bluuebunny/crossref_metadata_2025 huggingface dataset:
Non-pharmacological interventions for psychotic symptoms in people with dementia: a Delphi consensus
Authors: Choi A , McDermid J , Mills K , Sweetnam A , Fossey J , Khan Z , Ballard C
Published: September 2024

Background

Psychotic symptoms such as delusion and hallucinations are common in people with dementia. They are associated with various deleterious outcomes including reduced quality of life and increased caregiver burden. Pharmacological interventions to combat psychotic symptoms have shown limited efficacy and can be associated with significant adverse events. Non-pharmacological interventions are recommended as the first line option for treatment, however there is a paucity of evidence for specific non-pharmacological options to primarily target psychotic symptoms in people with dementia. Further work is needed to identify, adapt and develop possible non-pharmacological options to target psychotic symptoms in dementia.

Aim

To establish which non-pharmacological interventions could be used or adapted to treat psychotic symptoms and/or confer benefits in people with dementia

Design

Modified Delphi consensus process. Two rounds of feedback were conducted and included a directed scoping review, based on the interventions recommended in the first round of the Delphi.

Participants

An expert panel consisted of 12 members with clinical and research expertise in managing psychotic symptoms in people with dementia

Results

There were three top nominated treatment options: cognitive behavioural therapy (CBT), family intervention, and personalized activities/environmental/sensory interventions, without a clear priority between the 3 approaches.

The WHELD/Brief Psychosocial Therapy programme focussing on personalized activities improves concurrent neuropsychiatric symptoms in people with dementia related psychosis. Preliminary studies also suggest that combining personalized activities with family training may improve the direct impact on psychosis. There are also opportunities to adapt CBT interventions for people with psychosis related to early or mild dementia.

Conclusions

There were clear recommendations for three non-pharmacological options that could be used or adapted to benefit people with psychosis in the context of dementia.
The preferential injury of outer renal medulla after ischemia-reperfusion relies on high oxidative metabolism
Authors: Arnoux Grégoire , Serre Justine , Verissimo Thomas , Tihy Matthieu , Placier Sandrine , Verney Charles , Sangla Frédéric , Paolucci Deborah , Fernandez Marylise , de Seigneux Sophie , Sgardello Sebastian , Naesens Maarten , Hadchouel Juliette , Feraille Éric , Khodo Stellor Nlandu , Galichon Pierre , Legouis David
Published: September 2024

Acute kidney injury (AKI) is a prevalent and significant complication in critically ill patients, and its management remains a considerable challenge. The kidney is a highly metabolic organ, consuming and producing substantial amounts of ATP, mainly through mitochondrial oxidative phosphorylation. Recently, mitochondrial dysfunction has been identified as a key factor in the pathophysiology of AKI and the progression to chronic kidney disease. The kidney is a complex organ, comprising millions of structural and functional units. These nephrons are composed of different cell types dwelling within specific metabolic microenvironment. Whether the metabolic spatialization in the kidney has consequences on tubular injury distribution and severity remains unclear.

In this study, we identified the high metabolic rate of the outer stripe of the outer medulla (OSOM) and its substrate preference flexibility, relying on both glycolysis and fatty acid oxidation (FAO) to fulfill its ATP demands. We demonstrated that the OSOM is susceptible to mitochondrial and FAO impairment induced by propofol, the most used sedative in intensive care settings, which exacerbates tubular injury during AKI. In the clinical setting, the cumulative dose of propofol is positively correlated with oxidative metabolism disruption and histological and function outcomes in renal allograft recipients. Finally, we found that the loop of Henle, the OSOM major constituent, was the most injured segment during AKI in patients.

This study shows how renal metabolic spatialization impacts tubular injury severity. We identified the OSOM as the most metabolically active and the most injured region of the kidney both in humans and mice. We demonstrated that propofol is a potent inhibitor of renal mitochondrial function and FAO exacerbating tubular injury in the OSOM upon IRI.

Translational Statement

Aerobic metabolism is basally enhanced in the renal OSOM, including the S3 proximal tubule, the thick ascending limb of the loop of Henle and Distal Convoluted Tubule

PT cells as well as TAL cells are significantly targeted by injury in human AKI.

Propofol impairs renal mitochondrial function worsening tubular injury during ischemia reperfusion.
Extended Phenotype Influences Collective Behaviour and Survival in a Social Spider
Authors: Parthasarathy Bharat , Shaikh Naeem Yusuf , V Sai Abhinay , C Varun Sai , MV Sai Krishna , Dasu Krishna Kiran Vamsi
Published: September 2024

