bluuebunny/crossref_metadata_2025 huggingface dataset:
Reply to Bridgewater (2021), ‘Response to Davies
Authors: Davies G. T. , Finlayson C. M. , Okuno E. , Davidson N. C. , Gardner R. C. , Moomaw W. R. , Pritchard D. E.
Published: September 2021

We reply to the main concerns raised by Bridgewater (2021) in his response to Davies et al. (2021a), ‘Towards a Universal Declaration of the Rights of Wetlands’. We appreciate the contribution of Bridgewater (2021) to this emerging conversation and, although we disagree with some of his assessments and statements, we do not find his points to be incompatible with support for the Declaration of the Rights of Wetlands (ROW). This reply focuses on four areas of concern raised by Bridgewater (2021). First, we describe why a wetlands-specific declaration will add important value to other Rights of Nature declarations. Second, we discuss how the ROW does not detract from, but rather can contribute to and complement, existing conservation and management approaches and mechanisms. Third, we agree on the importance of weaving Indigenous and local knowledge with other knowledges and emphasise that the ROW should not be confused with or misused to undermine the rights of Indigenous peoples and local communities. Finally, we explain how legal rights can and have been granted to non-humans, including elements of Nature, such as wetlands.
Assembly and organization of the N-terminal region of mucin MUC5AC: Indications for structural and functional distinction from MUC5B
Authors: Carpenter Jerome , Wang Yang , Gupta Richa , Li Yuanli , Haridass Prashamsha , Subramani Durai B. , Reidel Boris , Morton Lisa , Ridley Caroline , O’Neal Wanda K. , Buisine Marie-Pierre , Ehre Camille , Thornton David J. , Kesimer Mehmet
Published: September 2021

Significance

Gel-forming mucins, MUC5AC and MUC5B, are the essential components of the protective mucus layer of the lungs. MUC5B is crucial for lung innate defense, and MUC5AC is generally secreted disproportionately in response to cigarette smoke and allergens. MUC5AC’s role in airway defense and chronic airway disease pathogenesis and how this emerges from its macromolecular assembly/gel-making properties are not known. We demonstrate MUC5AC binds significantly more to hydrophobic surfaces and forms stiffer and more viscoelastic layers compared to MUC5B. Also, MUC5AC forms higher-order oligomers in addition to dimers. These observations may generate insight into why/how MUC5AC forms a stagnant, “tethered” mucus layer in muco-obstructive lung diseases and could guide the development of strategies to intervene with more effective therapeutic agents.
“If you follow me, I might (mis)lead you”
Authors: Ariel Yaron , Elishar Malka Vered , Weimann Saks Dana , Avidar Ruth
Published: September 2021

This study investigates the effects of the two leading prime ministerial candidates’ personal Facebook and Twitter
accounts and the effects of exposure to the general social media and web discourse in Hebrew on voters’ agendas during Israel’s
April 2019 election. All the posts that appeared on the contenders’ accounts at a point in time in each of the four pre-election
campaign weeks were analyzed to identify prominent issues. Social media and web content in Hebrew were also analysed over the same
period. The data was compared with 2,217 responses to questionnaires completed on the four dates. The questionnaires also surveyed
voters’ political orientations and the likelihood of their following the candidates’ accounts. The results revealed a significant
correlation between contenders’ and voters’ agendas. However, significant differences were identified in agendas between those
respondents who followed both leading candidates, those who followed a single candidate, and those who followed neither.
Gut-associated cGMP mediates colitis and dysbiosis in a mouse model of an activating mutation in GUCY2C
Authors: Mishra Vishwas , Bose Avipsa , Kiran Shashi , Banerjee Sanghita , Shah Idrees A. , Chaukimath Pooja , Reshi Mudasir M. , Srinivas Swarna , Barman Anaxee , Visweswariah Sandhya S.
Published: September 2021

Activating mutations in receptor guanylyl cyclase C (GC-C), the target of gastrointestinal peptide hormones guanylin and uroguanylin, and bacterial heat-stable enterotoxins cause early-onset diarrhea and chronic inflammatory bowel disease (IBD). GC-C regulates ion and fluid secretion in the gut via cGMP production and activation of cGMP-dependent protein kinase II. We characterize a novel mouse model harboring an activating mutation in Gucy2c equivalent to that seen in an affected Norwegian family. Mutant mice demonstrated elevated intestinal cGMP levels and enhanced fecal water and sodium content. Basal and linaclotide-mediated small intestinal transit was higher in mutant mice, and they were more susceptible to DSS-induced colitis. Fecal microbiome and gene expression analyses of colonic tissue revealed dysbiosis, up-regulation of IFN-stimulated genes, and misregulation of genes associated with human IBD and animal models of colitis. This novel mouse model thus provides molecular insights into the multiple roles of intestinal epithelial cell cGMP, which culminate in dysbiosis and the induction of inflammation in the gut.
The distinct role of the four voltage sensors of the skeletal CaV1.1 channel in voltage-dependent activation
Authors: Savalli Nicoletta , Angelini Marina , Steccanella Federica , Wier Julian , Wu Fenfen , Quinonez Marbella , DiFranco Marino , Neely Alan , Cannon Stephen C. , Olcese Riccardo
Published: September 2021

