Reduced Cerebrovascular Oxygenation in Individuals with Post-Acute COVID-19 Syndrome (PACS) ("long COVID").

There is evidence that hypoxia occurs in the brain of some individuals who contracted the COVID-19 disease. Furthermore, it has been widely reported that about 13% of individuals who contracted the COVID-19 disease report persistent symptoms after the acute infection stage (>2 months post-acute infection). This is termed post-acute COVID-19 syndrome (PACS) or ("long COVID"). In this study, we aimed to determine if hypoxia measured non-invasively with frequency domain near-infrared spectroscopy (fdNIRS) occurs in asymptomatic and symptomatic individuals with post-acute COVID-19 disease. We show that 26% of our symptomatic group, measured on average 9.6 months post-acute COVID-19 disease, were hypoxic and 12% of the asymptomatic group, measured on average 2.5 months post-acute infection, were hypoxic. Our study indicates that fdNIRS measure of hypoxia in the brain may be a useful tool to identify individuals that are likely to respond to treatments targeted at reducing inflammation and improving oxygenation.

Molecular characterization and phylogenetic analysis of Marek's disease virus in chickens from Ogun State, Nigeria.

Marek's disease (MD) is caused by oncogenic MD virus serotype 1 (MDV1) and is characterized by lymphoproliferative lesions resulting in high morbidity and mortality in chickens. Despite being ubiquitous on poultry farms, there is a dearth of information on its molecular characteristics in Nigeria. This study aimed at characterizing three virulence genes (Meq, pp38, and vIL-8) of MDV1 from chickens in Ogun state, Nigeria. Blood, feather quill, and tumour samples of chickens from different commercial poultry farms in Ogun State were pooled, spotted on 107 FTA cards, and screened for MDV1 by polymerase chain reaction (PCR). Phylogenetic analysis was carried out to compare Nigerian MDV1 Meq, pp38, and vIL-8 genes sequences with the published references. Thirteen samples were MDV1-positive and the Meq, as well as pp38, and vIL-8 genes from the different samples were 100% identical. The Meq genes contained 339 amino acids (aa) with three PPPP motifs in the transactivation domain and two interruptions of the PPPP motifs due to proline-to-arginine substitutions at positions 176 and 217 resulting in a 20.88% proline composition. Phylogenetic analysis revealed that the Meq gene clustered with strains from Egypt and very virulent ATE2539 strain from Hungary. Mutations were observed in the pp38 protein (at positions 107 and 109) and vIL-8 protein (at positions 4 and 31). Based on the molecular analysis of the three genes, the results indicate the presence of MDV1 with virulence signatures; therefore, further studies on in vivo pathotyping of Nigerian MDV1 from all states should be performed.RESEARCH HIGHLIGHTS Meq, pp38 and vIL-8 genes were 100% identical between Nigerian MDV strains.Proline content in Nigerian meq gene was 20.88% with two PPPP motifs interruptions.Meq, pp38 and vIL-8 genes of Nigerian MDV were similar to Egyptian and Indian strains.

Multiple staging investigations may not change management in patients with high-grade dysplasia or early esophageal adenocarcinoma.

The clinical value of multiple staging investigations for high-grade dysplasia or early adenocarcinoma of the esophagus is unclear. A single-center prospective cohort of patients treated for early esophageal cancer between 2000 and 2019 was analyzed. This coincided with a transition period from esophagectomy to endoscopic mucosal resection (EMR) as the treatment of choice. Patients were staged with computed tomography (CT), endoscopic ultrasound (EUS) and 2-deoxy-2-[18F]fluoro-d-glucose (FDG) positron emission tomography(PET)/CT. The aim of this study was to assess their accuracy and impact on clinical management. 297 patients with high-grade dysplasia or early adenocarcinoma were included (endoscopic therapy/EMR n = 184; esophagectomy n = 113 [of which a 'combined' group had surgery preceded by endoscopic therapy n = 23]). Staging accuracy was low (accurate staging EMR: CT 40.1%, EUS 29.6%, FDG-PET/CT 11.0%; Esophagectomy: CT 43.3%, EUS 59.7%, FDG-PET/CT 29.6%; Combined: CT 28.6%, EUS46.2%, FDG-PET/CT 30.0%). Staging inaccuracies across all groups that could have changed management by missing T2 disease were CT 12%, EUS 12% and FDG-PET/CT 1.6%. The sensitivity of all techniques for detecting nodal disease was low (CT 12.5%, EUS 12.5%, FDG-PET/CT0.0%). Overall, FDG-PET/CT and EUS changed decision-making in only 3.2% of patients with an early cancer on CT and low-risk histology. The accuracy of staging with EUS, CT and FDG-PET/CT in patients with high-grade dysplasia or early adenocarcinoma of the esophagus is low. EUS and FDG-PET/CT added relevant staging information over standard CT in very few cases, and therefore, these investigations should be used selectively. Factors predicting the need for esophagectomy are predominantly obtained from EMR histology rather than staging investigations.

