bluuebunny/crossref_metadata_2025_split huggingface dataset:
Model-based deconstruction of cortical evoked potentials generated by subthalamic nucleus deep brain stimulation
Authors: Kumaravelu Karthik , Oza Chintan S. , Behrend Christina E. , Grill Warren M. 
Published: April 2018

Parkinson’s disease is associated with altered neural activity in the motor cortex. Chronic high-frequency deep brain stimulation (DBS) of the subthalamic nucleus (STN) is effective in suppressing parkinsonian motor symptoms and modulates cortical activity. However, the anatomical pathways responsible for STN DBS-mediated cortical modulation remain unclear. Cortical evoked potentials (cEP) generated by STN DBS reflect the response of cortex to subcortical stimulation, and the goal of this study was to determine the neural origin of STN DBS-generated cEP using a two-step approach. First, we recorded cEP over ipsilateral primary motor cortex during different frequencies of STN DBS in awake healthy and unilateral 6-OHDA-lesioned parkinsonian rats. Second, we used a detailed, biophysically based model of the thalamocortical network to deconstruct the neural origin of the recorded cEP. The in vivo cEP included short (R1)-, intermediate (R2)-, and long-latency (R3) responses. Model-based cortical responses to simulated STN DBS matched remarkably well the in vivo responses. The short-latency response was generated by antidromic activation of layer 5 pyramidal neurons, whereas recurrent activation of layer 5 pyramidal neurons via excitatory axon collaterals reproduced the intermediate-latency response. The long-latency response was generated by polysynaptic activation of layer 2/3 pyramidal neurons via the cortico-thalamic-cortical pathway. Antidromic activation of the hyperdirect pathway and subsequent intracortical and cortico-thalamo-cortical synaptic interactions were sufficient to generate cortical potential evoked by STN DBS, and orthodromic activation through basal ganglia-thalamus-cortex pathways was not required. These results demonstrate the utility of cEP to determine the neural elements activated by STN DBS that might modulate cortical activity and contribute to the suppression of parkinsonian symptoms. NEW & NOTEWORTHY Subthalamic nucleus (STN) deep brain stimulation (DBS) is increasingly used to treat Parkinson’s disease (PD). Cortical potentials evoked by STN DBS in patients with PD exhibit consistent short-latency (1–3 ms), intermediate-latency (5–15 ms), and long-latency (18–25 ms) responses. The short-latency response occurs as a result of antidromic activation of the hyperdirect pathway comprising corticosubthalamic axons. However, the neural origins of intermediate- and long-latency responses remain elusive, and the dominant view is that these are produced through the orthodromic pathway (basal ganglia-thalamus-cortex). By combining in vivo electrophysiology with computational modeling, we demonstrate that antidromic activation of the cortico-thalamic-cortical pathway is sufficient to generate the intermediate- and long-latency cortical responses to STN DBS.
ASTX660, a Novel Non-peptidomimetic Antagonist of cIAP1/2 and XIAP, Potently Induces TNFα-Dependent Apoptosis in Cancer Cell Lines and Inhibits Tumor Growth
Authors: Ward George A. , Lewis Edward J. , Ahn Jong Sook , Johnson Christopher N. , Lyons John F. , Martins Vanessa , Munck Joanne M. , Rich Sharna J. , Smyth Tomoko , Thompson Neil T. , Williams Pamela A. , Wilsher Nicola E. , Wallis Nicola G. , Chessari Gianni 
Published: April 2018

