bluuebunny/crossref_metadata_2025 huggingface dataset:
Diagnostic biomarkers for adult haemophagocytic lymphohistiocytosis in critically ill patients (HEMICU): a prospective observational study protocol
Authors: Lachmann Gunnar , Knaak Cornelia , von Haefen Clarissa , Paeschke Nadine , Meisel Christian , Nyvlt Peter , Schuster Friederike S , Piper Sophie K , Kruppa Jochen , Vorderwülbecke Gerald , Balzer Felix , La Rosée Paul , Schenk Thomas , Unterwalder Nadine , Kölsch Uwe , Lachmann Nils , Akyüz Levent , Brunkhorst Frank M , Volk Hans-Dieter , Keh Didier , Spies Claudia
Published: October 2019

Introduction

Haemophagocytic lymphohistiocytosis (HLH) in adults is characterised by toxic immune activation and a sepsis-like syndrome, leading to high numbers of undiagnosed cases and mortality rates of up to 68%. Early diagnosis and specific immune suppressive treatment are mandatory to avoid fatal outcome, but the diagnostic criteria (HLH-2004) are adopted from paediatric HLH and have not been validated in adults. Experimental studies suggest biomarkers to sufficiently diagnose HLH. However, biomarkers for the diagnosis of adult HLH have not yet been investigated.

Methods and analysis

The HEMICU (Diagnostic biomarkers for adult haemophagocytic lymphohistiocytosis in critically ill patients) study aims to estimate the incidence rate of adult HLH among suspected adult patients in intensive care units (ICUs). Screening for HLH will be performed in 16 ICUs of Charité – Universitätsmedizin Berlin. The inclusion criteria are bicytopaenia, hyperferritinaemia (≥500 µg/L), fever or when HLH is suspected by the clinician. Over a period of 2 years, we expect inclusion of about 100 patients with suspected HLH. HLH will be diagnosed if at least five of the HLH-2004 criteria are fulfilled, together with an expert review; all other included patients will serve as controls. Second, a panel of potential biomarker candidates will be explored. DNA, plasma and serum will be stored in a biobank. The primary endpoint of the study is the incidence rate of adult HLH among suspected adult patients during ICU stay. Out of a variety of measured biomarkers, this study furthermore aims to find highly potential biomarkers for the diagnosis of adult HLH in ICU. The results of this study will contribute to improved recognition and patient outcome of adult HLH in clinical routine.

Ethics and dissemination

The institutional ethics committee approved this study on 1 August 2018 (Ethics Committee of Charité – Universitätsmedizin Berlin, EA4/006/18). The results of the study will be disseminated in an international peer-reviewed journal and presented at international conferences.

Trial registration number

NCT03510650.
Pain perception with cervical tenaculum placement during intrauterine device insertion: a randomised controlled trial
Authors: Lambert Tashima , Truong Tracy , Gray Beverly
Published: October 2019

Introduction

'Slow’ and ‘cough’ techniques for tenaculum placement are commonly used. This trial sought to determine if one method of placement resulted in less pain for patients.

Methods

This study was a randomised controlled trial of patients presenting for intrauterine device placement. Sixty-six participants were randomised to tenaculum placement via the 'slow' method (closure of tenaculum over a 5-s period) versus the 'cough' method (closure of tenaculum at the time of patient’s cough). The primary outcome was pain at time of tenaculum placement measured on a 100 mm visual analogue scale. The study was powered to detect a 16 mm difference in pain. Secondary outcomes included pain with insertion and provider satisfaction with tenaculum grasp. Pain scores were analysed with Wilcoxon rank-sum test.

Results

Sixty-six women were enrolled, 33 randomised to each group. Demographics were similar in each group. The primary outcome of pain with tenaculum placement showed a median pain score of 44 (IQR=21, 63) with slow placement and 32 (IQR=19, 54) with cough placement. There was no significant difference in pain scores between methods of tenaculum placement (p=0.16). There was no significant difference in overall pain scores (p=0.12). Provider satisfaction was not associated with one method of placement (p=1). Pre-procedure anxiety was significantly associated with pain at the time of tenaculum placement (p=0.01).

Conclusions

Neither the slow method nor cough method is superior for pain reduction or provider satisfaction. Pain with tenaculum use is significantly associated with anxiety.

Clinical trial registration

NCT02969421.
The “T’s” of snakebite injury in the USA: fact or fiction?
Authors: Jaramillo Joshua D , Hakes Nicholas A , Tennakoon Lakshika , Spain David , Forrester Joseph D
Published: October 2019

Background

Venomous snakebites can result in serious morbidity and mortality. In the USA, the “T’s of snakebites” (testosterone, teasing, touching, trucks, tattoos & toothless (poverTy), Texas, tequila, teenagers, and tanks) originate from anecdotes used to colloquially highlight venomous snakebite risk factors. We performed an epidemiologic assessment of venomous snakebites in the USA with the objective of evaluating the validity of the “T’s of snakebites” at a national level.

Methods

We performed a retrospective analysis of the National Emergency Department Sample. Data from January 1, 2016 to December 31, 2016 were obtained. All emergency department (ED) encounters corresponding to a venomous snakebite injury were identified using the International Classification of Diseases, 10th Revision, Clinical Modification (ICD-10-CM) codes. Primary outcomes were mortality and inpatient admission. Demographic, injury, and hospital characteristics were assessed. Data were analyzed according to survey methodology. Weighted values are reported.

