bluuebunny/crossref_metadata_2025 huggingface dataset:
Loss of regulation of complement C5 activation in HIV associated Preeclampsia
Authors: Govender Sumeshree , Mduluza Takafira , Nandlal Louansha , Naicker Thajasvarie
Published: July 2022

Objective

Maternal mortality remains a global health concern in developing countries that are also affected by HIV infection. Complement components are anaphylatoxin that mediate several growth factors necessary during pregnancy. An extensive stimulation of the complement system contributes to the pathogenesis of preeclampsia; hence its inhibition facilitates a successful pregnancy. The study evaluated the expression of complement components C2 and C5a in HIV and the association with preeclampsia.

Materials and Methods

Serum samples were collected from 76 pregnant women of which 38 were preeclamptic and 38 normotensive pregnant. The participants were further stratified according to HIV infection status. Bio-Plex multiplex immunoassay method was used to quantify serum concentration of C5a and C2 complement components.

Results

The C2 complement concentration was not significantly different between preeclamptic and normotensive pregnant women, irrespective of HIV status as well as pregnancy type. However, based on preeclampticvsnormotensive pregnancy type, the expression of C5a was significantly different (p= 0.05). The C5a levels were downregulated in preeclampsia compared to normotensive women, irrespective of HIV status. Both C2 and C5a concentrations did not differ across all study groups.

Conclusion

This novel study reports a loss of regulation of complement activation shown by the downregulation of C5a in preeclamptic compared to normotensive pregnant women, regardless of HIV status. Complement dysregulation affects the host innate defence, and as a consequence, intensifies placental and fetal injury. Moreover, HIV status did not influence the expression of both C5a and C2, irrespective of pregnancy type, this may be attributed to Highly Active Antiretroviral Therapy.
A dataset of multi-contrast unbiased average MRI templates of a Parkinson’s disease population
Authors: Madge Victoria , Fonov Vladimir S , Xiao Yiming , Zou Lucy , Jackson Courtney , Postuma Ronald B , Dagher Alain , Fon Edward A , Collins D Louis
Published: July 2022

Parkinson’s disease (PD) is a complex neurodegenerative disorder affecting regions such as the substantia nigra (SN), red nucleus (RN) and locus coeruleus (LC). Processing MRI data from patients with PD requires anatomical structural references for spatial normalization and structural segmentation. Extending our previous work [1][2], we present multi-contrast unbiased MRI templates using nine 3T MRI modalities: T1w, T2*w, T1-T2* fusion, R2*, T2w, PDw, fluid-attenuated inversion recovery (FLAIR), improved susceptibility-weighted imaging (CLEAR-SWI) [3], and neuromelanin-sensitive MRI (NM). Using our previous methods to build unbiased average templates [4], 1 mm isotropic voxel size templates were created, along with 0.5 mm isotropic whole brain templates and 0.3 mm isotropic templates of the midbrain. All templates were created from 126 PD patients (44 female; ages=40-87), and 17 healthy controls (13 female; ages=39-84), except the NM template, which was created from 85 PD patients and 13 controls, respectively. The dataset is available on the NIST MNI Repository via the following link: http://nist.mni.mcgill.ca/multi-contrast-pd126-and-ctrl17-templates/.
Large deletions perturb peripheral transcriptomic and metabolomic profiles in Phelan-McDermid syndrome
Authors: Breen Michael S. , Fan Xuanjia , Levy Tess , Pollak Rebecca , Collins Brett , Osman Aya , Tocheva Anna S. , Sahin Mustafa , Berry-Kravis Elizabeth , Soorya Latha , Thurm Audrey , Powell Craig M. , Bernstein Jonathan A. , Kolevzon Alexander , Buxbaum Joseph D.
Published: July 2022

Phelan-McDermid syndrome (PMS) is a rare neurodevelopmental disorder caused at least in part by haploinsufficiency of the SHANK3 gene, due to sequence variants in SHANK3 or subtelomeric 22q13.3 deletions. Phenotypic differences have been reported between PMS participants carrying small ‘Class I’ mutations and large ‘Class II’ mutations, however the molecular perturbations underlying these divergent phenotypes remain obscure. Using peripheral blood transcriptome and serum metabolome profiling, we examined the molecular perturbations in the peripheral circulation associated with a full spectrum of PMS genotypes spanning Class I (n=37) and Class II mutations (n=39). Transcriptomic data revealed 52 genes with blood expression profiles that tightly scale with 22q.13.3 deletion size. Further, we uncover 208 under-expressed genes in PMS participants with Class II mutations, which were unchanged in Class I mutations. These genes were not linked to 22q13.3 and were strongly enriched for glycosphingolipid metabolism, NCAM1 interactions and cytotoxic natural killer (NK) immune cell signatures.In silicopredictions estimated a reduction in CD56+ CD16-NK cell proportions in Class II mutations, which was validated by mass cytometry time of flight. Global metabolomics profiling identified 24 metabolites that were significantly altered with PMS participants with Class II mutations, and confirmed a general reduction in sphingolipid metabolism. Collectively, these results provide new evidence linking PMS participants carrying Class II mutations with decreased expression of cytotoxic cell signatures, reduced relative proportions of NK cells, and lower sphingolipid metabolism. These findings highlight alternative avenues for therapeutic development and offer new mechanistic insights supporting genotype-to-phenotype associations in PMS.
Multi-trait Analysis of GWAS (MTAG) of Substance Use Traits Identifies Novel Genetic Loci and Phenomic Associations
Authors: Xu Heng , Toikumo Sylvanus , Crist Richard C. , Glogowska Klaudia , Deak Joseph D. , Gelernter Joel , Johnson Emma C. , Kranzler Henry R. , Kember Rachel L.
Published: July 2022

Introduction

A large majority of genome-wide significant (GWS) loci identified for substance use traits (SUTs) in genome-wide association studies (GWAS) have been for alcohol and smoking-related phenotypes. GWAS of opioid use disorder (OUD) and cannabis use disorder (CUD) have lagged those of the two historically legal substances.

