bluuebunny/crossref_metadata_2025 huggingface dataset:
Vaccine-induced antibody level predicts the clinical course of breakthrough infection of COVID-19 caused by delta and omicron variants: a prospective observational cohort study
Authors: Kim Min Hyung , Nam Yooju , Son Nak-Hoon , Heo Namwoo , Kim Bongyoung , Kang Eawha , Shin Areum , Yang Andrew Jihoon , Park Yoon Soo , Kim Heejung , Kyong Taeyoung , Kim Yong Chan
Published: March 2022

Background

Omicron variant viruses spread rapidly, even in individuals with high vaccination rates. This study aimed to determine the utility of the antibody against the spike protein level as a predictor of the disease course of COVID-19 in vaccinated patients.

Methods

Between 11 December 2021 and 10 February 2022, we performed a prospective observational cohort study in South Korea, which included patients infected with delta –and –omicron variants. Multivariable logistic regression analysis to determine the association between antibody levels and the outcomes was conducted.The relationship between antibody levels and cycle threshold (Ct) values was confirmed using a generalised linear model.

Results

From 106 vaccinated patients (39 delta and 67 omicron), the geometric mean titres of antibodies in patients withfever (≥37.5 °C), hypoxia (≤94% of SpO2), pneumonia, C-reactive protein (CRP) elevation (>8 mg/L), or lymphopenia (<1,100 cells/μL) were 1,201.5 U/mL, 98.8 U/mL, 774.1 U/mL, 1,335.1 U/mL, and 1,032.2 U/mL, respectively. Increased antibody levels were associated with a decrease in the fever occurrence (adjusted odds ratio [aOR], 0.23; 95% confidence interval [CI], 0.12–0.51), hypoxia (aOR, 0.23; 95% CI, 0.08–0.7), CRP elevation (aOR, 0.52; 95% CI, 0.29–0.0.94), and lymphopenia (aOR, 0.57; 95% CI, 0.33–0.98). Ct values showed a positive correlation between antibody levels (P =0.02).

Conclusion

Antibody levels are predictive of the clinical course of COVID-19 in vaccinated patients with delta and omicron variant infections. Our data highlight the need for concentrated efforts to monitor patients with SARS-CoV-2 infection who are at risk of low antibody levels.

In this prospective observation cohort study, antibody level predicts clinical course of breakthrough infection of COVID-19. Fever (aOR 0.23[0.12-0.51], hypoxia (aOR 0.23[0.08-0.7]), CRP elevation(aOR 0.52[0.29-0.0.94] and lymphopenia (aOR 0.57[0.33-0.98]) were inversely correlated with antibody levels.
Amputation in Kingdom of Saudi Arabia: Etiology, Characteristics and Clinical status from a Large Tertiary Rehabilitation Center
Authors: Shahine Enas M. , Silarbi Mohamed T. , Alzeer Abdullah , Bukhamseen Mostafa , Alzaraa Khalid Mohammed , Saba Iram
Published: March 2022

Introduction

Limb amputation significantly impacts the patient’s physical, emotional, and social life. Multiple etiological factors may lead to limb amputation. Unfortunately, there is limited data about amputation in Saudi Arabia. Since Sultan Bin Abdulaziz Humanitarian City (SBAHC) is a tertiary centre receiving such patients, we collected data from ten years to look at the etiology, characteristics, and clinical impact of amputations in the Kingdom.

Methods

A retrospective study of 1409 amputee patients’ data at SBAHC collected over ten years included demographic variables, etiology, site, level, and type of amputation. We also collected Functional independent measurement (FIM) scores for 618 patients.

Result

Males constitute the majority of amputees (75.7%) and the average age in males was higher in males compared to females (45 vs 36 years respectively, p<0.001). Vascular diseases (42.3%) and Trauma (36.8%) were the leading cause of amputation in this cohort. Diabetes mellitus was the most frequent comorbidity (40.5%), followed by hypertension (26.2%). Transtibial amputations were the most typical (22.58%), followed by trans-femoral amputation (14.12%). Traumatic trans-femoral amputation was more prevalent among young adults than traumatic trans-tibial amputation. Trauma-related amputation cases were highest in the age group of 21-30 years (69.2%), while vascular related amputations were highest in the age group of 70 and above years (89.5%). FIM scores improved significantly in locomotion (33.6%) followed by transfer (30.6%) and self-care (16.4%) at six-month post discharge compared to admission (all p-values<0.01).

Conclusion

Vascular pathology arising due to chronic diseases is the primary risk factor that may lead to amputation and warrant primary and secondary prevention programs. Seatbelt enforcement can significantly decrease amputation related to Road Traffic Accidents, which has been the second most familiar cause of amputation.
Assessment of Androgen Receptor splice variant-7 as a biomarker of clinical response in castration-sensitive prostate cancer
Authors: Sowalsky Adam G. , Figueiredo Ines , Lis Rosina T. , Coleman Ilsa , Gurel Bora , Bogdan Denisa , Yuan Wei , Russo Joshua W. , Bright John R. , Whitlock Nichelle C. , Trostel Shana Y. , Ku Anson T. , Patel Radhika A. , True Lawrence D. , Welti Jonathan , Jimenez-Vacas Juan M. , Rodrigues Daniel Nava , Riisnaes Ruth , Neeb Antje , Sprenger Cynthia T. , Swain Amanda , Wilkinson Scott , Karzai Fatima , Dahut William L. , Balk Steven P. , Corey Eva , Nelson Peter S. , Haffner Michael C. , Plymate Stephen R. , de Bono Johann S. , Sharp Adam
Published: March 2022

Background

Therapies targeting the androgen receptor (AR) have improved the outcome for patients with castration-sensitive prostate cancer (CSPC). Expression of the constitutively active AR splice variant-7 (AR-V7) has shown clinical utility as a predictive biomarker of AR-targeted therapy resistance in castration-resistant prostate cancer (CRPC), but its importance as predictive biomarker in CSPC remains understudied.

