bluuebunny/crossref_metadata_2025 huggingface dataset:
Group phenotypic composition drives task performances in ants
Authors: Martin Rayanne , Leroy Chloé , Maák István , d'Ettorre Patrizia
Published: January 2024

Differences in individual behaviour within a group can give rise to functional dissimilarities between groups, particularly in social animals. However, how individual behavioural phenotypes translate into the group phenotype remains unclear. Here, we investigate whether individual behavioural type affects group performance in a eusocial species, the ant
Aphaenogaster senilis
. We measured individual behavioural traits and created groups of workers with similar behavioural type, either high-exploratory or low-exploratory workers. We tested these groups in four different, ecologically relevant, tasks: reaction to an intruder, prey retrieval from a maze, nest relocation and tool use. We show that, compared to groups of low-exploratory workers, groups of high-exploratory workers were more aggressive towards intruders, more efficient in collecting prey, faster in nest relocation and more likely to perform tool use. Our results demonstrate a strong link between individual and collective behaviour in ants. This supports the ‘behavioural type hypothesis' for group dynamics, which suggests that an individual's behaviour in a social environment reflects its own behavioural type. The average behavioural phenotype of a group can therefore be predicted from the behavioural types of individual group members.
High connectivity and human movement limits the impact of travel time on infectious disease transmission
Authors: John Reju Sam , Miller Joel C. , Muylaert Renata L. , Hayman David T. S.
Published: January 2024

The speed of spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during the coronavirus disease 2019 (COVID-19) pandemic highlights the importance of understanding how infections are transmitted in a highly connected world. Prior to vaccination, changes in human mobility patterns were used as non-pharmaceutical interventions to eliminate or suppress viral transmission. The rapid spread of respiratory viruses, various intervention approaches, and the global dissemination of SARS-CoV-2 underscore the necessity for epidemiological models that incorporate mobility to comprehend the spread of the virus. Here, we introduce a metapopulation susceptible–exposed–infectious–recovered model parametrized with human movement data from 340 cities in China. Our model replicates the early-case trajectory in the COVID-19 pandemic. We then use machine learning algorithms to determine which network properties best predict spread between cities and find travel time to be most important, followed by the human movement-weighted personalized PageRank. However, we show that travel time is most influential locally, after which the high connectivity between cities reduces the impact of travel time between individual cities on transmission speed. Additionally, we demonstrate that only significantly reduced movement substantially impacts infection spread times throughout the network.
Adhesive properties of Aphrophoridae spittlebug foam
Authors: Hoch Hannelore , Pingel Martin , Voigt Dagmar , Wyss Urs , Gorb Stanislav
Published: January 2024

Aphrophora alni
spittlebug nymphs produce a wet foam from anal excrement fluid, covering and protecting themselves against numerous impacts. Foam fluid contact angles on normal (26°) and silanized glass (37°) suggest that the foam wets various substrates, including plant and arthropod surfaces. The pull-off force depends on the hydration state and is higher the more dry the fluid. Because the foam desiccates as fast as water, predators once captured struggle to free from drying foam, becoming stickier. The present study confirms that adhesion is one of the numerous foam characteristics resulting in multifunctional effects, which promote spittlebugs' survival and render the foam a smart, biocompatible material of biological, biomimetic and biomedical interest. The sustainable ‘reuse' of large amounts of excrement for foam production and protection of the thin nymph integument suggests energetic and evolutionary advantages. Probably, that is why foam nests have evolved in different groups of organisms, such as spittlebugs, frogs and fish.
Human growth factor-mediated signalling through lipid rafts regulates stem cell proliferation, development and survival of
Schistosoma mansoni
Authors: Maharjan Shradha , Kirk Ruth S. , Lawton Scott P. , Walker Anthony J.
Published: January 2024

Although the mechanisms by which schistosomes grow and develop in humans are poorly defined, their unique outer tegument layer, which interfaces with host blood, is considered vital to homeostasis of the parasite. Here, we investigated the importance of tegument lipid rafts to the biology of
Schistosoma mansoni
in the context of host–parasite interactions. We demonstrate the temporal clustering of lipid rafts in response to human epidermal growth factor (EGF) during early somule development, concomitant with the localization of anteriorly orientated EGF receptors (EGFRs) and insulin receptors, mapped using fluorescent EGF/insulin ligand. Methyl-
β
-cyclodextrin (M
β
CD)-mediated depletion of cholesterol from lipid rafts abrogated the EGFR/IR binding at the parasite surface and led to modulation of protein kinase C, extracellular signal-regulated kinase, p38 mitogen-activated protein kinase and Akt signalling pathways within the parasite. Furthermore, M
β
CD-mediated lipid raft disruption, and blockade of EGFRs using canertinib, profoundly reduced somule motility and survival, and attenuated stem cell proliferation and somule growth and development particularly to the fast-growing liver stage. These findings provide a novel paradigm for schistosome development and vitality in the host, driven through host–parasite interactions at the tegument, that might be exploitable for developing innovative therapeutic approaches to combat human schistosomiasis.
Functional performance of a bi-layered chitosan-nano-hydroxyapatite osteochondral scaffold: a pre-clinical
in vitro
tribological study
Authors: Cowie Raelene M. , Macri-Pellizzeri Laura , McLaren Jane , Sanderson William J. , Felfel Reda M. , Scotchford Colin A. , Scammell Brigitte E. , Grant David M. , Sottile Virginie , Jennings Louise M.
Published: January 2024

