bluuebunny/crossref_metadata_2025 huggingface dataset:
Development and validation of the Collaborative Health Outcomes Information Registry body map
Authors: Scherrer Kristen Hymel , Ziadni Maisa S. , Kong Jiang-Ti , Sturgeon John A. , Salmasi Vafi , Hong Juliette , Cramer Eric , Chen Abby L. , Pacht Teresa , Olson Garrick , Darnall Beth D. , Kao Ming-Chih , Mackey Sean
Published: January 2021

Introduction:

Critical for the diagnosis and treatment of chronic pain is the anatomical distribution of pain. Several body maps allow patients to indicate pain areas on paper; however, each has its limitations.

Objectives:

To provide a comprehensive body map that can be universally applied across pain conditions, we developed the electronic Collaborative Health Outcomes Information Registry (CHOIR) self-report body map by performing an environmental scan and assessing existing body maps.

Methods:

After initial validation using a Delphi technique, we compared (1) pain location questionnaire responses of 530 participants with chronic pain with (2) their pain endorsements on the CHOIR body map (CBM) graphic. A subset of participants (n = 278) repeated the survey 1 week later to assess test–retest reliability. Finally, we interviewed a patient cohort from a tertiary pain management clinic (n = 28) to identify reasons for endorsement discordances.

Results:

The intraclass correlation coefficient between the total number of body areas endorsed on the survey and those from the body map was 0.86 and improved to 0.93 at follow-up. The intraclass correlation coefficient of the 2 body map graphics separated by 1 week was 0.93. Further examination demonstrated high consistency between the questionnaire and CBM graphic (<10% discordance) in most body areas except for the back and shoulders (≈15–19% discordance). Participants attributed inconsistencies to misinterpretation of body regions and laterality, the latter of which was addressed by modifying the instructions.

Conclusions:

Our data suggest that the CBM is a valid and reliable instrument for assessing the distribution of pain.
Brief High Oxygen Concentration Induces Oxidative Stress in Leukocytes and Platelets: A Randomized Cross-over Pilot Study in Healthy Male Volunteers
Authors: Hafner Christina , Pramhas Sibylle , Schaubmayr Wolfgang , Assinger Alice , Gleiss Andreas , Tretter Eva Verena , Klein Klaus Ulrich , Scharbert Gisela
Published: January 2021

Background:

Supplemental oxygen is administered routinely in the clinical setting to relieve or prevent tissue hypoxia, but excessive exposure may induce oxidative damage or disrupt essential homeostatic functions. It is speculated that oxidative stress in leukocytes and platelets may contribute to vascular diseases by promoting inflammation and cell aggregation.

Methods:

In this pilot study 30 healthy male volunteers (18–65 years) were exposed to high oxygen concentration (non-rebreather mask, 8 L/min, 100% O2) and synthetic air (non-rebreather mask, 8 L/min, 21% O2) in a cross-over design for 20 min at a 3-week interval. Venous blood samples were obtained at baseline and 1, 3, and 6 h postintervention. Primary outcome was generation of reactive oxygen species in leukocytes as measured by the redox-sensitive fluorescent dye dihydrorhodamine 123. Additional outcomes were oxidative stress in platelets and platelet aggregation as measured by thromboelastography (ROTEM) and Multiplate analyses.

Findings:

High oxygen exposure induced oxidative stress in leukocytes as evidenced by significantly higher mean fluorescence intensity (MFI) compared with synthetic air at 3 h postintervention (47% higher, P = 0.015) and 6 h postintervention (37% higher, P = 0.133). Oxidative stress was also detectable in platelets (33% higher MFI in comparison with synthetic air at 6 h, P = 0.024; MFI 20% above baseline at 3 h, P 
= 0.036; 37% above baseline at 6 h, P = 0.002). ROTEM analyses demonstrated reduced mean clotting time 1 h postintervention compared with baseline (−4%, P = 0.049), whereas there were no significant effects on other surrogate coagulation parameters.

Conclusion:

Clinically relevant oxygen exposure induces oxidative stress in leukocytes and platelets, which may influence the immune and clotting functions of these cells.
A Novel Human Glucocorticoid Receptor Variant, G459V, is Hyperactive in Response to Steroids
Authors: Grigsby Melissa J. , Green Tajia L. , Lim Debora , Cho Kiho , Greenhalgh David G.
Published: January 2021

A potential cause of the variable response to injury and sepsis is the variability of a patient's human glucocorticoid receptor (hGR) profile. To identify hGR variants, blood samples were collected on admission and biweekly thereafter from hospitalized patients who sustained at least a 20% total body surface area burn injury. A hyperactive G1376T single-nucleotide polymorphism (SNP) isoform was identified. This SNP led to a single amino acid change of glutamine to valine at site 459, “G459V,” in the DNA-binding domain. The isoform's activity was tested in a reporter assay after treatment with steroids, the hGR antagonist RU486 (mifepristone) alone, or RU486 followed by steroids. When treated with hydrocortisone, the hGR G459V isoform had a hyperactive response; its activity was over 30 times greater than the reference hGRα. Unexpectedly, G459V had significantly increased activity when treated with the hGR antagonist RU486. With the combination of both RU486 and hydrocortisone, G459V activity was repressed, but greater than that of RU486 alone. Finally, when hGRα was cotransfected with G459V to simulate isoform interaction, the activity was closer to that of the hGRα profile than the G459V isoform. The unique activity of the G459V isoform shows that some variants of hGR have the potential to alter a person's response to stress and steroid treatment and may be a factor as to why mitigating the clinical response to sepsis and other stressors has been so elusive.
Increased Intracranial Hemorrhage Amid Elevated Inflammatory Markers in Those With COVID-19 Supported With Extracorporeal Membrane Oxygenation
Authors: Bermea Rene S. , Raz Yuval , Sertic Federico , Rubin Jonah , Wolf Molly , Olia Salim , Richards Thomas , Crowley Jerome , Funamoto Masaki , Shelton Kenneth , Bermudez Christian
Published: January 2021

