bluuebunny/crossref_metadata_2025 huggingface dataset:
The heritable legacy of diethylstilbestrol: a bellwether for endocrine disruption in humans
Authors: Robotti Suzanne
Published: August 2021

Millions of women and their fetuses were exposed to the toxic pregnancy drug diethylstilbestrol (DES) from the 1940s into the 1970s, a time when the medical profession had little knowledge about potential developmental consequences of fetal drug exposures. Pathological consequences of DES exposure to the pregnant mothers and their offspring are well documented, but now generational research is finding that the grandchildren of women given DES in pregnancy are also at risk. This commentary summarizes presentations on this subject from the Beyond Genes panel “Heritable Impacts of Diethylstilbestrol (DES).”
Cloud-Based Environmental Monitoring to Streamline Remote Sensing Analysis for Biologists
Authors: Stahl Amanda T , Fremier Alexander K , Heinse Laura
Published: August 2021

Timely, policy-relevant monitoring data are essential for evaluating the effectiveness of environmental policies and conservation measures. Satellite and aerial imagery can fill data gaps at low cost but are often underused for ongoing environmental monitoring. Barriers include a lack of expertise or computational resources and the lag time between image acquisition and information delivery. Online image repositories and cloud computing platforms are increasingly used by researchers because they offer near-real-time, centralized access to local-to-global-scale data sets and analytics with minimal in-house computational requirements. We aim to broaden knowledge of these open access resources for biologists whose work routinely informs policy and management. To illustrate potential applications of cloud-based environmental monitoring (CBEM), we developed an adaptable approach to detect changes in natural vegetative cover in an agricultural watershed. The steps we describe can be applied to identify opportunities and caveats for applying CBEM in a wide variety of monitoring programs.
Intravenous delivery of adeno-associated viral gene therapy in feline GM1 gangliosidosis
Authors: Gross Amanda L , Gray-Edwards Heather L , Bebout Cassie N , Ta Nathan L , Nielsen Kayly , Brunson Brandon L , Lopez Mercado Kalajan R , Osterhoudt Devin E , Batista Ana Rita , Maitland Stacy , Seyfried Thomas N , Sena-Esteves Miguel , Martin Douglas R
Published: August 2021

GM1 gangliosidosis is a fatal neurodegenerative disease caused by a deficiency of lysosomal β-galactosidase. In its most severe form, GM1 gangliosidosis causes death by 4 years of age, and no effective treatments exist. Previous work has shown that injection of the brain parenchyma with an adeno-associated viral (AAV) vector provides pronounced therapeutic benefit in a feline GM1 model. To develop a less invasive treatment for the brain and increase systemic biodistribution, intravenous injection of AAV9 was evaluated.

AAV9 expressing feline β-galactosidase was intravenously administered at 1.5×1013 vector genomes/kg body weight to six GM1 cats at ∼1 month of age. The animals were divided into two cohorts: (i) a long-term group, which was followed to humane end point; and (ii) a short-term group, which was analysed 16 weeks post-treatment. Clinical assessments included neurological exams, CSF and urine biomarkers, and 7 T MRI and magentic resonance spectroscopy (MRS). Post-mortem analysis included β-galactosidase and virus distribution, histological analysis and ganglioside content.

Untreated GM1 animals survived 8.0 ± 0.6 months while intravenous treatment increased survival to an average of 3.5 years (n = 2) with substantial improvements in quality of life and neurological function. Neurological abnormalities, which in untreated animals progress to the inability to stand and debilitating neurological disease by 8 months of age, were mild in all treated animals. CSF biomarkers were normalized, indicating decreased CNS cell damage in the treated animals. Urinary glycosaminoglycans decreased to normal levels in the long-term cohort. MRI and MRS showed partial preservation of the brain in treated animals, which was supported by post-mortem histological evaluation. β-Galactosidase activity was increased throughout the CNS, reaching carrier levels in much of the cerebrum and normal levels in the cerebellum, spinal cord and CSF. Ganglioside accumulation was significantly reduced by treatment. Peripheral tissues such as heart, skeletal muscle, and sciatic nerve also had normal β-galactosidase activity in treated GM1 cats. GM1 histopathology was largely corrected with treatment. There was no evidence of tumorigenesis or toxicity.

Restoration of β-galactosidase activity in the CNS and peripheral organs by intravenous gene therapy led to profound increases in lifespan and quality of life in GM1 cats. These data support the promise of intravenous gene therapy as a safe, effective treatment for GM1 gangliosidosis.
The contribution of beta-amyloid to dementia in Lewy body diseases: a 1-year follow-up study
Authors: Biundo Roberta , Weis Luca , Fiorenzato Eleonora , Pistonesi Francesca , Cagnin Annachiara , Bertoldo Alessandra , Anglani Mariagiulia , Cecchin Diego , Antonini Angelo
Published: August 2021