Osteochondral grafts are used for repair of focal osteochondral lesions. Autologous grafts are the gold standard treatment; however, limited graft availability and donor site morbidity restrict use. Therefore, there is a clinical need for different graft sources/materials which replicate natural cartilage function. Chitosan has been proposed for this application. The aim of this study was to assess the biomechanics and biotribology of a bioresorbable chitosan/chitosan-nano-hydroxyapatite osteochondral construct (OCC), implanted in an
in vitro
porcine knee experimental simulation model. The OCC implanted in different surgical positions (flush, proud and inverted) was compared to predicate grafts in current clinical use and a positive control consisting of a stainless steel graft implanted proud of the cartilage surface. After 3 h (10 800 cycles) wear simulation under a walking gait, subsidence occurred in all OCC samples irrespective of surgical positioning, but with no apparent loss of material and low meniscus wear. Half the predicate grafts exhibited delamination and scratching of the cartilage surfaces. No graft subsidence occurred in the positive controls but wear and deformation of the meniscus were apparent. Implanting a new chitosan-based OCC either optimally (flush), inverted or proud of the cartilage surface resulted in minimal wear, damage and deformation of the meniscus.
Assessment of DNA extraction methods for human gut mycobiome analysis
Authors: Rintarhat Piyapat , Cho Yong-Joon , Koh Hong , Park Sowon , Lee Eun Joo , Lim Hyeji , Noh Jihye , Lee Dong-Woo , Jung Won Hee
Published: January 2024

The gut mycobiome plays an important role in the health and disease of the human gut, but its exact function is still under investigation. While there is a wealth of information available on the bacterial community of the human gut microbiome, research on the fungal community is still relatively limited. In particular, technical methodologies for mycobiome analysis, especially the DNA extraction method for human faecal samples, varied in different studies. In the current study, two commercial kits commonly used in DNA extraction, the QIAamp® Fast DNA Stool Mini Kit and DNeasy PowerSoil Pro Kit, and one manual method, the International Human Microbiome Standards Protocol Q, were compared. Furthermore, the effectiveness of two different bead-beating machines, the Mini-Beadbeater-16 and FastPrep-24
TM
5G, was compared in parallel. A mock fungal community with a known composition of fungal strains was also generated and included to compare different DNA extraction methods. Our results suggested that the method using the DNeasy PowerSoil Pro Kit and Mini-Beadbeater-16 provides the best results to extract DNA from human faecal samples. Based on our data, we propose a standard operating procedure for DNA extraction from human faecal samples for mycobiome analysis.
Comparing acoustic and satellite telemetry: an analysis quantifying the space use of
Chelonia mydas
in Bimini, Bahamas
Authors: Hardin Emily E. , Cullen Joshua A. , Fuentes Mariana M. P. B.
Published: January 2024

Passive acoustic and Argos satellite telemetry are common methods for tracking marine species and are often used similarly to quantify space use. However, data-driven comparisons of these methods and their associated ecological inferences are limited. To address this, we compared temporal durations, spatial resolutions, financial costs and estimates of occurrence and range distributions for each tracking approach using nine juvenile green turtles (
Chelonia mydas
) in Bimini, Bahamas. Tracking durations were similar, although acoustic tracking provided higher spatiotemporal resolution than satellite tracking. Occurrence distributions (95%) estimated from satellite telemetry were 12 times larger than those from acoustic telemetry, while satellite range distributions (95%) were 89 times larger. While individuals generally remained within the extent of the acoustic receiver array, gaps in coverage were identified. These gaps, combined with the lower accuracy of satellite telemetry, were likely drivers for the larger satellite distributions. Costs differed between telemetry methods, with acoustic telemetry being less expensive at larger sample sizes with a previously established array. Our results suggest that acoustic and satellite telemetry may not provide similar inferences of individual space use. As such, we provide recommendations to identify telemetry methods appropriate for specific study objectives and provide discussion on the biases of each.
Facial growth and development trajectories based on three-dimensional images: geometric morphometrics with a deformation perspective
Authors: Zhong Yu Jie , Cui Dan , Wen Patrick Yi Feng , Wong Hai Ming
Published: January 2024

Developmental changes of facial shape are commonly investigated through geometric morphometrics. A limitation with this approach is the inability to investigate patterns of morphological changes at local scale. This could be addressed through quantifying the deformation required to deform one shape to another. This study aimed to investigate changes in mean, rate and variance of facial shape at local scale using geometric morphometrics through deformation perspective. A total of 2112 Europeans 3 to 40 years old from the three-dimensional Facial Norms project were included. Shape and rate trajectories from partial least-squares regressions revealed that the developmentally protrusive nasal bridge was due to local expansion in surrounding tissues as opposed to shape changes in nasal bridge
per se
. Local expansion of the supraorbital region, in particular the medial part in males, resulted in the sloping forehead and deep-situated eyes with development. Facial shape variation increased nonlinearly with age (
p
< 0.05), with features having larger rate of change becoming more developmentally diversified. In summary, our deformation perspective facilitates unravelling morphogenetic processes underlying shape changes. Our extended analytical scope inspires novel measures worthy of consideration while establishing facial growth charts. The analytical framework in this study is broadly applicable for analysis of shape changes in general.
Bare parts in the Galliformes: the evolution of a multifunctional structure
Authors: Zhao Min , Kurtis Sarah M. , Humbel Ellen A. , Griffith Emily V. , Liu Tong , Braun Edward L. , Buchholz Richard , Kimball Rebecca T.
Published: January 2024

