Cervical spondylotic myelopathy (CSM) is a neurologic condition that develops insidiously over time as degenerative changes of the spine result in compression of the cord and nearby structures. It is the most common form of spinal cord injury in adults; yet, its diagnosis is often delayed. The purpose of this article is to review the pathophysiology, natural history, diagnosis, and management of CSM with a focus on the recommended timeline for physicians suspecting CSM to refer patients to a spine surgeon. Various processes underlie spondylotic changes of the canal and are separated into static and dynamic factors. Not all patients with evidence of cord compression will present with symptoms, and the progression of disease varies by patient. The hallmark symptoms of CSM include decreased hand dexterity and gait instability as well as sensory and motor dysfunction. magnetic resonance imaging is the imaging modality of choice in patients with suspected CSM, but computed tomography myelography may be used in patients with contraindications. Patients with mild CSM may be treated surgically or nonoperatively, whereas those with moderate-severe disease are treated operatively. Due to the long-term disability that may result from a delay in diagnosis and management, prompt referral to a spine surgeon is recommended for any patient suspected of having CSM. This review provides information and guidelines for practitioners to develop an actionable awareness of CSM.

Inhaled corticosteroid (ICS)–based therapy is often used for patients with chronic obstructive pulmonary disease (COPD). However, this approach is under scrutiny because of ICS overuse in patients for whom it is not recommended and because of concerns about adverse events, particularly pneumonia, with long-term ICS use. Evidence suggests ICS may be beneficial in specific patients, namely, those with high blood eosinophil counts (eg, ≥300 cells/µL) or who are at a high risk of exacerbations. According to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2020 ABCD assessment tool, these patients belong in group D. For these patients, recommended initial treatment includes ICS in combination with long-acting β2-agonists (LABAs) when blood eosinophil counts are ≥300 cells/µL or LABA + long-acting muscarinic antagonist (LAMA) when patients are highly symptomatic, that is, with greater dyspnea and/or exercise limitation. Follow-up treatments for patients with persistent dyspnea and/or exacerbations may include LABA + ICS, LABA + LAMA, or LABA + LAMA + ICS, with use of ICS being guided by blood eosinophil counts. In this review, differences in the inflammatory mechanism underlying COPD and asthma and the role of ICS treatment in COPD are summarized. Furthermore, findings from recent clinical trials where use of ICS-based dual or triple therapy in COPD was compared with LABA + LAMA therapy and trials in which ICS withdrawal was evaluated in patients with COPD are reviewed. Finally, a step-by-step guide for ICS withdrawal in patients who are unlikely to benefit from this treatment is proposed. A video of the author discussing the overall takeaway of the review article could be downloaded from the link provided: https://www.youtube.com/watch?v=Uq7Sr5jqPDI.

Background:

Facilitation is an effective approach for helping practices implement sustainable evidence-based practice improvements. Few studies examine the facilitation infrastructure and support needed for large-scale dissemination and implementation initiatives.

Access to services related to reproductive and sexual health is critical to the health of women but has been threatened in recent years. Family physicians are trained to provide a range of women’s health care services and are an essential part of the health care workforce in rural and underserved areas, where access to these services may be limited.

Fredrik Andreasson, Arne Hegemann, Andreas Nord, and Jan-Ake Nilsson

The capacity to get rid of excess heat produced during hard work is a possible constraint on parental effort during reproduction [heat dissipation limit (HDL) theory]. We released hard-working blue tits (Cyanistes caeruleus) from this constraint by experimentally removing ventral plumage. We then assessed whether this changed their reproductive effort (feeding rate and nestling size) and levels of self-maintenance (change in body mass and innate immune function). Feather-clipped females reduced the number of feeding visits and increased levels of constitutive innate immunity compared with unclipped females but did not fledge smaller nestlings. Thus, they increased self-maintenance without compromising current reproductive output. In contrast, feather clipping did not affect the number of feeding visits or innate immune function in males, despite increased heat loss rate. Our results show that analyses of physiological parameters, such as constitutive innate immune function, can be important when trying to understand sources of variation in investment in self-maintenance versus reproductive effort and that risk of overheating can influence innate immune function during reproduction.

Ana Gabriela Jimenez, Emily Cornelius Ruhs, Kailey J. Tobin, Katie N. Anderson, Audrey Le Pogam, Lyette Regimbald, and Francois Vezina

Seasonal changes in maximal thermogenic capacity (M_sum) in wild black-capped chickadees suggests that adjustments in metabolic performance are slow and begin to take place before winter peaks. However, when mean minimal ambient temperature (T_a) reaches –10°C, the chickadee phenotype appears to provide enough spare capacity to endure days with colder T_a, down to –20°C or below. This suggests that birds could also maintain a higher antioxidant capacity as part of their cold-acclimated phenotype to deal with sudden decreases in temperature. Here, we tested how environmental mismatch affected oxidative stress by comparing cold-acclimated (–5°C) and transition (20°C) phenotypes in chickadees exposed to an acute 15°C drop in temperature with that of control individuals. We measured superoxide dismutase, catalase and glutathione peroxidase activities, as well as lipid peroxidation damage and antioxidant scavenging capacity in pectoralis muscle, brain, intestine and liver. We generally found differences between seasonal phenotypes and across tissues, but no differences with respect to an acute cold drop treatment. Our data suggest oxidative stress is closely matched to whole-animal physiology in cold-acclimated birds compared with transition birds, implying that changes to the oxidative stress system happen slowly.

