Miracle-dz/UniFAR-FTUs huggingface dataset:
Heterozygous loss of function of IQSEC2/Iqsec2 leads to increased activated Arf6 and severe neurocognitive seizure phenotype in females

We show that the loss of Iqsec2 function in mice recapitulates key aspects of the human phenotype, irrespective of the X-inactivation status of the gene between species. Our understanding of the traditional X-chromosome inheritance with heterozygous female sparing needs revisiting. Clinical presentations of mutations in the IQSEC2 gene on the X-chromosome initially implicated to cause non-syndromic intellectual disability (ID) in males have expanded to include early onset seizures in males as well as in females. The molecular pathogenesis is not well understood, nor the mechanisms driving disease expression in heterozygous females. Using a CRISPR/Cas9–edited Iqsec2 KO mouse model, we confirm the loss of Iqsec2 mRNA expression and lack of Iqsec2 protein within the brain of both founder and progeny mice. Both male (52%) and female (46%) Iqsec2 KO mice present with frequent and recurrent seizures. Focusing on Iqsec2 KO heterozygous female mice, we demonstrate increased hyperactivity, altered anxiety and fear responses, decreased social interactions, delayed learning capacity and decreased memory retention/novel recognition, recapitulating psychiatric issues, autistic-like features, and cognitive deficits present in female patients with loss-of-function IQSEC2 variants. Despite Iqsec2 normally acting to activate Arf6 substrate, we demonstrate that mice modelling the loss of Iqsec2 function present with increased levels of activated Arf6. We contend that loss of Iqsec2 function leads to altered regulation of activated Arf6-mediated responses to synaptic signalling and immature synaptic networks. We highlight the importance of IQSEC2 function for females by reporting a novel nonsense variant c.566C > A, p.(S189*) in an elderly female patient with profound intellectual disability, generalised seizures, and behavioural disturbances. Our human and mouse data reaffirm IQSEC2 as another disease gene with an unexpected X-chromosome heterozygous female phenotype. Our Iqsec2 mouse model recapitulates the phenotypes observed in human patients despite the differences in the IQSEC2/Iqsec2 gene X-chromosome inactivation between the species.
Design and Performance Evaluation of a Low-Cost Autonomous Sensor Interface for a Smart IoT-Based Irrigation Monitoring and Control System

Irrigation systems are becoming increasingly important, owing to the increase in human population, global warming, and food demand. This study aims to design a low-cost autonomous sensor interface to automate the monitoring and control of irrigation systems in remote locations, and to optimize water use for irrigation farming. An internet of things-based irrigation monitoring and control system, employing sensors and actuators, is designed to facilitate the autonomous supply of adequate water from a reservoir to domestic crops in a smart irrigation systems. System development lifecycle and waterfall model design methodologies have been employed in the development paradigm. The Proteus 8.5 design suite, Arduino integrated design environment, and embedded C programming language are commonly used to develop and implement a real working prototype. A pumping mechanism has been used to supply the water required by the soil. The prototype provides power supply, sensing, monitoring and control, and internet connectivity capabilities. Experimental and simulation results demonstrate the flexibility and practical applicability of the proposed system, and are of paramount importance, not only to farmers, but also for the expansion of economic activity. Furthermore, this system reduces the high level of supervision required to supply irrigation water, enabling remote monitoring and control.
Pilot clinical and validation study of the PROPKD score in clinical practice amongst patients with Autosomal Dominant Polycystic Kidney Disease

1. Millán Díaz B, González Tabarés L, Cobelo Casas C, Cillero Rego S, López Vázquez M, Calviño Varela J. Eikenella corrodens and Prevotella oralis peritonitis in patients on peritoneal dialysis. Nefrologia 2018; 38: 341–2. 2. Nagy E. Anaerobic infections: Update on treatment considerations. Drugs 2010; 70: 841–58. 3. Claridge JE 3rd, Attorri S, Musher DM, Hebert J, Dunbar S. Streptococcus intermedius, Streptococcus constellatus, and Streptococcus anginosus ("Streptococcus milleri group") are of different clinical importance and are not equally associated with abscess. Clin. Infect. Dis. 2001; 32: 1511–5. 4. Mikamo H, Matsumizu M, Nakazuru Y, Nagashima M. Efficacy and safety of metronidazole injection for the treatment of infectious peritonitis, abdominal abscess and pelvic inflammatory diseases in Japan. J. Infect. Chemother. 2015; 21: 96–104.
White Matter Microstructural Change Contributes to Worse Cognitive Function in Patients With Type 2 Diabetes

