource pooling, payment methods, revenue generation for the health sector, and a definition of a basic benefits package. The subthemes ofgovernance and leadershipconsist of social insurance policies’ integration, compliance of providers, a designation of the Ministry of Health and Medical Education (MoHME) as the regulator and the steward of health resources, a payer-provider split, and stakeholders’ participation. The subthemesof health workforceemphasizes balancing the quality and quantity of the health workforce with populations’ health needs and the health system’s requirements. The subthemes ofhealth information systems consist of the electronic health records for Iranians, information systems for organization and delivery functions, and information systems for the financing function. The subthemes of theorganization and deliveryconsider improving effectiveness and efficiency of healthcare delivery, strengthening the family physician program and referral system, and extending the pre-hospital emergency system. Lastly,access to medicinefocuses on the design and implementation of an essential drug list and drug systems for approving the coverage and provision of generic medicine.

Conclusions

The 6NPD introduced policies for strengthening the 6 building blocks of the health system. It introduced policies to improve financing particularly resource pooling and the sustainability of financial resources. As mandated by 6NPD, centering the health system’s governance/leadership in MoHME may exacerbate the existing conflict of interests and provoke various arguments, which impede the enforcement of rules and regulation. The 6NPD is a step forward in terms of improving financial protection, yet several other policies need to be made to adequately meet the requirement of UHC regarding equity and effective coverage.
Exosomal circRNAs: new players in colorectal cancer
Authors: Vakhshiteh Faezeh , Hassani Shokoufeh , Momenifar Navid , Pakdaman Fatemeh
Published: September 2021

Colorectal cancer (CRC) is one of the most malignant cancer types, characterized by elevated mortality rate and treatment resistance. Despite the progress achieved in the explanation of the molecular basis of the disease as well as introducing potential biomarkers in the clinical practice, further investigation is essential to identify innovative molecules that contribute to colorectal carcinogenesis. Circular RNAs (circRNAs) are a novel and unexplored RNA type, associated with various human pathological conditions. Recently, circRNAs have been identified to be enriched and stable in exosomes and can exert their functions when exosomes reach neighboring or distant cells. Increasing evidence indicates that these so called exosomal circRNAs (exo-circRNAs) act as signaling molecules to regulate cancer proliferation, metastasis, and sensitivity to radio- and chemotherapy. This review aims to discuss the latest progress in exo-circRNAs studies in CRC with an emphasis on their potential as promising diagnostic molecular markers and therapeutic targets.
PREparedness, REsponse and SySTemic transformation (PRE-RE-SyST): a model for disability-inclusive pandemic responses and systemic disparities reduction derived from a scoping review and thematic analysis
Authors: Jesus Tiago S. , Kamalakannan Sureshkumar , Bhattacharjya Sutanuka , Bogdanova Yelena , Arango-Lasprilla Juan Carlos , Bentley Jacob , Landry Michel D. , Papadimitriou Christina ,   Refugee Empowerment Task Force and International Networking Group of the American Congress of Rehabilitation Medicine
Published: September 2021

Background

People with disabilities (PwD) have been facing multiple health, social, and economic disparities during the COVID-19 pandemic, stemming from structural disparities experienced for long time. This paper aims to present the PREparedness, RESponse and SySTemic transformation (PRE-RE-SyST): a model for a disability-inclusive pandemic responses and systematic disparities reduction.

Methods

Scoping review with a thematic analysis was conducted on the literature published up to mid-September 2020, equating to the initial stages of the COVID-19 pandemic. Seven scientific databases and three preprint databases were searched to identify empirical or perspective papers addressing health and socio-economic disparities experienced by PwD as well as reporting actions to address them. Snowballing searches and experts’ consultation were also conducted. Two independent reviewers made eligibility decisions and performed data extractions on any action or recommended action to address disparities. A thematic analysis was then used for the model construction, informed by a systems-thinking approach (i.e., the Iceberg Model).

Results

From 1027 unique references, 84 were included in the final analysis. The PRE-RE-SyST model articulates a four-level strategic action to: 1) Respond to prevent or reduce disability disparities during a pandemic crisis; 2) Prepare ahead for pandemic and other crises responses; 3) Design systems and policies for a structural disability-inclusiveness; and 4) Transform society’s cultural assumptions about disability. ‘Simple rules’ and literature-based examples on how these strategies can be deployed are provided.

