bluuebunny/crossref_metadata_2025_split huggingface dataset:
Novel experimental model of brain arteriovenous malformations using conditional Alk1 gene deletion in transgenic mice
Authors: Han Chul , Lang Michael J. , Nguyen Candice L. , Luna Melendez Ernesto , Mehta Shwetal , Turner Gregory H. , Lawton Michael T. , Oh S. Paul 
Published: November 2021

OBJECTIVE
Hereditary hemorrhagic telangiectasia is the only condition associated with multiple inherited brain arteriovenous malformations (AVMs). Therefore, a mouse model was developed with a genetics-based approach that conditionally deleted the causative activin receptor-like kinase 1 (Acvrl1 or Alk1) gene. Radiographic and histopathological findings were correlated, and AVM stability and hemorrhagic behavior over time were examined.

METHODS
Alk1-floxed mice were crossed with deleter mice to generate offspring in which both copies of the Alk1 gene were deleted by Tagln-Cre to form brain AVMs in the mice. AVMs were characterized using MRI, MRA, and DSA. Brain AVMs were characterized histopathologically with latex dye perfusion, immunofluorescence, and Prussian blue staining.

RESULTS
Brains of 55 Tagln-Cre+;Alk12f/2f mutant mice were categorized into three groups: no detectable vascular lesions (group 1; 23 of 55, 42%), arteriovenous fistulas (AVFs) with no nidus (group 2; 10 of 55, 18%), and nidal AVMs (group 3; 22 of 55, 40%). Microhemorrhage was observed on MRI or MRA in 11 AVMs (50%). AVMs had the angiographic hallmarks of early nidus opacification, a tangle of arteries and dilated draining veins, and rapid shunting of blood flow. Latex dye perfusion confirmed arteriovenous shunting in all AVMs and AVFs. Microhemorrhages were detected adjacent to AVFs and AVMs, visualized by iron deposition, Prussian blue staining, and macrophage infiltration using CD68 immunostaining. Brain AVMs were stable on serial MRI and MRA in group 3 mice (mean age at initial imaging 2.9 months; mean age at last imaging 9.5 months).

CONCLUSIONS
Approximately 40% of transgenic mice satisfied the requirements of a stable experimental AVM model by replicating nidal anatomy, arteriovenous hemodynamics, and microhemorrhagic behavior. Transgenic mice with AVFs had a recognizable phenotype of hereditary hemorrhagic telangiectasia but were less suitable for experimental modeling. AVM pathogenesis can be understood as the combination of conditional Alk1 gene deletion during embryogenesis and angiogenesis that is hyperactive in developing and newborn mice, which translates to a congenital origin in most patients but an acquired condition in patients with a confluence of genetic and angiogenic events later in life. This study offers a novel experimental brain AVM model for future studies of AVM pathophysiology, growth, rupture, and therapeutic regression.
Automated operative workflow analysis of endoscopic pituitary surgery using machine learning: development and preclinical evaluation (IDEAL stage 0)
Authors: Khan Danyal Z. , Luengo Imanol , Barbarisi Santiago , Addis Carole , Culshaw Lucy , Dorward Neil L. , Haikka Pinja , Jain Abhiney , Kerr Karen , Koh Chan Hee , Layard Horsfall Hugo , Muirhead William , Palmisciano Paolo , Vasey Baptiste , Stoyanov Danail , Marcus Hani J. 
Published: November 2021

OBJECTIVE
Surgical workflow analysis involves systematically breaking down operations into key phases and steps. Automatic analysis of this workflow has potential uses for surgical training, preoperative planning, and outcome prediction. Recent advances in machine learning (ML) and computer vision have allowed accurate automated workflow analysis of operative videos. In this Idea, Development, Exploration, Assessment, Long-term study (IDEAL) stage 0 study, the authors sought to use Touch Surgery for the development and validation of an ML-powered analysis of phases and steps in the endoscopic transsphenoidal approach (eTSA) for pituitary adenoma resection, a first for neurosurgery.

