bluuebunny/crossref_metadata_2025 huggingface dataset:
Using the Remnant Anterior Cruciate Ligament to Improve Knee Stability: Biomechanical Analysis Using a Cadaveric Model
Authors: Nhan Derek T. , Belkoff Stephen M. , Singh Prerna , Sullivan Brian T. , Klyce Walter , Lee R. Jay
Published: April 2021

Background:

Injured anterior cruciate ligament (ACL) tissue retains proprioceptive nerve fibers, vascularity, and biomechanical properties. For these reasons, remnant ACL tissue is often preserved during the treatment of ACL injuries.

Purpose:

To assess through a cadaveric model whether reorienting and retensioning the residual ACL via an osteotomy improves knee stability after partial ACL tear, with substantial remnant tissue and intact femoral and tibial attachments.

Study Design:

Controlled laboratory study.

Methods:

In 8 adult cadaveric knees, we measured anterior tibial translation and rotational laxity at 30° and 90° of flexion with the ACL in its native state and in 3 conditions: partial tear, retensioned, and ACL-deficient. The partial-tear state consisted of a sectioned anteromedial ACL bundle.

Results:

In the native state, the translation was 10 ± 2.7 mm (mean ± SD) at 30° of flexion and 8.4 ± 3.6 mm at 90° of flexion. Anterior translation of the knees in the partial-tear state (14 ± 2.7 mm at 30° and 12 ± 2.7 mm at 90°) was significantly greater than baseline ( P < .001 for both). Translation in the ACL-retensioned state (9.2 ± 1.7 mm at 30° and 7.2 ± 2.1 mm at 90°) was significantly less than in the ACL-deficient state ( P < .001 for both), and translation was not significantly different from that of the intact state. For ACL-deficient knees, translation (20 ± 4.3 mm at 30° and 16 ± 4.4 mm at 90°) was significantly greater than all other states ( P < .001 for all). Although rotational testing demonstrated the least laxity at 30° and 90° of flexion in the retensioned and intact states and the most laxity in the ACL-deficient state, rotation was not significantly different among any of the experimental states.

Conclusion:

In a cadaveric model of an incomplete ACL tear, a reorienting and retensioning core osteotomy at the tibial insertion of the remnant ACL improved anteroposterior translation of the knee without compromising its rotational laxity.

Clinical Relevance:

The findings of this study support the concept of ACL tissue reorienting and retensioning in the treatment of ACL laxity as an area for future investigation.
Sequential Infusion of Anti-CD22 and Anti-CD19 Chimeric Antigen Receptor T Cells for Adult Patients with Refractory/Relapsed B-Cell Acute Lymphoblastic Leukemia
Authors: Huang Liang , Wang Na , Li Chunrui , Cao Yang , Xiao Yi , Xiao Min , Zhang Yicheng , Zhang Tongcun , Zhou Jianfeng
Published: April 2021

Clinical trials of second generation chimeric antigen receptor engineered T cells (CAR-T cells) have yielded unprecedented efficacy in refractory/relapsed B-cell acute lymphoblastic leukemia (B-ALL), especially in children and young adult. However, antigen loss relapse has been observed in approximately 14% of patients in anti-CD19 CAR-T cell therapy across institutions, which emerges as a challenge for the long-term disease control of this promising immunotherapy. Recently, CD19/CD20 and CD19/CD22 dual antigen targeting have been proposed to overcome antigen loss relapse after the administration of anti-CD19 CAR-T cells. This strategy may result in enhanced anti-tumor activity, while safety concern regarding the risk of cytokine release syndrome (CRS) due to significant CAR-T cell activation and cytokine release needs to be addressed.

Here, we conducted an open-label, single-center and single-arm pilot study of sequential infusion of anti-CD22 and anti-CD19 CAR-T cells. We aimed to evaluate its safety and efficacy in adult patients with refractory or relapsed B-ALL. This trial is registered with ChiCTR, number ChiCTR-OPN-16008526.

Between March 2016 and March 2017, 27 patients with refractory or relapsed B-ALL were enrolled in this clinical trial, with a median age of 30±12 years (range, 18-62 years). Thirteen patients (48.1%) had a history of at least two prior relapsed or primary refractory disease. Twenty-six patients received fludarabine and cyclophosphamide before the infusion of CAR-T cells. The median cell dosages of anti-CD22 and anti-CD19 CAR-T cells were 2.44 ± 1.02 × 106 /kg and 1.98 ± 1.05 × 106 /kg, respectively. 24/29 (88.9%) patients achieved CR or Cri, including 7 patients who received prior hematopoietic stem cell transplantation, and 13/27 (48.1%) patients achieved minimal residual disease negative (MRD-) CR accessed by flow cytometry. Sustained remission was achieved with a 6-month overall survival rate of 79% (95% CI, 66-97) and an event-free survival rate of 72% (95% CI, 55-95). 24/29 (88.9%) patients experienced CRS and 6/27 (22.2%) patients had reversible sever CRS (grade 3-4). And 3/27 (11.1%) patients developed neurotoxicity. Multi-color flow cytometry was used to screen and quantitate MRD in blood, bone marrow and cerebrospinal fluid. Antigen escape of CD19 and CD22 was not detected in any relapsed patient post-CAR-T cell therapy.

Our results indicated that sequential infusion of third generation Anti-CD22 and Anti-CD19 CAR-T cell therapy is feasible and safe for patients with refractory/relapsed B-ALL. Dual antigen targeting should be a promising approach for overcoming antigen escape relapse, while needs to be further determined in our clinical trial.