Methods

We applied multi-trait analysis of GWAS (MTAG) to 2,888,727 single nucleotide polymorphisms (SNPs) common to GWAS of four SUTs (OUD, CUD, alcohol use disorder [AUD], and smoking initiation [SMK]) in European-ancestry (EUR) subjects. We calculated polygenic risk scores (PRS) for the four traits in an independent sample (i.e., the Yale-Penn sample; N=5,692 EUR) and examined the power increment for each set of MTAG-GWAS summary statistics relative to those of the input GWAS.

Results

MTAG increased the effective sample size for all four SUTs, which showed high pairwise genetic correlations. After clumping, MTAG identified independent GWS SNPs for all 4 traits: 41 SNPs in 36 loci (including 5 novel loci not previously associated with any SUT) for OUD; 74 SNPs in 60 loci (including 4 novel loci) for CUD; 63 SNPs in 52 loci (including 10 novel loci) for AUD; and 183 SNPs in 144 loci (including 8 novel loci) for SMK. In PRS analyses in the Yale-Penn sample, the MTAG-derived PRS consistently yielded more significant associations with both the corresponding substance use disorder diagnosis and multiple related phenotypes than each of the 4 GWAS-derived PRS.

Conclusions

MTAG boosted the number of GWS loci for the 4 SUTs, including identifying genes not previously linked to any SUT. MTAG-derived PRS also showed stronger associations with expected phenotypes than PRS for the input GWAS. MTAG can be used to identify novel associations for SUTs, especially those with sample sizes smaller than for historically legal substances.
Following the evolution of Homo sapiens across Africa using a uniparental genetic guide
Authors: Cabrera Vicente M.
Published: July 2022

The origin and evolution of modern humans in Africa has reached a multidisciplinary consensus but the age and regions where it originated and evolved are current topics of discussion. In this study I put forward an integrative model guided by the phylogeny and phylogeography of mitochondrial DNA (and Y-chromosome) haplogroups. I propose an early origin of modern humans in northwest Africa in a temporal window of 257-345 thousand years ago. A first population split in central Africa around 175-288 thousand years ago. A subsequent northward spread with additional population subdivisions during a long statistical interval that culminated in a first successful out of Africa migration around 130 thousand years ago. A population constriction in southwest Asia motivated an early return to Africa between 79 and 107 thousand years ago. This ample Eurasian-ebb to Africa, detected by mitochondrial haplogroup L3 and Y-chromosome haplogroup E preceded other later and geographically more limited Eurasian backflows. The archaeological and fossil finds that could be coetaneous to this molecular journey have been integrated into this interdisciplinary model.
Transcriptional and spatial profiling of the kidney allograft unravels a central role for FcyRIII+ innate immune cells in rejection
Authors: Lamarthée Baptiste , Callemeyn Jasper , Herck Yannick Van , Antoranz Asier , Anglicheau Dany , Becker Jan Ulrich , Debyser Tim , Smet Frederik De , Vusser Katrien De , Eloudzeri Maëva , Franken Amelie , Gwinner Wilfried , Koshy Priyanka , Kuypers Dirk , Lambrechts Diether , Marquet Pierre , Rabant Marion , Sprangers Ben , Tinel Claire , Brussel Thomas Van , Craenenbroeck Amaryllis Van , Loon Elisabet Van , Vaulet Thibaut , Bosisio Francesca , Naesens Maarten
Published: July 2022

Rejection remains the main cause of premature graft loss after kidney transplantation, despite the use of potent immunosuppression. This highlights the need to better understand the composition and the interactions of the alloreactive inflammatory infiltrate. We performed droplet-based single-cell RNA sequencing of 35,152 transcriptomes from 16 kidney transplant biopsies and generated cell-type specific gene expression signatures for deconvolution of bulk tissue. A specific association was identified between recipient-derivedFCGR3A+monocytes,FCGR3A+NK cells and the severity of intragraft inflammation. ActivatedFCGR3A+monocytes overexpressedCD47andLILRgenes and increased paracrine signaling pathways promoting T cell infiltration.FCGR3A+NK cells overexpressedFCRL3, suggesting that antibody-dependent cytotoxic activity is a central mechanism of NK cell mediated graft injury. Multiplexed immunohistochemistry using 38 markers on 18 independent biopsy slides confirmed this role of FcγRIII+ NK and FcγRIII+ nonclassical monocytes in antibody-mediated rejection, with specificity to the glomerular area. These results uncovered the central involvement of innate immune cells in the pathogenesis of allograft rejection and indicate several potential therapeutic targets to improve allograft longevity.
SHEAR Saliva Collection Device Augments Sample Properties for Improved Analytical Performance
Authors: Song Shang Wei , Gupta Rashi , Niharika Jothilingam , Qian Xinlei , Gu Yue , Lee V Vien , Sapanel Yoann , Allen David Michael , Wong John Eu Li , MacAry Paul A , Ho Dean , Blasiak Agata
Published: July 2022

