Mosaic Brains? A Methodological Critique of Joel et al. (2015)

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TIA1 Mutations in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Promote Phase Separation and Alter Stress Granule Dynamics.

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are age-related neurodegenerative disorders with shared genetic etiologies and overlapping clinical and pathological features. Here we studied a novel ALS/FTD family and identified the P362L mutation in the low-complexity domain (LCD) of T cell-restricted intracellular antigen-1 (TIA1). Subsequent genetic association analyses showed an increased burden of TIA1 LCD mutations in ALS patients compared to controls (p = 8.7 × 1

Sex differences in spatial abilities: Methodological problems in Hoffman et al.

Hoffman et al. (1) claimed to provide evidence that “nurture” (i.e., residing in a patrilineal vs. matrilineal tribe in India) critically affects sex differences in spatial abilities. Unfortunately, their conclusion is undermined by major problems with their measures of spatial ability and sex equality. The first and biggest problem is with their measure of spatial abilities. “Spatial abilities” are a complex cognitive domain, with facets ranging from location memory (favoring women) to navigation in 3D virtual space (favoring men) (2). The puzzle used by Hoffman et al. (1) is similar to the Object Assembly subtest of the Wechsler Adult Intelligence Scale (3); sex differences on this task are extremely small (d = 0.10), at least 10-fold smaller than those found for spatial measures showing the largest sex differences. It is odd that Hoffman et al. (1) chose to investigate sex differences with this kind of sex-insensitive task. The second problem is the lack of a control task. The insensitivity of the task used by Hoffman et al. (1) suggests that their finding that men outperform women in a patrilineal tribe but not a matrilineal tribe is not related to sex differences in spatial abilities per se but to other factors instead. Education, as they noted, is likely one of these. The use of a cognitive control task tapping nonspatial abilities would have allowed for an assessment of the specificity of the effect, but, unfortunately, such a task was not included. Third, defining sex equality as matrilineality is problematic, because cross-cultural studies generally show that equality (a multidimensional construct) is not systematically correlated with descent system (4). From the descriptions of Hoffman et al. (1), it appears that women in the matrilineal Khasi have more economic power and better education, but this ignores other sex equality dimensions, such as positions of political and religious leadership, domestic authority, and autonomy. Without such measures, it is unclear whether the Khasi are, in fact, more sexegalitarian than the Karbi. Furthermore, a recent 53-nation cross-cultural study has shown that sex differences favoring men on validated, reliable, multi-item spatial measures are positively associated with United Nation indices of sex development and empowerment (5), a pattern opposite to that reported by Hoffman et al. (1). For all these reasons, the study by Hoffman et al. (1) failed to support their conclusions

Millimeter Mapping at z ∼ 1:Dust-obscured Bulge Building and Disk Growth

A randomly chosen star in today's Universe is most likely to live in a galaxy with a stellar mass between that of the Milky Way and Andromeda. Yet it remains uncertain how the structural evolution of these bulge-disk systems proceeded. Most of the unobscured star formation we observe building Andromdeda progenitors at 0.790% of their star formation is reprocessed by dust and remains unaccounted for. Here we map 500micron dust continuum emission in an Andromeda progenitor at z=1.25 to probe where it is growing through dust-obscured star formation. Combining resolved dust measurements from the NOEMA interferometer with Hubble Space Telescope Halpha maps and multicolor imaging (including new UV data from the HDUV survey), we find a bulge growing by dust-obscured star formation: while the unobscured star formation is centrally suppressed, the dust continuum is centrally concentrated, filling in the ring-like structures evident in the Halpha and UV emission. Reflecting this, the dust emission is more compact than the optical/UV tracers of star formation with r_e(dust)=3.4kpc, r_e(Halpha)/r_e(dust)=1.4, and r_e(UV)/r_e(dust)=1.8. Crucially, however, the bulge and disk of this galaxy are building simultaneously; although the dust emission is more compact than the rest-optical emission (r_e(optical)/r_e(dust)=1.4), it is somewhat less compact than the stellar mass (r_e(M_*)/r_e(dust)=0.9). Taking the 500micron emission as a tracer of star formation, the expected structural evolution of this galaxy can be accounted for by star formation: it will grow in size by Delta(r_e)/Delta(M_*)~0.3 and central surface density by Delta(Sigma_cen)/Delta(M_*)~0.9. Finally, our observations are consistent with a picture in which merging and disk instabilities drive gas to the center of galaxies, boosting global star formation rates above the main sequence and building bulges.Comment: Submitted to ApJ, key new result of paper shown in Fig.

The impact of surgical delay on resectability of colorectal cancer: An international prospective cohort study

AIM: The SARS-CoV-2 pandemic has provided a unique opportunity to explore the impact of surgical delays on cancer resectability. This study aimed to compare resectability for colorectal cancer patients undergoing delayed versus non-delayed surgery. METHODS: This was an international prospective cohort study of consecutive colorectal cancer patients with a decision for curative surgery (January-April 2020). Surgical delay was defined as an operation taking place more than 4 weeks after treatment decision, in a patient who did not receive neoadjuvant therapy. A subgroup analysis explored the effects of delay in elective patients only. The impact of longer delays was explored in a sensitivity analysis. The primary outcome was complete resection, defined as curative resection with an R0 margin. RESULTS: Overall, 5453 patients from 304 hospitals in 47 countries were included, of whom 6.6% (358/5453) did not receive their planned operation. Of the 4304 operated patients without neoadjuvant therapy, 40.5% (1744/4304) were delayed beyond 4 weeks. Delayed patients were more likely to be older, men, more comorbid, have higher body mass index and have rectal cancer and early stage disease. Delayed patients had higher unadjusted rates of complete resection (93.7% vs. 91.9%, P = 0.032) and lower rates of emergency surgery (4.5% vs. 22.5%, P < 0.001). After adjustment, delay was not associated with a lower rate of complete resection (OR 1.18, 95% CI 0.90-1.55, P = 0.224), which was consistent in elective patients only (OR 0.94, 95% CI 0.69-1.27, P = 0.672). Longer delays were not associated with poorer outcomes. CONCLUSION: One in 15 colorectal cancer patients did not receive their planned operation during the first wave of COVID-19. Surgical delay did not appear to compromise resectability, raising the hypothesis that any reduction in long-term survival attributable to delays is likely to be due to micro-metastatic disease