Abstract
Because of their roles in the evasion of apoptosis, inhibitor of apoptosis proteins (IAP) are considered attractive targets for anticancer therapy. Antagonists of these proteins have the potential to switch prosurvival signaling pathways in cancer cells toward cell death. Various SMAC-peptidomimetics with inherent cIAP selectivity have been tested clinically and demonstrated minimal single-agent efficacy. ASTX660 is a potent, non-peptidomimetic antagonist of cIAP1/2 and XIAP, discovered using fragment-based drug design. The antagonism of XIAP and cIAP1 by ASTX660 was demonstrated on purified proteins, cells, and in vivo in xenograft models. The compound binds to the isolated BIR3 domains of both XIAP and cIAP1 with nanomolar potencies. In cells and xenograft tissue, direct antagonism of XIAP was demonstrated by measuring its displacement from caspase-9 or SMAC. Compound-induced proteasomal degradation of cIAP1 and 2, resulting in downstream effects of NIK stabilization and activation of noncanonical NF-κB signaling, demonstrated cIAP1/2 antagonism. Treatment with ASTX660 led to TNFα-dependent induction of apoptosis in various cancer cell lines in vitro, whereas dosing in mice bearing breast and melanoma tumor xenografts inhibited tumor growth. ASTX660 is currently being tested in a phase I–II clinical trial (NCT02503423), and we propose that its antagonism of cIAP1/2 and XIAP may offer improved efficacy over first-generation antagonists that are more cIAP1/2 selective. Mol Cancer Ther; 17(7); 1381–91. ©2018 AACR.
ГУМКИ ЖУВАЛЬНІ ЛІКУВАЛЬНІ: ПРИЗНАЧЕННЯ, ТЕХНОЛОГІЯ І АНАЛІЗ
Authors: Koval V. M. , Denys A. I. , Hroshovyi T. A. , Vronska L. V. 
Published: April 2018

Мета роботи. Аналіз і систематизація даних літератури щодо призначення і класифікації гумок жувальних лікувальних, їх технології, методів дослідження і показників якості.Матеріали і методи. У роботі використано методи інформаційного пошуку, аналізу даних літератури щодо лікарської форми – гумка жувальна лікувальна.Результати й обговорення. Гумка жувальна лікувальна є зручною системою доставки лікарського засобу і може забезпечувати високу комплаєнтність пацієнта. Для виготовлення гумки жувальної лікувальної використовують метод плавлення; метод замороження, подрібнення і таблетування; метод прямого пресування. Фармакопейними показниками якості гумок є опис, ідентифікація, середня маса, однорідність маси, однорідність вмісту, розчинення, мікробіологічна чистота, кількісне визначення. У процесі розробки складу і технології гумок набір фармако-технологічних показників і методик випробувань суттєво відрізняється від фармакопейних і включає визначення численних органолептичних властивостей, вивчення текстури інструментальними методами.Висновок. Гумка жувальна лікувальна – це мобільна система доставки ліків, яка містить один або кілька активних інгредієнтів, що вивільняються шляхом жування. Розглянуто методи та особливості технології, фармако-технологічні показники і показники якості гумок жувальних лікувальних. Дана лікарська форма має переваги порівняно з традиційними системами доставки ліків, характеризується високим комплаєнсом. Серед трьох відомих методів отримання гумок, за рахунок появи готових основ промислового виробництва, все більшого застосування набуває метод прямого пресування.
Brain Ischemia Induces Diversified Neuroantigen-Specific T-Cell Responses That Exacerbate Brain Injury
Authors: Jin Wei-Na , Gonzales Rayna , Feng Yan , Wood Kristofer , Chai Zhi , Dong Jing-Fei , La Cava Antonio , Shi Fu-Dong , Liu Qiang 
Published: April 2018

Background and Purpose—
Autoimmune responses can occur when antigens from the central nervous system are presented to lymphocytes in the periphery or central nervous system in several neurological diseases. However, whether autoimmune responses emerge after brain ischemia and their impact on clinical outcomes remains controversial. We hypothesized that brain ischemia facilitates the genesis of autoimmunity and aggravates ischemic brain injury.

Methods—

Using a mouse strain that harbors a transgenic T-cell receptor to a central nervous system antigen, MOG
35-55
(myelin oligodendrocyte glycoprotein) epitope (2D2), we determined the anatomic location and involvement of antigen-presenting cells in the development of T-cell reactivity after brain ischemia and how T-cell reactivity impacts stroke outcome. Transient middle cerebral artery occlusion and photothrombotic stroke models were used in this study. We also quantified the presence and status of T cells from brain slices of ischemic patients.

Results—

By coupling transfer of labeled MOG
35-55
-specific (2D2) T cells with tetramer tracking, we show an expansion in reactivity of 2D2 T cells to MOG
91-108
and MOG
103-125
in transient middle cerebral artery occlusion and photothrombotic stroke models. This reactivity and T-cell activation first occur locally in the brain after ischemia. Also, microglia act as antigen-presenting cells that effectively present MOG antigens, and depletion of microglia ablates expansion of 2D2 reactive T cells. Notably, the adoptive transfer of neuroantigen-experienced 2D2 T cells exacerbates Th1/Th17 responses and brain injury. Finally, T-cell activation and MOG-specific T cells are present in the brain of patients with ischemic stroke.

