Reduced lateralization of multiple functional brain networks in autistic males.

BACKGROUND: Autism spectrum disorder has been linked to a variety of organizational and developmental deviations in the brain. One such organizational difference involves hemispheric lateralization, which may be localized to language-relevant regions of the brain or distributed more broadly. METHODS: In the present study, we estimated brain hemispheric lateralization in autism based on each participant's unique functional neuroanatomy rather than relying on group-averaged data. Additionally, we explored potential relationships between the lateralization of the language network and behavioral phenotypes including verbal ability, language delay, and autism symptom severity. We hypothesized that differences in hemispheric asymmetries in autism would be limited to the language network, with the alternative hypothesis of pervasive differences in lateralization. We tested this and other hypotheses by employing a cross-sectional dataset of 118 individuals (48 autistic, 70 neurotypical). Using resting-state fMRI, we generated individual network parcellations and estimated network asymmetries using a surface area-based approach. A series of multiple regressions were then used to compare network asymmetries for eight significantly lateralized networks between groups. RESULTS: We found significant group differences in lateralization for the left-lateralized Language (d = -0.89), right-lateralized Salience/Ventral Attention-A (d = 0.55), and right-lateralized Control-B (d = 0.51) networks, with the direction of these group differences indicating less asymmetry in autistic males. These differences were robust across different datasets from the same participants. Furthermore, we found that language delay stratified language lateralization, with the greatest group differences in language lateralization occurring between autistic males with language delay and neurotypical individuals. CONCLUSIONS: These findings evidence a complex pattern of functional lateralization differences in autism, extending beyond the Language network to the Salience/Ventral Attention-A and Control-B networks, yet not encompassing all networks, indicating a selective divergence rather than a pervasive one. Moreover, we observed an association between Language network lateralization and language delay in autistic males.

Parsing Brain Network Specialization: A Replication and Expansion of Wang et al. (2014).

One organizing principle of the human brain is hemispheric specialization, or the dominance of a specific function or cognitive process in one hemisphere or the other. Previously, Wang et al. (2014) identified networks putatively associated with language and attention as being specialized to the left and right hemispheres, respectively; and a dual-specialization of the executive control network. However, it remains unknown which networks are specialized when specialization is examined within individuals using a higher resolution parcellation, as well as which connections are contributing the most to a given network's specialization. In the present study, we estimated network specialization across three datasets using the autonomy index and a novel method of deconstructing network specialization. After examining the reliability of these methods as implemented on an individual level, we addressed two hypotheses. First, we hypothesized that the most specialized networks would include those associated with language, visuospatial attention, and executive control. Second, we hypothesized that within-network contributions to specialization would follow a within-between network gradient or a specialization gradient. We found that the majority of networks exhibited greater within-hemisphere connectivity than between-hemisphere connectivity. Among the most specialized networks were networks associated with language, attention, and executive control. Additionally, we found that the greatest network contributions were within-network, followed by those from specialized networks.

Evidence for a Compensatory Relationship between Left- and Right-Lateralized Brain Networks.

The two hemispheres of the human brain are functionally asymmetric. At the network level, the language network exhibits left-hemisphere lateralization. While this asymmetry is widely replicated, the extent to which other functional networks demonstrate lateralization remains a subject of Investigation. Additionally, it is unknown how the lateralization of one functional network may affect the lateralization of other networks within individuals. We quantified lateralization for each of 17 networks by computing the relative surface area on the left and right cerebral hemispheres. After examining the ecological, convergent, and external validity and test-retest reliability of this surface area-based measure of lateralization, we addressed two hypotheses across multiple datasets (Human Connectome Project = 553, Human Connectome Project-Development = 343, Natural Scenes Dataset = 8). First, we hypothesized that networks associated with language, visuospatial attention, and executive control would show the greatest lateralization. Second, we hypothesized that relationships between lateralized networks would follow a dependent relationship such that greater left-lateralization of a network would be associated with greater right-lateralization of a different network within individuals, and that this pattern would be systematic across individuals. A language network was among the three networks identified as being significantly left-lateralized, and attention and executive control networks were among the five networks identified as being significantly right-lateralized. Next, correlation matrices, an exploratory factor analysis, and confirmatory factor analyses were used to test the second hypothesis and examine the organization of lateralized networks. We found general support for a dependent relationship between highly left- and right-lateralized networks, meaning that across subjects, greater left lateralization of a given network (such as a language network) was linked to greater right lateralization of another network (such as a ventral attention/salience network) and vice versa. These results further our understanding of brain organization at the macro-scale network level in individuals, carrying specific relevance for neurodevelopmental conditions characterized by disruptions in lateralization such as autism and schizophrenia.

