bluuebunny/crossref_metadata_2025_split huggingface dataset:
Methodological Approaches to Preclinical Evaluation of General Toxicity of Therapeutic Radiopharmaceuticals
Authors: Klementyeva O. E. , Lunev A. S. , Lunyova C. A. 
Published: December 2021

Radiopharmaceuticals differ from other medicines mainly by the specific nature of their pharmacological action based on radioactivity, by absence of multiple-dose regimens, and by miniscule concentrations of the active pharmaceutical ingredient (10-9–10-12 mol/L). However, the official regulations and standards do not contain specific requirements for preclinical evaluation of radiopharmaceuticals. The aim of the study was to summarise preclinical data on general toxicity of therapeutic radiopharmaceuticals, which were obtained by the Laboratory of Preclinical and Clinical Studies of Radiopharmaceuticals of the Federal State Budgetary Institution ‘State Research Center of the Russian Federation¾Burnasyan Federal Medical Biophysical Center’ of the Federal Medical Biological Agency. Results: the authors analysed criteria for: selection of the study design based on physico-chemical nature of the active pharmaceutical ingredient; calculation of doses and selection of dosage regimens for radiopharmaceuticals with different administration routes; radiation safety for personnel performing the study. The authors used the data on three therapeutic radiopharmaceuticals to formulate methodological approaches to preclinical evaluation of their general toxic properties. The analysis of long-term experience in preclinical studies of therapeutic radiopharmaceuticals demonstrated the need for a judicious individual approach to the development of a preclinical study design. The authors proposed methodological approaches to preclinical evaluation of general toxic properties of therapeutic radiopharmaceuticals, which make it possible to adequately assess potential toxic effects and obtain meaningful study results. Conclusions: there is a need for a specific guideline for preclinical studies of therapeutic radiopharmaceuticals, which would take into account specific pharmacological action and nuclear-physical characteristics of radionuclides.
SIMULASI KEBIJAKAN PADA IMPLEMENTASI PERJANJIAN KOMPREHENSIF INDONESIA-AUSTRALIA (IA-CEPA) TERHADAP PASAR DAGING SAPI DOMESTIK
Authors: Helmiah Najia , Nasrudin  
Published: December 2021

Abstrak
Beberapa tahun terakhir, pemenuhan permintaan daging sapi di Indonesia masih bergantung pada impor khususnya dari Australia. Impor daging sapi dapat menstabilkan harga daging sapi domestik, tetapi di lain sisi dapat menekan pendapatan peternak lokal. Implementasi dari IA-CEPA adalah penghapusan tarif impor dan TRQ (Tariff Rate Quota) untuk komoditas sapi hidup. Penghapusan tarif menyebabkan harga sapi yang masuk ke Indonesia menjadi lebih murah dan memperbesar peluang peningkatan volume impor sapi hidup. Penelitian ini bertujuan untuk menganalisis skenario terbaik untuk meningkatkan kesejahteraan pelaku ekonomi dengan menggunakan model persamaan simultan 2SLS (two stage least square). Simulasi dilakukan untuk tiga skenario yaitu skenario penghapusan tarif, penetapan kuota, dan TRQ. Hasilnya menunjukkan bahwa skenario penghapusan tarif memberikan total peningkatan kesejahteraan pelaku ekonomi terbesar yaitu 115 miliar dengan rincian defisit 736 miliar bagi produsen, surplus 936 miliar bagi konsumen, dan defisit 85 miliar untuk penerimaan pemerintah. Oleh karena itu, skenario yang direkomendasikan adalah skenario penghapusan tarif pada impor sapi dari Australia.
Kata Kunci: 2SLS, IA-CEPA, Pasar Daging Sapi

Abstract
Recently, demand fulfillment of beef in Indonesia depended on imports, especially from Australia. import can stabilize the domestic price of beef, but the other hand can suppress the income of local farmers. Implementation of IA-CEPA policies is the elimination of import tariff and TRQ (tariff rate quota) for live cattle commodities. Elimination of import tariff causes the price of cattle to enter Indonesia to be cheaper and increases the opportunity to increase the import volume of live cattle. The study aims to investigate the best scenario that can improve the welfare of economic actors using simultaneous equation model 2SLS (two-stage least squares). Three scenarios that simulated are eliminating tariff, setting quota, and TRQ. The result shows that eliminating tariffs gives the largest total welfare increase of economic actors that is 115 billion, with a 736 billion deficit for producers, 936 billion surplus for consumers, and 85 billion deficit for government revenue. Therefore, the policy recommendation is the scenario of eliminating tariffs on cattle imports from Australia.
Keywords: 2SLS, IA-CEPA, Beef Market
JEL Classification: C53, F12, F13
On Anselm’s Ontological Argument in Proslogion II
Authors: Oppenheimer Paul E. , Zalta Edward N. 
Published: December 2021

