bluuebunny/crossref_metadata_2025 huggingface dataset:
Trajectories of compliance with COVID-19 related guidelines: longitudinal analyses of 50,000 UK adults
Authors: Wright Liam , Steptoe Andrew , Fancourt Daisy
Published: April 2021

Background: Governments have implemented a range of measure to tackle COVID-19, primarily focusing on changing citizens' behaviours in order to lower transmission of the virus. Some policymakers have expressed concern that citizens would not maintain high levels of compliance with these behaviours over the pandemic and would instead exhibit so-called "behavioural fatigue". While the concept has been criticized, there have been few tests of behavioural fatigue using data from the COVID-19 pandemic, and none that have tracked individuals' compliance trajectories. Methods: We used longitudinal data on self-reported compliance from 50,851 adults in the COVID-19 Social Study collected across two waves of the pandemic in the UK (01 April 2020 - 22 February 2021). We modelled typical compliance trajectories using latent growth curve analysis (LGCA) and tested for behavioural fatigue by attempting to identify a set of participants whose compliance decreased substantially over the study period. Results: We selected a four-class LGCA solution. Most individuals maintained high levels of compliance over the pandemic and reported similar levels of compliance across the first and second waves. Approximately one in seven participants had decreasing levels of compliance across the pandemic, reporting noticeably lower levels of compliance in the second wave, a pattern compatible with behavioural fatigue. Individuals with declining compliance levels differed from those with consistently high compliance on multiple characteristics, including (young) age, better physical health, lower empathy and conscientiousness and greater general willingness to take risks. Conclusion: While a minority, not all individuals have maintained high compliance across the pandemic. Decreasing compliance is related to several psychological traits. The results suggest that targeting of behaviour change messages later in the pandemic may be needed to increase compliance.
Life without mismatch repair
Authors: Sanders Mathijs A. , Vöhringer Harald , Forster Victoria J. , Moore Luiza , Campbell Brittany B. , Hooks Yvette , Edwards Melissa , Bianchi Vanessa , Coorens Tim H. H. , Butler Timothy M. , Lee-Six Henry , Robinson Philip S. , Flensburg Christoffer , Bilardi Rebecca A. , Majewski Ian J. , Reschke Agnes , Cairney Elizabeth , Crooks Bruce , Lindhorst Scott , Stearns Duncan , Tomboc Patrick , McDermott Ultan , Stratton Michael R. , Shlien Adam , Gerstung Moritz , Tabori Uri , Campbell Peter J.
Published: April 2021

Mismatch repair (MMR) is a critical defence against mutation, but we lack quantification of its activity on different DNA lesions during human life. We performed whole-genome sequencing of normal and neoplastic tissues from individuals with constitutional MMR deficiency to establish the roles of MMR components, tissue type and disease state in somatic mutation rates. Mutational signatures varied extensively across genotypes, some coupled to leading-strand replication, some to lagging-strand replication and some independent of replication, implying that the various MMR components engage different forms of DNA damage. Loss ofMSH2orMSH6(MutSα), but notMLH1orPMS2(MutLα), caused 5-methylcytosine-dependent hypermutation, indicating that MutSα is the pivotal complex for repairing spontaneous deamination of methylated cytosines in humans. Neoplastic change altered the distribution of mutational signatures, particularly accelerating replication-coupled indel signatures. Each component of MMR repairs 1-10 lesions/day per normal human cell, and many thousands of additional events during neoplastic transformation.

Highlights

MMR repairs 1-10 lesions/day in every normal cell and thousands more in tumor cells

MMR patterns and rates are shaped by genotype, tissue type and malignant transformation

MSH2 and MSH6 are pivotal for repairing spontaneous deamination of methylated cytosine

Replication indels and substitutions vary by leading versus lagging strand and genotype
Postnatal inflammation inApoe−/−mice is associated with immune training and atherosclerosis
Authors: Noye Ellesandra C. , Bekkering Siroon , Limawan Albert P. , Nguyen Maria U. , Widiasmoko Lisa K. , Lu Hui , Pepe Salvatore , Cheung Michael M. , Menheniott Trevelyan R. , Wallace Megan J , Moss Timothy J. , Burgner David P. , Short Kirsty R.
Published: April 2021

Background and aims

Preterm birth is associated with increased risk of cardiovascular disease (CVD). This may reflect a legacy of inflammatory exposures such as chorioamnionitis, that complicate pregnancies delivering preterm, or recurrent early-life infections, common in preterm infants. We previously reported that experimental chorioamnionitis followed by postnatal inflammation has additive and deleterious effects on atherosclerosis inApoe−/−mice. Here, we aimed to investigate whether innate immune training is a contributory inflammatory mechanism in this murine model of atherosclerosis.

Methods

Bone marrow-derived macrophages and peritoneal macrophages were isolated from 13 week-oldApoe−/−mice, previously exposed to prenatal intra-amniotic (experimental choriomanionitis) and/or repeated postnatal (peritoneal) lipopolysaccharide (LPS). Innate immune responses were assessed by cytokine responses following 24-hourex vivostimulation with toll-like receptor (TLR) agonists (LPS, Pam3Cys), and RPMI for 24 hours. Bone marrow progenitor populations were studied using flow cytometric analysis.

