Miracle-dz/UniFAR-FTUs huggingface dataset:
Efficacy of oral brush cytology cell block immunocytochemistry in the diagnosis of oral leukoplakia and oral squamous cell carcinoma.

OBJECTIVES This study assessed the efficacy of using oral liquid-based brush cytology and cell block immunocytochemistry in the diagnosis of oral leukoplakia as minimally invasive diagnostic adjuncts. METHODS Seventy-two patients diagnosed clinically with either oral leukoplakia (OLK) or oral squamous cell carcinoma were included. Oral brush samples using Orcellex® brushes were obtained from all participants directly before undergoing surgical biopsy. Cell blocks were prepared for all samples and assessed for cytomorphology and immunocytochemistry of DNA mismatch repair proteins (MSH-6, MSH-2, MLH-1, and PMS-2). A combined index score of immunocytochemistry expression and cytology grading was compared against the gold standard (histopathological diagnosis). RESULTS A significant association was observed between the cytological assessments of oral liquid-based brush cytology samples and the histopathological diagnosis (p < 0.005). In addition, there was a significant inverse correlation between the grade of oral epithelial dysplasia and the cumulative score of the studied DNA mismatch repair proteins (p < 0.005). Grading criteria for both oral liquid-based brush cytology and immunocytochemistry cumulative index scores are proposed based on the analysis of receiver operating characteristic curve coordinates. The diagnostic accuracy of this approach was outstanding in terms of discrimination between the presence or absence of oral epithelial dysplasia (0.961) and squamous cell carcinoma (0.977) separately. CONCLUSION Oral liquid-based brush cytology cell block immunocytochemistry provides a reliable strategy to investigate oral mucosal epithelial disorders. This approach presents a minimally invasive, highly accurate, and non-technically demanding method for the surveillance of oral potentially malignant disorders and squamous cell carcinoma.
Narrative review of glycogen storage disorder type III with a focus on neuromuscular, cardiac and therapeutic aspects

Glycogen storage disorder type III (GSDIII) is a rare inborn error of metabolism due to loss of glycogen debranching enzyme activity, causing inability to fully mobilize glycogen stores and its consequent accumulation in various tissues, notably liver, cardiac and skeletal muscle. In the pediatric population, it classically presents as hepatomegaly with or without ketotic hypoglycemia and failure to thrive. In the adult population, it should also be considered in the differential diagnosis of left ventricular hypertrophy or hypertrophic cardiomyopathy, myopathy, exercise intolerance, as well as liver cirrhosis or fibrosis with subsequent liver failure. In this review article, we first present an overview of the biochemical and clinical aspects of GSDIII. We then focus on the recent findings regarding cardiac and neuromuscular impairment associated with the disease. We review new insights into the pathophysiology and clinical picture of this disorder, including symptomatology, imaging and electrophysiology. Finally, we discuss current and upcoming treatment strategies such as gene therapy aimed at the replacement of the malfunctioning enzyme to provide a stable and long‐term therapeutic option for this debilitating disease.
CLOUD HEIGHT IN SOLIDS SUSPENSION AGITATION

The focus of this work is the experimental determination of cloud height (the height to which solids are suspendedrpar; in an agitated slurry as a function of the agitation intensity, solid physical properties, impeller type (pitched-blade or high efficiency), and system geometry. Cloud height is not strongly dependent on impeller type or solid physical properties, except for extremely rapidly-settling particles. However, it is dependent on the impeller diameter to tank diameter ratio (D/T), impeller off-botiom clearance to tank diameter ratio (C/T), and solids loading. The use of multiple impellers allows solids to be suspended to higher levels in tall batches. An intermediate impeller separation leads to optimal performance in terms of the power requirement to achieve a desired cloud height. Lower impeller separations do not yield significant performance improvements over a single impeller, while higher impeller separations lead to poor performance caused by “zoning” between the impellers.
Oral microbiota and atherothrombotic carotid plaque vulnerability in periodontitis patients. A cross-sectional study.