Patients with type 2 diabetes mellitus (T2DM) have a considerably high risk of developing dementia, especially for those with mild cognitive impairment (MCI). The investigation of the microstructural change of white matter (WM) between T2DM with amnesic MCI (T2DM-aMCI) and T2DM with normal cognition (T2DM-NC) and their relationships to cognitive performances can help to understand the brain variations in T2DM-related amnesic cognitive impairment. In the current study, 36 T2DM-aMCI patients, 40 T2DM-NC patients, and 40 healthy control (HC) individuals underwent diffusion tensor image and T1-weighted MRI scans and comprehensive cognition assessments. All of these cognitive functions exhibited intergroup ranking differences in patients. The T2DM-NC patients and HC individuals did not reveal any significant differences in WM integrity. The T2DM-aMCI patients showed disrupted integrity in multiple WM tracts compared with HC and T2DM-NC. Specifically, the damaged WM integrity of the right inferior fronto-occipital fasciculus and the right inferior longitudinal fasciculus exhibited significant correlations with episodic memory and attention function impairment in T2DM patients. Furthermore, cognitive impairment-related WM microstructural damage was associated with the degeneration of cortex connected to the affected WM tract. These findings indicate that degeneration exists extensively in WM tracts in T2DM-aMCI, whereas no brain WM damage is evident in T2DM-NC.
Model Performance Metrics in Assessing the Value of Adding Intraoperative Data for Death Prediction: Applications to Noncardiac Surgery

We tested the value of adding data from the operating room to models predicting in-hospital death. We assessed model performance using two metrics, the area under the receiver operating characteristic curve (AUROC) and the area under the precision-recall curve (AUPRC), to illustrate the differences in information they convey in the setting of class imbalance. Data was collected on 74,147 patients who underwent major noncardiac surgery and 112 unique features were extracted from electronic health records. Sets of features were incrementally added to models using logistic regression, naïve Bayes, random forest, and gradient boosted machine methods. AUROC increased as more features were added, but changes were small for some modeling approaches. In contrast, AUPRC, which reflects positive predicted value, exhibited improvements across all models. Using AUPRC highlighted the added value of intraoperative data, not seen consistently with AUROC, and that with class imbalance AUPRC may serve as the more clinically relevant criterion.
Inpatient Palliative Care Consult: A Marker for High Risk of Readmission or Death in Discharged Oncology Inpatients

Background: Emergency department visits or readmission to hospital are common particularly among those with advanced illness. Little prospective data exist on early outcomes specifically for patients seen by a palliative care consult service during their acute care admission, who are subsequently discharged home. Methods: This study followed 62 oncology patients who had had a palliative care consult during their admission to acute care with weekly phone calls postdischarge for 4 weeks. Events recorded included death, readmission, emergency department visits, and admission to a palliative care unit. Results: By the end of the study, 32 (52%) of 62 had had at least 1 event, (readmission, emergency department visit, or death), with the majority of these occurring in the first 2 weeks postdischarge. The overall 4-week death rate was 14 (22.6%) of 62. Conclusions: These data suggest that the need for a palliative care consult identifies inpatients at very high risk for early deterioration and underlines the critical importance of advance care planning/goals-of-care discussions by the oncology and palliative care teams to ensure patients and families understand their disease process and have the opportunity to direct their care decisions.
Clinical Controversy in Transplantation: Tacrolimus Versus Cyclosporine in Statin Drug Interactions

