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BACKGROUND: Craniopharyngiomas, primary brain tumors of the pituitary-hypothalamic axis, can cause clinically significant sequelae. Treatment with the use of surgery, radiation, or both is often associated with substantial morbidity related to vision loss, neuroendocrine dysfunction, and memory loss. Genotyping has shown that more than 90% of papillary craniopharyngiomas carry BRAF V600E mutations, but data are lacking with regard to the safety and efficacy of BRAF-MEK inhibition in patients with papillary craniopharyngiomas who have not undergone previous radiation therapy. METHODS: Eligible patients who had papillary craniopharyngiomas that tested positive for BRAF mutations, had not undergone radiation therapy previously, and had measurable disease received the BRAF-MEK inhibitor combination vemurafenib-cobimetinib in 28-day cycles. The primary end point of this single-group, phase 2 study was objective response at 4 months as determined with the use of centrally determined volumetric data. RESULTS: Of the 16 patients in the study, 15 (94%; 95% confidence interval [CI], 70 to 100) had a durable objective partial response or better to therapy. The median reduction in the volume of the tumor was 91% (range, 68 to 99). The median follow-up was 22 months (95% CI, 19 to 30) and the median number of treatment cycles was 8. Progression-free survival was 87% (95% CI, 57 to 98) at 12 months and 58% (95% CI, 10 to 89) at 24 months. Three patients had disease progression during followup after therapy had been discontinued; none have died. The sole patient who did not have a response stopped treatment after 8 days owing to toxic effects. Grade 3 adverse events that were at least possibly related to treatment occurred in 12 patients, including rash in 6 patients. In 2 patients, grade 4 adverse events (hyperglycemia in 1 patient and increased creatine kinase levels in 1 patient) were reported; 3 patients discontinued treatment owing to adverse events. CONCLUSIONS: In this small, single-group study involving patients with papillary craniopharyngiomas, 15 of 16 patients had a partial response or better to the BRAF-MEK inhibitor combination vemurafenib-cobimetinib. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT03224767). [ABSTRACT FROM AUTHOR]

Purpose: Little is known about cancer-related cognitive impairments (CRCI) in women with metastatic breast cancer (MBC). The purpose of this study is to (1) comprehensively describe CRCI and any associated psychosocial and behavioral symptoms, (2) determine observable sociodemographic and clinical risk factors for CRCI, and (3) explore cognitive and psychosocial predictors of quality of life and social functioning in women living with MBC., Methods: Using a cross-sectional design, women with MBC completed assessments (objective and subjective measures of CRCI including 3 open-ended questions, measures of psychosocial and behavioral factors, and assessments of quality of life and social function), and data were analyzed using descriptive statistics, qualitative content analysis, correlation analyses, t tests, analysis of variance, and linear regression models., Results: Data from 52 women were analyzed. 69.2% of the sample reported clinically significant CRCI and 46% of the sample scored < 1 standard deviation below the standardized mean on one or more cognitive tests. Those with triple-negative MBC (compared to HER2+), recurrent MBC (compared to de novo), and no history of chemotherapy had worse subjective CRCI, and those without history of surgery and older age had worse objective CRCI. Subjective CRCI, but not objective CRCI, was significantly associated with quality of life and social functioning., Conclusion: Subjective and objective CRCI are likely a common problem for those with MBC. Subjective CRCI is associated with poorer quality of life and lower social functioning. Healthcare providers should acknowledge cognitive symptoms, continually assess cognitive function, and address associated unmet needs across the MBC trajectory., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Cellulitis is a bacterial skin infection that tends to recur. Previous studies have identified several risk factors that may contribute to its pathogenesis. Obesity is an increasingly prevalent worldwide disease that has been associated with skin and soft tissue infections., Objective: The aim of our systematic review and meta-analysis was to investigate the association of cellulitis with obesity., Methods: The Ovid MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and Web of Science databases were searched for the relevant studies from the inception of each respective database to March 13, 2021. Case-control, cross-sectional, or cohort studies that examined the odds or risk of increased BMI in patients with cellulitis were included. This study was carried out in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. The Newcastle-Ottawa scale (NOS) was used to evaluate the risk of bias in included studies., Results: In total, 9 case-control studies were included in our quantitative meta-analysis with a total of 68,148 study participants. A significant association was found between cellulitis and obesity (pooled odds ratio [OR] 2.67, 95% CI 1.91-3.71). No significant association was observed between cellulitis and being overweight (pooled OR 1.69, 95% CI 0.99-2.88). Patients with cellulitis were also found to have 1.63-fold increased odds of being male (pooled OR 1.63, 95% CI 1.12-2.38)., Conclusions: Our findings suggest that cellulitis is significantly associated with obesity. Maintaining a healthy BMI may be indicated for patients presenting with cellulitis., (©Kimi Gabriella Taira, Madelyn Wang, William Guo, Olivia Kam, Tara Kaufmann. Originally published in JMIR Dermatology (http://derma.jmir.org), 20.08.2024.)

