Vorasidenib in IDH1- or IDH2-Mutant Low-Grade Glioma.

BACKGROUND: Isocitrate dehydrogenase (IDH)-mutant grade 2 gliomas are malignant brain tumors that cause considerable disability and premature death. Vorasidenib, an oral brain-penetrant inhibitor of mutant IDH1 and IDH2 enzymes, showed preliminary activity in IDH-mutant gliomas. METHODS: In a double-blind, phase 3 trial, we randomly assigned patients with residual or recurrent grade 2 IDH-mutant glioma who had undergone no previous treatment other than surgery to receive either oral vorasidenib (40 mg once daily) or matched placebo in 28-day cycles. The primary end point was imaging-based progression-free survival according to blinded assessment by an independent review committee. The key secondary end point was the time to the next anticancer intervention. Crossover to vorasidenib from placebo was permitted on confirmation of imaging-based disease progression. Safety was also assessed. RESULTS: A total of 331 patients were assigned to receive vorasidenib (168 patients) or placebo (163 patients). At a median follow-up of 14.2 months, 226 patients (68.3%) were continuing to receive vorasidenib or placebo. Progression-free survival was significantly improved in the vorasidenib group as compared with the placebo group (median progression-free survival, 27.7 months vs. 11.1 months; hazard ratio for disease progression or death, 0.39; 95% confidence interval [CI], 0.27 to 0.56; P<0.001). The time to the next intervention was significantly improved in the vorasidenib group as compared with the placebo group (hazard ratio, 0.26; 95% CI, 0.15 to 0.43; P<0.001). Adverse events of grade 3 or higher occurred in 22.8% of the patients who received vorasidenib and in 13.5% of those who received placebo. An increased alanine aminotransferase level of grade 3 or higher occurred in 9.6% of the patients who received vorasidenib and in no patients who received placebo. CONCLUSIONS: In patients with grade 2 IDH-mutant glioma, vorasidenib significantly improved progression-free survival and delayed the time to the next intervention. (Funded by Servier; INDIGO ClinicalTrials.gov number, NCT04164901.).

Europe PMC in 2023.

Europe PMC (https://europepmc.org/) is an open access database of life science journal articles and preprints, which contains over 42 million abstracts and over 9 million full text articles accessible via the website, APIs and bulk download. This publication outlines new developments to the Europe PMC platform since the last database update in 2020 (1) and focuses on five main areas. (i) Improving discoverability, reproducibility and trust in preprints by indexing new preprint content, enriching preprint metadata and identifying withdrawn and removed preprints. (ii) Enhancing support for text and data mining by expanding the types of annotations provided and developing the Europe PMC Annotations Corpus, which can be used to train machine learning models to increase their accuracy and precision. (iii) Developing the Article Status Monitor tool and email alerts, to notify users about new articles and updates to existing records. (iv) Positioning Europe PMC as an open scholarly infrastructure through increasing the portion of open source core software, improving sustainability and accessibility of the service.

Anti-N-Methyl-D-Aspartate Receptor Encephalitis: A Review of Psychiatric Phenotypes and Management Considerations: A Report of the American Neuropsychiatric Association Committee on Research.

OBJECTIVE: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an autoimmune disorder characterized by prominent neuropsychiatric symptoms. Given the nature of its pathophysiology, psychiatrists tend to be one of the first clinicians encountering patients with the disease. METHODS: In the present review of patients described in the literature with psychiatric symptoms, the authors aimed to characterize the psychiatric symptoms of the disease and its management in adults and adolescents as well as children (≤12 years old). A total of 544 patients fulfilled the inclusion criteria. RESULTS: The authors found that 77% of patients with NMDAR encephalitis presented initially with psychiatric symptoms. These were mostly agitation (59%) and psychotic symptoms (in 54%, especially disorganized behavior and visual-auditory hallucinations), with agitation even more commonly being the presenting symptom in children (66%). Where psychotic symptoms were detailed, visual (64%) and auditory (59%) hallucinations were the most common, as well as persecutory delusions (73%). However, delusions were not clearly characterized in most cases. Catatonia was described in 42% of adult patients and 35% of children. Of the patients with documented exposure to antipsychotics, 33% were suspected to have an adverse drug reaction (notably, neuroleptic malignant syndrome in 22% of the cases). CONCLUSIONS: On the basis of these findings, it is important to consider anti-NMDAR encephalitis in the differential diagnosis of patients with an acute onset psychosis, especially in association with agitation, catatonia, or adverse response to antipsychotics. Furthermore, it is important to use antipsychotics with caution in patients with suspected or confirmed anti-NMDAR encephalitis.