Results

Following postnatal LPS exposure, bone marrow-derived macrophages and peritoneal macrophages produced more pro-inflammatory cytokines following TLR stimulation than those from LPS unexposed mice, characteristic of a trained phenotype. Cytokine productionex vivocorrelated with atherosclerosis severityin vivo. Prenatal LPS did not affect cytokine production capacity. Combined prenatal and postnatal LPS exposure was associated with a reduction in common myeloid progenitor cells in the bone marrow.

Conclusions

Postnatal inflammation results in a trained phenotype in atherosclerosis-prone mice that is not enhanced by prenatal inflammation. If analogous mechanisms occur in humans, then there may be novel early life opportunities to reduce CVD risk in infants with early life infections.
Palaeogenomic analysis of black rat (Rattus rattus) reveals multiple European introductions associated with human economic history
Authors: Yu He , Jamieson Alexandra , Hulme-Beaman Ardern , Conroy Chris J. , Knight Becky , Speller Camilla , Al-Jarah Hiba , Eager Heidi , Trinks Alexandra , Adikari Gamini , Baron Henriette , Böhlendorf-Arslan Beate , Bohingamuwa Wijerathne , Crowther Alison , Cucchi Thomas , Esser Kinie , Fleisher Jeffrey , Gidney Louisa , Gladilina Elena , Gol’din Pavel , Goodman Steven M. , Hamilton-Dyer Sheila , Helm Richard , Hillman Chris , Kallala Nabil , Kivikero Hanna , Kovács Zsófia E. , Karl Kunst Günther , Kyselý René , Linderholm Anna , Maraoui-Telmini Bouthéina , Morales-Muñiz Arturo , Nabais Mariana , O’Connor Terry , Oueslati Tarek , Quintana Morales Eréndira M. , Pasda Kerstin , Perera Jude , Perera Nimal , Radbauer Silvia , Ramon Joan , Rannamäe Eve , Sanmartí Grego Joan , Treasure Edward , Valenzuela-Lamas Silvia , van der Jagt Inge , Van Neer Wim , Vigne Jean-Denis , Walker Thomas , Wynne-Jones Stephanie , Zeiler Jørn , Dobney Keith , Boivin Nicole , Searle Jeremy B. , Krause-Kyora Ben , Krause Johannes , Larson Greger , Orton David
Published: April 2021

The distribution of the black rat (Rattus rattus) has been heavily influenced by its association with humans. The dispersal history of this non-native commensal rodent across Europe, however, remains poorly understood, and different introductions may have occurred during the Roman and medieval periods. Here, in order to reconstruct the population history of European black rats, we generated ade novogenome assembly of the black rat, 67 ancient black rat mitogenomes and 36 ancient nuclear genomes from sites spanning the 1st-17thcenturies CE in Europe and North Africa. Analyses of mitochondrial DNA confirm that black rats were introduced into the Mediterranean and Europe from Southwest Asia. Genomic analyses of the ancient rats reveal a population turnover in temperate Europe between the 6thand 10thcenturies CE, coincident with an archaeologically attested decline in the black rat population. The near disappearance and re-emergence of black rats in Europe may have been the result of the breakdown of the Roman Empire, the First Plague Pandemic, and/or post-Roman climatic cooling.
Repression of CHROMOMETHYLASE 3 Prevents Epigenetic Collateral Damage in Arabidopsis
Authors: Papareddy Ranjith K. , Páldi Katalin , Smolka Anna D. , Hüther Patrick , Becker Claude , Nodine Michael D.
Published: April 2021

DNA methylation has evolved to silence mutagenic transposable elements (TEs) while typically avoiding the targeting of endogenous genes. Mechanisms that prevent DNA methyltransferases from ectopically methylating genes are expected to be of prime importance during periods of dynamic cell cycle activities including plant embryogenesis. However, virtually nothing is known regarding how DNA methyltransferase activities are precisely regulated during embryogenesis to prevent the induction of potentially deleterious and mitotically stable genic epimutations. Here, we report that microRNA-mediated repression of CHROMOMETHYLASE 3 (CMT3) and the chromatin features that CMT3 prefers help prevent ectopic methylation of thousands of genes during embryogenesis that can persist for weeks afterwards. Moreover, CMT3-induced ectopic methylation of genes undergoing transcriptional activation can reduce their corresponding transcript levels. Therefore, the repression of CMT3 prevents epigenetic collateral damage on endogenous genes. We also provide a model that may help reconcile conflicting viewpoints regarding the functions of gene-body methylation that occurs in nearly all flowering plants.
Specific transcriptomic signatures and dual regulation of steroidogenesis between fetal and adult mouse Leydig cells
Authors: Sararols Pauline , Stévant Isabelle , Neirijnck Yasmine , Rebourcet Diane , Darbey Annalucia , Curley Michael K. , Kühne Françoise , Dermitzakis Emmanouil , Smith Lee B. , Nef Serge
Published: April 2021