Methods

We explored multiple approaches to quantify AR-V7 mRNA and protein in prostate cancer cell lines and patient-derived xenograft (PDX) models, in both publicly available and independent institutional clinical cohorts, to identify reliable approaches for detecting AR-V7 mRNA and protein, and its association with clinical outcome.

Results

In publicly available benign prostate, CSPC and CRPC cohorts, AR-V7 mRNA was much less abundant when detected using reads across splice boundaries than when considering isoform-specific exonic reads. The RM7 AR-V7 antibody had increased sensitivity and specificity for AR-V7 protein detection by immunohistochemistry (IHC) in CRPC cohorts and identified AR-V7 protein reactivity very rarely in CSPC cohorts, when compared to the EPR15656 AR-V7 antibody. Using multiple CRPC PDX models, we demonstrated that AR-V7 expression was exquisitely sensitive to hormonal manipulation. In CSPC cohorts, AR-V7 protein quantification by either assay did not associate with time to development of castration-resistance or overall survival, and intense neoadjuvant androgen-deprivation therapy did not lead to significant detectable AR-V7 mRNA or staining following treatment, and neither pre- nor post-treatment AR-V7 levels associated with the volume of residual disease after therapy.

Conclusion

This study demonstrates that further analytical validation and clinical qualification is required before AR-V7 can be considered for clinical use in CSPC as a predictive biomarker.
Current epidemiological situation of COVID-19 in the Republic of Belarus: characteristics of the epidemic process, sanitary and anti-epidemic measures
Authors: Dashkevich Ala M , Kolomiets Natalia D , Vysotskaya Veronika S , Hlinskaya Iryna N , Skuranovich Anzhela L , Tarasenka Aliaksandr A , Karaban Inna A , Gasich Elena L
Published: March 2022

This is an analysis of the features of the COVID-19 pandemic the population of the Republic of Belarus from February 2020 to January 2022, the characteristics of sanitary and anti-epidemic measures carried out in the country, assessment of study the safety (tolerance) of the vaccines used the epidemiological efficacy of the vaccination.

A retrospective analysis of COVID-19 cases in the Republic of Belarus from the beginning of registration (February 28, 2020) to January, 3, 2022 was performed. Vaccine safety (tolerance) and efficacy were assessed in an observational study. Safety (tolerance) was assessed by presence/absence of adverse reactions: general (fever, malaise, headache, muscle pain, runny nose, nausea, vomiting, sore throat, etc) and local ones (redness, swelling, soreness at the injection place).

The COVID-19 pandemic in the Republic of Belarus is characterized by successive development stages: from no cases in early 2020 to detected cases where most individuals had no history of contact with COVID-19 patients; periods of rising and falling incidence

Vaccines against COVID-19 (Gam-COVID-Vac (Russia), inactivated vaccine against SARS-CoV-2 (Vero Cell) Sinopharm / BIBP (China) demonstrated a high safety profile in mass vaccination of the population of the Republic of Belarus.
Prevalence and Predictors of Depression, Anxiety and Stress among Elderly in the aftermath of COVID-19: A Quantitative Study from Central India
Authors: Malhotra Varun , Javed Danish , Bharshankar Rajay , Singh Vijender , Gautam Namita , Mishra Shweta , Chundawat Digpal S. , Kushwah Anuradha , Singh Gyanendra
Published: March 2022

Background

Elderly persons have been more prone to depression, anxiety and stress during COVID-19 pandemic. They need more care and support towards mental health during these difficult times.

Methodology

This was a cross-sectional and quantitative study conducted in the state of Madhya Pradesh, during the month of March 2021 to August 2021. Participants were recruited from a population aged more than 60 years, those who were able to read and write Hindi/English or having at least one family member; reporting to a tertiary care teaching hospital during the second wave of COVID-19 in India. Those who were confirmed COVID-19 cases & undergoing treatment, with diagnosed mental health disorders and who didn’t give consent were excluded. A semi-structured questionnaire along with DASS-21 scale was completed by participants online.

Results

Out of 690 subjects, 7.25% had mild and moderate depression, 0.58% had severe and extremely severe depression. Mild and moderate anxiety symptoms were reported by 9.56%, 2.46% reported severe and extremely severe anxiety. Mild and moderate stress was reported by 4.78%, while 0.42% were severely and extremely stressed. A positive statistical association was found between alcohol addiction and depression (p=0.028). The elderly subjects had a nap the day time were significantly less depressed during COVID-19 pandemic (p=0.033). It was found that older the subjects, more were they anxious during the pandemic (p=0.042). An association was found between alcohol addiction and stress (p=0.043).

Conclusions

Depressive symptoms in participants were positively correlated with alcohol addiction. Females reported higher level of stress. There is a felt need to formulate psychological interventions for elderly to improve their mental health and psychological resilience. We need to tackle and fight the stigma, fear and anxiety related to the COVID-19, which is greater than disease itself.

Key message

What is already known

Psychological problems like anxiety, depressive symptoms, fearfulness, a state of uncertainty and stress are common in all age groups; furthermore older adults are more prone to develop mental health issues in wake of stressful situations.

