Background: We evaluated vorasidenib (VOR), a dual inhibitor of mIDH1/2, in patients with mIDH1/2 glioma (Phase 3; NCT04164901). Methods: Patients with residual/recurrent grade 2 mIDH1/2 oligodendroglioma or astrocytoma were enrolled (age ≥12; Karnofsky Performance Score ≥80; measurable non-enhancing disease; surgery as only prior treatment; not in immediate need of chemoradiotherapy). Patients were stratified by 1p19q status and baseline tumor size and randomized 1:1 to VOR 40 mg or placebo (PBO) daily in 28-day cycles. Endpoints included imaging-based progression-free survival (PFS), time to next intervention (TTNI), tumor growth rate (TGR), health-related quality of life (HRQoL), neurocognition and seizure activity. Results: 331 patients were randomized (VOR, 168; PBO, 163). The median age was 40.0 years. 172 and 159 patients had histologically confirmed oligodendroglioma and astrocytoma, respectively. Treatment with VOR significantly improved PFS and TTNI. Median PFS: VOR, 27.7 mos; PBO, 11.1 mos (P=0.000000067). Median TTNI: VOR, not reached; PBO, 17.8 mos (P=0.000000019). Treatment with VOR resulted in shrinkage of tumor volume. Post-treatment TGR: VOR, -2.5% (95% CI: -4.7, -0.2); PBO, 13.9% (95% CI: 11.1, 16.8). HRQoL and neurocognition were preserved and seizure control was maintained. VOR had a manageable safety profile. Conclusions: VOR was effective in mIDH1/2 diffuse glioma not in immediate need of chemoradiotherapy.

The effects of cage enrichments and additional space were studied in 60 pairs of mink kits kept in standard cages (STD) and 67 pairs of mink kits kept in enriched cages (ENR). During the period from mid July to the end of September both groups had alternate access to one and two connected cages. From October, half of the mink in each group had permanent access to one cage and the other half permanent access to two cages. The enrichment of the cages consisted of extra resting places (tubes made of wire mesh and plastic) and occupational materials in terms of table-tennis balls and ropes to pull and chew. The mink were observed for an experimental period of nine months, from late lactation until the beginning of the following mating season. The welfare was assessed through behavioural traits (use of nest box and enrichments, activity out in the cage, stereotypies and fur-chewing) consumption of food and straw, bodyweight and level of faecal corticoid metabolites. The presence of enrichments resulted in less tail-chewing, fewer stereotypies, and a reduced level of faecal corticoid metabolites. In addition, the presence of enrichments led to fewer social interactions and reduced the consumption of straw. Regarding the frequency of utilising different occupational materials, the mink did not use the table-tennis balls, but the tubes and pull-ropes were given extensive use. Access to one or double cages had no effect on stereotypies, fur-chewing and physiology linked to welfare, but mink with access to double cages used the nest box less, had a lower consumption of straw and pull-ropes than the mink with access to only one cage. However, there were no indications of frustration when the mink were deprived of using double cages. We conclude that increased environmental complexity in the form of occupational materials improved the welfare of the mink, whereas doubling the cage size had little or no effect in relation to mink welfare.

Use of a privacy panel in the home cage of female pair-housed rhesus monkeys has been reported to increase time spent in close proximity and time spent in affiliative behaviours. In the current study we measured these behaviours in more diverse populations; including male-male and male-female pairs of monkeys actively participating in cognitive experiments. We observed twenty-five pairs of rhesus macaques (Macaca mulatta) both with and without the presence of a privacy divider. Monkeys spent significantly more time in the same half of the pair-cage when the divider was in place. A significant increase in affiliative behaviour was not observed. The effects of privacy dividers previously reported for female monkeys partially extend to male pairs and mixed sex pairs under conditions typical of an active research setting.

The opportunity to perform play behaviour may be an important ontogenic activity that stimulates behavioural variability and may enhance an individual's coping capacity later in life. Play behaviour in juveniles may be enhanced by the presence of cage enrichments relevant to the animal's motivations and natural behavioural repertoire. The present study aimed to investigate play behaviour in juvenile farmed mink reared and housed with the cage enrichments standard for the Dutch housing system (ie a cylinder and platform) and in an experimental group of animals with the same standard enrichments but with additional access to swimming water. Juvenile mink with access to swimming water played significantly more in the main cage than mink reared and housed with the cylinder and platform but without swimming water. The results suggest that swimming water presents the animals with biologically relevant stimuli that directly or indirectly influence the development of play behaviour. Specific implications for the animals' long-term welfare are discussed. Future studies should elucidate the effects of juvenile play on the occurrence of abnormal behavioural patterns in adulthood more precisely and more thoroughly.

