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Glucocerebrosidase (GCase, deficient in Gaucher disease) enzymatic activity measured in dried blood spots of Parkinson's Disease (PD) cases is within healthy range but reduced compared to controls. It is not known whether activities of additional lysosomal enzymes are reduced in dried blood spots in PD. To test whether reduction in lysosomal enzymatic activity in PD is specific to GCase, we measured GCase, acid sphingomyelinase (deficient in Niemann–Pick disease types A and B), alpha galactosidase A (deficient in Fabry), acid alpha-glucosidase (deficient in Pompe) and galactosylceramidase (deficient in Krabbe) enzymatic activities in dried blood spots of PD patients (n = 648) and controls (n = 317) recruited from Columbia University. Full sequencing of glucocerebrosidase (GBA) and the LRRK2 G2019S mutation was performed. Enzymatic activities were compared between PD cases and controls using t-test and regression models adjusted for age, gender, and GBA and LRRK2 G2019S mutation status. Alpha galactosidase A activity was lower in PD cases compared to controls both when only non-carriers were included (excluding all GBA and LRRK2 G2019S carriers and PD cases with age-at-onset below 40) [2.85 μmol/l/h versus 3.12 μmol/l/h, p = 0.018; after controlling for batch effect, p = 0.006 (468 PD cases and 296 controls)], and when including the entire cohort (2.89 μmol/l/h versus 3.10 μmol/l/h, p = 0.040; after controlling for batch effect, p = 0.011). Because the alpha galactosidase A gene is X-linked, we stratified the analyses by sex. Among women who were non-carriers of GBA and LRRK2 G2019S mutations (PD, n = 155; control, n = 194), alpha galactosidase A activity was lower in PD compared to controls (2.77 μmol/l/h versus 3.10 μmol/l/h, p = 0.044; after controlling for a batch effect, p = 0.001). The enzymatic activity of acid sphingomyelinase, acid alpha-glucosidase and galactosylceramidase was not significantly different between PD and controls. In non-carriers, most lysosomal enzyme activities were correlated, with the strongest association in GCase, acid alpha-glucosidase, and alpha galactosidase A (Pearson correlation coefficient between 0.382 and 0.532). In a regression model with all five enzymes among non-carriers (adjusted for sex and age), higher alpha galactosidase A activity was associated with lower odds of PD status (OR = 0.54; 95% CI:0.31–0.95; p = 0.032). When LRRK2 G2019S PD carriers (n = 37) were compared to non-carriers with PD, carriers had higher GCase, acid sphingomyelinase and alpha galactosidase A activity. We conclude that alpha galactosidase A may have a potential independent role in PD, in addition to GCase.

Chronic disease rates are produced from the Public Health Agency of Canada's Canadian Chronic Disease Surveillance System (CCDSS) using administrative health data from provincial/territorial health ministries. Denominators for these rates are based on estimates of populations derived from health insurance files. However, these data may not be accessible to all researchers. Another source for population size estimates is the Statistics Canada census. The purpose of our study was to calculate the major differences between the CCDSS and Statistics Canada's population denominators and to identify the sources or reasons for the potential differences between these data sources. Methods: We compared the 2009 denominators from the CCDSS and Statistics Canada. The CCDSS denominator was adjusted for the growth components (births, deaths, emigration and immigration) from Statistics Canada's census data. Results: The unadjusted CCDSS denominator was 34 429 804, 3.2% higher than Statistics Canada's estimate of population in 2009. After the CCDSS denominator was adjusted for the growth components, the difference between the two estimates was reduced to 431 323 people, a difference of 1.3%. The CCDSS overestimates the population relative to Statistics Canada overall. The largest difference between the two estimates was from the migrant growth component, while the smallest was from the emigrant component. Conclusion: By using data descriptions by data source, researchers can make decisions about which population to use in their calculations of disease frequency.

Introduction : Les taux de maladies chroniques du Système canadien de surveillance des maladies chroniques (SCSMC) de l’Agence de la santé publique du Canada sont fondés sur les données administratives sur la santé fournies par les ministères de la Santé des provinces et des territoires. Les dénominateurs utilisés pour calculer ces taux reposent sur des estimations de population tirées des dossiers d’assurance-maladie, données toutefois pas systématiquement accessibles à tous les chercheurs. Le recensement de Statistique Canada constitue quant à lui une autre source d’estimation de la taille de la population. Notre étude visait d’abord à calculer les principaux écarts entre les dénominateurs de population à partir des estimations du SCSMC et à partir de celles de Statistique Canada et ensuite à déterminer les causes à l’origine des écarts entre ces sources de données. Méthodologie : Nous avons comparé pour 2009 les dénominateurs fournis par le SCSMC et ceux fournis par Statistique Canada. Le dénominateur du SCSMC a été ajusté pour tenir compte des composantes de la croissance (naissances, décès, émigrants et immigrants) tirées des données de recensement de Statistique Canada. Résultats : Le dénominateur non ajusté du SCSMC était de 34 429 804 personnes, soit une différence de + 3,2 % par rapport à l’estimation de population de Statistique Canada pour 2009. Après ajustement du dénominateur du SCSMC pour tenir compte des composantes de la croissance, la différence entre les deux estimations s’est trouvé réduite à 431 323 personnes, soit un écart de 1,3 %. L’estimation tirée du SCSMC constitue une surestimation par rapport à celle de Statistique Canada. Le plus grand écart entre les deux estimations relève de la composante de croissance liée à l’immigration, alors que l’écart le moindre provient de la composante de croissance liée à la population émigrante. Conclusions : Disposant des descriptions de données par source de données, les chercheurs peuvent choisir quelle estimation de la population utiliser dans leurs calculs des fréquences de maladies.