What this study adds to

About one fourth of elderly developed anxiety, depression and stress during the COVID-19 pandemic.

Effect on practice and policy

There is a need for proactive identification through screening of elderly for mental health issues following unprecedented stress like COVID-19 pandemic.
Victimization and witnessing of workplace bullying and physician-diagnosed physical and mental health and organizational outcomes: a cross-sectional study of a nationally representative sample in Japan
Authors: Tsuno Kanami , Kawakami Norito , Tsutsumi Akizumi , Shimazu Akihito , Inoue Akiomi , Odagiri Yuko , Shimomitsu Teruichi
Published: March 2022

Background

Compared to the numerous reports on mental health outcomes of workplace bullying victims, research on organizational outcomes of witnesses and physical health outcomes of victims and witnesses is scarce. Therefore, the purpose of this study was to investigate the relationship between bullying victimization and witnessing and various physical and mental health outcomes and organizational outcomes such as sickness absence, work performance, and job satisfaction.

Methods

This study used cross-sectional data from a nationally representative, community-based sample of 5,000 Japanese residents aged 20-60. We analyzed data from 1,496 respondents after excluding those not working at the time of the survey and those with missing values. Workplace bullying, psychological distress, physical complaints, and job satisfaction were assessed with the New Brief Job Stress Questionnaire and work performance with the World Health Organization’s Health and Work Performance Questionnaire. In addition, subjective health status, physician-diagnosed mental or physical illness, and sickness absence were asked as one item. Hierarchical multiple regression analysis or Poisson regression analysis was conducted to assess the association between victimization/witnessing workplace bullying and health and organizational outcomes.

Results

Both victimization and witnessing workplace bullying were significantly associated with psychological distress, physical complaints, subjective poor health, physician-diagnosed mental disorders, and job dissatisfaction. Victimization of workplace bullying was further associated with physician-diagnosed respiratory diseases, sickness absence (≥7 days), and poor work performance. Victims were absent from work for 4.5 more sick days and had 11.2% lower work performance than non-victims.

Conclusions

The results showed that both victimization and witnessing workplace bullying were significantly associated with physical and mental outcomes and various organizational outcomes. Organizations should implement further measures to prevent personal and organizational losses due to workplace bullying.
Cellular and humoral immune response to a third dose of BNT162b2 COVID-19 vaccine – a prospective observational study
Authors: Herzberg Jonas , Fischer Bastian , Becher Heiko , Becker Ann-Kristin , Honarpisheh Human , Guraya Salman Yousuf , Strate Tim , Knabbe Cornelius
Published: March 2022

Background

Since the introduction of various vaccines against SARS-CoV-2 at the end of 2020, rates of infection have continued to climb worldwide. This led to the establishment of a third dose vaccination in several countries, known as a booster. To date, there has been little real-world data about the immunological effect of this strategy.

Methods

We compared the humoral- and cellular immune response before and after the third dose of BioNTech/Pfizer vaccine BNT162b2, following different prime-boost regimes. Humoral immunity was assessed by determining anti-SARS-CoV-2 binding antibodies using a standardized quantitative assay. In addition, neutralizing antibodies were measured using a commercial surrogate ELISA-assay. Interferon-gamma release was measured after stimulating blood-cells with SARS-CoV-2 specific peptides using a commercial assay to evaluate the cellular immune response.

Results

The median antibody level increased significantly after the third dose to 2663.1 BAU/ml vs. 101.4 BAU/ml (p < 0.001) before administration of the boosting dose. This was also detected for neutralizing antibodies with a binding inhibition of 99.68% ± 0.36% vs. 69.06% ± 19.88% after the second dose (p < 0.001).

96.3% of the participants showed a detectable T-cell-response after the third dose with a mean interferon-gamma level of 2207.07 mIU/ml ± 1905 mIU/ml.

Conclusion

This study detected a BMI-dependent increase after the third dose of BNT162b2 following different vaccination protocols, whereas all participants showed a significant increase of their immune response. This, in combination with the limited post-vaccination-symptoms underlines the potential beneficial effect of a BNT162b2-boosting dose.
Correlates of circulating extracellular vesicle cargo with key clinical features of type 1 diabetes
Authors: Casu Anna , Lopez Yury O. Nunez , Yu Gongxin , Clifford Christopher , Bilal Anika , Petrilli Alejandra M. , Cornnell Heather , Corbin Karen , Iliuk Anton , Maahs David , Mayer-Davis Elizabeth J. , Pratley Richard E.
Published: March 2022

