bluuebunny/crossref_metadata_2025 huggingface dataset:
The UK Biobank Mental Health Enhancement 2022: Methods and Results
Authors: Davis Katrina A.S. , Coleman Jonathan R.I. , Adams Mark , Breen Gerome , Cai Na , Davies Helena , Davies Kelly , Dregan Alexandru , Eley Thalia C. , Fox Elaine , Holliday Jo , Huebel Christopher , John Ann , Kassam Aliyah S. , Kempton Matthew J. , Lee William , Li Danyang , Maina Jared , McCabe Rose , McIntosh Andrew M. , Oram Sian , Richards Marcus , Skelton Megan , Starkey Fenella , ter Kuile Abigail R , Thronton Laura M , Wang Rujia , Yu Zhaoying , Zvrskovec Johan , Hotopf Matthew
Published: November 2024

Background

This paper introduces the UK Biobank (UKB) second mental health questionnaire (MHQ2), describes its design, the respondents and some notable findings. UKB is a large cohort study with over 500,000 volunteer participants aged 40-69 years when recruited in 2006-2010. It is an important resource of extensive health, genetic and biomarker data. Enhancements to UKB enrich the data available. MHQ2 is an enhancement designed to enable and facilitate research with psychosocial and mental health aspects.

Methods

UKB sent participants a link to MHQ2 by email in October-November 2022. The MHQ2 was designed by a multi-institutional consortium to build on MHQ1. It characterises lifetime depression further, adds data on panic disorder and eating disorders, repeats ‘current’ mental health measures and updates information about social circumstances. It includes established measures, such as the PHQ-9 for current depression and CIDI-SF for lifetime panic, as well as bespoke questions. Algorithms and R code were developed to facilitate analysis.

Results

At the time of analysis, MHQ2 results were available for 169,253 UKB participants, of whom 111,275 had also completed the earlier MHQ1. Characteristics of respondents and the whole UKB cohort are compared. The major phenotypes are lifetime: depression (18%); panic disorder (4.0%); a specific eating disorder (2.8%); and bipolar affective disorder I (0.4%). All mental disorders are found less with older age and also seem to be related to selected social factors. In those participants who answered both MHQ1 (2016) and MHQ2 (2022), current mental health measure showed that fewer respondents have harmful alcohol use than in 2016 (relative risk 0.84), but current depression (RR 1.07) and anxiety (RR 0.98) have not fallen, as might have been expected given the relationship with age. We also compare lifetime concepts for test-retest reliability.

Conclusions

There are some drawbacks to UKB due to its lack of population representativeness, but where the research question does not depend on this, it offers exceptional resources that any researcher can apply to access. This paper has just scratched the surface of the results from MHQ2 and how this can be combined with other tranches of UKB data, but we predict it will enable many future discoveries about mental health and health in general.
Implementing the mhGAP-HIG: The process and evaluation of training primary health care workers in Khyber Pakhtunkhwa, Pakistan
Authors: Humayun Asma , Najmussaqib Arooj
Published: November 2024

Background

Building the capacity of primary care staff is crucial for integrating mental health care into primary healthcare to reduce the significant treatment gap for psychiatric disorders prevalent in low- and middle-income countries. This research investigates the effectiveness of adapted mhGAP-HIG guidelines in Khyber Pakhtunkhwa (KP).

Methods

A team of seven trained experts conducted six five-day training workshops in six districts of KP. A total of 105 primary care physicians and clinical psychologists were trained. Mix method analysis was performed. Paired sample t-tests were used to compare knowledge scores pre- and post-training and after 8 months. Thematic analysis was conducted to examine feedback of the participants regarding the training, whereas content analysis was performed on the reflections of the trainers on the adapted guide.

Results

Findings demonstrated significant improvements in knowledge of the participants to identify and manage common mental health conditions. The percentage of correctly answered questions in the pre-test was 73.86%, which increased to 85.94% in the post-test, indicating a 12.08% increase in knowledge. Most noticeable improvements in knowledge were observed in harmful use of substances (22.56), General principles of care and other significant mental health complaints (15.15%), stress (13.80%), suicide, and epilepsy (13.13%). The thematic analyses highlighted the strengths and gaps of training and made recommendations to strengthen preservice training and provide regular refresher courses.

Conclusion

The study underscores the feasibility of implementing an adapted mhGAP-HIG for training primary care physicians and clinical psychologists within existing healthcare resources of KP. The preliminary findings endorse the scalability across other provinces in the country.
The relationships between impulsivity and mood in bipolar disorder: An ecological momentary assessment study
Authors: Ramírez-Martín Almudena , Sirignano Lea , Foo Jerome C. , Streit Fabian , Frank Josef , Witt Stephanie H. , Rietschel Marcella , Mayoral-Cleries Fermin , Moreno-Küstner Berta , Guzmán-Parra Jose
Published: November 2024

Background

Impulsivity is a key feature of bipolar disorder (BD) associated with various negative outcomes. Recent use of ecological momentary assessment (EMA) has allowed for nuanced examination of the mechanisms of mood and impulsivity dysregulation. However, few existing studies have used an ecological momentary assessment of impulsivity in multiplex families with BD and examined its associations with mood.

Objective

Using EMA, this study investigated the concurrent and predictive relationships between impulsivity and mood.

Methods

Multiplex family members with BD (n=8), unaffected family members (n=6), individuals with BD not from families (n=8) and healthy controls (n=8), completed daily EMA surveys about mood and impulsivity for 6-12 weeks. Mixed-effects regression concurrent and lagged models were employed to analyze the relationship between impulsivity and mood.

