bluuebunny/crossref_metadata_2025 huggingface dataset:
Accuracy of a Seventh-Generation Continuous Glucose Monitoring System in Children and Adolescents With Type 1 Diabetes
Authors: Laffel Lori M. , Bailey Timothy S. , Christiansen Mark P. , Reid Jennifer L. , Beck Stayce E.
Published: April 2022

Background:

Accuracy of a seventh-generation “G7” continuous glucose monitoring (CGM) system was evaluated in children and adolescents with type 1 diabetes (T1D).

Methods:

Sensors were worn on the upper arm and abdomen. The CGM data were available from 127 of 132 participants, ages 7 to 17 years, across 10.5 days of use, various glucose concentration ranges, and various rates of glucose change for comparisons with temporally matched venous blood glucose measurements (YSI). Data were also available from 28 of 32 participants, ages 2 to 6 years, for whom capillary (fingerstick) blood provided comparator glucose values. Accuracy metrics included the mean absolute relative difference (MARD) between CGM and comparator glucose pairs, the proportion of CGM values within 15 mg/dL or 15% of comparator values <100 or ≥100 mg/dL, respectively, and the analogous %20/20 and %30/30 agreement rates.

Results:

For participants aged 7 to 17, a total of 15 437 matched pairs were obtained from 122 arm-placed and 118 abdomen-placed sensors. For arm-placed sensors, the overall MARD was 8.1% and overall %15/15, %20/20, and %30/30 agreement rates were 88.8%, 95.3%, and 98.7%, respectively. For abdomen-placed sensors, the overall MARD was 9.0% and overall %15/15, %20/20, and %30/30 agreement rates were 86.0%, 92.9%, and 97.7%, respectively. Good accuracy was maintained across wear days, glucose ranges, and rates of glucose change. Among those aged 2 to 6, a total of 343 matched pairs provided an overall MARD of 9.3% and an overall %20/20 agreement rate of 91.5%.

Conclusions:

The G7 CGM placed on the arm or abdomen was accurate in children and adolescents with T1D. NCT#: NCT04794478
Brain magnetic resonance imaging findings and brain volumetric differences in a large series of benign rolandic epilepsy
Authors: Salman Rida , Nasreddine Wassim , Hannoun Salem , Chaar Widad Abou , Asmar Karl , Beydoun Ahmad , Hourani Roula
Published: April 2022

Background

Several studies with a small sample size have investigated the relationship between structural and functional changes on MRI and the clinical and natural history of BRE. We aim to assess the frequency of incidental epileptogenic lesions on brain MRI in a large cohort of patients diagnosed with BRE and to assess the difference in volumetric brain measurements in BRE patients compared to healthy controls.

Methods

The case–control study includes 214 typical BRE cases and 197 control children with non-epileptic spells. Brain MRIs were evaluated for abnormalities which were classified into normal and abnormal with or without epileptogenic lesions with categorization of epileptogenic lesions. Brain segmentation was also performed for a smaller group of BRE patients and another healthy control group. Pearson’s chi-squared test and two-tailed independent samples t-test were used.

Results

In patients with BRE, 7% had an epileptogenic lesion on their MRI. The frequency of epileptogenic lesion in the control group was 10.2% and not significantly different from those with BRE ( p= 0.2). Significantly higher intracranial and white matter volumes were found in BRE patients compared to the healthy group while lower gray matter volume was found in BRE patients. Cortical and subcortical regions showed either higher or lower volumes with BRE. Interestingly, altered subcallosal cortex development which has a known association with depression was also found in BRE.

Conclusions

Our findings confirm the absence of any association between specific brain MRI abnormalities and BRE. However, the altered cortical and subcortical development in BRE patients suggests a microstructural-functional correlation.
Cardiovascular risk factors and clinical outcomes of patients hospitalized with COVID-19 pneumonia in Somalia
Authors: Ahmed Mohammed A.M. , Hussein Ahmed Mohamud , Abdullahi Aweis Ahmed Moalim , Ahmed Abdirizak Yusuf , Hussain Hamdi M.A. , Ali Abdiaziz Mohamed , Barre Abdulqadir Abdinur , Yusuf Farhia Mohamud , Olum Ronald , Sereke Senai Goitom , Elfadul Maisa Ahmed , Colebunders Robert , Bongomin Felix
Published: April 2022

Background:

Coronavirus disease-2019 (COVID-19) is a potentially life-threatening illness with no established treatment. Cardiovascular risk factors (CRFs) exacerbate COVID-19 morbidity and mortality.

Objective:

To determine the prevalence of CRF and clinical outcomes of patients hospitalized with COVID-19 in a tertiary hospital in Somalia.

Methods:

We reviewed the medical records of patients aged 18 years or older with a real-time polymerase chain reaction (RT-PCR)–confirmed COVID-19 hospitalized at the De Martino Hospital in Mogadishu, Somalia, between March and July 2020.

Results:

We enrolled 230 participants; 159 (69.1%) males, median age was 56 (41–66) years. In-hospital mortality was 19.6% ( n = 45); 77.8% in the intensive care unit (ICU) compared with 22.2%, in the general wards ( p < 0.001). Age ⩾ 40 years [odds ratio (OR): 3.6, 95% confidence interval (CI): 1.2–10.6, p = 0.020], chronic heart disease (OR: 9.3, 95% CI: 2.2–38.9, p = 0.002), and diabetes mellitus (OR: 3.2, 95% CI: 1.6–6.2, p < 0.001) were associated with increased odds of mortality. Forty-three (18.7%) participants required ICU admission. Age ⩾ 40 years (OR: 7.5, 95% CI: 1.7–32.1, p = 0.007), diabetes mellitus (OR: 3.2, 95% CI: 1.6–6.3, p < 0.001), and hypertension (OR: 2.5, 95% CI: 1.2–5.2, p = 0.014) were associated with ICU admission. For every additional CRF, the odds of admission into the ICU increased threefold (OR: 2.7, 95% CI: 1.2–5.2, p < 0.001), while the odds of dying increased twofold (OR: 2.1, 95% CI: 1.3–3.2, p < 0.001).

