bluuebunny/crossref_metadata_2025 huggingface dataset:
Avidity sequencing of whole genomes from retinal degeneration pedigrees identifies causal variants
Authors: Biswas Pooja , Villanueva Adda , Krajacich Benjamin J. , Moreno Juan , Zhao Junhua , Berry Anne Marie , Lazaro Danielle , Lajoie Bryan R. , Kruglyak Semyon , Ayyagari Radha
Published: December 2022

Whole genome sequencing has been an effective tool in the discovery of variants that cause rare disease. In this study, we determined the suitability of a novel avidity sequencing approach for rare disease applications. We built a sample to results workflow, combining the novel sequencing technology with standard library preparation kits, analysis workflows, and interpretation tools. We applied the workflow to ten pedigrees with inherited retinal degeneration (IRD) phenotype. Candidate variants of interest identified through whole genome sequencing were further evaluated using segregation analysis. Mutations in known IRD genes were detected in five of the ten cases. Genes with identified high confidence variants associated with retinal degeneration includedPEX6, ABCA4, CERKL, MAK, andRDH12. Pending confirmatory clinical sequencing, we observed a 50% diagnostic yield, consistent with previously reported outcomes of IRD patient analysis. The study confirms that avidity sequencing is effective in detection of causal mutations when used for whole genome sequencing in rare disease applications.
Regional disparities in Dementia-free Life Expectancy in Japan: an ecological study, using the Japanese long-term care insurance claims database
Authors: Yoshikawa Mikako , Goto Etsu , Shin Jung-ho , Imanaka Yuichi
Published: December 2022

Background

The number of people with dementia increases in an aging society; therefore, promoting policies for dementia throughout the community is crucial to creating a dementia-friendly society. Understanding the status of older adults with dementia in each region of Japan will be a helpful indicator. We calculated Dementia-free Life Expectancy and aimed to examine regional disparities and their associated factors.

Methods

We calculated Dementia-free Life Expectancy and Life Expectancy with Dementia for each secondary medical area in Japan based on the Degree of Independence in Daily Living for the Demented Elderly, using data extracted from the Japanese long-term care insurance claims database. We then conducted a partial least squares regression analysis, the objective variables being Dementia-free Life Expectancy and Life Expectancy with Dementia for both sexes at age 65, and explanatory regional-level variables included demographic, socioeconomic, and healthcare resources variables.

Results

The mean estimated regional-level Dementia-free Life Expectancy at age 65 was 17.33 years (95% confidence interval [CI] 17.27–17.38) for males and 20.05 years (95% CI 19.99–20.11) for females. Three latent components identified by partial least squares regression analysis represented urbanicity, socioeconomic conditions, and health services-related factors of the secondary medical areas. The second component explained the most variation in Dementia-free Life Expectancy of the three, indicating that higher socioeconomic status was associated with longer Dementia-free Life Expectancy.

Conclusions

There were regional disparities in secondary medical area level Dementia-free Life Expectancy. Our results suggest that socioeconomic conditions are more related to Dementia-free Life Expectancy than urbanicity and health services-related factors.
A Semi-Supervised Contrastive Learning Approach to Alzheimer’s Disease Diagnostics using Convolutional Autoencoders
Authors: Jung Edward , Kashyap Anshul , Hsu Brandon , Moreland Mason , Chantaduly Chanon , Chang Peter D.
Published: December 2022

PURPOSE

Alzheimer’s Disease (AD) is a neurodegenerative disease that progressively deteriorates memory and cognitive abilities. PET 18F-AV45 (florbetapir) is a common imaging modality used to characterize the distribution of beta-amyloid deposits in the brain, however interpretation may be subjective and the misdiagnosis rate of AD ranges from 12-23%. Automated algorithms for PET 18F-AV45 interpretation including those derived from deep learning may facilitate more objective and accurate AD diagnosis.

MATERIALS & METHODS

A total of 1232 PET AV45 scans (207 - AD; 1025 - normal) were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). A semi-supervised deep learning framework was developed to differentiate AD and normal patients. The framework consists of an autoencoder (AE), a contrastive learning loss, and a categorical classification head. A contrastive learning paradigm is used to improve the discriminative properties of latent feature vectors in multidimensional space.

RESULTS

Upon five-fold cross-validation, the best-performing semi-supervised contrastive model achieved validation accuracy of 82% to 86%. Secondary analysis included visualization of intermediate activations, classification report verification, and principal component analysis (PCA) of latent feature vectors. The training process yielded optimal converging losses for all three loss frameworks.

CONCLUSION

A deep learning model can accurately diagnose AD using PET 18F-AV45 scans. Such models require large amounts of labeled data during training. The use of a semi-supervised contrastive learning objective and AE regularizer helps to improve model performance, especially when dataset sizes are constrained. Latent representations extracted by the model are visually clustered strongly with the addition of a contrastive learning mechanism.

Summary Statement

A semi-supervised contrastive learning deep learning system optimizes latent feature vector representations and yields strong model classification performance for larger data distributions within the Alzheimer’s Disease diagnostics domain.

Key Points

A common diagnostic procedure used by trained radiologists in the clinical setting is the visual analysis of PET 18F-AV45 neuroimaging scans to diagnose the different stages of Alzheimer’s Disease in a patient.

Contrastive learning is a strategy that allows for the optimization of latent feature representations in multidimensional space through the use of a loss function that maximizes the distance between feature vectors of different classes and minimizes the distance of feature vectors of the same class.

