bluuebunny/crossref_metadata_2025 huggingface dataset:
Standup comedy principles and the personal monologue to explore interpersonal bias: experiential learning in a health disparities course
Authors: Chin Marshall H. , Aburmishan Mona M. , Zhu Mengqi
Published: February 2022

Background

Interpersonal biases between clinicians and patients contribute to disparities in health care and outcomes by race, ethnicity, and socioeconomic status. We used standup comedy principles and exercises to help medical students recognize how others perceive them and how they perceive others, and engage in difficult discussions around implicit biases and interpersonal racism.

Methods

90 min Zoom workshop with 40 first-year medical students in urban medical school. Intervention consisted of three exercises: Naming icebreaker, Rant and Rave (communicate strong perspective clearly), and Personal Monologue about how others perceive you and how you perceive yourself. Discussion debriefed the personal monologue exercise. Likert scale questions on post-session survey evaluated workshop overall, whether workshop increased skills, and safety of learning environment. Open-ended questions included what trainees liked about the module, what could be improved, and what impact the module had on them?

Results

Seventeen (42.5%) students responded to survey. Six respondents identified as white, 4 as Asian, 1 as Black, 1 as multiracial, and 5 did not identify. Seventy-six percent rated the module as “very good” or “excellent”, and 94% would recommend the module to others. Most respondents reported the workshop helped them become better listeners (75%) and more observant (82%). Eighty-three percent reported the training could help them take better care of patients with lived experiences different than their own. All respondents believed the learning environment was safe, and 94% reported that instructors created an atmosphere in which they could take risks. Thirty-six percent felt stressed. Students reported the workshop helped them recognize their own identities, others’ perceptions, and bidirectional biases, and inspired them to strive for more accurate, authentic interactions with patients.

Conclusions

Standup comedy principles show promise for engaging students in meaningful, safe discussions about perceptions and interpersonal biases rooted in their own personal experiences and those of their classmates.
Developing a patient-centered community-based model for management of multi-drug resistant tuberculosis in Uganda: a discrete choice experiment
Authors: Makabayi-Mugabe Rita , Musaazi Joseph , Zawedde-Muyanja Stella , Kizito Enock , Namwanje Hellen , Aleu Philip , Charlet Danielle , Freitas Lopez Debora B. , Brightman Haley , Turyahabwe Stavia , Nkolo Abel
Published: February 2022

Background

The advent of all-oral regimens for the management of multi-drug resistant tuberculosis (MDR-TB) makes the implementation of community-based directly observed therapy (CB-DOT) a possibility for this group of patients. We set out to determine patient preferences for different attributes of a community-based model for the management of MDR-TB in Uganda.

Methods

The study was conducted at five tertiary referral hospitals. We used a parallel convergent mixed methods study design. To collect quantitative data, we conducted a discrete choice experiment (DCE) with three different attributes of community-based care (DOT provider, location of care, and type of support) combined into eight choice sets, each with two options and an opt-out. We elicited patient reasons for selection of each choice set using qualitative methods. We fitted a mixed logit choice model to determine patient preferences for different attributes of community-based care and estimated the relative importance of each attribute using the range method. and used deductive thematic analysis to understand the reasons for the choices made.

Results

From December 2019 to January 2020, we interviewed 103 patients with MDR-TB. We found that all the three attributes considered were important predicators of choice. The relative importance of each attribute was as follows; the type of additional support (relative importance 36.2%), the location of treatment delivery (33.5%), and the type of DOT provider (30.3%). Participants significantly valued treatment delivered by community health workers (CHWs) or expert clients over that delivered by a family member, treatment delivered at home over that delivered at the workplace, and monthly travel vouchers as the form of additional support over phone call or SMS reminders. Subgroup analyses showed significant differences in preference across HIV status, age groups and duration on MDR-TB treatment, but not across gender.

The preferred model consisted of a CHW giving DOT at home and travel vouchers to enable attendance of monthly clinic follow-up visits to tertiary referral hospitals for treatment monitoring. Qualitative interviews revealed that patients perceived CHWs as knowledgeable and able to offer psychosocial support. Patients also preferred to take medication at home to save both time and money and lower the risk of facing TB stigma.

Conclusion

People with MDR-TB prefer to be supported to take their medicine at home by a member of their community. The effectiveness of this model of care is being further evaluated.
Development of a prognostic pyroptosis-related gene signature for head and neck squamous cell carcinoma patient
Authors: Zhu Weiwen , Zhang Jiayi , Wang Mengyao , Zhai Rundong , Xu Yanbin , Wang Jie , Wang Mengqi , Zhang Hang , Liu Laikui
Published: February 2022

Objective

Head and neck squamous cell carcinoma (HNSCC) is a major threat to public health. Pyroptosis is a form of inflammatory programmed cell death that is still incompletely understood. The role of pyroptotic cell death in HNSCC remains to be fully defined. As such, the present study was developed to explore the potential prognostic utility of a pyroptosis-related gene (PRG) signature in HNSCC.

Methods

PRG expression patterns and the associated mutational landscape in HNSCC were analyzed, after which a 6-gene prognostic model was constructed through least absolute shrinkage and selection operator (LASSO) and Cox regression analyses using the TCGA dataset, followed by validation with two GEO datasets (GSE41643 and GSE65858). The relative expression of the genes in the prognostic model was assessed via RT-qPCR in tumor and paired adjacent normal tissue samples from a 32-patient cohort. Potential predictors of patient outcomes associated with this 6-gene model were identified through topological degree analyses of a protein–protein interaction network. Moreover, the prognostic value of NLRP3 as a predictor of HNSCC patient prognosis was established through immunohistochemical (IHC) analyses of samples from 176 HNSCC patients. Lastly, in vitro studies were performed to further demonstrate the relevance of NLRP3 in the context of HNSCC development.