Type 1 diabetes (T1D) is a heterogeneous disease with a slower evolution in individuals diagnosed at older ages. There are no validated clinical or laboratory biomarkers to predict the rate of insulin secretion decline either before or after the clinical onset of the disease, or the rate of progression to chronic complications of the disease. This pilot study aimed to characterize the proteomic and phosphoproteomic landscape of circulating extracellular vesicles (EVs) across a range of obesity in carefully matched established T1D and control subjects. We used archived serum samples from 17 human subjects (N=10 with T1D and N=7 normal healthy volunteers) from the ACME study (NCT03379792). EVs were isolated using EVtrap® technology (Tymora). Mass spectrometry-based methods were used to detect the global circulating EV proteome and phosphoproteome. Differential expression, coexpression network (WGCNA), and pathway enrichment analyses were implemented. The detected proteins and phosphoproteins were highly enriched (75%) in exosomal proteins cataloged in the ExoCarta database. A total of 181 differentially expressed EV proteins and 15 differentially expressed EV phosphoproteins were identified, with 8 upregulated EV proteins (i.e., CD63, RAB14, VCP, BSG, FLNA, GNAI2, LAMP2, and EZR) and 1 downregulated EV phosphoprotein (i.e., TUBA1B) listed among the top 100 ExoCarta proteins. This suggests that T1D could indeed modulate EV biogenesis and secretion. Enrichment analyses of both differentially expressed EV proteins and EV phosphoproteins identified associations of upregulated features with neutrophil, platelet, and immune response functions, as well as prion disease and other neurodegenerative diseases, among others. On the other hand, downregulated EV proteins were involved in MHC class II signaling and the regulation of monocyte differentiation. Potential novel key roles in T1D for C1q, plasminogen, IL6ST, CD40, HLA-DQB1, and phosphorylated S100A9, are highlighted. Remarkably, WGCNA uncovered two protein modules significantly associated with pancreas size, which may be implicated in the pathogenesis of T1D. Similarly, these modules showed significant enrichment for membrane compartments, processes associated with inflammation and the immune response, and regulation of viral processes, among others. This study demonstrates the potential of EV proteomic and phosphoproteomic signatures to provide insight into the pathobiology of type 1 diabetes and its complications.
Malaria burden and associated risk factors in an area of pyrethroid-resistant vectors in southern Benin
Authors: Accrombessi Manfred , Akogbeto Martin C. , Dangbenon Edouard , Akpovi Hilaire , Sovi Arthur , Yovogan Boulais , Adoha Constantin , Assongba Landry , Ogouyemi-Hounto Aurore , Padonou Germain Gil , Thickstun Charles , Rowland Mark , Ngufor Corine , Protopopoff Natacha , Cook Jackie
Published: March 2022

Malaria remains the main cause of morbidity and mortality in Benin despite the scale-up of long-lasting insecticidal nets (LLINs), indoor residual spraying, and malaria case management. This study aimed to determine the malaria burden and its associated risk factors in a rural area of Benin characterized by high net coverage and pyrethroid-resistant mosquito vectors. A community-based cross-sectional survey was conducted in three districts in southern Benin. Approximately 4,320 randomly selected participants of all ages were tested for malaria using rapid diagnostic tests within 60 clusters. Risk factors for malaria infection were evaluated using mixed-effect logistic regression models. Despite high population net use (96%), malaria infection prevalence was 43.5% (cluster range: 15.1-72.7%). Children (58.7%) were more likely to be infected than adults (31.2%), with a higher malaria prevalence among older children (5-10 years: 69.1%; 10-15 years: 67.9%) compared to young children (<5 years: 42.1%); however, young children were more likely to be symptomatic. High household density, low socioeconomic status, young age (<15years), poor net conditions, and low net usage during the previous week were significantly associated with malaria infection. Malaria prevalence remains high in this area of intense pyrethroid resistance despite high net use. New classes of LLINs effective against resistant vectors are therefore crucial to further reduce malaria in this area.
Relative assessment of cloth mask protection against ballistic droplets: a frugal approach
Authors: Márquez-Alvarez V. , Amigó-Vera J. , Rivera A. , Batista-Leyva A. J. , Altshuler E.
Published: March 2022

During the COVID-19 pandemic, the relevance of evaluating the effectiveness of face masks –especially those made at home using a variety of materials– has become obvious. However, quantifying mask protection often requires sophisticated equipment. Using a frugal stain technique, here we quantify the “ballistic” droplets reaching a receptor from a jet-emitting source which mimics a coughing, sneezing or talking human –in real life, such droplets may host active SARS-CoV-2 virus able to replicate in the nasopharynx. We demonstrate that materials often used in home-made face masks block most of the droplets. Mimicking situations eventually found in daily life, we also show quantitatively that less liquid carried by ballistic droplets reaches a receptor when a blocking material is deployed near the source than when located near the receptor, which supports the paradigm that your face mask does protect you, but protects others even better than you. Finally, the blocking behavior can be quantitatively explained by a simple mechanical model.
The changing impact of vaccines in the COVID-19 pandemic
Authors: Cohen Jamie A. , Stuart Robyn M. , Panovska-Griffiths Jasmina , Mudimu Edinah , Abeysuriya Romesh G. , Kerr Cliff C. , Famulare Michael , Klein Daniel J.
Published: March 2022

The Omicron wave has left a global imprinting of immunity which changes the COVID landscape. In this study, we simulate six hypothetical variants emerging over the next year and evaluate the impact of existing and improved vaccines. We base our study on South Africa’s infection- and vaccination-derived immunity. Our findings illustrate that variant-chasing vaccines will only add value above existing vaccines in the setting where a variant emerges if we can shorten the window between variant introduction and vaccine deployment to under three weeks, an impossible time-frame without significant NPI use. This strategy may have global utility, depending on the rate of spread from setting to setting. Broadly neutralizing and durable next-generation vaccines could avert over three-times as many deaths from an immune-evading variant compared to existing vaccines. Our results suggest it is crucial to develop next-generation vaccines and redress inequities in vaccine distribution to tackle future emerging variants.
Establishing a baseline for human cortical folding morphological variables: a multicenter study
Authors: Hansen Pacheco de Moraes Fernanda , Mello Victor B. B. , Tovar-Moll Fernanda , Mota Bruno
Published: March 2022

