A neural network for religious fundamentalism derived from patients with brain lesions.

Religious fundamentalism, characterized by rigid adherence to a set of beliefs putatively revealing inerrant truths, is ubiquitous across cultures and has a global impact on society. Understanding the psychological and neurobiological processes producing religious fundamentalism may inform a variety of scientific, sociological, and cultural questions. Research indicates that brain damage can alter religious fundamentalism. However, the precise brain regions involved with these changes remain unknown. Here, we analyzed brain lesions associated with varying levels of religious fundamentalism in two large datasets from independent laboratories. Lesions associated with greater fundamentalism were connected to a specific brain network with nodes in the right orbitofrontal, dorsolateral prefrontal, and inferior parietal lobe. This fundamentalism network was strongly right hemisphere lateralized and highly reproducible across the independent datasets (r = 0.82) with cross-validations between datasets. To explore the relationship of this network to lesions previously studied by our group, we tested for similarities to twenty-one lesion-associated conditions. Lesions associated with confabulation and criminal behavior showed a similar connectivity pattern as lesions associated with greater fundamentalism. Moreover, lesions associated with poststroke pain showed a similar connectivity pattern as lesions associated with lower fundamentalism. These findings are consistent with the current understanding of hemispheric specializations for reasoning and lend insight into previously observed epidemiological associations with fundamentalism, such as cognitive rigidity and outgroup hostility.

Lesions Causing Alice in Wonderland Syndrome Map to a Common Brain Network Linking Body and Size Perception.

OBJECTIVE: Alice in Wonderland syndrome (AIWS) profoundly affects human perception of size and scale, particularly regarding one's own body and the environment. Its neuroanatomical basis has remained elusive, partly because brain lesions causing AIWS can occur in different brain regions. Here, we aimed to determine if brain lesions causing AIWS map to a distributed brain network. METHODS: A retrospective case-control study analyzing 37 cases of lesion-induced AIWS identified through systematic literature review was conducted. Using resting-state functional connectome data from 1,000 healthy individuals, the whole-brain connections of each lesion were estimated and contrasted with those from a control dataset comprising 1,073 lesions associated with 25 other neuropsychiatric syndromes. Additionally, connectivity findings from lesion-induced AIWS cases were compared with functional neuroimaging results from 5 non-lesional AIWS cases. RESULTS: AIWS-associated lesions were located in various brain regions with minimal overlap (≤33%). However, the majority of lesions (≥85%) demonstrated shared connectivity to the right extrastriate body area, known to be selectively activated by viewing body part images, and the inferior parietal cortex, involved in size and scale judgements. This pattern was uniquely characteristic of AIWS when compared with other neuropsychiatric disorders (family-wise error-corrected p < 0.05) and consistent with functional neuroimaging observations in AIWS due to nonlesional causes (median correlation r = 0.56, interquartile range 0.24). INTERPRETATION: AIWS-related perceptual distortions map to one common brain network, encompassing regions critical for body representation and size-scale processing. These findings lend insight into the neuroanatomical localization of higher-order perceptual functions, and may inform future therapeutic strategies for perceptual disorders. ANN NEUROL 2024.

Efficacy and safety of avacincaptad pegol in patients with geographic atrophy (GATHER2): 12-month results from a randomised, double-masked, phase 3 trial.