Abstract Infections caused by antimicrobial-resistant Acinetobacter baumannii pose a significant threat to human health, particularly in the context of hospital-acquired infections. As existing antibiotics lose efficacy against Acinetobacter isolates, there is an urgent need for the development of novel antimicrobial agents. In this study, we assessed 400 structurally diverse compounds from the Medicines for Malaria Pandemic Response Box for their activity against two clinical isolates of A. baumannii: A. baumannii 5075, known for its extensive drug resistance, and A. baumannii QS17-1084, obtained from an infected wound in a Thai patient. Among the compounds tested, seven from the Pathogen box exhibited inhibitory effects on the in vitro growth of A. baumannii isolates, with IC50s ≤ 48 µM for A. baumannii QS17-1084 and IC50s ≤ 17 µM for A. baumannii 5075. Notably, two of these compounds, MUT056399 and MMV1580854, shared chemical scaffolds resembling triclosan. Further investigations involving drug combinations identified five synergistic drug combinations, suggesting potential avenues for therapeutic development. The combination of MUT056399 and brilacidin against A. baumannii QS17-1084 and that of MUT056399 and eravacycline against A. baumannii 5075 showed bactericidal activity. These combinations significantly inhibited biofilm formation produced by both A. baumannii strains. Our findings highlight the drug combinations as promising candidates for further evaluation in murine wound infection models against multidrug-resistant A. baumannii. These compounds hold potential for addressing the critical need for effective antibiotics in the face of rising antimicrobial resistance.

BackgroundDigital mental health technologies (DMHTs) have the potential to enhance mental health care delivery. However, there is little information on how DMHTs are evaluated and what factors influence their use. ObjectiveA systematic literature review was conducted to understand how DMHTs are valued in the United States from user, payer, and employer perspectives. MethodsArticles published after 2017 were identified from MEDLINE, Embase, PsycINFO, Cochrane Library, the Health Technology Assessment Database, and digital and mental health congresses. Each article was evaluated by 2 independent reviewers to identify US studies reporting on factors considered in the evaluation of DMHTs targeting mental health, Alzheimer disease, epilepsy, autism spectrum disorder, or attention-deficit/hyperactivity disorder. Study quality was assessed using the Critical Appraisal Skills Program Qualitative and Cohort Studies Checklists. Studies were coded and indexed using the American Psychiatric Association’s Mental Health App Evaluation Framework to extract and synthesize relevant information, and novel themes were added iteratively as identified. ResultsOf the 4353 articles screened, data from 26 unique studies from patient, caregiver, and health care provider perspectives were included. Engagement style was the most reported theme (23/26, 88%), with users valuing DMHT usability, particularly alignment with therapeutic goals through features including anxiety management tools. Key barriers to DMHT use included limited internet access, poor technical literacy, and privacy concerns. Novel findings included the discreetness of DMHTs to avoid stigma. ConclusionsUsability, cost, accessibility, technical considerations, and alignment with therapeutic goals are important to users, although DMHT valuation varies across individuals. DMHT apps should be developed and selected with specific user needs in mind.

Abstract Malaria genomic surveillance often estimates parasite genetic relatedness using metrics such as Identity-By-Decent (IBD), yet strong positive selection stemming from antimalarial drug resistance or other interventions may bias IBD-based estimates. In this study, we use simulations, a true IBD inference algorithm, and empirical data sets from different malaria transmission settings to investigate the extent of this bias and explore potential correction strategies. We analyze whole genome sequence data generated from 640 new and 3089 publicly available Plasmodium falciparum clinical isolates. We demonstrate that positive selection distorts IBD distributions, leading to underestimated effective population size and blurred population structure. Additionally, we discover that the removal of IBD peak regions partially restores the accuracy of IBD-based inferences, with this effect contingent on the population’s background genetic relatedness and extent of inbreeding. Consequently, we advocate for selection correction for parasite populations undergoing strong, recent positive selection, particularly in high malaria transmission settings.

