bluuebunny/crossref_metadata_2025 huggingface dataset:
Monolithic and local time-stepping decoupled algorithms for transport problems in fractured porous media
Authors: Cao Yanzhao , Hoang Thi-Thao-Phuong , Huynh Phuoc-Toan
Published: April 2024

The objective of this paper is to develop efficient numerical algorithms for the linear advection-diffusion equation in fractured porous media. A reduced fracture model is considered where the fractures are treated as interfaces between subdomains and the interactions between the fractures and the surrounding porous medium are taken into account. The model is discretized by a backward Euler upwind-mixed hybrid finite element method in which the flux variable represents both the advective and diffusive fluxes. The existence, uniqueness, as well as optimal error estimates in both space and time for the fully discrete coupled problem are established. Moreover, to facilitate different time steps in the fracture-interface and the subdomains, global-in-time, nonoverlapping domain decomposition is utilized to derive two implicit iterative solvers for the discrete problem. The first method is based on the time-dependent Steklov–Poincaré operator, while the second one employs the optimized Schwarz waveform relaxation (OSWR) approach with Ventcel-Robin transmission conditions. A discrete space-time interface system is formulated for each method and is solved iteratively with possibly variable time step sizes. The convergence of the OSWR-based method with conforming time grids is also proved. Finally, numerical results in two dimensions are presented to verify the optimal order of convergence of the monolithic solver and to illustrate the performance of the two decoupled schemes with local time-stepping on problems of high Péclet numbers.
High Frequency of Prior Severe Acute Respiratory Syndrome Coronavirus 2 Infection by Sensitive Nucleocapsid Assays
Authors: Nkolola Joseph P , Liu Jinyan , Collier Ai-ris Y , Jacob-Dolan Catherine , Senussi Yasmeen , Borberg Ella , Swank Zoe , Walt David R , Barouch Dan H
Published: April 2024

Prior infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is typically measured by nucleocapsid serology assays. In this study, we show that the Simoa serology assay and T-cell intracellular cytokine staining assay are more sensitive than the clinical Elecsys assay for detection of nucleocapsid-specific immune responses. These data suggest that the prevalence of prior SARS-CoV-2 infection in the population may be higher than currently appreciated.
Why Online Consumption Communities Brutalize
Authors: Sibai Olivier , Luedicke Marius K , de Valck Kristine
Published: April 2024

Consumers who socialize in online consumption communities sometimes become alarmingly hostile, toxic, and otherwise verbally violent toward one another—a phenomenon known in sociology as brutalization. Research indicates that short-lived, situational outbursts of verbal violence—such as gross insults, harassment, or trolling—are common in online consumption contexts. However, it does not explain why such behaviors sometimes become endemic, turning entire communities into toxic social spaces. To address this question, the authors studied 18 years of interactions in an online electronic dance music community. Their interpretive analysis reveals three constellations of interacting, mutually reinforcing, forms of direct, structural, and cultural violence—sadistic entertainment, clan warfare, and popular justice—that fuel community brutalization in distinct ways. This article introduces these brutalization constellations, substantiates them with empirical data, and discusses their implications for theories of violence in consumption communities as well as the wider social media sphere.
The influence of fragmented landscapes on speciation
Authors: Ciccheto Juliana Rosa Matias , Carnaval Ana Carolina , Araujo Sabrina Borges Lino
Published: April 2024

In the face of unprecedented global transformations, unravelling the intricate mechanisms governing biodiversity patterns is imperative for predicting and interpreting species responses. An important element in this interplay is fragmentation and the spatial mosaic or arrangement of suitable sites within the landscape. Beyond its well-documented impact on biodiversity loss, fragmented landscapes also influence the origin of biodiversity, by influencing speciation dynamics. This research employs a model that integrates spatial configuration and dispersal abilities of individuals to investigate the impact of landscape configuration on species’ evolutionary trajectories. Specifically, we propose a microevolutionary model where individuals are characterized by their dispersal ability and a genome, allowing population evolution and diversification. Space is explicitly characterized by suitable and unsuitable sites that define fragmented landscapes. Our model demonstrates how intermediate dispersal abilities enhance diversification. However, simulations of more fragmented landscapes result in a lower total number of individuals and a lower percentage of occupied sites by individuals, particularly when species have limited dispersal abilities. Furthermore, we have found that intermediate levels of fragmentation can stimulate greater species richness, while higher levels of speciation and extinction events tend to occur under higher fragmentations. Our results also show a non-monotonic dependence of richness on dispersal, supporting the intermediate dispersal hypothesis as a promotor of diversification, demonstrating the synergistic effects of landscape configuration and species dispersal ability in the processes of speciation, extinction, and diversification. This impact of fragmentation poses a real challenge for biodiversity in the context of a dynamic world.
Well-leg compartment syndrome after laparoscopic low anterior resection in the lithotomy position: a case report and literature review
Authors: Nakayama Yoko , Yamaguchi Minekazu , Inoue Keisuke , Sasaki Masaki , Tamaki Kaho , Hidaka Masaaki
Published: April 2024