A semi-supervised contrastive learning approach can lead to improved performance and generalization of deep learning models optimized using small training datasets as encountered in Alzheimer’s Disease and other neurodegenerative conditions.
Multimodal neuroimaging data from a 5-week heart rate variability biofeedback randomized clinical trial
Authors: Yoo Hyun Joo , Nashiro Kaoru , Min Jungwon , Cho Christine , Mercer Noah , Bachman Shelby L. , Nasseri Padideh , Dutt Shubir , Porat Shai , Choi Paul , Zhang Yong , Grigoryan Vardui , Feng Tiantian , Thayer Julian F. , Lehrer Paul , Chang Catie , Stanley Jeffrey A. , Marmarelis Vasilis Z. , Narayanan Shrikanth , Nation Daniel A. , Wisnowski Jessica , Mather Mara
Published: December 2022

We present data from the Heart Rate Variability and Emotion Regulation (HRV-ER) randomized clinical trial testing effects of HRV biofeedback. Younger (N = 121, ages 18-31, 61 female) and older (N = 72, ages 55-80, 45 female) participants completed baseline magnetic resonance imaging (MRI) including T1-weighted, functional MRI (fMRI), pulsed continuous arterial spin labeling (PCASL), and proton magnetic resonance spectroscopy (1H MRS). They also completed an emotion regulation task during fMRI. During fMRI scans, physiological measures (blood pressure, pulse, respiration, and end-tidal CO2) were continuously acquired. Participants were randomized to either increase heart rate oscillations or decrease heart rate oscillations during daily sessions. After 5 weeks of HRV biofeedback, they repeated the baseline measurements in addition to a few new measures (ultimatum game fMRI, training mimicking during blood oxygen level dependent (BOLD) and PCASL fMRI). Participants also wore a wristband sensor to estimate sleep time. Psychological assessment comprised three cognitive tests as well as ten questionnaires related to emotional well-being. Data is publicly available via the OpenNeuro data sharing platform.
Characterizing gun violence by time, day of the week, and holidays in six US cities 2015-2021
Authors: Klerman Elizabeth B. , Affouf Mahmoud , Robbins Rebecca , Iyer Jay , Masiakos Peter T. , Sacks Chana A.
Published: December 2022

Developing interventions to prevent firearm-related violence and to address its consequences requires an improved understanding of when these violent events are most likely to occur. We explored gunshot events by time of day, day of week, and holiday/non-holiday in six major US cities. We utilized publicly available police department datasets that report the date and time of day of gunshot events from six major US cities. In these cities, shootings occurred most often at night and on holidays and weekends, with significant interaction effects. Primary prevention efforts should consider this differential risk.
Outcomes After Percutaneous Tracheostomy in Patients with COVID-19: A Single-Center Series of 377 Cases
Authors: Alshukry Abdullah , Alhindi Abdulrazzaq , Alzuabi Majdah , Husain Seema , Tarakmeh Mohammad , Al Qattan Shaima , Al Bader Abdullah , Al Habib Ali , Ali Yaseen , Al-Mulla Fahd , Ali Hamad , Bu Abbas Mohammad
Published: December 2022

Introduction

The COVID 19 pandemic was highlighted by a rise in hospital admissions secondary to respiratory decompensation. This was accompanied by an increase in ICU admissions, endotracheal intubation and mechanical ventilation. As a consequence, tracheostomies became essential in preventing complications of prolonged intubation and to facilitate weaning from sedation and mechanical ventilation. With the lack of international consensus on tracheostomy technique and optimal timing, we present our experience with 377 percutaneous tracheostomies performed on critically ill COVID 19 patients.

Objective

To report the outcomes of critically ill patients with COVID-19 who underwent percutaneous tracheostomy during a period of 24 months.

Methods

A retrospective single-center electronic chart review was performed on all ICU patients who underwent percutaneous tracheostomy after respiratory failure secondary to COVID-19 between March 2020 to March 2022.

Results

A total of 377 percutaneous tracheostomies were performed. The mean duration between intubation and percutaneous tracheostomy was 17.4 days (3-61). The study included 222 males (59%) and 155 females (41%).

The mean age of patients was 56.2 years (17-94), with a mean BMI was 31.3 (14-68).

The commonest comorbidities among patients were diabetes mellitus (50%) and hypertension (48%).

Complications were encountered in 85 cases (23%), with the commonest overall complication being minor bleeding.

203 patients (54%) were weaned from sedation. The mean duration between tracheostomy and weaning from sedation was 7.5 days (1 – 47 days). 156 patients (41%) were weaned from MV. The mean duration between tracheostomy and weaning from MV was 12.9 days (1 – 58 days). There was a total of 236 (63%) deaths reported during the period of this study.

No deaths were attributable to the surgical procedure.

Conclusion

Percutaneous tracheostomy can be safely performed in patients with COVID-19. With lack of conclusive objective data regarding the optimal timing for tracheostomy, we recommend that tracheostomy be performed as soon as possible after the 7thday endotracheal intubation.
Chronic pain gene expression changes in the brain and relationships with clinical traits
Authors: Johnston Keira JA , Cote Alanna C. , Hicks Emily , Johnson Jessica , Huckins Laura M.
Published: December 2022

Background

Chronic pain is a common, poorly-understood condition. Genetic studies including genome wide association studies (GWAS) identify many relevant variants, which have yet to be translated into full understanding of chronic pain. Transcriptome wide association study using transcriptomic imputation (TI) methods such as S-PrediXcan can help bridge this genotype-phenotype gap.