The Incidence and Outcomes of Breast Implants Among 1696 Women over more than 50 Years.

OBJECTIVE: To investigate the incidence of women with breast implants in 1964-2017 MATERIALS AND METHODS: All women with breast implants in Olmsted County, MN between January 1, 1992 and December 31, 2017 were identified, and a comprehensive review of individual medical records was performed, adding to a previously identified cohort of women with breast implants in 1964-1991. Incidence rates were calculated and were age- and sex-adjusted to the US white female 2010 population. RESULTS: In 1992-2017, 948 women with breast implants were identified, totaling 1696 Olmsted County, MN women with breast implants in 1964-2017. Overall incidence was 63.3 (95% CI 60.2-66.4) per 100,000 women, but incidence varied significantly over time. Women in 1964-1991 were more likely to have implants for cosmetic reasons and more likely to have silicone implants compared to the 1992-2017 cohort. The overall standardized mortality ratio was 1.17 (95% CI 0.99-1.38) in 1964-1991 and 0.94 (95% CI 0.66-1.29) in 1992-2017. In 1992-2017, breast reconstruction patients had a significantly elevated risk of implant rupture and implant removal versus breast augmentation patients. CONCLUSION: The incidence of breast implants among women in Olmsted County, MN has varied drastically over the past five decades, with significant changes in the trends for implant type and reason. The findings of this study may provide further insight regarding how risks associated with implants may vary over time. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Validating the Fracture Risk Assessment Tool Score in a US Population-Based Study of Patients With Rheumatoid Arthritis.

OBJECTIVE: The World Health Organization fracture risk assessment tool (FRAX) algorithm for risk prediction of major osteoporotic and hip fractures accounts for several risk factors, including rheumatoid arthritis (RA), since individuals with RA have an excess burden of fractures. FRAX has not been validated in population-based RA cohorts in the US. We aimed to determine the accuracy of FRAX predictions for individuals with RA in the US. METHODS: This retrospective population-based cohort study included residents of Olmsted County, Minnesota, who were followed until death, migration, or last medical record review. Each patient with RA (1987 American College of Rheumatology criteria met in 1980-2007, age 40-89 years) was matched 1:1 on age and sex to an individual without RA from the same underlying population. Ten-year predictions for major osteoporotic and hip fractures were estimated using the FRAX tool. Fractures were ascertained through follow-up, truncated at 10 years. Standardized incidence ratios (SIRs) and 95% CI were calculated to compare observed and predicted fractures. RESULTS: The study included 662 patients with RA and 658 non-RA comparators (66.8% vs 66.9% female and a mean age of 60.6 vs 60.5 years, respectively). Among patients with RA, 76 major osteoporotic fractures and 21 hip fractures were observed during follow-up (median follow-up: 9.0 years) compared to 67.0 predicted major osteoporotic fractures (SIR 1.13, 95% CI 0.91-1.42) and 23.3 predicted hip fractures (SIR 0.90, 95% CI 0.59-1.38). The observed and predicted major osteoporotic and hip fracture risks were similar for patients with RA and non-RA comparators. CONCLUSION: The FRAX tool is an accurate method for estimating major osteoporotic and hip fracture risk in patients with RA.

Endergonic Hydrogenation at Ambient Conditions Using an Electrochemical Membrane Reactor.