Conclusions:

We report a very high prevalence of CRF among patients hospitalized with COVID-19 in Somalia. Mortality rates were unacceptably high, particularly among those with advanced age, underlying chronic heart disease, and diabetes.
Acute Myocarditis Following Vaccination With the First Dose of the mRNA-1273 Vaccine
Authors: Olagunju Abdulbaril , Moradi Ali , Johnson Benjamin , Lebaron Zachary , Johnson Ross , Mehdizadeh Azar
Published: April 2022

Viral infections are a common cause of acute myocarditis. However, vaccines including influenza and smallpox have also been rarely implicated. Recently, the coronavirus disease 2019 (COVID-19) vaccines have been associated with acute myocarditis. We describe a case of acute myocarditis in a 19-year-old male 2 days after the initial dose of the COVID-19 mRNA-1273 vaccine. He presented with chest pain radiating to his left arm and bilateral shoulders. COVID, influenza, coxsackie, respiratory syncytial virus polymerase chain reaction (PCR) tests were negative. Electrocardiogram revealed diffuse ST-segment elevation. Initial Troponin was 15.7 ng/mL. A coronary angiogram revealed patent coronary arteries and no wall motion abnormality. A transthoracic echocardiogram showed diffuse hypokinesis with an ejection fraction of 49%. Cardiac magnetic resonance scan was aborted after 2 attempts due to severe claustrophobia. His chest pain resolved following initiation of aspirin, tylenol, colchicine, lisinopril, and metoprolol.
Cystic Lung Disease as a Sequela of Severe COVID-19: Case Series
Authors: Patti Ravi Karan , Dalsania Nishil , De Araujo Duarte Claudia , Randhawa Gurchetan , Somal Navjot , Kupfer Yizhak
Published: April 2022

Coronavirus disease 2019 (COVID-19) presented in December 2019 and has persisted since. The global pandemic has given rise to a novel acute disease process with a continually rapidly increasing prevalence of chronic disease and associated complications. There is minimal information on the long-term pulmonary complications of this disease. We present a series of 9 patient case reports and their respective imaging admitted with COVID-19 acute respiratory distress syndrome (ARDS) to highlight the cystic lung disease complications which may arise due to severity and disease progression. Our aim is to raise awareness of the sequela of COVID-19 ARDS, including its potentially catastrophic long-term consequences to the respiratory tract involving cystic lung disease.
Water governance
Authors: Querejazu Amaya
Published: April 2022

This essay is about water governance and relationality. It reflects on the questions that articulate this forum on relational International Relations (IR): what do relational theories of IR offer to the field and add to the debate about IR? What are the promises or limits of relational approaches, and how can or should discussion proceed? I narrate my personal story about exploring and experiencing relationality to offer some reflections and thoughts on these questions which are relevant not only for IR, but to the ways we engage reality. I illustrate the potential of relationality by referring to three dimensions where relationality provides with alternative thinking: the problem of ontological difference; the pluralization and diversification of ways of thinking and being and the engagement with the other than other-than-human. These aspects are some among many others, but they announce opportunities, challenges, tensions, contradictions and possibilities. In the end, the essay reveals not only a transformative experience but a very different approach to water governance providing the reader a general understanding of the alternative thinking derived from relational standpoints and the possibilities it opens to theorize IR and beyond.
A Characterization and Pedagogical Analysis of Youth Entrepreneurship
Authors: Hadley Gregory R. L.
Published: April 2022

This paper proposes a characterization of the youth entrepreneur and, subsequently, explores pedagogies that can assist in the development of entrepreneurial knowledge, skills and attitudes (KSAs) among youth in a secondary school context. Data was collected via a mixed methods approach. A small cross-section of high school students from the Canadian province Nova Scotia participated in a semi structured interview on entrepreneurship and pedagogy, while a larger cross-section completed a survey that assessed perceived degree of entrepreneurialism. The study concluded that young people possess, to varying degrees, a variety of entrepreneurial knowledge, skills and attitudes. Furthermore, it was found that those KSAs are largely gathered, refined and mobilized in extra-curricular contexts, leaving secondary schools to consider how to better support the entrepreneurialism of their students. The various implications of these findings, as they relate to pedagogy, practice, and educational policy are explored in detail.
The Value of Conducting a Longitudinal Study on Well-Being and Risk for Work-Related Musculoskeletal Injuries in Ultrasound Users
Authors: Evans Kevin D. , Sommerich Carolyn M. , Bloom Isaiah W. , Roll Shawn C. , Stigall-Weikle A. Nicole
Published: April 2022

This article discusses the importance of conducting a longitudinal data collection concerning well-being and the risk for work-related musculoskeletal injuries (WRMSI) among sonographers and vascular technologists. There is a need for changes in the manner that sonographic work is done, but this should be nested in empirical evidence. This gives the rational for conducting the study titled Documenting the overall wellness of ultrasound users and the risk of progressive WRMSI: A national longitudinal study. The objective of this longitudinal work is to better understand collective practice patterns and examine the relationship of sonographic work conditions and performance to the user’s health and well-being. This symposium provides the foundational understanding of the strength of this type of study and how it may help to influence behavior and organizational change.
Diagnostic Value of Ultrasound for Detecting Carpal Tunnel Syndrome in Patients With Rheumatoid Arthritis: A Three-Arm Cross-Sectional Study
Authors: Bayat Masume , Bagheri Zohreh , Raeissadat Seyed Ahmad , Rayegani Seyed Mansoor , Ahmadzadeh Arman , Shirani Fatemeh
Published: April 2022

Objective:

This study was conducted to assess the diagnostic value of sonography in detecting carpal tunnel syndrome (CTS) in patients with rheumatoid arthritis (RA) and to compare the results with a normal control group.

