bluuebunny/crossref_metadata_2025 huggingface dataset:
A Randomized Phase II Trial of Adjuvant Hepatic Arterial Infusion and Systemic Therapy With or Without Panitumumab After Hepatic Resection of KRAS Wild-type Colorectal Cancer
Authors: Kemeny Nancy E. , Chou Joanne F. , Capanu Marinela , Chatila Walid K. , Shi Hongyu , Sanchez-Vega Francisco , Kingham Thomas Peter , Connell Louise Catherine , Jarnagin William R. , D’Angelica Michael I.
Published: May 2021

Objective/Background:

The purpose was to determine whether adding Pmab versus no Pmab to an adjuvant regimen of hepatic arterial infusion (HAI) of floxuridine (FUDR) plus systemic (SYS) leucovorin, fluorouracil, and irinotecan (FOLFIRI) improves 15-month recurrence-free survival for patients with RAS wild-type colorectal cancer. Secondary endpoints included overall survival, toxicity, and influence of predictive biomarkers.

Methods:

This phase II trial randomized patients with KRAS wild-type resected colorectal liver metastases to adjuvant HAI FUDR + SYS FOLFIRI +/– Pmab (NCT01312857). Patients were stratified by clinical risk score and previous chemotherapy. Based on an exact binomial design, if one arm had ≥24 patients alive and disease-free at 15 months that regimen was considered promising for further investigation.

Results:

Seventy-five patients were randomized. Patient characteristics and toxicity were not different in the 2 arms, except for rash in +Pmab arm. Grade 3/4 elevation in bilirubin or alkaline phosphatase did not differ in the 2 arms. Twenty-five (69%; 95% CI, 53–82) patients in the Pmab arm versus 18 (47%; 95% CI, 32–63) patients in the arm without Pmab were alive and recurrence-free at 15 months. Only the Pmab arm met the decision rule, while the other arm did not. After median follow-up of 56.6 months, 3-year recurrence-free survival was 57% (95% CI, 43–76) and 42% (95% CI, 29–61), and 3-year overall survival was 97% (95% CI, 90–99) and 91% (95% CI, 83–99), +/– Pmab, respectively.

Conclusions:

The addition of Pmab to HAI FUDR + SYS FOLFIRI showed promising activity without increased biliary toxicity and should be further investigated in a larger trial.
Intracorporeal Versus Extracorporeal Anastomosis in Patients Undergoing Laparoscopic Right Hemicolectomy: A Multicenter Randomized Clinical Trial (The IVEA-study)
Authors: Ferrer-Márquez Manuel , Rubio-Gil Francisco , Torres-Fernández Rocio , Moya-Forcén Pedro , Belda-Lozano Ricardo , Arroyo-Sebastián Antonio , Benavides-Buleje Jorge , Reina-Duarte Angel
Published: May 2021

Objective:

The aim of this study was to evaluate short-term outcomes of performing intracorporeal versus extracorporeal anastomosis in laparoscopic right hemicolectomy for right colon neoplasm.

Background:

Despite advances in the laparoscopic approach in colorectal surgery and the clear benefit of this approach over open surgery, because of the technical difficulty in performing intracorporeal anastomosis (IA), some continue to perform it extracorporeally in right colon surgery.

Materials and Methods:

This study was a prospective multicenter randomized trial with 2 parallel groups on which either IA or extracorporeal anastomosis was performed in laparoscopic right hemicolectomy for right colon neoplasm, carried out between January 2016 and December 2018.

Results:

A total of 168 patients were randomized during the study period. At baseline, the 2 groups were comparable for age, sex, body mass index, surgical risk, and comorbidity. The median length of postoperative hospital stay was 7 days with no differences between the groups. About 70% of patients had an uneventful postoperative period without complications. The most common complications were paralytic ileus (20.63%; 33), surgical site infection (SSI) (10%; 16), and anastomotic leakage (6.25%; 10). The results show a lower level of SSI in the IA group (3.65% vs. 16.67%, P=0.008). Other complications do not show statistically significant differences between groups. Likewise, the incision for the extraction of the specimen was smaller in the IA group (P=0.000) and creation of the anastomosis intracorporeally decreased postoperative pain (P=0.000).

Conclusions:

In comparison to the extracorporeal technique, IA decreased postoperative pain, incision size, and SSI. Further studies will be needed to verify our findings.
The Value of a Support Person During the Surgical Consent Process: A Prospective Cohort Study
Authors: Sappenfield Elisabeth C. , O’Sullivan David M. , Steinberg Adam C.
Published: May 2021

Objective

The objective of this study is to investigate the impact of support person participation during the preoperative appointment.

Methods

This is a prospective cohort study involving patients scheduled to undergo pelvic reconstructive surgery. Eligible patients were enrolled at the preoperative appointment and compared by presence or absence of a support person. Questionnaires were completed before and after the preoperative appointment, 1–3 days before surgery, and at the postoperative appointment. Previsit questionnaires included the Generalized Anxiety Disorder-7, 6-item short form of the Spielberger State-Trait Anxiety Inventory (STAI-6), and Brief Health Literacy screen. Postvisit questionnaires included the STAI-6, satisfaction with decision scale for pelvic floor disorders, preoperative preparedness questionnaire, and knowledge questionnaire. At the postoperative appointment, participants completed the patient global impression of improvement and postoperative symptom and satisfaction questionnaire. Primary outcome was patient anxiety measured by the STAI-6.