Ayelen M. Blanco, Juan I. Bertucci, Jose L. Soengas, and Suraj Unniappan

This research assessed the direct effects of insulin on nutrient-sensing mechanisms in the brain of rainbow trout (Oncorhynchus mykiss) using an in vitro approach. Cultured hypothalamus and hindbrain were exposed to 1 µmol l^–1 insulin for 3 h, and signals involved in appetite regulation and nutrient-sensing mechanisms were measured. Additionally, the involvement of the phosphatidylinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway in the actions of insulin was studied by using the inhibitor wortmannin. Treatment with insulin alone did not elicit many changes in the appetite regulators and nutrient-sensing-related genes and enzymes tested in the hypothalamus and hindbrain. However, we found that, when insulin and nutrients were added together, insulin reversed most of the effects exerted by nutrients alone, suggesting that insulin changes responsiveness to nutrients at the central level. Effects reversed by insulin included expression levels of genes related to the sensing of both glucose (slc2a2, slc5a1, gck, pck1, pklr, g6pcb, gys1, tas1r3 and nr1h3 in the hindbrain, and slc2a2, pklr and pck1 in the hypothalamus) and fatty acid (cd36 in the hindbrain, and cd36 and acly in the hypothalamus). Nutrient-induced changes in the activity of Acly and Cpt-1 in the hindbrain and of Pepck, Acly, Fas and Hoad in the hypothalamus were also reversed by insulin. Most of the insulin effects disappeared in the presence of wortmannin, suggesting the PI3K/Akt pathway is a mediator of the effects of insulin reported here. This study adds new information to our knowledge of the mechanisms regulating nutrient sensing in fish.

Rohini Singh and Timothy A. Linksvayer

Wolbachia is a widespread group of maternally-transmitted endosymbiotic bacteria that often manipulates the reproductive strategy and life history of its hosts to favor its own transmission. Wolbachia mediated phenotypic effects are well characterized in solitary hosts, but effects in social hosts are unclear. The invasive pharaoh ant, Monomorium pharaonis, shows natural variation in Wolbachia infection between colonies and can be readily bred under laboratory conditions. We previously showed that Wolbachia-infected pharaoh ant colonies had more queen-biased sex ratios than uninfected colonies, which is expected to favor the spread of maternally-transmitted Wolbachia. Here, we further characterize the effects of Wolbachia on the short- and longer-term reproductive and life history traits of pharaoh ant colonies. First, we characterized the reproductive differences between naturally infected and uninfected colonies at three discrete time points and found that infected colonies had higher reproductive investment (i.e. infected colonies produced more new queens), particularly when existing colony queens were three months old. Next, we compared the long-term growth and reproduction dynamics of infected and uninfected colonies across their whole life cycle. Infected colonies had increased colony-level growth and early colony reproduction, resulting in a shorter colony life cycle, when compared to uninfected colonies.

Background

Clinically significant CKD following surgery for kidney cancer is associated with increased morbidity and mortality, but identifying patients at increased CKD risk remains difficult. Simple methods to stratify risk of clinically significant CKD after nephrectomy are needed.

Background

The utility of kidney organoids in regenerative medicine will rely on the functionality of the glomerular and tubular structures in these tissues. Recent studies have demonstrated the vascularization and subsequent maturation of human pluripotent stem cell–derived kidney organoids after renal subcapsular transplantation. This raises the question of whether the glomeruli also become functional upon transplantation.

Growing evidence indicates that oxidative and endoplasmic reticular stress, which trigger changes in ion channels and inflammatory pathways that may undermine cellular homeostasis and survival, are critical determinants of injury in the diabetic kidney. Cells are normally able to mitigate these cellular stresses by maintaining high levels of autophagy, an intracellular lysosome-dependent degradative pathway that clears the cytoplasm of dysfunctional organelles. However, the capacity for autophagy in both podocytes and renal tubular cells is markedly impaired in type 2 diabetes, and this deficiency contributes importantly to the intensity of renal injury. The primary drivers of autophagy in states of nutrient and oxygen deprivation—sirtuin-1 (SIRT1), AMP-activated protein kinase (AMPK), and hypoxia-inducible factors (HIF-1α and HIF-2α)—can exert renoprotective effects by promoting autophagic flux and by exerting direct effects on sodium transport and inflammasome activation. Type 2 diabetes is characterized by marked suppression of SIRT1 and AMPK, leading to a diminution in autophagic flux in glomerular podocytes and renal tubules and markedly increasing their susceptibility to renal injury. Importantly, because insulin acts to depress autophagic flux, these derangements in nutrient deprivation signaling are not ameliorated by antihyperglycemic drugs that enhance insulin secretion or signaling. Metformin is an established AMPK agonist that can promote autophagy, but its effects on the course of CKD have been demonstrated only in the experimental setting. In contrast, the effects of sodium-glucose cotransporter–2 (SGLT2) inhibitors may be related primarily to enhanced SIRT1 and HIF-2α signaling; this can explain the effects of SGLT2 inhibitors to promote ketonemia and erythrocytosis and potentially underlies their actions to increase autophagy and mute inflammation in the diabetic kidney. These distinctions may contribute importantly to the consistent benefit of SGLT2 inhibitors to slow the deterioration in glomerular function and reduce the risk of ESKD in large-scale randomized clinical trials of patients with type 2 diabetes.

Functions of eukaryotic mRNAs are characterized by intramolecular interactions between their ends. We have addressed the question whether 5' and 3' ends meet by diffusion-controlled encounter "through solution" or by a mechanism involving the RNA backbone. For this purpose, we used a translation system derived from Drosophila embryos that displays two types of 5'–3' interactions: Cap-dependent translation initiation is stimulated by the poly(A) tail and inhibited by Smaug recognition elements (SREs) in the 3' UTR. Chimeric RNAs were made consisting of one RNA molecule carrying a luciferase coding sequence and a second molecule containing SREs and a poly(A) tail; the two were connected via a protein linker. The poly(A) tail stimulated translation of such chimeras even when disruption of the RNA backbone was combined with an inversion of the 5'–3' polarity between the open reading frame and poly(A) segment. Stimulation by the poly(A) tail also decreased with increasing RNA length. Both observations suggest that contacts between the poly(A) tail and the 5' end are established through solution, independently of the RNA backbone. In the same chimeric constructs, SRE-dependent inhibition of translation was also insensitive to disruption of the RNA backbone. Thus, tracking of the backbone is not involved in the repression of cap-dependent initiation. However, SRE-dependent repression was insensitive to mRNA length, suggesting that the contact between the SREs in the 3' UTR and the 5' end of the RNA might be established in a manner that differs from the contact between the poly(A) tail and the cap.