Dementia in Lewy Body Diseases (Parkinson’s disease and dementia with Lewy Bodies) affects progression of disabilities, quality of life and well-being. Understanding its pathogenetic mechanisms is critical to properly implement disease-modifying strategies. It has been hypothesized that synuclein- and amyloid-pathology act synergistically aggravating cognitive decline in elderly patients but their precise contribution to dementia is debated. In this study, we aimed at exploring if presence of amyloid deposits influences clinical, cognitive and neuroanatomical correlates of mental decline in a cohort of 40 Parkinson’s disease patients with normal cognition (n = 5), mild cognitive impairment (n = 22), and dementia (n = 13) as well as in Dementia with Lewy Bodies (n = 10). Patients underwent simultaneous 3 T PET/MRI with [18F]-flutemetamol and were assessed with an extensive baseline motor and neuropsychological examination, which allowed level II diagnosis of mild cognitive impairment and dementia. The role of amyloid positivity on each cognitive domain, and on the rate of conversion to dementia at 1-year follow-up was explored. A Kaplan Meier and the Log Rank (Mantel–Cox) test were used to assess the pairwise differences in time-to-develop dementia in Parkinson’s disease patients with and without significant amyloidosis. Furthermore, the presence of an Alzheimer’s dementia-like morphological pattern was evaluated using visual and automated assessment of T1-weighted and T2-weighted MRI images. We observed similar percentage of amyloid deposits in Parkinson’s disease dementia and dementia with Lewy Bodies cohorts (50% in each group) with an overall prevalence of 34% of significant amyloid depositions in Lewy Body Diseases. PET amyloid positivity was associated with worse global cognition (Montreal Cognitive Assessment and Mini Mental State Examination), executive and language difficulties. At 12-month follow-up, amyloid positive Parkinson’s disease patients were more likely to have become demented than those without amyloidosis. Moreover, there was no difference in the presence of an Alzheimer’s disease-like atrophy pattern and in vascular load (at Fazekas scale) between Lewy Body Diseases with and without significant amyloid deposits. Our findings suggest that in Lewy Body Diseases, amyloid deposition enhances cognitive deficits, particularly attention-executive and language dysfunctions. However, the large number of patients without significant amyloid deposits among our cognitively impaired patients indicates that synuclein pathology itself plays a critical role in the development of dementia in Lewy Body Diseases.
Posterior cortical atrophy phenotypic heterogeneity revealed by decoding 18F-FDG-PET
Authors: Townley Ryan A , Botha Hugo , Graff-Radford Jonathan , Whitwell Jennifer , Boeve Bradley F , Machulda Mary M , Fields Julie A , Drubach Daniel A , Savica Rodolfo , Petersen Ronald C , Senjem Matthew L , Knopman David S , Lowe Val J , Jack Clifford R , Josephs Keith A , Jones David T
Published: August 2021

Posterior cortical atrophy is a neurodegenerative syndrome with a heterogeneous clinical presentation due to variable involvement of the left, right, dorsal and ventral parts of the visual system, as well as inconsistent involvement of other cognitive domains and systems. 18F-fluorodeoxyglucose (FDG)-PET is a sensitive marker for regional brain damage or dysfunction, capable of capturing the pattern of neurodegeneration at the single-participant level. We aimed to leverage these inter-individual differences on FDG-PET imaging to better understand the associations of heterogeneity of posterior cortical atrophy. We identified 91 posterior cortical atrophy participants with FDG-PET data and abstracted demographic, neurologic, neuropsychological and Alzheimer’s disease biomarker data. The mean age at reported symptom onset was 59.3 (range: 45–72 years old), with an average disease duration of 4.2 years prior to FDG-PET scan, and a mean education of 15.0 years. Females were more common than males at 1.6:1. After standard preprocessing steps, the FDG-PET scans for the cohort were entered into an unsupervised machine learning algorithm which first creates a high-dimensional space of inter-individual covariance before performing an eigen-decomposition to arrive at a low-dimensional representation. Participant values (‘eigenbrains’ or latent vectors which represent principle axes of inter-individual variation) were then compared to the clinical and biomarker data. Eight eigenbrains explained over 50% of the inter-individual differences in FDG-PET uptake with left (eigenbrain 1) and right (eigenbrain 2) hemispheric lateralization representing 24% of the variance. Furthermore, eigenbrain-loads mapped onto clinical and neuropsychological data (i.e. aphasia, apraxia and global cognition were associated with the left hemispheric eigenbrain 1 and environmental agnosia and apperceptive prosopagnosia were associated with the right hemispheric eigenbrain 2), suggesting that they captured important axes of normal and abnormal brain function. We used NeuroSynth to characterize the eigenbrains through topic-based decoding, which supported the idea that the eigenbrains map onto a diverse set of cognitive functions. These eigenbrains captured important biological and pathophysiologic data (i.e. limbic predominant eigenbrain 4 patterns being associated with older age of onset compared to frontoparietal eigenbrain 7 patterns being associated with younger age of onset), suggesting that approaches that focus on inter-individual differences may be important to better understand the variability observed within a neurodegenerative syndrome like posterior cortical atrophy.
The geopolitics behind the routes data travel: a case study of Iran
Authors: Salamatian Loqman , Douzet Frédérick , Salamatian Kavé , Limonier Kévin
Published: August 2021

