bluuebunny/crossref_metadata_2025 huggingface dataset:
The ‘burn’ of ranitidine recall: current insights and mitigation strategies
Authors: Perisetti Abhilash , Goyal Hemant , Tharian Benjamin
Published: April 2021

Ranitidine was one of the most commonly used medications for the treatment of gastroesophageal reflux disease. On 1 April 2020, the US Food and Drug Administration requested all manufacturers to immediately withdraw ranitidine from the market because of concern of higher than acceptable levels of N-nitrosodimethylamine, a potential carcinogen. Herein, we highlight the reason for this recall, along with the effects of this recall on both the patients and healthcare practitioners, and offer insights on management strategies.
Comparison of an in-house acquired brain F-18 FDG PET normal database with commercially available normal data
Authors: Waterschoot Robbe , D’Asseler Yves , Goethals Ingeborg
Published: April 2021

Introduction

Current guidelines recommend the use of semiautomated assessment of F-18 FDG PET brain studies. Accuracy is influenced by the normal data, which requires knowledge of the included subjects and how they were acquired. Due to confidentiality, such information is often not completely disclosed. Our aim was to determine the variation in FDG uptake between several commercially available and our in-house normal database.

Methods

Our database contains 83 healthy subjects. Outlier detection using SPM further ensured normality, resulting in exclusion of three subjects. The remaining 80 subjects were analyzed using three commercially available software packages. Z-score data per patient and per lobe were extracted and pooled in predefined age groups (18–40, 41–60 and 61–80 years old) with a calculation of mean Z-scores and SD. Correlation between Z-score output of different software was investigated.

Results

In the 18–40 years age group, frontotemporal hypermetabolism was found with all software. Decreased cerebellar uptake was found with two software packages. Mean Z-scores are closer to zero in the 41–60 years age group compared to the younger group, and mostly within the normal range in the 61–80 years age group with all software. A moderate to high linear correlation between Z-score output was found, but individual Z-scores varied widely.

Conclusions

The three software packages yielded varying Z-score output, partially explained by an age mismatch between our subjects and subjects in their normal databases. A definitive explanation for the remaining differences is lacking. This emphasizes the importance of age-matched normal data and knowledge of the included databases to allow adequate preprocessing.
A retrospective multicenter study of quantitative bone SPECT/CT to predict the surgical removal of the accessory navicular bone
Authors: Kim Ji-Young , Kim Ji Young , Park Soo Bin , Kim Chulhan , Lee Won Woo
Published: April 2021

Objective

The maximum standardized uptake value (SUVmax) in single-photon emission computed tomography/computed tomography (SPECT/CT) can help quantify disease activity of the accessory navicular bone (ANB). In this multicenter quantitative bone SPECT/CT study, we investigated whether SUVmax was correlated with ANB severity, thereby allowing prediction of surgical resection for ANB treatment.

Methods

Two-hundred forty-six patients (men:women = 135:111, mean age = 39.3 years), who had undergone quantitative Tc-99m diphosphonate SPECT/CT of the feet, were recruited from four hospitals. SUVmax was measured using vendor-provided quantitation software. The SUVmax values were compared in relation to ANB type (type 1 = 62, type 2 = 136 and type 3 = 14), presence of pain and surgical treatment.

Results

SUVmax (mean ± SD) was the highest in type 2 ANB (4.41 ± 5.2; P = 0.0101). The 17 resected ANBs showed greater SUVmax (8.27 ± 5.23; P < 0.0001) than the 141 asymptomatic ANBs (2.30 ± 1.68) or the 54 symptomatic ANBs without surgery (6.15 ± 4.40). Since surgery is exclusively indicated for ANB type 2, surgical resection was investigated only in these cases. In univariate analysis, young age and SUVmax were significantly associated with surgical treatment, but only SUVmax was a significant predictor of surgery in multivariate analysis (P < 0.0001). Type 2 ANBs were treated by surgery in 32.5% (13/40) of the cases when SUVmax was ≥5, and in only 1.35% (1/74) of the cases when SUVmax was <5 (P < 0.0001).

Conclusion

ANB disease activity and excision were strongly associated with the SUVmax derived from quantitative bone SPECT/CT. Our study suggests an absolute SUVmax cutoff for ultimate ANB surgical treatment, but additional prospective studies are required to validate this finding.
Lipids Responsible for Intestinal or Hepatic Disorder
Authors: Sissaoui Samira , Cochet Manon , Poinsot Pierre , Bordat Claire , Collardeau‐Frachon Sophie , Lachaux Alain , Lacaille Florence , Peretti Noël
Published: April 2021

Familial intestinal hypocholesterolemias, such as abetalipoproteinemia, hypobetalipoproteinemia, and chylomicron retention disease, are rare genetic diseases that result in a defect in the synthesis or secretion of lipoproteins containing apolipoprotein B.

In children, these conditions present with diarrhoea and growth failure, whereas adults present with neuromuscular, ophthalmological, and hepatic symptoms. Simple laboratory investigations have shown that diagnosis can be made from findings of dramatically decreased cholesterol levels, deficiencies in fat‐soluble vitamins (mostly vitamin E), endoscopic findings of the characteristic white intestinal mucosa, and fat‐loaded enterocytes in biopsy samples. Genetic analysis is used to confirm the diagnosis. Treatment is based on a low‐fat diet with essential fatty acid supplementation, high doses of fat‐soluble vitamins, and regular and life‐long follow‐up.