Results

Differentially expressed PRGs were able to readily differentiate between HNSCC tumors and normal tissues. Risk scores derived from the 6-gene PRG model were independent predictors of HNSCC patient prognosis, and genes that were differentially expressed between low- and high-risk groups were associated with tumor immunity. RT-qPCR assays also showed the potential protective role of NLRP3 in HNSCC patients. IHC analyses further supported the value of NLRP3 as a predictor of HNSCC patient outcomes. Invasion and migration assays demonstrated the potential role of NLRP3 in the inhibition of HNSCC development.

Conclusions

Overall, these results highlight a novel prognostic gene signature that offers value in the context of HNSCC patient evaluation, although additional research will be essential to elucidate the mechanisms linking these PRGs to HNSCC outcomes.
Economic evaluation of severe malaria in children under 14 years in Zambia
Authors: Mtalimanja Michael , Abasse Kassim Said , Mtalimanja James Lamon , Yuan Xu Zheng , Wenwen Du , Xu Wei
Published: February 2022

Introduction

Malaria exerts a significant economic burden on health care providers and households and our study attempts to make claims on the cost effectiveness of artesunate against quinine in patients under 14 years of age in Zambia. Also, to find the average total costs involved in the treatment of severe malaria in children and their impact on household expenditure.

Methods

Cost-effectiveness analysis of severe malaria treatment was conducted from a healthcare provider perspective using a Markov model. Standard costing was performed for the identification, measurement and assessment phases with data from quantification reports for anti-malaria commodities as these documents provides drug procurement costs from suppliers and freight costs. Average and incremental cost-effectiveness ratio were estimated and uncertainties were assessed through probabilistic sensitivity analysis.

Results

In Zambia severe malaria in children has been shown to account for over 45% of the total monthly curative healthcare costs incurred by households compared to the mean per capita monthly income. The cost of treating severe malaria depleted 7.67% of the monthly average household income. According, to the cost effectiveness analysis the of artesunate with quinine the ICER was $105 per death averted.

Conclusion

The use of artesunate over quinine in the treatment of severe malaria in children under 14 years is a highly cost-effective strategy for the healthcare provider in Zambia.
Sex-specific differences in plasma lipid profiles are associated with Gulf War Illness
Authors: Oberlin Sarah , Nkiliza Aurore , Parks Megan , Evans James E. , Klimas Nancy , Keegan Andrew P. , Sullivan Kimberly , Krengel Maxine H. , Mullan Michael , Crawford Fiona , Abdullah Laila
Published: February 2022

Background

Nearly 250,000 veterans from the 1990–1991 Gulf War have Gulf War Illness (GWI), a condition with heterogeneous pathobiology that remains difficult to diagnose. As such, availability of blood biomarkers that reflect the underlying biology of GWI would help clinicians provide appropriate care to ill veterans. In this study, we measured blood lipids to examine the influence of sex on the association between blood lipids and GWI diagnosis.

Methods

Plasma lipid extracts from GWI (n = 100) and control (n = 45) participants were subjected to reversed-phase nano-flow liquid chromatography-mass spectrometry analysis.

Results

An influence of sex and GWI case status on plasma neutral lipid and phospholipid species was observed. Among male participants, triglycerides, diglycerides, and phosphatidylcholines were increased while cholesterol esters were decreased in GWI cases compared to controls. In female participants, ceramides were increased in GWI cases compared to controls. Among male participants, unsaturated triglycerides, phosphatidylcholine and diglycerides were increased while unsaturated cholesterol esters were lower in GWI cases compared to controls. The ratio of arachidonic acid- to docosahexaenoic acid-containing triglyceride species was increased in female and male GWI cases as compared to their sex-matched controls.

Conclusion

Differential modulation of neutral lipids and ratios of arachidonic acid to docosahexaenoic acid in male veterans with GWI suggest metabolic dysfunction and inflammation. Increases in ceramides among female veterans with GWI also suggest activation of inflammatory pathways. Future research should characterize how these lipids and their associated pathways relate to GWI pathology to identify biomarkers of the disorder.
Clinical utility of cerebrospinal fluid-derived circular RNAs in lung adenocarcinoma patients with brain metastases
Authors: Wang Zhen , Yu Ruoying , Chen Xiaoxi , Bao Hua , Cao Ran , Li An-Na , Ou Qiuxiang , Tu Hai-Yan , Zhou Qing , Wu Xue , Lin Zhi-Bo , Wu Yi-Long
Published: February 2022

Background

Free circular RNAs(circRNAs) escaping from primary lesion of cancer to brain are strictly regulated by blood–brain barrier and therefore cerebrospinal fluid (CSF) circRNAs have potential advantage in exploring biomarkers and mechanism of brain metastasis in lung cancer.

Methods

We collected paired cerebrospinal fluid, plasma and tumor tissues from 21 lung adenocarcinoma (ADC) patients with brain metastases (BM) and performed RNA sequencing.