BACKGROUND An increased risk of atherothrombotic vascular events has been reported in periodontitis patients. Periodontitis is associated with dysbiotic subgingival biofilms and bacteremia. OBJECTIVE We hypothesized (a) that the oral microbiome is associated with the carotid microbiome and (b) that periodontitis could contribute to plaque vulnerability. The aim of this study was to determine the associations between periodontitis, the carotid microbiome, and the local innate immune response in carotid atherothrombotic plaques vulnerable to rupture. METHODS In this cross-sectional study, 45 patients admitted for carotid endarterectomy underwent a preoperative periodontal examination. The volume of intraplaque hemorrhage reflected by the hemoglobin level released in carotid-conditioned media was considered as a criterion of carotid plaque vulnerability. Levels of antibodies against periodontal bacteria were determined in sera. The signature of the oral microbiota was assessed by microbial whole-genome sequencing, nested PCR, and immunostaining in carotid plaque samples. Markers of neutrophil recruitment (leukotriene B4), neutrophil activation (myeloperoxidase, defensins), and cytokines were measured in carotid-conditioned media and/or plasma. RESULTS All patients exhibited periodontitis. One hundred and forty-four bacterial genera were detected in the carotid microbiome. While Streptococcus was found in 84% of the carotid samples, periodontitis-associated genera were detected in 21%. P. gingivalis DNA and gingipains were also identified in carotid samples. There were significant inverse correlations between periodontal attachment loss/serum anti-P. gingivalis Immunoglobulin A and cytokine inhibiting neutrophils (all P < .01). There were also significant positive correlations between lipopolysaccharides, myeloperoxidase/human neutrophil peptides1-3, and hemoglobin levels (all P < .01). CONCLUSIONS In patients at risk of stroke, the carotid plaque microbiome was highly diverse and compatible with an oral origin. Periodontitis was significantly associated with neutrophil activation markers and plaque vulnerability to rupture.
Lithocholic Acid Derivatives as Potent Vitamin D Receptor Agonists.

Lithocholic acid (2) was identified as a second endogenous ligand of vitamin D receptor (VDR), though its activity is very weak. In this study, we designed novel lithocholic acid derivatives based on the crystal structure of VDR-ligand-binding domain (LBD) bound to 2. Among the synthesized compounds, 6 bearing a 2-hydroxy-2-methylprop-1-yl group instead of the 3-hydroxy group at the 3α-position of 2 showed dramatically increased activity in HL-60 cell differentiation assay, being at least 10 000 times more potent than lithocholic acid (2) and 3 times more potent than 1α,25-dihydroxyvitamin D3 (1). Although the binding affinities of 6 and its epimer 7 were less than that of 1, their transactivation activities were greater than that of 1. X-ray structure analyses of VDR LBD bound to 6 or 7 showed that the binding positions of these compounds in the ligand-binding pocket are similar to that of 1.
Scandcleft trial of primary surgery for unilateral cleft lip and palate: Craniofacial cephalometrics at 8 years.

BACKGROUND The Scandcleft trial is a randomized controlled trial that includes children with unilateral cleft lip and palate where registrations are standardized and therefore provides the opportunity to describe craniofacial characteristics in a very large sample of patients. OBJECTIVES The aim of this study was to describe craniofacial growth and morphology in a large study sample of 8-year-old children with unilateral cleft lip and palate (UCLP); before orthodontic treatment and before secondary alveolar bone grafting; and to compare the cephalometric values with age-matched non-cleft children from previous growth studies to identify the differences between untreated cleft- and non-cleft children. MATERIALS There are 429 eight-year-old UCLP patients in the Scandcleft study group. A total of 408 lateral cephalograms with a mean age of 8.1 years were analysed. Cephalometric analyses were performed digitally. The results from three previously published growth studies on non-cleft children were used for comparison. RESULTS Cephalometric analyses showed a large variation in craniofacial morphology among the UCLP group. In general, they present with significant maxillary retrusion and reduced intermaxillary relationships compared to the age-matched non-cleft children. In addition, the vertical jaw relationship was decreased, mainly due to decreased maxillary inclination. The upper and lower incisors were retroclined. It can be expected that these differences will increase in significance as the children age. CONCLUSION Results from this study provide proposed norms for the young UCLP before any orthodontic treatment and can be valuable for the clinician in future treatment planning. TRIAL REGISTRATION ISRCTN29932826.
Abrogating GPT2 in triple‐negative breast cancer inhibits tumor growth and promotes autophagy