Results

The diagnosis of BD was associated with lower mood and higher impulsivity levels. Belonging to a multiplex family (i.e. high genetic load for BD) was associated with lower mood but not with higher impulsivity. BD participants showed a negative association between impulsivity and concurrent mood measured with EMA. Time-lagged analyses revealed a significant negative association between prior impulsivity and mood at the next assessment independent of diagnosis.

Conclusions

These results contribute to the understanding of the complex interactions between BD, the genetic load of the disorder, impulsivity and mood. Furthermore, these findings indicate the potential benefits of addressing impulsivity as a means to improve mood outcomes at an early stage.
Impact of Vitamin D supplementation on cognition in adults with mild to moderate vitamin D deficiency: Outcomes from the VitaMIND randomised controlled trial
Authors: Corbett Anne , Taylor Rod , Llewellyn David , Ranson Janice M. , Hampshire Adam , Pickering Ellie , Palmer Abbie , Aarsland Dag , Cader Dorina , Frost Diana , Ballard Clive
Published: November 2024

Background

Preserved cognitive health with ageing is a public health imperative. Vitamin D deficiency is associated with poor cognition, but it is unclear whether supplementation would provide benefit, particularly in individuals with mild/moderate deficiencies which do not have other clinical risks. The objective of this study was to establish the impact of daily vitamin D supplementation on cognition in older adults with mild to moderate vitamin D deficiency.

Methods and Findings

Two-arm parallel 24-month randomised controlled trial, with Vitamin D supplementation compared with a placebo. This was a remote trial, completed from home involving 620 adults 50 years or older with mild to moderate vitamin D deficiency and early cognitive impairment. The primary outcome was executive function measured through Trail making B and other secondary measures of cognition, function and wellbeing.

Vitamin D supplementation conferred no significant benefit to executive function compared to placebo at follow-up on the primary outcome (between-group difference: 5770, 95% CI: -2189 to 13730) or cognition, function, or wellbeing. Secondary analyses in defined subgroups and a per-protocol analysis also showed no significant impact on any outcome measures.

Conclusions

Vitamin D supplementation produced no measurable improvement in cognitive outcomes in older adults with mild to moderate vitamin D deficiency. The remote trial methodology provides an innovative approach to large-scale trials.

Trial Registration

ISRCTN79265514https://www.isrctn.com/ISRCTN79265514
Rapid establishment of public sector COVID-19 test and treatment programs across seven low- and middle-income countries: Implementation strategies and program monitoring results
Authors: Boeke Caroline E. , Hamza Nervine , Agwuocha Chukwuemeka , Amako Okechukwu , Detluexay Khamsay , Gao Michelle , Griffith Bridget C. , Gumulira Yamikani , Hodges Elina Urli , Joseph Jessica , Lufesi Norman , Macharia Emily , Mbewe Nyuma , McCarthy Elizabeth , Mintah Faustina O. , Mukiibi Moses , Mulenga Mwaba , Ngwije Alida , Ofori-Boadu Lawrence , Okoli Ijeoma Uzondu , Phongphila Sompasong , Ramers Christian , Regan Sean , Twinomujuni Evarist , Rwagasore Edson , Tebor Jessica , Udayakumar Krishna
Published: November 2024

The COVID-19 Treatment QuickStart Consortium[1] worked with governments in 7 low- and middle-income countries, Ghana, Laos, Malawi, Nigeria, Rwanda, Uganda, and Zambia, to implement COVID-19 test-and-treat programs at 776 health facilities, including training over 5,000 staff and facilitating a donation of 11,300 courses of the oral antiviral nirmatrelvir/ritonavir for treatment. This paper describes the process of implementing COVID-19 test-and-treat programs in each country, provides aggregate program monitoring data on numbers tested and treated from program initiation through June 2024, and analyzes program enablers and challenges. Between country-level program initiation (ranging from December 2022 for Zambia to September 2023 for Uganda) and June 2024, a total of 731,970 SARS-CoV-2 tests were conducted. Of 6,724 positive tests, a subset were documented to meet eligibility criteria for nirmatrelvir/ritonavir initiation, and 3,041 patients were prescribed nirmatrelvir/ritonavir. The largest number of prescriptions was in Zambia. Program enablers included decentralization of services, task-shifting from higher to lower health worker cadres, increased access to point of care antigen tests - including self-tests, and the integration of COVID-19 with other health services. Challenges included COVID-19 de-prioritization at the time of program rollout, test commodity stockouts and expiries, and dwindling national surveillance efforts. Learnings from rapid initiation and scale-up of COVID-19 test-and-treat programs in these 7 countries can be used to inform future pandemic preparedness strategies in LMICs.
Removing array-specific batch effects in GWAS mega-analyses by applying a two-step imputation workflow reveals new associations for thyroid volume and goiter
Authors: Kamal Nasr M. , König Eva , Fuchsberger Christian , Ghasemi Sahar , Völker Uwe , Völzke Henry , Grabe Hans J. , Teumer Alexander
Published: November 2024

Background

Combining individual-level data in genetic association studies (mega-analyses) enhances statistical power for identifying gene-trait associations. However, batch effects from combining variants of different arrays pose a major limitation. Here, we developed a two-step imputation workflow to overcome the array type bias.

