Miracle-dz/UniFAR-FTUs huggingface dataset:
Oligodendroglial connexin 47 regulates neuroinflammation upon autoimmune demyelination in a novel mouse model of multiple sclerosis

Significance In multiple sclerosis plaques, oligodendroglial connexin (Cx) 47 constituting main gap junction channels with astroglia is persistently lost. The roles of Cx47 remain undefined. Here, we show that oligodendroglia-specific conditional ablation of Cx47 exacerbated acute and chronic relapsing experimental autoimmune encephalomyelitis induced by myelin oligodendrocyte glycoprotein peptide (MOG35-55) immunization, with florid infiltration of CD3+ T cells, especially helper T (Th) 17 cells, and pronounced demyelination without influencing MOG-specific T cell induction. Microarray and immunohistochemistry analyses revealed stronger activation of proinflammatory and injury-response microglia with increased expressions of chemokines that can attract Th17 cells, and A1 astroglia at the acute phase. These findings suggest that oligodendroglia-specific Cx47 loss can augment inflammation upon autoimmune demyelination, underscoring a role for Cx47 in neuroinflammation. In multiple sclerosis plaques, oligodendroglial connexin (Cx) 47 constituting main gap junction channels with astroglial Cx43 is persistently lost. As mice with Cx47 single knockout exhibit no demyelination, the roles of Cx47 remain undefined. We aimed to clarify the effects of oligodendroglia-specific Cx47 inducible conditional knockout (icKO) on experimental autoimmune encephalomyelitis (EAE) induced by myelin oligodendrocyte glycoprotein peptide (MOG35-55) in PLP/CreERT;Cx47fl/fl mice at 14 d after tamoxifen injection. Cx47 icKO mice demonstrated exacerbation of acute and chronic relapsing EAE with more pronounced demyelination than Cx47 flox (fl)/fl littermates. CD3+ T cells more abundantly infiltrated the spinal cord in Cx47 icKO than in Cx47 fl/fl mice throughout the acute to chronic phases. CXCR3-CCR6+CD4+ and IL17+IFNγ-CD4+ helper T (Th) 17 cells isolated from spinal cord and brain tissues were significantly increased in Cx47 icKO mice compared with Cx47 fl/fl mice, while MOG35-55-specific proliferation and proinflammatory cytokine production of splenocytes were unaltered. Microarray analysis of isolated microglia revealed stronger microglial activation toward proinflammatory and injury-response phenotypes with increased expressions of chemokines that can attract Th17 cells, including Ccl2, Ccl3, Ccl4, Ccl7, and Ccl8, in Cx47 icKO mice compared with Cx47 fl/fl mice. In Cx47 icKO mice, NOS2+ and MHC class II+ microglia were more enriched immunohistochemically, and A1-specific astroglial gene expressions and astroglia immunostained for C3, a representative A1 astrocyte marker, were significantly increased at the acute phase, compared with Cx47 fl/fl mice. These findings suggest that oligodendroglia-specific Cx47 ablation induces severe inflammation upon autoimmune demyelination, underscoring a critical role for Cx47 in regulating neuroinflammation.
Molecular patterns of response and treatment failure after frontline venetoclax combinations in older patients with AML.

The BCL-2 inhibitor venetoclax combined with hypomethylating agents or low-dose cytarabine represents an important new therapy for older or unfit patients with acute myeloid leukemia (AML). We analyzed 81 patients receiving these venetoclax-based combinations to identify molecular correlates of durable remission, response followed by relapse (adaptive resistance) or refractory disease (primary resistance). High response rates and durable remissions were typically associated with NPM1 or IDH2 mutations (mut), with prolonged molecular remissions prevalent for NPM1mut. Primary and adaptive resistance to venetoclax-based combinations were most commonly characterized by acquisition or enrichment of clones activating signaling pathways such as FLT3 or RAS, or bi-allelically perturbing TP53. Single cell studies highlighted the polyclonal nature of intra-tumoral resistance mechanisms in some cases. Among cases that were primary refractory, we identified heterogeneous and sometimes divergent interval changes in leukemic clones within a single cycle of therapy, highlighting the dynamic and rapid occurrence of therapeutic selection in AML. In functional studies, FLT3-ITD gain or TP53 loss conferred cross-resistance to both venetoclax and cytotoxic-based therapies. Collectively, we highlight molecular determinants of outcome with clinical relevance to patients with AML receiving venetoclax-based combination therapies.
Annexin-coated particles induce antigen-specific immunosuppression