Verbal Learning and Memory Deficits across Neurological and Neuropsychiatric Disorders: Insights from an ENIGMA Mega Analysis.

Deficits in memory performance have been linked to a wide range of neurological and neuropsychiatric conditions. While many studies have assessed the memory impacts of individual conditions, this study considers a broader perspective by evaluating how memory recall is differentially associated with nine common neuropsychiatric conditions using data drawn from 55 international studies, aggregating 15,883 unique participants aged 15-90. The effects of dementia, mild cognitive impairment, Parkinson's disease, traumatic brain injury, stroke, depression, attention-deficit/hyperactivity disorder (ADHD), schizophrenia, and bipolar disorder on immediate, short-, and long-delay verbal learning and memory (VLM) scores were estimated relative to matched healthy individuals. Random forest models identified age, years of education, and site as important VLM covariates. A Bayesian harmonization approach was used to isolate and remove site effects. Regression estimated the adjusted association of each clinical group with VLM scores. Memory deficits were strongly associated with dementia and schizophrenia (p 0.05). Differences associated with clinical conditions were larger for longer delayed recall duration items. By comparing VLM across clinical conditions, this study provides a foundation for enhanced diagnostic precision and offers new insights into disease management of comorbid disorders

Bridging big data in the ENIGMA consortium to combine non-equivalent cognitive measures

Investigators in neuroscience have turned to Big Data to address replication and reliability issues by increasing sample size. These efforts unveil new questions about how to integrate data across distinct sources and instruments. The goal of this study was to link scores across common auditory verbal learning tasks (AVLTs). This international secondary analysis aggregated multisite raw data for AVLTs across 53 studies totaling 10,505 individuals. Using the ComBat-GAM algorithm, we isolated and removed the component of memory scores associated with site effects while preserving instrumental effects. After adjustment, a continuous item response theory model used multiple memory items of varying difficulty to estimate each individual’s latent verbal learning ability on a single scale. Equivalent raw scores across AVLTs were then found by linking individuals through the ability scale. Harmonization reduced total cross-site score variance by 37% while preserving meaningful memory effects. Age had the largest impact on scores overall (− 11.4%), while race/ethnicity variable was not significant (p > 0.05). The resulting tools were validated on dually administered tests. The conversion tool is available online so researchers and clinicians can convert memory scores across instruments. This work demonstrates that global harmonization initiatives can address reproducibility challenges across the behavioral sciences.publishedVersio

Verbal Learning and Memory Deficits across Neurological and Neuropsychiatric Disorders: Insights from an ENIGMA Mega Analysis.

Deficits in memory performance have been linked to a wide range of neurological and neuropsychiatric conditions. While many studies have assessed the memory impacts of individual conditions, this study considers a broader perspective by evaluating how memory recall is differentially associated with nine common neuropsychiatric conditions using data drawn from 55 international studies, aggregating 15,883 unique participants aged 15–90. The effects of dementia, mild cognitive impairment, Parkinson’s disease, traumatic brain injury, stroke, depression, attention-deficit/hyperactivity disorder (ADHD), schizophrenia, and bipolar disorder on immediate, short-, and long-delay verbal learning and memory (VLM) scores were estimated relative to matched healthy individuals. Random forest models identified age, years of education, and site as important VLM covariates. A Bayesian harmonization approach was used to isolate and remove site effects. Regression estimated the adjusted association of each clinical group with VLM scores. Memory deficits were strongly associated with dementia and schizophrenia (p \u3c 0.001), while neither depression nor ADHD showed consistent associations with VLM scores (p \u3e 0.05). Differences associated with clinical conditions were larger for longer delayed recall duration items. By comparing VLM across clinical conditions, this study provides a foundation for enhanced diagnostic precision and offers new insights into disease management of comorbid disorders

Mechanism of KMT5B haploinsufficiency in neurodevelopment in humans and mice.

Pathogenic variants in KMT5B, a lysine methyltransferase, are associated with global developmental delay, macrocephaly, autism, and congenital anomalies (OMIM# 617788). Given the relatively recent discovery of this disorder, it has not been fully characterized. Deep phenotyping of the largest (n = 43) patient cohort to date identified that hypotonia and congenital heart defects are prominent features that were previously not associated with this syndrome. Both missense variants and putative loss-of-function variants resulted in slow growth in patient-derived cell lines. KMT5B homozygous knockout mice were smaller in size than their wild-type littermates but did not have significantly smaller brains, suggesting relative macrocephaly, also noted as a prominent clinical feature. RNA sequencing of patient lymphoblasts and Kmt5b haploinsufficient mouse brains identified differentially expressed pathways associated with nervous system development and function including axon guidance signaling. Overall, we identified additional pathogenic variants and clinical features in KMT5B-related neurodevelopmental disorder and provide insights into the molecular mechanisms of the disorder using multiple model systems