Leydig cells (LC) are the main testicular androgen-producing cells. In eutherian mammals, two types of LCs emerge successively during testicular development, fetal Leydig cells (FLCs) and adult Leydig cells (ALCs). Both display significant differences in androgen production and regulation. Using bulk RNA sequencing, we compared the transcriptomes of both LC populations to characterise their specific transcriptional and functional features. Despite similar transcriptomic profiles, a quarter of the genes show significant variations in expression between FLCs and ALCs. Non-transcriptional events, such as alternative splicing was also observed, including a high rate of intron retention in FLCs compared to ALCs. The use of single-cell RNA sequencing data also allowed the identification of nine FLC-specific genes and 50 ALC-specific genes. Expression of the corticotropin-releasing hormone 1 (Crhr1) receptor and the ACTH receptor melanocortin type 2 receptor (Mc2r) specifically in FLCs suggests a dual regulation of steroidogenesis. The androstenedione synthesis by FLCs is stimulated by luteinizing hormone (LH), CRH and ACTH whereas the testosterone synthesis by ALCs is dependent exclusively on LH. Overall, our study provides a useful database to explore LC development and function.
Disruption of the surfactant protein A receptor SP-R210L(CD245α/MYO18Aα) alters respiratory function and iron sequestration in alveolar macrophages of aged mice
Authors: Yau Eric , Umstead Todd M , Abdulqadir Raz , Fino Kristin , Guan Zhiwei , Hu Sanmei , DiAngelo Susan , Hassan Kavitha , Bingaman Sarah S. , Atkins Hannah , Cooper Timothy K , Arnold Amy C. , Halstead E. Scott , Chroneos Zissis C.
Published: April 2021

Previous studies demonstrated that the host defense collectins, surfactant protein A and complement component 1q, modulate tissue-dependent macrophage activation, pathogen clearance, and regulatory macrophage functions through the receptor SP-R210, which consists of two isoforms SP-R210Land SP-R210S. These isoforms are encoded by alternatively spliced mRNAs of theMyo18a MYO18Agene in mice and humans. The present study in conditional transgenic mice revealed novel age-related functions of the SP-R210Lisoform in modulating pulmonary mechanics, iron sequestration in alveolar macrophages (AMs), and life-long maintenance of the alveolar macrophage population. Our findings support the novel idea that SP-R210L-deficient AMs undergo bi-directional epigenetic adaptation that results in chronic dysregulation of broncho-alveolar function, immune homeostasis, and maintenance of oncotic balance at the airway-capillary interface. Disruption of SP-R210Lincreases the risk for development of severe interstitial lung disease during development and aging.
Mapping Transcription Factor-Nucleosome Dynamics from Plasma cfDNA
Authors: Rao Satyanarayan , Han Amy L. , Zukowski Alexis , Kopin Etana , Sartorius Carol A. , Kabos Peter , Ramachandran Srinivas
Published: April 2021

Cell-free DNA (cfDNA) contains a composite map of the epigenomes of its cells-of-origin. Tissue-specific transcription factor (TF) binding inferred from cfDNA could enable us to track disease states in humans in a minimally invasive manner. Here, by enriching for short cfDNA fragments, we directly map TF footprints at single binding sites from plasma. We show that the enrichment of TF footprints in plasma reflects the binding strength of the TF in cfDNA tissue-of-origin. Based on this principle, we were able to identify the subset of genome-wide binding sites for selected TFs that leave TF-specific footprints in plasma. These footprints enabled us to not only identify the tissue-of-origin of cfDNA but also map the chromatin structure around the factor-bound sites in their cells-of-origin. To ask if we can use these plasma TF footprints to map cancer states, we first defined pure tumor TF signatures in plasmain vivousing estrogen receptor-positive (ER+) breast cancer xenografts. We found that the tumor-specific cfDNA protections of ER-α could distinguish WT, ER-amplified, and ER-mutated xenografts. Further, tumor-specific cfDNA protections of ER-α and FOXA1 reflect TF-specific accessibility across human breast tumors, demonstrating our ability to capture tumor TF binding in plasma. We then scored TF binding in human plasma samples and identified specific binding sites whose plasma TF protections can identify the presence of cancer and specifically breast cancer. Thus, plasma TF footprints enable minimally invasive mapping of the regulatory landscape of cancer in humans.
Wilson disease: intersecting DNA methylation and histone acetylation regulation of gene expression in a mouse model of hepatic copper accumulation
Authors: Sarode Gaurav V. , Neier Kari , Shibata Noreene M. , Shen Yuanjun , Goncharov Dmitry A , Goncharova Elena A. , Mazi Tagreed A. , Joshi Nikhil , Settles Matthew L. , LaSalle Janine M. , Medici Valentina
Published: April 2021

The pathogenesis of Wilson disease (WD) is multi-factorial, involving hepatic and brain copper accumulation due to pathogenic variants affecting theATP7Bgene and downstream epigenetic and metabolic mechanisms. Prior DNA methylation investigations in human WD liver and blood and in a WD mouse model revealed an epigenetic signature of WD, including alterations in the histone deacetylase HDAC5. To test the hypothesis that histone acetylation is altered with respect to copper overload and aberrant DNA methylation in WD, we investigated class IIa histone deacetylases (HDAC4 and HDAC5) and H3K9/H3K27 histone acetylation in the Jackson Laboratory toxic milk (tx-j) mouse model of WD compared to C3HeB/FeJ (C3H) control in response to 3 treatments: 60% kcal fat diet (HFD), D-penicillamine (PCA, copper chelator), and choline (methyl group donor). HDAC5 levels significantly increased in 9-week tx-j livers after 8 days of HFD compared to chow. In 24-week tx-j livers, HDAC4/5 levels were reduced 5- to 10-fold compared to C3H likely through mechanisms involving HDAC phosphorylation. HDAC4/5 levels were also affected by disease progression and accompanied by increased acetylation. PCA and choline partially restored HDAC4, HDAC5, H3K9ac, and H3K27ac levels to that of CH3 liver. Integrated RNA and chromatin immunoprecipitation sequencing analyses revealed genes regulating energy metabolism and cellular stress/development were, in turn, regulated by histone acetylation in tx-j mice compared to C3H, withPparαandPparγamong the most relevant targets. These results suggest dietary modulation of class IIa HDAC4/5, and subsequent H3K9/H3K27 acetylation/deacetylation, can regulate gene expression in key metabolic pathways in the pathogenesis of WD.