A morphological trait can have multiple functions shaped by varying selective forces. Bare parts in birds, such as wattles, casques and combs, are known to function in both signalling and thermoregulation. Studies have demonstrated such structures are targets of sexual selection via female choice in several species of Galliformes (junglefowl, turkeys and grouse), though other studies have shown some role in thermoregulation (guineafowl). Here, we tested fundamental hypotheses regarding the evolution and maintenance of bare parts in Galliformes. Using a phylogeny that included nearly 90% of species in the order, we evaluated the role of both sexual and natural selection in shaping the function of bare parts across different clades. We found a combination of both environmental and putative sexually selected traits strongly predicted the variation of bare parts for both males and females across Galliformes. When the analysis is restricted to the largest family, Phasianidae (pheasants, junglefowl and allies), sexually selected traits were the primary predictors of bare parts. Our results suggest that bare parts are important for both thermoregulation and sexual signalling across Galliformes but are primarily under strong sexual selection within the Phasianidae.
Mycolicibacterium arseniciresistens sp. nov., isolated from lead–zinc mine tailing, and reclassification of two Mycobacterium species as Mycolicibacterium palauense comb. nov. and Mycolicibacterium grossiae comb. nov.
Authors: Zhu Guo-Xing , Chen Xiu , Wu Ya-Jie , Wang Hai-Long , Lu Chun-Mei , Wang Xiao-Ming , Zhang Yue , Liu Zi-Chao , He Jiang-Bo , Tang Shu-Kun , Cao Yan-Ru
Published: January 2024

A Gram-positive, acid-fast, aerobic, rapidly growing and non-motile strain was isolated from lead–zinc mine tailing sampled in Lanping, Yunnan province, Southwest China. 16S rRNA gene sequence analysis showed that the most closely related species of strain KC 300T was

Mycolicibacterium litorale

CGMCC 4.5724T (98.47 %). Additionally, phylogenomic and specific conserved signature indel analysis revealed that strain KC 300T should be a member of genus

Mycolicibacterium

, and

Mycobacterium palauense

CECT 8779T and

Mycobacterium grossiae

DSM 104744T should also members of genus

Mycolicibacterium

. The genome size of strain KC 300T was 6.2 Mb with an in silico DNA G+C content of 69.2 mol%. Chemotaxonomic characteristics of strain KC 300T were also consistent with the genus

Mycolicibacterium

. The average nucleotide identity, digital DNA–DNA hybridization and average amino acid identity values, as well as phenotypic, physiological and biochemical characteristics, support that strain KC 300T represents a new species within the genus

Mycolicibacterium

, for which the name Mycolicibacterium arseniciresistens sp. nov. is proposed, with the type strain KC 300T (=CGMCC 1.19494T=JCM 35915T). In addition, we reclassified

Mycobacterium palauense

and

Mycobacterium grossiae

as Mycolicibacterium palauense comb. nov. and Mycolicibacterium grossiae comb. nov., respectively.
Analysis of the relative frequencies of the multipartite BNYVV genomic RNAs in different plants and tissues
Authors: Dall'Ara M. , Guo Y. , Poli D. , Gilmer D. , Ratti C.
Published: January 2024

Multipartite virus genomes are composed of two or more segments, each packaged into an independent viral particle. A potential advantage of multipartitism is the regulation of gene expression through changes in the segment copy number. Soil-borne beet necrotic yellow vein virus (BNYVV) is a typical example of multipartism, given its high number of genomic positive-sense RNAs (up to five). Here we analyse the relative frequencies of the four genomic RNAs of BNYVV type B during infection of different host plants (Chenopodium quinoa, Beta macrocarpa and Spinacia oleracea) and organs (leaves and roots). By successfully validating a two-step reverse-transcriptase digital droplet PCR protocol, we show that RNA1 and -2 genomic segments always replicate at low and comparable relative frequencies. In contrast, RNA3 and -4 accumulate with variable relative frequencies, resulting in distinct RNA1 : RNA2 : RNA3 : RNA4 ratios, depending on the infected host species and organ.
Diverse and weakly immunogenicvargene expression facilitates malaria infection
Authors: Bhardwaj Inayat , Nyarko Prince B. , Ashn Asrar Ba , Cohen Camille , Ceesay Sukai , Achan Jane , Dabira Edgard , Nakajima Rike , Jain Aarti , Taghavian Omid , Jasinskas Algis , Felgner Philip L. , D’Alessandro Umberto , Bousema Teun , Travassos Mark , Radulescu Ovidiu , Claessens Antoine
Published: January 2024