Well-leg compartment syndrome (WLCS) develops in healthy lower limbs because of surgical factors such as operative position, lower limb compression, and long operative time during abdominopelvic surgery. WLCS can lead to irreversible muscle and nerve damage if a prompt diagnosis and appropriate treatment are not provided. We report the case of a 57-year-old male who developed rectal cancer immediately after laparoscopic low anterior resection and was successfully treated with fasciotomy without sequelae. Patients who undergo surgery in the lithotomy position for a prolonged period are at risk of WLCS. Therefore, when determining the differential diagnosis of postoperative lower leg pain, it is necessary to consider WLCS because it is a complication caused by the intraoperative position.
The viability of low-mass subhaloes as targets for gamma-ray dark matter searches
Authors: Aguirre-Santaella Alejandra , Sánchez-Conde Miguel A
Published: April 2024

In this work, we investigate the discovery potential of low-mass Galactic dark matter (DM) subhaloes for indirect searches of DM. We use data from the Via Lactea II (VL-II) N-body cosmological simulation, which resolves subhaloes down to $\mathcal {O}(10^4)$ solar masses and it is thus ideal for this purpose. First, we characterize the abundance, distribution and structural properties of the VL-II subhalo population in terms of both subhalo masses and maximum circular velocities. Then, we repopulate the original simulation with millions of subhaloes of masses down to about five orders of magnitude below the minimum VL-II subhalo mass (more than one order of magnitude in velocities). We compute subhalo DM annihilation astrophysical ‘J-factors’ and angular sizes for the entire subhalo population, by placing the Earth at a random position but at the right Galactocentric distance in the simulation. Thousands of these realizations are generated in order to obtain statistically meaningful results. We find that some nearby low-mass Galactic subhaloes, not massive enough to retain stars or gas, may indeed yield DM annihilation fluxes comparable to those expected from other, more massive and acknowledgeable DM targets like dwarf satellite galaxies. Typical angular sizes are of the order of the degree, thus subhaloes potentially appearing as extended sources in gamma-ray telescopes, depending on instrument angular resolution and sensitivity. Our work shows that low-mass Galactic subhaloes with no visible counterparts are expected to play a relevant role in current and future indirect DM search searches and should indeed be considered as excellent DM targets.
H3.1/3.2 regulate the initial progression of the gene expression program
Authors: Funaya Satoshi , Takahashi Yusuke , Suzuki Masataka G , Suzuki Yutaka , Aoki Fugaku
Published: April 2024

In mice, transcription from the zygotic genome is initiated at the mid-one-cell stage, and occurs promiscuously in many areas of the genome, including intergenic regions. Regulated transcription from selected genes is established during the two-cell stage. This dramatic change in the gene expression pattern marks the initiation of the gene expression program and is essential for early development. We investigated the involvement of the histone variants H3.1/3.2 in the regulation of changes in gene expression pattern during the two-cell stage. Immunocytochemistry analysis showed low nuclear deposition of H3.1/3.2 in the one-cell stage, followed by a rapid increase in the late two-cell stage. Where chromatin structure is normally closed between the one- and two-cell stages, it remained open until the late two-cell stage when H3.1/3.2 were knocked down by small interfering RNA. Hi-C analysis showed that the formation of the topologically associating domain was disrupted in H3.1/3.2 knockdown (KD) embryos. Promiscuous transcription was also maintained in the late two-cell stage in H3.1/3.2 KD embryos. These results demonstrate that H3.1/3.2 are involved in the initial process of the gene expression program after fertilization, through the formation of a closed chromatin structure to execute regulated gene expression during the two-cell stage.
Climate change and heat stress
Authors: Ponsonby Will , Di Corleto Ross
Published: April 2024

Climate change is increasing the incidences of extreme weather. Record high temperatures are being experienced more frequently and for extended periods. Subsequently, there is an increased risk of occupational exposures resulting in heat-related illnesses, both acute and chronic. The editorial reviews the processes and tools that are available to assess heat exposure and develop effective controls to help address current and future exposures.
Genetic Basis for Mucormycosis Progression in COVID-19 Patients: From Susceptibility to Severity
Authors: Muruganantham Jethendra Kumar , Veerabathiran Ramakrishnan
Published: April 2024

The dynamics of COVID-19 and mucormycosis reveal a complex interplay of genetic factors that influence the susceptibility, severity, and immune responses. COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), exhibits an increased incidence of mucormycosis, particularly in individuals with comorbidities or corticosteroid therapy. Mucormycosis is a fungal infection that affects the sinuses, orbits, and lungs and demands timely intervention with antifungal medications and surgery because of its life-threatening nature. Research on the genetic underpinnings of this intersection has unveiled key insights into the pathogenicity of Mucorales. Breakthroughs in genetic tools have exposed virulence factors, such as the CotH protein family and high-affinity iron-uptake mechanisms. Genetic susceptibility is a pivotal element in identifying individuals at risk of developing COVID-19, facilitating early detection, and allowing for personalized treatment strategies. DPP9, MIF, and TYK2 are among the genes implicated in COVID-19 severity, emphasizing the intricate relationship between genetic makeup and viral response. The genetic landscape extends to viral entry mechanisms, thereby affecting infection efficiency. Specific polymorphisms in genes such as IFNAR2, OAS3, and TYK2 are associated with COVID-19 severity, indicating shared genetic bases between severe and hospitalized cases. Mucormycosis is genetically predisposed, particularly in immunocompromised individuals. The challenge lies in understanding the genetic factors influencing susceptibility and offering insights into pathogenesis and potential therapeutic avenues. Organ transplantation adds another layer, increasing susceptibility to infections such as COVID-19 and mucormycosis. The impact of immunosuppression on COVID-19 severity remains elusive, necessitating ongoing research on the immunological mechanisms. Despite the challenges posed by emerging SARS-CoV-2 variants, the intricate connection between genetic factors and the interplay of COVID-19 and mucormycosis presents an opportunity for personalized treatment, targeted interventions, and refined public health strategies.
Role of Uncertainty in Illness and Coping Strategies in Advance Directive Completion in Patients With End-stage Liver Disease
Authors: Fuson Olivia , Mitra Arnab , Little Carley , Hiatt Shirin , Franklin Heather , Dieckmann Nathan F. , Hansen Lissi
Published: April 2024

Objective:

We examined the associations among advance directives (ADs) completion, coping, uncertainty in illness, and optimism and pessimism in patients with end-stage liver disease (ESLD).