Methods

We carried out TI using S-PrediXcan to identify genetically regulated gene expression (GREX) in thirteen brain tissues and whole blood associated with Multisite Chronic Pain (MCP). We then imputed GREX for over 31,000 Mount Sinai BioMe™ participants and performed phenome-wide association study (PheWAS) to investigate clinical relationships in chronic pain associated gene expression changes.

Results

We identified 95 experiment-wide significant gene-tissue associations (p<7.97×10−7), including 35 unique genes, and an additional 134 gene-tissue associations reaching within-tissue significance, including 53 additional unique genes. Of 89 unique genes total, 59 were novel for MCP and 18 are established drug targets. Chronic pain GREX for 10 unique genes was significantly associated with cardiac dysrhythmia, metabolic syndrome, disc disorders/ dorsopathies, joint/ligament sprain, anemias, and neurological disorder phecodes. PheWAS analyses adjusting for mean painscore showed associations were not driven by mean painscore.

Conclusions

We carried out the largest TWAS of any chronic pain trait to date. Results highlight potential causal genes in chronic pain development, and tissue and direction of effect. Several gene results were also drug targets. PheWAS results showed significant association for phecodes including cardiac dysrhythmia and metabolic syndrome, indicating potential shared mechanisms.
A Statistical Analysis on COVID-19 Pandemic in the City of Toronto
Authors: Kaazempur-Mofrad Ali R.
Published: December 2022

As with many viruses, a main topic of concern that has arisen during the COVID-19 pandemic is the nature of the virus’ spread and the impact it presents for varying age groups. Using statistical methods and numerical summaries, I analysed the impact that age has on the incubation period, death rates, and case outcomes of COVID-19 cases in the city of Toronto. The results of this study illustrate that the elderly have shorter incubation periods, higher death rates, and a higher count of cases which result in fatality. The analysis concludes that the impact of COVID-19 is most felt by the elderly.
The kinetics of humoral and cellular responses after the booster dose of COVID-19 vaccine in inflammatory arthritis patients
Authors: Wroński Jakub , Jaszczyk Bożena , Roszkowski Leszek , Felis-Giemza Anna , Bonek Krzysztof , Kornatka Anna , Plebańczyk Magdalena , Burakowski Tomasz , Lisowska Barbara , Kwiatkowska Brygida , Maśliński Włodzimierz , Wisłowska Małgorzata , Massalska Magdalena , Kuca-Warnawin Ewa , Ciechomska Marzena
Published: December 2022

Introduction

Impaired immunogenicity of COVID-19 vaccinations in inflammatory arthritis (IA) patients results in diminished immunity. However, optimal booster vaccination regimens are still unknown, due to not unstudied kinetics of the immune response after booster vaccinations. Therefore, this study aimed to assess the kinetics of humoral and cellular responses in IA patients after the COVID-19 booster.

Patients and Methods

In 29 IA patients and 16 healthy controls (HC) humoral responses (level of IgG antibodies) and cellular responses (IFN-γ production) were assessed before (T0), after 4 weeks (T1), and after more than 6 months (T2) from the booster vaccination with BNT162b2.

Results

IA patients, but not HC, showed lower anti-S-IgG concentration and IGRA fold change at T2 compared to T1 (p=0.026 and p=0.031). Furthermore, in IA patients the level of cellular response at T2 returned to the pre-booster level (T0). All immunomodulatory drugs, except IL-6 and IL-17 inhibitors for the humoral and IL-17 inhibitors for the cellular response, impaired the immunogenicity of the booster dose at T2. However, none of the immunomodulatory drugs affected the kinetics of both humoral and cellular responses (measured as the difference between response rates at T1 and T2).

Conclusion

Our study showed impaired kinetics of both humoral and cellular responses after the booster dose of the COVID-19 vaccine in IA patients, which, in the case of cellular response, did not allow the vaccination effect to be maintained for more than 6 months. Repetitive vaccination with subsequent booster doses seems to be necessary for IA patients.
Mass Spectrometry-Based Proteomic Profiling of Sonicate Fluid DifferentiatesStaphylococcus aureusPeriprosthetic Joint Infection from Non-Infectious Failure: A pilot study
Authors: Fisher Cody R. , Mangalaparthi Kiran K. , Greenwood-Quaintance Kerryl E. , Abdel Matthew P. , Pandey Akhilesh , Patel Robin
Published: December 2022

Purpose

This study aims to use proteomic profiling of sonicate fluid samples to compare host response duringStaphylococcus aureus-associated periprosthetic joint infection (PJI) and non-infected arthroplasty failure (NIAF) and investigate novel biomarkers to increase diagnostic accuracy.

Experimental Design

In this pilot study, eight sonicate fluid samples (four from NIAF and four fromStaphylococcus aureusPJI) were studied. Samples were reduced, alkylated and trypsinized overnight, followed by analysis using liquid chromatography-tandem mass spectrometry (LC-MS/MS) on a high-resolution Orbitrap Eclipse mass spectrometer. MaxQuant software suite was used for protein identification, filtering, and label-free quantitation.

Results

Principal component analysis of the identified proteins clearly separatedS. aureusPJI and NIAF samples. Overall, 810 proteins were quantified in any three samples from each group and 35 statistically significant differentially abundant proteins (DAPs) were found (2-sample t-test p-values ≤0.05 and log2fold-change values ≥2 or ≤-2). Gene ontology pathway analysis found that microbial defense responses, specifically those related to neutrophil activation, were increased inS. aureusPJI compared to NIAF samples.

