bluuebunny/crossref_metadata_2025 huggingface dataset:
Exploring Factors Influencing Adherence to HIV Medication among patients using Community Pharmacies and Public Hospital: A Qualitative Study
Authors: Olaleye Odunayo Betty , Ilesanmi Olayinka Stephen
Published: April 2024

Introduction

HIV/AIDS is a major global health emergency as it is estimated that close to 40 million people live with HIV/AIDS, among which the majority are adults. Despite the availability of ARVs at community, secondary, and tertiary health facilities in Nigeria, adherence rates remain low. This study conducted in Ibadan, Nigeria, investigated factors influencing adherence to antiretroviral therapy (ART) among HIV patients.

Methods

The research employed a cross-sectional approach, utilizing qualitative techniques, including in-depth interviews (IDI) with patients and key informant interviews (KII) with healthcare providers and pharmacists. The target population consisted of HIV patients receiving ART at the Community Pharmacies and Public Hospital University in Ibadan. Data saturation determined sample sizes for the interviews.

Results

In the in-depth interviews, two primary themes emerged from the findings: “Socio-economic factors influencing adherence” and “Factors related to the process of care.” Socio-economic factors encompassed issues such as transportation costs, societal pressure, food costs, advice from third parties, and religious reasons. These factors were further categorized into economic reasons and societal pressure/misinformation, shedding light on patients’ challenges and choices. Factors related to the process of care included the cost of medication, side effects, drug-drug interactions, the quantity and duration of drug use, and discontinuation after feeling better.

Key informant interviews with healthcare providers and pharmacists revealed insights into compliance by gender, financial constraints, and treatment-related factors such as side effects, drug interactions, and medication volume. Socio Cultural and religious factors, including advice from third parties, stigmatization, disclosure of status to partners, social support, and religious beliefs, played significant roles in influencing patients’ adherence.

Conclusion

These findings shed light on the complex interplay of factors affecting ART adherence and highlight the importance of considering economic, social, and medical aspects when designing interventions to improve adherence in HIV care. The study’s findings hold implications for healthcare programs and interventions aimed at enhancing the quality of care and support for HIV patients, particularly in resource-limited settings like Southwestern Nigeria.
Emergence of SARS-CoV-2 Omicron Variant JN.1 in Tamil Nadu, India - Clinical Characteristics and Novel Mutations
Authors: Selvavinayagam Sivaprakasam T. , Sankar Sathish , Yong Yean K. , Murugesan Amudhan , Suvaithenamudhan Suvaiyarasan , Hemashree Kannan , Rajeshkumar Manivannan , Kumaresan Anandhazhvar , Pandey Ramendra P. , Shanmugam Saravanan , Arthydevi Parthiban , Kumar Masilamani S. , Gopalan Natarajan , Kannan Meganathan , Cheedarla Narayanaiah , Tan Hong Y. , Zhang Ying , Larsson Marie , Balakrishnan Pachamuthu , Velu Vijayakumar , Byrareddy Siddappa N. , Shankar Esaki M. , Raju Sivadoss
Published: April 2024

In December 2023, we observed a notable shift in the COVID-19 landscape, when the JN.1 emerged as a predominant SARS-CoV-2 variant with a 95% incidence. We characterized the clinical profile, and genetic changes in JN.1, an emerging SARS-CoV-2 variant of interest. Whole genome sequencing was performed on SARS-CoV-2 positive samples, followed by sequence analysis. Mutations within the spike protein sequences were analyzed and compared with the previous lineages and sublineages of SARS-CoV-2, to identify the potential impact of these unique mutations on protein structure and possible functionality. Several unique and dynamic mutations were identified herein. Our data provides key insights into the emergence of newer variants of SARS-CoV-2 in our region and highlights the need for robust and sustained genomic surveillance of SARS-CoV-2.
How many microbial species are there in human tumor and normal tissues?
Authors: Ma Zhanshan (Sam)
Published: April 2024

The study of tissue microbiomes is a recent endeavor in human microbiome research, particularly in the area of blood microbiomes. This is primarily due to their low biomass, which presents inadvertent operational contamination as a significant experimental obstacle. The critical role of the tissue microbiomes in cancer development has brought this topic to the forefront of cancer research. However, a fundamental question regarding the potential biodiversity, as stated in the title, has not been addressed to our knowledge. In this study, we estimate the potential microbial diversity or “dark” biodiversity in human tumor and normal tissues using the Diversify-Area Relationship (DAR) method (Ma 2018, 2019) based on large datasets from TCGA (The Cancer Genome Atlas) database (Pooreet al. 2021). We found that the total species richness (number), typical species equivalents (number), and dominant species equivalents (number) of tumor tissues are approximately 1948, 36, and 22, respectively. Among the total species richness, the proportions of archaea, bacteria, and viruses are about 3%-5%, 78%-79%, and 17%-18%, respectively. Moreover, the tissue species richness is approximately 12.5% of skin microbiomes, and 25% of gut microbiomes. We also found that tumor growth does not significantly influence the global or pan-tumor scale diversity, which means that the previous numbers also represent the potential microbial diversity of human tissues, including blood. On a local or single cancer-type scale, tumors may influence the potential diversity in approximately 5% of cases. We hypothesize that, globally, local diversity variations would offset each other.