Background:

Although associations among ADs, coping, and uncertainty have been studied in patients with other life-limiting illnesses, these concepts have not been studied together in patients with ESLD.

Patients and Methods:

Patients were recruited at 2 health care institutions as part of a larger prospective study. They were enrolled if they had a diagnosis of nonhepatocellular carcinoma ESLD, Sodium Model for End-Stage Liver Disease ≥15, and no prior history of liver transplantation. Uncertainty, coping, optimism, and pessimism were assessed using the Uncertainty in Illness Scale for Adults, Revised Ways of Coping Checklist, and Life Orientation Test–revised. AD documentation at the time of study enrollment was retrospectively extracted from patient medical records.

Results:

In the sample [N = 181; median age = 57 y, 115 (64%) males], male sex [odds ratio (OR) = 4.66; 95% CI: 1.53, 14.17], being listed or under evaluation for liver transplantation (OR = 3.09; 95% CI: 1.10, 8.67), greater Sodium Model for End-Stage Liver Disease scores (OR = 1.10; 95% CI: 1.01, 1.20), and greater uncertainty (OR = 1.04; 95% CI: 1.01, 1.07) were positively associated with AD documentation. Higher coping avoidance was negatively associated with AD documentation (OR = 0.915; 95% CI: 0.840, 0.997).

Conclusions:

Clinicians should consider the role of uncertainty and coping measures to improve patient-specific advance care planning conversations and expand opportunities for all patients with ESLD to file an AD, especially women and patients not listed or under evaluation for transplantation.
Physical Therapy Services During COVID-19 Pandemic: Perception of Families of Brazilian Children With Physical Disabilities
Authors: Bittencourt de Oliveira Pedro , Pessóta Sudati Isabella , Lima Gonçalves Laura Gabrielle , de Campos Ana Carolina
Published: April 2024

Purpose:

To describe the perspective of caregivers about physical therapy (PT) during the COVID-19 pandemic and the effect of social distancing on the health of children with physical disabilities.

Methods:

This survey research used a remote questionnaire to identify the perceptions of caregivers about the effect of the COVID-19 pandemic on the health of children and adolescents with physical disabilities and on PT services. Data were analyzed using the frequency of responses; open-ended questions were analyzed through a hybrid approach to thematic analysis.

Results:

Caregivers of 47 children with cerebral palsy were included. Although most received regular PT services during the pandemic, worsened children's physical conditions and anxiety were prevalent. Caregivers believed that they lacked technical skills.

Conclusions:

Social distancing impacted the health of children with physical disabilities, especially their physical conditions. Identifying facilitators and barriers for PT services can be helpful in future similar scenarios.

Video abstract Supplemental Digital Content available at:
http://links.lww.com/PPT/A503.
Actomonas aquatica gen. nov., sp. nov., a marine lineage in the phylum Verrucomicrobiota with genetic potential for carbon and nitrogen fixation
Authors: Zhang Ai Hua , Tang Hao , Wang Lu , He Wei , Gao Tian Heng , Gao Zhi Gang , Zhang Dao-Feng
Published: April 2024

A novel bacterial strain, designated WL0086T, was isolated from a marine sediment sample collected in Lianyungang city, Jiangsu province, PR China. This strain showed the highest 16S rRNA gene sequence similarity to Geminisphaera colitermitum TAV2T (92.7 %) of the family Opitutaceae, and all the unclassified cultured and uncultured isolates with similarities >95 % were from marine environments. Cells were Gram-stain-negative, aerobic, non-motile cocci with a size of 0.6–0.8 µm in diameter. Strain WL0086T was positive for both oxidase and catalase, and grew at 20–37 °C (optimum, 28 °C), with 1.5–11.0 % NaCl (w/v; optimum, 2.5–4.0 %) and at pH 5.0–9.0 (optimum, pH 7.0). The major polar lipid profile of strain WL0086T consisted of phosphatidylethanolamine, phosphatidylglycerol, diphosphatidylglycerol, and phosphatidylcholine. The major isoprenoid quinone was menaquinone-7 and the predominant fatty acids were iso-C14 : 0, anteiso-C15 : 0, C16 : 0 and C16 : 1
 ω9c. The complete genome consisted of a chromosome with 6 109 182 bp. The G+C content of genomic DNA was 64.0%. Results of phylogenomic analysis based on the 16S rRNA gene sequence and the whole genome suggested that strain WL0086T formed a distinct clade closely neighbouring the members of the family Opitutaceae. On the basis of phylogenetic, phenotypic, and chemotaxonomic evidences, strain WL0086T should represent a novel genus of the family Opitutaceae, for which the name Actomonas aquatica gen. nov., sp. nov. is proposed. The type strain is WL0086T (=MCCC 1K05844T=JCM 34677T=GDMCC 1.2411T).
Rubellicoccus peritrichatus gen. nov., sp. nov., isolated from crustose coralline algae in a coral aquarium
Authors: Luo Jixin , Li Jin , Wang Chenyan , Li Mi , Hu Siyu , Lu Kun , Wang Guanghua
Published: April 2024