Significance Statement

Wilson disease is considered a monogenic disease caused by pathogenic variants in the ATP7B copper transporter, resulting in hepatic and brain copper accumulation. Given the lack of genotype-phenotype correlation, evidence of epigenetic and metabolic mechanisms regulating phenotype in patients and in animal models could explain the high phenotype variability observed in WD. In this study, we identify class IIa histone deacetylases as players involved in the epigenetic regulation of key metabolic pathways that can affect WD severity as well as targets sensitive to dietary modulations, which is an important characteristic for designing effective and feasible therapies. Understanding the epigenetic mechanisms in WD pathogenesis contributes to a better understanding of the phenotypic variability in WD and other common liver conditions.
α-Synuclein pathology in Parkinson disease activates homeostatic NRF2 anti-oxidant response
Authors: Delaidelli Alberto , Richner Mette , Jiang Lixiang , van der Laan Amelia , Christiansen Ida Bergholdt Jul , Ferreira Nelson , Nyengaard Jens R. , Vægter Christian B. , Jensen Poul H. , Mackenzie Ian R. , Sorensen Poul H. , Jan Asad
Published: April 2021

Circumstantial evidence points to a pathological role of alpha-synuclein (aSyn; gene symbolSNCA), conferred by aSyn misfolding and aggregation, in Parkinson disease (PD) and related synucleionpathies. Several findings in experimental models implicate perturbations in the tissue homeostatic mechanisms triggered by pathological aSyn accumulation, including impaired redox homeostasis, as significant contributors in the pathogenesis of PD. The nuclear factor erythroid 2-related factor (NRF2) is recognized as ‘the master regulator of cellular anti-oxidant response’, both under physiological as well as in pathological conditions. Using immunohistochemical analyses, we show a robust nuclear NRF2 accumulation in post-mortem PD midbrain, detected by NRF2 phosphorylation on serine residue 40 (nuclear active p-NRF2, S40). Curated gene expression analyses of four independent publicly available microarray datasets revealed considerable alterations in NRF2-responsive genes in the disease affected regions in PD, including substantia nigra, dorsal motor nucleus of vagus, locus coeruleus and globus pallidus. To further examine the putative role of pathological aSyn accumulation on nuclear NRF2 response, we employed a transgenic mouse model of synucleionopathy (M83 line, Prnp-SNCA*Ala53Thr), which manifest widespread aSyn pathology (phosphorylated aSyn; S129) in the nervous system following intramuscular inoculation of exogenous fibrillar aSyn. We observed strong immunodetection of nuclear NRF2 in neuronal populations harboring p-aSyn (S129), and found an aberrant anti-oxidant and inflammatory gene response in the affected neuraxis. Taken together, our data support the notion that pathological aSyn accumulation impairs the redox homeostasis in nervous system, and boosting neuronal anti-oxidant response is potentially a promising approach to mitigate neurodegeneration in PD and related diseases.
Chlamydia coinfection inhibits HPV-induced safeguards of the cellular and genomic integrity in patient-derived ectocervical organoids
Authors: Koster Stefanie , Gurumurthy Rajendra Kumar , Berger Hilmar , Drabkina Marina , Mollenkopf Hans-Joachim , Goosmann Christian , Brinkmann Volker , Nagel Zachary , Mangler Mandy , Meyer Thomas F , Chumduri Cindrilla
Published: April 2021

Cervical mucosa is continually confronted by coinfections with pathogenic microbes. In addition to human papillomavirus, coinfections withChlamydia trachomatishave been associated with an increased risk of cervical cancer. However, the dynamics of coinfections, their impact on the epithelia, and their contribution to pathogenesis remain obscure. Using a novel human ectocervical squamous stratified epithelial organoids, we recapitulated the natural infections of the cervix by Chlamydia, HPV, and their coinfections. Towards this, we genetically manipulated the healthy organoids to mimic in vivo HPV persistence by introducing E6E7 oncogenes into the host genome. HPV persistent organoids show enhanced tissue regeneration, increased proliferation and differentiation of stem cells, and nuclear atypia resembling cervical intraepithelial neoplasia grade 1. We found that HPV interferes with normal Chlamydia development. Further, a unique transcriptional host response induced by Chlamydia and HPV leads to distinct reprogramming of host cell processes. Strikingly, in coinfections, Chlamydia impedes HPV-induced mechanisms that maintain cellular and genome integrity, including mismatch repair (MMR). Distinct post-translational proteasomal-degradation and E2F-mediated transcriptional regulation delineate the inverse regulation of MMR during coinfections. Our study employing organoids demonstrates the jeopardy of multiple sequential infection processes and the unique cellular microenvironment they create, accelerating neoplastic progression.
Use of extreme risk protection orders to reduce gun violence in Oregon
Authors: Zeoli April M. , Paruk Jennifer , Branas Charles C. , Carter Patrick M. , Cunningham Rebecca , Heinze Justin , Webster Daniel W.
Published: April 2021

Research Summary

We examined petition and respondent characteristics from extreme risk protection order (ERPO) cases in Oregon for the 15 months after implementation (n = 93). Most petitions were filed by law enforcement (65%) a were more likely to be granted than petitions filed by family/household members (p < 0.001). Most ERPO respondents were reported by petitioners to have histories of suicidality (73%) or interpersonal violence (75%), with over half of death threats, suicide threats, or suicide attempts with known timing occurring within 1 week of the petition being filed.