Despite human saliva representing a convenient and non-invasive clinical substrate for disease diagnosis and biomonitoring, its widespread utilization has been hampered by technical challenges. The non-Newtonian, heterogenous and highly viscous nature of clinical saliva samples complicate the development of automated fluid handling processes that are vital for accurate diagnoses. Furthermore, conventional saliva processing methods are either resource and/or time intensive precluding certain testing capabilities in low- and middle-income countries, with these challenges aggravated during a pandemic outbreak. The conventional approaches can also potentially alter analyte structure, reducing application opportunities in Point-of-Care diagnostics. To overcome these challenges, we introduce the SHEAR saliva collection device that preprocesses saliva for enhanced interfacing with downstream assays. We demonstrate the device’s impact on reducing saliva’s viscosity, improving sample uniformity and, increasing diagnostic performance of COVID-19 Rapid Antigen Tests. Importantly, in addition to reporting technical advances and to address downstream implementation factors, we conducted a formal user experience study, which resulted in generally positive comments. Effective implementation of this device could be of support to realize the potential of saliva, particularly in large-scale and/or resource-limited settings for global and community health diagnostics.
Genome-wide determinants of mortality and motor progression in Parkinson’s disease
Authors: Tan Manuela MX , Lawton Michael A , Pollard Miriam I , Brown Emmeline , Real Raquel , Martinez Carrasco Alejandro , Bekadar Samir , Jabbari Edwin , Reynolds Regina H , Iwaki Hirotaka , Blauwendraat Cornelis , Kanavou Sofia , Hubbard Leon , Malek Naveed , Grosset Katherine A , Bajaj Nin , Barker Roger A , Burn David J , Bresner Catherine , Foltynie Thomas , Wood Nicholas W , Williams-Gray Caroline H , Andreassen Ole A , Toft Mathias , Elbaz Alexis , Artaud Fanny , Brice Alexis , Corvol Jean-Christophe , Aasly Jan , Farrer Matthew J , Nalls Michael A , Singleton Andrew B , Williams Nigel M , Ben-Shlomo Yoav , Hardy John , Hu Michele TM , Grosset Donald G , Shoai Maryam , Pihlstrøm Lasse , Morris Huw R
Published: July 2022

Background

There are 90 genetic risk variants for Parkinson’s disease (PD) but currently only five nominated loci for PD progression. The biology of PD progression is likely to be of central importance in defining mechanisms that can be used to develop new treatments.

Methods

We studied 6,766 PD patients, over 15,340 visits with a mean follow-up of between 4.2 and 15.7 years and carried out a genome wide survival study for time to a motor progression endpoint, defined by reaching Hoehn and Yahr stage 3 or greater, and death (mortality).

Findings

There was a robust effect of theAPOEε4 allele on mortality in PD. We identified three novel loci for mortality and motor progression, and nominated genes based on physical proximity and/or expression quantitative trait loci data. One locus within theTBXAS1gene encoding thromboxane A synthase 1 was associated with mortality in PD (HR = 2.04 [95% CI 1.63 to 2.56], p-value = 7.71 x 10-10). Another locus near theSYT10gene encoding synaptotagmin 10 was associated with mortality just above genome-wide significance (HR=1.36 [95% CI 1.21 to 1.51], p-value=5.31×10-8). We also report 4 independent loci associated with motor progression: the top locus withinMORN1(HR=2.76 [95% CI 1.97 to 3.87], p-value=3.1×10-9), the second most significant locus nearASNS, the third most significant locus nearPDE5A, and a fourth locus withinXPO1. We have nominated causal genes based on physical position, however we also discuss other possible causal genes based on expression quantitative trait loci, colocalization analysis, and tagging of rare variants. Only the non-Gaucher disease causingGBA1PD risk variant E326K, of the known PD risk variants, was associated with mortality in PD.

Interpretation

We report six novel loci associated with PD motor progression or mortality. Further work is needed to understand the links between these genomic variants and the underlying disease biology. However, thromboxane synthesis, vesicular peptidergic neurotransmitter release, and phosphodiesterase inhibition may represent new candidates for disease modification in PD.

Funding sources

Parkinson’s UK, Aligning Science Across Parkinson’s through the Michael J Fox Foundation for Parkinson’s Research, Southern and Eastern Norway Regional Health Authority
Changing temporal trends in patient volumes in a pediatric emergency department during a COVID-19 pandemic lockdown: a retrospective cohort study
Authors: Mullan Paul C. , Vazifedan Turaj
Published: July 2022

Objective

Emergency department (ED) teams have had to adjust limited staffing resources to meet the fluctuating levels of patient volume and acuity during the COVID-19 pandemic. Historically, Mondays have had the highest reported ED volumes. We are unaware of any studies reporting on the change of this Monday effect during the COVID-19 pandemic.

Methods

This retrospective, observational study of a single pediatric ED compared a pandemic lockdown period (3/23/2020-11/1/2020) with a seasonally comparative period (3/25/2019-11/3/2019). We compared the mean number of patients who arrived on Monday versus any other specific weekday (Tuesday, Wednesday, Thursday, or Friday) and the aggregate of other weekdays (Tuesday to Friday) for both study periods. Secondary analyses investigated overall mean volumes, admission rates, and differences in triage acuity levels.