Abstract
Formulations of Anselm’s ontological argument have been the subject of a number of recent studies. We examine these studies in light of Anselm’s text and (a) respond to criticisms that have surfaced in reaction to our earlier representations of the argument, (b) identify and defend a more refined representation of Anselm’s argument on the basis of new research, and (c) compare our representation of the argument, which analyzes that than which none greater can be conceived as a definite description, to a representation that analyzes it as an arbitrary name.
Estimating the prevalence of neurosurgical interventions in adults with spina bifida using the Health Facts data set: implications for transition planning and the development of adult clinics
Authors: Domino Joseph S. , Lundy Paige , Glynn Earl F. , Partington Michael 
Published: December 2021

OBJECTIVE
As the care of patients with spina bifida continues to evolve, life expectancy is increasing, leading to a critical need for transition planning from pediatric-based to adult-based care. The burden of neurosurgical care for adults with spina bifida remains unknown. In this study, the authors sought to use a large national data set to estimate the prevalence of neurosurgical interventions in adults with spina bifida.

METHODS
This study utilized Health Facts, which is a de-identified proprietary data set abstracted from all Cerner electronic health records. It includes 69 million unique patients with > 500 million encounters in 580 centers. Validation, technical exclusions, and data filters were applied to obtain an appropriate cohort of patients. The ICD-9 and ICD-10 codes for all types of spinal dysraphism, as well as the Current Procedural Terminology (CPT) codes for hydrocephalus procedures, spinal cord untethering, and Chiari decompression, were queried and records were retrieved. Demographic variables along with differences in age groups and temporal trends were analyzed.

RESULTS
Overall, 24,764 unique patients with ≥ 1 encounter with a spinal dysraphism diagnosis between 2000 and 2017 were identified. The pediatric cohort included 11,123 patients with 60,027 separate encounters, and the adult cohort included 13,641 patients with 41,618 separate encounters. The proportion of females was higher in the adult (62.9%) than in the pediatric (51.4%) cohort. Annual encounters were stable from 2 to 18 years of age, but then decreased by approximately half with a precipitous drop after age 21 years. The sex distribution of adults and children who underwent procedures was similar (54.6% female adults vs 52.4% female children). Surgical interventions in adults were common. Between 2013 and 2017, there were 4913 procedures for hydrocephalus, with 2435 (49.6%) adult patients. Similarly, 273 (33.3%) of the 819 tethered cord procedures were performed in adults, as were 307 (32.9%) of 933 Chiari decompressions.

CONCLUSIONS
The Health Facts database offered another option for studying care delivery and utilization in patients aging with spina bifida. The median age of this population has now reached early adulthood, and a significant number of neurosurgical procedures were performed in adults. An abrupt drop in the rate of encounters occurred at 21 years of age, possibly reflecting transition issues such as access-to-care problems and lack of coordinated care.
Electrically evoked and spontaneous neural activity in the subthalamic nucleus under general anesthesia
Authors: Sinclair Nicholas C. , McDermott Hugh J. , Lee Wee-Lih , Xu San San , Acevedo Nicola , Begg Angus , Perera Thushara , Thevathasan Wesley , Bulluss Kristian J. 
Published: December 2021

OBJECTIVE
Deep brain stimulation (DBS) surgery is commonly performed with the patient awake to facilitate assessments of electrode positioning. However, awake neurosurgery can be a barrier to patients receiving DBS. Electrode implantation can be performed with the patient under general anesthesia (GA) using intraoperative imaging, although such techniques are not widely available. Electrophysiological features can also aid in the identification of target neural regions and provide functional evidence of electrode placement. Here we assess the presence and positional variation under GA of spontaneous beta and high-frequency oscillation (HFO) activity, and evoked resonant neural activity (ERNA), a novel evoked response localized to the subthalamic nucleus.

METHODS
ERNA, beta, and HFO were intraoperatively recorded from DBS leads comprising four individual electrodes immediately after bilateral awake implantation into the subthalamic nucleus of 21 patients with Parkinson’s disease (42 hemispheres) and after subsequent GA induction deep enough to perform pulse generator implantation. The main anesthetic agent was either propofol (10 patients) or sevoflurane (11 patients).