In November 2019, in the wake of political demonstrations against the regime, Iran managed to selectively cut off most traffic from the global Internet while fully operating its own domestic network. It seemingly confirmed the main hypothesis our research had led us to, based on prior observation of data routing: Iran’s architecture of connectivity enables selective censorship of international traffic. This paper examines, through the case of Iran, how states can leverage the Border Gateway Protocol (BGP) as a tool of geopolitical control and what are the trade-offs they face. This question raises a methodological question that we also address: how the analysis of BGP can infer and document these strategies of territorialization of cyberspace. The Internet is a network of networks where each network is an autonomous system. Autonomous systems (ASes) are independent administrative entities controlled by a variety of actors such as governments, companies and universities. Their administrators have to agree and communicate on the path followed by packets travelling across the Internet, which is made possible by BGP. Agreements between ASes are often confidential but BGP requires neighbouring ASes to interact with each other in order to coordinate routing through the constant release of connectivity update messages. These messages announce the availability (or withdrawal) of a sequence of ASes that can be followed to reach an IP address prefix. In our study, we inferred the structure of Iran's connectivity through the capture and analysis of these BGP announcements. We show how the particularities of Iran's BGP and connectivity structure can enable active measures, such as censorship, both internally and externally throughout the network. We argue that Iran has found a way to reconcile a priori conflicting strategic goals: developing a self-sustaining and resilient domestic Internet, but with tight control at its borders. It thus enables the regime to leverage connectivity as a tool of censorship in the face of social instability and as a tool of regional influence in the context of strategic competition.
Laminopathies: should Wenckebach be a cause for concern? A case report
Authors: Sen Gautam , Jackson Tom
Published: August 2021

Background

LMNA cardiomyopathy is a cause of dilated cardiomyopathy (DCM) characterized by aggressive heart failure, high risk of arrhythmias, and sudden cardiac death. We present a case of a male presenting with an LMNA mutation with an aggressive DCM leading to sudden cardiac death (SCD).

Case summary

A 42-year-old male presented with the feeling of lethargy and intermittent dizziness. Electrocardiogram demonstrated atrioventricular block in keeping with Mobitz type 1, at a rate of 40 b.p.m. and cardiac monitoring showed non-sustained ventricular tachycardia. Cardiac magnetic resonance imaging showed preserved left ventricular (LV) ejection function (59%) but features suggesting DCM. These included mild LV dilatation with an end diastolic volume (EDV) of 213 mL and late enhancement showing a single mid myocardial focus of high signal over the distal right ventricular insertion point inferiorly and a linear area of high signal over the basal septum. After discussion at the cardiology multi-disciplinary meeting, a pacemaker was implanted so that beta-blockers could be initiated to suppress the ventricular arrhythmias. A laminopathy was suspected and if this was confirmed from genetic testing the plan was to upgrade to an implantable defibrillator. Due to stability, this was decided to be done in an outpatient setting. He unfortunately had an out-of-hospital VF arrest and died. Post-mortem showed subtle cardiomyopathy in keeping with a DCM. Genetic tests results were returned a few months later which confirmed a pathogenic variant in LMNA.

Discussion

Because of the complexity of LMNA-related cardiac disease, they should be managed and followed up in centres with special expertise in inherited cardiomyopathy.
Fusion cardiac resynchronization therapy in an left ventricular assist device patient from two devices and crossing leads: a case report
Authors: Egorova Anastasia D , van Erven Lieselot , Beeres Saskia L M A , Tops Laurens F
Published: August 2021

Background

Cardiac implanted electronic devices (CIED) have significantly improved the survival and quality of life in heart failure patients. Although implantable cardioverter-defibrillators (ICD) and cardiac resynchronization therapy (CRT) have a major role in patients with moderate to severe heart failure symptoms, the role of these devices in patients with a left ventricular assist device (LVAD) is not yet well defined. The burden of CIED-related procedures in patients with an LVAD is high. The price of lead malfunctions and pocket complications requires creative approaches to tackle CIED-related issues in this patient population.

Case summary

Here, we describe the clinical course of a 67-year-old ventricular pacing dependent LVAD patient with an ICD indication based on recurrent monomorphic ventricular tachycardias and a CRT indication due to previous deterioration of (right-sided) heart failure in the absence of biventricular pacing. We were confronted with impending right ventricular lead failure and bilateral venous access problems due to chronic subclavian vein occlusion in a patient with a total of five transvenous leads, therapeutic anticoagulation, and pronounced thoracic collaterals. We sought for a creative solution to be able to deliver effective biventricular fusion pacing with the existing leads from two contralateral pulse generators resulting in biventricular fusion pacing. This provided the solution to deliver effective CRT.

Discussion

This case illustrates the complexity of care and CIED-related decision-making in pacing dependent LVAD patients, in particularly those with an ICD and CRT indication.
Determinants of outcomes following surgery for type A acute aortic dissection: the UK National Adult Cardiac Surgical Audit
Authors: Benedetto Umberto , Dimagli Arnaldo , Kaura Amit , Sinha Shubhra , Mariscalco Giovanni , Krasopoulos George , Moorjani Narain , Field Mark , Uday Trivedi , Kendal Simon , Cooper Graham , Uppal Rakesh , Bilal Haris , Mascaro Jorge , Goodwin Andrew , Angelini Gianni , Tsang Geoffry , Akowuah Enoch
Published: August 2021

Aims 

Operability of type A acute aortic dissections (TAAAD) is currently based on non-standardized decision-making process, and it lacks a disease-specific risk evaluation model that can predict mortality. We investigated patient, intraoperative data, surgeon, and centre-related variables for patients who underwent TAAAD in the UK.