Affect-induced reflex seizures (AIRS): A case series based on a systematic literature review.

Seizures are commonly thought to occur in a spontaneous, unpredictable manner. However, it is well-established that a subset of patients with epilepsy can experience reflex seizures that are consistently elicited by a specific stimulus. While various forms of reflex epilepsy have been documented in the literature, acute affective states have not been commonly described as a potential reflex seizure trigger. We performed a systematic literature review to determine if acute emotional states can trigger reflex seizures. We included any case in which reflex seizures repeatedly occurred in response to a patient-specific stimulus that was reported as emotionally relevant by the authors. This yielded our case series of ten patients who have been described to have reflex seizures in response to emotional stimuli. We characterized features of these cases including the following: age, gender, developmental and psychiatric history, seizure semiology and duration, emotional triggers, other reflex triggers, relationship between reflex triggers and seizures, investigations, localization, final diagnosis, treatment, and outcome. Considerable variability was found between cases. A trend toward limbic seizure semiology with psychic aura originating in networks involved in emotional processing was noted, with temporal lobe epilepsy being the most common, although without clear laterality or gender predominance. In addition, the report of a significant life stressor occurring at epilepsy onset in three of ten patients as well as the initial suspicion that reflex epileptic seizures were psychogenic in three cases both emphasize the role of electroencephalography in assessment of such presentations to avoid missing a diagnosis of epilepsy. Findings from these ten cases suggest that a patient-specific affective stimulus may trigger reflex seizures in a subset of patients, and that this could be underrecognized or mislabeled as nonepileptic. We encourage future studies with larger numbers to further characterize this phenomenon. Insights gained may enhance our understanding of seizure localization and bear potential treatment implications.

Design guidelines of triboelectric nanogenerator for water wave energy harvesters.

Ocean waves are one of the cleanest and most abundant energy sources on earth, and wave energy has the potential for future power generation. Triboelectric nanogenerator (TENG) technology has recently been proposed as a promising technology to harvest wave energy. In this paper, a theoretical study is performed on a duck-shaped TENG wave harvester recently introduced in our work. To enhance the design of the duck-shaped TENG wave harvester, the mechanical and electrical characteristics of the harvester's overall structure, as well as its inner configuration, are analyzed, respectively, under different wave conditions, to optimize parameters such as duck radius and mass. Furthermore, a comprehensive hybrid 3D model is introduced to quantify the performance of the TENG wave harvester. Finally, the influence of different TENG parameters is validated by comparing the performance of several existing TENG wave harvesters. This study can be applied as a guideline for enhancing the performance of TENG wave energy harvesters.

Evaluation of corticotomy-facilitated orthodontics and piezocision in rapid canine retraction.

INTRODUCTION: The purpose of this study was to evaluate the efficiency of corticotomy-facilitated orthodontics and piezocision in rapid canine retraction. METHODS: The sample consisted of 20 patients (15-25 years old) with Class II Division 1 malocclusions. The suggested treatment plan was extraction of the maxillary first premolars with subsequent canine retraction. The sample was divided into 2 equal groups. In the first group, 1 side of the maxillary arch was randomly chosen for treatment with corticotomy, and in the second group, piezocision treatment was used. The contralateral sides of both groups served as the controls. Cuts and perforations were performed with a piezotome, and canine retraction was initiated bilaterally in both groups with closed-coil nickel-titanium springs that applied 150 g of force on each side. The following variables were examined over a 3-month follow-up period: rate of canine crown tip, molar anchorage loss, canine rotation, canine inclination, canine root resorption, plaque index, gingival index, probing depth, attachment level, and gingival recession. The rate of canine crown tip was assessed every 2 weeks after the start of canine retraction at 6 time points. RESULTS: The rates of canine crown tip were greater in the experimental sides than in the control sides in both groups. Corticotomies produced greater rates of canine movement than did piezocision at 4 time points. Canine root resorption was greater in the control sides. The remaining studied variables exhibited no differences between the control and the experimental sides. CONCLUSIONS: Corticotomy-facilitated orthodontics and piezocision are efficient treatment modalities for accelerating canine retraction.