Here, we determine how the hydrogen loading (x) of an electrochemical palladium membrane reactor (ePMR) varies with electrochemical conditions (e.g., applied current density, electrolyte concentration). We detail how x influences the thermodynamic driving force of an ePMR. These studies are accomplished by measuring the fugacity (P) of hydrogen desorbing from the palladium-hydrogen membrane and subsequently relating P to pressure-composition isotherms to determine x. We find that x increases with both applied current density and electrolyte concentration, but plateaus at a loading of x ≅ 0.92 in 1.0 M H2SO4 at -200 mA·cm-2. The validity of the fugacity measurements is supported experimentally and computationally by: (a) electrochemical hydrogen permeation studies; and (b) a palladium-hydrogen porous flow finite element analysis (FEA) model. Both (a) and (b) agree with the fugacity measurements on the following x-dependent properties of the palladium-hydrogen system during electrolysis: (i) the onset for spontaneous hydrogen desorption; (ii) the point of steady-state hydrogen loading; and (iii) the function describing hydrogen desorption between (i) and (ii). We proceed to detail how x defines the free energy of palladium-hydrogen alloy formation (ΔG(x)PdH), which is a descriptor for the thermodynamic driving force of hydrogenation at the PdHx surface of an ePMR. A maximum value ΔGPdH of 11 kJ·mol-1 is observed, suggesting that an ePMR is capable of driving endergonic hydrogenation reactions. We empirically demonstrate this capability by reducing carbon dioxide to formate (ΔGCO2/HCO2H = 3.4 kJ·mol-1) at ambient conditions and neutral pH.

No difference in extra-axial cerebrospinal fluid volumes across neurodevelopmental and psychiatric conditions in later childhood and adolescence.

BACKGROUND: While autism spectrum disorder has been associated with various organizational and developmental aberrations in the brain, an increase in extra-axial cerebrospinal fluid volume has recently garnered attention. A series of studies indicate that an increased volume between the ages of 6 months and 4 years was both predictive of the autism diagnosis and symptom severity regardless of genetic risk for the condition. However, there remains a minimal understanding regarding the specificity of an increased volume of extra-axial cerebrospinal fluid to autism. METHODS: In the present study, we explored extra-axial cerebrospinal fluid volumes in children and adolescents ages 5-21 years with various neurodevelopmental and psychiatric conditions. We hypothesized that an elevated extra-axial cerebrospinal fluid volume would be found in autism compared with typical development and the other diagnostic group. We tested this hypothesis by employing a cross-sectional dataset of 446 individuals (85 autistic, 60 typically developing, and 301 other diagnosis). An analysis of covariance was used to examine differences in extra-axial cerebrospinal fluid volumes between these groups as well as a group by age interaction in extra-axial cerebrospinal fluid volumes. RESULTS: Inconsistent with our hypothesis, we found no group differences in extra-axial cerebrospinal fluid volume in this cohort. However, in replication of previous work, a doubling of extra-axial cerebrospinal fluid volume across adolescence was found. Further investigation into the relationship between extra-axial cerebrospinal fluid volume and cortical thickness suggested that this increase in extra-axial cerebrospinal fluid volume may be driven by a decrease in cortical thickness. Furthermore, an exploratory analysis found no relationship between extra-axial cerebrospinal fluid volume and sleep disturbances. CONCLUSIONS: These results indicate that an increased volume of extra-axial cerebrospinal fluid may be limited to autistic individuals younger than 5 years. Additionally, extra-axial cerebrospinal fluid volume does not differ between autistic, neurotypical, and other psychiatric conditions after age 4.

Reduced Lateralization of Multiple Functional Brain Networks in Autistic Males.

