bluuebunny/crossref_metadata_2025 huggingface dataset:
Randomized evaluation of quizartinib and low-dose ara-C vs low-dose ara-C in older acute myeloid leukemia patients
Authors: Dennis Mike , Thomas Ian F. , Ariti Cono , Upton Laura , Burnett Alan K. , Gilkes Amanda , Radia Rohini , Hemmaway Claire , Mehta Priyanka , Knapper Steven , Clark Richard E. , Copland Mhairi , Russell Nigel , Hills Robert K.
Published: October 2021

Survival for older patients with acute myeloid leukemia (AML) unsuitable for intensive chemotherapy is unsatisfactory. Standard nonintensive therapies have low response rates and only extend life by a few months. Quizartinib is an oral Fms-like tyrosine kinase 3 (FLT3) inhibitor with reported activity in wild-type patients. As part of the AML LI trial, we undertook a randomized evaluation of low-dose ara-C (LDAC) with or without quizartinib in patients not fit for intensive chemotherapy. Overall, survival was not improved (202 patients), but in the 27 FLT3-ITD patients, the addition of quizartinib to LDAC improved response (P = .05) with complete remission/complete remission with incomplete haematological recovery for quizartinib + LDAC in 5/13 (38%) vs 0/14 (0%) in patients receiving LDAC alone. Overall survival (OS) in these FLT3-ITD+ patients was also significantly improved at 2 years for quizartinib + LDAC (hazard ratio 0.36; 95% confidence intervals: 0.16, 0.85, P = .04). Median OS was 13.7 months compared with 4.2 months with LDAC alone. This is the first report of an FLT3-targeted therapy added to standard nonintensive chemotherapy that has improved survival in this population. Quizartinib merits consideration for future triplet-based treatment approaches. This trial was registered at www.clinicaltrials.gov as ISRCTN #ISRCTN40571019 and EUDRACT @2011-000749-19.
Evans syndrome in adults: an observational multicenter study
Authors: Fattizzo Bruno , Michel Marc , Giannotta Juri Alessandro , Hansen Dennis Lund , Arguello Maria , Sutto Emanuele , Bianchetti Nicola , Patriarca Andrea , Cantoni Silvia , Mingot-Castellano María Eva , McDonald Vickie , Capecchi Marco , Zaninoni Anna , Consonni Dario , Vos Josephine Mathilde , Vianelli Nicola , Chen Frederick , Glenthøj Andreas , Frederiksen Henrik , González-López Tomás José , Barcellini Wilma
Published: October 2021

Evans syndrome (ES) is a rare condition, defined as the presence of 2 autoimmune cytopenias, most frequently autoimmune hemolytic anemia and immune thrombocytopenia (ITP) and rarely autoimmune neutropenia. ES can be classified as primary or secondary to various conditions, including lymphoproliferative disorders, other systemic autoimmune diseases, and primary immunodeficiencies, particularly in children. In adult ES, little is known about clinical features, disease associations, and outcomes. In this retrospective international study, we analyzed 116 adult patients followed at 13 European tertiary centers, focusing on treatment requirements, occurrence of complications, and death. ES was secondary to or associated with underlying conditions in 24 cases (21%), mainly other autoimmune diseases and hematologic neoplasms. Bleeding occurred in 42% of patients, mainly low grade and at ITP onset. Almost all patients received first-line treatment (steroids with or without intravenous immunoglobulin), and 23% needed early additional therapy for primary refractoriness. Additional therapy lines included rituximab, splenectomy, immunosuppressants, thrombopoietin receptor agonists, and others, with response rates >80%. However, a remarkable number of relapses occurred, requiring ≥3 therapy lines in 54% of cases. Infections and thrombotic complications occurred in 33% and 21% of patients, respectively, mainly grade ≥3, and correlated with the number of therapy lines. In addition to age, other factors negatively affecting survival were severe anemia at onset and occurrence of relapse, infection, and thrombosis. These data show that adult ES is often severe and marked by a relapsing clinical course and potentially fatal complications, pinpointing the need for high clinical awareness, prompt therapy, and anti-infectious/anti-thrombotic prophylaxis.
Overexpression of γ-glutamylcysteine synthetase gene from Caragana korshinskii decreases stomatal density and enhances drought tolerance
Authors: Lu Baiyan , Luo Xinjuan , Gong Chunmei , Bai Juan
Published: October 2021

Background

Gamma-glutamylcysteine synthetase (γ-ECS) is a rate-limiting enzyme in glutathione biosynthesis and plays a key role in plant stress responses. In this study, the endogenous expression of the Caragana korshinskiiγ-ECS (Ckγ-ECS) gene was induced by PEG 6000-mediated drought stress in the leaves of C. korshinskii. and the Ckγ-ECS overexpressing transgenic Arabidopsis thaliana plants was constructed using the C. korshinskii. isolated γ-ECS.

Results

Compared with the wildtype, the Ckγ-ECS overexpressing plants enhanced the γ-ECS activity, reduced the stomatal density and aperture sizes; they also had higher relative water content, lower water loss, and lower malondialdehyde content. At the same time, the mRNA expression of stomatal development-related gene EPF1 was increased and FAMA and STOMAGEN were decreased. Besides, the expression of auxin-relative signaling genes AXR3 and ARF5 were upregulated.