Endogenous viral elements (EVEs) are found in many eukaryotic genomes. Despite considerable knowledge about genomic elements such as transposons (TEs) and retroviruses, we still lack information about nonretroviral EVEs. Aedes aegypti mosquitoes have a highly repetitive genome that is covered with EVEs. Here, we identified 129 nonretroviral EVEs in the AaegL5 version of the A. aegypti genome. These EVEs were significantly associated with TEs and preferentially located in repeat-rich clusters within intergenic regions. Genome-wide transcriptome analysis showed that most EVEs generated transcripts although only around 1.4% were sense RNAs. The majority of EVE transcription was antisense and correlated with the generation of EVE-derived small RNAs. A single genomic cluster of EVEs located in a 143 kb repetitive region in chromosome 2 contributed with 42% of antisense transcription and 45% of small RNAs derived from viral elements. This region was enriched for TE-EVE hybrids organized in the same coding strand. These generated a single long antisense transcript that correlated with the generation of phased primary PIWI-interacting RNAs (piRNAs). The putative promoter of this region had a conserved binding site for the transcription factor Cubitus interruptus, a key regulator of the flamenco locus in Drosophila melanogaster. Here, we have identified a single unidirectional piRNA cluster in the A. aegypti genome that is the major source of EVE transcription fueling the generation of antisense small RNAs in mosquitoes. We propose that this region is a flamenco-like locus in A. aegypti due to its relatedness to the major unidirectional piRNA cluster in Drosophila melanogaster.

Transposable elements (TEs) can damage genomes, thus organisms use a variety of mechanisms to repress TE expression. The PIWI–piRNA pathway is a small RNA pathway that represses TE expression in the germline of animals. Here we explore the function of the pathway in the somatic stem cells of Hydra, a long-lived freshwater cnidarian. Hydra have three stem cell populations, all of which express PIWI proteins; endodermal and ectodermal epithelial stem cells (ESCs) are somatic, whereas the interstitial stem cells have germline competence. To study somatic function of the pathway, we isolated piRNAs from Hydra that lack the interstitial lineage and found that these somatic piRNAs map predominantly to TE transcripts and display the conserved sequence signatures typical of germline piRNAs. Three lines of evidence suggest that the PIWI–piRNA pathway represses TEs in Hydra ESCs. First, epithelial knockdown of the Hydra piwi gene hywi resulted in up-regulation of TE expression. Second, degradome sequencing revealed evidence of PIWI-mediated cleavage of TE RNAs in epithelial cells using the ping-pong mechanism. Finally, we demonstrated a direct association between Hywi protein and TE transcripts in epithelial cells using RNA immunoprecipitation. Altogether, our data reveal that the PIWI–piRNA pathway represses TE expression in the somatic cell lineages of Hydra, which we propose contributes to the extreme longevity of the organism. Furthermore, our results, in combination with others, suggest that somatic TE repression is an ancestral function of the PIWI–piRNA pathway.

The importance of noncoding RNA sequences has become increasingly clear over the past decade. New RNA families are often detected and analyzed using comparative methods based on multiple sequence alignments. Accordingly, a number of programs have been developed for aligning and deriving secondary structures from sets of RNA sequences. Yet, the best tools for these tasks remain unclear because existing benchmarks contain too few sequences belonging to only a small number of RNA families. RNAconTest (RNA consistency test) is a new benchmarking approach relying on the observation that secondary structure is often conserved across highly divergent RNA sequences from the same family. RNAconTest scores multiple sequence alignments based on the level of consistency among known secondary structures belonging to reference sequences in their output alignment. Similarly, consensus secondary structure predictions are scored according to their agreement with one or more known structures in a family. Comparing the performance of 10 popular alignment programs using RNAconTest revealed that DAFS, DECIPHER, LocARNA, and MAFFT created the most structurally consistent alignments. The best consensus secondary structure predictions were generated by DAFS and LocARNA (via RNAalifold). Many of the methods specific to noncoding RNAs exhibited poor scalability as the number or length of input sequences increased, and several programs displayed substantial declines in score as more sequences were aligned. Overall, RNAconTest provides a means of testing and improving tools for comparative RNA analysis, as well as highlighting the best available approaches. RNAconTest is available from the DECIPHER website (http://DECIPHER.codes/Downloads.html).

BACKGROUND:In this study, we aimed to validate the agreement between pulmonary function measurements obtained with a portable spirometer and measurements obtained with conventional spirometry in Chinese pediatric and adult populations.METHODS:Pulmonary function testing was performed to evaluate subjects enrolled at Shanghai Zhongshan Hospital (n = 104) and Shanghai Children's Medical Center (n = 103). The portable spirometers and conventional devices were applied to each subject with a 20-min quiescent period between each measurement. Pulmonary function parameters of FVC, FEV1, peak expiratory flow, maximum expiratory flow at 25%, 50%, and 75% of FVC (MEF25, MEF50, and MEF75, respectively), and FEV1/FVC% were compared with intraclass correlation and Bland-Altman methods.RESULTS:A satisfactory concordance of pulmonary function was observed between spirometry measurements obtained with portable versus conventional spirometers. Intraclass correlation indicated excellent reliability (>0.75) for all pulmonary function indicators in pediatric and adult subjects. Significant positive correlations of all variables measured with different spirometers were observed (all P < .001). No significant bias was observed in either group, although limits of agreement varied. Funnel effects were observed for peak expiratory flow in pediatric subjects and for FVC, FEV1, MEF50, and MEF25 in adult subjects.CONCLUSIONS:The portable spirometer is an alternative to the conventional device for the measurement of pulmonary function. Compared with the conventional device, the portable spirometer is expected to provide convenient, operational, and financial advantages.

Tumor cells can spread to distant sites through their ability to switch between mesenchymal and amoeboid (bleb-based) migration. Because of this difference, inhibitors of metastasis must account for each migration mode. However, the role of vimentin in amoeboid migration has not been determined. Because amoeboid leader bleb–based migration (LBBM) occurs in confined spaces and vimentin is known to strongly influence cell-mechanical properties, we hypothesized that a flexible vimentin network is required for fast amoeboid migration. To this end, here we determined the precise role of the vimentin intermediate filament system in regulating the migration of amoeboid human cancer cells. Vimentin is a classic marker of epithelial-to-mesenchymal transition and is therefore an ideal target for a metastasis inhibitor. Using a previously developed polydimethylsiloxane slab–based approach to confine cells, RNAi-based vimentin silencing, vimentin overexpression, pharmacological treatments, and measurements of cell stiffness, we found that RNAi-mediated depletion of vimentin increases LBBM by ∼50% compared with control cells and that vimentin overexpression and simvastatin-induced vimentin bundling inhibit fast amoeboid migration and proliferation. Importantly, these effects were independent of changes in actomyosin contractility. Our results indicate that a flexible vimentin intermediate filament network promotes LBBM of amoeboid cancer cells in confined environments and that vimentin bundling perturbs cell-mechanical properties and inhibits the invasive properties of cancer cells.