Histological evidence of superficial inflammation is associated with lower recurrence of equine sarcoids following surgical removal: A follow-up study of 106 tumours in 64 horses.

Although the equine sarcoid is the most common skin neoplasm in domesticated horses, histopathological characteristics have not previously been evaluated for association with recurrence. The aim of this retrospective cohort study was to investigate clinical and histopathological features of excised equine sarcoids and to evaluate their association with recurrence at the original surgical site and at new sites. Clinical records and excisional biopsies from 106 equine sarcoids from 64 horses referred to Leahurst Equine Hospital, University of Liverpool, between March 2010 and February 2015 were retrieved. Biopsies were re-evaluated histologically. Clinical data were obtained from hospital records, and owner-reported follow-up data were obtained by telephone questionnaire. Associations between clinical and histopathological features of sarcoids and their recurrence at the surgical site were determined using uni- and multivariable mixed effects logistic regression. Recurrence of sarcoids at the surgical site occurred in 30 horses (46.9%). Sarcoids developed at a distant site in 21 horses (32.8%). In the final mixed effects logistic regression model, only superficial inflammation was associated with reduced odds of recurrence at the surgical site (adjusted odds ratio, 0.32; 95% confidence intervals, 0.10-0.96; P = 0.04). This suggests that the inflammatory process may play a role in protecting horses against the recurrence of sarcoids.

The frequency of change in five-point scale score with a Bayesian penalised likelihood PET reconstruction algorithm on interim FDG PET-CT and its potential implications for therapy decisions in Hodgkin's lymphoma.

AIM: To assess the effect of a Bayesian penalised likelihood (BPL) reconstruction algorithm on the five-point scale (5-PS) score, response categorisation, and potential implications for therapy decisions after interim 2-[18F]-fluoro-2-deoxy-d-glucose (FDG) positron-emission tomography (PET)-computed tomography (CT) (iPET-CT) to guide treatment in classical Hodgkin's lymphoma (HL). MATERIALS AND METHODS: The present study included new patients with HL undergoing iPET-CT from 2014-2019 after two cycles of doxorubicin (Adriamycin), bleomycin, vincristine, and dacarbazine (ABVD). Two reporters categorised response using the 5-PS and measured maximum standardised uptake values (SUVmax) of the most avid tumour residuum, mediastinal blood pool, and normal liver with ordered subset expected maximisation (OSEM) and BPL reconstructions. RESULTS: Eighty-one iPET-CT examinations were reviewed. Compared with OSEM, BPL increased the 5-PS score by a single score in 18/81 (22.2%) patients. The frequency of potential treatment intensification by changing a score of 3-4 was 13.6% (11/81) and represented 25% (11/44) of patients with a score of 3 on OSEM. All 11 patients remained in remission without a change in therapy (mean 63 months) except one who required second-line treatment for refractory disease. Median SUVmax of tumour residuum was significantly higher with BPL compared with OSEM (2.7 versus 2.4, p<<0.0001), whilst liver SUVmax was significantly lower for both reporters (up to 6.6%, p<0.0001). CONCLUSION: BPL PET reconstruction increased the 5-PS score on iPET-CT in 22% of HL patients and can potentially result in unnecessary treatment escalation in over half of these patients.

NB housing study protocol: investigating the relationship between subsidized housing, mental health, physical health and healthcare use in New Brunswick, Canada.

