Miracle-dz/UniFAR-FTUs huggingface dataset:
Neurocognitive functioning of HIV positive children attending the comprehensive care clinic at Kenyatta national hospital: exploring neurocognitive deficits and psychosocial risk factors

ABSTRACT Children and adolescents are affected in different ways by HIV/AIDS. Neurocognitive deficits are one of the most significant long term effects on HIV infected children and adolescents. Several factors are thought to influence cognitive outcomes and this include immune status, Highly Active Antiretroviral Therapy (HAART), education and social support. The aim of the study was to assess the neurocognitive function of HIV infected children and adolescents and correlate it with psychosocial factors. A cross sectional study was carried out involving a sample of 90 children living with HIV between 8 and 15 years (M = 11.38, SD = 2.06) attending Comprehensive Care Clinic (CCC) at Kenyatta National Hospital (KNH). Samples were selected by using purposive sample technique. Kaufman Assessment Battery for Children-Second Edition was used to assess cognitive function and psychosocial issues were assessed using HEADS-ED. Data was analyzed using SPSS v23 and independent T-tests, Pearson’s correlation and linear regression were used. The prevalence of neurocognitive deficits among HIV positive children attending CCC at KNH was 60% with neurocognitive performance of 54 children being at least 2SD below the mean based on the KABC-II scores. There was no significant correlation between mental processing index and CD4 count (Pearson’s rho = −0.01, p = 0.39). There was no significant association between Mental Processing Index and viral load (p = 0.056) and early ARV initiation (0.27). Using the HEADS-ED, risks factors related to education (β = −5.67, p = 0.02) and activities and peer support (β = −9.1, p = 0.002) were significantly associated with poor neurocognitive performance. Neurocognitive deficits are prevalent among HIV positive children attending CCC-KNH. This extent of the deficits was not associated with low CD4 count, high viral load or early initiation in HIV care. However, poor school performance and problem with peers was associated with poor neurocognitive performance.
Variation in Patient Utilities for Outcomes of the Management of Chronic Stable Angina: Implications for Clinical Practice Guidelines

Objective. —Although practice guidelines sometimes make recommendations based on symptom severity, they rarely account for how patients feel about their symptoms. To investigate the possible importance of patient preferences in treatment of ischemic heart disease, we assessed attitudes toward symptoms in patients with angina pectoris. Design. —Case series. Setting. —Ambulatory cardiology clinics at two tertiary care medical centers. Patients. —A total of 220 subjects were selected from 589 patients with chronic stable angina referred from cardiologists to achieve patient samples balanced for sex, race, and angina severity. Main Outcome Measures. —We measured patients' attitudes toward their angina using the rating scale, time trade-off, and standard gamble utility metrics. Reliability of measurements was evaluated by repeating the assessments 2 weeks later on 50 willing patients. Results. —While the mean responses followed the expected patterns (those with more severe Canadian Cardiovascular Society scores chose lower utilities), attitudes toward symptoms varied substantially among patients with similarly severe angina. For example, there was a 33% chance that a patient with class II angina had a time trade-off utility that was lower (ie, more bothered by symptoms) than a patient with more severe angina (class III/IV). This variation in utilities was not due to random error in the assessments. Conclusions. —Angina patients with similar functional limitation vary considerably in their tolerance for their symptoms, as measured by utilities. Our findings suggest that guidelines for the management of ischemic heart disease should be based on the preferences of the individual patient rather than on symptom severity alone. (JAMA. 1995;273:1185-1190)
The power of interdisciplinary collaboration in hospice

Abstract The purpose of this study was to identify collaborative communication and extend the theoretical framework of interdisciplinary collaboration in a hospice setting. Ethnographic observations and the Modified Index of Collaboration were used to identify and analyse perceived interdisciplinary collaboration and observed collaborative communication. Taken together, both qualitative and quantitative findings suggest that interdisciplinary collaboration also occurs outside of hospice, namely with primary care doctors and nursing home staff. Future research should explore collaborative communication between hospice interdisciplinary team members and non-hospice staff.
Strategies to address mental health through schools with examples from China

