Miracle-dz/UniFAR-FTUs huggingface dataset:
Six-Month Randomized, Multicenter Trial of Closed-Loop Control in Type 1 Diabetes.

BACKGROUND Closed-loop systems that automate insulin delivery may improve glycemic outcomes in patients with type 1 diabetes. METHODS In this 6-month randomized, multicenter trial, patients with type 1 diabetes were assigned in a 2:1 ratio to receive treatment with a closed-loop system (closed-loop group) or a sensor-augmented pump (control group). The primary outcome was the percentage of time that the blood glucose level was within the target range of 70 to 180 mg per deciliter (3.9 to 10.0 mmol per liter), as measured by continuous glucose monitoring. RESULTS A total of 168 patients underwent randomization; 112 were assigned to the closed-loop group, and 56 were assigned to the control group. The age range of the patients was 14 to 71 years, and the glycated hemoglobin level ranged from 5.4 to 10.6%. All 168 patients completed the trial. The mean (±SD) percentage of time that the glucose level was within the target range increased in the closed-loop group from 61±17% at baseline to 71±12% during the 6 months and remained unchanged at 59±14% in the control group (mean adjusted difference, 11 percentage points; 95% confidence interval [CI], 9 to 14; P<0.001). The results with regard to the main secondary outcomes (percentage of time that the glucose level was >180 mg per deciliter, mean glucose level, glycated hemoglobin level, and percentage of time that the glucose level was <70 mg per deciliter or <54 mg per deciliter [3.0 mmol per liter]) all met the prespecified hierarchical criterion for significance, favoring the closed-loop system. The mean difference (closed loop minus control) in the percentage of time that the blood glucose level was lower than 70 mg per deciliter was -0.88 percentage points (95% CI, -1.19 to -0.57; P<0.001). The mean adjusted difference in glycated hemoglobin level after 6 months was -0.33 percentage points (95% CI, -0.53 to -0.13; P = 0.001). In the closed-loop group, the median percentage of time that the system was in closed-loop mode was 90% over 6 months. No serious hypoglycemic events occurred in either group; one episode of diabetic ketoacidosis occurred in the closed-loop group. CONCLUSIONS In this 6-month trial involving patients with type 1 diabetes, the use of a closed-loop system was associated with a greater percentage of time spent in a target glycemic range than the use of a sensor-augmented insulin pump. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases; iDCL ClinicalTrials.gov number, NCT03563313.).
Probabilistic Graphical Modeling for Estimating Risk of Coronary Artery Disease: Applications of a Flexible Machine-Learning Method

Objectives. Coronary artery disease (CAD) is the leading cause of death and disease burden worldwide, causing 1 in 7 deaths in the United States alone. Risk prediction models that can learn the complex causal relationships that give rise to CAD from data, instead of merely predicting the risk of disease, have the potential to improve transparency and efficacy of personalized CAD diagnosis and therapy selection for physicians, patients, and other decision makers. Methods. We use Bayesian networks (BNs) to model the risk of CAD using the Z-Alizadehsani data set—a published real-world observational data set of 303 Iranian patients at risk for CAD. We also describe how BNs can be used for incorporation of background knowledge, individual risk prediction, handling missing observations, and adaptive decision making under uncertainty. Results. BNs performed on par with machine-learning classifiers at predicting CAD and showed better probability calibration. They achieved a mean 10-fold area under the receiver-operating characteristic curve (AUC) of 0.93 ± 0.04, which was comparable with the performance of logistic regression with L1 or L2 regularization (AUC: 0.92 ± 0.06), support vector machine (AUC: 0.92 ± 0.06), and artificial neural network (AUC: 0.91 ± 0.05). We describe the use of BNs to predict with missing data and to adaptively calculate prognostic values of individual variables under uncertainty. Conclusion. BNs are powerful and versatile tools for risk prediction and health outcomes research that can complement traditional statistical techniques and are particularly useful in domains in which information is uncertain or incomplete and in which interpretability is important, such as medicine.
Within-subject variability in human retinal nerve fiber bundle width