The present study examines cases and literature findings of these conditions, and emphasises the need to explore severe hypocholesterolemia and deficiencies in fat‐soluble vitamins to not miss these rare, but easy to diagnose and treat, disorders.
Effect of standing and sitting positions on energy expenditure in people with transtibial amputation compared to age- and sex-matched controls
Authors: Cheever Sarah M. , Kramer Patricia A. , Morgan Sara J. , Hafner Brian J.
Published: April 2021

Background:

Energy expenditure (EE) is often greater in people with lower-limb amputation, compared with healthy controls, because of the biomechanical compensations needed to walk with a prosthesis. Compensatory movements are required to stand with a prosthesis; however, little is known about whether standing with a prosthesis also requires greater EE.

Objective:

The goal of this study was to examine the effect of standing and sitting positions on EE in people with transtibial amputation and matched controls.

Study Design:

This is a secondary analysis.

Methods:

Energy expenditure data from people with unilateral, transtibial amputation because of nondysvascular causes were compared with data from age- and sex-matched controls without amputation. Energy expenditure was defined as the mean volumetric rate of oxygen consumed over the last 2 of 5 minutes in each position and measured with a portable breath-by-breath metabolic analyzer. Repeated-measures analysis of variance was used to examine the effects of position (sitting and standing) and group (amputation and control) on EE.

Results:

A significant interaction effect indicated participants with amputation showed a significantly greater increase in standing EE relative to sitting EE (26.2%) than did controls (13.4%). Simple main effects showed EE in standing was significantly greater than EE in sitting for both groups, but there were no significant differences in EE between groups during sitting or standing.

Conclusions:

Energy expenditure in standing, when measured relative to EE in sitting, is significantly greater in people with amputation. This result indicates that additional energy may be required to maintain an upright position with a lower-limb prosthesis.
Identifying HIV-related digital social influencers using an iterative deep learning approach
Authors: Zheng Cheng , Wang Wei , Young Sean D.
Published: April 2021

Objective(s):

Community popular opinion leaders have played a critical role in HIV prevention interventions. However, it is often difficult to identify these ‘HIV influencers’ who are qualified and willing to promote HIV campaigns, especially online, because social media influencers change frequently. We sought to use an iterative deep learning framework to automatically discover HIV-related online social influencers.

Design and method:

Out of 1.15 million Twitter users’ data from March 2018 to March 2020, we extracted tweets from 1099 Twitter users who had mentioned the keywords ‘HIV’ or ‘AIDS’. Two Twitter users determined to be ‘online HIV influencers’ based on their conversation topics and engagement were hand-picked by domain experts and used as a seed training dataset. We modelled social influence and discovered new potential influencers based on these seeds using a graph neural network model. We tested the model's precision and recall compared with other baseline model approaches. We validated the results through manual verification.

Results:

The model identified 23 new (manually verified) HIV-related influencers, including health and research organizations and local HIV advocates across the United States. Our proposed model achieved the highest accuracy/recall, with an average improvement of 38.5% over the other baseline models.

Conclusion:

Results suggest that iterative deep learning models can be used to automatically identify new and changing key HIV-related influencers online. We discuss the implications and potential of HIV researchers/departments applying this approach across online big data (e.g. hundreds of millions of social media posts per day) to help promote HIV prevention campaigns to affected communities.
The impact of immune checkpoint therapy on the latent reservoir in HIV-infected individuals with cancer on antiretroviral therapy
Authors: Lau Jillian S.Y. , McMahon James H. , Gubser Celine , Solomon Ajantha , Chiu Chris Y.H. , Dantanarayana Ashanti , Chea Socheata , Tennakoon Surekha , Zerbato Jennifer M. , Garlick Jill , Morcilla Vincent , Palmer Sarah , Lewin Sharon R. , Rasmussen Thomas A.
Published: April 2021

Objective:

The aim of this study was to quantify HIV-specific immunological and virological changes in people with HIV (PWH) on antiretroviral therapy (ART) with malignancy who received immune checkpoint blockade (ICB).

Design:

An observational cohort study.

Methods:

Blood samples were collected before and after four cycles of ICB in HIV-positive adults on ART. Virological assessments performed on CD4+ T cells included cell-associated unspliced HIV RNA, cell-associated HIV DNA, Tat/rev-induced limiting dilution assay (TILDA) and plasma HIV RNA using a single copy assay (SCA). Flow cytometry was used to assess the frequency of precursor exhausted T cells (Tpex) and exhausted T cells (Tex), and Gag-specific CD4+ and CD8+ T cells positive for IFN-γ, TNF-α or CD107a by intracellular cytokine staining (ICS).

Results:

Participant (P)1 received avelumab (anti-PD-L1) for Merkel cell carcinoma. P2 and P3 received ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) for metastatic melanoma. An increase in CA-US RNA following each infusion was noted in all three participants. There were no consistent changes in HIV DNA or the proportion of cells with inducible MS HIV RNA. P2 demonstrated a striking increase in the frequency of gag-specific central and effector memory CD8+ T cells producing IFN-γ, TNF-α and CD107a following anti-PD1 and anti-CTLA-4. The frequency of CD8+ Tpex cells pre-ICB was also highest in this participant.