Conclusion

The PRE-RE-SyST model articulates main strategies, ‘simple rules’ and possible means whereby public health authorities, policy-makers, and other stakeholders can address disability disparities in pandemic crises, and beyond. Beyond immediate pandemic responses, disability-inclusiveness is needed to develop everyday equity-oriented policies and practices that can transform societies towards greater resiliency, as a whole, to pandemic and other health and social emergencies.
Gender, health and ageing in Fiji: a mixed methods analysis
Authors: Dodd Rebecca , Shanthosh Janani , Lung Thomas , Robaigau Aporosa , Perman Mai Ling , Rafai Eric , Poulos Roslyn , Zwi Anthony B. , John Renu , Palagyi Anna
Published: September 2021

Background

Women are disadvantaged by ageing: older women are more likely than older men to suffer from ill-health, have less access to health care and suffer discrimination within the health care system. Globally, there is a dearth of health research on gender and ageing with substantial knowledge gaps in low and middle-income country contexts. Part of a wider investigation on health and ageing in Fiji, our objective was to identify and describe gendered differences in healthy ageing in this Pacific Island context. We believe this to be the first such study in the Pacific region.

Methods

Applying a health systems lens, we used a mixed-methods approach, encompassing analysis of cause of death data; focus group discussion to gather community and family attitudes to health services; and policy analysis, and then used data triangulation techniques to draw out key themes and insights.

Results

We found that gender affects health outcomes among older persons, attitudes towards and experience of healthy ageing, and an older person’s access to and use of health services. We also found that while Fiji’s policy response to ageing has recognised the importance of gender, to-date there has been limited action to address gender differences. Gender (as oppose to sex differences) has direct and indirect implications for the health of older Fijians, while gendered inequalities and patriarchal norms appear to affect both men and women’s experience of ageing and the health system response. Further, gender and age discrimination may be intersecting, intensifying their separate effects.

Conclusion

This study demonstrates the feasibility and importance of applying a gender lens to the study of healthy ageing. Our findings from Fiji may be relevant to other island nations in the south Pacific which share similar challenges of population ageing, a constrained health budget and geographically-dispersed populations. The data triangulation methodology may be considered an efficient and insightful way to examine gendered responses to healthy ageing elsewhere.
Clinical outcome of patients with COVID-19 Pneumonia treated with corticosteroids and colchicine in Colombia
Authors: Pinzón Miguel Alejandro , Cardona Arango Doris , Betancur Juan Felipe , Ortiz Santiago , Holguín Héctor , Arias Arias Carolina , Muñoz Palacio Bernardo J. , Amarillo Michael , Llano Juan Felipe , Montoya Pablo
Published: September 2021

Background

To date, there is no specific antiviral therapy for severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) that causes Coronavirus disease 2019 (Covid-19). Since there is no specific therapy against SARS-CoV2, current efforts aim to prevent contagion through public health measures and develop a protective vaccine. While waiting for the latter, it is necessary to evaluate the drugs that at least, in initial studies, suggested some degree of utility in the management of Covid-19 or its complications. The main objective of the study was to describe the clinical manifestations and outcomes of patients with severe Covid-19 Pneumonia treated with corticosteroids and colchicine.

Materials and methods

A cross sectional study of 301 adult patients with Covid-19 Pneumonia confirmed by Real-Time Polymerase Chain Reaction for SARS-CoV2 (RT-PCR SARS-CoV2), Berlin protocol, who required hospitalization in three hospitals in Antioquia, Colombia. Patients were treated according to the institutional protocol (from March 20, 2020 to June 30, 2020) with corticosteroid if the patient required supplemental oxygen. From July 1, 2020, the management protocol changed with the addition of colchicine to all patients admitted to the institutions. The treatment was supervised and monitored by the same specialist in Infectology of the institutions. We describe the clinical manifestations and outcomes of the patients who received these treatments. The information of the patients was analyzed according to the outcome of interest (alive/dead) with univariate, bivariate, and multivariate measures to adjust the variables that presented statistical association.

Results

All patients had pneumonia documented by chest computed tomography with ground glass images and presented an alveolar pressure/inspired oxygen fraction (PaFi) less than 300. Three hundred one patients were included, 240 (79.7%) received corticosteroids, within these 145 (48.2%) received colchicine also, and the remaining 61 (20.3%) patients did not receive corticosterioids or colchicine. Mortality in the group that received colchicine was lower compared to the group that did not receive it (9.6 vs 14.6%, p-value = 0.179).

Conclusions

Treatment with corticosteroids and colchicine for managing patients with severe Covid-19 Pneumonia was associated with low mortality at the hospital level. Randomized, placebo-controlled studies are required to evaluate the effect of corticosteroids and colchicine on complications or death from Covid-19.
Contextualization of cost-effectiveness evidence from literature for 382 health interventions for the Ethiopian essential health services package revision
Authors: Hailu Alemayehu , Eregata Getachew Teshome , Yigezu Amanuel , Bertram Melanie Y. , Johansson Kjell Arne , Norheim Ole F.
Published: September 2021

Background

Cost-effectiveness of interventions was a criterion decided to guide priority setting in the latest revision of Ethiopia’s essential health services package (EHSP) in 2019. However, conducting an economic evaluation study for a broad set of health interventions simultaneously is challenging in terms of cost, timeliness, input data demanded, and analytic competency. Therefore, this study aimed to synthesize and contextualize cost-effectiveness evidence for the Ethiopian EHSP interventions from the literature.