With the growing availability of high-resolution imaging there has been increased interest in developing new metrics for integrity of the retinal nerve fiber layer. In particular, it has been suggested that measurement of width of retinal nerve fiber bundles (RNFBs) may be useful in glaucoma, due to low between-subject variability in mean RNFB width. However, there have also been reports of substantial within-subject variability in the width of individual RNFBs. To assess within-subject variability as a potential source of selection bias in measurements of RNFB width, we used an adaptive optics scanning laser ophthalmoscope (AOSLO) to measure widths of individual RNFBs in one eye each of 11 young adults in good ocular health. In a pilot study we analyzed a large AOSLO image of RNFL in one participant then, based on those findings, in the main study we used AOSLO to image a smaller region in 10 additional healthy young adults. The pilot study of one eye found RNFB widths ranging from 10 μm to 44 μm. This suggested that biological variability was too high for measuring small changes arising from disease processes. This was confirmed in measurements of 10 eyes in the main study, RNFB widths ranged from 9 μm to 55 μm and every eye had large within-subject variability (exceeding 19 μm in all eyes) in RNFB width for nearby bundles. The within-subject variability in RNFB width, as well as variation in the width of single RNFBs over relatively short distances (<300 um) depending on the precise location of measurement, suggests that bundle width measurements would be highly susceptible to selection bias and therefore of limited clinical use.
Circular RNAs in nucleus pulposus cell function and intervertebral disc degeneration

Intervertebral disc degeneration (IDD) is a common cause of low back pain, which inflicts more global disability than any other condition. Although IDD was deemed to be a natural process that comes with ageing, a growing body of evidence suggested that both genetic and environmental factors could modify the development of IDD. In this connection, aberrant function of nucleus pulposus cells has been implicated in IDD pathogenesis. Circular RNAs are a novel class of endogenous non‐coding RNAs that play crucial regulatory roles in diverse cellular processes. Recently, deregulation of circRNAs in nucleus pulposus cells was found to functionally participate in IDD development. In this review, we summarize the current knowledge regarding the deregulation of circRNAs in IDD in relation to their actions on nucleus pulposus cell functions, including cell proliferation, apoptosis and extracellular matrix synthesis/degradation. The potential clinical utilities of circRNAs as therapeutic targets for the management of IDD are also discussed.
Bioinformatics analysis of the prognosis and biological significance of HMGB1, HMGB2, and HMGB3 in gastric cancer

High mobility group box (HMGB) consists primarily of HMGB1, HMGB2, and HMGB3 proteins. Although abnormal HMGB expression is associated with various tumors, the relationship with gastric cancer (GC) remains unclear. In this study, HMGB1, HMGB2, and HMGB3 expression was analyzed using the Oncomine and TCGA databases. Correlations between HMGB1, HMGB2, and HMGB3 and clinicopathological factors were analyzed. cBioPortal was used to analyze HMGB1, HMGB2, and HMGB3 genetic alterations and its gene regulation network in GC tissue. HMGB1, HMGB2, and HMGB3 expression was higher in tumor tissues than in normal tissues, especially in GC. High HMGB1, HMGB2, and HMGB3 expression may predict a poor prognosis among patients with GC (hazard ratios [HR] = 1.90; 95% confidence interval [CI]: [1.30−2.78]) and human digestive system neoplasm (HR = 1.85; 95% CI [1.64−2.10]). These findings suggest that HMGB1, HMGB2, and HMGB3 may be useful prognostic indicators for patients with GC.
Differential Diagnosis in Dermatopathology

This is a seductive book. The volume is a superb product of printing excellence—the urbane dermatopathologist might well be tempted to leave it on his coffee table, perhaps in the company of say, Country Gentleman or Punch . Apparently no cost was spared; the format is lavish, the printing and color reproduction are essentially impeccable. The book is easy to read and a delight to look at but, as I noted, seductive. And, like many affairs common to the bibliophile, a brief encounter is often more rewarding than a lasting relationship. Clearly, part of the substantial cost of this volume is related to the generous layout; each presentation begins on the left-hand page with double columns of enumerated telegraphic sentences. On the opposite page there is a brace of clinical photographs and three-paired color photomicrographs in which each comparable pair of photomicrographs is printed at, or near, the same magnification. Following
Comparison of Proteomic Biodosimetry Biomarkers Across Five Different Murine Strains