A Gram-stain-negative, motile, aerobic, non-spore-forming coccus, designated strain CR14T, was isolated from crustose coralline algae. Cells grew at 20–30 °C (optimum, 25 °C), at pH 6–9 (optimum, pH 7.6) and with NaCl concentrations of 0.5–9 % (w/v; optimum, 2–4 %). Global alignment based on 16S rRNA gene sequences indicated strain CR14T is closest to Ruficoccus amylovorans JCM 31066T with an identity of 92 %. The average nucleotide identity and average amino acid identity values between CR14T and R. amylovorans JCM 31066T were 68.4 and 59.9 %, respectively. Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain CR14T forms an independent branch within the family Cerasicoccaeae, which was consistent with the phylogenomic results. The sole isoprenoid quinone was MK-7. The major fatty acids were C14 : 0, C18 : 1 ω9c, C19 : 0 cyc 9,10 DMA, C16 : 0, and C18 : 2 ω6c. The major cellular polar lipids were phosphatidylethanolamine, phosphatidylglycerol, diphosphatidylglycerol, and two unidentified lipids. The genome DNA G+C content was 48.7 mol%. Based on morphological, physiological and chemotaxonomic characteristics, strain CR14T is suggested to represent a novel species in a new genus, for which the name Rubellicoccus peritrichatus gen. nov., sp. nov. is proposed. The type strain is CR14T (=MCCC 1K03845T=KCTC 72139T).
Investigating the impact of insertion sequences and transposons in the genomes of the most significant phytopathogenic bacteria
Authors: Fernandes Alexia Suellen , Campos Kiara França , de Assis Jéssica Catarine Silva , Gonçalves Osiel Silva , Queiroz Marisa Vieira de , Bazzolli Denise Mara Soares , Santana Mateus Ferreira
Published: April 2024

Genetic variability in phytopathogens is one of the main problems encountered for effective plant disease control. This fact may be related to the presence of transposable elements (TEs), but little is known about their role in host genomes. Here, we performed the most comprehensive analysis of insertion sequences (ISs) and transposons (Tns) in the genomes of the most important bacterial plant pathogens. A total of 35 692 ISs and 71 transposons were identified in 270 complete genomes. The level of pathogen–host specialization was found to be a significant determinant of the element distribution among the species. Some Tns were identified as carrying virulence factors, such as genes encoding effector proteins of the type III secretion system and resistance genes for the antimicrobial streptomycin. Evidence for IS-mediated ectopic recombination was identified in Xanthomonas genomes. Moreover, we found that IS elements tend to be inserted in regions near virulence and fitness genes, such ISs disrupting avirulence genes in X. oryzae genomes. In addition, transcriptome analysis under different stress conditions revealed differences in the expression of genes encoding transposases in the Ralstonia solanacearum, X. oryzae, and P. syringae species. Lastly, we also investigated the role of Tns in regulation via small noncoding regulatory RNAs and found these elements may target plant-cell transcriptional activators. Taken together, the results indicate that TEs may have a fundamental role in variability and virulence in plant pathogenic bacteria.
Adaptive response of Pseudomonas aeruginosa under serial ciprofloxacin exposure
Authors: Huynh Thuc Quyen , Tran Nguyen Bao Vy , Pham Thi Thuy Vy , Le Vo Bao Tran , Truong Thien Phu , Huynh Van An , Tong Thi Hang , Trinh Thi Truc Ly , Nguyen Van Dung , Pham Le Nhat Minh , Nguyen Thi Hiep , Lin Qifeng , Lim Teck Kwang , Lin Qingsong , Nguyen Thi Thu Hoai
Published: April 2024

Graphical Abstract

Sub-MICs of ciprofloxacin result in DNA breakage, triggering DNA damage stress and the SOS stress response. This, in turn, induces changes in regulatory factors and the translation machinery. Modifications to regulatory components, including MvaT, RpoS and RpoB, lead to the upregulation (depicted in green) of efflux pumps such as MexEF-OprN and the downregulation (depicted in red) of porins. Additionally, there are alterations in the expression of virulence factors. Concurrently, ciprofloxacin affects metabolic processes, shortens cell lengths and induces the formation of multinucleated filaments due to disruptions in cell replication.
Field comparison of STANDARD™ Q Filariasis Antigen Test (QFAT) with Bioline Filariasis Test Strip (FTS) for the detection of Lymphatic Filariasis in Samoa, 2023
Authors: Scott Jessica L , Mayfield Helen J , Sinclair Jane , Martin Beatris Mario , Howlett Maddison , Muttucumaru Ramona , Won Kimberly Y , Thomsen Robert , Viali Satupaitea , Tofaeono-Pifeleti Rossana , Graves Patricia M , Lau Colleen L
Published: April 2024

Background

To monitor the progress of lymphatic filariasis (LF) elimination programmes, field surveys to assess filarial antigen (Ag) prevalence require access to reliable, user-friendly rapid diagnostic tests. We aimed to evaluate the performance of the new Q Filariasis Antigen Test (QFAT) with the currently recommended Filariasis Test Strip (FTS) for detecting the Ag ofWuchereria bancrofti, the causative agent of LF, under field conditions.