Lay Summary

This study focused on microbiomes - the tiny microbes that live in our tissues, especially blood. Studying them is challenging due to their low biomass and risk of contamination. Microbiomes may play a key role in cancer, but their diversity within tissues remains unclear. Using diversity-area relationship modeling with data from “The Cancer Genome Atlas” database, we estimated the potential microbial diversity of human tumor and normal tissues. We found approximately 1,948 microbial species in tumors, comprising archaea (5%), bacteria (78%) and viruses (17%). However, dominant or common microbial species number only about two to three dozen. Tissue microbe diversity was 12.5% of that found in skin microbiomes and 25% of gut microbiomes. Tumor growth did not significantly impact overall diversity. Therefore, the previous diversity numbers also represent the microbiome diversity of general human tissues and blood. However, some cancer types may affect it locally. While local diversity changes can occur, globally these variations between tissues likely balance out.
Hemispheric difference of adaptation lifetime in human auditory cortex measured with MEG
Authors: Dar Asim H , Haertwich Nina , Hajizadeh Aida , Brosch Michael , Koenig Reinhard , May Patrick J. C.
Published: April 2024

Adaptation is the attenuation of a neuronal response when a stimulus is repeatedly presented. The phenomenon has been linked to sensory memory, but its exact neuronal mechanisms are under debate. One defining feature of adaptation is its lifetime, that is, the timespan over which the attenuating effect of previous stimulation persists. This can be revealed by varying the stimulus-onset interval (SOI) of the repeated stimulus. As SOI is increased, the peak amplitude of the response grows before saturating at large SOIs. The rate of this growth can be quantified and used as an estimate of adaptation lifetime. Here, we studied whether adaptation lifetime varies across the left and the right auditory cortex of the human brain. Event-related fields of whole-head magnetoencephalograms (MEG) were measured in 14 subjects during binaural presentation of pure tone stimuli. To make statistical inferences on the single-subject level, additional event-related fields were generated by resampling the original single-trial data via bootstrapping. For each hemisphere and SOI, the peak amplitude of the N1m response was then derived from both original and bootstrap-based data sets. Finally, the N1m peak amplitudes we used for deriving subject- and hemisphere-specific estimates of adaptation lifetime. Comparing subject-specific adaptation lifetime across hemispheres, we found a significant difference, with longer adaptation lifetimes in the left than in the right auditory cortex (p = 0.004). This difference might have a functional relevance in the context of temporal binding of auditory stimuli, leading to larger integration time windows in the left than in the right hemisphere.
Antibody-mediated cellular responses are dysregulated in Multisystem Inflammatory Syndrome in Children (MIS-C)
Authors: Dick Jenna K , Sangala Jules A , Krishna Venkatramana D , Khaimraj Aaron , Hamel Lydia , Erickson Spencer M , Hicks Dustin , Soigner Yvette , Covill Laura E , Johnson Alexander , Ehrhardt Michael J , Ernste Keenan , Brodin Petter , Koup Richard A , Khaitan Alka , Baehr Carly , Thielen Beth K , Henzler Christine M , Skipper Caleb , Miller Jeffrey S , Bryceson Yenan T , Wu Jianming , John Chandy C , Panoskaltsis-Mortari Angela , Orioles Alberto , Steiner Marie E , Cheeran Maxim C-J , Pravetoni Marco , Hart Geoffrey T
Published: April 2024

Multisystem Inflammatory Syndrome in Children (MIS-C) is a severe complication of SARS-CoV-2 infection characterized by multi-organ involvement and inflammation. Testing of cellular function ex vivo to understand the aberrant immune response in MIS-C is limited. Despite strong antibody production in MIS-C, SARS-CoV-2 nucleic acid testing can remain positive for 4-6 weeks after infection. Therefore, we hypothesized that dysfunctional cell-mediated antibody responses downstream of antibody production may be responsible for delayed clearance of viral products in MIS-C. In MIS-C, monocytes were hyperfunctional for phagocytosis and cytokine production, while natural killer (NK) cells were hypofunctional for both killing and cytokine production. The decreased NK cell cytotoxicity correlated with an NK exhaustion marker signature and systemic IL-6 levels. Potentially providing a therapeutic option, cellular engagers of CD16 and SARS-CoV-2 proteins were found to rescue NK cell function in vitro. Together, our results reveal dysregulation in antibody-mediated cellular responses unique to MIS-C that likely contribute to the immune pathology of this disease.
Localised Astrocyte Ca2+ Activity Regulates Neurovascular Coupling Responses to Active Sensing
Authors: Stelzner Jakob Akbar , Krogsgaard Aske , Kulkoviene Gabriele , Sperling Leonora , Lind Barbara Lykke
Published: April 2024