Methods and results

We identified 4203 patients undergoing TAAAD surgery in the UK (2009–18), who were enrolled into the UK National Adult Cardiac Surgical Audit dataset. The primary outcome was operative mortality. A multivariable logistic regression analysis was performed with fast backward elimination of variables and the bootstrap-based optimism-correction was adopted to assess model performance. Variation related to hospital or surgeon effects were quantified by a generalized mixed linear model and risk-adjusted funnel plots by displaying the individual standardized mortality ratio against expected deaths. Final variables retained in the model were: age [odds ratio (OR) 1.02, 95% confidence interval (CI) 1.02–1.03; P < 0.001]; malperfusion (OR 1.79, 95% CI 1.51–2.12; P < 0.001); left ventricular ejection fraction (moderate: OR 1.40, 95% CI 1.14–1.71; P = 0.001; poor: OR 2.83, 95% CI 1.90–4.21; P < 0.001); previous cardiac surgery (OR 2.29, 95% CI 1.71–3.07; P < 0.001); preoperative mechanical ventilation (OR 2.76, 95% CI 2.00–3.80; P < 0.001); preoperative resuscitation (OR 3.36, 95% CI 1.14–9.87; P = 0.028); and concomitant coronary artery bypass grafting (OR 2.29, 95% CI 1.86–2.83; P < 0.001). We found a significant inverse relationship between surgeons but not centre annual volume with outcomes.

Conclusions 

Patient characteristics, intraoperative factors, cardiac centre, and high-volume surgeons are strong determinants of outcomes following TAAAD surgery. These findings may help refining clinical decision-making, supporting patient counselling and be used by policy makers for quality assurance and service provision improvement.
Interaction of sex, age, body mass index and race on hypertension risk in the American population: a cross-sectional study
Authors: Zhang Zhenhong , Zhang Tao , Zhao Enhui , Ding Shihan , Kang Xiao , Zhang Wenwen , Liu Bingkun , Liu Haoran , Cheng Anlan , Li Guoju , Wang Qiuzhen
Published: August 2021

Background

The joint effects of sex, age, body mass index (BMI) and race on hypertension have not been fully addressed. Herein, we carried out this study aiming to investigate the possible effects of the interaction of sex, age, BMI and race on risk of hypertension.

Methods

By using the data of a sample-adjusted 2656 women and 2515 men in American National Health and Nutrition Examination Survey 2015–16, we analyzed the interaction of sex, age, BMI and race by logistic regression models, followed by strata-specific analyses. Hypertension was defined as a systolic blood pressure ≥130 mmHg/diastolic blood pressure ≥80 mmHg or taking anti-hypertensive medication.

Results

A total of 5171 participants were included in analysis, and the prevalence of hypertension was 53.68%. The interactive effect of sex and age, BMI and age, race and age were statistically significant on hypertension. Strata-specific analyses showed that female at 40 years and above were positively associated with hypertension than those at 20–39 years. The associations also persistence in male. The risk estimates for age ≥40 on hypertension were consistently positive across all overweight/obesity and race groups. The effect was most prominent among overweight populations aged 60–80 years and Other Hispanic aged 40 years and above.

Conclusion

There exists interactive effect of sex and age, BMI and age, race and age on hypertension in American population. The effect of age on hypertension was more prominent in female, overweight populations and Other Hispanic populations. Differences in age, BMI and race should be considered when providing corresponding antihypertensive measures.
Public perceptions and behavioural responses to the first COVID-19 pandemic wave in Italy: results from the iCARE study
Authors: Stojanovic Jovana , Raparelli Valeria , Boccia Stefania , Bacon Simon L , Lavoie Kim L ,   for the iCARE Study Team
Published: August 2021

Background

Italy was the first European country to be affected by COVID-19. Considering that many countries are currently battling the second wave of the pandemic, understanding people’s perceptions and responses to government policies remain critical for informing on-going mitigation strategies. We assessed attitudes towards COVID-19 policies, levels of adherence to preventive behaviours, and the association between COVID-19 related concerns and adherence levels.

Methods

We recruited a convenience sample of Italian individuals from an international cross-sectional survey (www.icarestudy.com) from 27 March to 5 May 2020. Multivariate regression models were used to test the association between concerns and the adoption of preventive measures.

Results

The survey included 1332 participants [female (68%), younger than 25 (57%)] that reported high awareness (over 96%) and perceived importance (88%) of policies. We observed varied levels of adherence to: hand-washing (96%), avoiding social gatherings (96%), self-isolation if suspected or COVID-19 positive (77%). Significantly lower adherence to self-isolation was reported by individuals with current employment. High levels of concerns regarding health of other individuals and country economy were reported. Only health concerns for others were significantly associated with higher adherence to hand-washing behaviour.

Conclusions

In order to inform current/future government strategies, we provide insights about population’s responses to the initial pandemic phase in Italy. Communication approaches should consider addressing people’s concerns regarding the health of other individuals to motivate adherence to prevention measures. Provision of social and economic support is warranted to avoid unequal impacts of governmental policies and allow effective adherence to self-isolating measures.
Invasion of the choroid plexus epithelium byNeisseria meningitidisis differently mediated by Arp2/3 signaling and possibly by dynamin dependent on the presence of the capsule
Authors: Herold Rosanna , Sünwoldt Gina , Stump-Guthier Carolin , Weiss Christel , Ishikawa Hiroshi , Schroten Horst , Adam Rüdiger , Schwerk Christian
Published: August 2021