Methodology/Principal Findings

During an LF survey in Samoa, 344 finger-prick blood samples were tested using FTS and QFAT. Microfilariae (Mf) status was determined from blood slides prepared from Ag-positive samples. Each test was re-read at 1 hour and the next day to determine the stability of results over time. Overall Ag-positivity by FTS was 29% and 30% by QFAT. Concordance between the two tests was 94% (Kappa=0.85). Of the 105 Mf slides available, 38.1% were Mf-positive, and all were Ag-positive by both tests. Darker test line intensities from Ag-positive FTS were found to predict Mf-positivity (compared to same/lighter line intensities). QFAT had significantly higher reported test result changes than FTS, mostly reported the next day. The field laboratory team preferred QFAT over FTS due to the smaller blood volume required, better usability, and easier readability.

Conclusion/Significance

QFAT could be a suitable and user-friendly diagnostic alternative for use in the monitoring and surveillance of LF in field surveys based on its similar performance to FTS under field conditions.

Author Summary

Lymphatic filariasis (LF) is a debilitating tropical disease caused by an infection with parasitic filarial worms that are transmitted by mosquitoes. Long-term infection can lead to stigmatising chronic conditions like lymphoedema and elephantiasis. The World Health Organization initiated the global programme to eliminate lymphatic filariasis (GPELF) in 2000, which focuses on the mass administration of anti-LF drugs to stop transmission in endemic countries. However, to monitor the success of this programme and to make informed decisions to stop costly mass drug administrations, it is crucial to have access to accurate and reliable rapid diagnostics. Here, we evaluated the performance of a new rapid antigen test called the Q Filariasis antigen test and compared it to the currently recommended filariasis test strip under field conditions in Samoa. This study showed that the new rapid test could be a suitable alternative to the currently recommended test for use in GPELF-related activities with more user-friendly features.
Distal Protein-Protein Interactions Contribute to SARS-CoV-2 Main Protease Substrate Binding and Nirmatrelvir Resistance
Authors: Lewandowski Eric M. , Zhang Xiujun , Tan Haozhou , Jaskolka-Brown Aiden , Kohaal Navita , Frazier Aliaksandra , Madsen Jesper J. , Jacobs Lian M.C. , Wang Jun , Chen Yu
Published: April 2024

SARS-CoV-2 main protease, Mpro, is responsible for the processing of the viral polyproteins into individual proteins, including the protease itself. Mprois a key target of anti-COVID-19 therapeutics such as nirmatrelvir (the active component of Paxlovid). Resistance mutants identified clinically and in viral passage assays contain a combination of active site mutations (e.g. E166V, E166A, L167F), which reduce inhibitor binding and enzymatic activity, and non-active site mutations (e.g. P252L, T21I, L50F), which restore the fitness of viral replication. Although the mechanism of resistance for the active site mutations is apparent, the role of the non-active site mutations in fitness rescue remains elusive. In this study, we use the model system of a Mprotriple mutant (L50F/E166A/L167F) that confers not only nirmatrelvir drug resistance but also a similar fitness of replication compared to the wild-type both in vitro and in vivo. By comparing peptide and full-length Mproprotein as substrates, we demonstrate that the binding of Mprosubstrate involves more than residues in the active site. In particular, L50F and other non-active site mutations can enhance the Mprodimer-dimer interactions and help place the nsp5-6 substrate at the enzyme catalytic center. The structural and enzymatic activity data of MproL50F, L50F/E166A/L167F, and others underscore the importance of considering the whole substrate protein in studying Mproand substrate interactions, and offers important insights into Mprofunction, resistance development, and inhibitor design.
An exploratory study on becoming a traditional spiritual healer among Baganda in Central Uganda
Authors: Sekagya Yahaya H. K. , Muchunguzi Charles , Unnikrishnan Payyappallimana , Mulogo Edgar M.
Published: April 2024

Traditional medicinal knowledge and healing practices of indigenous spiritual healers play important roles in health care, and contribute towards achieving Universal Health Care. Traditional spiritual healers (TSHs) are grouped into three categories. One category of Baganda TSHs,Balubaale, engage ancestral spirits during health management.Balubaaleare socially significant but not legally accepted. Their initiation and training practices have not been documented in Uganda. The study purpose was to understand and establish the training of traditional spiritual healers. Twelve (10M, 2F); practicing TSHs in Central Uganda were purposively selected and recruited between 15thJuly 2019 and 29thApril 2020, and were prospectively interacted with for 24 months. Transcribed data was coded and thematically analyzed using ATLAS ti. 22 computer software and presented based on an inductive approach. Findings show key areas of TSHs training include connecting with ancestral spirits and the spiritual powers of non-materials and materials such as living and non-living things through rituals. Spiritual healers train in diagnosis and health management based on ancestral spirits and they finally pass out in a communal ceremony witnessed by family and community members. We conclude that TSHs undergo training and are supervised and supported by experienced spiritualists, family and the community. We recommend similar studies among other ethnic groups to contextualize the process of becoming a TSH, compare and harmonize findings to facilitate inter-medical systems communication and policy considerations.
By the numbers and in their own words: A mixed methods study of unmet needs and humanitarian inclusion of older Syrian refugees in Lebanon
Authors: Al Omari Sarah , Honein-AbouHaidar Gladys , Mehio Sibai Abla
Published: April 2024