Materials and Methods:

In this three-arm cross-sectional study, the sonographically measured median nerve cross-sectional area (MNCSA) was compared in three groups: RA patients with CTS, RA patients without CTS, and normal subjects (no RA, no CTS). A nerve conduction study (NCS) was performed for all enrolled participants, across the three study arms.

Results:

In this study, 38 RA patients (17 in CTS group and 21 in no CTS group) and 19 healthy subjects were recruited. The MNCSAs were 11.86 (±1.87) mm2 in RA patients with CTS, 10.16 (±1.71) mm2 in RA patients without CTS, and 9.42 (±1.46) mm² in healthy control patients. The accuracy of sonography in detecting CTS was 0.79 (95% confidence interval, 0.67–0.91), with a sensitivity and specificity of 88% and 57%, respectively. The MNCSA in CTS group was significantly higher than the control group ( P = .02).

Conclusion:

In this cohort, the sonographic measurement of MNCSA was an accurate and sensitive method for the diagnosis of CTS, especially in its early stages. In addition, in this cohort, RA without CTS did not increase the MNCSA.
Asciminib: a new therapeutic option in chronic-phase CML with treatment failure
Authors: Yeung David T. , Shanmuganathan Naranie , Hughes Timothy P.
Published: April 2022

Asciminib, a first-in-class allosteric inhibitor of BCR::ABL1 kinase activity, is now approved for the treatment of patients with chronic-phase chronic myeloid leukemia who failed 2 lines of therapy or in patients with the T315I mutation. Promising attributes include high specificity and potency against BCR::ABL1, activity against most kinase domain mutations, and potential for combination therapy with ATP-competitive tyrosine kinase inhibitors. Clinicians now have expanded third-line options, which in most cases will involve a choice between asciminib and ponatinib.
Npm1 haploinsufficiency in collaboration with MEIS1 is sufficient to induce AML in mice
Authors: Muranyi Andrew , Ammer Tobias , Kechter Anna , Rawat Vijay P. S. , Sinha Amit , Gonzalez-Menendez Irene , Quintanilla-Martinez Leticia , Azoitei Anca , Günes Cagatay , Mupo Annalisa , Vassiliou George , Bamezai Shiva , Buske Christian
Published: April 2022

NPM1 is among the most frequently mutated genes in acute myeloid leukemia (AML). Mutations in the NPM1 gene result in the increased export of NPM1 to the cytoplasm (NPM1c) and are associated with multiple transforming events including the aberrant upregulation of MEIS1 that maintains stem cell and cell cycle–associated pathways in NPM1c AML. However, another consequence of the NPM1c mutation is the inadequate levels of NPM1 wild-type in the nucleus and nucleolus, caused by the loss of one wild-type allele in addition to enforced NPM1 nuclear export. The contribution of NPM1 haploinsufficiency independently of the NPM1 mutation to AML development and its relationship with MEIS1 function is poorly understood. Using mouse models, our study shows that NPM1 haploinsufficiency paired with MEIS1 overexpression is sufficient to induce a fully penetrant AML in mice that transcriptionally resembles human NPM1c AML. NPM1 haploinsufficiency alters MEIS1-binding occupancies such that it binds the promoter of the oncogene structural maintenance of chromosome protein 4 (SMC4) in NPM1 haploinsufficient AML cells but not in NPM1 wild-type–harboring Hoxa9/Meis1-transformed cells. SMC4 is higher expressed in haploinsufficient and NPM1c+ AML cells, which are more vulnerable to the disruption of the MEIS1-SMC4 axis compared with AML cells with nonmutated NPM1. Taken together, our study underlines that NPM1 haploinsufficiency on its own is a key factor of myeloid leukemogenesis and characterizes the MEIS1-SMC4 axis as a potential therapeutic target in this AML subtype.
2′,3′,4′-Trihydroxychalcone changes estrogen receptor α regulation of genes and breast cancer cell proliferation by a reprogramming mechanism
Authors: Herber Candice B. , Yuan Chaoshen , Chang Anthony , Wang Jen-Chywan , Cohen Isaac , Leitman Dale C.
Published: April 2022

Background

Menopausal hormone therapy (MHT) is recommended for only five years to treat vasomotor symptoms and vulvovaginal atrophy because of safety concerns with long-term treatment. We investigated the ability of 2′,3′,4′-trihydroxychalcone (2′,3′,4′-THC) to modulate estrogen receptor (ER)-mediated responses in order to find drug candidates that could potentially prevent the adverse effects of long-term MHT treatment.

Methods

Transfection assays, real time-polymerase chain reaction, and microarrays were used to evaluate the effects of 2′,3′,4′-THC on gene regulation. Radioligand binding studies were used to determine if 2′,3′,4′-THC binds to ERα. Cell proliferation was examined in MCF-7 breast cancer cells by using growth curves and flow cytometry. Western blots were used to determine if 2′,3′,4′-THC alters the E2 activation of the MAPK pathway and degradation of ERα. Chromatin immunoprecipitation was used to measure ERα binding to genes.