Abstract Deep brain stimulation (DBS) of the subcallosal cingulate cortex (SCC) is an experimental therapy for treatment-resistant depression (TRD). Chronic SCC DBS leads to long-term changes in the electrophysiological dynamics measured from local field potential (LFP) during wakefulness, but it is unclear how it impacts sleep-related brain activity. This is a crucial gap in knowledge, given the link between depression and sleep disturbances, and an emerging interest in the interaction between DBS, sleep, and circadian rhythms. We therefore sought to characterize changes in electrophysiological markers of sleep associated with DBS treatment for depression. We analyzed key electrophysiological signatures of sleep—slow-wave activity (SWA, 0.5–4.5 Hz) and sleep spindles—in LFPs recorded from the SCC of 9 patients who responded to DBS for TRD. This allowed us to compare the electrophysiological changes before and after 24 weeks of therapeutically effective SCC DBS. SWA power was highly correlated between hemispheres, consistent with a global sleep state. Furthermore, SWA occurred earlier in the night after chronic DBS and had a more prominent peak. While we found no evidence for changes to slow-wave power or stability, we found an increase in the density of sleep spindles. Our results represent a first-of-its-kind report on long-term electrophysiological markers of sleep recorded from the SCC in patients with TRD, and provides evidence of earlier NREM sleep and increased sleep spindle activity following clinically effective DBS treatment. Future work is needed to establish the causal relationship between long-term DBS and the neural mechanisms underlying sleep.

Cognitive impairment has a profound deleterious impact on long-term outcomes of glioma surgery. The human insula, a deep cortical structure covered by the operculum, plays a role in a wide range of cognitive functions including interceptive thoughts and salience processing. Both low-grade (LGG) and high-grade gliomas (HGG) involve the insula, representing up to 25% of LGG and 10% of HGG. Surgical series from the past 30 years support the role of primary cytoreductive surgery for insular glioma patients; however, reported cognitive outcomes are often limited to speech and language function. The breath of recent neuroscience literature demonstrates that the insula plays a broader role in cognition including interoceptive thoughts and salience processing. This article summarizes the vast functional role of the healthy human insula highlighting how this knowledge can be leveraged to improve the care of patients with insular gliomas.

ObjectiveTo collect evidence on the possibility that patients with depression experience self-stigmatization based on label information for medications.MethodsWe developed a discrete-choice experiment (DCE) survey instrument that asked respondents to make choices between hypothetical treatments for major depressive disorder (MDD). We also included treatment type (antidepressants versus antipsychotics) and approved indications for the medication. The choice questions mimicked the information presented in product inserts and required systematic tradeoffs between treatment efficacy, treatment type, and indication. We calculated how many patients were willing to forgo efficacy to avoid treatments with information associated with self-stigmatization, and how much efficacy they were willing to forgo. We also evaluated the impact of contextualizing the treatment information to reduce self-stigmatization by randomizing respondents who received additional context.ResultsA total of 501 patients with MDD were recruited to complete the DCE survey. Respondents had well-defined preferences for treatment outcomes. Over 60% (63.4%) of respondents were found to be significantly affected by treatment indication. These respondents were willing to forgo about 2.5 percentage points in the chance of treatment efficacy to avoid treatments indicated for schizophrenia. We also find that some level of contextualization of the treatment details could help reduce the negative impact of treatment type and indications.ConclusionsProduct-label treatment indication can potentially lead to patient self-stigmatization as shown by patients' avoidance of treatments that are also used to treat schizophrenia. While the effect appears to be relatively small, results suggests that the issue is likely pervasive.

This article examines the impact of the COVID-19 pandemic on Latino immigrants age sixty and older from Cuba, Dominican Republic, El Salvador, Mexico, Puerto Rico, and Venezuela. Based on 178 interviews with immigrants in Florida and Massachusetts, this study identifies the financial and health hardships they endured, the kinds of government and nonprofit aid they accessed, the factors keeping many from accessing aid, and the coping strategies they adopted. Respondents faced unemployment, hunger, and loss of income. Unauthorized immigrants and people in mixed-status families were deliberately excluded from federal aid. Many other immigrants who qualified were reluctant or refused it. Immigrants without legal status and those who had more recently arrived were the most severely affected. Individuals and families responded to these challenges by doubling up, going without food and medicine, and working while sick. Greater outreach and more humane public policies could have prevented much of this suffering.

The SHANK3 gene is linked to autism spectrum disorder and Phelan McDermid syndrome, which have been associated with social memory deficits. Here, authors show activation of the hippocampal CA2-ventral CA1 circuit in adult Shank3B knockout mice restores social memory.

