Miracle-dz/UniFAR-FTUs huggingface dataset:
Population pharmacokinetics of mycophenolic acid in Mexican patients with lupus nephritis

Background Mycophenolic acid (MPA) is an effective oral immunosuppressive drug used to treat lupus nephritis (LN), which exhibits large pharmacokinetic variability. This study aimed to characterize MPA pharmacokinetic behaviour in Mexican LN patients and to develop a population pharmacokinetic model which identified factors that influence MPA pharmacokinetic variability. Methods Blood samples from LN patients treated with mycophenolate mofetil (MMF) were collected pre dose and up to six hours post dose. MPA concentrations were determined by a validated ultra-performance liquid chromatography tandem mass spectrometry technique. Patients were genotyped for polymorphisms in enzymes (UGT1A8, 1A9 and 2B7) and transporters (ABCC2 and SLCO1B3). The anthropometric, clinical, genetic and co-medication characteristics of each patient were considered as potential covariates to explain the variability. Results A total of 294 MPA concentrations from 40 LN patients were included in the development of the model. The data were analysed using NONMEM software and were best described by a two-compartment linear model. MPA CL, Vc, Vp, Ka and Q were 15.4 L/h, 22.86 L, 768 L, 1.28 h−1 and 20.3 L/h, respectively. Creatinine clearance and prednisone co-administration proved to have influence on clearance, while body weight influenced Vc. The model was internally validated, proving to be stable. MMF dosing guidelines were obtained through stochastic simulations performed with the final model. Conclusions This is the first MPA population pharmacokinetic model to have found that co-administration of prednisone results in a considerable increase on clearance. Therefore, this and the other covariates should be taken into account when prescribing MMF in order to optimize the immunosuppressant therapy in patients with LN.
Attentional efficiency does not explain the mental state × domain effect

The reduced importance of intent when judging purity (vs. harm) violations is some of the strongest evidence for distinct moral modules or systems: moral pluralism. However, research has indicated that some supposed differences between purity and harm moral domains are due to the relative weirdness of purity vignettes. This weirdness might lead to a failure to attend to or correctly process relevant mental state information. Such attentional failures could offer an alternative explanation (to separate moral systems) for the reduced exculpatory value of innocent intentions for purity violations. We tested if the different role of intent in each domain was moderated by individual differences in attentional efficiency, as measured by the Attention Network Task. If attentional efficiency explains the reduced exculpatory value of innocent intentions in purity (vs. harm) violations, then we would expect those high (vs. low) in attentional efficiency not to show the reduced exculpatory effect of innocent intentions in the purity (vs. harm) domain. Consistent with moral pluralism, results revealed no such moderation. Findings are discussed in relation to various ways of testing domain-general and domain-specific accounts of the mental state × domain effect, so that we might better understand the architecture of our moral minds.
Management of chemotherapy-induced neutropenia in patients with cancer: 2019 guidelines of the Italian Medical Oncology Association (AIOM)

Neutropenia is the most frequent side effect of commercially available myelosuppressive drugs and its most significant complication is febrile neutropenia. It is associated with increased hospital admissions and higher probability of death. Prophylaxis with the administration of granulocyte colony-stimulating factor can prevent neutropenia caused by anticancer drugs. The correct administration of these drugs and the management of febrile neutropenia are extremely important in the treatment of patients with cancer.
In vivo recordings from the human vagus nerve using ultrasound‐guided microneurography

The vagus nerve is the largest cranial nerve and innervates many structures in the neck, thorax and abdomen. Although single‐unit recordings from the vagus nerve have been performed in experimental animals for several decades, no recordings have ever been made from the human vagus nerve. The vagus nerve is routinely stimulated clinically, yet we know little of its physiology in humans. We describe the methodology and provide preliminary results of the first intraneural single‐unit recordings from the cervical vagus in awake humans, using tungsten microelectrodes inserted into the nerve through ultrasound guidance.
Reconstruction of Large Bone Defects and Complex Non-Unions Using a Free Fibular Bone Graft and a Supplementary Allograft Rekonstruktion großer Knochendefekte sowie komplexer Pseudarthrosen mittels freier Fibulatransplantation und eines additiven Allografts