Increasing human interference has been shown to not only destroy habitats, but also alter the architecture of animal-built extended phenotypes. However, the impact of such architectural changes on the behaviour and survival of organisms remains poorly understood. To address this knowledge gap, we examined the impact of habitat modification using Indian social spider, Stegodyphus sarasinorum, as a model organism. S. sarasinorum colonies typically construct a three-dimensional (3D) capture web. Due to increasing habitat modification by humans, these spiders are now constrained to build two-dimensional (2D) capture webs adapting to man-made structures like fences. We investigated how these differing web architectures influence the collective behaviours and survival of S. sarasinorum. Our findings reveal that spiders with 2D capture webs emerged from their nests sooner, attacked prey faster, and had higher number of attacking spiders compared to those with 3D webs, suggesting 2D webs may be more efficient for hunting. However, despite their hunting advantages, spiders in 2D webs more frequently attacked the dangerous body parts of honeybees and were susceptible to honeybee stings. These results suggest that human-induced architectural modifications of the extended phenotype can have both benefits and costs for the organisms that built it. The survival benefits conferred by 3D capture webs against risky prey may have played a significant role in the evolutionary selection of this web architecture in S. sarasinorum.
Ongoing evolution of Middle East Respiratory Syndrome Coronavirus, Kingdom of Saudi Arabia, 2023-2024
Authors: Hassan Ahmed M. , Mühlemann Barbara , Al-Subhi Tagreed L. , Rodon Jordi , El-Kafrawy Sherif A. , Memish Ziad , Melchert Julia , Bleicker Tobias , Mauno Tiina , Perlman Stanley , Zumla Alimuddin , Jones Terry C. , Müller Marcel A. , Corman Victor M. , Drosten Christian , Azhar Esam I.
Published: September 2024

Middle East respiratory syndrome coronavirus (MERS-CoV) circulates in dromedary camels in the Arabian Peninsula and occasionally causes spillover infections in humans. Due to lack of sampling during the SARS-CoV-2 pandemic, current MERS-CoV diversity is poorly understood. Of 558 dromedary camel nasal swabs from Saudi Arabia, sampled November 2023 to January 2024, 39% were positive for MERS-CoV RNA by RT-PCR. We generated 42 MERS-CoV and seven human 229E-related CoV by high-throughput sequencing. For both viruses, the sequences fell into monophyletic clades apical to the most recent available genomes. The MERS-CoV sequences were most similar to those from lineage B5. The new MERS-CoVs sequences harbor unique genetic features, including novel amino acid polymorphisms in the Spike protein. The new variants require further phenotypic characterization to understand their impact. Ongoing MERS-CoV spillovers into humans pose significant public health concerns, emphasizing the need for continued surveillance and phenotypic studies.
The Draparnaldia genome: alternative mechanisms for multicellularity and terrestrialization in green plants
Authors: Caisova Lenka , Crombez Ewout , Arellano Minerva Susana Trejo , Gut Marta , Alioto Tyler Scott , Gomez-Garrido Jessica , Dabad Marc , Esteve-Codina Anna , Petrik Ivan , Pencik Ales , Novak Ondrej , Van de Peer Yves , Vicoso Beatriz , Friml Jiri
Published: September 2024

Green plants contain two algal lineages: Streptophyte algae that diverged into land plants and Chlorophyte algae that are mostly aquatic. Draparnaldia is a Chlorophyte alga morphologically resembling mosses and living in both, the aquatic and terrestrial habitats. Because of its complex morphology and terrestrial adaptations, Draparnaldia can provide new insights into the evolution of multicellularity and terrestrialization in green plants. To develop Draparnaldia into a model, we de novo sequenced its genome and transcriptomes, and profiled its phytohormone repertoire. We found that 1) Expanded gene families in Draparnaldia with respect to unicellular Chlamydomonas are linked to multicellularity and abiotic stresses. 2) Draparnaldias terrestrial adaptations are reflected at both the morphological and molecular levels. 3) Draparnaldia synthesizes most of the phytohormones used by land plants to thrive in terrestrial habitats. All of this makes Draparnaldia a powerful model to uncover and study alternative evolutionary trajectories towards multicellularity and terrestrialization in plants.
DiatOmicBase, a gene-centered platform to mine functional omics data across diatom genomes
Authors: Villar Emilie , Zweig Nathanaël , Vincens Pierre , Cruz de Carvalho Helena , Duchene Carole , Liu Shun , Monteil Raphael , Dorrell Richard G. , Fabris Michele , Vandepoele Klaas , Bowler Chris , Falciatore Angela
Published: September 2024

Diatoms are prominent microalgae found in all aquatic environments. Over the last 20 years, thanks to the availability of genomic and genetic resources, diatom species such asPhaeodactylum tricornutumhave emerged as valuable experimental model systems for exploring topics ranging from evolution to cell biology, (eco)physiology and biotechnology. Since the first genome sequencing in 2008, numerous genome-enabled datasets have been generated, based on RNA-Seq and proteomics, epigenomes, and ecotype variant analysis. Unfortunately, these resources, generated by various laboratories, are often in disparate formats and challenging to access and analyze. Here we present DiatOmicBase, a genome portal gathering comprehensive omics resources fromP. tricornutumand two other diatoms to facilitate the exploration of dispersed public datasets and the design of new experiments based on the prior-art.

DiatOmicBase provides gene annotations, transcriptomic profiles and a genome browser with ecotype variants, histone and methylation marks, transposable elements, non-coding RNAs, and read densities from RNA-Seq experiments. We developed a semi-automatically updated transcriptomic module to explore both publicly available RNA-Seq experiments and users’ private datasets. Using gene-level expression data, users can perform exploratory data analysis, differential expression, pathway analysis, biclustering, and co-expression network analysis. Users can create heatmaps to visualize precomputed comparisons for selected gene subsets. Automatic access to other bioinformatic resources and tools for diatom comparative and functional genomics is also provided. Focusing on the resources currently centralized forP. tricornutum, we showcase several examples of how DiatOmicBase strengthens molecular research on diatoms, making these organisms accessible to a broad research community.

