Miracle-dz/UniFAR-FTUs huggingface dataset:
Skewed B cell receptor repertoire and reduced antibody avidity in patients with DOCK8 deficiency

DOCK8 immunodeficiency syndrome (DIDS) is a combined immunodeficiency characterized by recurrent viral infections, severe atopy and early onset malignancy. Immunological abnormalities include lymphopenia, CD8+ T‐cell cytoskeleton dysfunction, defective B cell memory and variable serum immunoglobulin levels. Here, we analyse the B cell receptor repertoire (BCR) characteristics and antibody avidity of four DIDS patients, attempt to understand the dysregulated humoral immunity in DIDS patients with a normal antibody titre and suggest a scientific basis for intravenous immunoglobulin (IVIG) replacement therapy for these patients. We analysed BCR characteristics, including somatic hypermutation (SHM) frequency, using deep sequencing of multiplex PCR products derived from BCR heavy chain CDR3 regions from DIDS patients and controls. The antibody avidity of human tetanus and hemophilus influenza B antibodies was determined by ELISA using thiocyanate elution. IVIG replacement treatment and infection conditions were investigated retrospectively. We found skewing of the BCR repertoire and decreased antibody avidity in patients with DIDS. DIDS patients had fewer negatively charged amino acids than healthy controls. The SHM frequency of the IGHV3 gene was lower in patients with DIDS. Patients received regular IVIG therapy, resulting in fewer and less severe infections. We conclude that although IgG levels are normal in most DIDS patients, IVIG replacement therapy is still necessary.
A Single-Center Retrospective Study of Patients with Double Primary Cancers: Breast Cancer and EGFR-Mutant Non-Small Cell Lung Cancer

Background: Second primary malignancies (SPM) in the lung are not common in breast cancer (BC) patients. EGFR-mutant lung cancer (LC) is a separate molecular subset, and the co-existence of EGFR-mutant LC and BC has not been explored. We hypothesized that EGFR-mutant LC patients could have higher rates of primary BC than those with EGFR-wild type (WT). Methods: We collected data on clinical and molecular characteristics and outcomes of female patients with LC and a previous or simultaneous history of primary BC treated in our hospital from 2008 to 2014. Results: Data on treatment, follow-up, and EGFR mutation status were available for 356 patients. 17.7% (11/62) of patients with EGFR mutations had BC, compared to 1.02% (3/294) of EGFR-WT patients (p < 0.001). Both tumors were metachronous in 81.8%, with LC diagnosed 9 years after the diagnosis of BC. 5 of the 6 (83.3%) BC patients treated with radiotherapy developed LC in an area within the radiation field. No EGFR mutations were detected in BC tissue and no HER2 expression was detected in LC samples. Conclusion: SPM in the lung and breast occur more frequently among EGFR-mutant compared to EGFR-WT LC patients. Radiotherapy for BC may increase the risk of developing primary LC.
Agonist‐induced desensitisation of β3‐adrenoceptors: Where, when, and how?

β3‐Adrenoceptor agonists have proven useful in the treatment of overactive bladder syndrome, but it is not known whether their efficacy during chronic administration may be limited by receptor‐induced desensitisation. Whereas the β2‐adrenoceptor has phosphorylation sites that are important for desensitisation, the β3‐adrenoceptor lacks these; therefore, it had been assumed that β3‐adrenoceptors are largely resistant to agonist‐induced desensitisation. While all direct comparative studies demonstrate that β3‐adrenoceptors are less susceptible to desensitisation than β2‐adrenoceptors, desensitisation of β3‐adrenoceptors has been observed in many models and treatment settings. Chimeric β2‐ and β3‐adrenoceptors have demonstrated that the C‐terminal tail of the receptor plays an important role in the relative resistance to desensitisation but is not the only relevant factor. While the evidence from some models, such as transfected CHO cells, is inconsistent, it appears that desensitisation is observed more often after long‐term (hours to days) than short‐term (minutes to hours) agonist exposure. When it occurs, desensitisation of β3‐adrenoceptors can involve multiple levels including down‐regulation of its mRNA and the receptor protein and alterations in post‐receptor signalling events. The relative contributions of these mechanistic factors apparently depend on the cell type under investigation. Which if any of these factors is applicable to the human urinary bladder remains to be determined.
First spine surgery utilizing real-time image-guided robotic assistance