BACKGROUND: Geographic atrophy is an advanced form of dry age-related macular degeneration that can lead to irreversible vision loss and high burden of disease. We aimed to assess efficacy and safety of avacincaptad pegol 2 mg in reducing geographic atrophy lesion growth. METHODS: GATHER2 is a randomised, double-masked, sham-controlled, 24-month, phase 3 trial across 205 retina clinics, research hospitals, and academic institutions globally. To be eligible, patients had to be aged 50 years or older with non-centrepoint-involving geographic atrophy and best corrected visual acuity between 20/25 and 20/320 in the study eye. Eligible patients were randomly assigned (1:1) to monthly avacincaptad pegol 2 mg administered as a 100 µL intravitreal injection or sham for the first 12 months. Randomisation was performed using an interactive response technology system with stratification by factors known to be of prognostic importance in age-related macular degeneration. Patients, investigators, study centre staff, sponsor personnel, and data analysts were masked to treatment allocation. The primary endpoint was geographic atrophy lesion size measured by fundus autofluorescence at baseline, month 6, and month 12. Efficacy and safety analyses were done in the modified intention-to-treat and safety populations, respectively. This trial is registered with ClinicalTrials.gov, NCT04435366. FINDINGS: Between June 22, 2020, and July 23, 2021, 1422 patients were screened for eligibility, of whom 448 were enrolled and randomly assigned to avacincaptad pegol 2 mg (n=225) or sham (n=223). One patient in the sham group did not receive study treatment and was excluded from analyses. There were 154 (68%) female patients and 71 (32%) male patients in the avacincaptad pegol 2 mg group, and 156 (70%) female patients and 66 (30%) male patients in the sham group. From baseline to month 12, the mean rate of square-root-transformed geographic atrophy area growth was 0·336 mm/year (SE 0·032) with avacincaptad pegol 2 mg and 0·392 mm/year (0·033) with sham, a difference in growth of 0·056 mm/year (95% CI 0·016-0·096; p=0·0064), representing a 14% difference between the avacincaptad pegol 2 mg group and the sham group. Ocular treatment-emergent adverse events in the study eye occurred in 110 (49%) patients in the avacincaptad pegol 2 mg group and 83 (37%) in the sham group. There were no endophthalmitis, intraocular inflammation, or ischaemic optic neuropathy events over 12 months. To month 12, macular neovascularisation in the study eye occurred in 15 (7%) patients in the avacincaptad pegol 2 mg group and nine (4%) in the sham group, with exudative macular neovascularisation occurring in 11 (5%) in the avacincaptad pegol 2 mg group and seven (3%) in the sham group. INTERPRETATION: Monthly avacincaptad pegol 2 mg was well tolerated and showed significantly slower geographic atrophy growth over 12 months than sham treatment, suggesting that avacincaptad pegol might slow disease progression and potentially change the trajectory of disease for patients with geographic atrophy. FUNDING: Iveric Bio, An Astellas Company.

DEFINING "STRONG" VERSUS "WEAK" RESPONSE TO ANTIVASCULAR ENDOTHELIAL GROWTH FACTOR TREATMENT FOR CENTER-INVOLVED DIABETIC MACULAR EDEMA.

BACKGROUND/PURPOSE: To define "strong" versus "weak" antivascular endothelial growth factor (anti-VEGF) treatment response in eyes with center-involved diabetic macular edema (CI-DME). METHODS: Exploratory analyses of three DRCR Retina Network randomized trials of eyes with CI-DME treated with aflibercept, bevacizumab, or ranibizumab. Thresholds of 5-, 10-, and 15-letter gain defined strong visual acuity (VA) response when baseline VA was 20/25-20/32, 20/40-20/63, or 20/80-20/320, respectively. Thresholds of 50, 100, or 200- µ m reduction defined strong anatomical response when baseline central subfield thickness (CST) was <75, ≥75 to <175, or ≥175- µ m above standard thresholds. Additional thresholds from regression equations were calculated. RESULTS: At 24 weeks, outcomes for strong response were achieved by 476 of 958 eyes (50%) for VA and 505 eyes (53%) for CST. At 104 weeks among the 32% of eyes with strong VA and CST response at 24 weeks, 195 of 281 (69%) maintained strong VA and CST response, whereas 20 (7%) had neither strong VA nor strong CST response. Outcomes rates were similar across protocols and when defined using regression equations. CONCLUSION: These phenotypes are suitable for efforts to identify predictive biomarkers for response to anti-VEGF therapy for DME and might facilitate comparison of treatment response among diverse cohorts with DME.

Mega-analysis methods in ENIGMA: The experience of the generalized anxiety disorder working group.

