Miracle-dz/UniFAR-FTUs huggingface dataset:
Evaluation of Anterolateral Ligament Healing After Anatomic Anterior Cruciate Ligament Reconstruction

Background: Few studies have reported the healing process of anterolateral ligament (ALL) injuries. Purpose/Hypothesis: This study investigated the healing status of ALL injuries after primary anterior cruciate ligament (ACL) reconstruction (ACLR). Additionally, we investigated the association between the healing status of ALL injuries and associated lesions such as osseous lesions and meniscal tears occurring at the time of an ACL rupture. We hypothesized that acute ALL injuries show a high rate (more than two-thirds) of healing at the 1-year follow-up after ACLR and that concomitant lesions observed at the time of an ACL rupture affect the healing status of the ALL. Study Design: Case-control study; Level of evidence, 3. Methods: We retrospectively investigated patients with ALL injuries who underwent primary ACLR between March 2015 and February 2017. Using magnetic resonance imaging (MRI), we evaluated the features of ALL injuries and concomitant lesions, and MRI was performed at the 1-year follow-up to assess the healing status of the ALL. We investigated the association between the healing status of the ALL and concomitant lesions observed at the time of an ACL rupture. A subjective assessment was performed using the Lysholm score, International Knee Documentation Committee subjective score, and Tegner activity scale. Objective tests included an isokinetic strength assessment and functional performance testing. Results: With respect to the severity of ALL injuries, of 54 patients, a complete rupture occurred in 16 (29.6%) of the 54 patients and a partial rupture in 38 (70%). A significant association was observed between the severity of ALL injuries and bone contusions (lateral tibial plateau and medial tibial plateau [MTP]) and meniscus ramp lesions (Fisher exact test: P = .023, .012, and .023, respectively). Good and partial healing of the ALL occurred in 16 (29.6%) and 23 (42.6%) of 54 patients, respectively. Scar formation occurred in 12 (22.2%), and nonvisualization of the ALL was observed in 3 (5.6%) of 54 patients. Poor healing of the ALL was associated with preoperative MTP bone contusions and a high-grade pivot shift. Multivariate analysis showed that an MTP bone contusion was an independent risk factor associated with poor healing of the ALL. Among the functional tests performed, significant differences were observed between the good and poor healing groups with respect to the carioca test (P = .039). The good healing group (n = 16) showed a negative pivot shift at the last follow-up, whereas 5 (13.2%) of the patients from the poor healing group (n = 38) showed a positive pivot shift, including 2 (5.3%) with a high-grade pivot shift. Conclusion: Approximately 70% of acute ALL injuries showed poor healing at the 1-year follow-up. Poor healing of ALL injuries was significantly associated with preoperative MTP bone contusions and a high-grade pivot shift. Therefore, a careful assessment of posteromedial bone contusions at the time of an ACL rupture is warranted, particularly in patients with a high-grade pivot shift.
STUB1 is targeted by the SUMO-interacting motif of EBNA1 to maintain Epstein-Barr Virus latency

Latent Epstein-Barr virus (EBV) infection is strongly associated with several malignancies, including B-cell lymphomas and epithelial tumors. EBNA1 is a key antigen expressed in all EBV-associated tumors during latency that is required for maintenance of the EBV episome DNA and the regulation of viral gene transcription. However, the mechanism utilized by EBV to maintain latent infection at the levels of posttranslational regulation remains largely unclear. Here, we report that EBNA1 contains two SUMO-interacting motifs (SIM2 and SIM3), and mutation of SIM2, but not SIM3, dramatically disrupts the EBNA1 dimerization, while SIM3 contributes to the polySUMO2 modification of EBNA1 at lysine 477 in vitro. Proteomic and immunoprecipitation analyses further reveal that the SIM3 motif is required for the EBNA1-mediated inhibitory effects on SUMO2-modified STUB1, SUMO2-mediated degradation of USP7, and SUMO1-modified KAP1. Deletion of the EBNASIM motif leads to functional loss of both EBNA1-mediated viral episome maintenance and lytic gene silencing. Importantly, hypoxic stress induces the SUMO2 modification of EBNA1, and in turn the dissociation of EBNA1 with STUB1, KAP1 and USP7 to increase the SUMO1 modification of both STUB1 and KAP1 for reactivation of lytic replication. Therefore, the EBNA1SIM motif plays an essential role in EBV latency and is a potential therapeutic target against EBV-associated cancers.
Prevalence and interrelationships of foot ulcer, risk-factors and antibiotic resistance in foot ulcers in diabetic populations: A systematic review and meta-analysis