Older people constitute an overlooked vulnerable population in humanitarian crises. Lebanon is a small country that hosts the largest number of refugees per capita in the world. With exacerbating socioeconomic conditions, exclusionary policies against refugees, and a fragmented humanitarian system, the status of older Syrian refugees (OSRs) requires special attention. This study aimed to explore OSRs’ unmet needs, coping strategies, available humanitarian services, and some indicators of the humanitarian inclusion standards focusing on the shelter, health, nutrition and food security, and water, sanitation and hygiene sectors. We conducted a convergent mixed-methods study between December 2021 and March 2022 in the North and Bekaa, including a cross-sectional survey with 461 participants and 14 semi-structured interviews. Results show that OSRs lived in inappropriate shelters (cold, leaking rainwater), especially in informal tented settlements. High rent prices pushed refugee households with elderly to prioritize paying rent at the expense of other needs such as food and medication, particularly when food cash transfer is the sole source of income, jeopardizing food security and intake. Access to dignifying and accessible bathing facilities was compromised in ITSs with shared facilities. Substantial medical costs hindered OSRs access to healthcare such as surgeries. Due to the crisis, chronic medications are not always available in dispensaries for subsidized cost, pushing OSRs to non-compliance and selling food assistance to buy medications. Soaring fuel prices hindered OSRs access to heating and transportation to receive healthcare. No efforts were reported in collecting data on OSRs’ needs, targeting them with information on services, or soliciting feedback for programming, especially in the absence of any age-tailored interventions. Findings shed light on the precarious living conditions of OSRs in Lebanon and add to the body of evidence documenting their invisibility to the humanitarian response. An age-inclusive response is needed through holistic, tailored, and sustainable interventions.
Shared genetic etiology between hypothyroidism and complex diseases: a large-scale genome-wide cross-trait analysis
Authors: Li Shifang , Gong Meijiao
Published: April 2024

Hypothyroidism is a common condition of thyroid hormone insufficiency, and there is growing evidence of its link with additional diseases. It remains unclear whether these associations share a common genetic architecture. To address this gap, by leveraging summary-level genetic data from the UK Biobank of hypothyroidism and the FinnGen study of three complex diseases (sarcoidosis, chronic sinusitis, and interstitial lung disease (ILD) endpoints), we evaluated their shared genetic etiology. A significant genetic correlation was found between hypothyroidism and the three diseases. Cross-trait analyses utilizing the MTAG and CPASSOC models revealed 12, 2, and 12 shared loci between hypothyroidism and chronic sinusitis, ILD endpoints, and sarcoidosis, respectively. The SNP heritability enrichment analysis across 37 tissues and 136 cell types at the single-cell level identified candidate tissues and cell types that were shared by the diseases. Interestingly, we found a positive genetic relationship between these four diseases and central memory CD4+ T cells in the blood, supported by strong colocalization evidence (posterior probability >0.9). Mendelian randomization and colocalization analysis showed a link between hypothyroidism and sarcoidosis with two genes (DOCK6 and CD226) in the blood. Furthermore, among the hypothyroidism-driven plasma proteins, RIPK2 was identified as a potentially actionable mediator of hypothyroidism’s effect on ILD endpoints. Overall, our findings contribute to improving our understanding of the molecular basis of these diseases’ intricate relationships, as well as providing insights toward disease prevention and comorbidity management.
Generative Modeling of the Circle of Willis Using 3D-StyleGAN
Authors: Aydin Orhun Utku , Hilbert Adam , Koch Alexander , Lohrke Felix , Rieger Jana , Tanioka Satoru , Frey Dietmar
Published: April 2024

The circle of Willis (CoW) is a network of cerebral arteries with significant inter-individual anatomical variations. Deep learning has been used to characterize and quantify the status of the CoW in various applications for the diagnosis and treatment of cerebrovascular disease. In medical imaging, the performance of deep learning models is limited by the diversity and size of training datasets. To address medical data scarcity, generative adversarial networks (GANs) have been applied to generate synthetic vessel neuroimaging data. However, the proposed methods produce synthetic data with limited anatomical fidelity or downstream utility in tasks concerning vessel characteristics.

We adapted the StyleGANv2 architecture to 3D to synthesize Time-of-Flight Magnetic Resonance Angiography (TOF MRA) volumes of the CoW. For generative modeling, we used 1782 individual TOF MRA scans from 6 open source datasets. To train the adapted 3D StyleGAN model with limited data we employed differentiable data augmentations and used mixed precision and a cropped region of interest of size 32×128×128 to tackle computational constraints. The performance was evaluated quantitatively using the Fréchet Inception Distance (FID), MedicalNet distance (MD) and Area Under the Curve of the Precision and Recall Curve for Distributions (AUC-PRD). Qualitative analysis was performed via a visual Turing test. We demonstrated the utility of generated data in a downstream task of multiclass semantic segmentation of CoW arteries. Vessel segmentation performance was assessed quantitatively using the Dice coefficient and the Hausdorff distance.

The best-performing 3D StyleGANv2 architecture generated high-quality and diverse synthetic TOF MRA volumes (FID: 12.17, MD: 0.00078, AUC-PRD: 0.9610). Multiclass vessel segmentation models trained on synthetic data alone achieved comparable performance to models trained using real data in most arteries.