BACKGROUND: Income and housing are pervasive social determinants of health. Subsidized housing is a prominent affordability mechanism in Canada; however, waitlists are lengthy. Subsidized rents should provide greater access to residual income, which may theoretically improve health outcomes. However, little is known about the health of tenants who wait for and receive subsidized housing. This is especially problematic for New Brunswick, a Canadian province with low population density, whose inhabitants experience income inequality, social exclusion, and challenges with healthcare access.  METHODS: This study will use a longitudinal, prospective matched cohort design. All 4,750 households on New Brunswick's subsidized housing wait list will be approached to participate. The survey measures various demographic, social and health indicators at six-month intervals for up to 18 months as they wait for subsidized housing. Those who receive housing will join an intervention group and receive surveys for an additional 18 months post-move date. With consent, participants will have their data linked to a provincial administrative database of medical records.  DISCUSSION: Knowledge of housing and health is sparse in Canada. This study will provide stakeholders with a wealth of health information on a population that is historically under-researched and underserved.

Non-invasive Detection of Persistent Cortical Hypoxia in Multiple Sclerosis Using Frequency Domain Near-Infrared Spectroscopy (fdNIRS).

There may be a relationship between hypoxia and inflammation, which is important in the outcomes of a wide array of human diseases. Multiple sclerosis (MS) is one such disease. There is evidence that hypoxia may influence inflammation in MS. We showed previously that about 40% of participants with MS had hypoxia in the cortical grey matter using frequency-domain near-infrared spectroscopy (fdNIRS). In this study, we aimed to determine if hypoxia in MS persists chronically (for a year or more) by measuring at baseline and ≥12 months later. We found that hypoxia persists for at least a year in 80% of participants with MS. As more individuals remained hypoxic than returned to normoxia, the development of hypoxia may relate to disease progression.

Colostrum management practices that improve the transfer of passive immunity in neonatal dairy calves: A scoping review.

The objective of this scoping review was to describe the literature on the characteristics and management practices of colostrum feeding and their associations with the level of transfer of passive immunity (TPI) in dairy calves. Observational and experimental studies were searched in 5 electronic databases and 3 conference proceedings. Two reviewers independently screened primary studies, either analytic observational or experimental studies written in English. Studies on dairy or dual-purpose calves with passive immunity analyzed by blood sampling between 1 to 9 days of age were included. All studies had to compare at least one colostrum intervention or risk factor and their association with passive immunity. Of the 3,675 initially identified studies, 256 were included in this synthesis. One hundred and ninety-five were controlled trials, 57 were cohort studies, and 4 were cross-sectional studies. The effect of colostral quantity at first feeding was investigated in 30 controlled studies including studies that were comparable to each other. The effect of colostral quality was explored in 24 controlled studies with inconsistent criteria used to define the quality. The effect of the timing of first feeding of colostrum was investigated in 21 controlled studies, where the timing of feeding ranged widely from immediately after birth to 60 h of age. Only 4 controlled studies evaluated the relationship between bacterial load in the colostrum and TPI in dairy calves. Of the 256 total studies, 222 assessed blood IgG concentration while 107 measured blood total protein concentration. We identified a gap in knowledge on the association between passive immunity in dairy calves and the bacterial load in colostrum, or the timing of harvesting colostrum from the dam. A possible quantitative synthesis could be conducted among the studies that evaluated colostral quantity at the first feeding in relation to TPI in dairy calves.

Prognostic stratification of HPV-associated oropharyngeal cancer based on CD103+ immune cell abundance in patients treated on TROG 12.01 and De-ESCALaTE randomized trials.

BACKGROUND: High CD103+ intratumoral immune cell (ITIC) abundance is associated with better prognosis in unselected patients with human papilloma virus-associated oropharyngeal squamous cell carcinoma (HPV-associated OPSCC) treated with cisplatin and radiotherapy (CIS/RT). Substituting cetuximab (CETUX) for CIS with RT in HPV-associated OPSCC resulted in inferior efficacy. Our aim was to determine whether quantification of CD103 ITIC could be used to identify a population of HPV-associated OPSCC with superior prognosis. PATIENTS AND METHODS: We pooled data from the TROG 12.01 and De-ESCALaTE randomized trials that compared CETUX/70GyRT with CIS/70GyRT in low-risk HPV-associated OPSCC: American Joint Committee on Cancer 7 stage III (excluding T1-2N1) or stage IV (excluding N2b-c if smoking history >10 pack-years and/or distant metastases), including all patients with available tumor samples. The primary endpoint was failure-free survival (FFS) in patients receiving CETUX/RT comparing CD103+ ITIC high (≥30%) versus low (<30%). High and low CD103 were compared using Cox regression adjusting for age, stage and trial. RESULTS: Tumor samples were available in 159/182 patients on TROG 12.01 and 145/334 on De-ESCALaTE. CD103+ ITIC abundance was high in 27% of patients. The median follow-up was 3.2 years. The 3-year FFS in patients treated with CETUX/RT was 93% [95% confidence interval (CI) 79% to 98%] in high CD103 and 74% (95% CI 63% to 81%) in low CD103 [adjusted hazard ratio = 0.22 (95% CI 0.12-0.41), P < 0.001]. The 3-year overall survival in patients treated with CETUX/RT was 100% in high CD103 and 86% (95% CI 76% to 92%) in low CD103, P < 0.001. In patients treated with CIS/RT, there was no significant difference in FFS. CONCLUSIONS: CD103+ ITIC expression separates CETUX/RT-treated low-risk HPV-associated OPSCC into excellent and poor prognosis subgroups. The high CD103 population is a rational target for de-intensification trials.