In the event of a radiological or nuclear attack, advanced clinical countermeasures are needed for screening and medical management of the exposed population. Such a population will represent diverse heterogeneity in physiological response to radiation exposure. The current study seeks to compare the expression levels of five previously established proteomic biodosimetry biomarkers of radiation exposure, i.e., Flt3 ligand (FL), matrix metalloproteinase 9 (MMP9), serum amyloid A (SAA), pentraxin 3 (PTX3) and fibrinogen (FGB), across multiple murine strains and to test a multivariate dose prediction model based on a single C57BL6 strain against other murine strains. Female mice from five different murine strains (C57BL6, BALB/c, C3H/HeJ, CD2F1 and outbred CD-1 mice) received a single whole-body dose of 1–8 Gy from a Pantak X-ray source at a dose rate of 3.59 Gy/min. Plasma was collected by cardiac puncture at days 1, 2, 3 and 7 postirradiation. Plasma protein levels were determined via commercially available ELISA assay. Significant differences were found between radiation-induced expression levels of FL, MMP9, SAA, PTX3 and FGB among the C57BL6, BALB/c, C3H/HeJ, CD2F1 and CD-1 strains (P < 0.05). The overall trends of dose-dependent biomarker elevation, however, were similar between strains, with FL and PTX3 showing the highest degree of correlation. Application of a previous C57BL6 multivariate dose prediction model using additional murine strains showed the limitations of a model based on a single strain and the need for data normalization for variance generated by technical assay variables. Our findings indicate that strain specific differences do exist between expression levels of FL, MMP9, SAA, PTX3 and FGB in C57BL6, BALB/c, C3H/HeJ, CD2F1 and CD-1 murine strains and that use of multiple biomarkers for dose prediction strengthens the predictive accuracy of a model when challenged with a heterogeneous population.
Genetic analysis on body weight at different ages in broiler chicken raised in commercial environment.

A multivariate model was developed and used to estimate genetic parameters of body weight (BW) at 1-6 weeks of age of broilers raised in a commercial environment. The development of model was based on the predictive ability of breeding values evaluated from a cross-validation procedure that relied on half-sib correlation. The multivariate model accounted for heterogeneous variances between sexes through standardization applied to male and female BWs differently. It was found that the direct additive genetic, permanent environmental maternal and residual variances for BW increased drastically as broilers aged. The drastic increase in variances over weeks of age was mainly due to scaling effects. The ratio of the permanent environmental maternal variance to phenotypic variance decreased gradually with increasing age. Heritability of BW traits ranged from 0.28 to 0.33 at different weeks of age. The direct genetic effects on consecutive weekly BWs had high genetic correlations (0.85-0.99), but the genetic correlations between early and late BWs were low (0.32-0.57). The difference in variance components between sexes increased with increasing age. In conclusion, the permanent environmental maternal effect on broiler chicken BW decreased with increasing age from weeks 1 to 6. Potential bias of the model that considered identical variances for sexes could be reduced when heterogeneous variances between sexes are accounted for in the model.
Neuron Replacement and Brain Repair; Sex Does Matter