BACKGROUND Diabetic foot ulceration (DFU) is the prime health concern globally. It accounts for the major burden related to disease mortality and morbidity and economic cost. The timely and early recognition of the DFU can help present its occurrence and improve clinical outcomes. AIM To evaluate interrelationships between foot ulcers, risk factors, and antibiotic resistance among diabetic patients having ulcers in their foot. METHODS The databases such as PubMed, ERIC, Medline, and Google Scholar were extensively used for the extraction of studies. The selected studies were published within the time-period of 2014-2018. Ten studies were selected, which were found to be completely relevant to the current study. RESULTS The prevalence of diabetic foot ulcers among the population was evaluated, and the associated risk factors with its prevalence. Moreover, few studies also reported on the bacteria that are found to be most prevailing among diabetic patients. A narrative discussion was drawn through this analysis, which was used to highlight the specific area of research through selected studies, extraction of the significant information that matched with the topic of research, and analysis of problem through the findings of the selected articles. The results helped in assessing significant knowledge regarding the risk factors of diabetic foot ulcers and the role of antimicrobial resistant in its treatment. CONCLUSION The gram-negative bacteria were found to be the most common reason for diabetic foot ulcers. The study only included 10 studies that are not sufficient to produce generalized results, and no information was reported on the tests required to analyze antimicrobial susceptibility that can guide clinicians to propose better and sound treatment plans. It is evident that most study results depicted that the most common risk factors were found to be hypertension and neuropathy.
Measurement and reporting of physical rehabilitation interventions in pediatric critical care: a scoping review

Abstract Purpose To describe and evaluate physical rehabilitation research in critically ill children, including physical rehabilitation intervention reporting. Methods We searched five electronic databases to 31 December 2018 for prospective physical rehabilitation studies conducted in pediatric intensive care units (PICU). Screening was conducted independently in duplicate. Study characteristics, outcomes, and interventions were extracted from included studies. Quality of study reporting was assessed using standardized tools. Completeness of physical rehabilitation intervention reporting was assessed using the Consensus on Exercise Reporting Template (CERT). Results We included 20 studies enrolling a total of 2644 patients. Median (Q1,Q3) sample size was 57 (44,104). Seven studies (35%) were randomized controlled trials. Eleven studies (55%) evaluated respiratory interventions, most commonly multicomponent chest physiotherapy (73%). Nine studies (45%) evaluated physical activity interventions, most commonly progressive mobility (56%). The majority of stated outcomes (92.5%) were limited to the PICU setting. Median [Q1,Q3] quality of study reporting was good (77.2% [66.7%,87.4%]), and completeness of physical rehabilitation intervention reporting was moderate (61.9% [45.9%,71.5%]). Conclusion Physical rehabilitation studies in critically ill children were small, and focused on evaluating respiratory-based interventions and short-term PICU-based outcomes. Reporting of physical rehabilitation interventions was suboptimal. Use of CERT may improve design and reporting in future studies. Implications for rehabilitation While physical rehabilitation research in critically ill children is a growing field, there are currently few studies evaluating physical rehabilitation interventions in this population. Physical rehabilitation studies to date have been small, focused on evaluating respiratory-based interventions and short-term outcomes limited to the PICU setting. The reporting of physical rehabilitation interventions in this population is suboptimal, making it challenging for clinicians to reproduce interventions and appraise their efficacy or safety.
So far, so good… Similar fitness consequences and overall energetic costs for short and long-distance migrants in a seabird