Conclusion:

In three PWH with cancer on ART, we found that ICB activated latent HIV and enhanced HIV-specific T cell function but with considerable variation.
High Prevalence of NRTI and NNRTI Drug Resistance Among ART-Experienced, Hospitalized Inpatients
Authors: Bossard Claire , Schramm Birgit , Wanjala Stephen , Jain Lakshmi , Mucinya Gisèle , Opollo Valarie , Wiesner Lubbe , van Cutsem Gilles , Poulet Elisabeth , Szumilin Elisabeth , Ellman Tom , Maman David
Published: April 2021

Background:

Patients hospitalized with advanced HIV have a high mortality risk. We assessed viremia and drug resistance among differentiated care services and explored whether expediting the switching of failing treatments may be justified.

Setting:

Hospitals in the Democratic Republic of (DRC) Congo (HIV hospital) and Kenya (general hospital including HIV care).

Methods:

Viral load (VL) testing and drug resistance (DR) genotyping were conducted for HIV inpatients ≥15 years, on first-line antiretroviral therapy (ART) for ≥6 months, and CD4 ≤350 cells/µL. Dual-class DR was defined as low-, intermediate-, or high-level DR to at least 1 nucleoside reverse transcriptase inhibitor and 1 non-nucleoside reverse transcriptase inhibitor. ART regimens were considered ineffective if dual-class DR was detected at viral failure (VL ≥1000 copies/mL).

Results:

Among 305 inpatients, 36.7% (Kenya) and 71.2% (DRC) had VL ≥1000 copies/mL, of which 72.9% and 73.7% had dual-class DR. Among viral failures on tenofovir disoproxil fumarate (TDF)-based regimens, 56.1% had TDF-DR and 29.8% zidovudine (AZT)-DR; on AZT regimens, 71.4% had AZT-DR and 61.9% TDF-DR, respectively. Treatment interruptions (≥48 hours during past 6 months) were reported by 41.7% (Kenya) and 56.7% (DRC). Approximately 56.2% (Kenya) and 47.4% (DRC) on TDF regimens had tenofovir diphosphate concentrations <1250 fmol/punch (suboptimal adherence). Among viral failures with CD4 <100 cells/µL, 76.0% (Kenya) and 84.6% (DRC) were on ineffective regimens.

Conclusions:

Many hospitalized, ART-experienced patients with advanced HIV were on an ineffective first-line regimen. Addressing ART failure promptly should be integrated into advanced disease care packages for this group. Switching to effective second-line medications should be considered after a single high VL on non-nucleoside reverse transcriptase inhibitor–based first-line if CD4 ≤350 cells/µL or, when VL is unavailable, among patients with CD4 ≤100 cells/µL.
Virtual Surgical Planning and Three-Dimensional Printing to Aid the Anatomical Reduction of an Old Malunited Fracture of the Mandible
Authors: Ding Qian , Fu Zhen-Zhen , Yue Jin , Xu Yao-Xiang , Xue Ling-Fa , Xiao Wen-Lin
Published: April 2021

Mandible fracture is a common injury in maxillofacial surgery. It causes not only maxillofacial dysfunction but also facial deformities. Malunited fractures of the mandible have been a vast challenge in clinical treatment due to the misalignment of the broken ends and the occurrence of occlusal disorders. This case report describes using virtual surgical planning and three-dimensional printing to treat a patient with malunited fracture of the mandible. Failing to perform mandibular surgery due to severe brain trauma after the car accident, the patient got malunited healing of mandible. The authors applied virtual surgical planning to perform preoperative analysis and surgical design on this patient, three-dimensional printing to fabricate occlusal plate, and models of the preoperative and postoperative mandible to guide the operation. Finally, the authors achieved the reduction and reconstruction of the mandible with satisfactory clinical results.
Examining the Relationship Between Wound Complications and the Use of Resorbable Plates in Cranial Vault Reconstruction
Authors: Reilly Frank O.F. , Clinton Susan , Dillon Paul , Carr Shane , Bracken Shirley , Caird John , Murray Dylan J.
Published: April 2021

Background:

Resorbable plates are commonly used in cranial vault reconstruction surgery. There are few published papers examining their safety profile. The authors examined the prevalence of wound complications associated with the use of resorbable plates (Inion CPS Fixation System) in pediatric patients undergoing cranial vault reconstruction.

Methods:

A retrospective review of patients (n = 182) who underwent cranial vault reconstruction using resorbable plate fixation was undertaken. All procedures were performed by a single Craniofacial Surgeon at the National Pediatric Craniofacial Center from 2008 to 2016. Wound complications were identified from a prospectively maintained database and medical note review. Several key patient characteristics and surgical variables were also recorded and tested for associations with wound complications.

Results:

A total of 58.8% (107 of 182) of patients were male with a median age at surgery of 16.2 months. Overall, 12.1% (22 of 182) experienced a postoperative wound complication requiring hospital admission. A total of 2.73% (5 of 182) of the patients that returned to theatre had remnants of plates removed. The authors had a mean time from primary operation to secondary reoperation of 103 days. In univariate statistical analysis, females were more likely to develop a wound complication. However, in stratified analyses excluding patients with an underlying genetic syndrome, increasing age, and lower weight but not gender were associated with wound complications.