The brain is one of the main targets of gonadal steroid hormones. In addition, it contains many of the steroid metabolizing enzymes. The effect of gonadal steroids on brain development and maturation has been well documented [1,2]. The vast literature on the subject has introduced the common belief that gonadal steroids may be the only effectors of the brain sexual differ‐ entiation, overshadowing other key elements. Although there is no doubt about its importance, the dogma of the gonadal origin of somatic differentiation, including neuronal cells, usually implies that XX and XY cells, accordingly stem cells, are functionally equivalent unless gonadal secretions act on them in a sex-specific manner. The human Y chromosome encodes 27 different proteins [3] eight of which are expressed in the male brain and could have a male-specific effect on the brain, independent of any gonadal hormone influence [4,5]. Furthermore, XX cells contain an X chromosome that received a paternal genomic imprint, whereas XY cells do not, a fact that is likely to contribute to autonomous differences between male and female cells. De Vries and colleagues [6] generated mice in which the testis-determining gene sry was deleted from the Y chromosome and subsequently inserted onto an autosome. This experiment resulted in the generation of mice where the development of the testis occurred independently of the complement of X or Y chromosome. Although most of the sexual dimorphism correlated with the presence of testis or ovary (and therefore associated with gonadal hormones), XY mice (with testes or ovaries) were found to be more masculine than the XX mice (with testes or ovaries) in the density of vasopressin-immunoreactive fibers in the lateral septum, suggesting that sex chromosome genes contribute to the development of a sex difference in the brain. These results also suggest that one should not consider that female and male neural stem cells (NSC) are equal and react in the same manner to a specific environment or pharmacological agent. Furthermore, there are no data to support the a priori consideration that transplanting
A Sparse Orthogonal Collimator for Small Animal Intensity Modulated Radiation Therapy Part I: Planning System Development and Commissioning.

PURPOSE To achieve more translatable preclinical research results, small animal irradiation needs to more closely simulate human radiotherapy. Although the clinical gold standard is intensity modulated radiation therapy (IMRT), the direct translation of this method for small animals is impractical. In this study we describe the treatment planning system for a novel dose modulation device to address this challenge. METHODS Using delineated target and avoidance structures, a rectangular aperture optimization (RAO) problem was formulated to penalize deviations from a desired dose distribution and limit the number of selected rectangular apertures. RAO was used to create IMRT plans with highly concave targets in the mouse brain, and the plan quality was compared to that using a hypothetical miniaturized multileaf collimator (MLC). RAO plans were also created for a realistic application of mouse whole liver irradiation and for a highly complex 2D dose distribution as a proof-of-principle. Beam commissioning data, including output and off-axis factors and percent depth dose (PDD) curves, was acquired for our small animal irradiation system and incorporated into the treatment planning system. A plan post-processing step was implemented for aperture-size-specific dose recalculation and aperture weighting reoptimization. RESULTS The first RAO test case achieved highly conformal doses to concave targets in the brain, with substantially better dose gradient, conformity, and target dose homogeneity than the hypothetical miniaturized MLC plans. In the second test case, a highly conformal dose to the liver was achieved with significant sparing of the kidneys. RAO also successfully replicated a complex 2D dose distribution with three prescription dose levels. Energy spectra for field sizes 1 to 20 mm were calculated to match the measured PDD curves, with maximum and mean dose deviations of 4.47 ± 0.30% and 1.71 ± 0.18%. The final reoptimization of aperture weightings for the complex RAO test plan was able to reduce the maximum and mean dose deviations between the optimized and recalculated dose distributions from 10.3 to 6.6% and 4.0 to 2.8%, respectively. CONCLUSIONS By using advanced optimization techniques, complex IMRT plans were achieved using a simple dose modulation device. Beam commissioning data was incorporated into the treatment planning process to more accurately predict the resulting dose distribution. This platform substantially reduces the gap in treatment plan quality between clinical and preclinical radiotherapy, potentially increasing the value and flexibility of small animal studies.
S100a9 knockout contributes to neuroprotection and functional improvement after traumatic brain injury.

S100a9, a proinflammatory protein, has been shown to be involved in the development of neuroinflammatory disorders and neurodegenerative diseases. Upregulation of S100a9 in the brain during acute brain injury has been proposed to be associated with acute neuroinflammation. However, it remains unclear whether eliminating S100a9 expression will show beneficial outcomes after traumatic brain injury (TBI). Using S100a9 knockout mice, this study has demonstrated that S100a9 deletion ameliorates post-TBI anxiety, improves TBI-impaired motor and cognitive function, reduces lesion size, prevents peri-lesional neuron loss and neurodegeneration, diminishes neuroinflammation and TBI-induced neurogenesis, and enhances peri-lesional expression of neuroplasticity protein. These findings suggest that S100a9 plays a detrimental role in TBI. Genetic deletion of S100a9 enhances neuroprotection and improves functional outcome after TBI. This study sheds light on the pathological involvement of S100a9 in TBI, which would provide a new therapeutic target to minimize TBI-induced brain damage.
[Identification of rotavirus I- and E-genotypes by multiplex PCR method.]