Methods

Genotype data of 10,647 individuals generated using five different arrays were included. Intermediate array-specific panels were generated and subsequently imputed against the 1000 Genomes Project Phase3 reference panel. Genetic principal component (PC) analysis assessed batch effects in the cohort-combined imputed data. The workflow’s performance was evaluated by comparing imputation quality r2and allele frequency difference of the proposed two-step imputation to the conventional array-specific imputation as well as its matching with a whole-genome sequenced subgroup for further validation. We performed a genome-wide association study (GWAS) to test for genetic associations with goiter risk and thyroid gland volume, comparing summary statistics of both approaches.

Results

The proposed workflow eliminated the batch effect from the first twenty genetic PCs. The outcome of the workflow also showed high correlation with the conventional approach for allele frequencies (r2> 0.99). GWAS results from the two-step imputation confirmed known associations on thyroid traits and revealed novel loci for thyroid volume (TG, PAX8, IGFBP5, NRG1), and one novel locus for goiter (XKR6), which was not statistically significant following the GWAS meta-analysis of conventional imputation.

Conclusion

Our imputation workflow provides high-quality imputation results without technical batch effects, fostering mega-analysis involving multiple genotyping arrays for different genetic association analysis.
The Moderating Role of Genetic and Environmental Risk Factors for Schizophrenia on the Relationship between Autistic Traits and Psychosis Expression in the General Population
Authors: Karacam Dogan Melike , Prachason Thanavadee , Lin Bochao , Pries Lotta-Katrin , Arias-Magnasco Angelo , Bortoletto Riccardo , Menne-Lothmann Claudia , Decoster Jeroen , van Winkel Ruud , Collip Dina , Delespaul Philippe , Hert Marc De , Derom Catherine , Thiery Evert , Jacobs Nele , van Os Jim , Rutten Bart , Brondino Natascia , Colizzi Marco , Luykx Jurjen , Fusar-Poli Laura , Guloksuz Sinan
Published: November 2024

Background and Hypothesis

Psychosis-related environmental risks are common in autism, with identified genetic connections to psychosis. Therefore, we hypothesized these risks may moderate the relationship between autistic traits (ATs) and psychotic experiences (PEs).

Study Design

First-wave data from 792 twins and siblings in the TwinssCan Project were analysed (n=792). PEs and ATs were assessed using the Community Assessment of Psychic Experiences and the Autism-Spectrum Quotient. Polygenic risk scores for schizophrenia and psychosis-associated environmental factors (childhood trauma (CT), bullying, negative life events, obstetric complications, cannabis use, winter birth, and hearing impairment) were tested for independent and interactive effects with ATs using separate multilevel linear regression models.

Study Results

ATs, all five CT subtypes, bullying, and negative life events were significantly associated with PEs (all P < 0.004). Emotional abuse (B: 0.08, 95% CI:0.05 to 0.11, P < 0.001), physical abuse (B: 0.11, 95% CI: 0.05 to 0.18, P = 0.001), sexual abuse (B: 0.09, 95% CI: 0.03 to 0.15, P = 0.002), and physical neglect (B: 0.06, 95% CI: 0.03 to 0.10, P = 0.001) significantly amplified the positive relationship between ATs and PEs, whereas emotional neglect (B: 0.04, 95% CI: 0.01 to 0.07, P = 0.007) and negative life events (B: 0.007, 95% CI: 0.0005 to 0.014, P = 0.04) only showed a trend of interactions. No significant main or interacting effects of genetic and other risk factors were found.

Conclusions

These findings imply that CT might be a potential preventive target for psychosis expression in people with high ATs.
Work Expectations, Employment Transitions, and Psychological Distress During the Great Recession Among Older Americans and South Koreans
Authors: Dang Linh , Antonucci Toni , Mendes de Leon Carlos , Mezuk Briana
Published: November 2024

Background and objectives

Perceived uncertainty about future employment and work transitions during economic crises can negatively affect mental health of workers. This study examined the association between work expectations and psychological distress among “Baby Boomers” (born 1948-1965) in the United States and South Korea and explored how employment transitions moderated this association before, during, and after the Great Recession.

Research Design and Methods

Data came from 2006-2018 waves of the Health and Retirement Study (n=2,647) and Korean Longitudinal Study of Aging (n=1,454). Perceived expectations of working in the next five years were reported on a probability scale (0-100%). Psychological distress was assessed by the Center for Epidemiologic Studies Depression Scale. Six mutually-exclusive employment transitions during the Recession were constructed: entrance to full-time employment, precarious employment, stable full-time employment, self-employment, exit from the labor force, and consistently out of the labor force. Multivariate mixed-effects logistic regression models were used to assess the association between work expectations, employment transitions, and psychological distress.

Results

Higher work expectations were associated with lower odds of psychological distress; this association was most robustly observed during the recession (ORUS=0.93 [0.89, 0.98], ORKorea=0.92 [0.84, 1.01]) and recovery (ORUS=0.95 [0.92, 0.98], ORKorea=0.84 [0.80, 0.89]). The relationship between expectations and distress was pronounced among respondents who were self-employed or transitioning into self-employment. Findings were broadly similar comparing two countries.