Results

Seventy-six patients participated in the study: 37 were categorized in the support person cohort and 39 were categorized in the no support person cohort. The mean scores of the STAI-6 did not differ between the support person and no support person cohorts at all time points (previsit: 42.97 ± 13.23 vs 41.53 ± 17.11, P = 0.68; postvisit: 38.11 ± 12.76 vs 36.33 ± 11.72, P = 0.53, and 1–3 days before surgery: 42.61 ± 13.0 vs 41.05 ± 16.39, P = 0.65). Overall preparedness, satisfaction with decision scale for pelvic floor disorders, and knowledge questionnaire did not differ between cohorts at both time points. Perioperative phone calls were similar between cohorts.

Conclusion

Our study suggests that the presence of a support person at preoperative counseling for pelvic floor surgery should be a personal preference and not a recommendation.
‘She come like a sister to me’: a qualitative study of volunteer social support for disadvantaged women in the transition to motherhood in England
Authors: McLeish Jenny , Redshaw Maggie
Published: May 2021

This qualitative study explores the ways in which disadvantaged women benefit from social support from a trained volunteer during pregnancy and the postnatal period, using the theoretical frameworks of stress and coping and a multi-dimensional model of social support. Forty-seven mothers took part in semi-structured interviews. The mothers, who had received social support through nine volunteer projects in England, faced many potentially stressful challenges besides having a baby (such as poverty, poor housing, histories of abuse, motherhood at a young age, living with physical or mental health difficulties, migration and insecure immigration status). Analysis was in two distinct stages: first, an inductive thematic analysis of mothers' experiences, and second, mapping of the results onto the theoretical frameworks chosen. Volunteers built relationships of trust with mothers and gave skilled emotional support, positive appraisal support, informational support and practical support according to mothers’ individual needs, thereby assisting mothers exposed to multiple stressors with problem-focused, emotion-focused and perception-focused coping. This helped to reduce social isolation, increase effective access to services and community resources, and build mothers' confidence, self-esteem and self-efficacy. Volunteer social support may have particular salience for mothers who lack structural support and need skilled functional support.

This article is part of the theme issue ‘Multidisciplinary perspectives on social support and maternal–child health’.
Relatively speaking? Partners' and family members’ views and experiences of supporting breastfeeding: a systematic review of qualitative evidence
Authors: Chang Yan-Shing , Li Kan Man Carmen , Li Kan Yan Chloe , Beake Sarah , Lok Kris Yuet Wan , Bick Debra
Published: May 2021

This review aimed to synthesize qualitative evidence of views and experiences of partners and other family members who provided breastfeeding support for a relative. The Joanna Briggs Institute (JBI) methodology for systematic reviews of qualitative evidence was followed. Seven databases: CINAHL, MEDLINE, EMBASE, PsycINFO, Scopus, Maternal and Infant Care, and Web of Science were searched. Partners and other family members (e.g. grandmothers, siblings) of women in any countries were included. Included papers were critically appraised. The JBI meta-aggregative approach was used to analyze data and form synthesized findings. Seventy-six papers from 74 studies were included. Five synthesized findings were: (i) spectrum of family members' breastfeeding knowledge, experiences and roles; (ii) the complexity of infant feeding decision making; (iii) the controversy of breastfeeding in front of others; (iv) impact of breastfeeding on family; and (v) it takes more than just family members: support for family members. Partners' and family members’ views and experiences of breastfeeding support reflected multi-faceted personal, social, financial, cultural, religious, emotional, psychological, and societal factors of the support they provided (or not). Healthcare professionals should engage them in breastfeeding discussions with the woman, and offer tailored and practical guidance relevant to help them to appropriately support the woman.

This article is part of the theme issue ‘Multidisciplinary perspectives on social support and maternal–child health’.
Is WHO International Standard for Anti-SARS-CoV-2 Immunoglobulin Clinically Useful?
Authors: Lukaszuk Krzysztof , Kiewisz Jolanta , Rozanska Karolina , Podolak Amira , Jakiel Grzegorz , Woclawek-Potocka Izabela , Rabalski Lukasz , Lukaszuk Aron
Published: May 2021

Background

The introduction of vaccination against SARS-CoV-2 infection needs precise instruments for quality control of vaccination procedure, detection of poor immunological response and estimation of the achieved protection against the disease but also against infection and being infective.

Objective

To compare new automated SARS-CoV 2 Ig assay performance characteristics from the automated Elecsys SARS-CoV-2 S (Roche) with the new LIAISON® SARS-CoV-2 TrimericS IgG (DiaSorin) assay and their compatibility with WHO International Standard for anti-SARS-CoV-2 immunoglobulin. In the context of the mass vaccination programs, we undertook the investigation of clinical utility of the two new automated assays by analyzing results in samples collected at specified time points relative to the vaccination time.

Design

Prospective assay evaluation.

Patients

Medical staff undergoing vaccination with BioNTech/Pfizer Comirnaty vaccine between January and March 2021 (n = 79) and referred for serum antiSARS-CoV 2 Ig testing prior to vaccination, 21 days after the first dose, and 8, 14 and 30 days after the second dose. Main Outcome Measure(s): Serum antibody levels measured with Roche and DiaSorin assays.

Results

Intra-assay imprecision was low with DiaSorin at 3.46%; and Roche at 2.5%. The Passing-Bablok regression equation for all tested samples was y (DiaSorin) = 184.61 + (1.03 x Roche) and the correlation between the assays (r=0.587; p < 0.0001).