COVID-19-related coagulopathy is a known complication of SARS-CoV-2 infection and can lead to intracranial hemorrhage (ICH), one of the most feared complications of extracorporeal membrane oxygenation (ECMO). We sought to evaluate the incidence and etiology of ICH in patients with COVID-19 requiring ECMO. Patients at two academic medical centers with COVID-19 who required venovenous-ECMO support for acute respiratory distress syndrome (ARDS) were evaluated retrospectively. During the study period, 33 patients required ECMO support; 16 (48.5%) were discharged alive, 13 died (39.4%), and 4 (12.1%) had ongoing care. Eleven patients had ICH (33.3%). All ICH events occurred in patients who received intravenous anticoagulation. The ICH group had higher C-reactive protein (P = 0.04), procalcitonin levels (P = 0.02), and IL-6 levels (P = 0.05), lower blood pH before and after ECMO (P < 0.01), and higher activated partial thromboplastin times throughout the hospital stay (P < 0.0001). ICH-free survival was lower in COVID-19 patients than in patients on ECMO for ARDS caused by other viruses (49% vs. 79%, P = 0.02). In conclusion, patients with COVID-19 can be successfully bridged to recovery using ECMO but may suffer higher rates of ICH compared to those with other viral respiratory infections.
Prognostic Value of Angiopoietin-like 4 in Patients with Acute Respiratory Distress Syndrome
Authors: Hu Jun , Liu Lian , Zeng Xianghu , Wang Ke , Wang Hao , Zeng Zijian , Cao Yufang , Gao Lijuan , Cheng Mengxin , Wang Tao , Wen Fuqiang
Published: January 2021

Background:

Angiopoietin-like 4 (ANGPTL4) is a secreted glycoprotein that plays an important role in endothelial injury and the inflammatory response. Experimental models have implicated ANGPTL4 in acute respiratory distress syndrome (ARDS), but its impact on the progression of ARDS is unclear.

Methods:

Paired bronchoalveolar lavage fluid (BALF) and serum samples were obtained from patients with ARDS (n = 56) within 24 h of diagnosis and from control subjects (n = 32). ANGPTL4, angiopoietin-2, interleukin (IL)-6, and TNF-α levels were measured by magnetic Luminex assay. BALF albumin (BA) and serum albumin (SA) were evaluated by enzyme-linked immunosorbent assay.

Results:

BALF and serum ANGPTL4 concentrations were higher in patients with ARDS than in controls and were even higher in non-survivors than in survivors. The serum ANGPTL4 level was higher in indirect (extrapulmonary) ARDS than in direct (pulmonary) ARDS. Furthermore, BALF and serum ANGPTL4 levels correlated well with angiopoietin-2, IL-6, and TNF-α levels in BALF and serum. BALF ANGPTL4 was positively correlated with the BA/SA ratio (an indicator of pulmonary vascular permeability), and serum ANGPTL4 was associated with the severity of multiple organ dysfunction syndrome based on SOFA and APACHE II scores. Moreover, serum ANGPTL4 was better able to predict 28-day ARDS-related mortality (AUC 0.746, P < 0.01) than the APACHE II score or PaO2/FiO2 ratio. Serum ANGPTL4 was identified as an independent risk factor for mortality in a univariate Cox regression model (P < 0.001).

Conclusion:

ANGPTL4 levels were elevated in patients with ARDS and significantly correlated with disease severity and mortality. ANGPTL4 may be a novel prognostic biomarker in ARDS.
Clinical Significance of Pro-inflammatory Cytokines and Their Correlation with Disease Severity and Blood Coagulation in Septic Patients with Bacterial Co-infection
Authors: Wang Xin , Zhang Qi , Yan Yong , Yang Yang , Shang Xueyi , Li Yan
Published: January 2021

Purpose:

To evaluate the clinical significance of pro-inflammatory cytokines for disease severity and coagulation in septic patients with bacterial co-infection.

Methods:

A total of 92 patients with sepsis admitted to intensive care unit (ICU) from January 2017 to August 2020 were enrolled and their clinical data were retrospectively analyzed. Forty-seven patients (51.1%) had a single infection by Klebsiella pneumoniae or Acinetobacter baumannii (single-infection group), and 45 patients (48.9%) were infected by both species (co-infection group). We compared the clinical characteristics and disease severity among the 92 patients. Disease severity was defined as ICU stay time and 30-day mortality. Plasma concentrations of pro-inflammatory cytokines and their correlation with disease severity and blood coagulation were analyzed.