Results

Compared to tumor tissue and plasma, circRNAs in CSF were characterized by lower number of spieces but higher abundance. Notably, CSF-circRNAs displayed high heterogeneity among different BM lung ADC patients. A total of 60 CSF-circRNAs was identified and associated with shorten overall survival. The circRNA-miRNA-mRNA network analysis revealed that the 60 CSF-circRNAs involved in cancer-associated pathways, and five of them showed strong association with WNT signaling pathway. Validation by RT-PCR of CSF and in vitro experiments of the five candidate circRNAs support their potential roles in cell proliferation and invasion.

Conclusions

In summary, our results depicted the heterogenous CSF-circRNAs profiles among BM lung ADC and implied that CSF-circRNAs may be promising prognosis-related biomarkers.
Macitentan attenuates cardiovascular remodelling in infant rats with chronic lung disease
Authors: Baumann Philipp , Greco Francesco , Wiegert Susanne , Wellmann Sven , Pellegrini Giovanni , Cannizzaro Vincenzo
Published: February 2022

Background

Cardiovascular impairment contributes to increased mortality in preterm infants with chronic lung disease. Macitentan, an endothelin-1 receptor antagonist, has the potential to attenuate pulmonary and cardiovascular remodelling.

Methods

In a prospective randomized placebo-controlled intervention trial, Sprague–Dawley rats were exposed to 0.21 or 1.0 fraction of inspired oxygen (FiO2) for 19 postnatal days. Rats were treated via gavage with placebo or macitentan from days of life 5 to 19. Alveoli, pulmonary vessels, α-smooth muscle actin content in pulmonary arterioles, size of cardiomyocytes, right to left ventricular wall diameter ratio, and endothelin-1 plasma concentrations were assessed.

Results

FiO2 1.0 induced typical features of chronic lung disease with significant alveolar enlargement (p = 0.012), alveolar (p = 0.048) and pulmonary vessel rarefaction (p = 0.024), higher α-smooth muscle actin content in pulmonary arterioles (p = 0.009), higher right to left ventricular wall diameter ratio (p = 0.02), and larger cardiomyocyte cross-sectional area (p < 0.001). Macitentan treatment significantly increased pulmonary vessel count (p = 0.004) and decreased right to left ventricular wall diameter ratios (p = 0.002). Endothelin-1 plasma concentrations were higher compared to placebo (p = 0.015). Alveolar number and size, α-smooth muscle actin, and the cardiomyocyte cross-sectional area remained unchanged (all p > 0.05).

Conclusion

The endothelin-1 receptor antagonist macitentan attenuated cardiovascular remodelling in an infant rat model for preterm chronic lung disease. This study underscores the potential of macitentan to reduce cardiovascular morbidity in preterm infants with chronic lung disease.
Number of antenatal care utilization and associated factors among pregnant women in Ethiopia: zero-inflated Poisson regression of 2019 intermediate Ethiopian Demography Health Survey
Authors: Arefaynie Mastewal , Kefale Bereket , Yalew Melaku , Adane Bezawit , Dewau Reta , Damtie Yitayish
Published: February 2022

Background

The frequency of antenatal care utilization enhances the effectiveness of the maternal health programs to maternal and child health. The aim of the study was to determine the number of antenatal care and associated factors in Ethiopia by using 2019 intermediate EDHS.

Methods

Secondary data analysis was done on 2019 intermediate EDHS. A total of 3916.6 weighted pregnant women were included in the analysis. Zero-inflated Poisson regression analysis was done by Stata version 14.0. Incident rate ratio and odds ratio with a 95% confidence interval were used to show the strength and direction of the association.

Result

About one thousand six hundred eighty eight (43.11%) women were attending four and more antenatal care during current pregnancy. Attending primary education (IRR = 1.115, 95% CI: 1.061, 1.172), secondary education (IRR = 1.211, 95% CI: 1.131, 1.297) and higher education (IRR = 1.274, 95% CI: 1.177, 1.378), reside in poorer household wealth index (IRR = 1.074, 95% CI: 1.01, 1.152), middle household wealth index (IRR = 1.095, 95% CI: 1.018, 1.178), rich household wealth index (IRR = 1.129, 95% CI: 1.05, 1.212) and richer household wealth index (IRR = 1.186, 95% CI: 1.089, 1.29) increases the number of antenatal care utilization. The frequency of antenatal care was less likely become zero among women attending primary (AOR = 0.434, 95% CI: 0.346, 0.545), secondary (AOR = 0.113, 95% CI: 0.053, 0.24), higher educational level (AOR = 0.052, 95% CI: 0.007, 0.367) in the inflated part.

Conclusion

The number of antenatal care utilization is low in Ethiopia. Being rural, poorest household index, uneducated and single were factors associated with low number of antenatal care and not attending antenatal care at all. Improving educational coverage and wealth status of women is important to increase the coverage and frequency of antenatal care.
The molecular determinants of antigenic drift in a novel avian influenza A (H9N2) variant virus
Authors: Zheng Yiqing , Guo Yanna , Li Yingfei , Liang Bing , Sun Xiaoyuan , Li Shijia , Xia Huizhi , Ping Jihui
Published: February 2022

Background

In early 2020, a novel H9N2 AIV immune escape variant emerged in South China and rapidly spread throughout mainland China. The effectiveness of the current H9N2 vaccine is being challenged by emerging immune escape strains. Assessing key amino acid substitutions that contribute to antigenic drift and immune escape in the HA gene of circulating strains is critical for understanding virus evolution and in selecting more effective vaccine components.