Background: Adolescence is a time of heightened risk for developing depression and also a critical period for the development and integration of self-identity. Despite this, the relation between the neurophysiological correlates of self-referential processing and major depressive symptoms in youth is not well understood. Here, we leverage computational modeling of the self-referential encoding task (SRET) to identify behavioral moderators of the association between the posterior late positive potential (LPP), an event-related potential associated with emotion regulation, and youth self-reported symptoms of depression. Specifically, within a drift-diffusion framework, we evaluated whether the association between the posterior LPP and youth symptoms of major depression was moderated by drift rate, a parameter reflecting processing efficiency during self-evaluative decisions. Methods: A sample of 106 adolescents, aged 12 to 17 (53% male; Mage = 14.49, SD = 1.70), completed the SRET with concurrent high-density electroencephalography and self-report measures of depression and anxiety. Results: Findings indicated a significant moderation: for youth showing greater processing efficiency (drift rate) when responding to negative compared to positive words, larger posterior LPPs predicted greater depressive symptom severity. Limitations: We relied on a community sample and our study was cross-sectional in nature. Future longitudinal work with clinically depressed youth would be beneficial. Conclusions: Our results suggest a neurobehavioral model of adolescent depression wherein efficient processing of negative information co-occurs with increased demands on affective self-regulation. Our findings also have clinical relevance; youth's neurophysiological response (posterior LPP) and performance during the SRET may serve as a novel target for tracking treatment-related changes in one's self-identity.

Creating a STEM-driven culture incorporating engineering habits of mind and 21st century skills at an early age could impact students’ STEM interests and knowledge. Therefore, early exposure to effective engineering design practices could create a foundation for a STEM program. This exploratory case study examined the integration of a STEM program in an elementary-level school. Survey, interview, focus group, and observational data were analyzed and coded to determine effective practices of the STEM program. This paper focuses on the emergent themes of the (a) critical role of the specialist, (b) instructional design, and (c) integration of the engineering laboratory. The STEM specialist at Gemini Elementary School provided the teachers with the foundation for the in-depth acquisition of STEM content and pedagogical skills. Teachers were provided with team planning time that focused on the instructional design of the STEM Block lessons. Through collaborative settings, teachers and the specialist were able to design modern real-world problems for students that allowed students to apply engineering design practices to find solutions. The results of this study point to the need to increase the number of STEM programs embrace engineering design in elementary schools.

Background: The efficacy of psychiatric DBS is thought to be driven by the connectivity of stimulation targets with mood-relevant fronto-temporal networks, which is typically evaluated using diffusion-weighted tractography. Objective: Leverage intracranial electrophysiology recordings to better predict the circuit-wide effects of neuromodulation to white matter targets. We hypothesize strong convergence between tractography-predicted structural connectivity and stimulation-induced electrophysiological responses. Methods: Evoked potentials were elicited by single-pulse stimulation to two common DBS targets for treatment-resistant depression – the subcallosal cingulate (SCC) and ventral capsule/ventral striatum (VCVS) – in two patients undergoing DBS with stereo-electroencephalographic (sEEG) monitoring. Evoked potentials were compared with predicted structural connectivity between DBS leads and sEEG contacts using probabilistic, patient-specific diffusion-weighted tractography. Results: Evoked potentials and tractography showed strong convergence in both patients in orbitofrontal, ventromedial prefrontal, and lateral prefrontal cortices for both SCC and VCVS stimulation targets. Low convergence was found in anterior cingulate (ACC), where tractography predicted structural connectivity from SCC targets but produced no evoked potentials during SCC stimulation. Further, tractography predicted no connectivity to ACC from VCVS targets, but VCVS stimulation produced robust evoked potentials. Conclusion: The two connectivity methods showed significant convergence, but important differences emerged with respect to the ability of tractography to predict electrophysiological connectivity between SCC and VCVS to regions of the mood-related network. This multimodal approach raises intriguing implications for the use of tractography in surgical targeting and provides new data to enhance our understanding of the network-wide effects of neuromodulation.

The synaptonemal complex (SC) is an ultrastructurally conserved proteinaceous structure that holds homologous chromosomes together and is required for the stabilization of pairing interactions and the completion of crossover (CO) formation between homologs during meiosis I. Here, we identify a novel role for a central region component of the SC, SYP-4, in negatively regulating formation of recombination-initiating double-strand breaks (DSBs) via a feedback loop triggered by crossover designation in C. elegans. We found that SYP-4 is phosphorylated dependent on Polo-like kinases PLK-1/2. SYP-4 phosphorylation depends on DSB formation and crossover designation, is required for stabilizing the SC in pachytene by switching the central region of the SC from a more dynamic to a less dynamic state, and negatively regulates DSB formation. We propose a model in which Polo-like kinases recognize crossover designation and phosphorylate SYP-4 thereby stabilizing the SC and making chromosomes less permissive for further DSB formation.