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Systems vaccinology studies have been used to build computational models that predict individual vaccine responses and identify the factors contributing to differences in outcome. Comparing such models is challenging due to variability in study designs. To address this, we established a community resource to compare models predicting B. pertussis booster responses and generate experimental data for the explicit purpose of model evaluation. We here describe our second computational prediction challenge using this resource, where we benchmarked 49 algorithms from 53 scientists. We found that the most successful models stood out in their handling of nonlinearities, reducing large feature sets to representative subsets, and advanced data preprocessing. In contrast, we found that models adopted from literature that were developed to predict vaccine antibody responses in other settings performed poorly, reinforcing the need for purpose-built models. Overall, this demonstrates the value of purpose-generated datasets for rigorous and open model evaluations to identify features that improve the reliability and applicability of computational models in vaccine response prediction.

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BACKGROUND: MicroRNAs (miRNAs) are presented in the uterine lumen of many mammals, and in vitro experiments have determined that several miRNAs are important for the regulation of endometrial and trophoblast functions. Our aim was to identify and contrast the miRNAs present in extracellular vesicles (EVs) in the uterine lumen fluid (ULF) at the onset of attachment in cattle pregnancies (gestation d 18) initiated by artificial insemination (AI) or by the transfer of an in vitro-produced blastocyst (IVP-ET). A third group had no conceptus after the transfer of an IVP embryo. RESULTS: The abundance of 263 annotated miRNAs was quantified in the EVs collected from ULF. There was an increase in the transcript abundance of 20 miRNAs in the ULF EVs from the AI pregnant group, while 4 miRNAs had a lower abundance relative to the group not containing a conceptus. Additionally, 4 miRNAs were more abundant in ULF EVs in the AI pregnant group relative to IVP-ET group (bta-mir-17, bta-mir-7-3, MIR7-1, MIR18A). Specific miRNAs in the ULF EVs were co-expressed with messenger RNAs expressed in extra-embryonic tissues and endometrium, including genes that are known to be their targets. CONCLUSIONS: The results provide biological insights into the participation of miRNAs in the regulation of trophoblast proliferation and differentiation, as well as in endometrium receptivity. The knowledge that in vitro cultured embryos can contribute to the altered abundance of specific miRNAs in the uterine lumen can lead to the development of corrective approaches to reduce conceptus losses during the first month of pregnancy in cattle.

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OBJECTIVES: Neuromodulation is an effective treatment for chronic pain; however, socioeconomic differences may influence decision-making to initiate this therapy. This review investigated potential differences in accessibility of neuromodulation for patients with chronic pain due to socioeconomic determinants. MATERIALS AND METHODS: Four electronic databases were used for this systematic review: MEDLINE, Embase, Scopus, and Web of Science. Risk of bias was assessed using the modified version of the Downs and Black checklist. The study protocol was prospectively registered on PROSPERO (CRD42023426035). RESULTS: The initial database search identified a total of 1118 unique studies, of which 36 were eventually included in the systematic review. Of the 36 included studies, six studies reported on education, 24 on employment status, ten on insurance, five on household income, and three on miscellaneous topics. Neuromodulation seems accessible for patients with different education levels and different types of insurance. Additionally, it is not restricted to patients who are (un)employed. When comparing patients who initiated neuromodulation with those who did not, a significantly higher number of patients in the top quartile for education were found in the group without neuromodulation. Regarding insurance, inconclusive evidence was found. CONCLUSIONS: Although neuromodulation was accessible for patients with varying levels of socioeconomic determinants, disparities were noted. When comparing the socioeconomic profiles of patients who receive neuromodulation and those who do not, education levels differ. Health-related inequality should be carefully monitored in chronic pain management with neuromodulation to ensure that potential disparities do not increase.

