bluuebunny/crossref_metadata_2025 huggingface dataset:
Meeting complex multidimensional needs in older patients and their families during and beyond critical illness
Authors: Santangelo Erminio , Wozniak Hannah , Herridge Margaret S.
Published: August 2024

Purpose of review

To highlight the emerging crisis of critically ill elderly patients and review the unique burden of multidimensional morbidity faced by these patients and caregivers and potential interventions.

Recent findings

Physical, psychological, and cognitive sequelae after critical illness are frequent, durable, and robust across the international ICU outcome literature. Elderly patients are more vulnerable to the multisystem sequelae of critical illness and its treatment and the resultant multidimensional morbidity may be profound, chronic, and significantly affect functional independence, transition to the community, and quality of life for patients and families. Recent data reinforce the importance of baseline functional status, health trajectory, and chronic illness as key determinants of long-term functional disability after ICU. These risks are even more pronounced in older patients.

The current article is an overview of the outcomes of older survivors of critical illness, putative interventions to mitigate the long-term morbidity of patients, and the consequences for families and caregivers. A multimodal longitudinal approach designed to follow patients for one or more years may foster a better understanding of multidimensional morbidity faced by vulnerable older patients and families and provides a detailed understanding of recovery trajectories in this unique population to optimize outcome, goals of care directives, and ongoing informed consent to ICU treatment.
Neuroprognostication, withdrawal of care and long-term outcomes after cardiopulmonary resuscitation
Authors: Bazbaz Adela , Varon Joseph
Published: August 2024

Purpose of review

Survivors of cardiac arrest often have increased long-term risks of mortality and disability that are primarily associated with hypoxic-ischemic brain injury (HIBI). This review aims to examine health-related long-term outcomes after cardiac arrest.

Recent findings

A notable portion of cardiac arrest survivors face a decline in their quality of life, encountering persistent physical, cognitive, and mental health challenges emerging years after the initial event. Within the first-year postarrest, survivors are at elevated risk for stroke, epilepsy, and psychiatric conditions, along with a heightened susceptibility to developing dementia. Addressing these challenges necessitates establishing comprehensive, multidisciplinary care systems tailored to the needs of these individuals.

HIBI remains the leading cause of disability among cardiac arrest survivors. No single strategy is likely to improve long term outcomes after cardiac arrest. A multimodal neuroprognostication approach (clinical examination, imaging, neurophysiology, and biomarkers) is recommended by guidelines, but fails to predict long-term outcomes. Cardiac arrest survivors often experience long-term disabilities that negatively impact their quality of life. The likelihood of such outcomes implements a multidisciplinary care an integral part of long-term recovery.
Dietary protein in the ICU in relation to health outcomes
Authors: Bear Danielle E. , Summers Matthew J. , Chapple Lee-anne S.
Published: August 2024

Purpose of review

Critical care nutrition guidelines recommend provision of higher protein doses than recommended in health. These recommendations have been predominately based on lower quality evidence and physiological rationale that greater protein doses may attenuate the significant muscle loss observed in critically ill patients. This review discusses the mechanistic action of protein in the critically ill, details results from recent trials on health outcomes, discusses considerations for interpretation of trial results, and provides an overview of future directions.

Recent findings

Two recent large clinical trials have investigated different protein doses and the effect on clinical outcome. Important findings revealed potential harm in certain sub-groups of patients. This harm must be balanced with the potential for beneficial effects on muscle mass and physical function given that two recent systematic reviews with meta-analyses demonstrated attenuation of muscle loss with higher protein doses. Utilizing biological markers such as urea: creatinine ratio or urea levels may prove useful in monitoring harm from higher protein doses.

Future research should focus on prospectively investigating biological signatures of harm as well as taking into the consideration elements that will likely enhance the effectiveness of protein dose.
Choanal atresia: a review of contemporary treatment strategies
Authors: De Jong Russell W. , Heydari Sahar , Fordham M. Taylor
Published: August 2024

Purpose of review

Choanal atresia (CA) is a congenital nasal airway anomaly that, when present bilaterally, requires urgent surgical intervention. Surgical technique has evolved since its inception with most practices now favoring an endoscopic repair. Restenosis requiring revision surgery is a frequent complication, occurring in as many as 50% of cases. This review aims to highlight the most common surgical approaches, techniques used to prevent restenosis, and newer adjuncts to surgery that may improve outcomes.

Recent findings

Bioabsorbable, steroid-eluting stents were first developed for the adult chronic rhinosinusitis population but have been adapted for use in choanal atresia since 2017. The existing literature consists of multiple case series and one case-control study comparing these stents to traditional stents. To date, there have been no reports of restenosis or stent-related complications with these newer products.

Choanal atresia remains a difficult surgical pathology for which sustainable surgical results can be challenging. There is reason for optimism in bioabsorbable, steroid-eluting stents as an adjunct to CA repair if future studies expound upon their safety and efficacy.
The use of digital health interventions to deliver prehabilitation in solid organ transplant recipients: are we there yet?
Authors: Briggs Juliet , Chilcot Joseph , Greenwood Sharlene A.
Published: August 2024

Purpose of review

Prehabilitation, defined as preparing the body physically and psychologically for upcoming surgery is of increasing prominence in presurgical care. The aim of this review is to discuss the evidence base around prehabilitation in solid organ transplantation, the use of digital health as a tool to deliver these interventions, and consider future directions.