Initiation of skeletal muscle contraction is triggered by rapid activation of RYR1 channels in response to sarcolemmal depolarization. RYR1 is intracellular and has no voltage-sensing structures, but it is coupled with the voltage-sensing apparatus of CaV1.1 channels to inherit voltage sensitivity. Using an opto-electrophysiological approach, we resolved the excitation-driven molecular events controlling both CaV1.1 and RYR1 activations, reported as fluorescence changes. We discovered that each of the four human CaV1.1 voltage-sensing domains (VSDs) exhibits unique biophysical properties: VSD-I time-dependent properties were similar to ionic current activation kinetics, suggesting a critical role of this voltage sensor in CaV1.1 activation; VSD-II, VSD-III, and VSD-IV displayed faster activation, compatible with kinetics of sarcoplasmic reticulum Ca2+ release. The prominent role of VSD-I in governing CaV1.1 activation was also confirmed using a naturally occurring, charge-neutralizing mutation in VSD-I (R174W). This mutation abolished CaV1.1 current at physiological membrane potentials by impairing VSD-I activation without affecting the other VSDs. Using a structurally relevant allosteric model of CaV activation, which accounted for both time- and voltage-dependent properties of CaV1.1, to predict VSD-pore coupling energies, we found that VSD-I contributed the most energy (~75 meV or ∼3 kT) toward the stabilization of the open states of the channel, with smaller (VSD-IV) or negligible (VSDs II and III) energetic contribution from the other voltage sensors (<25 meV or ∼1 kT). This study settles the longstanding question of how CaV1.1, a slowly activating channel, can trigger RYR1 rapid activation, and reveals a new mechanism for voltage-dependent activation in ion channels, whereby pore opening of human CaV1.1 channels is primarily driven by the activation of one voltage sensor, a mechanism distinct from that of all other voltage-gated channels.
A CMOS-based neuromorphic device for seizure detection from LFP signals
Authors: Ronchini Margherita , Zamani Milad , Huynh Hai Au , Rezaeiyan Yasser , Panuccio Gabriella , Farkhani Hooman , Moradi Farshad
Published: September 2021

Recent research provides examples of neuromorphic systems applied to process biological signals or to interface biological tissues. Usually, in such contexts, the neuromorphic system is used for automatic anomaly detection. The automation of the long-term monitoring of biological signals holds promise for lightening the burden placed on clinicians. At the same time, the adoption of such devices potentially allows processing to be performed locally, without the need to transfer data to an external processor. In turn, on-site signal analysis makes closed-loop intervention feasible, to correct the source of the anomalies. So far, the common approach has been to deploy the network of spiking neurons either on multi-core neuromorphic platforms or on programmable units (field programmable gate array). However, if the aim is to develop wearable or even chronically implantable devices, it is imperative to move in the direction of embedded solutions, tailored and optimized for the specific application. To this end, the present study proposes a neuromorphic device implemented in CMOS technology for the detection of epileptic seizures (ictal events) from local field potential (LFP) signals. The LFP data have been acquired by a multi-electrode array in a slice of mouse hippocampus-cortex. The system includes an analog-to-event converter (AEC) encoding the recorded signals into trains of spikes, and a small spiking neural network (SNN) of 2 × 1 neurons with online biological-plausible learning. The AEC yields two spike-trains: UP spikes that account for the positive slope signal and DOWN spikes that correspond to the negative slope signal. The synapses among the input and output layers are plastic and follow the spike-timing-dependent plasticity rule. Early results show that the SNN module is able to detect ictal events with a delay of 64.98 ± 30.92 ms, consuming

<

50 pW. The layout of the entire system occupies 528 µm × 278 µm.
Noise generation in a bilayer ferromagnet-piezoelectric heterostructure at the converse magnetoelectric effect
Authors: Burdin Dmitry A , Ekonomov Nikolai A , Preobrazhenskii Vladimir L , Fetisov Yuri K
Published: September 2021

The paper describes first observation of parametric generation of noise in a composite multiferroic resonator. Resonator of a disk shape contains two mechanically coupled layers, one of which is the amorphous ferromagnet (FM) FeBSiC and the other is the piezoelectric (PE) lead zirconate titanate. DC magnetic field of 0–100 Oe is applied parallel to the plane of the resonator. Resonator is excited in the frequency range f = 2–10 kHz by a harmonic electric field with amplitude of up to 330 V cm−1 applied to the PE layer. Changes in the magnetization of the resonator caused by the converse magnetoelectric effect were recorded using an electromagnetic coil. With an increase in the excitation field to the threshold value, the parametric generation of harmonics and subharmonics with a discrete spectrum is observed, which then turns into a stochastic mode and a continuous spectrum of frequencies is generated. Noise density is hysterically dependent on the excitation field and non-monotonically depends on the dc magnetic field. Theory of parametric generation of the noise in a multiferroic resonator is developed, taking into account excitation of acoustic resonances and magnetoacoustic nonlinearity of the FM layer of the resonator. Theory, qualitatively describes the main characteristics of noise generation.
Medical consequences of radiation exposure of the bronchi—what can we learn from high-dose precision radiation therapy?
Authors: Lindberg Karin , Onjukka Eva
Published: September 2021