Results:

The 30-day mortality in the co-infection group (35.5%) was significantly higher than in the single-infection group (19.1%). The levels of IL-6 and TNF-α in the co-infection group were higher than in the single-infection group. Moreover, high levels of IL-6, IL-8, and TNF-α were positively correlated with disease severity (Spearman P value < 0.05). High levels of IL-6 and TNF-α were negatively correlated with the platelet count (Spearman P value < 0.05) and positively correlated with prothrombin time, and plasma levels of fibrin degradation product and D-dimer levels (Spearman P value < 0.05 for all).

Conclusion:

Septic patients with bacterial co-infection had increased plasma levels of pro-inflammatory cytokines. Furthermore, a positive correlation between high levels of pro-inflammatory cytokines and increased disease severity and depressed blood coagulation function for septic patients with co-infection was identified.
Trap and kill of environmental microbes: Validation of a novel decontamination technology in Hospital ICU setting
Authors: Jose Sanju , Phadke Kruttika S. , Venkatraman Janani , Krishna Bhuvana , Sampath Sriram , Datta Santanu , Nagaraj Savitha , Ghatak Arindam
Published: January 2021

Nosocomial infections, also known as hospital-acquired infections (HAI), appear 48 hours or more after hospital admission and are independent of the original infirmity of the patient. To prevent or to reduce HAI, the central paradigm is to construct protective barriers between the large number of people who are sick and whose immune systems are compromised in the precincts of the hospital. Microbes that result in HAI do so by two routes of infection: touch and aerosol. We describe here ZeBox technology, a voltage induced synergistic killing of the microbe on designed surfaces, as a game-changer in this domain. Its kill rate is hitherto unmatched by any known chemical or non-chemical (viz; UV, ionisation) technology. In an enclosed test chamber, under challenge conditions, ZeBox technology can kill about a billion microbes in 10 minutes. When tested under clinical settings, the device could effectively reduce microbes, both from air and surfaces with more than 90% efficiency. The optimum requirement to reduce HAI would be to construct an online microbicidal device that operates in a continuous trap and kill mode in the background of people and patient movement, and decontaminates air and surfaces. We present unequivocal data to fortify our claims of online, continuous, safe, trap and kill mechanism of ZeBox technology.
Spatio-temporal analysis between the incidence of COVID-19 and human development in Mato Grosso do Sul, Brazil
Authors: de Souza Amaury , Abreu Marcel Carvalho , de Oliveira-Júnior José Francisco
Published: January 2021

Objetive

To analyze the spatial distribution of the Covid-19 incidence and its correlation with the municipal human development index (IDHM) in the state of Mato Grosso do Sul (MS), Brazil.

Methods

This is an ecological, exploratory and analytical study whose units of analysis were the 79 municipalities that make up the state of MS. Covid-19 incidence coefficients, death numbers, lethality rate, mortality rate and Human Development Index for municipalities (IDHM) in the period from March 2020 to December 31, 2020 were used. spatial correlations between the variables mentioned above.

Results

The incidence of Covid-19 has spatial dependence with moderate positive correlation and formation of clusters located in the Metropolitan Region of Campo Grande (RMCG) and municipalities in the region.

Conclusion

The uneven mapping of Covid-19 and its relationship with IDHM in the Ministry of Health can contribute to actions to address the regional pandemic.
SARS-CoV-2 B.1.1.7 lineage-related perceptions, COVID-19 vaccine acceptance and travel worry among healthcare workers
Authors: Temsah Mohamad-Hani , Barry Mazin , Aljamaan Fadi , Alhuzaimi Abdullah N , Al-Eyadhy Ayman , Saddik Basema , Alsohime Fahad , Alhaboob Ali , Alhasan Khalid , Alaraj Ali , Halwani Rabih , Jamal Amr , Alamro Nurah , Temsah Reem , Esmaeil Samia A. , Alanazi Shelaweeh , Alzamil Fahad , Alsomaily Ali , Al-Tawfiq Jafar A.
Published: January 2021

Background

Healthcare workers’ (HCWs’) travel-related anxiety needs to be assessed in light of the emergence of SARS-CoV-2 mutations.

Methods

An online, cross-sectional questionnaire among HCWs between December 21, 2020 to January 7, 2021. The outcome variables were HCWs’ knowledge and awareness of the SARS-CoV-2 B.1.1.7 lineage, and its associated travel worry and Generalized Anxiety Disorder (GAD-7) score.

Results

A total of 1,058 HCWs completed the survey; 66.5% were female, 59.0% were nurses. 9.0% indicated they had been previously diagnosed with COVID-19. Regarding the B.1.1.7 lineage, almost all (97.3%) were aware of its emergence, 73.8% were aware that it is more infectious, 78.0% thought it causes more severe disease, and only 50.0% knew that current COVID-19 vaccines are effective in preventing it. Despite this, 66.7% of HCWs were not registered to receive the vaccine. HCWs’ most common source of information about the new variant was social media platforms (67%), and this subgroup was significantly more worried about traveling. Nurses were more worried than physicians (P=0.001).

