Miracle-dz/UniFAR-FTUs huggingface dataset:
Venetoclax Is Synergistic with Idelalisib or MK2206 Against Primary CLL Cells in an in Vitro Model of the Microenvironment

Background The PI3-kinase signaling pathway and the Bcl-2-family of proteins play crucial roles in regulating the survival and proliferation of chronic lymphocytic leukemia (CLL) cells in the bone marrow and lymph nodes. Trials of ibrutinib, idelalisib and venetoclax illustrate the potential of targeting the B-cell receptor (BCR) signaling pathway and Bcl-2, however disease relapse is still common. Several pre-clinical studies and on-going clinical trials [Rogers et al., 2018, Jain et al., 2019] suggest that combinations of BCR inhibitors with venetoclax may be an effective treatment strategy for CLL patients with high risk disease. We sought to investigate the effects of combining idelalisib or the AKT inhibitor MK2206 with venetoclax against CLL cells under in vitro conditions that mimic the tumor microenvironment. Methods Primary CLL cells were co-cultured with CD40L-expressing mouse L-fibroblasts. Cell viability was assessed using the mitochondrial membrane potential dye DilC1(5), propidium iodide and flow cytometry (n = 6). Synergy between idelalisib or MK2206 and venetoclax was evaluated by calculating combination indices (CI) using the Compusyn software. The mechanisms of action of the drugs and synergies between the drugs were investigated by immunoblotting (n = 6). Results Venetoclax was highly synergistic in combination with idelalisib or MK2206 against CLL cells co-cultured with CD40L-fibroblasts, with CI values of 0.2 and 0.5 at a fractional effect of 0.9, respectively (Figure 1). This synergy was consistent with a significant (P < 0.05) reduction in the IC50 for venetoclax, idelalisib and MK2206. Immunoblotting suggests that MK2206, as a single agent or in combination with venetoclax, was more effective than idelalisib in inhibiting the phosphorylation of AKT and NF-κB. Both MK2206 and idelalisib as single agents and in combination with venetoclax significantly reduced expression of Mcl-1 and Bfl-1, two pro-survival members of the Bcl-2 family of proteins in primary CLL cells co-cultured with CD40L-fibroblasts. Conclusions The synergy observed, which was associated with a significant decrease in the IC50s for idelalisib and MK2206, may mitigate some of the toxicities associated with PI3-kinase pathway inhibitors. Comparison of the two PI3-kinase-pathway inhibitors suggests that MK2206 may be more effective than idelalisib at blocking BCR-mediated signaling as a single agent and in combination with venetoclax. The mechanisms underlying the synergy include down-regulation of expression of Bcl-2 family proteins that are not targeted by venetoclax as a single agent. The data presented support the rationale for on-going and future clinical trials of combination therapies incorporating a PI3-kinase inhibitor with venetoclax for the treatment of high risk CLL. Figure 1 No relevant conflicts of interest to declare.
Brain Anomalies in Children with Severe Factor VIII Deficiency- a Pilot Study

