bluuebunny/crossref_metadata_2025 huggingface dataset:
Influence of sex hormone use on sleep architecture in a transgender cohort: findings from the prospective RESTED study
Authors: Morssinkhof Margot W. L. , van der Werf Ysbrand D. , van den Heuvel Odile A. , van den Ende Daan A. , van der Tuuk Karin , den Heijer Martin , Broekman Birit F. P.
Published: June 2023

Sex differences in sleep architecture are well-documented, with females experiencing longer total sleep time (TST), more slow wave sleep (SWS) and shorter Rapid Eye Movement (REM) sleep duration than males. Although studies imply that sex hormones could affect sleep, effects of exogenous sex hormones on sleep architecture remain unclear. This study examined sleep architecture changes in transgender individuals after 3 months of gender-affirming hormone therapy (GAHT).

We assessed sleep architecture in 73 transgender individuals: 38 transmasculine participants who started using testosterone and 35 transfeminine participants who started using estrogens and anti-androgens. Sleep architecture was measured before GAHT and after 3 months of GAHT for 7 nights using an ambulatory single-electrode sleep EEG device. Changes in sleep architecture were analyzed using linear mixed models, and non-normally distributed outcomes were log-transformed and reported as percentages.

In transmasculine participants, SWS decreased by 7 minutes (95% CI: −12; −3) and 1.7% (95% CI: −3%; - 0.5%), REM sleep latency decreased by 39% (95% CI: −52%; −22%) and REM sleep duration increased by 17 minutes (95% CI: 7; 26) after 3 months of GAHT. In transfeminine participants, sleep architecture showed no significant changes after 3 months of GAHT.

Sleep architecture changes after three months of masculinizing GAHT in line with sleep in cisgender males, while it shows no changes after feminizing GAHT. The sex-specific nature of these changes raises new questions on sex hormones and sleep. Future research should focus on studying possible underlying neural mechanisms and clinical consequences of these changes.

Statement of significance

Sleep architecture shows differences between men and women, with women showing longer sleep, longer slow wave sleep and shorter REM sleep than men. Rodent research indicates that sex hormones can alter sleep architecture, but research on sex hormones and sleep architecture in humans is still lacking. This study examined effects of three months of gender-affirming hormone use in transgender individuals. Results show that testosterone use in persons assigned female at birth resulted in sleep architecture changes similar to cisgender males, whereas estradiol- and anti-androgen use by persons assigned male at birth did not change sleep architecture. These novel findings indicate that sex hormones could change sleep architecture in a sex-specific manner, warranting further studies into causal mechanisms underlying these changes.
Motoric Cognitive Risk syndrome trajectories and incident dementia over 10 years
Authors: Mullin Donncha S. , Gadd Danni , Russ Tom C. , Luciano Michelle , Muniz-Terrera Graciela
Published: June 2023

Background

Motoric Cognitive Risk (MCR) syndrome is a high-risk state for adverse health outcomes in older adults characterised by measured slow gait speed and self-reported cognitive complaints. The recent addition to the Lothian Birth Cohort 1936 of robust dementia outcomes enabled us to assess the prognostic value of MCR for dementia and explore the various trajectories of participants diagnosed with MCR.

Methods

We classified 680 community-dwelling participants free from dementia into non-MCR or MCR groups at mean [SD] age 76.3 [0.8] years. We used Cox and competing risk regression methods, adjusted for potential confounders, to evaluate the risk of developing all-cause incident dementia over 10 years of follow-up. Secondarily, we followed the trajectories for individuals with and without MCR at baseline and categorised them into subgroups based on whether MCR was still present at the next research wave, three years later.

Results

The presence of MCR increased the risk of incident dementia (adjusted HR 2.34, 95%CI 1.14-4.78, p=0.020), as did fewer years of education and higher depression symptoms. However, MCR has a heterogenous progression trajectory. The MCR progression subgroups each have different prognostic values for incident dementia.

Conclusion

MCR showed similar prognostic ability for dementia in a Scottish cohort as for other populations. MCR could identify a target group for early interventions of modifiable risk factors to prevent incident dementia. This study illustrates the heterogeneous nature of MCR progression. Exploring the underlying reasons will be important work in future work.
Interpretational fallacies in sibling comparison designs with social exposures: A case study of childhood income and mental disorders
Authors: Ejlskov Linda , Esen Buket Öztürk , Hakulinen Christian , Weye Nanna , Formanek Tomas , McGrath John J. , Pedersen Carsten Bøcker , Plana-Ripoll Oleguer
Published: June 2023

Sibling comparison designs are increasingly used to address unmeasured familial confounding in observational studies. We propose that three key interpretational fallacies – sibling characteristics, exposure correlation and non-shared confounding, and unmet life course model assumptions – can mislead causal conclusions. We demonstrate these fallacies by investigating childhood family income and mental health.

A nationwide Danish cohort of individuals born between 1986 and 1996 (n = 643,814; 404,179 siblings) was followed-up from age 15 until onset of severe mental disorders. Population-wide and within-sibling adjusted hazard ratios (aHR) between childhood family income and offspring mental disorders were estimated, supplemented by descriptive statistics and pseudo-sibling analyses.