METHODS
The surgical phases and steps of 50 anonymized eTSA operative videos were labeled by expert surgeons. Forty videos were used to train a combined convolutional and recurrent neural network model by Touch Surgery. Ten videos were used for model evaluation (accuracy, F1 score), comparing the phase and step recognition of surgeons to the automatic detection of the ML model.

RESULTS
The longest phase was the sellar phase (median 28 minutes), followed by the nasal phase (median 22 minutes) and the closure phase (median 14 minutes). The longest steps were step 5 (tumor identification and excision, median 17 minutes); step 3 (posterior septectomy and removal of sphenoid septations, median 14 minutes); and step 4 (anterior sellar wall removal, median 10 minutes). There were substantial variations within the recorded procedures in terms of video appearances, step duration, and step order, with only 50% of videos containing all 7 steps performed sequentially in numerical order. Despite this, the model was able to output accurate recognition of surgical phases (91% accuracy, 90% F1 score) and steps (76% accuracy, 75% F1 score).

CONCLUSIONS
In this IDEAL stage 0 study, ML techniques have been developed to automatically analyze operative videos of eTSA pituitary surgery. This technology has previously been shown to be acceptable to neurosurgical teams and patients. ML-based surgical workflow analysis has numerous potential uses—such as education (e.g., automatic indexing of contemporary operative videos for teaching), improved operative efficiency (e.g., orchestrating the entire surgical team to a common workflow), and improved patient outcomes (e.g., comparison of surgical techniques or early detection of adverse events). Future directions include the real-time integration of Touch Surgery into the live operative environment as an IDEAL stage 1 (first-in-human) study, and further development of underpinning ML models using larger data sets.
IDH–wild-type glioblastoma cell density and infiltration distribution influence on supramarginal resection and its impact on overall survival: a mathematical model
Authors: Tripathi Shashwat , Vivas-Buitrago Tito , Domingo Ricardo A. , Biase Gaetano De , Brown Desmond , Akinduro Oluwaseun O. , Ramos-Fresnedo Andres , Sherman Wendy , Gupta Vivek , Middlebrooks Erik H. , Sabsevitz David S. , Porter Alyx B. , Uhm Joon H. , Bendok Bernard R. , Parney Ian , Meyer Fredric B. , Chaichana Kaisorn L. , Swanson Kristin R. , Quiñones-Hinojosa Alfredo 
Published: November 2021

OBJECTIVE
Recent studies have proposed resection of the T2 FLAIR hyperintensity beyond the T1 contrast enhancement (supramarginal resection [SMR]) for IDH–wild-type glioblastoma (GBM) to further improve patients’ overall survival (OS). GBMs have significant variability in tumor cell density, distribution, and infiltration. Advanced mathematical models based on patient-specific radiographic features have provided new insights into GBM growth kinetics on two important parameters of tumor aggressiveness: proliferation rate (ρ) and diffusion rate (D). The aim of this study was to investigate OS of patients with IDH–wild-type GBM who underwent SMR based on a mathematical model of cell distribution and infiltration profile (tumor invasiveness profile).

METHODS
Volumetric measurements were obtained from the selected regions of interest from pre- and postoperative MRI studies of included patients. The tumor invasiveness profile (proliferation/diffusion [ρ/D] ratio) was calculated using the following formula: ρ/D ratio = (4π/3)2/3 × (6.106/[VT21/1 − VT11/1])2, where VT2 and VT1 are the preoperative FLAIR and contrast-enhancing volumes, respectively. Patients were split into subgroups based on their tumor invasiveness profiles. In this analysis, tumors were classified as nodular, moderately diffuse, or highly diffuse.