Abstract Robotics in spinal surgery has significant potential benefits for both surgeons and patients, including reduced surgeon fatigue, improved screw accuracy, decreased radiation exposure, greater options for minimally invasive surgery, and less time required to train residents on techniques that can have steep learning curves. However, previous robotic systems have several drawbacks, which are addressed by the innovative ExcelsiusGPSTM robotic system. The robot is secured to the operating room floor, not the patient. It has a rigid external arm that facilitates direct transpedicular drilling and screw placement, without requiring K-wires. In addition, the ExcelsisuGPSTM has integrated neuronavigation, not present in other systems. It also has surveillance marker that immediately alerts the surgeon in the event of loss of registration, and a lateral force meter to alert the surgeon in the event of skiving. Here, we present the first spinal surgery performed with the assistance of this newly approved robot. The surgery was performed with excellent screw placement, minimal radiation exposure to the patient and surgeon, and the patient had a favorable outcome. We report the first operative case with the ExcelsisuGPSTM, and the first spine surgery utilizing real-time image-guided robotic assistance.
Occurrence of diseases in fish used for experimental research

The objective of the present study was to evaluate the occurrence of pathogens and diseases in laboratory fish over a 10-year period at the Centre for Experimental Fish Pathology of Sicily, University of Messina. This report also emphasizes the adverse effects of subclinical infections on research endpoints, as well as the importance of animal health with respect to welfare. Infections in fish used for research can alter experimental outcomes, increase the variability of data, and impede experimental reproducibility. For this purpose, 411 diseased fish of different species (out of a total of 2820 fish) that belonged to four marine species (Dicentrarchus labrax, Sparus aurata, Argyrosomus regius and Mugil cephalus) and to four fresh water species (Danio rerio, Carassius auratus, Xiphophorus variatus and Poecilia reticulata) were examined in this study. Our results showed that mycobacteriosis and myxosporidiosis were the most important diseases found in our research fish, and the results represent a useful tool to obtain wider knowledge on the incidence of various diseases in different fish species. Further studies in this field are necessary to improve knowledge on the state of the health of fish used for research.
‘I am dead’: Cotard syndrome and dementia

Abstract Background: Cotard syndrome is a rare condition whose main feature is a nihilistic delusion ranging from the denial of body parts to that of the existence of one’s own life or even the entire universe. Objectives: The aim of this article is to review the nosological significance of Cotard syndrome and to explore the disorder among patients with dementia. Methods: Medline and Google Scholar searches were conducted for relevant articles, chapters and books published before 2018. Search terms used included Cotard delusion, Cotard syndrome and dementia, nihilistic delusion. Publications found through this indexed search were reviewed for further relevant references. Results and conclusion: In this narrative review we emphasise the fact that cases of Cotard syndrome involving patients with dementia are reported quite infrequently. Published studies are limited to very short series or isolated cases. Clinicians are obliged to treat the disorder. They should be alert to the potential high risk inherent in this condition. Keypoints Cotard syndrome is a rare condition characterised by nihilistic delusions that may range from negation of existence of parts of the body to delusion of being dead. The prevalence and incidence of this rare syndrome are not known. Since Cotard’s syndrome is conceptualised as part of an underlying disorder, several psychiatric and somatic diseases have been associated with the syndrome. The syndrome may occur in patients suffering from dementia.
Model-Based Conditional Weighted Residuals Analysis for Structural Model Assessment