Conclusions

Most HCWs were aware of the emergence of SARS-CoV-2 B.1.1.7 variant and expressed substantial travel worries. Increased worry levels were found among HCWs who used social media as their main source of information, those with lower levels of COVID-19 vaccine uptake, and those with higher GAD-7 scores. The utilization of official social media platforms could improve accurate information dissemination among HCWs regarding the pandemic’s evolving mutations. Targeted vaccine campaigns are warranted to assure HCWs about the efficacy of COVID-19 vaccines toward SARS-CoV-2 variants.
Excessive matrix metalloproteinase-1 and hyperactivation of endothelial cells occurred in COVID-19 patients and were associated with the severity of COVID-19
Authors: Syed Fahim , Li Wei , Relich Ryan F. , Russell Patrick M. , Zhang Shanxiang , Zimmerman Michelle K. , Yu Qigui
Published: January 2021

COVID-19 starts as a respiratory disease that can progress to pneumonia, severe acute respiratory syndrome (SARS), and multi-organ failure. Growing evidence suggests that COVID-19 is a systemic illness that primarily injures the vascular endothelium, yet the underlying mechanisms remain unknown. SARS-CoV-2 infection is believed to trigger a cytokine storm that plays a critical role in the pathogenesis of endothelialitis and vascular injury, eventually leading to respiratory and multi-organ failure in COVID-19 patients. We used a multiplex immunoassay to systematically profile and compare 65 inflammatory cytokines/chemokines/growth factors in plasma samples from 24 hospitalized (severe/critical) COVID-19 patients, 14 mild/moderate cases, and 13 healthy controls (HCs). Patients with severe/critical and mild/moderate COVID-19 had significantly higher plasma levels of 20 analytes than HCs. Surprisingly, only one cytokine (MIF) was among these altered analytes, while the rest were chemokines and growth factors. In addition, only MMP-1 and VEGF-A were significantly elevated in hospitalized COVID-19 patients when compared to mild/moderate cases. Given that excessive MMP-1 plays a central role in tissue destruction in a wide variety of vascular diseases and that elevated VEGF-A, an EC activation marker, increases vascular permeability, we further studied MMP-1 enzymatic activity and other EC activation markers such as soluble forms of CD146, ICAM-1, and VCAM-1. We found that plasma MMP-1 enzymatic activity and plasma levels of MMP-1 and EC activation markers were highly dysregulated in COVID-19 patients. Some dysregulations were associated with patients’ age or gender, but not with race. Our results demonstrate that COVID-19 patients have distinct inflammatory profiles that are distinguished from the cytokine storms in other human diseases. Excessive MMP-1 and hyperactivation of ECs occur in COVID-19 patients and are associated with the severity of COVID-19.
Deficient hand washing facilities in public toilets in the time of the COVID-19 pandemic: A survey in one high-income country
Authors: Wilson Nick , Thomson George
Published: January 2021

Aims

To identify the extent of the provision of water and soap for hand washing in public toilets at the time of the COVID-19 pandemic. To also make comparisons with a pre-pandemic survey that included a sample of the same facilities.

Methods

We collected data from 400 toilets that were open to the public; all those in three contiguous city council territories (228) and a further convenience sample of 172 around the rest of New Zealand. Comparisons were made with the data on the same facilities included in a 2012/2013 survey.

Results

For all the toilets in this survey, 2.5% had no water for hand washing and 14.8% had no soap. There was COVID-19 related health messaging signage in 19.5% of toilets, with posters of the COVID-19 QR code used to facilitate contact tracing in 12.3%, and generic hand washing signage in 1.8%. The hand washing water had “no touch” activation at 28.0% of toilets and at 18.5% for toilet bowl flushing. Toilet bowl lids were not present at 32.8%, and 2.3% of toilets had damage which would impair their functionality (eg, broken toilet seats). For the 128 sites that had also been examined in the previous survey, this new survey found significantly increased provision of soap (risk ratio = 1.47; 95%CI: 1.25 to 1.72), but no increased provision of water.

Conclusions

Despite the serious threat of the COVID-19 pandemic, the majority of hand washing facilities in public toilets sampled required tap touching, and did not have health messaging. Nevertheless there has been some modest improvements in soap (but not water) provision since the previous survey eight years before.
Sleep in Frontline Healthcare Workers on Social Media During the COVID-19 Pandemic
Authors: Stewart Nancy H , Koza Anya L , Dhaon Serena , Shoushtari Christiana , Martinez Maylyn , Arora Vineet M
Published: January 2021

Importance

During the pandemic, healthcare workers on social media are sharing their challenges, including sleep disturbances.

Objective

To assess sleep using validated measures among frontline healthcare workers on social media

Design

A self-selection survey was distributed on Facebook, Twitter, and Instagram for 16 days (August 31-September 15, 2020) targeting healthcare workers (HCW) who were clinically active during the pandemic. Study participants completed the Pittsburgh Sleep Quality Index (PSQI), Insomnia Severity Index (ISI), and reported demographic/career information. Poor sleep quality was defined as PSQI>5. Moderate-to-severe insomnia was defined as an ISI>14. The mini-Z was used to measure burnout. Multivariate logistic regression tested associations between demographics, career characteristics, and sleep outcomes.

Setting

Online self-selection survey on social media

Participants

963 surveys were completed. Participants were predominantly White (92.8%), female (73.4%), aged 30-49 (71.9%), and physicians (64.4%). Mean sleep duration was 6.1 (SD 1.2) hours. Nearly 90% reported poor sleep (PSQI). One third (33.0%) reported moderate or severe insomnia. Many (60%) experienced sleep disruptions due to device usage or had bad dreams at least once per week (45%). Over 50% reported burnout. In multivariable logistic regressions, non-physician (OR 2.4; CI: 1.7, 3.4), caring for COVID-19 patients (OR 1.8; CI 1.2, 2.8), Hispanic ethnicity (OR 2.2; CI: 1.4, 3.5), being female (OR 1.6; CI 1.1, 2.4), and having a sleep disorder (OR 4.3; CI 2.7,6.9) were associated with increased odds of insomnia. In open-ended comments (n=310), poor sleep mapped to four categories: children and family, work demands, personal health, and pandemic-related sleep disturbances.