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Potential associations between periconception dolutegravir (DTG) exposure and neural tube defects (NTDs) reported in 2018 caused shifting international and national antiretroviral treatment (ART) guidelines. They sometimes required women to use contraception prior to initiating DTG. To better understand the tensions between ART and family planning (FP) choices, and explore the decision-making processes of women living with HIV (WLHIV) and their healthcare providers (HCPs) employed, we conducted interviews with WLHIV exposed to DTG and their providers in western Kenya from July 2019 to August 2020. For the interviews with WLHIV, we sampled women at varying ages who either continued using DTG, switched to a different ART, or became pregnant while using DTG. We utilized inductive coding and thematic analysis. We conducted 44 interviews with WLHIV and 10 with providers. We found four dominant themes: (1) a range of attitudes about birth defects, (2) nuanced knowledge of DTG and its potential risk of birth defects, (3) significant tensions at the intersection of DTG and FP use with varying priorities amongst WLHIV and their providers for navigating the tensions, and (4) WLHIV desiring autonomy, and provider support for this, in such decision-making. Variations in beliefs were noted between WLHIV and HCPs. WLHIV highlighted the impact of community and social beliefs when discussing their attitudes while HCPs generally reported more medicalized views towards DTG utilization, potential adverse outcomes, and FP selection. Decisions pertaining to ART and FP selection are complex, and HIV treatment guidelines need to better support women's agency and reproductive health justice.

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Approval of induced pluripotent stem cells (iPSCs) for the manufacture of cell therapies to support clinical trials is now becoming realized after 20 years of research and development. In 2022 the International Society for Cell and Gene Therapy (ISCT) established a Working Group on Emerging Regenerative Medicine Technologies, an area in which iPSCs-derived technologies are expected to play a key role. In this article, the Working Group surveys the steps that an end user should consider when generating iPSCs that are stable, well-characterised, pluripotent, and suitable for making differentiated cell types for allogeneic or autologous cell therapies. The objective is to provide the reader with a holistic view of how to achieve high-quality iPSCs from selection of the starting material through to cell banking. Key considerations include: (i) intellectual property licenses; (ii) selection of the raw materials and cell sources for creating iPSC intermediates and master cell banks; (iii) regulatory considerations for reprogramming methods; (iv) options for expansion in 2D vs. 3D cultures; and (v) available technologies and equipment for harvesting, washing, concentration, filling, cryopreservation, and storage. Some key process limitations are highlighted to help drive further improvement and innovation, and includes recommendations to close and automate current open and manual processes.

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INTRODUCTION: One of the most common questions patients ask when they are contemplating deep brain stimulation (DBS) is how long it will last. To guide physicians in answering this query, we performed a scoping review to assess the current state of the literature and to identify the gaps that need to be addressed. MATERIALS AND METHODS: The authors performed a MEDLINE search inclusive of articles from January 1987 (advent of DBS literature) to June 2023 including human and modeling studies written in English. For longevity of therapy data, only studies with a mean follow-up of ≥three years were included. Using the Rayyan platform, two reviewers (JP and RM) performed a title screen. Of the 734 articles, 205 were selected by title screen and 109 from abstract review. Ultimately, a total of 122 articles were reviewed. The research questions we explored were 1) how long can the different components of the DBS system maintain functionality? and 2) how long can DBS remain efficacious in treating Parkinson's disease (PD), essential tremor (ET), dystonia, and other disorders? RESULTS: We showed that patients with PD, ET, and dystonia maintain a considerable long-term benefit in motor scores seven to ten years after implant, although the percentage improvement decreases over time. Stimulation off scores in PD and ET show worsening, consistent with disease progression. Battery life varies by the disease treated and the programming settings used. There remains a paucity of literature after ten years, and the impact of new device technology has not been classified to date. CONCLUSION: We reviewed existing data on DBS longevity. Overall, outcomes data after ten years of therapy are substantially limited in the current literature. We recommend that physicians who have data for patients with DBS exceeding this duration publish their results.