RESULTS
A total of 101 patients were included. Tumors were classified as nodular (n = 34), moderately diffuse (n = 34), and highly diffuse (n = 33). On multivariate analysis, increasing SMR had a significant positive correlation with OS for moderately and highly diffuse tumors (HR 0.99, 95% CI 0.98–0.99; p = 0.02; and HR 0.98, 95% CI 0.96–0.99; p = 0.04, respectively). On threshold analysis, OS benefit was seen with SMR from 10% to 29%, 10% to 59%, and 30% to 90%, for nodular, moderately diffuse, and highly diffuse, respectively.

CONCLUSIONS
The impact of SMR on OS for patients with IDH–wild-type GBM is influenced by the degree of tumor invasiveness. The authors’ results show that increasing SMR is associated with increased OS in patients with moderate and highly diffuse IDH–wild-type GBMs. When grouping SMR into 10% intervals, this benefit was seen for all tumor subgroups, although for nodular tumors, the maximum beneficial SMR percentage was considerably lower than in moderate and highly diffuse tumors.
Analysis of risk factors for venous air embolism in the semisitting position and its impact on outcome in a consecutive series of 740 patients
Authors: Al-Afif Shadi , Elkayekh Hesham , Omer Mazin , Heissler Hans E. , Scheinichen Dirk , Palmaers Thomas , Nakamura Makoto , Hermann Elvis J. , Samii Madjid , Krauss Joachim K. 
Published: November 2021

OBJECTIVE
Routine use of the semisitting position, which offers several advantages, remains a matter of debate. Venous air embolism (VAE) is a potentially serious complication associated with the semisitting position. In this study, the authors aimed to investigate the safety of the semisitting position by analyzing data over a 20-year period.

METHODS
The incidence of VAE and its perioperative management were analyzed retrospectively in a consecutive series of 740 patients who underwent surgery between 1996 and 2016. The occurrence of VAE was defined by detection of bubbles on transthoracic Doppler echocardiography (TTDE) or transesophageal echocardiography (TEE) studies, a decrease of end-tidal CO2 (ETCO2) by 4 mm Hg or more, and/or an unexplained drop in systolic arterial blood pressure (≥ 10 mm Hg). From 1996 until 2013 TTDE was used, and from 2013 on TEE was used. The possible risk factors for VAE and its impact on surgical performance were analyzed.

RESULTS
There were 404 women and 336 men with a mean age at surgery of 49 years (range 1–87 years). Surgery was performed for infratentorial lesions in 709 patients (95.8%), supratentorial lesions in 17 (2.3%), and cervical lesions in 14 (1.9%). The most frequent pathology was vestibular schwannoma. TEE had a higher sensitivity than TTDE. While TEE detected VAE in 40.5% of patients, TTDE had a detection rate of 11.8%. Overall, VAE was detected in 119 patients (16.1%) intraoperatively. In all of these patients, VAE was apparent on TTDE or TEE. Of those, 23 patients also had a decrease of ETCO2, 18 had a drop in blood pressure, and 23 had combined decreases in ETCO2 and blood pressure. VAE was detected in 24% of patients during craniotomy before opening the dura mater, in 67% during tumor resection, and in 9% during wound closure. No risk factors were identified for the occurrence of VAE. Two patients had serious complications due to VAE. Surgical performance in vestibular schwannoma surgery was not affected by the presence of VAE.

CONCLUSIONS
This study shows that the semisitting position is overall safe and that VAE can be managed effectively. Persistent morbidity is very rare. The authors suggest that the semisitting position should continue to have a place in the standard armamentarium of neurological surgery.
Resection of symptomatic non–small cell lung cancer brain metastasis in the setting of multiple brain metastases
Authors: Jünger Stephanie T. , Reinecke David , Meissner Anna-Katharina , Goldbrunner Roland , Grau Stefan 
Published: November 2021

OBJECTIVE
Current guidelines primarily suggest resection of brain metastases (BMs) in patients with limited lesions. With a growing number of highly effective local and systemic treatment options, this view may be challenged. The purpose of this study was to evaluate the role of metastasectomy, disregarding BM count, in a comprehensive treatment setting.