Methods

In this study, a representative immune escape strain, A/chicken/Fujian/11/2020 (FJ/20), differed from current H9N2 vaccine strain, A/chicken/Anhui/LH99/2017 (AH/17) by 18 amino acids in the head domain in HA protein. To investigate the molecular determinants of antigenic drift of FJ/20, a panel of mutants were generated by reverse genetics including specific amino acids changes in the HA genes of FJ/20 and AH/17. The antigenic effect of the substitutions was evaluated by hemagglutination inhibition (HI) assay and antigenic cartography.

Results

Fujian-like H9N2 viruses had changed antigenicity significantly, having mutated into an antigenically distinct sub-clade. Relative to the titers of the vaccine virus AH/17, the escape strain FJ/20 saw a 16-fold reduction in HI titer against antiserum elicited by AH/17. Our results showed that seven residue substitutions (D127S, G135D, N145T, R146Q, D179T, R182T and T183N) near the HA receptor binding sites were critical for converting the antigenicity of both AH/17 and FJ/20. Especially, the combined mutations 127D, 135G, 145N, and 146R could be a major factor of antigenic drift in the current immune escape variant FJ/20. The avian influenza A (H9N2) variant virus need further ongoing epidemiological surveillance.

Conclusions

In this study, we evaluated the relative contributions of different combinations of amino acid substitutions in the HA globular head domain of the immune escape strain FJ/20 and the vaccine strain AH/17. Our study provides more insights into the molecular mechanism of the antigenic drift of the H9N2 AIV immune escape strain. This work identified important markers for understanding H9N2 AIV evolution as well as for improving vaccine development and control strategies in poultry.
Prolonged culturing of iPSC-derived brain endothelial-like cells is associated with quiescence, downregulation of glycolysis, and resistance to disruption by an Alzheimer’s brain milieu
Authors: Williams Lindsey M. , Fujimoto Takashi , Weaver Riley R. , Logsdon Aric F. , Evitts Kira M. , Young Jessica E. , Banks William A. , Erickson Michelle A.
Published: February 2022

Background

Human induced pluripotent stem cell (hiPSC)-derived brain endothelial-like cells (iBECs) are a robust, scalable, and translatable model of the human blood–brain barrier (BBB). Prior works have shown that high transendothelial electrical resistance (TEER) persists in iBECs for at least 2 weeks, emphasizing the utility of the model for longer term studies. However, most studies evaluate iBECs within the first few days of subculture, and little is known about their proliferative state, which could influence their functions. In this study, we characterized iBEC proliferative state in relation to key BBB properties at early (2 days) and late (9 days) post-subculture time points.

Methods

hiPSCs were differentiated into iBECs using fully defined, serum-free medium. The proportion of proliferating cells was determined by BrdU assays. We evaluated TEER, expression of glycolysis enzymes and tight and adherens junction proteins (TJP and AJP), and glucose transporter-1 (GLUT1) function by immunoblotting, immunofluorescence, and quantifying radiolabeled tracer permeabilities. We also compared barrier disruption in response to TNF-α and conditioned medium (CM) from hiPSC-derived neurons harboring the Alzheimer’s disease (AD)-causing Swedish mutation (APPSwe/+).

Results

A significant decline in iBEC proliferation over time in culture was accompanied by adoption of a more quiescent endothelial metabolic state, indicated by downregulation of glycolysis-related proteins and upregulation GLUT1. Interestingly, upregulation of GLUT1 was associated with reduced glucose transport rates in more quiescent iBECs. We also found significant decreases in claudin-5 (CLDN5) and vascular endothelial-cadherin (VE-Cad) and a trend toward a decrease in platelet endothelial cell adhesion molecule-1 (PECAM-1), whereas zona occludens-1 (ZO-1) increased and occludin (OCLN) remained unchanged. Despite differences in TJP and AJP expression, there was no difference in mean TEER on day 2 vs. day 9. TNF-α induced disruption irrespective of iBEC proliferative state. Conversely, APPSwe/+ CM disrupted only proliferating iBEC monolayers.

Conclusion

iBECs can be used to study responses to disease-relevant stimuli in proliferating vs. more quiescent endothelial cell states, which may provide insight into BBB vulnerabilities in contexts of development, brain injury, and neurodegenerative disease.
k-Shape clustering for extracting macro-patterns in intracranial pressure signals
Authors: Martinez-Tejada Isabel , Riedel Casper Schwartz , Juhler Marianne , Andresen Morten , Wilhjelm Jens E.
Published: February 2022

Background

Intracranial pressure (ICP) monitoring is a core component of neurosurgical diagnostics. With the introduction of telemetric monitoring devices in the last years, ICP monitoring has become feasible in a broader clinical setting including monitoring during full mobilization and at home, where a greater diversity of ICP waveforms are present. The need for identification of these variations, the so-called macro-patterns lasting seconds to minutes—emerges as a potential tool for better understanding the physiological underpinnings of patient symptoms.

Methods

We introduce a new methodology that serves as a foundation for future automatic macro-pattern identification in the ICP signal to comprehensively understand the appearance and distribution of these macro-patterns in the ICP signal and their clinical significance. Specifically, we describe an algorithm based on k-Shape clustering to build a standard library of such macro-patterns.

Results

In total, seven macro-patterns were extracted from the ICP signals. This macro-pattern library may be used as a basis for the classification of new ICP variation distributions based on clinical disease entities.

