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Background: Monitoring gender representation is critical to achieve diversity and equity in academia. One way to evaluate gender representation in academia is to examine the authorship of research publications. This study sought to determine the gender of first and senior authors of articles in leading medical journals and assess trends in the gender gap over time., Methods: We gather bibliometric data on original research articles (n = 10,558) published in 2010-2019 in five leading medical journals to audit publication and citation frequency by gender. We explored their association with scientific fields, geographical regions, journals, and collaboration scope., Results: We show that there are fewer women as senior (24.8%) than leading authors (34.5%, p < 0.001). The proportion of women varied by country with 9.1% last authors from Austria, 0.9% from Japan, and 0.0% from South Korea. The gender gap decreased longitudinally and faster for the last (-24.0 articles/year, p < 0.001) than first authors (-14.5 articles/year, p = 0.024) with pronounced country-specific variability. We also demonstrate that usage of research keywords varied by gender, partly accounting for the difference in citation counts., Conclusions: In summary, gender representation has increased, although with country-specific variability. The study frame can be easily applied to any journal and time period to monitor changes in gender representation in science., (© 2023. The Author(s).)

Background: The Supporting Harm Reduction through Peer Support (SHARPS) study involved designing and implementing a peer-delivered, harm reduction intervention for people experiencing homelessness and problem substance use. Normalisation Process Theory (NPT) provided a framework for the study., Methods: Four Peer Navigators (individuals with personal experience of problem substance use and/or homelessness) were recruited and hosted in six third sector (not-for-profit) homelessness services in Scotland and England (United Kingdom). Each worked with participants to provide practical and emotional support, with the aim of reducing harms, and improving well-being, social functioning and quality of life. NPT guided the development of the intervention and, the process evaluation, which assessed the acceptability and feasibility of the intervention for this cohort who experience distinct, and often unmet, health challenges. While mixed-methods data collection was undertaken, this paper draws only on the qualitative data., Results: The study found that, overall, the intervention is feasible, and acceptable to, the intervention participants, the Peer Navigators and staff in host settings. Some challenges were encountered but these were outweighed by benefits. NPT is particularly useful in encouraging our team to focus on the relationship between different aspects of the intervention and context(s) and identify ways of maximising 'fit'., Conclusions: To our knowledge, this is the first application of NPT to this cohort, and specifically by non-clinicians (peers) in non-healthcare settings (homelessness services). Our application of NPT helped us to identify ways in which the intervention could be enhanced, with the key aim of improving the health/well-being of this underserved group., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Background: Clinical metagenomics involves the genomic sequencing of all microorganisms in clinical samples ideally after depletion of human DNA to increase sensitivity and reduce turnaround times. Current human DNA depletion methods preferentially preserve either DNA or RNA containing microbes, but not both simultaneously. Here we describe and present data using a practical and rapid mechanical host-depletion method allowing simultaneous detection of RNA and DNA microorganisms linked with nanopore sequencing., Methods: The human cells from respiratory samples are lysed mechanically using 1.4 mm zirconium-silicate spheres and the human DNA is depleted using a nonspecific endonuclease. The RNA is converted to dsDNA to allow the simultaneous sequencing of DNA and RNA., Results: The method decreases human DNA concentration by a median of eight Ct values while detecting a broad range of RNA & DNA viruses, bacteria, including atypical pathogens (Legionella, Chlamydia, Mycoplasma) and fungi (Candida, Pneumocystis, Aspergillus). The first automated reports are generated after 30 min sequencing from a 7 h end-to-end workflow. Sensitivity and specificity for bacterial detection are 90% and 100%, respectively, and viral detection are 92% and 100% after 2 h of sequencing. Prospective validation on 33 consecutive lower respiratory tract samples from ventilated patients with suspected pneumonia shows 60% concordance with routine testing, detection of additional pathogens in 21% of samples and pathogen genomic assembly achieve for 42% of viruses and 33% of bacteria., Conclusions: Although further workflow refinement and validation on samples containing a broader range of pathogens is required, it holds promise as a clinically deployable workflow suitable for evaluation in routine microbiology laboratories., (© 2024. The Author(s).)