Significance statement

In recent years, diatoms have become the subject of increasing interest because of their ecological importance and their biotechnological potential for natural products such as pigments and polyunsaturated fatty acids. Here, we present an interactive web-based server that integrates public diatom ‘omics data (genomics, transcriptomics, epigenomics, proteomics, sequence variants) to connect individual diatom genes to broader-scale functional processes.
A gene-based model of fitness and its implications for genetic variation: linkage disequilibrium
Authors: Johri Parul , Charlesworth Brian
Published: September 2024

A widely used model of the effects of mutations on fitness (the “sites” model) assumes that heterozygous recessive or partially recessive deleterious mutations at different sites in a gene complement each other, similarly to mutations in different genes. However, the general lack of complementation between major effect allelic mutations suggests an alternative possibility, which we term the “gene” model. This assumes that a pair of heterozygous deleterious mutations intransbehave effectively as homozygotes, so that the fitnesses oftransheterozygotes are lower than those ofcisheterozygotes. We examine the properties of the two different models, using both analytical and simulation methods. We show that the gene model predicts positive linkage disequilibrium (LD) between deleterious variants within the coding sequence, under conditions when the sites model predicts zero or slightly negative LD. We also show that focussing on rare variants when examining patterns of LD, especially with Lewontin’sD’ measure, is likely to produce misleading results with respect to inferences concerning the causes of the sign of LD. Synergistic epistasis between pairs of mutations was also modeled; it is less likely to produce negative LD under the gene model than the sites model. The theoretical results are discussed in relation to patterns of LD in natural populations of several species.
Altered Cytokine Profile in Clinically Suspected Seronegative Autoimmune Associated Epilepsy
Authors: Motovilov Katherine , Maguire Cole , Briggs Deborah , Melamed Esther
Published: September 2024

Background and Objectives

Autoimmune-associated epilepsy (AAE), a condition which responds favorably to immune therapies but not traditional anti-seizure interventions, is emerging as a significant contributor to cases of drug-resistant epilepsy. Current standards for the diagnosis of AAE rely on screening for known neuronal autoantibodies in patient serum or cerebrospinal fluid. However, this diagnostic method fails to capture a subset of drug-resistant epilepsy patients with suspected AAE who respond to immunotherapy yet remain seronegative (snAAE) for known autoantibodies.

Methods

To identify potential biomarkers for snAAE, we evaluated the most comprehensive panel of assayed cytokines and autoantibodies to date, comparing patients with snAAE, anti-seizure medication (ASM) responsive epilepsy, and patients with other neuroinflammatory diseases.

Results

We found a unique signature of 14 cytokines significantly elevated in snAAE patients including: GM-CSF, MCP-2/CCL8, MIP-1a/CCL3, IL-1RA, IL-6, IL-8, IL-9, IL-10, IL-15, IL-20, VEGF-A, TNF-b, LIF, and TSLP. Based on prior literature, we highlight IL-6, IL-8, IL-10, IL-13, VEGF-A, and TNF-b as potentially actionable cytokine biomarkers for snAAE, which could be of diagnostic utility in clinical evaluations of snAAE patients. Autoantibody-ome screening failed to identify autoantibodies targeting neuronal channel proteins in snAAE patients. Interestingly, ASM-responsive epilepsy patients displayed elevations in the proportion of autoantibodies targeting brain plasma membrane proteins, possibly pointing to the presence of immune hyperactivity/dysfunction despite well-controlled seizure activity and suggesting ASM-responsive patients may experience disease progression independent of seizure activity (PISA).

Discussion

Overall, our findings suggest that simply expanding existing autoantibody screens may not sufficiently enhance diagnostic power for snAAE. Instead, we propose that cytokine analysis may serve as a promising diagnostic avenue for identifying immune dysregulation in AAE patients and enabling opportunities for trials of immunotherapies.
Conceptualising care pathways for neglected tropical diseases in sub-Saharan Africa: A systematic scoping review
Authors: Frischer Sandrena Ruth , Ockenden Eloise S , Reitzug Fabian , Parker Michael , Chami Goylette F
Published: September 2024

Background: There is a lack of synthesized evidence on how best to support care continuity for neglected tropical diseases (NTDs) in sub-Saharan Africa (SSA). Methods: To identify all SSA NTD care pathways, we conducted a systematic search of six scientific databases from inception to 18 February 2023. All studies were required to include care pathways for NTDs, defined at minimum as having both NTD diagnosis and treatment or referral to treatment for care continuity. Using an iterative approach to establish an understanding of care pathways relevant for NTDs, concept development drew from data extraction of variables relating to study characteristics; approaches to diagnosis, treatment, and referrals as pathway components; barriers to care and strategies for their resolution; and ethical challenges. Findings: Searches returned 2178 studies where after de-duplication and eligibility screening, 164 were systematically reviewed. Medical referrals were used to support care continuity in 62.2% (102/164) of studies, and community health workers played roles in patient care in 22.6% (37/164) of studies. Only 6.7% (11/164) of studies explicitly mapped care pathways, none of which were for NTDs where preventive chemotherapy is the primary management strategy. The majority of studies (82.9%; 136/164) presented unmapped care pathways, which were primarily biomedical research studies that provided diagnosis and/or treatment of NTD patients (66.9%; 91/136). Of biomedical research studies, 36.3% (33/91) described strategies to support continuity of care. While there is no singular care pathway for all NTDs in SSA, we proposed a conceptual framework relevant for implementation of biomedical research. Interpretation: Further research is needed on morbidity management of NTDs typically addressed through mass drug administration in sub-Saharan Africa. To conduct this research, there is a need for guidance on how research sponsors should collaborate with local health systems to enable continuity of care in low-income, NTD-endemic settings.
APOE4and Infectious Diseases Jointly Contribute to Brain Glucose Hypometabolism, a Biomarker of Alzheimer’s Pathology: New Findings from the ADNI
Authors: Lathika Rajendrakumar Aravind , Arbeev Konstantin G. , Bagley Olivia , Duan Matt , Yashin Anatoliy I. , Ukraintseva Svetlana ,   Alzheimer’s Disease Neuroimaging Initiative
Published: September 2024