Results

The 2′,3′,4′-THC/E2 combination produced a synergistic activation with ERα on reporter and endogenous genes in human U2OS osteosarcoma cells. Microarrays identified 824 genes that we termed reprogrammed genes because they were not regulated in U2OS-ERα cells unless they were treated with 2′,3′,4′-THC and E2 at the same time. 2′,3′,4′-THC blocked the proliferation of MCF-7 cells by preventing the E2-induced activation of MAPK and c-MYC transcription. The antiproliferative mechanism of 2′,3′,4′-THC differs from selective estrogen receptor modulators (SERMs) because 2′,3′,4′-THC did not bind to the E2 binding site in ERα like SERMs.

Conclusion

Our study suggests that 2′,3′,4′-THC may represent a new class of ERα modulators that do not act as a direct agonists or antagonists. We consider 2′,3′,4′-THC to be a reprogramming compound, since it alters the activity of ERα on gene regulation and cell proliferation without competing with E2 for binding to ERα. The addition of a reprogramming drug to estrogens in MHT may offer a new strategy to overcome the adverse proliferative effects of estrogen in MHT by reprogramming ERα as opposed to an antagonist mechanism that involves blocking the binding of estrogen to ERα.
Functionality, satisfaction, and global impression of change with ubrogepant for the acute treatment of migraine in triptan insufficient responders: a post hoc analysis of the ACHIEVE I and ACHIEVE II randomized trials
Authors: Lipton Richard B. , Singh Rashmi B. Halker , Revicki Dennis A. , Zhao Sihui , Shewale Anand R. , Lateiner Jordan E. , Dodick David W.
Published: April 2022

Background

Triptans are the first-line option for the acute treatment of migraine attacks; however, triptans are contraindicated in people with certain underlying cardiovascular risk factors and are associated with inadequate efficacy or poor tolerability in some individuals. Ubrogepant is an oral calcitonin gene–related peptide receptor antagonist approved for the acute treatment of migraine.

Methods

This post hoc analysis of the phase 3 ACHIEVE trials examined the impact of ubrogepant on the Functional Disability Scale (FDS), satisfaction with medication, and Patient Global Impression of Change (PGIC) in participants who were self-reported triptan insufficient responders (TIRs), defined as those who are unable to take triptans due to contraindications, tolerability issues, or insufficient efficacy. Responder definitions for the FDS, satisfaction measures, and PGIC were based on qualitative interpretation of the respective response options for the pooled ubrogepant 50 mg and placebo groups.

Results

In the pooled analysis population (n = 1799), 451 (25%) participants were TIRs, with most (80%) reporting insufficient efficacy with triptan use. A significantly higher proportion of TIRs treated with ubrogepant vs placebo reported being able to function normally from 2 to 8 h post dose (P < 0.05). Notably, significance was demonstrated at the time of the primary outcome assessments (2 h post dose), where rates of normal function were 38% for ubrogepant vs 29% for placebo (P = 0.048). A greater proportion of TIRs in the ubrogepant arm vs the placebo arm were satisfied with treatment at 2 (33% vs 21%,P = 0.006) and 24 h (58% vs 28%,P < 0.001) and indicated that their migraine improved at 2 h vs placebo (30% vs 18%,P = 0.006). Results were generally similar in the insufficient efficacy subpopulation of TIRs as in the overall TIRs group. Ubrogepant was safe and well tolerated in TIRs, with no new safety signals identified.

Conclusions

In people with migraine who are TIRs, individuals treated with ubrogepant had favorable 2-h outcomes, as measured by the FDS, satisfaction with medication, and PGIC, compared with placebo.

Trial registration

ClinicalTrials.gov:NCT02828020(ACHIEVE I), registered July 11, 2016;NCT02867709(ACHIEVE II), registered August 16, 2016.
Identification of accession-specific variants and development of KASP markers for assessing the genetic makeup of Brassica rapa seeds
Authors: Hong Seongmin , Choi Su Ryun , Kim Jihyeong , Jeong Young-Min , Kim Ju-Sang , Ahn Chun-Hee , Kwon Suk-Yoon , Lim Yong Pyo , Shin Ah-Young , Kim Yong-Min
Published: April 2022

Background

Most crop seeds are F1 hybrids. Seed providers and plant breeders must be confident that the seed supplied to growers is of known, and uniform, genetic makeup. This requires maintenance of pure genotypes of the parental lines and testing to ensure the genetic purity of the F1 seed. Traditionally, seed purity has been assessed with a grow-out test (GOT) in the field, a time consuming and costly venture. Early in the last decade, seed testing with molecular markers was introduced as a replacement for GOT, and Kompetitive allele specific PCR (KASP) markers were recognized as promising tools for genetic testing of seeds. However, the markers available at that time could be inaccurate and applicable to only a small number of accessions or varieties due to the limited genetic information and reference genomes available.

Results

We identified 4,925,742 SNPs in 50 accessions of the Brasscia rapa core collection. From these, we identified 2,925 SNPs as accession-specific, considering properties of flanking region harboring accession-specific SNPs and genic region conservation among accessions by the Next Generation Sequencing (NGS) analysis. In total, 100 accession-specific markers were developed as accession-specific KASP markers. Based on the results of our validation experiments, the accession-specific markers successfully distinguised individuals from the mixed population including 50 target accessions from B. rapa core collection and the outgroup. Additionally, the marker set we developed here discriminated F1 hybrids and their parental lines with distinct clusters.