Abstract Apoptotic cells mediate the development of tolerogenic dendritic cells (DC) and thus facilitate induction and maintenance of peripheral tolerance. Following the identification of the evolutionary conserved annexin core domain (Anx) as a specific signal on apoptotic cells which antagonises Toll-like receptor (TLR) signalling, we examined whether the tolerogenic capacity of Anx can be exploited to downregulate antigen-specific immune responses. The treatment of bone marrow-derived dendritic cells (BMDC) with particles harbouring Anx as well as the model antigen ovalbumin (OVA) attenuated the response of OVA-specific OT-II T cells. The co-culture of Anx-particle-treated DC and T cells resulted in an anergy-like phenotype characterized by reduced proliferation and cytokine secretion. Here we demonstrate that the anti-inflammatory effects of Anx which are mediated through DC can be used as a tool to generate a particle-based antigen delivery system that promotes antigen-specific immunosuppression. Such Anx-particles may be a new therapeutic approach for the treatment of autoimmune diseases.
Minimally invasive oesophagectomy with a total two-field lymphadenectomy after neoadjuvant chemoradiotherapy for locally advanced squamous cell carcinoma of the oesophagus: A prospective study

Introduction: In the era of neoadjuvant chemoradiotherapy (NACTRT), the safety and clinical significance of radical lymphadenectomy specifically lymphadenectomy along the recurrent laryngeal nerve (RLN) has been questioned. Furthermore, the compliance to NACTRT with the CROSS regimen has not been well studied in the Indian population. This prospective study aimed to determine the compliance with CROSS regimen, feasibility and short-term outcomes of minimally invasive oesophagectomy (MIE) with a total two-field lymphadenectomy after NACTRT. Methods: A prospective study (January 2014 to December 2018) of patients with locally advanced oesophageal squamous cell carcinoma (SCC) eligible for NACTRT (cT1-4a, N0-1, M0) with CROSS regimen followed by MIE with total two-field lymphadenectomy. The compliance rate, post-operative complications and the pathological response rate were assessed. Results: Of the 166 patients with locally advanced SCC, 76 (45.8%) were eligible for NACTRT and 34 completed NACTRT followed by MIE with a total two-field lymphadenectomy (study group). Twenty-nine (38.1%) patients did not complete NACTRT due to complications or poor compliance. Median (range) blood loss was 125 (50–450) ml and the median (range) operation time for the thoracoscopic phase was 205 (155–325) min. Total median (range) lymph node count and mediastinal lymph node counts were 20 (11–33) and 12, (8–21) respectively. Most common post-operative complications were pneumonia (n = 12, 35.3%) followed by RLN palsy (n = 10, 29.4%). Of the 22 patients who had a complete pathological response of the primary tumour, 7 (31.8%) patients had a node-positive disease. Conclusion: NACTRT followed by MIE is feasible in patients with locally advanced SCC. The nodal disease is common even in patients with the complete pathological response of the primary tumour. The dropout rate with NACTRT using the CROSS regimen is high in the present study.
Relationship between BRAF V600E gene mutation and the clinical and pathologic characteristics of papillary thyroid microcarcinoma.