Neisseria meningitis (Nm) is a human-specific bacterial pathogen that can cause sepsis and meningitis. To cause meningitis Nm must enter the central nervous system (CNS) across one of the barriers between the blood and the brain. We have previously shown that a capsule-depleted Serogroup B strain of Nm displays enhanced invasion into human choroid plexus (CP) epithelial papilloma (HIBCPP) cells, which represent an in vitro model of the blood–cerebrospinal fluid barrier (BCSFB). Still, the processes involved during CNS invasion by Nm, especially the role of host cell actin cytoskeleton remodeling, are not investigated in detail. Here, we demonstrate that invasion into CP epithelial cells by encapsulated and capsule-depleted Nm is mediated by distinct host cell pathways. Whereas a Serogroup B wild-type strain enters HIBCPP cells by a possibly dynamin-independent, but actin related protein 2/3 (Arp2/3)-dependent mechanism, invasion by a capsule-depleted mutant is reduced by the dynamin inhibitor dynasore and Arp2/3-independent. Both wild-type and mutant bacteria require Src kinase activity for entry into HIBCPP cells. Our data show that Nm can employ different mechanisms for invasion into the CP epithelium dependent on the presence of a capsule.
The ins and outs of Bacillus proteases: activities, functions and commercial significance
Authors: Harwood Colin R , Kikuchi Yoshimi
Published: August 2021

Because the majority of bacterial species divide by binary fission, and do not have distinguishable somatic and germline cells, they could be considered to be immortal. However, bacteria ‘age’ due to damage to vital cell components such as DNA and proteins. DNA damage can often be repaired using efficient DNA repair mechanisms. However, many proteins have a functional ‘shelf life’; some are short lived, while others are relatively stable. Specific degradation processes are built into the life span of proteins whose activities are required to fulfil a specific function during a prescribed period of time (e.g. cell cycle, differentiation process, stress response). In addition, proteins that are irreparably damaged or that have come to the end of their functional life span need to be removed by quality control proteases. Other proteases are involved in performing a variety of specific functions that can be broadly divided into three categories: processing, regulation and feeding. This review presents a systematic account of the proteases of Bacillus subtilis and their activities. It reviews the proteases found in, or associated with, the cytoplasm, the cell membrane, the cell wall and the external milieu. Where known, the impacts of the deletion of particular proteases are discussed, particularly in relation to industrial applications.
The Molecular Basis of Glucose Galactose Malabsorption in a Large Swedish Pedigree
Authors: Lostao M Pilar , Loo Donald D , Hernell Olle , Meeuwisse Gunnar , Martin Martin G , Wright Ernest M
Published: August 2021

Glucose-galactose malabsorption (GGM) is due to mutations in the gene coding for the intestinal sodium glucose cotransporter SGLT1 (SLC5A1). Here we identify the rare variant Gln457Arg (Q457R) in a large pedigree of patients in the Västerbotten County in Northern Sweden with the clinical phenotype of GGM. The functional effect of the Q457R mutation was determined in protein expressed in Xenopus laevis oocytes using biophysical and biochemical methods. The mutant failed to transport the specific SGLT1 sugar analog α-methyl-D-glucopyranoside (αMDG). Q457R SGLT1 was synthesized in amounts comparable to the wild-type (WT) transporter. SGLT1 charge measurements and freeze-fracture electron microscopy demonstrated that the mutant protein was inserted into the plasma membrane. Electrophysiological experiments, both steady-state and presteady-state, demonstrated that the mutant bound sugar with an affinity lower than the WT transporter. Together with our previous studies on Q457C and Q457E mutants, we established that the positive charge on Q457R prevented the translocation of sugar from the outward-facing to inward-facing conformation. This is contrary to other GGM cases where missense mutations caused defects in trafficking SGLT1 to the plasma membrane. Thirteen GGM patients are now added to the pedigree traced back to the late 17th century. The frequency of the Q457R variant in Västerbotten County genomes, 0.0067, is higher than in the general Swedish population, 0.0015, and higher than the general European population, 0.000067. This explains the high number of GGM cases in this region of Sweden.
Analysis of blood group antigens on MUC5AC in mucinous ovarian cancer tissues using in situ proximity ligation assay
Authors: Mateoiu Constantina , Vitiazeva Varvara , Kristjansdottir Björg , Weijdegård Birgitta , Örnros Jessica , Gallini Radiosa , Kamali-Moghaddam Masood , Sundfeldt Karin , Karlsson Niclas G
Published: August 2021

MUC5AC has been indicated to be a marker for mucinous ovarian cancer (OC). We investigated the use of in situ proximity ligation assay (PLA) for blood group ABH expressing MUC5AC to differentiate between serous and mucinous OC, to validate preceding observations that also MUC5AC ABH expression is increased in mucinous OC. We developed PLA for anti-A, B, and H/anti-MUC5AC and a PLA using a combined lectin Ulex europaeus agglutinin I (UEA I)/anti-MUC5AC assay. The PLAs were verified with mass spectrometry, where mucinous OC secretor positive patients’ cysts fluids containing ABH O-linked oligosaccharides also showed positive OC tissue PLA staining. A nonsecretor mucinous OC cyst fluid was negative for ABH and displayed negative PLA staining of the matched tissue. Using the UEA I/MUC5AC PLA, we screened a tissue micro array of 410 ovarian tissue samples from patients with various stages of mucinous or serous OC, 32 samples with metastasis to the ovaries and 34 controls. The PLA allowed differentiating mucinous tumors with a sensitivity of 84% and a specificity of 97% both against serous cancer but also compared to tissues from controls. This sensitivity is close to the expected incidence of secretor individuals in a population. The recorded sensitivity was also found to be higher compared to mucinous type cancer with metastasis to the ovaries, where only 32% were positive. We conclude that UEA 1/MUC5AC PLA allows glycospecific differentiation between serous and mucinous OC in patients with positive secretor status and will not identify secretor negative individuals with mucinous OC.
Curvature effects and radial homoclinic snaking
Authors: Gomila Damià , Knobloch Edgar
Published: August 2021