Results

In 2016, 11 138 patients presented to an ED with a venomous snakebite. There were 4173 (37%) persons aged 18 to 44, and 7213 (65%) were male. Most snakebites were reported from the South (n=9079; 82%), although snakebites were reported from every region in the USA. Only 3792 (34%) snakebites occurred in rural counties. Persons in the lowest income quartile by zip code were the most heavily represented (n=4337; 39%). The most common site of injury was the distal upper extremity (n=4884; 44%). Multivariate analysis revealed that species of snake (OR=0.81; 95% CI 0.73 to 0.88) and older age (OR=1.42; 95% CI 1.08 to 1.87) were associated with hospital admission. There were <10 inpatient deaths identified, and no variables were predictive of death.

Discussion

Some of the “T’s of snakebites” may be valid colloquial predictors of the risk for venomous snakebites. Based on national data, common demographics of venomous snakebite victims include lower income, Caucasian, and adult men in the South who are bit on the upper extremity. Understanding common demographics of venomous snakebite victims can effectuate targeted public health prevention messaging.

Level of evidence

IV.
Pain management of a mandibular fracture in an alpaca (Vicugna pacos) via epidural catheter placement in the mandibular foramen
Authors: Stathopoulou Thaleia , Seymour Christopher , McSloy Alex , Adams James , Viscasillas Jaime
Published: October 2019

A nine‐year‐old female alpaca with a history of a recurrent tooth root abscess presented for further investigation of a swelling of the left mandible and possible tooth extraction. During the manipulation of the mandible in surgery, the mandibular body fractured, and due to active infection it was left to heal by secondary intention. After surgery, the alpaca became dull and inappetent. Analgesic drugs included buprenorphine and meloxicam, which were ineffective according to the alpaca’s clinical appearance. An inferior alveolar nerve block was achieved by repeated administration of local anaesthetic (ropivacaine 0.75 per cent) every six hours via an epidural catheter placed in the mandibular foramen under CT guidance. Despite the adequate level of comfort achieved, discharge from surgical site resumed and the owner elected euthanasia. In conclusion, the placement of an epidural catheter in the mandibular canal, under CT guidance, was proven to successfully provide analgesia to an alpaca suffering from mandibular fractures.
Modifying a meshless method to solving κ−ε turbulent natural convection heat transfer
Authors: Sheikhi Nasrin , Najafi Mohammad , Enjilela Vali
Published: October 2019

The conventional meshless local Petrov–Galerkin method is modified to enable the method to solve turbulent convection heat transfer problems. The modifications include developing a new computer code which empowers the method to adopt nonlinear equations. A source term expressed in terms of turbulent viscosity gradients is appended to the code to optimize the accuracy for turbulent flow domains. The standard [Formula: see text] transport equations, one of the most applicable two equation turbulent viscosity models, is incorporated, appropriately, into the developed code to bring about both versibility and stability for turbulent natural heat transfer applications. The amenability of the new developed technique is tested by applying the modified method to two conventional turbulent fluid flow test cases. Upon the obtained acceptable results, the modified technique is, next, applied to two conventional natural heat transfer test cases for their turbulent domain. Based on comparing the results of the new technique with those of the available experimental or conventional numerical methods, the proposed method shows good adaptability and accuracy for both the fluid flow and convection heat transfer applications in turbulent domains. The new technique, now, furthers the applicability of the mesh-free local Petrov-Galerkin (MLPG) method to turbulent flow and heat transfer problems and provides much closer results to those of the available experimental or conventional numerical methods.
The asymptotic solution for the particle growth in the undercooled melt driven by a straining flow
Authors: Chen Mingwen , Liu Weina , Wang Zidong
Published: October 2019

The moving boundary problem of particle growth in the convective undercooled melt driven by a straining flow is studied by means of the multiple variable expansion method. The resulting uniformly valid asymptotic solution shows the growth behavior of a spherical particle in the straining flow. The straining flow enhances the energy transfer rate and results in higher local growth velocity of the particle near the interface where the flow is incoming, whereas near the interface where the flow is outgoing, the straining flow decreases the energy transfer rate and results in lower local growth velocity of the particle. Because of the difference in local interface growth velocities of the particle, the interface of the particle opposite to the incoming straining flow protrudes outward more significantly than that facing the outgoing straining flow, an initially spherical particle in the undercooled melt with the straining flow evolves to be gravely distorted into different shapes.
A Building Energy Consumption Prediction Method Based on Integration of a Deep Neural Network and Transfer Reinforcement Learning
Authors: Fu Qiming , Liu QingSong , Gao Zhen , Wu Hongjie , Fu Baochuan , Chen Jianping
Published: October 2019

With respect to the problem of the low accuracy of traditional building energy prediction methods, this paper proposes a novel prediction method for building energy consumption, which is based on the seamless integration of the deep neural network and transfer reinforcement learning (DNN-TRL). The method introduces a stack denoising autoencoder to extract the deep features of the building energy consumption, and shares the hidden layer structure to transfer the common information between different building energy consumption problems. The output of the DNN model is used as the input of the Sarsa algorithm to improve the prediction performance of the target building energy consumption. To verify the performance of the DNN-TRL algorithm, based on the data recorded by American Power Balti Gas and Electric Power Company, and compared with Sarsa, ADE-BPNN, and BP-Adaboost algorithms, the experimental results show that the DNN-TRL algorithm can effectively improve the prediction accuracy of the building energy consumption.
Wirtinger numbers for virtual links
Authors: Pongtanapaisan Puttipong
Published: October 2019