Conclusions

We provide the starting point for future researchers to use a computational approach to characterize ICP recordings from a wide cohort of disorders.
Comparison of the distribution of lymph node metastases compared to healthy lymph nodes in breast cancer
Authors: Borm Kai J. , Ernst Lucia , Voppichler Julia , Oechsner Markus , Düsberg Mathias , Buschner Gabriel , Weber Wolfgang , Combs Stephanie E. , Duma Marciana N.
Published: February 2022

Background

Current literature lacks a comparison of lymph node metastases and non-pathological lymph nodes distribution in breast cancer patients. The aim of the current retrospective study was to generate a comprehensive atlas of the lymph node system.

Methods

143 breast cancer patients underwent F-18-FDG-PET/CT (PET/CT) imaging for staging purposes and were diagnosed with regional lymph node metastases. Based on the PET/CT data set a total of 326 lymph node metastases and 1826 non-pathological lymph nodes were detected and contoured manually in the patient collective. Using rigid and deformable registration algorithms all structures were transferred to a template planning CT of a standard patient. Subsequently, a 3D-atlas of the distribution of lymph node metastases and non-pathological lymph nodes were generated and compared to each other.

Results

Both, lymph node metastases and non-pathological lymph nodes, accumulated in certain areas (“hot-spots”) within the lymphatic drainage system. However large differences regarding the distribution patterns were detected: lymph node metastases hot spots occurred in close proximity to the subclavian vein in level I-III, whereas the non-pathological lymph nodes accumulated mostly (within a wider range) in level I. In level II and III lymph node metastases exceeded clearly the areas in which non-pathological lymph nodes occurred.

Conclusion

Lymph node metastases and non-pathological lymph node distribution within the lymph node system differ clearly. Based on our results, an individual adjustment of the CTV in order to include visible lymph nodes in level II and III should be discussed.
Survival impact of prophylactic cranial irradiation in small-cell lung cancer in the modern era of magnetic resonance imaging staging
Authors: Lim Yu Jin , Song Changhoon , Kim Hak Jae ,   Korean Association for Lung Cancer,   Korea Central Cancer Registry
Published: February 2022

Background

In the modern era of magnetic resonance imaging (MRI) staging, the benefit of prophylactic cranial irradiation (PCI) in patients with small-cell lung cancer (SCLC) has been controversial. This study evaluated the prognostic impact of PCI in patients with limited- or extensive-stage SCLC who had no brain metastases at diagnosis according to MRI.

Methods

Data from newly diagnosed patients in 2014 from the Korean Association for Lung Cancer Registry database were used. Patients with limited- or extensive-stage SCLC who had no brain metastases according to MRI were identified. Univariate and multivariate survival analyses were conducted to assess the prognostic association of PCI.

Results

Of 107 and 122 patients with limited- and extensive-stage SCLC, 24% and 14% received PCI, respectively. In the limited-stage SCLC group, the 2-year overall survival (OS) rates of patients who received PCI and those who did not were 50% and 29% (P = 0.018), respectively. However, there was no significant difference in OS for patients with extensive-stage SCLC (P = 0.336). After adjusting for other covariates, PCI was found to be associated with improved OS in the limited-stage SCLC group (P = 0.005). Based on the time-course hazard rate function plots in the limited-stage SCLC group, the OS benefit of PCI was maximized within the first year of follow-up.

Conclusions

In the modern era of MRI staging, PCI might be beneficial for patients with limited-stage SCLC but not for those with extensive-stage SCLC. Further studies with a large sample size are needed to verify the prognostic association of PCI.
Utility of next-generation sequencing in genetic testing and counseling of disorders involving the musculoskeletal system—trends observed from a single genetic unit
Authors: Iyer Gayatri R. , Kumar Roshan , Poornima Subhadra , Kamireddy Aruna Priya , Juturu Keerthi Konda , Bhatnagar Lekhangda , Arora Srinka , Suresh Vaishnavi , Utage Prashant R. , Bailur Sarah , Pujar Akhilesh N. , Hasan Qurratulain
Published: February 2022

Background

Disorders involving the musculoskeletal system are often identified with short stature and a range of orthopedic problems. The clinical and genetic heterogeneity of these diseases along with several characteristic overlaps makes definitive diagnosis difficult for clinicians. Hence, using molecular testing in addition to conventional tests becomes essential for appropriate diagnosis and management.

Methods

Comprehensive clinical examination, detailed pretest and posttest counseling, molecular diagnosis with next-generation sequencing (NGS), genotype–phenotype correlation and Sanger sequencing for targeted variant analysis.

Results

This manuscript reports a molecular spectrum of variants in 34 orthopedic cases referred to a single genetic unit attached to a tertiary care hospital. The diagnostic yield of NGS-based tests coupled with genetic counseling and segregation analysis was 79% which included 7 novel variants. In about 53% (i.e. 18/34 cases), molecular testing outcome was actionable since 8 of the 18 underwent prenatal diagnosis, as they were either in their early gestation or had planned a pregnancy subsequent to molecular testing, while ten cases were premaritally/prenatally counseled for the families to take informed decisions as they were in the reproductive age.

Conclusions

The report highlights the importance of NGS-based tests even in a low resource setting as it helps patients, families and healthcare providers in reducing the economic, social and emotional burden of these disorders.
Patients’ access to rare neuromuscular disease therapies varies across US private insurers
Authors: Margaretos Nikoletta M. , Bawa Komal , Engmann Natalie J. , Chambers James D.
Published: February 2022

Background

The extent to which different US private insurers require their enrollees to meet the same coverage criteria before gaining access to treatment is unclear. Our objective was to scrutinize the patient access criteria imposed by US private insurers for a set of rare neuromuscular disease (NMD) disease-modifying therapies (DMTs).