Recent findings

Prehabilitation is of increasing interest as an adjunct to pretransplant care for individuals working up for solid organ transplantation. To date, research has shown that prehabilitation is acceptable and feasible; however, the literature base remains small. The majority of research has been delivered using in-person rehabilitation programmes, and the evidence base utilizing digital health as a means to deliver prehabilitation is limited.

To date, the research evidence base in prehabilitation for solid organ transplantation is limited. Evidence in other surgical populations has demonstrated promising results, particularly in aerobic capacity, physical function and postoperative complications. Further high-quality randomized controlled clinical trials are required to strengthen the evidence base, understand how digital health can be harnessed and utilized to deliver multimodal prehabilitation with an aim to see how this may form part of routine care in the solid organ transplantation pathway.
Operation STICK Improves Vascular Access Outcomes in a Specialty Team
Authors: Gibson Steven Matthew , Sarlabous Jessica , Adair Lauren , Bahl Amit
Published: August 2024

Background:

Education and training may improve outcomes within an experienced vascular access team.

Purpose:

The purpose of this study was to measure the impact of a standardized peripheral intravenous catheter insertion educational program (Operation STICK) on vascular access outcomes.

Methods:

A quasi-experimental study design was used. Adult inpatients with difficult intravenous access (DIVA) requiring ultrasound-guided insertion by a vascular access specialty team were eligible. Data were collected before and 7 months after the educational training program.

Results:

A total of 54 subjects were included (24 pre- and 30 post-implementation). Significant improvements were found for mean peripheral intravenous catheter dwell time (3.62 to 14.97 days, P < .001), completion of therapy (58.3% to 96.7%, P = .001), and first-stick success rate (79.2% to 100%, P = .013). Catheter-to-vein ratio significantly decreased (P = .007).

Conclusions:

Standardized education/training in vascular access focusing on best practices yields favorable outcomes for DIVA patients within an established specialty team.
Dorsal Carpal Artery Perforator Flaps
Authors: Singh Apoorva Pratap , Dixit Pawan Kumar , Kala Prakash Chandra , Agrawal Dushyant , Katrolia Deepti , Karmakar Shilpi , Singla Priyanka , Humnekar Akhilesh
Published: August 2024

Background

Hand injuries pose challenges due to complexity and aesthetic–functional concerns. Dorsum of hand injuries are difficult to treat due to thin skin cover and increased propensity to exposure of underlying structures. Perforator-based flaps can provide better outcomes with minimal donor site morbidity. This study aims to bridge the gap in anatomical knowledge and explore the potential benefits of dorsal carpal artery perforator flap.

Materials and Methods

A prospective study was done from July 2021 to June 2023, focused on study of dorsal carpal artery perforators on 12 fresh frozen cadaveric hands. Anatomical study involved injection of red latex into arteries at the wrist, followed by dissection and measurements. During the clinical phase, we used the inferences gained from the anatomical study to identify and mark perforator of dorsal carpal arteries. We performed V-Y advancement flap based on the DCPs in 5 patients who had dorsum of hand defects due to trauma.

Results

The study was carried out on 6 fresh frozen cadavers (12 hands). Anatomical findings revealed the anatomical location, caliber, and consistent number of dorsal carpal artery perforators supplying the dorsum of the hand arranged in 2 rows. Clinically, we applied this insight to create V-Y flaps in 5 patients with successful outcomes, thus, offering DCP-based flap as an alternative to distant flaps.

Conclusion

DCP-based flaps offer an efficient solution for reconstructing proximal hand defects over the dorsum, with minimal complications, enhancing our understanding of hand reconstruction options. The study's comprehensive anatomical insights and clinical outcomes contribute to improving hand defect management and surgical techniques
Quality of Video Content Related to Deep Inferior Epigastric Perforator Flap Breast Reconstruction
Authors: Viñuela Florido Manuel , Suárez Aguilar Javier , Maldonado Andrés A. , Cristóbal Velasco Lara
Published: August 2024

Introduction

The deep inferior epigastric perforator (DIEP) flap is currently one of the main options in breast reconstruction. The information about this surgery is critical for the patient, in order to choose the breast reconstruction method. Our study aims to analyze and compare the quality and accuracy of the information related to the DIEP flap reconstruction method provided by social media platforms (SMPs) and the new large language models (LLMs).

Materials and Methods

A total of 50 videos in English and Spanish were selected from the main SMPs (YouTube, Instagram, and Facebook) using the keywords “DIEP flap” and “colgajo DIEP.” The duration, number of likes, dislikes, number of visits, upload date, author, and the video category (institutional video, media, patient experience, academic, and surgery) were analyzed. 3 specific questions were asked to 2 new LLMs (ChatGPT and Google Bard). The quality of information in SMPs and LLMs was analyzed and compared by 2 independent board-certified plastic surgeons using the Journal of American Medical Association and DISCERN scales.

Results

LLMs showed a statistically significant higher quality of information when compared with SMPs based on the DISCERN scores. The average DISCERN scores for answers given by ChatGPT and Google Bard were 54 ± 6.841 and 61.17 ± 6.306, respectively (good quality). In SMPs, the average scores were 2.31 ± 0.67 (insufficient quality) and 32.87 ± 9.62 (low quality) for the Journal of American Medical Association and DISCERN scales respectively. Thirty-eight percent of the videos in SMPs were performed by nonmedical authors.