Results

There were 31,377 and 18,098 patients in the comparative and pandemic periods. The mean number of ED visits on Mondays in the comparative period was significantly more than any other weekday and the aggregate of weekdays (latter p<0.001). In contrast, there were no significant differences in the mean number of ED visits on Mondays in the pandemic period relative to any other weekday and the aggregate of weekdays (all p>0.05). The pandemic period had significantly lower mean volumes, higher admission rates, and more patients with higher acuity levels.

Conclusion

The previously experienced Monday effect of increased relative ED patient volumes was not seen during the pandemic period. This change has operational implications for scheduling ED staffing resources. Larger database studies are needed to determine the generalizability of these findings.
Feasibility of and Experience with Telehealth Based Patient Self-referral for COVID-19 Monoclonal Antibody Therapy
Authors: Gupta Ishaan , Purekal Sophia , Shaikh Yahya , Michtalik Henry J. , Eid Shaker M. , Wortman Laura , Vaeth MaryJane E. , Locke Charles F S , Hoemeke Elizabeth , Hariharan Raena , Callahan Charles D. , Ficke James R. , Pimenta Isabel , Auwaerter Paul G. , Kantsiper Melinda E. ,   CONQUER COVID Consortium, Siddiqui Zishan K.
Published: July 2022

Background

Monoclonal antibody (mAb) treatment for COVID-19 has been underutilized due to logistical challenges, lack of access and variable treatment awareness among patients and providers. The use of telehealth during the pandemic provides an opportunity to increase access to COVID care.

Methods

This is a single-center descriptive study of telehealth-based patient self-referral for mAb therapy between March 1, 2021 to October 31, 2021 at Baltimore Convention Center Field Hospital (BCCFH).

Results

Among the 1001 self-referral patients, the mean age was 47, and most were female (57%) white (66%), and had a primary care provider (62%). During the study period, self-referrals increased from 14 per month in March to 427 in October resulting in a 30-fold increase. About 57% of self-referred patients received a telehealth visit, and of those 82% of patients received mAb infusion therapy, either onsite or at other infusion sites. The median time from self-referral to onsite infusion was 2 days (1-3 IQR).

Discussion

Our study shows the integration of telehealth with a self-referral process improved access to mAb infusion. A high proportion of self-referrals were appropriate and led to timely treatment. Incorporation of self-referral and telehealth for monoclonal antibody therapy led to successful timely infusions. This approach helped those without traditional avenues for care and avoided potential delay for patients seeking referral from their medical providers.
Altered affinity to ACE2 and reduced Fc functional antibodies to SARS-CoV-2 RBD variants
Authors: Haycroft Ebene R , Davis Samantha K , Ramanathan Pradhipa , Lopez Ester , Purcell Ruth A , Tan Li Lynn , Pymm Phillip , Wines Bruce D , Hogarth P Mark , Wheatley Adam K , Juno Jennifer A. , Redmond Samuel , Gheradin Nicholas A , Godfrey Dale I , Tham Wai-Hong , Selva Kevin John , Kent Stephen J , Chung Amy W
Published: July 2022

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants remains a formidable challenge to worldwide public health. The receptor binding domain (RBD) of the SARS-CoV-2 spike protein is a hotspot for mutations, reflecting its critical role at the ACE2 interface during viral entry. We comprehensively investigated the impact of RBD mutations, including 6 variants of concern (VOC) or interest (Alpha, Beta, Gamma, Delta, Kappa and Omicron) and 33 common point mutations, on IgG recognition, FcγR-engagement, and ACE2-binding inhibition in plasma from BNT162b2-vaccine recipients (two-weeks following second dose) and mild-to-moderate COVID-19 convalescent subjects using our custom bead-based 39-plex array. We observed that IgG-recognition and FcγR-binding antibodies were most profoundly decreased against Beta and Omicron RBDs, as well as point mutations G446S, found in Omicron, and N501T, a key mutation found in animal adapted SARS-CoV-2 viruses. Measurement of RBD-ACE2 binding affinity via Biolayer Interferometry showed all VOC RBDs have enhanced affinity to human ACE2. Furthermore we demonstrate that human ACE2 polymorphisms, E35K (rs1348114695), K26R (rs4646116) and S19P (rs73635825), have altered binding kinetics to the RBD of VOCs potentially affecting virus-host interaction and thereby host susceptibility.
Abnormal thrombosis and neutrophil activation increases the risk of hospital-acquired sacral pressure injuries and morbidity in patients with COVID-19
Authors: Narang Jatin , Jatana Samreen , Ponti András K. , Musich Ryan , Gallop Joshua , Wei Angela H. , Seck Sokhna , Johnson Jessica , Kokoczka Lynne , Nowacki Amy S. , McBride Jeffrey D. , Mireles-Cabodevila Eduardo , Gordon Steven , Cooper Kevin , Fernandez Anthony P. , McDonald Christine
Published: July 2022