Conclusions

These changes suggest that transgenic Arabidopsis improved drought tolerance, and Ckγ-ECS may act as a negative regulator in stomatal development by regulating the mRNA expression of EPF1 and STOMAGEN through auxin signaling.
Trimetazidine offers myocardial protection in elderly coronary artery disease patients undergoing non-cardiac surgery: a randomized, double-blind, placebo-controlled trial
Authors: Dai Zhong-Liang , Song Yi-Feng , Tian Ya , Li Yin , Lin Miao , Lin Juan , Wang Qi , Wang Ping , Gao Wen-Li
Published: October 2021

Background

Trimetazidine (TMZ) pretreatment protects cardiomyocytes during cardiac surgery. TMZ may protect elderly patients with ischaemic heart disease (IHD) undergoing non-cardiac surgery.

Methods

This was a randomized, double-blind, placebo-controlled trial (registration #ChiCTR1900025018) of patients with IHD scheduled to undergo non-cardiac surgery at Shenzhen People’s Hospital (Shenzhen, Guangdong Province, China) between June 2014 and September 2015, randomized to 60 mg TMZ or placebo 12 h before surgery. The primary endpoint was the occurrence of in-hospital cardiovascular events. The secondary endpoints were myocardial ischaemia on five-lead electrocardiogram (cECG), cardiac troponin I (cTnI) elevation, cardiac death, acute coronary events, heart failure, and arrhythmia requiring treatments.

Results

Compared with the placebo group, the TMZ group showed a lower occurrence of in-hospital cardiovascular events (primary endpoint, 20.0% vs. 37.5%, P = 0.02), myocardial ischaemia (15.0% vs. 32.5%, P < 0.01), cTnI elevation (2.5% vs. 10%, P < 0.01), acute coronary events (10.0% vs. 20.0%, P < 0.05), heart failure (0% vs. 2.5%, P < 0.05), and arrhythmia requiring treatment (17.5% vs. 35.0%, P < 0.05). There was no acute myocardial infarction during the 30-day postoperative period.

Conclusions

In elderly patients with IHD undergoing non-cardiac surgery, TMZ pretreatment was associated with myocardial protective effects.

Trial registration The trial was prospectively registered at http://www.chictr.org.cn/showproj.aspx?proj=41909 with registration number [ChiCTR1900025018] (7/8/2019).
Impact of the HOP-UP-PT program on older adults at risk to fall: a randomized controlled trial
Authors: Arena Sara K. , Wilson Christopher M. , Boright Lori , Peterson Edward
Published: October 2021

Background

Reduced falls and fall risks have been observed among older adults referred to the HOP-UP-PT (Home-based Older Persons Upstreaming Prevention-Physical Therapy) program. The purpose of this study was to describe outcomes of HOP-UP-PT program participants and then to compare these outcomes to non-participants.

Methods

Six Michigan senior centers referred adults ≥65 years who were at-risk for functional decline or falls. 144 participants (n = 72 per group) were randomized to either the experimental group (EG) or the control group (CG). Physical therapists (PTs) delivered physical, environmental, and health interventions to the EG over nine encounters (six in-person, three telerehabilitation) spanning seven months. The CG participants were told to continue their usual physical activity routines during the same time frame. Baseline and re-assessments were conducted at 0-, 3-, and 7-months in both groups. Descriptions and comparisons from each assessment encounter were analyzed.

Results

Participants ages were: EG = 76.6 (7.0) years and CG = 77.2 (8.2). Baseline measures were not significantly different apart from the Short Physical Performance Battery (SPPB) which favored the EG (P = 0.02). While no significant differences were identified in the survey outcomes or home environment assessments, significant differences in favor of the EG were identified in common fall risk indicators including the Timed Up and Go (P = 0.04), Four Test Balance Scale (P = 0.01), and the modified SPPB (P = 0.02) at the 3-month assessment visit. However, these differences were not sustained at the 7-month assessment as, notably, both groups demonstrated positive improvements in the Four Test Balance Score and SPPB. For individuals at a moderate/high fall risk at baseline, 47.8% of CG reported falling at seven months; whereas, only 6.3% of EG participants meeting the same criteria reported a fall after HOP-UP-PT participation.

Conclusions

A prevention-focused multimodal program provided by PTs in older adults’ homes proved beneficial and those with the highest fall risk demonstrated a significant decrease in falls. A collaboration between PTs and community senior centers resulted in upstreaming care delivery that may reduce both the financial and personal burdens associated with falls in an older adult population.

Trial registration

This study was retrospective registered at Clinical Trials.gov, TRN: NCT04814459 on 24/03/2021.
People living with HIV easily lose their immune response to SARS-CoV-2: result from a cohort of COVID-19 cases in Wuhan, China
Authors: Liu Yanbin , Xiao Yanling , Wu Songjie , Marley Gifty , Ming Fangzhao , Wang Xiaoya , Wu Mengmeng , Feng Ling , Tang Weiming , Liang Ke
Published: October 2021

Background

To date, whether the immune response for SARS-CoV-2 infection among people living with HIV(PLWH) is different from HIV-naïve individuals is still not clear.

Methods

In this cohort study, COVID-19 patients admitted to hospitals in Wuhan between January 15 and April 1, 2020, were enrolled. Patients were categorized into PLWH and HIV-naïve group. All patients were followed up regularly (every 15 days) until November 30, 2020, and the immune response towards SARS-CoV-2 was observed.