Conclusions

The quality of information for breast reconstruction using DIEP flaps from LLMs was considered good and significantly better than in SMPs. The information found in SMPs was insufficient and of low quality. Academic plastic surgeons have an opportunity to provide quality content on this type of reconstruction in LLM and SMPs.
Predicting the Timing and Cause of Microvascular Free Flap Failure
Authors: Gupta Yash , Moisidis Elias , Clarke Fred , Haddad Roger , Illie Vlad , Southwell-Keely James
Published: August 2024

Background

The aim of the study is to assess the possible predictors of microvascular free flap failure and determine the critical postoperative timing of flap failure, thereby minimizing this adverse outcome.

Methods

This is a retrospective single-institutional review of 1569 free flap operations. All free flaps with outcome status recorded were analyzed for possible predictors in the development of microvascular compromise. Compromised cases were then analyzed for differences in time to compromise and time to theater takeback between salvaged versus failed free flaps.

Results

Of the assessable 1569 free flaps, 31 developed microvascular compromise (2.0%); the salvage rate was 20.0%, and overall failure rate was 1.5%. Osteocutaneous free flaps in head and neck had increased risk of developing free flap failure compared to other flaps (odds ratio = 3.8, 95% confidence interval: 1.2–12.7). Among breast patients, previous radiotherapy had a significant association with flap failure (P < 0.001). Free flap salvage rates dropped from 38.5% to 7.7% for compromises detected after 24 hours (P = 0.160), and from 57.1% to 11.1% for free flaps taken back to theater greater than 3 hours after compromise detection (P = 0.032).

Conclusions

Delays in compromise detection and flap takeback to theater resulted in reduced salvage rates, with the critical timing of takeback being under 3 hours. Standardized flap monitoring protocols and incorporation of newer technologies could see faster detection and improved salvage rates. Additional care is required when reconstructing: osteocutaneous head and neck free flaps and previously irradiated breast patients.
Impact of Collagenase Injection on Dupuytren Disease Treatment in Japan
Authors: Yoneda Hidemasa , Curley James , Yamamoto Michiro , Hirata Hitoshi
Published: August 2024

Background

Collagenase Clostridium histolyticum (CCH) injection, an effective enzymatic fasciotomy treatment for Dupuytren disease (DD), was abruptly withdrawn from the healthcare market outside the United States in 2020. The impact on patients, physicians and hospitals of this helpful surgical alternative no longer being available has been little studied.

Methods

To investigate the impact of the withdrawal of CCH in Japan, we used the National Database Open Data Japan from 2014 to 2020. Published by the government, it contains summary data of the National Database of Health Insurance Claims and Specific Health Checkups of Japan. We extracted the numbers of CCH injections with Xiaflex, the product name in Japan, and surgeries identified by “Dupuytren contracture surgery codes.” Each treatment was further parsed into one of 12 predefined regions in which it had taken place and by whether it had been delivered on an inpatient or outpatient basis.

Results

From its introduction in 2015, the number of DD patients treated with CCH increased in each successive year, reaching a peak in 2019, while the number of surgeries decreased with time. After the withdrawal in 2020, the number of surgeries increased to 1.5 times the 2019 number notwithstanding the impact of COVID-19, but the total number of patients treated decreased by 43%. In the initial regional analysis, CCH accounted for approximately 40% of all DD treatments in the less populous areas, with the exception of the Tohoku region, and more than 50% in the other regions. By 2019, the share of CCH treatment had increased in all regions. There was no significant correlation between the number of hand surgeons authorized to use CCH and the number of CCH cases within each region.

Conclusions

CCH increased treatment options for patients and surgeons. The withdrawal of this valuable pharmaceutical resulted in an increase in the number of surgeries amidst a decrease in the total number of treatments and lost opportunities for patients.
Association of Visual Impairment With Neuropsychiatric Symptoms of Dementia
Authors: Li Melissa , Hamedani Ali G.
Published: August 2024

Background:

Visual impairment is a risk factor for cognitive impairment and hallucinations in older adults, but associations with other neuropsychiatric symptoms (NPS) of dementia have not been examined.

Methods:

We analyzed cross-sectional data from the Aging, Demographics, and Memory Study (ADAMS), a nationally representative sample of the US population aged 70+ years. Vision was measured by self-report and using a near card. Dementia was ascertained through cognitive testing with expert consensus, and NPS were screened using the Neuropsychiatric Inventory. We used logistic regression to measure the association between visual impairment and prevalent NPS adjusting for sociodemographic factors and comorbidities. Analyses incorporated sample weights to account for the complex survey design of ADAMS.

Results:

Of 624 participants with dementia, 332 (53%) had self-reported visual impairment and 193 (31%) had best-corrected acuity of 20/40 or worse. In unadjusted models, self-reported visual impairment was significantly associated with hallucinations (OR 2.88; 95% CI 1.12–7.44), depression (OR 2.79; 95% CI 1.7–4.57), and agitation (OR 1.61; 95% CI 1.05–2.48). Reduced visual acuity was associated with hallucinations (OR 10.13; 95% CI 2.93–34.98), psychosis (OR 6.69, 95% CI 2.53–17.7), and mania (OR 5.92, 95% CI 1.77–19.82). However, these associations did not remain significant after covariate adjustment.