Whole-genome doubling (WGD) is a critical driver of tumor development and is linked to drug resistance and metastasis in solid malignancies. Here, we demonstrate that WGD is an ongoing mutational process in tumor evolution. Using single-cell whole-genome sequencing, we measured and modeled how WGD events are distributed across cellular populations within tumors and associated WGD dynamics with properties of genome diversification and phenotypic consequences of innate immunity. We studied WGD evolution in 65 high-grade serous ovarian cancer (HGSOC) tissue samples from 40 patients, yielding 29,481 tumor cell genomes. We found near-ubiquitous evidence of WGD as an ongoing mutational process promoting cell-cell diversity, high rates of chromosomal missegregation, and consequent micronucleation. Using a novel mutation-based WGD timing method, doubleTime , we delineated specific modes by which WGD can drive tumor evolution: (i) unitary evolutionary origin followed by significant diversification, (ii) independent WGD events on a pre-existing background of copy number diversity, and (iii) evolutionarily late clonal expansions of WGD populations. Additionally, through integrated single-cell RNA sequencing and high-resolution immunofluorescence microscopy, we found that inflammatory signaling and cGAS-STING pathway activation result from ongoing chromosomal instability and are restricted to tumors that remain predominantly diploid. This contrasted with predominantly WGD tumors, which exhibited significant quiescent and immunosuppressive phenotypic states. Together, these findings establish WGD as an evolutionarily 'active' mutational process that promotes evolvability and dysregulated immunity in late stage ovarian cancer.

Sex and gender differences exist in the prevalence and clinical manifestation of common brain disorders. Identifying their neural correlates may help improve clinical care.

An important question in cell biology is how cytoskeletal proteins evolved and drove the development of novel structures and functions. Here we address the origin of SPIRE actin nucleators. Mammalian SPIREs work with RAB GTPases, formin (FMN)-subgroup actin assembly proteins and class-5 myosin (MYO5) motors to transport organelles along actin filaments towards the cell membrane. However, the origin and extent of functional conservation of SPIRE among species is unknown. Our sequence searches show that SPIRE exist throughout holozoans (animals and their closest single-celled relatives), but not other eukaryotes. SPIRE from unicellular holozoans (choanoflagellate), interacts with RAB, FMN and MYO5 proteins, nucleates actin filaments and complements mammalian SPIRE function in organelle transport. Meanwhile SPIRE and MYO5 proteins colocalise to organelles in Salpingoeca rosetta choanoflagellates. Based on these observations we propose that SPIRE originated in unicellular ancestors of animals providing an actin-myosin driven exocytic transport mechanism that may have contributed to the evolution of complex multicellular animals., (© 2024. The Author(s).)

Methylenetetrahydrofolate reductase (MTHFR) is key to the metabolism of folic acid, with loss of function mutations resulting in elevated homocysteine levels, a known risk factor for cardiovascular disease. Psoriasis patients may demonstrate hyperhomocysteinemia. To assess for the association between psoriasis and MTHFR C677T and A1298C polymorphisms. A systematic literature search was conducted in MEDLINE, Embase, Cochrane CENTRAL, and Web of Science. Case reports, case-control, cohort, and cross-sectional studies with full-text availability in English were considered. Meta-analysis was conducted with pooled ORs calculated via the random effects model (I2 > 50%). Of 917 records identified, 10 studies were selected for review of 1965 psoriasis patients and 2030 controls. Meta-analysis demonstrated that for MTHFR C677T, there were positive associations between psoriasis and the allele contrast model (C vs T, pooled OR = 1.69, 95% CI = 1.10-2.59), the additive model (CC vs TT, pooled OR = 2.44, 95% CI = 1.06-5.60), the dominant model (CC vs CT + TT, pooled OR = 1.77, 95% CI = 1.06-2.98), and the recessive model (CC + CT vs TT, pooled OR = 2.08, 95% CI = 1.05-4.13). For MTHFR A1298C, there were positive associations between psoriasis and the allele contrast model (A vs C, pooled OR = 3.57, 95% CI = 1.19-10.68), the dominant model (AA vs AC + CC, pooled OR = 4.44, 95% CI = 1.12-17.66), and the overdominant model (AC vs AA + CC, pooled OR = 0.26, 95% CI = 0.07-0.91). There may be a link between the C677T and A1298C polymorphisms with psoriasis diagnosis., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Sex differences exist in the prevalence and clinical manifestation of several mental disorders, suggesting that sex-specific brain phenotypes may play key roles. Previous research used machine learning models to classify sex from imaging data of the whole brain and studied the association of class probabilities with mental health, potentially overlooking regional specific characteristics., Methods: We here investigated if a regionally constrained model of brain volumetric imaging data may provide estimates that are more sensitive to mental health than whole brain-based estimates. Given its known role in emotional processing and mood disorders, we focused on the limbic system. Using two different cohorts of healthy subjects, the Human Connectome Project and the Queensland Twin IMaging, we investigated sex differences and heritability of brain volumes of limbic structures compared to non-limbic structures, and subsequently applied regionally constrained machine learning models trained solely on limbic or non-limbic features. To investigate the biological underpinnings of such models, we assessed the heritability of the obtained sex class probability estimates, and we investigated the association with major depression diagnosis in an independent clinical sample. All analyses were performed both with and without controlling for estimated total intracranial volume (eTIV)., Results: Limbic structures show greater sex differences and are more heritable compared to non-limbic structures in both analyses, with and without eTIV control. Consequently, machine learning models performed well at classifying sex based solely on limbic structures and achieved performance as high as those on non-limbic or whole brain data, despite the much smaller number of features in the limbic system. The resulting class probabilities were heritable, suggesting potentially meaningful underlying biological information. Applied to an independent population with major depressive disorder, we found that depression is associated with male-female class probabilities, with largest effects obtained using the limbic model. This association was significant for models not controlling for eTIV whereas in those controlling for eTIV the associations did not pass significance correction., Conclusions: Overall, our results highlight the potential utility of regionally constrained models of brain sex to better understand the link between sex differences in the brain and mental disorders., (© 2024. The Author(s).)