Background

Impaired brain glucose metabolism is a preclinical feature of neurodegenerative diseases such as Alzheimer’s disease (AD). Infections may promote AD-related pathology. Therefore, we investigated the interplay between infections andAPOE4, a strong genetic risk factor for AD.

Methods

We analyzed data on 1,509 participants in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database using multivariate linear regression models. The outcomes were rank- normalized hypometabolic convergence index (HCI), statistical regions of interest (SROI) for AD, and mild cognitive impairment (MCI). Marginal mean estimates for infections, stratified byAPOE4carrier status, were then computed.

Results

Prior infections were associated with greater HCI [β=0.15, 95% CI: 0.03, 0.27, p=0.01]. The combined effects of infections andAPOE4carriers on HCI levels were significantly greater than either variable alone. AmongAPOE4carriers, the estimated marginal mean was 0.62, rising to 0.77, with infections (p<0.001), indicating an interaction effect. Carriers with multiple infections showed greater hypometabolism (higher HCI), with an estimate of 0.44 (p=0.01) compared to 0.11 (p=0.08) for those with a single infection, revealing a dose-response relationship. The estimates for the association of infections with SROI AD and SROI MCI were β=-0.01 (p=0.02) and β=-0.01 (p=0.04), respectively.

Conclusion

Our findings suggest that infections andAPOE4jointly contribute to brain glucose hypometabolism and AD pathology, supporting a “multi-hit” mechanism in AD development.
A multi-omics bidirectional mendelian randomization study and meta-analysis on the causal relationship between gut microbiota, inflammatory proteins, and fibromyalgia.
Authors: Niu Mengqi , Li Jing , Sarafian Victoria , Maes Michael
Published: September 2024

Background: Fibromyalgia (FM) is a chronic disorder characterized by widespread pain and immune dysregulation. Emerging evidence suggests that gut microbiota and inflammatory proteins may contribute to the development of FM. Objective: The aim of this study was to investigate the causal relationships between gut microbiota, inflammatory proteins (cytokines/chemokines), and FM using bidirectional Mendelian randomization (MR) and meta-analysis approaches. Methods: MR analyses were conducted using genetic data from European populations, employing methods such as MR-IVW, MR-Egger, and MR-weighted median. Reverse MR was also performed, with FM treated as the exposure. A meta-analysis was conducted to consolidate the findings. Results: Ruminococcus gauvreauii was identified as a risk factor for FM, while Enterorhabdus, Parabacteroides, Butyricicoccus, and Prevotella 9 were found to be protective. Five inflammatory proteins C-X-C motif chemokine 5 (CXCL5), S100-A12, Leukemia inhibitory factor receptor (LIFR), Monocyte chemoattractant protein 2 (MCP-2/CCL8), and Tumor necrosis factor (TNF-α) exhibited protective associations, while Natural killer cell receptor 2B4 (NKCR-2B4/CD244) and Interleukin-12 subunit beta (IL-12β) were associated with an increased risk of FM. Conclusion: This study highlights the role of gut microbiota and inflammatory proteins (cytokines/chemokines) in the pathogenesis of FM. Through Gene Ontology (GO) functional enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses, the findings suggest their involvement in immune regulation, inflammatory responses, and viral pathways. These findings provide new insights into potential therapeutic targets for modulating gut health and immune responses, opening new avenues for future research and clinical interventions.
The VIPR-1 trial (Visualizing Ischemia in the Pancreatic Remnant) - Assessing the role of intraoperative indocyanine green perfusion of the transected pancreas in predicting postoperative pancreatic leaks: protocol for a phase II clinical trial
Authors: Salgado-Garza Gustavo , Willy Annika , Rocha Flavio G. , Mayo Skye C. , Sheppard Brett C. , Worth Patrick J.
Published: September 2024