Conclusions:

A 12.1% (22 of 182) wound complication rate with the use of the Inion CPS Fixation System was observed. Inion plates appear to have an equivalent safety profile to other fixation devices. Increasing age and lower weight were associated with an increased risk of wound complications in nonsyndromic patients.
Safe Zone for Dissection in Frontotemporal Region to Avoid Injury to the Temporal Branch of Facial Nerve
Authors: Hashmi Asra , Zahed Adil , Hamamdjian Christopher , McGee Catherine , Barry Mohammad , Asali Danah , Khan Faraz Ali , Al-Mufarrej Faisal
Published: April 2021

The objective of this study is to provide a reliable roadmap for temporal branch of the facial nerve, in order to minimize, the risk of injury to the nerve during surgical dissections. A literature search was conducted on temporal branch of facial nerve. The date search range was 1950 to 2017. Databases searched included Medline, Web of science, Biosis, SciELO, Data Citation, and Zoologic Records. Data were collected on, author specialty, date of publication, and the relationship of the temporal branch of facial nerve to various landmarks in the frontotemporal region reported in human anatomic studies. Among the 48 studies reviewed, a total of 3477 anatomic dissections were performed in the craniofacial region. Temporal branch of facial nerve was located between 2.5 and 3 cm from lateral orbital rim. In relation to the zygomatic arch, it was found anywhere from the midpoint of the arch to 1 finger breath posterior to the arch. For the plane, it was most commonly described as being under the superficial temporal fascia (STF) or within the loose areolar tissue. Most anatomic dissections found 2 to 4 twigs of the temporal branch of facial nerve. In relation to the lateral canthus, it was found to be 2.85 +/– 0.69 cm superior and 2.54 +/– 0.43 cm lateral to the lateral canthus. Our study suggests consolidated data on surgical landmarks in order to ensure safe dissection in temporal region and prevent injury to the temporal branch of facial nerve.
The Epidemiology and Management of Maxillofacial Fractures at a Tertiary Care Hospital in a Conflict-Torn Region in Somalia
Authors: Tekin Ahmet M. , Ali Ismail M.
Published: April 2021

The etiology of maxillofacial fractures (MFFs) varies according to the geographical location and density of the population. This study aimed to analyze the etiology, pattern, and treatment of MFFs. Epidemiological characteristics and treatment modalities of MFFs have never been evaluated in Somalia. The study included 45 patients who were operated on for MFFs at a tertiary care hospital in Somalia (2018–2019). Patient demographics, fracture causes, types, associated non-facial injuries, treatment modalities, and hospitalization-time were evaluated. The most common etiological factors of the MFFs were explosion (24.4%) and assault (24.4%), followed by gunshot (22.2%), sports accident (15.6%), motor vehicle accident (11.1%), and fall from height (2.2%) patients, respectively. The main site of injury was the mandible bone (64.4%) followed by nasal bone, maxilla, zygomatic, and orbital region. The most common non-facial injuries of the MFFs were soft tissue laceration (37.8%) followed by femoral fracture (6.7%), clavicle fracture (4.4%), and femoral fracture with chest injuries (2.2%). The most applied treatment was open reduction microplate +/− intermaxillary fixation (77.8%). Due to the size of the mandible fractures, an iliac autograft (6.7%) was performed. The mean length of the hospital stay was 11.8 ± 8.4 days (range, 1–45 days), and some patients (15.6%) needed intensive care due to severe injuries. This will be the first study aiming to analyze the etiology, pattern, and treatment of MFFs in Somalia. This study deals with the social aspects of Somalia, and it shows that MFFs develop as a result of highly interpersonal violence in a young man.
A Modified Minimally Invasive Approach for the Treatment of Mandibular Condylar Fracture
Authors: Yang Yao , Wang Piao , Jin Hexiu , Chen Renji , Wang Xuejiu
Published: April 2021

In this study, we introduced a small “V” shaped incision around the ear lobe modified from fact-lift approach to treat the mandibular condylar neck and subcondylar fractures to further minimize and hide the postsurgical scars. A total of 15 cases with mandibular condylar fractures from low levels of condylar neck to high levels of subcondylar region were treated by this approach. An incision was designed from the posterior rim of the tragus down to the anterior skin wrinkle to the ear lobe, surrounding it, continually up and backward for a little distance, forming a “V”-like shape. After cutting and elevation of the skin flap, the remaining steps were the same as those in trans-parotid mini-invasive approaches. The surgical scars introduced in this study were more hidden than those in other mini-invasive approaches and all patients were satisfied with their aesthetic appearances. We suggested that the modified “V” shaped mini-invasive approach has an advantage in achieving aesthetic results and could be an alternative incision in treating some types of mandibular condylar and subcondylar fractures.
Teaching Physiotherapy Students Physical Examination Skills by Using Photogrammetry
Authors: Lo Chi Ngai , Abdelkader Tarek , Choi Yik Ming , Goff Anthony James , Suresh Krishnasamy , Carpio Guiller Augustin Cea , Soon Benjamin
Published: April 2021

Introduction

Education research explains how healthcare professional training could be more efficient and effective by integrating simulation technology. Despite its relevance in training medical students, the evidence of its effectiveness in the manual skill training of physiotherapy students remains limited. The aim of this study was to compare the effectiveness of 3-dimensional (3D) images of real objects produced by photogrammetry and traditional 2-dimensional (2D) images when introducing manual therapy skills to undergraduate physiotherapy students via an online course.