Conclusion

During the COVID-19 pandemic, 90% of frontline healthcare workers surveyed on social media reported poor sleep, over one-third reported insomnia, and over half reported burnout. Many also reported sleep disruptions due to device usage and nightmares. Sleep interventions for frontline healthcare workers are urgently needed.

Key points

Question

How are frontline healthcare workers on social media sleeping during the pandemic?

Findings

During the COVID-19 pandemic, 90% of frontline healthcare workers on social media are reporting poor sleep, and one third are reporting insomnia. Those who report sleep disturbances were more likely to report burnout.

Meaning

Interventions aimed at improving the sleep of frontline healthcare workers are warranted.
A SARS-CoV-2 Label-Free Surrogate Virus Neutralization Test and a Longitudinal Study of Antibody Characteristics in COVID-19 Patients
Authors: Luo Yiqi Ruben , Yun Cassandra , Chakraborty Indrani , Wu Alan H.B. , Lynch Kara L.
Published: January 2021

Background

The laboratory-based methods to measure the SARS-CoV-2 humoral response include virus neutralization tests (VNTs) to determine antibody neutralization potency. For ease of use and universal applicability, surrogate virus neutralization tests (sVNTs) based on antibody-mediated blockage of molecular interactions have been proposed.

Methods

A surrogate virus neutralization test established on a label-free immunoassay platform (LF-sVNT). The LF-sVNT analyzes the binding ability of RBD to ACE2 after neutralizing RBD with antibodies in serum.

Results

The LF-sVNT neutralizing antibody titers (IC50) were determined from serum samples (n=246) from COVID-19 patients (n=113), as well as the IgG concentrations and the IgG avidity indices. Although there is variability in the kinetics of the IgG concentrations and neutralizing antibody titers between individuals, there is an initial rise, plateau and then in some cases a gradual decline at later timepoints after 40 days post-symptom onset. The IgG avidity indices, in the same cases, plateau after the initial rise and did not show a decline.

Conclusions

The LF-sVNT can be a valuable tool in clinical laboratories for the assessment of the presence of neutralizing antibodies to COVID-19. This study is the first to provide longitudinal neutralizing antibody titers beyond 200 days post-symptom onset. Despite the decline of IgG concentration and neutralizing antibody titer, IgG avidity index increases, reaches a plateau and then remains constant up to 8 months post-infection. The decline of antibody neutralization potency can be attributed to the reduction in antibody quantity rather than the deterioration of antibody avidity, a measure of antibody quality.

A surrogate virus neutralization test established on a label-free immunoassay platform (LF-sVNT). Using the LF-sVNT and other assays, 246 serum samples from 113 COVID-19 patients were measured. We observed the time course of antibody characteristics beyond 200 days post-symptom onset.
Analysis of HIV Reservoirs in Cellular Conjugates from Peripheral Blood
Authors: Pérez Liliana , Crespo-Vélez Daniel , Lee Max , Zakaria Saami , Poole April , Bell Jennifer , Migueles Stephen A. , Chun Tae-Wook , Moir Susan , Maldarelli Frank , Boritz Eli A.
Published: January 2021

Defining distinctive attributes of HIV-infected cells will inform development of HIV cure-directed therapies. Priorex vivostudies of blood and tissue have suggested that some HIV-infected CD4 T cells are found in conjugates with other cell types. Here, we analyzed levels and sequences of HIV nucleic acids in sorted cellular conjugates from PBMC. Compared to single CD4 T cells, conjugates containing CD4 T cells showed no enrichment for HIV DNA or RNA. However, in several HIV controllers, HIV DNA sequences from sorted conjugates were enriched for sequences closely related to plasma viruses. In ART-treated people, although subgenomic HIV DNA sequences in sorted conjugates and single cells were genetically intermingled, intact proviruses were more frequent in whole blood cells than in magnetically-purified CD4 T cells. We conclude that some HIV-infected cells have attributes that predict preferential loss during sample processing, and that may also reflect vulnerability to therapeutic targetingin vivo.
Welfare at group and individual level: optical flow patterns of broiler chicken flocks are correlated with the behaviour of individual birds
Authors: Gebhardt-Henrich Sabine , Stratmann Ariane , Dawkins Marian Stamp
Published: January 2021

Group level measures of welfare such as the optical flow patterns made by broiler chicken flocks have been criticized on the grounds that they give only average measures and overlook the welfare of individual animals. However, we here show that by using the skew and kurtosis in addition to the mean, optical flow patterns can be used to deliver information not just about the flock average but also about the proportion of individuals in different movement categories. We correlated flock optical flow patterns with the behaviour of a sample of 16 birds per flock in two runway tests and a water (latency-to-lie) test. In the runway tests, there was a positive correlation between the time taken to complete the runway and the skew and kurtosis of optical flow on day 28 of flock life (slow individuals came from flocks with a high skew and kurtosis). In the water test, there was a positive correlation between the length of time the birds remained standing and the mean and variance of flock optical flow (the most mobile individuals came from flocks with the highest mean). Patterns at flock level thus contain valuable information about the welfare of the individuals that compose the flock.