In this work, we revisit some general results on the dynamics of circular fronts between homogeneous states and the formation of localized structures in two dimensions (2D). We show how the bifurcation diagram of axisymmetric structures localized in radius fits within the framework of collapsed homoclinic snaking. In 2D, owing to curvature effects, the collapse of the snaking structure follows a different scaling that is determined by the so-called nucleation radius. Moreover, in the case of fronts between two symmetry-related states, the precise point in parameter space to which radial snaking collapses is not a ‘Maxwell’ point but is determined by the curvature-driven dynamics only. In this case, the snaking collapses to a ‘zero surface tension’ point. Near this point, the breaking of symmetry between the homogeneous states tilts the snaking diagram. A different scaling law is found for the collapse of the snaking curve in each case. Curvature effects on axisymmetric localized states with internal structure are also discussed, as are cellular structures separated from a homogeneous state by a circular front. While some of these results are well understood in terms of curvature-driven dynamics and front interactions, a proper mathematical description in terms of homoclinic trajectories in a radial spatial dynamics description is lacking.
The clinical correlates of vaccine-induced immune thrombotic thrombocytopenia after immunisation with adenovirus vector-based SARS-CoV-2 vaccines
Authors: Gaunt Eleanor R , Mabbott Neil A
Published: August 2021

We are at a critical stage in the COVID-19 pandemic where vaccinations are being rolled out globally, in a race against time to get ahead of the SARS-CoV-2 coronavirus and the emergence of more highly transmissible variants. A range of vaccines have been created and received either emergency approval or full licensure. To attain the upper hand, maximum vaccine synthesis, deployment, and uptake as rapidly as possible is essential. However, vaccine uptake, particularly in younger adults is dropping, at least in part fuelled by reports of rare complications associated with specific vaccines. This review considers how vaccination with adenovirus vector-based vaccines against the SARS-CoV-2 coronavirus might cause rare cases of thrombosis and thrombocytopenia in some recipients. A thorough understanding of the underlying cellular and molecular mechanisms that mediate this syndrome may help to identify methods to prevent these very rare, but serious side effects. This will also help facilitate the identification of those at highest risk from these outcomes, so that we can work towards a stratified approach to vaccine deployment to mitigate these risks.
Kinetics of Archived M184V Mutation in Treatment-Experienced Virally Suppressed HIV-Infected Patients
Authors: Palich Romain , Teyssou Elisa , Sayon Sophie , Abdi Basma , Soulie Cathia , Cuzin Lise , Tubiana Roland , Valantin Marc-Antoine , Schneider Luminita , Seang Sophie , Wirden Marc , Pourcher Valérie , Katlama Christine , Calvez Vincent , Marcelin Anne-Geneviève
Published: August 2021

Background

We aimed to assess the kinetics of drug-resistant viral variants (DRVs) harboring the M184V mutation in proviral DNA of long-term virally suppressed patients, and factors associated with DRV persistence.

Methods

Human immunodeficiency virus (HIV) DNA from blood cells stored in 2016 and 2019 was sequenced using Sanger and ultradeep sequencing (SS and UDS; detection threshold 1%) in antiretroviral therapy (ART)-treated patients with HIV RNA < 50 copies/mL for at least 5 years, with past M184V mutation documented in HIV RNA.

Results

Among 79 patients, by combining SS and UDS, M184V was found to be absent in 26/79 (33%) patients and persistent in 53/79 (67%). M184V-positive patients had a longer history of ART, lower CD4 nadir, and higher pretherapeutic HIV RNA. Among 37 patients with viral sequences assessed by UDS, the proportion of M184V-positive DRVs significantly decreased between 2016 and 2019 (40% vs 14%, P = .005). The persistence of M184V was associated with duration and level of HIV RNA replication under lamivudine/emtricitabine (3TC/FTC; P = .0009 and P = .009, respectively).

Conclusions

While it decreased over time in HIV DNA, M184V mutation was more frequently persistent in HIV DNA of more treatment-experienced patients with longer past replication under 3TC/FTC.
Early antiretroviral therapy initiation effect on metabolic profile in vertically HIV-1-infected children
Authors: Tarancón-Diez Laura , Rull Anna , Herrero Pol , Vazquez-Alejo Elena , Peraire Joaquim , Guillén Sara , Navarro-Gomez Maria Luisa , Viladés Consuelo , Muñoz-Fernandez Mª Ángeles , Vidal Francesc
Published: August 2021

Background

Early combined antiretroviral treatment (cART) in perinatally acquired HIV-1 children has been associated with a rapid viral suppression, small HIV-1 reservoir size and reduced mortality and morbidity. Immunometabolism has emerged as an important field in HIV-1 infection offering both relevant knowledge regarding immunopathogenesis and potential targets for therapies against HIV-1.

Objectives

To characterize the proteomic, lipidomic and metabolomic profile of HIV-1-infected children depending on their age at cART initiation.

Patients and methods

Plasma samples from perinatally HIV-1-infected children under suppressive cART who initiated an early cART (first 12 weeks after birth, EARLY, n = 10) and late cART (12–50 weeks after birth, LATE, n = 10) were analysed. Comparative plasma proteomics, lipidomics and metabolomics analyses were performed by nanoLC-Orbitrap, UHPLC-qTOF and GC-qTOF, respectively.

Results

Seven of the 188 proteins identified exhibited differences comparing EARLY and LATE groups of HIV-1-infected children. Despite no differences in the lipidomic (n = 115) and metabolomic (n = 81) profiles, strong correlations were found between proteins and lipid levels as well as metabolites, including glucidic components and amino acids, with clinical parameters. The ratio among different proteins showed high discriminatory power of EARLY and LATE groups.