Methods

In a randomized controlled trial, a group of first-year physiotherapy bachelor honor degree students participated in a 2-hour online course on 3 manual assessment skills: cervical compression, distraction, and flexion-rotation tests. They demonstrated 2 sets of learning materials, including either 3D images of real rotating objects using close-range photogrammetry (experimental group) or traditional 2D images (control group). After their respective training, an Objective Structured Clinical Evaluation procedure was conducted to demonstrate their knowledge about the techniques. A standardized 9-item practical performance test was used as the primary outcome measure for the analyses.

Results

Seventy-seven students participated in the study. The average Objective Structured Clinical Evaluation score for the experimental group (n = 40) was 41.3/50 (±3.9) and the control group (n = 37) was 39.1/50 (±4.5, P = 0.02).

Conclusions

For learning 3 cervical spine assessment skills, this study shows that photogrammetry creates 3D images of real rotating objects that are more effective than 2D images for first-year physiotherapy students.
Sutured Versus Mesh-augmented Hiatus Hernia Repair
Authors: Petric Josipa , Bright Tim , Liu David S. , Wee Yun Melissa , Watson David I.
Published: April 2021

Objective:

This meta-analysis systematically reviewed published randomized control trials comparing sutured versus mesh-augmented hiatus hernia (HH) repair. Our primary endpoint was HH recurrence at short- and long-term follow-up. Secondary endpoints were: surgical complications, operative times, dysphagia and quality of life.

Summary Background Data:

Repair of large HHs is increasingly being performed. However, there is no consensus for the optimal technique for hiatal closure between sutured versus mesh-augmented (absorbable or nonabsorbable) repair.

Methods:

A systematic review of Medline, Scopus (which encompassed Embase), Cochrane Central Register of Controlled Trials, Web of Science, and PubMed was performed to identify relevant studies comparing mesh-augmented versus sutured HH repair. Data were extracted and compared by meta-analysis, using odds ratio and mean differences with 95% confidence intervals.

Results:

Seven randomized control trials were found which compared mesh-augmented (nonabsorbable mesh: n = 296; absorbable mesh: n = 92) with sutured repair (n = 347). There were no significant differences for short-term hernia recurrence (defined as 6–12 months, 10.1% mesh vs 15.5% sutured, P = 0.22), long-term hernia recurrence (defined as 3–5 years, 30.7% mesh vs 31.3% sutured, P = 0.69), functional outcomes and patient satisfaction. The only statistically significant difference was that the mesh repair required a longer operation time (P = 0.05, OR 2.33, 95% confidence interval 0.03–24.69).

Conclusions:

Mesh repair for HH does not offer any advantage over sutured hiatal closure. As both techniques deliver good and comparable clinical outcomes, a suture only technique is still an appropriate approach.
How does epigenetics influence the course of evolution?
Authors: Ashe Alyson , Colot Vincent , Oldroyd Benjamin P.
Published: April 2021

Epigenetics is the study of changes in gene activity that can be transmitted through cell divisions but cannot be explained by changes in the DNA sequence. Epigenetic mechanisms are central to gene regulation, phenotypic plasticity, development and the preservation of genome integrity. Epigenetic mechanisms are often held to make a minor contribution to evolutionary change because epigenetic states are typically erased and reset at every generation, and are therefore, not heritable. Nonetheless, there is growing appreciation that epigenetic variation makes direct and indirect contributions to evolutionary processes. First, some epigenetic states are transmitted intergenerationally and affect the phenotype of offspring. Moreover,
bona fide
heritable ‘epialleles' exist and are quite common in plants. Such epialleles could, therefore, be subject to natural selection in the same way as conventional DNA sequence-based alleles. Second, epigenetic variation enhances phenotypic plasticity and phenotypic variance and thus can modulate the effect of natural selection on sequence-based genetic variation. Third, given that phenotypic plasticity is central to the adaptability of organisms, epigenetic mechanisms that generate plasticity and acclimation are important to consider in evolutionary theory. Fourth, some genes are under selection to be ‘imprinted' identifying the sex of the parent from which they were derived, leading to parent-of-origin-dependent gene expression and effects. These effects can generate hybrid disfunction and contribute to speciation. Finally, epigenetic processes, particularly DNA methylation, contribute directly to DNA sequence evolution, because they act as mutagens on the one hand and modulate genome stability on the other by keeping transposable elements in check.