Conclusions:

Visual impairment was associated with hallucinations, depression, agitation, psychosis, and mania in patients with dementia, but at least some of this relationship is explained by age, comorbidities, and other factors.
Characteristics of soil origin Pseudomonas batumici Koz11 isolated from a remote island in Japan
Authors: Zuo Hui , Morimoto Yuh , Muroi Kenzo , Baba Tadashi
Published: August 2024

Soil samples from a remote Japanese island (Kozushima) were processed and investigated for organisms exhibiting antimicrobial activity against pathogenic strains. A Pseudomonas strain demonstrating antimicrobial activity against Staphylococcus aureus (S. aureus) was identified, prompting further investigation. Whole-genome sequencing was employed to identify the species and conduct phylogenetic analysis, followed by in silico molecular analysis. Chemotaxonomic and biochemical analyses were conducted to further characterize the strain. Genomic analysis identified the strain of interest as Pseudomonas batumici (P. batumici), originally isolated from soil of the Black Sea coast of the Caucasus in 1980. P. batumici Koz11 is the second P. batumici strain to be isolated and identified outside its initial area of discovery. Similar to the type strain, P. batumici Koz11 showed antimicrobial activity against various S. aureus strains, including methicillin-resistant S. aureus (MRSA) and vancomycin-resistant S. aureus (VRSA). However, the previously reported ‘batumin gene cluster’, which synthesizes antimicrobial compounds, was absent from P. batumici Koz11. This study provides new insights into P. batumici. Since the type strain of P. batumici is exclusively deposited in the Ukrainian Collection of Microorganisms, the Koz11 strain may serve as a surrogate to facilitate continued study of P. batumici.
Circulating extracellular microRNAs in the blood promote sociability in mice
Authors: Dohi Eisuke , Matoba Ken , Garcia Phoebe A. , Francis-Oliveira Jose , Anguiano Frida , Kochi Takahiro , Badrani Jana , See Julia , Ito Norimichi , Mitani Rei , Rose Indigo V.L. , Choi Eric Y. , Imai Takashi , Crossman David K. , Pletnikov Mikhail V. , Witwer Kenneth W. , Niwa Minae , Kano Shin-ichi
Published: August 2024

Extracellular vesicles (EVs) are cell-derived membrane vesicles that circulate throughout the body. Accordingly, circulating EVs and their associated molecules, such as RNAs and proteins, are regarded as promising sources of molecular biomarkers for various disorders. Cell culture-derived EVs have also drawn substantial attention as possible delivery tools for therapeutic molecules. Nevertheless, the biological impact of circulating EVs onin vivophysiology and pathology remains elusive. Here we report that systemic exposure to blood circulating EVs from wild-type (WT) mice attenuates sociability deficits inRag1-/-mice. Intravenously injected WT mouse blood EVs reach the brain and restore postsynaptic inhibitory signals in theRag1-/-medial prefrontal cortex (PFC) pyramidal neurons. Mechanistically, WT EV-associated microRNAs, miR-23a-3p and miR-103-3p, reduce PKCε expression, increasing postsynaptic GABAA receptors in the mPFC pyramidal neurons. Our findings reveal a sociability-promoting effect of blood circulating EVs and associated miRNAs with therapeutic potential for sociability deficits.
Low-pass nanopore sequencing for measurement of global methylation levels in plants
Authors: Liau Yusmiati , Whibley Annabel , Hill Amy , Vanga Bhanupratap , Pither-Joyce Meeghan , Hilario Elena , Bailey Sarah , Thomson Susan J. , Lizamore Darrell
Published: August 2024

Nanopore sequencing enables detection of DNA methylation at the same time as identification of canonical sequence. A recent study validated low pass nanopore sequencing to accurately estimate global methylation levels in vertebrates with sequencing coverage as low as 0.01x. We investigated the applicability of this approach to plants by testing three plant species and analysed the effect of technical and biological parameters on estimate precision and accuracy. Our results indicate that a higher coverage (0.1x) is required to assess plant global methylation at an equivalent accuracy to vertebrates. Shorter read length and a closer sequence match between sample and reference genome improved measurement accuracy. Application of this method inVitis viniferashowed consistent global methylation levels across different leaf sizes, and different sample preservation and DNA extraction methods, whereas different varieties and tissue types did exhibit methylation differences. Similarly, distinct methylation patterns could be observed in different genomic features. Our findings suggest the suitability of this method as a low-cost screening tool for validation of experimental parameters, developmental time courses and to assess methylation status for different modification types and sequence contexts at the level of whole genome or for abundant genomic features such as transposable elements.
Spatial mapping of immunosuppressive CAF gene signatures in H&E-stained images using additive multiple instance learning
Authors: Markey Miles , Kim Juhyun , Goldstein Zvi , Gerardin Ylaine , Brosnan-Cashman Jacqueline , Javed Syed Ashar , Juyal Dinkar , Pagidela Harshith , Yu Limin , Rahsepar Bahar , Abel John , Hennek Stephanie , Khosla Archit , Taylor-Weiner Amaro , Parmar Chintan
Published: August 2024