Although there is a consensus about the evolutionary drivers of animal migration, considerable work is necessary to identify the mechanisms that underlie the great variety of strategies observed in nature. The study of differential migration offers unique opportunities to identify such mechanisms and allows comparisons of the costs and benefits of migration. The purpose of this study was to compare the characteristics of short and long-distance migrations, and fitness consequences, in a long-lived seabird species. We combined demographic monitoring (survival, phenology, hatching success) of 58 Northern Gannets (Morus bassanus) breeding on Bonaventure Island (Canada) and biologging technology (Global Location Sensor or GLS loggers) to estimate activity and energy budgets during the non-breeding period for three different migration strategies: to the Gulf of Mexico (GM), southeast (SE) or northeast (NE) Atlantic coast of the U.S. Survival, timing of arrival at the colony and hatching success are similar for short (NE, SE) and long-distance (GM) migrants. Despite similar fitness consequences, we found, as expected, that the overall energetic cost of migration is higher for long-distance migrants, although the daily cost during migration was similar between strategies. In contrast, daily maintenance and thermoregulation costs were lower for GM migrants in winter, where sea-surface temperature of the GM is 4-7o C warmer than SE and NE. In addition, GM migrants tend to fly 30 min less per day in their wintering area than other migrants. Considering lower foraging effort and lower thermoregulation costs during winter for long-distance migrants, this suggests that the energetic benefits during the winter of foraging in the GM outweigh any negative consequences of the longer-distance migration. These results support the notion that the costs and benefits of short and long-distance migration is broadly equal on an annual basis, i.e. there are no apparent carry-over effects in this long-lived bird species, probably because of the favourable conditions in the furthest wintering area.
The spectrum of macrophage activation by immunometabolism.

Macrophages are heterogeneous and plastic, and play several diverse functions in immune responses. Emerging data provide evidence of multiple roles for metabolic pathways in the control of macrophage effector functions. The diverse functions of macrophages are categorized into two main subsets: classical activated macrophages (M1) and alternative activated macrophages (M2). M1 macrophages secrete pro-inflammatory cytokines and reactive oxygen species and migrate into inflamed sites as a part of host defenses. On the other hand, M2 macrophages are involved in immune homeostasis by producing anti-inflammatory cytokines and phagocytosing apoptotic cells. Metabolic reprogramming of environmental or cellular nutrients such as glucose, lipids, and amino acids supports this diversity. Mechanistically, the mammalian target of rapamycin (mTOR) network plays important roles in the effector functions of macrophages by modulating cellular metabolism and regulating gene expression at the transcriptional and translational levels. In this review, we outline immunometabolism and provide insights into metabolic regulation by mTOR in macrophages.
Metabolic Alterations Associated with Early-Stage Hepatocellular Carcinoma and Their Correlation with Aging and Enzymatic Activity in Patients with Viral Hepatitis-Induced Liver Cirrhosis: A Preliminary Study

Liver cirrhosis (LC) can develop hepatocellular carcinoma (HCC). However, noninvasive early diagnosis of HCCs in the cirrhotic liver is still challenging. We aimed to quantify the hepatic metabolites in normal control (NC), cirrhotic liver without HCC, cirrhotic liver with HCC (CLH), and early-stage HCC groups using proton magnetic resonance spectroscopy (1H-MRS) with a long echo-time (TE) and to assess the potential association between the levels of hepatic metabolites in these four groups and aging and enzymatic activity. Thirty NCs, 30 viral hepatitis-induced LC patients without HCC, and 30 viral hepatitis-induced LC patients with HCC were included in this study. 1H-MRS measurements were performed on a localized voxel of the normal liver parenchyma (n = 30) from NCs, cirrhotic liver parenchyma (n = 30) from LC patients without HCC, and each of the cirrhotic liver parenchyma (n = 30) and HCC (n = 30) from the same patients in the CLH group. Generalized estimating equations were used to evaluate potential risk factors for changes in metabolite levels. Potential associations between metabolite levels and age and serum enzymatic activities were assessed by correlation analysis. The levels of lactate+triglyceride (Lac+TG) and choline (Cho) in HCC were significantly higher compared to those in LC and CLH. A potential risk factor for changes in the Lac+TG and Cho levels was age, specifically 60–80 years of age. In particular, the Lac+TG level was associated with a high odds ratio of HCC in males aged 60–80 years. The Lac+TG and Cho concentrations were positively correlated with lactate dehydrogenase and alkaline phosphatase activities, respectively. Our findings suggested that 1H-MRS measurement with a long TE was useful in quantifying hepatic Lac+TG and Cho levels, where higher Lac+TG and Cho levels were most likely associated with HCC-related metabolism in the viral hepatitis-induced cirrhotic liver. Further, the level of Lac+TG in HCC was highly correlated with older age and lactate dehydrogenase activity.
Circuit Stability to Perturbations Reveals Hidden Variability in the Balance of Intrinsic and Synaptic Conductances