Policy Implications

ERPO petitions and orders are overwhelmingly being used as intended, that is, specifically for cases of imminent risk of harm to self or others. Greater dissemination of public information about ERPOs may increase their appropriate use and the proportion of high‐risk individuals and families who may benefit. Legal aid assistance for family or household members in filling out petitions is advisable.
Diabetic ketoacidosis drives COVID‐19 related hospitalizations in children with type 1 diabetes
Authors: Alonso Guy Todd , Ebekozien Osagie , Gallagher Mary Pat , Rompicherla Saketh , Lyons Sarah K. , Choudhary Abha , Majidi Shideh , Pinnaro Catherina T. , Balachandar Sadana , Gangat Mariam , Curda Roberts Alissa Jeanne , Marks Brynn E. , Creo Ana , Sanchez Janine , Seeherunvong Tossaporn , Jimenez‐Vega Jose , Patel Neha S. , Wood Jamie R. , Gabriel Liana , Sumpter Kathryn M. , Wilkes Meredith , Rapaport Robert , Cymbaluk Anna , Wong Jenise C. , Sanda Srinath , Albanese‐O'neill Anastasia
Published: April 2021

Background

Diabetes is a risk factor for poor COVID‐19 outcomes, but pediatric patients with type 1 diabetes are poorly represented in current studies.

Methods

T1D Exchange coordinated a US type 1 diabetes COVID‐19 registry. Forty‐six diabetes centers submitted pediatric cases for patients with laboratory confirmed COVID‐19. Associations between clinical factors and hospitalization were tested with Fisher's Exact Test. Logistic regression was used to calculate odds ratios for hospitalization.

Results

Data from 266 patients with previously established type 1 diabetes aged <19 years with COVID‐19 were reported. Diabetic ketoacidosis (DKA) was the most common adverse outcome (n = 44, 72% of hospitalized patients). There were four hospitalizations for severe hypoglycemia, three hospitalizations requiring respiratory support (one of whom was intubated and mechanically ventilated), one case of multisystem inflammatory syndrome in children, and 10 patients who were hospitalized for reasons unrelated to COVID‐19 or diabetes. Hospitalized patients (n = 61) were more likely than nonhospitalized patients (n = 205) to have minority race/ethnicity (67% vs 39%, P < 0.001), public insurance (64% vs 41%, P < 0.001), higher A1c (11% [97 mmol/mol] vs 8.2% [66 mmol/mol], P < 0.001), and lower insulin pump and lower continuous glucose monitoring use (26% vs 54%, P < 0.001; 39% vs 75%, P < 0.001). Age and gender were not associated with risk of hospitalization. Higher A1c was significantly associated with hospitalization, with an odds ratio of 1.56 (1.34‐1.84) after adjusting for age, gender, insurance, and race/ethnicity.

Conclusions

Higher A1c remained the only predictor for hospitalization with COVID‐19. Diabetic ketoacidosis is the primary concern among this group.
The history of pneumatic retinopexy: have we come full circle?
Authors: Fernández‐Vega González Alvaro , Muni Rajeev H.
Published: April 2021

The historical literature on the treatment of rhegmatogenous retinal detachment (RRD) was reviewed from 1911 to the present, focusing on the role of intravitreal air and gas. The history of the pneumatic retinopexy (PnR) technique is described from its original roots to the current day procedure. The treatment of RRD has evolved tremendously over the past century. The introduction of intravitreal gas as a tamponade to reattach the retina was critical in the development of modern day PnR. Although PnR is not a new technique, relatively recent randomized trials have demonstrated the numerous advantages of this procedure compared to pars plana vitrectomy (PPV) and scleral buckle. From a historical perspective, PnR has its origin in 1911 when Ohm performed intravitreal air injection after external subretinal fluid drainage in an attempt to treat RRD. The evolution of the procedure was driven by the introduction and experience with inert expansile intravitreal gas injections, and several great surgeons made critical contributions to the development of the procedure. There is substantial controversy pertaining to the original description of PnR in the literature. Credit has generally been given to Hilton and Grizzard from the United States, although Alfredo Dominguez from Spain published the first description of the procedure and he went to great lengths in an attempt to be rightfully recognized for this. The first randomized trial in retinal detachment repair was led by Dr. Paul Tornambe, comparing PnR to scleral buckle and an additional randomized trial was subsequently carried out demonstrating functional advantages of PnR compared to PPV.
Indian Costumes through the Ages: Insights into Sartorial Choices Using Mathematical Biology
Authors: Raghavan M. , Maigur R. K.
Published: April 2021

Costumes of a civilization are studied as a means of understanding people, their thinking, tastes, and culture. However, the subjective ‘feel’ of costume due to their interaction with human body is an important personal aspect of costumes that has not been studied. We hypothesize that this aspect can explain the motivation behind features of costumes that change or remain immutable over time. We propose a novel numerical encoding of costumes based on the interaction of costumes with human anatomy. Using methods from machine classification on a set of costumes from ancient to contemporary periods, we show that costumes of different epochs and cultures are separable in the two dimensional principal component space. We use the Eigen costumes to analyze the immutable similarity in Indic costumes through the ages and the contrasting features between Indic and non‐Indic. We further dwell into primary sources to demonstrate that these characteristic features of Indic costumes were very likely considered and deliberate choices motivated by yoga in order to induce beneficial effects on prāṇa. We hope that this work will be a small first step for an alternate way of deriving insights into sartorial trends in various archeological specimen using methods from life sciences and computation.
Acquired severe aplastic anaemia: how medical therapy evolved in the 20th and 21st centuries
Authors: Scheinberg Phillip
Published: April 2021