The ENIGMA group on Generalized Anxiety Disorder (ENIGMA-Anxiety/GAD) is part of a broader effort to investigate anxiety disorders using imaging and genetic data across multiple sites worldwide. The group is actively conducting a mega-analysis of a large number of brain structural scans. In this process, the group was confronted with many methodological challenges related to study planning and implementation, between-country transfer of subject-level data, quality control of a considerable amount of imaging data, and choices related to statistical methods and efficient use of resources. This report summarizes the background information and rationale for the various methodological decisions, as well as the approach taken to implement them. The goal is to document the approach and help guide other research groups working with large brain imaging data sets as they develop their own analytic pipelines for mega-analyses.

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.

Registration-free analysis of diffusion MRI tractography data across subjects through the human lifespan.

Diffusion MRI tractography produces massive sets of streamlines that need to be clustered into anatomically meaningful white-matter bundles. Conventional clustering techniques group streamlines based on their proximity in Euclidean space. We have developed AnatomiCuts, an unsupervised method for clustering tractography streamlines based on their neighboring anatomical structures, rather than their coordinates in Euclidean space. In this work, we show that the anatomical similarity metric used in AnatomiCuts can be extended to find corresponding clusters across subjects and across hemispheres, without inter-subject or inter-hemispheric registration. Our proposed approach enables group-wise tract cluster analysis, as well as studies of hemispheric asymmetry. We evaluate our approach on data from the pilot MGH-Harvard-USC Lifespan Human Connectome project, showing improved correspondence in tract clusters across 184 subjects aged 8-90. Our method shows up to 38% improvement in the overlap of corresponding clusters when comparing subjects with large age differences. The techniques presented here do not require registration to a template and can thus be applied to populations with large inter-subject variability, e.g., due to brain development, aging, or neurological disorders.

Longitudinal changes in cortical thickness in autism and typical development.

The natural history of brain growth in autism spectrum disorders remains unclear. Cross-sectional studies have identified regional abnormalities in brain volume and cortical thickness in autism, although substantial discrepancies have been reported. Preliminary longitudinal studies using two time points and small samples have identified specific regional differences in cortical thickness in the disorder. To clarify age-related trajectories of cortical development, we examined longitudinal changes in cortical thickness within a large mixed cross-sectional and longitudinal sample of autistic subjects and age- and gender-matched typically developing controls. Three hundred and forty-five magnetic resonance imaging scans were examined from 97 males with autism (mean age = 16.8 years; range 3-36 years) and 60 males with typical development (mean age = 18 years; range 4-39 years), with an average interscan interval of 2.6 years. FreeSurfer image analysis software was used to parcellate the cortex into 34 regions of interest per hemisphere and to calculate mean cortical thickness for each region. Longitudinal linear mixed effects models were used to further characterize these findings and identify regions with between-group differences in longitudinal age-related trajectories. Using mean age at time of first scan as a reference (15 years), differences were observed in bilateral inferior frontal gyrus, pars opercularis and pars triangularis, right caudal middle frontal and left rostral middle frontal regions, and left frontal pole. However, group differences in cortical thickness varied by developmental stage, and were influenced by IQ. Differences in age-related trajectories emerged in bilateral parietal and occipital regions (postcentral gyrus, cuneus, lingual gyrus, pericalcarine cortex), left frontal regions (pars opercularis, rostral middle frontal and frontal pole), left supramarginal gyrus, and right transverse temporal gyrus, superior parietal lobule, and paracentral, lateral orbitofrontal, and lateral occipital regions. We suggest that abnormal cortical development in autism spectrum disorders undergoes three distinct phases: accelerated expansion in early childhood, accelerated thinning in later childhood and adolescence, and decelerated thinning in early adulthood. Moreover, cortical thickness abnormalities in autism spectrum disorders are region-specific, vary with age, and may remain dynamic well into adulthood.

Complexity of low-frequency blood oxygen level-dependent fluctuations covaries with local connectivity.