Simple Summary

Technology on farms potentially brings benefits of improved animal health, welfare and productivity as well as reduction in disease, waste and environmental impact. However, it also raises public concern about the welfare of individual animals, particularly when applied to large groups such as broiler (meat) chickens. We here address this issue by showing that camera technology can both provide life-long continuous monitoring of the welfare of whole flocks and also give crucial information about the individuals making up the flock. The cameras detect variation between individuals and are also sensitive to birds moving abnormally. By testing birds individually, we show that slow-moving birds tended to come from flocks that moved slowly overall and showed large variation between individuals whereas fast-moving birds were more likely to come from more active flocks that moved more uniformly. Properly used, camera technology can thus monitor the welfare of flocks continuously throughout their lives while reflecting the behaviour of individual birds.
Translation Inhibitory Elements from Hox a3 and a11 mRNAs use uORFs for translation inhibition
Authors: Alghoul Fatima , Schaeffer Laure , Eriani Gilbert , Martin Franck
Published: January 2021

During embryogenesis, Hox mRNA translation is tightly regulated by a sophisticated molecular mechanism that combines two RNA regulons located in their 5’UTR. First, an Internal Ribosome Entry Site (IRES) enables cap-independent translation. The second regulon is a Translation Inhibitory Element or TIE, which ensures concomitant cap-dependent translation inhibition. In this study, we deciphered the molecular mechanisms of Hox a3 and a11 TIE elements. Both TIEs possess an upstream Open Reading Frame (uORF) that is critical to inhibit cap-dependent translation. However, the molecular mechanisms used are different. In TIE a3, we identify a uORF which inhibits cap-dependent translation and we show the requirement of the non-canonical initiation factor eIF2D for this process. The mode of action of TIE a11 is different, it also contains a uORF but it is a minimal uORF formed by an uAUG followed immediately by a stop codon, namely a ‘start-stop’. The a11 ‘start-stop’ sequence is located upstream of a highly stable stem loop structure which stalls the 80S ribosome and thereby inhibits cap-dependent translation of Hox a11 main ORF.
Topological analysis of single-cell data reveals shared glial landscape of macular degeneration and neurodegenerative diseases
Authors: Kuchroo Manik , DiStasio Marcello , Calapkulu Eda , Ige Maryam , Zhang Le , Sheth Amar H. , Menon Madhvi , Xing Yu , Gigante Scott , Huang Jessie , Dhodapkar Rahul M. , Rieck Bastian , Wolf Guy , Krishnaswamy Smita , Hafler Brian P.
Published: January 2021

1

One Sentence Summary

A novel topological machine learning approach applied to single-nucleus RNA sequencing from human retinas with age-related macular degeneration identifies interacting disease phase-specific glial activation states shared with Alzheimer’s disease and multiple sclerosis.

2

Neurodegeneration occurs in a wide range of diseases, including age-related macular degeneration (AMD), Alzheimer’s disease (AD), and multiple sclerosis (MS), each with distinct inciting events. To determine whether glial transcriptional states are shared across phases of degeneration, we sequenced 50,498 nuclei from the retinas of seven AMD patients and six healthy controls, generating the first single-cell transcriptomic atlas of AMD. We identified groupings of cells implicated in disease pathogenesis by applying a novel topologically-inspired machine learning approach called ‘diffusion condensation.’ By calculating diffusion homology features and performing persistence analysis, diffusion condensation identified activated glial states enriched in the early phases of AMD, AD, and MS as well as an AMD-specific proangiogenic astrocyte state promoting pathogenic neovascularization in advanced AMD. Finally, by mapping the expression of disease-associated genes to glial states, we identified key signaling interactions creating hypotheses for therapeutic intervention. Our topological analysis identified an integrated disease-phase specific glial landscape that is shared across neurodegenerative conditions affecting the central nervous system.
Quickomics: exploring omics data in an intuitive, interactive and informative manner
Authors: Gao Benbo , Zhu Jing , Negi Soumya , Zhang Xinmin , Gyoneva Stefka , Casey Fergal , Wei Ru , Zhang Baohong
Published: January 2021

We developed Quickomics, a feature-rich R Shiny-powered tool to enable biologists to fully explore complex omics statistical analysis results and perform advanced analysis in an easy-to-use interactive interface. It covers a broad range of secondary and tertiary analytical tasks after primary analysis of omics data is completed. Each functional module is equipped with customizable options and generates both interactive and publication-ready plots to uncover biological insights from data. The modular design makes the tool extensible with ease.

Availability

Researchers can experience the functionalities with their own data or demo RNA-Seq and proteomics datasets by using the app hosted athttp://quickomics.bxgenomics.comand following the tutorial,https://bit.ly/3rXIyhL. The source code under GPLv3 license is provided athttps://github.com/interactivereport/Quickomicsfor local installation.