Plasmodium falciparumis believed to escape immunity via antigenic variation, mediated in part by 60vargenes. These genes undergo mutually exclusive expression and encode the PfEMP1 surface antigen. The frequency ofvarswitching and the immunogenicity of each expressed PfEMP1 remain unclear. To this end, we carried out a Controlled Human Malaria Infection (CHMI) study with 19 adult African volunteers in The Gambia to gain insight into the effect of naturally acquired immunity on the expressedvargene repertoire during early phase of an infection. Our findings demonstrated a strong correlation between the diversity ofvarexpression, quantified through entropy, and infection outcome. Low-immunity individuals were characterised by highvarentropy profiles, higher parasitaemia, and lower sero-recognised PfEMP1 domains compared to high-immunity individuals. For the first time we recorded the probability ofvargene switchingin vitroand of turnoverin vivo, enabling us to estimate both intrinsic switching and negative-selection effects. These processes are rapid, resulting in estimated turnover/switching probabilities of 69% - 97% and 7% - 57% per generation,in vivoandin vitro, respectively.Var(PfEMP1) expression triggered time-dependent humoral immune responses in low immunity individuals, with many PfEMP1 domains remaining weakly immunogenic. We conclude that the role of intrinsicvarswitching is to reset and maintain a diversevarrepertoire. The highvarswitching rates and weak PfEMP1 immunogenicity benefit parasite survival during the CHMI.
Surgical diagnoses and post-operative outcomes of intestinal obstruction among adults at regional referral hospitals in Dar-es-Salaam, Tanzania: a prospective, observational hospital-based study
Authors: Mponzi Shadrack Samwel , Wandwi Wambura Boniphace , Mbembati Naboth Almasi , Leshabari Kelvin Melkizedeck
Published: January 2024

Background

There is limited available published information regarding surgical diagnoses and post-operative outcomes of intestinal obstruction among adult patients in East African hospitals. The observation is despite available anecdotal evidence of the condition to be among the commonest surgical emergencies in the area.

Objective

To assess the surgical diagnoses and outcomes of intestinal obstruction among adult patients treated at the regional referral hospitals in Dar-es-salaam - Tanzania.

Methods & Findings

This was a prospective, observational, hospital-based study. Data were collected using a pre-validated Clinical Research Form (CRF). All adult patients with post-operative surgical diagnoses of intestinal obstruction at Amana, Mwananyamala and Temeke hospitals in Dar es Salaam were the target population. Data were analyzed using a generalized linear model via SAS version 9.7. Multivariable logistic regression model was the final fitted model. Intra-operative findings (surgical diagnoses) of intestinal obstruction was an outcome variable. Unless otherwise stated, an α-level of 5% was used as a limit of type 1 error in findings. The study analysed an average of 1411 patients-days of follow-up. Participants’ median age and duration of hospital stay were 47 (IQR: 35-67) years and 4 (IQR: 3-6) days respectively. Intra-operative findings included adhesions (aOR=5.66), abdominal tumors (aOR=1.028), hernia (aOR=2.04) and volvulus (aOR=4.2). Moreover, 12 (5.26%) clients died and 20 (9%) had surgical sites infection. No statistically significant difference of hospital on surgical outcomes (χ2test value = 4.992; df = 10).

Conclusion

Adhesions was the commonest intraoperative cause of intestinal obstruction in this study population. One-in-twenty of all followed-up clients died. Significant proportion of patients had evidence of post-operative complications.
Cardiac Troponin T is a Serum Biomarker of Respiratory Dysfunction in Amyotrophic Lateral Sclerosis
Authors: Koch Teresa , Fabian Rachel , Weinhold Leonie , Koch Franz-W. , Barakat Saman , Castro-Gomez Sergio , Grehl Torsten , Bernsen Sarah , Weydt Patrick
Published: January 2024

Objective

Informative biomarkers are an urgent need in management and therapy development of amyotrophic lateral sclerosis. Serum cardiac troponin T is elevated in most amyotrophic lateral sclerosis patients and not correlated with neurofilaments. We sought to delineate the functional implications and the informative value of serum troponin T with regard to respiratory function, a major prognostic factor in amyotrophic lateral sclerosis.

Methods

We analyzed two independent hospital-based amyotrophic lateral sclerosis cohorts (d=discovery cohort; v= validation cohort) with data available on serum cardiac troponin T levels (nd=297; nv=49), serum neurofilament light chain levels (nd=116; nv=17), and routine respiratory test results (nd=86; nv=49).

Results

Serum cardiac troponin T levels, unlike serum neurofilaments, were strongly associated with the respiratory domain of the revised amyotrophic lateral sclerosis functional rating score (rd= - 0.29, pd= 0.001; rv= - 0.48, pv= 0.007) and with relevant pulmonary function parameters (nd), namely SVC% (r = - 0.45; p = 0.001), FVC% (r = - 0.43; p = 0.001), FEV1% (r = −0.37, p = 0.007), and PEF (r = - 0.34, p = 0.027).

Serum cardiac Troponin T reliably discriminated benchmarks of SVC% < 80%: (AUC 0.75, p = 0.003), FVC % < 80%: (AUC 0.72, p = 0.011) and PEF% <75%: (AUC 0.72, p = 0.015).

Interpretation

Our findings confirm cardiac Troponin T as an informative serum biomarker in amyotrophic lateral sclerosis, complementing neurofilaments. Serum Troponin T can flag compromised respiratory function in amyotrophic lateral sclerosis and might prove useful as a proxy of respiratory impairment with prognostic implications.
Capability and reliability of deep learning models to make density predictions on low dose mammograms
Authors: Squires Steven , Mackenzie Alistair , Evans D. Gareth , Howell Sacha J , Astley Susan M
Published: January 2024

Purpose

Breast density is associated with risk of developing cancer and can be automatically estimated, using deep learning models, from digital mammograms. Our aim is to estimate the capacity and reliability of such models to estimate density from low dose mammograms taken to enable risk estimates for younger women.