Discussion and Implications

Expectations regarding, and transitions in, employment impact psychological distress. Findings emphasize the need to support the mental health of older adults nearing retirement during periods of economic crisis.
APOE4 and Chronic Health Risk Factors are Associated with Sex-Specific Preclinical Alzheimers Disease Neuroimaging Biomarkers
Authors: Losinski Genna M , Key Mickeal N , Vidoni Eric D , Clutton Jonathan , Morris Jill K , Burns Jeffrey M , Watts Amber
Published: November 2024

Introduction: Two thirds of Alzheimers disease (AD) patients are female. Genetic and chronic health risk factors for AD affect females more negatively compared to males. Objective: This exploratory multimodal neuroimaging study aimed to examine sex differences in cognitively unimpaired older adults on: (1) amyloid-β via 18F-AV-45 Florbetapir PET imaging, (2) neurodegeneration via T1 weighted MRI volumetrics, (3) cerebral blood flow via ASL-MRI. We identified AD risk factors including genetic (APOE genotype status) and health markers (fasting glucose, mean arterial pressure, waist-to-hip ratio, and android and gynoid body fat) associated with neuroimaging outcomes for which we observed sex differences. Methods: Participants were sedentary, amyloid-β positive older adults (N = 112, ages 65-87 years) without evidence of cognitive impairment (CDR = 0). Results: Multivariate analysis of covariance models adjusted for intracranial volume, age, and years of education demonstrated lower volume (F (7, 102) = 2.67, p = 0.014) and higher blood flow F (6, 102) = 4.25, p =<0.001) among females compared to males in regions of interest connected to AD pathology and the estrogen receptor network. We did not observe sex differences in amyloid-β levels. Higher than optimal waist to hip ratio was most strongly associated with lower volume, while higher android fat percentage and APOE ε4 carrier status were most strongly associated with higher blood flow among female participants. Discussion: Findings suggest genetic and chronic health risk factors are associated with sex-specific AD neuroimaging biomarkers. Underlying sex-specific biological pathways may explain these findings. Our results highlight the importance of considering sex differences in neuroimaging studies and when developing effective interventions for AD prevention and risk reduction.
Seroprevalence of dengue, Zika, yellow fever and West Nile viruses in Senegal, West Africa
Authors: Gallon Sebastian , Sy Mouhamad , Tonto Prince Baffour , Ndiaye Ibrahima Mbaye , Toure Mariama , Gaye Amy , Aidara Mariama , Mbaye Amadou Moctar , Dia Abdoulaye Kane , Diallo Mamadou Alpha , Gomis Jules Francois , Yade Mamadou Samba , Diedhiou Younous , Dieye Baba , Diongue Khadim , Seck Mame Cheikh , Badiane Aida S. , Ndiaye Daouda , Herrera Bobby Brooke
Published: November 2024

West Africa serves as a critical region for the co-circulation of mosquito-borne flaviviruses, which often precipitate sporadic outbreaks. This study investigated the seroprevalence of dengue virus serotypes 1-4 (DENV-1-4), Zika virus (ZIKV), yellow fever virus (YFV), and West Nile virus (WNV) in three regions of Senegal: Sindia, Thies, and Kedougou. We retrospectively analyzed 470 serum samples for flavivirus immunoglobulin G (IgG) using a DENV-2 envelope (E) ELISA. Our findings revealed a seroprevalence of 37.23% for DENV-2 E IgG, indicative of a prior flavivirus exposure rate. The IgG seroprevalence rates for DENV-1-4, ZIKV, YFV, or WNV NS1 were 57.14%, 12.57%, 80.57% and 17.14%, respectively, with 72% of individuals harboring neutralizing antibodies against two or more flaviviruses. We also identified that residing in Sindia (ZIKV, OR, 9.428; 95% CI: 1.882-47.223 & WNV, OR, 6.039; 95% CI: 1.855-19.658) and Kedougou (ZIKV, OR, 7.487; 95% CI: 1.658-33.808 & WNV, OR, 1.142; 95% CI: 0.412-3.164) was a significant risk factor for ZIKV and WNV exposure. In contrast, history of malaria significantly reduced the risk of WNV exposure (aOR, 0.402; 95% CI: 0.203-0.794). This study underscores the complexity of flavivirus epidemiology in West Africa and the necessity for enhanced surveillance to inform public health strategies.
Klebsiella pneumoniae infection increases risk of Alzheimer’s Disease in the UK Biobank cohort
Authors: Lehrer Steven , Rheinstein Peter H.
Published: November 2024

Background

Infections, including bacterial pathogens, have been implicated in Alzheimer’s disease (AD) risk. Klebsiella pneumoniae (K. pneumoniae) is a common hospital-acquired pathogen associated with significant inflammation, which may contribute to neurodegeneration. This study investigates the relationship between K. pneumoniae infections and AD in the UK Biobank cohort.

Methods

Using UK Biobank data, we assessed AD diagnoses based on linked healthcare records and identified K. pneumoniae infections using ICD-10 codes B96.1 and J15.0. A cohort of 502,494 participants was analyzed for AD incidence in relation to demographic factors, educational years, APOE isoforms, and history of K. pneumoniae infection. Logistic regression was used to assess the association between K. pneumoniae infection and AD risk.

Results

AD incidence was significantly higher among participants with a history of K. pneumoniae infection (1.0%) compared to those without (0.2%; p < 0.001, Fisher’s exact test two tailed). Logistic regression analysis revealed that K. pneumoniae infection was associated with an increased risk of AD (OR = 3.32, p < 0.001), independent of age, sex, education, and APOE isoform. Additionally, AD risk was higher among ε4ε4 carriers and increased with age but decreased with additional years of education.

Conclusion

Our findings suggest that K. pneumoniae infection may be an independent risk factor for AD. This association underscores the need for further research into infection control and its role in mitigating neurodegenerative disease risk, particularly in populations susceptible to healthcare-associated infections.