Very low-frequency blood oxygen level-dependent (BOLD) fluctuations have emerged as a valuable tool for describing brain anatomy, neuropathology, and development. Such fluctuations exhibit power law frequency dynamics, with largest amplitude at lowest frequencies. The biophysical mechanisms generating such fluctuations are poorly understood. Using publicly available data from 1,019 subjects of age 7-30, we show that BOLD fluctuations exhibit temporal complexity that is linearly related to local connectivity (regional homogeneity), consistently and significantly covarying across subjects and across gray matter regions. This relationship persisted independently of covariance with gray matter density or standard deviation of BOLD signal. During late neurodevelopment, BOLD fluctuations were unchanged with age in association cortex while becoming more random throughout the rest of the brain. These data suggest that local interconnectivity may play a key role in establishing the complexity of low-frequency BOLD fluctuations underlying functional magnetic resonance imaging connectivity. Stable low-frequency power dynamics may emerge through segmentation and integration of connectivity during development of distributed large-scale brain networks.

Multimodal imaging of white and dark without pressure fundus lesions.

PURPOSE: To describe multimodal imaging findings in patients with dark or white without pressure lesions of the fundus. METHODS: Retrospective observational case series of 10 patients with white or dark without pressure lesions. We analyzed multimodal imaging using spectral domain optical coherence tomography, color and near-infrared fundus photography, and fundus autofluorescence imaging to explore the findings associated with these lesions. RESULTS: All patients had geographic dark or white lesions on clinical examination and color photography, which were either hyporeflective or hyperreflective on near-infrared reflectance imaging, respectively. On optical coherence tomography, these lesions correlated with an abrupt change of the photoreceptor reflectivity, with relative hyporeflectivity of photoreceptor zones (ellipsoid and interdigitation zones, as well as outer segments) within the dark, and relative hyperreflectivity within white lesions. Ten patients underwent fundus autofluorescence, which showed well-defined zones of relative hypo-autofluorescence within the lesion, compared with neighboring uninvolved regions, whether dark or white without pressure. In two patients who had a lesion combining white and dark without pressure, we observed the transition in photoreceptor reflectivity from the dark lesion (hyporeflective) to the white lesion (hyperreflective), relative to the surrounding retina. CONCLUSION: Both white and dark without pressure lesions are associated with changes in outer retinal reflectivity on optical coherence tomography, which occur in opposite directions compared with the surrounding unaffected areas. In the face of normal visual field testing to date, the clinical significance of this finding remains uncertain. Recognition of the optical coherence tomography appearance will help clinicians avoid unnecessary workup of these patients for outer retinal dystrophy or degeneration.

Small-Gauge Vitrectomy for Macular Surgery Using a Systematic Approach to Wound Closure: 27-Gauge vs 25-Gauge.

Purpose: To evaluate the effectiveness of and to compare vitrectomy performed with 25-gauge or 27-gauge instrumentation for macular surgery by assessing the surgical duration, wound closure, and complication rate using a systematic approach to wound closure. Methods: In this retrospective chart review, 125 25-gauge and 125 27-gauge consecutive small-gauge vitrectomy surgeries for epiretinal membrane, macular hole, vitreomacular adhesion, or a combination were analyzed during and immediately after surgery. Wound closure was performed using a systematic protocol. Results: Baseline characteristics were not statistically different between the 2 groups. The surgical duration was similar with 25-gauge vitrectomy and 27-gauge vitrectomy (P = .07). Although spontaneous wound closure was common in both groups, it was more common in the 27-gauge group (P = .22). Intraoperative and postoperative complications were uncommon in both groups. Conclusions: Findings show that 27-gauge vitrectomy is a safe, effective alternative to the more commonly used 25-gauge vitrectomy for macular surgery. Less manipulation was required to achieve wound closure with 27-gauge vitrectomy using a standardized wound-closure protocol. Smaller 27-gauge vitrectomy did not increase surgical time or complications over 25-gauge vitrectomy for macular surgery.

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.

The MOSAIC Study: A Mixed-Methods Study of the Clinical, Emotional, and Financial Burden of Geographic Atrophy Among Patients and Caregivers in the US.