RESULTS
GA reduced the amplitude of ERNA, beta, and HFO activity (p < 0.001); however, ERNA amplitudes remained large in comparison to spontaneous local field potentials. Notably, a moderately strong correlation between awake ERNA amplitude and electrode distance to an “ideal” therapeutic target within dorsal STN was preserved under GA (awake: ρ = −0.73, adjusted p value [padj] < 0.001; GA: ρ = −0.69, padj < 0.001). In contrast, correlations were diminished under GA for beta (awake: ρ = −0.45, padj < 0.001; GA: ρ = −0.13, padj = 0.12) and HFO (awake: ρ = −0.69, padj < 0.001; GA: ρ = −0.33, padj < 0.001). The largest ERNA occurred at the same electrode (awake vs GA) for 35/42 hemispheres (83.3%) and corresponded closely to the electrode selected by the clinician for chronic therapy at 12 months (awake ERNA 77.5%, GA ERNA 82.5%). The largest beta amplitude occurred at the same electrode (awake vs GA) for only 17/42 (40.5%) hemispheres and 21/42 (50%) for HFO. The electrode measuring the largest awake beta and HFO amplitudes corresponded to the electrode selected by the clinician for chronic therapy at 12 months in 60% and 70% of hemispheres, respectively. However, this correspondence diminished substantially under GA (beta 20%, HFO 35%).

CONCLUSIONS
ERNA is a robust electrophysiological signal localized to the dorsal subthalamic nucleus subregion that is largely preserved under GA, indicating it could feasibly guide electrode implantation, either alone or in complementary use with existing methods.
Role of resective surgery in patients older than 60 years with therapy-resistant epilepsy
Authors: Bottan Juan S. , Suller Marti Ana , Burneo Jorge G. , Parrent Andrew G. , MacDougall Keith W. , McLachlan Richard S. , Mirsattari Seyed , Diosy David C. , Steven David A. 
Published: December 2021

OBJECTIVE
Epilepsy surgery for older adults is controversial owing to their longer duration of epilepsy and perceived higher surgical risk. However, because of an aging population and documented benefit of epilepsy surgery, surgery is considered more frequently for these patients. The authors’ objective was to analyze the role of resective surgery in patients older than 60 years and to assess outcomes and safety.

METHODS
The authors conducted a retrospective analysis of 595 patients who underwent resective epilepsy surgery at their center from 1999 to 2018. Thirty-one patients aged 60 years or older were identified. Sixty patients younger than 60 years were randomly selected as controls. Population characteristics, results of presurgical evaluations, outcomes, and complications were analyzed.

RESULTS
No significant differences were found between the groups in terms of hemisphere dominance, side of surgery, presence of a lesion, and incidence of temporal lobe epilepsy. Epilepsy duration was greater in the older cohort (p = 0.019), and invasive EEG was more commonly employed in younger patients (p = 0.030). The rates of Engel class I outcome at 6 months, 1 year, and 2 years were 89.7%, 96.2%, and 94.7% for the older group and 75% (p = 0.159), 67.3% (p = 0.004), and 75.8% (p = 0.130) for the younger group, respectively. The proportion of seizure-free patients was greatest among those with temporal lobe epilepsy, particularly in the older group. Neurological complication rates did not differ significantly between groups, however medical and other minor complications occurred more frequently in the older group.

CONCLUSIONS
Patients older than 60 years had equal or better outcomes at 1 year after epilepsy surgery than younger patients. A trend toward a greater proportion of patients with lesional temporal lobe epilepsy was found in the older group. These results suggest that good seizure outcomes can be obtained in older patients despite longer duration of epilepsy.
Combined stereotactic radiosurgery and tyrosine kinase inhibitor therapy versus tyrosine kinase inhibitor therapy alone for the treatment of non–small cell lung cancer patients with brain metastases
Authors: Chiou Guan-Ying , Chiang Chi-Lu , Yang Huai-Che , Shen Chia-I , Wu Hsiu-Mei , Chen Yu-Wei , Chen Ching-Jen , Luo Yung-Hung , Hu Yong-Sin , Lin Chung-Jung , Chung Wen-Yuh , Shiau Cheng-Ying , Guo Wan-Yuo , Pan David Hung-Chi , Lee Cheng-Chia 
Published: December 2021

OBJECTIVE
Whether combined radiation and tyrosine kinase inhibitor (TKI) therapy in non–small cell lung cancer (NSCLC) patients with brain metastases (BMs) and epidermal growth factor receptor (EGFR) mutations confers additional benefits over TKI therapy alone remains a matter of debate. The goal of this study was to compare outcomes between combined TKI therapy with stereotactic radiosurgery (SRS) versus TKI therapy alone in NSCLC patients with BMs and EGFR mutations.