Alveolar bone mapping in subjects with different vertical facial dimensions.

OBJECTIVE: The purpose of this study was to investigate differences in alveolar and skeletal dimensions among subjects with different vertical facial dimensions using cone beam computed tomography (CBCT). To date, this is the first study that investigates the relationship between facial type and posterior alveolar thickness in both maxilla and mandible, using CBCT data. MATERIALS AND METHODS: From a sample of 152 CBCT scans, 45 scans were selected to be included in the study. CBCT-synthesized lateral cephalograms were used to categorize subjects into three groups based on their vertical skeletal pattern. Using iCATVision™ software, measurements of alveolar height and thickness were carried out in the entire tooth-bearing region. In addition, AutoCAD™ software was used to carry out measurements for the anatomical limitation to labio-lingual incisor movement. Kruskal-Wallis and Mann-Whitney U-tests with the Bonferroni adjustment were done for statistical analyses. RESULTS: Compared to the other two groups, high-angle group had larger anterior dentoalveolar height with no significant differences in alveolar height posteriorly, in both the maxilla and mandible. Furthermore, high-angle group presented thinner alveolus anteriorly in the maxilla and at almost all sites in the mandible. Low-angle group had higher mean values for some measurements of the anatomical limitation to labio-lingual incisor movement for all upper and lower incisors. LIMITATIONS: Inherent limitations of CBCT scanning as related to physical spatial resolution of the image and limitations posed by the study sample size should be considered. CONCLUSIONS: There is a statistically significant relationship between facial type and alveolar height and thickness. High-angle subjects can be at increased risk of moving incisors beyond alveolar bone support when subjected to marked antero-posterior incisor movement.

A case report of large testicular mass: An Eastern Province report from KSA.

Large testicular tumor is not a commonly seen entity in the modern era. While treatment of large testicular tumors is via inguinal radical orchiectomy, large testicular tumors carry the dilemma of delivering these large masses via the inguinal or scrotal approach. Here, we present a case of a 53-year-old male patient with a testicular tumor weighing 2.170 kg, measuring 22 cm × 16 cm × 12 cm, who was treated via inguinal orchiectomy with the extension of the surgical wound to the neck of the scrotum, with pathological report showing seminoma with no spermatic cord invasion. We review some case reports of such large tumors to illustrate this treatment dilemma.

A novel surgical technique for treatment of cervical vertebral stenotic myelopathy (wobbler syndrome) in a filly.

Cervical vertebral stenotic myelopathy (CVSM), also known as equine wobbler syndrome or cervical ataxia, is a devastating neurological syndrome resulting from compression of the spinal cord at the cervical region. This report describes a novel surgical technique for treatment of 16-month-old Arabian filly with CVSM. The filly showed grade 4 ataxia, hypermetria, weakness of the hind limbs, stumbling during walking, and abnormal gait. Case history, clinical signs and myelography revealed spinal cord compression between the C3 and C4 and C4-C5. The filly underwent a novel surgical interference for decompression and stabilization of the point of stenosis using specially designed titanium plate and intervertebral spacer. Evidence of arthrodesis with absence of complications was confirmed by periodic radiography over eight months of postoperative care. The new technique applied in this cervical surgery was efficient for the decompression and stabilization of the vertebrae, allowing arthrodesis development and remission of the clinical signs. The obtained results encourage further assessment of this novel procedure in horses clinically affected by CVSM.

Vorasidenib and ivosidenib in IDH1-mutant low-grade glioma: a randomized, perioperative phase 1 trial.