Objective: To review the available literature that provides evidence for the absence of statin interactions with tacrolimus compared with cyclosporine. Data Sources: A literature search of PubMed was performed (1990 to June 2019) using the following search terms: calcineurin inhibitors, tacrolimus, cyclosporine, statins, atorvastatin, simvastatin, and drug interactions. Clinical practice guidelines, article bibliographies, drug interaction database references, and product monographs were also reviewed. Study Selection and Data Extraction: Relevant English-language studies describing the mechanism of interaction, the magnitude of pharmacokinetic alterations, and safety were evaluated. In vitro data and studies conducted in adult humans were considered. Data Synthesis: Studies demonstrate pharmacokinetic differences between cyclosporine and tacrolimus, particularly with regard to inhibition of 2 hepatic transporters: P-glycoprotein and organic anion transporting polypeptide (OATP). Compared with cyclosporine, tacrolimus does not affect these transporters, does not enhance statin exposure, and does not increase statin-associated safety events. Relevance to Patient Care and Clinical Practice: Clinical practice guidelines allude to the need to reduce statin doses in the setting of tacrolimus. Some providers have adopted this practice, and doing so may prevent transplant recipients from attaining cardiovascular benefit, especially when increased or high-intensity doses are required. The pharmacokinetic differences between tacrolimus and cyclosporine highlight different interaction potential with statins. Conclusions: Clinicians need to be aware that tacrolimus and cyclosporine are not the same with regard to causing drug interactions with statins. Tacrolimus can be used with statins without the need for dose adjustments because of lack of an interaction.
An approach for vascular tumor growth based on a hybrid embedded/homogenized treatment of the vasculature within a multiphase porous medium model

The aim of this work is to develop a novel computational approach to facilitate the modeling of angiogenesis during tumor growth. The preexisting vasculature is modeled as a 1D inclusion and embedded into the 3D tissue through a suitable coupling method, which allows for nonmatching meshes in 1D and 3D domain. The neovasculature, which is formed during angiogenesis, is represented in a homogenized way as a phase in our multiphase porous medium system. This splitting of models is motivated by the highly complex morphology, physiology, and flow patterns in the neovasculature, which are challenging and computationally expensive to resolve with a discrete, 1D angiogenesis and blood flow model. Moreover, it is questionable if a discrete representation generates any useful additional insight. By contrast, our model may be classified as a hybrid vascular multiphase tumor growth model in the sense that a discrete, 1D representation of the preexisting vasculature is coupled with a continuum model describing angiogenesis. It is based on an originally avascular model which has been derived via the thermodynamically constrained averaging theory. The new model enables us to study mass transport from the preexisting vasculature into the neovasculature and tumor tissue. We show by means of several illustrative examples that it is indeed capable of reproducing important aspects of vascular tumor growth phenomenologically.
The Importance of the Social Sciences in Reducing Tail Biting Prevalence in Pigs

Simple Summary Tail lesions are a major welfare concern within pig farming. Tail lesions result from biting and chewing of the tail of one pig by another and can indicate boredom and frustration within the herd. While extensive research has been carried out to understand and eliminate tail biting in pigs, findings from scientific studies have often not been applied in practice. This may be due, in part, to a failure to consider the role of farmer behaviour in improving animal welfare. If farmer behaviour does not change, it is unlikely that tail lesion prevalence will change from current levels. In this paper, the shortcomings of traditional behaviour change theories were discussed and a guide for designing human behaviour change interventions for pig farmers was provided. It is essential that collaborations between social scientists and animal welfare scientists occur if research findings are to be put into practice on farms. Abstract Tail biting in pigs has been recognised as a welfare problem for several decades, being referred to in scientific literature as far back as the 1940s. Today, animal welfare scientists have a solid understanding of the aetiology of tail biting. Despite this, there has been a major failure in applying research findings on commercial farms. Consequently, tail biting remains a significant problem in modern intensive pig farming. Of all farming industry stakeholders, farmers have the greatest influence over the welfare of their animals. Despite this, little animal welfare research has focused on changing farmer behaviour. Understanding the reasons why farmers act or fail to act to improve animal welfare is key if research findings are to be translated into practical on-farm change. Adopting the principles of behavioural science, this review discussed theory-based methods of identifying barriers to effective tail biting management. A guide was provided for designing behaviour change interventions for farmers using The Behaviour Change Wheel, a systematic framework that links the source of behaviour to suitable interventions. It was concluded that the social sciences are of great importance to ensuring that theory is put into practice.
GLOBAL REACH 2018: REDUCED FLOW-MEDIATED DILATION STIMULATED BY SUSTAINED INCREASES IN SHEAR STRESS IN HIGH-ALTITUDE EXCESSIVE ERYTHROCYTOSIS.