Purpose: Geographic atrophy (GA) impacts both patients and caregivers, yet little is understood about their respective burdens. The MOSAIC study aimed to identify the clinical, emotional, and financial burden among patients with GA and caregivers. Methods: A total of 28 patients with GA and 17 caregivers from the United States (US), the United Kingdom, and Australia participated in individualized qualitative interviews followed by a cross-sectional quantitative survey of 102 patients and 102 caregivers in the US. Interview transcripts were analyzed to develop conceptual models, which were then used to guide the design of quantitative surveys. Data were described at the item level and score level when appropriate (National Eye Institute Visual Function Questionnaire [NEI VFQ]-39 and Zarit Burden Interview [ZBI]). For the patient/caregiver dyad sample, the association between the NEI VFQ-39 scores and ZBI score was explored through correlation coefficients and scatterplots. Results: GA had a substantial impact on patients' vision-related quality of life, activities of daily living, and instrumental activities of daily living. There was considerable overlap between perspectives and key concerns identified by patients and caregivers. Eighty-three percent of caregivers reported having to drive patients to appointments due to limited patient mobility, for example, and 41% reported a change in their employment status after becoming a caregiver, with 50% of them unable to work due to caregiving. The burden of patients and caregivers had a correlation ranging from -0.63 to -0.21 between NEI VFQ-39 subscale and composite scores and ZBI score. Conclusion: This study confirms the paucity of support for both patients with GA and caregivers. Both groups require expanded access to financial, social, and mental health resources.

What is this summary about? People with geographic atrophy, also called GA, can lose their eyesight and have a hard time driving, reading, and recognizing faces. This can worsen their quality of life. Often, people with GA need someone to care for them. The MOSAIC study was done to find out how GA affects health, happiness, and finances of people with GA and their caregivers. What were the results? One hundred and two people with GA and 102 caregivers in the United States were interviewed. The average age of people with GA was 68 years and of caregivers was 46 years. The findings showed that most people with GA did not drive because of their poor eyesight and instead counted on their caregivers to drive them to doctor appointments and other places. They also had a reading and doing things around their home because of their worsened eyesight. Both people with GA and caregivers said they felt stressed. They both worried about spending money on things they need to make living with GA easier. They also felt stressed about their finances because they could not work as much. People with GA worried most about losing their independence and caregivers worried most about the future of their loved one with GA. What do the results mean? This study showed that GA has a serious effect on people's health and quality of life while also having a major impact on their caregivers.

Supplemental Intravitreal Ranibizumab Injections in Eyes Treated with the Port Delivery System with Ranibizumab in the Archway Trial.

PURPOSE: To determine the proportion and characteristics of eyes with neovascular age-related macular degeneration (nAMD) treated with the Port Delivery System (PDS) with ranibizumab that receive supplemental intravitreal ranibizumab injections because of changes in best-corrected visual acuity (BCVA) or central subfield thickness (CST), or both, and to investigate the safety and efficacy of supplemental injections in eyes with the PDS. DESIGN: Post hoc analyses of data from the phase III, randomized, multicenter, open-label, active-comparator Archway trial (NCT03677934). PARTICIPANTS: Adults with nAMD diagnosed within 9 months of screening previously responsive to anti-VEGF therapy. INTERVENTION: Four hundred eighteen patients were randomized to the PDS with ranibizumab 100 mg/ml with fixed refill-exchanges every 24 weeks (Q24W) or monthly intravitreal ranibizumab 0.5 mg for 96 weeks. RESULTS: Of the 246 eyes treated with the PDS Q24W and assessed for supplemental treatment criteria, the vast majority (94.6%-98.4%) did not receive supplemental treatment during each retreatment interval, with 87.4% not receiving supplemental treatment at any point during the trial. Of the 31 eyes receiving supplemental treatment, 58.1% received 1 injection and 32.3% received 2. At baseline, eyes receiving supplemental treatment were significantly more likely to have thicker retinas (mean CST, 370.5µm vs. 304.4µm; P = 0.0001), subretinal fluid (54.8% vs. 21.2%; P < 0.0001), and larger pigment epithelial detachment height (215.7 µm vs. 175.9 µm; P = 0.003). These features have previously been associated with difficult-to-treat nAMD. Although BCVA and CST generally remained constant throughout the trial in eyes without supplemental treatment, the small number of eyes receiving supplemental treatment on average lost 1 line of vision from baseline to week 96 (mean, -5.7 ETDRS score letters) and CST continued to increase over time. Absolute BCVA at week 96 was similar irrespective of supplemental treatment status (71.1 and 73.7 letters). Best-corrected visual acuity and CST generally improved within 28 days of supplemental treatment. CONCLUSIONS: Although the PDS Q24W effectively maintains vision and retinal stability in most eyes with nAMD, a small proportion of patients with features of difficult-to-treat nAMD may benefit from supplemental intravitreal anti-VEGF injections and initial close monitoring is recommended. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

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.