The relative abundance of cancer-associated fibroblast (CAF) subtypes influences a tumor’s response to treatment, especially immunotherapy. However, the extent to which the underlying tumor composition associates with CAF subtype-specific gene expression is unclear. Here, we describe an interpretable machine learning (ML) approach, additive multiple instance learning (aMIL), to predict bulk gene expression signatures from H&E-stained whole slide images (WSI), focusing on an immunosuppressive LRRC15+ CAF-enriched TGFβ-CAF signature. aMIL models accurately predicted TGFβ-CAF across various cancer types. Tissue regions contributing most highly to slide-level predictions of TGFβ-CAF were evaluated by ML models characterizing spatial distributions of diverse cell and tissue types, stromal subtypes, and nuclear morphology. In breast cancer, regions contributing most to TGFβ-CAF-high predictions (“excitatory”) were localized to cancer stroma with high fibroblast density and mature collagen fibers. Regions contributing most to TGFβ-CAF-low predictions (“inhibitory”) were localized to cancer epithelium and densely inflamed stroma. Fibroblast and lymphocyte nuclear morphology also differed between excitatory and inhibitory regions. Thus, aMIL enables a data-driven link between tissue phenotype and transcription, offering biological interpretability beyond typical black-box models.
DeepAge: Harnessing Deep Neural Network for Epigenetic Age Estimation From DNA Methylation Data of human blood samples
Authors: Dip Sajib Acharjee , Ma Da , Zhang Liqing
Published: August 2024

Accurate prediction of biological age from DNA methylation data is a critical endeavor in understanding the molecular mechanisms of aging and developing age-related disease interventions. Traditional epigenetic clocks rely on linear regression or basic machine learning models, which often fail to capture the complex, non-linear interactions within methylation data. This study introduces DeepAge, a novel deep learning framework utilizing Temporal Convolutional Networks (TCNs) to enhance the prediction of biological age from DNA methylation profiles using selected CpGs by a Dual-Correlation based apparoach. DeepAge leverages a sequence-based approach with dilated convolutions to effectively capture long-range dependencies between CpG sites, addressing the limitations of prior models by incorporating advanced network architectures including residual connections and dropout regularization. The dual correlation feature selection enhances our model’s predictive capabilities by identifying the most age-relevant CpG sites. Our model outperforms existing epigenetic clocks across multiple datasets, offering significant improvements in accuracy and providing deeper insights into the epigenetic determinants of aging. The proposed method not only sets a new standard in age estimation but also highlights the potential of deep learning in biologically relevant feature extraction and interpretation, contributing to the broader field of computational biology and precision medicine.
AAB-seq: An antigen-specific and affinity-readable high-throughput BCR sequencing method
Authors: Hu Mengzhu , Lian Qiuyu , Cui Xiaonan , Dong Xue , Xin Hongyi , Shi Weiyang
Published: August 2024

B-cell receptor (BCR) sequencing is a powerful antibody discovery tool but current methodology is often inefficient, and lead generation often requires the production and testing of numerous antibody candidates, and it is difficult to provide affinity information for their antibodies at the same time. Here, we introduce AAB-seq (antigen affinity-readable High-throughput BCR sequencing), an efficient antibody screening tool to identify antigen binding affinity of thousands of paired BCRs. It employs fluorophore and DNA barcode-labeled antigen and secondary antibody targeting Ig light chain to label B cells and uses high throughput single cell BCR sequencing and surface protein profiling to obtain the ratio of surface bound antigen to surface BCR in thousands of B-cells. Using AAB-seq, we accurately identified valuable candidate antibodies 1743-3 and 1743-13 from SARS-CoV-2 RBD immunized mouse, providing a basis for further development of SARS-CoV-2 antibody drugs. Thus, AAB-seq allows high throughput identification of antibody sequences paired with antigen affinity, which improves the screening efficiency of functional antibodies and provides an effective solution for the rapid discovery and development of new therapeutic monoclonal antibodies.
Complete genome sequences of two new strains of the shipworm endosymbiont,Teredinibacter turnerae
Authors: Gasser Mark T. , Flatau Ron , Altamia Marvin , Filone Claire Marie , Distel Dan
Published: August 2024

We present the complete genome sequences of two strains ofTeredinibacter turnerae, SR01903 and SR02026, shipworm endosymbionts isolated from the gills ofLyrodus pedicellatusandTeredo bartschi, respectively, and derived from Oxford Nanopore sequencing. These sequences will aid in the comparative genomics of shipworm endosymbionts and understanding of host-symbiont selection.
Identification of biomarkers for COVID-19 associated secondary hemophagocytic lymphohistiocytosis
Authors: Canny Susan P. , Stanaway Ian B. , Holton Sarah E. , Mitchem Mallorie , O’Rourke Allison R. , Pribitzer Stephan , Baxter Sarah K. , Wurfel Mark M. , Malhotra Uma , Buckner Jane H. , Bhatraju Pavan K. , Morrell Eric D. , Speake Cate , Mikacenic Carmen , Hamerman Jessica A.
Published: August 2024

OBJECTIVES

We aimed to define and validate novel biomarkers that could identify individuals with COVID-19 associated secondary hemophagocytic lymphohistiocytosis (sHLH) and to test whether fatalities due to COVID-19 in the presence of sHLH were associated with specific defects in the immune system.

DESIGN

In two cohorts of adult patients presenting with COVID-19 in 2020 and 2021, clinical lab values and serum proteomics were assessed. Subjects identified as having sHLH were compared to those with COVID-19 without sHLH. Eight deceased patients defined as COVID-sHLH underwent genomic sequencing in order to identify variants in immune-related genes.

SETTING

Two tertiary care hospitals in Seattle, Washington (Virginia Mason Medical Center and Harborview Medical Center).