Methods

We examined coverage policies issued by 17 large US private insurers for the following NMD treatments: nusinersen and onasemnogene abeparvovec for spinal muscular atrophy, edaravone for amyotrophic lateral sclerosis, and eteplirsen for Duchenne muscular dystrophy. We reviewed the plans’ coverage policies and identified the patient access criteria, including clinical prerequisites, step therapy protocols, and prescriber requirements. We compared the plans’ patient access criteria with the therapies’ US Food and Drug Administration (FDA)-labeled indications.

Results

The included insurers issued 65 coverage policies for the included therapies. Plans imposed coverage restrictions beyond the FDA-approved indications in 60 coverage policies; plans did not cover eteplirsen in five policies. No therapy was covered the same way by all insurers. Plans applied clinical criteria beyond the FDA label indication in 56 policies and step therapy protocols in three policies. Plans required that a neurologist prescribe the therapy in 37 policies, 22 of which required the neurologist to have expertise in the particular disease. Plans often required patients to suffer from symptoms of particular severity; e.g. for eteplirsen, plans differed in their 6-min walk test requirements; for edaravone, some plans required that patients had normal respiratory function, while others required only that patients did not require ventilation; for nusinersen and onasemnogene abeparvovec, plans differed in the number of SMN2 gene copies they required patients to have (SMN2 copy number is correlated with disease severity).

Conclusions

The evaluated large US private insurers tended to impose coverage restrictions beyond the FDA label indication for the included set of rare NMD DMTs. Plans rarely applied the same patient access criteria in their coverage policies for the same products. Inconsistent coverage criteria mean that patients with different insurers have variable access to the same therapies across insurers.
Effectiveness of non-specialist delivered psychological interventions on glycemic control and mental health problems in individuals with type 2 diabetes: a systematic review and meta-analysis
Authors: Oyedeji Ayodeji D. , Ullah Ibrahim , Weich Scott , Bentall Richard , Booth Andrew
Published: February 2022

Background

Typically, specialist mental health professionals deliver psychological interventions for individuals with poorly controlled type 2 diabetes mellitus (T2DM) and related mental health problems. However, such interventions are not generalizable to low- and middle-income countries, due to the dearth of trained mental health professionals. Individuals with little or no experience in the field of mental health (referred to as non-specialists) may have an important role to play in bridging this treatment gap.

Aim

To synthesise evidence for the effectiveness of non-specialist delivered psychological interventions on glycaemic control and mental health problems in people with T2DM.

Methods

Eight databases and reference lists of previous reviews were systematically searched for randomized controlled trials (RCTs). Outcome measures were glycated hemoglobin (HbA1c), diabetes distress and depression. The Cochrane Collaboration Risk of Bias Tool was used for risk of bias assessment. Data from the included studies were synthesized using narrative synthesis and random effects meta-analysis.

Results

16 RCTs were eligible for inclusion in the systematic review. The 11 studies that were pooled in the meta-analysis demonstrated a reduction in HbA1c in favor of non-specialist delivered psychological interventions when compared with control groups (pooled mean difference = − 0.13; 95% CI − 0.22 to − 0.04, p = 0.005) with high heterogeneity across studies (I2 = 71%, p = 0.0002). The beneficial effects of the interventions on diabetes distress and depression were not consistent across the different trials.

Conclusion

Non-specialist delivered psychological interventions may be effective in improving HbA1c. These interventions have some promising benefits on diabetes distress and depression, although the findings are inconclusive. More studies of non-specialist delivered psychological interventions are needed in low- and middle-income countries to provide more evidence of the potential effectiveness of these interventions for individuals living with T2DM.
Extracorporeal membrane oxygenation for COVID-19 and influenza H1N1 associated acute respiratory distress syndrome: a multicenter retrospective cohort study
Authors: Fanelli Vito , Giani Marco , Grasselli Giacomo , Mojoli Francesco , Martucci Gennaro , Grazioli Lorenzo , Alessandri Francesco , Mongodi Silvia , Sales Gabriele , Montrucchio Giorgia , Pizzi Costanza , Richiardi Lorenzo , Lorini Luca , Arcadipane Antonio , Pesenti Antonio , Foti Giuseppe , Patroniti Nicolò , Brazzi Luca , Ranieri VMarco
Published: February 2022

Background

Extracorporeal membrane oxygenation (ECMO) has become an established rescue therapy for severe acute respiratory distress syndrome (ARDS) in several etiologies including influenza A H1N1 pneumonia. The benefit of receiving ECMO in coronavirus disease 2019 (COVID-19) is still uncertain. The aim of this analysis was to compare the outcome of patients who received veno-venous ECMO for COVID-19 and Influenza A H1N1 associated ARDS.

Methods

This was a multicenter retrospective cohort study including adults with ARDS, receiving ECMO for COVID-19 and influenza A H1N1 pneumonia between 2009 and 2021 in seven Italian ICU. The primary outcome was any-cause mortality at 60 days after ECMO initiation. We used a multivariable Cox model to estimate the difference in mortality accounting for patients’ characteristics and treatment factors before ECMO was started. Secondary outcomes were mortality at 90 days, ICU and hospital length of stay and ECMO associated complications.