Surgery of the pancreas has come a long way since its inception; however, postoperative morbidity is still high. Pancreatic leaks and fistulas are common complications in patients undergoing surgery to remove the pancreas. Fistulas delay subsequent oncological care after surgery and prolong the hospital stay. Hypoperfusion to the pancreas has been characterized as one factor leading to fistulas. Indocyanine green (ICG) injection allows the surgeon to evaluate blood perfusion to tissue in real-time. This protocol describes a trial that aims to assess the effectiveness of intraoperative ICG metrics of the cut edge of the pancreas to predict postoperative fistulas. A single group will participate in an observational, surgeon-blinded, phase II trial. ICG measurements of the cut edge of the pancreas will be recorded before reconstruction. International Study Group on Pancreatic Surgery criteria for pancreatic fistula will be used to define leaks and fistulas. The primary outcome will be the correlation between ICG measurements and the development or absence of fistula formation. Currently, limited objective intraoperative predictors exist for predicting postoperative fistulas. Having a reliable predictive tool could decrease the healthcare burden posed by fistulas. The findings of this trial will provide conclusions on the usefulness of ICG measurements in predicting postoperative pancreatic fistulas and leaks. This clinical trial is registered inClinicalTrials.govwith the IDNCT06084013. The current protocol version is v1.0.
Comparative Effectiveness of the mRNA-1273 and BNT162b2 COVID-19 Vaccines Among Adults With Underlying Medical Conditions: A Systematic Literature Review and Pairwise Meta-Analysis Using GRADE
Authors: Wang Xuan , Pahwa Ankit , Bausch-Jurken Mary T. , Chitkara Anushri , Sharma Pawana , Malmenäs Mia , Vats Sonam , Gordon Whitfield Michael , Zhi Hua Lai Kira , Dasari Priyadarsini , Gupta Ritu , Nassim Maria , Van de Velde Nicolas , Green Nathan , Beck Ekkehard
Published: September 2024

Introduction

This systematic literature review and pairwise meta-analysis evaluated the comparative effectiveness of mRNA-1273 versus BNT162b in patients with at least one underlying medical condition at high risk for severe COVID-19.

Methods

MEDLINE, Embase, and Cochrane databases were searched for relevant articles from January 1, 2019 to February 9, 2024. Studies reporting effectiveness data from at least two doses of mRNA-1273 and BNT162b2 vaccination in adults with medical conditions at high risk of developing severe COVID-19 according to the US Centers for Disease Control and Prevention were included. Outcomes of interest were SARS-CoV-2 infection (overall, symptomatic, and severe), hospitalization due to COVID-19, and death due to COVID-19. Risk ratios (RRs) were calculated with random effects models. Subgroup analyses by specific medical conditions, number of vaccinations, age, and SARS-CoV-2 variant were conducted. Heterogeneity between studies was estimated with chi-square testing. The certainty of evidence was assessed using the Grading of Recommendations, Assessments, Development, and Evaluations framework.

Results

Sixty-five observational studies capturing the original/ancestral-containing primary series to Omicron-containing bivalent original-BA4-5 vaccinations were included in the meta-analysis. mRNA-1273 was associated with significantly lower risk of SARS-CoV-2 infection (RR, 0.85 [95% CI, 0.79–0.92];I2=92.5%), symptomatic SARS-CoV-2 infection (RR, 0.75 [95% CI, 0.65–0.86];I2=62.3%), severe SARS-CoV-2 infection (RR, 0.83 [95% CI, 0.78–0.89];I2=38.0%), hospitalization due to COVID-19 (RR, 0.88 [95% CI, 0.82–0.94];I2=38.7%), and death due to COVID-19 (RR, 0.84 [95% CI, 0.76–0.93];I2=1.3%) than BNT162b2. Findings were generally consistent across subgroups. Evidence certainty was low or very low because sufficiently powered randomized controlled trials are impractical in this heterogeneous population.

Conclusion

Meta-analysis of 65 observational studies showed that vaccination with mRNA-1273 was associated with a significantly lower risk of SARS-CoV-2 infection and COVID-19-related hospitalization and death than BNT162b2 in patients with medical conditions at high risk of severe COVID-19.
The Breast Cancer Genetic Testing Experience: Probing the Potential Utility of an Online Decision Aid in Risk Perception and Decision Making
Authors: Vaynrub Anna , Salazar Brian , Feng Yilin Eileen , West Harry , Michel Alissa , Umakanth Subiksha , Crew Katherine D. , Kukafka Rita
Published: September 2024

Background

Despite the role of pathogenic variants (PVs) in cancer predisposition genes conferring significantly increased risk of breast cancer (BC), uptake of genetic testing (GT) remains low, especially among ethnic minorities. Our prior study identified that a patient decision aid,RealRisks,improved patient-reported outcomes relative to standard educational materials. This study examined patients’ GT experience and its influence on subsequent actions. We also sought to identify areas for improvement inRealRisksthat would expand its focus from improved GT decision-making to understanding results.

Methods

Women enrolled in the parent randomized controlled trial were recruited and interviewed. Demographic data was collected from surveys in the parent study. Interviews were conducted, transcribed, and coded to identify recurring themes. Descriptive statistics were generated to compare the interviewed subgroup to the original study cohort of 187 women.

Results

Of the 22 women interviewed, 11 (50%) had positive GT results, 2 (9.1%) with aBRCA1/2PV, and 9 (40.9%) with variants of uncertain significance (VUS). Median age was 40.5 years and 15 (71.4%) identified as non-Hispanic. Twenty (90.9%) reported a family history of BC, and 2 (9.1%) reported a family history ofBRCA1/2PV. The emerging themes included a preference for structured communication of GT results and the need for more actionable knowledge to mitigate BC risk, especially among patients with VUS or negative results. Few patients reported lifestyle changes following the return of their results, although they did understand that their behaviors can impact their BC risk.