Conclusions

Protein signature show a different proinflammatory state associated with a late cART introduction. Its associations with lipid levels and the relationships found between metabolites and clinical parameters may potentially trigger premature non-AIDS events in this HIV-1 population, including atherosclerotic diseases and metabolic disorders. Antiretroviral treatment should be started as soon as possible in perinatally acquired HIV-1-infected children to prevent them from future long-life complications.
When to change treatment of acute invasive aspergillosis: an expert viewpoint
Authors: Slavin Monica A , Chen Yee-Chun , Cordonnier Catherine , Cornely Oliver A , Cuenca-Estrella Manuel , Donnelly J Peter , Groll Andreas H , Lortholary Olivier , Marty Francisco M , Nucci Marcio , Rex John H , Rijnders Bart J A , Thompson George R , Verweij Paul E , White P Lewis , Hargreaves Ruth , Harvey Emma , Maertens Johan A
Published: August 2021

Invasive aspergillosis (IA) is an acute infection affecting patients who are immunocompromised, as a result of receiving chemotherapy for malignancy, or immunosuppressant agents for transplantation or autoimmune disease. Whilst criteria exist to define the probability of infection for clinical trials, there is little evidence in the literature or clinical guidelines on when to change antifungal treatment in patients who are receiving prophylaxis or treatment for IA. To try and address this significant gap, an advisory board of experts was convened to develop criteria for the management of IA for use in designing clinical trials, which could also be used in clinical practice. For primary treatment failure, a change in antifungal therapy should be made: (i) when mycological susceptibility testing identifies an organism from a confirmed site of infection, which is resistant to the antifungal given for primary therapy, or a resistance mutation is identified by molecular testing; (ii) at, or after, 8 days of primary antifungal treatment if there is increasing serum galactomannan, or galactomannan positivity in serum, or bronchoalveolar lavage fluid when the antigen was previously undetectable, or there is sudden clinical deterioration, or a new clearly distinct site of infection is detected; and (iii) at, or after, 15 days of primary antifungal treatment if the patient is clinically stable but with ≥2 serum galactomannan measurements persistently elevated compared with baseline or increasing, or if the original lesions on CT or other imaging, show progression by >25% in size in the context of no apparent change in immune status.
Detection of archived lamivudine-associated resistance mutations in virologically suppressed, lamivudine-experienced HIV-infected adults by different genotyping techniques (GEN-PRO study)
Authors: Montejano Rocio , Dominguez-Dominguez Lourdes , de Miguel Rosa , Rial-Crestelo David , Esteban-Cantos Andrés , Aranguren-Rivas Paula , García-Álvarez Mónica , Alejos Belén , Bisbal Otilia , Santacreu-Guerrero Mireia , Hernando Asunción , Bermejo-Plaza Laura , Cadiñanos Julen , Mayoral Mario , Castro Juan Miguel , Moreno Victoria , Martin-Carbonero Luz , Rodés Berta , Delgado Rafael , Rubio Rafael , Pulido Federico , Arribas José Ramón
Published: August 2021

Background

Previously selected lamivudine resistance-associated mutations (RAMs) may remain archived within the proviral HIV-DNA.

Objectives

To evaluate the ability of proviral DNA genotyping to detect lamivudine RAMs in HIV-1 virologically suppressed participants; the correlation between Sanger and next generation sequencing (NGS); and predictive factors for detection of lamivudine RAMs in proviral DNA.

Methods

Cross-sectional study of participants on stable antiretroviral therapy and suppressed for ≥1 year. Analysis of proviral DNA was performed by Sanger sequencing in whole blood and by NGS in PBMCs.

Results

We analysed samples from 102 subjects (52 with and 50 without lamivudine RAMs in historical plasma RNA-genotypes). Among participants with previous lamivudine resistance, Sanger sequencing detected RAMs in 26.9%. Detection rates significantly increased using NGS: 47.9%, 64.6%, 75% and 87.5% with the 20%, 10%, 5% and 1% thresholds, respectively. As for participants without historical lamivudine resistance, Sanger detected the RAMs in 1/49 (2%), and NGS (5% threshold) in 8/45 (17.8%). Multivariate models fitted to the whole population revealed that having a history of lamivudine resistance was a risk factor for detection of lamivudine RAMs by NGS. Among participants with historical lamivudine resistance, multivariate analysis showed that a longer time since HIV diagnosis was associated with persistence of archived mutations by NGS at thresholds of >10% [OR 1.10 (95% CI: 1.00–1.24)] and >5% [OR 1.16 (95% CI: 1.02–1.32)].

Conclusions

Proviral DNA Sanger sequencing does not detect the majority of historical lamivudine RAMs. NGS increases the sensitivity of detection at lower thresholds, although the relevance of these minority populations with lamivudine RAMs needs further evaluation.
The Role of Autoantibodies in the Diagnosis of Autoimmune Liver Disease: Lessons Learned from Clinical Practice
Authors: van Beers Joyce J B C , Koek Ger H , Damoiseaux Jan G M C
Published: August 2021

Background

Primary biliary cholangitis (PBC), autoimmune hepatitis (AIH) and primary sclerosing cholangitis (PSC) are autoimmune liver diseases associated with distinct autoantibodies. Diagnosis is based upon clinical, serological, and histopathology findings. The role of autoantibodies in the diagnosis of these autoimmune liver diseases, with the focus on PBC and AIH, will be discussed.