Abstract Large bone defects or complex pseudarthrosis represent an interdisciplinary challenge. Established surgical procedures include autogenous cancellous bone graft, the Masquelet technique or bone transfer via segment transport as well as free microvascular bone transplantation. However, the successful use of all these techniques requires a specialized center with great interdisciplinary expertise. In the following case series we describe the technique of free fibula transplantation and additional allograft. In both cases a good functional result with full mechanical strength of the affected extremity and satisfactory patient comfort has been achieved. In the second case, implant failure with the necessity of revision endoprosthetics occurred during the procedure. Zusammenfassung Höhergradige größere Knochendefekte oder komplexe Pseudarthrosen stellen eine interdisziplinäre Herausforderung dar. Als etablierte Operationsverfahren stehen die autologe Spongiosaplastik, die Masquelet-Technik oder der Knochentransfer über einen Segmenttransport, aber auch die freie Knochentransplantation zur Verfügung. Prinzipiell erfordert der erfolgreiche Einsatz aller genannten Techniken ein spezialisiertes Zentrum mit großen interdisziplinären Kompetenzen. In 2 Kasuistiken wird die Technik der freien Fibulatransplantation mit additivem Allograft dargestellt. In beiden Fällen konnte letztendlich ein gutes funktionelles Ergebnis mit voller Belastbarkeit der betroffenen Extremität und zufriedenstellendem Patientenkomfort erzielt werden. Im 2. Fall kam es im Verlauf zu einem Implantatversagen mit der Notwendigkeit der revisionsendoprothetischen Versorgung.
DERL3 suppresses colorectal cancer metastasis through negatively regulating MYCN level.

BACKGROUND To illustrate the role of DERL3 in regulating the development of Colorectal cancer (CRC) and the underlying molecular mechanisms. METHODS Relative levels of DERL3 in CRC tissues and adjacent normal ones were detected by quantitative real-time polymerase chain reaction (qRT-PCR). The relationship between DERL3 level and clinical indicators in CRC patients was analyzed by Chi-square test. After intervening DERL3 level in HT29 and HCT-8 cells, phenotype changes were assessed by cell counting kit-8 (CCK-8) and Transwell assay. The interaction between DERL3 and its downstream target MYCN, and their involvement in the malignant development of CRC were explored. The influence of DERL3 on in vivo growth of CRC was determined by establishing xenograft model in nude mice bearing CRC. RESULTS DERL3 was lowly expressed in CRC tissues than adjacent normal ones. Compared with CRC patients expressing a high level of DERL3, those with a low level presented high rate of lymphatic metastasis or distant metastasis. Overexpression of DERL3 in HT29 cells suppressed proliferative, migratory and invasive capacities, and knockdown of DERL3 in HCT-8 cells yielded the opposite results. MYCN was the downstream target binding DERL3, which was upregulated in CRC tissues and cell lines. MYCN was capable of reversing the regulatory effects of DERL3 on proliferative, migratory and invasive capacities in CRC cells. In vivo overexpression of DERL3 in nude mice bearing CRC inhibited tumor growth by reducing the average tumor volume and tumor weight of CRC tissues. CONCLUSIONS DERL3 is downregulated in CRC samples. Its level is closely linked to lymphatic metastasis or distant metastasis rate in CRC patients. Through negatively regulating MYCN level, DERL3 suppresses proliferative, migratory and invasive capacities in CRC.
High-fat-diet induced obesity increases the proportion of linoleic acyl residues in dam serum and milk and in suckling neonate circulation

Abstract Maternal obesity increases the risk of offspring to become obese and develop related pathologies. Exposure to maternal high-fat diet (HFD) only during lactation increases the risk of obesity-related diseases, suggesting that factors in milk affect long-term health. We hypothesized that prepregnancy obesity induced by HFD alters milk lipidome, and in turn, alterations may affect neonate serum lipidome. The objective of this study was to determine the effect of prepregnancy obesity induced by HFD on circulating lipids in dams and neonates and in milk. Female mice were fed an HFD (60% kcal fat) or control diet (CON, 10% kcal fat) beginning 4 weeks before breeding. On postnatal day 2 (PND2), pups were cross-fostered to create pup groups exposed to HFD during pregnancy, lactation, or both or exposed to CON. On PND12, dams were milked and then euthanized along with pups to collect blood. Serum and milk were processed for multiple reaction monitoring (MRM) lipidomics profiling to quantify the relative expression of lipid classes. Lipidome of HFD dam serum and milk had increased proportion of C18:2 free fatty acid and fatty acyl residues in all lipid classes. Lipidome of serum from pups exposed to maternal HFD during lactation was similarly affected. Thus, maternal HFD induced redistribution of fatty acyl residues in the dam's circulation, which was associated with modification in milk and suckling neonate's lipidome. Further studies are needed to determine if increased circulating levels of C18:2 in neonate affects development and predisposes offspring to obesity and metabolic syndrome. Graphical Abstract Summary Sentence Maternal prepregnancy obesity induced by high-fat diet significantly impacts circulating lipids and similarly modifies the lipid composition of milk and circulating lipid of suckling neonates.
High prevalence of cardiometabolic risk features in adolescents with 47,XXY/Klinefelter syndrome