Uncontrolled proliferation and altered metabolic reprogramming are hallmarks of cancer. Active glycolysis and glutaminolysis are characteristic features of these hallmarks and required for tumorigenesis. A fine balance between cancer metabolism and autophagy is a prerequisite of homeostasis within cancer cells. Here we show that glutamate pyruvate transaminase 2 (GPT2), which serves as a pivot between glycolysis and glutaminolysis, is highly upregulated in aggressive breast cancers, particularly the triple‐negative breast cancer subtype. Abrogation of this enzyme results in decreased tricarboxylic acid cycle intermediates, which promotes the rewiring of glucose carbon atoms and alterations in nutrient levels. Concordantly, loss of GPT2 results in an impairment of mechanistic target of rapamycin complex 1 activity as well as the induction of autophagy. Furthermore, in vivo xenograft studies have shown that autophagy induction correlates with decreased tumor growth and that markers of induced autophagy correlate with low GPT2 levels in patient samples. Taken together, these findings indicate that cancer cells have a close network between metabolic and nutrient sensing pathways necessary to sustain tumorigenesis and that aminotransferase reactions play an important role in maintaining this balance.
Impact of Cardiac Risk Factors in the Postsurgical Outcomes of Patients With Cleft Lip: An Analysis of 2126 Patients.

ABSTRACT Congenital cardiac comorbidities represent a potentially elevated risk for complications in patients undergoing cleft lip repair. National databases, such as the National Surgical Quality Improvement Program Pediatric (NSQIP-P) allow for analysis of large national datasets to assess these risks and potential complications. The aim of this study is to assess the risk of complications in patients undergoing cleft lip repair with congenital cardiac co-morbidities using the NSQIP-P.The 2012 to 2014 NSQIP-P databases were queried for patients undergoing cleft lip repair. Data abstracted for analysis included demographic, clinical, and outcomes data. Patients with cleft lip were stratified based on the presence or absence of congenital cardiac comorbidities. Univariate analysis and step-wise, forward logistic regression were performed to compare these groups.Nationally, between 2012 and 2014, 2126 patients underwent cleft lip repair, 227 with cardiac disease, and 1899 without cardiac disease. Weights were similar between the groups at the time of surgery, though patients with cardiac comorbidities were older. Postoperatively, cardiac disease patients were more likely to experience an adverse event. Specifically, they were more likely to experience reintubation, reoperation, longer length of stay, and death. Rates of surgical site infection and dehiscence were not different between the groups.This study demonstrates that cleft lip repair in patients with congenital heart defects is safe. However, patients undergoing cleft lip repair with comorbid congenital cardiac disease were more likely to experience adverse events. Cardiac patients require special preoperative evaluation before repair of their cleft lip, but do not appear to experience worse wound-related outcomes.
Evaluation of Organ Dysfunction Scores for Allocation of Scarce Resources in Critically Ill Children and Adults During a Healthcare Crisis.

OBJECTIVES When healthcare systems are overwhelmed, accurate assessments of patients' predicted mortality risks are needed to ensure effective allocation of scarce resources. Organ dysfunction scores can serve this essential role, but their evaluation in this context has been limited so far. In this study, we sought to assess the performance of three organ dysfunction scores in both critically ill adults and children at clinically relevant mortality thresholds and timeframes for resource allocation and compare it with two published prioritization schemas. DESIGN Retrospective observational cohort study. SETTING Three large academic medical centers in the United States. PATIENTS Critically ill adults and children. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS We calculated the daily Sequential Organ Failure Assessment score in adults and the Pediatric Logistic Organ Dysfunction 2 score and the Pediatric Sequential Organ Failure Assessment score in children. There were 49,290 (11.6% mortality) and 19,983 children (2.5% mortality) included in the analysis. Both the Sequential Organ Failure Assessment and Pediatric Sequential Organ Failure Assessment scores had adequate discrimination across relevant timeframes and adequate distribution across relevant mortality thresholds. Additionally, we found that the only published state prioritization schema that includes pediatric and adult patients had poor alignment of mortality risks, giving adults a systematic advantage over children. CONCLUSIONS In the largest analysis of organ dysfunction scores in a general population of critically ill adults and children to date, we found that both the Sequential Organ Failure Assessment and Pediatric Sequential Organ Failure Assessment scores had adequate performance across relevant mortality thresholds and timeframes for resource allocation. Published prioritization schemas that include both pediatric and adult patients may put children at a disadvantage. Furthermore, the distribution of patient and mortality risk in the published schemas may not adequately stratify patients for some high-stakes allocation decisions. This information may be useful to bioethicists, healthcare leaders, and policy makers who are developing resource allocation policies for critically ill patients.
Lack of Neural Evidence for Implicit Language Learning in 9-Month-Old Infants at High Risk for Autism.