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INTRODUCTION: The International Neuromodulation Society convened a multispecialty group of physicians based on expertise and international representation to establish evidence-based guidance on the mitigation of neuromodulation complications. This Neurostimulation Appropriateness Consensus Committee (NACC)® project intends to update evidence-based guidance and offer expert opinion that will improve efficacy and safety. MATERIALS AND METHODS: Authors were chosen on the basis of their clinical expertise, familiarity with the peer-reviewed literature, research productivity, and contributions to the neuromodulation literature. Section leaders supervised literature searches of MEDLINE, BioMed Central, Current Contents Connect, Embase, International Pharmaceutical Abstracts, Web of Science, Google Scholar, and PubMed from 2017 (when NACC last published guidelines) to October 2023. Identified studies were graded using the United States Preventive Services Task Force criteria for evidence and certainty of net benefit. Recommendations are based on the strength of evidence or consensus when evidence was scant. RESULTS: The NACC examined the published literature and established evidence- and consensus-based recommendations to guide best practices. Additional guidance will occur as new evidence is developed in future iterations of this process. CONCLUSIONS: The NACC recommends best practices regarding the mitigation of complications associated with neurostimulation to improve safety and efficacy. The evidence- and consensus-based recommendations should be used as a guide to assist decision-making when clinically appropriate.

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Objectives: The purpose of this scoping review is to explore research studies on the association between chronic pain and polycystic ovary syndrome to create local (U.S.-based) and global recommendations to improve access to and quality of affordable symptom management and treatment options for patients with polycystic ovary syndrome. Methods: The study sections used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews as a checklist reference. The review followed the York methodology by Arksey and O'Malley for the extraction, analysis, and presentation of results in scoping reviews. Results: Final analysis included two conference abstracts published in peer-reviewed journals and two peer-reviewed articles. The relationship between pain perception and health-related quality of life warrants further investigation in patients with polycystic ovary syndrome as the interconnected pathophysiology of symptoms renders exploring associations between the two factors difficult. A comprehensive understanding of the causes of polycystic ovary syndrome-associated symptoms, particularly those relating to pain perceptions can provide more insight into polycystic ovary syndrome pathophysiology and aid in the development of innovative therapeutic approaches for long-term polycystic ovary syndrome management and care. Conclusion: Future studies are necessary to examine associations between the disease and pathophysiological symptoms for a better quality of life for patients with polycystic ovary syndrome.

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The potential of artificial intelligence (AI) in medicine lies in its ability to enhance clinicians' capacity to analyse medical images, thereby improving diagnostic precision and accuracy and thus enhancing current tests. However, the integration of AI within health care is fraught with difficulties. Heterogeneity among health care system applications, reliance on proprietary closed-source software, and rising cybersecurity threats pose significant challenges. Moreover, before their deployment in clinical settings, AI models must demonstrate their effectiveness across a wide range of scenarios and must be validated by prospective studies, but doing so requires testing in an environment mirroring the clinical workflow, which is difficult to achieve without dedicated software. Finally, the use of AI techniques in health care raises significant legal and ethical issues, such as the protection of patient privacy, the prevention of bias, and the monitoring of the device's safety and effectiveness for regulatory compliance. This review describes challenges to AI integration in health care and provides guidelines on how to move forward. We describe an open-source solution that we developed that integrates AI models into the Picture Archives Communication System (PACS), called PACS-AI. This approach aims to increase the evaluation of AI models by facilitating their integration and validation with existing medical imaging databases. PACS-AI may overcome many current barriers to AI deployment and offer a pathway toward responsible, fair, and effective deployment of AI models in health care. In addition, we propose a list of criteria and guidelines that AI researchers should adopt when publishing a medical AI model to enhance standardisation and reproducibility.

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Large language models (LLMs) have emerged as powerful tools in artificial intelligence, demonstrating remarkable capabilities in natural language processing and generation. In this article, we explore the potential applications of LLMs in enhancing cardiovascular care and research. We discuss how LLMs can be used to simplify complex medical information, improve patient-physician communication, and automate tasks such as summarising medical articles and extracting key information. In addition, we highlight the role of LLMs in categorising and analysing unstructured data, such as medical notes and test results, which could revolutionise data handling and interpretation in cardiovascular research. However, we also emphasise the limitations and challenges associated with LLMs, including potential biases, reasoning opacity, and the need for rigourous validation in medical contexts. This review provides a practical guide for cardiovascular professionals to understand and harness the power of LLMs while navigating their limitations. We conclude by discussing the future directions and implications of LLMs in transforming cardiovascular care and research.