Neurovascular coupling (NVC) ensures sufficient and targeted blood flow during increased neuronal activity. Astrocytic participation in NVC has long been debated, likely due to the intricacy of the intracellular Ca2+ fluxes and the diversity of their regulatory capacities. As astrocyte signaling changes with brain states, we focused on their involvement in voluntary sensing in freely behaving mice. We used 2-photon microscopy to record cellular and vascular activity in the whisker barrel cortex of awake head-fixed animals. The NVC initiated by volitional whisking in the resting mouse was compared to the whisking preceding locomotion and experimenter-evoked whisker deflections. We developed an analysis method to detect early, subcellular astrocytic activity and found it corresponded with neuronal and vascular responses under all three conditions. After the depletion of noradrenaline (NA), the early astrocytic Ca2+ response to volitional whisking was only moderately reduced and primarily in astrocytic processes closest to the blood vessels. Meanwhile, the dilation of 1storder capillaries was also reduced. Together, these findings demonstrate significant disruptions in the focal regulation of cerebral blood flow, potentially limiting the sustenance of activated neurons. This disruption appeared to translate into behavioral aberrations, as NA-depleted mice exhibited an extended period of exploratory whisking prior to locomotion. Remarkably, NA-depletion did not alter cellular or blood flow responses to locomotion or experimenter-evoked whisking. Our study confirms an astrocytic contribution to NVC, which is relevant during volitional sensing. It also suggests that self-directed sensory processing depends on an appropriate NVC response, which itself depends on NA and astrocyte activity.
Lipid Nanoparticle-Associated Inflammation is Triggered by Sensing of Endosomal Damage: Engineering Endosomal Escape Without Side Effects
Authors: Omo-Lamai Serena , Wang Yufei , Patel Manthan N. , Essien Eno-Obong , Shen Mengwen , Majumdar Aparajeeta , Espy Carolann , Wu Jichuan , Channer Breana , Tobin Michael , Murali Shruthi , Papp Tyler E. , Maheshwari Rhea , Wang Liuqian , Chase Liam S. , Zamora Marco E. , Arral Mariah L. , Marcos-Contreras Oscar A. , Myerson Jacob W. , Hunter Christopher A. , Tsourkas Andrew , Muzykantov Vladimir , Brodsky Igor , Shin Sunny , Whitehead Kathryn A. , Gaskill Peter , Discher Dennis , Parhiz Hamideh , Brenner Jacob S.
Published: April 2024

Lipid nanoparticles (LNPs) have emerged as the dominant platform for RNA delivery, based on their success in the COVID-19 vaccines and late-stage clinical studies in other indications. However, we and others have shown that LNPs induce severe inflammation, and massively aggravate pre-existing inflammation. Here, using structure-function screening of lipids and analyses of signaling pathways, we elucidate the mechanisms of LNP-associated inflammation and demonstrate solutions. We show that LNPs’ hallmark feature, endosomal escape, which is necessary for RNA expression, also directly triggers inflammation by causing endosomal membrane damage. Large, irreparable, endosomal holes are recognized by cytosolic proteins called galectins, which bind to sugars on the inner endosomal membrane and then regulate downstream inflammation. We find that inhibition of galectins abrogates LNP-associated inflammation, bothin vitroandin vivo. We show that rapidly biodegradable ionizable lipids can preferentially create endosomal holes that are smaller in size and reparable by the endosomal sorting complex required for transport (ESCRT) pathway. Ionizable lipids producing such ESCRT-recruiting endosomal holes can produce high expression from cargo mRNA with minimal inflammation. Finally, we show that both routes to non-inflammatory LNPs, either galectin inhibition or ESCRT-recruiting ionizable lipids, are compatible with therapeutic mRNAs that ameliorate inflammation in disease models. LNPs without galectin inhibition or biodegradable ionizable lipids lead to severe exacerbation of inflammation in these models. In summary, endosomal escape induces endosomal membrane damage that can lead to inflammation. However, the inflammation can be controlled by inhibiting galectins (large hole detectors) or by using biodegradable lipids, which create smaller holes that are reparable by the ESCRT pathway. These strategies should lead to generally safer LNPs that can be used to treat inflammatory diseases.
Different functions of Lhcx isoforms in photoprotective mechanism in the marine diatomThalassiosira pseudonana
Authors: Nakayasu Mana , Akimoto Seiji , Yoneda Kohei , Ikuta Soichiro , Shimakawa Ginga , Matsuda Yusuke
Published: April 2024

Photosynthesis needs light energy, but that exceeding the maximal capacity of photosynthesis enhances formation of reactive oxygen species, which potentially causes photodamages. Therefore, light-harvesting complexes (Lhc) in phototrophs harbor various proteins and pigments to function in both light capture and energy dissipation. Diatom Lhcx proteins are reported to be a critical component for thermal dissipation of excess light energy, but the molecular mechanism of photoprotection is still not fully understood and the functions of each Lhcx isoform are not yet differentiated. Here, we focused on two types of Lhcx isoforms inThalassiosira pseudonana: TpLhcx1/2, putative major components for energy-dependent fluorescence quenching (qE); and TpLhcx6_1, functionally unknown isoform uniquely conserved in Thalassiosirales. TpLhcx1/2 proteins accumulated more under high light than under low light, while the TpLhcx6_1 protein level was constitutive irrespective of light intensities and CO2 concentrations. High-light induced photodamage of photosystem II was increased in the genome-editing transformants of these Lhcx isoforms relative to the wild-type. Transformants lacking TpLhcx1/2 showed significantly lowered qE capacities, strongly suggesting that these proteins are important for the fast thermal energy dissipation. While in contrast, genome-editing transformants lacking the TpLhcx6_1 protein rather increased the qE capacity. TpLhcx6_1 transformants were further evaluated by the low-temperature time-resolved chlorophyll fluorescence measurement, showing the longer fluorescence lifetime in transformants than that in the wild type cells even at the dark-acclimated state of these cells. These results suggest that TpLhcx6_1 functions in photoprotection through non-photochemical energy dissipation in the different way from qE.