Methods

We trained deep learning models on standard and simulated low dose mammograms. The models were then tested on a mammography data-set with paired standard and low-dose image. The effect of different factors (including age, density and dose ratio) on the differences between predictions on standard and low dose are analysed. Methods to improve performance are assessed and factors that reduce model quality are demonstrated.

Results

We showed that whilst many factors have no significant effect on the quality of low dose density prediction both density and breast area have an impact. For example correlation between density predictions on low and standard dose images of breasts with the largest breast area is 0.985 (0.949-0.995) while with the smallest is 0.882 (0.697-0.961). We also demonstrated that averaging across CC-MLO images and across repeatedly trained models can improve predictive performance.

Conclusion

Low dose mammography can be used to produce density and risk estimates that are comparable to standard dose images. Averaging across CC-MLO and across model predictions should improve this performance. Model quality is reduced when making predictions on denser and smaller breasts. Code is available at:https://github.com/stevensquires/
Building sustainable local training capacity in maternal and newborn health within the public system-A training intervention research in Palghar District, western Maharashtra, India
Authors: Karvande Shilpa , Purohit Vidula , Balakrishnan Subha Sri , Allott Helen , Serle Elisabeth , Jha Reeta , Mullick Shubhro , Chavan Milind , Kulkarni Prashant , Mathai Matthews , Mistry Nerges
Published: January 2024

Introduction

Constant investment for professional development of health workforce is paramount and can be implemented through locally available competent trainers. However, guidelines for selection and recruitment of trainers, and for approaches and processes of training and nurturing them are lacking. A training intervention research in western Maharashtra, India focusing on maternal and newborn health (MNH) attempted to address these gaps.

Methods

During the pilot project in Pune District (2016-19), 38 health workers were trained as trainers in MNH with support from the United Kingdom (UK) based technical partners (obstetricians and pediatrician). From these, eight were selected and further trained to become core trainers (CTs) for MNH training during scale-up phase in Palghar District (2019-22). A local cadre of skilled master trainers (MTs) in Palghar (n=32) was developed by these CTs with support from the UK team, through a six-steps approach starting with pre-training of trainers (TOT) screening, TOT with pre– and post-training assessment, staggered induction of MTs, continuous support, regular quality assessment, and virtual refresher training. A mixed-methods approach was adopted to assess the process and outcome of this six-step approach.

Results

The six-steps approach of developing Palghar MTs helped in optimal resource utilization during TOT. It allowed more time and non-threatening support to MTs to excel through peer learning. Pune CTs became competent and confident mentors through critical feedback and appreciation and provided long term support to the newly trained Palghar MTs. Regular assessment by the UK team was an essential quality control step. The virtual learning served as an effective mode for refresher training without interruptions during COVID-19. Considerable improvement in clinical knowledge and skills of the trainee health providers from Palghar (n=505) was evidence of quality training delivered by the Palghar MTs. The training intervention contributed to increased clinical competency, confidence, recognition, motivation, and contribution to career growth of the Palghar MTs.

Discussion

The TOT model used in Palghar demonstrated the importance of recruiting right candidates with essential attributes as trainers, conscious shift in their teaching style for making them adult-learner-centric facilitators, longer time frames and hybrid platform. A methodical approach for nurturing talent of trainers through opportunities for teaching as well as learning was highlighted. However, a systematic evaluation for assessing long term effects of this model on retention of clinical and teaching competencies of these trainers and their trainees and its application in provision of MNH care is required.
Identifying direct risk factors in UK Biobank with simultaneous Bayesian-frequentist model-averaged hypothesis testing using Doublethink
Authors: Arning Nicolas , Fryer Helen R. , Wilson Daniel J.
Published: January 2024

Big data approaches to discovering non-genetic risk factors have lagged behind genome-wide association studies that routinely uncover novel genetic risk factors for diverse diseases. Instead, epidemiology typically focuses on candidate risk factors. Since modern biobanks contain thousands of potential risk factors, candidate approaches may introduce bias, inadequately control for multiple testing, and miss important signals. Bayesian model averaging offers a solution, but classical statistics predominates, perhaps because of concern that the prior unduly influences results. Here we show that simultaneous Bayesian and frequentist discovery of direct risk factors is possible via a model-averaged hypothesis testing approach for large samples called ‘Doublethink’. Doublethink produces interchangeable posterior odds andp-values that control the false discovery rate (FDR) and familywise error rate (FWER). We implement the Doublethink approach in R and apply it to discover direct risk factors for COVID-19 hospitalization in 2020 among 1,912 variables in UK Biobank. We find nine exposome-wide significant variables at 9% FDR and 0.05% FWER. These include several commonly reported risk factors (e.g. age, sex, obesity) but exclude others (e.g. diabetes, cardiovascular disease, hypertension) which might be mediated through variables measuring general comorbidity (e.g. numbers of medications). We identify significant direct effects among infrequently reported risk factors (psychiatric disorders, infection, dementia and aging), and show how testing groups of correlated variables is a useful alternative to pre-analysis variable selection. We discuss the potential for impact and limitations of joint Bayesian-frequentist inference, and the mutual insights afforded into the long-standing differences on statistical approaches to scientific discovery.
Widespread adoption of precision anticancer therapies after implementation of pathologist-directed comprehensive genomic profiling across a large US health system
Authors: Dowdell Alexa K. , Meng Ryan , Vita Ann , Bapat Bela , Hanes Douglas , Chang Shu-Ching , Harold Lauren , Schmidt Mark , Wong Cliff , Poon Hoifung , Schroeder Brock , Weerasinghe Roshanthi , Leidner Rom , Urba Walter J. , Bifulco Carlo B. , Piening Brian D.
Published: January 2024