Hospitalized patients have an increased risk of developing hospital-acquired sacral pressure injury (HASPI). However, it is unknown whether SARS-CoV-2 infection affects HASPI development. To explore the role of SARS-CoV-2 infection in HASPI development, we conducted a single institution, multi-hospital, retrospective study of all patients hospitalized for ≥5 days from March 1, 2020 to December 31, 2020. Patient demographics, hospitalization information, ulcer characteristics, and 30-day-related morbidity were collected for all patients with HASPIs, and intact skin was collected from HASPI borders in a patient subset. We determined the incidence, disease course, and short-term morbidity of HASPIs in COVID-19(+) patients, and characterized the skin histopathology and tissue gene signatures associated with HASPIs in COVID-19 disease. COVID-19(+) patients had a 63% increased HASPI incidence rate, HASPIs of more severe ulcer stage (OR 2.0, p<0.001), and HASPIs more likely to require debridement (OR 3.1, p=0.04) compared to COVID-19(-) patients. Furthermore, COVID-19(+) patients with HASPIs had 2.2x odds of a more severe hospitalization course compared to COVID-19(+) patients without HASPIs. HASPI skin histology from COVID-19(+) patients predominantly showed thrombotic vasculopathy, with the number of thrombosed vessels being significantly greater than HASPIs from COVID-19(-) patients. Transcriptional signatures of COVID-19(+) samples were enriched for innate immune responses, thrombosis, and neutrophil activation genes. SARS-CoV-2 viral transcripts were detected in skin tissue of COVID-19(+) patients with severe disease. Overall, our results suggest that immunologic dysregulation secondary to SARS-CoV-2 infection, including neutrophil dysfunction and abnormal thrombosis, may play a pathogenic role in development of HASPIs in patients with severe COVID-19.

One Sentence Summary

SARS-CoV-2-induced immune dysregulation contributes to pressure-induced sacral skin ulceration in hospitalized patients with severe COVID-19.
Application of ARIMA, hybrid ARIMA and Artificial Neural Network Models in predicting and forecasting tuberculosis incidences among children in Homa Bay and Turkana Counties, Kenya
Authors: Stephen Siamba , Argwings Otieno , Julius Koech
Published: July 2022

Background

Tuberculosis (TB) infections among children (below 15 years) is a growing concern, particularly in resource-limited settings. However, the TB burden among children is relatively unknown in Kenya where two-thirds of estimated TB cases are undiagnosed annually. Very few studies have used Autoregressive Integrated Moving Average (ARIMA), hybrid ARIMA, and Artificial Neural Networks (ANNs) models to model infectious diseases globally. We applied ARIMA, hybrid ARIMA, and Artificial Neural Network models to predict and forecast TB incidences among children in Homa bay and Turkana Counties in Kenya.

Methods

The ARIMA, ANN, and hybrid models were used to predict and forecast monthly TB cases reported in the Treatment Information from Basic Unit (TIBU) system for Homa bay and Turkana Counties between 2012 and 2021. The data were split into training data, for model development, and testing data, for model validation using an 80:20 split ratio respectively.

Results

The hybrid ARIMA model (ARIMA-ANN) produced better predictive and forecast accuracy compared to the ARIMA (0,0,1,1,0,1,12) and NNAR (1,1,2) [12] models. Furthermore, using the Diebold-Mariano (DM) test, the predictive accuracy of NNAR (1,1,2) [12] versus ARIMA-ANN, and ARIMA-ANN versus ARIMA (0,0,1,1,0,1,12) models were significantly different, p<0.001, respectively. The 12-month forecasts showed a TB prevalence of 175 to 198 cases per 100,000 children in Homa bay and Turkana Counties in 2022.

Conclusion

The hybrid (ARIMA-ANN) model produces better predictive and forecast accuracy compared to the single ARIMA and ANN models. The findings show evidence that the prevalence of TB among children below 15 years in Homa bay and Turkana Counties is significantly under-reported and is potentially higher than the national average.
Episodic memory impairment in patients with repetitive head injury: Initial findings of the SNAP-CTE cohort study
Authors: Erskine Ellen , Batchelor Jennifer , Maddren Michelle , Brown Eamon , Lystad Reidar , Mobbs Rowena
Published: July 2022

Background

Traumatic encephalopathy syndrome (TES) is considered a long-term, neurodegenerative consequence of repetitive head injury (RHI). This cohort study aimed to characterise the episodic memory profiles (specifically, immediate and delayed memory) of individuals with RHI history through neuropsychological assessment. Hypotheses included participants demonstrating reduced episodic memory functioning, and greater reductions in functioning observed with greater years of RHI exposure.

Methods

Neuropsychological assessment was conducted on 34 adults with ≥10 years of RHI exposure as a cohort study. Main outcome measures were auditory memory indices (AMI), immediate memory indices (AII), and auditory delayed memory indices (ADI). Other potential predictors of outcome variables (in addition to years of exposure duration) were also measured and factored into analysis so that they could be controlled for.

Results

AMI [t (33) = -2.4, p = .020), AII (t = -2.7, p = .012), and ADI (t = -2.7, p = .44) were all significantly below normative levels. AMI [t (33) = 4.1, p <.001), AII (t = 4.3, p <.001), and ADI (t = 3.7, p <.001) were also significantly below participants’ measured premorbid functioning. None of the comorbidities that were considered as possible confounding variables predicted the relationship of any outcome variables.

Conclusions

Previous research (1) indicated that immediate episodic memory (i.e., encoding) impairments do not appear to be associated with RHI, and our study provides evidence to the contrary. However, further research is required on larger sample sizes to further understand the relationship between RHI and encoding deficits in this complex population.

What is already known on this topic?

Chronic Traumatic Encephalopathy (CTE) identified at autopsy, has been loosely associated with a history of repetitive head injury (RHI) sustained in life, yet factors that account for symptoms such as defined in life as Traumatic Encephalopathy Syndrome (TES) which can include abnormal cognitive function, behavioural dysregulation and mood disturbances in this patient cohort are yet to be comprehensively investigated.