The bronchial tolerance to high doses of radiation is not fully understood. However, in the event of a radiological accident with unintended exposure of the central airways to high doses of radiation it would be important to be able to anticipate the clinical consequences given the magnitude of the absorbed dose to different parts of the bronchial tree. Stereotactic body radiation therapy (SBRT) is a radiation treatment technique involving a few large fractions of photon external-beam radiation delivered to a well-defined target in the body. Despite generally favourable results, with high local tumour control and low-toxicity profile, its utility for tumours located close to central thoracic structures has been questioned, considering reports of severe toxic symptoms such as haemoptysis (bleedings from the airways), bronchial necrosis, bronchial stenosis, fistulas and pneumonitis. In conjunction with patient- and tumour-related risk factors, recent studies have analysed the absorbed radiation dose to different thoracic structures of normal tissue to better understand their tolerance to these high doses per fraction. Although the specific mechanisms behind the toxicity are still partly unknown, dose to the proximal bronchial tree has been shown to correlate with high-grade radiation side effects. Still, there is no clear consensus on the tolerance dose of the different bronchial structures. Recent data indicate that a too high dose to a main bronchus may result in more severe clinical side effects as compared to a smaller sized bronchus. This review analyses the current knowledge on the clinical consequences of bronchial exposure to high dose hypofractionated radiation delivered with the SBRT technique, and the tolerance doses of the bronchi. It presents the current literature regarding types of high-grade clinical side effects, data on dose response and comments on other risk factors for high-grade toxic effects.
Decommissioning procedure and induced activation levels, calculations and measurements in an 18 MeV medical cyclotron
Authors: Calandrino Riccardo , Manenti Simone , Groppi Flavia , Broggi Francesco , Bergamaschi Carlo , Ferrari Andrea , Manenti Simona , Nizzi Massimiliano , Loria Alessandro , del Vecchio Antonella
Published: September 2021

The present article describes the decommissioning of a self-shielded 18 MeV medical cyclotron IBA Cyclone 18/9 after 14 years of operation. A Monte Carlo simulation of the possible nuclear reactions was performed in order to plan the decommissioning activities. During the cyclotron dismantling, the activities of the cyclotron components, concrete wall and floor samples were measured. Residual activities were analysed by means of an HPGe detector and liquid scintillation counting, and compared with simulation data. Dosimetry of the staff involved in the decommissioning procedure was monitored by individual TL dosimeters and/or digital dosimeter. The cyclotron component analysis confirmed the presence of gamma and pure beta emitters, 22Na, 54Mn, 60Co, 65Zn, 207Bi, 55Fe, 63Ni at different values of specific activity, depending on the positioning of the sample point and on the alloy of the sampled part. In these components the presence of gamma and pure beta emitters was measured 5 years after the shutdown at levels far above clearance limits as defined by the ‘Recommended radiological protection criteria for the recycling of metals from the dismantling of nuclear installations’ (RP89) guidelines. The simulation, carried out by FLUKA Code (version 2020.0.5) on the cyclotron components, provided good agreement with measurements, with a maximum discrepancy of the same order as the uncertainties. Four engineers of the cyclotron maintenance staff were involved in the dismounting of the hottest components and rigging of the cyclotron in the deposit 6 months after shutdown and two engineers were involved during the drilling phase 3.5 years after shutdown. The measured dose from external exposure of the involved staff was lower than 100 μSv person−1 during the first phase and lower than 20 μSv person−1 during the final drilling phase. Measured doses from intake were negligible. In conclusion, the decommissioning of the 18 MeV cyclotron does not represent a risk for the involved staff, but, due to the presence of long-lived radioisotopes, the cyclotron components are to be treated as low level radioactive waste, and stored in an authorised storage area for at least 25 years after shutdown.
Religion
Authors: Harris James A.
Published: September 2021

‘Religion' discusses Hume’s various treatments of religion, particularly in the essay ‘Of Miracles’, Dialogues concerning Natural Religion, and ‘The Natural History of Religion’. Hume's earlier writings show some interesting implications for religion, including A Treatise of Human Nature and the essay ‘Of National Characters’. Looking at ‘Of Miracles’ shows that Hume’s theme was not the possibility of miracles as such, but rather the rational grounds of belief in reports of miracles. Considering the Dialogues emphasizes the distinction between scepticism and atheism. Meanwhile, ‘Natural History’ emphasizes Hume’s interest in the dangerous moral consequences of monotheism. What is the future for religion? Perhaps Hume was unlikely to have supposed that his writings would do anything to reduce religion’s hold on the vast majority of human beings.
4. Big ideas from the 20th century
Authors: Thomas Gary
Published: September 2021

‘Big ideas from the 20th century’ explores how the changes in the 20th century created the conditions for John Dewey to talk about the relationship of education to democracy. For Dewey, reflective thinking is at the centre of education: education is not about learning facts—it is about being sceptical and critical. Dewey’s thought provided one of the foundation stones for the introduction of the comprehensive schools. In the UK, it is the Plowden Report of the 1960s that is generally credited with the more systematic introduction of progressive ideas. The turn to neoliberalism has had a profound effect on education in terms at segregation in schools and marketization in education.
2. Embryonic stem cells
Authors: Slack Jonathan
Published: September 2021