Word segmentation is a fundamental aspect of language learning, since identification of word boundaries in continuous speech must occur before the acquisition of word meanings can take place. We previously used functional magnetic resonance imaging (fMRI) to show that youth with autism spectrum disorder (ASD) are less sensitive to statistical and speech cues that guide implicit word segmentation. However, little is known about the neural mechanisms underlying this process during infancy and how this may be associated with ASD risk. Here we examined early neural signatures of language-related learning in 9-month-old infants at high (HR) and low familial risk (LR) for ASD. During natural sleep, infants underwent fMRI while passively listening to three speech streams containing strong statistical and prosodic cues, strong statistical cues only, or minimal statistical cues to word boundaries. Compared to HR infants, LR infants showed greater activity in the left amygdala for the speech stream containing statistical and prosodic cues. While listening to this same speech stream, LR infants also showed more learning-related signal increases in left temporal regions as well as increasing functional connectivity between bilateral primary auditory cortex and right anterior insula. Importantly, learning-related signal increases at 9 months positively correlated with expressive language outcome at 36 months in both groups. In the HR group, greater signal increases were additionally associated with less severe ASD symptomatology at 36 months. These findings suggest that early differences in the neural networks underlying language learning may predict subsequent language development and altered trajectories associated with ASD risk.
Tregs facilitate obesity and insulin resistance via a Blimp-1/IL-10 axis

Interleukin-10 (IL-10) is a critical cytokine used by immune cells to suppress inflammation. Paradoxically, immune cell–derived IL-10 can drive insulin resistance in obesity by suppressing adipocyte energy expenditure and thermogenesis. However, the source of IL-10 necessary for the suppression of adipocyte thermogenesis is unknown. We show here that CD4+Foxp3+ regulatory T cells (Tregs) are a substantial source of IL-10 and that Treg-derived IL-10 can suppress adipocyte beiging. Unexpectedly, Treg-specific loss of IL-10 resulted in increased insulin sensitivity and reduced obesity in high-fat diet–fed male mice. Mechanistically, we determined that Treg-specific loss of the transcription factor Blimp-1, a driver of IL-10 expression by Tregs, phenocopied the Treg-specific IL-10–deficient mice. Loss of Blimp-1 expression in Tregs resulted in reduced ST2+KLRG1+, IL-10-secreting Tregs, particularly in the white adipose tissue. Blimp-1–deficient mice were protected from glucose intolerance, insulin resistance, and diet-induced obesity, through increased white adipose tissue browning. Taken together, our data show that Blimp-1–regulated IL-10 secretion by Tregs represses white adipose tissue beiging to maintain adipose tissue homeostasis.
Preserved MAIT cell numbers and function in idiopathic CD4 lymphocytopenia.

Mucosal-associated invariant T (MAIT) cells constitute a subset of unconventional, MR1-restricted T-cells involved in antimicrobial responses as well as inflammatory, allergic and autoimmune diseases. Chronic infection and inflammatory disorders as well as immunodeficiencies are often associated with decline and/or dysfunction of MAIT cells. Herein, we investigate the MAIT cells in patients with idiopathic CD4 + lymphocytopenia (ICL), a syndrome characterized by consistently low CD4 T-cell counts (<300 cell/µL) in the absence of HIV infection or other known immunodeficiency, and by susceptibility to certain opportunistic infections. The numbers, phenotype and function of MAIT cells in peripheral blood were preserved in ICL patients compared to healthy controls. Furthermore, administration of IL-7 to ICL patients expanded the CD8 + MAIT cell subset, with maintained responsiveness and effector functions after IL-7 treatment. In conclusion, ICL patients maintain normal levels and function of MAIT cells preserving some antibacterial responses despite the deficiency in CD4 + T cells.
Arsenate-Induced Changes in Bacterial Metabolite and Lipid Pools during Phosphate Stress