Conclusion and Clinical Relevance

Proteomic profiling of sonicate fluid using LC-MS/MS, alone or in combination with complementary protein analyses, differentiatedS. aureusPJI and NIAF in this pilot study.
Association between recent COVID-19 diagnosis on depression and anxiety symptoms among slum residents in Kampala, Uganda
Authors: Wafula Solomon T. , Ninsiima Lesley L. , Mendoza Hilbert , Ssempebwa John C. , Walter Florian , Musoke David
Published: December 2022

Background

An increase in mental health problems has been reported since the beginning of the COVID-19 pandemic. However, little is known about the prevalence of depressive and anxiety disorders, and how recent COVID-19 diagnosis may influence risk of these conditions especially in low-income settings. In this study, we assessed the association between recent COVID-19 diagnosis and depressive and anxiety symptoms among residents in an urban slum setting in Uganda.

Methods

A cross-sectional study was conducted among 284 individuals in a slum settlement in Kampala, Uganda between April and May 2022. We assessed generalized anxiety and depression symptoms using two validated questionnaires. We collected data on sociodemographic characteristics, and self-reported recent COVID-19 diagnosis (in the previous 30 days). Using a modified Poisson regression, adjusted for age, sex, gender and household income, we separately provided prevalence ratios and 95% confidence intervals for the associations between recent COVID-19 diagnosis and depressive and anxiety symptoms.

Results

Overall, 33.8% and 13.4% of the participants met the depression and generalized anxiety screening criteria respectively. People with recent COVID-19 diagnosis were more likely to be depressed (53.1%) than those with no recent diagnosis (31.4%). Participants who were recently diagnosed with COVID-19 reported higher prevalence of anxiety (34.4%) compared to those with no recent diagnosis of COVID-19 (10.7%). After adjusting for confounding, recent diagnosis with COVID-19 was associated with depression (PR= 1.60, 95% CI 1.09 – 2.34) and anxiety (PR = 2.83, 95% CI 1.50 – 5.31).

Conclusion

This study suggests an increased risk of depressive symptoms and GAD in adults following a COVID-19 diagnosis. We recommend additional mental health support for recently diagnosed persons. The long-term of COVID-19 on mental health effects also need to be investigated.
Modulatory effect of Human immunodeficiency virus on serum miR-21, miR-125b and p53 gene: Any prognostic implication?
Authors: Okoye Jude Ogechukwu , Ngokere Anthony Ajuluchukwu , Onyenekwe Charles Chinedum , Omotuyi Olaposi Idowu , Ogenyi Samuel Ifedioranma , Obi Chioma Maureen , Fasogbon Samuel Ayobami
Published: December 2022

Introduction

Identifying individuals at a high risk of developing cervical cancer remains a major challenge, especially among individuals living with HIV. This study evaluated the levels of normally downregulated oncomirs (miR-21, miR-146a, miR-155, miR-182, and miR-200c) and normally upregulated tumor suppressors (miR-let-7b, miR-125b, miR-143, miR-145, and p53 expression) associated with cervical cancer in the serum of women living with and without HIV.

Methods

This case-control study was carried out between the months of May (2017) and April (2019). It included 173 women without abnormal Pap smears and negative for Human papillomavirus and Epstein-Barr virus; confirmed HIV seropositive women (HIV+; n= 103) and HIV seronegative women (HIV-; n= 70). Relative expressions of miRNAs, and the p53 gene in serum were determined using reverse transcriptase PCR and gel electrophoresis. T-test and Pearson’s correlation analyses were carried out on the generated data. Statistical significance was set atp≤ 0.05 and 0.01.

Results

A significantly higher level of miR-21 and lower levels of miR-125b and p53 gene were observed among HIV+ women compared with their HIV-counterparts at p= 0.028, 0.050, and 0.049, respectively. Among HIV+ women, significant direct correlations were observed between miR-21 and other oncomirs, including miR-145 (p< 0.05) while a significant inverse correlation was observed between miR-21 and miR-let-7b level (p= 0.013).

Conclusion

This study suggests that a high circulating level of miR-21 and a low circulating level of miR-125b could be used as biomarkers for identifying individuals at risk of developing cervical cancer, especially among HAART-naïve women who are living with HIV.
Quality of life and its associated factors among epileptic patients on treatment follow up in North Shoa administration, Amhara National State, Ethiopia
Authors: Guday Esubalew , Engdaye Getabalew , Tekleyohannes Belachew , Alemnew Nigus , Eshete Akne , Sewale Yihenew
Published: December 2022

Background

Epilepsy is a common condition worldwide and has been observed to affect quality of life. Epilepsy patients have a lower quality of life than the general population as well as many other chronic disease patients. However, aside from focusing on symptom reduction, no attention is paid to the quality of life of those with epilepsy. This study aims to evaluate quality of life and associated characteristics among epilepsy patients who visited North Shoa zone hospitals in Ethiopia.

Methods

An institution-based cross-sectional study design was conducted from April -May 2021 at North Shoa zone hospitals. A systematic random sampling technique was used to get a total number of 472 samples. Data on quality of life was assessed through interviews using the World Health Organization Quality of Life—Brief (WHOQOLBREF) Version. The collected data were coded, entered into Epi Data 3.1, and analyzed by using SPSS version 25. Simple and multiple linear regression analysis models were fitted and the unstandardized β coefficient at 95% confidence interval was employed. The statistical significance was accepted atp-value <0.05.

