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Actively avoiding danger is necessary for survival. Most research has focused on the behavioral and neurobiological processes when individuals avoid danger alone, under solitary conditions. Therefore, little is known about how social context affects active avoidance. Using a modified version of the platform-mediated avoidance task in rats, we investigated whether the presence of a social partner attenuates conditioned freezing and enhances avoidance learning compared to avoidance learned under solitary conditions. Rats spent a similar percentage of time avoiding during the tone under both conditions; however, rats trained under social conditions exhibited greater freezing during the tone as well as lower rates of darting and food seeking compared to solitary rats. Under solitary conditions, we observed higher levels of avoidance in females compared to males, which was not present in rats trained under social conditions. To gain greater mechanistic insight, we optogenetically inactivated glutamatergic projection neurons in the anterior cingulate cortex (ACC) following avoidance training. Photoinactivation of ACC neurons reduced expression of avoidance under social conditions both in the presence and absence of the partner. Under solitary conditions, photoinactivation of ACC delayed avoidance in males but blocked avoidance in females. Our findings suggest that avoidance is mediated by the ACC, regardless of social context, and may be dysfunctional in those suffering from trauma-related disorders. Furthermore, sex differences in prefrontal circuits mediating active avoidance warrant further investigation, given that females experience a higher risk of developing anxiety disorders.

In his book 'A Beautiful Question' ¹, physicist Frank Wilczek argues that symmetry is 'nature's deep design,' governing the behavior of the universe, from the smallest particles to the largest structures ^1-4. While symmetry is a cornerstone of physics, it has not yet been found widespread applicability to describe biological systems ⁵, particularly the human brain. In this context, we study the human brain network engaged in language and explore the relationship between the structural connectivity (connectome or structural network) and the emergent synchronization of the mesoscopic regions of interest (functional network). We explain this relationship through a different kind of symmetry than physical symmetry, derived from the categorical notion of Grothendieck fibrations ⁶. This introduces a new understanding of the human brain by proposing a local symmetry theory of the connectome, which accounts for how the structure of the brain's network determines its coherent activity. Among the allowed patterns of structural connectivity, synchronization elicits different symmetry subsets according to the functional engagement of the brain. We show that the resting state is a particular realization of the cerebral synchronization pattern characterized by a fibration symmetry that is broken ⁷ in the transition from rest to language. Our findings suggest that the brain's network symmetry at the local level determines its coherent function, and we can understand this relationship from theoretical principles.

One of the most common genetic risk factors for Parkinson's disease (PD) are variants in GBA1, which encodes the lysosomal enzyme glucocerebrosidase (GCase). GCase deficiency has been associated with an increased PD risk, but not all individuals with low GCase activity are carriers of GBA1 mutations, suggesting other factors may be acting as modifiers. We aimed to discover common variants associated with GCase activity, as well as replicate previously reported associations, by performing a genome-wide association study using two independent cohorts: a Columbia University cohort consisting of 697 PD cases and 347 controls and the Parkinson's Progression Markers Initiative (PPMI) cohort consisting of 357 PD cases and 163 controls. As expected, GBA1 variants have the strongest association with decreased activity, led by p.N370S (beta = -4.36, se = 0.32, p = 5.05e-43). We also identify a novel association in the GAA locus (encoding for acid alpha-glucosidase, beta = -0.96, se = 0.17, p = 5.23e-09) that may be the result of an interaction between GCase and acid alpha-glucosidase based on various interaction analyses. Lastly, we show that several PD-risk loci are potentially associated with GCase activity. Further research will be needed to replicate and validate our findings and to uncover the functional connection between acid alpha-glucosidase and GCase.

Introduction: Clinical notes, biomarkers, and neuroimaging have been proven valuable in dementia prediction models. Whether commonly available structured clinical data can predict dementia is an emerging area of research. We aimed to predict Alzheimer's disease (AD) and Alzheimer's disease related dementias (ADRD) in a well-phenotyped, population-based cohort using a machine learning approach.

Methods: Administrative healthcare data (k=163 diagnostic features), in addition to Census/vital record sociodemographic data (k = 6 features), were linked to the Cache County Study (CCS, 1995-2008).

Results: Among successfully linked UPDB-CCS participants (n=4206), 522 (12.4%) had incident AD/ADRD as per the CCS "gold standard" assessments. Random Forest models, with a 1-year prediction window, achieved the best performance with an Area Under the Curve (AUC) of 0.67. Accuracy declined for dementia subtypes: AD/ADRD (AUC = 0.65); ADRD (AUC = 0.49).

Discussion: Commonly available structured clinical data (without labs, notes, or prescription information) demonstrate modest ability to predict AD/ADRD, corroborated by prior research.