Deep learning approaches for clinical predictions based on magnetic resonance imaging data have shown great promise as a translational technology for diagnosis and prognosis in neurological disorders, but its clinical impact has been limited. This is partially attributed to the opaqueness of deep learning models, causing insufficient understanding of what underlies their decisions. To overcome this, we trained convolutional neural networks on structural brain scans to differentiate dementia patients from healthy controls, and applied layerwise relevance propagation to procure individual-level explanations of the model predictions. Through extensive validations we demonstrate that deviations recognized by the model corroborate existing knowledge of structural brain aberrations in dementia. By employing the explainable dementia classifier in a longitudinal dataset of patients with mild cognitive impairment, we show that the spatially rich explanations complement the model prediction when forecasting transition to dementia and help characterize the biological manifestation of disease in the individual brain. Overall, our work exemplifies the clinical potential of explainable artificial intelligence in precision medicine., (© 2024. The Author(s).)

The difference between venous and arterial carbon dioxide pressure (pCO 2 gap), has been used as a diagnostic and prognostic tool. We aimed to assess whether perioperative pCO 2 gaps can predict postoperative complications. This was a secondary analysis of a multicenter RCT comparing goal-directed therapy (GDT) to standard care in which 464 patients undergoing high-risk elective abdominal surgery were included. Arterial and central venous blood samples were simultaneously obtained at four time points: after induction, at the end of surgery, at PACU/ICU admission, and PACU/ICU discharge. Complications within the first 30 days after surgery were recorded. Similar pCO 2 gaps were found in patients with and without complications, except for the pCO 2 gap at the end of surgery, which was higher in patients with complications (6.0 mmHg [5.0-8.0] vs. 6.0 mmHg [4.1-7.5], p = 0.005). The area under receiver operating characteristics curves for predicting complications from pCO 2 gaps at all time points were between 0.5 and 0.6. A weak correlation between ScvO 2 and pCO 2 gaps was found for all timepoints (ρ was between - 0.40 and - 0.29 for all timepoints, p < 0.001). The pCO 2 gap did not differ between GDT and standard care at any of the selected time points. In our study, pCO 2 gap was a poor predictor of major postoperative complications at all selected time points. Our research does not support the use of pCO 2 gap as a prognostic tool after high-risk abdominal surgery. pCO 2 gaps were comparable between GDT and standard care. Clinical trial registration Netherlands Trial Registry NTR3380., (© 2024. The Author(s).)

Purpose: Limited research exists on translation of in-vitro glucose measurement interfering compounds to the in-vivo situation. We investigated whether Point-of-Care glucose measurements by Accu Chek Inform II (ACI II) were accurate to monitor glucose concentrations during surgery with general anesthesia by comparing with the reference laboratory hexokinase plasma glucose test., Method: Patients undergoing surgery with general anesthesia were included. Anesthesia was maintained with either Sevoflurane or Total intravenous anesthesia (TIVA). Prior to and after induction, blood glucose was measured with ACI II and the hexokinase test. Bland-Altman analysis was performed to assess method agreement. Subgroup analyses on glucose measurement differences per type of maintenance anesthesia were performed., Results: Thirty-nine patients were included, and 78 measurements were performed. All paired measurements had clinically acceptable agreement with a percentage error of 10.0% (95% CI 8.0 to 11.9). The mean difference (95% limits of agreement) between ACI II and hexokinase for all measurements was 0.0 mmol/L (-0.7 to 0.7 mmol/L). Before induction (n = 39), mean difference was -0.1 mmol/L (-0.6 to 0.4 mmol/L), and after induction (n = 39), mean difference was 0.1 mmol/L (-0.8 to 0.9 mmol/L). Further investigation showed the difference varied per test for patients receiving Sevoflurane compared to patients receiving TIVA (-0.2 ± 0.4 mmol/L vs. 0.4 ± 0.3 mmol/L, p < 0.001). Before and after induction, the difference between ACI II and hexokinase measurements increased for patients receiving Sevoflurane compared to patients receiving TIVA (0.4 ± 0.4 mmol/L vs. -0.4 ± 0.3 mmol/L, p < 0.001)., Conclusion: The agreement between glucose measurements using ACI II and the reference laboratory hexokinase test was clinically acceptable with a percentage error of 10.0% (95% CI 8.0 to 11.9). The use of TIVA may negatively affect the measurement performance of the ACI II., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