‘Embryonic stem cells’ focuses on embryonic stem (ES) cells, which are grown in tissue culture from the inner cell mass of a mammalian blastocyst-stage embryo. Human ES cells offer a potential route to making the kinds of cells needed for cell therapy. ES cells were originally prepared from mouse embryos. Although somewhat different, cells grown from inner cell masses of human embryos share many properties with mouse ES cells, such as being able to grow without limit and to generate differentiated cell types. Mouse ES cells have so far been of greater practical importance than those of humans because they have enabled a substantial research industry based on the creation of genetically modified mice.
3. Personalized pluripotent stem cells
Authors: Slack Jonathan
Published: September 2021

‘Personalized pluripotent stem cells’ discusses cloning and its connection to stem cell biology. Somatic cell nuclear transplantation into oocytes can make personalized pluripotent stem cells as a perfect genetic match to a specific patient that provoke no immune rejection on grafting. Because this procedure involves generation of cells but no formation of an actual cloned individual, it has become known as human therapeutic cloning. Induced pluripotent stem cells (iPS cells) are made by introducing a few specific genes into normal cells. They are also a perfect genetic match to the individual donating the normal cells and because they are easy to make are now the preferred source.
Prevalence of malnutrition risk among older French adults with culinary dependence
Authors: Van Wymelbeke-Delannoy Virginie , Maître Isabelle , Salle Agnès , Lesourd Bruno , Bailly Nathalie , Sulmont-Rossé Claire
Published: September 2021

Objective

The term ‘culinary dependence’ denotes a situation in which someone delegates all or part of their daily meal-related activities to a third party. The present study aimed to explore nutritional risk among older people (≥65 years) with culinary dependence.

Method

The first survey included 559 people either living at home without help, with help unrelated to food activities, with help related to food activities or living in nursing home. The second survey included 319 people with food help provided by a caregiver, by meals-on-wheels or by a nursing home. Nutritional status was assessed with the Mini-Nutritional Assessment. Sociological background and wellness variables (health, cognitive and mental status) were collected.

Results

The first survey found a strong association between culinary dependence and nutritional risk. About half of the people who delegated their food-related activities were malnourished or at risk of malnutrition compared with only 4% for people with no help and 12% for people with help unrelated to food activity. According to the second survey, this prevalence varied slightly depending on who the tasks were delegated to (46% for those who had the support of a caregiver; 60% for those who used a meals-on-wheels service; 69% for those living in nursing home). According to multivariate analyses, dependence categories, depressive symptoms and cognitive status were identified as independent determinants of malnutrition.

Conclusion

Without inferring a causal relationship between dependence and malnutrition, there is a strong need for care structures to take into account the issue of malnutrition when developing services targeting older people.
Genome-wide analysis identifies impaired axonogenesis in chronic overlapping pain conditions
Authors: Khoury Samar , Parisien Marc , Thompson Scott J , Vachon-Presseau Etienne , Roy Mathieu , Martinsen Amy E , Winsvold Bendik S ,   HUNT All-In Pain, Skogholt Anne Heidi , Brumpton Ben , Willer Cristen J , Fors Egil Andreas , Heuch Ingrid , Nielsen Jonas Bille , Storheim Kjersti , Hagen Knut , Nilsen Kristian Bernhard , Hveem Kristian , Fritsche Lars , Thomas Laurent F , Pedersen Linda M , Gabrielsen Maiken E , Johnsen Marianne Bakke , Lie Marie Udnesseter , Holmen Oddgeir , Børte Sigrid , Stensland Synne Øien , Zhou Wei , Mundal Ingunn P , Zwart John-Anker , Kania Artur , Mogil Jeffrey S , Diatchenko Luda
Published: September 2021

Chronic pain is often present at more than one anatomical location, leading to chronic overlapping pain conditions. Whether chronic overlapping pain conditions represent a distinct pathophysiology from the occurrence of pain at only one site is unknown. Using genome-wide approaches, we compared genetic determinants of chronic single-site versus multisite pain in the UK Biobank. We found that different genetic signals underlie chronic single-site and multisite pain with much stronger genetic contributions for the latter. Among 23 loci associated with multisite pain, nine loci replicated in the HUNT cohort, with the DCC netrin 1 receptor (DCC) as the top gene. Functional genomics identified axonogenesis in brain tissues as the major contributing pathway to chronic multisite pain. Finally, multimodal structural brain imaging analysis showed that DCC is most strongly expressed in subcortical limbic regions and is associated with alterations in the uncinate fasciculus microstructure, suggesting that DCC-dependent axonogenesis may contribute to chronic overlapping pain conditions via corticolimbic circuits.
High-throughput imaging of ATG9A distribution as a diagnostic functional assay for adaptor protein complex 4-associated hereditary spastic paraplegia
Authors: Ebrahimi-Fakhari Darius , Alecu Julian E , Brechmann Barbara , Ziegler Marvin , Eberhardt Kathrin , Jumo Hellen , D’Amore Angelica , Habibzadeh Parham , Faghihi Mohammad Ali , De Bleecker Jan L , Vuillaumier-Barrot Sandrine , Auvin Stéphane , Santorelli Filippo M , Neuser Sonja , Popp Bernt , Yang Edward , Barrett Lee , Davies Alexandra K , Saffari Afshin , Hirst Jennifer , Sahin Mustafa
Published: September 2021