OBJECTIVE This study aims to investigate the relationship between BRAF V600E gene mutation and the clinical and pathologic characteristics of patients with papillary thyroid microcarcinoma (PTMC). METHODS A retrospective analysis was conducted on the clinical and pathologic characteristics of 89 patients with PTMC, who had complete medical records. The BRAF V600E gene mutation was detected by real-time immunofluorescence quantitative PCR. Then, the BRAF V600E gene mutation and the clinical and pathologic data of these patients were statistically analyzed. RESULTS Among the 89 patients with PTMC, 67 patients had a BRAF V600E mutation with a mutation rate of 75.3%. 38 patients (42.6%) had cervical lymph node metastasis. 43 patients had capsular invasion (48.3%) and 40 patients (44.9%) had tumor multifocality confirmed by postoperative pathology. BRAF V600E mutation was not associated with gender, age, capsular invasion, tumor multifocality, cervical lymph node metastasis, or higher TNM stage. However, cervical lymph node metastasis was associated with age and tumor invasion of the capsule. Thus, cervical lymph node metastasis was most likely in patients < 45 years old and patients with capsular invasion. CONCLUSION BRAF V600E mutation is common in PTMC, but is not associated with clinicopathologic factors, such as age, gender, tumor multifocality, cervical lymph node metastasis, capsular invasion, or tumor TNM stage. Cervical lymph node metastasis is more likely in patients < 45 years old and patients with capsular invasion.
A Systematic Review Evaluating Psychometric Properties of Parent or Caregiver Report Instruments on Child Maltreatment: Part 1: Content Validity

Aims: Child maltreatment (CM) is a serious public health issue, affecting over half of all children globally. Although most CM is perpetrated by parents or caregivers and their reports of CM is more accurate than professionals or children, parent or caregiver report instruments measuring CM have never been systematically evaluated for their content validity, the most important psychometric property. This systematic review aimed to evaluate the content validity of all current parent or caregiver report CM instruments. Methods: A systematic literature search was performed in CINAHL, Embase, ERIC, PsycINFO, PubMed, and Sociological Abstracts; gray literature was retrieved through reference checking. Eligible studies needed to report on content validity of instruments measuring CM perpetrated and reported by parents or caregivers. The quality of studies and content validity of the instruments were evaluated using the COnsensus-based Standards for the selection of health Measurement INstruments guidelines. Results: Fifteen studies reported on the content validity of 15 identified instruments. The study quality was generally poor. The content validity of the instruments was overall sufficient, but most instruments did not provide high-quality evidence for content validity. Conclusions: Most instruments included in this review showed promising content validity. The International Society for the Prevention of Child Abuse and Neglect Child Abuse Screening Tool for use in Trial appears to be the most promising, followed by the Family Maltreatment–Child Abuse criteria. However, firm conclusions cannot be drawn due to the low quality of evidence for content validity. Further studies are required to evaluate the remaining psychometric properties for recommending parent or caregiver report CM instruments.
Children’s Self-Reports About Illness-Related Information and Family Communication When a Parent Has a Life-Threatening Illness

Children’s experiences of information and family communication when a parent has a life-threatening illness have been sparsely studied, though such information is important for the child’s wellbeing. The aim of this study was to explore children’s reports of illness-related information and family communication when living with a parent with a life-threatening illness. Forty-eight children, aged 7 to 19 years, were recruited from four specialized palliative home care units in Stockholm, Sweden. All but one child reported that someone had told them about the parent’s life-threatening illness; however, two thirds wanted more information. A quarter of the teenagers reported that they had questions about the illness that they did not dare to ask. Half of the children, aged 8 to 12, reported that they felt partially or completely unable to talk about how they felt or show their feelings to someone in the family. Interventions are needed that promote greater family communication and family–professional communication.
Comparison of endothelial cell- and endothelial progenitor cell-derived exosomes in promoting vascular endothelial cell repair.