An elevated percentage of medical personnel reports using alcohol to relieve stress. Levels of alcohol addiction are almost double that of the general population. Robotic surgery is becoming more widespread. The purpose of this study is to evaluate the effects of alcohol ingestion on performance of a standardized curriculum using a robotic training platform. Surgeons and surgical trainees were recruited. Candidates performed 4 standardized exercises (Vitruvian Operation (VO), Stacking Challenge (SC), Ring Tower (RT), Suture Sponge (SS)) at 0.0 blood alcohol concentration (BAC), followed by testing in the elimination phase at a target BAC of 0.8‰. Learning effects were minimised through prior training. A total of 20 participants were recruited. Scores for RT and SS exercises were significantly worse under the influence of alcohol [instruments out of view (SS (z = 2.012; p = 0.044), RT (z score 1.940, p = 0.049)), drops (SS (z = 3.250; p = 0.001)), instrument collisions (SS (z = 2.460; p = 0.014)), missed targets (SS (z = 2.907; p = 0.004)]. None of the scores improved with alcohol consumption, and there were measurable deleterious effects on the compound indicators risk affinity and tissue handling. Despite the potential mitigating features of robotic surgery including tremor filtration, motion scaling, and improved three-dimensional visualization, alcohol consumption was associated with a significant increase in risk affinity and rough tissue handling, along with a deterioration of performance in select virtual robotic tasks. In the interest of patient safety, alcohol should not be consumed prior to performing robotic surgery and sufficiently long intervals between alcohol ingestion and surgical performance are mandatory., (© 2024. The Author(s), under exclusive licence to Springer-Verlag London Ltd., part of Springer Nature.)

Background: Puberty depicts a period of profound and multifactorial changes ranging from social to biological factors. While brain development in youths has been studied mostly from an age perspective, recent evidence suggests that pubertal measures may be more sensitive to study adolescent neurodevelopment, however, studies on pubertal timing in relation to brain development are still scarce., Methods: We investigated if pre- vs. post-menarche status can be classified using machine learning on cortical and subcortical structural magnetic resonance imaging (MRI) data from strictly age-matched adolescent females from the Adolescent Brain Cognitive Development (ABCD) cohort. For comparison of the identified menarche-related patterns to age-related patterns of neurodevelopment, we trained a brain age prediction model on data from the Philadelphia Neurodevelopmental Cohort and applied it to the same ABCD data, yielding differences between predicted and chronological age referred to as brain age gaps. We tested the sensitivity of both these frameworks to measures of pubertal maturation, specifically age at menarche and puberty status., Results: The machine learning model achieved moderate but statistically significant accuracy in the menarche classification task, yielding for each subject a class probability ranging from 0 (pre-) to 1 (post- menarche). Comparison to brain age predictions revealed shared and distinct patterns of neurodevelopment captured by both approaches. Continuous menarche class probabilities were positively associated with brain age gaps, but only the menarche class probabilities-not the brain age gaps-were associated with age at menarche., Conclusions: This study demonstrates the use of a machine learning model to classify menarche status from structural MRI data while accounting for age-related neurodevelopment. Given its sensitivity towards measures of puberty timing, our work suggests that menarche class probabilities may be developed toward an objective brain-based marker of pubertal development., (© 2024. The Author(s).)

Background: Schizophrenia is a highly heritable brain disorder with a typical symptom onset in early adulthood. The 2-hit hypothesis posits that schizophrenia results from differential early neurodevelopment, predisposing an individual, followed by a disruption of later brain maturational processes that trigger the onset of symptoms., Study Design: We applied hierarchical clustering to transcription levels of 345 genes previously linked to schizophrenia, derived from cortical tissue samples from 56 donors across the lifespan. We subsequently calculated clustered-specific polygenic risk scores for 743 individuals with schizophrenia and 743 sex- and age-matched healthy controls., Study Results: Clustering revealed a set of 183 genes that was significantly upregulated prenatally and downregulated postnatally and 162 genes that showed the opposite pattern. The prenatally upregulated set of genes was functionally annotated to fundamental cell cycle processes, while the postnatally upregulated set was associated with the immune system and neuronal communication. We found an interaction between the 2 scores; higher prenatal polygenic risk showed a stronger association with schizophrenia diagnosis at higher levels of postnatal polygenic risk. Importantly, this finding was replicated in an independent clinical cohort of 3233 individuals., Conclusions: We provide genetics-based evidence that schizophrenia is shaped by disruptions of separable biological processes acting at distinct phases of neurodevelopment. The modeling of genetic risk factors that moderate each other's effect, informed by the timing of their expression, will aid in a better understanding of the development of schizophrenia., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

Background: Carriers of the 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants exhibit regional and global brain differences compared with noncarriers. However, interpreting regional differences is challenging if a global difference drives the regional brain differences. Intraindividual variability measures can be used to test for regional differences beyond global differences in brain structure., Methods: Magnetic resonance imaging data were used to obtain regional brain values for 1q21.1 distal deletion (n = 30) and duplication (n = 27) and 15q11.2 BP1-BP2 deletion (n = 170) and duplication (n = 243) carriers and matched noncarriers (n = 2350). Regional intra-deviation scores, i.e., the standardized difference between an individual's regional difference and global difference, were used to test for regional differences that diverge from the global difference., Results: For the 1q21.1 distal deletion carriers, cortical surface area for regions in the medial visual cortex, posterior cingulate, and temporal pole differed less and regions in the prefrontal and superior temporal cortex differed more than the global difference in cortical surface area. For the 15q11.2 BP1-BP2 deletion carriers, cortical thickness in regions in the medial visual cortex, auditory cortex, and temporal pole differed less and the prefrontal and somatosensory cortex differed more than the global difference in cortical thickness., Conclusions: We find evidence for regional effects beyond differences in global brain measures in 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants. The results provide new insight into brain profiling of the 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants, with the potential to increase understanding of the mechanisms involved in altered neurodevelopment., (Copyright © 2023. Published by Elsevier Inc.)