Assembled α-synuclein in nerve cells and glial cells is the defining pathological feature of neurodegenerative diseases called synucleinopathies. Seeds of α-synuclein can induce the assembly of monomeric protein. Here, we used sucrose gradient centrifugation and transiently transfected HEK 293T cells to identify the species of α-synuclein from the brains of homozygous, symptomatic mice transgenic for human mutant A53T α-synuclein (line M83) that seed aggregation. The most potent fractions contained Sarkosyl-insoluble assemblies enriched in filaments. We also analyzed six cases of idiopathic Parkinson's disease (PD), one case of familial PD, and six cases of multiple system atrophy (MSA) for their ability to induce α-synuclein aggregation. The MSA samples were more potent than those of idiopathic PD in seeding aggregation. We found that following sucrose gradient centrifugation, the most seed-competent fractions from PD and MSA brains are those that contain Sarkosyl-insoluble α-synuclein. The fractions differed between PD and MSA, consistent with the presence of distinct conformers of assembled α-synuclein in these different samples. We conclude that α-synuclein filaments are the main driving force for amplification and propagation of pathology in synucleinopathies.

Motor protein-based active transport is essential for mRNA localization and local translation in animal cells, yet how mRNA granules interact with motor proteins remains poorly understood. Using an unbiased yeast two–hybrid screen for interactions between murine RNA-binding proteins (RBPs) and motor proteins, here we identified protein interaction with APP tail-1 (PAT1) as a potential direct adapter between zipcode-binding protein 1 (ZBP1, a β-actin RBP) and the kinesin-I motor complex. The amino acid sequence of mouse PAT1 is similar to that of the kinesin light chain (KLC), and we found that PAT1 binds to KLC directly. Studying PAT1 in mouse primary hippocampal neuronal cultures from both sexes and using structured illumination microscopic imaging of these neurons, we observed that brain-derived neurotrophic factor (BDNF) enhances co-localization of dendritic ZBP1 and PAT1 within granules that also contain kinesin-I. PAT1 is essential for BDNF-stimulated neuronal growth cone development and dendritic protrusion formation, and we noted that ZBP1 and PAT1 co-locate along with β-actin mRNA in actively transported granules in living neurons. Acute disruption of the PAT1–ZBP1 interaction in neurons with PAT1 siRNA or a dominant-negative ZBP1 construct diminished localization of β-actin mRNA but not of Ca2+/calmodulin-dependent protein kinase IIα (CaMKIIα) mRNA in dendrites. The aberrant β-actin mRNA localization resulted in abnormal dendritic protrusions and growth cone dynamics. These results suggest a critical role for PAT1 in BDNF-induced β-actin mRNA transport during postnatal development and reveal a new molecular mechanism for mRNA localization in vertebrates.

Premature infants have a higher incidence of indirect hyperbilirubinemia than term infants. Management of neonatal indirect hyperbilirubinemia in late preterm and term neonates has been well addressed by recognized, consensus-based guidelines. However, the extension of these guidelines to the preterm population has been an area of uncertainty because of limited evidence. This leads to variation in clinical practice and lack of recognition of the spectrum of bilirubin-induced neurologic dysfunction (BIND) in this population. Preterm infants are metabolically immature and at higher risk for BIND at lower bilirubin levels than their term counterparts. Early use of phototherapy to eliminate BIND and minimize the need for exchange transfusion is the goal of treatment in premature neonates. Although considered relatively safe, phototherapy does have side effects, and some NICUs tend to overuse phototherapy. In this review, we describe the epidemiology and pathophysiology of BIND in preterm neonates, and discuss our approach to standardized management of indirect hyperbilirubinemia in the vulnerable preterm population. The proposed treatment charts suggest early use of phototherapy in preterm neonates with the aim of reducing exposure to high irradiance levels, minimizing the need for exchange transfusions, and preventing BIND. The charts are pragmatic and have additional curves for stopping phototherapy and escalating its intensity. Having a standardized approach would support future research and quality improvement initiatives that examine dose and duration of phototherapy exposure with relation to outcomes.

Interpretation of a 3D seismic survey located on the western margin of the Northern North Sea Basin demonstrates how the propagation, overlap and linkage of two north–south-striking, en echelon normal fault segments exerted a powerful influence over prospective subtle stratigraphic traps. The relay ramp that formed between the segments appears to have focused sediment dispersal, controlled reservoir distribution and aided post-depositional petroleum migration. Integration of electrical well log data, root-mean-square (RMS)-amplitude analysis and biostratigraphy with seismic interpretation demonstrates that a series of elongate, linear, sand-prone (reservoir) channel complexes characterize the depositional slopes generated by fault growth. The combination of synsedimentary rotation of bedding due to fault propagation and associated footwall uplift led to erosion and truncation of a laterally extensive, older channelized system (Lower Sequence), the downdip parts of which extend beyond the relay ramp. Its subsequent drape by transgressive shales created the subtle stratigraphic trap that now hosts the Cladhan Field, with charge occurring because the sandstones belonging to the Lower Sequence extend as far as the active kitchen in the neighbouring (hanging-wall) depocentre situated downdip and to the east. In contrast, the exploration of a younger, Upper Sequence of sandstones has proven to be disappointing due to their more restricted distribution, lack of access to charge, and occurrence of faults that offset and breach the thin end of the stratigraphic wedge. The implication is that partially breached relay ramps not only provide a preferential site for syn-rift clastic reservoirs to develop but also form important migration pathways through which oil passed from a petroleum kitchen into a trap.