BACKGROUND Timely endothelial repair after intervention-associated vascular injury is critical to prevent restenosis and thrombosis. Compared to living cell therapies, exosomes may be a better alternative. Thus, we aimed to compare the role of exosomes derived from human umbilical vein endothelial cells (HUVECs) versus those derived from endothelial progenitor cells (EPCs) in vascular endothelial repair. MATERIAL/METHODS Exosomes secreted from HUVECs and EPCs were isolated and characterized respectively. In vitro, the effects of the two types of exosomes on migration and proliferation of endothelial cells were studied. In vivo, rats were systemically treated with the two exosome groups respectively after carotid artery endothelial injury induced by a balloon. The efficacy in promoting re-endothelialization was measured by Evans blue dye and histological examination. RESULTS Both types of exosomes, sized from 30 nm to 100 nm, had sphere-shaped or cupped morphology, and expressed CD63, CD9, and CD81; but the total yield of exosomes (particles/mL) based on number of cells, was 4.2 times higher from EPCs than HUVECs. Compared with control treatment, both exosome treated groups manifested significant enhancement of migration and proliferation in vitro and vascular recovery at an early stage in vivo. The two exosome-treated groups, however, did not statistically significantly differ. CONCLUSION In conclusion, our results indicated that exosomes derived from HUVECs and EPCs had similar morphology, size distributions and characteristics, but those derived from EPCs were more abundant with comparable biologic activity. Therefore, EPCs may be a robust source of exosomes to promote vascular repair.
Participant Perceptions on a Fitbit and Facebook Intervention for Young Adult Cancer Survivors: A Qualitative Study.

Purpose: Among cancer survivors, physical activity (PA) is associated with reductions in cancer recurrence, morbidity, and mortality. Most young adult (YA) survivors do not attain adequate PA. Digital modalities, specifically wearable activity monitors with a paired mobile application and private social media group for support offer a promising approach for promoting PA among YAs. We conducted a pilot randomized controlled trial of this intervention. To evaluate its acceptability and perceptions of the intervention components, we conducted qualitative interviews with those in the intervention. The results of our interviews serve to refine future interventions to better serve this population. Methods: Semistructured qualitative interviews with 13 YA cancer survivors ages 20-39 who participated in the intervention assessed perceptions of the digital components of the study and buddy system of nominating a friend to participate in PA with the survivor. Analyses included a qualitative thematic analysis of the interview transcripts and coded interview segments into three predetermined categories: facilitators, limitations, and suggestions. Results: Participants described wide-ranging benefits of the intervention, citing the Fitbit device and buddy system as major motivators to engage in PA and reach goals. Most participants noted feelings of increased physical and emotional wellness. The most-cited limitation of the intervention was the automated text messages, which participants found impersonal. Suggestions for improvement included integrating more elements of competition and group challenges. Conclusion: This digital PA intervention was perceived as feasible and acceptable to YA cancer survivors and appears promising for promoting PA and improving long-term health and quality of life. Clinicaltrial.gov identifier number: NCT03233581; Date of registration: July 28, 2017.
Development of a risk score for scoliosis in children with cerebral palsy

Background and purpose — Children and young adults with cerebral palsy (CP) have an increased risk of developing scoliosis, with a prevalence ranging from 11% to 29%. Information on risk factors for the emergence and progression of scoliosis is inconclusive. This study aimed to develop a risk score based on 5-year-old children with CP to predict the risk of scoliosis before the age of 16. Patients and methods — This prospective registry study included 654 children with CP in Sweden born in 2000 to 2003 and registered with the Swedish CP follow-up program (CPUP) at the age of 5 years, including all Gross Motor Function Classification System (GMFCS) levels. 92 children developed a scoliosis before the age of 16 years. Univariable and multivariable logistic regressions were used to analyze 8 potential predictors for scoliosis: GMFCS, sex, spastic subtype, epilepsy, hip surgery, migration percentage, and limited hip or knee extension. Results — 4 predictors for scoliosis remained significant after analyses: female sex, GMFCS levels IV and V, epilepsy, and limited knee extension, and a risk score was constructed based on these factors. The predictive ability of the risk score was high, with an area under the receiver operating characteristics curve of 0.87 (95% CI 0.84–0.91). Interpretation — The risk score shows high discriminatory ability for differentiating between individuals at high and low risk for development of scoliosis before the age of 16. It may be useful when considering interventions to prevent or predict severe scoliosis in young children with CP.
Thyroid Status in First Trimester of Pregnancy-A Hospital Based Study.