A $15,000 increase in family income at age 14 was associated with a reduced rate of severe mental disorders (aHR = 0.78; 95% CI: 0.76-0.81), with comparable estimates across measurement ages 1-14 (range: 0.67-0.82). Null results were observed in both a pseudo-sibling cohort of unrelated individuals with the same income differences as the true sibling cohort (aHR = 0.93; 95% CI: 0.85-1.01) and the true sibling cohort (aHR = 1.02; 95% CI: 0.94-1.11). Siblings were typically born three years apart, with an average monthly income difference of $496 at age 14 (IQR;$150-$641).

This study advocates for cautious causal interpretation of null results in sibling comparison studies because (1) it may not capture meaningful differences in family income across siblings due to minor income fluctuations; (2) the pseudo-sibling cohort showed evidence of unmeasured non-shared confounding; (3) sibling comparison designs test a critical periods life course model, but the results favour an accumulating/vulnerable model. We present guidelines and R syntax to assess these interpretational fallacies.
Single nuclei transcriptomics reveal the differentiation trajectories of periosteal skeletal/stem progenitor cells in bone regeneration
Authors: Perrin Simon , Ethel Maria , Bretegnier Vincent , Goachet Cassandre , Wotawa Cécile-Aurore , Luka Marine , Coulpier Fanny , Masson Cécile , Ménager Mickael , Colnot Céline
Published: June 2023

Bone regeneration is mediated by skeletal stem/progenitor cells (SSPCs) that are mainly recruited from the periosteum after bone injury. The composition of the periosteum and the steps of SSPC activation and differentiation remain poorly understood. Here, we generated a single-nuclei atlas of the periosteum at steady-state and of the fracture site during early stages of bone repair (https://fracture-repair-atlas.cells.ucsc.edu). We identified periosteal SSPCs expressing stemness markers (Pi16andLy6a/SCA1) and responding to fracture by adopting an injury-induced fibrogenic cell (IIFC) fate, prior to undergoing osteogenesis or chondrogenesis. We identified distinct gene cores associated with IIFCs and their engagement into osteogenesis and chondrogenesis involving Notch, Wnt and the circadian clock signaling respectively. Finally, we show that IIFCs are the main source of paracrine signals in the fracture environment, suggesting a crucial paracrine role of this transient IIFC population during fracture healing. Overall, our study provides a complete temporal topography of the early stages of fracture healing and the dynamic response of periosteal SSPCs to injury, redefining our knowledge of bone regeneration.

Graphical Abstract
Is HDL-c plasma concentration a possible marker of HIV replication? A cross-sectional analysis in untreated HIV-infected individuals accessing HIV care in Italy
Authors: Piconi Stefania , Bottanelli Martina , Marchetti Giulia , Gori Andrea , Castagna Antonella , Squillce Nicola , Cicalini Stefania , Orofino Giancarlo , Ceccherini-Silverstein Francesca , Di Biagio Antonio , d’Arminio Monforte Antonella , Cozzi-Lepri Alessandro ,   Icona Foundation Study Cohort
Published: June 2023

Aims

HIV infection is associated with dyslipidemia and an increased risk for cardiovascular diseases. HIV Nef protein downregulates the generation of nascent HDL. The interplay between HIV-RNA, HDL-c level and CD4/CD8 ratio in naïve HIV patients remains to be elucidated.

Methods

We included untreated persons living with HIV (PLWH) of the ICONA Foundation Study cohort if they also had ≥2 viral load (VL) measurements prior to ART initiation. We performed unadjusted correlation and linear regression analyses evaluating the effect of VLset on HDL-C. Vlset and CD4/CD8 ratio were fit in the log10scale, while HDL-c, was fitted in the untransformed raw scale.

Results

We included 3,980 untreated PLWH. Fifty-eighty (1.5%) were aviremic. We observed a negative correlation between HDL-c and VLset (Pearson R2=0.03), from fitting an unadjusted linear regression model -8.5 mg/dl (95% CI: -15,9 --0,84 p<0.03). There was a dose-response relationship between HDL-c levels and VLset, however, this association was somewhat attenuated after further controlling for gender. Despite a positive correlation between HDL-c and CD4/CD8 ratio, the HDL-c plasma concentration does not satisfy the criteria for a strong surrogate marker.

Conclusions

Our data show that HDL-c plasma concentration is significantly lower per higher level of VLSet although this was in part explained by gender. Further analyses should be promoted to better understand the molecular mechanisms that underline the relationship between HIV replication, HDL-c formation, and diseases progression.
Preparedness in practice: An outbreak science approach to studying public health emergency response
Authors: Moore Mackenzie , Robertson Hailey , Rosado David , Graeden Ellie , Carlson Colin J. , Katz Rebecca
Published: June 2023

Outbreak response, as a technical and specialized field of practice, is struggling to keep pace with the evolving dynamics of modern public health emergencies. Extensive scholarship across disciplines and epidemics has highlighted the importance of early action, the costs associated with delayed mobilization, the necessity of effective preparedness plans for complex crises, and the growing need for response to operate in spite of both uncertain information and social disruptions. Here, we present and analyze a new dataset of 235 different multisectoral activities that comprise outbreak preparedness and response. We explore the conditions under which these activities are applicable, including different phases of response, different operating circumstances, and different disease etiologies, and find that the core activities required for outbreak response largely apply across etiology and scale, but are more substantial during the early phases of response. To validate this framework with real-world examples, we then examine 279 reports from the WHO Disease Outbreak News (DON), a narrative record of outbreak history through time, and examine which of our activities are reported or implied in these narratives. We find that the core components of response are applicable across the vast majority of biological events, especially as they relate to basic epidemiology, infection prevention, and governance, and that many different kinds of real-world outbreaks require the same core set of responses. These findings point to a nearly-universal set of outbreak response activities that could be directly incorporated into national and international response plans, significantly reducing the risk and impact of infectious disease outbreaks.
Admission and discharge profiles of people with MS accessing in-patient rehabilitation in Canada
Authors: Mate Kedar K. V. , Ow Nikki , Hum Stanley , Mayo Nancy
Published: June 2023