What this study adds?

This research is beneficial to the scientific community mainly because it contributes to the pre-existing body of literature on the neuropsychological profile of RHI. Previous research (1) has indicated that immediate episodic memory (i.e., encoding) impairments do not appear to be associated with RHI, and our study provides evidence to the contrary.

How might this study affect research, practice, or policy?

This research represents progress towards further discerning a neuropsychological profile of TES, thereby potentially aiding a better clinical diagnostic presentation of the disease, which can build on potential earlier diagnosis, prevention strategies and treatment pathways.
Global health open-source goggles for fluorescence-guided surgery
Authors: Shmuylovich Leonid , O’Brien Christine M. , Nwosu Karen , Achilefu Samuel
Published: July 2022

Fluorescence-guided surgery (FGS), coupled with novel near infrared (NIR) fluorescent contrast agents, has significant potential to improve health but in current practice is less suitable for low resource settings. Although there are efforts to simplify FGS systems, technical, economic, and logistic challenges have hampered its global adoption. To overcome these impediments, we developed a low-cost, open-source, battery-powered and fully wearable FGS system called the fluorescence imaging augmented reality Raspberry Pi-based goggle system (FAR-Pi). Compared to current technologies that are expensive, bulky, and wall-powered, FAR-Pi has higher spatial resolution, depth of focus and fluorescence sensitivity. The FAR-Pi system has broad appeal by detecting the diverse fluorescence of NIR contrast agents undergoing clinical trials, as demonstrated by the successful identification of tumors in vivo with LS301, a tumor-targeting NIR contrast agent. As an open-source, inexpensive, and modifiable system, FAR-Pi promises to broaden access to FGS, thereby improving health worldwide.
OpenCap: 3D human movement dynamics from smartphone videos
Authors: Uhlrich Scott D. , Falisse Antoine , Kidziński Łukasz , Muccini Julie , Ko Michael , Chaudhari Akshay S. , Hicks Jennifer L. , Delp Scott L.
Published: July 2022

Measures of human movement dynamics can predict outcomes like injury risk or musculoskeletal disease progression. However, these measures are rarely quantified in clinical practice due to the prohibitive cost, time, and expertise required. Here we present and validate OpenCap, an open-source platform for computing movement dynamics using videos captured from smartphones. OpenCap’s web application enables users to collect synchronous videos and visualize movement data that is automatically processed in the cloud, thereby eliminating the need for specialized hardware, software, and expertise. We show that OpenCap accurately predicts dynamic measures, like muscle activations, joint loads, and joint moments, which can be used to screen for disease risk, evaluate intervention efficacy, assess between-group movement differences, and inform rehabilitation decisions. Additionally, we demonstrate OpenCap’s practical utility through a 100-subject field study, where a clinician using OpenCap estimated movement dynamics 25 times faster than a laboratory-based approach at less than 1% of the cost. By democratizing access to human movement analysis, OpenCap can accelerate the incorporation of biomechanical metrics into large-scale research studies, clinical trials, and clinical practice.
Detection and quantification of introgression using Bayesian inference based on conjugate priors
Authors: Pfeifer Bastian , Kapan Durrell D.
Published: July 2022

Introgression (the flow of genes between species) is a major force structuring the evolution of genomes, potentially providing raw material for adaptation. Here, we present a versatile Bayesian model selection approach for the detection and quantification of introgression. The proposed df-BF approach builds upon the recently published distance-based df statistic. Unlike df, df-BF takes into account the number of variant sites within a genomic region. The df-BF method quantifies introgression with the inferred θ parameter, and at the same time enables weighing the strength of evidence for introgression based on Bayes Factors. To ensure fast computation we make use of conjugate priors with no need for computational demanding MCMC iterations. We compare our method with other approaches including df, fd, and Patterson’s D using a wide range of coalescent simulations. Furthermore, we showcase the applicability of the df-BF approach using whole genome mosquito data. Finally, we integrate the new method into the powerful genomics R-package PopGenome.
PACT - Prediction of Amyloid Cross-interaction by Threading
Authors: Wojciechowski Jakub W. , Szczurek Witold , Szulc Natalia , Szefczyk Monika , Kotulska Malgorzata
Published: July 2022

Amyloids are protein aggregates usually associated with their contribution to several diseases e.g., Alzheimer’s and Parkinson’s. However, they are also beneficially utilized by many organisms in physiological roles, such as microbial biofilm formation or hormone storage. Recent studies showed that an amyloid aggregate can affect aggregation of another protein. Such cross-interactions may be crucial for understanding the comorbidity of amyloid diseases or the influence of microbial amyloids on human amyloidogenic proteins. However, due to demanding experiments, understanding of interaction phenomena is still limited. Moreover, no dedicated computational method to predict potential amyloid interactions has been available until now. Here, we present PACT - a computational method for prediction of amyloid cross-interactions. The method is based on modeling a heterogenous fibril formed by two amyloidogenic peptides. The stability of the resulting structure is assessed using a statistical potential that approximates energetic stability of a model. Importantly, the method can work with long protein fragments and, as a purely physicochemical approach, it relies very little on training data. PACT was evaluated on data collected in the AmyloGraph database and it achieved high values of AUC (0.88) and F1 (0.82). The new method opens the possibility of high throughput studies of amyloid interactions. We used PACT to study interactions of CsgA, a bacterial biofilm protein from several bacterial species inhabiting human intestines, and human Alpha-synuclein protein which is involved in the onset of Parkinson’s disease. We show that the method correctly predicted the interactions, performing experimental validation, and highlighted the importance of specific regions in both proteins.