The World Health Organization estimates that approximately one in five young people under the age of 18 experiences some form of developmental, emotional or behavioural problem, and one in eight experiences a mental disorder. Because research shows that half of adult mental disorders begin before the age of 14 and that early intervention can prevent and reduce more serious consequences later in life, it is critical to expand the role of mental health professionals with schools worldwide. Schools have the potential to affect the mental health of millions of young people, as well as those who work in schools. Research indicates that programmes promoting mental health are among the most effective of health promoting school efforts. This paper discusses the health promoting schools framework, reviews effective strategies for promoting mental health in schools, and provides examples from Zhejiang Province, China. This article also discusses the key roles that mental health professionals can play in promoting mental health through schools. As advocates, policy makers, researchers and teachers, mental health professionals can bridge the sectors of education, mental health and public health. Developing common frameworks and interdisciplinary training will create a foundation of shared understanding to achieve this goal.
CHOROIDAL VOLUME IN BRANCH RETINAL VEIN OCCLUSION BEFORE AND AFTER INTRAVITREAL ANTI-VEGF INJECTION

Purpose: The aim of this study is to evaluate the subfoveal choroidal volume change in the patients with branch retinal vein occlusion before and after intravitreal anti-vascular endothelial growth factor injection using the enhanced depth imaging optical coherence tomography. Methods: We measured the bilateral subfoveal choroidal volume in 15 patients (mean age, 64.47 ± 7.13 years) with unilateral branch retinal vein occlusion by using the enhanced depth imaging methods of the Spectralis optical coherence tomography system. After an injection of intravitreal bevacizumab, we measured the subfoveal choroidal volume of the eye with regressed macular edema. Results: The mean subfoveal choroidal volume measured in 15 eligible eyes of 15 patients was 7.74 ± 0.70 mm3, which was significantly greater than the volume of the fellow eyes (6.38 ± 0.69 mm3; P = 0.001, Wilcoxon signed-rank test). The subfoveal choroidal volume of the eye with regressed macular edema was 6.56 ± 0.79 mm3, which was significantly lower than the volume before the treatment (P = 0.001, Wilcoxon signed-rank test). Conclusion: The subfoveal choroidal volume of the branch retinal vein occlusion eyes was significantly greater than the volume of the fellow eyes and decreased significantly after an intravitreal anti-vascular endothelial growth factor treatment.
Jostling for Position: Optimizing Linker Location in the Design of Estrogen Receptor‐Targeting PROTACs

Estrogen receptor‐α (ER) antagonists have been widely used for breast cancer therapy. Despite initial responsiveness, hormone‐sensitive ER‐positive cancer cells eventually develop resistance to ER antagonists. It has been shown that in most of these resistant tumor cells, the ER is expressed and continues to regulate tumor growth. Recent studies indicate that tamoxifen initially acts as an antagonist, but later functions as an ER agonist, promoting tumor growth. This suggests that targeted ER degradation may provide an effective therapeutic approach for breast cancers, even those that are resistant to conventional therapies. With this in mind, we previously demonstrated that proteolysis targeting chimeras (PROTACs) effectively induce degradation of the ER as a proof‐of‐concept experiment. Herein we further refined the PROTAC approach to target the ER for degradation. The ER‐targeting PROTACs are composed of an estradiol on one end and a hypoxia‐inducing factor 1α (HIF‐1α)‐derived synthetic pentapeptide on the other. The pentapeptide is recognized by an E3 ubiquitin ligase called the von Hippel Lindau tumor suppressor protein (pVHL), thereby recruiting the ER to this E3 ligase for ubiquitination and degradation. Specifically, the pentapeptide is attached at three different locations on estradiol to generate three different PROTAC types. With the pentapeptide linked through the C7α position of estradiol, the resulting PROTAC shows the most effective ER degradation and highest affinity for the estrogen receptor. This result provides an opportunity to develop a novel type of ER antagonist that may overcome the resistance of breast tumors to conventional drugs such as tamoxifen and fulvestrant (Faslodex).
The application of tDCS for the treatment of psychiatric diseases