Klinefelter syndrome (KS) occurs in 1:600 males and is associated with high morbidity and mortality due to diabetes and cardiovascular disease. Up to 50% of men with KS have metabolic syndrome, a cluster of features conferring increased risk for diabetes and cardiovascular disease. These cardiometabolic (CM) risk features have not been studied in adolescents with KS. The objective of this cohort study was to compare CM risk features in adolescents with KS to controls matched for sex, age, and BMI z score. Fifty males with KS (age 10–17 years) were well‐matched to male controls (n = 50) for age (14.0 ± 1.7 vs. 14.0 ± 1.5 years) and BMI z score (0.3 ± 1.3 vs. 0.4 ± 1.2). Three CM risk features were present in 30% of adolescents with KS compared to 12% of controls (RR 2.5, 95% CI 1.1–5.9, p = .048). The KS group had significantly lower HDL cholesterol (p = .006), higher triglycerides (p < .001), and greater waist circumference percentile (p < .001). Despite a normal BMI, the prevalence of CM risk features was very high in adolescents with KS, particularly for central adiposity and dyslipidemia. The pathophysiology of this metabolic profile independent of obesity needs further investigation to facilitate prevention of the high morbidity of cardiovascular disease and diabetes in this population. ClinicalTrials.gov identifiers: NCT01585831 and NCT02723305.
Differences in Substance Use and Sexual Risk by Sexual Orientation and Gender Identity Among University and Community Young Adults in a U.S.-Mexico Border City

Ethnic and sexual minority young adults in El Paso, Texas, are at high risk for substance use, human immunodeficiency virus (HIV), and hepatitis C virus (HCV). In 2014, a Hispanic-serving higher education institution partnered with two community-based organizations to implement integrated substance use interventions and HIV and HCV prevention among young adults on campus and in surrounding communities. Among the 95 young adults, aged 18–24 years, who responded to a needs assessment survey, 91.5% were Hispanic, 53.7% were female, and 27.4% were sexual or gender minorities (SGMs) as defined by behavior and identity. SGMs had significantly higher rates of current smoking, drinking when bored, and of being told they had a drinking problem. Compared with the other young adult survey respondents, SGMs had lower health risk perceptions for tobacco, alcohol, and marijuana use and reported similar or higher rates of lifetime drug use during sex and higher rates of HIV risk behaviors. Study findings have implications for including measures for sexual orientation and gender identity in substance use studies, examining regional and cultural norms that may intersect to shape substance use among SGMs, and incorporating unique risk contexts for SGMs in interventions for substance use.
Phenotyping peach‐allergic patients sensitized to lipid transfer protein and analysing severity biomarkers

Patients with peach allergy due to nsLTP sensitization constitute a heterogeneous group in terms of sensitization profile and severity. This could be due to the presence of additional allergies to pollens. The aim of this study was to analyse the clinical characteristics, sensitization profile and severity of reactions in peach‐allergic patients sensitized to nsLTP from two Mediterranean areas with different pollen exposure.
Efficacy of a Standardized Perioperative Clinical Care Pathway for Below Knee Amputation.

tandardizing perioperative care through clinical pathways develS oped from evidence-based guidelines can significantly improve patient outcomes and reduce healthcare costs. Despite their value, there are no published evaluations of clinical pathways applied to all causes of below-knee amputation (BKA). The incidence of lower extremity amputations is increasing worldwide and BKAs account for 73% of major unilateral lower extremity amputations performed in the United States. It is; therefore, vital to improve perioperative care to enhance patient outcomes and reduce healthcare costs. We developed, implemented, and evaluated a standardized perioperative care pathway for all patients undergoing BKA at a regional level 1 trauma center.
Investigation of the impact of blur under mobile attentional orientation using a vision simulator

It is well-known that correction of blur can improve visual perception. However, it is unclear how the beneficial effect of correction is affected by the regions of correction and the spatial uncertainty introduced by the retinal stimulation. The purpose of this study was two-fold: first, to compare the impacts of blur correction between isoeccentric locations of the visual field; and second, to evaluate the effect of spatial cueing in each corrected location on performing a simple task. Five subjects were asked to complete a simple detection task of a small dark spot stimulus presented randomly at four cardinal retinal locations (eccentricity: 5°) under manipulation of attention via an exogenous cue. Both clear and blurred targets were randomly displayed across the visual field and viewed monocularly through a vision simulator, used to minimize peripheral ocular aberrations. Results confirmed the advantage of clear vs/ blurred images under spatial uncertainty. It was also found that the visual benefit from blur correction is unequal at isoeccentric locations, even for a simple detection task. While manipulation of attention in the presence of spatial uncertainty significantly modulated response time (RT) performance, no differential effect was observed for clear and blurred stimuli, suggesting that attention has only a small effect on the optical benefit for a simple detection task when the display is depleted (no distractor). Those observations highlight the importance of field performance asymmetries in optical interventions and may offer useful implications for the design of extrafoveal refractive correction. Further studies are needed to elucidate how the focus of attention interacts with the perceived gain of vision correction.
Japanese Perceptual Epenthesis is Modulated by Transitional Probability