Adaptor protein complex 4-associated hereditary spastic paraplegia is caused by biallelic loss-of-function variants in AP4B1, AP4M1, AP4E1 or AP4S1, which constitute the four subunits of this obligate complex. While the diagnosis of adaptor protein complex 4-associated hereditary spastic paraplegia relies on molecular testing, the interpretation of novel missense variants remains challenging. Here, we address this diagnostic gap by using patient-derived fibroblasts to establish a functional assay that measures the subcellular localization of ATG9A, a transmembrane protein that is sorted by adaptor protein complex 4. Using automated high-throughput microscopy, we determine the ratio of the ATG9A fluorescence in the trans-Golgi-network versus cytoplasm and ascertain that this metric meets standards for screening assays (Z′-factor robust >0.3, strictly standardized mean difference >3). The ‘ATG9A ratio’ is increased in fibroblasts of 18 well-characterized adaptor protein complex 4-associated hereditary spastic paraplegia patients [mean: 1.54 ± 0.13 versus 1.21 ± 0.05 (standard deviation) in controls] and receiver-operating characteristic analysis demonstrates robust diagnostic power (area under the curve: 0.85, 95% confidence interval: 0.849–0.852). Using fibroblasts from two individuals with atypical clinical features and novel biallelic missense variants of unknown significance in AP4B1, we show that our assay can reliably detect adaptor protein complex 4 function. Our findings establish the ‘ATG9A ratio’ as a diagnostic marker of adaptor protein complex 4-associated hereditary spastic paraplegia.
PET Metabolic Imaging of Time-Dependent Reorganization of Olfactory Cued Fear Memory Networks in Rats
Authors: Mouly Anne-Marie , Bouillot Caroline , Costes Nicolas , Zimmer Luc , Ravel Nadine , Litaudon Philippe
Published: September 2021

Memory consolidation involves reorganization at both the synaptic and system levels. The latter involves gradual reorganization of the brain regions that support memory and has been mostly highlighted using hippocampal-dependent tasks. The standard memory consolidation model posits that the hippocampus becomes gradually less important over time in favor of neocortical regions. In contrast, this reorganization of circuits in amygdala-dependent tasks has been less investigated. Moreover, this question has been addressed using primarily lesion or cellular imaging approaches thus precluding the comparison of recent and remote memory networks in the same animals. To overcome this limitation, we used microPET imaging to characterize, in the same animals, the networks activated during the recall of a recent versus remote memory in an olfactory cued fear conditioning paradigm. The data highlighted the drastic difference between the extents of the two networks. Indeed, although the recall of a recent odor fear memory activates a large network of structures spanning from the prefrontal cortex to the cerebellum, significant activations during remote memory retrieval are limited to the piriform cortex. These results strongly support the view that amygdala-dependent memories also undergo system-level reorganization, and that sensory cortical areas might participate in the long-term storage of emotional memories.
Statistical Learning of Frequent Distractor Locations in Visual Search Involves Regional Signal Suppression in Early Visual Cortex
Authors: Zhang Bei , Weidner Ralph , Allenmark Fredrik , Bertleff Sabine , Fink Gereon R , Shi Zhuanghua , Müller Hermann J
Published: September 2021

Observers can learn locations where salient distractors appear frequently to reduce potential interference—an effect attributed to better suppression of distractors at frequent locations. But how distractor suppression is implemented in the visual cortex and within the frontoparietal attention networks remains unclear. We used fMRI and a regional distractor-location learning paradigm with two types of distractors defined in either the same (orientation) or a different (color) dimension to the target to investigate this issue. fMRI results showed that BOLD signals in early visual cortex were significantly reduced for distractors (as well as targets) occurring at the frequent versus rare locations, mirroring behavioral patterns. This reduction was more robust with same-dimension distractors. Crucially, behavioral interference was correlated with distractor-evoked visual activity only for same- (but not different-) dimension distractors. Moreover, with different- (but not same-) dimension distractors, a color-processing area within the fusiform gyrus was activated more when a distractor was present in the rare region versus being absent and more with a distractor in the rare versus frequent locations. These results support statistical learning of frequent distractor locations involving regional suppression in early visual cortex and point to differential neural mechanisms of distractor handling with different- versus same-dimension distractors.
A Financial and Global Demand Analysis to Inform Decisions for Funding and Clinical Development of Group BStreptococcusVaccines for Pregnant Women
Authors: Malvolti Stefano , Pecenka Clint , Mantel Carsten F , Malhame Melissa , Lambach Philipp
Published: September 2021

Background

Despite group B Streptococcus (GBS) being a leading cause of maternal and infant morbidity and mortality, no vaccine is currently available. To inform vaccine developers, countries, and funders, we analyzed the key factors likely to influence the demand for a GBS vaccine and the long-term financial sustainability for a vaccine developer.

Methods

Using population-based forecasting, we estimated the demand for a GBS vaccine; using a discounted cash flow model we estimated the financial viability for a vaccine developer.

Results

Demand for this vaccine can be significant if countries adopt policy recommendations for use, in particular, the largest ones, most of which have a burden that justifies use of the vaccine, and if financing for the vaccine is made available either by countries or by funding mechanisms such as Gavi, the Vaccine Alliance.