Conclusions—
Our findings suggest that brain ischemia activates and diversifies T-cell responses locally, which exacerbates ischemic brain injury.
Distribution of Lacunar Infarcts in Asians With Intracerebral Hemorrhage
Authors: Tsai Hsin-Hsi , Pasi Marco , Tsai Li-Kai , Chen Ya-Fang , Lee Bo-Ching , Tang Sung-Chun , Fotiadis Panagiotis , Huang Chen-Yu , Yen Ruoh-Fang , Gurol M. Edip , Jeng Jiann-Shing 
Published: April 2018

Background and Purpose—
We evaluated whether lacunes in centrum semiovale (lobar lacunes) were associated with cerebral amyloid angiopathy (CAA) markers in an Asian intracerebral hemorrhage (ICH) population.

Methods—
One hundred ten patients with primary ICH were classified as CAA-ICH (n=24; mean age, 70.9±13.9) or hypertensive ICH (n=86; mean age, 59.3±13.0) according to the presence of strictly lobar (per modified Boston criteria) or strictly deep bleeds (both ICH and cerebral microbleeds), respectively. Lacunes were evaluated in the supratentorial area and classified as lobar or classical deep based on the location. A subgroup of 36 patients also underwent Pittsburgh Compound B positron emission tomography to measure cerebral amyloid deposition and global standardized uptake value ratio were calculated.

Results—

Lobar lacunes were more frequent in CAA-ICH than hypertensive ICH (29.2 versus 11.6%;
P
=0.036). In multivariable models, lobar lacunes were associated with lobar cerebral microbleed (odds ratio, 6.8; 95% confidence interval, 1.6–29.9;
P
=0.011) after adjustment for age, sex, hypertension, and white matter hyperintensity. In 15 CAA-ICH and 21 hypertensive ICH patients with Pittsburgh Compound B positron emission tomography, correlation analyses between lobar lacune counts and global standardized uptake value ratio showed positive association (ρ=0.40;
P
=0.02) and remained significant after adjustment for age (
r
=0.34;
P
=0.04).

Conclusions—
Our findings expand on recent work showing that lobar lacunes are more frequent in CAA-ICH than hypertensive ICH. Their independent association with lobar cerebral microbleeds and brain amyloid deposition suggests a relationship with CAA even in an Asian cohort with overall higher hypertensive load.
An Operational Rapid Intensification Prediction Aid for the Western North Pacific
Authors: Knaff John A. , Sampson Charles R. , Musgrave Kate D. 
Published: April 2018

Abstract
This work describes tropical cyclone rapid intensification forecast aids designed for the western North Pacific tropical cyclone basin and for use at the Joint Typhoon Warning Center. Two statistical methods, linear discriminant analysis and logistic regression, are used to create probabilistic forecasts for seven intensification thresholds including 25-, 30-, 35-, and 40-kt changes in 24 h, 45- and 55-kt in 36 h, and 70-kt in 48 h (1 kt = 0.514 m s−1). These forecast probabilities are further used to create an equally weighted probability consensus that is then used to trigger deterministic forecasts equal to the intensification thresholds once the probability in the consensus reaches 40%. These deterministic forecasts are incorporated into an operational intensity consensus forecast as additional members, resulting in an improved intensity consensus for these important and difficult to predict cases. Development of these methods is based on the 2000–15 typhoon seasons, and independent performance is assessed using the 2016 and 2017 typhoon seasons. In many cases, the probabilities have skill relative to climatology and adding the rapid intensification deterministic aids to the operational intensity consensus significantly reduces the negative forecast biases.
Long-term follow-up of clozapine prescribing
Authors: Gee Siobhan H , Shergill Sukhwinder S , Taylor David M 
Published: April 2018