PATIENTS

186 patients with COVID-19

INTERVENTIONS

None

MEASUREMENTS AND MAIN RESULTS

Nine percent of enrolled COVID-19 subjects met our defined criteria for sHLH. Using broad serum proteomic approaches (O-link and SomaScan), we identified three biomarkers for COVID-19 associated sHLH (soluble PD-L1, TNF-R1, and IL-18BP), supporting a role for proteins previously associated with other forms of sHLH (IL-18BP and sTNF-R1). We also identified novel biomarkers and pathways of COVID-sHLH, including sPD-L1 and the syntaxin pathway. We detected variants in several genes involved in immune responses in individuals with COVID-sHLH, including inDOCK8and inTMPRSS15, suggesting that genetic alterations in immune-related genes may contribute to hyperinflammation and fatal outcomes in COVID-19.

CONCLUSIONS

Biomarkers of COVID-19 associated sHLH, such as soluble PD-L1, and pathways, such as the syntaxin pathway, and variants in immune genes in these individuals, suggest critical roles for the immune response in driving sHLH in the context of COVID-19.

Key Points

QUESTION

To define biomarkers that could identify individuals with COVID-19 associated secondary hemophagocytic lymphohistiocytosis (sHLH) and to test whether fatalities due to COVID-19 in the presence of sHLH were associated with specific defects in the immune system.

FINDINGS

In two independent cohorts using two different platforms, we identified sPD-L1, IL-18BP, and sTNF-R1 as COVID-sHLH biomarkers. We identified the syntaxin pathway as important in COVID-sHLH and variants in immune-related genes in a subset of deceased COVID-sHLH subjects.

MEANING

Immune related proteins and pathways are dysregulated in COVID-sHLH.
Differential EBV protein-specific antibody response between responders and non-responders to EBVSTs immunotherapy
Authors: Sarathkumara Yomani D. , Van Bibber Nathan W. , Liu Zhiwei , Heslop Helen E. , Rouce Rayne H , Coghill Anna E. , Rooney Cliona M , Proietti Carla , Doolan Denise L.
Published: August 2024

Epstein–Barr virus (EBV) is associated with a diverse range of lymphomas. EBV-specific T-cell (EBVST) immunotherapies have shown promise in safety and clinical effectiveness in treating EBV-associated lymphomas, but not all patients respond to treatment.

To identify the set of EBV-directed antibody responses associated with clinical response in patients with EBV-associated lymphomas, we comprehensively characterized the immune response to the complete EBV proteome using a custom protein microarray in 56 EBV-associated lymphoma patients who were treated with EBVST infusions enrolled in Phase I clinical trials.

Significant differences in antibody profiles between responders and non-responders emerged at 3 months post-EBVST infusion. Twenty-five IgG antibodies were present at significantly higher levels in non-responders compared to responders at 3 months post-EBVST infusion, and 10 of these IgG antibody associations remained after adjustment for sex, age, and cancer diagnosis type. Random forest prediction analysis further confirmed that these 10 antibodies were important for predicting clinical response. Differential IgG antibody responses were directed against LMP2A (four fragments), BGRF1/BDRF1 (two fragments), LMP1, BKRF2, BKRF4, and BALF5.

Paired analyses using blood samples collected at both pre-infusion and 3 months post-EBVST infusion indicated an increase in the mean antibody level for six other anti-EBV antibodies (IgG: BGLF2, LF1, BGLF3; IgA: BGLF3, BALF2, BBLF2/3) in non-responders. Overall, our results indicate that EBV-directed antibodies can be biomarkers for predicting the clinical response of individuals with EBV-associated lymphomas treated with EBVST infusions.
Randomized Clinical Trial of ICECaP (Individualized Coordination and Empowerment for Care Partners of Persons with Dementia): Primary Mental Health and Burden Outcomes
Authors: Gallagher Virginia T. , Arp Anna , Thompson Ryan , Rossetti Agustina , Patrie James , Reilly Shannon E , Manning Carol A.
Published: August 2024

Efficacy of the Individualized Coordination and Empowerment for Care Partners of Persons with Dementia (ICECaP), an intervention that involves one-on-one individualized support from a dementia care coordinator for a dementia care partner, compared to an active control group. At least once monthly contact is made from a dementia care coordinator to the dementia care partner by telephone, video conferencing, email, or in-person support at clinical visits for the person with dementia. In this pilot randomized unblinded control trial of ICECaP, n=61 (n=90 randomized) care partners completed 12-months of the ICECaP intervention and n=69 (n=92 randomized) care partners received routine clinical support (controls) in an outpatient memory care clinic at an academic medical center, from which the participants were recruited (ClinicalTrials.gov:NCT04495686, funded by Department of Defense and Virginia Department for Aging and Rehabilitative Services). Early termination endpoints (death and higher level of care) and trial drop out were comparable across groups. Primary efficacy outcomes were evaluated by comparing changes in care partner mental health, burden, and quality of life from baseline to 12-months between ICECaP and controls. Linear-mixed ANCOVA revealed no significant group differences in longitudinal changes on measures of caregiving burden, care partner depression, anxiety, quality of life, or reactions to the behavioral symptoms of the person with dementia. Hypothesized reasons for lack of initial efficacy on primary 12-month outcomes are discussed.
Training AI to identify diagnostic criteria and treatment methods for advanced and delayed circadian sleep disorders in humans.
Authors: Kunorozva Lovemore , Okafor Ebeleyichem , Lane Jacqueline M
Published: August 2024