In conclusion, generative modeling of the Circle of Willis via synthesis of 3D TOF MRA data paves the way for generalizable deep learning applications in cerebrovascular disease. In the future, the extensions of the provided methodology to other medical imaging problems or modalities with the inclusion of pathological datasets has the potential to advance the development of more robust models for clinical applications.
Comparing microbiological and molecular diagnostic tools for the surveillance of anthrax
Authors: Ochai Sunday O. , Hassim Ayesha , Dekker Edgar H. , Magome Thuto , Lekota Kgaugelo E. , Makgabo S. Marcus , de Klerk-Loris Lin-Mari , van Schalkwyk O. Louis , Kamath Pauline L. , Turner Wendy C. , van Heerden Henriette
Published: April 2024

The diagnosis of anthrax, a zoonotic disease caused byBacillus anthraciscan be complicated by detection of closely related species. Conventional diagnosis of anthrax involves microscopy, culture identification of bacterial colonies and molecular detection. Genetic markers used are often virulence gene targets such asBacillus anthracisprotective antigen (pagA,as also called BAPA, occurring on plasmid pXO1), lethal factor (lef,on pXO1), as well as chromosomal (Ba-1) and plasmid (capsule-encodingcapB/C, located on pXO2). Combinations of genetic markers using real-time/quantitative polymerase chain reaction (qPCR) are used to confirmB. anthracisfrom culture but can also be used directly on diagnostic samples to avoid propagation and its associated biorisks and for faster identification. We investigated how the presence of closely related species could complicate anthrax diagnoses with and without culture to standardise the use of genetic markers using qPCR for accurate anthrax diagnosis. Using blood smears from 2012-2020 from wildlife mortalities (n=1708) in Kruger National Park in South Africa where anthrax is endemic, we contrasted anthrax diagnostic results based on qPCR, microscopy, and culture. From smears, 113/1708 grew bacteria in culture, from which 506 isolates were obtained. Of these isolates, only 24.7% (125 isolates) were positive forB. anthracisbased on genetic markers or microscopy. However, among these, merely 4/125 (3.2%) were confirmedB. anthracisisolates (based on morphology, microscopy, and sensitivity testing to penicillin and gamma-phage) from the blood smear, likely due to poor survival of spores on stored smears. This study identifiedB. cereus sensu lato, which includedB. cereusandB. anthracis, Peribacillus spp., andPriestia spp.clusters usinggyrB gene in selected bacterial isolates positive for BAPA. Using qPCR on blood smears, 52.1% (890 samples) tested positive forB. anthracisbased on one or a combination of genetic markers which included the 25 positive controls. Notably, the standardlefprimer set displayed the lowest specificity and accuracy. Interestingly, various marker combinations, such as Ba-1+capB, BAPA+capB, Ba-1+BAPA+capB+lef, and BAPA+lef+capB, all demonstrated 100.0% specificity and 98.7% accuracy, while maintaining a sensitivity of 96.6%. The BAPA+lef+Ba-1 combination showed 100% specificity, sensitivity, and accuracy. Using Ba-1+BAPA+lef+capB, as well as Ba-1+BAPA+lefwith molecular diagnosis accurately detectsB. anthracisin the absence of bacterial culture. Systematically combining microscopy and molecular markers holds promise for notably reducing false positives, thereby significantly enhancing the detection and surveillance of diseases like anthrax in southern Africa and beyond and reducing the need for propagation of the bacteria in culture.
VIRAL LOAD SUPPRESSION AND ASSOCIATED FACTORS AMONG HIV-INFECTED PATIENTS ON SECOND-LINE ANTIRETROVIRAL THERAPY AT PUBLIC HEALTH FACILITIES OF WEST GUJI, GUJI AND BORENA ZONES, SOUTHERN ETHIOPIA: FACILITY BASED CROSS-SECTIONAL STUDY
Authors: Hailu Digafe , Jara Dube , Edin Alo , Awol Abdurazak , Ayele Angefa , Fekadu Yohannes , Endale Dereje , Gelchu Miesa , Lemma Kebebew
Published: April 2024

Background

Ethiopia is one of the nation’s most severely impacted by HIV, with an estimated 700,000 people living with HIV/AIDS. Hence, many health facilities were providing second-line antiretroviral therapy, however little was known about viral load suppression among second-line users. This study aimed to assess the proportion of viral load suppression and associated factors among HIV-infected patients on second-line antiretroviral therapy at public health facilities of west Guji, Guji and Borena zones, Southern Ethiopia.

Methods

A facility-based cross-sectional study was conducted among 256 HIV-infected patients on second-line antiretroviral therapy from January 1, 2019, to December 30, 2022, by using census after obtaining ethical clearance from Bule Hora University ethical review committee. Data were extracted using a structured, pre-tested checklist, entered into the EPI data version 3.1.0, and exported to SPSS version 25 for analysis. The proportion of viral load suppression was determined. A binary logistic regression model was fitted to identify factors associated with viral load suppression. Statistical significance was declared at a 95% confidence interval (CI) with a P-value <0.05.

Results

This study revealed that the proportion of viral load suppression among HIV-infected patients on second-line antiretroviral therapy was 73.8% (95% CI, 68.0–79.1). Those who missed the second-line antiretroviral regimen [AOR = 0.315, 95% CI (0.162–0.612)], a baseline viral load count of <10,000 copies/mm3 [AOR = 2.291, 95% CI (1.216-4.316)], and a baseline body mass index of ≥18.5 kg/m2 [AOR = 2.438, 95% CI (1.098–5.414)] were significantly associated with viral load suppression.