Conclusions

Patients preferred a structured explanation of their GT results to facilitate a more personal testing experience. While most did not change lifestyle behaviors in response to their GT results, there was a consistent call for further guidance following the initial discussion of GT results. Empowering patients, especially those with negative or VUS results, with the knowledge and context to internalize the implications of their results and form accurate risk perception represents a powerful opportunity to mediate subsequent risk management strategies. Informed by this study, future work will expandRealRisksto foster an accurate perception of GT results and include decision support to navigate concrete next steps.
A plasma proteomic signature for atherosclerotic cardiovascular disease risk prediction in the UK Biobank cohort
Authors: Gupte Trisha P. , Azizi Zahra , Kho Pik Fang , Zhou Jiayan , Chen Ming-Li , Panyard Daniel J. , Guarischi-Sousa Rodrigo , Hilliard Austin T. , Sharma Disha , Watson Kathleen , Abbasi Fahim , Tsao Philip S. , Clarke Shoa L. , Assimes Themistocles L.
Published: September 2024

Background

While risk stratification for atherosclerotic cardiovascular disease (ASCVD) is essential for primary prevention, current clinical risk algorithms demonstrate variability and leave room for further improvement. The plasma proteome holds promise as a future diagnostic and prognostic tool that can accurately reflect complex human traits and disease processes. We assessed the ability of plasma proteins to predict ASCVD.

Method

Clinical, genetic, and high-throughput plasma proteomic data were analyzed for association with ASCVD in a cohort of 41,650 UK Biobank participants. Selected features for analysis included clinical variables such as a UK-based cardiovascular clinical risk score (QRISK3) and lipid levels, 36 polygenic risk scores (PRSs), and Olink protein expression data of 2,920 proteins. We used least absolute shrinkage and selection operator (LASSO) regression to select features and compared area under the curve (AUC) statistics between data types. Randomized LASSO regression with a stability selection algorithm identified a smaller set of more robustly associated proteins. The benefit of plasma proteins over standard clinical variables, the QRISK3 score, and PRSs was evaluated through the derivation of Δ AUC values. We also assessed the incremental gain in model performance using proteomic datasets with varying numbers of proteins. To identify potential causal proteins for ASCVD, we conducted a two-sample Mendelian randomization (MR) analysis.

Result

The mean age of our cohort was 56.0 years, 60.3% were female, and 9.8% developed incident ASCVD over a median follow-up of 6.9 years. A protein-only LASSO model selected 294 proteins and returned an AUC of 0.723 (95% CI 0.708-0.737). A clinical variable and PRS-only LASSO model selected 4 clinical variables and 20 PRSs and achieved an AUC of 0.726 (95% CI 0.712-0.741). The addition of the full proteomic dataset to clinical variables and PRSs resulted in a Δ AUC of 0.010 (95% CI 0.003-0.018). Fifteen proteins selected by a stability selection algorithm offered improvement in ASCVD prediction over the QRISK3 risk score [Δ AUC: 0.013 (95% CI 0.005-0.021)]. Filtered and clustered versions of the full proteomic dataset (consisting of 600-1,500 proteins) performed comparably to the full dataset for ASCVD prediction. Using MR, we identified 11 proteins as potentially causal for ASCVD.

Conclusion

A plasma proteomic signature performs well for incident ASCVD prediction but only modestly improves prediction over clinical and genetic factors. Further studies are warranted to better elucidate the clinical utility of this signature in predicting the risk of ASCVD over the standard practice of using the QRISK3 score.
Circulating Biomarkers as Predictors of Improvement in Physical Function in Hospitalized Older Adults with Geriatric Syndromes: Findings from the REHAB-HF Trial
Authors: Damluji Abdulla A. , Bruce Scott A. , Reeves Gordon , Pastva Amy M. , Bertoni Alain G. , Mentz Robert J. , Whellan David J. , Kitzman Dalane W. , deFilippi Christopher R.
Published: September 2024

Introduction

Circulating biomarkers play an important role in patients with heart failure (HF) for risk stratification and mechanistic insights. We aimed to examine if a diverse set of biomarkers in the REHAB-HF trial would predict improvement in physical function following a 12-week tailored physical therapy rehabilitation intervention compared to attention control.

Methods

The study population consisted of participants ≥60 years of age who were hospitalized with acute HF and randomized to a subsequent multidomain outpatient physical rehabilitation intervention vs. attention control with outcomes of 12-week functional change including the Short Physical Performance Battery (SPPB) and six-minute walk distance (6MWD). Blood was collected prior to randomization and at 12-weeks for cardiac, renal, and inflammatory biomarkers. Linear trends across progressively higher biomarker values versus improvement in functional outcomes based on treatment assignment were evaluated. Classification and regression trees (CART) were created to estimate optimal biomarker levels associated with differential improvement in the two functional outcomes.

Results

A total of 242 of 349 participants (69%) had baseline biomarkers measured. In an adjusted regression model, higher baseline cardiac troponin (cTn) I and T were associated with greater gains in SPPB and 6MWD respectively with the rehabilitation intervention (P=0.04 and 0.03 for interaction) versus attention control. In the CART analysis of the physical rehabilitation and attention control participants, those with baseline C-reactive protein (CRP) ≥9.9 mg/L and hs-cTnT ≥36 ng/L receiving the rehabilitation intervention had a 129 m (95% CI 78-180m) greater 12-week 6MWD increase vs attention control. In contrast, for participants with CRP<9.9 mg/L there was no significant incremental 6MWD difference (30m, 95% CI -0.5m, 60.2m). For SPPB, a CRP ≥9.9 mg/L and creatinine ≥1.4 mg/dL optimally identified a differential improvement with the rehabilitation intervention versus attention control. The biomarkers (except for creatinine) decreased by 12 weeks post hospitalization but with no differences based on treatment assignment.