Conclusions

The novel automated assays exhibit strong concordance in calibration, with assay-specific interpretation required for routine clinical use. These results highlight the need for further work on the international standard of measurement of SARS-CoV 2 Ig especially in era of vaccination. The serological assays can be useful to detect IgG/IgM antibodies, to assess the degree of immunization, to trace the contacts, and to support the decision to readmit people to work or vaccinate them again. However, the values generated by both assays can be markedly different, and assay-specific and personalized interpretation is required.
HIV and the Seroprevalence of SARS-CoV-2
Authors: Stout Robert L. , Rigatti Steven J.
Published: May 2021

Importance

Healthy HIV-positive insurance applicants have a similar risk of infection and produce a similar antibody response as HIV-negative applicants infected with COVID-19.

Objective

Study the seroprevalence and immune response to COVID-19 in healthy HIV-positive life insurance applicants.

Design

From January 2020 to March 2021, we examined the seroprevalence of COVID-19 in all HIV-positive applicants. Antibody level in 340 age and sex matched COVID-19 positive applicants, 170 HIV-positive and 170 HIV negative, are compared. The data was de-identified of all personal information and separated by month, age and sex.

Participants

Self-reported healthy HIV positive life insurance applicants were tested for antibodies to COVID-19.
System inference via field inversion for the spatio-temporal progression of infectious diseases: Studies of COVID-19 in Michigan and Mexico
Authors: Wang Z. , Carrasco-Teja M. , Zhang X. , Teichert G.H. , Garikipati K.
Published: May 2021

We present an approach to studying and predicting the spatio-temporal progression of infectious diseases. We treat the problem by adopting a partial differential equation (PDE) version of the Susceptible, Infected, Recovered, Deceased (SIRD) compartmental model of epidemiology, which is achieved by replacing compartmental populations by their densities. Building on our recent work (Computational Mechanics, 66, 1177, 2020), we replace our earlier use of global polynomial basis functions with those having local support, as epitomized in the finite element method, for the spatial representation of the SIRD parameters. The time dependence is treated by inferring constant parameters over time intervals that coincide with the time step in semi-discrete numerical implementations. In combination, this amounts to a scheme of field inversion of the SIRD parameters over each time step. Applied to data over ten months of 2020 for the pandemic in the US state of Michigan and to all of Mexico, our system inference via field inversion infers spatio-temporally varying PDE SIRD parameters that replicate the progression of the pandemic with high accuracy. It also produces accurate predictions, when compared against data, for a three week period into 2021. Of note is the insight that is suggested on the spatio-temporal variation of infection, recovery and death rates, as well as patterns of the population’s mobility revealed by diffusivities of the compartments.
Quantifying COVID-19 vaccination hesitancy during early vaccination rollout in Canada
Authors: Tang Xuyang , Gelband Hellen , Nagelkerke Nico , Bogoch Isaac I. , Brown Patrick , Morawski Ed , Tam Theresa , Reid Angus , Jha Prabhat ,   for the Action to beat coronavirus/Action pour battre le coronavirus (Ab-C) Study Investigators
Published: May 2021

Background

Understanding vaccination hesitancy during early vaccination rollout in Canada can help the government’s vaccination efforts in education and outreach, which may help eventually achieving herd immunity. This study uses an online survey to assess vaccination hesitancy in population subgroups in Canada.

Method

Panel members from the nationally representative Angus Reid Forum were randomly invited to complete an online survey on their experiencing with COVID-19 symptoms and testing, as well as intention to vaccination against COVID-19. Respondents were asked “when a vaccine against the coronavirus becomes available to you, will you get vaccinated or not?” Vaccination hesitancy was defined as choosing “No – I will not get a coronavirus vaccination” as a response.

Results

14,621 panel members (46% male and 53% female) completed the survey. Although the respondents overrepresent age 60+ and higher levels of education, other demographics, the prevalences of smoking, obesity, diabetes and hypertension were comparable to the Canadian national census and health surveys. COVID-19 vaccination hesitancy is relatively low overall (9%). Being a resident of Alberta (predicted probability = 15%), aged 40-59 (OR = 0.87, 0.78 – 0.97, predicted probability = 12%), identifying as a visible minority (OR = 0.56, 0.37 – 0.84, predicted probability = 15%), having some college level education or lower (predicted probability = 14%), or living in households of at least 5 are related to greater vaccination hesitancy (OR = 0.82, 0.76 – 0.88, predicted probability = 13%).

Conclusion

Our study enhances the understanding of COVID-19 vaccination hesitancy and identifies key population groups with higher vaccination hesitancy. As the Canadian COVID-19 vaccination effort continues, policymakers may focus outreach, education, and other efforts on these groups, which also represent groups with higher risks for contracting and dying from COVID-19. Furthermore, Canada would need to vaccinate virtually the entire population to reach herd immunity due to its relatively low infection level, and a high vaccination hesitancy would be a major hurdle to achieving that.
Women’s views on accepting COVID-19 vaccination during and after pregnancy, and for their babies: A multi-methods study in the UK
Authors: Skirrow Helen , Barnett Sara , Bell Sadie , Riaposova Lucia , Mounier-Jack Sandra , Kampmann Beate , Holder Beth
Published: May 2021

Background

COVID-19 vaccines are the cornerstone of the pandemic response and now advised for pregnant women in the United Kingdom(UK) however COVID-19 vaccine acceptance among pregnant women is unknown.

Methods

An online survey and semi-structured interviews were used to investigate pregnant women’s views on COVID-19 vaccine acceptability for themselves when pregnant, not pregnant and for their babies. 1,181 women, aged over 16 years, who had been pregnant since 23rd March 2020, were surveyed between 3rdAugust–11thOctober 2020. Ten women were interviewed.