Abstract Neuroplasticity represents the dynamic structural and functional reorganization of the central nervous system, including its connectivity, due to environmental and internal demands. It is recognized as a major physiological basis for adaption of cognition and behaviour, and, thus, of utmost importance for normal brain function. Cognitive dysfunctions are major symptoms in psychiatric disorders, which are often associated with pathological alteration of neuroplasticity. Transcranial direct current stimulation (tDCS), a recently developed non-invasive brain stimulation technique, is able to induce and modulate cortical plasticity in humans via the application of relatively weak current through the scalp of the head. It has the potential to alter pathological plasticity and restore dysfunctional cognitions in psychiatric diseases. In the last decades, its efficacy to treat psychiatric disorders has been explored increasingly. This review will give an overview of pathological alterations of plasticity in psychiatric diseases, gather clinical studies involving tDCS to ameliorate symptoms, and discuss future directions of application, with an emphasis on optimizing stimulation effects.
High‐Resolution Crystal Structure of a Lasso Peptide

Lasso peptides are a group of a growing class of bioactive peptides of microbial origin. The first crystal structure of a member of this family, the glucagon receptor antagonist BI-32169, shows that the fold is built predominantly by regular secondary structural elements and a tight network of hydrogen bonds that are partially shielded from solvent by hydrophobic amino acid side chains. This results in an extraordinary stable structure that is resistant to thermal unfolding or proteolytic digestion, which facilitates its biological function.
Inflammatory muscle pain is dependent on the activation of kinin B1 and B2 receptors and intracellular kinase pathways

B1 and B2 kinin receptors are involved in pain transmission but they may have different roles in the muscle pain induced by intense exercise or inflammation. We investigated the contribution of each of these receptors, and the intracellular pathways involved, in the initial development and maintenance of the muscle pain associated with inflammation‐induced tissue damage.
The Prognosis of Patients with Chronic Kidney Disease and Diabetes Mellitus

Abstract Background and Aims: Diabetes mellitus (DM) is a chronic disease which can evolve towards devastating micro and macro-vascular complications. Chronic kidney disease (CKD) is a worldwide public health problem, with adverse outcomes of kidney failure, cardiovascular disease (CVD) and premature death. The aim of our study was to evaluate the prognosis in patients with DM and CKD, depending on estimated glomerular filtration rate (eGFR) and albuminuria, according to the classification of Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease (KDIGO) from 2013 Materials and Methods: The study was epidemiological, transversal, non interventional type, with 600 subjects unselected patients divided into three subgroups: 200 patients with T1DM, 200 patients with T2DM and 200 age matched subjects without DM. The recorded data have been analyzed using the Statistic Package for Social Sciences (SPSS), the 17.00 software (IBM Corporation, Armonk, NY, United States of America). Results:. We found a statistically significant difference among the three study groups (p < 0.0001) regarding the prognosis of CKD. Conclusions: DM represents an important risk factor for the appearance of CKD but also a negative prognosis factor for the patients with CKD.
Corticosteroids and β2‐agonists upregulate mitogen‐activated protein kinase phosphatase 1: in vitro mechanisms

Airway remodelling is a consequence of long‐term inflammation and MAPKs are key signalling molecules that drive pro‐inflammatory pathways. The endogenous MAPK deactivator – MAPK phosphatase 1 (MKP‐1) – is a critical negative regulator of the myriad pro‐inflammatory pathways activated by MAPKs in the airway.
Remote Instruction and Support Using a Shared-View System with Head Mounted Display (HMD)

背景と目的:遠隔からの指示・支援には電話,さらに画像も加わるテレビ電話等が利用されているが,いまだ手当や処置等を具体的に指示するには限界がある。 head mounted display(頭部搭載型ディスプレイ,以下HMD)を用いたshared-view systemは,行為実施者の視野を遠隔地の指示者が見ることができ,指示は音声に加えHMDに指示者の指さしをディスプレイすることができる。 本研究の目的はこのシステムの有用性の評価にある。 対象と方法:一般人20人を被験者とした。 実験(1)HMDを装着させ,心マッサージを遠隔より指導しその実施内容を評価した(n=10)。 実験(2)全員にHMDを装着させ,気道確保・脈拍確認・心マッサージを遠隔より指導した。 10人を5人ずつの2群に分け,音声のみの指導と音声と指さしによる指導を行い,各手技の実施内容と要した時間を評価・比較した。 また脈拍確認についてはレサシアンの頸動脈を15秒間拍動させそのうち何%正しく触知できたか,胸骨圧迫心マッサージを15回行い,間違った圧迫を何回したかを評価・比較した。 結果:実験(1)全例で手掌を正しい部位に誘導し,心マッサージの指導が可能であった。 実験(2)各手技の指導に要した時間は音声と指さしによる指導をした群が有意に短かった(p<0.05)。 方法については気道確保は両群において正しく行うことができた。 脈拍を正しく触知できた回数の割合は両群で有意差を認めなかった。 心マッサージでは適切な圧迫回数は音声と指さしによる指導をした群が有意に少なかった(p<0.05)。 結語:shared-view systemでは,遠隔の指導者がCRT画面で処置実施者の視野を共有し,この視野のなかで指さしによる指示をすることができる。 これは遠隔医療を単なる情報転送のレベルから,遠隔の共同作業者として医療実践そのものに参加することを可能にするものである。
Urolithin as a Converging Scaffold Linking Ellagic acid and Coumarin Analogues: Design of Potent Protein Kinase CK2 Inhibitors