Nonlinear mixed effects models are widely used to describe longitudinal data to improve the efficiency of drug development process or increase the understanding of the studied disease. In such settings, the appropriateness of the modeling assumptions is critical in order to draw correct conclusions and must be carefully assessed for any substantial violations. Here, we propose a new method for structure model assessment, based on assessment of bias in conditional weighted residuals (CWRES). We illustrate this method by assessing prediction bias in two integrated models for glucose homeostasis, the integrated glucose-insulin (IGI) model, and the integrated minimal model (IMM). One dataset was simulated from each model then analyzed with the two models. CWRES outputted from each model fitting were modeled to capture systematic trends in CWRES as well as the magnitude of structural model misspecifications in terms of difference in objective function values (ΔOFVBias). The estimates of CWRES bias were used to calculate the corresponding bias in conditional predictions by the inversion of first-order conditional estimation method’s covariance equation. Time, glucose, and insulin concentration predictions were the investigated independent variables. The new method identified correctly the bias in glucose sub-model of the integrated minimal model (IMM), when this bias occurred, and calculated the absolute and proportional magnitude of the resulting bias. CWRES bias versus the independent variables agreed well with the true trends of misspecification. This method is fast easily automated diagnostic tool for model development/evaluation process, and it is already implemented as part of the Perl-speaks-NONMEM software.
Clinical Evaluation of Intravitreal Injection of Ganciclovir in Refractory Corneal Endotheliitis

ABSTRACT Purpose: To evaluate the efficacy and safety of intravitreal ganciclovir (GCV) injection in refractory endotheliitis. Methods: Retrospectively recruited 25 eyes with endotheliitis, proved by clinical manifestations, positive PCR for viral DNA and responded poor to topical and systemic antiviral medications. All patients received additional continued intravitreal GCV injections. Results: Cytomegalovirus (CMV), varicella zoster virus (VZV), and herpes simplex virus (HSV) DNA were detected in 64.0%, 28.0%, and 8.0% of the eyes, respectively. Within 2 weeks after the last injection, 16/25 eyes recovered corneal clarity; active keratic precipitates (KPs) were eliminated in 21/25 eyes; intraocular pressure (IOP) was controlled in 12/15 eyes with elevated IOP on study entry. Best-corrected visual acuity increased at the last follow-up (p = 0.016). Clinical recurrence occurred in three patients. No complications were detected. Conclusions: CMV endotheliitis was the main type of refractory endotheliitis. Despite its invasive nature, intravitreal GCV injection appears to be an effective method for refractory endotheliitis.
Beta band oscillatory deficits during working memory encoding in adolescents with attention‐deficit hyperactive disorder

Attention‐deficit hyperactivity disorder (ADHD) is a neurobehavioural disorder, characterized by symptoms of inattention and/or hyperactivity/impulsivity, in addition to various cognitive deficits, including working memory impairments. This pathology arises from a complex constellation of genetic, structural and neurotransmission abnormalities, which give rise to the aberrant electrophysiological patterns evident in patients with ADHD. Among such, findings have consistently provided support in favour of weaker power across the beta frequency range. Evidence has also emerged that beta rhythmic decrements are linked to working memory encoding. The catecholaminergic modulation of both working memory and beta oscillations may suggest that the link between the two might be rooted at the neurotransmission level. Studies have consistently shown that ADHD involves significant catecholaminergic dysregulation, which is also supported by other clinical studies that demonstrate stimulant‐induced amelioration of ADHD symptomology. In this study, we explore the possible ways that might relate ADHD, working memory, beta rhythms and catecholaminergic signalling altogether by investigating the integrity of encoding‐relevant electroencephalographic beta rhythms in medication‐naïve and stimulant‐medicated adolescent patients. The aberrant parietal and frontal encoding‐related beta rhythm revealed in the ADHD patients together with a working memory (WM) deficit as observed herein was reversed by methylphenidate in the latter case but not with regard to the beta rhythm. This finding per se raises the issue of the role played by beta rhythms in the WM deficits associated with ADHD.
Why do depressed people prefer sad music?

One of the cardinal symptoms of major depressive disorder (MDD) is persistent sadness. Do people with MDD actually prefer sad stimuli, potentially perpetuating their depression? Millgram, Joormann, Huppert, and Tamir (2015) observed such preferences and interpreted them as reflecting a maladaptive emotion regulatory goal to upregulate sad feelings. We assessed emotional music choice among both those with MDD and healthy controls (HC), and assessed the reasons for music preferences in these two groups. Seventy-six female participants (38 per group) completed two tasks: (1) Millgram et al.'s (2015) music task wherein participants listened to happy, neutral, and sad music excerpts and chose the one they wanted to listen to most, and (2) a novel Emotional Music Selection Task (EMST) wherein participants chose preferred music clips, varying in emotion and energy level, in paired-choice trials. In the replication music task, MDD people were more likely to choose sad music. However, inconsistent with any motivation to upregulate sadness, people with MDD reported that they chose sad music because it was low in energy levels (e.g., relaxing). EMST results revealed that MDD people had a stronger preference for both low energy and sad music, relative to HC. The strong appeal of sad music to people with MDD may be related to its calming effects rather than any desire to increase or maintain sad feelings. (PsycINFO Database Record (c) 2019 APA, all rights reserved).
The effect of N‐acetylcysteine supplementation on the oxidative stress levels, apoptosis, DNA damage, and hematopoietic effect in pesticide‐exposed fish blood