The progress in aplastic anaemia (AA) management is one of success. Once an obscure entity resulting in death in most affected can now be successfully treated with either haematopoietic stem cell transplantation (HSCT) or immunosuppressive therapy (IST). The mechanisms that underly the diminution of haematopoietic stem cells (HSCs) are now better elucidated, and include genetics and immunological alterations. Advances in supportive care with better antimicrobials, safer blood products and iron chelation have greatly impacted AA outcomes. Working somewhat ‘mysteriously’, anti‐thymocyte globulin (ATG) forms the base for both HSCT and IST protocols. Efforts to augment immunosuppression potency have not, unfortunately, led to better outcomes. Stimulating HSCs, an often‐sought approach, has not been effective historically. The thrombopoietin receptor agonists (Tpo‐RA) have been effective in stimulating early HSCs in AA despite the high endogenous Tpo levels. Dosing, timing and best combinations with Tpo‐RAs are being defined to improve HSCs expansion in AA with minimal added toxicity. The more comprehensive access and advances in HSCT and IST protocols are likely to benefit AA patients worldwide. The focus of this review will be on the medical treatment advances in AA.
Insulin secretion is a strong predictor for need of insulin therapy in patients with new‐onset diabetes and HbA1c of more than 10%: A post hoc analysis of the EDICT study
Authors: Abdelgani Siham , Puckett Curtiss , Adams John , Triplitt Curtis , DeFronzo Ralph A. , Abdul‐Ghani Muhammad
Published: April 2021

Aim

To identify predictors of response to glucose‐lowering therapy in patients with new‐onset diabetes and very high HbA1c (>10%).

Methods

The study included EDICT participants with an initial HbA1c of more than 10% (N = 104). All subjects received a 75‐g oral glucose tolerance test (OGTT) before initiation of therapy, and then were randomized to receive: (a) initial triple therapy with metformin, pioglitazone and exenatide versus (b) stepwise conventional therapy with metformin followed by glipizide and then glargine insulin to reduce HbA1c to less than 6.5%. Insulin secretion and insulin resistance were calculated with OGTT‐derived indices.

Results

Sixty‐one per cent of participants in the conventional therapy group achieved HbA1c of less than 6.5% at 6 months without need of insulin therapy compared with 78% in the triple therapy group (P = NS). Insulin secretion at baseline was the strongest predictor of subjects who did not require insulin therapy; a cut point of CPEP120/CPEP0—the ratio between plasma C‐peptide concentration at 120 minutes during the OGTT and fasting plasma C‐peptide concentration—of more than 1.7 predicted subjects who achieved the treatment target without insulin, irrespective of the fasting plasma glucose (FPG) concentration and whether or not they were started on conventional or triple therapy. Subjects with a CPEP120/CPEP0 of less than 1.7 plus FPG of 269 mg/dL or less (≤14.9 mmoL/L) also achieved the treatment goal with triple therapy.

Conclusion

Insulin secretion in response to a 75‐g OGTT predicts the need for insulin therapy at the time of type 2 diabetes (T2D) diagnosis. A cut point of 1.7 of CPEP120/CPEP0 provides a useful clinical tool to individualize glucose‐lowering therapy in patients with new‐onset T2D and HbA1c of more than 10%.
Management of cluster headache and other trigeminal autonomic cephalalgias in pregnancy and breastfeeding
Authors: Bjørk Marte‐Helene , Kristoffersen Espen Saxhaug , Tronvik Erling , Egeland Nordeng Hedvig Marie
Published: April 2021

Many clinicians lack experience in managing trigeminal autonomic cephalalgias (TACs) in pregnancy and lactation. In addition to cluster headache, TACs include hemicrania continua, paroxysmal hemicrania, and short‐lasting unilateral neuralgiform headache with conjunctival injection and tearing/autonomic symptoms (SUNCT/SUNA). Treating these rare, severe headache conditions often requires off‐label drugs that have uncertain teratogenic potential. In the last few years, several new treatment options and safety documentation have emerged, but clinical guidelines are lacking. This narrative review aimed to provide an updated clinical guide and good clinical practice recommendations for the management of these debilitating headache disorders in pregnancy and lactation.
Youth perceptions and experiences of type 2 diabetes: Protocol for a collaborative knowledge translation approach and qualitative study
Authors: Archibald Mandy M. , Dart Allison , Wicklow Brandy , Pundyk Katherine J. , Marks Seth D. , Sellers Elizabeth A. C.
Published: April 2021

Aims

The aim of this study is to generate an in‐depth understanding of youth perceptions and experiences of living with type 2 diabetes to inform knowledge translation, research and intervention development.

Design

Interpretive descriptive qualitative study.

Methods

Twenty to 25 youth aged 10–18 years with a diagnosis of type 2 diabetes will be purposively recruited through the Diabetes Education Resource for Children and Adolescents in Winnipeg, Manitoba, and through the Improving Renal Complications in Adolescents With Type 2 Diabetes Through the REsearch [iCARE] cohort. Socio‐demographic information will be collected. Semi‐structured interviews will occur iteratively with inductive thematic analysis. Data will be professionally transcribed and managed using NVivo 1.0 software. The University Ethics Committee approved this study (May 2020).