METHODS
Consecutive cases of NSCLC patients with EGFR mutations and BMs treated with TKIs were selected for inclusion in this study. Patients were categorized into two groups based on SRS: TKI therapy alone (group I) and combined SRS and TKI therapy (group II). Patients who had SRS or TKI as salvage therapy and those with prior radiation treatment for BMs were excluded. Tumor control (< 10% increase in tumor volume) and overall survival (OS) rates were compared using Kaplan-Meier analyses. Independent predictors of tumor control and OS were identified using multivariable Cox regression analyses.

RESULTS
The study cohort comprised 280 patients (n = 90 in group I and n = 190 in group II). Cumulative tumor control rates were higher in group II than in group I (79.8% vs 31.2% at 36 months, p < 0.0001). Cumulative OS rates were comparable between groups I and II (43.8% vs 59.4% at 36 months, p = 0.3203). Independent predictors of tumor control were older age (p < 0.01, HR 1.03), fewer BMs (p < 0.01, HR 1.09), lack of extracranial metastasis (p < 0.02, HR 0.70), and combined SRS and TKI therapy (p < 0.01, HR 0.25). Independent predictors of OS were fewer BMs (p < 0.01, HR 1.04) and a higher Karnofsky Performance Status score (p < 0.01, HR 0.97).

CONCLUSIONS
Although the OS rate did not differ between TKI therapy with and without SRS, the addition of SRS to TKI therapy resulted in improvement of intracranial tumor control. The lack of effect on survival rate with the addition of SRS may be attributable to extracranial disease progression. The addition of SRS to TKI therapy is recommended for intracranial disease control in NSCLC patients with BMs and EGFR mutations. Potential benefits may include prevention of neurological deficits and seizures. Future prospective studies may help clarify the clinical outcome benefits of SRS in these patients.
A multicenter cohort study of early complications after cranioplasty: results of the German Cranial Reconstruction Registry
Authors: Sauvigny Thomas , Giese Henrik , Höhne Julius , Schebesch Karl Michael , Henker Christian , Strauss Andreas , Beseoglu Kerim , Spreckelsen Niklas von , Hampl Jürgen A. , Walter Jan , Ewald Christian , Krigers Aleksandrs , Petr Ondra , Butenschoen Vicki M. , Krieg Sandro M. , Wolfert Christina , Gaber Khaled , Mende Klaus Christian , Bruckner Thomas , Sakowitz Oliver , Lindner Dirk , Regelsberger Jan , Mielke Dorothee 
Published: December 2021

OBJECTIVE
Cranioplasty (CP) is a crucial procedure after decompressive craniectomy and has a significant impact on neurological improvement. Although CP is considered a standard neurosurgical procedure, inconsistent data on surgery-related complications after CP are available. To address this topic, the authors analyzed 502 patients in a prospective multicenter database (German Cranial Reconstruction Registry) with regard to early surgery-related complications.

METHODS
Early complications within 30 days, medical history, mortality rates, and neurological outcome at discharge according to the modified Rankin Scale (mRS) were evaluated. The primary endpoint was death or surgical revision within the first 30 days after CP. Independent factors for the occurrence of complications with or without surgical revision were identified using a logistic regression model.

RESULTS
Traumatic brain injury (TBI) and ischemic stroke were the most common underlying diagnoses that required CP. In 230 patients (45.8%), an autologous bone flap was utilized for CP; the most common engineered materials were titanium (80 patients [15.9%]), polyetheretherketone (57 [11.4%]), and polymethylmethacrylate (57 [11.4%]). Surgical revision was necessary in 45 patients (9.0%), and the overall mortality rate was 0.8% (4 patients). The cause of death was related to ischemia in 2 patients, diffuse intraparenchymal hemorrhage in 1 patient, and cardiac complications in 1 patient. The most frequent causes of surgical revision were epidural hematoma (40.0% of all revisions), new hydrocephalus (22.0%), and subdural hematoma (13.3%). Preoperatively increased mRS score (OR 1.46, 95% CI 1.08–1.97, p = 0.014) and American Society of Anesthesiologists Physical Status Classification System score (OR 2.89, 95% CI 1.42–5.89, p = 0.003) were independent predictors of surgical revision. Ischemic stroke, as the underlying diagnosis, was associated with a minor rate of revisions compared with TBI (OR 0.18, 95% CI 0.06–0.57, p = 0.004).