Thematic collection: This article is part of the Under-explored plays and frontier basins of the UK continental shelf collection available at: http://www.lyellcollection.org/cc/under-explored-plays-and-frontier-basins-of-the-uk-continental-shelf

Discovery of the Breagh gas field in the Southern North Sea (SNS) has demonstrated the potential that the Lower Carboniferous (Visean, 346.7–330.9 Ma) Farne Group reservoirs have to contribute to the UK's future energy mix. New biostratigraphic correlations provide a basis to compare Asbian and Brigantian sedimentary cores from the Breagh Field and age-equivalent sediments exposed on the Northumberland Coast, which has proved critical in gaining an understanding of exploration and development opportunities. Thirteen facies associations characterize the mixed carbonate–siliciclastic system, grouped into: marine, delta front, delta shoreface, lower delta plain and upper delta plain gross depositional environments. The facies associations are interpreted as depositing in a mixed carbonate and siliciclastic fluvio-deltaic environment, and are arranged into coarsening- and cleaning-upward cycles (parasequences) bounded by flooding surfaces. Most cycles are characterized by mouth bars, distributary channels, interdistributary bays and common braided rivers, interpreted as river-dominated deltaic deposits. Some cycles include rare shoreface and tidally-influenced deposits, interpreted as river-dominated and wave- or tide-influenced deltaic deposits. The depositional processes that formed each cycle have important implications for the reservoir net/gross ratio (where this ratio indicates the proportion of sandstone beds in a cycle), thickness and lateral extent. The deltaic deposits were controlled by a combination of tectonic and eustatic (allocyclic) events and delta avulsion (autocyclic) processes, and are likely to reflect a changing tectonic regime, from extension within elongate fault-bounded basins (synrift) to passive regional thermal subsidence (post-rift). Deep incision by the Base Permian Unconformity across the Breagh Field has removed the Westphalian, Namurian and upper Visean, to leave the more prospective thicker clastic reservoirs within closure.

Thematic collection: This article is part of the Under-explored plays and frontier basins of the UK continental shelf collection available at: https://www.lyellcollection.org/cc/under-explored-plays-and-frontier-basins-of-the-uk-continental-shelf

The progressive development of microfabrics from initial deposition to slump deformation and then a submarine slide was investigated in an active subduction zone using cores recovered during the Integrated Ocean Drilling Program Expedition 333. A Pleistocene–Holocene sequence was recovered at Site C0018A, which was located on a slope basin on the footwall of the megasplay fault in the Nankai Trough, SW Japan. Six mass-transport deposit units intercalated with coherent intervals were recovered from the upper 190 m of the drilled succession. The initial microfabrics in the undeformed hemipelagic sediments were characterized by random and porous fabrics composed predominantly of clay aggregations and connectors. The initial fabrics were cardhouse fabrics, which consist of clay flakes with edge-to-edge (E–E) and/or edge-to-face (E–F) contacts. These initial microfabrics developed into compacted microfabrics, which are random and consolidated fabrics (bookhouse fabrics) that consist of clay flakes with E–F and/or face-to-face (F–F) contacts and develop during burial as a pure shear deformation. During slumping, these fabrics were then deformed under simple shear to become predominantly F–F contacts and form clay chains. Thus, the microfabrics in these submarine slides are a sedimentary mélange that developed locally into a preferred clay orientation with F–F contacts.

Supplementary material: A schematic illustration showing sedimentation processes and fabrics is available at https://doi.org/10.6084/m9.figshare.c.4483385

Thematic collection: This article is part of the Polygenetic mélanges collection available at: https://www.lyellcollection.org/cc/polygenetic-melanges

The Dukla Nappe in the Skrzydlna area exposes two types of mélange reflecting two different phases of basinal and tectonic evolution of the Outer West Carpathian orogen in its Polish sector. The Oligocene-age sedimentary mélange (olistostrome) is related to growth of the accretionary wedge, whereas the Miocene-age diapiric mélange postdates the orogenic thrusting. Textural and structural features of the very coarse-grained sedimentary mélange suggest non-cohesive debris flows and high-density turbidity currents as predominant emplacement mechanisms. Growth strata, associated with progressive unconformities, and facies contrast between the underlying fine-grained unit and the overlying olistostrome reflect a considerable uplift of the source area and rotation of the adjacent part of the basin floor. The olistostrome and the overlying turbidite succession form a retrogressive sequence interpreted as a submarine canyon infill grading to a small submarine fan. The diapiric mélange, injected into the Oligocene-age succession of the Dukla Nappe, contains the Early and Late Cretaceous-age blocks and matrix derived from the underlying Silesian Nappe. The features reflecting diapiric emplacement include matrix proportion increase and block content decrease towards the mélange margins, scaly fabric and shear zones. Both mélanges, interpreted in the past as chaotic bodies, upon detailed examination reveal genesis-related subtle internal organization.

In the Northern Apennine (Italy), the Internal Ligurian Units consist of Middle–Late Jurassic ophiolites covered by thick sedimentary deposits whose top is represented by the Early Paleocene Bocco Shale. This formation is characterized by mass-transport deposits interlayered with thin-bedded siliciclastic turbidites. The sedimentological and structural features of these mass-transport deposits reveal a long-lived history of recycling of heterogeneous material in a subduction setting. This history started with the frontal accretion of a fragment of oceanic crust into an accretionary prism whose lower slope was subsequently affected by tectonic erosion and consequent instability, leading to the production of mass-transport deposits and the transfer of material to the lower plate. These mass-transport deposits were subsequently underthrust and then again transferred to the base of the accretionary prism by coherent underplating, before their exhumation to the surface. The Bocco Shale is thus representative of a subduction setting where both accretionary and erosive events occurred, depending on changing boundary conditions. The reconstructed history for the Bocco Shale indicates that the sedimentary and gravitational processes both at the prism front and on the prism slope, possibly induced by alternating accretion and erosion events, are the most efficient mechanisms of lithological mixing and recycling in subduction margins.