This article is part of the theme issue ‘How does epigenetics influence the course of evolution?'
Epigenetic inheritance and evolution: a historian's perspective
Authors: Loison Laurent
Published: April 2021

The aim of this article is to put the growing interest in epigenetics in the field of evolutionary theory into a historical context. First, I assess the view that epigenetic inheritance could be seen as vindicating a revival of (neo)Lamarckism. Drawing on Jablonka's and Lamb's considerable output, I identify several differences between modern epigenetics and what Lamarckism was in the history of science. Even if Lamarckism is not back, epigenetic inheritance might be appealing for evolutionary biologists because it could potentiate two neglected mechanisms: the Baldwin effect and genetic assimilation. Second, I go back to the first ideas about the Baldwin effect developed in the late nineteenth century to show that the efficiency of this mechanism was already linked with a form of non-genetic inheritance. The opposition to all forms of non-genetic inheritance that prevailed at the time of the rise of the Modern Synthesis helps to explain why the Baldwin effect was understood as an insignificant mechanism during the second half of the twentieth century. Based on this historical reconstruction, in §4, I examine what modern epigenetics can bring to the picture and under what conditions epigenetic inheritance might be seen as strengthening the causal relationship between adaptability and adaptation. Throughout I support the view that the Baldwin effect and genetic assimilation, even if they are quite close, should not be conflated, and that drawing a line between these concepts is helpful in order to better understand where epigenetic inheritance might endorse a new causal role.

This article is part of the theme issue ‘How does epigenetics influence the course of evolution?’
The epiallelic potential of transposable elements and its evolutionary significance in plants
Authors: Baduel Pierre , Colot Vincent
Published: April 2021

DNA provides the fundamental framework for heritability, yet heritable trait variation need not be completely ‘hard-wired’ into the DNA sequence. In plants, the epigenetic machinery that controls transposable element (TE) activity, and which includes DNA methylation, underpins most known cases of inherited trait variants that are independent of DNA sequence changes. Here, we review our current knowledge of the extent, mechanisms and potential adaptive contribution of epiallelic variation at TE-containing alleles in this group of species. For the purpose of this review, we focus mainly on DNA methylation, as it provides an easily quantifiable readout of such variation. The picture that emerges is complex. On the one hand, pronounced differences in DNA methylation at TE sequences can either occur spontaneously or be induced experimentallyen masseacross the genome through genetic means. Many of these epivariants are stably inherited over multiple sexual generations, thus leading to transgenerational epigenetic inheritance. Functional consequences can be significant, yet they are typically of limited magnitude and although the same epivariants can be found in nature, the factors involved in their generation in this setting remain to be determined. On the other hand, moderate DNA methylation variation at TE-containing alleles can be reproducibly induced by the environment, again usually with mild effects, and most of this variation tends to be lost across generations. Based on these considerations, we argue that TE-containing alleles, rather than their inherited epiallelic variants, are the main targets of natural selection. Thus, we propose that the adaptive contribution of TE-associated epivariation, whether stable or not, lies predominantly in its capacity to modulate TE mobilization in response to the environment, hence providing hard-wired opportunities for the flexible exploration of the phenotypic space.

This article is part of the theme issue ‘How does epigenetics influence the course of evolution?’
Parent-of-origin effects, allele-specific expression, genomic imprinting and paternal manipulation in social insects
Authors: Oldroyd Benjamin P. , Yagound Boris
Published: April 2021

Haplo-diploidy and the relatedness asymmetries it generates mean that social insects are prime candidates for the evolution of genomic imprinting. In single-mating social insect species, some genes may be selected to evolve genomic mechanisms that enhance reproduction by workers when they are inherited from a female. This situation reverses in multiple mating species, where genes inherited from fathers can be under selection to enhance the reproductive success of daughters. Reciprocal crosses between subspecies of honeybees have shown strong parent-of-origin effects on worker reproductive phenotypes, and this could be evidence of such genomic imprinting affecting genes related to worker reproduction. It is also possible that social insect fathers directly affect gene expression in their daughters, for example, by placing small interfering RNA molecules in semen. Gene expression studies have repeatedly found evidence of parent-specific gene expression in social insects, but it is unclear at this time whether this arises from genomic imprinting, paternal manipulation, an artefact of cyto-nuclear interactions, or all of these.

This article is part of the theme issue ‘How does epigenetics influence the course of evolution?’
Standard pleural interventions are not high-risk aerosol generating procedures
Authors: Arnold DT , Gregson FKA , Sheikh S , Hamilton FW , Welch H , Dipper A , Nava GW ,   AERATOR group, Dodd JW , Clive AO , Bzdek BR , Reid JP , Maskell NA
Published: April 2021

No evidence exists regarding the risk of aerosolisation from pleural procedures. This study used two discrete methodologies, in an environment with no background aerosol interference, to measure aerosol generation from 10 different pleural procedures (3 medical thoracoscopies, 3 indwelling pleural catheter insertions, 1 therapeutic thoracentesis, and 3 indwelling pleural catheter removals). The measurements indicated that, any aerosol production during these procedures was significantly lower than aerosols produced by the patient breathing or coughing. Pleural procedures should not be considered aerosol generating. We hope this study informs future iterations of guidelines on the appropriate use of PPE when performing these procedures.
Investigating the health effects of 3 coexisting tobacco and nicotine products using system dynamics population modeling: An Italian population case study
Authors: Camacho Oscar M , Hill Andrew , Fiebelkorn Stacy , Williams Aaron , Murphy James J
Published: April 2021