Objectives: The objective of this review was to evaluate the diagnosis and treatment of advanced and delayed sleep-wake phase disorders (ASWPD, DSWPD), both forms of circadian rhythm sleep-wake disorders (CRSWDs) using both human reviewers and ChatGTP to summarize relevant content. Methods: PubMed-Medline, EbscoHost, and Web of Science were searched for peer reviewed articles. Original research articles published in English were searched for full-text studies. Studies that reported quantitative data on ASWPD and DSWPD diagnosing tools and treatment options in individuals of all ages were assessed. We assessed ChatGTP 4.0s capacity to extract and summarize data from these studies and evaluated it alongside human reviewers. Results: Our review of 49 articles on CRSWD from the past 20 years found that 91% focused on DSWPD. The most common diagnostic tools were the MEQ, MCQ, Pittsburgh Sleep Quality Index, and Epworth Sleepiness Scale, with primary methods including actigraphy and dim-light-melatonin-onset. Melatonin, often combined with light therapy and CBT, was the predominant treatment. ChatGPT-4.0 facilitated the review process with about 92% accuracy but required manual oversight for optimal results. Conclusions: Our review identified key diagnostic tools, such as MEQ and MCQ surveys, and common treatment options for ASWPD and DSWPD, including melatonin, light therapy, and CBT. The findings underscore the need for comprehensive and individualized treatment approaches for CRSWDs, with a particular focus on expanding research on ASWPD and increasing data representation across age groups. While ChatGPT shows potential in streamlining data extraction for CRSWDs, it still requires human oversight to ensure accuracy.
“Characteristics and Predictors of Pediatric and Adult Patients with Inherited Retinal Degenerations at Time of Presentation: Tertiary Care Ophthalmology Clinic Data”
Authors: McLaughlin Matthew T. , Ganansky Caleb P. , Taher Ayman W. , Trudrung Melissa A. , Van De Car William , Le Jonathan , Peterson Kyle D. , Stepien Kimberly E. , Schmitt Melanie A.
Published: August 2024

Inherited Retinal Degenerations (IRDs) are a group of diseases where genetic variants lead to retinal photoreceptor dysfunction and subsequent visual impairment. We aimed to compare the characteristics of pediatric versus adult IRD patients at the time of presentation at a tertiary care IRD clinic. A retrospective chart review of 538 patients with IRDs was conducted. Information obtained included age, diagnosis, presenting characteristics, demographics, distance from the clinic, and referring physician. This study found that high hyperopia, congenital syndactyly, high refractive error, high astigmatism, and a history of developmental delay were most predictive of pediatric presentation. In adults, we found reduced central vision, peripheral vision loss, color vision deficits, nyctalopia, flashes/floaters, cataracts, diabetes mellitus, obesity, cardiac conditions, and a family history of cataract were most predictive of presentation. There was a greater proportion of pediatric patients presenting from 20 or more miles away. Additionally, there was no significant difference between the type of healthcare provider referring adult or pediatric patients. This study identifies characteristics predictive of pediatric and adult presentation in IRD patients thus addressing current knowledge gaps. A better understanding of these characteristics may provide for quicker recognition, education of clinicians likely to encounter IRDs, and allow for earlier treatment.
Daxx mediated histone H3.3 deposition on HSV-1 DNA restricts genome decompaction and the progression of immediate-early transcription
Authors: Roberts Ashley P.E. , Orr Anne , Iliev Victor , Orr Lauren , McFarlane Steven , Yang Zhousiyu , Epifano Ilaria , Loney Colin , Collados Rodriguez Milagros , Cliffe Anna R. , Conn Kristen L. , Boutell Chris
Published: August 2024

Herpesviruses are ubiquitous pathogens that cause a wide range of disease. Upon nuclear entry, their genomes associate with histones and chromatin modifying enzymes that regulate the progression of viral transcription and outcome of infection. While the composition and modification of viral chromatin has been extensively studied on bulk populations of infected cells by chromatin immunoprecipitation, this key regulatory process remains poorly defined at single-genome resolution. Here we use high-resolution quantitative imaging to investigate the spatial proximity of canonical and variant histones at individual Herpes Simplex Virus 1 (HSV-1) genomes within the first 90 minutes of infection. We identify significant population heterogeneity in the stable enrichment and spatial proximity of canonical histones (H2A, H2B, H3.1) at viral DNA (vDNA) relative to established promyelocytic leukaemia nuclear body (PML-NB) host factors that are actively recruited to viral genomes upon nuclear entry. We show the replication-independent histone H3.3/H4 chaperone Daxx to cooperate with PML to mediate the enrichment and spatial localization of variant histone H3.3 at vDNA that limits the rate of HSV-1 genome decompaction to restrict the progress of immediate-early (IE) transcription. This host response is counteracted by the viral ubiquitin ligase ICP0, which degrades PML to disperse Daxx and variant histone H3.3 from vDNA to stimulate the progression of viral genome expansion, IE transcription, and onset of HSV-1 replication. Our data support a model of intermediate and sequential histone assembly initiated by Daxx that limits the rate of HSV-1 genome decompaction independently of the stable enrichment of histones H2A and H2B at vDNA required to facilitate canonical nucleosome assembly. We identify HSV-1 genome decompaction upon nuclear infection to play a key role in the initiation and functional outcome of HSV-1 lytic infection, findings pertinent to the transcriptional regulation of many nuclear replicating herpesvirus pathogens.
Methanogenesis inhibition remodels microbial fermentation and stimulates acetogenesis in ruminants
Authors: Ni Gaofeng , Walker Nicola , Fischer André , Stemmler René T. , Schmidt Oliver , Jain Surbhi , Jespersen Marion , Grinter Rhys , Wang Min , Pope Phillip B. , Müller Volker , Watson Mick , Ver Loren van Themaat Emiel , Kindermann Maik , Greening Chris
Published: August 2024