Background

Rehabilitation is the mainstay of management for people with disabilities of neurological origin to maximize function and reduce disability. Access to in-patient rehabilitation is usually reserved for people after crises or those who are discharged from acute care such as in stroke or trauma. Access to people with Multiple Sclerosis (MS) differs across countries and unknown for Canada. With the progression of MS, quality of life (QOL) becomes more closely coupled with independence and hence timely access to rehabilitation is important. The objectives of this paper are (i) to characterize the disability profiles of people with MS admitted to in-patient rehabilitation in Canada; and (ii) to estimate the extent to which disability profiles differ from admission to discharge.

Methods

A longitudinal study of a rehabilitation admission-to-discharge cohort of 3500 people with MS was conducting using latent class analysis on the five Functional Independence Measure (FIM) subscales for Self-care, Transfers, Locomotion, Bladder/Bowel, and Cognition. The extent to which age, sex, and calendar time was associated with latent class membership, at both admission and discharge, was estimated using ordinal logistic regression, and proportional odds model was calculated for each age and sex.

Results

A five-class model fit the data at admission and a four-class model fit the data at discharge determined using likelihood ratio G2, Akaike’s Information Criterion, and Bayesian Information Criterion.

Conclusion

At admission, the disability profiles showed a hierarchical progression across the FIM subscales. The least disabled profile was characterized by locomotion dependency only; the most disabled profile was characterized by dependencies in all subscales except cognition. At discharge, the least disabled class, representing 28% of discharges, was characterized by no dependencies; the most disabled class remained with dependencies (23%) in all areas. The study highlights the importance of reserving scarce rehabilitation services to those with more disability.
Machine Learning Interpretability Methods to Characterize Brain Network Dynamics in Epilepsy
Authors: Upadhyaya Dipak P. , Prantzalos Katrina , Thyagaraj Suraj , Shafiabadi Nassim , Fernandez-BacaVaca Guadalupe , Sivagnanam Subhashini , Majumdar Amitava , Sahoo Satya S.
Published: June 2023

The rapid adoption of machine learning (ML) algorithms in a wide range of biomedical applications has highlighted issues of trust and the lack of understanding regarding the results generated by ML algorithms. Recent studies have focused on developing interpretable ML models and establish guidelines for transparency and ethical use, ensuring the responsible integration of machine learning in healthcare. In this study, we demonstrate the effectiveness of ML interpretability methods to provide important insights into the dynamics of brain network interactions in epilepsy, a serious neurological disorder affecting more than 60 million persons worldwide. Using high-resolution intracranial electroencephalogram (EEG) recordings from a cohort of 16 patients, we developed high accuracy ML models to categorize these brain activity recordings into either seizure or non-seizure classes followed by a more complex task of delineating the different stages of seizure progression to different parts of the brain as a multi-class classification task. We applied three distinct types of interpretability methods to the high-accuracy ML models to gain an understanding of the relative contributions of different categories of brain interaction patterns, including multi-focii interactions, which play an important role in distinguishing between different states of the brain. The results of this study demonstrate for the first time that post-hoc interpretability methods enable us to understand why ML algorithms generate a given set of results and how variations in value of input values affect the accuracy of the ML algorithms. In particular, we show in this study that interpretability methods can be used to identify brain regions and interaction patterns that have a significant impact on seizure events. The results of this study highlight the importance of the integrated implementation of ML algorithms together with interpretability methods in aberrant brain network studies and the wider domain of biomedical research.
FM3VCF: A Software Library for Accelerating the Loading of Large VCF Files in Genotype Data Analyses
Authors: Zuo Zhen , Li Qi , Li Zhuo , Tang You , Huang Meng
Published: June 2023

Background

The increasing size of genotype data has led to the loading of VCF files becoming a computational bottleneck in various analyses, including imputation and genome-wide association studies (GWAS). To address this issue, we developed a software library, FM3VCF (fast M3VCF), that utilizes multiple CPU threads to accelerate this process.

Findings

FM3VCF can convert VCF files into the exclusive data format of MINIMAC4[1], M3VCF[1], and efficiently read and parse data from VCF files. In comparison to m3vcftools[1], FM3VCF is approximately 20 times faster for compressing VCF files to M3VCF format. Furthermore, FM3VCF is approximately 3 times faster than HTSlib[2], including decompressing and parsing, for reading compressed VCF files. FM3VCF is written in C and is open-source, available for download fromhttps://github.com/Oliver-111/m3vcfunder the MIT/BSD license.