Results

Data from 308 patients with COVID-19 (N = 146) and H1N1 (N = 162) associated ARDS who had received ECMO support were included. The estimated cumulative mortality at 60 days after initiating ECMO was higher in COVID-19 (46%) than H1N1 (27%) patients (hazard ratio 1.76, 95% CI 1.17–2.46). When adjusting for confounders, specifically age and hospital length of stay before ECMO support, the hazard ratio decreased to 1.39, 95% CI 0.78–2.47. ICU and hospital length of stay, duration of ECMO and invasive mechanical ventilation and ECMO-associated hemorrhagic complications were higher in COVID-19 than H1N1 patients.

Conclusion

In patients with ARDS who received ECMO, the observed unadjusted 60-day mortality was higher in cases of COVID-19 than H1N1 pneumonia. This difference in mortality was not significant after multivariable adjustment; older age and longer hospital length of stay before ECMO emerged as important covariates that could explain the observed difference.

Trial registration number: NCT05080933, retrospectively registered.
Single-cell isoform analysis in human immune cells
Authors: Volden Roger , Vollmers Christopher
Published: February 2022

High-throughput single-cell analysis today is facilitated by protocols like the 10X Genomics platform or Drop-Seq which generate cDNA pools in which the origin of a transcript is encoded at its 5′ or 3′ end. Here, we used R2C2 to sequence and demultiplex 12 million full-length cDNA molecules generated by the 10X Genomics platform from ~3000 peripheral blood mononuclear cells. We use these reads, independent from Illumina data, to identify B cell, T cell, and monocyte clusters and generate isoform-level transcriptomes for cells and cell types. Finally, we extract paired adaptive immune receptor sequences unique to each T and B cell.
The modulatory role of internet-supported mindfulness-based cognitive therapy on extracellular vesicles and psychological distress in people who have had cancer: a protocol for a two-armed randomized controlled study
Authors: Pereira Diana R. , Silva Eunice R. , Carvalho-Maia Carina , Monteiro-Reis Sara , Lourenço Catarina , Calisto Rita , Teixeira Ricardo João , Carlson Linda E. , Bart Genevieve , Vainio Seppo J. , Sales M. Goreti F. , Jerónimo Carmen , Henrique Rui
Published: February 2022

Background

Mindfulness-based interventions (MBIs) have been used in oncology contexts as a promising tool with numerous benefits for various health-related and psychosocial outcomes. Despite the increasing popularity of MBIs, few randomized controlled trials (RCTs) have examined their effects upon biological parameters. Specifically, no previous study has examined the effects of MBIs on extracellular vesicles (EVs), which are potentially important markers of health, disease, and stress. Moreover, the lack of RCTs is even more limited within the context of technology-mediated MBIs and long-term effects.

Methods

The current study protocol presents a two-arm, parallel, randomized controlled study investigating the effects of internet-supported mindfulness-based cognitive therapy (MBCT) compared with treatment as usual (TAU). Primary outcomes are psychological distress and EV cargo of distressed participants with previous breast, colorectal, or prostate cancer diagnoses. Secondary outcomes are self-reported psychosocial and health-related measures, and additional biological markers. Outcomes will be assessed at baseline, 4 weeks after baseline (mid-point of the intervention), 8 weeks after baseline (immediately post-intervention), 24 weeks after baseline (after booster sessions), and 52 weeks after baseline. Our goal is to recruit at least 111 participants who have been diagnosed with breast, prostate, or colorectal cancer (cancer stage I to III), are between 18 and 65 years old, and have had primary cancer treatments completed between 3 months and 5 years ago. Half of the participants will be randomized to the TAU group, and the other half will participate in an 8-week online MBCT intervention with weekly group sessions via videoconference. The intervention also includes asynchronous homework, an online retreat after the fifth week, and 4 monthly booster sessions after completion of the 8-week programme.

Discussion

This study will allow characterizing the effects of internet-based MBCT on psychosocial and biological indicators in the context of cancer. The effects on circulating EVs will also be investigated, as a possible neurobiological pathway underlying mind-body intervention effects.

Trial registration

ClinicalTrials.govNCT04727593 (date of registration: 27 January 2021; date of record verification: 6 October 2021).
CCR2-overexpressing mesenchymal stem cells targeting damaged liver enhance recovery of acute liver failure
Authors: Xu Ruixuan , Ni Beibei , Wang Li , Shan Jiarou , Pan Lijie , He Yizhan , Lv Guo , Lin Huizhu , Chen Wenjie , Zhang Qi
Published: February 2022

Background

Mesenchymal stem cell (MSC) transplantation is emerging as a promising cell therapeutic strategy in acute liver failure (ALF) clinical research. The potency of MSCs to migrate and engraft into targeted lesions could largely determine their clinical efficacy, in which chemokine/receptor axes play a crucial role. Unfortunately, the downregulation of chemokine receptors expression after in vitro expansion results in a poor homing capacity of MSCs.

Methods

By evaluating the chemokine expression profile in the liver of ALF patients and ALF mice, we found that CCL2 expression was highly upregulated in damaged livers, while the corresponding receptor, CCR2, was lacking in cultured MSCs. Thus, we genetically modified MSCs to overexpress CCR2 and investigated the targeted homing capacity and treatment efficacy of MSCCCR2compared to those of the MSCvectorcontrol.