Conclusion

Higher baseline levels of biomarkers of inflammation, cardiac injury, and renal dysfunction identified older adults after a HF hospitalization with the greatest differential improvement in physical function with a rehabilitation intervention. Biomarkers may help clinicians predict the benefits of this treatment.

(Funded by the National Institutes of Health and others; REHAB-HFClinicalTrials.govnumber,NCT02196038).
is metallic perception a taste, an aroma or a flavor ?
Authors: Buiret Guillaume , Thierry Thomas-Danguin , Gilles Feron
Published: September 2024

Aim

Metallic taste is known to vanish with nasal occlusion, suggesting it should be termed metallic “aroma” rather than metallic “taste.” However, it also appears after neurological injuries, such as a chorda tympani section, which suppresses taste perception mediated by the facial nerve.

Methods

In 120 healthy volunteers, the perception of an iron sulfate solution was assessed at different lingual locations—corresponding to the facial and glossopharyngeal nerves—and with either open (n=60) or closed (n=60) noses to evaluate if it is a taste or an aroma.

Results

Nasal occlusion significantly reduced the perception of iron sulfate. It prevented perception in 31.7% of participants, though it did not completely eliminate it in the remaining 68.3%. Additionally, in open-nosed subjects, the intensity of iron sulfate perception was significantly greater when applied to the base of the tongue (glossopharyngeal nerve) than to the tip (facial nerve). These differences did not persist with nasal occlusion.

Conclusion

Nasal occlusion diminished but did not abolish the perception of iron sulfate. With an open nose, a differential taste perception was significant, but not with a closed nose. Therefore, metallic perception involves both retro-olfactory and gustatory components, suggesting it is a metallic flavor.
The Survival of β-lactoglobulin Peptides in the Archaeological Record: Vulnerability vs. Sequence Variation
Authors: Fonseca Beatriz , Freeman Colin L. , Collins Matthew James
Published: September 2024

It is a strange observation, given the cultural co-evolution of dairying, that milk proteins are more commonly reported than any other food proteins in the archaeological record. The whey protein β-lactoglobulin and in particular its eleven amino acid long peptide T125PEVDXEALEK135seems to be preferentially preserved in both ceramic vessels and teeth (dental calculus). An amino acid substitution in the middle of the chain is valuable to track livestock management because it permits differentiation between key animal species used in dairying. The persistence of this peptide is, however, unusual as its acidic nature makes it more vulnerable to hydrolysis. Moreover, selection for the ability to digest raw milk - more specifically, the continued production of the milk sugar enzyme lactase beyond the age of normal weaning - did not begin until the early Bronze Age. It is therefore unclear why it is a milk peptide, in particular a peptide associated with the lactose-rich whey fraction, that is one of the most commonly recovered dietary peptides. The unexpected preservation of T125PEVDXEALEK135thus presents a good case study to uncover patterns of protein survival in the archaeological record. We have previously explored the dynamics of the bovine variation of the peptide (X=Asp130) and its likelihood to undergo hydrolysis in solution. In this study, we turn our attention to the ovine (X=Asn130) and the caprine (X=Lys130) variations of the β-lactoglobulin peptide to determine how the mutation in the amino acid in position 6 affects peptide conformations and vulnerability in bulk water. To do this, we use Molecular Dynamics as implemented in GROMACS 2020, with the Amber14SB forcefield and the SPC/E water model. We first perform extensive conformational analysis of both peptides in solution to determine stable structures. Then, using analogous methodology to that developed in our earlier study of the bovine peptide, we identify geometric arrangements between water and peptide that may be more prone to hydrolysis.
CodonTransformer: a multispecies codon optimizer using context-aware neural networks
Authors: Fallahpour Adibvafa , Gureghian Vincent , Filion Guillaume J. , Lindner Ariel B. , Pandi Amir
Published: September 2024

The genetic code is degenerate allowing a multitude of possible DNA sequences to encode the same protein. This degeneracy impacts the efficiency of heterologous protein production due to the codon usage preferences of each organism. The process of tailoring organism-specific synonymous codons, known as codon optimization, must respect local sequence patterns that go beyond global codon preferences. As a result, the search space faces a combinatorial explosion that makes exhaustive exploration impossible. Nevertheless, throughout the diverse life on Earth, natural selection has already optimized the sequences, thereby providing a rich source of data allowing machine learning algorithms to explore the underlying rules. Here, we introduce CodonTransformer, a multispecies deep learning model trained on over 1 million DNA-protein pairs from 164 organisms spanning all kingdoms of life. The model demonstrates context-awareness thanks to the attention mechanism and bidirectionality of the Transformers we used, and to a novel sequence representation that combines organism, amino acid, and codon encodings. CodonTransformer generates host-specific DNA sequences with natural-like codon distribution profiles and with negative cis-regulatory elements. This work introduces a novel strategy of Shared Token Representation and Encoding with Aligned Multi-masking (STREAM) and provides a state-of-the-art codon optimization framework with a customizable open-access model and a user-friendly interface.
Bacterial growth temperature as a horizontally acquired polygenic trait
Authors: Farrell Anne A. , Nesbø Camilla L. , Zhaxybayeva Olga
Published: September 2024