Objective: Clozapine is uniquely effective for treatment-resistant schizophrenia, and so treatment continuation is essential. We aimed to identify factors associated with an increased likelihood of clozapine discontinuation in a cohort of patients in South East London. Methods: We gathered demographic and treatment information such as duration of illness and antipsychotic treatment history. t-tests, chi-square tests and binary logistic regression were used to compare patients who continued and discontinued clozapine during the study and to identify predictor variables for discontinuation. Results: Out of the study population of 133 patients, 48 discontinued clozapine at least once during the study period. The majority of these (75%) stopped treatment within the first 4 years of clozapine therapy. Age, ethnicity, diagnosis and antipsychotic treatment history were not predictive of the risk of clozapine discontinuation. However, male patients were more likely to stop taking clozapine (χ2 = 6.81, p = 0.009). The odds of discontinuing clozapine were 2.15 times higher for male patients. The most common reason for discontinuation was patient refusal of treatment. Conclusion: We found that patients who discontinue clozapine are more likely to be male, but no other demographic variable was found to predict treatment cessation. Discontinuation usually occurred due to patient refusal of treatment.
Identification of Inequalities in the Selection of Liver Surgery for Colorectal Liver Metastases in Sweden
Authors: Norén A. , Sandström P. , Gunnarsdottir K. , Ardnor B. , Isaksson B. , Lindell G. , Rizell M. 
Published: April 2018

Background: Liver resection for colorectal liver metastases offers a 5-year survival rate of 25%–58%. This study aimed to analyze whether patients with colorectal liver metastases undergo resection to an equal extent and whether selection factors play a role in the selection process. Material and Methods: Data were retrieved from the Swedish Colorectal Cancer Registry (2007–2011) for colorectal cancer and colorectal liver metastases. The patients identified were linked to the Swedish Registry of Liver and Bile surgery and the National Patient Registry to identify whether liver surgery or ablative treatment was performed. Analyses for age, sex, type of primary tumor and treating hospital (university, county, or district), American Society of Anesthesiologists class, and radiology for detection of metastatic disease were performed. Results: Of 28,355 patients with colorectal cancer, 21.6% (6127/28,355) presented with liver metastases. Of the patients with liver metastases, 18.5% (1134/6127) underwent liver resection or ablation. The cumulative proportion of liver resection/ablation was 4% (1134/28,355) of all colorectal cancer. If “not bowel resected” were excluded, the proportion slightly increased to 4.7% (1134/24,262). Around 15% of the patients with metastases were registered as referrals for liver surgery. In a multivariable analysis patients treated at a university hospital for primary tumor were more frequently surgically treated for liver metastases (p < 0.0001). Patients with liver metastases from rectal cancer (p < 0.0001) and men more often underwent liver resection (p = 0.006). A difference was found between health-care regions for the frequency of liver surgery (p < 0.0001). Patients >70 years and those with American Society of Anesthesiologists class >2 underwent liver resection less frequently. Magnetic resonance imaging of the liver was more often used in diagnostic work-up in men. Conclusion: Patients with colorectal liver metastases are unequally treated in Sweden, as indicated by the low referral rate. The proximity to a hepatobiliary unit seems important to enhance the patient’s chances of being offered liver surgery.
Age-related differences in the rate and diagnosis of 30-day readmission after hospitalization for acute ischemic stroke
Authors: Hirayama Atsushi , Goto Tadahiro , Faridi Mohammad K , Camargo Carlos A , Hasegawa Kohei 
Published: April 2018

Background Little is known about the association between age and readmission within 30 days after hospitalization for acute ischemic stroke. Aim To examine the age-related differences in rate and principal reason of 30-day readmissions in patients hospitalized for acute ischemic stroke. Methods In this retrospective, population-based cohort study using State Inpatient Databases from eight US states, we identified all adults hospitalized for acute ischemic stroke. We grouped the patients into four age categories: < 65, 65–74, 75–84, and ≥85 years. Outcomes were any-cause readmission within 30 days of discharge from the index hospitalization for acute ischemic stroke and the principal diagnosis of 30-day readmission. Results We identified 620,788 hospitalizations for acute ischemic stroke. The overall 30-day readmission rate was 16.6% with an increase with advanced age. Compared to patients aged <65 years, the readmission rate was significantly higher in age 65–74 years (OR 1.19; 95% CI 1.16–1.21), in age 75–84 years (OR 1.29; 95% CI 1.27–1.31), and in ≥ 85 years (OR 1.24; 95% CI 1.22–1.27; all P<0.001). There was heterogeneity in the age-readmission rate association between men and women (Pinteraction < 0.001). Overall, 45.8% of readmissions were assigned stroke-related conditions or rehabilitation care. Compared to younger adults, older adults were more likely to present with non-stroke-related conditions (46.1% in < 65 years, 50.6% in 65–74 years, 57.1% in 75–84 years, and 62.9% in ≥ 85 years; P<0.001). Conclusions Advanced age was associated with a higher 30-day readmission rate after acute ischemic stroke. Compared with younger adults, older adults were more likely to be readmitted for non-stroke-related conditions.
Reconciling hospital-acquired complications and CHADx+ in Victorian coded hospital data
Authors: Shepheard Jennie , Lapiz Elsa , Read Carla , Jackson Terri J 
Published: April 2018