Introduction: Bleeding resulting from factor VIII deficiency (hemophilia A) can occur in any tissue including the brain. While significant progress has been made in prevention and treatment of hemophilia-related joint and muscle disease with prophylaxis, there is a paucity of research to understand, treat, or prevent brain disease in hemophilia patients. People with hemophilia are recognized to be at risk for neuropsychiatric and neurocognitive disorders even when treated with factor VIII (FVIII) primary prophylaxis. This is especially problematic given that brain injury is difficult to detect early, and consequences are often delayed. Therefore, our study aims to evaluate brain structure and cognitive function in pediatric patients with severe FVIII deficiency in order to improve outcomes. Methods: After IRB approval, a single-center pilot study enrolled seven pediatric subjects with severe FVIII deficiency and 23 healthy controls to evaluate brain structure and function. Inclusion criteria included males aged 6 - 16 years. All subjects with severe hemophilia A had a FVIII level of less than 1% completed at the Iowa Hemophilia and Thrombosis Center. Any subject was excluded due to a known diagnosis of traumatic brain injury, brain tumor, major chromosomal anomalies, or intellectual disability. Subjects with a known diagnosis of intracranial hemorrhage or FVIII inhibitor were excluded. Neurocognitive assessments included the Behavioral Regulation Index of Executive Function (BRIEF) which measures executive function. Magnetic resonance imaging sequences included T1, T2, and diffusion tensor imaging. Freesurfer and Brain Research: Analysis of Images, Networks, and Systems (BRAINS2) software were used to preprocess imaging and generate volumetric data. Results: Mean age for PWH was 10.4 years and 11.8 years for controls (p = 0.24). Both groups had similar height, weight, and socioeconomic status. Despite normal IQ, PWH demonstrate impaired behavior regulation and globally impaired executive composition compared to controls (p = 0.001 and p = 0.038, respectively). Volumetric brain quantification revealed subjects with hemophilia had decreased whole brain volumes compared to controls (p = 0.019). Our analysis suggests that these differences are in discrete regions. Future analysis will investigate if volumetric differences correlate with neurocognitive assessments. Conclusions: PWH demonstrated abnormal brain structure and function compared to healthy controls. Further evaluation is warranted to understand why and how FVIII deficiency and its treatment alter neurological outcomes. Staber: UniQure: Honoraria; Genentech: Honoraria; Bayer: Honoraria; Spark: Honoraria; Novo Nordisk: Honoraria.
Attitudes, Knowledge and Practice of Herbal Remedy Use among the Population Visiting Pharmacies and Health Care Providers in Alexandria, Egypt: A Cross-Sectional Study

Aims: To show the levels of awareness, attitude, practices and socioeconomic factors related to consuming herbal products among Alexandrian citizen visiting pharmacies. The findings of this study are meant also to show the practices and beliefs of healthcare providers regarding using herbal remedies in treatment, including advising patients, reporting adverse effects and possessing knowledge about specific herb-drug interactions. Study Design: people visiting pharmacies as well as pharmacists in their pharmacies and physicians in their clinics were invited to complete a questionnaire about their knowledge and personal experience in the consumption of herbal remedy. Anonymity was guaranteed. Questionnaire consists of three parts: demographic data, personal experience and a part concerning health care providers. Original Research Article Fathy et al.; EJMP, 30(2): 1-10, 2019; Article no.EJMP. 52613 2 Place and Duration of Study: Study area is the city of Alexandria, Egypt from the 1 st July through September 2018. Methodology: This is a descriptive cross-sectional study that used a self-administered, questionnaire from 213 participants (153+ 60 health care providers HCPs). Results: Almost half the respondents preferred to be treated with herbs because they believed that herbs are safe. But they are not the proper choice to cure chronic diseases. Only 25% of herb users recorded suffering from side effects. The most common source of information about herbs was via internet, followed by family and friends, television and other types of media. Herbal remedies were purchased mainly from outlets other than pharmacies. The willingness to buy such products was not affected by participants’ education level or their monthly income. The public didn’t feel it’s important to mention any herbal remedy they consume to their physician; similarly HCPs did not ask them. Generally, it was shown that HCPs have inadequate knowledge about herbs. Conclusion: The prevalence of herb usage is moderate among the Alexandrian population. And it is imperative to educate HCPs about the benefits, risks and interactions of herbal supplements.
Social Media Use By People With Diabetes In Saudi Arabia: A Survey About Purposes, Benefits And Risks