One sentence summary

The marine diatomThalassiosira pseudonanadissipates excess light energy for photoprotectionviatwo types of mechanisms supported by different Lhc isofoms.
Gamified closed-loop non-pharmacological intervention enhances tic suppression in children
Authors: Rotstein Michael S. , Zimmerman-Brenner Sharon , Davidovitch Shiri , Ben-Haim Yael , Koryto Yuval , Sion Romi , Rubinstein Einat , Djerassi Meshi , Lubiniaker Nitzan , Peleg Tammy Pilowsky , Steinberg Tamar , Leitner Yael , Raz Gal
Published: April 2024

Background

Thegamificationof behavioral intervention for tic disorders (TDs) may not only enhance compliance with treatment protocols but also offer a key clinical advantage. By providing immediate positive feedback when tics are suppressed, games can counteract negative reinforcement processes that reinforce tics, which assumingly alleviates unpleasant premonitory urges. We developed a gamified protocol (XTics), which leverages this potential by combining gamified tic triggers with immediate reinforcement of tic suppression. We evaluate the clinical value of immediate reward contingency in enhancing tic suppression performance.

Methods

XTics comprises two conditions: tic-contingent and non-contingent. In the ticcontingent version, game progression was determined by real-time input from an experimenter who monitored the participant’s tics, rewarding tic suppression with favorable outcomes. Conversely, in the non-contingent version, game events occurred randomly. Using a crossover design, we trained 35 participants (aged 7-15) in both versions, with each participant undergoing a preliminary behavioral training and three hourly sessions for each condition. We both evaluated the overall protocol’s four-week impact on tic severity measures and compared contingent and non-contingent conditions.

Results

We achieved complete adherence to the protocol, while the participants increased their tic-free intervals by an average of 558% from the first to the last training day. YGTSS, a clinical measure of tic severity, showed an average clinically meaningful reduction of 25.69±23.39%, which was larger than that observed in control interventions and comparable to the effects of longer non-pharmacological treatments. Parent-reported tic severity decreased by 42.99±31.69% from baseline to three months post-treatment. When contrasting the ticcontingent with the tic-non-contingent training versions, we observed a larger improvement in tic-free interval duration in the former case (t(67)=3.15, p=.0025). Additionally, Rush, another measure of tic severity, demonstrated a greater reduction following training with the contingent compared to the non-contingent version (t(47)=3.47, p=.002).

Conclusion

The combination of gamified tic triggering with immediate and contingent rewards demonstrates a promising approach for enhancing treatment efficacy in TDs, offering an engaging boost to traditional therapeutic methods.
Integrating Preconception Risk Assessment and Counseling with Primary Health Care: A Feasibility Assessment
Authors: Dunlop Anne L. , Alfonso Susana , Hansen Nora , Williams Dionne , Marshall Ariela L. , Anderson Victoria M.
Published: April 2024

Background

Professional association recommendations call for integrating preconception health promotion with primary care, yet there are scarce tools and implementation research to support practices in doing so.

Purpose

To evaluate the feasibility of integrating a preconception health digital risk assessment and virtual coaching into women’s primary care encounters.

Methods

In the Emory Family Medicine Clinic (Atlanta, Georgia), female patients 21-40 years of age with a well-woman or chronic condition encounter scheduled between 9/1/2022 and 5/1/2023 were invited to participate. Consenting patients were provided theFrame Your Futureweblink to complete the digital risk assessment followed by virtual counseling, and their family physicians were provided with a pdf summary to discuss during the primary care encounter. Demographic and clinical information was collected via medical record abstraction and patient and physician experiences via survey.

Results

Of 46 enrolled patients, 44 (96%) made a Frame account, 38 (86%) completed the risk assessment, 34 (89%) completed virtual coaching, and 24 (71%) had a physician discuss their preconception health assessment during the primary care encounter. Nearly 80% of patients reported an increase in confidence in discussing fertility with their physician, and 50% reported they would not otherwise have brought up fertility and preconception health during the encounter. Both patients and physicians were satisfied with the process and viewed it as helping motivate positive changes in patient health and health behaviors.

Conclusion

The completion of preconception digital risk assessment and virtual counseling facilitates discussion of preconception health during primary care encounters and shows promise for improving women’s health.
Projecting international mpox spread in Asia: ongoing global health risk
Authors: Asakura Toshiaki R. , Jung Sung-mok , Murayama Hiroaki , Ghaznavi Cyrus , Sakamoto Haruka , Teshima Ayaka , Miura Fuminari , Endo Akira
Published: April 2024

The global mpox outbreak affected many Asian countries in 2023, following a sustained local transmission in Japan. Given the large population sizes and limited vaccine rollout in Asia, the potential risk of global mpox reemergence arising from Asia is of concern. Using a mathematical model incorporating heterogeneous sexual networks among MSM, calibrated to incidence data in Japan, we projected the patterns of international mpox spread across 42 Asian countries. Our simulations highlight countries at a high risk of mpox introductions, many of which were low- and middle-income countries (LMICs) in South-eastern Asia. Our analysis also suggests a shifting focus of importation risk from Eastern Asia to South-eastern Asia, and subsequently to Central, Southern and Western Asia, which roughly coincided with the observed spread patterns in 2023. Global cooperation and support are warranted, especially for LMICs with an elevated risk of mpox introduction, to minimise the risk of continued circulation in Asia and beyond.
Topical Steroid Withdrawal is a Targetable Excess of Mitochondrial NAD+
Authors: Shobnam Nadia , Saksena Sarini , Ratley Grace , Yadav Manoj , Chaudhary Prem Prashant , Sun Ashleigh A , Howe Katherine N , Gadkari Manasi , Franco Luis M , Ganesan Sundar , McCann Katelyn J , Hsu Amy P , Kanakabandi Kishore , Ricklefs Stacy , Lack Justin , Yu Weiming , Similuk Morgan , Walkiewicz Magdalena A ,   NIAID Centralized Sequencing Program, Gardner Donna D , Barta Kelly , Tullos Kathryn , Myles Ian A
Published: April 2024