Methods

The evidence synthesis was conducted in five key steps: search, screen, evaluate, extract, and contextualize. We searched MEDLINE and EMBASE research databases for peer-reviewed published articles to identify average cost-effectiveness ratios (ACERs). Only studies reporting cost per disability-adjusted life year (DALY), quality-adjusted life year (QALY), or life years gained (LYG) were included. All the articles were evaluated using the Drummond checklist for quality, and those with a score of at least 7 out of 10 were included. Information on cost, effectiveness, and ACER was extracted. All the ACERs were converted into 2019 US dollars using appropriate exchange rates and the GDP deflator.

Results

In this study, we synthesized ACERs for 382 interventions from seven major program areas, ranging from US$3 per DALY averted (for the provision of hepatitis B vaccination at birth) to US$242,880 per DALY averted (for late-stage liver cancer treatment). Overall, 56% of the interventions have an ACER of less than US$1000 per DALY, and 80% of the interventions have an ACER of less than US$10,000 per DALY.

Conclusion

We conclude that it is possible to identify relevant economic evaluations using evidence from the literature, even if transferability remains a challenge. The present study identified several cost-effective candidate interventions that could, if scaled up, substantially reduce Ethiopia’s disease burden.
Cancer derived exosomes induce macrophages immunosuppressive polarization to promote bladder cancer progression
Authors: Jiang Ziming , Zhang Yiming , Zhang Yu , Jia Zhankui , Zhang Zhengguo , Yang Jinjian
Published: September 2021

Background

Exosomes mediated crosstalk between tumor cells and other stromal cells including tumor associated macrophages plays an essential role in reprogramming tumor microenvironment (TME) to facilitate tumor progression. However, the mechanism of tumor derived exosomes promotes bladder cancer progression have not been defined.

Methods

Exosomes were extracted from bladder cancer cells MB49 conditioned medium by ultracentrifugation. The effects of MB49-derived exosomes on macrophages polarization were analyzed by qPCR, flow cytometry, and Western blot. The immunosuppressive phenotype and function of MB49-derived exosomes stimulated macrophages were verified by tumor xenograft assays and T cell co-culture experiments. Exosomal miRNAs were analyzed by microarray to identify potential targets regulating macrophage polarization.

Results

MB49-derived exosomes could be ingested by macrophages, consequently promoting macrophages immunosuppressive polarization. Mechanically, the MB49-derived exosomes induced macrophage M2 polarization was mediated by down-regulation of PTEN and activation of AKT/STAT3/6 signaling. Moreover, hindrance of the generation or secretion of exosomes by GW4869 inhibited macrophages differentiation into immunosuppressive phenotype and function, thereby suppressed tumor growth in a mouse subcutaneous tumor model.

Conclusion

Our study confirmed the contribution of bladder cancer derived exosomes on the establishment of immunosuppressive TME and provided a potential therapeutic target for bladder cancer treatment.
Reasons for canakinumab initiation among patients with periodic fever syndromes: a retrospective medical chart review from the United States
Authors: Hur Peter , Lomax Kathleen G. , Ionescu-Ittu Raluca , Manceur Ameur M. , Xie Jipan , Cammarota Jordan , Gautam Raju , Sanghera Navneet , Kim Nina , Grom Alexei A.
Published: September 2021

Background

Although canakinumab has demonstrated efficacy in multiple trials in patients with periodic fever syndromes (PFS), the evidence on initiation of canakinumab among PFS patients in real world setting is not well understood. We aimed to characterize the reasons for canakinumab initiation among patients with PFS, specifically, cryopyrin-associated periodic syndrome (CAPS), hyperimmunoglobulin D syndrome/mevalonate kinase deficiency (HIDS/MKD), TNF receptor-associated periodic syndrome (TRAPS) and familial Mediterranean fever (FMF).

Methods

Physicians retrospectively reviewed the medical charts of PFS patients prescribed canakinumab between 2016 and 2018. Information collected included patient clinical characteristics, reasons for previous treatment discontinuation and canakinumab initiation. The results were summarized for overall patients, and by children (< 18 years) and adults and by subtype of PFS.