Purpose The aim of this study was to analyze the use of social media by people with diabetes in Saudi Arabia and to know the purposes, benefits and risks of its use. Methods In this study a cross-sectional survey was carried out with a random sample of 158 people with all type of diabetes living in Saudi Arabia. The survey was distributed using WhatsApp and Twitter accounts of diabetic associations in Saudi Arabia. Descriptive statistics was used to analyze the data. Results The majority of the respondents were females (69%), and most of them had type 1 diabetes (70%). Almost half (47%) of the sampled population stated that they used social media for obtaining information related to diabetes; 34% employed these platforms to get information not linked to diabetes; and the rest, 19%, were not users of social media. Also, the participants used these tools for different purposes; and the most used social media for obtaining diabetes related information were WhatsApp (67%), Twitter (54%) and Snapchat (39%). The principal benefits involved in the utilization of social media were raising awareness about diabetes (78%), improving education among patients (78%), and facilitation of communication between patients and doctors (44%). The respondents pondered that breaching of patient privacy (5%) and dissemination of inaccurate information (30%) were dangers implicated in the use of social media. Conclusion The outcomes indicated that WhatsApp was the social media most used by the participants to communicate and obtain information about diabetes. According to the participants, social media platforms were useful to improve education, awareness and communication among people with diabetes, family and doctors. However, due to the risks involved in the use of social media, health and educational organizations must work to ensure that the published information is accurate and does not affect the privacy of patients and healthcare providers.
Study of Malnutrition Factors in Market Gardeners Children in Burkina Faso: Case of Drinking Water and Intestinal Parasitic

Malnutrition, intestinal parasitic infections and diarrheal diseases are public health problems in children in lowand middle-income countries (Prüss et al., 2014; WHO, 2015). After malaria, diarrheal diseases and malnutrition are the second cause of death in children under the age of 5in Burkina Faso (Somé, 2011). In the western central region, International Journal of Current Microbiology and Applied Sciences ISSN: 2319-7706 Volume 8 Number 10 (2019) Journal homepage: http://www.ijcmas. com
Inflammation and Preclinical AD: Associations between Peripheral Inflammatory Biomarkers, Cognition, and Amyloid-B deposition in Non-demented Older Adults

The central role of inflammatory processes in the development of beta-amyloid (Aβ) pathology has been widely shown in rodent models, but has yet to be elucidated in humans, particularly prior to the onset of clinical symptoms. We examined associations between peripheral inflammatory mediators, cognition, and two neuroimaging Alzheimer’s disease (AD) biomarkers, Aβ plaques and hippocampal atrophy, in non-demented older adults. Cross-sectional and longitudinal data were used to assess associations between peripheral inflammatory biomarkers (soluble CD14, TNF-α receptor concentrations, and IL-6) and memory performance on the California Verbal Learning Test (CVLT) and Rey-Osterrieth Complex Figure Test in 173 non-demented older adults. Of these 173 participants, 134 were cognitively normal (CN) and 34 had MCI. Ninety of these participants underwent repeated assessments at 24 months. Structural MRI and Pittsburgh compound B-PET imaging were used to quantify hippocampal volume and Aβ plaque deposition. After adjusting for demographics, linear regression analysis revealed that higher levels of TNF-α and IL-6 predicted poorer global and verbal memory performance in the full sample, and the CN subsample. Elevated concentrations of pro-inflammatory markers were also associated with higher global Aβ deposition, specifically among those that also exhibited greater hippocampal atrophy. Secondary analysis using template-derived regions of interest showed that these moderation effects were specific to PiB uptake in the anterior cingulate gyrus, frontal cortex, and precuneus. These associations remained after adjusting for hypertension, diabetes, heart disease and white matter lesions (all p<0.05). Furthermore, higher levels of circulating IL-6 predicted subsequent conversion to MCI and increased longitudinal accumulation of Aβ pathology in regions susceptible to early amyloid deposition. Hippocampal volume moderated the association between inflammatory markers and Aβ deposition, suggesting potential disease-state-dependent differences in peripheral inflammatory profiles during the preclinical phase of AD. These findings highlight potential protein signatures that may vary depending on the prodromal phase of disease progression, and could help identify those in specific preclinical stages. from CN to MCI. Moreover, chronic, low-level systemic inflammation may accelerate the deposition of Aβ pathology and, consequently, place individuals at a higher risk of developing clinically significant cognitive impairment.
How does race and ethnicity effect the precision treatment of asthma?