Background

Topical corticosteroids (TCS) are first-line therapies for numerous skin conditions. Topical Steroid Withdrawal (TSW) is a controversial diagnosis advocated by patients with prolonged TCS exposure who report severe systemic reactions upon treatment cessation. However, to date there have been no systematic clinical or mechanistic studies to distinguish TSW from other eczematous disorders.

Methods

A re-analysis of a previous survey with eczematous skin disease was performed to evaluate potential TSW distinguishing symptoms. We subsequently conducted a pilot study of 16 patients fitting the proposed diagnostic criteria. We then performed: tissue metabolomics, transcriptomics, and immunostaining on skin biopsies; serum metabolomics and cytokine assessments; shotgun metagenomics on microbiome skin swabs; genome sequencing; followed by functional, mechanistic studies using human skin cell lines and mice.

Results

Clinically distinct TSW symptoms included burning, flushing, and thermodysregulation. Metabolomics and transcriptomics both implicated elevated NAD+ oxidation stemming from increased expression of mitochondrial complex I and conversion of tryptophan into kynurenine metabolites. These abnormalities were induced by glucocorticoid exposure bothin vitroand in a cohort of healthy controls (N=19) exposed to TCS. Targeting complex I via either metformin or the herbal compound berberine improved outcomes in both cell culture and in an open-label case series for patients with TSW.

Conclusion

Taken together, our results suggest that TSW has a distinct dermatopathology. While future studies are needed to validate these results in larger cohorts, this work provides the first mechanistic evaluation into TSW pathology, and offers insights into clinical identification, pharmacogenomic candidates, and directed therapeutic strategies.
Immune escape and attenuated severity associated with the SARS-CoV-2 BA.2.86/JN.1 lineage
Authors: Lewnard Joseph A. , Mahale Parag , Malden Debbie , Hong Vennis , Ackerson Bradley K. , Lewin Bruno J. , Link-Gelles Ruth , Feldstein Leora R. , Lipsitch Marc , Tartof Sara Y.
Published: April 2024

The SARS-CoV-2 BA.2.86 lineage, and its sublineage JN.1 in particular, achieved widespread transmission in the US during winter 2023-24. However, the increase in infections was not accompanied by increases in COVID-19 hospitalizations and mortality commensurate with prior waves. To understand shifts in COVID-19 epidemiology associated with JN.1 emergence, we compared characteristics and clinical outcomes of time-matched cases infected with BA.2.86- derived lineages (predominantly representing JN.1) versus co-circulating XBB-derived lineages in December, 2023 and January, 2024. Cases infected with BA.2.86-derived lineages received greater numbers of COVID-19 vaccine doses, including XBB.1.5-targeted and BA.4/BA.5-targeted boosters, in comparison to cases infected with XBB-derived lineages. Additionally, cases infected with BA.2.86-derived lineages experienced greater numbers of documented prior SARS-CoV-2 infections. These associations of BA.2.86-derived lineages with immune escape were confirmed when comparing cases diagnosed during periods when JN.1 was the predominant circulating lineage to cases diagnosed during November, 2023. Cases infected with BA.2.86-derived lineages, or during periods when JN.1 was the predominant circulating lineage, also experienced lower risk of progression to severe clinical outcomes requiring emergency department consultations or hospital admission. Sensitivity analyses suggested under-ascertainment of prior infections, even if differential between cases infected with BA.2.86-derived lineages and non-BA.2.86 lineages, could not explain this apparent attenuation of severity. Our findings implicate escape from immunity acquired from prior vaccination or infection in the emergence of the JN.1 lineage and suggest infections with this lineage are less likely to experience clinically-severe disease. Monitoring of immune escape and clinical severity in emerging SARS-CoV-2 variants remains a priority to inform responses.
The landscape and level of alcohol policy enforcement in Tanzania
Authors: Madundo Kim , Hudda Aliza , Seekles Maaike L. , Mmbaga Blandina , Obasi Angela
Published: April 2024