Discussion

There is a critical gap in understanding youth experiences of type 2 diabetes. Research involving youth with type 2 diabetes is predominantly quantitative in nature, largely reflecting risk factors, underlying mechanisms and treatment outcomes associated with diabetes management. In‐depth qualitative research on youth experiences can help identify youth priorities, provide insight into critical misalignments between stakeholder perspectives, and drive forward a more consolidated youth‐centred research agenda.

Impact

Understanding and applying knowledge of youth experiences is critical as the prevalence of, and challenges associated with, youth onset type 2 diabetes continues to increase worldwide. This research will generate a robust interpretive description of youth lived experiences and perceptions of type 2 diabetes where such research is lacking, to inform basic and applied research within an interdisciplinary investigative and clinical research team with relevance to other jurisdictions. In response to calls for youth‐oriented research in type 2 diabetes, this work will catalyse collaborative knowledge translation using creative and youth‐directed initiatives.
Aquatic micro‐ and nano‐plastics in life cycle assessment: Development of an effect factor for the quantification of their physical impact on biota
Authors: Lavoie Jérôme , Boulay Anne‐Marie , Bulle Cécile
Published: April 2021

Plastic litter of all sizes has been acknowledged as a serious threat to biodiversity, especially in the marine environment. The fact that life cycle assessment (LCA) does not properly consider these issues is a serious problem for the aspirations of LCA in the public sphere. This paper focuses on micro‐ and nano‐sized plastics (MNPs), which have the potential to cause a substantial impact on ecosystem quality because of their increased presence in the marine compartment and capacity to affect a greater range of species. The data regarding MNPs’ effect on different aquatic species were extracted from the academic literature. These data were then explored and analyzed to bring to light the possibilities in terms of effect factor (EF) developments and the existing relations between effect on aquatic ecosystems and different parameters such as particle size, polymer type, and shape. No significant difference could be observed between the effect of the different subgroups of MNPs tested when considering a single species. However, when including many species in the analysis, differences could be noted between polystyrene (PS) and other polymer types. The high uncertainty on the developed EFs combined with this lack of statistical difference among subgroups at the single species level suggest that the use of a single generic EF could be appropriate for now. This EF is provided along with Species Sensitivity Distributions developed to allow for a quick visualization of the gathered data used to generate the EFs. This EF can now be used to quantify the physical impact of all MNPs in life cycle impact assessment.
The natural history of insomnia: Does sleep extension differentiate between those that do and do not develop chronic insomnia?
Authors: Perlis Michael L. , Morales Knashawn H. , Vargas Ivan , Posner Donn A. , Grandner Michael A. , Muench Alexandria L. , Seewald Mark W. , Gooneratne Nalaka S. , Kloss Jacqueline D. , Gencarelli Amy M. , Khader Waliuddin S. , Thase Michael E. , Ellis Jason G.
Published: April 2021

According to the “3P model” of insomnia, the variable that mediates the transition from acute insomnia (AI) to chronic insomnia is “sleep extension” (the behavioural tendency to expand sleep opportunity to compensate for sleep loss). In the present analysis, we sought to evaluate how time in bed (TIB) varies relative to the new onset of AI and chronic insomnia. A total of 1,248 subjects were recruited as good sleepers (GS). Subjects were monitored over 1 year with sleep diaries. State transitions were defined, a priori, for AI, recovered from AI (AI‐REC), and for chronic insomnia (AI‐CI). Two additional groupings were added based on profiles that were unanticipated: subjects that exhibited persistent poor sleep following AI (AI‐PPS [those that neither recovered or developed chronic insomnia]) and subjects that recovered from chronic insomnia (CI‐REC). All the groups (GS, AI‐REC, AI–CI, AI‐PPS and CI‐REC) were evaluated for TIB differences with longitudinal mixed effects models. Post hoc analyses for the percentage of the groups that were typed as TIB “restrictors, maintainers, and expanders” were conducted using longitudinal mixed effects models and contingency analyses. Significant differences for pre–post AI TIB were not detected for the insomnia groups. Trends were apparent for the AI‐CI group, which suggested that minor increases in TIB occurred weeks before the declared onset of AI. Additionally, it was found that a significantly larger percentage of AI‐CI subjects engaged in sleep extension (as compared to GS). The present data suggest that transition from AI to chronic insomnia does not appear to be initiated by sleep extension and the transition may occur before the elapse of 3 months of ≥3 nights of sleep continuity disturbance. Given these findings, it may be that the mismatch between sleep ability and sleep opportunity is perpetuated over time given the failure to “naturally” engage in sleep restriction (as opposed to sleep extension).
Evidence for role of capillaries in regulation of skeletal muscle oxygen supply
Authors: Ghonaim Nour W. , Fraser Graham M. , Goldman Daniel , Milkovich Stephanie , Yang Jun , Ellis Christopher G.
Published: April 2021

How oxygen (O2) supply to capillaries is regulated to match the tissue's demand is unknown. Erythrocytes have been proposed as sensors in this regulatory mechanism since they release ATP, a vasodilator, in an oxygen saturation (SO2)‐dependent manner. ATP causes hyperpolarization of endothelial cells resulting in conducted vasodilation to arterioles.