The Wirtinger number of a virtual link is the minimum number of generators of the link group over all meridional presentations in which every relation is an iterated Wirtinger relation arising in a diagram. We prove that the Wirtinger number of a virtual link equals its virtual bridge number. Since the Wirtinger number is algorithmically computable, it gives a more effective way to calculate an upper bound for the virtual bridge number from a virtual link diagram. As an application, we compute upper bounds for the virtual bridge numbers and the quandle counting invariants of virtual knots with 6 or fewer crossings. In particular, we found new examples of nontrivial virtual bridge number one knots, and by applying Satoh’s Tube map to these knots we can obtain nontrivial weakly superslice links.
On the sum of the distance signless Laplacian eigenvalues of a graph and some inequalities involving them
Authors: Alhevaz A. , Baghipur M. , Hashemi E. , Paul S.
Published: October 2019

The distance signless Laplacian matrix of a connected graph [Formula: see text] is defined as [Formula: see text], where [Formula: see text] is the distance matrix of [Formula: see text] and [Formula: see text] is the diagonal matrix of vertex transmissions of [Formula: see text]. If [Formula: see text] are the distance signless Laplacian eigenvalues of a simple graph [Formula: see text] of order [Formula: see text] then we put forward the graph invariants [Formula: see text] and [Formula: see text] for the sum of [Formula: see text]-largest and the sum of [Formula: see text]-smallest distance signless Laplacian eigenvalues of a graph [Formula: see text], respectively. We obtain lower bounds for the invariants [Formula: see text] and [Formula: see text]. Then, we present some inequalities between the vertex transmissions, distance eigenvalues, distance Laplacian eigenvalues, and distance signless Laplacian eigenvalues of graphs. Finally, we give some new results and bounds for the distance signless Laplacian energy of graphs.
A Coumarin-Based Fluorescence Probe for Selective Recognition of Cu2+ Ions and Live Cell Imaging
Authors: He Guangjie , Ma Nana , Li Linlin , Xie Chenyan , Yang Linlin , Xu Jinhe , Wang Junli
Published: October 2019

A new fluorescence probe L was rationally designed and synthesized for the recognition of Cu2+ ions by the combination of coumarin hydrazide and 2-acetylpyrazine. The photochemical properties and selectivity of L for Cu2+ ions in a CH3CN/HEPES (3 : 2, v/v) buffer were investigated by UV-vis absorption and fluorescence emission spectra. A highly selective and sensitive response of L for Cu2+ ions over other competing metal ions was observed with limit of detection in 3 μM. The coordination stoichiometry of L to Cu2+ ions was determined to be 1 : 1 by the UV-vis absorption spectrum, the fluorescence titrations, and density functional theory (DFT) calculations. Moreover, L was applied successfully for recognition of intracellular Cu2+ ions in living cells.
A Highly Effective Data Preprocessing in Side-Channel Attack Using Empirical Mode Decomposition
Authors: Zhang ShuaiWei , Yang XiaoYuan , Chen Lin , Zhong Weidong
Published: October 2019

Side-channel attacks on cryptographic chips in embedded systems have been attracting considerable interest from the field of information security in recent years. Many research studies have contributed to improve the side-channel attack efficiency, in which most of the works assume the noise of the encryption signal has a linear stable Gaussian distribution. However, their performances of noise reduction were moderate. Thus, in this paper, we describe a highly effective data-preprocessing technique for noise reduction based on empirical mode decomposition (EMD) and demonstrate its application for a side-channel attack. EMD is a time-frequency analysis method for nonlinear unstable signal processing, which requires no prior knowledge about the cryptographic chip. During the procedure of data preprocessing, the collected traces will be self-adaptably decomposed into sum of several intrinsic mode functions (IMF) based on their own characteristics. And then, meaningful IMF will be reorganized to reduce its noise and increase the efficiency of key recovering through correlation power analysis attack. This technique decreases the total number of traces for key recovering by 17.7%, compared to traditional attack methods, which is verified by attack efficiency analysis of the SM4 block cipher algorithm on the FPGA power consumption analysis platform.
Molecular Subtypes Recognition of Breast Cancer in Dynamic Contrast-Enhanced Breast Magnetic Resonance Imaging Phenotypes from Radiomics Data
Authors: Li Wei , Yu Kun , Feng Chaolu , Zhao Dazhe
Published: October 2019