Supplementary information

Supplementary materials are available athttps://bit.ly/37HP17g.
Extreme C-to-A Hypermutation at a Site of Cytosine-N4 Methylation
Authors: Cherry Joshua L.
Published: January 2021

Methylation of cytosine in DNA at position C5 increases the rate of C→T mutations in bacteria and eukaryotes. Methylation at the N4 position, employed by some restriction-modification systems, is not known to increase the mutation rate. Here I report that aSalmonella entericaType III restriction-modification system that includes a cytosine-N4 methyltransferase causes an enormous increase in the rate of mutation of the methylated cytosines, which occur at the overlined C in the motif. Mutations consist mainly of C→A transversions, the rate of which is increased ~500-fold by the restriction-modification system. The rate of C→T transitions is also increased, and somewhat exceeds that at C5-methylated cytosines inDcmsites. Two otherSalmonellaN4 methyltransferases investigated do not have such dramatic effects, although in one case there is a modest increase in C→A mutations along with an increase in C→T mutations. Sensitivity of the C→A rate to orientation with respect to both DNA replication and transcription is higher at hypermutable sites than at other cytosines, suggesting a fundamental mechanistic difference between hypermutation and ordinary mutation.

IMPORTANCE

Mutation produces the raw material for adaptive evolution, but also imposes a burden because most mutations are deleterious. The rate of mutation at a particular site is affected by a variety of factors. In both prokaryotes and eukaryotes, methylation of C at the C5 position, a naturally-occurring DNA modification, greatly increases the rate of C→T mutation. A distinct C modification that occurs in prokaryotes, methylation at N4, is not known to increase mutation rate. Here I report that a bacterial restriction-modification system, found in someSalmonella, increases the rate of C→A mutation by a factor of 500 at sites that it methylates at N4. This rate increase is much greater than that caused by C5 methylation. Although fewer than one in 1600 positions analyzed are methylation sites, over 10% of all mutations occur at these sites. Like other examples of extremely high mutation rate, whether naturally-occurring or the result of laboratory mutation, this phenomenon may shed light on the mechanism of mutation in general.
Tandem-Cleavage Linkers Improve the In Vivo Stability and Tolerability of Antibody-Drug Conjugates
Authors: Chuprakov Stepan , Ogunkoya Ayodele O. , Barfield Robyn M. , Bauzon Maxine , Hickle Colin , Kim Yun Cheol , Yeo Dominick , Zhang Fangjiu , Rabuka David , Drake Penelope M.
Published: January 2021

Although peptide motifs represent the majority of cleavable linkers used in clinical-stage antibody-drug conjugates (ADCs), the sequences are often sensitive to cleavage by extracellular enzymes, such as elastase, leading to systemic release of the cytotoxic payload. This action reduces the therapeutic index by causing off-target toxicities that can be dose-limiting. For example, a common side-effect of ADCs made using peptide-cleavable linkers is myelosuppression, including neutropenia. Only a few reports describe methods for optimizing peptide linkers to maintain efficient and potent tumor payload delivery while enhancing circulating stability. Herein, we address these critical limitations through the development of a tandem-cleavage linker strategy, where two sequential enzymatic cleavage events mediate payload release. We prepared dipeptides that are protected from degradation in the circulation by a sterically-encumbering glucuronide moiety. Upon ADC internalization and lysosomal degradation, the monosaccharide is removed and the exposed dipeptide is degraded, liberating the attached payload inside the target cell. We used CD79b-targeted monomethyl auristatin E (MMAE) conjugates as our model system, and compared the stability, efficacy, and tolerability of ADCs made with tandem-cleavage linkers to ADCs made using standard technology with the vedotin linker. The results—where rat studies showed dramatically improved tolerability in the hematopoietic compartment—highlight the role that linker stability plays in efficacy and tolerability, and offer a means of improving an ADC’s therapeutic index for improved patient outcomes.
Cooperative and aggressive behaviours vary between ranks in anemonefish social hierarchies
Authors: Rueger T , Heatwole SJ , Wong MY
Published: January 2021

Many animal groups consist of individuals organised in dominance hierarchies, based on age, size or fighting ability. Lower ranked individuals often do not reproduce themselves but perform cooperative behaviours to help the reproductive output of dominant individuals or the group as a whole. Theoretical models suggest that individuals of higher rank should show increased amounts of aggressive behaviours, such as aggressions towards other group members, but should decrease the amount of cooperative behaviours, such as brood care or territory maintenance. Most empirical tests of these models focus on insect or mammalian systems where kin selection plays a large role, rather than animals that live in groups of unrelated individuals. Here we use two anemonefish species to test hypotheses of variation in cooperation and aggression with respect to social rank and species, for social systems where group members are unrelated. We assessed the behaviours of each rank in 20 groups ofAmphiprion perculaand 12 groups ofA. perideraionin Kimbe Bay, Papua New Guinea. We also performed a removal experiment to test if cooperative and aggressive behaviours are likely adaptive, i.e., if they change as an individual ascends in rank. Our results show differences between the two species, withA. perculashowing more cooperative behaviours andA. perideraionshowing more aggressive behaviours, despite them being closely related and sharing a very similar ecology. With respect to both cooperation and aggression we found consistent differences between ranks in both species, with higher ranks performing more aggressive as well as more cooperative behaviours. When we experimentally provided lower ranked individuals (rank 4) an opportunity to ascend in the hierarchy, they showed more aggression and more cooperation in line with our observations for rank 3 individuals. Thus, we show that rank specific behavioural patterns are likely adaptive in anemonefishes and that some model predictions do not hold in systems where kin selection benefits are absent. Rather, future fitness benefits through territory inheritance and group augmentation likely motivate cooperative and aggressive behaviours by subordinates in groups of unrelated vertebrates.
Tianeptine, but not fluoxetine, decreases avoidant behavior in a mouse model of early developmental exposure to fluoxetine
Authors: Pekarskaya Elizabeth A , Holt Emma S , Gingrich Jay A , Ansorge Mark S , Javitch Jonathan A , Canetta Sarah E
Published: January 2021