Precision therapies and immunotherapies have revolutionized cancer care, resulting in significant gains in patient survival across tumor types. Despite this transformation in care, there is variability in the utilization of tumor molecular profiling. To standardize testing, we designed a pathologist-directed test ordering system at time of diagnosis utilizing a 523-gene DNA/RNA hybrid comprehensive genomic profiling (CGP) panel. We assessed actionability rates, therapy choices, and outcomes among 3,216 patients. 49% of cases had at least one actionable genomic biomarker-driven (GBD) approved and/or guideline-recommended targeted or immunotherapy and 53% of patients would have been eligible for a precision therapy clinical trial from three large basket trials. When assessing CGP versus aninsilico50 gene panel, 67% of tumors compared to 33% harbored actionable alterations. Among patients with 6-months or more of follow-up, over 52% received a targeted therapy or immunotherapy, versus 32% that received conventional chemotherapy alone, a phenomenon not previously observed.

Statement of Significance

This study represents the first report where precision therapies (targeted and immunotherapy) have overtaken traditional cytotoxic treatments in the routine community-based care of advanced cancer patients, resulting in better overall survival. This represents an important milestone in the evolution and adoption of precision oncology and highlights the importance of CGP.
A novel comprehensive Tuberculosis (TB) control programme methodology based on the nexus of participatory action research inspired public health and precision treatment approach
Authors: Mitra Shirsajit , Saikia Partha Jyoti , Dutta Anuja , Das Rupam , Das Gokul , Baishya Tutumoni , Das Chayanika , Sarma Tulika , Das Sonali , Pathak Lekhika , Das Bikul
Published: January 2024

Tuberculosis is emerging as a major global health issue for the under-developed regions across the world including India’s North East. Importantly, the incidence of multidrug-resistant (MDR) strain of Mycobacterium tuberculosis (MTB), the causative agent of TB is increasing. Furthermore, the disease is associated with stigma, and therefore people’s wholehearted participation in care, and research support is lacking. Here, we report the development of novel research methodologies through a process of participatory action research (PAR) in India’s Northeast region (NER). The region is economically and socially underdeveloped having approximately 10% higher incidences of TB cases reported than the rest of the country. We have taken an indigenous knowledge system (IKS) based PAR approach, where a century-old local philosophy, Vedic altruism (Jiva Upakara Cikitsha Tantra) has been integrated into our research. Our goal has been to integrate philosophy, clinical care, and the latest clinical, microbiology, and cell biology research tools into one cohesive “knowledge emergence” hub, and then connect it with world’s outstanding research hubs to develop a global PAR against TB. Through this unique PAR-based approach, we were able to identify the stem cell niche as an important factor in TB dormancy, reactivation and MDR evolution. Importantly, we also discovered a natural aerosol-based TB vaccination mechanism. In this paper, we describe various methodologies that we have established as a part of the IKS/PAR-based TB research process. These methodologies include the PAR-based clinical care and monitoring, isolation of live MTB from the peripheral blood and bone marrow-derived progenitor cells, culture and drug-sensitivity test, the challenge of MTB DNA extraction and whole genome sequencing (WGS) from a small population of MTB intracellular to stem cells. We have also developed methodologies to detect viable but non culturable (VBNC) MTB of smear-negative pulmonary TB patients, as well as patients suffering from non-tuberculosis mycobacterium (NTM) infections. These methodologies now enable us to detect patients with an early stage of MDR evolution and compensatory mutation by isolating MTB intracellular to circulating progenitor cells. Importantly, the PAR setup now enables us to collaborate with the world’s leading scientific communities to further our knowledge of TB pathogenesis.
A Device to Prevent Night-time Sudden Unexpected Death in Epilepsy
Authors: Lee Jong Woo , Bansal Pranav , Smanis Ioannis , Nguyen Justin , Rodriguez Andres
Published: January 2024

Background

Sudden Unexpected Death in Epilepsy (SUDEP) is the leading cause of death in epilepsy children and otherwise healthy adult epilepsy patients. About 70% of SUDEP occurs during sleep, and nearly 90% are found in the prone (face-down) position. SUDEP can likely be prevented by simple interventions such as turning and stimulating. Such intervention must be performed quickly within a 3-minute window prior to death. There are currently no products that detect the prone position or have the ability to physically reposition a patient into a recovery position.

Methods

We address this critical unmet medical need with a smart mattress, the Korus, consisting of an array of inflatable cells. We developed 1) a sensor system to rapidly detect body change with high accuracy; 2) an advanced expandable cell that is capable of generating the required lift at sufficient velocity to reposition a patient from the prone to the recovery (sideways) position.