Abstract

Differences in the way human cerebral cortices fold have been correlated to health, disease, development, and aging. But to obtain a deeper understating of the mechanisms that generate such differences it is useful to derive one’s morphometric variables from first principles. This work explores one such set of variables that arise naturally from a model for universal self-similar cortical folding that was validated on comparative neuroanatomical data. We aim to establish a baseline for these variables across the human lifespan using a heterogeneous compilation of cross-sectional datasets, as the first step to extend the model to incorporate the time evolution of brain morphology. We extracted the morphological features from structural MRI of 3650 subjects: 3095 healthy controls (CTL) and 555 Alzheimer’s Disease (AD) patients from 9 datasets, which were harmonized with a straightforward procedure to reduce the uncertainty due to heterogeneous acquisition and processing. The unprecedented possibility of analyzing such a large number of subjects in this framework allowed us to compare CTL and AD subjects’ lifespan trajectories, testing if AD is a form of accelerated aging at the brain structural level. After validating this baseline from development to aging, we estimate the variables’ uncertainties and show that Alzheimer’s Disease is similar to premature aging when measuring global and local degeneration. This new methodology may allow future studies to explore the structural transition between healthy and pathological aging and may be essential to generate data for the cortical folding process simulations.

Significance Statement

Understating Cortical folding is of increasing interest in neurosciences as it has been used to discriminate disease in humans while integrating pieces of knowledge from compared neuroanatomy and neuroproliferations programs. Here we propose estimating the baseline of cortical folding variables from multi-site MRI human images, evaluating the changing rate of its independent variables through the human lifespan, and proposing a simple harmonization procedure to combine multicentric datasets. Finally, we present a practical application of these techniques comparing Alzheimer’s Disease and Cognitive Unimpaired Controls based on the estimated changing rates.

Highlights

Baseline of independent cortical folding variables from 3650 multi-site human MRI

Propose a simple harmonization procedure to combine multicentric datasets

Evaluate the changing rate of independent variables through the human lifespan

Practical application comparing Alzheimer’s Disease and Controls rates
HIV testing uptake according to opt-in, opt-out or risk-based testing approaches: a systematic review and meta-analysis
Authors: Soh Qi Rui , Oh Leon Y.J. , Chow Eric P.F. , Johnson Cheryl C. , Jamil Muhammad S. , Ong Jason J.
Published: March 2022

Purpose of review

Improving HIV testing uptake is essential to ending the HIV pandemic. HIV testing approaches can be opt-in, opt-out or risk-based. This systematic review examines and compares the uptake of HIV testing in opt-in, opt-out and risk-based testing approaches.

Recent findings

There remains missed opportunities for HIV testing in a variety of settings using different approaches: opt-in (a person actively accepts to be tested for HIV), opt-out (a person is informed that HIV testing is routine/standard of care, and they actively decline if they do not wish to be tested for HIV) or risk-based (using risk-based screening tools to focus testing on certain individuals or sub-populations at greater risk of HIV). It is not clear how the approach could impact HIV test uptake when adjusted for other factors (e.g. rapid testing, country-income level, test setting and population tested).

We searched four databases for studies reporting on HIV test uptake. In total, 18,238 records were screened, and 150 studies were included in the review. Most studies described an opt-in approach (87 estimates), followed by opt-out (76) and risk-based (19). Opt-out testing was associated with 64.3% test uptake (I2=99.9%), opt-in testing with 59.8% (I2=99.9%), and risk-based testing with 54.4% (I2=99.9%). When adjusted for settings that offered rapid testing, country income level, setting and population tested, opt-out testing had a significantly higher uptake (+12% (95% confidence intervals: 3-21), p=0.007) than opt-in testing. We also found that emergency department patients and hospital outpatients had significantly lower HIV test uptake than other populations.
Nocturnal Respiratory Rate Dynamics Enable Early Recognition of Impending Hospitalizations
Authors: Harrington Nicholas , Barba David Torres , Bui Quan M. , Wassell Andrew , Khurana Sukhdeep , Rubarth Rodrigo B. , Sung Kevin , Owens Robert L. , Agnihotri Parag , King Kevin R.
Published: March 2022

The days and weeks preceding hospitalization are poorly understood because they transpire before patients are seen in conventional clinical care settings. Home health sensors offer opportunities to learn signatures of impending hospitalizations and facilitate early interventions, however the relevant biomarkers are unknown. Nocturnal respiratory rate (NRR) is an activity-independent biomarker that can be measured by adherence-independent sensors in the home bed. Here, we report automated longitudinal monitoring of NRR dynamics in a cohort of high-risk recently hospitalized patients using non-contact mechanical sensors under patients’ home beds. Since the distribution of nocturnal respiratory rates in populations is not well defined, we first quantified it in 2,000 overnight sleep studies from the NHLBI Sleep Heart Health Study. This revealed that interpatient variability was significantly greater than intrapatient variability (NRR variances of 11.7 brpm2and 5.2 brpm2respectively, n=1,844,110 epochs), which motivated the use of patient-specific references when monitoring longitudinally. We then performed adherence-independent longitudinal monitoring in the home beds of 34 high-risk patients and collected raw waveforms (sampled at 80 Hz) and derived quantitative NRR statistics and dynamics across 3,403 patient-nights (n= 4,326,167 epochs). We observed 23 hospitalizations for diverse causes (a 30-day hospitalization rate of 20%). Hospitalized patients had significantly greater NRR deviations from baseline compared to those who were not hospitalized (NRR variances of 3.78 brpm2and 0.84 brpm2respectively, n= 2,920 nights). These deviations were concentrated prior to the clinical event, suggesting that NRR can identify impending hospitalizations. We analyzed alarm threshold tradeoffs and demonstrated that nominal values would detect 11 of the 23 clinical events while only alarming 2 times in non-hospitalized patients. Taken together, our data demonstrate that NRR dynamics change days to weeks in advance of hospitalizations, with longer prodromes associating with volume overload and heart failure, and shorter prodromes associating with acute infections (pneumonia, septic shock, and covid-19), inflammation (diverticulitis), and GI bleeding. In summary, adherence-independent longitudinal NRR monitoring has potential to facilitate early recognition and management of pre-symptomatic disease.
JAK signaling was involved in the pathogenesis of Polymyalgia Rheumatica
Authors: Yang Fan , Ma Xinlei , Xu Bei , Sun Yiduo , Jiang Mengdi , Ren Chunyun , Sun Chuanying , Liang Junyu , Cao Heng , Xu Danyi , Yue Lihuan , Xu Liqin , Lin Jin , Chen Weiqian
Published: March 2022