Results

The majority of women surveyed (81.2%) reported that they would ‘definitely’ or were ‘leaning towards’ accepting a COVID-19 vaccine when not pregnant. COVID-19 vaccine acceptance was significantly lower during pregnancy (62.1%, p<0.005) and for their babies (69.9%, p<0.005). Ethnic minority women were twice as likely to reject a COVID-19 vaccine for themselves when not pregnant, pregnant and for their babies compared to women from White ethnic groups (p<0.005). Women from lower-income households, aged under 25-years, and from some geographic regions were more likely to reject a COVID-19 vaccine when not pregnant, pregnant and for their babies. Multivariate analysis revealed that income and ethnicity were the main drivers of the observed age and regional differences. Women unvaccinated against pertussis in pregnancy were over four times more likely to reject COVID-19 vaccines when not pregnant, pregnant and for their babies. Thematic analysis of the survey freetext responses and interviews found safety concerns about COVID-19 vaccines were common though wider mistrust in vaccines was also expressed. Trust in vaccines and the health system were also reasons women gave for accepting COVID-19 vaccines.

Conclusion

Safety information on COVID-19 vaccines must be clearly communicated to pregnant women to provide reassurance and facilitate informed pregnancy vaccine decisions. Targeted interventions to promote COVID-19 vaccine uptake among ethnic minority and lower-income women may be needed.
Predicting remission after internet-delivered psychotherapy in patients with depression using machine learning and multi-modal data
Authors: Wallert John , Boberg Julia , Kaldo Viktor , Mataix-Cols David , Flygare Oskar , Crowley James J , Halvorsen Matthew , Abdesslem Fehmi Ben , Boman Magnus , Andersson Evelyn , Isacsson Nils Hentati , Ivanova Ekaterina , Rück Christian
Published: May 2021

BACKGROUND

Whether a patient benefits from psychotherapy or not is arguably a complex process and heterogeneous information extracted from process, genetic, demographic, and clinical data could contribute to the prediction of remission status after psychotherapy. This study applied supervised machine learning with such multi-modal baseline data to predict remission in patients with major depressive disorder (MDD) after completed psychotherapy.

METHODS

Eight-hundred ninety-four genotyped adult patients (65.5% women, age range 18-75 years) diagnosed with MDD and treated with guided Internet-based Cognitive Behaviour Therapy (ICBT) at the Internet Psychiatry Clinic in Stockholm were included (2008-2016). Predictor variables from multiple domains were available: demographic, clinical, process (e.g. time to complete online questionnaires), and genetic (polygenic risk scores for depression, education and more). The outcome was remission status post ICBT (cut-off ≤10 on MADRS-S). Data were split into train (60%) and validation (40%) sets based on treatment start date. Predictor selection employed human domain knowledge followed by Recursive Feature Elimination. Model derivation was internally validated through repeated cross-validation resampling. The final random forest model was externally validated against a (i) null, (ii) logit, (iii) XGBoost, and (iv) blended meta-ensemble model on the hold-out validation set. Model transparency was explored through partial dependence and Local Interpretable Model-agnostic Explanations (LIME) analysis.

RESULTS

Feature selection retained 45 predictors representing all four predictor types. With unseen validation data, the final random forest model proved reasonably accurate at classifying post ICBT remission (Accuracy 0.656 [0.604, 0.705], P vs null model = 0.004; AUC 0.687 [0.631, 0.743]), slightly better vs logit (bootstrap D =1.730, P = 0.084) but not vs XGBoost (D = 0.463, P = 0.643). Transparency analysis showed model usage of all predictor types at both the group and individual patient level.

CONCLUSION

A new, multi-modal classifier for predicting MDD remission status after ICBT treatment in routine psychiatric care was derived and empirically validated. The multi-modal approach to predicting remission may inform tailored treatment, and deserves further investigation.

One-sentence Summary

Predicting remission of depression in adults after psychotherapy
Attitude and Perceived Barriers towards Research among Undergraduate Medical Students of Bangladesh
Authors: Ferdoush Jannatul , Johora Fatema , Khan IkramUllah , Towfiq Hossain Sharif Mohammad , Sadia Halima , Jeenia Fatiha Tasmin , Chowdhury Sameera Shafique , Sultana Nagina , Sharmeen Shagorika
Published: May 2021

Background

Undergraduate research opportunities teach students not only how to conduct research, but they too learn problem-solving aptitudes. Participating in research also increases students’ interest is being involved and making special contributions to the academic field. Therefore, the aim of our study was intended to assess the attitude and perceived barriers toward research among the medical undergraduates of Bangladesh.

Methods

A cross-sectional questionnaire survey was conducted among third, fourth, and fifth year students across medical colleges in Bangladesh, during the month of July, 2020 to December, 2020. A Google-linked questionnaire was disseminated to the students via different social platform and the responses were received through Google drive.

Result

The questionnaire survey received responses from 1279 students, with 94% claiming to be familiar with the scientific method. 82.7% of students mentioned they could design and execute a research project as well as can write scientific articles. More than half of the respondents (66.4%) expressed an interest in participating in research. Almost all respondents (96.7%) agreed that research is beneficial as it aid critical thinking and policy implementation. 79.8% of respondents opined that education on research methodology should be required in the medical curriculum. Majority of the respondents reported that lack of time and priorities to do research work because of compact academic tasks (89.1%), insufficient guidance (86.6%), lack of familiarities with research methodology (87.5%) and statistical analysis (85.2%) are the barriers of research.