Disclosures

No relevant conflicts of interest to declare.
Genome Editing Strategies to Treat Beta-Hemoglobinopathies
Authors: Weiss Mitchell J
Published: April 2021

Genetic forms of anemia caused by HBB gene mutations that impair beta globin production are extremely common worldwide. The resultant disorders, mainly sickle cell disease (SCD) and beta-thalassemia, cause substantial morbidity and early mortality. Treatments for these diseases include medical therapies and bone marrow transplantation (BMT), which can be curative. However, medical therapies are suboptimal and BMT is associated with serious toxicities, particularly because HLA-matched allogeneic sibling donors are not available for most patients. Thus, new therapies are urgently needed for millions of affected individuals. Gene therapy offers great promise to cure SCD and beta thalassemia and emerging genome editing technologies represent a new form of gene therapy. Approaches to cure SCD and beta-thalassemia via genome editing include: 1) Correction of HBB mutations by homology directed repair (HDR); 2) use of non-homologous end joining (NHEJ) to activate gamma globin production and raise fetal hemoglobin (HbF) levels; 3) NHEJ to disrupt alpha-globin genes (HBA1 or HBA2) and thereby alleviate globin chain imbalance in intermediately severe forms of beta thalassemia. Challenges for these approaches include selection of the most effective genome editing tools, optimizing their delivery to hematopoietic stem cells (HSCs), improving specificity and better understanding potential off target effects, particularly those that are biologically relevant. Technologies for genome editing are advancing rapidly and being tested in preclinical models for HBB-mutated disorders. Ultimately, however, the best strategies can only be identified in clinical trials. This will require close collaborations between basic/translational researchers who study genome editing, clinical hematologists and collaboration between experts in academia and the bio-pharmaceutical industry.

Disclosures

No relevant conflicts of interest to declare.
New Bone Marrow Failure Genes: DNAJC21 and ERCC6L2
Authors: Dokal Inderjeet
Published: April 2021

A significant number of cases with bone marrow failure present with one or more extra-hematopoietic abnormality. This suggests a constitutional or genetic basis, and yet many of them remain uncharacterized. Through exome sequencing, we have recently identified two sub groups of these cases, one defined by germline biallelic mutations in DNAJC21 (DNAJ homolog subfamily C member 21) and the other in ERCC6L2 (excision repair cross complementing 6 like-2).

Patients with DNAJC21 mutations are characterized by global bone marrow failure in early childhood. They can also have a variable number of extra-hematopoietic abnormalities such as short stature and retinal dystrophy. The encoded protein associates with ribosomal RNA (rRNA) and plays a highly conserved role in the maturation of the 60S ribosomal subunit. Lymphoblastoid patient cells exhibit increased sensitivity to the transcriptional inhibitor actinomycin D and reduced levels of rRNA. Characterisation of mutations has revealed impairment in interactions with cofactors (PA2G4, HSPA8 and ZNF622) involved in 60S maturation. DNAJC21 deficiency results in cytoplasmic accumulation of the 60S nuclear export factor PA2G4, aberrant ribosome profiles and increased cell death. Collectively these findings demonstrate that biallelic mutations in DNAJC21 cause disease due to defects in early nuclear rRNA biogenesis and late cytoplasmic maturation of the 60S subunit.

Patients harbouring biallelic ERCC6L 2 mutations are characterized by bone marrow failure (in childhood or early adulthood) and one or more extra-hematopoietic abnormality such as microcephaly. Knockdown of ERCC6L2 in human cells significantly reduces their viability upon exposure to the DNA damaging agent irofulven but not etoposide and camptothecin suggesting a role in nucleotide excision repair. ERCC6L2 knockdown cells and patient cells harbouring biallelic ERCC6L2 mutations also display H2AX phosphorylation that significantly increases upon genotoxic stress, suggesting an early DNA damage response. ERCC6L2 is seen to translocate to mitochondria as well as the nucleus in response to DNA damage and its knockdown induces intracellular reactive oxygen species (ROS). Treatment with the ROS scavenger, N-acetyl-cysteine, attenuates the irofulven-induced cytotoxicity in ERCC6L2 knockdown cells and abolishes its traffic to mitochondria and nucleus in response to this DNA damaging agent. Collectively, these observations suggest that ERCC6L2has a pivotal rolein DNA repair and mitochondrial function.

In conclusion, ERCC6L2 and DNAJC21 have an important role in maintaining genomic stability and ribosome biogenesis, respectively. They bring into focus new biological connections/pathways whose constitutional disruption is associated with defective hematopoiesis since patients harbouring germline biallelic mutations in these genes uniformly have bone marrow failure.