Neurons and circuits each with a distinct balance of intrinsic and synaptic conductances can generate similar behavior but sometimes respond very differently to perturbation. Examining a large family of circuit models with non-identical neurons and synapses underlying rhythmic behavior, we analyzed the circuits' response to modifications in single and multiple intrinsic conductances in the individual neurons. To summarize these changes over the entire range of perturbed parameters, we quantified circuit output by defining a global stability measure. Using this measure, we identified specific subsets of conductances that when perturbed generate similar behavior in diverse individuals of the population. Our unbiased clustering analysis enabled us to quantify circuit stability when simultaneously perturbing multiple conductances as a nonlinear combination of single conductance perturbations. This revealed surprising conductance combinations that can predict the response to specific perturbations, even when the remaining intrinsic and synaptic conductances are unknown. Therefore, our approach can expose hidden variability in the balance of intrinsic and synaptic conductances of the same neurons across different versions of the same circuit solely from the circuit response to perturbations. Developed for a specific family of model circuits, our quantitative approach to characterizing high-dimensional degenerate systems provides a conceptual and analytic framework to guide future theoretical and experimental studies on degeneracy and robustness. SIGNIFICANCE STATEMENT Neural circuits can generate nearly identical behavior despite neuronal and synaptic parameters varying several-fold between individual instantiations. Yet, when these parameters are perturbed through channel deletions and mutations or environmental disturbances, seemingly identical circuits can respond very differently. What distinguishes inconsequential perturbations that barely alter circuit behavior from disruptive perturbations that drastically disturb circuit output remains unclear. Focusing on a family of rhythmic circuits, we propose a computational approach to reveal hidden variability in the intrinsic and synaptic conductances in seemingly identical circuits based solely on circuit output to different perturbations. We uncover specific conductance combinations that work similarly to maintain stability and predict the effect of changing multiple conductances simultaneously, which often results from neuromodulation or injury.
Ruxolitinib for treatment of steroid-refractory graft-versus-host disease in adults: a systematic review and meta-analysis

ABSTRACT Objectives Authors assessed the impact of ruxolitinib (RUX) on steroid-refractory graft-versus-host disease (SR-GVHD) patients. Methods Studies published before January 2019 were identified by electronic search of MEDLINE, EMBASE, Cochrane Library, Clinical Trials.Gov and Web of Science databases. Results Sixteen cohort studies (414 adults) were included whose methodological quality ranged from poor to good. Pooled outcomes such as the response rates, steroid dose reduction, 1-year overall survival, overall infection, and grade 3 to 4 cytopenia were calculated separately for adults with steroid-refractory acute GVHD (aGVHD) and chronic GVHD (cGVHD). Further, the overall response rates were analyzed according to the affected organ. Adults with aGVHD as well as cGVHD showed high response with RUX, and steroid dose reduction was observed in both cases. Infection rates and cytopenia were important safety concerns for both aGVHD and cGVHD. Conclusion Notwithstanding the need of randomized controlled trials to confirm the effect of RUX on SR-GVHD, response rates among adults with aGVHD and cGVHD seem to be high with the use of RUX as a salvage treatment, particularly in cases with gastrointestinal and cutaneous involvement. However, high rates of myelosuppression and infection remain a cause for concern regardless of aGVHD or cGVHD.
NF-κB mediates lipopolysaccharide-induced alternative pre-mRNA splicing of MyD88 in mouse macrophages