Results

Fifty-eight physicians in the US (rheumatologists, 44.8 %; allergists/immunologists, 29.3 %; dermatologists, 25.9 %) abstracted information for 147 patients (children, 46.3 %; males, 57.1 %; CAPS, 36.7 %; TRAPS, 26.5 %; FMF, 26.5 %; HIDS/MKD, 6.8 %; Mixed, 3.4 %). Overall, most patients (90.5 %) received treatment directly preceding canakinumab (NSAIDs, 27.8 % [40.0 % in HIDS/MKD]; anakinra, 24.1 % [32.7 % in CAPS]; colchicine, 21.8 % [35.9 % in FMF]), which were discontinued due to lack of efficacy/effectiveness (39.5 %) and availability of a new treatment (36.1 %). The common reasons for canakinumab initiation were physician perceived efficacy/effectiveness (81.0 %; children, 75.0 %; adults, 86.1 %), lack of response to previous treatment (40.8 %; children, 38.2 %; adults, 43.0 %) and favorable safety profile/tolerability (40.1 %; children, 42.6 %; adults, 38.0 %). Within subtypes, efficacy/effectiveness was the most stated reason for canakinumab initiation in HIDS/MKD (90.9 %), lack of response to previous treatment in FMF (52.4 %) and convenience of administration/dosing in CAPS (27.1 %).

Conclusions

This study provided insights into how canakinumab is initiated in US clinical practice among PFS patients, with physician perceived efficacy/effectiveness of canakinumab, lack of response to previous treatment and favorable safety profile/tolerability of canakinumab being the dominant reasons for canakinumab initiation in all patients and in children and adults and PFS subtypes. Notably, the favorable safety profile/tolerability of canakinumab was more often the reason for initiation among children versus adults.
Cholbam® and Zellweger spectrum disorders: treatment implementation and management
Authors: Anderson Janaina Nogueira , Ammous Zineb , Eroglu Yasemen , Hernandez Erick , Heubi James , Himes Ryan , Palle Sirish
Published: September 2021

Background

Zellweger spectrum disorders (ZSDs) are a rare, heterogenous group of autosomal recessively inherited disorders characterized by reduced peroxisomes numbers, impaired peroxisomal formation, and/or defective peroxisomal functioning. In the absence of functional peroxisomes, bile acid synthesis is disrupted, and multisystem disease ensues with abnormalities in the brain, liver, kidneys, muscle, eyes, ears, and nervous system.

Main body

Liver disease may play an important role in morbidity and mortality, with hepatic fibrosis that can develop as early as the postnatal period and often progressing to cirrhosis within the first year of life. Because hepatic dysfunction can have numerous secondary effects on other organ systems, thereby impacting the overall disease severity, the treatment of liver disease in patients with ZSD is an important focus of disease management. Cholbam® (cholic acid), approved by the U.S. Food and Drug Administration in March 2015, is currently the only therapy approved as adjunctive treatment for patients with ZSDs and single enzyme bile acid synthesis disorders. This review will focus on the use of CA therapy in the treatment of liver disease associated with ZSDs, including recommendations for initiating and maintaining CA therapy and the limitations of available clinical data supporting its use in this patient population.

Conclusions

Cholbam is a safe and well-tolerated treatment for patients with ZSDs that has been shown to improve liver chemistries and reduce toxic bile acid intermediates in the majority of patients with ZSD. Due to the systemic impacts of hepatic damage, Cholbam should be initiated in patients without signs of advanced liver disease.
The non-canonical mechanism of ER stress-mediated progression of prostate cancer
Authors: Pachikov Artem N. , Gough Ryan R. , Christy Caroline E. , Morris Mary E. , Casey Carol A. , LaGrange Chad A. , Bhat Ganapati , Kubyshkin Anatoly V. , Fomochkina Iryna I. , Zyablitskaya Evgeniya Y. , Makalish Tatiana P. , Golubinskaya Elena P. , Davydenko Kateryna A. , Eremenko Sergey N. , Riethoven Jean-Jack M. , Maroli Amith S. , Payne Thomas S. , Powers Robert , Lushnikov Alexander Y. , Macke Amanda J. , Petrosyan Armen
Published: September 2021

Background

The development of persistent endoplasmic reticulum (ER) stress is one of the cornerstones of prostate carcinogenesis; however, the mechanism is missing. Also, alcohol is a physiological ER stress inducer, and the link between alcoholism and progression of prostate cancer (PCa) is well documented but not well characterized. According to the canonical model, the mediator of ER stress, ATF6, is cleaved sequentially in the Golgi by S1P and S2P proteases; thereafter, the genes responsible for unfolded protein response (UPR) undergo transactivation.