Conclusion

FM3VCF is a powerful tool for accelerating the loading of large VCF files in genotype data analyses. By fully utilizing multiple CPU threads, FM3VCF can significantly reduce the computational burden in various genomic analyses.
The role of binocular disparity and attention in the neural representation of multiple moving stimuli in the visual cortex
Authors: Chakrala Anjani Sreeprada , Xiao Jianbo , Huang Xin
Published: June 2023

Segmenting visual scenes into distinct objects and surfaces is a fundamental visual process, with stereoscopic depth and motion serving as crucial cues. However, how the visual system uses these cues to segment multiple objects is not fully understood. We investigated how neurons in the middle-temporal (MT) cortex of macaque monkeys represent overlapping surfaces at different depths, moving in different directions. Neuronal activity was recorded from three male monkeys during discrimination tasks under varying attention conditions. We found that neuronal responses to overlapping surfaces showed a robust bias toward the binocular disparity of one surface over the other. The disparity bias of a neuron was positively correlated with the neuron’s disparity preference for a single surface. In two animals, neurons preferring near disparities of single surfaces (near neurons) showed a near bias for overlapping stimuli, while neurons preferring far disparities (far neurons) showed a far bias. In the third animal, both near and far neurons displayed a near bias, though the near neurons showed a stronger near bias. All three animals exhibited an initial near bias across neurons relative to the average of the responses to the individual surfaces. Although attention modulated neuronal responses, the disparity bias was not caused by attention. We also found that the effect of attention was consistent with object-based, rather than feature-based attention. We proposed a model in which the pool size of the neuron population that weighs the responses to individual stimulus components can be variable. This model is a novel extension of the standard normalization model and provides a unified explanation for the disparity bias across animals. Our results reveal how MT neurons encode multiple stimuli moving at different depths and present new evidence of response modulation by object-based attention. The disparity bias allows subgroups of neurons to preferentially represent individual surfaces of multiple stimuli at different depths, thereby facilitating segmentation.
What works and for whom in treating depression in older adults in deprived communities in Brazil: Findings from a causal mediation analyses of the PROACTIVE trial that overlapped with the COVID-19 pandemic
Authors: Seward Nadine , Nakamura Carina Akemi , Peters Tim J , Loh Wen Wei , McMillan Dean , Gilbody Simon , Scazufca Marcia , Araya Ricardo
Published: June 2023

Background

The PROACTIVE trial was a task-shared, collaborative care, psychosocial intervention that was highly effective at improving recovery from depression in older adults in Brazil that overlapped with the COVID-19 pandemic. Here we investigate mediators of the intervention’s effectiveness.

Methods

Causal mediation analysis using interventional indirect effects, decomposed the total effect of PROACTIVE on recovery from depression (PHQ-9<10), into multiple indirect effects including: dose of intervention (number of sessions and number of activities completed); social support measured through Luben Social Network Scale; perceived loneliness through the three-item UCLA questionnaire; conditions associated with frailty; and extra sessions offered to participants who did not respond to the intervention.

Findings

Of the intervention’s total effect (difference in probability of recovery from depression between the intervention and control arms 0·211 [bias-corrected 95% CI: 0·139, 0·274]): 14% was mediated through improved conditions associated with frailty 0·030 [0·003, 0·065]); 6% through reduced loneliness (0·013 [0·001, 0·028]); and 20% through attending extra sessions for participants who did not respond to the intervention (0·042 [0·007, 0·105]).

Interpretation

Our findings emphasise the importance of a home-based intervention to improve depression outcomes where participants are encouraged to self-select activities to mitigate against loneliness and are referred to primary care to manage health issues relating to frailty. Importantly, our findings suggest that offering extra sessions to participants who did not respond to the intervention shows promise in ensuring a sustained recovery from depression.

Funding

São Paulo Research Foundation and Joint Global Health Trials UK.
Meta-analysis of CYP2C19 and CYP2D6 metabolic activity on antidepressant response from 13 clinical studies using genotype imputation
Authors: Li Danyang , Pain Oliver , Fabbri Chiara , Wong Win Lee Edwin , Lo Chris Wai Hang , Ripke Stephan , Cattaneo Annamaria , Souery Daniel , Dernovsek Mojca Z. , Henigsberg Neven , Hauser Joanna , Lewis Glyn , Mors Ole , Perroud Nader , Rietschel Marcella , Uher Rudolf , Maier Wolfgang , Baune Bernhard T. , Biernacka Joanna M. , Bondolfi Guido , Domschke Katharina , Kato Masaki , Liu Yu-Li , Serretti Alessandro , Tsai Shih-Jen , Weinshilboum Richard ,   the GSRD Consortium,   the Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, McIntosh Andrew M. , Lewis Cathryn M.
Published: June 2023

Cytochrome P450 enzymes including CYP2C19 and CYP2D6 are important for antidepressant metabolism and polymorphisms of these genes have been determined to predict metabolite levels. Nonetheless, more evidence is needed to understand the impact of genetic variations on antidepressant response. In this study, individual clinical and genetic data from 13 studies of European and East Asian ancestry populations were collected. The antidepressant response was clinically assessed as remission and percentage improvement. Imputed genotype was used to translate genetic polymorphisms to metabolic phenotypes (poor, intermediate, normal, and rapid+ultrarapid) of CYP2C19 and CYP2D6. The association of CYP2C19 and CYP2D6 metabolic phenotypes with treatment response was examined using normal metabolizers as the reference. Among 5843 depression patients, a higher remission rate was found in CYP2C19 poor metabolizers compared to normal metabolizers at nominal significance but did not survive after multiple testing correction (OR=1.46, 95% CI [1.03, 2.06], p=0.033, heterogeneity I2=0%, subgroup difference p=0.72). No metabolic phenotype was associated with percentage improvement from baseline. After stratifying by antidepressants primarily metabolized by CYP2C19 and CYP2D6, no association was found between metabolic phenotypes and antidepressant response. Metabolic phenotypes showed differences in frequency, but not effect, between European- and East Asian-ancestry studies. In conclusion, metabolic phenotypes imputed from genetic variants using genotype were not associated with antidepressant response. CYP2C19 poor metabolizers could potentially contribute to antidepressant efficacy with more evidence needed. CYP2D6 structural variants cannot be imputed from genotype data, limiting inference of pharmacogenetic effects. Sequencing and targeted pharmacogenetic testing, alongside information on side effects, antidepressant dosage, depression measures, and diverse ancestry studies, would more fully capture the influence of metabolic phenotypes.
Early life seizures and epileptic spasms inSTXBP1-related disorders
Authors: Thalwitzer Kim M , Xian Julie , deCampo Danielle , Parthasarathy Shridhar , Magielski Jan , Sullivan Katie Rose , Goss James , Rigby Charlene Son , Boland Michael , Prosser Ben , Ruggiero Sarah M , Syrbe Steffen , Helbig Ingo
Published: June 2023