Rumen microbiota enable ruminants to grow on fibrous plant materials but also produce methane, driving 5% of global greenhouse gas emissions and leading to a loss of gross energy content. Methanogenesis inhibitors such as 3-nitrooxypropanol (3-NOP) decrease methane emissions in ruminants when supplemented in feed. Yet we lack a system-wide, species-resolved understanding of how the rumen microbiota remodels following inhibition and how this influences animal production. Here, we conducted a large-scale trial with 51 dairy calves to analyse microbiota responses to 3-NOP, pairing host performance, emissions, and nutritional profiles with genome-resolved metagenomic and metatranscriptomic data. 3-NOP supplementation decreased methane emissions by an average of 62%, modulated short-chain fatty acid and H2levels, and did not affect dietary intake or animal performance. We created a rumen microbial genome catalogue with an unprecedented mapping rate. We observed a strong reduction of methanogens and stimulation of reductive acetogens, primarily novel uncultivated lineages such asCandidatusFaecousia. However, there was a shift in major fermentative communities away from acetate production in response to hydrogen gas accumulation. Thus, the divergent responses of the fermentative and hydrogenotrophic communities limit potential productivity gains from methane reduction. Reporting one of the largest reductions in methane emissions in a field trial to date, this study links ruminant greenhouse gas emissions and productivity to specific microbial species. These findings also emphasise the importance of microbiota-wide analysis for optimising methane mitigation strategies and identify promising strategies to simultaneously reduce emissions while increasing animal production.

Significance Statement

One strategy to increase the sustainability and productivity of livestock production is to modulate ruminant microbiota to produce absorbable nutrients rather than the potent greenhouse gas methane. Previous studies show supplementing feed with methanogenesis inhibitors such as 3-nitrooxypropanol reduces methane emissions, but also leads to inconsistent productivity gains. Here we report a definitive field trial, combining animal data, meta-omics, and structural modelling, to resolve the key microbes and pathways controlling nutrient and methane production in ruminants. We show that shifts in composition and gene expression of hydrogen-cycling microbes reduce emissions but limit productivity gains. These findings offer insights at unprecedented resolution, while the data and analytical framework provide valuable resources to develop solutions to enhance livestock productivity and sustainability.
Working memory processing boosts the neural representation of long-term memories
Authors: Sabo Melinda , Klatt Laura-Isabelle , Schneider Daniel
Published: August 2024

Understanding the interaction between short-term and long-term memory systems is essential for advancing our knowledge of human memory. This study investigates whether working memory processes, specifically attentional prioritization (Experiments 1 and 2) and testing (Experiment 2), can enhance the neural activity associated with recently encoded long- term memories. A total of 86 participants completed a novel three-phase memory task that integrated a traditional long-term memory learning task with a working memory paradigm. In the first phase, participants encoded object-location associations. During the second phase, these associations were reintroduced in a working memory task that manipulated attentional prioritization; participants were required to report the location of the cued object. In the final phase, participants recalled the locations associated with each object. By analyzing both behavioral performance and electroencephalogram (EEG) data collected during this retrieval phase, we found that attentional prioritization in working memory significantly improved long- term memory retrieval, a finding supported by corresponding neural evidence. Additionally, Experiment 2 demonstrated that both prioritization and testing in working memory jointly enhance the neural representation of long-term memories. These findings indicate that working memory processes can dynamically alter the neural patterns underlying long-term memory representations, revealing a more integrated role for working memory in long-term memory consolidation.
Predicting rifampicin resistance inM. tuberculosisusing machine learning informed by protein structural and chemical features
Authors: Lynch Charlotte I , Adlard Dylan , Fowler Philip W
Published: August 2024

Background

Rifampicin remains a key antibiotic in the treatment of tuberculosis. Despite advances in cataloguing resistance-associated variants (RAVs), novel and rare mutations in the relevent gene,rpoB, will be encountered in clinical samples, complicating the task of using genetics to predict whether a sample is resistant or not to rifampicin. We have trained a series of machine learning models with the aim of complementing genetics-based drug susceptibility testing.

Methods

We built a Test+Train dataset comprising 219 susceptible mutations and 46 RAVs. Features derived from the structure of the RNA polymerase or the change in chemistry introduced by the mutation were considered, however, only a few, notably the distance from the rifampicin binding site, were found to be predictive on their own. Due to the paucity of RAVs we used Monte Carlo cross-validation with 50 repeats to train four different machine learning models.

Results

All four models behaved similarly with sensitivities and specificities in the range 0.84-0.88 and 0.94-0.97 although we preferred the ensemble of Decision Tree models as they are easy to inspect and understand. We showed that measuring distances from molecular dynamics simulations did not improve performance.

Conclusions

It is possible to predict whether a mutation inrpoBconfers resistance to rifampicin using a machine learning model trained on a combination of structural, chemical and evolutionary features, however performance is moderate and training is complicated by the lack of data.