Background and Objective. Breast cancer is a major cause of mortality among women if not treated in early stages. Recognizing molecular markers from DCE-MRI directly to distinguish the four molecular subtypes without invasive biopsy is helpful for guiding treatment plans for breast cancer, which provides a fast way to consequential treatment plan decision in early time and best opportunity for patients. Methods. This study presents an approach of molecular subtypes recognition from breast cancer image phenotypes by radiomics. An improved region growth algorithm with dynamic threshold without user interaction is proposed for cancer lesion segmentation, which gives the precise border of lesion other than area with background. The lesions are extracted automatically based on radiologists’ annotation which guarantees the lesion is segmented correctly. Various features are extracted on lesions data including texture, morphology, dynamic kinetics, and statistics features carried out on a large patient cohort, which are used to validate the relationship between image phenotypes and the molecular subtypes. A new algorithm of multimodel-based recursive feature elimination is applied on the radiomics data generated by the feature extraction process. This method obtains the feature subset with stable performance for different classification models, and the gradient boosting decision tree model gets the best results of both classification performance and imbalance performance on molecular subtypes. Result. From the experimental results, 69 optimal features from 143 original features are found by the multimodel-based recursive feature elimination algorithms and the gradient boosting decision tree classifier obtains a good performance with accuracy 0.87, precise 0.88, recall 0.87, and F1-score 0.87. The dataset with 637 patients in this paper has serious imbalance problem on different molecular subtypes, and the the robust features that are generated by multimodel-based recursive feature eliminiation algorithm make the gradient boosting decision tree classifier have good behaviors. The recognition precision for the four molecular subtypes of luminal A, luminal B, HER-2, and basal-like are 0.91, 0.89, 0.83, and 0.87, respectively. Conclusions. The improved lesion segmentation method gives more precise lesion edge, which not only saves the time of automatic extraction of lesion region of interest without threshold setting for each case, but also prevents the segmentation error by manual and prejudice from different radiologists. The feature selection algorithm of multimodel-based recursive feature elimination has the ability to find robust and optimal features that distinguish the four molecular subtypes from image phenotypes. The gradient boosting decision tree classifier rather plays a main role in recognition than other models used in this paper.
Night-Shift Work Duration and Risk of Colorectal Cancer According to IRS1 and IRS2 Expression
Authors: Shi Yan , Liu Li , Hamada Tsuyoshi , Nowak Jonathan A. , Giannakis Marios , Ma Yanan , Song Mingyang , Nevo Daniel , Kosumi Keisuke , Gu Mancang , Kim Sun A. , Morikawa Teppei , Wu Kana , Sui Jing , Papantoniou Kyriaki , Wang Molin , Chan Andrew T. , Fuchs Charles S. , Meyerhardt Jeffrey A. , Giovannucci Edward , Ogino Shuji , Schernhammer Eva S. , Nishihara Reiko , Zhang Xuehong
Published: October 2019

Background:

We hypothesized that the risk of colorectal cancer in night-shift workers might be different according to insulin receptor substrate status.

Methods:

Among 77,470 eligible women having night work assessed in the Nurses' Health Study, we documented a total of 1,397 colorectal cancer cases, of which 304 or 308 had available data on IRS1 and IRS2, respectively. We used duplication-method Cox proportional hazards regression analysis for competing risks to calculate HRs and 95% confidence intervals (CI) for each colorectal cancer subtype. We measured tumor IRS1 or IRS2 expression by immunohistochemistry (IHC).

Results:

Compared with women who never worked night shifts, those working ≥15 years night shifts had a marginal trend of increased overall risk of colorectal cancer (Ptrend = 0.06; multivariable HR = 1.20; 95% CI, 0.99–1.45). Longer duration of night-shift work was associated with a higher risk of IRS2-positive tumors (multivariable HR = 2.69; 95% CI, 1.48–4.89; Ptrend = 0.001, ≥15 years night shifts vs. never) but not with IRS2-negative tumors (multivariable HR = 0.90; 95% CI, 0.54–1.51; Ptrend = 0.72; Pheterogeneity for IRS2 = 0.008). Similarly, the corresponding multivariable HRs were 1.81 for IRS1-positive tumors (95% CI, 0.94–3.48; Ptrend = 0.06) and 1.13 for IRS1-negative tumors (95% CI, 0.71–1.80; Ptrend = 0.56; Pheterogeneity for IRS1 = 0.02).

Conclusions:

Our molecular pathologic epidemiology data suggest a potential role of IRS in mediating carcinogenesis induced by night-shift work.

Impact:

Although these findings need validation, rotating night shift might increase colorectal cancer risk in women with abnormal insulin receptor pathways.
Impact and Cost-Effectiveness of Human Papillomavirus Vaccination Campaigns
Authors: Portnoy Allison , Campos Nicole G. , Sy Stephen , Burger Emily A. , Cohen Jamie , Regan Catherine , Kim Jane J.
Published: October 2019

Background:

Data to inform evidence-based policy of human papillomavirus (HPV) vaccine delivery strategies in low- and middle-income countries are limited. We examined the cost-effectiveness of campaign compared with routine delivery strategies of adolescent female HPV vaccination in Uganda.

Methods:

We used a multiple modeling approach that captured HPV transmission, cervical carcinogenesis, and population demographics to project health and economic outcomes associated with HPV vaccination. Costs included vaccination and operational costs and cervical cancer costs over the lifetimes of the current female population in Uganda. Health outcomes included number of cervical cancer cases and disability-adjusted life years (DALY). Incremental cost-effectiveness ratios (i.e., cost per DALY averted) were calculated and compared against gross domestic product (GDP) per capita.

Results:

Compared with routine HPV vaccination of 9-year-old girls at 70% coverage, campaign vaccination yielded greater health benefits if campaigns occurred frequently and targeted a wide age range. Campaign delivery strategies were both less costly and more effective than routine HPV vaccination. Campaign vaccination of 9- to 30-year-old girls/women at a 3-year frequency (40% coverage) was considered cost-effective compared with the GDP per capita threshold for Uganda ($674 in U.S. 2015 dollars).

Conclusions:

We projected that campaign HPV vaccination would provide substantial population health benefits compared with routine vaccination. Expanding the target age range of campaign vaccination up to age 30 years may be an efficient strategy, depending on the achievable coverage level and campaign frequency.