Disclosures

No relevant conflicts of interest to declare.
Normal Plasma Cell Biology: Natural Achilles Heels as Targets in Myeloma
Authors: Georgopoulos Katia
Published: April 2021

Normal Plasma Cell Biology: Natural Achilles Heels as Targets in MyelomaÊ Primary exposure to antigen leads to affinity maturation, selection and terminal differentiation of mature B cells to antibody-secreting plasma cells. Long-lived high-affinity plasma cells and their immediate precursors reside in the bone marrow and are responsible for rapid recall reactions and a life-time production of high affinity antibodies. Members of the IKAROS gene family have been specifically implicated in the generation of long-lived plasma cells. Mice deficient for Aiolos, the B cell specific member of the IKAROS gene family fail to produce high affinity plasma cells in the bone marrow and to sustain serum antibody titers after both primary or secondary immunization with a range of hapten concentrations. Chimera reconstitutions have demonstrated that the bone marrow plasma cell defect is B cell intrinsic. However, lack of AIOLOS does not alter expression of any of the previously described factors required for B cell differentiation into the plasma cell stage. No defect in somatic hyper-mutation, the generation of memory B cells, or short-lived high affinity plasma cells in the spleen is observed upon challenge or re-challenge. Thus this IKAROS family member is critically required for high-affinity bone plasma cells possibly by regulating their interaction with the bone marrow microenvironment, a process that is likely critical for long-term survival. High-affinity bone marrow plasma cells are the normal counterpart of the devastating B cell malignancy multiple myeloma. Multiple myeloma is treatable with immune modulatory drugs (IMiD) such as lenalidomide. Recent studies have shown that IMiD alter the specificity of the CRL4-CEREBLON (CRL4CRBN) E3 ubiquitin ligase complex. Among the new targets for the CRL4CRBN complex are two of the IKAROS family members, AIOLOS and IKAROS, whose degradation adversely affects the cellular fitness of multiple myeloma cells. Recent studies in B cell precursors have implicated the IKAROS gene family in the regulation of bone marrow stromal interactions. IKAROS and AIOLOS activities balance self-renewal, survival, and pre-B cell differentiation by engaging epigenetic and transcriptional machineries through discrete lineage-specific superenhancers. Such AIOLOS and IKAROS-dependent regulatory pathways engaged in early B cell precursors may also be involved in controlling bone marrow stromal interactions with high affinity plasma cells and their malignant counterparts thereby contributing to long-term growth and survival. Further exploitation of IKAROS family-targeted pathways in bone marrow plasma cells and multiple myeloma is warranted.

Disclosures

No relevant conflicts of interest to declare.
Spatial matching on the urban labor market: estimates with unique micro data
Authors: Wozniak Marcin
Published: April 2021

In the paper, we investigate spatial relationship on the labor market of Poznań agglomeration (Poland) with unique data on job vacancies. We have developed spatial panel models to assess the search and matching process with a particular focus on spatial spillovers. In general, spatial models may provide different findings than regular panel models regarding returns to scale in matching technology. Moreover, we have identified global spillover effects as well as other factors that impact the job-worker matching. We underline the role of data on job vacancies: the data retrieved from commercial job portals produced much more reliable estimates than underestimated registered data.
Adaptation of codon and amino acid use for translational functions in highly expressed cricket genes
Authors: Whittle Carrie A. , Kulkarni Arpita , Chung Nina , Extavour Cassandra G.
Published: April 2021

Background

For multicellular organisms, much remains unknown about the dynamics of synonymous codon and amino acid use in highly expressed genes, including whether their use varies with expression in different tissue types and sexes. Moreover, specific codons and amino acids may have translational functions in highly transcribed genes, that largely depend on their relationships to tRNA gene copies in the genome. However, these relationships and putative functions are poorly understood, particularly in multicellular systems.

Results

Here, we studied codon and amino acid use in highly expressed genes from reproductive and nervous system tissues (male and female gonad, somatic reproductive system, brain and ventral nerve cord, and male accessory glands) in the cricket Gryllus bimaculatus. We report an optimal codon, defined as the codon preferentially used in highly expressed genes, for each of the 18 amino acids with synonymous codons in this organism. The optimal codons were mostly shared among tissue types and both sexes. However, the frequency of optimal codons was highest in gonadal genes. Concordant with translational selection, a majority of the optimal codons had abundant matching tRNA gene copies in the genome, but sometimes obligately required wobble tRNAs. We suggest the latter may comprise a mechanism for slowing translation of abundant transcripts, particularly for cell-cycle genes. Non-optimal codons, defined as those least commonly used in highly transcribed genes, intriguingly often had abundant tRNAs, and had elevated use in a subset of genes with specialized functions (gametic and apoptosis genes), suggesting their use promotes the translational upregulation of particular mRNAs. In terms of amino acids, we found evidence suggesting that amino acid frequency, tRNA gene copy number, and amino acid biosynthetic costs (size/complexity) had all interdependently evolved in this insect model, potentially for translational optimization.

Conclusions

Collectively, the results suggest a model whereby codon use in highly expressed genes, including optimal, wobble, and non-optimal codons, and their tRNA abundances, as well as amino acid use, have been influenced by adaptation for various functional roles in translation within this cricket. The effects of expression in different tissue types and the two sexes are discussed.
Gene co-expression network analysis reveals key pathways and hub genes in Chinese cabbage (Brassica rapa L.) during vernalization
Authors: Dai Yun , Sun Xiao , Wang Chenggang , Li Fei , Zhang Shifan , Zhang Hui , Li Guoliang , Yuan Lingyun , Chen Guohu , Sun Rifei , Zhang Shujiang
Published: April 2021

Background

Vernalization is a type of low temperature stress used to promote rapid bolting and flowering in plants. Although rapid bolting and flowering promote the reproduction of Chinese cabbages (Brassica rapaL.ssp. pekinensis), this process causes their commercial value to decline. Clarifying the mechanisms of vernalization is essential for its further application. We performed RNA sequencing of gradient-vernalization in order to explore the reasons for the different bolting process of two Chinese cabbage accessions during vernalization.