Results

From a total of 472 participants the response rate was 98%. The mean score of quality of life was 57.2±12.3. Age (β=5, 95% CI: 2.301, 7.699), marital status (β=-6.914, 95%CI: -8.867, - 4.961),seizure frequency (β=-.2.307, 95%CI: -4.795, .020), Anti-epileptic drug non-adherence (β=-.11.016, 95%CI: -13.642, -8.389), anxiety (β-4.062, 95%CI: (−6.503, -1.621), poor social support (β=-6.220, 95%CI: (−8.422, -4.017) and moderate social support (β=-5.58, 95%CI: -7.792, -3.368) were significantly associated with quality of life.

Conclusion

The mean quality of life of people living with epilepsy in this study was low. Age, marital status, seizure frequency, concomitant anxiety, antiepileptic drug non-adherence, number of anti-epileptic drugs/day, moderate and poor social support were all found to be predictors of quality of life in this study. As a suggestion, the patient treatment plan should include a quality of life assessment that addresses psychosocial concerns; professional counseling on how to cope with psychological, environmental, and social difficulties should be increased.
Direct Detection and Identification of Viruses in Saliva Using a SpecID™ Ionization Modified Mass Spectrometer
Authors: Alusta Pierre , Parades Angel , Azevedo Marli , Mullis Lisa , Buzatu Dan
Published: December 2022

Disclaimer

The authors have withdrawn their manuscript because their institution requires the obtention of additional clearances. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.
Healthcare Performance of Leprosy Management in Peripheral Health Facilities of Dhanusa and Mahottari, Nepal
Authors: Mahato Ram Kumar , Ghimire Uttam , Bajracharya Bijay , Binod KC , Bam Deepak , Ghimire Deepak , Pyakurel Uttam Raj , Hayman David TS , Pandey Basudev , Das Chuman Lal , Paudel Krishna Prasad
Published: December 2022

Background

The global elimination of leprosy transmission by 2030 is a World Health Organization (WHO) target. Nepal’s leprosy elimination program depends on early case diagnosis and the performance of health workers and facilities. The knowledge and skills of paramedical staff (Leprosy Focal Person, LFP) and case documentation and management by health facilities is therefore key to the performance of health care services.

Methods

The performance of health workers and facilities was evaluated through a combined cross sectional and retrospective study approach of 31 health facilities and their LFPs in Dhanusa and Mahottari Districts in Madhesh Province, Nepal. An average of 6 patients (paucibacillary, PB, or multibacillary, MB) per health facility registered within the 2018/2019 fiscal year were also enrolled in the study. LFP knowledge (e.g., of the three cardinal signs) and skills (e.g., nerve palpation) and facility processes (e.g., record keeping) were scored (e.g., 0, 1) and then rescaled to a proportion, where 1 is perfect. Internal benchmarking was used to guide performance management.

Results

Overall LFP knowledge and skill scores ranged from 0.16 to 0.63 (median 0.53, 95% confidence interval (CI), 0.46-0.6). Case documentation scores ranged from 0.15 to 0.87 (median 0.37, 95% CI 0.36-0.38), case management scores from 0.38 to 0.79 (median 0.54, 95% CI 0.53-0.55) and the overall healthcare scores ranged from 0.36-0.62 (median 0.48, 95% CI 0.47-0.49). Leprosy-related training was significantly related to the knowledge and skill of the health workers. All identified cases (n =187) adhered to the complete treatment and release after treatment (RFT) scheme, out of which 84.5% were satisfied with the service they were provided. Leprosy disability and Ear Hand and Feet (EHF) scores were not significantly reduced in treated patients during the study period, but counseling by LFPs significantly improved cases’ positive belief and practices regarding self-care.

Conclusion

Overall leprosy care performance was low (43%) and can be improved by evidenced-based training, onsite coaching, monitoring, and supervision to facilitate leprosy transmission elimination. The results highlight many of the challenges facing leprosy elimination programs.
Trends in self-reported cost barriers to dental care in Ontario
Authors: Abdelrehim Mona , Ravaghi Vahid , Quiñonez Carlos , Singhal Sonica
Published: December 2022

Background

The affordability of dental care continues to receive attention in Canada. Since most dental care is privately financed, the use of dental care is largely influenced by insurance coverage and the ability to pay-out-of pocket.

Objectives

1) To explore trends in self-reported cost barriers to dental care in Ontario; 2) To determine the socio-economic and demographic characteristics of Ontarians reporting cost barriers to dental care; and 3) To identify what predicts reporting cost barriers to dental care in Ontario.

Methods

A secondary data analysis of five cycles (2003, 2005, 2009-10, 2013-14 and 2017-18) of the Canadian Community Health Survey (CCHS) was undertaken. The CCHS is a cross-sectional survey that collects information related to health status, health care utilization, and health determinants for the Canadian population. Univariate and bivariate analyses were conducted to determine the characteristics of Ontarians who reported cost barriers to dental care. Poisson regression was used to calculate unadjusted and adjusted prevalence ratios to determine the predictors of reporting a cost barrier to dental care.

Results

In 2014, 34% of Ontarians avoided visiting a dental professional in past three years due to cost, up from 22% in 2003. Having no insurance was the strongest predictor for reporting cost barriers to dental care, followed by being 20-39 years of age and having a lower income.