Results

Totally, 18 PLWH and 185 HIV-naïve individuals with COVID-19 were enrolled. The positive conversion rates of IgG were 56% in PLWH and 88% in HIV-naïve patients respectively, and the peak was on the 45th day after COVID-19 onset. However, the positive rate of IgG dropped to 12% in PLWH and 33% among HIV-naïve individuals by the end of the study. The positive conversion rate of IgG among asymptomatic carriers is significantly lower than that among patients with moderate disease (AOR = 0.24, 95% CI 0.07–0.85). PLWH had a lower IgG seroconversion rate (AOR = 0.11, 95% CI 0.03–0.39) and shorter IgG duration (AHR = 3.99, 95% CI 1.43–11.13) compared to HIV-naïve individuals. Patients with higher lymphocyte counts at onset had a lower positive conversion rate (AOR = 0.30, 95% CI 0.10–0.87) and shorter duration for IgG (AHR = 4.01, 95% CI 1.78–9.02).

Conclusions

The positive conversion rate of IgG for SARS-CoV-2 was relatively lower and quickly lost in PLWH.
Genotypic and phenotypic characteristics of Streptococcus pneumoniae from community-acquired pneumonia patients and healthy asymptomatic participants in Sichuan province, China
Authors: Peng Shihui , Ren Hongyu , Deng Jianping , Zhao Na , Li Yinan , Li Ming , Yuan Qiwu , Zhang Zhengdong , Luo Longze , Zeng Linzi , Wang Bin , Zou Nianli , Gu Changguo , Huang Xin , Liao Zheng , Chen Shenen , Chen Haiying , Li Qun , Qin Tian
Published: October 2021

Background

Streptococcus pneumoniae (S. pneumoniae) is the common cause of community-acquired pneumonia (CAP) and is also found in the upper respiratory tract of healthy people. Hence, the study aimed to compare the serotypes, virulence/pili genes, and antibiotic susceptibility of S. pneumoniae from healthy asymptomatic participants and CAP patients.

Methods

Streptococcus pneumoniae were retrospectively collected from health asymptomatic participants and CAP patients in Sichuan, China. The serotypes were tested by multiplex polymerase chain reaction (PCR) or Quellung reaction. Antibiotic susceptibility testing was performed using the broth microdilution method. The molecular epidemiology of S. pneumoniae was analyzed by multilocus sequence typing (MLST). Additionally, the presence of virulence/pili genes were detected using PCR.

Results

A total of 83 pneumococcal isolates were collected in the current study. Of these, 52 and 31 isolates were from healthy asymptomatic participants and CAP patients, respectively. Most of S. pneumoniae were resistant to erythromycin (ERY), clindamycin (CLI), tetracycline (TET) and trimethoprim-sulfamethoxazole (SXT). 90.4% isolates were classified as multidrug resistant (MDR). The predominant serotypes were 3, 19F and 19A in the CAP carriers, whereas 3, 6 and 19F were the main serotypes among the asymptomatic carriers. The overall coverage rates of pneumococcal conjugate vaccine (PCV) 10 and PCV13 serotypes were 34.9% and 66.3%, respectively. The predominant sequence types (STs) were ST271, ST320, and ST3397. There were significant differences in some resistance and virulence characteristics between CAP patients and asymptomatic carriers. Additionally, clonal complex (CC) 271 strains had higher percentage in resistance to cefuroxime (CXM) and cefotaxime (CEF), meropenem (MER) and cefepime (CFP), which mainly carried the rlrA and sipA genes.

Conclusions

High coverage rate of PCV13 and high prevalence of MDR indicated the necessity to expand immunization with PCV13 and rationally use the antibiotics in Sichuan, China. Importantly, long-term surveillance should be conducted to assess effectiveness brought by vaccines. Our findings may supply new guidance for developing new pneumococcal vaccines.
Factors associated with the use of complementary therapies in Taiwanese patients with systemic lupus erythematosus: a cross-sectional study
Authors: Lu Ming-Chi , Lo Hui-Chin , Chang Hsiu-Hua , Hsu Chia-Wen , Koo Malcolm
Published: October 2021

Background

This study aimed to investigate the prevalence of and the factors associated with the regular use of complementary therapies for Taiwanese patients with systemic lupus erythematosus (SLE).

Methods

In this cross-sectional study, 351 patients with SLE were consecutively recruited from a regional hospital in southern Taiwan from April to August 2019. Demographic and clinical information, including the use of different types of complementary therapies, was ascertained using a self-constructed questionnaire. Disease-specific quality of life was measured using the Lupus Quality of Life (LupusQoL) questionnaire. SLE disease activity was assessed using the rheumatologist-scored Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2 K). Factors associated with the regular use of complementary therapies were evaluated using multiple logistic regression analyses.

Results

Of the 351 patients with SLE, 90.3% were female, and 60.1% were ≥ 40 years of age. The prevalence of the regular use of any type of complementary therapy was 85.5%. The five most popular types of complementary therapy used were (1) fitness walking or strolling, (2) Buddhist prayer or attending temple, (3) vitamin consumption, (4) calcium supplementation, and (5) fish oil supplementation. Multiple logistic regression analyses revealed that the significant and independent factors associated with the regular use of complementary therapies in patients with SLE were age ≥ 40 years (adjusted odds ratio [aOR] 2.76, p = 0.013), nonoverweight or nonobesity (aOR 0.29, p = 0.004), engagement in vigorous exercise in the past year (aOR 4.62, p = 0.002), a lower SLEDAI-2 K score (aOR 0.90, p = 0.029), and a lower score in the physical health domain of the LupusQoL (aOR 0.57, p = 0.001).