Background and Objectives

Individuals with disease-causing variants inSTXBP1frequently have epilepsy onset in the first year of life with a variety of seizure types, including epileptic spasms. However, the impact of early-onset seizures and anti-seizure medication (ASM) on the risk of developing epileptic spasms and impact on their trajectory is poorly understood, limiting informed and anticipatory treatment, as well as trial design.

Methods

We retrospectively reconstructed seizure and medication histories in weekly intervals for individuals withSTXBP1-related disorders with epilepsy onset in the first year of life and quantitatively analyzed longitudinal seizure histories and medication response.

Results

We included 61 individuals with early onset seizures, 29 of whom had epileptic spasms. Individuals with neonatal seizures were likely to have continued seizures after the neonatal period (25/26). The risk of developing epileptic spasms was not increased in individuals with neonatal seizures or early infantile seizures (21/41 vs. 8/16; OR 1, 95% CI 0.3-3.9,p= 1). We did not find any ASM associated with the development of epileptic spasms following prior seizures. Individuals with prior seizures (n = 16/21, 76%) had a higher risk to develop refractory epileptic spasms (n = 5/8, 63%, OR =1.9, 95% CI 0.2-14.6,p= 0.6). Individuals with refractory epileptic spasms had a later onset of epileptic spasms (n = 20, median 20 weeks) compared to individuals with non-refractory epileptic spasms (n = 8, median 13 weeks;p= 0.08). When assessing treatment response, we found that clonazepam (n = 3, OR 12.6, 95% CI 2.2-509.4;p< 0.01), clobazam (n=7, OR 3, 95% CI 1.6-6.2;p< 0.01), topiramate (n=9, OR 2.3, 95% CI 1.4-3.9;p< 0.01), and levetiracetam (n=16, OR 1.7, 95% CI 1.2-2.4;p< 0.01) were more likely to reduce seizure frequency and/or to maintain seizure freedom with regards to epileptic spasms than other medications.

Discussion

We provide a comprehensive assessment of early-onset seizures inSTXBP1-related disorders and show that the risk of epileptic spasms is not increased following a prior history of early-life seizures, nor by certain ASM. Our study provides baseline information for targeted treatment and prognostication in early-life seizures inSTXBP1-related disorders.
The effect of residential aged care facility COVID-19 lockdowns on resident mortality
Authors: Uribe Gabriela , Fotheringham Penelope , Moore Corey
Published: June 2023

Aims

This perspective is exploring the effect of residential aged care facility COVID-19 lockdowns on resident mortality.

Relevance

People living in residential aged care facilities (RACFs) are at increased risk of COVID-19 infection and death.

In Australia, COVID-19 infections in RACF residents represented seven percent of recorded infections and the case fatality rate (CFR) was 33%. RACFs were categorised as high-risk settings for COVID-19 and a number of measures to reduce the risk of acquiring COVID-19 were implemented at the National and State and Territory levels, such as strict infection control, monitoring, testing, vaccination and increased clinical capacity

Methods

All COVID-19 infections and deaths in the 12-months from 15 October 2021 to 14 October 2022 for the cohort of residents living in an Australian RACF (except Western Australia) at the beginning of this period were analysed.

Key points

Lockdowns of RACFs were successful in substantially reducing the number of COVID-19 infections and deaths in RACF residents. This was largely because the infection and mortality rates of COVID-19 were high in 2020 and 2021.

The findings of this study could be used to evaluate and inform national and local states and territories’ guidelines on the management of COVID-19 in RACFs.
Harmonizing Healthy Cohorts to Support Multicenter Studies on Migraine Classification using Brain MRI Data
Authors: Yoon Hyunsoo , Schwedt Todd J. , Chong Catherine D. , Olatunde Oyekanmi , Wu Teresa
Published: June 2023

Multicenter and multi-scanner imaging studies might be needed to provide sample sizes large enough for developing accurate predictive models. However, multicenter studies, which likely include confounding factors due to subtle differences in research participant characteristics, MRI scanners, and imaging acquisition protocols, might not yield generalizable machine learning models, that is, models developed using one dataset may not be applicable to a different dataset. The generalizability of classification models is key for multi-scanner and multicenter studies, and for providing reproducible results. This study developed a data harmonization strategy to identify healthy controls with similar (homogenous) characteristics from multicenter studies to validate the generalization of machine-learning techniques for classifying individual migraine patients and healthy controls using brain MRI data. The Maximum Mean Discrepancy (MMD) was used to compare the two datasets represented in Geodesic Flow Kernel (GFK) space, capturing the data variabilities for identifying a “healthy core”. A set of homogeneous healthy controls can assist in overcoming some of the unwanted heterogeneity and allow for the development of classification models that have high accuracy when applied to new datasets. Extensive experimental results show the utilization of a healthy core. One dataset consists of 120 individuals (66 with migraine and 54 healthy controls) and another dataset consists of 76 (34 with migraine and 42 healthy controls) individuals. A homogeneous dataset derived from a cohort of healthy controls improves the performance of classification models by about 25% accuracy improvements for both episodic and chronic migraineurs.