With the proliferation of tobacco and nicotine products, there might be a need for more complex models than current two-product models. We have developed a three-product model able to represent interactions between 3 products in the marketplace. We also investigate if using several implementations of two-product models could provide sufficient information to assess 3 coexisting products. Italy is used as case-study with THPs and e-cigarettes as the products under investigation. We use transitions rates estimated for THPs in Japan and e-cigarettes in the USA to project what could happen if the Italian population were to behave as the Japanese for THP or USA for e-cigarettes. Results suggest that three-product models may be hindered by data availability while two product models could miss potential synergies between products. Both, THP and E-Cigarette scenarios, led to reduction in life-years lost although the Japanese THP scenario reductions were 3 times larger than the USA e-cigarette projections.
Interplay between nucleoid-associated proteins and transcription factors in controlling specialized metabolism inStreptomyces
Authors: Zhang Xiafei , Andres Sara N. , Elliot Marie A.
Published: April 2021

Lsr2 is a small nucleoid-associated protein found throughout the actinobacteria. Lsr2 functions similarly to the well-studied H-NS, in that it preferentially binds AT-rich sequences and represses gene expression. InStreptomyces venezuelae, Lsr2 represses the expression of many specialized metabolic clusters, including the chloramphenicol antibiotic biosynthetic gene cluster, and deletinglsr2leads to significant upregulation of chloramphenicol cluster expression. We show here that Lsr2 likely exerts its repressive effects on the chloramphenicol cluster by polymerizing along the chromosome, and by bridging sites within and adjacent to the chloramphenicol cluster. CmlR is a known activator of the chloramphenicol cluster, but expression of its associated gene is not upregulated in anlsr2mutant strain. We demonstrate that CmlR is essential for chloramphenicol production, and further reveal that CmlR functions to ‘counter-silence’ Lsr2’s repressive effects by recruiting RNA polymerase and enhancing transcription, with RNA polymerase effectively clearing bound Lsr2 from the chloramphenicol cluster DNA. Our results provide insight into the interplay between opposing regulatory proteins that govern antibiotic production inS. venezuelae, which could be exploited to maximize the production of bioactive natural products in other systems.

IMPORTANCE

Specialized metabolic clusters inStreptomycesare the source of many clinically-prescribed antibiotics. However, many clusters are not expressed in the laboratory due to repression by the nucleoid-associated protein Lsr2. Understanding how Lsr2 represses cluster expression, and how repression can be alleviated, are key to accessing the metabolic potential of these bacteria. Using the chloramphenicol biosynthetic cluster fromStreptomyces venezuelaeas a model, we explored the mechanistic basis underlying Lsr2-mediated repression, and activation by the pathway-specific regulator CmlR. Lsr2 polymerized along the chromosome and bridged binding sites located within and outside of the cluster, promoting repression. Conversely, CmlR was essential for chloramphenicol production, and further functioned to counter-silence Lsr2 repression by recruiting RNA polymerase and promoting transcription, ultimately removing Lsr2 polymers from the chromosome. Manipulating the activity of both regulators led to >130× increase in chloramphenicol levels, suggesting that combinatorial regulatory strategies can be powerful tools for maximizing natural product yields.
Population genomics of Salmonella enterica serovar Weltevreden ST365, an emerging predominant causative agent of diarrheal disease
Authors: Zhang Jianmin , Peng Zhong , Chen Kaifeng , Zhan Zeqiang , Shen Haiyan , Feng Saixiang , Gou Hongchao , Qu Xiaoyun , Ziemann Mark , Layton Daniel S. , Wu Bin , Xu Xuebin , Liao Ming
Published: April 2021

Salmonella enterica serovar Weltevreden is a recently emerged pathogen, and as such we lack a comprehensive knowledge of its microbiology, genomics, epidemiology and biogeography. In this study, we analyzed 174 novel S. Weltevreden isolates including 111 isolates recovered from diarrheal patients in China between 2006 and 2017. Our results demonstrate that the ST365 clone was the predominant causative agent of the diarrhea-outbreak during this period, as vast majority of the isolates recovered from diarrheal patients belonged to this sequence type (97.37%, 74/76). We also determined the ST365 clone as the predominant sequence type of S. Weltevreden from diarrheal patients globally from previously published sequences (97.51%, 196/201). In order to determine the possible antimicrobial genes and virulence factors associated with S. Weltevreden, we performed whole genome sequencing on our novel isolates. We were able to identify a range of key virulence factors associated with S. Weltevreden that are likely to be beneficial to their fitness and pathogenesis. Furthermore, we were able to isolate a novel 100.03-kb IncFII(S) type virulence plasmid that used the same replicon as pSPCV virulence plasmid. Importantly, we demonstrated through plasmid elimination a functional role for this plasmid in bacterial virulence. These findings are critical to further our knowledge of this high consequence pathogen.

Importance

Salmonella Weltevreden is a newly emerged foodborne pathogen and has caused several outbreaks of diarrheal diseases in some regions in the world. However, comprehensive knowledge of microbiology, genomics, epidemiology and biogeography of this newly emerged pathogen is still lack. In this study, we made an unexpected discovery that S. Weltevreden sequence type (ST) 365 is the causative agent in the diarrhea-outbreak in China and many other regions of the world. We also shown that this sequence type was widely recovered from animal, food, and environmental samples collected in different regions in the world. Importantly, we discovered a novel IncFII(S) type virulence plasmid commonly carried by S. Weltevreden strains of both human, animal, and food origins. These data facilitate future studies investigating the emergence of S. Weltevreden involved in diarrheal outbreaks and the global spread of S. Weltevreden strains.
Enumerating asymptomatic COVID-19 cases and estimating SARS-CoV-2 fecal shedding rates via wastewater-based epidemiology
Authors: Schmitz Bradley W. , Innes Gabriel K. , Prasek Sarah M. , Betancourt Walter Q. , Stark Erika R. , Foster Aidan R. , Abraham Alison G. , Gerba Charles P. , Pepper Ian L.
Published: April 2021