ABSTRACT Introduction: Asthma is a common condition that affects large numbers of children and adults, yet the burden of disease is not equally distributed amongst groups. In the United States, African Americans and Puerto Ricans have higher rates of asthma and its complications when compared with European Americans. However, clinical trials and genetic studies have largely focused on the latter group. Areas covered: Here we examine what is known regarding differences in asthma treatment response by race-ethnicity. We also review existing genetic studies related to the use of asthma medications, paying special attention to studies that included substantial numbers of nonwhite population groups. Publicly accessible search engines of the medical literature were queried using combinations of the terms asthma, race, ethnicity, pharmacogenomics, and pharmacogenetics, as well as the names of individual asthma medication classes. The list of articles reviewed was supplemented by bibliographies and expert knowledge. Expert opinion: A substantial and coordinated effort is still needed to both identify and validate genetic biomarkers of asthma medication response, as currently there are no clinically actionable genetic markers available for this purpose. The path to identifying such markers in nonwhite populations is even more formidable, since these groups are underrepresented in existing data.
A promising and low-cost prototype to evaluate the motor pattern of nutritive and non-nutritive suction in newborns

Introduction: Non-nutritive sucking (NNS) plays an important role in stabilizing the preterm, providing oral muscle training opportunity for nutritive sucking (NS). We aim to determine if the prototype tested allows a precise evaluation of suction pattern characteristics (rhythmic structure and pressure). We also aim to investigate the role of maturation in the variation of NNS an NS pattern in preterm infants. Methods: The patented prototype is non-invasive, low-cost and easily applicable to clinical ecological practice, measures the pressure exerted on a pacifier in newborn’s mouth. Samples were acquired continuously during a 10-minute period in 12 preterm (mean gestational age [GA] 29.9 ± 1.6 weeks) and 4 term neonates (GA 39.5 ± 1.4 weeks). Bursts, suctions per burst, pauses, suction frequency and pressure were analyzed to describe temporal structure and dynamic characteristics of NNS. Results: The NNS pattern was characterized by bursts duration 4.3 ± 2.2 s, number of sucks per burst 7.4 ± 3.2, sucking frequency 2.1 ± 0.4 Hz and sucking pressure 10.3 ± 4.5 mmHg. There were significant differences between the preterm and term groups in NNS sucking frequency (2.1 Hz vs 1.6 Hz; p = 0.008). Conclusion: The device is non-invasive and can easily be used in clinical practice in low GA newborns, in an ecological environment. It allows the evaluation of NNS patterns maturation and, at the same time, the use of the device pacifier promotes NNS, which is important in the process of acquiring feeding autonomy in preterm infants.
Klasifikasi Penyakit Chronic Kidney Disease (CKD) Dengan Menggunakan Metode Extreme Learning Machine (ELM)

Ginjal merupakan organ penting yang berfugsi untuk menjaga komposisi darah dengan mencegah menumpuknya limbah dan mengendalikan keseimbangan cairan di dalam tubuh. Chronic Kidney Disease (CKD) merupakan salah satu penyakit pada ginjal yang disebabkan oleh infeksi pada ginjal dan juga penyumbatan yang disebabkan oleh batu ginjal. Dalam kasus ini tenaga medis maupun pakar masih belum maksimal di dalam mengklasifikasikan penyakit CKD, penulis menerapkan metode Extreme Learning Machine (ELM) pada persoalan klasifikasi penyakit CKD. ELM adalah salah satu metode klasifikasi jaringan saraf tiruan yang memiliki learning speed yang cepat dan berdasarkan penelitian sebelumnya memiliki nilai akurasi yang baik dibandingkan dengan metode yang ada dalam jaringan saraf tiruan. Pada penelitian ini didapatkan perbandingan data latih dan data uji yang optimal dengan rasio 70:30 dan jumlah hidden neuron sebanyak 50 hidden neuron menghasilkan nilai akurasi sebesar 96,7%. Dapat disimpulkan bahwa metode Extreme Learning Machine (ELM) cukup baik diimplementasikan untuk proses klasifikasi penyakit Chronic Kidney Disease (CKD).
Do Febrile Seizures Influence Neurodevelopment?