Highlights

The harmonization method was established by Healthy Core Construction.

The inclusion of a healthy core addresses intrinsic heterogeneity that exists within a healthy control cohort and in multicenter studies.

The utilization of a healthy core can increase the accuracy and generalizability of brain imaging-based classification models.

The proposed harmonization method offers flexible utilities for multicenter studies.
Prognostic impact of atrial cardiomyopathy: Long-term follow-up of patients with and without low-voltage areas following atrial fibrillation ablation
Authors: Masuda Masaharu , Matsuda Yasuhiro , Uematsu Hiroyuki , Sugino Ayako , Ooka Hirotaka , Kudo Satoshi , Fujii Subaru , Asai Mitsutoshi , Okamoto Shin , Ishihara Takayuki , Nanto Kiyonori , Tsujimura Takuya , Hata Yosuke , Higashino Naoko , Nakao Sho , Mano Toshiaki
Published: June 2023

Background

Atrial cardiomyopathy is known as an underlying pathophysiological factor in the majority of AF patients. Left atrial low-voltage areas (LVAs) are reported to coincide with fibrosis, and to likely represent atrial cardiomyopathy. This study aimed to delineate differences in the long-term prognosis of patients stratified by the size of LVAs.

Methods

This observational study included 1,488 consecutive patients undergoing initial ablation for AF. LVAs were defined as regions with a bipolar peak-to-peak voltage of < 0.50 mV. The total study population was divided into 3 groups stratified by LVA size: patients with no LVAs (n=1136), those with small (< 20 cm2, n=250) LVAs, and those with extensive (≥ 20 cm2, n=102) LVAs. Composite endpoints of death, heart failure, and stroke were followed for up to 5 years.

Results

Composite endpoints developed in 105 (7.1%) of 1488 patients, and AF recurrence occurred in 410 (27.6%). Composite endpoints developed more frequently in the order of patients with extensive LVAs (19.1%), small LVAs (10.8%), and no LVAs (5.1%; p for trend<0.0001). Multivariable analysis revealed that LVA presence was independently associated with higher incidence of composite endpoints, irrespective of AF recurrence (modified hazard ratio=1.73, 95% confidence interval=1.13-2.64, p=0.011)

Conclusions

LVA presence and its extent were both associated with poor long-term composite endpoints of death, heart failure, and stroke, irrespective of AF recurrence or other confounders. Underlying atrial cardiomyopathy appears to define a poor prognosis after AF ablation.

Clinical perspective

What is Known

Patients with left atrial low-voltage area has high incidence of atrial fibrillation recurrence after ablation

What the study adds

Presence of low-voltage areas was associated with poor prognosis including death, heart failure hospitalization, and stroke.

Graphic abstract
Focusing antibody responses to the fusion peptide in rhesus macaques
Authors: Cottrell Christopher A. , Pratap Payal P. , Cirelli Kimberly M. , Carnathan Diane G. , Enemuo Chiamaka A , Antanasijevic Aleksandar , Ozorowski Gabriel , Sewall Leigh M. , Gao Hongmei , Greene Kelli M. , Allen Joel D. , Ngo Julia T. , Choe Yury , Nogal Bartek , Silva Murillo , Bhiman Jinal , Pauthner Matthias , Irvine Darrell J. , Montefiori David , Crispin Max , Burton Dennis R. , Silvestri Guido , Crotty Shane , Ward Andrew B.
Published: June 2023

Immunodominance of antibodies targeting non-neutralizing epitopes and the high level of somatic hypermutation within germinal centers (GCs) required for most HIV broadly neutralizing antibodies (bnAbs) are major impediments to the development of an effective HIV vaccine. Rational protein vaccine design and non-conventional immunization strategies are potential avenues to overcome these hurdles. Here, we report using implantable osmotic pumps to continuously deliver a series of epitope-targeted immunogens to rhesus macaques over the course of six months to elicit immune responses against the conserved fusion peptide. Antibody specificities and GC responses were tracked longitudinally using electron microscopy polyclonal epitope mapping (EMPEM) and lymph node fine-needle aspirates, respectively. Application of cryoEMPEM delineated key residues for on-target and off-target responses that can drive the next round of structure-based vaccine design.
Uncovering Ghost Introgression Through Genomic Analysis of a Distinct East Asian Hickory Species
Authors: Zhang Wei-Ping , Ding Ya-Mei , Cao Yu , Li Pan , Yang Yang , Pang Xiao-Xu , Bai Wei-Ning , Zhang Da-Yong
Published: June 2023