Multicenter Evaluation of the Simplexa VZV Direct Assay for Detection of Varicella-Zoster Virus in Cerebrospinal Fluid and Lesion-Swab Specimens.

Varicella-zoster virus (VZV) is the etiologic agent of varicella (chickenpox) and herpes zoster (shingles) infections commonly involving skin, mucous membranes, and less frequently the central nervous system. Traditional methods for the laboratory diagnosis of these infections are time-consuming, labor-intensive, and often insensitive. As such, these tests are being replaced by more sensitive and rapid molecular methods. This study evaluated the performance of two different molecular assays, the Simplexa VZV Direct and Simplexa VZV Swab Direct, to detect VZV DNA in cerebrospinal fluid (CSF) and lesion-swab specimens, respectively. The Simplexa VZV Direct and Simplexa VZV Swab Direct assays were compared against individual composite reference methods that varied depending on the sample cohort examined. A total of 883 CSF and 452 cutaneous and mucocutaneous prospective, retrospective, and contrived specimens were evaluated in this multicenter study. The results of this study showed that the Simplexa assays demonstrated near perfect agreement (k = 0.98) compared to the composite reference methods for the detection of VZV in CSF and lesion swab specimens. A further comparison between the standard of care molecular assays employed at the site of specimen collection and the Simplexa assays demonstrated excellent agreement (k = 1.0). The Simplexa assays offer rapid and reliable alternatives for the detection of VZV in certain clinical specimens without the need for nucleic acid extraction.

The Effect of the ENJOY Seniors Exercise Park Physical Activity Program on Falls in Older People in the Community: A Prospective Pre-Post Study Design.

BACKGROUND: The ENJOY project (Exercise interveNtion outdoor proJect in the cOmmunitY for older people) is a community-based research project actively promoting physical activity engagement through the delivery of an exercise program using outdoor multimodal exercise equipment. This study investigated the impact of the physical activity program on falls in older people. METHOD: This study was a multi-site prospective study with a pre-post intervention design and 12-month follow up. Eighty older people with increased falls risk underwent a 12-week supervised outdoors exercise program followed by a 6-month maintenance phase. The proportion of fallers and falls incidence were compared between the preceding and the prospective years. RESULTS: A sample of 54 (age 72.4±7.3, 79.6% women) was available for the 12 months analysis (due to COVID19 lockdowns, data of 19 participants were excluded and 4 dropped out). Number of fallers (from 51.8% to 31.4%, p=0.03) and falls incidence (from 42 to 29 falls, p<0.01) were significantly reduced at the 12-months follow up. CONCLUSION: The ENJOY Seniors Exercise Park program integrates outdoor multimodal exercise stations including specific exercises designed to challenge dynamic balance during functional daily movements. The outcomes provide preliminary evidence for the potential positive impact of the ENJOY Seniors Exercise Park in reducing falls for older people.

Forest maturity has a stronger influence on the prevalence of spider monkeys than howler monkeys in an anthropogenically impacted rainforest landscape.