Harmful use of alcohol causes more deaths in Sub-Saharan Africa than in any other region. In Tanzania, where alcohol use disorders rates are twice the overall African average, harmful alcohol consumption is a public health concern. Given the lack of a contemporary overview of the alcohol policy landscape, we conducted a mixed-methods review of key alcohol-related policies, implementers, and initiatives in Tanzania. We conducted a desk-based review of policy-related documents, and in-depth interviews with eight key informants guided by the 10-composite-indicator framework of a tool for measuring alcohol policy implementation developed by World Health Organization. Representatives were from health-service delivery, community-based organizations, governmental organizations, research, and policymakers whose work is related to alcohol in Tanzania. Data was collected in October 2021, June 2022, and finalized in March 2023. Findings were analyzed using Microsoft Word v2021. Themes were identified, collected, combined, and tabulated. Differences were then resolved by first and second authors. Our findings revealed no single comprehensive national alcohol policy. Pending finalization of a draft policy, various documents and actors govern alcohol production, distribution, licensing, and consumption. Little intersectoral linkage between entities contributes to poor enforcement of these regulations. Regulation is stronger in urban areas, and restrictions more effective on industrial alcohol. However, the majority of consumed alcohol in Tanzania is informally-produced, especially in rural settings. Socio-cultural context plays a key role in alcohol production and consumption, contributing to early-age exposure to alcohol. Alcohol is a growing source of revenue for the Tanzanian government and, therefore, imposing further restrictions is a low priority. There are important policy gaps in various sectors pertaining to alcohol regulation. Our results strongly suggest the need for a comprehensive approach to developing an overarching alcohol policy, with involvement of key stakeholders, stronger enforcement, and increased awareness, resources, and collaborations.
A Framework for Evaluating the Efficacy of Foundation Embedding Models in Healthcare
Authors: Xu Sonnet , Gui Haiwen , Rotemberg Veronica , Wang Tongzhou , Chen Yiqun T. , Daneshjou Roxana
Published: April 2024

Recent interest has surged in building large-scale foundation models for medical applications. In this paper, we propose a general framework for evaluating the efficacy of these foundation models in medicine, suggesting that they should be assessed across three dimensions: general performance, bias/fairness, and the influence of confounders. Utilizing Google’s recently released dermatology embedding model and lesion diagnostics as examples, we demonstrate that: 1) dermatology foundation models surpass state-of-the-art classification accuracy; 2) general-purpose CLIP models encode features informative for medical applications and should be more broadly considered as a baseline; 3) skin tone is a key differentiator for performance, and the potential bias associated with it needs to be quantified, monitored, and communicated; and 4) image quality significantly impacts model performance, necessitating that evaluation results across different datasets control for this variable. Our findings provide a nuanced view of the utility and limitations of large-scale foundation models for medical AI.
Phylogenomic reconstruction ofCryptosporidiumspp. captured directly from clinical samples reveals extensive genetic diversity
Authors: Khan A. , Alves-Ferreira E.V.C. , Vogel H. , Botchie S. , Ayi I. , Pawlowic M.C. , Robinson G. , Chalmers R.M. , Lorenzi H. , Grigg M.E.
Published: April 2024

Cryptosporidiumis a leading cause of severe diarrhea and mortality in young children and infants in Africa and southern Asia. More than twentyCryptosporidiumspecies infect humans, of whichC. parvumandC. hominisare the major agents causing moderate to severe diarrhea. Relatively few genetic markers are typically applied to genotype and/or diagnoseCryptosporidium. Most infections produce limited oocysts making it difficult to perform whole genome sequencing (WGS) directly from stool samples. Hence, there is an immediate need to apply WGS strategies to 1) develop high-resolution genetic markers to genotype these parasites more precisely, 2) to investigate endemic regions and detect the prevalence of different genotypes, and the role of mixed infections in generating genetic diversity, and 3) to investigate zoonotic transmission and evolution. To understandCryptosporidiumglobal population genetic structure, we applied Capture Enrichment Sequencing (CES-Seq) using 74,973 RNA-based 120 nucleotide baits that cover ∼92% of the genome ofC. parvum. CES-Seq is sensitive and successfully sequencedCryptosporidiumgenomic DNA diluted up to 0.005% in human stool DNA. It also resolved mixed strain infections and captured new species ofCryptosporidiumdirectly from clinical/field samples to promote genome-wide phylogenomic analyses and prospective GWAS studies.
Genotypic Characterization and Antimicrobial Susceptibility of HumanCampylobacter jejuniIsolates in Southern Spain
Authors: Fernández-Palacios Pablo , Galán-Sánchez Fátima , Casimiro-Soriguer Carlos S , Jurado-Tarifa Estefanía , Arroyo Federico , Lara María , Chaves J. Alberto , Dopazo Joaquín , Rodríguez-Iglesias Manuel A.
Published: April 2024

Campylobacter jejuniis the main cause of bacterial gastroenteritis and a public health problem worldwide. Little information is available on the genotypic characteristics of humanCampylobacter jejuniin Spain. This study is based on an analysis of the resistome, virulome and phylogenetic relationship, antibiogram prediction and antimicrobial susceptibility of 114 human isolates ofC. jejunifrom a tertiary hospital in southern Spain from October 2020 to June 2023. The isolates were sequenced using Illumina technology, and bioinformatic analysis was subsequently performed. The susceptibility ofC. jejuniisolates to ciprofloxacin, tetracycline, and erythromycin was tested. A high resistance rate was obtained for ciprofloxacin (90.6%) and tetracycline (66.7%), and a low resistance rate for erythromycin (0.85%) was detected among theC. jejuniisolates. CC-21 (n=23), ST-572 (n = 13) and ST-6532 (n=13) were the most prevalent clonal complexes (CCs) and sequence types (STs). Concerning the virulome, thecadF, ciaB, andcdtABCgenes were detected in all the isolates. A prevalence of 20.1% was obtained for the geneswlaNandcstIII, which are related to the pathogenesis of Guillain-Barré syndrome (GBS). The prevalence of the main antimicrobial resistance markers detected werecmeABC(92.1%),RE-cmeABC(7.9%), the T86I substitution ingyrA(88.9%),blaOXA-61(72.6%), tet(O)(65.8%) andant(6)-Ia(17.1%). High antibiogram prediction rates (>97%) were obtained except for the erythromycin-resistant phenotype. This study contributes significantly to the knowledge ofCampylobacter jejunigenomics for the prevention, treatment and control of infections caused by this pathogen, which is relevant to public health.