Graphical abstract

Klebsiella pneumoniae infection increases risk of Alzheimer’s Disease. The gut-brain axis may be involved.
Racial Composition in K-12 Schooling and Cognitive Health of Older Black Adults
Authors: Best Merci N. , Laurent Sarah E. , Doyle Cassidy , Torres Elisa R. , Mahmoudi Elham , Zahodne Laura B.
Published: November 2024

Systemic educational factors have implications for cognitive health across the life course. Due tode jureandde factorracial segregation in the United States (U.S.), K-12 school quality varies by racial composition, which we hypothesize contributes to higher risk of Alzheimer’s disease and related dementias among non-Hispanic Black (NHB) older adults. This study adopts a life course perspective to investigate the association between K-12 schools’ racial composition and later-in-life cognitive health among U.S.– born and educated NHB older adults in the Health and Retirement Study (N=2,105). Using the 2015, 2017, and 2019 Life History Mail Survey, we categorized racial composition of K-12 schools as only majority non-Hispanic White (NHW) schools (n=193), only majority NHB schools (n=1,387), or both school types (n=525). Multiple linear regressions assessed relationships between school racial composition and total cognition, episodic memory, and vocabulary, controlling for age, gender, childhood factors, and U.S. region of residence at age 10. Attending only NHW schools or both school types was associated with better total cognition (p<.01 andp<.001, respectively) and episodic memory (p<.05 andp<.01, respectively) than attending only NHB schools. Attending both school types was also associated with better vocabulary (p<.0001). Structural equation models revealed that 45-66% of these associations were mediated by participants’ educational attainment. Our findings highlight the long-term cognitive benefits of attending some NHW schools and underscore the need for initiatives promoting equity in NHB schools. Further, our findings suggest bicultural education may provide language benefits, despite potential interpersonal discrimination toward NHB students.
DNA-guided CRISPR/Cas12 for RNA targeting
Authors: Orosco Carlos , Rananaware Santosh R. , Huang Boyu , Hanna Michael P. , Ahmadimashhadi M. Reza , Lewis Jordan G. , Baugh Michael P. , Bodin August P. , Flannery Sarah J. , Lange Ian H. , Fang Zoe R. , Karalkar Vedant N. , Meister Katelyn S. , Jain Piyush K.
Published: November 2024

CRISPR-Cas nucleases are transforming genome editing, RNA editing, and diagnostics but have been limited to RNA-guided systems. We present ΨDNA, a DNA-based guide for Cas12 enzymes, engineered for specific and efficient RNA targeting. ΨDNA mimics a crRNA but with a reverse orientation, enabling stable Cas12-RNA assembly and activating trans-cleavage without RNA components. ΨDNAs are effective in sensing short and long RNAs and demonstrated 100% accuracy for detecting HCV RNA in clinical samples. We discovered that ΨDNAs can guide certain Cas12 enzymes for RNA targeting in cells, enhancing mRNA degradation via ribosome stalling and enabling multiplex knockdown of multiple RNA transcripts. This study establishes ΨDNA as a robust alternative to RNA guides, augmenting the potential of CRISPR-Cas12 for diagnostic applications and targeted RNA modulation in cellular environments.
Validation of the PETS-stroke-A patient reported measure (PRM) of treatment burden after stroke
Authors: Taylor-Rowan Martin , Eton David T , McLeod Hamish J. , Rizeq Jala , Kidd Lisa , Currie Grace , Quinn Terry J , Mair Frances S , Gallacher Katie I
Published: November 2024

Introduction

Treatment burden is the workload of healthcare for people with long-term conditions and the impact on wellbeing. A validated measure of treatment burden for use as an outcome measure in stroke trials is needed. We adapted a patient-reported measure (PRM) of treatment burden in multimorbidity, PETS (Patient Experience with Treatment and Self-Management version 2.0), to create a stroke-specific measure, PETS-stroke, and examined its psychometric properties.

Patients and Methods

We recruited stroke and transient ischaemic attack (TIA) survivors between Feb 2022-June 2023 from 10 hospitals in the UK and through the Scottish Health Research Register (SHARE). Participants completed the PETS-stroke questionnaire along with 3 other PRM’s (Stroke Southampton Self-Management Questionnaire, The Satisfaction with Stroke Care Measure, The Shortened Stroke Impact Scale). We performed confirmatory factor analysis to test the factor structure of the PETS-stroke. We assessed Spearman’s rank correlations between PETS-stroke and other PRMs to determine convergent validity. Intra-class coefficient was performed to assess test-retest reliability. Proportions of missing data along with feedback from qualitative interviews were used to determine feasibility. T-tests were conducted to examine variations in PETS-stroke scores based on multimorbidity and socioeconomic factors.

Results

Three-hundred-eighty-one participants were included. The best fit was achieved with a 9-factor structure and internal consistency was good (Omega values 0.729 to 0.921). The factor loadings for the individual indicator items across eight of the nine domains were moderate to strong. All domains of PETS-stroke showed moderate to strong correlations with at least one other PRM. Test-retest reliability was good for all domains (ICC>0.7). Qualitative feedback on feasibility was positive and missing data was within acceptable limits for 7 domains. PETS-stroke scores significantly differed based on multimorbidity in 3 domains and in 8 domains based on socioeconomic status.

Discussion

Psychometric performance suggests PETS-stroke is a highly promising measure of treatment burden after stroke.
Poxviruses induce a nuclear environment in the cytoplasm to promote viral replication
Authors: Veratti Pia , Wyler Emanuel , Read Clarissa , Scherer Myriam , Tan Jiang , Walther Paul , Wider Stephanie , Weidl Daniel , Full Florian
Published: November 2024

The family Orthopoxviridae comprises several members that can cause disease in humans, including Small-, Cow-, Camel-, and Monkeypoxvirus. In 2022 a global outbreak of the zoonotic monkeypoxvirus started with human- to- human transmission and more than 100 000 global cases in all continents. This outbreak emphasizes the need for more basic research to get a better understanding of poxvirus biology.