Conclusions

This analysis suggests the potential for financial and commercial viability for a vaccine developer pursuing the commercialization of a GBS vaccine. Risks exists in relation to the clinical trial design and costs, the level of competition, countries’ ability to pay, the administration schedule, and the availability of policies that encourage use of the vaccine. To reduce those risks and ensure equitable access to a GBS vaccine, the role of donors or financers can prove very important, as can a coordinated operational research agenda that aims at clarifying those areas of uncertainty.
Safety and Immunogenicity of a Recombinant Adenovirus Type-5–Vectored Coronavirus Disease 2019 (COVID-19) Vaccine With a Homologous Prime-Boost Regimen in Healthy Participants Aged ≥6 Years: A Randomized, Double-Blind, Placebo-Controlled, Phase 2b Trial
Authors: Zhu Fengcai , Jin Pengfei , Zhu Tao , Wang Wenjuan , Ye Huayue , Pan Hongxing , Hou Lihua , Li Jingxin , Wang Xue , Wu Shipo , Wang Ying , Gou Jinbo , Huang Haitao , Wu Hongbin , Wang Xuewen , Chen Wei
Published: September 2021

Background

We assessed the safety and immunogenicity of a recombinant adenovirus type-5 (Ad5)–vectored coronavirus disease 2019 (COVID-19) vaccine with homologous prime-boost regimens in healthy participants aged ≥6 years.

Methods

In this randomized, double-blind, placebo-controlled trial, participants received vaccine or placebo 56 days apart. Enzyme-linked immunosorbent assay (ELISA) antibodies to the receptor binding domain (RBD) and pseudovirus neutralizing antibodies were detected. Adverse events were monitored for 28 days following each vaccination.

Results

A total of 430 participants were enrolled in the study, with 30 participants aged 18–55 years (MID cohort), 250 aged ≥56 years (OLD cohort), and 150 aged 6–17 years (MIN cohort). Ad5-vectored COVID-19 vaccine induced significant RBD-specific ELISA antibodies that decreased with increasing age, with geometric mean titers (GMTs) of 1037.5 in the MIN cohort, 647.2 in the MID cohort, and 338.0 in the OLD cohort receiving 5 × 1010 viral particles on day 28 following boost vaccination. Pseudovirus neutralizing antibodies showed a similar pattern, with GMTs of 168.0 in the MIN cohort, 76.8 in the MID cohort, and 79.7 in the OLD cohort. A single dose in children and adolescents induced higher antibody responses than that elicited by 2 doses in adults, with GMTs of 1091.6 and 96.6 for ELISA antibody and neutralizing antibody, respectively. Homologous prime-boost vaccination was safe and tolerable.

Conclusions

Ad5-vectored COVID-19 vaccine with a single dose was safe and induced robust immune responses in children and adolescents aged 6–17 years. A prime-boost regimen needs further exploration for Ad5-vectored COVID-19 vaccine.

Ad5-vectored COVID-19 vaccine with a single dose was safe and tolerated, and induced robust immune responses in children and adolescents aged 6-17 years. The boosting effect on immune responses of the homologous prime-boost regime given 56 days apart was limited.

Clinical Trials Registration

NCT04566770.
Creative strategies for spatial policy making in Brazilian ‘new left regionalism’: fighting inequalities and COVID-19 in the north-east region
Authors: Siqueira Hipólita , Brandão Carlos
Published: September 2021

The literature on the new regionalism has highlighted the leading role played by regions in the contemporary process of state rescaling and the governance of policy-making. We argue that a (re)politicisation of North-east Brazil and the emergence of a new left regionalism are underway. We examine the political and socioeconomic circumstances of this process through the creation of the Interstate Consortium for the Sustainable Development of the North-east. We conclude that while many challenges still lie ahead, this experience has demonstrated potential for the coherence of policies, and for constituting new political actors and arenas for the concertation of interests.
Recent Advances in Rapid Antimicrobial Susceptibility Testing
Authors: Datar Rucha , Orenga Sylvain , Pogorelcnik Romain , Rochas Olivier , Simner Patricia J , van Belkum Alex
Published: September 2021

Background

Antimicrobial susceptibility testing (AST) is classically performed using growth-based techniques that essentially require viable bacterial matter to become visible to the naked eye or a sophisticated densitometer.

Content

Technologies based on the measurement of bacterial density in suspension have evolved marginally in accuracy and rapidity over the 20th century, but assays expanded for new combinations of bacteria and antimicrobials have been automated, and made amenable to high-throughput turn-around. Over the past 25 years, elevated AST rapidity has been provided by nucleic acid-mediated amplification technologies, proteomic and other “omic” methodologies, and the use of next-generation sequencing. In rare cases, AST at the level of single-cell visualization was developed. This has not yet led to major changes in routine high-throughput clinical microbiological detection of antimicrobial resistance.

We here present a review of the new generation of methods and describe what is still urgently needed for their implementation in day-to-day management of the treatment of infectious diseases.
Loss-of-function mutations in cardiac ryanodine receptor channel cause various types of arrhythmias including long QT syndrome
Authors: Hirose Sayako , Murayama Takashi , Tetsuo Naoyuki , Hoshiai Minako , Kise Hiroaki , Yoshinaga Masao , Aoki Hisaaki , Fukuyama Megumi , Wuriyanghai Yimin , Wada Yuko , Kato Koichi , Makiyama Takeru , Kimura Takeshi , Sakurai Takashi , Horie Minoru , Kurebayashi Nagomi , Ohno Seiko
Published: September 2021

Aims

Gain-of-function mutations in RYR2, encoding the cardiac ryanodine receptor channel (RyR2), cause catecholaminergic polymorphic ventricular tachycardia (CPVT). Whereas, genotype–phenotype correlations of loss-of-function mutations remains unknown, due to a small number of analysed mutations. In this study, we aimed to investigate their genotype–phenotype correlations in patients with loss-of-function RYR2 mutations.