Evolutionary events leading to organismal preference for a specific growth temperature, as well as genes whose products are needed for a proper function at that temperature, are poorly understood. Using 64 bacteria from phylumThermotogotaas a model system, we examined how optimal growth temperature changed throughoutThermotogotahistory. We inferred thatThermotogota’s last common ancestor was a thermophile and that someThermotogotaevolved the mesophilic and hyperthermophilic lifestyles secondarily. By modeling gain and loss of genes throughoutThermotogotahistory and by reconstructing their phylogenies, we demonstrated that adaptations to lower and higher growth temperature require both the acquisition of necessary genes and loss of unnecessary genes. Via a pangenome-wide association study, we correlated presence/absence of 68 gene families with specific optimal growth temperature intervals. While some of these genes are poorly characterized, most are involved in metabolism of amino acids, nucleotides, carbohydrates, and lipids, as well as in signal transduction and regulation of transcription. Most of the 68 genes have a history of horizontal gene transfer to/from other bacteria and archaea, suggesting that parallel acquisitions of genes likely promote independent adaptations of differentThermotogotaspecies to specific growth temperatures.

Significance

While the currently known range of life-permitting temperatures spans from −15°C to +122°C, most living organisms, including microbes, can grow only in a narrow temperature interval around their optimal growth temperature. The genetic and genomic determinants of such preference remain poorly understood. Using genomes fromThermotogota, a group of bacteria that collectively can grow between 20° and 90°C, we detected 68 genes, presence of which strongly correlates with growth at specific optimal growth temperature. Our findings dramatically expand a list of genes that are likely important for both lowering and increasing preferred growth temperature of a microorganism. We also demonstrated that these genes were usually horizontally acquired from other bacteria and archaea that likely share environment withThermotogota, highlighting the importance of gene exchange in microbial adaptation.
The Relationship Between Electrodermal Activity and Cardiac Troponin in Patients with Paroxysmal Sympathetic Hyperactivity
Authors: Beers Louis , Bouvain Jana , Reinsberger Claus , Jakobsmeyer Rasmus , Sarkis Rani , Lee Jong Woo
Published: September 2024

Objective

To determine the relationship between electrodermal activity (EDA) and cardiac troponin in patients with paroxysmal sympathetic hyperactivity (PSH).

Methods

This was a study with prospectively-identified patients and a retrospective analysis utilizing electrodermal data taken from the wrist-worn Empatica E4 device (Empatica Srl, Milan, Italy) and troponin values obtained from critically-ill patients with suspected PSH (N=10). The maximum EDA value and temporally-nearest cardiac troponin were correlated to test for significance using Pearson correlation coefficient.

Results

A moderate correlation was found between EDA and troponin in 10 patients using the most temporally-proximal troponin to each patient’s maximal EDA (r=0.634; p = 0.049). A subanalysis was performed excluding any patients whose available troponin data did not fall within seven days of their maximal EDA, which demonstrated a strong correlation (r=0.943; p = 0.005). No relationships between troponin and pulse, blood pressure, or temperature were found.

Conclusions

This study establishes an association between wrist-worn EDA and a measure of possible myocardial injury in critically ill patients with PSH. Patients with elevated sympathetic activity may be at increased risk for concurrent cardiac injury or dysfunction, and thus EDA data from wrist-worn monitors may provide clinically significant data regarding sympathetic function.
The Impact of Chlorinated Drinking Water Exposure on Gut Microbiota Development in Infants: a Randomised Controlled Trial
Authors: Parkin Kimberley , Christophersen Claus T. , Verhasselt Valerie , Palmer Debra J. , Cooper Matthew N. , Prescott Susan L. , Silva Desiree , Martino David
Published: September 2024

Background

Early gut microbiota disruptions can increase the risk for dysbiosis and predispose to chronic diseases. While chlorinated drinking water is generally considered safe, the antimicrobial effects of chlorine-based disinfectants may negatively impact the developing infant microbiota, which is particularly vulnerable during this critical period. This study investigates the specific effects of chlorinated water on the gut microbiome in infants.

Methods

The waTer qUality and Microbiome Study (TUMS) is a double-blinded, randomized controlled trial (RCT). Six-month old infants (n=197) received either de-chlorinated drinking water (via benchtop filtration), or regular tap water for twelve months. Stool samples were collected at six-months (baseline) and at eighteen-months of age. Metagenomic sequencing was used for faecal microbiome analysis. Samples of participant tap water was also collected pre- and post-intervention.

Results

Participants were balanced for sex, delivery method, and breast-feeding status at time of recruitment between the control (n=98) and treatment (n=99) groups. We collected a total of 170 baseline stool samples (83 in the control group and 87 in the treatment group), and 130 follow-up stool samples (65 in the control group and 65 in the treatment group). Interindividual variation was higher at six-months compared to eighteen months. No significant differences in overall community structure (beta diversity (p=0.35), richness (p=0.98) or Shannon Index (p=0.45)) were found between treatment groups. However, 55 genera were differentially abundant at follow-up (adjusted p-value < 0.01), primarily within the Firmicutes phylum. Analysis of metabolic pathways revealed the chlorinated water group showed significantly higher abundance of antibiotic resistance genes mostly attributable toEscherichiaandKlebsiellaspecies.

Conclusion

Water chlorination induces predominantly minor changes in infant gut microbiome composition; but appears to increase the abundance of antibiotic-resistant genes. While water chlorination remains a vital public health tool for ensuring safe drinking water, our findings underscore the need for continued research into the potential for increased antibiotic resistance and suggest there may be value in exploring alternative disinfectant strategies.