Conclusions

This study provides efficient methods for developing KASP markers to distinguish individuals from the mixture comprised of breeding lines and germplasms from the resequencing data of Chinese cabbage (Brassica rapa spp. pekinensis).
High resolution HLA-DRB1 analysis and shared molecular amino acid signature of DRβ1 molecules in Occult hepatitis B infection
Authors: Wang Tianju , Shen Chunmei , Li Hengxin , Chen Liping , Liu Sheng , Qi Jun
Published: April 2022

Aim

To investigate the association of human leukocyte antigen (HLA)-DRB1 alleles and the variations of polymorphic amino acid changes in DRβ1 chain in Shaanxi Han population with Occult hepatitis B infection (OBI).

Methods

High-resolution HLA-DRB1 genotyping was performed in 107 OBI carriers and 280 normal controls. Sequence information was used to assign which amino acids were encoded at all polymorphic positions. Three-dimensional modeling was performed to explore the effect of the key residues on the HLA-DRB1 molecule.

Results

Strong susceptible association for allele DRB1*07:01 was observed in OBI carriers. The amino acid variation at HLA-DRβ1 molecule revealed susceptible associations for residues Gln4β, Val57β(P9), Ser60β(P9) and Val78β(P4), the amino acids Arg4β, Asp57β(P9), Tyr60β(P9) and Tyr78β(P4) showed protective associations.

Conclusion

Alleles DRB1*07:01 showed strong susceptible associations in OBI carriers. The amino acid variations in DRβ molecules revealed significant molecular markers for susceptibility and protection from OBI in Shaanxi Han population.
Mutations in SilS and CusS/OmpC represent different routes to achieve high level silver ion tolerance in Klebsiella pneumoniae
Authors: Woolley Charlotte A. , Sutton J. Mark , Wand Matthew E.
Published: April 2022

Background

Silver ions have potent broad-spectrum antimicrobial activity and are widely incorporated into a variety of products to limit bacterial growth. In Enterobacteriaceae, decreased silver susceptibility has been mapped to two homologous operons; the chromosomally located cus operon and the plasmid based sil operon. Here we characterised the mechanisms and clinical impact of induced silver tolerance in Klebsiella pneumoniae.

Results

In K. pneumoniae carriage of the sil operon alone does not give elevated silver tolerance. However, when exposed to increasing concentrations of silver nitrate (AgNO3), K. pneumoniae strains which contain the sil operon, will preferentially mutate SilS, resulting in overexpression of the genes encoding the RND efflux pump silCBA. Those strains which do not carry the sil operon also adapt upon exposure to increasing silver concentrations through mutations in another two-component regulator CusS. Secondary mutations leading to disruption of the outer membrane porin OmpC were also detected. Both routes result in a high level of silver tolerance with MIC’s of >512 mg/L. When exposed to a high concentration of AgNO3 (400 mg/L), only strains that contained the sil operon were able to survive, again through mutations in SilS. The AgNO3 adapted strains were also resistant to killing by challenge with several clinical and commercial silver containing dressings.

Conclusions

This study shows that K. pneumoniae has two possible pathways for development of increased silver tolerance but that the sil operon is preferentially mutated. This operon is essential when K. pneumoniae is exposed to high concentrations of silver. The potential clinical impact on wound management is shown by the increased survivability of these adapted strains when exposed to several silver impregnated dressings. This would make infections with these strains more difficult to treat and further limits our therapeutic options.
Synaptic loss in a mouse model of euthyroid Hashimoto’s thyroiditis: possible involvement of the microglia
Authors: Wang Fen , Cai Yao-Jun , Ma Xiao , Wang Nan , Wu Zhang-Bi , Sun Yan , Xu Yong-xia , Yang Hao , Liu Tian-tian , Xia Qin , Yu Zhen , Zhu De-Fa
Published: April 2022

Background

Hashimoto’s thyroiditis (HT) is an autoimmune illness that renders individuals vulnerable to neuropsychopathology even in the euthyroid state, the mechanisms involved remain unclear. We hypothesized that activated microglia might disrupt synapses, resulting in cognitive disturbance in the context of euthyroid HT, and designed the present study to test this hypothesis.

Methods

Experimental HT model was induced by immunizing NOD mice with thyroglobulin and adjuvant twice. Morris Water Maze was measured to determine mice spatial learning and memory. The synaptic parameters such as the synaptic density, synaptic ultrastructure and synaptic-markers (SYN and PSD95) as well as the interactions of microglia with synapses were also determined.

Results

HT mice had poorer performance in Morris Water Maze than controls. Concurrently, HT resulted in a significant reduction in synapse density and ultrastructure damage, along with decreased synaptic puncta visualized by immunostaining with synaptophysin and PSD-95. In parallel, frontal activated microglia in euthyroid HT mice showed increased engulfment of PSD95 and EM revealed that the synaptic structures were visible within the microglia. These functional alterations in microglia corresponded to structural increases in their attachment to neuronal perikarya and a reduction in presynaptic terminals covering the neurons.