Conclusion

Our findings indicated that Bangladeshi medical students have a positive attitude toward research and that research methodology should be taught in undergraduate medical education. In order to increase participation in research, the challenges identified by students should be addressed.
Deubiquitinase-Targeting Chimeras for Targeted Protein Stabilization
Authors: Henning Nathaniel J. , Boike Lydia , Spradlin Jessica N. , Ward Carl C. , Belcher Bridget , Brittain Scott M. , Hesse Matthew , Dovala Dustin , McGregor Lynn M. , McKenna Jeffrey M. , Tallarico John A. , Schirle Markus , Nomura Daniel K.
Published: May 2021

Targeted protein degradation is a powerful therapeutic modality that uses heterobifunctional small-molecules to induce proximity between E3 ubiquitin ligases and target proteins to ubiquitinate and degrade specific proteins of interest. However, many proteins are ubiquitinated and degraded to drive disease pathology; in these cases targeted protein stabilization (TPS), rather than degradation, of the actively degraded target using a small-molecule would be therapeutically beneficial. Here, we present the Deubiquitinase-Targeting Chimera (DUBTAC) platform for TPS of specific proteins. Using chemoproteomic approaches, we discovered the covalent ligand EN523 that targets a non-catalytic allosteric cysteine C23 in the K48 ubiquitin-specific deubiquitinase OTUB1. We then developed a heterobifunctional DUBTAC consisting of our EN523 OTUB1 recruiter linked to lumacaftor, a drug used to treat cystic fibrosis that binds ΔF508-CFTR. We demonstrated proof-of-concept of TPS by showing that this DUBTAC robustly stabilized ΔF508-CFTR in human cystic fibrosis bronchial epithelial cells in an OTUB1-dependent manner. Our study underscores the utility of chemoproteomics-enabled covalent ligand discovery approaches to develop new induced proximity-based therapeutic modalities and introduces the DUBTAC platform for TPS.

Editorial summary

We have developed the Deubiquitinase Targeting Chimera (DUBTAC) platform for targeted protein stabilization. We have discovered a covalent recruiter against the deubiquitinase OTUB1 that we have linked to the mutant ΔF508-CFTR targeting cystic fibrosis drug Lumacaftor to stabilize mutant CFTR protein in cells.
GLUCOCORTICOIDS REGULATE MITOCHONDRIAL FATTY ACID OXIDATION IN FETAL CARDIOMYOCYTES
Authors: Ivy Jessica R. , Carter Roderic N. , Zhao Jin-Feng , Buckley Charlotte , Urquijo Helena , Rog-Zielinska Eva A. , Panting Emma , Hrabalkova Lenka , Nicholson Cara , Agnew Emma J. , Kemp Matthew W. , Morton Nicholas M. , Stock Sarah J. , Wyrwoll Caitlin , Ganley Ian G. , Chapman Karen E.
Published: May 2021

The late gestational rise in glucocorticoids contributes to the structural and functional maturation of the perinatal heart. Here, we hypothesised that glucocorticoid action contributes to the metabolic switch in perinatal cardiomyocytes from carbohydrate to fatty acid oxidation. In primary mouse fetal cardiomyocytes, dexamethasone treatment induced expression of genes involved in fatty acid oxidation and increased mitochondrial oxidation of palmitate, dependent upon glucocorticoid receptor (GR). Dexamethasone did not, however, induce mitophagy or alter the morphology of the mitochondrial network. In neonatal mice, dexamethasone treatment induced cardiac expression of fatty acid oxidation genesin vivo.However, dexamethasone treatment of pregnant C57Bl/6 mice at embryonic day (E)13.5 or E16.5 failed to induce fatty acid oxidation genes in fetal hearts assessed 24 hours later. Instead, at E17.5, fatty acid oxidation genes were down-regulated by dexamethasone, as was GR itself. PGC-1α, required for glucocorticoid-induced maturation of primary mouse fetal cardiomyocytesin vitro, was down-regulatedin vivoin fetal hearts at E17.5, 24 hours after dexamethasone administration. Similarly, following a course of antenatal corticosteroids in a sheep model of preterm birth, both GR and PGC-1α were down-regulated in fetal heart. These data suggest endogenous glucocorticoids support the perinatal switch to fatty acid oxidation in cardiomyocytes through changes in gene expression rather than gross changes in mitochondrial volume or mitochondrial turnover. Moreover, our data suggest that treatment with exogenous glucocorticoids may interfere with normal fetal heart maturation, possibly by down-regulating GR. This has implications for clinical use of antenatal corticosteroids when preterm birth is considered a possibility.
Myofibroblast transcriptome indicates SFRP2+ fibroblast progenitors in systemic sclerosis skin
Authors: Tabib Tracy , Huang Mengqi , Morse Nina , Papazoglou Anna , Behera Rithika , Jia Minxue , Bulik Melissa , Monier Daisy E. , Benos Panayiotis V. , Chen Wei , Domsic Robyn , Lafyatis Robert
Published: May 2021