Objective: Families are often concerned that febrile seizures may have negative effects on the neurodevelopment of their children. The aim of our study was to demonstrate the effects of febrile seizure on the neurodevelopment in children using the Denver Developmental Screening Test II (DDST). Materials and Methods : This cross-sectional and prospective study included 28 patients hospitalized for febrile seizures during a six-month period. The children's age, sex, number of seizures, number of recurrences, and family history of seizure were recorded. The DDST was performed at admission (1 st DDST) and one year later (2 nd DDST). The results were evaluated in three categories as ‘normal,’ ‘suspicious,’ and ‘abnormal. ’ Results: The 1 st DDSTs were found as normal, suspicious, and abnormal at the rates of 53.6%, 39.3%, and 7.1%, respectively. The 2 nd DDST’s were normal, suspicious, and abnormal at the rates of 67.9%, 28.6%, and 3.6%, respectively. Fourteen of the 15 found as normal were normal, but 1 was suspicious. Six of the 11 found as suspicious remained suspicious, 4 were normal, and 1 was abnormal. One of the 2 patients found as abnormal was normal, the other was suspicious. There were no significant differences between the scores of the 1 st and 2 nd DDSTs (p=0.423). Conclusion: We found that febrile seizures were not associated with neurodevelopmental delay when using the DDST II. According to the results of this study, it may be possible to reassure parents about the normal neurodevelopment expectations for their children despite having febrile seizures.
Aspirin for primary prevention of cardiovascular disease: Advice for a decisional strategy based on risk stratification

The need for aspirin therapy as part of primary prevention of cardiovascular (CV) disease is currently being highly debated, especially after 3 studies in different settings reported that a reduction in ischemic events is largely counterbalanced by an increase in bleeding events. One possible explanation for these results is the progressive reduction in the risk of major adverse cardiovascular events (MACE) as a result of primary prevention, which has accompanied global education programs that have led to patients smoking less, exercising more, and increasingly undertaking lipid-lowering therapies. Based on a meta-regression of the benefits and harmful effects of aspirin therapy in primary prevention as a function of the 10-year risk of MACE, we favor a differentiated and personalized approach that acknowledged differences between patients and emphasized an individualized assessment of benefits and risks. Following general preventive measures (physical exercise, cessation of smoking, treatment of hypertension and hypercholesterolemia, etc.), an individualized approach to prescribing aspirin is still warranted. When patients are less than 70 years of age, clinicians should assess the 10-year CV risk. Aspirin treatment should be considered only when the CV risk is very high and the bleeding risk is low, after taking into account the patient’s preferences.
In Situ Simulation for Ventilator Management in Emergency Medicine

Emergency physicians have a residency graduation milestone to effectively manage the airway and initiate mechanical ventilation. However, many emergency medicine (EM) residents report rarely or never feeling comfortable managing mechanically ventilated patients. Our goal was to determine the effectiveness of an in situ simulation program for EM residents to successfully manage a ventilator on a high‐fidelity patient simulator.
The histopathological landscape of the major psoriasiform dermatoses

Abstract Psoriasiform dermatoses represent a wide spectrum of inflammatory conditions, with several major forms represented by psoriasis, as the prototype of this category, followed by pustular psoriasis, Reiter’s syndrome, pityriasis rubra pilaris, lichen simplex chronicus and large-plaques parapsoriasis. They create a diagnostic challenge, both clinical and histopathological, because of their complexity and frequent overlapping of the microscopical features. The characteristic histopathological features of psoriasiform reaction comprise extensive hyperkeratosis, with horizontally confluent but vertically intermittent parakeratosis, which alternate with orthokeratosis, thin granular layer, with relative frequent mitoses, uniform elongated and fused rete ridges, edematous superficial papillary dermis, with dilated capillaries, perivascular lymphocytic infiltrate, Munro’s microabscesses, and spongiform pustules of Kogoj. Our paper aims to review the histopathology of major form of psoriasiform dermatoses and to emphasize the characteristic microscopical differences between them, for a better approach of the diagnosis as an important key for clinical and therapeutical management. Using the clinicopathological correlations, a thoroughly evaluation of the microscopical features and compartments distribution or special stainings and techniques, the range of differential diagnosis can be decreased and a more accurate diagnostic can be usually achieved. The insights into the pathogenic mechanisms can lead to new therapeutic opportunities targeted to the specific type of inflammatory lesion.