Introduction: Acute myeloid leukemia (AML) is a cancer of the hematopoietic system characterized by hyperproliferation of undifferentiated cells of the myeloid lineage. While most of AML therapies are focused toward tumor debulking, all-trans retinoic acid (ATRA) induces neutrophil differentiation in the AML subtype acute promyelocytic leukemia (APL). Macroautophagy has been extensively investigated in the context of various cancers and is often dysregulated in AML where it can have context-dependent pro- or anti-leukemogenic effects. On the contrary, the implications of chaperone-mediated autophagy (CMA) on the pathophysiology of diseases are still being explored and its role in AML remains elusive., Methods: We took advantage of human AML primary samples and databases to analyze CMA gene expression and activity. Furthermore, we used ATRA-sensitive (NB4) and -resistant (NB4-R1) APL cells to further dissect a potential function for CMA in ATRA-mediated neutrophil differentiation. NB4-R1 cells are unique in that they do respond to retinoic acid transcriptionally but do not mature in response to retinoid signaling alone unless maturation is triggered by adding cyclic adenosine monophosphate., Results: Here, we report that CMA-related mRNA transcripts are significantly higher expressed in immature hematopoietic cells as compared to neutrophils, contrasting the macroautophagy gene expression patterns. Accordingly, lysosomal degradation of an mCherry-KFERQ CMA reporter decreases during ATRA-induced differentiation of APL cells. On the other hand, using NB4-R1 cells we found that macroautophagy flux primed ATRA-resistant NB4-R1 cells to differentiate upon ATRA treatment but reduced the association of lysosome-associated membrane protein type 2A (LAMP-2A) and heat shock protein family A (Hsp70) member 8 (HSPA8), necessary for complete neutrophil maturation. Accordingly, depletion of HSPA8 attenuated CMA activity and facilitated APL cell differentiation. In contrast, maintaining high CMA activity by ectopic expression of LAMP-2A impeded APL differentiation., Conclusion: Overall, our findings suggest that APL neutrophil differentiation requires CMA inactivation and that this pathway predominantly depends on HSPA8 and is possibly assisted by other co-chaperones., (© 2024 S. Karger AG, Basel.)

Paracetamol (acetaminophen, APAP) overdose severely damages mitochondria and triggers several apoptotic processes in hepatocytes, but the final outcome is fulminant necrotic cell death, resulting in acute liver failure and mortality. Here, we studied this switch of cell death modes and demonstrate a non-canonical role of the apoptosis-regulating BCL-2 homolog BIM/Bcl2l11 in promoting necrosis by regulating cellular bioenergetics. BIM deficiency enhanced total ATP production and shifted the bioenergetic profile towards glycolysis, resulting in persistent protection from APAP-induced liver injury. Modulation of glucose levels and deletion of Mitofusins confirmed that severe APAP toxicity occurs only in cells dependent on oxidative phosphorylation. Glycolytic hepatocytes maintained elevated ATP levels and reduced ROS, which enabled lysosomal recycling of damaged mitochondria by mitophagy. The present study highlights how metabolism and bioenergetics affect drug-induced liver toxicity, and identifies BIM as important regulator of glycolysis, mitochondrial respiration, and oxidative stress signaling., (© 2023. The Author(s).)

Background: Whereas genetic variants influencing total amygdala volume have been identified, the genetic architecture of its distinct nuclei has yet to be explored. We aimed to investigate whether increased phenotypic specificity through nuclei segmentation aids genetic discoverability and elucidates the extent of shared genetic architecture and biological pathways with related disorders., Methods: T1-weighted brain magnetic resonance imaging scans (N = 36,352, 52% female) from the UK Biobank were segmented into 9 amygdala nuclei with FreeSurfer (version 6.1). Genome-wide association analyses were performed on the entire sample, a European-only subset (n = 31,690), and a generalization (transancestry) subset (n = 4662). We estimated single nucleotide polymorphism-based heritability; derived polygenicity, discoverability, and power estimates; and investigated genetic correlations and shared loci with psychiatric disorders., Results: The heritability of the nuclei ranged from 0.17 to 0.33. Across the whole amygdala and the nuclei volumes, we identified 28 novel genome-wide significant (p adj < 5 × 10 -9 ) loci in the European analysis, with significant en masse replication for the whole amygdala and central nucleus volumes in the generalization analysis, and we identified 10 additional candidate loci in the combined analysis. The central nucleus had the highest statistical power for discovery. The significantly associated genes and pathways showed unique and shared effects across the nuclei, including immune-related pathways. Shared variants were identified between specific nuclei and autism spectrum disorder, Alzheimer's disease, Parkinson's disease, bipolar disorder, and schizophrenia., Conclusions: Through investigation of amygdala nuclei volumes, we have identified novel candidate loci in the neurobiology of amygdala volume. These nuclei volumes have unique associations with biological pathways and genetic overlap with psychiatric disorders., (Copyright © 2023 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Puberty demarks a period of profound brain dynamics that orchestrates changes to a multitude of neuroimaging-derived phenotypes. This complexity poses a dimensionality problem when attempting to chart an individual's brain development over time. Here, we illustrate that shifts in subject similarity of brain imaging data relate to pubertal maturation in the longitudinal ABCD study. Given that puberty depicts a critical window for emerging mental health issues, we additionally show that our model is capable of capturing variance in the adolescent brain related to psychopathology in a population-based and a clinical cohort. These results suggest that low-dimensional reference spaces based on subject similarities render useful to chart variance in brain development in youths., (© 2023. Springer Nature Limited.)