CONCLUSIONS
The authors have presented class II evidence–based data on surgery-related complications after CP and have identified specific preexisting risk factors. These results may provide additional guidance for optimized treatment of these patients.
Development of a miniaturized robotic guidance device for stereotactic neurosurgery
Authors: Minchev Georgi , Wurzer Ayguel , Ptacek Wolfgang , Kronreif Gernot , Micko Alexander , Dorfer Christian , Wolfsberger Stefan 
Published: December 2021

OBJECTIVE
Consistently high accuracy and a straightforward use of stereotactic guidance systems are crucial for precise stereotactic targeting and a short procedural duration. Although robotic guidance systems are widely used, currently available systems do not fully meet the requirements for a stereotactic guidance system that combines the advantages of frameless surgery and robotic technology. The authors developed and optimized a small-scale yet highly accurate guidance system that can be seamlessly integrated into an existing operating room (OR) setup due to its design. The aim of this clinical study is to outline the development of this miniature robotic guidance system and present the authors’ clinical experience.

METHODS
After extensive preclinical testing of the robotic stereotactic guidance system, adaptations were implemented for robot fixation, software usability, navigation integration, and end-effector application. Development of the robotic system was then advanced in a clinical series of 150 patients between 2013 and 2019, including 111 needle biopsies, 13 catheter placements, and 26 stereoelectroencephalography (SEEG) electrode placements. During the clinical trial, constant modifications were implemented to meet the setup requirements, technical specifications, and workflow for each indication. For each application, specific setup, workflow, and median procedural accuracy were evaluated.

RESULTS
Application of the miniature robotic system was feasible in 149 of 150 cases. The setup in each procedure was successfully implemented without adding significant OR time. The workflow was seamlessly integrated into the preexisting procedure. In the course of the study, procedural accuracy was improved. For the biopsy procedure, the real target error (RTE) was reduced from a mean of 1.8 ± 1.03 mm to 1.6 ± 0.82 mm at entry (p = 0.05), and from 1.7 ± 1.12 mm to 1.6 ± 0.72 mm at target (p = 0.04). For the SEEG procedures, the RTE was reduced from a mean of 1.43 ± 0.78 mm in the first half of the procedures to 1.12 ± 0.52 mm (p = 0.002) at entry in the second half, and from 1.82 ± 1.13 mm to 1.57 ± 0.98 mm (p = 0.069) at target, respectively. No healing complications or infections were observed in any case.

CONCLUSIONS
The miniature robotic guidance device was able to prove its versatility and seamless integration into preexisting workflow by successful application in 149 stereotactic procedures. According to these data, the robot could significantly improve accuracy without adding time expenditure.
The Impact of the hAPP695SW Transgene and Associated Amyloid-β Accumulation on Murine Hippocampal Biochemical Pathways
Authors: Khorani Mona , Bobe Gerd , Matthews Donald G. , Magana Armando Alcazar , Caruso Maya , Gray Nora E. , Quinn Joseph F. , Stevens Jan F. , Soumyanath Amala , Maier Claudia S. 
Published: December 2021

Background: Alzheimer’s disease (AD) is a neurodegenerative disease characterized by the accumulation of amyloid-β (Aβ) peptide in the brain. Objective: To gain a better insight into alterations in major biochemical pathways underlying AD. Methods: We compared metabolomic profiles of hippocampal tissue of 20-month-old female Tg2576 mice expressing the familial AD-associated hAPP695SW transgene with their 20-month-old wild type female littermates. Results: The hAPP695SW transgene causes overproduction and accumulation of Aβ in the brain. Out of 180 annotated metabolites, 54 metabolites differed (30 higher and 24 lower in Tg2576 versus wild-type hippocampal tissue) and were linked to the amino acid, nucleic acid, glycerophospholipid, ceramide, and fatty acid metabolism. Our results point to 1) heightened metabolic activity as indicated by higher levels of urea, enhanced fatty acid β-oxidation, and lower fatty acid levels; 2) enhanced redox regulation; and 3) an imbalance of neuro-excitatory and neuro-inhibitory metabolites in hippocampal tissue of aged hAPP695SW transgenic mice. Conclusion: Taken together, our results suggest that dysregulation of multiple metabolic pathways associated with a concomitant shift to an excitatory-inhibitory imbalance are contributing mechanisms of AD-related pathology in the Tg2576 mouse.