Conclusions

A high prevalence of complementary therapy use in Taiwanese patients with SLE was observed. Rheumatologists should routinely ask patients about their use of supplements to minimize the risk of interaction with medical therapy.
Potential antiviral effects of some native Iranian medicinal plants extracts and fractions against influenza A virus
Authors: Mehrbod Parvaneh , Safari Hanieh , Mollai Zeinab , Fotouhi Fatemeh , Mirfakhraei Yasaman , Entezari Hanieh , Goodarzi Saied , Tofighi Zahra
Published: October 2021

Background

Influenza A virus (IAV) infection is a continual threat to the health of animals and humans globally. Consumption of the conventional drugs has shown several side effects and drug resistance. This study was aimed to screen some Iranian medicinal plants extracts and their fractions against influenza A virus.

Methods

Glycyrrhiza glabra (rhizome), Myrtus  commonis (leaves), Melissa officinalis (leaves), Hypericum perforatum (aerial parts), Tilia platyphyllos (flower), Salix alba (bark), and Camellia sinensis (green and fermented leaves) were extracted with 80% methanol and fractionated with chloroform and methanol, respectively. The cytotoxicity of the compounds were determined by MTT colorimetric assay on MDCK cells. The effective concentrations (EC50) of the compounds were calculated from the MTT results compared to the negative control with no significant effects on cell viability. The effects of EC50 of the compounds on viral surface glycoproteins and viral titer were tested by HI and HA virological assays, respectively and compared with oseltamivir and amantadine. Preliminary phytochemical analysis were done for promising anti-IAV extracts and fractions.

Results

The most effective samples against IAV titer (P ≤ 0.05) were crude extracts of G. glabra, M. officinalis and S. alba; methanol fractions of M. communis and M. officinalis; and chloroform fractions of M. communis and C. sinensis (fermented) mostly in co- and pre-penetration combined treatments. The potential extracts and fractions were rich in flavonoids, tannins, steroids and triterpenoids.

Conclusion

The outcomes confirmed a scientific basis for anti-influenza A virus capacity of the extracts and fractions from the selected plants for the first time, and correlated their effects with their phytochemical constituents. It is worth focusing on elucidating pure compounds and identifying their mechanism(s) of action.
Pharmacogenetics: Knowledge assessment amongst Syrian pharmacists and physicians
Authors: Albitar Lina , Alchamat Ghalia Abou
Published: October 2021

Background

Pharmacogenetics targets genetic variations that influence drug response. It is relatively a new science that has not been vastly employed in most developing countries including Syria. Therefore we aimed at evaluating the depth of knowledge in pharmacogenetics and the attitude towards it amongst Syrian pharmacists and physicians.

Methods

We carried out an internet-based questionnaire consisted of 26 questions, sent through specialized websites and private groups with a large number of pharmacists and physicians members. The survey was available online for a period of 1 month.

Results

The total number of respondents was 154, mostly female pharmacists. Our statistical analysis showed a strong positive association between profession (in favour of pharmacists) and pharmacogenetics knowledge p = 0.049; however, no correlation with experience p = 0.811 was found. A significant difference was reported between the knowledge of pharmacists and physicians p = 0.001 concerning drugs that need pharmacogenetics testing before being prescribed. The majority of respondents had no information about applying genetic tests in Syria before prescribing medications nor did they possess the knowledge regarding drugs that show differential responses in patients according to their unique genotypes. In our study, the percentage knowledge assessment score was low in general (mean ± Standard deviation, SD) (46% ± 13.9%). The majority of the respondents agreed that pharmacists should provide counselling to patients on the subject of pharmacogenetics. Respondents’ opinions varied concerning making pharmacogenetics learning a priority.

Conclusion

Lack of pharmacogenetics knowledge was found amongst respondents in general. Our findings raise concerns about the lack of awareness amongst physicians, which may hinder the implementation of this crucial field in Syria. We suggest an emphasis on the role of education, training, and conducting genotyping research on the Syrian population.
Causes of multidrug-resistant tuberculosis from the perspectives of health providers: challenges and strategies for adherence to treatment during the COVID-19 pandemic in Brazil
Authors: Souza Ludmilla Leidianne Limirio , Santos Felipe Lima dos , Crispim Juliane de Almeida , Fiorati Regina Célia , Dias Sónia , Bruce Alexandre Tadashi Inomata , Alves Yan Mathias , Ramos Antônio Carlos Vieira , Berra Thaís Zamboni , da Costa Fernanda Bruzadelli Paulino , Alves Luana Seles , Monroe Aline Aparecida , Fronteira Inês , Arcêncio Ricardo Alexandre
Published: October 2021

Background

Multidrug-resistant tuberculosis (MDR-TB) is a serious phenomenon on a global scale that can worsen with the COVID-19 pandemic. The study aimed to understand the perceptions of health professionals about MDR-TB, their strategies to ensure adherence to treatment and their challenges in the context of the COVID-19 pandemic in a priority municipality for disease control.