Upper Lutetian–Bartonian sedimentary mélanges, corresponding to ancient mud-rich submarine mass transport deposits, are widely distributed over an area c. 300 km long and tens of kilometres wide along the exhumed outer part of the External Ligurian accretionary wedge in the Northern Apennines. The occurrence of methane-derived carbonate concretions (septarians) in a specific tectonostratigraphic position below these sedimentary mélanges allows us to document the relationships among a significant period of regional-scale slope failure, climate change (the Early and Mid-Eocene Optimum stages), the dissociation of gas hydrates and accretionary tectonics during the Ligurian Tectonic Phase (early–mid-Lutetian). The distribution of septarians at the core of thrust-related anticlines suggests that the dissociation of gas hydrates was triggered by accretionary tectonics rather than climate change. The different ages of slope failure emplacement and the formation of the septarians support the view that the dissociation of gas hydrates was not the most important trigger for slope failure. The latter occurred during a tectonic quiescence stage associated with a regressive depositional trend, and probably minor residual tectonic pulses, which followed the Ligurian Tectonic Phase, favouring the dynamic re-equilibrium of the External Ligurian accretionary wedge. Our findings provide useful information for a better understanding of the factors controlling giant slope failure events in modern accretionary settings, where they may cause tsunamis.

A significant part of mélanges recognized in exhumed convergent margins around the world has been recently documented to have chiefly originated from masse transport and subsurface remobilization and disruption (i.e. mélanges, from sedimentary and mud–serpentinite diapiric processes and from in situ fluidification–disruption). Tectonic and/or sedimentary processes occurring during subsequent multiple deformational events of convergent margin evolution commonly overprint and significantly rework the primary (sedimentary or diapiric) mélange fabric, forming polygenetic mélanges. This ultimately complicates their distinction from true tectonic mélanges, masking part of the recorded tectono-sedimentary evolution of the associated convergent margin. The contributions gathered in this thematic collection explore with different approaches (from field structural and stratigraphic observations to geophysical analyses) different types of polygenetic mélange, at various scales, around the world. These studies conclude that the understanding of this type of mélange may provide crucial insights for a more detailed interpretation of the evolution of ancient and modern convergent margins, and of processes and mechanisms triggering potential natural hazards (earthquakes and tsunamis). Case studies include the Apennines in the Central Mediterranean region, the Carpathians in Central Europe and the Nankai Prism in Japan.

Thematic collection: This article is part of the ‘Polygenetic mélanges: a glimpse on tectonic sedimentary and diapiric recycling in convergent margins’ collection available at https://www.lyellcollection.org/cc/polygenetic-melanges

Mechanical heterogeneity of a sedimentary sequence exerts a primary control on the geometry of fault zones and the proportion of offset accommodated by folding. The Wildensbuch Fault Zone in the Swiss Molasse Basin, with a maximum throw of 40 m, intersects a Mesozoic section containing a thick (120 m) clay-dominated unit (Opalinus Clay) over- and underlain by more competent limestone units. Interpretation of a 3D seismic reflection survey indicates that the fault zone formed by upward propagation of an east–west-trending basement structure, through the Mesozoic section, in response to NE–SW Miocene extension. This configuration formed an array of left-stepping normal fault segments above and below the Opalinus Clay. In cross-section a broad monoclinal fold is observed in the Opalinus Clay. Folding, however, is not ubiquitous and occurs in the Opalinus Clay where fault segments above and below are oblique to one another; where they are parallel the fault passes through the Opalinus Clay with little folding. These observations demonstrate that, even in strongly heterogeneous sequences, here a four-fold difference in both Young's modulus and cohesion between layers, the occurrence of folding may depend on the local relationship between fault geometry and applied stress field rather than rheological properties alone.

The Northern Paraguai Belt, at the SE border of the Amazonian Craton, central Brazil, has been interpreted as a Brasiliano–Pan-African (c. 650–600 Ma) belt with a foreland basin, recording collisional polyphase tectonism and greenschist-facies metamorphism extending from the late Precambrian to the Cambrian–Ordovician. New structural investigations indicate that the older metasedimentary rocks of the Cuiabá Group represent a Tonian–Cryogenian basement assemblage deformed in two contemporaneous fault-bounded structural sub-domains of wrench-dominated (rake <10°) and contraction-dominated (rake ~30–40°) sinistral transpression, with tectonic vergence towards the SE. The younger late Cryogenian to early Cambrian sedimentary rocks lying to the NW of the Cuiabá Group are non-metamorphic and display only pervasive brittle transtension characterized by normal-oblique faults, fractures and forced drag folds with no consistent vergence pattern. Our analyses suggest that an unconformity separates the metasedimentary Cuiabá Group basement of the Northern Paraguai Belt from the unmetamorphosed sedimentary cover. It is proposed that the latter units were deposited during a post-glacial marine transgression (after c. 635 Ma) in a post-collisional basin. The Paraguai Belt basement and its post-collisional sedimentary cover share a number of significant geological similarities with sequences in the Bassarides Belt and Taoudéni Basin in the SW portion of the West African Craton.

Select agents (SA) pose unique challenges for licensing vaccines and therapies. In the case of toxin-mediated diseases, HHS assigns guidelines for SA use, oversees vaccine and therapy development, and approves animal models and approaches to identify mechanisms for toxin neutralization. In this commentary, we discuss next-generation vaccines and therapies against ricin toxin and botulinum toxin, which are regulated SA toxins that utilize structure-based approaches for countermeasures to guide rapid response to future biothreats.

The presence of antinuclear antibodies (ANAs) is a hallmark of a number of systemic autoimmune rheumatic diseases, and testing is usually performed as part of the initial diagnostic workup when suspicion of an underlying autoimmune disorder is high. The indirect immunofluorescence antibody (IFA) technique is the preferred method for detecting ANAs, as it demonstrates binding to specific intracellular structures within the cells, resulting in a number of staining patterns that are usually categorized based on the cellular components recognized and the degree of binding, as reflected by the fluorescence intensity or titer. As a screening tool, the ANA patterns can guide confirmatory testing useful in elucidating a specific clinical diagnosis or prognosis. However, routine use of ANA IFA testing as a global screening test is hampered by its labor-intensiveness, subjectivity, and limited diagnostic specificity, among other factors. This review focuses on current efforts to standardize the nomenclature of ANA patterns and on alternative methods for ANA determination, as well as on recent advances in image-based computer algorithms to automate IFA testing in clinical laboratories.