The tool is available as a web server at:https://pact.e-science.pl/pact/. The local version can be downloaded from:https://github.com/KubaWojciechowski/PACT
Longitudinal structural change of gray matter before and after hemispherotomy
Authors: Yu Hao , Chen Yijun , Luo Junhao , Liu Qingzhu , Qin Peipei , Wang Changtong , Qu Jingli , Cai Lixin , Gong Gaolang
Published: July 2022

Background

Hemispherotomy is an effective surgery developed to treat refractory epilepsy caused by diffuse unihemispheric pathologies. Post-surgery neuroplastic mechanisms supporting behavioral recovery after left and right hemispherotomy as well as their difference remain largely unclear.

Methods

In a large cohort of 57 pediatric patients who underwent hemispherotomy, voxel-wise GMV in unaffected regions (contralesional cerebrum and bilateral cerebellum) and behavioral abilities were assessed before and after surgery. Using linear mixed models, we evaluated changes in GMV and behavioral scores, and how GMV changes correlated with improvements in behavioral scores. In addition, three machine learning regression algorithms were applied to assess whether preoperative GMV can predict postoperative behavior.

Results

In the two patient groups (29 left hemispherotomy patients, age of surgery mean ± standard deviation = 3.5 ± 2.5; 28 right hemispherotomy patients, age of surgery 4.6 ± 2.5), widespread increases in the postoperative GMV in the contralateral cerebrum and ipsilateral cerebellum but decreases in the postoperative GMV in the contralateral cerebellum were consistently observed. Importantly, the decrease in GMV in the contralateral cerebellum was significantly correlated with improvement in behavioral scores in right but not left hemispherotomy patients. Moreover, the preoperative GMV around the most longitudinally changed locations significantly predicted postoperative behavioral scores in left but not right hemispherotomy patients.

Conclusions

Our findings indicate an important role for the contralateral cerebellum in the recovery after right hemispherotomy, and postoperative behavioral scores can be predicted with preoperative GMV features.

What is already known on this topic

The contralesional cerebrum plays a key role in the recovery after hemispherotomy.

What this study adds

Despite suffering from gray matter atrophy, GMV decrease in contralesional cerebellum is associated with improvement in behavioral score in patients after hemispherotomy.

How this study might affect research, practice or policy

These results provide novel insight into the prominence of the contralateral cerebellum in the recovery after hemispherotomy and highlight the clinical role of presurgery GMV in the prediction of postsurgery behavior.
Corticostriatal Beta Power Changes Associated with Cognitive Function in Parkinson’s Disease
Authors: Paulo DL , Qian H , Subramanian D , Johnson GW , Hett K , Kao C , Roy N , Dhima K , Claassen DO , Bick SK
Published: July 2022

Cognitive impairment (CI) is the most frequent nonmotor symptom in Parkinson’s Disease (PD) and is associated with deficits in executive functions such as working memory. Previous studies have demonstrated that caudate beta power is involved in learning and working memory. Decreased dopamine in motor cortico-striato-thalamo-cortical (CSTC) circuits results in increased beta power and PD motor symptoms. Analogous changes in cognitive CSTC circuits, including the caudate and dorsolateral prefrontal cortex (DLPFC), may contribute to PD CI. The objective of our study is to evaluate whether beta power changes in caudate and DLPFC contribute to cognitive impairment in PD patients. To investigate this, we used local field potential (LFP) recordings during deep brain stimulation surgery in 15 PD patients. LFP signals from DLPFC and caudate were performed at rest and during a verbal working memory task. We examined beta power changes during the working memory task and relationship of beta power to pre-operative neuropsychological testing results. Beta power decreased in both DLPFC and caudate during encoding of correct trials, whereas beta power increased in DLPFC and caudate during feedback for correct responses. Subjects with cognitive impairment showed smaller decreases in caudate and DLPFC beta power during encoding, greater increases in beta power during feedback, and lower average resting-state beta power. Additionally, reduced caudate beta power during encoding correlated with better memory scores on pre-operative neuropsychological testing, while greater DLPFC beta power during feedback correlated with worse scores in the attention domain. Our findings suggest that similar to the relationship between beta power in motor CSTC circuits and PD motor symptoms, beta power changes in parallel cognitive CSTC circuits may be correlated with cognitive symptoms in PD patients.
The age of reason: Functional brain network development during childhood
Authors: Tooley Ursula A. , Park Anne T. , Leonard Julia A. , Boroshok Austin L. , McDermott Cassidy L. , Tisdall M. Dylan , Bassett Dani S. , Mackey Allyson P.
Published: July 2022

Human childhood is characterized by dramatic changes in the mind and brain. However, little is known about the large-scale intrinsic cortical network changes that occur during childhood due to methodological challenges in scanning young children. Here, we overcome this barrier by using sophisticated acquisition and analysis tools to investigate functional network development in children between the ages of 4 and 10 years (n = 92). At multiple spatial scales, age is positively associated with brain network segregation. At the system level, age was associated with segregation of systems involved in attention from those involved in abstract cognition, and with integration among attentional and perceptual systems. Associations between age and functional connectivity are most pronounced in visual and medial prefrontal cortex, the two ends of a gradient from perceptual, externally oriented cortex to abstract, internally oriented cortex. These findings suggest that both ends of the sensory-association gradient may develop early, in contrast to the classical theories that cortical maturation proceeds from back to front, with sensory areas developing first and association areas developing last. More mature patterns of brain network architecture, controlling for age, were associated with better visuospatial reasoning abilities. Our results suggest that as cortical architecture becomes more specialized, children become more able to reason about the world and their place in it.