Skin and lung fibrosis in systemic sclerosis (SSc) is driven by myofibroblasts, alpha-smooth muscle actin expressing cells that arise from a variety of cell types in murine fibrosis models. Utilizing single cell RNA-sequencing to examine the transcriptome changes, we show that SSc dermal myofibroblasts arise from an SFRP2/DPP4-expressing progenitor fibroblast population that globally upregulates expression of transcriptome markers, such as PRSS23 and THBS1. Only a fraction of SSc fibroblasts differentiate into myofibroblasts, as shown by expression of additional markers, SFRP4 and FNDC1. The myofibroblast transcriptome implicates upstream transcription factors that drive myofibroblast differentiation.
A Novel In Situ Activity Assay for Lysyl Oxidases
Authors: Wang Huilei , Poe Alan , Pak Lydia , Jandu Sandeep , Nandakumar Kavitha , Steppan Jochen , Löser Reik , Santhanam Lakshmi
Published: May 2021

The lysyl oxidase family of enzymes (LOXs) catalyze oxidative deamination of lysine side chains on collagen and elastin to initialize cross-linking that is essential for the formation of the extracellular matrix (ECM). Elevated expression of LOXs is highly associated with diverse disease processes. To date, the inability to detect total LOX catalytic function in situ has limited the ability to fully elucidate the role of LOXs in pathobiological mechanisms. Using LOXL2 as a representative member of the LOX family, we developed an in situ activity assay by utilizing the strong reaction between hydrazide and aldehyde to label the LOX-catalyzed allysine (-CHO) residues with biotin-hydrazide. The biotinylated ECM proteins are then labeled via biotin-streptavidin interaction and detected by fluorescence microscopy. This assay detects the total LOX activity in situ for both overexpressed and endogenous LOXs in cells and tissue samples and can be used for studies of LOXs as therapeutic targets.
Incidence and outcome of delirium during Helmet CPAP treatment in COVID-19 patients
Authors: Samartin Federica , Salvi Emanuele , Brambilla Anna Maria , Torre Alessandro , Ingrassia Stella , Gidaro Antonio
Published: May 2021

It is estimated that almost one-third of patients with COVID-19 develop delirium in the course of disease, actually it may be the only presenting symptom, especially in dementia patients. In COVID-19 patients delirium is associated with higher mortality rate, increased length of stay and a greater rate of admission in Intensive Care Unit and ventilator utilisation. We hypothesized a greater rate of delirium in Helmet CPAP COVID-19 ventilated patients because many known risk factors for delirium co-exist in these kind of patients (i.e. isolation, noise, dehydration). The first aim of our study is to investigate the incidence of delirium occurring during Helmet CPAP therapy in COVID-19 patients. Moreover, we wanted to verify if there are predictable risk factors for delirium and to determine if delirium increases the risk of adverse outcomes (need of endotracheal intubation and death). The cohort of CPAP ventilated COVID-19 patients were composed by 194 patients. Of them, 57 patients (29.3%) developed delirium during CPAP, more than two third in the first 48h. Age over 70 years, previous diagnosis of dementia or psychiatric condition, P/F < 150 after starting CPAP and Gr/Lys >8 resulted risk factors for delirium. Delirium group had a significantly higher mortality rate (47% vs 23%) and lower intubation rate (12% vs 26%) compared to non-delirious ones. Despite many potential predisposing factors are common in CPAP ventilated patients, delirium incidence in our population seems not to differ from what reported by other studies. Moreover, the occurrence of delirium seems not to be related to prolonged CPAP treatment, indeed no correlation between time spent in CPAP and delirium onset was found.
Naming Human Diseases: Ethical Principles of Curating Exclusive Substitute for Inopportune Nosology
Authors: Hu Zhiwen , Chen Ya , Song Yuling , Yang Zhongliang , Huang Hui
Published: May 2021

Background

In the medical sphere, understanding naming conventions strengthen the integrity of naming human diseases remains nominal rather than substantial yet. Since the current nosology-based standard for human diseases could not offer a one-size-fits-all corrective mechanism, many idiomatic but flawed names frequently appear in scientific literature and news outlets at the cost of sociocultural impacts.

Objective

We attempt to examine the ethical oversights of current naming practices and propose heuristic rationales and approaches to determine a pithy name instead of an inopportune nosology.

Methods

First, we examined the compiled global online news volumes and emotional tones on some inopportune nosology likeGerman measles, Middle Eastern Respiratory Syndrome, Spanish flu, Hong Kong flu, andHuntington’s diseasein the wake of COVID-19. Second, we prototypically scrutinize the lexical dynamics and pathological differentials ofGerman measlesand common synonyms by leveraging the capacity of the Google Books Ngram Corpus. Third, we demonstrated the empirical approaches to curate an exclusive substitute for an anachronistic nosologyGerman measlesbased on deep learning models andpost-hocexplanations.

Results

The infodemiological study shows that the public informed the offensive names with extremely negative tones in textual and visual narratives. The findings of the historiographical study indicate that many synonyms ofGerman measlesdid not survive, whileGerman measlesbecame an anachronistic usage, andrubellahas taken the dominant place since 1994. The PubMedBERT model could identifyrubellaas a potential substitution forGerman measleswith the highest semantic similarity. The results of the semantic drift experiments further indicate thatrubellatends to survive during the ebb and flow of semantic drift.