Methods and results

We performed targeted gene sequencing for 710 probands younger than 16-year-old with inherited primary arrhythmia syndromes (IPAS). RYR2 mutations were identified in 63 probands, and 3 probands displayed clinical features different from CPVT. A proband with p.E4146D developed ventricular fibrillation (VF) and QT prolongation whereas that with p.S4168P showed QT prolongation and bradycardia. Another proband with p.S4938F showed short-coupled variant of torsade de pointes (scTdP). To evaluate the functional alterations in these three mutant RyR2s and p.K4594Q previously reported in a long QT syndrome (LQTS), we measured Ca2+ signals in HEK293 cells and HL-1 cardiomyocytes as well as Ca2+-dependent [3H]ryanodine binding. All mutant RyR2s demonstrated a reduced Ca2+ release, an increased endoplasmic reticulum Ca2+, and a reduced [3H]ryanodine binding, indicating loss-of-functions. In HL-1 cells, the exogenous expression of S4168P and K4594Q reduced amplitude of Ca2+ transients without inducing Ca2+ waves, whereas that of E4146D and S4938F evoked frequent localized Ca2+ waves.

Conclusion

Loss-of-function RYR2 mutations may be implicated in various types of arrhythmias including LQTS, VF, and scTdP, depending on alteration of the channel activity. Search of RYR2 mutations in IPAS patients clinically different from CPVT will be a useful strategy to effectively discover loss-of-function RYR2 mutations.
Cardiometabolic multimorbidity and activity limitation: a cross-sectional study of adults using the Canadian Longitudinal Study on Aging data
Authors: Fishbook Brayden N , Brinton Christopher D , Siever Jodi , Klassen Tara D , Sakakibara Brodie M
Published: September 2021

Background

Cardiometabolic multimorbidity (CM) is the diagnosis of 2 or more cardiometabolic conditions. Multimorbidity and individual cardiometabolic conditions have been associated with activity limitation, a common form of disability, but few studies have investigated the association between CM and activity limitation.

Objectives

To estimate the prevalence of activity limitation among Canadians with CM and to quantify the association between CM and activity limitation.

Methods

Using data from the Canadian Longitudinal Study on Aging, we conducted a cross-sectional analysis of activity limitation among Canadians aged 45–85 (n = 50,777; weighted n = 13,118,474). CM was defined as the diagnosis of 2 or more of diabetes/prediabetes, myocardial infarction, and stroke, and activity limitation was evaluated using the Older Americans Resources and Services scale. Descriptive statistics and logistic and multinomial logistic regression analyses were conducted to determine the association between CM and activity limitation.

Results

The estimated prevalence of activity limitation among participants living with CM was 27.4% compared with 7.5% with no cardiometabolic conditions. Activity limitation increased in prevalence and severity with the number of cardiometabolic conditions. People with CM had increased odds of activity limitation compared with those without any cardiometabolic conditions (adjusted relative risk ratio = 3.99, 95% confidence interval [3.35–4.75]), and the odds increased with each additional condition. Stroke survivors had greater odds of activity limitation than those without a history of stroke and the same number of cardiometabolic conditions.

Conclusion

Activity limitation is common among Canadians living with CM. Odds of activity limitation increase with each additional cardiometabolic condition, especially for stroke survivors.
Sexual risk behaviour reduction interventions in primary care in Organization of Economic Cooperation and Development countries. A systematic review
Authors: Onaisi Racha , Joseph Jean-Philippe , Castera Philippe , Pontgratz Camille
Published: September 2021

Background

Sexually transmitted infections are a major public health issue, both in France and worldwide. Primary healthcare professionals play a key role in sexual health and prevention, but few take on this subject. Prevention strategies are diverse, thus risk reduction strategies focussing on behavioural changes are still needed.

Purpose

We conducted a systematic review to analyse risk reduction interventions focussing on behavioural change in OECD countries in primary healthcare settings to help develop a prevention tool easy to apply in primary care.

Methods

We searched for English- or French-language controlled trials in PubMed, Cochrane Library, Scopus, PsycINFO, PsycArticle, PBSC, SocINDEX, Google Scholar, and CAIRN, supplemented with the bibliographies of previous systematic reviews. Thirty controlled, randomized, or nonrandomized trials were included in the systematic review. We did not conduct any meta-analysis due to the diversity of populations, outcomes and study designs.

Results

There are efficient interventions in primary healthcare settings for reducing sexual risk behaviours and/or incident STI. Their efficiency seems to grow with the length and intensity of the intervention. Most interventions target only young, high-risk patients, and their long-term impact is uncertain. Most included studies had an overall risk of bias estimated as high or with some concerns.