Results

There was considerable variation in gene expression between different-bolting Chinese cabbage accessions during vernalization. Comparative transcriptome analysis and weighted gene co-expression network analysis (WGCNA) were performed for different-bolting Chinese cabbage during different vernalization periods. The biological function analysis and hub gene annotation of highly relevant modules revealed that shoot system morphogenesis and polysaccharide and sugar metabolism caused early-bolting ‘XBJ’ to bolt and flower faster; chitin, ABA and ethylene-activated signaling pathways were enriched in late-bolting ‘JWW’; and leaf senescence and carbohydrate metabolism enrichment were found in the two Chinese cabbage-related modules, indicating that these pathways may be related to bolting and flowering. The high connectivity of hub genes regulated vernalization, includingMTHFR2,CPRD49,AAP8, endoglucanase 10,BXLs,GATLs, andWRKYs. Additionally, five genes related to flower development,BBX32(binds to theFTpromoter),SUS1(increasesFTexpression),TSF(the closest homologue ofFT),PAOandNAC029(plays a role in leaf senescence), were expressed in the two Chinese cabbage accessions.

Conclusion

The present work provides a comprehensive overview of vernalization-related gene networks in two different-bolting Chinese cabbages during vernalization. In addition, the candidate pathways and hub genes related to vernalization identified here will serve as a reference for breeders in the regulation of Chinese cabbage production.
Mitogenomic phylogeny of Callithrix with special focus on human transferred taxa
Authors: Malukiewicz Joanna , Cartwright Reed A. , Curi Nelson H. A. , Dergam Jorge A. , Igayara Claudia S. , Moreira Silvia B. , Molina Camila V. , Nicola Patricia A. , Noll Angela , Passamani Marcello , Pereira Luiz C. M. , Pissinatti Alcides , Ruiz-Miranda Carlos R. , Silva Daniel L. , Stone Anne C. , Zinner Dietmar , Roos Christian
Published: April 2021

Background

Callithrixmarmosets are a relatively young primate radiation, whose phylogeny is not yet fully resolved. These primates are naturally para- and allopatric, but three species with highly invasive potential have been introduced into the southeastern Brazilian Atlantic Forest by the pet trade. There, these species hybridize with each other and endangered, native congeners. We aimed here to reconstruct a robustCallithrixphylogeny and divergence time estimates, and identify the biogeographic origins of autochthonous and allochthonousCallithrixmitogenome lineages. We sequenced 49 mitogenomes from four species (C. aurita,C. geoffroyi,C. jacchus,C. penicillata) and anthropogenic hybrids (C. auritaxCallithrixsp.,C. penicillataxC. jacchus,Callithrixsp. xCallithrixsp.,C. penicillataxC. geoffroyi) via Sanger and whole genome sequencing. We combined these data with previously publishedCallithrixmitogenomes to analyze fiveCallithrixspecies in total.

Results

We report the complete sequence and organization of theC. auritamitogenome. Phylogenetic analyses showed thatC. auritawas the first to diverge withinCallithrix3.54 million years ago (Ma), whileC. jacchusandC. penicillatalineages diverged most recently 0.5 Ma as sister clades. MtDNA clades ofC. aurita,C. geoffroyi, andC. penicillatashow intraspecific geographic structure, butC. penicillataclades appear polyphyletic. Hybrids, which were identified by phenotype, possessed mainlyC. penicillataorC. jacchusmtDNA haplotypes. The biogeographic origins of mtDNA haplotypes from hybrid and allochthonousCallithrixwere broadly distributed across naturalCallithrixranges. Our phylogenetic results also evidence introgression ofC. jacchusmtDNA intoC. aurita.

Conclusion

Our robustCallithrixmitogenome phylogeny showsC. auritalineages as basal andC. jacchuslineages among the most recent withinCallithrix. We provide the first evidence that parental mtDNA lineages of anthropogenic hybrid and allochthonous marmosets are broadly distributed inside and outside of the Atlantic Forest. We also show evidence of cryptic hybridization between allochthonousCallithrixand autochthonousC. aurita. Our results encouragingly show that further development of genomic resources will allow to more clearly elucidateCallithrixevolutionary relationships and understand the dynamics ofCallithrixanthropogenic introductions into the Brazilian Atlantic Forest.
Genome-scale analyses of transcriptional start sites in Mycobacterium marinum under normoxic and hypoxic conditions
Authors: Huang Shaojia , Zhou Wei , Tang Wei , Zhang Yong , Hu Yangbo , Chen Shiyun
Published: April 2021

Background

Hypoxic stress plays a critical role in the persistence of Mycobacterium tuberculosis (Mtb) infection, but the mechanisms underlying this adaptive response remain ill defined.

Material and methods

In this study, using M. marinum as a surrogate, we analyzed hypoxic responses at the transcriptional level by Cappable-seq and regular RNA-seq analyses.

Results

A total of 6808 transcriptional start sites (TSSs) were identified under normoxic and hypoxic conditions. Among these TSSs, 1112 were upregulated and 1265 were downregulated in response to hypoxic stress. Using SigE-recognized consensus sequence, we identified 59 SigE-dependent promoters and all were upregulated under hypoxic stress, suggesting an important role for SigE in this process. We also compared the performance of Cappable-seq and regular RNA-seq using the same RNA samples collected from normoxic and hypoxic conditions, and confirmed that Cappable-seq is a valuable approach for global transcriptional regulation analyses.