Objectives

Polymyalgia Rheumatica (PMR) is a common inflammatory disease in elderly persons whose pathogenesis is unclear. We aimed to explore the pathogenetic features of PMR and find a new therapeutic strategy.

Methods

We included 11 patients with PMR and 20 age-matched and sex-matched healthy controls (HC) in this study. The disease features were described. The gene expression profiles were analyzed in peripheral blood mononuclear cells (PBMCs) by RNA sequencing and were confirmed by RT-PCR. We also tested gene expression profiles in five patients with PMR after tofacitinib therapy.

Results

Patients with PMR experienced pain with high disease activity scores. The gene expression of PBMCs in patients with PMR differed from that in HC by RNA sequencing. GO and KEGG analysis demonstrated that inflammatory response and cytokine-cytokine receptor interaction were the most remarkable pathways. There were markedly expanded IL6R, IL1B, IL1R1, JAK2, TLR2, TLR4, TLR8, CCR1, CR1, S100A8, S100A12, and IL17RA expressions. Those genes may trigger the JAK signaling. Furthermore, tofacitinib, a pan JAK inhibitor, effectively treated five patients with PMR, leading to clinical remission and a significant decrease in inflammatory genes.

Conclusions

Many inflammatory genes associated with JAK signaling were increased in patients with PMR, suggesting an important role of JAK signaling in PMR disease development. JAK inhibitors may effectively treat PMR.

Key messages

Patients with PMR had significant inflammatory genes expression. JAK signaling may be highly activated.

Tofacitinib may treat PMR with clinical remission and a significant decrease in inflammatory genes.
Anatomical, ontogenetic, and genomic homologies guide reconstructions of the teeth-to-baleen transition in mysticete whales
Authors: Gatesy John , Ekdale Eric G. , Deméré Thomas A. , Lanzetti Agnese , Randall Jason , Berta Annalisa , El Adli Joseph J. , Springer Mark S. , McGowen Michael R.
Published: March 2022

The transition in Mysticeti (Cetacea) from capture of individual prey using teeth to bulk filtering batches of small prey using baleen ranks among the most dramatic evolutionary transformations in mammalian history. We review phylogenetic work on the homology of mysticete feeding structures from anatomical, ontogenetic, and genomic perspectives. Six characters with key functional significance for filter-feeding behavior are mapped to cladograms based on 11 morphological datasets to reconstruct evolutionary change across the teeth-to-baleen transition. This comparative summary within a common parsimony framework reveals extensive conflicts among independent systematic efforts but also broad support for the newly named clade Kinetomenta (Aetiocetidae + Chaeomysticeti). Complementary anatomical studies using CTscans and ontogenetic series hint at commonalities between the developmental programs for teeth and baleen, lending further support for a ‘transitional chimaeric feeder’ scenario that best explains current knowledge on the transition to filter feeding. For some extant mysticetes, the ontogenetic sequence in fetal specimens recapitulates the inferred evolutionary transformation: from teeth, to teeth and baleen, to just baleen. Phylogenetic mapping of inactivating mutations reveals mutational decay of ‘dental genes’ related to enamel formation before the emergence of crown Mysticeti, while ‘baleen genes’ that were repurposed or newly derived during the evolutionary elaboration of baleen currently are poorly characterized. Review and meta-analysis of available data suggest that the teeth-to-baleen transition in Mysticeti ranks among the best characterized macroevolutionary shifts due to the diversity of data from the genome, the fossil record, comparative anatomy, and ontogeny that directly bears on this remarkable evolutionary transformation.
Taxonomic investigation of the zooplanktivorous Lake Malawi cichlids Copadichromis mloto (Iles) and C. virginalis (Iles)
Authors: Turner G.F. , Crampton D.A. , van Huysduynen A. Hooft , Svardal H.
Published: March 2022

The taxonomic status of the zooplanktivorous cichlids Copadichromis mloto and C. virginalis has been confused since their original descriptions by lles in 1960. While two forms of C. virginalis, Kaduna and Kajose, were distinguished in the type material, C. mloto has not been positively identified since its original description. Here we re-examined the types as well as 54 recently collected specimens from multiple sampling locations. Genome sequencing of 51 recent specimens revealed two closely related but reciprocally monophyletic clades. Geometric morphological analysis indicated that one clade morphologically encompasses the type specimens of C. virginalis identified by Iles as the ‘Kaduna’ form, including the holotype, while the other clade encompasses not only the paratypes identified as the ‘Kajose’ form, but also the type series of C. mloto. Given that all three forms have the same type locality, that there are no meristic or character states to differentiate them and that there are no records of adult male C. mloto in breeding colours, we conclude that the ‘Kajose’ form previously identified as C. virginalis represents relatively deeper bodied sexually active or maturing individuals of C. mloto.
Systemic circulating microRNA landscape in Lynch syndrome
Authors: Sievänen Tero , Korhonen Tia-Marje , Jokela Tiina , Ahtiainen Maarit , Lahtinen Laura , Kuopio Teijo , Lepistö Anna , Sillanpää Elina , Mecklin Jukka-Pekka , Seppälä Toni T. , Laakkonen Eija K.
Published: March 2022