Background: Brain extraction is a computational necessity for researchers using brain imaging data. However, the complex structure of the interfaces between the brain, meninges and human skull have not allowed a highly robust solution to emerge. While previous methods have used machine learning with structural and geometric priors in mind, with the development of Deep Learning (DL), there has been an increase in Neural Network based methods. Most proposed DL models focus on improving the training data despite the clear gap between groups in the amount and quality of accessible training data between., Methods: We propose an architecture we call Efficient V-net with Additional Conditional Random Field Layers (EVAC+). EVAC+ has 3 major characteristics: (1) a smart augmentation strategy that improves training efficiency, (2) a unique way of using a Conditional Random Fields Recurrent Layer that improves accuracy and (3) an additional loss function that fine-tunes the segmentation output. We compare our model to state-of-the-art non-DL and DL methods., Results: Results show that even with limited training resources, EVAC+ outperforms in most cases, achieving a high and stable Dice Coefficient and Jaccard Index along with a desirable lower Surface (Hausdorff) Distance. More importantly, our approach accurately segmented clinical and pediatric data, despite the fact that the training dataset only contains healthy adults., Conclusions: Ultimately, our model provides a reliable way of accurately reducing segmentation errors in complex multi-tissue interfacing areas of the brain. We expect our method, which is publicly available and open-source, to be beneficial to a wide range of researchers., (© 2024. The Author(s).)

Background: Precision medicine has the potential to improve cardiovascular disease (CVD) risk prediction in individuals with Type 2 diabetes (T2D)., Methods: We conducted a systematic review and meta-analysis of longitudinal studies to identify potentially novel prognostic factors that may improve CVD risk prediction in T2D. Out of 9380 studies identified, 416 studies met inclusion criteria. Outcomes were reported for 321 biomarker studies, 48 genetic marker studies, and 47 risk score/model studies., Results: Out of all evaluated biomarkers, only 13 showed improvement in prediction performance. Results of pooled meta-analyses, non-pooled analyses, and assessments of improvement in prediction performance and risk of bias, yielded the highest predictive utility for N-terminal pro b-type natriuretic peptide (NT-proBNP) (high-evidence), troponin-T (TnT) (moderate-evidence), triglyceride-glucose (TyG) index (moderate-evidence), Genetic Risk Score for Coronary Heart Disease (GRS-CHD) (moderate-evidence); moderate predictive utility for coronary computed tomography angiography (low-evidence), single-photon emission computed tomography (low-evidence), pulse wave velocity (moderate-evidence); and low predictive utility for C-reactive protein (moderate-evidence), coronary artery calcium score (low-evidence), galectin-3 (low-evidence), troponin-I (low-evidence), carotid plaque (low-evidence), and growth differentiation factor-15 (low-evidence). Risk scores showed modest discrimination, with lower performance in populations different from the original development cohort., Conclusions: Despite high interest in this topic, very few studies conducted rigorous analyses to demonstrate incremental predictive utility beyond established CVD risk factors for T2D. The most promising markers identified were NT-proBNP, TnT, TyG and GRS-CHD, with the highest strength of evidence for NT-proBNP. Further research is needed to determine their clinical utility in risk stratification and management of CVD in T2D., (© 2024. The Author(s).)

Background: Racial and ethnic minoritized groups are disproportionately at risk for Alzheimer's Disease (AD), but are not sufficiently recruited in AD neuroimaging research in the United States. This is important as sample composition impacts generalizability of findings, biomarker cutoffs, and treatment effects. No studies have quantified the breadth of race/ethnicity representation in the AD literature., Methods: This review identified median race/ethnicity composition of AD neuroimaging US-based research samples available as free full-text articles on PubMed. Two types of published studies were analyzed: studies that directly report race/ethnicity data (i.e., direct studies), and studies that do not report race/ethnicity but used data from a cohort study/database that does report this information (i.e., indirect studies)., Results: Direct studies (n = 719) have median representation of 88.9% white or 87.4% Non-Hispanic white, 7.3% Black/African American, and 3.4% Hispanic/Latino ethnicity, with 0% Asian American, Native Hawaiian/Pacific Islander, and American Indian/Alaska Native, Multiracial, and Other Race participants. Cohort studies/databases (n = 44) from which indirect studies (n = 1745) derived are more diverse, with median representation of 84.2% white, 83.7% Non-Hispanic white, 11.6% Black/African American, 4.7% Hispanic/Latino, and 1.75% Asian American participants. Notably, 94% of indirect studies derive from just 10 cohort studies/databases. Comparisons of two time periods using a median split for publication year, 1994-2017 and 2018-2022, indicate that sample diversity has improved recently, particularly for Black/African American participants (3.39% from 1994-2017 and 8.29% from 2018-2022)., Conclusions: There is still underrepresentation of all minoritized groups relative to Census data, especially for Hispanic/Latino and Asian American individuals. The AD neuroimaging literature will benefit from increased representative recruitment of ethnic/racial minorities. More transparent reporting of race/ethnicity data is needed., (© 2023. The Author(s).)