Importance

Despite being the pathogen with the greatest number of gastroenteritis cases worldwide,Campylobacter jejuniremains a poorly studied microorganism. The development of whole-genome sequencing (WGS) techniques has led to a better understanding of the genotypic characteristics of this pathogen. These techniques complement the data obtained from the phenotypic analysis ofC. jejuniisolates. The zoonotic transmission ofC. jejunithrough the consumption of contaminated poultry implies approaching the study of this pathogen through the term “One Health.” This is the first study, using WGS, conducted on human isolates ofC. jejuniin Spain to date, which allows comparison of the results obtained with similar studies conducted in other countries and with animal and environmental isolates.
Proinflammatory stress activates neutral sphingomyelinase 2 based generation of a ceramide-enriched β cell EV subpopulation
Authors: Xu Jerry , Harris-Kawano Arianna , Enriquez Jacob R. , Mirmira Raghavendra G. , Sims Emily K.
Published: April 2024

β cell extracellular vesicles (EVs) play a role as paracrine effectors in islet health, yet mechanisms connecting β cell stress to changes in EV cargo and potential impacts on diabetes remain poorly defined. We hypothesized that β cell inflammatory stress engages neutral sphingomyelinase 2 (nSMase2)-dependent EV formation pathways, generating ceramide-enriched EVs that could impact surrounding β cells. Consistent with this, proinflammatory cytokine treatment of INS-1 β cells and human islets concurrently increased β cell nSMase2 and ceramide expression, as well as EV ceramide staining. Direct chemical activation or genetic knockdown of nSMase2, or treatment with a GLP-1 receptor agonist also modulated cellular and EV ceramide. Small RNA sequencing of ceramide-enriched EVs identified a distinct set of miRNAs linked to β cell function and identity. Coculture experiments using CD9-GFP tagged INS-1 cell EVs demonstrated that either cytokine treatment or chemical nSMase2 activation increased EV transfer to recipient cells. Children with recent-onset T1D showed no abnormalities in circulating ceramide-enriched EVs, suggesting a localized, rather than systemic phenomenon. These findings highlight nSMase2 as a regulator of β cell EV cargo and identify ceramide-enriched EV populations as a contributor to EV-related paracrine signaling under conditions of β cell inflammatory stress.

Article Highlights

a.Why did we undertake this study?

Mechanisms connecting β cell stress to changes in extracellular vesicle (EV) cargo and potential impacts on diabetes are poorly defined.

b.What is the specific question we wanted to answer?

Does β cell inflammatory stress engage neutral sphingomyelinase 2 (nSMase2)-dependent EV formation pathways to generate ceramide-enriched EVs.

c.What did we find?

Proinflammatory cytokine treatment of β cells increased β cell ceramide expression, along with EV ceramide in part via increases in nSMase2. Ceramide-enriched EVs housed a distinct set of miRNAs linked to insulin signaling. Both cytokine treatment and nSMase2 activation increase EV transfer to other β cells.

d.What are the implications of our findings?

Our findings highlight nSMase2 as a regulator of β cell EV cargo and identify ceramide-enriched EV populations as a contributor to EV-related paracrine signaling under conditions of β cell inflammatory stress.
Long-term multi-meta-omics resolves the ecophysiological controls of seasonal N2O emissions
Authors: Roothans Nina , Pabst Martin , Menno van Diemen , Mexicano Claudia Herrera , Zandvoort Marcel , Abeel Thomas , Mark van Loosdrecht , Laureni Michele
Published: April 2024

The potent greenhouse gas nitrous oxide (N2O) originates primarily from natural and engineered microbiomes. Emission seasonality is widely reported while the underlying metabolic controls remain largely unresolved, hindering effective mitigation. We use biological wastewater treatment as tractable model ecosystem over nearly two years. Long-term metagenomic-resolved metaproteomics is combined withex situkinetic and full-scale operational characterization. By leveraging the evidence independently obtained at multiple ecophysiological levels, from individual genetic potential to actual metabolism and emergent community phenotype, the cascade of environmental and operational triggers driving N2O emissions is resolved. We explain the dynamics in nitrite accumulation with the kinetic unbalance between ammonia and nitrite oxidisers, and identify nitrifier denitrification as the prime N2O-producing pathway. The dissolved O2emerged as the key actionable parameter for emission control. This work exemplifies the yet-to-be-realized potential of multi-meta-omics approaches for the mechanistic understanding and ecological engineering of microbiomes, ultimately advancing sustainable biotechnological developments.
De novo design of protein minibinder agonists of TLR3
Authors: Adams Chloe S. , Kim Hyojin , Burtner Abigail E. , Lee Dong Sun , Dobbins Craig , Criswell Cameron , Coventry Brian , Kim Ho Min , King Neil P.
Published: April 2024