METHODS
In this monocentric retrospective analysis, the authors included patients who underwent resection for at least 1 BM and collected demographic, clinical, and tumor-associated parameters. Prognostic factors for local control and overall survival (OS) were analyzed with the log-rank test and Cox proportional hazards analysis.

RESULTS
The authors analyzed 216 patients. One hundred twenty-nine (59.7%) patients were diagnosed with a single/solitary BM, whereas 64 (29.6%) patients had 2–3 BMs and the remaining 23 (10.6%) had more than 3 BMs. With resection of symptomatic BMs, a significant improvement in Karnofsky Performance Scale (KPS) was achieved (p < 0.001), thereby enabling adjuvant radiotherapy for 199 (92.1%) patients and systemic treatment for 119 (55.1%) patients. During follow-up, 83 (38.4%) patients experienced local recurrence. BM count did not significantly influence local control rates. By the time of analysis, 120 (55.6%) patients had died; the leading cause of death was systemic tumor progression. The mean (range) OS after surgery was 12.7 (0–88) months. In univariate analysis, the BM count did not influence OS (p = 0.844), but age < 65 years (p = 0.007), preoperative and postoperative KPS ≥ 70 (p = 0.002 and p = 0.005, respectively), systemic metastases other than BM (p = 0.004), adjuvant radiation therapy (p < 0.001), and adjuvant systemic treatment (p < 0.001) were prognostic factors. In regression analysis, the presence of extracranial metastases (HR 2.30, 95% CI 1.53–3.48, p < 0.001), adjuvant radiation therapy (HR 0.97, 95% CI 0.23–0.86, p = 0.016), and adjuvant systemic treatment (HR 0.37, 95% CI 0.25–0.55, p < 0.001) remained as independent factors for survival.

CONCLUSIONS
Surgery for symptomatic BM from non–small cell lung cancer may be indicated even for patients with multiple lesions in order to alleviate their neurological symptoms and to consequently facilitate further treatment.
Antiplatelet therapy and delayed cerebral ischemia in aneurysmal subarachnoid hemorrhage: a systematic review and meta-analysis
Authors: Snyder M. Harrison , Ironside Natasha , Kumar Jeyan S. , Doan Kevin T. , Kellogg Ryan T. , Provencio J. Javier , Starke Robert M. , Park Min S. , Ding Dale , Chen Ching-Jen 
Published: November 2021

OBJECTIVE
Delayed cerebral ischemia (DCI) is a potentially preventable cause of morbidity and mortality after aneurysmal subarachnoid hemorrhage (aSAH). The authors performed a meta-analysis to assess the effect of antiplatelet therapy (APT) on DCI in patients with aSAH.

METHODS
A systematic review of the PubMed and MEDLINE databases was performed. Study inclusion criteria were 1) ≥ 5 aSAH patients; 2) direct comparison between aSAH management with APT and without APT; and 3) reporting of DCI, angiographic, or symptomatic vasospasm rates for patients treated with versus without APT. The primary efficacy outcome was DCI. The outcomes of the APT versus no-APT cohorts were compared. Bias was assessed using the Downs and Black checklist.

RESULTS
The overall cohort comprised 2039 patients from 15 studies. DCI occurred less commonly in the APT compared with the no-APT cohort (pooled = 15.9% vs 28.6%; OR 0.47, p < 0.01). Angiographic (pooled = 51.6% vs 68.7%; OR 0.46, p < 0.01) and symptomatic (pooled = 23.6% vs 37.7%; OR 0.51, p = 0.01) vasospasm rates were lower in the APT cohort. In-hospital mortality (pooled = 1.7% vs 4.1%; OR 0.53, p = 0.01) and functional dependence (pooled = 21.0% vs 35.7%; OR 0.53, p < 0.01) rates were also lower in the APT cohort. Bleeding event rates were comparable between the two cohorts. Subgroup analysis of cilostazol monotherapy compared with no APT demonstrated a lower DCI rate in the cilostazol cohort (pooled = 10.6% vs 28.1%; OR 0.31, p < 0.01). Subgroup analysis of surgically treated aneurysms demonstrated a lower DCI rate for the APT cohort (pooled = 18.4% vs 33.9%; OR 0.43, p = 0.02).