Conclusions

Our results provide insights and information for further characterization of responses to hypoxia in mycobacteria, and prove that Cappable-seq is a valuable approach for global transcriptional studies in mycobacteria.
Temporal dynamics of the plasma microbiome in recipients at early post-liver transplantation: a retrospective study
Authors: Okumura Toshihiko , Horiba Kazuhiro , Kamei Hideya , Takeuchi Suguru , Suzuki Takako , Torii Yuka , Kawada Jun-ichi , Takahashi Yoshiyuki , Ogura Yasuhiro , Ogi Tomoo , Ito Yoshinori
Published: April 2021

Background

Immunosuppression during liver transplantation (LT) enables the prevention and treatment of organ rejection but poses a risk for severe infectious diseases. Immune modulation and antimicrobials affect the plasma microbiome. Thus, determining the impact of immunosuppression on the microbiome may be important to understand immunocompetence, elucidate the source of infection, and predict the risk of infection in LT recipients. We characterized the plasma microbiome of LT recipients at early post-LT and assessed the association between the microbiome and clinical events.

Results

In this study, 51 patients who received LT at Nagoya University Hospital from 2016 to 2018 were enrolled. Plasma samples were retrospectively collected at the following time points: 1) within a week after LT; 2) 4 ± 1 weeks after LT; 3) 8 ± 1 weeks after LT; and 4) within 2 days after a positive blood culture. A total of 111 plasma samples were analyzed using shotgun next-generation sequencing (NGS) with the PATHDET pipeline. Relative abundance of Anelloviridae, Nocardiaceae, Microbacteriaceae, and Enterobacteriaceae significantly changed during the postoperative period. Microbiome diversity was higher within a week after LT than that at 8 weeks after LT. Antimicrobials were significantly associated with the microbiome of LT recipients. In addition, the proportion of Enterobacteriaceae was significantly increased and the plasma microbiome diversity was significantly lower in patients with acute cellular rejection (ACR) than non-ACR patients. Sequencing reads of bacteria isolated from blood cultures were predominantly identified by NGS in 8 of 16 samples, and human herpesvirus 6 was detected as a causative pathogen in one recipient with severe clinical condition.

Conclusions

The metagenomic NGS technique has great potential in revealing the plasma microbiome and is useful as a comprehensive diagnostic procedure in clinical settings. Temporal dynamics of specific microorganisms may be used as indirect markers for the determination of immunocompetence and ACR in LT recipients.
Comparative genomic analysis of Mycobacterium intracellulare: implications for clinical taxonomic classification in pulmonary Mycobacterium avium-intracellulare complex disease
Authors: Tateishi Yoshitaka , Ozeki Yuriko , Nishiyama Akihito , Miki Mari , Maekura Ryoji , Fukushima Yukari , Nakajima Chie , Suzuki Yasuhiko , Matsumoto Sohkichi
Published: April 2021

Background

Mycobacterium intracellulareis a representative etiological agent of emerging pulmonaryM. avium-intracellularecomplex disease in the industrialized countries worldwide. The recent genome sequencing of clinical strains isolated from pulmonaryM. avium-intracellularecomplex disease has provided insight into the genomic characteristics of pathogenic mycobacteria, especially forM. avium; however, the genomic characteristics ofM. intracellulareremain to be elucidated.

Results

In this study, we performed comparative genomic analysis of 55 M. intracellulareand related strains such asM. paraintracellulare(MP),M. indicus pranii(MIP) andM. yonogonense. Based on the average nucleotide identity, the clinicalM. intracellularestrains were phylogenetically grouped in two clusters: (1) the typicalM. intracellulare(TMI) group, including ATCC13950 and virulent M.i.27 and M.i.198 that we previously reported, and (2) the MP-MIP group. The alignment of the genomic regions was mostly preserved between groups. Plasmids were identified between groups and subgroups, including a plasmid common among some strains of the M.i.27 subgroup. Several genomic regions including those encoding factors involved in lipid metabolism (e.g.,fadE3,fadE33), transporters (e.g.,mce3), and type VII secretion system (genes of ESX-2 system) were shown to be hypermutated in the clinical strains.M. intracellularewas shown to be pan-genomic at the species and subspecies levels. Themcegenes were specific to particular subspecies, suggesting that these genes may be helpful in discriminating virulence phenotypes between subspecies.

Conclusions

Our data suggest that genomic diversity amongM. intracellulare,M. paraintracellulare,M. indicus praniiandM. yonogonenseremains at the subspecies or genovar levels and does not reach the species level. Genetic components such asmcegenes revealed by the comparative genomic analysis could be the novel focus for further insight into the mechanism of human pathogenesis forM. intracellulareand related strains.
Ectopic pancreas appearing as a giant gastric cyst mimicking gastric lymphangioma: a case report and a brief review
Authors: Liu Xuemei , Wu Xinglong , Tuo Biguang , Wu Huichao
Published: April 2021

Background

Ectopic pancreas (EP) is defined as pancreatic tissue that lacks anatomical or vascular communication with the normal body of the pancreas. Despite improvements in diagnostic endoscopy and imaging studies, differentiating ectopic pancreatic tissue from gastric submucosal diseases remains a challenge.

Case presentation

Here, we present a case of a 44-year-old woman with severe epigastric pain. Initially, gastric lymphangioma was highly suspected due to a well-demarcated protruding mass with a large size that occurred in the submucosal layer of the gastric antrum and appeared as a cystic lesion. The final correct diagnosis of gastric EP was made during surgery.