The transformation and depletion of primary forest over the past few decades have placed almost half of the world's primate species under the threat of extinction. Developing any successful conservation program for primates requires distribution and demography data, as well as an understanding of the relationships between these factors and their habitat. Between March and June 2010 and 2011 we collected data on the presence and demographic parameters of howler and spider monkeys by carrying out surveys, and validated our findings using local knowledge. We then examined the relationship between forest type and the presence of these primates at 54 sites in the northern area of the Selva Zoque Corridor, Mexico. We detected 86 spider monkey groups across 31 plots and censused 391 individuals (mean ± SD = 5.9 ± 3.0 individuals per sub-group, n = 67 sub-groups). We also detected 69 howler monkey groups across 30 plots and censused 117 individuals (mean ± SD = 5.3 ± 2.4 individuals per group, n = 22 groups). Howler monkey presence was not related to any specific vegetation type, while spider monkeys were present in areas with a higher percentage of tall forest (trees > 25 m high). Overall, spider monkeys were more prevalent than howler monkeys in our sampling sites and showed demographic characteristics similar to those in better protected areas, suggesting that the landscape features in the Uxpanapa Valley are suitable for their needs. Conversely, howler monkey presence was found to be more limited than in other regions, possibly due to the extended presence of spider monkeys.

Distal Brachial Artery Perforator flap: a new chimeric option for complex hand and digits defects.

INTRODUCTION: Reconstruction of fingers pose unique challenges, as a thin and flexible flap is needed in order to guarantee a good functional outcome. For the first time, in this report, we present the DBAp (distal brachial artery perforator) flap, based on the distal perforator closer to the medial epicondyle. The DBAp flap was used to reconstruct complex digit defects as free flap, and to cover an elbow defect while raised as a propeller. METHODS: Four patients underwent finger reconstruction (free flaps): two patients presented an unstable finger scar following previous surgery, whereas the other two patients presented a terminalized finger at the level of the middle phalanx. A further patient presented a post-traumatic loss of substance at the elbow and was reconstructed using a perforator propeller DBAP flap. RESULTS: Loss of tissues included skin and subcutaneous tissue in all patients and in one patient it included a bone component. Flap dimensions ranged from 48 to 18 cm2 (average: 32 cm2). Among complications, patient n.2 flap presented a marginal flap necrosis requiring a small skin graft after necrosis debridement. CONCLUSION: The DBAp flap provides a slim, glabrous and pliable skin tissue with a well-hidden donor site scar and thanks to the anatomic location of the distal perforator can be designed to include a vascularized bone graft from the medial epicondyle. Despite the low number of cases, we believe that this flap should be considered as a dependable and effective source for complex reconstructions of both soft tissue and bone in fingers.

Characterizing the literature surrounding transportation of young dairy calves: A scoping review.

Transportation is a stressful event for cattle, as it may involve various handling practices, commingling, deprivation of food and water, and fluctuating temperatures. Calves are particularly susceptible to these stressors because their physiological and immune systems are still developing. There has been no formal synthesis of the scientific literature evaluating the effect of transportation on young dairy calf health and performance; the aim of this scoping review is to describe and characterize this body of work. We targeted both descriptive and analytic studies examining transport of calves, including listing how the effect of transport has been evaluated. Eight databases were searched for relevant articles with eligible studies being primary research articles investigating transportation of calves of either sex who were younger than 60 d of age or weighed less than 100 kg. Two reviewers independently screened the title and abstracts of 6,859 articles with 361 potentially relevant articles screened at full text. Of these, 46 were relevant and had data extracted. Articles reporting study location were conducted in the United States (n = 5), Australia (n = 3), Japan (n = 3), and New Zealand (n = 3). Common transport-related variables evaluated included time in transit (n = 13), distance of transportation (n = 8), vehicle-related factors (n = 8), and age at time of transportation (n = 4). Outcome measures varied greatly, including blood parameters (n = 28), health assessments (n = 20), weight (n = 17), behavioral metrics (n = 14), mortality (n = 7), feed intake following transportation (n = 4), salivary cortisol concentrations (n = 3), morbidity (n = 3), and isolation of Salmonella Dublin in fecal samples (n = 2). Outcome parameters were measured during transport or ranged from immediately after to one year following transportation. As the transport-related risk factors and outcomes measured assessed varied widely between studies, future quantitative synthesis (e.g., meta-analysis) in this area may be limited. Several knowledge gaps were identified, including methods to prepare calves for transportation, such as improving nutrition, administering medication, or transporting calves at an older age or weight. Further research could also focus on consistent and clear reporting of key items related to study conduct and analysis, as well as the development of a core outcome set for calf transport studies.