Conclusion

Self-reported cost barriers to dental care have generally increased in Ontario but more so for those with no insurance, low income, and aged 20-39 years.
A probabilistic view of protein stability, conformational specificity, and design
Authors: Stern Jacob A. , Free Tyler J. , Stern Kimberlee L. , Gardiner Spencer , Dalley Nicholas A. , Bundy Bradley C. , Price Joshua L. , Wingate David , Corte Dennis Della
Published: December 2022

Several recently introduced approaches use neural networks as probabilistic models for protein sequence design. These models use various objective functions and optimization schemes. The choice of objective function and optimization scheme comes with trade-offs that are not always well explained. We introduce probabilistic definitions of protein stability and conformational specificity and show how these chemical properties relate to thep(structure| seq) objective used in recent protein design algorithms. This links probabilistic objective functions to experimentally testable outcomes. We present a new sequence decoding algorithm, termed “BayesDesign”, that uses Bayes’ Rule to maximize thep(structure| seq) objective. We evaluate BayesDesign in the context of two protein model systems, the NanoLuc enzyme and the WW structural motif.
The BRUTUS-LIKE E3 ligases BTSL1 and BTSL2 fine-tune transcriptional responses to balance Fe and Zn homeostasis
Authors: Stanton Camilla , Rodríguez-Celma Jorge , Kraemer Ute , Sanders Dale , Balk Janneke
Published: December 2022

The mineral micronutrients zinc (Zn) and iron (Fe) are essential for plant growth and human nutrition, but interactions between the homeostatic networks of these two elements are not fully understood. Here we show that loss-of-function ofBTSL1andBTSL2, which encode partially redundant E3 ubiquitin ligases that negatively regulate Fe uptake, confers tolerance to Zn excess inArabidopsis thaliana. Doublebtsl1 btsl2mutant seedlings grown on high Zn medium accumulated similar amounts of Zn in roots and shoots as the wild type, but suppressed the accumulation of excess Fe in roots. RNA-seq analysis showed that roots of mutant seedlings had relatively higher expression of genes involved in Fe uptake (IRT1, FRO2, NAS) and in Zn storage (MTP3, ZIF1). Surprisingly, mutant shoots did not show the transcriptional Fe-deficiency response which is normally induced by Zn excess. Split-root experiments suggested that within roots the BTSL proteins act locally and downstream of systemic Fe deficiency signals. Together, our data show that constitutive low-level induction of the Fe-deficiency response protectsbtsl1 btsl2mutants from Zn toxicity. We propose that BTSL protein function is disadvantageous in situations of external Zn and Fe imbalances, and formulate a general model for Zn-Fe interactions in plants.

Highlight

Mutation of two E3 ligases that suppress iron uptake in roots also confers tolerance to zinc toxicity, identifying a regulatory point of interaction between iron and zinc homeostasis.
Bariatric surgery: preparations and quality of life consequences
Authors: Lozano Liis , Põder Triin , Lozano George A.
Published: December 2022

Introduction

Obesity is a major threat to global health. When more conventional methods have failed, obesity can be addressed via bariatric surgery. Here we examine the reasons why patients choose bariatric surgery and the behavioral consequences thereafter.

Methods

A qualitative study with a phenomenological design was used to analyze detailed interview responses from recipients of bariatric surgery.

Results

Before surgery, (a) bariatric surgery was chosen for obvious reasons: patients had been overweight, had obesity-related health problems, and had difficulties moving. (b) Information was obtained from medical practitioners and online discussion groups. (c) Fear, anxiety, and apprehension were common. Friends and family were sometimes supportive and sometimes disapproving. After surgery, (1) many chronic health problems disappeared or eased significantly. (2) Subjects had difficulties adjusting to small portions and altered food preferences. (3) Physical activity increased. (4) Self-esteem increased but the worry of regaining the weight remained. (5) As before surgery, there were both supportive and condemning attitudes by relatives, friends, and society. (6) A desire for further nutritional and psychological counseling was indicated. (7) Relationships and quality of sex improved in most cases but not always. Single women, particularly, became more active in potential relationships.

Discussion

With a few exceptions, our results agree with the literature, supporting the idea that bariatric surgery leads to extensive physical, psychological, and social changes. Hence, patients ought to be better prepared for these changes, and medical practitioners ought to be aware of the magnitude of the changes this surgery will bring about in their patients’ lives.
Untargeted serum metabolomics reveals novel metabolite associations and disruptions in amino acid and lipid metabolism in Parkinson’s disease
Authors: Paul Kimberly C , Zhang Keren , Walker Douglas I , Sinsheimer Janet , Yu Yu , Kusters Cynthia , Rosario Irish Del , Folle Aline Duarte , Keener Adrienne M , Bronstein Jeff , Jones Dean P , Ritz Beate
Published: December 2022

Objectives

Recent advances in high-resolution metabolomics platforms allow the simultaneous measurement of thousands of small molecules produced from metabolism (metabolites), providing a map of disease-related perturbations across interconnected pathways. We used high performance, untargeted metabolomics to identify metabolic disturbances and molecular events associated with Parkinson’s disease (PD) in two population-based studies.

Methods

We performed a metabolome-wide association study (MWAS) on PD, using serum-based untargeted metabolomics data derived from high resolution liquid chromatography, mass spectrometry (LCMS). We used two independent, case-control populations for discovery and replication (n=642 PD patients, n=277 controls).