Background: Autism spectrum disorder has been linked to a variety of organizational and developmental deviations in the brain. One such organizational difference involves hemispheric lateralization, which may be localized to language-relevant regions of the brain or distributed more broadly. Methods: In the present study, we estimated brain hemispheric lateralization in autism based on each participant's unique functional neuroanatomy rather than relying on group-averaged data. Additionally, we explored potential relationships between the lateralization of the language network and behavioral phenotypes including verbal ability, language delay, and autism symptom severity. We hypothesized that differences in hemispheric asymmetries in autism would be limited to the language network, with the alternative hypothesis of pervasive differences in lateralization. We tested this and other hypotheses by employing a cross-sectional dataset of 118 individuals (48 autistic, 70 neurotypical). Using resting-state fMRI, we generated individual network parcellations and estimated network asymmetries using a surface area-based approach. A series of multiple regressions were then used to compare network asymmetries for eight significantly lateralized networks between groups. Results: We found significant group differences in lateralization for the left-lateralized Language (d = -0.89), right-lateralized Salience/Ventral Attention-A (d = 0.55), and right-lateralized Control-B (d = 0.51) networks, with the direction of these group differences indicating less asymmetry in autistic individuals. These differences were robust across different datasets from the same participants. Furthermore, we found that language delay stratified language lateralization, with the greatest group differences in language lateralization occurring between autistic individuals with language delay and neurotypical individuals. Limitations: The generalizability of our findings is restricted due to the male-only sample and greater representation of individuals with high verbal and cognitive performance. Conclusions: These findings evidence a complex pattern of functional lateralization differences in autism, extending beyond the Language network to the Salience/Ventral Attention-A and Control-B networks, yet not encompassing all networks, indicating a selective divergence rather than a pervasive one. Furthermore, a differential relationship was identified between Language network lateralization and specific symptom profiles (namely, language delay) of autism.

Risk of rheumatoid arthritis diagnosis in statin users in a large nationwide US study.

OBJECTIVE: To evaluate the association between statin use and the risk of developing rheumatoid arthritis (RA) in a large, US case-control study. METHODS: Using the OptumLabs Data Warehouse, RA cases were identified as patients aged ≥18 years with ≥2 RA diagnoses between January 1, 2010 and June 30, 2019 and ≥1 prescription fills for methotrexate within 1 year of the first RA diagnosis. The first RA diagnosis was the index date. Cases were matched 1:1 to controls on age, sex, region, year of index date, and length of baseline coverage. Statin users were defined by having ≥2 statin prescription fills at least 90 days pre-index. Patients identified as statin users were further classified by statin user status (current or former), statin use duration, and intensity of statin exposure. Odds ratios for RA risk with statin use were estimated using logistic regression. RESULTS: 16,363 RA cases and 16,363 matched controls were identified. Among RA cases, 5509 (33.7%) patients were statin users compared to 5164 (31.6%) of the controls. Statin users had a slightly increased risk of RA compared to non-users (OR 1.12, 95% CI 1.06-1.18), and former statin users had an increased RA risk compared to current users (OR 1.21, 95% CI 1.13-1.28). However, risk was eliminated following adjustment for hyperlipidemia. The risk estimates for statin use duration and intensity did not reach significance. CONCLUSION: This study demonstrates no significant increase in the risk of developing RA for statin users compared to non-users after adjustment for hyperlipidemia in addition to other relevant confounders. However, more information from prospective studies would be necessary to further understand this relationship.

Evidence for normal extra-axial cerebrospinal fluid volume in autistic males from middle childhood to adulthood.

Autism spectrum disorder has long been associated with a variety of organizational and developmental abnormalities in the brain. An increase in extra-axial cerebrospinal fluid volume in autistic individuals between the ages of 6 months and 4 years has been reported in recent studies. Increased extra-axial cerebrospinal fluid volume was predictive of the diagnosis and severity of the autistic symptoms in all of them, irrespective of genetic risk for developing the disorder. In the present study, we explored the trajectory of extra-axial cerebrospinal fluid volume from childhood to adulthood in both autism and typical development. We hypothesized that an elevated extra-axial cerebrospinal fluid volume would be found in autism persisting throughout the age range studied. We tested the hypothesis by employing an accelerated, multi-cohort longitudinal data set of 189 individuals (97 autistic, 92 typically developing). Each individual had been scanned between 1 and 5 times, with scanning sessions separated by 2-3 years, for a total of 439 T1-weighted MRI scans. A linear mixed-effects model was used to compare developmental, age-related changes in extra-axial cerebrospinal fluid volume between groups. Inconsistent with our hypothesis, we found no group differences in extra-axial cerebrospinal fluid volume in this cohort of individuals 3 to 42 years of age. Our results suggest that extra-axial cerebrospinal fluid volume in autistic individuals is not increased compared with controls beyond four years of age.