Although a robust inflammatory response is needed to combat infection, this response must ultimately be terminated to prevent chronic inflammation. One mechanism that terminates inflammatory signaling is the production of alternative mRNA splice forms in the Toll-like receptor (TLR) signaling pathway. Whereas most genes in the TLR pathway encode positive mediators of inflammatory signaling, several, including that encoding the MyD88 signaling adaptor, also produce alternative spliced mRNA isoforms that encode dominant-negative inhibitors of the response. Production of these negatively acting alternatively spliced isoforms is induced by stimulation with the TLR4 agonist lipopolysaccharide (LPS); thus, this alternative pre-mRNA splicing represents a negative feedback loop that terminates TLR signaling and prevents chronic inflammation. In the current study, we investigated the mechanisms regulating the LPS-induced alternative pre-mRNA splicing of the MyD88 transcript in murine macrophages. We found that 1) the induction of the alternatively spliced MyD88 form is due to alternative pre-mRNA splicing and not caused by another RNA regulatory mechanism, 2) MyD88 splicing is regulated by both the MyD88- and TRIF-dependent arms of the TLR signaling pathway, 3) MyD88 splicing is regulated by the NF-κB transcription factor, and 4) NF-κB likely regulates MyD88 alternative pre-mRNA splicing per se rather than regulating splicing indirectly by altering MyD88 transcription. We conclude that alternative splicing of MyD88 may provide a sensitive mechanism that ensures robust termination of inflammation for tissue repair and restoration of normal tissue homeostasis once an infection is controlled.
Alterations in vascular reactivity in a transgenic mouse model of sickle cell trait

Additional supporting information may be found online in the Supporting Information section at the end of the article. Data S1. Supplemental data. Fig S1. Supercoiled and linear spike-in control: MRD estimation comparison. Fig S2. Read fraction and qPCR versus NGS mean absolute error per spike-in subset. Fig S3. Frequency of spike-in reads by total VDJ reads. Fig S4. Spike-in controls amplification per VH family. Fig S5. Universal versus Family/Universal fitting comparison. Fig S6. Accuracy of NGS MRD is not influenced by spikein read fraction. Fig S7. D0 and D35 leukaemia clones for notable cases. Fig S8. Comparison of MRD values for samples analysed both in the pilot and main studies. Fig S9. Copy number-based subsets of spike-in control produce similar NGS MRD values. Table SI. Sequences of the complete IGH rearrangements used as spike-in control. Table SII. BIOMED-2-based FR2 primers with non-complementary 5ʹ overhangs for complete IGH rearrangements amplification and NGS library construction. Table SIII. Paired qPCR and NGS MRD values for 129 leukaemia markers. Table SIV. Mean Absolute Errors of NGS MRD calculated by Universal or Family/Universal fitting against qPCR MRD. Table SV. qPCR+/NGS MRD patients results. Table SVI. qPCR /NGS+ MRD patients results.
COVID-19 in Children: Initial Characterization of the Pediatric Disease

* Abbreviation: COVID-19 — : coronavirus disease of 2019 The impact of the coronavirus disease of 2019 (COVID-19), which is caused by the novel coronavirus, severe acute respiratory syndrome coronavirus 2,1 has been widespread, with >500 000 cases diagnosed in >170 countries since the virus was identified in January 2020.2 The preliminary data have been focused on severe respiratory manifestations, which are seen predominantly in adults, with scant initial data on the burden of COVID-19 in children.3 We, therefore, read with interest the findings of Dong et al,4 who reported in this issue of Pediatrics a series of >2000 children with suspected or confirmed COVID-19. The authors found that 4% of virologically confirmed cases had asymptomatic infection, and this rate almost certainly understates the true rate of asymptomatic infection because many children who are asymptomatic are unlikely to be tested. Among children who were symptomatic, 5% had dyspnea or hypoxemia (a substantially lower percentage than what has been reported for adults3), and 0.6% progressed to acute respiratory distress syndrome or multiorgan system dysfunction (a rate that is also lower than that seen in adults). Preschool-aged children and infants were more likely than older children to have severe clinical manifestations. There are several salient points … Address correspondence to Andrea T. Cruz, MD, MPH, Department of Pediatrics, Baylor College of Medicine, 6621 Fannin St, Suite A2210, Houston, TX 77030. E-mail: acruz{at}bcm.edu