MicroRNAs (miRs) are non-coding RNA-molecules that regulate gene expression. Global circulating miR (c-miR) expression patterns (c-miRnome) change with carcinogenesis in various sporadic cancers. Therefore, aberrantly expressed c-miRs could have diagnostic, predictive and prognostic potential in molecular profiling of cancers. c-miR functions in carriers of inherited pathogenic mismatch-repair gene variants (path_MMR), also known as Lynch syndrome (LS), have remained understudied. LS cohort provides an ideal population for biomarker mining due to increased lifelong cancer risk and excessive cancer occurrence. Using high-throughput sequencing and bioinformatic approaches, we conducted an exploratory analysis to characterize systemic c-miRnomes ofpath_MMRcarriers. Our discovery cohort included 81 healthypath_MMRcarriers and 37 non-LS controls. Our analysis also included cancer cohort comprised of 13path_MMRcarriers with varying cancers and 24 sporadic rectal cancer patients. We showed for the first time that c-miRnome can discern healthypath_MMRcarriers from non-LS controls but does not distinguish healthypath_MMRcarriers from cancer patients with or withoutpath_MMR. Our c-miR expression analysis combined within silicotools suggest ongoing alterations of biological pathways shared in LS and sporadic carcinogenesis. We observed that these alterations can produce a c-miR signature which can be used to track oncogenic stress in cancer-freepath_MMRcarriers. Thus, c-miRs hold potential in monitoring which cancer patients would require more intensive surveillance or clinical management.

Significance

C-miRnome can discern between healthy persons with or withoutpath_MMRbut does not distinguish healthypath_MMRcarriers from cancer patients with or withoutpath_MMR, indicating an ongoing alteration of biological pathways that can be used to track oncogenic stress at cancer-free state.
Familial ALS-associated SFPQ variants promote the formation of SFPQ cytoplasmic aggregates that reduce surface AMPA receptor expression in primary neurons
Authors: Widagdo Jocelyn , Udagedara Saumya , Bhembre Nishita , Tan Jing Zhi Anson , Neureiter Lara , Huang Jie , Anggono Victor , Lee Mihwa
Published: March 2022

SFPQ is a nuclear RNA-binding protein that is involved in a wide range of physiological processes including neuronal development and homeostasis. However, the mislocalization and cytoplasmic aggregation of SFPQ are associated with the pathophysiology of amyotrophic lateral sclerosis (ALS). We have previously reported that zinc mediates SFPQ polymerization and promotes the formation of cytoplasmic aggregates in neurons. Here we characterize two familial ALS (fALS)-associated SFPQ variants, which cause amino acid substitutions in the proximity of the SFPQ zinc-coordinating center (N533H and L534I). Both mutants display increased zinc-binding affinities, which can be explained by the presence of a secondary zinc-binding site revealed by the 1.83Å crystal structure of the human SFPQ L534I mutant. Overexpression of these fALS-associated mutants significantly increases the number of SFPQ cytoplasmic aggregates in primary neurons. Although they do not affect the density of dendritic spines, the presence of SFPQ cytoplasmic aggregates causes a marked reduction in the levels of the GluA1, but not the GluA2 subunit of AMPA-type glutamate receptors on the neuronal surface. Taken together, our data demonstrate that fALS-associated mutations enhance the propensity of SFPQ to bind zinc and form aggregates, leading to the dysregulation of AMPA receptor subunit composition, which may contribute to neuronal dysfunction in ALS.
Identifying transcription factor-DNA interactions using machine learning
Authors: Bang Sohyun , Galli Mary , Crisp Peter A. , Gallavotti Andrea , Schmitz Robert J.
Published: March 2022

Machine learning approaches have been applied to identify transcription factor (TF)-DNA interaction important for gene regulation and expression. However, due to the enormous search space of the genome, it is challenging to build models capable of surveying entire reference genomes, especially in species where models were not trained. In this study, we surveyed a variety of methods for classification of epigenomics data in an attempt to improve the detection for 12 members of the Auxin Response Factor (ARF) binding DNAs from maize and soybean as assessed by DNA Affinity Purification and sequencing (DAP-seq). We used the classification for prediction by minimizing the genome search space by only surveying unmethylated regions (UMRs). For identification of DAP-seq binding events within the UMRs, we achieved 93.54% accuracy, 6.2% false positive, and a 43.29% false negative rate across 12 members of ARFs of maize on average by encoding DNA with count vectorization for k-mer with a logistic regression classifier with up-sampling and feature selection. Importantly, feature selection helps to uncover known and potentially novel ARF binding motifs. This demonstrates an independent method for identification of transcription factor binding sites. Finally, we tested the model built with maize DAP-seq data and applied it directly to the soybean genome and found unacceptably high false positive rates, which accounted for more than 40% across the ARF TFs tested. The findings in this study suggest the potential use of various methods to predict TF-DNA interactions within and between species with varying degrees of success.
Continuous extraction and concentration of secreted metabolites from engineered microbes using membrane technology
Authors: Overmans Sebastian , Ignacz Gergo , Beke Aron K. , Xu Jiajie , Saikaly Pascal , Szekely Gyorgy , Lauersen Kyle J.
Published: March 2022