Conclusions

Some tools could be used in primary care, with possible efficiency though results are difficult to generalize, and value should be assessed in daily practice. Future research should also focus on older population given the epidemiological evolutions, but also lower-risk population to target all patients seen in primary care settings.
Lithological tomography with the correlated pseudo-marginal method
Authors: Friedli L , Linde N , Ginsbourger D , Doucet A
Published: September 2021

We consider lithological tomography in which the posterior distribution of (hydro)geological parameters of interest is inferred from geophysical data by treating the intermediate geophysical properties as latent variables. In such a latent variable model, one needs to estimate the intractable likelihood of the (hydro)geological parameters given the geophysical data. The pseudo-marginal (PM) method is an adaptation of the Metropolis–Hastings algorithm in which an unbiased approximation of this likelihood is obtained by Monte Carlo averaging over samples from, in this setting, the noisy petrophysical relationship linking (hydro)geological and geophysical properties. To make the method practical in data-rich geophysical settings with low noise levels, we demonstrate that the Monte Carlo sampling must rely on importance sampling distributions that well approximate the posterior distribution of petrophysical scatter around the sampled (hydro)geological parameter field. To achieve a suitable acceptance rate, we rely both on (1) the correlated PM (CPM) method, which correlates the samples used in the proposed and current states of the Markov chain and (2) a model proposal scheme that preserves the prior distribution. As a synthetic test example, we infer porosity fields using crosshole ground-penetrating radar (GPR) first-arrival traveltimes. We use a (50 × 50)-dimensional pixel-based parametrization of the multi-Gaussian porosity field with known statistical parameters, resulting in a parameter space of high dimension. We demonstrate that the CPM method with our proposed importance sampling and prior-preserving proposal scheme outperforms current state-of-the-art methods in both linear and non-linear settings by greatly enhancing the posterior exploration.
Using deep generative neural networks to account for model errors in Markov chain Monte Carlo inversion
Authors: Levy Shiran , Hunziker Jürg , Laloy Eric , Irving James , Linde Niklas
Published: September 2021

Most geophysical inverse problems are non-linear and rely upon numerical forward solvers involving discretization and simplified representations of the underlying physics. As a result, forward modelling errors are inevitable. In practice, such model errors tend to be either completely ignored, which leads to biased and over-confident inversion results, or only partly taken into account using restrictive Gaussian assumptions. Here, we rely on deep generative neural networks to learn problem-specific low-dimensional probabilistic representations of the discrepancy between high-fidelity and low-fidelity forward solvers. These representations are then used to probabilistically invert for the model error jointly with the target geophysical property field, using the computationally cheap, low-fidelity forward solver. To this end, we combine a Markov chain Monte Carlo (MCMC) inversion algorithm with a trained convolutional neural network of the spatial generative adversarial network (SGAN) type, whereby at each MCMC step, the simulated low-fidelity forward response is corrected using a proposed model-error realization. Considering the crosshole ground-penetrating radar traveltime tomography inverse problem, we train SGAN networks on traveltime discrepancy images between: (1) curved-ray (high fidelity) and straight-ray (low fidelity) forward solvers; and (2) finite-difference-time-domain (high fidelity) and straight-ray (low fidelity) forward solvers. We demonstrate that the SGAN is able to learn the spatial statistics of the model error and that suitable representations of both the subsurface model and model error can be recovered by MCMC. In comparison with inversion results obtained when model errors are either ignored or approximated by a Gaussian distribution, we find that our method has lower posterior parameter bias and better explains the observed traveltime data. Our method is most advantageous when high-fidelity forward solvers involve heavy computational costs and the Gaussian assumption of model errors is inappropriate. Unstable MCMC convergence due to non-linearities introduced by our method remain a challenge to be addressed in future work.
Non-Gaussian Waves in Šeba’s Billiard
Authors: Kurlberg Pär , Ueberschär Henrik
Published: September 2021

The Šeba billiard, a rectangular torus with a point scatterer, is a popular model to study the transition between integrability and chaos in quantum systems. Whereas such billiards are classically essentially integrable, they may display features such as quantum ergodicity [11], which are usually associated with quantum systems whose classical dynamics is chaotic. Šeba proposed that the eigenfunctions of toral point scatterers should also satisfy Berry’s random wave conjecture, which implies that the value distribution of the eigenfunctions ought to be Gaussian. However, Keating, Marklof, and Winn formulated a conjecture that suggested that Šeba billiards with irrational aspect ratio violate the random wave conjecture, and we show that this is indeed the case. More precisely, for tori having diophantine aspect ratio, we construct a subsequence of the set of new eigenfunctions having even/even symmetry, of essentially full density, and show that its 4th moment is not consistent with a Gaussian value distribution. In fact, given any set $\Lambda $ interlacing with the set of unperturbed eigenvalues, we show non-Gaussian value distribution of the Green’s functions $G_{\lambda }$, for $\lambda $ in an essentially full density subsequence of $\Lambda $.
Deformed Double Current Algebras via Deligne Categories
Authors: Kalinov Daniil
Published: September 2021

In this paper, we give an alternative construction of a certain class of deformed double current algebras. These algebras are deformations of $ U(\textrm {End}(\Bbbk ^r)[x,y]) $ and they were initially defined and studied by N. Guay in his papers. Here, we construct them as algebras of endomorphisms in Deligne category. We do this by taking an ultraproduct of spherical subalgebras of the extended Cherednik algebras of finite rank.