Methods

Cell lines used were non-malignant prostate epithelial RWPE-1 cells, androgen-responsive LNCaP, and 22RV1 cells, as well as androgen-refractory PC-3 cells. We also utilized PCa tissue sections from patients with different Gleason scores and alcohol consumption backgrounds. Several sophisticated approaches were employed, including Structured illumination superresolution microscopy, Proximity ligation assay, Atomic force microscopy, and Nuclear magnetic resonance spectroscopy.

Results

Herein, we identified the trans-Golgi matrix dimeric protein GCC185 as a Golgi retention partner for both S1P and S2P, and in cells lacking GCC185, these enzymes lose intra-Golgi situation. Progression of prostate cancer (PCa) is associated with overproduction of S1P and S2P but monomerization of GCC185 and its downregulation. Utilizing different ER stress models, including ethanol administration, we found that PCa cells employ an elegant mechanism that auto-activates ER stress by fragmentation of Golgi, translocation of S1P and S2P from Golgi to ER, followed by intra-ER cleavage of ATF6, accelerated UPR, and cell proliferation. The segregation of S1P and S2P from Golgi and activation of ATF6 are positively correlated with androgen receptor signaling, different disease stages, and alcohol consumption. Finally, depletion of ATF6 significantly retarded the growth of xenograft prostate tumors and blocks production of pro-metastatic metabolites.

Conclusions

We found that progression of PCa associates with translocation of S1P and S2P proteases to the ER and subsequent ATF6 cleavage. This obviates the need for ATF6 transport to the Golgi and enhances UPR and cell proliferation. Thus, we provide the novel mechanistic model of ATF6 activation and ER stress implication in the progression of PCa, suggesting ATF6 is a novel promising target for prostate cancer therapy.
Descriptive study on subjective experience of genetic testing with respect to relationship, family planning and psychosocial wellbeing among women with lynch syndrome
Authors: Kalamo Mari , Mäenpää Johanna , Seppälä Toni , Mecklin Jukka-Pekka , Pylvänäinen Kirsi , Staff Synnöve
Published: September 2021

Background

Due to increased risk of endometrial and ovarian cancer, women belonging to known Lynch Syndrome (LS) families are recommended to undergo germline testing. Current practice in Finland is to offer counselling to women with pathogenic variant and advocate risk-reducing surgery (RRS) after completion of childbirth. The present study aimed to clarify the impacts of positive germline testing on family planning and reproductive decisions of these women, which are relatively unknown.

Methods

Seventy-nine carriers of germline MMR gene pathogenic variant (path_MMR)were identified from the Finnish LS Registry as having genetic testing performed before the age of 45 years and not having undergone hysterectomy or oophorectomy. These women were sent a questionnaire concerning family planning, intimate relationships and psychosocial wellbeing.

Results

Thirty-five women (44.3%) responded. Parity ofpath_MMRcarriers (2.1) was slightly higher than parity among Finnish women in general (1.8). No significant differences were found between parity, number of induced abortions or sterilizations before and after genetic testing. Only minority of subjects reported any influence on family planning (20%) or negative impact on feminine self and body image (14%).

Conclusions

The positive germline testing does not seem to have a major negative impact on family planning, intimate relationships or feminine self and body image. According to the open comments, counselling, supportive and empathic attitude of the professionals seem to have a significant impact on this. These results are a valuable addition to the counselling of LS women at reproductive age.
Regulatory regions in natural transposable element insertions drive interindividual differences in response to immune challenges in Drosophila
Authors: Ullastres Anna , Merenciano Miriam , González Josefa
Published: September 2021

Background

Variation in gene expression underlies interindividual variability in relevant traits including immune response. However, the genetic variation responsible for these gene expression changes remains largely unknown. Among the non-coding variants that could be relevant, transposable element insertions are promising candidates as they have been shown to be a rich and diverse source of cis-regulatory elements.

Results

In this work, we use a population genetics approach to identify transposable element insertions likely to increase the tolerance of Drosophila melanogaster to bacterial infection by affecting the expression of immune-related genes. We identify 12 insertions associated with allele-specific expression changes in immune-related genes. We experimentally validate three of these insertions including one likely to be acting as a silencer, one as an enhancer, and one with a dual role as enhancer and promoter. The direction in the change of gene expression associated with the presence of several of these insertions is consistent with an increased survival to infection. Indeed, for one of the insertions, we show that this is the case by analyzing both natural populations and CRISPR/Cas9 mutants in which the insertion is deleted from its native genomic context.