Conclusions

The proportion of patients with viral load suppression fell below the WHO’s and national level. Viral load suppression was significantly influenced by missed second-line antiretroviral doses, a baseline viral load count of <10,000 copies/ml, and a baseline body mass index of ≥18.5 kg/m2. Hence interventions targeting counseling to patients that missed their antiretroviral therapy, keeping patient’s viral load to be less than 10,000 copies/ml through adequate adherence counseling among second-line antiretroviral therapy were recommended.
Factors influencing survival outcomes in patients with stroke in Zimbabwe: A 12-month longitudinal study
Authors: Kaseke Farayi , Gwanzura Lovemore , Musarurwa Cuthbert , Gori Elizabeth , Nyengerai Tawanda , Kaseke Timothy , Stewart Aimee
Published: April 2024

Background

In this longitudinal study, we aimed to determine factors influencing survival outcomes among patients with stroke over a 12-month period. The investigation sought to uncover influential determinants to enhance the precision of prognostic assessments and inform targeted interventions for individuals affected by strokes.

Methods

Employing a longitudinal study design, participants were observed for 12 months from baseline, censoring survivors at the endpoint. The dataset originated from a comprehensive study involving stroke patients treated at three referral hospitals in Zimbabwe: Parirenyatwa, Sally Mugabe, and Chitungwiza Central Hospital. The primary outcome variable, the duration of survival until death, was measured in days from the initiation of stroke treatment. Gompertz parametric regression analysis was utilized for data modeling following Accelerated Failure Time (AFT) model diagnostics.

Results

In our study, 188 stroke patients were enrolled at baseline. However, 51 patients were excluded from the analysis due to either missing information or loss to follow-up. Among the remaining 137 patients who were tracked over a 12-month period, 42% were censored, and 58% were deceased. Individuals utilizing ’Free Service (older than 65/pensioners/retirees)’ hospital bill payment methods showed a decreased risk of death (HR: 0.4, 95% CI: 0.20, 0.80), suggesting a protective effect compared to cash paying patients. Those with a secondary school level education displayed a significantly lower risk of death (HR: 0.2, 95% CI: 0.04, 0.69) compared to those without formal education. Age was a significant factor, with individuals aged 45-65 and those over 65 years showing higher adjusted hazard ratios (HR: 4.9, 95% CI: 1.80, 13.25; HR: 5.5, 95% CI: 1.92, 15.95, respectively) relative to those below 45 years of age. Housing status revealed a protective effect for those residing with parents/relatives (adjusted HR: 0.4, 95% CI: 0.20, 0.66), while individuals with a ’Very severe’ functional outcome showed an increased hazard (adjusted HR: 4.9, 95% CI: 1.12, 21.33).

Conclusion

The study findings demonstrate that hospital bill payment methods, housing status, educational attainment, functional outcome, and age significantly affect survival outcomes among stroke patients. This highlights the need to consider socio-demographic and clinical variables in the development of prognostic assessments and targeted interventions for individuals recovering from stroke.
Cas9 RNP Physiochemical Analysis for Enhanced CRISPR-AuNP Assembly and Function
Authors: Lane Daniel D. , Gottimukkala Karthikeya S.V. , Cunningham Rachel A. , Jwa Shirley , Cassidy Molly E. , Castelli Jack M.P. , Adair Jennifer E.
Published: April 2024

CRISPR therapy for hematological disease has proven effective for transplant dependent beta thalassemia and sickle cell anemia, with additional disease targets in sight. The success of these therapies relies on high rates of CRISPR-induced double strand DNA breaks in hematopoietic stem and progenitor cells (HSPC). To achieve these levels, CRISPR complexes are typically delivered by electroporation ex vivo which is toxic to HSPCs. HSPCs are then cultured in stimulating conditions that promote error-prone DNA repair, requiring conditioning with chemotherapy to facilitate engraftment after reinfusion. In vivo delivery by nanocarriers of CRISPR gene editing tools has the potential to mitigate this complexity and toxicity and make this revolutionary therapy globally available. To achieve in vivo delivery, the inherent restriction factors against oligonucleotide delivery into HSPCs, that make ex vivo manipulation including electroporation and stimulation essential, must be overcome. To this end, our group developed a CRISPR carrying gold nanoparticle (CRISPR-AuNP) capable of delivering either Cas9 or Cas12a CRISPRs as ribonucleoprotein complexes (RNP) without compromising HSPC fitness. However, the most commonly used CRISPR, Cas9, demonstrated inconsistent activity in this delivery system, with lower activity relative to Cas12a. Investigation of Cas9 RNP biophysics relative to Cas12a revealed duplex RNA instability during the initial loading onto Au cores, resulting in undetectable Cas9 loading to the particle surface. Here we demonstrate preformation of RNP before loading, coupled with optimization of the loading chemistry and conditions, resulted in 39.6 ± 7.0 Cas9 RNP/AuNP without compromising RNP activity in both in vitro assays and primary human HSPC. The same alterations improved Cas12a RNP/AuNP loading 10-fold over previously reported levels. To achieve particle stability, the reported polyethyleneimine outer coating was altered to include PEGylation and the resulting 2ndgeneration CRISPR-AuNP demonstrates favorable nanoformulation characteristics for in vivo administration, with a hydrophilic, more neutral nanoparticle surface. Direct treatment of HSPC in vitro showed 72.5 ± 7.37% uptake of 2ndgeneration CRISPR-AuNP in primary human HSPC, but with endosomal accumulation and low rates of gene editing consistent with low levels of endosomal escape.