CONCLUSIONS
APT is associated with improved outcomes in aSAH without an increased risk of bleeding events, particularly in patients who underwent surgical aneurysm repair and those treated with cilostazol. Although study heterogeneity is the most significant limitation of the analysis, the findings suggest that APT is worth exploring in patients with aSAH, particularly in a randomized controlled trial setting.
Direct brainstem somatosensory evoked potentials for cavernous malformations
Authors: Le Scheherazade , Nguyen Viet , Lee Leslie , Cho S. Charles , Malvestio Carmen , Jones Eric , Dodd Robert , Steinberg Gary , López Jaime 
Published: November 2021

OBJECTIVE
Brainstem cavernous malformations (CMs) often require resection due to their aggressive natural history causing hemorrhage and progressive neurological deficits. The authors report a novel intraoperative neuromonitoring technique of direct brainstem somatosensory evoked potentials (SSEPs) for functional mapping intended to help guide surgery and subsequently prevent and minimize postoperative sensory deficits.

METHODS
Between 2013 and 2019 at the Stanford University Hospital, intraoperative direct brainstem stimulation of primary somatosensory pathways was attempted in 11 patients with CMs. Stimulation identified nucleus fasciculus, nucleus cuneatus, medial lemniscus, or safe corridors for incisions. SSEPs were recorded from standard scalp subdermal electrodes. Stimulation intensities required to evoke potentials ranged from 0.3 to 3.0 mA or V.

RESULTS
There were a total of 1 midbrain, 6 pontine, and 4 medullary CMs—all with surrounding hemorrhage. In 7/11 cases, brainstem SSEPs were recorded and reproducible. In cases 1 and 11, peripheral median nerve and posterior tibial nerve stimulations did not produce reliable SSEPs but direct brainstem stimulation did. In 4/11 cases, stimulation around the areas of hemosiderin did not evoke reliable SSEPs. The direct brainstem SSEP technique allowed the surgeon to find safe corridors to incise the brainstem and resect the lesions.

CONCLUSIONS
Direct stimulation of brainstem sensory structures with successful recording of scalp SSEPs is feasible at low stimulation intensities. This innovative technique can help the neurosurgeon clarify distorted anatomy, identify safer incision sites from which to evacuate clots and CMs, and may help reduce postoperative neurological deficits. The technique needs further refinement, but could potentially be useful to map other brainstem lesions.
The standing T1–L1 pelvic angle: a useful radiographic predictor of proximal junctional kyphosis in adult spinal deformity
Authors: Takasawa Eiji , Kawamura Naohiro , Iizuka Yoichi , Ohya Junichi , Onishi Yuki , Kunogi Junichi , Chikuda Hirotaka 
Published: November 2021

OBJECTIVE
Proximal junctional kyphosis (PJK), which can worsen a patient’s quality of life, is a common complication following the surgical treatment of adult spinal deformity (ASD). Although various radiographic parameters have been proposed to predict the occurrence of PJK, the optimal method has not been established. The present study aimed to investigate the usefulness of the T1–L1 pelvic angle in the standing position (standing TLPA) for predicting the occurrence of PJK.

METHODS
The authors retrospectively extracted data for patients with ASD who underwent minimum 5-level fusion to the pelvis with upper instrumented vertebra between T8 and L1. In the present study, PJK was defined as ≥ 10° progression of the proximal junctional angle or reoperation due to progressive kyphosis during 1 year of follow-up. The following parameters were analyzed on whole-spine standing radiographs: the T1–pelvic angle, conventional thoracic kyphosis (TK; T4–12), whole-thoracic TK (T1–12), and the standing TLPA (defined as the angle formed by lines extending from the center of T1 and L1 to the femoral head axis). A logistic regression analysis and a receiver operating characteristic curve analysis were performed.