Depression and anxiety are two of the most common mental health disorders, often sharing symptoms and administrations. Most pharmacological agents available to treat these disorders target monoamine systems. Currently, finding the most effective treatment for an individual is a process of trial and error. Therefore, to better understand how disease etiology may predict treatment response, we studied mice exposeddevelopmentallyto the selective serotonin reuptake inhibitor (SSRI) fluoxetine (FLX). These mice show the murine equivalent of anxiety- and depression-like symptoms in adulthood and here we report that these mice are also behaviorally resistant to the antidepressant-like effects of adult SSRI administration. We investigated whether tianeptine (TIA), which exerts its therapeutic effects through the mu-opioid receptor (MOR) instead of directly targeting monoaminergic systems, would be more effective in this model.

We injected C57BL/6J (C57) pups with either FLX (10 mg/kg, i.p) or vehicle from postnatal (PN) day 2 to 11, a period in which mouse brain development parallels that of the third trimester of a human pregnancy. Prior work established that adult 129SvEv (129) mice exposed to FLX in this time period (PN-FLX) showed increased avoidant and decreased hedonic behaviors, which correspond to anxiety- and depressive-like symptoms in humans, respectively. We performed baseline testing in adulthood in C57 PN-FLX animals and confirmed a similar avoidant phenotype to that reported in 129 PN-FLX mice. We then treated these animals with chronic FLX (18 mg/kg in the drinking water) and evaluated effects on two tasks that measure avoidant behavior – the open field and novelty suppressed feeding (NSF) tasks. This administration failed to improve, and even exacerbated, avoidance symptoms in PN-FLX mice. The same animals then underwent chronic administration with TIA (30 mg/kg, 2x/day, i.p.) as an alternative treatment strategy. TIA administration decreased avoidance behavior as measured in the open field and NSF. Overall, this demonstrates that TIA may be a promising alternative treatment to typical antidepressants, especially in patients whose serotonergic system has been altered.
A tool for assessing alignment of biomedical data repositories with open, FAIR, citation and trustworthy principles
Authors: Murphy Fiona , Bar-Sinai Michael , Martone Maryann E.
Published: January 2021

Increasing attention is being paid to the operation of biomedical data repositories in light of efforts to improve how scientific data is handled and made available for the long term. Multiple groups have produced recommendations for functions that biomedical repositories should support, with many using requirements of the FAIR data principles as guidelines. However, FAIR is but one set of principles that has arisen out of the open science community. They are joined by principles governing open science, data citation and trustworthiness, all of which are important aspects for biomedical data repositories to support. Together, these define a framework for data repositories that we call OFCT: Open, FAIR, Citable and Trustworthy. Here we developed an instrument using the open source PolicyModels toolkit that attempts to operationalize key aspects of OFCT principles and piloted the instrument by evaluating eight biomedical community repositories listed by the NIDDK Information Network (dkNET.org). Repositories included both specialist repositories that focused on a particular data type or domain, in this case diabetes and metabolomics, and generalist repositories that accept all data types and domains. The goal of this work was both to obtain a sense of how much the design of current biomedical data repositories align with these principles and to augment the dkNET listing with additional information that may be important to investigators trying to choose a repository, e.g., does the repository fully support data citation? The evaluation was performed from March to November 2020 through inspection of documentation and interaction with the sites by the authors. Overall, although there was little explicit acknowledgement of any of the OFCT principles in our sample, the majority of repositories provided at least some support for their tenets.
TheabaI/abaRquorum sensing system effects pathogenicity inAcinetobacter baumannii
Authors: Sun Xiaoyu , Ni Zhaohui , Tang Jie , Ding Yue , Wang Xinlei , Li Fan
Published: January 2021

Acinetobacter baumanniiis a Gram-negative pathogen that has emerged as one of the most troublesome pathogens for health care institutions globally. Bacterial quorum sensing (QS) is a process of cell-to-cell communication that relies on the production, secretion and detection of autoinducer (AI) signals to share information about cell density and regulate gene expression accordingly. In this study, we performed a comprehensive set of experiments show that deletion of quorum sensing genes showed differences in growth characteristics, morphology, biofilm formation and virulence, and increased susceptibility to some antimicrobials and exhibited motility defects. RNA-seq analysis indicated that genes involved in various aspects of energy production and conversion, Valine, leucine and isoleucine degradation and lipid transport and metabolism showed different expression.

IMPORTANCE

Previous studies on bacterial quorum sensing mainly focused on biofilm formation and motility and antibiotic resistance. In this study, we focused on detecting the role of theabaI/abaRQS system in the virulence ofA. baumannii. Our work provides a new insight intoabaI/abaRquorum sensing system effects pathogenicity inA. baumannii. We propose that targeting the AHL synthase enzymeabaIcould provide an effective strategy for attenuating virulence. On the contrary, interdicting the autoinducer synthase–receptorabaRelicits unpredictable consequences, which may lead to enhanced bacterial virulence.