Arsenic is widespread in the environment and is one of the most ubiquitous environmental pollutants. Parodoxically, the growth of certain bacteria is enhanced by arsenic when phosphate is limited. ABSTRACT Agrobacterium tumefaciens GW4 is a heterotrophic arsenite-oxidizing bacterium with a high resistance to arsenic toxicity. It is now a model organism for studying the processes of arsenic detoxification and utilization. Previously, we demonstrated that under low-phosphate conditions, arsenate [As(V)] could enhance bacterial growth and be incorporated into biomolecules, including lipids. While the basic microbial As(V) resistance mechanisms have been characterized, global metabolic responses under low phosphate remain largely unknown. In the present work, the impacts of As(V) and low phosphate on intracellular metabolite and lipid profiles of GW4 were quantified using liquid chromatography-mass spectroscopy (LC-MS) in combination with transcriptional assays and the analysis of intracellular ATP and NADH levels. Metabolite profiling revealed that oxidative stress response pathways were altered and suggested an increase in DNA repair. Changes in metabolite levels in the tricarboxylic acid (TCA) cycle along with increased ATP are consistent with As(V)-enhanced growth of A. tumefaciens GW4. Lipidomics analysis revealed that most glycerophospholipids decreased in abundance when As(V) was available. However, several glycerolipid classes increased, an outcome that is consistent with maximizing growth via a phosphate-sparing phenotype. Differentially regulated lipids included phosphotidylcholine and lysophospholipids, which have not been previously reported in A. tumefaciens. The metabolites and lipids identified in this study deepen our understanding of the interplay between phosphate and arsenate on chemical and metabolic levels. IMPORTANCE Arsenic is widespread in the environment and is one of the most ubiquitous environmental pollutants. Parodoxically, the growth of certain bacteria is enhanced by arsenic when phosphate is limited. Arsenate and phosphate are chemically similar, and this behavior is believed to represent a phosphate-sparing phenotype in which arsenate is used in place of phosphate in certain biomolecules. The research presented here uses a global approach to track metabolic changes in an environmentally relevant bacterium during exposure to arsenate when phosphate is low. Our findings are relevant for understanding the environmental fate of arsenic as well as how human-associated microbiomes respond to this common toxin.
Safety, Efficacy, and Patient Satisfaction with Initial Peripherally Inserted Central Catheters Compared with Usual Intravenous Access in Terminally Ill Cancer Patients: A Randomized Phase II Study

Purpose The purpose of this study was to investigate whether routine insertion of peripherally inserted central catheter (PICC) at admission to a hospice-palliative care (HPC) unit is acceptable in terms of safety and efficacy and whether it results in superior patient satisfaction compared to usual intravenous (IV) access. Materials and Methods Terminally ill cancer patients were randomly assigned to two arms: routine PICC access and usual IV access arm. The primary endpoint was IV maintenance success rate, defined as the rate of functional IV maintenance until the intended time (discharge, transfer, or death). Results A total of 66 terminally ill cancer patients were enrolled and randomized to study arms. Among them, 57 patients (routine PICC, 29; usual IV, 28) were analyzed. In the routine PICC arm, mean time to PICC was 0.84 days (range, 0 to 3 days), 27 patients maintained PICC with function until the intended time. In the usual IV arm, 11 patients maintained peripheral IV access until the intended time, and 15 patients underwent PICC insertion. The IV maintenance success rate in the routine PICC arm (27/29, 93.1%) was similar to that in the usual IV arm (26/28, 92.8%, p=0.958). Patient satisfaction at day 5 was better in the routine PICC arm (97%, ‘a little comfort’ or ‘much comfort’) compared with the usual IV arm (21%) (p < 0.001). Conclusion Routine PICC insertion in terminally ill cancer patients was comparable in safety and efficacy and resulted in superior satisfaction compared with usual IV access. Thus, routine PICC insertion could be considered at admission to the HPC unit.