Results

In vivo and ex vivo near-infrared fluorescence imaging showed that MSCCCR2rapidly migrated and localized to injured livers in remarkably greater numbers following systemic infusion, and these cells were retained in liver lesions for a longer time than MSCvector. Furthermore, MSCCCR2exhibited significantly enhanced efficacy in the treatment of ALF in mice, which was indicated by a dramatically improved survival rate, the alleviation of liver injury with reduced inflammatory infiltration and hepatic apoptosis, and the promotion of liver regeneration.

Conclusions

Altogether, these results indicate that CCR2 overexpression enhances the targeted migration of MSCs to damaged livers, improves their treatment effect, and may provide a novel strategy for improving the efficacy of cell therapy for ALF.
The effect of hypoxia on myogenic differentiation and multipotency of the skeletal muscle-derived stem cells in mice
Authors: Elashry Mohamed I. , Kinde Mebrie , Klymiuk Michele C. , Eldaey Asmaa , Wenisch Sabine , Arnhold Stefan
Published: February 2022

Background

Skeletal muscle-derived stem cells (SC) have become a promising approach for investigating myogenic differentiation and optimizing tissue regeneration. Muscle regeneration is performed by SC, a self-renewal cell population underlying the basal lamina of muscle fibers. Here, we examined the impact of hypoxia condition on the regenerative capacity of SC either in their native microenvironment or via isolation in a monolayer culture using ectopic differentiation inductions. Furthermore, the effect of low oxygen tension on myogenic differentiation protocols of the myoblasts cell line C2C12 was examined.

Methods

Hind limb muscles of wild type mice were processed for both SC/fiber isolation and myoblast extraction using magnetic beads. SC were induced for myogenic, adipogenic and osteogenic commitments under normoxic (21% O2) and hypoxic (3% O2) conditions. SC proliferation and differentiation were evaluated using histological staining, immunohistochemistry, morphometric analysis and RT-qPCR. The data were statistically analyzed using ANOVA.

Results

The data revealed enhanced SC proliferation and motility following differentiation induction after 48 h under hypoxia. Following myogenic induction, the number of undifferentiated cells positive for Pax7 were increased at 72 h under hypoxia. Hypoxia upregulated MyoD and downregulated Myogenin expression at day-7 post-myogenic induction. Hypoxia promoted both SC adipogenesis and osteogenesis under respective induction as shown by using Oil Red O and Alizarin Red S staining. The expression of adipogenic markers; peroxisome proliferator activated receptor gamma (PPARγ) and fatty acid-binding protein 4 (FABP4) were upregulated under hypoxia up to day 14 compared to normoxic condition. Enhanced osteogenic differentiation was detected under hypoxic condition via upregulation of osteocalcin and osteopontin expression up to day 14 as well as, increased calcium deposition at day 21. Hypoxia exposure increases the number of adipocytes and the size of fat vacuoles per adipocyte compared to normoxic culture. Combining the differentiation medium with dexamethasone under hypoxia improves the efficiency of the myogenic differentiation protocol of C2C12 by increasing the length of the myotubes.

Conclusions

Hypoxia exposure increases cell resources for clinical applications and promotes SC multipotency and thus beneficial for tissue regeneration.
Human menstrual blood-derived stem cell transplantation suppresses liver injury in DDC-induced chronic cholestasis
Authors: Yang Ya , Chen Yanfei , Zhao Yalei , Ji Feiyang , Zhang Lingjian , Tang Shima , Zhang Sainan , Hu Qingqing , Li Zuhong , Zhang Fen , Li Qian , Li Lanjuan
Published: February 2022

Background

Cholestatic liver injury can lead to serious symptoms and prognoses in the clinic. Currently, an effective medical treatment is not available for cholestatic liver injury. Human menstrual blood-derived stem cells (MenSCs) are considered as an emerging treatment in various diseases. This study aimed to explore the treatment effect of MenSCs in cholestatic liver injury.

Methods

The treatment effect of MenSCs on chronic cholestatic liver injury was verified in 3,5-diethoxycarbonyl-1,4-dihydroxychollidine (DDC)-induced C57/BL6 mice. Pathological, fibrosis area in the liver tissue and serum liver enzymes were tested. Proteomics and western blot were used to explore the related targets and molecular mechanisms. Adeno-associated virus (AAV) 9-infected mice were applied for verification.

Results

MenSCs markedly improved the survival rate of the DDC-treated mice (60% vs. 100%), and decreased the mouse serum aspartate aminotransferase (AST) (169.4 vs. 108.0 U/L,p < 0.001), alanine aminotransferase (ALT) (279.0 vs. 228.9 U/L,p < 0.01), alkaline phosphatase (ALP) (45.6 vs. 10.6 U/L,p < 0.0001), direct bilirubin (DBIL) (108.3 vs. 14.0 μmol/L,p < 0.0001) and total bilirubin (TBIL) (179.2 vs. 43.3 μmol/L,p < 0.0001) levels as well as intrahepatic cholestasis, bile duct dilation and fibrotic areas (16.12 vs. 6.57%,p < 0.05). The results further indicated that MenSCs repaired the DDC-induced liver tight junction (TJ) pathway and bile transporter (OATP2, BSEP and NTCP1) injury, thereby inhibiting COL1A1, α-SMA and TGF-β1 activation by upregulating liver β-catenin expression.

Conclusions

MenSC transplantation could be an effective treatment method for cholestatic liver injury in mice. MenSCs may exhibit therapeutic effects by regulating β-catenin expression.