Results

From the LCMS, 5,145 metabolites were detected across the two study populations in ≥50% of the samples (HILIC: 2913 metabolites; C18: 2063 metabolites). Using logistic regression and an FDR to correct for multiple testing, we determined 236 metabolites were associated with PD in a meta-analysis at an FDR<0.05. Of these, 110 metabolites were independently associated with PD in both discovery and replication studies at p<0.05 (187 at p<0.10), while 24 were associated with levodopa-equivalent dose among the PD patients. Intriguingly, the microbial related metabolite, p-cresol (meta-OR=1.29, 95% CI=1.13, 1.47, FDR=0.01), and it’s two metabolites, p-cresol sulfate and p-cresol glucuronide, were found at higher intensity among the PD patients relative to controls. P-cresol glucuronide was also associated with motor symptoms among patients. Pyroglutamic acid (meta OR=3.79, 95% CI=2.60, 5.54; FDR=5.30E-09), the anti-inflammatory metabolite itaconate (meta OR=0.47, 95% CI=0.36, 0.61; FDR=8.44E-06), and cysteine-S-sulfate (meta OR=1.56, 95% CI=1.32, 1.83; FDR=1.66E-05) were also among the most strongly associated metabolites. Seventeen pathways were also enriched, including several related to amino acid and lipid metabolism.

Conclusions

Our results revealed PD-associated metabolites in two independent study populations, implicating individual metabolites including p-cresol and itaconate, as well as suggesting metabolic disturbances in amino acid and lipid metabolism and inflammatory processes.
Trans-ancestry epigenome-wide association meta-analysis of DNA methylation with lifetime cannabis use
Authors: Fang Fang , Quach Bryan , Lawrence Kaitlyn G. , van Dongen Jenny , Marks Jesse A. , Lundgren Sara , Lin Mingkuan , Odintsova Veronika V. , Costeira Ricardo , Xu Zongli , Zhou Linran , Mandal Meisha , Xia Yujing , Vink Jacqueline M. , Bierut Laura J , Ollikainen Miina , Taylor Jack A. , Bell Jordana T. , Kaprio Jaakko , Boomsma Dorret I. , Xu Ke , Sandler Dale P. , Hancock Dana B. , Johnson Eric O.
Published: December 2022

Cannabis is widely used worldwide, yet its links to health outcomes are not fully understood. DNA methylation can serve as a mediator to link environmental exposures to health outcomes. We conducted an epigenome-wide association study (EWAS) of peripheral blood-based DNA methylation and lifetime cannabis use (ever vs. never) in a meta-analysis including 9,436 participants (7,795 European and 1,641 African ancestry) from seven cohorts. Accounting for effects of cigarette smoking, our trans-ancestry EWAS meta-analysis revealed four CpG sites significantly associated with lifetime cannabis use at a false discovery rate of 0.05 (p< 5.85 × 10−7): cg22572071 near geneADGRF1, cg15280358 inADAM12, cg00813162 inACTN1, and cg01101459 nearLINC01132. Additionally, our EWAS analysis in participants who never smoked cigarettes identified another epigenome-wide significant CpG site, cg14237301 annotated toAPOBR. We used a leave-one-out approach to evaluate methylation scores constructed as a weighted sum of the significant CpGs. The best model can explain 3.79% of the variance in lifetime cannabis use. These findings unravel the DNA methylation changes associated with lifetime cannabis use that are independent of cigarette smoking and may serve as a starting point for further research on the mechanisms through which cannabis exposure impacts health outcomes.
Linking air pollution exposure to blood-based metabolic features in a community-based aging cohort
Authors: Kalia Vrinda , Kulick Erin R. , Vardarajan Badri , Gu Yian , Manly Jennifer J. , Elkind Mitchell S.V. , Kaufman Joel D. , Jones Dean P. , Baccarelli Andrea A. , Mayeux Richard P. , Kioumourtzoglou Marianthi-Anna , Miller Gary W.
Published: December 2022

Long-term exposure to air pollution has been associated with changes in levels of several metabolites measured in the peripheral blood. However, most work has been conducted in ethnically homogenous populations. We studied the relationship between the plasma metabolome and long-term exposure to three air pollutants: particulate matter (PM) less than 2.5 µm in aero diameter (PM2.5), PM less than 10 µm in aero diameter (PM10) and nitrogen dioxide (NO2) among 107 participants of the Washington Heights and Inwood Community Aging Project (WHICAP) in New York City. Plasma metabolomic profiles were generated using untargeted liquid chromatography coupled with high-resolution mass spectrometry. We estimated the association between each metabolic feature and predicted annual mean exposure to the air pollutants using three approaches: 1. A metabolome wide association study (MWAS) framework; 2. Feature selection using elastic net regression; and 3. A multivariate approach using partial least squares discriminant analysis. Additionally, we identified the pathways enriched by metabolic features associated with exposure through pathway analysis. The samples were collected from 1995 – 2015 and included non-Hispanic white, Caribbean Hispanic, and non-Hispanic Black older adults. Through the MWAS, we found 79 features associated with exposure to PM2.5(false discovery rate at 5%) but none associated with PM10or NO2. Pathway analysis revealed that PM2.5exposure was associated with altered amino acid metabolism, energy production, and oxidative stress response. Six features were found to be associated with PM2.5exposure through all three approaches, annotated as: cysteinylglycine disulfide, a diglyceride, and a dicarboxylic acid. Additionally, we found that the relationship between several features and PM2.5exposure was modified by diet and metabolic diseases. These signals, identified in a neighborhood-representative older population, could help understand the mechanisms through which PM2.5exposure can lead to altered metabolic outcomes in an older population.