Background: Controllability is a measure of the brain's ability to orchestrate neural activity which can be quantified in terms of properties of the brain's network connectivity. Evidence from the literature suggests that aging can exert a general effect on whole-brain controllability. Mounting evidence, on the other hand, suggests that parenthood and motherhood in particular lead to long-lasting changes in brain architecture that effectively slow down brain aging. We hypothesize that parenthood might preserve brain controllability properties from aging., Methods: In a sample of 814 healthy individuals (aged 33.9 ± 12.7 years, 522 females), we estimate whole-brain controllability and compare the aging effects in subjects with vs. those without children. We use diffusion tensor imaging (DTI) to estimate the brain structural connectome. The level of brain control is then calculated from the connectomic properties of the brain structure. Specifically, we measure the network control over many low-energy state transitions (average controllability) and the network control over difficult-to-reach states (modal controllability)., Results and Conclusion: In nulliparous females, whole-brain average controllability increases, and modal controllability decreases with age, a trend that we do not observe in parous females. Statistical comparison of the controllability metrics shows that modal controllability is higher and average controllability is lower in parous females compared to nulliparous females. In men, we observed the same trend, but the difference between nulliparous and parous males do not reach statistical significance. Our results provide strong evidence that parenthood contradicts aging effects on brain controllability and the effect is stronger in mothers., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Jamalabadi, Hahn, Winter, Nozari, Ernsting, Meinert, Leehr, Dohm, Bauer, Pfarr, Stein, Thomas-Odenthal, Brosch, Mauritz, Gruber, Repple, Kaufmann, Krug, Nenadić, Kircher, Dannlowski and Derntl.)

Background: Frontal fibrosing alopecia (FFA) is a cicatricial alopecia affecting the frontotemporal hairline. Given that this scarring, immune-mediated follicular destruction most commonly affects postmenopausal Caucasian women, researchers have postulated that there are hormonal and genetic components; however, the etiology of FFA is still unknown. Recently, dermatologists have reported cases of FFA as being potentially caused by cosmetic products, such as sunscreen and shampoo. Therefore, this systematic review and meta-analysis intend to be the first to analyze the relationship between FFA and cosmetic/personal care products and treatments, including sunscreen, moisturizer, foundation, shampoo, conditioner, hair mousse, hair gel, hair dye, hair straightening/rebonding, chemical/laser facial resurfacing, aftershave, and facial cleanser., Methods: The Cochrane, PubMed, EMBASE, and Medline (Ovid) databases were searched for the relevant studies from the date of inception to August 2022. Case-control, cross-sectional, and cohort studies examining the effects of cosmetic/personal care product use on FFA, available in English full-text, were included. Analyses were performed using Review Manager, version 5.4. Results were reported as an odds ratio (OR) with a 95% confidence interval (CI); p values < 0.05 were considered significant., Results: Nine studies were included in our quantitative analyses, totaling 1,248 FFA patients and 1,459 controls. There were significant positive associations found for FFA and sunscreen (OR 3.02, 95% CI 1.67-5.47; p = 0.0003) and facial moisturizer (OR 2.20, 95% CI 1.51-3.20; p < 0.0001) use. Gender sub-analyses demonstrated a positive association for FFA and facial moisturizer in men (OR 5.07, 95% CI 1.40-18.32; p = 0.01), but not in women (OR 1.58, 95% CI 0.83-2.98; p = 0.16). Both gender sub-analyses were significantly positive for the association with facial sunscreen (Male OR 4.61, 95% CI 1.54-13.78, p = 0.006; Female OR 2.74, 95% CI 1.32-5.70, p = 0.007). There was no association found for a facial cleanser (OR 1.14, 95% CI 0.33-1.52; p = 0.51), foundation (OR 1.13, 95% CI 0.83-1.55; p = 0.21), shampoo (OR 0.49, 95% CI 0.22-1.10; p = 0.08), hair conditioner (OR 0.81, 95% CI 0.52-1.26; p = 0.35), hair mousse (OR 1.37, 95% CI 0.75-2.51; p = 0.31), and hair gel (OR 0.90, 95% CI 0.48-1.69; p = 0.74), hair dye (OR 1.07, 95% CI 0.69-1.64; p = 0.77), hair straightening/rebonding (OR 0.88, 95% CI 0.08-9.32; p = 0.92), hair perming (OR 1.41, 95% CI 0.89-2.23; p = 0.14), facial toner (OR 0.51, 95% CI 0.12-2.21; p = 0.37), or aftershave (OR 1.64, 95% CI 0.28-9.49; p = 0.58)., Conclusions: This meta-analysis strongly suggests that leave-on facial products, facial sunscreen and moisturizer, are associated with FFA. While the association with facial moisturizer did not persist when stratifying for female populations, gender sub-analyses remained significant for a facial sunscreen. There was no significant relationship found with hair products or treatments. These findings suggest a potential environmental etiology in the development of FFA, particularly UV-protecting chemicals., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The impact of chromosomal inversions on human brain morphology remains underexplored. We studied 35 common inversions classified from genotypes of 33,018 adults with European ancestry. The inversions at 2p22.3, 16p11.2, and 17q21.31 reach genome-wide significance, followed by 8p23.1 and 6p21.33, in their association with cortical and subcortical morphology. The 17q21.31, 8p23.1, and 16p11.2 regions comprise the LRRC37, OR7E, and NPIP duplicated gene families. We find the 17q21.31 MAPT inversion region, known for harboring neurological risk, to be the most salient locus among common variants for shaping and patterning the cortex. Overall, we observe the inverted orientations decreasing brain size, with the exception that the 2p22.3 inversion is associated with increased subcortical volume and the 8p23.1 inversion is associated with increased motor cortex. These significant inversions are in the genomic hotspots of neuropsychiatric loci. Our findings are generalizable to 3,472 children and demonstrate inversions as essential genetic variation to understand human brain phenotypes., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Crystallized abilities are skills used to solve problems based on experience, while fluid abilities are linked to reasoning without evoke prior knowledge. To what extent crystallized and fluid abilities involve dissociated or overlapping neural systems is debatable. Due to often deployed small sample sizes or different study settings in prior work, the neural basis of crystallized and fluid abilities in childhood remains largely unknown. Here we analyzed within and between network connectivity patterns from resting-state functional MRI of 2707 children between 9 and 10 years from the ABCD study. We hypothesized that differences in functional connectivity at the default mode network (DMN), ventral, and dorsal attentional networks (VAN, DAN) explain differences in fluid and crystallized abilities. We found that stronger between-network connectivity of the DMN and VAN, DMN and DAN, and VAN and DAN predicted crystallized abilities. Within-network connectivity of the DAN predicted both crystallized and fluid abilities. Our findings reveal that crystallized abilities rely on the functional coupling between attentional networks and the DMN, whereas fluid abilities are associated with a focal connectivity configuration at the DAN. Our study provides new evidence into the neural basis of child intelligence and calls for future comparative research in adulthood during neuropsychiatric diseases., (© The Author(s) 2023. Published by Oxford University Press.)