This work aims to evaluate associations between self-reported sleep health and frailty in Botswana, a sub-Saharan Africa setting. Fifty persons living with HIV (PLWH) on suppressive antiretroviral therapy (ART) and fifty HIV seronegative control participants are enrolled in Botswana. Sleep quality is scored subjectively as "good" or "poor" based on self-report. A frailty index (FI) is constructed based on thirty-three health deficits related to body mass index, waist circumference, physical activity, emotional status, and fatigue, and scored ranging between 0 (no deficit present) and 1 (all deficits present). Sleep quality between PLWH and controls is compared using logistic regression; linear regression is performed to compare the FI between them. Linear regressions are performed to examine the association between the FI and sleep quality stratified by HIV serostatus. Age, sex, and comorbidities are adjusted; when relevant, CD4 cell and ART duration are controlled. PLWH display 2.88 (95% CI: 1.22-6.79, p = 0.02) higher odds of having poor sleep than controls. Having poor sleep is associated with increased FI in PLWH but not in controls. Specifically, compared with PLWH who have good sleep, PLWH who report poor sleep have a > 1 standard deviation (p < 0.0001) increase in their FI score.

We analyzed the risk-benefit of COVID-19 vaccine using a causal model to explain and weigh up possible risk factors of blood clots after vaccination. A self-controlled case series method was used to examine the association between blood clots and COVID-19 vaccination. To avoid bias due to the under-reported infection among non-hospitalized subjects, a case-control study was used to compare the risk of blood clots in infected subjects to control subjects who were hospitalized due to physical injury. We found increased risks of blood clots after vaccination (incidence rate ratio is 1.13, 95% CI: [1.03,1.24] after the first dose and 1.23, 95% CI: [1.13,1.34] after the second dose). Furthermore, vaccination attenuated the increased risk of blood clots associated with infection (odds ratio is 2.16, 95% CI: [1.93,2.42] in unvaccinated versus 1.46, 95% CI: [1.25,1.70] in vaccinated). After accounting for vaccine efficacy against infection and the protection against infection-associated blood clots, receiving the COVID-19 vaccines decreases the risk of blood clots, especially during high infection rate period.

Background: This parallel, randomized controlled trial examines intrinsic motivation, adherence and motor function improvement demonstrated by two groups of subjects that performed a twelve-week, home-based upper extremity rehabilitation program. Seventeen subjects played games presenting eight to twelve discrete levels of increasing difficulty. Sixteen subjects performed the same activities controlled by success algorithms that modify game difficulty incrementally.

Methods: 33 persons 20 to 80 years of age, at least six months post stroke with moderate to mild hemiparesis were randomized using a random number generator into the two groups. They were tested using the Action Research Arm Test, Upper Extremity Fugl Meyer Assessment, Stroke Impact Scale and Intrinsic Motivation Inventory pre and post training. Adherence was measured using timestamps generated by the system. Subjects had the Home Virtual Rehabilitation System [1]systems placed in their homes and were taught to perform rehabilitation games using it. Subjects were instructed to train twenty minutes per day but were allowed to train as much as they chose. Subjects trained for twelve weeks without appointments and received intermittent support from study staff. Group outcomes were compared using ANOVA. Correlations between subject demographics and adherence, as well as motor outcome, were evaluated using Pearson Correlation Coefficients. Classification and Regression Tree (CART) models were generated to predict responders using demographics and baseline measures.

Results: There were 5 dropouts and no adverse events. The main effect of time was statistically significant for four of the five clinical outcome measures. There were no significant training group by time interactions. Measures of adherence did not differ between groups. 21 subjects from both groups, demonstrated clinically important improvements in UEFMA score of at least 4.25 points. Subjects with pre training UEFMA scores below 53.5 averaged a seven-point UEFMA increase. IMI scores were stable pre to post training.

Conclusions: Scaffolding did not have a meaningful impact on adherence or motor function improvement. A sparsely supervised program of game-based treatment in the home was sufficient to elicit meaningful improvements in motor function and activities of daily living. Common factors considered barriers to the utilization of telerehabilitation did not impact adherence or motor outcome.

Trial registration: Clinical Trials.gov - NCT03985761, Registered June 14, 2019.

Childhood maltreatment and intimate partner violence (IPV) victimization are major psychiatric risk factors. Maltreatment substantially increases the likelihood of subsequent IPV victimization, but what drives this association is poorly understood. We analyzed retrospective self-reports of maltreatment and IPV in 12794 participants (58% women, 42% men) from the Twins Early Development Study at ages 21 and 26 using quantitative genetic methods. We estimated the etiological influences common to maltreatment and IPV, and the direct causal effect of maltreatment on IPV beyond such common influences. Participants exposed to maltreatment (~7% of the sample) were 3 times more likely to experience IPV victimization than their peers at age 21, 4 times more likely at 26. The association between maltreatment and IPV was mostly due to environmental influences shared by co-twins (42-43%) and genetic influences (30-33%). The association between maltreatment and IPV was similar for women and men, but its etiology partly differed by sex. Maltreatment had a moderate-to-large effect on IPV in phenotypic models (β = 0.23-0.34), decreasing to a small-to-moderate range in causal models accounting for their common etiology (β = 0.15-0.21). Risk factors common to maltreatment and IPV victimization are largely familial in origin, environmental and genetic. Even considering common risk factors, experiencing maltreatment is causally related to subsequent IPV victimization. Interventions promoting safe intimate relationships among young adults exposed to maltreatment are warranted and should address family-level environmental risk and individual-level risk shaped by genetics.