INTRODUCTION In recent years the presence of reassortant rotavirus strains is increasingly mentioned in the world due to the application of the full-genome based classification system. Information on the circulation of such strains in the territory of Russia is limited. The aim of this work was the development of the approach for determination of genotypes of segments encoding VP6 (I) and NSP4 (E) to reveal reassortant strains. MATERIAL AND METHODS Rotavirus-positive samples were studied by means of nucleotide sequencing and multiplex PCR. Phylogenetic analysis was conducted using the Bayesian approach. RESULTS Three alleles of the VP6 gene (I1-1, I2-IV, I2-VII) and seven alleles of the NSP4 gene (E1-I, E1-III, E2-VI, E2-VII, E2-X, E2-XII, E3) were detected on the base of nucleotide sequences of Nizhny Novgorod rotaviruses. Taking into account these results, the oligonucleotide primers specific to genotypes I1, I2, I3 and E1, E2, E3 were designed. Optimal conditions for multiplex PCR were chosen. The method was tested using the strains collected in Nizhny Novgorod in 2018. The diversity of I and E genotypes was determined and various combinations with G and P genotypes were identified. DISCUSSION G9-P[8]-I1-E1 rotaviruses were predominant (32.7 %) and G2-P[4]-I2-E2 rotaviruses were in second place (29.1 %). Strains with genotypes G4-P[8]-I1-E2, G3-P[8]-I2-E2 and G2-P[4]-I2-E1 were detected sporadically. They had genes of two rotavirus genogroups, so can be considered to be reassortant. CONCLUSION The proposed approach is a useful tool for the characterization of rotaviruses in the conditions of the beginning of vaccination against rotavirus infection in Russia.
Active surveillance of papillary thyroid microcarcinomas in South America: Are we ready?

DOI: 10.20945/2359-3997000000180 1 Laboratório de Endocrinologia Celular e Molecular (LIM25), Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo (HCFMUSP), São Paulo, SP, Brasil 2 Instituto do Câncer do Estado de São Paulo, Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, SP, Brasil 3 Laboratório de Endocrinologia Molecular e Translacional, Disciplina de Endocrinologia e Metabologia, Departamento de Medicina, Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP/ EPM), São Paulo, SP, Brasil 4 Unidade de Tireoide, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brasil Active surveillance of papillary thyroid microcarcinomas in South America: Are we ready?
Intégrité et fonctionnalité des mécanismes descendants d'inhibition de la douleur en contexte de douleur chronique : perspectives en recherche translationnelle

Descending pain inhibition is an endogenous pain control system thought to depend partially on the activation of bulbo-spinal monoaminergic pathways. Deficits in descending pain inhibition have been reported in numerous human chronic pain conditions, but there is currently no consensus regarding the neurochemical correlates responsible for this deficit. The aims of this study were to: [1] assess the efficacy of descending pain inhibition in painfree (PF) and chronic pain (CP) subjects, [2] screen for changes in centrally (i.e. cerebrospinal fluid; CSF) and peripherally (i.e. plasma) acting monoamines concentrations, and, [3] explore the relationship between descending pain inhibition and monoamine neurotransmitter concentrations. Our results clearly show a deficit in pain inhibition, along with lower plasma norepinephrine and metanephrine concentrations in CP subjects, compared to PF subjects. No differences in CSF neurotransmitter concentrations were found. Finally, our results revealed a positive relationship between blood-bound norepinephrine and metanephrine concentrations and the efficacy of descending pain inhibition. Thus, basal monoamine levels in blood were related to descending pain inhibition. This finding supports the emerging idea that individual differences in descending pain inhibition may be linked to individual differences in peripheral processes, such as monoamines release in blood, that are possibly related to cardiovascular control. Perspectives: This article presents psychophysical and neurochemical findings which indicate that the latent potential of descending pain inhibitory responses is associated with differential activity in peripheral processes governed by monoamine neurotransmitter release; bringing insights on the relation between descending pain inhibition and cardiovascular control in humans.