Impact:

In settings where routine health systems infrastructure may be limited, reaching adolescent populations with a campaign delivery strategy may be an efficient use of resources.
Understanding the Right to Try Act
Authors: Agarwal Rajiv , Saltz Leonard B.
Published: October 2019

Patients with cancer who have exhausted standard treatments often seek access to investigational drugs. Often, however, such access is unavailable, due to either the unavailability of a trial, lack of an open recruiting spot on the trial, even when the trial itself is open, or the inability of the patient to meet one or more trial eligibility criteria. In such settings patients often seek access to investigational agents outside of a trial. The federal “Right to Try” legislation was passed to create an additional avenue, different from the FDA's Expanded Access, or “Compassionate Use” Program, through which patients might obtain access to investigational drugs. A year after this legislation was signed into law, there remains both a limited awareness of it and a substantial degree of misunderstanding on the part of those who are aware of it. The law creates an avenue to greatly facilitate off-study administration when patient, physician, and the manufacturer are all in agreement regarding the off study use of an eligible investigational agent. The law does not, however, empower a patient to impose a demand on either a provider or a drug manufacturer, nor does it require any entity to provide financial coverage for the drug. Eligible drugs are those which are not approved by the FDA for any indication, have completed a phase I trial, have an ongoing pivotal trial, and have an active registration plan. We review the specific law with commentary on its implications for improved access to investigational drugs outside of clinical trials.
Clinical Utility of Plasma Cell-Free DNA in Adult Patients with Newly Diagnosed Glioblastoma: A Pilot Prospective Study
Authors: Bagley Stephen J. , Nabavizadeh S. Ali , Mays Jazmine J. , Till Jacob E. , Ware Jeffrey B. , Levy Scott , Sarchiapone Whitney , Hussain Jasmin , Prior Timothy , Guiry Samantha , Christensen Theresa , Yee Stephanie S. , Nasrallah MacLean P. , Morrissette Jennifer J.D. , Binder Zev A. , O'Rourke Donald M. , Cucchiara Andrew J. , Brem Steven , Desai Arati S. , Carpenter Erica L.
Published: October 2019

Purpose:

The clinical utility of plasma cell-free DNA (cfDNA) has not been assessed prospectively in patients with glioblastoma (GBM). We aimed to determine the prognostic impact of plasma cfDNA in GBM, as well as its role as a surrogate of tumor burden and substrate for next-generation sequencing (NGS).

Experimental Design:

We conducted a prospective cohort study of 42 patients with newly diagnosed GBM. Plasma cfDNA was quantified at baseline prior to initial tumor resection and longitudinally during chemoradiotherapy. Plasma cfDNA was assessed for its association with progression-free survival (PFS) and overall survival (OS), correlated with radiographic tumor burden, and subjected to a targeted NGS panel.

Results:

Prior to initial surgery, GBM patients had higher plasma cfDNA concentration than age-matched healthy controls (mean 13.4 vs. 6.7 ng/mL, P < 0.001). Plasma cfDNA concentration was correlated with radiographic tumor burden on patients' first post-radiation magnetic resonance imaging scan (ρ = 0.77, P = 0.003) and tended to rise prior to or concurrently with radiographic tumor progression. Preoperative plasma cfDNA concentration above the mean (>13.4 ng/mL) was associated with inferior PFS (median 4.9 vs. 9.5 months, P = 0.038). Detection of ≥1 somatic mutation in plasma cfDNA occurred in 55% of patients and was associated with nonstatistically significant decreases in PFS (median 6.0 vs. 8.7 months, P = 0.093) and OS (median 5.5 vs. 9.2 months, P = 0.053).

Conclusions:

Plasma cfDNA may be an effective prognostic tool and surrogate of tumor burden in newly diagnosed GBM. Detection of somatic alterations in plasma is feasible when samples are obtained prior to initial surgical resection.
XPO1 Inhibitor Selinexor Overcomes Intrinsic Ibrutinib Resistance in Mantle Cell Lymphoma via Nuclear Retention of IκB
Authors: Ming Mei , Wu Wenjun , Xie Bingqing , Sukhanova Madina , Wang Weige , Kadri Sabah , Sharma Shruti , Lee Jimmy , Shacham Sharon , Landesman Yosef , Maltsev Natalia , Lu Pin , Wang Y. Lynn
Published: October 2019

Inhibition of B-cell receptor (BCR) signaling through the BTK inhibitor, ibrutinib, has generated a remarkable response in mantle cell lymphoma (MCL). However, approximately one third of patients do not respond well to the drug, and disease relapse on ibrutinib is nearly universal. Alternative therapeutic strategies aimed to prevent and overcome ibrutinib resistance are needed. We compared and contrasted the effects of selinexor, a selective inhibitor of nuclear export, with ibrutinib in six MCL cell lines that display differential intrinsic sensitivity to ibrutinib. We found that selinexor had a broader antitumor activity in MCL than ibrutinib. MCL cell lines resistant to ibrutinib remained sensitive to selinexor. We showed that selinexor induced apoptosis/cell-cycle arrest and XPO-1 knockdown also retarded cell growth. Furthermore, downregulation of the NFκB gene signature, as opposed to BCR signature, was a common feature that underlies the response of MCL to both selinexor and ibrutinib. Meanwhile, unaltered NFκB was associated with ibrutinib resistance. Mechnistically, selinexor induced nuclear retention of IκB that was accompanied by the reduction of DNA-binding activity of NFκB, suggesting that NFκB is trapped in an inhibitory complex. Coimmunoprecipitation confirmed that p65 of NFκB and IκB were physically associated. In primary MCL tumors, we further demonstrated that the number of cells with IκB nuclear retention was linearly correlated with the degree of apoptosis. Our data highlight the role of NFκB pathway in drug response to ibrutinib and selinexor and show the potential of using selinexor to prevent and overcome intrinsic ibrutinib resistance through NFκB inhibition.
Clinical Heterogeneity in Patients with Glutamate Decarboxylase Antibody
Authors: Huang Jiehong , Li Huilu , Zhou Ruisi , Huang Wenyao , Lin Wenhui , Chen Ting , Long Youming
Published: October 2019