We characterized the cellular response to poxvirus infection and performed bulk RNA-sequencing of primary human fibroblasts infected with Modified-Vaccinia Ankara Virus (MVA), Vaccinia Virus, Cowpoxvirus, Camelpoxvirus and 4 different Monkeypoxvirus isolates (clade 1-2b) at various time points to compare the transcriptome of infected cells. We could demonstrate that MVA infection leads to a potent activation of innate immune genes that is absent in other samples. Camelpoxvirus infection results in a strong activation of NF-kB signaling 2h post infection whereas all other viruses inhibit NF-kB activation. In addition, we observed transport of cellular proteins like histone H1, lamin A/C, emerin and topoisomerase II A/B from the nucleus into cytoplasmic poxvirus factories. This correlates with drastic structural changes inside the nucleus in electron microscopy, namely formation of nuclear filaments, indicating intensive remodeling of the nuclear architecture. Accordingly, inhibition of topoisomerase using the clinically approved topoisomerase inhibitor epirubicin reduced viral replication of several Mpox strains. We observe a reduction of viral replication by epirubicin in cells of human and mouse species, indicating that the recruitment of TOP2B into viral factories is crucial for MPXV replication.
Genomes of two invasiveAdelgesspecies (hemlock woolly adelgid and pineapple gall adelgid)enable characterization of nicotinic acetylcholine receptors
Authors: Glendening AM , Stephens C , Vuruputoor VS , Stern DL , Hogenhout SA , Mathers TC , Chaganti T , Pauloski N , Cernak TA , Wegrzyn JL , Fetter KC
Published: November 2024

Two invasive hemipteran adelgids cause widespread damage to North American conifers.Adelges tsugae(the hemlock woolly adelgid) has decimatedTsuga canadensisandTsuga caroliniana(the Eastern and Carolina hemlocks, respectively).A. tsugaewas introduced from East Asia and reproduces parthenogenetically in North America, where it can kill trees rapidly.A. abietis,introduced from Europe, makes “pineapple” galls on several North American spruce species, and weakens trees, increasing their susceptibility to other stresses. Broad-spectrum insecticides that are often used to control adelgid populations can have off-target impacts on beneficial insects and the development of more selective chemical treatments could improve control methods and minimize ecological damage. Whole genome sequencing was performed on both species to aid in development of targeted pest control solutions and improve species conservation. The assembledA. tsugaeandA. abietisgenomes are 220.75 Mbp and 253.16 Mbp, respectively, each consisting of nine chromosomes and both genomes are over 96% complete based on BUSCO assessment. Genome annotation identified 11,424 and 14,118 protein-coding genes inA. tsugae and A. abietis, respectively. Comparative analysis across 29 Hemipteran species and 14 arthropod outgroups identified 31,666 putative gene families. Gene family expansions inA. abietisincluded ABC transporters and carboxypeptidases involved in carbohydrate metabolism, while both species showed contractions in core histone families and oxidoreductase pathways. Gene family expansions inA. tsugaehighlighted families associated with the regulation of cell differentiation and development (survival motor protein, SMN;juvenile hormone acid methyltransferaseJHAMT) as well as those that may be involved in the suppression of plant immunity (clip domain serine protease-D, CLIPD;Endoplasmic reticulum aminopeptidase 1, ERAP1). Among the analyzed gene families, Nicotinic acetylcholine receptors (nAChRs) maintained consistent copy numbers and structural features across species, a finding particularly relevant given their role as targets for current forestry management insecticides. Detailed phylogenetic analysis of nAChR subunits across adelgids and other ecologically important insects revealed remarkable conservation in both sequence composition and predicted structural features, providing crucial insights for the development of more selective pest control strategies.
Population regulation in semelparous deep-sea squid is driven by ecological conditions in surface waters and whale predation at depth
Authors: Rademaker Mark , ten Brink Hanna , Hoving Henk-Jan , Visser Fleur , van Leeuwen Anieke
Published: November 2024

Predator-prey interactions present a powerful framework for understanding population regulation in natural systems, including the vast and understudied pelagic deep sea. Oceanic squid are among the most abundant and important species groups in this habitat and function as primary prey for the largest marine top predators, deep-diving cetaceans. At the same time, these cryptic animals are highly data deficient. Insight into the dynamics of deep-sea squid populations and the impacts of predation by top-predators is crucial for designing conservation strategies and developing a general theory of deep-sea ecology. Here, we offer fundamental new insights into how individual life history and predation interact to shape population regulation in deep-sea squid. Using empirical data, we develop a size-structured population model for a highly abundant histioteuthid deep-sea squid. We show that population regulation is driven primarily by conditions experienced as paralarvae in the upper water column, where they face intense resource competition. Relaxation of this competition following ontogenetic migration as juveniles drives exponential-like growth curves. Population dynamics exhibit single-cohort cycles, producing regular ‘seasonal’ patterns in reproduction, even in the absence of any environmental seasonality. Furthermore, we demonstrate that predation by deep-diving cetaceans at different depths can lead to emergent facilitation between top predators. This reveals the complex interdependencies in trophic networks connecting the deep sea with surface waters. Our findings provide critical insights into the ecological functioning of the pelagic deep-sea and their link with surface waters. These insights are urgently needed to better understand and conserve this vast, data-deficient habitat, which endangered deep-diving predators depend on but is under major stress from anthropogenic activities.
Pathway Volcano: An interactive tool for pathway guided visualization of differential expression data
Authors: OConnell Thomas M
Published: November 2024