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In the dynamic field of medical artificial intelligence (AI), cardiology stands out as a key area for its technological advancements and clinical application. In this review we explore the complex issue of data bias, specifically addressing those encountered during the development and implementation of AI tools in cardiology. We dissect the origins and effects of these biases, which challenge their reliability and widespread applicability in health care. Using a case study, we highlight the complexities involved in addressing these biases from a clinical viewpoint. The goal of this review is to equip researchers and clinicians with the practical knowledge needed to identify, understand, and mitigate these biases, advocating for the creation of AI solutions that are not just technologically sound, but also fair and effective for all patients.

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BACKGROUND: Uranium exposure remains an important environmental legacy and physiological health concern, with hundreds of abandoned uranium mines located in the Southwestern United States largely impacting underserved indigenous communities. The negative effects of heavy metals on barrier permeability and inhibition of intestinal epithelial healing have been described; however, transcriptomic changes within the intestinal epithelial cells and impacts on lineage differentiation are largely unknown. OBJECTIVES: Herein, we sought to determine the molecular and cellular changes that occur in the colon in response to uranium bearing dust (UBD) exposure. METHODS: Human colonoids from three biologically distinct donors were acutely exposed to UBD then digested for single cell RNA sequencing to define the molecular changes that occur to specific identities of colonic epithelial cells. Validation in colonoids was assessed using morphological and imaging techniques. RESULTS: Human colonoids acutely exposed to UBD exhibited disrupted proliferation and hyperplastic differentiation of the secretory lineage cell, enteroendocrine cells (EEC). Single-cell RNA sequencing also showed more EEC subtypes present in UBD-exposed colonoids. DISCUSSION: These findings highlight the significance of crypt-based proliferative cells and secretory cell differentiation using human colonoids to model major colonic responses to uranium-bearing particulate dust exposure. https://doi.org/10.1289/EHP13855.

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Scanning Thermal Microscopy (SThM) has become an important measurement technique for characterizing the thermal properties of materials at the nanometer scale. This technique requires a SThM probe that combines an Atomic Force Microscopy (AFM) probe and a very sensitive resistive thermometer; the thermometer being located at the apex of the probe tip allows for the mapping of temperature or thermal properties of nanostructured materials with very high spatial resolution. The high interest of the SThM technique in the field of thermal nanoscience currently suffers from a low temperature sensitivity despite its high spatial resolution. To address this challenge, we developed a high vacuum-based AFM system hosting a highly sensitive niobium nitride (NbN) SThM probe to demonstrate its unique performance. As a proof of concept, we utilized this custom-built system to carry out thermal measurements using the 3ω method. By measuring the V3ω voltage on the NbN resistive thermometer under vacuum conditions, we were able to determine the SThM probe's thermal conductance and thermal time constant. The performance of the probe is demonstrated by performing thermal measurements in-contact with a sapphire sample.

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BACKGROUND: Lactotransferrin (LTF) has an immunomodulatory function, and its expression levels are associated with asthma susceptibility. OBJECTIVES: We sought to investigate LTF messenger RNA (mRNA) expression levels in human bronchial epithelial cells (BECs) as an anti-type 2 (T2) asthma biomarker. METHODS: Association analyses between LTF mRNA expression levels in BECs and asthma-related phenotypes were performed in the Severe Asthma Research Program (SARP) cross-sectional (n = 155) and longitudinal (n = 156) cohorts using a generalized linear model. Correlation analyses of mRNA expression levels between LTF and all other genes were performed by Spearman correlation. RESULTS: Low LTF mRNA expression levels were associated with asthma susceptibility and severity (P < .025), retrospective and prospective asthma exacerbations, and low lung function (P < 8.3 × 10-3). Low LTF mRNA expression levels were associated with high airway T2 inflammation biomarkers (sputum eosinophils and fractional exhaled nitric oxide; P < 8.3 × 10-3) but were not associated with blood eosinophils or total serum IgE. LTF mRNA expression levels were negatively correlated with expression levels of TH2 or asthma-associated genes (POSTN, NOS2, and MUC5AC) and eosinophil-related genes (IL1RL1, CCL26, and IKZF2) and positively correlated with expression levels of TH1 and inflammation genes (IL12A, MUC5B, and CC16) and TH17-driven cytokines or chemokines for neutrophils (CXCL1, CXCL6, and CSF3) (P < 3.5 × 10-6). CONCLUSIONS: Low LTF mRNA expression levels in BECs are associated with asthma susceptibility, severity, and exacerbations through upregulation of airway T2 inflammation. LTF is a potential anti-T2 biomarker, and its expression levels may help determine the balance of eosinophilic and neutrophilic asthma.