Conclusions

We show that transposable elements contribute to gene expression variation in response to infection in D. melanogaster and that this variation is likely to affect their survival capacity. Because the role of transposable elements as regulatory elements is not restricted to Drosophila, transposable elements are likely to play a role in immune response in other organisms as well.
Trycycler: consensus long-read assemblies for bacterial genomes
Authors: Wick Ryan R. , Judd Louise M. , Cerdeira Louise T. , Hawkey Jane , Méric Guillaume , Vezina Ben , Wyres Kelly L. , Holt Kathryn E.
Published: September 2021

While long-read sequencing allows for the complete assembly of bacterial genomes, long-read assemblies contain a variety of errors. Here, we present Trycycler, a tool which produces a consensus assembly from multiple input assemblies of the same genome. Benchmarking showed that Trycycler assemblies contained fewer errors than assemblies constructed with a single tool. Post-assembly polishing further reduced errors and Trycycler+polishing assemblies were the most accurate genomes in our study. As Trycycler requires manual intervention, its output is not deterministic. However, we demonstrated that multiple users converge on similar assemblies that are consistently more accurate than those produced by automated assembly tools.
Prevalence of malaria and scrub typhus co-infection in febrile patients: a systematic review and meta-analysis
Authors: Wilairatana Polrat , Kuraeiad Saruda , Rattaprasert Pongruj , Kotepui Manas
Published: September 2021

Background

Little information is available about malaria and scrub typhus co-infection. This study aimed to investigate the pooled prevalence of malaria and scrub typhus co-infection in febrile patients. Further, it aimed to estimate the prevalence of scrub typhus infection among patients with malaria and the odds of co-infection. This will aid the diagnosis and management of co-infected patients in endemic areas.

Methods

We searched for relevant studies in three databases: PubMed, Scopus, and Web of Science. We assessed the quality of the included studies using the Joanna Briggs Institute checklist for analytical cross-sectional studies. We estimated (1) the pooled prevalence of malaria and scrub typhus co-infection, (2) the pooled prevalence of scrub typhus infection in malaria-positive patients, and (3) the pooled odds of co-infection using the DerSimonian–Laird method for random-effects models. The study results and summary estimates were visualized on a forest plot as point estimates (effect size, prevalence) and 95% confidence intervals (CI). We assessed the heterogeneity of the studies by Cochrane Q orI2statistics. We performed subgroup analyses of countries and scrub typhus diagnostic tests to explore the sources of heterogeneity of the included studies. We assessed publication bias if more than 10 studies were used to estimate the outcome. All data analyses were conducted using Stata version 14 (StataCorp, College Station, TX, USA).

Results

Of the 542 studies retrieved from three databases, we included 14 meeting the inclusion criteria in the systematic review and meta-analysis. The pooled prevalence of malaria and scrub typhus co-infection (56 cases) among febrile patients (7920 cases) was 1% (95% CI: 0–1%,I2: 78.28%), while the pooled prevalence of scrub typhus infection (321 cases) in patients with malaria (1418 cases) was 21% (95% CI: 12–30%,I2: 98.15%). Subgroup analysis showed that the pooled prevalence of scrub typhus infection among patients with malaria in India was 8% (95% CI: 4–13%,I2: 85.87%, nine studies with 59/794 cases), while the pooled prevalence of scrub typhus infection among patients with malaria in Thailand was 35% (95% CI: 7–64%,I2: 98.9%, four studies with 262/624 cases). The co-infections did not occur by chance (P = 0.013, odds: 0.43, 95% CI: 0.22–0.84%,I2: 60.9%). In the sensitivity analysis, the pooled prevalence of malaria and scrub typhus co-infection among febrile patients was 0% (95% CI: 0–1%,I2: 59.91%).

Conclusions

The present study showed the pooled prevalence and a significant association between malaria and scrub typhus. The results show the status of co-infection. Further research into co-infection in endemic areas is needed, in particular, to determine whether co-infection can accelerate disease progression or protect against severe disease.

Graphical abstract
Proteoglycan-4 is an essential regulator of synovial macrophage polarization and inflammatory macrophage joint infiltration
Authors: Qadri Marwa , Jay Gregory D. , Zhang Ling X. , Schmidt Tannin A. , Totonchy Jennifer , Elsaid Khaled A.
Published: September 2021

Background

Synovial macrophages perform a multitude of functions that include clearance of cell debris and foreign bodies, tissue immune surveillance, and resolution of inflammation. The functional diversity of macrophages is enabled by distinct subpopulations that express unique surface markers. Proteoglycan-4 (PRG4) is an important regulator of synovial hyperplasia and fibrotic remodeling, and the involvement of macrophages in PRG4’s synovial role is yet to be defined. Our objectives were to study the PRG4’s importance to macrophage homeostatic regulation in the synovium and infiltration of pro-inflammatory macrophages in acute synovitis and investigate whether macrophages mediated synovial fibrosis in Prg4 gene-trap (Prg4GT/GT) murine knee joints.