Conclusions

Our findings indicate that the nosological evolution of anachronistic names could result in sociocultural impacts without a corrective mechanism. To mitigate such impacts, we introduce some ethical principles for formulating an improved naming scheme. Based on deep learning models andpost-hocexplanations, our illustrated experiments could provide hallmark references to the remedial mechanism of naming practices and pertinent credit allocations.
Detection of SARS-CoV-2 infection in gargle, spit and sputum specimens
Authors: Poukka Eero , Mäkelä Henna , Hagberg Lotta , Vo Thuan , Nohynek Hanna , Ikonen Niina , Liitsola Kirsi , Helve Otto , Savolainen-Kopra Carita , Dub Timothée
Published: May 2021

The gold standard for SARS-CoV-2 infection diagnosis is RT-PCR from nasopharyngeal specimen (NPS). Its collection involves a close contact between patients and healthcare workers requiring a significant amount of workforce and putting them at risk of infection. We evaluated self-collection of alternative specimens and compared their sensitivity and Ct values to NPS. We visited acute COVID-19 outpatients to collect concomitant nasopharyngeal and gargle specimens and had patients self-collect a gargle and either sputum or spit specimens on the next morning.

We included 40 patients and collected 40 concomitant nasopharyngeal and gargle specimens, as well as 40 gargle, 22 spit and 16 sputum specimens on the next day, as 2 patients could not produce sputum.

All specimens were as sensitive as NPS. Gargle specimens had a sensitivity of 0.97 (CI 95% 0.92-1,00), whether collected concomitantly to NPS or on the next morning. Next morning spit and sputum specimens showed a sensitivity of 1.00 CI (95% 1.00-1.00) and 0.94 (CI 95% 0.87-1.00), respectively. The gargle specimens had a significantly higher mean cycle threshold (Ct) values, 29.89 (SD 4.63) (p-value <0.001) and 29.25 (SD 3.99) (p-value <0.001) when collected concomitantly and on the next morning compared to NPS (22.07, SD 4.63). Ct value obtained with spit (23.51, SD 4.57, p-value 0.11) and sputum (25.82, SD 9.21, p-value 0.28) specimens were close to NPS.

All alternative specimen collection methods were as sensitive as NPS, but spit collection appeared more promising, with a low Ct value and ease of collection. Our findings warrant further investigation.
Reconstructing co-dependent cellular crosstalk in lung adenocarcinoma using REMI
Authors: Yu Alice , Li Yuanyuan , Li Irene , Yeh Christine , Chiou Aaron E. , Ozawa Michael G. , Taylor Jonathan , Plevritis Sylvia K.
Published: May 2021

Cellular crosstalk in tissue microenvironments is fundamental to normal and pathological biological processes. Global assessment of cell-cell interactions (CCI) is not yet technically feasible, but computational efforts to reconstruct these interactions have been proposed. Current computational approaches that identify CCI often make the simplifying assumption that pairwise interactions are independent of one another, which can lead to reduced accuracy. We present REMI (REgularized Microenvironment Interactome), a graph-based algorithm that predicts ligand-receptor (LR) interactions by accounting for LR dependencies on high-dimensional, small sample size datasets. We apply REMI to reconstruct the human lung adenocarcinoma (LUAD) interactome from a bulk flow-sorted RNA-seq dataset, then leverage single-cell transcriptomics data to increase its resolution and identify LR prognostic signatures. We experimentally confirmed colocalization of CTGF:LRP6 as an interaction predicted to be associated with LUAD progression. Our work presents a novel way to reconstruct interactomes and a new approach to identify clinically-relevant cell-cell interactions.
Scarf: A toolkit for memory efficient analysis of large-scale single-cell genomics data
Authors: Dhapola Parashar , Rodhe Johan , Olofzon Rasmus , Bonald Thomas , Erlandsson Eva , Soneji Shamit , Karlsson Göran
Published: May 2021

The increasing capacity to perform large-scale single-cell genomic experiments continues to outpace the computational requirements to efficiently handle growing datasets. Herein we present Scarf, a modularly designed Python package that seamlessly interoperates with other single-cell toolkits and allows for memory-efficient single-cell analysis of millions of cells on a laptop or low-cost devices like single board computers. We demonstrate Scarf’s memory and compute-time efficiency by applying it to the largest existing single-cell RNA-Seq and ATAC-Seq datasets. Scarf wraps memory-efficient implementations of a graph-based t-stochastic neighbour embedding and hierarchical clustering algorithm. Moreover, Scarf performs accurate reference-anchored mapping of datasets while maintaining memory efficiency. By implementing a novel data downsampling algorithm, Scarf additionally can generate representative sampling of cells from a given dataset wherein rare cell populations and lineage differentiation trajectories are conserved. Together, Scarf provides a framework wherein any researcher can perform advanced processing, downsampling, reanalysis, and integration of atlas-scale datasets on standard laptop computers.
Effects of gestational age at birth on perinatal structural brain development in healthy term-born babies
Authors: Gale-Grant Oliver , Fenn-Moltu Sunniva , França Lucas , Dimitrova Ralica , Christaens Daan , Cordero-Grande Lucilio , Chew Andrew , Falconer Shona , Harper Nicholas , Price Anthony N , Hutter Jana , Hughes Emer , O’Muircheartaigh Jonathan , Rutherford Mary , Counsell Serena J , Rueckert Daniel , Nosarti Chiara , Hajnal Joseph V , McAlonan Grainne , Arichi Tomoki , Edwards A David , Batalle Dafnis
Published: May 2021