There is an increasing requirement for tools to assess and improve animal welfare in an objective and scientifically based manner. In our research a concept of welfare is applied which states that welfare is determined by the balance between positive and negative experiences. This concept implies that an interaction exists between stress systems and reward systems in the brain and, as a consequence: (I) negative experiences induce an increased sensitivity (ie need) for positive experiences; and (II) negative experiences can be compensated for by positive experiences. On this basis, two uses of reward-related behaviour can be hypothesised: (I) reward sensitivity may be used as a tool to assess the state of an animal in terms of welfare because it can indicate the current state of the balance that is dependent on previous (stressful) experiences; and (II) regular presentation of rewards may serve as a tool to counteract stress by shifting the balance to the positive side and, thus, to improve welfare. In order to investigate this, we used the rat as a model. Reward sensitivity was determined by the spontaneous behavioural response shown during expectation of a reward (ie anticipatory behaviour). A third (III) use of reward-related behaviour derives from the fact that anticipatory behaviour is influenced by the (rewarding) properties of the forthcoming reward (or other event) and, thus, may serve as a tool to assess the animal's perception of this reward/event. This paper presents a descriptive overview of the evidence obtained thus far for the three proposed uses of reward-related behaviour. The biological background of our concept of welfare can be generalised to all (vertebrate) species, and anticipatory behaviour can be evoked in a wide range of other species. Therefore, this tool for measuring and improving the welfare of captive animals has great potential and will contribute to a good quality of life for captive animals.

Laboratory animals are frequently subjected to routine procedures, such as injections or the withdrawal of blood samples. Acute stress caused by such procedures is associated with physiological changes that can have a strong impact on experimental results. This study investigated the integrated effects of cage enrichment, social housing and handling on the acute stress response of animals subjected to routine experimental procedures. Female mice of two inbred strains (BALB/c and C57BL/6) were housed under either minimal husbandry conditions (MH: no cage enrichment, infrequent handling and a period of individual housing) or enriched husbandry conditions (EH: with cage enrichment, frequent handling and social housing at all times). One mouse in each cage was implanted with a radio-telemetry transmitter for measuring heart rate (HR) and body temperature (BT). The animals were subjected to intraperitoneal injections or short periods of restraint. In addition to telemetry measurements, thymus weight and tyrosine hydroxylase (TH) activity were assessed. It was found that individual housing under MH conditions, as compared with social housing under EH conditions, elevated both basal HR and BT, and significantly elevated the relative recovery time following routine experimental procedures. Thymus weight and TH activity suggested a long-term stress response under MH conditions following individual housing, although the influence of transmitter implantation and (repeated) acute stress remains to be investigated. The results emphasise that husbandry conditions should be taken into account when evaluating physiological measures after routine procedures.

Snake ownership is popular; however, housing and care may not always satisfy the animal's welfare needs. For example, snakes are often kept in environmental conditions that restrict their ability to stretch out fully or move around, using rectilinear locomotion. To date, little empirical data exist on the housing and husbandry of captive snakes and how these impact welfare. This study analyses survey responses from 744 snake owners worldwide and explores potential welfare concerns for snakes kept within private homes. It documents the most common housing and husbandry methods and compares the three most common families (Pythonids, Boids and Colubrids). Owner-reported data were used to derive scores for two potential welfare indicators: number of clinical signs of ill health and the number of reported negative (abnormal) behaviours. Using these indicators, associations were tested with snake-keeping variables, such as enclosure size, level of enrichment, temperature and humidity. Owners reported that 90.7% (n = 675) of snakes adopted rectilinear (straight-line or near straight-line) positions or movements. Snakes kept in enclosures > 1 snake length tended to have more enrichment types and were reported with fewer clinical signs of ill health. Some snakes were housed at unknown temperature (7.7%) or humidity (48.1%) ranges or in environmental conditions not in keeping with current recommended guidelines. Corn snakes (Pantherophis guttatus) were the most likely species to be kept at a humidity which did not match recommendations which may present a welfare concern. This study's results can be used to target husbandry guidance for future recommendations and care manuals.

Background: In 2016, the WHO Classification of Brain Tumors included brain invasion as a standalone diagnostic criterion for grade 2 meningioma diagnosis. In this study we explored the impact of this change on the incidence and distribution of meningioma grades. Methods: All cases of meningiomas diagnosed from 2007-2020 at a tertiary care hospital were identified. The distribution of meningioma grades before (WHO 2007) and after (WHO 2016) the introduction of the 2016 WHO criteria were compared. Each case in the 2007 cohort was re-graded according to the 2016 criteria to determine the intra-class correlation (ICC) between grading criteria. Results: Of 814 cases, 532 (65.4%) were in the 2007 WHO cohort and 282 (34.6%) were in the 2016 WHO cohort. There were no differences in the distribution of meningioma grades between cohorts (p=0.11). Upon re-grading, 21 cases (3.9%) were changed. ICC between original and revised grade was 0.92 (95% CIs: 0.91-0.93). Amongst Grade 2 meningiomas with brain invasion, 75.8% had three or more atypical histologic features or an elevated mitotic index. Conclusions: Brain invasion alone has minimal impact on the incidence or distribution of specific meningioma grade tumors, likely due to cosegregation of grade elevating features.

A 56 year-old man who presented with symptoms and signs of dementia was later diagnosed as having nasopharyngeal carcinoma.