Conclusion

Gastric EP with serous oligocystic adenoma appearing as a giant gastric cyst is extremely rare. The difficulty of making an accurate diagnosis and differential diagnosis is highlighted, which may provide additional clinical experience for the diagnosis of EP with serous oligocystic adenoma in the stomach.
Prognostic significance of MUC2, CDX2 and SOX2 in stage II colorectal cancer patients
Authors: Ribeirinho-Soares Sara , Pádua Diana , Amaral Ana Luísa , Valentini Elvia , Azevedo Daniela , Marques Cristiana , Barros Rita , Macedo Filipa , Mesquita Patrícia , Almeida Raquel
Published: April 2021

Background

Colorectal cancer (CRC) remains a serious health concern worldwide. Despite advances in diagnosis and treatment, about 15 to 30% of stage II CRC patients subjected to tumor resection with curative intent, develop disease relapse. Moreover, the therapeutic strategy adopted after surgery is not consensual for these patients. This supports the imperative need to find new prognostic and predictive biomarkers for stage II CRC.

Methods

For this purpose, we used a one-hospital series of 227 stage II CRC patient samples to assess the biomarker potential of the immunohistochemical expression of MUC2 mucin and CDX2 and SOX2 transcription factors. The Kaplan-Meier method was used to generate disease-free survival curves that were compared using the log-rank test, in order to determine prognosis of cases with different expression of these proteins, different mismatch repair (MMR) status and administration or not of adjuvant chemotherapy.

Results

In this stage II CRC series, none of the studied biomarkers showed prognostic value for patient outcome. However low expression of MUC2, in cases with high expression of CDX2, absence of SOX2 or MMR-proficiency, conferred a significantly worst prognosis. Moreover, cases with low expression of MUC2 showed a significantly clear benefit from treatment with adjuvant chemotherapy.

Conclusion

In conclusion, we observe that patients with stage II CRC with low expression of MUC2 in the tumor respond better when treated with adjuvant chemotherapy. This observation supports that MUC2 is involved in resistance to fluorouracil-based adjuvant chemotherapy and might be a promising future predictive biomarker in stage II CRC patients.
Designing and evaluation of E-health educational intervention on students’ physical activity: an application of Pender’s health promotion model
Authors: Sabooteh Sahar , Feizi Awat , Shekarchizadeh Parivash , Shahnazi Hossein , Mostafavi Firoozeh
Published: April 2021

Background

The present study was conducted to design and evaluate the software and web-based curriculum based on Pender Model in order to promote students’ physical activity.

Methods

This is a quasi-experimental study conducted on 225 eligible students who were randomly divided into two groups of web and software-based intervention and control. The sample size of the study was selected using stratified sampling method. The evaluation was done with pre-test and post-test and follow-up, which were performed immediately two and six months following the intervention. The data were analyzed employing statistical software SPSS using descriptive statistics, chi-square, one way ANOVA, and repeated measures ANOVA.

Results

The obtained results revealed that the level of physical activity after the intervention in the web and software groups significantly increased compared to the control group (p < 0.001). Moreover, the mean score of Pender model constructs, immediately two and six months after the intervention, was significantly different in the web and software groups (p < 0.001).

Conclusion

Our results indicated that, providing tailored message based on health promotion model’s constructs has a positive effect on promoting physical activity of students.

Trial registration

Name: Iranian Registry of Clinical Trials. Registration number: IRCT20181009041298N1. Registration date: 2018–12-02 [retrospectively registered].
Behavioral changes before lockdown and decreased retail and recreation mobility during lockdown contributed most to controlling COVID-19 in Western countries
Authors: Deforche Koen , Vercauteren Jurgen , Müller Viktor , Vandamme Anne-Mieke
Published: April 2021

Background

The COVID-19 pandemic has prompted a lockdown in many countries to control the exponential spread of the SARS-CoV-2 virus, hereby reducing the time-varying basic reproduction number (Rt) to below one. Governments are looking for evidence to balance the demand of their citizens to ease some of the restriction, against the fear of a new peak in infections. In this study, we wanted to quantify the relative contribution of mobility restrictions, and that of behavioral changes that occurred already before the lockdowns, on the reduction of transmission during lockdowns in Western countries in early 2020.

Methods

Incidence data of cases and deaths from the first wave of infections for 35 Western countries (32 European, plus Israel, USA and Canada) were analyzed using epidemiological compartment models in a Bayesian framework. Mobility data was used to estimate the timing of changes associated with a lockdown, and was correlated with estimated reductions of Rt.

Results

Across all countries, the initial median estimate for Rt was 3.6 (95% IQR 2.4–5.2), and it was reduced to 0.78 (95% IQR 0.58–1.01) during lockdown. 48% (18–65%) of the reduction occurred already in the week before lockdown, with lockdown itself causing the remaining drop in transmission. A lower Rt during lockdown was independently associated with an increased time spent at home (0.21 per 10% more time, p < 0.007), and decreased mobility related to retail and recreation (0.07 per 10% less mobility, p < 0.008).