Content

When AIH or PBC is suspected, testing for multiple autoantibodies can be requested. In this mini-review, the different ways in which autoantibodies can be tested (indirect immunofluorescence and antigen-specific tests) in the context of PBC and AIH are discussed, as well as the pitfalls in interpreting the test results.

For appropriate interpretation of test results, an important prerequisite is that the doctor knows which test is used in the laboratory of choice and that the laboratory specialist is aware of what the doctor wants to test for. Good communication between clinician and laboratory specialist can, therefore, aid in the diagnosis of autoimmune liver diseases.
Differentiation Between Chaenomelis Fructus and its Common Adulterant, Guangpi Mugua
Authors: Lyu Mengying , Liu Yang , Qiu Yixing , Yang Shuai , Yuan Hanwen , Wang Wei
Published: August 2021

Background

The dried fruit of Chaenomeles speciosa, known as Chaenomelis Fructus or Zhoupi Mugua, is a type of traditional Chinese medicine (TCM) that is widely used to treat many diseases. Guangpi Mugua, the dried fruit of the Chaenomeles sinensis, is its most commonly known adulterant.

Objective

To establish a robust approach for the quality control and identification of Chaenomelis Fructus.

Method

Thin-layer chromatography (TLC) was optimized and used to discriminate Chaenomelis Fructus from Guangpi Mugua. High-performance liquid chromatography (HPLC) combined with fingerprint analysis and partial least-squares (PLS) discrimination analysis (DA) was employed to study the chemical differences between Chaenomelis Fructus and Guangpi Mugua. The single standard to determine multi-components (SSDMC) method, with credible precision, repeatability, stability, and durability, was developed for quantitative analysis of the abundant markers.

Results

The developed TLC and HPLC methods were effective in the authentication of Chaenomelis Fructus. Moreover, oleanolic acid, ursolic acid, pomolic acid, corosolic acid, 3-O-acetylpomolic acid, and one unknown compound were identified to be critical markers for the discrimination of Chaenomelis Fructus from Guangpi Mugua.

Conclusion

Adulteration has always been a challenge in the development of TCM. This study presents useful insights that may help solve the problem of adulteration during the preparation of Chaenomelis Fructus.

Highlights

The present study provides a systematic method for the quality control of Chaenomelis Fructus. This is therefore the first step towards solving the problem of adulteration to improve the clinical safety and effectiveness of Chaenomelis Fructus.
The Invasion ofMegachile policaris(Hymenoptera: Megachilidae) to Hawai‘i
Authors: Koch Jonathan Berenguer Uhuad , Tabor Jesse Anjin , Montoya-Aiona Kristina , Eiben Jesse A
Published: August 2021

Islands are insular environments that are negatively impacted by invasive species. In Hawai‘i, at least 21 non-native bees have been documented to date, joining the diversity of >9,000 non-native and invasive species to the archipelago. The goal of this study is to describe the persistence, genetic diversity, and natural history of the most recently established bee to Hawai‘i, Megachile policaris Say, 1831 (Hymenoptera: Megachilidae). Contemporary surveys identify that M. policaris is present on at least O‘ahu, Maui, and Hawai‘i Island, with the earliest detection of the species in 2017. Furthermore, repeated surveys and observations by community members support the hypothesis that M. policaris has been established on Hawai‘i Island from 2017 to 2020. DNA sequenced fragments of the cytochrome oxidase I locus identify two distinct haplotypes on Hawai‘i Island, suggesting that at least two founders have colonized the island. In their native range, M. policaris is documented to forage on at least 21 different plant families, which are represented in Hawai‘i. Finally, ensemble species distribution models (SDMs) constructed with four bioclimatic variables and occurrence data from the native range of M. policaris predicts high habitat suitability on the leeward side of islands throughout the archipelago and at high elevation habitats. While many of the observations presented in our study fall within the predicted habitat suitability on Hawai‘i, we also detected the M. policaris on the windward side of Hawai‘i Island suggesting that the SDMs we constructed likely do not capture the bioclimatic niche flexibility of the species.
Lethal Effects of Commercial Kaolin Dust and Silica Aerogel Dust With and Without Botanical Compounds on Horn Fly Eggs, Larvae, Pupae, and Adults in the Laboratory
Authors: Showler Allan T , Harlien Jessica L
Published: August 2021

The horn fly, Haematobia irritans irritans (L.) (Diptera: Muscidae), is an important bloodsucking ectoparasite of cattle throughout much of the world. The fly is mostly controlled using conventional synthetic insecticides but as concerns about resistance increase, alternative tactics have come under heightened scrutiny. Four desiccant dust products: Surround WP, a kaolin clay-based wettable powder; CimeXa, comprised of silica aerogel; Drione, silica aerogel + pyrethrins; and EcoVia, silica aerogel + thyme oil, were assessed for their lethal effects against horn fly eggs, larvae, pupae, and adults, under laboratory conditions. Although Surround WP and CimeXa did not prevent egg hatching and (when mixed with manure substrate) pupal development, the two products were associated with moderate reductions of emerged adults, and with complete adult contact mortality within 6 hr and 24 hr, respectively. Drione and EcoVia eliminated egg hatching, pupal development, and adults within 15 min to 1 hr, respectively, whether the flies were exposed to treated filter paper substrate or exposed by immersion in the dusts. Implications for horn fly control and advantages of inert desiccant dust formulations are discussed.