RESULTS
A total of 50 patients with ASD were enrolled (84% female; mean age 74.4 years). PJK occurred in 19 (38%) patients. Preoperatively, the PJK group showed significantly greater T1–pelvic angle (49.2° vs 34.4°), conventional TK (26.6° vs 17.6°), and standing-TLPA (30.0° vs 14.9°) values in comparison to the non-PJK group. There was no significant difference in the whole-thoracic TK between the two groups. A multivariate analysis showed that the standing TLPA and whole-thoracic TK were independent predictors of PJK. The standing TLPA had better accuracy than whole-thoracic TK (AUC 0.86 vs 0.64, p = 0.03). The optimal cutoff value of the standing TLPA was 23.0° (sensitivity 0.79, specificity 0.74). Using this cutoff value, the standing TLPA was the best predictor of PJK (OR 8.4, 95% CI 1.8–39, p = 0.007).

CONCLUSIONS
The preoperative standing TLPA was more closely associated with the occurrence of PJK than other radiographic parameters. These results suggest that this easily measured parameter is useful for the prediction of PJK.
EFEKTIVITAS PENEGAKAN HUKUM TERHADAP PRODUSEN MAKANAN DI INDONESIA
Authors: Purnamasari Ruli , Solihan Solihan , Azzahra Viyola 
Published: November 2021

Abstrak

Efektivitas penegakan hukum terhadap produsen makanan berbahaya menuju Indonesia Sehat 2025 tersebut didasarkan apabila pelaku usaha memproduksi dan memperdagangkan produk makanan yang mengandung bahan kimia serta membahayakan kesehatan dan keselamatan konsumen, maka pelaku usaha/produsen melanggar Undang-Undang Nomor 36 Tahun 2009 tentang Kesehatan, Undang-Undang Nomor 18 Tahun 2012 tentang Pangan, Undang-Undang Nomor 8 Tahun 1999 tentang perlindungan Konsumen. Penelitian ini merupakan penelitian hukum normative yang bertujuan untuk mengetahui Faktor yang mempengaruhi terhadap efektivitas penegakan hukum terhadap produsen makanan berbahaya menuju Indonesia Sehat 2025. Faktor hukumnya, yaitu lemahnya sanksi terhadap pelanggarnya, proses penanganan masalah berbelit-belit, kurang profesionalnya para aparatur penegak hukum dan kurangnya koordinasi antar penegak hukum. Tanggung jawab pidana produsen terhadap kerugian yang diderita konsumen akibat makanan berbahaya yang diproduksi, dipasarkan, ditawarkan dan diperdagangkannya, secara yuridis, dalam konsepsi Undang-Undang Perlindungan Konsumen dan peraturan perundang-undangan terkait lainnya.

THE EFFECTIVENESS OF LAW ENFORCEMENT ON FOOD MANUFACTURERS IN INDONESIA

Abstract

The effectiveness of law enforcement against dangerous food producers towards Healthy Indonesia 2025 is based on if business actors produce and trade food products that contain chemicals and endanger the health and safety of consumers, then the business actor/producer violates Law Number 36 of 2009 concerning Health, Law No. Law Number 18 of 2012 concerning Food, Law Number 8 of 1999 concerning Consumer Protection. This research is a normative legal research that aims to determine the factors that influence the effectiveness of law enforcement against producers of dangerous food towards Healthy Indonesia 2025. The legal factors are the weakness of sanctions against violators, the process of handling problems is complicated, the lack of professionalism of law enforcement officials and the lack of coordination between law enforcement. The producer's criminal responsibility for the loss suffered by the consumer due to the dangerous food produced, marketed, offered and traded, legally, in the conception of the Consumer Protection Act and other relevant laws and regulations.

Keywords: Effectiveness, Law Enforcement, Food Producers