Conclusion

Our results provide initial evidence that HT can induce synaptic loss in the euthyroid state with deficits might be attributable to activated microglia, which may underlie the deleterious effects of HT on spatial learning and memory.
Vascular function of the T3/modern clade WUSCHEL-Related HOMEOBOX transcription factor genes predate apical meristem-maintenance function
Authors: Youngstrom Christopher E. , Withers Kelley A. , Irish Erin E. , Cheng Chi-Lien
Published: April 2022

Background

Plants have the lifelong ability to generate new organs due to the persistent functioning of stem cells. In seed plants, groups of stem cells are housed in the shoot apical meristem (SAM), root apical meristem (RAM), and vascular cambium (VC). In ferns, a single shoot stem cell, the apical cell, is located in the SAM, whereas each root initiates from a single shoot-derived root initial. WUSCHEL-RELATED HOMEOBOX (WOX) family transcription factors play important roles to maintain stem-cell identity. WOX genes are grouped phylogenetically into three clades. The T3WOX/modern clade has expanded greatly in angiosperms, with members functioning in multiple meristems and complex developmental programs. The model fern Ceratopteris richardii has only one well-supported T3WOX/modern WOX gene, CrWUL. Its orthologs in Arabidopsis, AtWUS, AtWOX5, and AtWOX4, function in the SAM, RAM, and VC, respectively. Identifying the function of CrWUL will provide insights on the progenitor function and the diversification of the modern WOX genes in seed plants.

Results

To investigate the role of CrWUL in the fern, we examined the expression and function of CrWUL and found it expresses during early root development and in vasculature but not in the SAM. Knockdown of CrWUL by RNAi produced plants with fewer roots and fewer phloem cells. When expressed in Arabidopsis cambium, CrWUL was able to complement AtWOX4 function in an atwox4 mutant, suggesting that the WOX function in VC is conserved between ferns and angiosperms. Additionally, the proposed progenitor of T3WOX genes from Selaginella kraussiana is expressed in the vasculature but not in the shoot apical meristem. In contrast to the sporophyte, the expression of CrWUL in the gametophyte exhibits a more general expression pattern and when knocked down, offered little discernable phenotypes.

Conclusions

The results presented here support the occurrence of co-option of the T3WOX/modern clade gene from the gametophyte to function in vasculature and root development in the sporophyte. The function in vasculature is likely to have existed in the progenitor of lycophyte T3WOX/modern clade genes and this function predates its SAM function found in many seed plants.
Variations of subtelomeric tandem repeats and rDNA on chromosome 1RS arms in the genus Secale and 1BL.1RS translocations
Authors: Luo Jie , Liao Ruiying , Duan Yanling , Fu Shulan , Tang Zongxiang
Published: April 2022

Background

The wheat-rye 1BL.1RS translocations have played an important role in common wheat breeding programs. Subtelomeric tandem repeats have been often used to investigate polymorphisms of 1RS arms, but further research about their organizations on the 1RS chromosome is needed.

Results

162 1RS arms from a wild rye species (Secale strictum) and six cultivated rye accessions (Secale cereale L.) (81 plants), 102 1BL.1RS and one 1AL.1RS translocations were investigated using oligo probes Oligo-TaiI, Oligo-pSc119.2–1, Oligo-pTa71A-2, Oligo-pSc200 and Oligo-pSc250, which were derived from tandem repeats TaiI, pSc119.2, pTa71, pSc200 and pSc250, respectively. The variations of 1RS arms were revealed by signal intensity of probes Oligo-pSc119.2–1, Oligo-pTa71A-2, Oligo-pSc200 and Oligo-pSc250. Proliferation of rDNA sequences on the 1RS chromosomes was observed. According to the presence of probe signals, 34, 127 and 144 of the 162 1RS arms contained TaiI, pSc200 and pSc250, respectively, and all of them contained pSc119.2 and pTa71. Most of the 1RS arms in rye contained three kinds of subtelomeric tandem repeats, the combination of pSc119.2, pSc200 and pSc250 was most common, and only eight of them contained TaiI, pSc119.2, pSc200 and pSc250. All of the 1RS arms in 1BL.1RS and 1AL.1RS translocations contained pSc119.2, pTa71, pSc200 and pSc250, but the presence of the TaiI family was not observed.

Conclusion

New organizations of subtelomeric tandem repeats on 1RS were found, and they reflected new genetic variations of 1RS arms. These 1RS arms might contain abundant allelic diversity for agricultural traits. The narrow genetic base of 1RS arms in 1BL.1RS and 1AL.1RS translocations currently used in agriculture is seriously restricting their use in wheat breeding programs. This research has found new 1RS sources for the future restructuring of 1BL.1RS translocations. The allelic variations of these 1RS arms should be studied more intensely as they may enrich the genetic diversity of 1BL.1RS translocations.
Instrumental variable analysis to estimate treatment effects: a simulation study showing potential benefits of conditioning on hospital
Authors: Ceyisakar I. E. , van Leeuwen N. , Steyerberg E. W. , Lingsma H. F.
Published: April 2022

Background

Instrumental variable (IV) analysis holds the potential to estimate treatment effects from observational data. IV analysis potentially circumvents unmeasured confounding but makes a number of assumptions, such as that the IV shares no common cause with the outcome. When using treatment preference as an instrument, a common cause, such as a preference regarding related treatments, may exist. We aimed to explore the validity and precision of a variant of IV analysis where we additionally adjust for the provider: adjusted IV analysis.

Methods

A treatment effect on an ordinal outcome was simulated (beta − 0.5 in logistic regression) for 15.000 patients, based on a large data set (the IMPACT data, n = 8799) using different scenarios including measured and unmeasured confounders, and a common cause of IV and outcome. We compared estimated treatment effects with patient-level adjustment for confounders, IV with treatment preference as the instrument, and adjusted IV, with hospital added as a fixed effect in the regression models.

Results

The use of patient-level adjustment resulted in biased estimates for all the analyses that included unmeasured confounders, IV analysis was less confounded, but also less reliable. With correlation between treatment preference and hospital characteristics (a common cause) estimates were skewed for regular IV analysis, but not for adjusted IV analysis.

Conclusion

When using IV analysis for comparing hospitals, some limitations of regular IV analysis can be overcome by adjusting for a common cause.