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Introduction: We present the evolution of GHD in adolescent males with persistent growth failure, in whom the diagnosis was established after a second GH stimulation test (GST). Methods: We performed a retrospective chart review of children who presented for short stature (height less < 2SD for mean/mid-parental height) and/or growth failure (sustained growth velocity < 0 SD) to pediatric endocrinology at Mount Sinai Kravis Children's Hospital, New York and who had 2 GSTs. Data collected from electronic medical records were analyzed using SPSS v28.0. Results: Of 53 patients included, 42 were males. Average GH peak on initial GST was 15.48 ± 4.92 ng/ml, at 10.07 ± 2.65 years, mean height -1.68 ± 0.56SD(28% had <2SD), IGF-1 -1.00 ± 0.88SD. After 2.23 ± 1.22 years, at 12.04 ± 2.41years, height SDs decreased to -1.82 ± 0.63SD and IGF-1 was -1.08 ± 0.84SD. At repeat GST, average GH peak was 7.59 ± 2.12 ng/dL, with 36% ≤7 ng/dl and 32% in puberty. 12 males reached adult height of 0.08 ± 0.69 SD with a mean height gain of 1.83 ± 0.56SD(p<0.005), IGF-1 of -1.15 ± 0.81SD after 4.64 ± 1.4 years of GH. Conclusion: We offer evidence for Evolving Growth Hormone Deficiency (EGHD) through repeat GST in children with persistent growth slowdown, even with pubertal progression; emphasizing the need for careful longitudinal follow-up to make accurate diagnosis.

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BACKGROUND: Influenza A virus (IAV) infection is a significant risk factor for respiratory diseases, but the host defense mechanisms against IAV remain to be defined. Immune regulators such as surfactant protein A (SP-A) and Toll-interacting protein (Tollip) have been shown to be involved in IAV infection, but whether SP-A and Tollip cooperate in more effective host defense against IAV infection has not been investigated. METHODS: Wild-type (WT), Tollip knockout (KO), SP-A KO, and Tollip/SP-A double KO (dKO) mice were infected with IAV for four days. Lung macrophages were isolated for bulk RNA sequencing. Precision-cut lung slices (PCLS) from WT and dKO mice were pre-treated with SP-A and then infected with IAV for 48 h. RESULTS: Viral load was significantly increased in bronchoalveolar lavage (BAL) fluid of dKO mice compared to all other strains of mice. dKO mice had significantly less recruitment of neutrophils into the lung compared to Tollip KO mice. SP-A treatment of PCLS enhanced expression of TNF and reduced viral load in dKO mouse lung tissue. Pathway analysis of bulk RNA sequencing data suggests that macrophages from IAV-infected dKO mice reduced expression of genes involved in neutrophil recruitment, IL-17 signaling, and Toll-like receptor signaling. CONCLUSIONS: Our data suggests that both Tollip and SP-A are essential for the lung to exert more effective innate defense against IAV infection.