Methods

Macrophage phenotyping in Prg4GT/GT and Prg4+/+ joints was performed by flow cytometry using pan-macrophage markers, e.g., CD11b, F4/80, and surface markers of M1 macrophages (CD86) and M2 macrophages (CD206). Characterizations of the various macrophage subpopulations were performed in 2- and 6-month-old animals. The expression of inflammatory markers, IL-6, and iNOS in macrophages that are CD86+ and/or CD206+ was studied. The impact of Prg4 recombination on synovial macrophage populations of 2- and 6-month-old animals and infiltration of pro-inflammatory macrophages in response to a TLR2 agonist challenge was determined. Macrophages were depleted using liposomal clodronate and synovial membrane thickness, and the expression of fibrotic markers α-SMA, PLOD2, and collagen type I (COL-I) was assessed using immunohistochemistry.

Results

Total macrophages in Prg4GT/GT joints were higher than Prg4+/+ joints (p<0.0001) at 2 and 6 months, and the percentages of CD86+/CD206− and CD86+/CD206+ macrophages increased in Prg4GT/GT joints at 6 months (p<0.0001), whereas the percentage of CD86−/CD206+ macrophages decreased (p<0.001). CD86+/CD206− and CD86+/CD206+ macrophages expressed iNOS and IL-6 compared to CD86−/CD206+ macrophages (p<0.0001). Prg4 re-expression limited the accumulation of CD86+ macrophages (p<0.05) and increased CD86−/CD206+ macrophages (p<0.001) at 6 months. Prg4 recombination attenuated synovial recruitment of pro-inflammatory macrophages in 2-month-old animals (p<0.001). Clodronate-mediated macrophage depletion reduced synovial hyperplasia, α-SMA, PLOD2, and COL-I expressions in the synovium (p<0.0001).

Conclusions

PRG4 regulates the accumulation and homeostatic balance of macrophages in the synovium. In its absence, the synovium becomes populated with M1 macrophages. Furthermore, macrophages exert an effector role in synovial fibrosis in Prg4GT/GT animals.
Acute respiratory distress syndrome caused by carbon monoxide poisoning and inhalation injury recovered after extracorporeal membrane oxygenation along with direct hemoperfusion with polymyxin B-immobilized fiber column: a case report
Authors: Jang Ji Hoon , Jang Hang Jea , Kim Hyun-Kuk , Park Jin Han , Kim Hyo-Jung , Jo Kyeong Min , Heo Woon , Kim Se Hun , No Tae-Hoon , Lee Jae Ha
Published: September 2021

Background

Inhalation injury from smoke or chemical products and carbon monoxide poisoning are major causes of death in burn patients from fire accidents. Respiratory tract injuries from inhalation injury and carbon monoxide poisoning can lead to acute respiratory distress syndrome and cytokine storm syndrome. In the case of acute respiratory failure needing mechanical ventilation accompanied by cytokine storm, mortality is high and immediate adequate treatment at the emergency department is very important.

Case presentation

This report describes a case of acute respiratory distress syndrome and cytokine storm followed by carbon monoxide poisoning in a 34-year-old Korean male patient who was in a house fire, and was successfully treated by extracorporeal membrane oxygenation and direct hemoperfusion with polymyxin B-immobilized fiber column at emergency department.

Conclusions

To prevent mortality in acute respiratory distress syndrome with cytokine storm from inhalation injury and to promote a better prognosis, we suggest that early implication of extracorporeal membranous oxygenation along with direct hemoperfusion with polymyxin B-immobilized fiber column even at the emergency department should be considered.
Microencapsulated phages show prolonged stability in gastrointestinal environments and high therapeutic efficiency to treat Escherichia coli O157:H7 infection
Authors: Yin Hanjie , Li Jing , Huang Haosheng , Wang Yuxin , Qian Xinjie , Ren Jianluan , Xue Feng , Dai Jianjun , Tang Fang
Published: September 2021

Escherichia coli (E. coli) O157:H7 bacterial infection causes severe disease in mammals and results in substantial economic losses worldwide. Due to the development of antibiotic resistance, bacteriophage (phage) therapy has become an alternative to control O157:H7 infection. However, the therapeutic effects of phages are frequently disappointing because of their low resistance to the gastrointestinal environment. In this study, to improve the stability of phages in the gastrointestinal tract, E. coli O157:H7 phages were microencapsulated and their in vitro stability and in vivo therapeutic efficiency were investigated. The results showed that compared to free phages, the resistance of microencapsulated phages to simulated gastric fluid and bile salts significantly increased. The microencapsulated phages were efficiently released into simulated intestinal fluid, leading to a better therapeutic effect in rats infected with E. coli O157:H7 compared to the effects of the free phages. In addition, the microencapsulated phages were more stable during storage than the free phages, showing how phage microencapsulation can play an essential role in phage therapy.
Country-level land carbon sink and its causing components by the middle of the twenty-first century
Authors: Jiang Lifen , Liang Junyi , Lu Xingjie , Hou Enqing , Hoffman Forrest M. , Luo Yiqi
Published: September 2021

Background

Countries have long been making efforts by reducing greenhouse-gas emissions to mitigate climate change. In the agreements of the United Nations Framework Convention on Climate Change, involved countries have committed to reduction targets. However, carbon (C) sink and its involving processes by natural ecosystems remain difficult to quantify.