Cysteine is important for protein synthesis, detoxification, and diverse metabolic functions. However, cysteine metabolism has been poorly described in fish, and the role of the therapeutic effect in pesticide toxicology on aquatic organisms is unknown. The aim of this study was to determine the effects of regular cysteine treatment on the hematology, biochemistry, apoptosis, oxidative DNA damage, and antioxidant parameters in fish blood after chemical application. Therefore, fish were exposed to cypermethrin for 2 weeks. Then two different concentrations of N‐acetylcysteine (NAC) were applied for a 4‐day treatment period and compared with the group of the self‐healing process. At the end of the treatment, the hematological index, blood biochemical parameters, paraoxonase (PON), arylesterase (ARE), and myeloperoxidase (MPO) activities in the fish blood samples were investigated. With regard to the hematological parameters, statistical differences were obtained except for mean corpuscular hemoglobin (MCH) and mean corpuscular hemoglobin concentration (MCHC) (P < 0.05). Enzyme activities (ARE, PON, and MPO), as well as some biochemical parameters (creatinin [Cre], alanine amino transferase, total glyceride, alkaline phosphatase, iron, calcium, low density lipoprotein‐cholesterol [LDL‐C], sodium, and potassium), were found to be importantly different among all groups at the P < 0.05 level, while 8‐hydroxydeoxyguanosine and caspase‐3 levels were determined to be high in the pesticide group but decreased significantly in NAC‐treated groups ( P < 0.05). According to the results of the study, acute cysteine treatment showed an ameliorative effect on the hematological index, biochemical parameters, PON, MPO, and ARE in the blood in the all the treatment group fish. The positive effect of NAC on protein synthesis, detoxification, and diverse metabolic functions against cypermethrin toxicity was more effective in 1.0 mM NAC. NAC has an important therapeutic effect on pesticide‐induced hematoxicity for fish in terms of all the data.
Evaluation of a wireless contralateral routing of signal (CROS) device with the Advanced Bionics Naída CI Q90 sound processor

Objectives: Cochlear implants (CIs) usually provide severe to profoundly deaf recipients with speech intelligibility in quiet. In difficult listening situations such as background noise however, communication often remains challenging. For unilateral CI recipients with a bilateral hearing loss, speech intelligibility for speech sources on the non-implanted side is further impaired by the head-shadow effect. One possibility to overcome this impairment is the use of Contralateral Routing of Signal (CROS) systems, which capture sounds from the non-implanted side and (wirelessly) transmit them to the implant processor, therefore increasing audibility. Such a CROS system was evaluated in this study. Methods: Speech intelligibility in noise was measured in several spatial listening setups using the Oldenburg matrix sentence test in ten cochlear implant users. Performance was compared between listening with the CI alone and listening with the CI in combination with a wireless CROS device. Following an extended trial phase, subjective feedback regarding the device benefit in everyday life was collected via the Bern Benefit in Single Sided Deafness (BBSS) questionnaire. Results: The addition of the wireless CROS device significantly improved speech intelligibility by 7.2 dB (median) in spatial noise. Using advanced directional microphones, a statistically significant benefit of 4.4 dB (median) could be shown in a diffuse noise field. Responses to the BBSS questionnaire revealed that subjects perceived benefit in their everyday lives when using the CROS device with their CI. Conclusion: The investigated CROS system presents a valuable addition to a unilateral CI in cases where bilateral implantation is not an option.
Novel genes for airway wall thickness identified with combined genome-wide association and expression analyses.