The increasing size and complexity of omics datasets can make effective visualization and interpretation very challenging. Differential expression datasets as from RNA-sequencing and proteomics can contain many thousands of features and even after filtering for significance there can be hundreds or thousands of features to consider. A common tool for visualizing this type of data is the volcano plot where each feature is plotted as log2 transformed fold change along the x-axis and the negative log10 of a p-value along the y-axis. These plots provide a useful visualization of the largest and most significant changes, but the majority of the features are often crowded and overlapping near the “cone” of the volcano. In order to provide a biologically informative way to simplify the visualization and interpretation of these types of datasets we developed the Pathway Volcano tool. This R-Shiny based software utilizes the Reactome API to select specific pathways and then filters the volcano plots to show only the data associated with those pathways. In this manner, many of the significant features in the crowded section of the volcano plot can be revealed to support the impact of specified pathways. This tool provides a range of interactive features to interrogate the data along with the ability to download png files and tables with pathway associated data.

Availability and implementation

Pathway Volcano is a freely available R Shiny package. The program was developed in R version 4.3.3 using R Studio version 2024.09.1 Build 394. Running the app locally requires the packages ggplot2 (1), plotly (2), shiny (3) dplyr (4) and ReactomeContentServer (5). The full code and documentation including example datasets are available athttps://github.com/thoconne/PathwayVolcano

Contact

thoconne@iu.edu
Sex-dependent effects of a glutamine supplementation on metabolic disorders, intestinal barrier function and gut microbiota in mice with diet-induced obesity
Authors: Lefebvre Candice , Tiffay Adam , Breemeersch Charles-Edward , Dreux Virginie , Bôle-Feysot Christine , Guérin Charlène , Breton Jonathan , Maximin Elise , Monnoye Magali , Déchelotte Pierre , Douard Véronique , Coëffier Moïse , Goichon Alexis
Published: November 2024

Rationale

Obesity is often associated with sex-dependent metabolic complications, in which altered intestinal barrier function and gut microbiota contribute. Glutamine (Gln) supplementation previously showed beneficial effects on gut barrier function and glycemic control. We thus aimed to characterize in mice the sex-dependent effects of a Gln supplementation during high fat diet induced obesity.

Methods

Male and female C57BL/6 mice received a standard (SD) or high fat diet (HFD; 60% kcal from fat) during 14 weeks (W14). From W12, mice received or not Gln in drinking water (2g/kg/day; n=12/group). Body composition, glucose tolerance, insulin sensitivity, intestinal permeability, colonic expression of 44 genes encoding factors involved in inflammatory response and gut barrier function, cecal microbiota and inflammatory/endocrine adipose response have been assessed. Data were analyzed usingt-test or Mann-Whitney test (HFD effect), and two-way ANOVA (HFD x Gln) followed by Bonferroni post-tests.

Results

In both male and female mice, Gln supplementation failed to improve body weight and body composition. However, Gln reduced glucose intolerance in HFD males (AUC reduced by 14.57%, p<0.05) that was associated to a partial restoration of plasma resistin and insulin and to a trend for a limitation of adipose inflammatory response. In males, Gln did not affect gut microbiota composition and colonic response. To the opposite, in females fed HFD, Gln supplementation led to gut microbiota changes (increase ofBacteroidotaandPseudomonadotaphyla; increase ofMuribaculaceaeandTannerellaceaefamilies), increased colonic inflammatory markers (TNFα, IL-1β, TLR4, Myd88, Irf3) that were associated to increased inflammatory response in subcutaneous adipose tissue and increased HOMA-IR.

Conclusions

High fat diet mice exhibit sex-dependent response to glutamine supplementation with protective effects in males and harmful effects in females. The role of gut microbiota should be deeply deciphered in further investigations.
The Impact of Excessive Muscle Co-contraction on Sit-to-Stand Performance in High-Heeled Footwear
Authors: Naik Ganesh R. , Pujari Amit N.
Published: November 2024

This study aimed to analyse the effects of co-contraction on quadriceps and hamstring muscles during sit-to-stand tasks for females wearing shoes with different heel heights. The study aimed to identify compensatory strategies during sit to stand task in response to excessive muscle co-contraction during high heeled gait. Sixteen healthy young women (age: 24.4±1.7 years, body mass index: 18.4±1kg/m2, weight: 50.2±5.2kg, height: 1.63±4.4m) participated in this study. Electromyography signals were recorded from three quadriceps (vastus medialis, vastus lateralis, and rectus femoris) and one hamstring (semitendinosus) muscles. The participants wore shoes with different heights, including 4cm, 6cm, 8cm, and 10cm. For each heel height, we computed co-contraction index to measure postural balance using quadriceps to hamstring muscle pairs. The results that were obtained and quantified with statistical measures show that for elevated shoes if co-contraction increases, both quadriceps and hamstring muscles tend to compensate. This suggests that the capacity of quadriceps and hamstring muscles to compensate is essential to retain normal walking and sit-to-stand (STS) tasks in co-contracted persons. However, the compensation mechanisms may induce imbalance, muscle stiffness, and fatigue for women who regularly use high-heeled shoes during sit-to-stand tasks.
SFPQ-TFE3gene fusion reciprocally regulates mTORC1 activity and induces lineage plasticity in a novel mouse model of renal tumorigenesis
Authors: Asrani Kaushal , Amaral Adrianna , Woo Juhyung , Abadchi Sanaz Nourmohammadi , Vidotto Thiago , Feng Kewen , Liu Hans B. , Kasbe Mithila , Baba Masaya , Oike Yuichi , Outeda Patricia , Watnick Terry , Rosenberg Avi Z. , Schmidt Laura S. , Linehan W. Marston , Argani Pedram , Lotan Tamara L.
Published: November 2024