Perceptual epenthesis is the perception of illusory vowels in consonantal sequences that violate native phonotactics. The consensus has been that each language has a single, predictable candidate for perceptual epenthesis, that vowel which is most minimal (i.e., shortest and/or quietest). However, recent studies have shown that alternate epenthetic vowels can be perceived when the perceptual epenthesis of the minimal vowel would violate native co-occurrence restrictions. We propose a potential explanation for these observed patterns: speech perception, and thus also vowel perceptual epenthesis, is modulated by transitional probability whereby epenthetic vowels must conform to the language specific expectations of the listener. To test this explanation, we present two experiments examining perceptual epenthesis of two Japanese vowels—/u/ and /i/—against their transitional probability in CV sequences. In Experiment 1, Japanese listeners assigned VCCV tokens to VCuCV and VCiCV categories. In Experiment 2, participants discriminated VCCV tokens from VCuCV and VCiCV tokens. The results show that sequences where /i/ is transitionally probable are more likely to elicit /i/ perceptual epenthesis.
Sevoflurane attenuates cognitive dysfunction and NLRP3-dependent caspase-1/11-GSDMD pathway-mediated pyroptosis in the hippocampus via upregulation of SIRT1 in a sepsis model

Abstract Septic encephalopathy (SE) is a devastating consequence of sepsis, a hyper-triggered host response against infectious challenge, which ultimately leads to brain damage. The present study examined whether sevoflurane (SVF), a volatile anaesthetic, can counteract the perturbation of homeostasis in a caecal ligation and puncture (CLP)-induced mouse model of SE. SVF enhances neurocognition in terms of spatial memory improvement via counter-regulation of activated oxidative-inflammatory stress and pyroptotic processes in SE. Further, the beneficial effects of SVF against SE are mediated by activation of silent information regulator 1 (SIRT1)-mediated reduction of reactive oxygen species (ROS) level, regulation of thioredoxin (TXN) and thioredoxin interacting protein (TIP) levels, reduction of inflammatory-pyroptotic signalling (NLRP3, caspase 1/11, GSDMD, TLR4 and TRIF) proteins, as well as a reduction of inflammatory cytokine (IL-1β and IL-18) levels. These findings suggest that SVF may have therapeutic potential for the treatment of SE and associated cognitive malfunction.
Effects of local injection and intravenous injection of allogeneic bone marrow mesenchymal stem cells on the structure and function of damaged anal sphincter in rats

Anal sphincter injury leads to damage to the anal structure and functions and has been identified as a major risk factor for fecal incontinence. Bone marrow mesenchymal stem cells (BMSCs) with capacities of multidifferentiation, paracrine, and low immunogenicity have been widely used in tissue repair and regeneration. The primary objective of this research was to compare the effects of different injection therapies of BMSCs on the injured anal sphincters. Ninety‐six Sprague‐Dawley female rats were randomly divided into four groups (n = 24 each): intravenous injection, local injection, sham operation, and normal control. For the first three groups, 25% removal of the anal sphincter complex was performed and 0.3‐ml phosphate‐buffered saline (PBS) (containing 107 green fluorescent protein‐labeled allogeneic BMSCs) was given accordingly to the treatment group 24 h after operation for 7 consecutive days. The sham operation group was injected with 0.3‐ml PBS only. All cases had undergone evaluation in the 1st, 7th, 14th, and 28th postoperative days. The rats were sacrificed on the 28th postoperative day, and the anal sphincters were dissected to be analyzed by morphological examination.
Improving long-term survival in diffuse intrinsic pontine glioma

ABSTRACT Introduction Diffuse intrinsic pontine glioma (DIPG) is an almost universally fatal pediatric brain cancer. There has been no improvement in event-free survival (EFS) or overall survival (OS) despite immense effort through a multitude of clinical trials to find a cure. Recently, there has been a surge in the knowledge of DIPG biology, including the discovery of a recurrent H3F3A mutation in over 80% of these tumors. Areas covered The authors review the most recent approaches to diagnosis and treatment of DIPG including chemotherapy, biologics, surgical approaches, and immunotherapy. Expert opinion The authors propose four main opportunities to improve long-term survival. First, patients should be enrolled in scientifically sound clinical trials that include molecularly profiling either via stereotactic biopsy or liquid biopsy. Second, clinical trials should include more innovative endpoints other than traditional EFS and OS such as MRI/PET imaging findings combined with surrogates of activity (e.g. serial liquid biopsies) to better ascertain biologically active treatments. Third, innovative clinical trial approaches are needed to help allow for the rapid development of combination therapies to be tested. Finally, effort should be concentrated on reversing the effects of the histone mutation, as this malfunctioning development program seems to be key to DIPG relentlessness.