Background Preoperative physical activity and intraoperative brain health are recognized to influence postoperative delirium (POD). Electroencephalogram (EEG) burst suppression and cerebral desaturation are indicators of abnormal intraoperative brain health. Our study aimed to investigate the associations between preoperative physical activity and intraoperative EEG burst suppression and cerebral desaturation. Methods We retrospectively analyzed data from 67 patients from one of the institutions participating in a multisite randomized controlled trial, PANDORA, involving patients undergoing cardiac surgery. The preoperative PCS12 score calculated using the SF12 questionnaire was used as an indicator of preoperative physical activity. Intraoperative EEG and cerebral oximetry data (not the current standard of care in this facility) were collected, and the anesthesiologists were blinded to the information. We analyzed the following associations between the PCS12 score and i) burst suppression duration, ii) the number of cerebral desaturations, and iii) the number of observations with concurrent cerebral desaturation and burst suppression using a generalized linear model. The results are presented as percentage changes in outcomes, and a 95% C.I. p value < 0.05 was considered to indicate statistical significance. Results Each unit increase in the PCS12 score was associated with a 3.3% decrease in the duration of burst suppression (-3.3 [-5.3, -1.2], p value = 0.002). The duration of burst suppression decreased by 29.2% with each successive quartile increase in the PCS-12 score, indicating a dose‒response relationship (-29.2 [-41.6, -16], p < 0.001). Specifically, the patients in the last three quartiles exhibited a 55.4% reduction in BSD compared to those in the first quartile (-55.4 [-74.4, -24.6], p = 0.002) (Fig. 2). We did not observe any significant association between the PCS12 score and cerebral desaturation. Conclusion Decreased preoperative physical activity, as measured by the SF-12 questionnaire, is significantly associated with increased EEG burst suppression duration. Preoperative physical activity did not show any association with cerebral desaturations and concurrent cerebral desaturation and burst suppression. Clinical Trial information ClinicalTrials.gov Identifier- NCT04093219 https://clinicaltrials.gov/ct2/show/NCT04093219 Principal Investigator - Balachundhar Subramaniam Date of registration - September 13, 2019.

Background: Permanent supportive housing (PSH) is an evidence-based practice for reducing homelessness that subsidizes permanent, independent housing and provides case management-including linkages to health services. Substance use disorders (SUDs) are common contributing factors towards premature, unwanted ("negative") PSH exits; little is known about racial/ethnic differences in negative PSH exits among residents with SUDs. Within the nation's largest PSH program at the Department of Veterans Affairs (VA), we examined relationships among SUDs and negative PSH exits (for up to five years post-PSH move-in) across racial/ethnic subgroups.

Methods: We used VA administrative data to identify a cohort of homeless-experienced Veterans (HEVs) (n = 2,712) who were housed through VA Greater Los Angeles' PSH program from 2016-2019. We analyzed negative PSH exits by HEVs with and without SUDs across racial/ethnic subgroups (i.e., African American/Black, Non-Hispanic White, Hispanic/Latino, and Other/Mixed [Asian, American Indian or Alaskan Native, and Native Hawaiian or Other Pacific Islander, and multi-race]) in controlled models and accounting for competing risk of death.

Results: In competing risk models, HEVs with at least one SUD had 1.3 times the hazard of negative PSH exits compared to those without SUDs (95% CI: 1.00, 1.61). When stratifying by race/ethnicity, Other/Mixed race residents with at least one SUD had 6.4 times the hazard of negative PSH exits compared to their peers without SUDs (95% CI: 1.61-25.50). Hispanic/Latino residents with at least one SUD had 1.9 times the hazard compared to those without SUDs, also indicating a strong relationship with negative PSH exits; however, this association was not statistically significant (95% CI: 0.85-4.37). Black residents with at least one SUD had 1.2 times the hazard compared to those without SUDs (95% CI: 0.85-1.64), indicating no evidence of an association with negative PSH exits. Similarly, Non-Hispanic White residents with at least one SUD had 1.1 times the hazard compared to those without SUDs (95% CI: 0.75-1.66).

Conclusions: These findings suggest relationships between SUDs and negative PSH exits differ between race/ethnic groups and suggest there may be value in culturally specific tailoring and implementation of SUD services for these subgroups.