Vorasidenib and ivosidenib inhibit mutant forms of isocitrate dehydrogenase (mIDH) and have shown preliminary clinical activity against mIDH glioma. We evaluated both agents in a perioperative phase 1 trial to explore the mechanism of action in recurrent low-grade glioma (IGG) and select a molecule for phase 3 testing. Primary end-point was concentration of D-2-hydroxyglutarate (2-HG), the metabolic product of mIDH enzymes, measured in tumor tissue from 49 patients with mIDH1-R132H nonenhancing gliomas following randomized treatment with vorasidenib (50 mg or 10 mg once daily, q.d.), ivosidenib (500 mg q.d. or 250 mg twice daily) or no treatment before surgery. Tumor 2-HG concentrations were reduced by 92.6% (95% credible interval (CrI), 76.1-97.6) and 91.1% (95% CrI, 72.0-97.0) in patients treated with vorasidenib 50 mg q.d. and ivosidenib 500 mg q.d., respectively. Both agents were well tolerated and follow-up is ongoing. In exploratory analyses, 2-HG reduction was associated with increased DNA 5-hydroxymethylcytosine, reversal of 'proneural' and 'stemness' gene expression signatures, decreased tumor cell proliferation and immune cell activation. Vorasidenib, which showed brain penetrance and more consistent 2-HG suppression than ivosidenib, was advanced to phase 3 testing in patients with mIDH LGGs. Funded by Agios Pharmaceuticals, Inc. and Servier Pharmaceuticals LLC; ClinicalTrials.gov number NCT03343197.

Foliar Application of Nano-Silicon Improves the Physiological and Biochemical Characteristics of 'Kalamata' Olive Subjected to Deficit Irrigation in a Semi-Arid Climate.

In Egypt's arid and semi-arid lands where the main olive production zone is located, evapotranspiration is higher than rainfall during winter. Limited research has used nanomaterials, especially nano-silicon (nSi) to improve the growth, development, and productivity of drought-stressed fruit trees, amid the global water scarcity problem. To assess the role of nSi on drought-sensitive 'Kalamata' olive tree growth, and biochemical and physiological changes under drought conditions, a split-plot experiment was conducted in a randomized complete block design. The trees were foliar sprayed with nSi in the field using nine treatments (three replicates each) of 0, 150, and 200 mg·L-1 under different irrigation regimes (100, 90, and 80% irrigation water requirements 'IWR') during the 2020 and 2021 seasons. Drought negatively affected the trees, but both concentrations of nSi alleviated drought effects at reduced irrigation levels, compared to the non-stressed trees. Foliar spray of both concentrations of nSi at a moderate level (90% IWR) of drought resulted in improved yield and fruit weight and reduced fruit drop percentage, compared to 80% IWR. In addition, there were reduced levels of osmoprotectants such as proline, soluble sugars, and abscisic acid (ABA) with less membrane damage expressed as reduced levels of malondialdehyde (MDA), H2O2 and electrolyte leakage at 90% compared to 80% IWR. These results suggest that 'Kalamata' olive trees were severely stressed at 80% compared to 90% IWR, which was not surprising as it is classified as drought sensitive. Overall, the application of 200 mg·L-1 nSi was beneficial for the improvement of the mechanical resistance, growth, and productivity of moderately-stressed (90% IWR) 'Kalamata' olive trees under the Egyptian semi-arid conditions.

Role of mineral nutrients, antioxidants, osmotic adjustment and PSII stability in salt tolerance of contrasting wheat genotypes.

Global food production is threatened due to increasing salinity and can be stabilized by improving salt tolerance of crops. In the current study, salt tolerance potential of 40 local wheat cultivars against 150 mM NaCl stress was explored. Salt treatment at seedling stage caused less reduction in biomass, K+ and P while more decline of Na+ in tolerant cultivars due to reduced translocation and enhanced exclusion of Na+ from leaves. Principal component analysis based selected S-24, LU-26S, Pasban-90 (salt tolerant) and MH-97, Kohistan-97, Inqilab-91 and Iqbal-2000 (salt sensitive) cultivars were evaluated at adult stage applying 150 mM salinity. Osmotic adjustment by accumulation of soluble sugars and proline and accelerated antioxidant enzymes activities caused efficient scavenging of reactive oxygen species making S-24 and LU-26S tolerant while in MH-97 and Kohistan-97, high MDA represent greater membrane damage due to oxidative stress making them salt sensitive. Chlorophyll a fluorescence transients confirmed better efficiency of photosystem II in S-24 and LU-26S based on energy fluxes (ABS/RC, TRo/RC, ETo/RC and DIo/RC), performance index (PIABS) and maximum quantum yield (Fv/Fm). These findings can be correlated using molecular techniques to identify genes for salt exclusion, osmotic adjustment and photosynthetic activity for use in molecular breeding programs.