Trial registration

We do not report the results of a health care intervention.
Burden and trend of colorectal cancer in 54 countries of Africa 2010–2019: a systematic examination for Global Burden of Disease
Authors: Awedew Atalel Fentahun , Asefa Zelalem , Belay Woldemariam Beka
Published: April 2022

Background

Colorectal cancer plays significant role in morbidity, mortality and economic cost in Africa.

Objective

To investigate the burden and trends of incidence, mortality, and disability-adjusted life-years (DALYs) of colorectal cancer in Africa from 2010 to 2019.

Methods

This study was conducted according to Global Burden of Disease (GBD) 2019 analytic and modeling strategies. The recent GBD 2019 study provided the most updated and compressive epidemiological evidence of cancer incidence, mortality, years lived with disability (YLDs), years of life lost (YLLs), and DALYs.

Results

In 2019, there were 58,000 (95% UI: 52,000–65,000), 49,000 (95% UI: 43,000–54,000), and 1.3 million (95% UI: 1.14–1.46) incident cases, deaths and DALYs counts of colorectal cancer respectively in Africa. Between 2010 and 2019, incidence cases, death, and DALY counts of CRC were significantly increased by 48% (95% UI: 34–62%), 41% (95% UI: 28–55%), and 41% (95% UI: 27–56%) respectively. Change of age-standardised rates of incidence, death and DALYs were increased by 11% (95% UI: 1–21%), 6% (95% UI: − 3 to 16%), and 6% (95% UI: − 5 to 16%) respectively from 2010 to 2019. There were marked variations of burden of colorectal cancer at national level from 2010 to 2019 in Africa.

Conclusion

Increased age-standardised death rate and DALYs of colorectal cancer indicates low progress in CRC standard care-diagnosis and treatment, primary prevention of modifiable risk factors and implementation of secondary prevention modality. This serious effect would be due to poor cancer infrastructure and policy, low workforce capacity, cancer center for diagnosis and treatment, low finical security and low of universal health coverage in Africa.
Identification of SARS-CoV-2 variants using viral sequencing for the Centers for Disease Control and Prevention genomic surveillance program
Authors: Goswami Chirayu , Sheldon Michael , Bixby Christian , Keddache Mehdi , Bogdanowicz Alexander , Wang Yihe , Schultz Jonathan , McDevitt Jessica , LaPorta James , Kwon Elaine , Buyske Steven , Garbolino Dana , Biloholowski Glenys , Pastuszak Alex , Storella Mary , Bhalla Amit , Charlier-Rodriguez Florence , Hager Russ , Grimwood Robin , Nahas Shareef A.
Published: April 2022

Background

The Centers for Disease Control and Prevention contracted with laboratories to sequence the SARS-CoV-2 genome from positive samples across the United States to enable public health officials to investigate the impact of variants on disease severity as well as the effectiveness of vaccines and treatment. Herein we present the initial results correlating RT-PCR quality control metrics with sample collection and sequencing methods from full SARS-CoV-2 viral genomic sequencing of 24,441 positive patient samples between April and June 2021.

Methods

RT-PCR confirmed (N Gene Ct value < 30) positive patient samples, with nucleic acid extracted from saliva, nasopharyngeal and oropharyngeal swabs were selected for viral whole genome SARS-CoV-2 sequencing. Sequencing was performed using Illumina COVIDSeq™ protocol on either the NextSeq550 or NovaSeq6000 systems. Informatic variant calling, and lineage analysis were performed using DRAGEN COVID Lineage applications on Illumina’s Basespace cloud analytical system. All sequence data and variant calls were uploaded to NCBI and GISAID.

Results

An association was observed between higher sequencing coverage, quality, and samples with a lower Ct value, with < 27 being optimal, across both sequencing platforms and sample collection methods. Both nasopharyngeal swabs and saliva samples were found to be optimal samples of choice for SARS-CoV-2 surveillance sequencing studies, both in terms of strain identification and sequencing depth of coverage, with NovaSeq 6000 providing higher coverage than the NextSeq 550. The most frequent variants identified were the B.1.617.2 Delta (India) and P.1 Gamma (Brazil) variants in the samples sequenced between April 2021 and June 2021. At the time of submission, the most common variant > 99% of positives sequenced was Omicron.

Conclusion

These initial analyses highlight the importance of sequencing platform, sample collection methods, and RT-PCR Ct values in guiding surveillance efforts. These surveillance studies evaluating genetic changes of SARS-CoV-2 have been identified as critical by the CDC that can affect many aspects of public health including transmission, disease severity, diagnostics, therapeutics, and vaccines.
Damaging novel mutations in PIGN cause developmental epileptic-dyskinetic encephalopathy: a case report
Authors: Tian Maoqiang , Chen Jing , Li Juan , Pan Hong , Lei Wenting , Shu Xiaomei
Published: April 2022

Background

Mutations in PIGN, resulting in a glycosylphosphatidylinositol (GPI) anchor deficiency, typically leads to multiple congenital anomalies-hypotonia-seizures syndrome. However, the link between PIGN and epilepsy or paroxysmal non-kinesigenic dyskinesia (PNKD) is not well-described. This study reported a patient with PIGN mutation leading to developmental and epileptic encephalopathy and PNKD, to expand upon the genotype–phenotype correlation of PIGN.