Excessive erythrocytosis (EE; hemoglobin concentration [Hb] ≥21 g dl-1 in adult males) is a maladaptive high-altitude pathology associated with increased cardiovascular risk and reduced reactive hyperemia flow-mediated dilation; however, whether a similar impairment occurs in response to more commonly-encountered sustained increases in shear stress (SS-FMD) over a range of overlapping stimuli is unknown. We characterized SS-FMD in response to handgrip exercise in Andeans with and without EE in Cerro de Pasco, Peru (4330 m). Andean highlanders with (n=17, Hb=23.2±1.2 g dl-1) and without EE (n=23, Hb=18.7±1.9 g dl-1) performed three-minutes of rhythmic handgrip exercise at 20%, 35%, and 50% of maximum voluntary contraction (MVC). Duplex ultrasound was used to continuously record blood velocity and diameter in the brachial artery, and blood viscosity was measured to accurately calculate shear stress. Although baseline shear stress did not differ, Andeans with EE had 22% lower shear stress than Andeans without at 50% MVC (P=0.004). At 35% and 50% MVC, SS-FMD was 2.1±2.0% and 2.8±2.7% in Andeans with EE compared to 4.1±3.4% and 7.5±4.5% in those without (P=0.048 and P<0.001). The stimulus-response slope (∆shear stress versus ∆diameter) was lower in Andeans with EE compared to Andeans without (P=0.028). This slope was inversely related to Hb in Andeans with EE (r2=0.396, P=0.007). A reduced SS-FMD in response to small muscle mass exercise in Andeans with EE indicates a generalized reduction in endothelial sensitivity to shear stress, which may contribute to increased cardiovascular risk in this population.
Maxwell®: An Unsupervised Learning Approach for 5P Medicine

In the 5P medicine (Personalized, Preventive, Participative, Predictive and Pluri-expert), the general trend is to process data by displacing the barycenter of the information from hospital centered systems to the patient centered ones through his personal medical records. Today, the use of artificial intelligence for supporting this transition shows real limitations in its implementation in operational practice, both at the level of patient care, but also in the general daily life of the health professional, because of the medico-legal imperatives induced by the promises of the '5P medicine'. In this paper, we propose to fill this gap by introducing an original artificial intelligence platform, named Maxwell, which follows an unsupervised learning approach in line with the medico-legal imperatives of the '5P medicine'. We describe the functional platform characteristics and illustrate them by two examples of clustering in genomics and magnetic resonance imaging.
Online Support Groups as a Source of Empowerment for People with Type 2 Diabetes

People with Type 2 Diabetes (T2D) control much of their illness by making daily decisions regarding their health behaviours. They require certain skills, information, and support, which might not be obtainable from healthcare providers, and they may seek support through other media, such as online support groups (OSGs). This study seeks to understand the role of OSGs in empowering people with T2D by thematically analysing threads and posts from two UK OSGs.
Generation of Surrogates for De-Identification of Electronic Health Records

Unstructured electronic health records are valuable resources for research. Before they are shared with researchers, protected health information needs to be removed from these unstructured documents to protect patient privacy. The main steps involved in removing protected health information are accurately identifying sensitive information in the documents and removing the identified information. To keep the documents as realistic as possible, the step of omitting sensitive information is often followed by replacement of identified sensitive information with surrogates. In this study, we present an algorithm to generate surrogates for unstructured electronic health records. We used this algorithm to generate realistic surrogates on a Health Science Alliance corpus, which is constructed specifically for the use of development of automated de-identification systems.
Developing Customizable Cancer Information Extraction Modules for Pathology Reports Using CLAMP