Objective: To explore the diversity and clinical features of anti-glutamate decarboxylase (GAD) antibody-associated neurological diseases. Methods: Clinical data of a series of 5 patients positive for anti-GAD antibodies were retrospectively analyzed. Results: All 5 patients were female, with a median age of 41.5 years (range 19–60 years). Their neurological symptoms included stiff-person syndrome (SPS), encephalitis, myelitis, cramp, visual loss, and paresthesia. Three patients (60%) were diagnosed with tumors, 2 cases of thymic tumor and 1 of breast cancer. On immunohistochemistry for tumor pathology, expression of GAD65 was found only in 1 patient. Four patients (80%) had abnormal brain MRI findings. All patients received immunotherapy and improved significantly after treatment, but 4 (80%) then experienced a relapse. Conclusions: Neurological manifestations in anti-GAD-positive patients are diverse and include SPS, encephalitis, myelitis, cramp, visual loss, and paresthesia.
Risk of Multiple System Atrophy and the Use of Anti-Inflammatory Drugs: A Danish Register-Based Case-Control Study
Authors: Starhof Charlotte , Hejl Anne-Mette , Korbo Lise , Winge Kristian , Friis Søren
Published: October 2019

Introduction: Multiple system atrophy (MSA) is a rare rapidly progressive atypical Parkinson disorder presenting clinically with parkinsonism and/or a cerebellar syndrome in combination with dysautonomia. Severe neuroinflammation develops along with hallmark neuropathological changes, and as in Parkinson’s disease, intake of anti-inflammatory medication has been hypothesized to be protective for development of disease. We aimed to investigate if use of non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs), low-dose aspirin, or statins were associated with a reduced risk of MSA. Methods: We performed a register-based case-control study in MSA (n = 155) cases and population controls (n= 7,750) matched on age, gender, and place of residency by risk-set sampling. Pharmacological exposure prior to diagnosis was assessed in 2 categories (user vs. nonuser, cumulated dose in tertiles [T1-T3]). In an unconditional logistic regression model, adjusted for age, gender, residency, and chronic obstructive pulmonary disease (COPD), we estimated ORs and 95% CIs. Results: Data suggested a trend towards non-aspirin NSAID use to be associated with a decreased risk of MSA (OR 0.72 [95% CI 0.49–1.06]) compared to nonusers, decreasing dose-dependently (T2 OR 0.77 [95% CI 0.43–1.38]; T3 OR 0.55 [95% CI 0.29–1.06]). However, data were based on small numbers. Use of statins and low-dose aspirin was not associated with a decreased risk of MSA. Results were lagged 5 years from index date to address reverse causation. Conclusion: A trend toward use of non-aspirin NSAID and an associated reduced risk of MSA was observed in this study. However, our analyses had limited statistical precision, and further studies including larger sample sizes and longer exposure periods are needed.
Mineralocorticoid Receptor Antagonists and Renal Outcomes in Heart Failure Patients with and without Chronic Kidney Disease
Authors: Mavrakanas Thomas A. , Giannetti Nadia , Sapir-Pichhadze Ruth , Alam Ahsan
Published: October 2019

Introduction: The effect of mineralocorticoid receptor antagonists (MRAs) on chronic kidney disease (CKD) progression in patients with heart failure (HF) and with or without preexisting CKD has not been adequately studied. Methods: We conducted a retrospective cohort study including consecutive adult patients followed at the HF clinic of a tertiary care center who had already been on an angiotensin-converting enzyme inhibitor (ACEI) or an angiotensin receptor blocker (ARB). Exposure to MRAs was assessed at 6 months from registration. Patients who were never exposed to an MRA were the control group. Results: A total of 314 patients who were prescribed an MRA were compared to 1,116 patients who never received an MRA. Among them, 121 and 408 patients, respectively, had CKD (estimated glomerular filtration rate <60 mL/min/1.73 m2). MRAs had to be discontinued in 36/121 patients with CKD (29.8%) and 57/165 patients without CKD (34.5%) (p = 0.39). MRA treatment was associated with a higher risk for persistent creatinine doubling among patients without CKD (hazard ratio 4.07, 95% confidence interval 1.41–11.73). A numerically lower risk was identified among CKD patients (hazard ratio 0.33, 95% confidence interval 0.04–2.78) (p for interaction = 0.009). The primary safety outcome, a composite of any doubling of serum creatinine or any episode of serious hyperkalemia (K+ >6 mmol/L), occurred more commonly in MRA users compared with nonusers in the subgroup of patients without CKD, but not in CKD patients (p for interaction = 0.02). Conclusion: MRA treatment in addition to an ACEI or an ARB could be safely prescribed in HF patients with CKD as it is not associated with persistent renal function decline, acute kidney injury, or serious hyperkalemia, compared with ACEI/ARB monotherapy.
MicroRNA-193a Downregulates HMGB1 to Alleviate Diabetic Neuropathic Pain in a Mouse Model
Authors: Wu Bin , Guo Yuanyuan , Chen Qibin , Xiong Qiuju , Min Su
Published: October 2019