Methods

We conducted a qualitative study and recruited 14 health providers (four doctors, three nurses, three nursing technicians, three nursing assistants and a social worker) working in a city in the state of São Paulo, Brazil. Remote semi-structured interviews were conducted with the participants. For data analysis, the thematic content analysis technique was applied according to the study’s theoretical framework.

Results

The study revealed the causes of MDR-TB are associated with poverty, vulnerability, and social risk. A pre-judgement from the providers was observed, namely, all patients do not adhere due their resistance and association with drug abuse or alcoholism. The study also observed difficulty among health providers in helping patients reconstruct and reframe their life projects under a care perspective, which would strengthen adherence. Other issues that weakened adherence were the cuts in social protection and the benefits really necessary to the patients and a challenge for the providers manage that. The participants revealed that their actions were impacted by the pandemic and insecurity and fear manifested by patients after acquiring COVID-19. For alleviating this, medical appointments by telephone, delivery of medicine in the homes of patients and visits by health professionals once per week were provided.

Conclusion

The study advances knowledge by highlighting the challenges faced by the health system with the adherence of patients with MDR-TB in a context aggravated by the pandemic. An improvement in DOT is really necessary to help the patients reframe their lives without prejudices, face their fears and insecurity, recover their self-esteem and motivate in concluding their treatment.
Comparison of Scanpy-based algorithms to remove the batch effect from single-cell RNA-seq data
Authors: Li Jiaqi , Yu Chengxuan , Ma Lifeng , Wang Jingjing , Guo Guoji
Published: October 2021

With the development of single-cell RNA sequencing (scRNA-seq) technology, analysts need to integrate hundreds of thousands of cells with multiple experimental batches. It is becoming increasingly difficult for users to select the best integration methods to remove batch effects. Here, we compared the advantages and limitations of four commonly used Scanpy-based batch-correction methods using two representative and large-scale scRNA-seq datasets. We quantitatively evaluated batch-correction performance and efficiency. Furthermore, we discussed the performance differences among the evaluated methods at the algorithm level.
The cellular niche for intestinal stem cells: a team effort
Authors: Zhu Guoli , Hu Jiulong , Xi Rongwen
Published: October 2021

The rapidly self-renewing epithelium in the mammalian intestine is maintained by multipotent intestinal stem cells (ISCs) located at the bottom of the intestinal crypt that are interspersed with Paneth cells in the small intestine and Paneth-like cells in the colon. The ISC compartment is also closely associated with a sub-epithelial compartment that contains multiple types of mesenchymal stromal cells. With the advances in single cell and gene editing technologies, rapid progress has been made for the identification and characterization of the cellular components of the niche microenvironment that is essential for self-renewal and differentiation of ISCs. It has become increasingly clear that a heterogeneous population of mesenchymal cells as well as the Paneth cells collectively provide multiple secreted niche signals to promote ISC self-renewal. Here we review and summarize recent advances in the regulation of ISCs with a main focus on the definition of niche cells that sustain ISCs.
Vertebrate cardiac regeneration: evolutionary and developmental perspectives
Authors: Cutie Stephen , Huang Guo N.
Published: October 2021

Cardiac regeneration is an ancestral trait in vertebrates that is lost both as more recent vertebrate lineages evolved to adapt to new environments and selective pressures, and as members of certain species developmentally progress towards their adult forms. While higher vertebrates like humans and rodents resolve cardiac injury with permanent fibrosis and loss of cardiac output as adults, neonates of these same species can fully regenerate heart structure and function after injury – as can adult lower vertebrates like many teleost fish and urodele amphibians. Recent research has elucidated several broad factors hypothesized to contribute to this loss of cardiac regenerative potential both evolutionarily and developmentally: an oxygen-rich environment, vertebrate thermogenesis, a complex adaptive immune system, and cancer risk trade-offs. In this review, we discuss the evidence for these hypotheses as well as the cellular participators and molecular regulators by which they act to govern heart regeneration in vertebrates.
Activation of the Melanocortin-4 receptor signaling by α-MSH stimulates nerve-dependent mouse digit regeneration
Authors: Xu Hanqian , Zhang Hailin , Fang Yanqing , Yang Huiran , Chen Ying , Zhang Chao , Lin Gufa
Published: October 2021

Background

Expression of Mc4r in peripheral organs indicates it has broader roles in organ homeostasis and regeneration. However, the expression and function of Mc4r in the mouse limb and digit has not been fully investigated. Our previous work showed that Mc4r−/− mice fail to regenerate the digit, but whether activation of MC4R signaling could rescue digit regeneration, or stimulate proximal digit regeneration is not clear.

Results

We analyzed the expression dynamics of Mc4r in the embryonic and postnatal mouse limb and digit using the Mc4r-gfp mice. We found that Mc4r-GFP is mainly expressed in the limb nerves, and in the limb muscles that are undergoing secondary myogenesis. Expression of Mc4r-GFP in the adult mouse digit is restricted to the nail matrix. We also examined the effect of α-MSH on mouse digit regeneration. We found that administration of α-MSH in the Mc4r+/− mice rescue the delayed regeneration of distal digit tip. α-MSH could rescue distal digit regeneration in denervated hindlimbs. In addition, α-MSH could stimulate regeneration of the proximally amputated digit, which is non-regenerative.