Casein kinase 2 (CK2) is a ubiquitous, essential, and highly pleiotropic protein kinase; its abnormally high constitutive activity is suspected to underlie its pathogenic potential in neoplasia and other relevant diseases. Previously, using different in silico screening approaches, two potent and selective CK2 inhibitors were identified by our group: ellagic acid, a naturally occurring tannic acid derivative (Ki=20 nM) and 3,8‐dibromo‐7‐hydroxy‐4‐methylchromen‐2‐one (DBC, Ki=60 nM). Comparing the crystallographic binding modes of both ellagic acid and DBC, an X‐ray structure‐driven merging approach was taken to design novel CK2 inhibitors with improved target affinity. A urolithin moiety is proposed as a possible bridging scaffold between the two known CK2 inhibitors, ellagic acid and DBC. Optimization of urolithin A as the bridging moiety led to the identification of 4‐bromo‐3,8‐dihydroxy‐benzo[c]chromen‐6‐one as a novel, potent and selective CK2 inhibitor, which shows a Ki value of 7 nM against the protein kinase, representing a significant improvement in affinity for the target compared with the two parent fragments.
Early clinical response to tofacitinib treatment as a predictor of subsequent efficacy: Results from two phase 3 studies of patients with moderate-to-severe plaque psoriasis

Abstract Background: The ability to predict response to psoriasis treatments has important implications. Tofacitinib is an oral JAK inhibitor being investigated for psoriasis. Objective: The objective of this study is to identify and validate the clinical predictors of responses in psoriasis patients treated with tofacitinib. Methods: Selected baseline characteristics or early improvement in Psoriasis Area and Severity Index (PASI) in the phase 3 tofacitinib study OPT 1 (NCT01276639) were evaluated as predictors for a clinical response (75% improvement in PASI [PASI75]) at week 16. Predictive ability was assessed by the area-under-the-receiver operating characteristic curve (AUC-ROC). The predictive ability of the identified variables was validated with study OPT 2 (NCT01309737). Results: PASI improvement at weeks 8 and 12 demonstrated good discriminatory abilities to predict PASI75 response at week 16 (AUC-ROC ≥86% and 94%, respectively) in OPT 1. Validation with PASI50 response at week 8 in OPT 2 to predict PASI75 response at week 16 showed that the sensitivity, specificity, PPV, and NPV were 88%, 69%, 80%, and 81%, respectively, in tofacitinib-treated subjects. Conclusion: Achieving a PASI50 response after 8 weeks of treatment with tofacitinib in psoriasis patients appears to be a reliable predictor of achieving a PASI75 response at week 16. Trial registration: clinicaltrials.gov: NCT01276639 and NCT01309737
Alzheimer's disease, β‐amyloid, glutamate, NMDA receptors and memantine – searching for the connections

β‐amyloid (Aβ) is widely accepted to be one of the major pathomechanisms underlying Alzheimer's disease (AD), although there is presently lively debate regarding the relative roles of particular species/forms of this peptide. Most recent evidence indicates that soluble oligomers rather than plaques are the major cause of synaptic dysfunction and ultimately neurodegeneration. Soluble oligomeric Aβ has been shown to interact with several proteins, for example glutamatergic receptors of the NMDA type and proteins responsible for maintaining glutamate homeostasis such as uptake and release. As NMDA receptors are critically involved in neuronal plasticity including learning and memory, we felt that it would be valuable to provide an up to date review of the evidence connecting Aβ to these receptors and related neuronal plasticity. Strong support for the clinical relevance of such interactions is provided by the NMDA receptor antagonist memantine. This substance is the only NMDA receptor antagonist used clinically in the treatment of AD and therefore offers an excellent tool to facilitate translational extrapolations from in vitro studies through in vivo animal experiments to its ultimate clinical utility.
Use of nonbiologic treatments in antihistamine-refractory chronic urticaria: a review of published evidence