Anti-VEGF Pharmaceutical Prior Authorization in Retina Practices.

Importance: Anti-vascular endothelial growth factor (VEGF) intravitreal injections, a mainstay of treatment for many retinal diseases to optimize visual outcomes, have been included in prior authorization (PA) initiatives. However, if clinicians are extremely accurate in their use of anti-VEGF medications, such administrative burdens may need reconsideration. Objective: To quantify PA for anti-VEGF medications (aflibercept, ranibizumab, and bevacizumab) that were approved and determine associated administrative burdens experienced by retina practices. Design, Setting, and Participants: Prospective multicenter quality improvement study conducted from January 2022 through June 2022, and participants were 9 private retina practices across the US. Main Outcomes and Measures: Overall rate of approval of PA requests, reasons for requesting PA, and overall rate of delay of care resulting from PA procedures. Results: In total, 2365 PA requests were recorded, 2225 of which met inclusion criteria. Overall, 2140 (96.2%) requests were approved. The most common reason for requesting PA, at 64% (1423 of 2225 requests), was reauthorization for a previously utilized medication. Of the 2140 approvals, 59.6% (1277) resulted in a delay in care greater than 24 hours, and 40% (863) were given on the date of service. In a granular analysis of a subset of delayed approvals, 23.9% (173 of 725) were approved within 1 day, 15.9% (115 of 725) were approved within 2 to 3 days, 21.5% (156 of 725) were approved within 4 to 7 days, 26.3% (191 of 725) were approved within 8 to 31 days, and 12.4% (90 of 725) were approved within more than 31 days. Overall, PA denial for step therapy was 2.9% (65 of 2225) of requests and uncovered diagnoses was 0.9% (20 of 2225) of requests. The median staff time spent to obtain a single PA was 100 (range, 0-200) minutes. Conclusions and Relevance: In this study, PA requests were almost always approved but led to a delay in patient care in most patients. The current study suggests that the PA process may not be effective for retina specialists if these results can be generalized to other practices in the US and if less burdensome and less costly approaches could result in similar approval rates. Potential short-term solutions may include eliminating the PA process for bevacizumab and reauthorizations for established patients.

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.

High-Dose Aflibercept for Neovascular AMD and DME in Suboptimal Responders to Standard-Dose Aflibercept.

Purpose: To assess the effect of higher dose (HD) aflibercept on visual acuity (VA), optical coherence tomography outcomes, and injection burden in eyes with neovascular age-related macular degeneration (nAMD) or diabetic macular edema (DME) that responded suboptimally to standard-dose aflibercept. Methods: This retrospective analysis included eyes with clinically significant disease activity on monthly therapy (AMT) (injection interval ≤35 days) or clinically significant increased activity on extension (IAE) (injection interval >36 days) that were switched from aflibercept 2 mg to aflibercept HD (3 mg to 4 mg). Outcomes were assessed at baseline, after injections 1 through 4, and at 6, 9, and 12 months. Results: Overall, 318 eyes of 288 adult patients were analyzed (eyes with nAMD: 59 AMT, 147 IAE; eyes with DME: 50 AMT, 62 IAE). Most of the study cohort received aflibercept HD 3 mg (nAMD: 73% AMT and 58% IAE; DME: 49% AMT and 68% IAE); the remainder received 4 mg. The mean best VA improved significantly with AMT and was maintained with IAE. In all groups, the central subfield thickness decreased significantly and the mean injection intervals increased or remained stable. No new safety signals were observed. Conclusions: Aflibercept HD might improve outcomes while decreasing treatment burden for eyes that respond suboptimally to standard dosing.

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.