Case presentation

During the first 10 days of life, a girl exhibited paroxysmal staring episodes with durations that ranged from several minutes to hours. These episodes occurred 2–5 times daily and always occurred during wakefulness. Ictal electroencephalography revealed no abnormalities, and PNKD was diagnosed. The patient also exhibited severely delayed psychomotor development and generalized seizures at the age of 4 months. Results of brain magnetic resonance imaging and metabolic screenings were normal, but trio-based whole-exome sequencing identified two novel compound heterozygous PIGN mutations (NM_176787; c.163C > T [p.R55 > X] and c.283C > T [p.R95W]). Flow cytometry analysis of the patient’s granulocytes revealed dramatically reduced expression of GPI-anchored proteins. This indicated that the mutations compromised GPI functions. The patient got seizure-free for 1 year, and her dyskinesia episodes reduced significantly (1–2 times/month) after treatment with levetiracetam (600 mg/day) and clonazepam (1.5 mg/day). No progress was observed with respect to psychomotor development; however, no craniofacial dysmorphic features, cleft lip/palate, brachytelephalangy with nail hypoplasia, and internal malformations have been observed until now (6 years of age).

Conclusion

This is the first study to document developmental and epileptic encephalopathy with PNKD in a human with PIGN mutations. This report expanded our understanding of the genotype–phenotype correlation of PIGN, and PIGN may be considered a potentially relevant gene when investigating cases of epilepsy or PNKD.
Advances in our understanding of the molecular pathogenesis of necrotizing enterocolitis
Authors: Cai Xue , Golubkova Alena , Hunter Catherine J.
Published: April 2022

Necrotizing enterocolitis (NEC) is a multifactorial and complex disease. Our knowledge of the cellular and genetic basis of NEC have expanded considerably as new molecular mechanisms have been identified. This article will focus on the current understanding of the molecular pathogenesis of NEC with a focus on the inflammatory, immune, infectious, and genetic mechanisms that drive disease development.
The experience of participating in an internet-based cognitive behavioral therapy program among patients with cardiovascular disease and depression: a qualitative interview study
Authors: Westas Mats , Mourad Ghassan , Andersson Gerhard , Neher Margit , Lundgren Johan , Johansson Peter
Published: April 2022

Background

Depression in conjunction with cardiovascular disease (CVD) is associated with worsening in CVD, higher mortality, and poorer quality of life. Despite the poor outcomes there is a treatment gap of depression in CVD patients. Recently we found that an Internet-based cognitive behavioral therapy (iCBT) tailored for CVD patients led to reduced symptoms of depression. However, we still have little knowledge about CVD patients’ experiences of working with iCBT. The aim of this study was therefore to explore CVD patients’ experiences of engaging in a tailored iCBT program.

Methods

A qualitative interview study using inductive thematic analysis. Data was obtained from 20 patients with CVD and depressive symptoms who had participated in a randomized controlled trial (RCT) evaluating the impact of a nine-week iCBT program on depression.

Results

Three main themes emerged: (1) Taking control of the disease, (2) Not just a walk in the park, and (3) Feeling a personal engagement with the iCBT program. The first theme included comments that the tailored program gave the patients a feeling of being active in the treatment process and helped them achieve changes in thoughts and behaviors necessary to take control of their CVD. The second theme showed that patients also experienced the program as demanding and emotionally challenging. However, it was viewed as helpful to challenge negative thinking about living with CVD and to change depressive thoughts. In the third theme patients reported that the structure inherent in the program, in the form of organizing their own health and the scheduled feedback from the therapist created a feeling of being seen as an individual. The feeling of being acknowledged as a person also made it easier to continuously work with the changes necessary to improve their health.

Conclusions

Engaging in an iCBT program tailored for patients with CVD and depression was by the patients perceived as helpful in the treatment of depression. They experienced positive changes in emotions, thoughts, and behaviors which a result of learning to take control of their CVD, being confirmed and getting support. The patients considered working with the iCBT program as demanding and emotionally challenging, but necessary to achieve changes in emotions, thoughts, and behaviors.
The effect of exercise on resilience, its mediators and moderators, in a general population during the UK COVID-19 pandemic in 2020: a cross-sectional online study
Authors: Lancaster Molly Rose , Callaghan Patrick
Published: April 2022

Background

Resilience is central to positive mental health and well-being especially when faced with adverse events. Factors such as exercise, location, sleep, mental health, and personality are moderators and mediators of resilience. However, the impact of these factors on resilience during severe adverse events are unknown. The present study examined how the COVID-19 pandemic affected resilience and its moderators and mediators by investigating whether there was a difference in resilience and quality of life between people with varying levels of exercise, including those who changed their exercise levels pre and during a COVID-19-related lockdown, and whether location affected the relationship between levels of exercise and resilience and quality of life.

Methods

Following ethical approval, a cross-sectional online survey capturing data on self-reported key moderators and mediators of resilience before and during the COVID-19 lockdown imposed on the 23rd March 2020 in the UK was distributed via social media and completed over a three week time period during July 2020 via a self-selecting sample of the general population (N = 85). The key moderators and mediators of resilience the survey assessed were exercise, location, life-orientation, mental health, and sleep quality. All data were self-reported.

Results

Participants’ exercise intensity level increased as resilience increased (F(2,82) = 4.22, p = .003: Wilks’ lambda = .82, partial n2 = 0.09). The relationship between exercise, and resilience and quality of life was independent of sleep and mental health status pre-lockdown (p = .013, p = .027 respectively). In the face of the COVID-19 pandemic, this relationship was dependent on mental health but not sleep quality (p = <.001 for resilience p = .010 for quality of life). There were no statistically significant differences between participants living in urban or rural locations.

Conclusion

Exercise is strongly correlated to resilience and during a pandemic such as COVID-19 it becomes a mechanism in which to moderate resilience. The relationship between exercise and resilience is supported by this study. The influence that a pandemic had on mental health is mediated by its effect on quality of life.