A vaccine against congenital human cytomegalovirus (CMV) infection is a major public health priority. Congenital CMV causes substantial long-term morbidity, particularly sensorineural hearing loss (SNHL), in newborns, and the public health impact of this infection on maternal and child health is underrecognized. Although progress toward development of a vaccine has been limited by an incomplete understanding of the correlates of protective immunity for the fetus, knowledge about some of the key components of the maternal immune response necessary for preventing transplacental transmission is accumulating. Moreover, although there have been concerns raised about observations indicating that maternal seropositivity does not fully prevent recurrent maternal CMV infections during pregnancy, it is becoming increasing clear that preconception immunity does confer some measure of protection against both CMV transmission and CMV disease (if transmission occurs) in the newborn infant. Although the immunity to CMV conferred by both infection and vaccination is imperfect, there are encouraging data emerging from clinical trials demonstrating the immunogenicity and potential efficacy of candidate CMV vaccines. In the face of the knowledge that between 20,000 and 30,000 infants are born with congenital CMV in the United States every year, there is an urgent and compelling need to accelerate the pace of vaccine trials. In this minireview, we summarize the status of CMV vaccines in clinical trials and provide a perspective on what would be required for a CMV immunization program to become incorporated into clinical practice.

Current pneumococcal vaccines cover the 10 to 23 most common serotypes of the 92 presently described. However, with the increased usage of pneumococcal-serotype-based vaccines, the risk of serotype replacement and an increase in disease caused by nonvaccine serotypes remains. Serotype surveillance of pneumococcal infections relies heavily on culture techniques, which are known to be insensitive, particularly in cases of noninvasive disease. Pneumococcal-serotype-specific urine assays offer an alternative method of serotyping for both invasive and noninvasive disease. However, the assays described previously cover mainly conjugate vaccine serotypes, give little information about circulating nonvaccine serotypes, and are currently available only in one or two specialist laboratories. Our laboratory has developed a Luminex-based extended-range antigen capture assay to detect pneumococcal-serotype-specific antigens in urine samples. The assay targets 24 distinct serotypes/serogroups plus the cell wall polysaccharide (CWP) and some cross-reactive serotypes. We report that the assay is capable of detecting all the targeted serotypes and the CWP at 0.1 ng/ml, while some serotypes are detected at concentrations as low as 0.3 pg/ml. The analytical serotype specificity was determined to be 98.4% using a panel of polysaccharide-negative urine specimens spiked with nonpneumococcal bacterial antigens. We also report clinical sensitivities of 96.2% and specificities of 89.9% established using a panel of urine specimens from patients diagnosed with community-acquired pneumonia or pneumococcal disease. This assay can be extended for testing other clinical samples and has the potential to greatly improve serotype-specific surveillance in the many cases of pneumococcal disease in which a culture is never obtained.

Neutralizing antibodies specific for respiratory syncytial virus (RSV) represent a major protective mechanism against RSV infection, as demonstrated by the efficacy of the immune-prophylactic monoclonal antibody palivizumab in preventing RSV-associated lower respiratory tract infections in premature infants. Accordingly, the RSV neutralization assay has become a key functional method to assess the neutralizing activity of serum antibodies in preclinical animal models, epidemiology studies, and clinical trials. In this study, we qualified a 24-h, fluorescent focus-based microneutralization (RSVA FFA-MN) method that requires no medium exchange or pre- or postinfection processing to detect green fluorescent protein-expressing RSV strain A2 (RSVA-GFP)-infected cells, using a high-content imaging system for automated image acquisition and focus enumeration. The RSVA FFA-MN method was shown to be sensitive, with a limit of detection (LOD) and limit of quantitation (LOQ) of 1:10, or 3.32 log₂; linear over a range of 4.27 to 9.65 log₂ 50% inhibitory concentration (IC₅₀); and precise, with intra- and interassay coefficients of variation of <21%. This precision allowed the choice of a statistically justified 3-fold-rise seroresponse cutoff criterion. The repeatability and robustness of this method were demonstrated by including a pooled human serum sample in every assay as a positive control (PC). Over 3 years of testing between two laboratories, this PC generated data falling within 2.5 standard deviations of the mean 98.7% of the time (n = 1,720). This high-throughput and reliable RSV microneutralization assay has proven useful for testing sera from preclinical vaccine candidate evaluation studies, epidemiology studies, and both pediatric and adult vaccine clinical trials.

The global burden of disease caused by extraintestinal pathogenic Escherichia coli (ExPEC) is increasing as the prevalence of multidrug-resistant strains rises. A multivalent ExPEC O-antigen bioconjugate vaccine could have a substantial impact in preventing bacteremia and urinary tract infections. Development of an ExPEC vaccine requires a readout to assess the functionality of antibodies. We developed an opsonophagocytic killing assay (OPA) for four ExPEC serotypes (serotypes O1A, O2, O6A, and O25B) based on methods established for pneumococcal conjugate vaccines. The performance of the assay was assessed with human serum by computing the precision, linearity, trueness, total error, working range, and specificity. Serotypes O1A and O6A met the acceptance criteria for precision (coefficient of variation for repeatability and intermediate precision, ≤50%), linearity (90% confidence interval of the slope of each strain, 0.80, 1.25), trueness (relative bias range, –30% to 30%), and total error (total error range, –65% to 183%) at five serum concentrations and serotypes O2 and O25B met the acceptance criteria at four concentrations (the lowest concentration for serotypes O2 and O25B did not meet the system suitability test of maximum killing of ≥85% of E. coli cells). All serotypes met the acceptance criteria for specificity (opsonization index value reductions of ≤20% for heterologous serum preadsorption and ≥70% for homologous serum preadsorption). The assay working range was defined on the basis of the lowest and highest concentrations at which the assay jointly fulfilled the target acceptance criteria for linearity, precision, and accuracy. An OPA suitable for multiple E. coli serotypes has been developed, qualified, and used to assess the immunogenicity of a 4-valent E. coli bioconjugate vaccine (ExPEC4V) administered to humans.