Significance

Anthropologists have called the transition from early to middle childhood the “age of reason”, when children across cultures become more independent. We employ cutting-edge neuroimaging acquisition and analysis approaches to investigate associations between age and functional brain architecture in childhood. Age was positively associated with segregation between cortical systems that process the external world, and those that process abstract phenomena like the past, future, and minds of others. Surprisingly, we observed pronounced development at both ends of the sensory-association gradient, challenging the theory that sensory areas develop first and association areas develop last. Our results open new directions for research into how brains reorganize to support rapid gains in cognitive and socioemotional skills as children reach the age of reason.
Variability in cognitive task performance in early adolescence is associated with stronger between-network anticorrelation and future attention problems
Authors: Chang Sarah E. , Lenartowicz Agatha , Hellemann Gerhard S. , Uddin Lucina Q. , Bearden Carrie E.
Published: July 2022

Background

Intra-individual variability (IIV) during cognitive task performance is a key behavioral index of attention and consistent marker of ADHD. In adults, lower IIV has been associated with anticorrelation between the default mode network (DMN) and dorsal attention network (DAN) - thought to underlie effective allocation of attention. However, whether these behavioral and neural markers of attention are (i) associated with each other and (ii) can predict future attention-related deficits has not been examined in a developmental, population-based cohort.

Methods

We examined relationships at the baseline visit between IIV on three cognitive tasks, DMN-DAN anticorrelation, and parent-reported attention problems using the Adolescent Brain and Cognitive Development Study (n=11,878 participants, aged 9-10, female=47.8%). We also investigated whether behavioral and neural markers of attention at baseline predicted attention problems, 1, 2, and 3 years later.

Results

At baseline, greater DMN-DAN anticorrelation was associated with lower IIV across all three cognitive tasks (unstandardized β: 0.22-0.25). Older age at baseline was associated with stronger DMN-DAN anticorrelation and lower IIV (β: -0.005--0.0004). Weaker DMN-DAN anticorrelation and IIV were cross-sectionally associated with attention problems (β: 1.41-7.63). Longitudinally, lower IIV at baseline was associated with less severe attention problems, 1-3 years later, after accounting for baseline attention problems (β: 0.288-0.77).

Conclusions

The results suggest that IIV in early adolescence is associated with worsening attention problems in a representative cohort of US youth. Attention deficits in early adolescence may be important for understanding and predicting future cognitive and clinical outcomes.
A neural substrate of sex-dependent modulation of motivation by value
Authors: Cox Julia , Minerva Adelaide R. , Fleming Weston T. , Zimmerman Christopher A. , Hayes Cameron , Zorowitz Samuel , Bandi Akhil , Ornelas Sharon , McMannon Brenna , Parker Nathan F. , Witten Ilana B.
Published: July 2022

While there is emerging evidence of sex differences in decision-making behavior, the neural substrates that underlie such differences remain largely unknown. Here, we demonstrate that in mice performing a value-based decision-making task, while choices are similar between the sexes, motivation to engage in the task is modulated by action value in females more strongly than in males. Inhibition of activity in anterior cingulate cortex (ACC) neurons that project to the dorsomedial striatum (DMS) disrupts this relationship between value and motivation preferentially in females, without affecting choice in either sex. In line with these effects, in females compared to males, ACC-DMS neurons have stronger representations of negative outcomes, and more neurons are active when the value of the chosen option is low. In contrast, the representation of each choice is similar between the sexes. Thus, we identify a neural substrate that contributes to sex-specific modulation of motivation by value.
Large-scale capture of hidden fluorescent labels for training generalizable markerless motion capture models
Authors: Butler Daniel J. , Keim Alexander P. , Ray Shantanu , Azim Eiman
Published: July 2022

Recent advances in deep learning-based markerless pose estimation have dramatically improved the scale and ease with which body landmarks can be tracked in studies of animal behavior. However, pose estimation for animals in a laboratory setting still faces some specific challenges. Researchers typically need to manually generate new training data for each experimental setup and visual environment, limiting the generalizability of this approach. With each network being trained from scratch, different investigators track distinct anatomical landmarks and analyze the resulting kinematic data in idiosyncratic ways. Moreover, much of the movement data is discarded: only a few sparse landmarks are typically labeled, due to the inherent scale and accuracy limits of manual annotation. To address these issues, we developed an approach, which we term GlowTrack, for generating large training datasets that overcome the relatively modest limits of manual labeling, enabling deep learning models that generalize across experimental contexts. The key innovations are: a) an automated, high-throughput approach for generating hidden labels free of human error using fluorescent markers; b) a multi-camera, multi-light setup for generating large amounts of training data under diverse visual conditions; and c) a technique for massively parallel tracking of hundreds of landmarks simultaneously using computer vision feature matching algorithms, providing dense coverage for kinematic analysis at a resolution not currently available. These advances yield versatile deep learning models that are trained at scale, laying the foundation for standardized behavioral pipelines and more complete scrutiny of animal movements.