Results

Each inflatable cell that comprises the Korus has the capacity to generate lift to 1000 lb/cell at a rate of 2 inches per second. The embedded sensor array can detect body position change within 5 seconds. A total of 10 normative control subjects were tested. Repositioning from a prone to recovery (sideways) position while manually controlling the cells was successful in 100% of attempts with an average time of 21.75 sec. Body position detection resulted in an accuracy in detecting the prone position of 96.8% and an overall accuracy of detecting the correct body position (supine, prone, left, right) of 92.4%. In long-term studies including sleep, Korus detected the correct position during 97.3% of the time during the recording. False body position change rate was 2.3 events/hour. There were no incorrect position detections when subjects switched into the prone position.

Discussion

This study demonstrates the feasibility of developing a smart mattress to detect the prone position and rapidly repositioning subjects into a recovery position. Future development include the development of a control system to automate repositioning based on sensor data. The completion of this device, when paired with a seizure detection device, has the potential to lower the risk of SUDEP by >50%.
Closing the gap towards a successful referral system. A case study of a tertiary teaching and referral hospital, Kenya: pre-posttest study design
Authors: Omondi Maxwell Philip
Published: January 2024

Inappropriate utilization of higher-level health facilities and ineffective management of the referral processes in resource-limited settings is increasingly becoming a concern in health care management in developing countries. This is characterized by self-referrals and frequent bypassing of nearest health facilities. On 1stJuly 2021, Kenyatta National Hospital (KNH) did enforce the national referral guidelines that required patients have a formal referral letter to reduce the number of self-referrals, decongest KNH and allow KNH to function as a referral facility as envisioned by Kenya Health Sector Referral Implementation Guidelines of 2014, Kenya 2010 constitution and KNH legal statue of 1987. The purpose of this study was to analyse the effect of enforcement of referral guidelines on facility referrals to KNH.This was a pre-posttest study design. The study was conducted amongst the orthopedic facility referrals in 2021 with 222 and 246 before and after enforcement of referral guidelines respectively. Data collection was done through data abstraction. Data was analyzed using frequency distribution, pearson chi-square test and logistic regression. Nairobi County and its environs constituted over four-fifth of all facility referrals to KNH. Over two-thirds of the facility referrals to KNH were from government facilities. There was significant reduction in health facilities tiers 2 and 3 referring patients directly to KNH after enforcement of referral guidelines (p=0.002). About 43 health facilities ceased referring patients to KNH with over two-thirds of these health facilities being private facilities. The major facility and patient factors that were associated with facility referrals to KNH were human resource capacity and availability and patient’s preference. In conclusion, enforcement of the referral guidelines significantly reduced the lower tiers health facilities referring to KNH. We recommend having written standard operating procedures on referrals based on the national referral guidelines with continued enforcement of the same to sustain the gains made.
Quantifying the impact of social activities on SARS-CoV-2 transmission using Google mobility reports
Authors: Günther Felix , Brustad Hilde Kjelgaard , Frigessi Arnoldo , Britton Tom
Published: January 2024

We developed a state-space model to investigate which social behaviours had biggest impact on the spread of SARS-CoV-2. The analyses were based on reported hospitalizations, together with information on vaccinations, weather data, virus strains and, most importantly, Google mobility reports on 4 different types of social activities. While our new approach is general, we studied Sweden and Norway on a regional level over 75 weeks, and the major regions of Berlin and Bavaria in Germany over 10 months. Most results are shared for all three countries: Activity in four social settings explain between 40-60% of all infections; Public transport appears as an important setting for infections in all countries; and the transmission potential drops by 40-50% during the summer as compared to the winter peak. However, the analyses for Germany differ in thatRetail and recreationis the other setting dominating transmission whereas it is contacts at theWorkplacein Norway and Sweden, showing how our model is able to adapt to specific cases. Transmissions not captured by the Google data may happen in other settings, in particular in households. The statistical model has a deterministic time and region specific transmission rate with an additive component for the four Google settings, and a multiplicative part taking seasonality and circulating virus strains into account. Inference is performed in a Bayesian setting using Stan.
Women Empowerment in Medical Imaging and Radiology: Status and Challenges
Authors: Alruwaili Ashwag Rafea S , Alzahrani Alanoud Abdullah , Almater Hajar Abdullah , Aldibas Lina Abdulaziz , Al anazi Nawal Farah , Albanyan Asma Mohammed , Alyami Wadha
Published: January 2024