Conclusions

In a Western population unaware of the risk, SARS-CoV-2 can be highly contagious with a reproduction number R0 > 5. Our results are consistent with evidence that recreational activities (including restaurant and bar visits) enable super-spreading events. Exiting from lockdown therefore requires continued physical distancing and tight control on this kind of activities.
Homebound by COVID19: the benefits and consequences of non-pharmaceutical intervention strategies
Authors: Oruc Buse Eylul , Baxter Arden , Keskinocak Pinar , Asplund John , Serban Nicoleta
Published: April 2021

Background

Recent research has been conducted by various countries and regions on the impact of non-pharmaceutical interventions (NPIs) on reducing the spread of COVID19. This study evaluates the tradeoffs between potential benefits (e.g., reduction in infection spread and deaths) of NPIs for COVID19 and being homebound (i.e., refraining from interactions outside of the household).

Methods

An agent-based simulation model, which captures the natural history of the disease at the individual level, and the infection spread via a contact network assuming heterogeneous population mixing in households, peer groups (workplaces, schools), and communities, is adapted to project the disease spread and estimate the number of homebound people and person-days under multiple scenarios, including combinations of shelter-in-place, voluntary quarantine, and school closure in Georgia from March 1 to September 1, 2020.

Results

Compared to no intervention, under voluntary quarantine, voluntary quarantine with school closure, and shelter-in-place with school closure scenarios 4.5, 23.1, and 200+ homebound adult-days were required to prevent one infection, with the maximum number of adults homebound on a given day in the range of 119 K–248 K, 465 K–499 K, 5388 K-5389 K, respectively. Compared to no intervention, school closure only reduced the percentage of the population infected by less than 16% while more than doubling the peak number of adults homebound.

Conclusions

Voluntary quarantine combined with school closure significantly reduced the number of infections and deaths with a considerably smaller number of homebound person-days compared to shelter-in-place.
Radiological tarsal bone morphology in adolescent age of congenital clubfeet treated with the Ponseti method
Authors: Hamel Johannes , Hörterer Hubert , Harrasser Norbert
Published: April 2021

Background

Major abnormalities of tarsal bone shape after surgical clubfoot treatment are well known from the literature. The Ponseti method has gained widespread acceptance in primary treatment of congenital clubfeet. Despite the longtime experience, data regarding the development of tarsal bones after this treatment are still rare. The aim of the study was therefore to evaluate radiographic parameters describing tarsal bone shape of clubfeet after Ponseti treatment and compare them to age-matched healthy feet.

Methods

Twenty two consecutive severe clubfeet in 14 patients were investigated by repeated diagnostic ultrasound during the corrective process. Extent and temporal course of correction were documented with standardized X-rays after a mean follow-up of 12 years (between the ages of 10–14 years) and compared to a group of age-matched normal feet.

Results

Reliability testing for all X-ray parameters showed good to excellent results. In comparison to the control group, all parameters except the radius of the trochlea (RT) were significantly altered in clubfeet with highest differences shown for the anterior talar motion segment (ATM), talonavicular coverage (TNC) and the talometatarsal index (TMT-Index). Differentiation between minor and major deformities showed significant differences only for the front tarsal index (FTI).

Conclusions

Tarsal bone shape of clubfeet treated by the Ponseti method differs significantly from normal feet. One of the most pronounced and clinically relevant difference of the clubfoot talus compared to the normal talus is the markedly reduced anterior talar motion segment.
COVID-19 outbreak and acute cholecystitis in a Hub Hospital in Milan: wider indications for percutaneous cholecystostomy
Authors: Barabino Matteo , Piccolo Gaetano , Trizzino Arianna , Fedele Veronica , Ferrari Carlo , Nicastro Vincenzo , Pisani Ceretti Andrea , De Nicola Enrico , Mariani Nicolò Maria , Giovenzana Marco , Scifo Giovanna , Mazza Massimiliano , Vercelli Ruggero , Santambrogio Roberto , Luigiano Carmelo , Opocher Enrico
Published: April 2021

Background

COVID-19 pandemic has impacted the Italian National Health Care system at many different levels, causing a complete reorganization of surgical wards. In this context, our study retrospectively analysed the management strategy for patients with acute cholecystitis.

Methods

We analysed all patients admitted to our Emergency Department for acute cholecystitis between February and April 2020 and we graded each case according to 2018 Tokyo Guidelines. All patients were tested for positivity to SARS-CoV-2 and received an initial conservative treatment. We focused on patients submitted to cholecystostomy during the acute phase of pandemic and their subsequent disease evolution.

Results

Thirty-seven patients were admitted for acute cholecystitis (13 grade I, 16 grade II, 8 grade III). According to Tokyo Guidelines (2018), patients were successfully treated with antibiotic only, bedside percutaneous transhepatic gallbladder drainage (PC) and laparoscopic cholecystectomy (LC) in 29.7%, 21.6% and 48.7% of cases respectively. Therapeutic strategy of three out of 8 cases, otherwise fit for surgery, submitted to bedside percutaneous transhepatic gallbladder drainage (37.5%), were directly modified by COVID-19 pandemic: one due to the SARS-CoV-2 positivity, while two others due to unavailability of operating room and intensive care unit for post-operative monitoring respectively. Overall success rate of percutaneous cholecystostomy was of 87.5%. The mean post-procedural hospitalization length was 9 days, and no related adverse events were observed apart from transient parietal bleeding, conservatively treated. Once discharged, two patients required readmission because of acute biliary symptoms. Median time of drainage removal was 43 days and only 50% patients thereafter underwent cholecystectomy.