Natural language processing (NLP) technologies have been successfully applied to cancer research by enabling automated phenotypic information extraction from narratives in electronic health records (EHRs) such as pathology reports; however, developing customized NLP solutions requires substantial effort. To facilitate the adoption of NLP in cancer research, we have developed a set of customizable modules for extracting comprehensive types of cancer-related information in pathology reports (e.g., tumor size, tumor stage, and biomarkers), by leveraging the existing CLAMP system, which provides user-friendly interfaces for building customized NLP solutions for individual needs. Evaluation using annotated data at Vanderbilt University Medical Center showed that CLAMP-Cancer could extract diverse types of cancer information with good F-measures (0.80-0.98). We then applied CLAMP-Cancer to an information extraction task at Mayo Clinic and showed that we can quickly build a customized NLP system with comparable performance with an existing system at Mayo Clinic. CLAMP-Cancer is freely available for academic use.
DHA-SBT-1214 Taxoid Nanoemulsion and Anti–PD-L1 Antibody Combination Therapy Enhances Antitumor Efficacy in a Syngeneic Pancreatic Adenocarcinoma Model

The goal of this study was to evaluate combination of a novel taxoid, DHA-SBT-1214 chemotherapy, in modulating immune checkpoint marker expression and ultimately in improving antibody-based checkpoint blockade therapy in pancreatic adenocarcinoma (PDAC). DHA-SBT-1214 was encapsulated in an oil-in-water nanoemulsion and administered systemically in Panc02 syngeneic PDAC-bearing C57BL/6 mice. Following treatment with DHA-SBT-1214, expression levels of PD-L1 were measured and anti–PD-L1 antibody was administered in combination. The effects of combination therapy on efficacy and the molecular basis of synergistic effects were evaluated. PD-L1 expression was lower on Panc02 pancreatic tumor cells in vitro, which significantly increased after exposure to different chemotherapy drugs. Administration of DHA-SBT-1214, gemcitabine, and PD-L1 antibody alone failed to increase CD8+ T-cell infiltration inside tumors. However, combination of anti–PD-L1 therapy with a novel chemotherapy drug DHA-SBT-1214 in nanoemulsion (NE-DHA-SBT-1214) significantly enhanced CD8+ T-cell infiltration and the therapeutic effects of the anti–PD-L1 antibody. Furthermore, in the Panc02 syngeneic model, the NE-DHA-SBT-1214 combination therapy group reduced tumor growth to a higher extend than paclitaxel, nab-paclitaxel (Abraxane), gemcitabine, or single anti–PD-L1 antibody therapy groups. Our results indicate that NE-DHA-SBT-1214 stimulated immunogenic potential of PDAC and provided an enhanced therapeutic effect with immune checkpoint blockade therapy, which warrants further evaluation.
The MCTP-SNARE Complex Regulates Florigen Transport in Arabidopsis

Endosomal trafficking mediated by the MCTP-SNARE complex is essential for the export of florigen from phloem companion cells to sieve elements to induce flowering in Arabidopsis. Multiple flowering pathways in Arabidopsis (Arabidopsis thaliana) converge on the transcriptional regulation of FLOWERING LOCUS T (FT), encoding a mobile floral stimulus that moves from leaves to the shoot apex. Despite our progress in understanding FT movement, the mechanisms underlying its transport along the endoplasmic reticulum–plasmalemma pathway in phloem companion cells remain largely unclear. Here, we show that the plasma membrane–resident syntaxin-like glutamine-soluble N-ethylmaleimide-sensitive factor protein attachment protein receptor (Q-SNARE), SYNTAXIN OF PLANTS121 (SYP121), interacts with QUIRKY (QKY), a member of the family of multiple C2 domain and transmembrane region proteins (MCTPs), to mediate FT transport in Arabidopsis. QKY and SYP121 coordinately regulate FT movement to the plasmalemma through the endosomal trafficking pathway and are required for FT export from companion cells to sieve elements, thus affecting FT transport through the phloem to the shoot apical meristem. These findings suggest that MCTP-SNARE complex-mediated endosomal trafficking is essential for the export of florigen from phloem companion cells to sieve elements to induce flowering.