Abstract Background: Knowledge of effectiveness and safety of the nonbiologic, nonantihistamine treatments used for chronic urticaria is important as in some cases the principal guideline-recommended drug; omalizumab, has limited effect, side effects or is too expensive or unavailable. Herein, we systematically review the evidence for the use of the nonbiologic treatments in antihistamine-refractory chronic urticaria. Methods: We performed a systematic review of the literature using PubMed and Webofscience and identified studies that reported use of one or more of the nonbiological, nonantihistamine treatment options for chronic urticaria. The studies were evaluated based on study design, number of patients, effect of treatment and safety. Results: We identified 118 studies or case series with 13 different treatments (azathioprine, chloroquine, colchicine, cyclosporine, dapsone, intravenous immunoglobulin (IVIG), methotrexate, montelukast, mycophenolate mofetil, plasmapheresis, sulfasalazine, tranexamic acid and ultraviolet light (UV) A, UVB) totaling 1682 patients. There was a paucity of controlled trials for most of the treatments reviewed albeit the strongest evidence in favor of a beneficial effect in chronic urticaria was, apart from montelukast and cyclosporine, seen for UV therapy and dapsone followed by IVIG. Conclusion: The treatment options reviewed should be seen as potential alternatives in treatment-resistant chronic urticaria where guideline-based selections have failed. However, larger controlled trials are warranted to advance the level of evidence, possibly supporting some treatments’ future recommendation in selected patients.
Allosteric nature of P2X receptor activation probed by photoaffinity labelling

BACKGROUND AND PURPOSE In P2X receptors, agonist binding at the interface between neighbouring subunits is efficiently transduced to ion channel gating. However, the relationship between binding and gating is difficult to study because agonists continuously bind and unbind. Here, we covalently incorporated agonists in the binding pocket of P2X receptors and examined how binding site occupancy affects the ability of the channel to gate.
Benzenesulfonamides: A Unique Class of Chemokine Receptor Type 4 Inhibitors

The interaction of CXCR4 with CXCL12 (SDF‐1) plays a critical role in cancer metastasis by facilitating the homing of tumor cells to metastatic sites. Based on our previously published work on CXCR4 antagonists, we have synthesized a series of aryl sulfonamides that inhibit the CXCR4/CXCL12 interaction. Analogue bioactivities were assessed with binding affinity and Matrigel invasion assays. Computer modeling was employed to evaluate a selection of the new analogues docked into the CXCR4 X‐ray structure and to rationalize discrepancies between the affinity and Matrigel in vitro assays. A lead compound displays nanomolar potency in the binding affinity assay (IC50=8.0 nM) and the Matrigel invasion assay (100 % blockade of invasion at 10 nM). These data demonstrate that benzenesulfonamides are a unique class of CXCR4 inhibitors with high potency.
Biological characteristics of carbon-ion therapy

Purpose: Radiotherapy using charged and/or high-linear energy transfer (LET) particles has a long history, starting with proton beams up to now carbon-ions. Radiation quality of particle beams is different from conventional photons, and therefore the biological effects of high-LET irradiation have attracted scientific interests of many scientists in basic and clinical fields. A brief history of particle radiotherapy in the past half-century is followed by the reviewed biological effectiveness of high-LET charged particles. Results: The latter includes 54 papers presenting 506 RBE (relative biological effectiveness) values for carbon ions and a total of 290 RBE values for other ions identified from 48 papers. By setting a selection window of LET up to 100 keV/μm, we fitted a linear regression line to an LET-RBE relation. The resulting slope of the regression line had a dimension of μm/keV, and showed different steepness for different cells/tissues and endpoints as well. The steepest regression was found for chromosome aberration of human malignant melanoma while the shallowest was for apoptosis of rodent cells/tissue. Both tumour and normal tissue showed relatively shallower slopes than colony formation. Conclusions: In general, there is a large variation of slope values, but the majority (25 out of 29 values) of data was smaller than 0.05 μm/keV.