Although the possibility of introgression from ghost lineages (all unsampled extant and extinct taxa) is now widely recognized, detecting and characterizing ghost introgression remains a challenge. Here, we propose a combined use of the popularD-statistic method, which tests for the presence of introgression, and the full-likelihood method BPP, which determines which of the possible gene-flow scenarios, including ghost introgression, is truly responsible. We illustrate the utility of this approach by investigating the reticulation and bifurcation history of the genusCarya(Juglandaceae), including the beaked hickoryCarya sinensis. To achieve this goal, we generated two chromosome-level reference genomes respectively forC. sinensisandC. cathayensis. Furthermore, we re-sequenced the whole genomes of 43 individuals fromC. sinensisand one individual from each of the 11 diploid species ofCarya. The latter dataset with one individual per species is used to reconstruct the phylogenetic networks and estimate the divergence time ofCarya. Our results unambiguously demonstrate the presence of ghost introgression from an extinct lineage into the beaked hickory, dispelling certain misconceptions about the phylogenetic history ofC. sinensis. We also discuss the profound implications of ghost introgression intoC. sinensisfor the historical biogeography of hickory species. [BPP;Carya;D-statistic; gene flow; ghost introgression]
Implicit model to capture electrostatic features of membrane environment
Authors: Samanta Rituparna , Gray Jeffrey J
Published: June 2023

Membrane protein structure prediction and design are challenging due to the complexity of capturing the interactions in the lipid layer, such as those arising from electrostatics. Accurately capturing electrostatic energies in the low-dielectric membrane often requires expensive Poisson-Boltzmann calculations that are not scalable for membrane protein structure prediction and design. In this work, we have developed a fast-to-compute implicit energy function that considers the realistic characteristics of different lipid bilayers, making design calculations tractable. This method captures the impact of the lipid head group using a mean-field-based approach and uses a depth-dependent dielectric constant to characterize the membrane environment. This energy function Franklin2023 (F23) is built upon Franklin2019 (F19), which is based on experimentally derived hydrophobicity scales in the membrane bilayer. We evaluated the performance of F23 on five different tests probing (1) protein orientation in the bilayer, (2) stability, and (3) sequence recovery. Relative to F19, F23 has improved the calculation of the tilt angle of membrane proteins for 90% of WALP peptides, 15% of TM-peptides, and 25% of the adsorbed peptides. The performances for stability and design tests were equivalent for F19 and F23. The speed and calibration of the implicit model will help F23 access biophysical phenomena at long time and length scales and accelerate the membrane protein design pipeline.

Author summary

Membrane proteins participate in many life processes. They constitute 30% of the human proteome and are targets for over 60% pharmaceuticals. Accurate and accessible computational tools to design membrane proteins will transform the platform to engineer membrane proteins for therapeutic, sensor, and separation processes. While soluble protein design has advanced, membrane protein design remains challenging due to the difficulties in modeling the lipid bilayer. Electrostatics plays an intimate role in the physics of membrane protein structure and function. However, accurately capturing electrostatic energies in the low-dielectric membrane often requires expensive calculations that are not scalable. In this work, we contribute a fast-to-compute electrostatic model that considers different lipid bilayers and their features, making design calculations tractable. We demonstrate that the updated energy function improves the calculation of the tilt angle of membrane proteins, stability, and confidence in designing charged residues.
SHARK enables homology assessment in unalignable and disordered sequences
Authors: Chow Chi Fung Willis , Ghosh Soumyadeep , Hadarovich Anna , Toth-Petroczy Agnes
Published: June 2023

Intrinsically disordered regions (IDRs) are structurally flexible protein segments with regulatory functions in multiple contexts, such as in the assembly of biomolecular condensates.

Since IDRs undergo more rapid evolution than ordered regions, identifying homology of such poorly conserved regions remains challenging for state-of-the-art alignment-based methods that rely on position-specific conservation of residues. Thus, systematic functional annotation and evolutionary analysis of IDRs have been limited, despite comprising ∼21% of proteins.

To accurately assess homology between unalignable sequences, we developed an alignment-free sequence comparison algorithm, SHARK (Similarity/Homology Assessment by Relating K-mers). We trained SHARK-dive, a machine learning homology classifier, which achieved superior performance to standard alignment in assessing homology in unalignable sequences, and correctly identified dissimilar IDRs capable of functional rescue in IDR-replacement experiments reported in the literature.

SHARK-dive not only predicts functionally similar IDRs, but also identifies cryptic sequence properties and motifs that drive remote homology, thereby facilitating systematic analysis and functional annotation of the unalignable protein universe.
Targeting Ovarian Cancer Stem Cells by Dual Inhibition of the Long Noncoding RNA HOTAIR and Lysine Methyltransferase EZH2
Authors: Wang Weini , Zhou Yanchi , Wang Ji , Zhang Shu , Ozes Ali , Gao Hongyu , Fang Fang , Wang Yue , Chu Xiaona , Liu Yunlong , Wan Jun , Mitra Anirban , O’Hagan Heather M. , Nephew Kenneth P.
Published: June 2023