Conclusions

Percutaneous cholecystostomy has shown to be an effective and safe treatment thus acquiring an increased relevance in the first phase of the pandemic. Nowadays, considering we are forced to live with the SARS-CoV-2 virus, PC should be considered as a virtuous, alternative tool for potentially all COVID-19 positive patients and selectively for negative cases unresponsive to conservative therapy and unfit for surgery.
A signature of 24 aging‑related gene pairs predict overall survival in gastric cancer
Authors: Zhang Yankai , Yan Yichao , Ning Ning , Shen Zhanlong , Ye Yingjiang
Published: April 2021

Background

Aging is the major risk factor for most human cancers. We aim to develop and validate a reliable aging-related gene pair signature (ARGPs) to predict the prognosis of gastric cancer (GC) patients.

Methods

The mRNA expression data and clinical information were obtained from two public databases, The Cancer Genome Atlas (TCGA) dataset, and Gene Expression Omnibus (GEO) dataset, respectively. The best prognostic signature was established using Cox regression analysis (univariate and least absolute shrinkage and selection operator). The optimal cut-off value to distinguish between high- and low-risk patients was found by time-dependent receiver operating characteristic (ROC). The prognostic ability of the ARGPS was evaluated by a log‐rank test and a Cox proportional hazards regression model.

Results

The 24 ARGPs were constructed for GC prognosis. Using the optimal cut-off value − 0.270, all patients were stratified into high risk and low risk. In both TCGA and GEO cohorts, the results of Kaplan–Meier analysis showed that the high-risk group has a poor prognosis (P < 0.001,P = 0.002, respectively). Then, we conducted a subgroup analysis of age, gender, grade and stage, and reached the same conclusion. After adjusting for a variety of clinical and pathological factors, the results of multivariate COX regression analysis showed that the ARGPs is still an independent prognostic factor of OS (HR, 4.919; 95% CI 3.345–7.235;P < 0.001). In comparing with previous signature, the novel signature was superior, with an area under the receiver operating characteristic curve (AUC) value of 0.845 vs. 0.684 vs. 0.695. The results of immune infiltration analysis showed that the abundance of T cells follicular helper was significantly higher in the low-risk group, while the abundance of monocytes was the opposite. Finally, we identified and incorporated independent prognostic factors and developed a superior nomogram to predict the prognosis of GC patients.

Conclusion

Our study has developed a robust prognostic signature that can accurately predict the prognostic outcome of GC patients.
The enrolment gap: who is not enrolling with primary health organizations in Aotearoa New Zealand and what are the implications? An exploration of 2015–2019 administrative data
Authors: Irurzun-Lopez Maite , Jeffreys Mona , Cumming Jacqueline
Published: April 2021

Background

Primary Health Care (PHC) is the entry point to accessing health services in many countries. Having a high proportion of the population enrolled with a PHC provider is key to ensuring PHC fulfils this role and that it contributes to achieving better equity in health. We aimed to understand the extent to which people in Aotearoa New Zealand are enrolling with Primary Health Organizations (PHOs), how enrolment rates have evolved over time, and variations across District Health Boards (DHBs) and socio-demographic groups.

Methods

We analysed administrative data on the proportion of people enrolled in PHOs and breakdowns across DHBs, and by age, ethnicity and deprivation, for the years 2015–2019.

Results

About 6% of the population was not enrolled in 2019. There are persistent differences across socio-demographic groups as well as geographically. Māori have lower enrolment rates than New Zealand European/Other groups. Young people (15–24 years) are the least likely to be enrolled. The most affluent areas have the highest enrolment rates. Auckland DHB shows the lowest enrolment rates.

Conclusions

Enrolments remain below full population coverage and inequities exist between socio-demographic and geographic groups. Potential reasons explaining these trends include methodological limitations as well as real issues in accessing services. We recommend (a) work towards minimising data issues in relation to this indicator to improve its accuracy and value in signalling trends in access to PHC services, and (b) investigating the reasons for the potential widening of the inequities identified, in particular issues preventing Māori and younger people from enrolling. This study deepens our understanding of enrolment rates as an indicator for tracking equity in PHC. Other countries can learn from the Aotearoa New Zealand case to draw lessons for improving equity in health care.
Burnout and depression among psychiatry residents during COVID-19 pandemic
Authors: Alkhamees Abdulmajeed A. , Assiri Hatem , Alharbi Hatim Yousef , Nasser Abdullah , Alkhamees Mohammad A.
Published: April 2021

Very few studies have been concerned with assessing the prevalence of burnout and depressive symptoms, especially during an infectious outbreak on non-frontline health care workers, such as a psychiatrist. In such instances, the role of psychiatrists and other mental health providers as a source of psychological support to the public and frontline workers is indispensable and valuable. This study aims to assess the prevalence of burnout and depressive symptoms, and their correlation, during the COVID-19 pandemic among psychiatry residents in Saudi Arabia. A total of 121 out of 150 psychiatry residents in Saudi Arabia completed the Maslach Burnout Inventory and Patient’s Health Questionnaire for the assessment of burnout and depressive symptoms. Burnout symptoms were found in 27.3%, and another 27.3% reported having depression symptoms. In addition, 16.5% reported having both burnout and depressive symptoms, with a significant relationship between them. Participants in the first 2 years of training and having a history of receiving mental health treatment in the past 2 years were at higher risk. The need is urgent to increase investment in mental health services and to construct a plan to reduce this risk of burnout and depression among psychiatrists by developing preventative strategies to prevent burnout and promote wellness is more important than ever.