Conclusions

Mc4r expression in the mouse limb and digit is closely related to nerve tissues, and α-MSH/MC4R signaling has a neurotrophic role in mouse digit tip regeneration.
Organoid: a powerful tool to study lung regeneration and disease
Authors: Lu Tiantian , Cao Yiyuan , Zhao Peng , Shen Shengxi , Xi Ying
Published: October 2021

Organoids are three-dimensional self-organizing structures formed by adult tissue stem cells or pluripotent stem cells. They recapitulate cell-cell, cell-niche interactions in tissue development, homeostasis, regeneration and disease, and provide an in vitro model for drug screening. This review summarizes the recent advances of organoid cultures derived from adult lung stem cells and human pluripotent stem cells, especially focusing on the organoids of the distal airway stem/progenitor cells. We also discuss the applications of organoids in studying lung regeneration and pulmonary diseases, including pulmonary fibrosis, airway diseases and Coronavirus disease 2019 (COVID-19).
Single cells and transposable element heterogeneity in stem cells and development
Authors: Hutchins Andrew P.
Published: October 2021

Recent innovations in single cell sequencing-based technologies are shining a light on the heterogeneity of cellular populations in unprecedented detail. However, several cellular aspects are currently underutilized in single cell studies. One aspect is the expression and activity of transposable elements (TEs). TEs are selfish sequences of DNA that can replicate, and have been wildly successful in colonizing genomes. However, most TEs are mutated, fragmentary and incapable of transposition, yet they are actively bound by multiple transcription factors, host complex patterns of chromatin modifications, and are expressed in mRNAs as part of the transcriptome in both normal and diseased states. The contribution of TEs to development and cellular function remains unclear, and the routine inclusion of TEs in single cell sequencing analyses will potentially lead to insight into stem cells, development and human disease.
Deciphering and reconstitution of positional information in the human brain development
Authors: Wang Yi-Fan , Liu Cong , Xu Peng-Fei
Published: October 2021

Organoid has become a novel in vitro model to research human development and relevant disorders in recent years. With many improvements on the culture protocols, current brain organoids could self-organize into a complicated three-dimensional organization that mimics most of the features of the real human brain at the molecular, cellular, and further physiological level. However, lacking positional information, an important characteristic conveyed by gradients of signaling molecules called morphogens, leads to the deficiency of spatiotemporally regulated cell arrangements and cell–cell interactions in the brain organoid development. In this review, we will overview the role of morphogen both in the vertebrate neural development in vivo as well as the brain organoid culture in vitro, the strategies to apply morphogen concentration gradients in the organoid system and future perspectives of the brain organoid technology.
Coordination of EZH2 and SOX2 specifies human neural fate decision
Authors: Zhao Yuan , Wang Tianyu , Zhang Yanqi , Shi Liang , Zhang Cong , Zhang Jingyuan , Yao Jiao , Chen Qianyu , Zhong Xiaofen , Wei Yanxing , Shan Yongli , Pan Guangjin
Published: October 2021

Polycomb repressive complexes (PRCs) are essential in mouse gastrulation and specify neural ectoderm in human embryonic stem cells (hESCs), but the underlying molecular basis remains unclear. Here in this study, by employing an array of different approaches, such as gene knock-out, RNA-seq, ChIP-seq, et al., we uncover that EZH2, an important PRC factor, specifies the normal neural fate decision through repressing the competing meso/endoderm program. EZH2−/− hESCs show an aberrant re-activation of meso/endoderm genes during neural induction. At the molecular level, EZH2 represses meso/endoderm genes while SOX2 activates the neural genes to coordinately specify the normal neural fate. Moreover, EZH2 also supports the proliferation of human neural progenitor cells (NPCs) through repressing the aberrant expression of meso/endoderm program during culture. Together, our findings uncover the coordination of epigenetic regulators such as EZH2 and lineage factors like SOX2 in normal neural fate decision.
The futility of long-term predictions in bipolar disorder: mood fluctuations are the result of deterministic chaotic processes
Authors: Ortiz Abigail , Bradler Kamil , Mowete Maxine , MacLean Stephane , Garnham Julie , Slaney Claire , Mulsant Benoit H. , Alda Martin
Published: October 2021

Background

Understanding the underlying architecture of mood regulation in bipolar disorder (BD) is important, as we are starting to conceptualize BD as a more complex disorder than one of recurring manic or depressive episodes. Nonlinear techniques are employed to understand and model the behavior of complex systems. Our aim was to assess the underlying nonlinear properties that account for mood and energy fluctuations in patients with BD; and to compare whether these processes were different in healthy controls (HC) and unaffected first-degree relatives (FDR). We used three different nonlinear techniques: Lyapunov exponent, detrended fluctuation analysis and fractal dimension to assess the underlying behavior of mood and energy fluctuations in all groups; and subsequently to assess whether these arise from different processes in each of these groups.

Results

There was a positive, short-term autocorrelation for both mood and energy series in all three groups. In the mood series, the largest Lyapunov exponent was found in HC (1.84), compared to BD (1.63) and FDR (1.71) groups [F (2, 87) = 8.42, p < 0.005]. A post-hoc Tukey test showed that Lyapunov exponent in HC was significantly higher than both the BD (p = 0.003) and FDR groups (p = 0.03). Similarly, in the energy series, the largest Lyapunov exponent was found in HC (1.85), compared to BD (1.76) and FDR (1.67) [F (2, 87) = 11.02; p < 0.005]. There were no significant differences between groups for the detrended fluctuation analysis or fractal dimension.