Since the pandemic’s beginning, there have been significant setbacks in social and economic inclusion of women. The resistance by public can be quite challenging too due to different reasons, such as religious beliefs or the dominance of custom and traditions creating a consistency in leadership perceptions and prototypes of leaders. The Saudi vision unleashed the exacerbated efforts to increase women involvement in the workforce and empower them in leadership roles. Yet the overall representation of women in leadership positions in health and academe in Saudi Arabia remains low compared to other countries. Exploring women status in medical imaging and the risks of reversals after the pandemic became necessary. An online questionnaire was distributed to female workers in both health and academic institutions in the field of medical imaging from December 31, 2021 to October 10, 2022. A total of 250 responses were received, and only 240 females consented and met the criteria for inclusion in the study. Results show that Saudi women still face the glass ceiling when it comes to administrative roles even though they have high level of self-esteem and efficacy along with the support from the Saudi government by fair wages compared to male counterparts. However, institutions imposed largely more constraints on women, creating difficult environment for gender diversity in work culture such as breastfeeding hour, rest during working hours, leave for accompanying family member in sickness or hospitalization such as children, sick leaves during pregnancy or monthly period. In a remarkably short span of time, the current Saudi government has undertaken commendable initiatives to empower women, achieving their predetermined targets with notable success. Despite that, there are many familial and cultural challenges that hinder them from leading positions. The perceived efficacy of women leaders and the disparities in their leadership philosophies are still up for research.
Twelve-Month Follow-Up of Patients With Generalized Myasthenia Gravis Receiving BCMA-Directed mRNA Cell Therapy
Authors: Chahin Nizar , Sahagian Gregory , Feinberg Marc H. , Stewart C. Andrew , Jewell Christopher M. , Kurtoglu Metin , Miljković Miloš D. , Vu Tuan , Mozaffar Tahseen , Howard James F.
Published: January 2024

We report the 12-month follow-up results of a phase 2 clinical of Descartes-08 (NCT04146051), BCMA-directed RNA chimeric antigen receptor T-cell (rCAR-T) therapy for myasthenia gravis (MG) given as an outpatient treatment without lymphodepletion. In the Phase 2a part of the study, all 7 participants who received six weekly infusions of Descartes-08 exhibited clinically meaningful improvement in common MG severity scales (MG Composite, MG Activities of Daily Living, Quantitative MG scores, and Quality of Life 15-revised) at Month 3. At Month 9 follow-up, all participants continued to experience marked clinical improvements. Five out of seven participants maintained clinical improvement at Month 12. Of the two participants who experienced loss of clinical effect at Month 12 and were eligible for retreatment, one was retreated and had rapid improvement in clinical scores with minimal symptom expression which was ongoing at Month 6 of follow-up. All three participants with detectable anti-acetylcholine receptor (AChR) antibody levels at baseline experienced autoantibody reductions by Month 6, which deepened further by Month 9, and were maintained at Month 12. These data support continued development of Descartes-08 in myasthenia gravis and other autoantibody-associated autoimmune disorders.
First-in-human trial evaluating safety and pharmacokinetics of AT-752, a novel nucleotide prodrug with pan-serotype activity against dengue virus
Authors: Zhou Xiao-Jian , Lickliter Jason , Montrond Maureen , Ishak Laura , Pietropaolo Keith , James Dayle , Belanger Bruce , Horga Arantxa , Hammond Janet
Published: January 2024

AT-752 is a novel guanosine nucleotide prodrug inhibitor of the dengue virus (DENV) polymerase with sub-micromolar, pan-serotype antiviral activity. This Phase 1, double-blind, placebo-controlled, first-in-human study evaluated the safety, tolerability, and pharmacokinetics of ascending single and multiple oral doses of AT-752 in healthy subjects. AT-752 was well tolerated when administered as a single dose up to 1500 mg, or when administered as multiple doses up to 750 mg three times daily (TID). No serious adverse events occurred, and the majority of treatment-emergent adverse events were mild in severity and resolved by the end of the study. In those receiving single ascending doses of AT-752, no pharmacokinetic ethnic sensitivity was observed in Asian subjects and no food effect was observed. Plasma exposure of the guanosine nucleoside metabolite AT-273, the surrogate of the active triphosphate metabolite of the drug, increased with increasing dose levels of AT-752 and exhibited a long half-life of approximately 15–25 h. Administration of AT-752 750 mg TID led to a rapid increase in plasma levels of AT-273 exceeding the targetin vitro90% effective concentration (EC90) of 0.64 μM in inhibiting DENV replication, and maintained this level over the treatment period. The favorable safety and pharmacokinetic results support evaluation of AT-752 as an antiviral for the treatment of dengue in future clinical studies.
A qualitative study of anaesthetic trainee and trainer perspectives on regional teaching programmes
Authors: Lee A , Clementi R , Jackman S , Rakic M , Smyth S , Wight R
Published: January 2024

Background

Regional teaching programmes are a common method of delivering postgraduate medical education in the United Kingdom. There is limited evidence available to guide the development of a successful regional teaching programme.

Methods

In this qualitative study, we interviewed stakeholders including trainers and trainee anaesthetists using a combination of purposive and convenience sampling. Semi- structured interviews were conducted on Microsoft Teams in a focus group format. Data was transcribed, anonymised, coded and analysed using thematic analysis.

Findings

All the college tutors and school board members for anaesthesia in the deanery, and five anaesthetic trainees at different training stages participated in the study in six focus groups. Analysis revealed concerns about the complicated nature of Stage 1 anaesthetic training and discussion about how the local training structure within the deanery could be further impeding the delivery of support and education to Stage 1 anaesthetic trainees. Despite the challenges identified, trainers and trainees were optimistic about implementing a regional teaching programme for Stage 1 anaesthetists within the deanery.

Conclusions

This study highlighted the challenges of delivering high-quality postgraduate education and training for Stage 1 anaesthetists in our deanery and considered possible solutions. The findings of this study informed the development of a quality improvement project to improve Stage 1 anaesthetic training in our deanery.