Background: The Council of Australian Governments has focused the attention of health service managers and state health departments on a list of hospital-acquired complications (HACs) proposed as the basis of funding adjustments for poor quality of hospital inpatient care. These were devised for the Australian Commission on Safety and Quality in Health Care as a subset of their earlier classification of hospital-acquired complications (CHADx) and designed to be used by health services to monitor safety performance for their admitted patients. Objective: To improve uptake of both classification systems by clarifying their purposes and by reconciling the ICD-10-AM code sets used in HACs and the Victorian revisions to the CHADx system (CHADx+). Method: Frequency analysis of individual clinical codes with condition onset flag (COF 1) included in both classification systems using the Victorian Admitted Episodes Dataset for 2014/2015 ( n = 2,623,275 separations). Narrative description of the resulting differences in definition of “adverse events” embodied in the two systems. Results: As expected, a high proportion of ICD-10-AM codes used in the HACs also appear in CHADx+, and given the wider scope of CHADx+, it uses a higher proportion of all COF 1 diagnoses than HACs (82% vs. 10%). This leads to differing estimates of rates of adverse events: 2.12% of cases for HACs and 11.13% for CHADx+. Most CHADx classes (70%) are not covered by the HAC system; discrepancies result from the exclusion from HACs of several major CHADx+ groups and from a narrower definition of detailed HAC classes compared with CHADx+. Case exclusion criteria in HACs (primarily mental health admissions) resulted in a very small proportion of discrepancies (0.13%) between systems. Discussion: Issues of purpose and focus of these two Australian systems, HACs for clinical governance and CHADx+ for local quality improvement, explain many of the differences between them, and their approach to preventability, and risk stratification. Conclusion: A clearer delineation between these two systems using routinely coded hospital data will assist funders, clinicians, quality improvement professionals and health information managers to understand discrepancies in case identification between them and support their different information needs.
Non-Destructive Spectroscopic Assessment of High and Low Weight Bearing Articular Cartilage Correlates with Mechanical Properties
Authors: Karchner James P. , Yousefi Farzad , Bitman Stephanie R. , Darvish Kurosh , Pleshko Nancy 
Published: April 2018

Objective Autologous articular cartilage (AC) harvested for repair procedures of high weight bearing (HWB) regions of the femoral condyles is typically obtained from low weight bearing (LWB) regions, in part due to the lack of non-destructive techniques for cartilage composition assessment. Here, we demonstrate that infrared fiber optic spectroscopy can be used to non-destructively evaluate variations in compositional and mechanical properties of AC across LWB and HWB regions. Design AC plugs ( N = 72) were harvested from the patellofemoral groove of juvenile bovine stifle joints, a LWB region, and femoral condyles, a HWB region. Near-infrared (NIR) and mid-infrared (MIR) fiber optic spectra were collected from plugs, and indentation tests were performed to determine the short-term and equilibrium moduli, followed by gravimetric water and biochemical analysis. Results LWB tissues had a significantly greater amount of water determined by NIR and gravimetric assay. The moduli generally increased in tissues from the patellofemoral groove to the condyles, with HWB condyle cartilage having significantly higher moduli. A greater amount of proteoglycan content was also found in HWB tissues, but no differences in collagen content. In addition, NIR-determined water correlated with short-term modulus and proteoglycan content ( R = −0.40 and −0.31, respectively), and a multivariate model with NIR data was able to predict short-term modulus within 15% error. Conclusions The properties of tissues from LWB regions differ from HWB tissues and can be determined non-destructively by infrared fiber optic spectroscopy. Clinicians may be able to use this modality to assess AC prior to harvesting osteochondral grafts for focal defect repair.