Multiple studies have demonstrated less favourable childhood outcomes in infants born in early term (37-38 weeks gestation) compared to those born at full term (40-41 weeks gestation). While this could be due to higher perinatal morbidity, gestational age at birth may also have a direct effect on the brain and subsequent neurodevelopment in term-born babies. Here we characterise structural brain correlates of gestational age at birth in healthy term-born neonates and their relationship to later neurodevelopmental outcome. We used T2 and diffusion weighted Magnetic Resonance Images acquired in the neonatal period from a cohort (n=454) of healthy babies born at term age (>37 weeks gestation) and scanned between 1 and 41 days after birth. Images were analysed using tensor based morphometry (TBM) and tract based spatial statistics (TBSS). Neurodevelopment was subsequently assessed at age 18 months using the Bayley-III Scales of Infant and Toddler Development, and the effects of gestational age at birth and related neuroimaging findings on outcome were analysed with linear regression. Infants born earlier had areas of higher relative ventricular volume, and lower relative brain volume in the basal ganglia, cerebellum and brainstem. Earlier birth was also associated with lower fractional anisotropy, higher mean, axial and radial diffusivity in major white matter tracts. Gestational age at birth was positively associated with all Bayley-III subscales at age 18 months. Linear regression models predicting outcome from gestational age at birth were significantly improved by adding neuroimaging features associated with gestational age at birth. This work adds to the growing body of evidence of the impact of early term birth and highlights the importance of considering the effect of gestational age at birth in future neuroimaging studies including term-born babies.
Neural correlates of audio-visual integration of socially meaningful information in macaque monkeys
Authors: Froesel Mathilda , Gacoin Maëva , Clavagnier Simon , Hauser Marc , Goudard Quentin , Hamed Suliann Ben
Published: May 2021

Social interactions rely on the ability to interpret semantic and emotional information, often from multiple sensory modalities. In human and nonhuman primates, both the auditory and visual modalities are used to generate and interpret communicative signals. In individuals with autism, not only are there deficits in social communication, but in the integration of audio-visual information. At present, we know little about the neural mechanisms that subserve the interpretation of complex social events, including the audio-visual integration that is often required with accompanying communicative signals. Based on heart rate estimates and fMRI in two macaque monkeys (Macaca mulatta), we show that individuals systematically associate affiliative facial expressions or social scenes with corresponding affiliative vocalizations, aggressive facial expressions or social scenes with corresponding aggressive vocalizations and escape visual scenes with scream vocalizations. In contrast, vocalizations that are incompatible with the visual information are fully suppressed, suggesting top-down regulation over the processing of sensory input. The process of binding audio-visual semantic and contextual information relies on a core functional network involving the superior temporal sulcus (STS) and lateral sulcus (LS). Peak activations in both sulci co-localize with face or voice patches that have been previously described. While all of these regions of interest (ROIs) respond to both auditory and visual information, LS ROIs have a preference for auditory and audio-visual congruent stimuli while STS ROIs equally respond to auditory, visual and audio-visual congruent stimuli. To further specify the cortical network involved in the control of this semantic association, we performed a whole brain gPPI functional connectivity analysis on the LS and STS cumulated ROIs. This gPPI analysis highlights a functional network connected to the LS and STS, involving the anterior cingulate cortex (ACC), area 46 in the dorsolateral prefrontal cortex (DLPFC), the orbitofrontal cortex (OFC), the intraparietal sulcus (IPS), the insular cortex and subcortically, the amygdala and the hippocampus. Comparing human and macaque results, we propose that the integration of audio-visual information for congruent, meaningful social events involves homologous neural circuitry, specifically, an emotional network composed of the STS, LS, ACC, OFC, and limbic areas, including the amygdala, and an attentional network including the STS, LS, IPS and DLPFC. As such, these networks are critical to the amodal representation of social meaning, thereby providing an explanation for some of deficits observed in autism.
Experimental evidence for delayed post-conflict management behaviour in wild dwarf mongooses
Authors: Morris-Drake Amy , Kern Julie M. , Radford Andrew N.
Published: May 2021

In many species, within-group conflict leads to immediate avoidance of potential aggressors or increases in affiliation, but no studies have investigated delayed post-conflict management behaviour. Here, we experimentally test that possibility using wild dwarf mongooses (Helogale parvula). First, we used natural and playback-simulated foraging displacements to demonstrate that bystanders take notice of the vocalisations produced during such within-group conflict events. We then used another playback experiment to assess delayed effects of within-group conflict on grooming interactions. Overall, fewer individuals groomed on evenings following an afternoon of simulated conflict, but those that did groomed more than on control evenings. Subordinate bystanders groomed with the simulated aggressor significantly less, and groomed more with one another, on conflict compared to control evenings. Our study provides experimental evidence that dwarf mongooses acoustically obtain information about within-group contests (including protagonist identity), retain that information and use it to inform conflict-management decisions with a temporal delay.
SeqScreen: Accurate and Sensitive Functional Screening of Pathogenic Sequences via Ensemble Learning
Authors: Balaji Advait , Kille Bryce , Kappell Anthony D. , Godbold Gene D. , Diep Madeline , Elworth R. A. Leo , Qian Zhiqin , Albin Dreycey , Nasko Daniel J. , Shah Nidhi , Pop Mihai , Segarra Santiago , Ternus Krista L. , Treangen Todd J.
Published: May 2021

The COVID-19 pandemic has emphasized the importance of detecting known and emerging pathogens from clinical and environmental samples. However, robust characterization of pathogenic sequences remains an open challenge. To this end, we developed SeqScreen, which can accurately characterize short nucleotide sequences using taxonomic and functional labels, and a customized set of curated Functions of Sequences of Concern (FunSoCs) specific to microbial pathogenesis. We show our ensemble machine learning model can label protein-coding sequences with FunSoCs with high recall and precision. SeqScreen is a step towards a novel paradigm of functionally informed pathogen characterization and is available for download at:www.gitlab.com/treangenlab/seqscreen