Microalgal cultivation in photobioreactors and membrane separations are both considered sustainable processes. Here we explore their synergistic combination to extract and concentrate a heterologous sesquiterpenoid produced by engineered green algal cells. A hydrophobic hollow-fiber membrane contactor was used to allow interaction of culture broth and cells with a dodecane solvent phase to accumulate algal produced patchoulol. Subsequent continuous membrane extraction of patchoulol from dodecane enabled product concentration in a methanol stream as well as dodecane recovery for its reuse. A structure-based prediction using machine learning was used to model a process whereby 100% patchoulol recovery from dodecane could be achieved with solvent-resistant nanofiltration membranes. Solvent consumption, E-factor, and economic sustainability were assessed and compared with existing patchoulol production processes. Our extraction and product purification process offers six- and two-orders of magnitude lower solvent consumption compared to synthetic production and thermal-based separation, respectively. Our proposed methodology is transferable to other microbial systems for the isolation of high-value isoprenoid and hydrocarbon products.
ATR-I774Yfs*5 promotes genomic instability through micronuclei formation
Authors: Holcomb Nathaniel , Dhar Bithika , Pu Hong , Bautista Robert-Marlo , Overmann Anna Heink , Corum Lauren , Shelton Brent , D’Orazio John
Published: March 2022

Although mismatch repair (MMR) defects are associated with high risk of malignancy, the specific oncogenic drivers pertinent to MMR-affected cancers are poorly characterized. The heterozygous ATR-I774Yfs*5 mutation, the result of strand slippage in a poly-A tract of the Ataxia Telangiectasia and Rad3 related (ATR) gene, is overexpressed in MMR-defective malignancies including colorectal carcinoma (CRC) and is the most common ATR mutation in cancer. Here, we explore the contribution of ATR-I774Yfs*5 to genomic integrity. Using heterozygous ATR-I774Yfs*5 HCT-116 cells to mimic the native mutation, we found this mutation reduced ATR activity as measured by damage-induced Chk1 phosphorylation at S317 and ATR autophosphorylation ATR at T1989. ATR-I774Yfs*5 expression impaired genomic stability as visualized by the appearance of micronuclei in two stable expression models as well as in cell lines transfected with ATR-I774Yfs*5. Micronucleus development was dependent on replication and independent of ATR copy number. ATR-I774Yfs*5 expression did not alter cellular viability, cell cycle progression, or replicative rate, suggesting this mutation is well-tolerated despite its destabilizing effect on the genome. Taken together, these data suggest that the ATR-I774Yfs*5, whose development is favored in the context of MMR deficiency, may represent an important driver of a mutator phenotype by promoting genomic instability.
Single-cell microfluidic analysis unravels individual cellular fates during Double-Strand Break Repair
Authors: Vertti-Quintero Nadia , Levien Ethan , Poggi Lucie , Amir Ariel , Richard Guy-Franck , Baroud Charles N.
Published: March 2022

Trinucleotide repeat expansions are responsible for two dozen human disorders. Contracting expanded repeats by Double-Strand Break Repair (DSBR) might be a therapeutic approach. Given the complexity of manipulating human cells, recent assays were made to quantify DSBR efficacy in yeast, using a fluorescent reporter. In this study DSBR is characterized with an interdisciplinary approach, linking large population dynamics and individual cells. Time-resolved molecular measurements of changes in the population are first confronted to a coupled differential equation model to obtain repair processes rates. Comparisons with measurements in microfluidic devices, where the progeny of 80-150 individual cells are followed, show good agreement between individual trajectories and mathematical and molecular results. Further analysis of individual progenies shows the heterogeneity of individual cell contributions to global repair efficacy. Three different categories of repair are identified: high-efficacy error-free, low-efficacy error-free and low-efficacy error-prone. These categories depend on the type of endonuclease used and on the target sequence.
The pho1;2a’-m1.1 allele of Phosphate1 conditions mis-regulation of the phosphorus starvation response in maize (Zea mays ssp. mays L.)
Authors: Alonso-Nieves Ana Laura , Salazar-Vidal M. Nancy , Torres-Rodríguez J. Vladimir , Chávez Montes Ricardo A. , Pérez-Vázquez Leonardo M. , Massange-Sánchez Julio A. , Gillmor C. Stewart , Sawers Ruairidh J. H.
Published: March 2022

PHO1 proteins play a central role in plant inorganic phosphorus translocation and sensing. The maize (Zea mays ssp. mays) genome encodes two co-orthologs of the Arabidopsis PHO1 gene, designated ZmPho1;2a and ZmPho1;2b. Here, we report the characterization of the transposon-footprint allele Zmpho1;2a’-m1.1, which we refer to hereafter as pho1;2a. The pho1;2a allele is a stable derivative formed by excision of an Activator element from the ZmPho1;2a gene. The pho1;2a allele contains an 8 bp insertion at the point of excision that disrupts the reading frame and is predicted to generate a premature translational stop. We show that the pho1;2a allele is linked to a dosage-dependent reduction in transcript accumulation and a mild reduction in seedling growth that is enhanced under nutrient deficient conditions. Characterization of the shoot and root transcriptomes of seedlings segregating the pho1;2a mutation under different nutrient conditions revealed pho1;2a to have a dominant effect on patterns of transcript accumulation. Gene set enrichment analysis of the transcripts mis-regulated in pho1;2a mutants suggests that Pho1;2a functions in the fine-tuning of the transcriptional phosphate starvation response. We discuss our results with reference to possible genetic redundancy among maize Pho1 genes and in the context of reports linking functional variation in Pho1;2a to agronomically important traits.