HIGHLIGHTS

Long-term exposure to PM2.5is associated with altered plasma metabolic features in an aging population

These associations are modified by a dementia diagnosis, history of diabetes, APOE-ε4 allele, and diet

Pathways related to energy production, amino acid metabolism, and redox homeostasis are associated with exposure to PM2.5

GRAPHICAL ABSTRACT
Drivers of plant intraspecific variation are trait-specific
Authors: Zhou Jianhong , Cieraad Ellen , van Bodegom Peter M.
Published: December 2022

The importance of intraspecific trait variation (ITV) in community dynamics is increasingly being recognised, but the drivers of ITV have not yet been well-studied. Here, we analysed whether environmental conditions, biotic interactions and species features are related to ITV on a global scale.

We compiled a global species’ ITV database including 2064 species which occurred in 1068 communities (plots) across 19 countries with 11 functional traits. The magnitudes of species’ ITV in this database were calculated according to the trait-gradient analysis which is independent of the length of the environmental gradient.

We found that different traits had different main drivers, so we consider the drivers of ITV to be trait-specific. However, our findings still brought some order among these idiosyncratic patterns: leaf economics spectrum traits were more related to environmental conditions and leaf morphology traits were more related to biotic interactions. Size-related traits were related to both abiotic and biotic conditions.

Our research suggests that the drivers of ITV deviated from the drivers of the mean trait values and that some trait coordination may fall apart upon climate change. Thus, our analysis enhances our understanding of trait variation and has important implications for models predicting vegetation responses to environmental change.
TAD border deletion at theKitlocus causes tissue-specific ectopic activation of a neighboring gene
Authors: Kabirova Evelyn , Ryzhkova Anastasiya , Lukyanchikova Varvara , Khabarova Anna , Korablev Alexey , Shnaider Tatyana , Nuriddinov Miroslav , Belokopytova Polina , Kontsevaya Galina , Serova Irina , Battulin Nariman
Published: December 2022

Topologically associated domains (TADs) restrict promoter-enhancer interactions, thereby maintaining the spatiotemporal pattern of gene activity. However, rearrangements of the TADs boundaries do not always lead to significant changes in the activity pattern. Here, we investigated the consequences of the TAD boundaries deletion on the expression of developmentally important genes encoding tyrosine kinase receptors:Kit, Kdr, Pdgfra. We used genome editing in mice to delete the TADs boundaries at theKitlocus and characterized chromatin folding and gene expression in pure cultures of fibroblasts, mast cells, and melanocytes. We found that althoughKitis highly active in both mast cells and melanocytes, deletion of the TAD boundary between theKitandKdrgenes results in ectopic activation only in melanocytes. Thus, the epigenetic landscape, namely the mutual arrangement of enhancers and actively transcribing genes, is important for predicting the consequences of the TAD boundaries removal. We also found that mice without a TAD border between theKitandKdrgenes have a phenotypic manifestation of the mutation — a lighter coloration. Thus, the data obtained shed light on the principles of interaction between the 3D chromatin organization and epigenetic marks in the regulation of gene activity.
How collectively integrated are ecological communities?
Authors: Zelnik Yuval R. , Galiana Nuria , Barbier Matthieu , Loreau Michel , Galbraith Eric , Arnoldi Jean-François
Published: December 2022

Beyond abiotic conditions, do population dynamics mostly depend on the species’ direct predators, preys and conspecifics? Or can indirect feedbacks that ripple across the whole community be equally important? Here we show that the spectral radius of a community’s interaction matrix controls the length of indirect interaction pathways that actually contribute to community-level dynamical patterns, such as the depth of a perturbation’s reach, or the contribution of biotic processes to realized species niches. The spectral radius is a measure of collectivity that integrates existing approaches to complexity, interaction structure and indirect interactions, while also being accessible from imperfect knowledge of biotic interactions. Our work provides an original perspective on the question of to what degree communities are more than loose collections of species or simple interaction motifs; and explains when reductionist approaches focusing on particular species and small interaction motifs, ought to suffice or fail when applied to ecological communities.
Genetic adaptation rates differ by trait and plant type --a comprehensive meta-analysis
Authors: Zhou Jianhong , Cieraad Ellen , van Bodegom Peter M.
Published: December 2022

Plants can respond to changing climatic conditions through genetic adaptation of their functional traits. Despite the relevance of adaptation to climate change, much remains unknown about plant genetic adaptation rates, including whether these rates differ among plant characteristics and trait types.

We performed a meta-analysis to investigate patterns of genetic adaptation rates and assess how these rates differ among plant species groups, growth forms and trait types, using a newly compiled database from 74 studies, comprising 35 functional traits across 72 angiosperm species. This database specifically focuses on genetic adaptation of plant functional traits, as separating from phenotypic plasticity.

Both annual and generational adaptation rates of plant traits decrease non-linearly with increasing elapsed time since divergence. Plants adapt fastest when first introduced to a changing environment, but these rates go slow subsequently. Overall, shrubs have higher adaptation rates than trees, which confers shrubs an adaptive advantage over trees. Different adaptation rates among growth forms, life histories and trait types suggest an important additional mechanism through which climate change may affect community composition.

Our study has important implications regarding plant adaptation to new environments and will improve the prediction of vegetation responses and ecosystem functioning upon climate change.