RATIONALE Airway wall thickness (AWT) is affected by both environmental and genetic factors and is strongly associated with airflow limitation in smaller airways. OBJECTIVES To investigate the genetic component of AWT. METHODS AWT was measured on low-dose computed tomography scans in male heavy smokers participating in a lung cancer screening study (n = 2,640). Genome-wide association studies on AWT were performed under an additive model using linear regression (adjusted for pack-years, lung volume), followed by metaanalysis. An independent cohort was used for validation of the most strongly associated single-nucleotide polymorphisms (SNPs). The functional relevance of significant SNPs was evaluated. MEASUREMENTS AND MAIN RESULTS Three significant loci on chromosomes 2q (rs734556; P = 6.2 × 10(-7)) and 10q (rs10794108, P = 8.6 × 10(-8); rs7078439, P = 2.3 × 10(-7)) were associated with AWT and confirmed in the metaanalysis in cohorts with comparable lung function: P values = 4.6 × 10(-8), 7.4 × 10(-8), and 7.5 × 10(-8), respectively. SNP rs734556 was associated with decreased lung tissue expression of SERPINE2, a susceptibility gene for emphysema. Two nominally significant SNPs showed effects with similar direction: rs10251504 in MAGI2 (P = 5.8 × 10(-7)) and rs4796712 in NT5C3B (P = 3.1 × 10(-6)). Higher MAGI2 expression in bronchial biopsies of patients with chronic obstructive pulmonary disease was significantly associated with fewer inflammatory cells. The presence of the NT5C3B risk allele was associated with higher lung tissue expression (P = 1.09 × 10(-41)). CONCLUSIONS Genetic variants contribute to AWT. Among others, the identified genes are also involved in emphysema, airway obstruction, and bronchial inflammation.
Challenges in high-sensitive troponin assay interpretation for intensive therapy

Cardiac troponins T and I are considered highly sensitive and specific markers for the diagnosis of acute myocardial infarction. Currently, a series of nonprimary cardiac abnormalities may manifest as an elevation in high-sensitive assays. The reduction in their detection limits has allowed earlier diagnosis and the use of evidence-based therapeutic measures; however, this characteristic has increased the spectrum of detectable noncoronary heart diseases, which poses challenges for characterizing acute coronary syndromes and creates a new role for these tests in known disorders in intensive care units, especially sepsis. Management of patients through a greater understanding of how these markers behave should be re-evaluated to ensure their correct interpretation.
Levels of Stewart's Wilt Resistance Necessary to Prevent Reductions in Yield of Sweet Corn Hybrids.

Stewart's wilt reactions and yield of a total of 69 sweet corn hybrids were evaluated in trials in 1999 and 2000 in order to determine the level of Stewart's wilt resistance necessary to prevent reduction in yield of sweet corn hybrids. Plants at the 2- to 3-leaf stage were inoculated with Erwinia stewartii using the pinprick method. Stewart's wilt symptoms were rated from 1 to 9, and incidence of systemic infection was determined as a percentage for each experimental unit. Primary ears were harvested about 21 days after midsilk, and yield was measured as ear weight and number of marketable ears. Percent yield was calculated for each hybrid by dividing yield from inoculated treatments by yield from noninoculated treatments and multiplying by 100. Hybrid means for Stewart's wilt ratings in inoculated treatments ranged from 2.0 to 7.3. The relationships between percent yield and Stewart's wilt severity ratings were described best by curvilinear regressions, whereas percent yield decreased linearly with the incidence of systemic infection in 2000. Ear weights of hybrids with ratings below 3 or 3.5 were estimated from the regression equations to be within 95 or 92%, respectively, of those from noninoculated treatments of the same hybrid. The number of marketable ears from hybrids with ratings of 3 or below was estimated from the regression equations to be within 90% of those from noninoculated treatments of the same hybrid. A level of resistance that resulted in Stewart's wilt ratings below 3 or 3.5 corresponded to nonsystemic infection of most plants (i.e., incidence of systemic infection below 5 or 10%, respectively). The adverse effects of Stewart's wilt on ear weight and marketability appeared to be minor for sweet corn hybrids with levels of resistance that prevented or minimized systemic infection.