The MiT/TFE family gene fusion proteins, such asSFPQ-TFE3, drive both epithelial (eg, translocation renal cell carcinoma, tRCC) and mesenchymal (eg, perivascular epithelioid cell tumor, PEComa) neoplasms with aggressive behavior. However, no prior mouse models forSFPQ-TFE3-related tumors exist and the mechanisms of lineage plasticity induced by this fusion remain unclear. Here, we demonstrate that constitutive murine renal expression of humanSFPQ-TFE3using Ksp Cadherin-Cre as a driver disrupts kidney development leading to early neonatal renal failure and death. In contrast, post-natal induction ofSFPQ-TFE3in renal tubular epithelial cells using Pax8 ERT-Cre induces infiltrative epithelioid tumors, which morphologically and transcriptionally resemble human PEComas. As seen in MiT/TFE fusion-driven human tumors,SFPQ-TFE3expression is accompanied by the strong induction of mTORC1 signaling, which is partially amino acid-sensitive and dependent on increasedSFPQ-TFE3-mediatedRRAGC/Dtranscription. Remarkably,SFPQ-TFE3expression is sufficient to induce lineage plasticity in renal tubular epithelial cells, with rapid down-regulation of the critical PAX2/PAX8 nephric lineage factors and tubular epithelial markers, and concomitant up-regulation of PEComa differentiation markers in transgenic mice, human cell line models and human tRCC. Pharmacologic or genetic inhibition of mTOR signaling downregulates expression of theSFPQ-TFE3fusion protein and rescues nephric lineage marker expression and transcriptional activityin vitro.These data provide evidence of a potential epithelial cell-of-origin forTFE3-driven PEComas and highlight a reciprocal role forSFPQ-TFE3and mTOR in driving lineage plasticity in the kidney, expanding our understanding of the pathogenesis of MiT/TFE-driven tumors.
Uncovering genetic linkages in the rhizosphere contributing to adaptation
Authors: Williams Jessica L. , Killian Erik Z. , Halpin-McCormick Anna , Kantar Michael B. , Sherman Jamie D. , Ewing Patrick M. , Eberly Jed O. , Lachowiec Jennifer
Published: November 2024

Microorganisms assembled into the plant rhizosphere from the surrounding soil can benefit the fitness of their host. Variation in plant genetics is associated with variation in rhizosphere microbial community composition leading to increased fitness and crop production and reducing reliance on synthetic agricultural inputs through selection. However, what impact the abiotic environment has on connections between microbes and host genetics, and whether those connections in turn impact crop performance in realistic agricultural scenarios is still unclear. We assessed agronomic performance and 16S sequence-based rhizosphere bacterial community composition on a large diverse barley population grown in seven field trials across four locations and two years. Within adapted regions, we observed consistent rhizosphere compositions across diverse soils, whereas in unadapted environments, distinct microbial communities were recruited, indicating environmental specificity in microbial assembly. Greenhouse trials further revealed that abiotic soil properties and microbial inoculants together interact to modulate rhizosphere composition and plant growth. Genome-wide association studies identified hundreds of quantitative trait loci (QTL) for microbial traits, with thirty of those loci co-localizing with agronomic traits, suggesting interspecies pleiotropy or genetic linkage. At specific loci, candidate genes associated with root-microbe interactions, including those related to pathogen response and root exudate production, suggest mechanisms that enable adaptation to local environments. These findings support the idea that genetic manipulation of rhizosphere microbiomes via selection of crops could enhance adaptation (i.e., yield, quality) across variable environments, advancing breeding strategies for improved crop resilience and productivity.
The C-terminus of the multi-drug efflux pump EmrE prevents proton leak by gating transport
Authors: Brousseau Merissa , Teng Da , Thomas Nathan E. , Voth Gregory A. , Henzler-Wildman Katherine A.
Published: November 2024

The model multi-drug efflux pump fromEscherichia coli, EmrE, can perform multiple types of transport leading to different biological outcomes, conferring resistance to some drug substrates and enhancing susceptibility to others. While transporters have traditionally been classified as antiporters, symporters, or uniporters, there is growing recognition that some transporters may exhibit mixed modalities. This raises new questions about the regulation and mechanisms of these transporters. Here we show that the C-terminal tail of EmrE acts as a secondary gate, preventing proton leak in the absence of drug. Substrate binding unlocks this gate, allowing transport to proceed. Truncation of the C-terminal tail (Δ107-EmrE) leads to altered pH regulation of alternating access, an important kinetic step in the transport cycle, as measured by NMR. Δ107-EmrE has increased proton leak in proteoliposome assays and bacteria expressing this mutant have reduced growth. MD simulations of Δ107-EmrE show formation of a water wire from the open face of the transporter to the primary binding site in the core, facilitating proton leak. In WT-EmrE, the C-terminal tail forms specific interactions that block formation of the water wire. Together these data strongly support the C-terminus of EmrE acting as a secondary gate that regulates access to the primary binding site in the core of the transporter.