Improvement in Dysphagia Outcomes Following Clinical Target Volume Reduction in the De-ESCALaTE Study.

AIMS: The De-ESCALaTE study showed an overall survival advantage for the administration of synchronous cisplatin chemotherapy with radiotherapy in low-risk oropharyngeal cancer when compared with synchronous cetuximab. During the trial, a radiotherapy quality assurance protocol amendment permitted centres to swap from the original radiotherapy contouring protocol (incorporating the whole oropharynx into the high-dose clinical target volume (CTV); anatomical protocol) to a protocol that incorporated the gross tumour volume with a 10 mm margin into the CTV (volumetric protocol). The purpose of this study was to examine both toxicity and tumour control related to this protocol amendment. MATERIALS AND METHODS: Overall survival and recurrence at 2 years were used to compare tumour control in the two contouring cohorts. For toxicity, the cohorts were compared by both the number of severe (grades 3-5) and all grades acute and late toxicities. In addition, quality of life and swallowing were compared using EORTC-C30 and MD Anderson Dysphagia Inventory, respectively. RESULTS: Of 327 patients included in this study, 185 were contoured according to the anatomical protocol and 142 by the volumetric protocol. The two cohorts were well balanced, with the exception of significantly more patients in the anatomical cohort undergoing prophylactic feeding tube insertion (P < 0.001). With a minimum of 2 years of follow-up there was no significant difference in overall survival or recurrence between the two contouring protocols. Similarly, there was no significant difference in the rate of reported severe or all grades acute or late toxicity and no sustained significant difference in quality of life. However, there was a significant difference in favour of volumetric contouring in several domains of the MD Anderson Dysphagia Inventory questionnaire at 1 year, which persisted to 2 years in the dysphagia functional (P = 0.002), dysphagia physical (P = 0.009) and dysphagia overall function (P = 0.008) domains. CONCLUSION: In the context of the unplanned post-hoc analysis of a randomised trial, measurable improvement in long-term dysphagia has been shown following a reduction in the CTV. Further reductions in the CTV should be subject to similar scrutiny within the confines of a prospective study.

Comparative survival analysis of multiparametric tests-when molecular tests disagree-A TEAM Pathology study.

Multiparametric assays for risk stratification are widely used in the management of both node negative and node positive hormone receptor positive invasive breast cancer. Recent data from multiple sources suggests that different tests may provide different risk estimates at the individual patient level. The TEAM pathology study consists of 3284 postmenopausal ER+ve breast cancers treated with endocrine therapy Using genes comprising the following multi-parametric tests OncotypeDx®, Prosigna™ and MammaPrint® signatures were trained to recapitulate true assay results. Patients were then classified into risk groups and survival assessed. Whilst likelihood χ2 ratios suggested limited value for combining tests, Kaplan-Meier and LogRank tests within risk groups suggested combinations of tests provided statistically significant stratification of potential clinical value. Paradoxically whilst Prosigna-trained results stratified Oncotype-trained subgroups across low and intermediate risk categories, only intermediate risk Prosigna-trained cases were further stratified by Oncotype-trained results. Both Oncotype-trained and Prosigna-trained results further stratified MammaPrint-trained low risk cases, and MammaPrint-trained results also stratified Oncotype-trained low and intermediate risk groups but not Prosigna-trained results. Comparisons between existing multiparametric tests are challenging, and evidence on discordance between tests in risk stratification presents further dilemmas. Detailed analysis of the TEAM pathology study suggests a complex inter-relationship between test results in the same patient cohorts which requires careful evaluation regarding test utility. Further prognostic improvement appears both desirable and achievable.

The evolution of mammalian brain size.

Relative brain size has long been considered a reflection of cognitive capacities and has played a fundamental role in developing core theories in the life sciences. Yet, the notion that relative brain size validly represents selection on brain size relies on the untested assumptions that brain-body allometry is restrained to a stable scaling relationship across species and that any deviation from this slope is due to selection on brain size. Using the largest fossil and extant dataset yet assembled, we find that shifts in allometric slope underpin major transitions in mammalian evolution and are often primarily characterized by marked changes in body size. Our results reveal that the largest-brained mammals achieved large relative brain sizes by highly divergent paths. These findings prompt a reevaluation of the traditional paradigm of relative brain size and open new opportunities to improve our understanding of the genetic and developmental mechanisms that influence brain size.