Background: Diabetic neuropathy is a serious complication for diabetic patients involving the nervous system. This disease is a quiet but painful condition caused by chronically high blood glucose levels. It is reported that high mobility group box 1 protein (HMGB1) participates in the development of neuropathic pain. This study aimed to explore the role of microRNA (miR)-193a in diabetic neuropathic pain through the regulation of HMGB1. Methods: A diabetic mouse model was established through the injection of streptozocin (STZ). Neuropathic pain development was shown by paw withdrawal thresholds and paw withdrawal latency. Expression levels of relative genes or miR were analyzed by qRT-PCR, while Western blot was employed to assess the protein levels. The interaction between miR-193a and HMGB1 mRNA 3′-UTR region was shown by luciferase assay. The levels of inflammation cytokines were measured by ELISA kits. Results: miR-193a expression was decreased and HMGB1 expression was upregulated in the lumbar spinal dorsal horn of STZ-induced diabetic mice. miR-193a inhibited HMGB1 expression in the lumbar spinal dorsal horn. Overexpression of miR-193a alleviated neuropathic pain in STZ-induced diabetic mice. Peripheral neuroinflammation in diabetic mice was suppressed by miR-193a overexpression. Conclusion: This research illustrates that miR-193a alleviates diabetic neuropathic pain in a mouse model through the inhibition of HMGB1 expression.
The Chronic Adverse Effect of Chloroquine on Kidney in Rats through an Autophagy Dependent and Independent Pathways
Authors: Wang Bin , Guo Honglei , Ling Lilu , Ji Jialing , Niu Jianying , Gu Yong
Published: October 2019

Background: Chloroquine (CQ), a classic autophagy inhibitor, is used clinically for malaria prophylaxis and pulmonary hypertension treatment. The adverse effects of CQ on morphological and functional changes in the kidney were investigated in the current study due to CQ accumulation in the kidney. Methods: Twelve male Sprague-Dawley rats were randomly divided into 2 groups for 4 weeks: group 1, control (n = 6); and group 2, CQ administration group (50 mg–1·kg per day ip; n = 6). Serum aldosterone and vasopressin were measured by radioimmunoassay. Immunofluorescence was used to colocalize Tunel with aquaporin 1, aquaporin 2 (AQP2), and Tamm-Horsfall protein. Expression of AQP2 and mineralocorticoid (MR) was detected by western blot and immunohistochemistry. Results: In the present study, 4 weeks of CQ administration were shown to induce severe kidney injury, including glomerular sclerosis and tubular cells apoptosis, especially distal tubular cells. Decreased expression of LC3II/I and p-AKT was demonstrated in CQ-treated rats. Glomerular and proximal tubule injury were associated with impaired autophagy flux, and distal tubule injury may be associated with downregulated cyclic adenosine monophosphate (cAMP)/PKA/AKT signaling. Both MR and AQP2, which are mainly located in the distal tubule and collecting duct, were significantly reduced in CQ-treated rats, thus leading to increased exosomal secretion of AQP2 in urine. Additionally, chronic CQ administration increased aldosterone and vasopressin levels in serum, but lowered the blood pressure, glomerular filtration rate, and urine concentration. Conclusions: CQ administration damages glomerular, proximal tubule autophagy, and severe distal tubular cells apoptosis by inhibiting cAMP/PKA/AKT signaling.
Implementation of World Health Organization Package of Essential Noncommunicable Disease Interventions for Cardiovascular Risk Management in Gaza/Palestine: A Retrospective Record Review Study
Authors: AlHelo Rula , Elessi Khamis
Published: October 2019

Background: Noncommunicable diseases (NCDs) are among the most common medical problems encountered in medical practice worldwide. The World Health Organization package of essential NCD (WHO PEN) interventions is a broad framework for integration of major NCDs into primary health care. These interventions include screening of diseases and their risk factors to prevent complications. WHO supports the adoption of WHO PEN into the Palestine Ministry of Health. PEN has been implemented in Gaza district since 2015, but only the protocols for cardiovascular disease and diabetes were selected for implementation. This study may help us to detect the impact of implementing PEN. Methods: A retrospective record review study was conducted using a random sample of 143 files from a total of 280 registered NCD patients who were followed up for 2 years at Alsourani clinic. Data were extracted manually from the medical records with the completion of a data sheet. Results: The study showed that most of the population was female (n = 86, 60.1%). The mean age was 58.8 ± 11.7 years. The vast majority were living a sedentary lifestyle (n = 141, 98.6%). Patients with one or more comorbidities were also tabulated according to the presence of each comorbidity among all subjects: hypertension (n = 92, 64.3%), any diabetes (n = 90, 62.9%), type 2 diabetes (n = 86, 60.1%), type 1 diabetes (n = 4, 2.8%), dyslipidemia (n = 41, 28.7%), neuropathy (n = 27, 18.9%), ischemic heart disease (n = 20, 14%), cerebrovascular disease (n = 4, 2.8%), retinopathy (n = 8, 5.6%), mental illness (n = 4, 2.8%), nephropathy (n = 3, 2.1%), cancer (n = 2, 1.4%), and respiratory diseases (n = 1, 0.7%). There was no statistically significant difference between pre- and post-parameter interventions for systolic and diastolic blood pressure, waist circumference, weight, body mass index, and cholesterol, as well as for tobacco use and cardiovascular risk (p > 0.05). In contrast, fasting blood sugar was lower, with a statistically significant difference (p = 0.049). Conclusion: NCDs in Palestine are a major health problem. Sustainability of WHO PEN interventions is recommended with insurance to support the needs of NCD patients and home visits. NCD interventions are compromised due to health care system gaps at primary care level. Therefore, we need strengthening of the primary health care system.
Sustained Monomorphic Ventricular Tachycardia in Nonischemic Heart Disease
Authors: Kanagasundram Arvindh , John Roy M. , Stevenson William G.
Published: October 2019