Conclusions

The underlying nature of mood variability is in keeping with that of a chaotic system, which means that fluctuations are generated by deterministic nonlinear process(es) in HC, BD, and FDR. The value of this complex modeling lies in analyzing the nature of the processes involved in mood regulation. It also suggests that the window for episode prediction in BD will be inevitably short.
Saroglitazar improved hepatic steatosis and fibrosis by modulating inflammatory cytokines and adiponectin in an animal model of non-alcoholic steatohepatitis
Authors: Akbari Rasoul , Behdarvand Tahereh , Afarin Reza , Yaghooti Hamid , Jalali Mohammad Taha , Mohammadtaghvaei Narges
Published: October 2021

Background

Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) have become significant global health concerns. In the present study, we aimed to investigate the effects of saroglitazar, a dual PPARα/γ agonist, fenofibrate, a PPAR-α agonist, and pioglitazone, a PPAR-γ agonist on an animal model of NASH.

Methods

Male Wistar rats were fed a high-fat (HF) emulsion via gavage for 7 weeks to induce NASH. The HF-treated rats were grouped into four groups to receive saroglitazar, pioglitazone, fenofibrate, or vehicle. We measured body and liver weight, liver enzymes, serum levels of adiponectin and leptin. We also performed histopathological examinations and gene expression analysis of interleukin 6 (IL-6), tumor necrosis factor-alpha (TNF- α), transforming growth factor-beta (TGF-β), and monocyte chemoattractant protein 1 (MCP-1).

Results

Body weight was markedly normalized by both saroglitazar and fenofibrate, while the liver index only decreased significantly with saroglitazar. Saroglitazar corrected ALT, AST, leptin, and adiponectin levels better than pioglitazone and fenofibrate. All PPAR agonists significantly attenuated the upregulation of the proinflammatory and TGF-β genes, which correlated with the improved steatosis, inflammation of liver tissue, and fibrotic lesions.

Conclusions

As documented by our results, the dual activation of PPARα/γ by saroglitazar could effectively improve steatosis, fibrosis, and aspects of necro-inflammation in the HF-induced NASH model more than fenofibrate and pioglitazone, and it can be more beneficial in the management of NASH.
The spatiotemporal evolution of ancient cities from the late Yangshao to Xia and Shang Dynasties in the Central Plains, China
Authors: Yan Lijie , Yang Ruixia , Lu Peng , Teng Fei , Wang Xia , Zhang Li , Chen Panpan , Li Xiang , Guo Lanbo , Zhao Dong
Published: October 2021

The Central Plains has a long history, rich culture, unique geographical advantages, and profound cultural heritage. The occurrence of ancient cities in the Central Plains marks the formation of Chinese state-level societies. The number, size, and distribution of ancient cities have changed greatly from the late Yangshao to the Xia and Shang Dynasties, which reflects the evolution of settlement and social organization. In this study, Geographic Information System (GIS) spatial database technology was used to establish a spatiotemporal database of ancient cities in the late Yangshao, Longshan, as well as Xia and Shang Dynasties in the Central Plains. This paper uses GIS spatial analysis technology to analyze the relationship between the ancient city distribution and the geographical environment, as well as the evolution of ancient city's shapes and sizes. Furthermore, by using the method of the nearest neighbor distance and gravity center analysis, this paper discusses the agglomeration characteristics and gravity center evolution of ancient cities. The results show that: (1) Most of the ancient cities were distributed in areas below 500 m and within 3 km from the river during the time interval from the late Yangshao to Xia and Shang Dynasties; (2) The shape of the ancient cities gradually changed from circles to squares in the Central Plains, which became a unified model for the later ancient city design; (3) The sizes of the 18 ancient cities in the Yangshao period shared high similarity, with an average area of 20 hectares. The sizes of 24 ancient cities in the Longshan period increased significantly, with an average of 39 hectares. During the Xia and Shang Dynasties, there were 22 ancient cities with an average size of 340 hectares, and the grade of sizes became obvious, marking the entrance into Chinese state-level societies; (4) Cities were scattered in the decentralized pattern during the late Yangshao and Longshan periods, whereas they became agglomerative in Xia and Shang Dynasties. This reflects the evolution of the spatial scopes and social organizational forms; and (5) From the late Yangshao to Xia and Shang Dynasties, the gravity center of ancient cities moved around the Songshan Mountain from the northwest to the southeast and again to the northeast.
Medication errors associated with direct-acting oral anticoagulants: analysis of data from national pharmacovigilance and local incidents reporting databases
Authors: Alrowily Abdulrhman , Jalal Zahraa , Abutaleb Mohammed H. , Osman Nermin A. , Alammari Maha , Paudyal Vibhu
Published: October 2021

Background

For more than a decade, direct oral anticoagulants (DOACs) have been approved in clinical practice for multiple indications such as stroke prevention in non-valvular atrial fibrillation treatment of deep vein thrombosis and pulmonary embolism. This study aimed to explore the nature and contributory factors related to medication errors associated with DOACs in hospital settings.

Methods

Analysis of error reports using data from (a) Saudi Food and Drug Authority pharmacovigilance database and (b) local incidents reporting system from two tertiary care hospitals were included. Errors reported between January 2010 to December 2020 were also included. Statistical analyses were performed using IBM (SPSS) Statistics Version 24.0 software.