Synthesis, characterization, and electrochemical properties of a first-row metal phthalocyanine series.

The synthesis and characterization of a 3d-metallophthalocyanine series (OEtPcM; OEtPc = 1,4,8,11,15,18,22,25-octaethoxy-phthalocyanine; M = VO, Cr, MnCl, MnN, Fe, Co, Ni, Cu, Zn) is presented. With the exception of OEtPcZn, all species were crystallographically characterized, including the protonated (OEtPcH2) and partially lithiated (OEtPcHLi) precursors. The electrochemical behavior of all species - displaying a mix of metal- and ligand-borne redox events - was investigated and tentatively correlated to the structural properties. It was found that non-labile axial metal-ligand substituents (O2-, N3-) and the use of coordinating solvents heavily influenced the reversibility of the electrochemical events, suggesting that aggregation is a dominant consideration for well-defined electrochemical behavior. We used this data to outline possible design criteria for Pc-based charge carrier applications in the context of redox-flow batteries and energy storage.

Switchable Aromaticity in an Isostructural Mn Phthalocyanine Series Isolated in Five Separate Redox States.

The synthesis and characterization of a new phthalocyanine (Pc) Mn-nitride complex, (OEtPc)MnN (2; OEtPc = 1,4,8,11,15,18,22,25-octaethoxy-Pc), as well as its stable, readily accessible oxidized (2+ and 22+) and reduced (2-, 22-) congeners is reported. This unique isostructural series displays switchable aromatic character spanning the aromatic (2), nonaromatic (22+), and antiaromatic (22-) triad, in addition to the open-shell radical states (2+, 2-). All complexes were structurally characterized and displayed significant structural distortions at the redox extrema (22+, 22-) consistent with proposed [16 or 18]annulene π ring circuit models. Spectroscopic and computational studies further support these models. This isolated, fully characterized, isostructural series spanning five redox states (22+, 2+, 2, 2-, 22-) is unique in both the Pc and related macrocyclic (ex. porphyrinoids) literature and may offer direct insight into structural-electronic correlations driven by switchable aromaticity.

Towards Catalytic Ammonia Oxidation to Dinitrogen: A Synthetic Cycle by Using a Simple Manganese Complex.

Oxidation of the nucleophilic nitride, (salen)Mn≡N (1) with stoichiometric [Ar3 N][X] initiated a nitride coupling reaction to N2 , a major step toward catalytic ammonia oxidation (salen=N,N'-bis(salicylidene)-ethylenediamine dianion; Ar=p-bromophenyl; X=[SbCl6 ]- or [B(C6 F5 )4 ]- ). N2 production was confirmed by mass spectral analysis of the isotopomer, 1-15 N, and the gas quantified. The metal products of oxidation were the reduced MnIII dimers, [(salen)MnCl]2 (2) or [(salen)Mn(OEt2 )]2 [B(C6 F5 )4 ]2 (3) for X=[SbCl6 ]- or [B(C6 F5 )4 ]- , respectively. The mechanism of nitride coupling was probed to distinguish a nitridyl from a nucleophilic/electrophilic coupling sequence. During these studies, a rare mixed-valent MnV /MnIII bridging nitride, [(salen)MnV (µ-N)MnIII (salen)][B(C6 F5 )4 ] (4), was isolated, and its oxidation-state assignment was confirmed by X-ray diffraction (XRD) studies, perpendicular and parallel-mode EPR and UV/Vis/NIR spectroscopies, as well as superconducting quantum interference device (SQUID) magnetometry. We found that 4 could subsequently be oxidized to 3. Furthermore, in view of generating a catalytic system, 2 can be re-oxidized to 1 in the presence of NH3 and NaOCl closing a pseudo-catalytic "synthetic" cycle. Together, the reduction of 1→2 followed by oxidation of 2→1 yield a genuine synthetic cycle for NH3 oxidation, paving the way to the development of a fully catalytic system by using abundant metal catalysis.