In the article "Neurologic syndromes related to anti-GAD65: Clinical and serologic response to treatment" by Muñoz-Lopetegi et al.,¹ published online March 2, 2020, the y-axis label for figure 5’s right graph should be "CSF anti-GAD65 concentration (IU/mL)." The editorial office regrets the error.

Objective

To assess possible adverse effects on breastfed infants of mothers receiving monoclonal antibodies (MAbs) during pregnancy and/or lactation.

Objective

To determine whether serum neurofilament light chain (sNfL) levels are associated with recent MRI activity in patients with relapsing-remitting MS (RRMS).

Most British railway embankments were constructed between 120 and 180 years ago without the benefit of modern design and construction methods. This can result in undesirable load-deformation characteristics and consequent disruption to present-day railway operations, for which there is unprecedented demand. Annual rail passenger kilometres have approximately doubled in the last 20 years and freight has increased by 60% over the same period. Whereas elements such as rails or bridges can be refurbished or replaced to meet increasing demand, the same is not usually feasible for embankments. Development of techniques to assess embankment performance risks posed by operational capacity enhancements is therefore of increasing significance to railway geotechnical asset management. The two case studies presented in this paper demonstrate how geospatial analysis and data management techniques may be applied to this challenge at both strategic (regional or national) and tactical (site-specific) scales for embankments incorporating plastic clay fill. The case studies also demonstrate, in a world of ever more abundant data, the growing need for engineering geologists and geotechnical engineers to augment their traditional knowledge with comprehensive data management and geospatial analysis skills, these being essential for modern infrastructure asset management.

Thematic collection: This article is part of the ‘Ground-related risk to transportation infrastructure’ collection available at: https://www.lyellcollection.org/cc/Ground-related-risk-to-transportation-infrastructure

Strategic geotechnical asset management considers the whole of an organization's earthworks portfolio and is concerned with setting an overall earthworks asset management policy with long-term objectives related to asset performance, safety and condition, and identifying how those objectives can best be met, now and into the future. A risk-based approach is adopted that requires an understanding of the likelihood that any of the earthworks may fail, combined with a knowledge of the consequences should they fail. Procedures are required to identify those earthworks that are most vulnerable to failure under the influence of triggering events, such as extreme weather. The risks are managed through a mix of interventions to reduce the likelihood of failure and mitigations to reduce the impact of failure. Many of the challenges of implementing a strategic earthworks policy have, or are, being met by the main UK transportation infrastructure organizations.

Thematic collection: This article is part of the Ground-related risk to transportation infrastructure collection available at https://www.lyellcollection.org/cc/Ground-related-risk-to-transportation-infrastructure

This case study aims to identify the cubic capacity and geometry of the geological body of silt–organic sediments in the environment of a former gravel pit situated in a drainless depression of the alluvium of the Čierna voda River. It is located in the well-known geotourism locality of Slnečné Jazera in Senec, in the SW of Slovakia. To identify the body, electrical resistivity tomography was combined with the use of sonar. The research shows that this approach is appropriate for a number of activities that are subjects of engineering-geological investigations. The cubic capacity and geometry of specific aqueous engineering-geological environments must be determined in connection with the need for the management, control, quantification and extraction of selected sedimentary bodies. In addition, the management of sustainable development of reservoirs, sedimentation basins, industrial ponds, settling pits and natural pools for recreation (the subject of the case study) is important to control the limit amounts of sediments in such environments. The results of this study may be applied in analogous engineering-geological conditions. The drainless depression Slnečné Jazera contained a body of silt–organic sediments amounting to 23 000 m³ (41 Olympic-size pools of 25 m x 12.5 m x 1.8 m). The maximum thickness of the bottom sediments was about 6.3 m on the alluvium with an articulated morphology owing to the submerged digging of gravel. The proposed approach improved the control of extraction of the sedimentary body and optimized the engineering-geological conditions in this geotourism locality.

In this paper, a decision tree is presented, constructed on the basis of hydrogeological characteristics (water table depth, freshwater thickness, surface area required and distance between wells), to choose the optimal groundwater extraction method in the case of a coastal unconfined aquifer. A comparison is made of the groundwater extraction methods in a freshwater aquifer of limited thickness occurring in coastal dunes in the eastern region of the Province of Buenos Aires (Argentina). The negative effects brought about by the wrong use of the groundwater extraction methods are analysed, because, as a result of excessive extraction, such methods lead to the dramatic decrease of the freshwater reserves. The decision tree is a useful tool to assist decision-makers as it suggests the most suitable groundwater extraction method options (vertical wells or wellpoints), as well as identifying areas that are unsuitable for sustainable groundwater extraction.

Screening for Chlamydia trachomatis and Neisseria gonorrhoeae at the pharyngeal, urogenital, and anorectal sites is recommended for men who have sex with men (MSM). Combining the three individual-site samples into a single pooled sample could result in significant cost savings, provided there is no significant sensitivity reduction. The aim of this study was to examine the sensitivity of pooled samples for detecting chlamydia and gonorrhea in asymptomatic MSM using a nucleic acid amplification test. Asymptomatic MSM who tested positive for chlamydia or gonorrhoea were invited to participate. Paired samples were obtained from participants prior to administration of treatment. To form the pooled sample, the anorectal swab was agitated in the urine specimen transport tube and then discarded. The pharyngeal swab and 2 ml of urine sample were then added to the tube. The difference in sensitivity between testing of pooled samples and individual-site testing was calculated against an expanded gold standard, where an individual is considered positive if either pooled-sample or individual-site testing returns a positive result. All samples were tested using the Aptima Combo 2 assay. A total of 162 MSM were enrolled in the study. Sensitivities of pooled-sample testing were 86% (94/109; 95% confidence interval [CI], 79 to 92%]) for chlamydia and 91% (73/80; 95% CI, 83 to 96%) for gonorrhea. The sensitivity reduction was significant for chlamydia (P = 0.02) but not for gonorrhea (P = 0.34). Pooling caused 22 infections (15 chlamydia and 7 gonorrhoea) to be missed, and the majority were single-site infections (19/22). Pooling urogenital and extragenital samples from asymptomatic MSM reduced the sensitivity of detection by approximately 10% for chlamydia but not for gonorrhea.