The interplay between functional brain network maturation and psychopathology during development remains elusive. To establish the structure of psychopathology and its neurobiological mechanisms, mapping of both shared and unique functional connectivity patterns across developmental clinical populations is needed. We investigated shared associations between resting-state functional connectivity and psychopathology in children and adolescents aged 5-21 (n = 1689). Specifically, we used partial least squares (PLS) to identify latent variables (LV) between connectivity and both symptom scores and diagnostic information. We also investigated associations between connectivity and each diagnosis specifically, controlling for other diagnosis categories. PLS identified five significant LVs between connectivity and symptoms, mapping onto the psychopathology hierarchy. The first LV resembled a general psychopathology factor, followed by dimensions of internalising- externalising, neurodevelopment, somatic complaints, and thought problems. Another PLS with diagnostic data revealed one significant LV, resembling a cross-diagnostic case-control pattern. The diagnosis-specific PLS identified a unique connectivity pattern for autism spectrum disorder (ASD). All LVs were associated with distinct patterns of functional connectivity. These dimensions largely replicated in an independent sample (n = 420) from the same dataset, as well as to an independent cohort (n = 3504). This suggests that covariance in developmental functional brain networks supports transdiagnostic dimensions of psychopathology., Competing Interests: Declaration of Competing Interest O.A.A. is a consultant to cortechs.ai and has received speaker’s honorarium from Janssen, Lundbeck, Sunovion., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The difference between chronological age and the apparent age of the brain estimated from brain imaging data-the brain age gap (BAG)-is widely considered a general indicator of brain health. Converging evidence supports that BAG is sensitive to an array of genetic and nongenetic traits and diseases, yet few studies have examined the genetic architecture and its corresponding causal relationships with common brain disorders. Here, we estimate BAG using state-of-the-art neural networks trained on brain scans from 53,542 individuals (age range 3-95 years). A genome-wide association analysis across 28,104 individuals (40-84 years) from the UK Biobank revealed eight independent genomic regions significantly associated with BAG (p < 5 × 10 -8 ) implicating neurological, metabolic, and immunological pathways - among which seven are novel. No significant genetic correlations or causal relationships with BAG were found for Parkinson's disease, major depressive disorder, or schizophrenia, but two-sample Mendelian randomization indicated a causal influence of AD (p = 7.9 × 10 -4 ) and bipolar disorder (p = 1.35 × 10 -2 ) on BAG. These results emphasize the polygenic architecture of brain age and provide insights into the causal relationship between selected neurological and neuropsychiatric disorders and BAG., (© 2023. The Author(s).)

Psychiatric disorders are complex clinical conditions with large heterogeneity and overlap in symptoms, genetic liability and brain imaging abnormalities. Building on a dimensional conceptualization of mental health, previous studies have reported genetic overlap between psychiatric disorders and population-level mental health, and between psychiatric disorders and brain functional connectivity. Here, in 30,701 participants aged 45-82 from the UK Biobank we map the genetic associations between self-reported mental health and resting-state fMRI-based measures of brain network function. Multivariate Omnibus Statistical Test revealed 10 genetic loci associated with population-level mental symptoms. Next, conjunctional FDR identified 23 shared genetic variants between these symptom profiles and fMRI-based brain network measures. Functional annotation implicated genes involved in brain structure and function, in particular related to synaptic processes such as axonal growth (e.g. NGFR and RHOA). These findings provide further genetic evidence of an association between brain function and mental health traits in the population., (© 2023. The Author(s).)