5-Aminolevulinic Acid and 24-Epibrassinolide Improve the Drought Stress Resilience and Productivity of Banana Plants.

Plant growth, development, and productivity are adversely affected under drought conditions. Previous findings indicated that 5-aminolevulinic acid (ALA) and 24-epibrassinolide (EBL) play an important role in the plant response to adverse environmental conditions. This study demonstrated the role of ALA and EBL on oxidative stress and photosynthetic capacity of drought-stressed 'Williams' banana grown under the Egyptian semi-arid conditions. Exogenous application of either ALA or EBL at concentrations of 15, 30, and 45 mg·L-1 significantly restored plant photosynthetic activity and increased productivity under reduced irrigation; this was equivalent to 75% of the plant's total water requirements. Both compounds significantly reduced drought-induced oxidative damages by increasing antioxidant enzyme activities (superoxide dismutase 'SOD', catalase 'CAT', and peroxidase 'POD') and preserving chloroplast structure. Lipid peroxidation, electrolyte loss and free non-radical H2O2 formation in the chloroplast were noticeably reduced compared to the control, but chlorophyll content and photosynthetic oxygen evolution were increased. Nutrient uptake, auxin and cytokinin levels were also improved with the reduced abscisic acid levels. The results indicated that ALA and EBL could reduce the accumulation of reactive oxygen species and maintain the stability of the chloroplast membrane structure under drought stress. This study suggests that the use of ALA or EBL at 30 mg·L-1 can promote the growth, productivity and fruit quality of drought-stressed banana plants.

Early volumetric, perfusion, and diffusion MRI changes after mutant isocitrate dehydrogenase (IDH) inhibitor treatment in IDH1-mutant gliomas.

Background: Inhibition of the isocitrate dehydrogenase (IDH)-mutant enzyme is a novel therapeutic target in IDH-mutant gliomas. Imaging biomarkers of IDH inhibitor treatment efficacy in human IDH-mutant gliomas are largely unknown. This study investigated early volumetric, perfusion, and diffusion MRI changes in IDH1-mutant gliomas during IDH inhibitor treatment. Methods: Twenty-nine IDH1-mutant glioma patients who received IDH inhibitor and obtained anatomical, perfusion, and diffusion MRI pretreatment at 3-6 weeks (n = 23) and/or 2-4 months (n = 14) of treatment were retrospectively studied. Normalized relative cerebral blood volume (nrCBV), apparent diffusion coefficient (ADC), and fluid-attenuated inversion recovery (FLAIR) hyperintensity volume were analyzed. Results: After 3-6 weeks of treatment, nrCBV was significantly increased (P = .004; mean %change = 24.15%) but not FLAIR volume (P = .23; mean %change = 11.05%) or ADC (P = .52; mean %change = -1.77%). Associations between shorter progression-free survival (PFS) with posttreatment nrCBV > 1.55 (P = .05; median PFS, 240 vs 55 days) and increased FLAIR volume > 4 cm3 (P = .06; 227 vs 29 days) trended toward significance. After 2-4 months, nrCBV, FLAIR volume, and ADC were not significantly different from baseline, but an nrCBV increase > 0% (P = .002; 1121 vs 257 days), posttreatment nrCBV > 1.8 (P = .01; 1121 vs. 270 days), posttreatment ADC < 1.15 µm2/ms (P = .02; 421 vs 215 days), median nrCBV/ADC ratio increase > 0% (P = .02; 1121 vs 270 days), and FLAIR volume change > 4 cm3 (P = .03; 421 vs 226.5 days) were associated with shorter PFS. Conclusions: Increased nrCBV at 3-6 weeks of treatment may reflect transient therapeutic and/or tumor growth changes, whereas nrCBV, ADC, and FLAIR volume changes occurring at 2-4 months of treatment may more accurately reflect antitumor response to IDH inhibition.