Methods

Using a transient traceability framework, we estimated country-level land C sink and its causing components by 2050 simulated by 12 Earth System Models involved in the Coupled Model Intercomparison Project Phase 5 (CMIP5) under RCP8.5.

Results

The top 20 countries with highest C sink have the potential to sequester 62 Pg C in total, among which, Russia, Canada, USA, China, and Brazil sequester the most. This C sink consists of four components: production-driven change, turnover-driven change, change in instantaneous C storage potential, and interaction between production-driven change and turnover-driven change. The four components account for 49.5%, 28.1%, 14.5%, and 7.9% of the land C sink, respectively.

Conclusion

The model-based estimates highlight that land C sink potentially offsets a substantial proportion of greenhouse-gas emissions, especially for countries where net primary production (NPP) likely increases substantially and inherent residence time elongates.
Ellagic acid exerts anti-fibrotic effects on hypertrophic scar fibroblasts via inhibition of TGF-β1/Smad2/3 pathway
Authors: Liu Xianjun , Gao Xinxin , Li Hao , Li Zhandong , Wang Xiaoe , Zhang Li , Wang Bo , Chen Xinxin , Meng Xianglong , Yu Jiaao
Published: September 2021

Hypertrophic scar (HS) is a kind of serious pathological scar with no currently effective treatment. HS fibroblasts (HSFs) are the main effector cells for HS formation. Ellagic acid (EA) exerts regulatory effects in some diseases, but its role in HS remains unclear. This study aimed to evaluate the effect of EA on the fibrotic phenotypes of HSFs and to further investigate the downstream signaling mechanism. The cell counting kit-8 (CCK-8) assay was used to perform cytotoxicity and proliferation assays. HSFs migration was assessed using wound healing and transwell assays. HSFs contraction was measured by a collagen lattice contraction assay and detection of α-smooth muscle actin (α-SMA) expression. The levels of mRNA and protein were determined by qPCR and western blotting, respectively. The results showed that EA inhibited the proliferation, migration, and contraction of HSFs and collagen expression in HSFs in a dose-dependent manner. Furthermore, EA not only suppressed the Smad2/3 pathway but also reversed TGF-β1-induced activation of the Smad2/3 pathway and up-regulation of the fibrotic cellular phenotypes in HSFs. These findings demonstrate that EA exerts anti-fibrotic effects on HSFs by blocking the TGF-β1/Smad2/3 pathway, which indicates that EA is a potential therapeutic candidate for treatment of HS.
Evaluation of a short version of the Experiences in Close Relationships-Revised questionnaire (ECR-RD8): results from a representative German sample
Authors: Ehrenthal Johannes C. , Zimmermann Johannes , Brenk-Franz Katja , Dinger Ulrike , Schauenburg Henning , Brähler Elmar , Strauß Bernhard
Published: September 2021

Background

Attachment insecurity is a prominent risk factor for the development and course of psychiatric and psychosomatic disorders. The Experiences in Close Relationships - Revised (ECR-R) questionnaire is a widely used self-report to assess attachment related anxiety and avoidance. However, its length has the potential to restrict its use in large, multi-instrument studies. The aim of this study was to develop and evaluate a brief version of the ECR-R, and provide norm values for the German population.

Methods

A screening version of the original ECR-R was developed through principal components analysis of datasets from several previous studies. In a representative sample of 2428 randomly selected individuals from the German population, we compared fit indices of different models by means of confirmatory factor analyses (CFA). We investigated the convergent validity of the screening version in an independent convenience sample of 557 participants. Correlations between the short and the full scale were investigated in a re-analysis of the original German ECR-R evaluation sample.

Results

CFA indicated a satisfactory model fit for an eight-item version (ECR-RD8). The ECR-RD8 demonstrated adequate reliability. The subscales correlated as expected with another self-report measure of attachment in an independent sample. Individuals with higher levels of attachment anxiety, but especially higher levels of attachment avoidance were significantly more likely to not be in a relationship, across all age groups. Correlations between the short and the full scale were high.

Conclusions

The ECR-RD8 appears to be a reliable, valid, and economic questionnaire for assessing attachment insecurity. In addition, the reported population-based norm values will help to contextualize future research findings.