Persistence of cancer stem cells (CSC) is believed to contribute to resistance to platinum-based chemotherapy and disease relapse in ovarian cancer (OC), the fifth leading cause of cancer- related death among US women. HOXC transcript antisense RNA (HOTAIR) is a long noncoding RNA (lncRNA) overexpressed in high-grade serous OC (HGSOC) and linked to chemoresistance. However, HOTAIR impacts chromatin dynamics in OCSC and how this oncogenic lncRNA contributes to drug resistant disease are incompletely understood. Here we generated HOTAIR knock-out (KO) HGSOC cell lines using paired CRISPR guide RNA design to investigate the function of HOTAIR. We show that loss of HOTAIR function re-sensitized OC cells to platinum treatment and decreased the population of OCSC. Furthermore, HOTAIR KO inhibited the development of stemness-related phenotypes, including spheroid formation ability, as well as expression of key stemness-associated genes ALDH1A1, Notch3, Sox9, and PROM1. HOTAIR KO altered both the cellular transcriptome and chromatin accessibility landscape of multiple oncogenic-associated genes and pathways, including the NF-kB pathway. HOTAIR functions as an oncogene by recruiting enhancer of zeste 2 (EZH2) to catalyze H3K27 tri-methylation to suppress downstream tumor suppressor genes, and it was of interest to inhibit both HOTAIR and EZH2. In vivo, combining a HOTAIR inhibitor with an EZH2 inhibitor and platinum chemotherapy decreased tumor formation and increased survival. These results suggest a key role for HOTAIR in OCSC and malignant potential. Targeting HOTAIR in combination with epigenetic therapies may represent a therapeutic strategy to ameliorate OC progression and resistance to platinum-based chemotherapy.
Optogenetics reveals roles for supporting cells in force transmission to and from outer hair cells in the mouse cochlea
Authors: Lukashkina Victoria A. , Levic Snezana , Simões Patricio , Xu Zhenhang , Li Yuju , Haugen Trevor , Zuo Jian , Lukashin Andrei N. , Russell Ian J.
Published: June 2023

Cochlear outer hair cells (OHCs), acting as bidirectional cellular mechanoelectrical-transducers, generate, receive, and exchange forces with other major elements of the cochlear partition, including inner hair cells (IHCs). Force exchange is mediated via a supporting cell scaffold, including Deiters’ (DC) and outer pillar cells (OPC), to enable the sensitivity and exquisite frequency selectivity of the mammalian cochlea. We conditionally expressed a hyperpolarizing halorhodopsin (HOP), a light-gated inward chloride ion pump in DCs and OPCs. We measured extracellular receptor potentials (ERPs) and their DC component (ERPDC) from the Cortilymph (CL) of HOP expressing mice and compared the responses with similar potentials from littermates without HOP expression. Compound action potentials (CAP) were measured as an indication of IHC activity. HOP laser activation suppressed cochlear amplification through changing timing of its feedback, altered basilar membrane (BM) responses to tones at all measured levels and frequencies, and reduced IHC excitation. Our HOP activation results here complement previous channelrhodopsin activation studies in exploiting optogenetics to measure and understand the roles of DCs and OPCsin vivoin controlling the mechanical and electrical responses of OHCs to sound and their contribution to timed and directed electromechanical feedback to the mammalian cochlea.

SIGNIFICANCE STATEMENT

Outer hair cells provide electromechanical feedback to the organ of Corti, mediated via a cellular scaffold of Deiters’ and outer pillar cells, that enables the sensitivity and fine frequency tuning of the cochlea. The role of this scaffold was explored by expressing the halorhodopsin HOP in Deiters’ and pillar cells which, when illuminated, hyperpolarized them. HOP activation suppressed cochlear amplification through altering the timing of outer hair cell forces to the Organ of Corti, altered basilar membrane responses to tones, including those at levels and frequencies not subject to amplification, and reduced neural excitation. The findings implicated roles for supporting cells in mediating force transmission to and from outer hair cells along all axes of the organ of Corti.
Cracked actin filaments as mechanosensitive receptors
Authors: Zsolnay Vilmos , Gardel Margaret L. , Kovar David R. , Voth Gregory A.
Published: June 2023

Actin filament networks are exposed to mechanical stimuli, but the effect of strain on actin filament structure has not been well-established in molecular detail. This is a critical gap in understanding because the activity of a variety of actin-binding proteins have recently been determined to be altered by actin filament strain. We therefore used all-atom molecular dynamics simulations to apply tensile strains to actin filaments and find that changes in actin subunit organization are minimal in mechanically strained, but intact, actin filaments. However, a conformational change disrupts the critical D-loop to W-loop connection between longitudinal neighboring subunits, which leads to a metastable cracked conformation of the actin filament, whereby one protofilament is broken prior to filament severing. We propose that the metastable crack presents a force-activated binding site for actin regulatory factors that specifically associate with strained actin filaments. Through protein-protein docking simulations, we find that 43 evolutionarily-diverse members of the dual zinc finger containing LIM domain family, which localize to mechanically strained actin filaments, recognize two binding sites exposed at the cracked interface. Furthermore, through its interactions with the crack, LIM domains increase the length of time damaged filaments remain stable. Our findings propose a new molecular model for mechanosensitive binding to actin filaments.

SIGNIFICANCE STATEMENT

Cells continually experience mechanical strain, which has been observed to alter the interactions between actin filaments and mechanosensitive actin-binding proteins in recent experimental studies. However, the structural basis of this mechanosensitivity is not well understood. We used molecular dynamics and protein-protein docking simulations to investigate how tension alters the actin filament binding surface and interactions with associated proteins. We identified a novel metastable cracked conformation of the actin filament, whereby one protofilament breaks before the other, presenting a unique strain-induced binding surface. Mechanosensitive LIM domain actin-binding proteins can then preferentially bind the cracked interface, and this association stabilizes damaged actin filaments.