Objective

We propose individual capillary units can regulate their own O2 supply by direct communication to upstream arterioles via electrically coupled endothelium.

Methods

To test this hypothesis, we developed a transparent micro‐exchange device for localized O2 exchange with surface capillaries of intact tissue. The device was fabricated with an O2 permeable micro‐outlet 0.2 × 1.0 mm. Experiments were performed on rat extensor digitorum longus (EDL) muscle using dual wavelength video microscopy to measure capillary hemodynamics and erythrocyte SO2. Responses to local O2 perturbations were measured with only capillaries positioned over the micro‐outlet.

Results

Step changes in the gas mixture %O2 caused physiological changes in erythrocyte SO2, and appropriate changes in flow to offset the O2 challenge if at least 3–4 capillaries were stimulated.

Conclusion

These results support our hypothesis that individual capillary units play a role in regulating their erythrocyte supply in response to a changing O2 environment.
Quality of alternatives positively associated with interest in opening up a relationship
Authors: MacDonald Geoff , Park Yoobin , Hayes Alathea , Vanasse Grosdidier Isabelle , Park Sun W.
Published: April 2021

We use the Investment Model framework to examine what relationship features are associated with interest in and positive evaluations of consensual non‐monogamy (CNM) among individuals in monogamous relationships. In data sets from the United States (Study 1), Europe (Study 2), and Korea (Study 3; total N = 886), perceptions of higher‐quality alternatives were consistently associated with more interest in CNM. Further, consistent with previous work on commitment‐motivated relationship maintenance processes, we found support for an indirect effect whereby lower commitment was associated with higher perceived attractiveness of alternatives, which in turn was associated with more interest in CNM. The data suggest that the idea of CNM is likely to be most attractive to those who see themselves as having higher‐quality relationship options.
Diagnostic performance of routine electrophoresis and immunofixation for the detection of immunoglobulin paraproteins (M‐Proteins) in dogs with multiple myeloma and related disorders: Part 2—Toward improved diagnostic performance
Authors: Moore A Russell , Harris R. Adam , Jeffries Christina , Ashton Laura , Avery Paul R.
Published: April 2021

Background

The diagnostic performance of routine electrophoresis (agarose gel electrophoresis [AGE] and capillary zone electrophoresis [CZE]) and species‐specific immunofixation (IF) for the detection of immunoglobulin paraproteins (M‐proteins) and diagnosis of secretory myeloma‐related disorders (sMRD) can be improved. Available canine IF targets were IgG‐FC, IgA, IgM, light chain (LC), IgG4, and free LC (fLC) antibodies.

Objective

We aimed to review specific features associated with the presence of M‐proteins in canine serum samples and the common features causing inaccurate reporting of M‐proteins to improve the diagnostic performance of routine electrophoresis and IF for the detection of M‐proteins.

Methods

Features found in AGE, CZE, routine IF, IgG4 IF, and fLC IF of 100 canine serum samples from Part 1 of this study were evaluated by simple and multivariate logistic regression to identify factors associated with the presence of M‐proteins. Cases falsely called negative or positive for M‐proteins were reviewed to identify the common features that could be used to increase the diagnostic performance of SPE and IF for M‐protein detection.

Results

The presence of hypogammaglobulinemia or any peak taller than albumin was associated with an M‐protein. Total protein concentrations, globulin concentrations, or peaks wider than albumin were not associated with an M‐protein. Free LC sMRD cases were not diagnosed by SPE and routine IF. Cases with infectious and inflammatory etiologies had a restricted polyclonal gammopathy with multiple γ‐globulin restrictions resulting in some false‐positive results. SPE combined with all available IF results and the specific features identified in this study had an estimated sensitivity of 95.1% and specificity of 81.4%.

Conclusions

The identified criteria of this study increase the diagnostic performance of the electrophoretic evaluation for M‐proteins.
Comparison of 18F‐sodium fluoride positron emission tomography and CT: An exploratory study in 12 dogs with elbow pain
Authors: McLarty Ehren , Spriet Mathieu , Beylin David , Chou Po‐Yen , Filliquist Barbro , Marcellin‐Little Denis J. , Kapatkin Amy S.
Published: April 2021

18F‐Sodium Fluoride (18F‐NaF) positron emission tomography (PET) provides high resolution functional information about bone activity and can be fused with CT images to improve three‐dimensional localization and characterization of lesions. This prospective, observational study assessed 18F‐NaF PET‐CT for imaging of canine elbows, compared PET with CT findings, and assessed correlation with lameness. Twelve patients with elbow pain were included. Cases included primarily young, large breed dogs. A three‐level clinical lameness score was assigned to each forelimb. All dogs had bilateral elbow joints imaged with CT and PET under general anesthesia, approximately 1.5 h after intravenous injection of 3 MBq/kg of 18F‐NaF. Imaging findings were independently reviewed by two radiologists using a three‐level scoring scheme over nine anatomical regions in the elbow. PET imaging identified areas of bone activity where minimal change was identified on CT. PET imaging also demonstrated absence of uptake in areas where modeling was present on CT. A stronger correlation was observed between clinical grades and PET scores (r2 = 0.38, P = .001) than between clinical grades and CT scores (r2 = 0.17, P = .048). The total PET scores were significantly different for each clinical grade (P = .013) but total CT scores did not differ (P = .139). This exploratory study suggests that PET improves the ability to detect lesions and to determine the clinical significance of CT findings in dogs with elbow pain.