Results

A total of 199 medication error incidents were included. The mean (range) age of affected patients was 63.5 (19–96) years. The mean reported duration of treatment when incidents happened was 90 days, with a very wide range from one day to 12 months. Prescribing error was the most common error type representing 81.4% of all errors. Apixaban was the most frequent drug associated with error reporting with 134 (67.3%) incidents, followed by rivaroxaban (18.6%) and dabigatran (14.1%). The majority of the patients (n = 188, 94.5%) showed comorbidities in addition to the conditions related to DOACs. Polypharmacy, an indication of treatment and duration of therapy were amongst the important contributory factors associated with errors.

Conclusions

This observational study demonstrates the nature of DOAC related medication errors in clinical practice. Developing risk prevention and reduction strategies using the expertise of clinical pharmacists are imperative in promoting patient safety associated with DOAC use.
Shadow banking: a bibliometric and content analysis
Authors: Nath Ridoy Deb , Chowdhury Mohammad Ashraful Ferdous
Published: October 2021

This study reports on our systematic review of 2008–2021 literature on shadow banking. We present an overview of the shadow banking sector, wherein we discuss the definitions, evolution, functions, and specific activities that comprise it. We conducted a bibliometric analysis using the VOSviewer bibliometric tool on articles collected from the Scopus database, after which we conducted content analysis on top articles from leading sources, and identified four major streams of shadow banking literature. Additionally, we identified gaps in the literature and proposed seven research questions to be addressed in future studies to advance knowledge of the shadow banking sector. The findings of this review may serve as a robust reference for scholars researching various aspects of shadow banking to develop our understanding of this sector.
Factors associated with medication adherence of hypertensive patients in the Philippines: a systematic review
Authors: Gutierrez Margarita M. , Sakulbumrungsil Rungpetch
Published: October 2021

Background

Diseases of the heart and vascular system are the leading cause of mortality in the Philippines. Hypertension, the most important modifiable risk factor, has a prevalence rate of 28% and a control rate of 20%. Despite the proven efficacy of pharmacologic treatment, medication adherence is reported to be as low as 66%. While there are publications that reported factors that affect adherence in Filipinos, there are no existing research that evaluated them systematically. This review is conducted to present and synthesize findings of published literatures.

Methods

Databases—PubMed, Scopus, Wiley Online library, Science Direct, JSTOR, Web of Science, SAGE journals, and Cochrane—were used to search for articles published from 2000 to 2020 that studied medication adherence in adult Filipino hypertensive population. Out of the initial 1514 articles, 15 articles met the criteria and were included in the analysis. The evidence from the included studies was summarized and discussed in a narrative review using the World Health Organization framework for adherence to long-term therapies as the framework.

Result

The factors that were positively associated with adherence were health care system-related factors: good patient-health provider relationship, accessibility of health services, use of specialty clinics and programs for hypertension, and health insurance. The factors found to be negatively associated with adherence are (1) social economic factors: younger age, single civil status, low educational attainment, and unemployment; (2) patient-related factors: low in health literacy and awareness, knowledge on hypertension, attitude towards hypertension, self-efficacy, and social support; (3) therapy-related factors: inconsistent drug regimen schedule, use of Thiazide and complementary and alternative medicines; (4) condition-related factors: low illness perception, and absence of comorbidities.

Conclusions

Findings should be interpreted with caution because of methodological limitations. Despite this, given that health systems related factors are modifiable, they can be the focus of interventions and future researches to increase medication adherence. Clinicians may also want to screen their Filipino hypertensive patients for factors that are associated to low adherence in order to provide a tailored advice. Longitudinal research studies with heterogeneous samples of hypertensive Filipinos are imperative so that targeted interventions can be developed for the population.
Retinopathy in newly-diagnosed systemic lupus erythematosus: should we screen for ocular involvement?
Authors: Bashiri Hamidreza , Karimi Nooshin , Mostafaei Shayan , Baghdadi Azarakhsh , Nejadhosseinian Mohammad , Faezi Seyedeh Tahereh
Published: October 2021

Background

Ocular manifestations are common in systemic lupus erythematosus (SLE). Retinopathy has previously been linked to disease severity and might have a significant impact on the patient’s quality of life and has also been associated with a poor prognosis in SLE. This study aimed to determine the prevalence of retinopathy among patients who are newly diagnosed with SLE.

Methods

In a cross-sectional study, patients diagnosed with SLE at a tertiary referral clinic were assessed for inclusion between March 2016 and March 2017. Patients who had received treatment for SLE at any time were excluded, as well as patients with hypertension, diabetes mellitus, and coagulopathy. Clinical findings and laboratory test results were recorded, and patients were examined by an ophthalmologist for evidence of retinal pathologies. SLE disease activity index was also calculated for all patients.

Results

With 114 patients included in the final analysis, we found a prevalence of 15.8% for retinopathy among newly-diagnosed SLE patients. Cotton-wool spots were the most common finding (78%). Patients with retinopathy had significantly lower hemoglobin levels, C3 and C4 concentrations, and higher ANA and Anti-dsDNA levels. Also, patients with retinopathy had a significantly higher SLE DAI score.

Conclusions

We found a relatively high rate of retinopathy in SLE patients at the time of their initial diagnosis. Our findings suggest that retinopathy is an early manifestation of the disease. Ophthalmologic screening might be considered for SLE patients at the time of diagnosis, especially for those with severe disease. We also encourage researchers to further evaluate the correlation between retinopathy and disease activity, and the prognosis of ocular involvement.