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INTRODUCTION: The International Neuromodulation Society convened a multispecialty group of physicians and scientists based on expertise with international representation to establish evidence-based guidance on intrathecal drug delivery in treating chronic pain. This Polyanalgesic Consensus Conference (PACC)® project, created more than two decades ago, intends to provide evidence-based guidance for important safety and efficacy issues surrounding intrathecal drug delivery and its impact on the practice of neuromodulation. MATERIALS AND METHODS: Authors were chosen on the basis of their clinical expertise, familiarity with the peer-reviewed literature, research productivity, and contributions to the neuromodulation literature. Section leaders supervised literature searches of MEDLINE, BioMed Central, Current Contents Connect, Embase, International Pharmaceutical Abstracts, Web of Science, Google Scholar, and PubMed from 2017 (when PACC® last published guidelines) to the present. Identified studies were graded using the United States Preventive Services Task Force criteria for evidence and certainty of net benefit. Recommendations are based on the strength of evidence or consensus when evidence is scant. RESULTS: The PACC® examined the published literature and established evidence- and consensus-based recommendations to guide best practices. Additional guidance will occur as new evidence is developed in future iterations of this process. CONCLUSIONS: The PACC® recommends best practices regarding intrathecal drug delivery to improve safety and efficacy. The evidence- and consensus-based recommendations should be used as a guide to assist decision-making when clinically appropriate.

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BACKGROUND AND OBJECTIVES: Previous mechanisms of opening the blood-brain barrier (BBB) created a hypertonic environment. Focused ultrasound (FUS) has recently been introduced as a means of controlled BBB opening. Here, we performed a scoping review to assess the advances in drug delivery across the BBB for treatment of brain tumors to identify advances and literature gaps. METHODS: A review of current literature was conducted through a MEDLINE search inclusive of articles on FUS, BBB, and brain tumor barrier, including human, modeling, and animal studies written in English. Using the Rayyan platform, 2 reviewers (J.P and C.Y) identified 967 publications. 224 were chosen to review after a title screen. Ultimately 98 were reviewed. The scoping review was designed to address the following questions: (1) What FUS technology improvements have been made to augment drug delivery for brain tumors? (2) What drug delivery improvements have occurred to ensure better uptake in the target tissue for brain tumors? RESULTS: Microbubbles (MB) with FUS are used for BBB opening (BBBO) through cavitation to increase its permeability. Drug delivery into the central nervous system can be combined with MB to enhance transport of therapeutic agents to target brain tissue resulting in suppression of tumor growth and prolonging survival rate, as well as reducing systemic toxicity and degradation rate. There is accumulating evidence demonstrating that drug delivery through BBBO with FUS-MB improves drug concentrations and provides a better impact on tumor growth and survival rates, compared with drug-only treatments. CONCLUSION: Here, we review the role of FUS in BBBO. Identified gaps in the literature include impact of tumor microenvironment and extracellular space, improved understanding and control of MB and drug delivery, further work on ideal pharmacologics for delivery, and clinical use.

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Emerging evidence suggests an association between chronic pain and elevated body fat. We sought to determine if individuals with higher body fat, measured by hip circumference (HC) and waist circumference (WC), are at risk for chronic pain when they demonstrate higher expression of inflammatory markers. We investigated the incidence and severity of pain in patients with varying WC/HC and inflammatory markers (C-Reactive Protein, IL-6, leptin) using the NIH-sponsored All of Us Database. For each inflammatory marker and sex, participants were divided into four groups based on combinations of normal/high marker levels and small/large WC/HC. We used statistical analysis to compare WC/HC and pain severity (mean NRS pain score) between groups of the same sex. In females, but not males, combinations of elevated CRP with large WC/HC exerted additive effects on the incidence of chronic pain (p < 0.01) and severe pain (p < 0.001), as well as on the severity of pain evaluated by the mean NRS pain score (p < 0.01). This relationship held true for females with high IL-6 or leptin and large WC or HC (p < 0.001 for chronic pain and severe pain incidence, and p < 0.05 for pain severity). Neither IL-6 nor leptin showed any significant impact on pain in males. Obesity status and CRP exert additive prognostic effects for chronic pain in females, but not in males. The concomitant evaluation of other inflammatory factors, such as IL-6 or leptin in females, may further augment the prediction of chronic pain. PERSPECTIVE: This article investigates the relationship between chronic pain, obesity, and inflammatory markers. It could help elucidating sex difference in pain mechanisms, as well as the risk factors for chronic pain, potentially improving patient diagnosis, follow-up and treatment.

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