Hidradenitis suppurativa (HS) is a chronic inflammatory skin condition associated with significant psychosocial comorbidity. To date, the relationship between HS and sexual dysfunction has not been assessed through meta-analysis. A systematic review was performed by OVID Medline, EMBASE, Cochrane Central, PsycINFO via EBSCO, Web of Science, and LILACS. Original English language studies assessing HS and sexual function published prior to April 2020 were screened. Scores from the Female Sexual Function Index (FSFI), International Index of Erectile Function (IIEF), Arizona Sexual Experiences Scale (ASEX), Frankfurt Self-Concept Scale for Sexuality (FKKS SEX), and Dermatology Life Quality Index (DLQI) were analyzed. Sixteen studies met inclusion criteria, and nine were eligible for meta-analysis. Pooled mean FSFI score for female HS patients met criteria for sexual dysfunction (mean = 20.32, P < 0.001). Females with HS reported worse FSFI scores than controls (pooled mean difference = -5.704, P = 0.003, I 2 =0). Mean IIEF score among males with HS was 47.96 (P < 0.001). Males with HS also reported worse IIEF scores than controls (pooled mean difference = -18.77, P = 0.00, I 2  = 0). Females with HS performed worse on sexual function inventories than males with HS (SMD = -0.72, P = 0.009, I 2  = 0). Both male and female HS patients reported significantly more sexual impairment than same-sex controls. Female HS patients also experience more sexual impairment than males and on average meet criteria for sexual dysfunction (FSFI <26.55). Clinicians should be aware that their patients with HS, especially females, may be suffering from sexual dysfunction and treated them appropriately., (© 2022 the International Society of Dermatology.)

Apoptosis is a form of regulated cell death (RCD) that involves proteases of the caspase family. Pharmacological and genetic strategies that experimentally inhibit or delay apoptosis in mammalian systems have elucidated the key contribution of this process not only to (post-)embryonic development and adult tissue homeostasis, but also to the etiology of multiple human disorders. Consistent with this notion, while defects in the molecular machinery for apoptotic cell death impair organismal development and promote oncogenesis, the unwarranted activation of apoptosis promotes cell loss and tissue damage in the context of various neurological, cardiovascular, renal, hepatic, infectious, neoplastic and inflammatory conditions. Here, the Nomenclature Committee on Cell Death (NCCD) gathered to critically summarize an abundant pre-clinical literature mechanistically linking the core apoptotic apparatus to organismal homeostasis in the context of disease., (© 2023. The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare.)

Background: Abnormalities in brain structure are shared across diagnostic categories. Given the high rate of comorbidity, the interplay of relevant behavioural factors may also cross these classic boundaries., Methods: We aimed to detect brain-based dimensions of behavioural factors using canonical correlation and independent component analysis in a clinical youth sample (n = 1732, 64 % male, age: 5-21 years)., Results: We identified two correlated patterns of brain structure and behavioural factors. The first mode reflected physical and cognitive maturation (r = 0.92, p = .005). The second mode reflected lower cognitive ability, poorer social skills, and psychological difficulties (r = 0.92, p = .006). Elevated scores on the second mode were a common feature across all diagnostic boundaries and linked to the number of comorbid diagnoses independently of age. Critically, this brain pattern predicted normative cognitive deviations in an independent population-based sample (n = 1253, 54 % female, age: 8-21 years), supporting the generalisability and external validity of the reported brain-behaviour relationships., Conclusions: These results reveal dimensions of brain-behaviour associations across diagnostic boundaries, highlighting potent disorder-general patterns as the most prominent. In addition to providing biologically informed patterns of relevant behavioural factors for mental illness, this contributes to a growing body of evidence in favour of transdiagnostic approaches to prevention and intervention., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: OAA is a consultant to HealthLytix and received speaker’s honoraria from Lundbeck. All other authors report no biomedical financial interests or potential conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Filopodia are dynamic, finger-like actin-filament bundles that overcome membrane tension by forces generated through actin polymerization at their tips to allow extension of these structures a few microns beyond the cell periphery. Actin assembly of these protrusions is regulated by accessory proteins including heterodimeric capping protein (CP) or Ena/VASP actin polymerases to either terminate or promote filament growth. Accordingly, the depletion of CP in B16-F1 melanoma cells was previously shown to cause an explosive formation of filopodia. In Ena/VASP-deficient cells, CP depletion appeared to result in ruffling instead of inducing filopodia, implying that Ena/VASP proteins are absolutely essential for filopodia formation. However, this hypothesis was not yet experimentally confirmed., Methods: Here, we used B16-F1 cells and CRISPR/Cas9 technology to eliminate CP either alone or in combination with Ena/VASP or other factors residing at filopodia tips, followed by quantifications of filopodia length and number., Results: Unexpectedly, we find massive formations of filopodia even in the absence of CP and Ena/VASP proteins. Notably, combined inactivation of Ena/VASP, unconventional myosin-X and the formin FMNL3 was required to markedly impair filopodia formation in CP-deficient cells., Conclusions: Taken together, our results reveal that, besides Ena/VASP proteins, numerous other factors contribute to filopodia formation.