Background: Increased requirement of thyroid hormones is a normal physiological phenomenon during pregnancy to meet the growing maternal metabolic demand and additional requirement of the developing product of conception. Body adapts to this demand by increasing the activity of the thyroid gland. The present study has been undertaken in the known Sub Himalayan iodine deficient belt of Upper Assam districts of Jorhat, Golaghat and Sibsagar.TT3, TT4 and TSH levels evaluated in women in their first trimester of pregnancy compared with a group of similar age and sex matched non pregnant control. Aim: 1. To evaluate the thyroid status (TT3, TT4 and TSH levels) in apparently euthyroid women in their first trimester of pregnancy. 2. To analyse the results by comparing with an age/sex matched non pregnant control group. 3. To compare the findings of the study with similar study results carried out elsewhere in the Globe. Methods: Serum TT3,TT4 and TSH levels evaluated in 132 1st trimester pregnant women and 131 non pregnant controls using Access Immunoassay Systems (Beckman Coulter) at the clinical Biochemistry wing of central clinical laboratory of Jorhat Medical College Hospital, Jorhat (Assam) Statistical analysis done using SPSS 16.0 version. Results: Highly significant increased values were obtained for TT3 and TT4 in the study group of pregnant women in 1st trimester when compared with the non pregnant controls. Conclusion: The study reaffirms the physiological hyperactive state of the thyroid gland in 1st trimester of pregnancy and emphasises for a region/ laboratory based pregnancy specific reference range for thyroid hormones and TSH.
Benefits and limitations of continuous glucose monitoring in type 1 diabetes

ABSTRACT Introduction: Type 1 diabetes (T1D) is a chronic condition characterized by a complete deficiency in insulin production. Optimal management requires constant knowledge of glucose levels for safe and effective insulin administration. Self-monitoring of blood glucose (SMBG) using capillary blood glucose meters is cumbersome and provides limited information to guide management. Continuous glucose monitoring (CGM) technology addresses many of these gaps, but itself has limitations which have prevented people with diabetes and their clinicians from fully embracing this technology. This review covers the benefits and limitations of CGM use, and looks toward future application of this technology in the management of T1D. Areas covered: Impact of CGM on physical and psychosocial outcomes in people with T1D. Barriers to CGM uptake. Integration with insulin pumps and other technologies. Opportunities for future application. Expert opinion: CGM technology will be utilized by the majority of people with T1D and increasing numbers of people with type 2 diabetes due to improved insurance coverage and easier-to-use systems. Its use as part of artificial pancreas systems will add further utility, as it will help to protect from both hypoglycemia and hyperglycemia. People with diabetes will spend more time in range and experience fewer acute and chronic complications.
Characterization of cold-tolerant trehalose-6-phosphate synthase from the deep-sea bacterium Microbacterium sediminis YLB-01

ABSTRACT A gene encoding the enzyme trehalose-6-phosphate synthase (TPS), which is part of the TPS trehalose synthesis pathway, was cloned from the deep-sea psychrotolerant bacterium Microbacterium sediminis YLB-01 and expressed in Escherichia coli BL21. The exogenously expressed TPS exhibited highest similarity (80.93% identity) to Microbacterium sp. TPS. The purified recombinant TPS was cold-tolerant, with low thermostability. The optimum temperature for TPS activity was 40°C, and the enzyme retained 72.6% of its maximal activity at 4°C. The optimum pH was 7.5. TPS activity was cation-dependent, with Mg2+, Co2+, or Ba2+ being essential for maximum activity. The kinetic constants of the recombinant TPS reaction rates confirmed that it was cold-tolerant. Molecular dynamics analysis showed that TPS was more flexible (0.8741Å) at 4°C than 1GZ5, its homolog in the mesophilic bacterium E. coli, and superposition of the 3D enzyme structures supported this. Graphical Abstract Enzymatic properties of recombinant trehalose-6-phosphate synthase (TPS).
The Impact of Home Health Physical Therapy on Medicare Beneficiaries With a Primary Diagnosis of Dementia

Dementia is a leading cause of disability for adults older than 65 years. Exercise intervention slows functional decline and improves balance; however, the efficacy of physical therapy (PT) services for persons with dementia is unknown. The purpose of this study is to assess the effect of home health PT services on physical function for Medicare beneficiaries with a primary diagnosis of dementia.