Toll-like Receptor 3 (TLR3) is a pattern recognition receptor that initiates antiviral immune responses upon binding double-stranded RNA (dsRNA). Several nucleic acid-based TLR3 agonists have been explored clinically as vaccine adjuvants in cancer and infectious disease, but present substantial manufacturing and formulation challenges. Here, we use computational protein design to create novel miniproteins that bind to human TLR3 with nanomolar affinities. Cryo-EM structures of two minibinders in complex with TLR3 reveal that they bind the target as designed, although one partially unfolds due to steric competition with a nearby N-linked glycan. Multimeric forms of both minibinders induce NF-κB signaling in TLR3-expressing cell lines, demonstrating that they may have therapeutically relevant biological activity. Our work provides a foundation for the development of specific, stable, and easy-to-formulate protein-based agonists of TLRs and other pattern recognition receptors.
Quantifying Leaf Symptoms of Sorghum Charcoal Rot in Images of Field-Grown Plants Using Deep Neural Networks
Authors: Gonzalez Emmanuel , Zarei Ariyan , Calleja Sebastian , Christenson Clay , Rozzi Bruno , Demieville Jeffrey , Hu Jiahuai , Eveland Andrea L. , Dilkes Brian , Barnard Kobus , Lyons Eric , Pauli Duke
Published: April 2024

Charcoal rot of sorghum (CRS) is a significant disease affecting sorghum crops, with limited genetic resistance available. The causative agent,Macrophomina phaseolina(Tassi) Goid, is a highly destructive fungal pathogen that targets over 500 plant species globally, including essential staple crops. Utilizing field image data for precise detection and quantification of CRS could greatly assist in the prompt identification and management of affected fields and thereby reduce yield losses. The objective of this work was to implement various machine learning algorithms to evaluate their ability to accurately detect and quantify CRS in red-green-blue (RGB) images of sorghum plants exhibiting symptoms of infection. EfficientNet-B3 and a fully convolutional network (FCN) emerged as the top-performing models for image classification and segmentation tasks, respectively. Among the classification models evaluated, EfficientNet-B3 demonstrated superior performance, achieving an accuracy of 86.97%, a recall rate of 0.71, and an F1 score of 0.73. Of the segmentation models tested, FCN proved to be the most effective, exhibiting a validation accuracy of 97.76%, a recall rate of 0.68, and an F1 score of 0.66. As the size of the image patches increased, both models’ validation scores increased linearly, and their processing time decreased exponentially. The models, in addition to being immediately useful for breeders and growers of sorghum, advance the domain of automated plant phenotyping and may serve as a base for drone-based or other automated field phenotyping efforts. Additionally, the models presented herein can be accessed through a web-based application where users can easily analyze their own images.

Core ideas

Automated phenotyping tools are required for the efficient detection and quantification of charcoal rot of sorghum.

Classification and segmentation models can distinguish between concurrent plant stresses with similar symptoms.

Larger image patch sizes generally improve model performance and reduce processing time.
Are text-message based programs targeting adolescents and their parents an acceptable approach to preventing adolescent e-cigarette use?
Authors: Barnes Courtney , Janssen Lisa , Mantach Stephanie , McCrabb Sam , Turon Heidi , Groombridge Daniel , Bartlem Kate , Bialek Caitlin , Couper Lucy , Wolfenden Luke
Published: April 2024

Adolescent e-cigarette use (also known as vaping), globally and within Australia, has steadily increased in recent years, with e-cigarettes now the most heavily used nicotine-containing products amongst adolescents. In response to the rise in prevalence, governments have introduced legislation to curb the supply of e-cigarettes to adolescents. To supplement these legislation measures, leading (inter)national public health agencies have called for the development of education and communication programs aimed at reducing adolescent e-cigarette uptake. Text-message programs for adolescents represent a potentially potent approach to achieve this. In this study, we assessed the acceptability of text-messages sent to adolescents and their parents to target factors associated with e-cigarette use. Text-messages were found to be acceptable to both adolescents and their parents however the effectiveness of the program on adolescent e-cigarette use still needs to be established prior to broader scale-up and investment.
Translation, cultural adaption, and validation of the PHQ-9 and GAD-7 in Kinyarwanda for primary care in the United States
Authors: Müller Frank , Hansen Alexis , Kube Megan , Arnetz Judith E. , Alshaarawy Omayma , Achtyes Eric D. , Holman Harland T.
Published: April 2024

Background

Depression and anxiety are significant health burdens that greatly impact the quality of life of refugees and migrants. In this study, we have translated and culturally adapted the Patient Health Questionnaire (PHQ-9) and Generalized Anxiety Disorder Screener (GAD-7) into Kinyarwanda and performed a validation study in a United States (US) primary care setting.

Methods

A committee of experts translated and culturally adapted the PHQ-9 and GAD-7, incorporating feedback from cognitive interviews with bilingual participants. The translated instruments were then tested in a cross-sectional validation study. Analyses include internal consistency, discriminative validity, principal component analyses, and confirmatory factor analyses.

Results

Analyses of 119 responses indicated overall good internal consistency with Cronbach’s α of 0.85 (PHQ-9) and 0.92 (GAD-7). Both scales showed acceptable factor loadings between 0.44 and 0.90 in the principal component analyses and showed strong correlations with health-related quality of life and depression/anxiety symptoms measured with visual analog scales. Significantly higher scores for PHQ-9 and GAD-7 were shown among participants with known psychiatric conditions.

Discussion

PHQ-9 and GAD-7 demonstrated commendable applicability for Kinyarwanda-speaking patients in primary healthcare settings in the US. Culturally adapted translations of these tools may aid in mitigating health disparities among refugee and migrant populations. Future research should further validate these tools against gold-standard diagnostics in larger, geographically diverse samples.