As the population of patients with implanted defibrillators has grown, an increasing number of patients nonischemic cardiomyopathies are requiring therapy to reduce ventricular arrhythmias. Most of these arrhythmias are related to areas of ventricular scar. Although the pathophysiology of scar development is not well understood in these diseases, advances in cardiac imaging and mapping are better characterizing the scar locations that give rise to the arrhythmias. Here, we review the pathophysiologic and electrocardiographic correlations that inform ablation strategies for ventricular tachycardia in these diseases.
Towards a History of the National-Popular in Bolivia, 1879–1980(Excerpt)
Authors: Zavaleta Mercado René
Published: October 2019

In this passage, Zavaleta describes the connections between the moment of real subsumption, social totalisation, the production of social-scientific knowledge that takes the resultant totality as its object, including Marxist theory, and finally, the emergence of a broad intersubjectivity with the capacity to become a revolutionary historical actor.
Introduction
Authors: Webber Jeffery R.
Published: October 2019

This introduction situates the work of Zavaleta in the field of Bolivian intellectual history, Latin American Studies, and Latin American Marxism. It also explains the objectives of the symposium and the logic underlying its constituent parts.
Ancient Art Meets Modern Science: American Medicine Investigates Acupuncture, 1970–1980
Authors: Jones Kelly Hacker
Published: October 2019

In the early 1970s, the so-called “acupuncture craze” swept America, introducing many Americans for the first time to this supposedly ancient therapy. Acupuncture was advertised as a cure-all, effective for everything from arthritis to smoking cessation, much to the dismay of the American Medical Association and other professional organizations. By April 1973, Nevada had passed a bill that legalized the use of acupuncture and established a State Board for Chinese Medicine, independent of its State Board for Medicine. In response, American physicians pursued two courses of action: they initiated biomedical studies that aimed at proving either a physiological or psychological effect generated by acupuncture, and they advocated for state-level regulations that restricted the use of acupuncture as an experimental therapy. Building on the work of historians of alternative medicine—including Anne Harrington and James Whorton—this paper contributes to our understanding of the position of alternative therapies within American medical practice.
The Life Sciences, 1900–2000: Analysis and Social Welfare from Mendel and Koch to Biotech and Conservation
Authors: Manning Patrick
Published: October 2019

The life sciences underwent a dramatic transformation during the twentieth century, with an expansion in fundamental knowledge of the process of evolution and its molecular basis, through advances in health care that greatly extended human life, and by the combination of these advances to address the problem of conserving the many forms of life threatened by expanding human society. The essay highlights the worldwide emphasis on social welfare in the years 1945–1980 and the expanding role of international collaboration, especially in the International Biological Program and its advances in ecology and the notion of the biosphere, and in the emergence of molecular biology. This was also the era of the Cold War, yet military confrontation had fewer implications for life sciences than for the natural sciences in that era. After 1980, deregulation and neoliberalism weakened programs for social welfare, yet links among the varying strands of life sciences continued to grow, bringing the development of genomics and its many implications, expanding epidemiology to include reliance on social sciences, and deepening ecological studies as the Anthropocene became more and more prevalent. In sum, the experience of the life sciences should make it clear to world historians that scientific advance goes beyond the achievements of brilliant but isolated researchers: those same advances rely substantially on social movements, migration, and the exchange of knowledge across intellectual and physical boundaries.
Historical Study of Societal Transformations in the Extended Indian Ocean Realm
Authors: Hall Kenneth R.
Published: October 2019

Western historiography placed the indigenous Asia beyond the court political centers and the most commercially prominent ports-of-trade in the background of an exogenous (colonial) foreground. Western historical research from the sixteenth century onward privileged selected aspects and voices of the exogenous, focusing on the Arabic and Persian Middle East, India, China, and the West, represented from the nineteenth century onward by the terms Islamization, Indianization, Sinification, and Westernization. Today, historians who study the Indian Ocean give “agency” to things indigenous when they are juxtaposed to things exogenous. Local activities, events, beliefs, institutions, communities, individuals, and historical narratives are emphasized, given weight, and “privileged” over dependency on the exogenous. Simply taking agency away from the exogenous and giving it to the indigenous may seem to be a more realistic approach to overcoming the “from the deck of a ship” critique, but the issue of emphasis and privileging at the expense of “another” remains. Historians researching the non-West have tempered their previously held stance on this issue and now admit the depth and scale of influence that major exogenous civilizations (e.g., the Middle East, China, India, and the West) have had on some local cultures.
Anahilapura: Understanding Its Expansive Network during the Time of the Chaulukyas
Authors: Ghosh Suchandra
Published: October 2019

Gujarat’s role in the international trade network has long been researched. During the first half of the second millennium CE, the Indian Ocean emerged as a vast trading zone; its western termini were Siraf/Basra/Baghdad in the Persian Gulf zone and Alexandria/Fustat (old Cairo) in the Red Sea area, while the eastern terminus extended up to the ports in China. However, this essay privileges a single place, Anahilapura, which acted as a hinterland to many of the ports of Gujarat.