The cortical metabolic patterns of 12 schizophrenics experiencing hallucinations and/or pseudo-hallucinations were investigated using positron tomography and 18F-fluoro-deoxy-glucose. Andreasen's scales were scored and the patients (all “mixed“) were classified in a “positive” or a “negative” group and compared to a group of 6 normal controls. The data were analyzed across groups for absolute metabolic rates, metabolic indices (cortical region/whole studied cortex), and specific indices exploring the sensory non-association/posterior parietal association and the prefrontal association/posterior parietal association dimensions. Whole-cortex metabolic rate in the negative group was found to be lower than both the control (P=0.02) and the positive group (P = 0.002) while the positive group did not differ significantly from the controls. We found “hypofrontality” to be without difference between the positive and the negative group (controls: 7±0.7, positive: 5.9±0.2, negative: 4.9±0.15, mean±SEM in mg/min/100 g). However, the prefrontal association/posterior parietal association ratio was increased in the negative group (P=0.02). A major finding was an increase in the posterior non-association/posterior parietal association ratio in the whole schizophrenic group as compared to the controls (P = 0.004), this being more marked in the negative (P=0.01) than in the positive group. Arguments are given to support the hypothesis that this particular increase could be related to the hallucinatory activity of the patients.

Background: The management of central cord syndrome (CCS) is controversial. There is a perception that CCS patients tend to improve without the need for surgical intervention. The purpose of this study was to compare the clinical improvements of patients with traumatic SCI, both with and without CCS. Methods: Nova Scotia Provincial Trauma Registry was retrospectively reviewed from 2005-2010. Improvement in the American Spinal Injury Association (ASIA) Impairment Scale (AIS) was determined after mean 5 months follow-up. Results: The study population comprised 96 cases with SCI, subdivided into cases with AIS grade A, non-CCS cases with AIS grades B-D and CCS cases. 88% of the non-CCS and 65% of the CCS patients underwent surgical decompression, with mean operative times being 71.6±137.8 and 102.9±144.6 post injury (p=0.45). The mean improvements in the mean ASIA motor scores for the three groups were 1.3±6.5 and 15.6±35.0 and 22.5±14.6 (p=0.004) respectively, with a statistically significant difference only between the CCS and AIS grade A groups (p<0.001). 20%, 54% and 10% of the patients respectively, underwent an improvement of ≥ one AIS grades (p=0.018, c2=8.0). Conclusions: This retrospective review investigates the natural history of CCS and explores the role of surgical intervention on optimizing patient outcome.

Introduction: Evaluating the suitability for surgery in patients with epilepsy requires determining if the epilepsy is focal or generalized. Presurgical workups can indicate focal epilepsy in certain cases of generalized epilepsy (GE). The purpose of this study was to identify distinctive features which characterize patients with primary GE that mimics focal epilepsy. Method: We retrospectively identified 19 children with generalized interictal discharges during scalp video-EEG (SVEEG) and underwent invasive monitoring and/or epilepsy surgery. Two children did not undergo resective surgery due to final diagnosis of primary GE (Group A). Seventeen children underwent a resective surgery (Group B). Scalp video-EEG, MEG, MRI, and intracranial video EEG (IVEEG) were reviewed. Results: On (SVEEG), the frequency of generalized spike-and-waves (GSW) was 3Hz in Group A and 1.5-2.5Hz in Group B. Group A had only absence seizures , whereas 80% in Group B had multiple types of seizures. Both groups had lateralized MEG dipoles. One patient in Group A had a focal MRI abnormality. In Group A, IVEEG showed GSW of 3 Hz frequency with inconsistent leading. In Group B, IVEEG showed consistent localization of ictal and interictal high frequency oscillations. Conclusion: Children with generalized 3 Hz spike-and-waves and only absence seizures may be a contraindication of resective surgery even though some presurgical workup shows focality.

Introduction: The mainstay of diagnosis in Idiopathic Epilepsies (IE) is the electroencephalogram (EEG). The characteristic EEG of each syndrome is an electrographic endophenotype of the larger clinical phenotype of each and more directly associated with potential gene defects than the full phenotype. Endophenotypes represents primary abnormalities elicited by the gene defect, which, in some patients, blossom into full seizures. Revealing the percentage of abnormal EEGs in asymptomatic relative of patients with IE may help to describe the mode of inheritance that would help the ongoing genetics studies to discover the pathologic gene defect. Method: This is a prospective cohort study to identify the percentage of abnormal EEG in asymptomatic first-degree relatives of patients with IE Results: 20 out of 141 EEGs (14%) of first-degree relatives were abnormal. The abnormalities included generalized polyspikes and waves , generalized 3-Hz spike and waves or centro-temporal spikes in 50% of the abnormal EEGs. 50% of the abnormalities were nonspecific. Conclusion: These results may indicate that the EEG endophenotypes in IEs do not follow a Mendelian pattern of inheritance. Nevertheless, the EEG endophenotype is relatively common and thus genetically simpler than the full epilepsy, which will aid in gene identification