Wastewater-based epidemiology (WBE) was utilized to monitor SARS-CoV-2 RNA in sewage collected from manholes specific to individual student dormitories (dorms) at the University of Arizona in the fall semester of 2020, which led to successful identification and reduction of transmission events. Positive wastewater samples triggered clinical testing of almost all residents within that dorm; thus, SARS-CoV-2 infected individuals were identified regardless of symptom expression. This current study examined clinical testing data to determine the abundance of asymptomatic versus symptomatic cases in these defined communities. Nasal and nasopharyngeal swab samples processed via antigen and PCR tests indicated that 79.2% of SARS-CoV-2 infections were asymptomatic, and only 20.8% of positive cases reported COVID- 19 symptoms at the time of testing. Clinical data was paired with corresponding wastewater virus concentrations, which enabled calculation of viral shedding rates in feces per infected person(s). Mean shedding rates averaged from positive wastewater samples across all dorms were 6.84 ± 0.77 log10 genome copies per gram of feces (gc/g-feces) based on the N1 gene and 7.74 ± 0.53 log10 gc/g-feces based on the N2 gene. Quantification of SARS-CoV-2 fecal shedding rates from infected persons has been the critical missing component necessary for WBE models to measure and predict SARS-CoV-2 infection prevalence in communities. The findings from this study can be utilized to create models that can be used to inform public health prevention and response actions.

Highlights

Wastewater-based epidemiology with clinical testing monitored SARS-CoV-2 in dorms.

79.2% of SARS-CoV-2 infections were asymptomatic, and 20.8% were symptomatic.

Clinical and wastewater data aggregated to estimate SARS-CoV-2 fecal shedding rate.

Mean fecal shedding rate based on the N1 gene was 6.84 ± 0.77 log10 gc/g-feces.

Mean fecal shedding rate based on the N2 gene was 7.74 ± 0.53 log10 gc/g-feces.

Graphical Abstract
Effect of RNA on morphology and dynamics of membraneless organelles
Authors: Ranganathan Srivastav , Shakhnovich Eugene
Published: April 2021

Membraneless organelles (MLOs) are spatiotemporally regulated structures that concentrate multi-valent proteins or RNA, often in response to stress. The proteins enriched within MLOs are often classified as high-valency “scaffolds” or low valency “clients”, with the former being associated with a phase-separation promoting role. In this study, we employ a minimal model for P-body components, with a defined protein-protein interaction network, to study their phase-separation at biologically realistic low protein concentrations. Without RNA multivalent proteins can assemble into solid-like clusters only in the regime of high concentration and stable interactions. RNA molecules promote cluster formation in an RNA-length dependent manner, even in the regime of weak interactions and low protein volume fraction. Our simulations reveal that long RNA chains act as super-scaffolds that stabilize large RNA-protein clusters by recruiting low-valency proteins within them while also ensuring functional “liquid-like” turnover of components. Our results suggest that RNA-mediated phase separation could be a plausible mechanism for spatiotemporally regulated phase-separation in the cell.
Gel Electrophoresis/Electroelution Sorting Fractionator combined with Filter Aided Sample preparation (FASP) for deep proteomic analysis
Authors: Ramos Yassel , Almeida Alexis , Carpio Jenis , Rodríguez-Ulloa Arielis , Perera Yasser , González Luis J. , Wiśniewski Jacek R. , Besada Vladimir
Published: April 2021

Sample preparation and protein fractionation are important issues in proteomic studies in spite of the technological achievements on protein mass spectrometry. Protein extraction procedures strongly affect the performance of fractionation methods by provoking protein dispersion in several fractions. The most notable exception is SDS-PAGE-based protein fractionation due to its extraordinary resolution and the effectiveness of SDS as a solubilizing agent. Its main limitation lies in the poor recovery of the gel-trapped proteins, where protein electro-elution is the most successful approach to overcome this drawback. We created a device to separate complex mixture of proteins and peptides (named “GEES fractionator”) that is based on the continuousGelElectrophoresis/Electro-elutionSorting of these molecules. In an unsupervised process, complex mixtures of proteins or peptides are fractionated into the gel while separated fractions are simultaneously and sequentially electro-eluted to the solution containing wells. The performance of the device was studied for SDS-PAGE-based protein fractionation in terms of reproducibility, protein recovery and loading capacity. In the SDS-free PAGE setup, complex peptide mixtures can also be fractionated. More than 11 700 proteins were identified in the whole-cell lysate of the CaSki cell line by using the GEES fractionator combined with the Filter Aided Sample Preparation (FASP) method and mass spectrometry analysis. GEES-based proteome characterization shows a 1.7 fold increase in the number of identified proteins compared to the unfractionated sample analysis. Proteins involved in the co-regulated transcription activity, as well as cancer related pathways such as apoptosis signaling, P53 and RAS pathways are more represented in the protein identification output of GEES-based fractionation approaches.