Background: Undiagnosed chronic kidney disease (CKD) is a common and usually asymptomatic disorder that causes a high burden of morbidity and early mortality worldwide. We developed a deep learning model for CKD screening from routinely acquired ECGs., Methods: We collected data from a primary cohort with 111,370 patients which had 247,655 ECGs between 2005 and 2019. Using this data, we developed, trained, validated, and tested a deep learning model to predict whether an ECG was taken within one year of the patient receiving a CKD diagnosis. The model was additionally validated using an external cohort from another healthcare system which had 312,145 patients with 896,620 ECGs between 2005 and 2018., Results: Using 12-lead ECG waveforms, our deep learning algorithm achieves discrimination for CKD of any stage with an AUC of 0.767 (95% CI 0.760-0.773) in a held-out test set and an AUC of 0.709 (0.708-0.710) in the external cohort. Our 12-lead ECG-based model performance is consistent across the severity of CKD, with an AUC of 0.753 (0.735-0.770) for mild CKD, AUC of 0.759 (0.750-0.767) for moderate-severe CKD, and an AUC of 0.783 (0.773-0.793) for ESRD. In patients under 60 years old, our model achieves high performance in detecting any stage CKD with both 12-lead (AUC 0.843 [0.836-0.852]) and 1-lead ECG waveform (0.824 [0.815-0.832])., Conclusions: Our deep learning algorithm is able to detect CKD using ECG waveforms, with stronger performance in younger patients and more severe CKD stages. This ECG algorithm has the potential to augment screening for CKD., (© 2023. The Author(s).)

The generation and distribution of hyper-partisan content on social media has gained millions of exposure across platforms, often allowing malevolent actors to influence and disrupt democracies. The spread of this content is facilitated by real users' engaging with it on platforms. The current study tests the efficacy of an 'inoculation' intervention via six online survey-based experiments in the UK and US. Experiments 1-3 (total N = 3276) found that the inoculation significantly reduced self-reported engagement with polarising stimuli. However, Experiments 4-6 (total N = 1878) found no effects on participants' self-produced written text discussing the topic. The implications of these findings are discussed in the context of the literature on polarisation and previous interventions to reduce engagement with disinformation., Competing Interests: Competing interests: YouGov UK undertook the fieldwork for Experiments 1 and 2 of this project free of charge. Fintan Smith is a former employee of YouGov. YouGov had no input on the formulation, design or any other specifics of the experiment, and does in no way endorse any of the views expressed in this paper. Other authors declare no competing interests., (© 2025. The Author(s).)

Background: Cochlear implants (CIs) are neuroprosthetic devices which restore hearing in severe-to-profound hearing loss through electrical stimulation of the auditory nerve. Current CIs use an externally worn audio processor. A long-term goal in the field has been to develop a device in which all components are contained within a single implant. Here, we present initial clinical results with the totally implantable cochlear implant (TICI). The primary objective of this study was to assess the safety of the device in adults who suffer from bilateral severe-to-profound sensorineural hearing loss., Methods: This study used a design with non-randomized single group assignment (trial registration: NCT04571333). Six implantations took place beginning in September 2020. Data collection took place at the two participating CI centers. Adverse events (the primary outcome), speech perception, patient reported outcomes, and device usage statistics were collected over the subsequent 52 weeks. A within-subjects comparison was used in which each participant was evaluated both with the TICI and with an external SONNET audio processor., Results: One anticipated serious adverse device effect (ASADE) occurred. After treatment the event resolved without sequelae. No unanticipated serious adverse device effects (USADE) occurred. Speech perception in quiet and in noise scores were comparable between the TICI and the SONNET audio processor. Scores on the validated patient reported outcome instruments HUI3, SSQ-12, and HISQUI-19 all increased over the duration of the study. User satisfaction scores as reported in their daily diary also increased over the duration of the study. Based on device usage metrics, all but one user used the TICI without an external processor the majority of the time., Conclusions: The primary outcome of assessing the safety of the device was achieved. The TICI provides high levels of hearing performance, comparable to those of a conventional CI. The development of the TICI expands the range of options for treatment of hearing loss., Competing Interests: Competing interests: The authors declare the following competing interests: G.M., F.S., and I.H. are employees of MED-EL. MED-EL provided both the funding and the implants used in this study. MED-EL was also involved in the study design, data analysis, and paper preparation. P.L. and J.M. declare no competing interests., (© 2024. The Author(s).)

Single-port surgical robots have gained popularity due to less patient trauma and quicker post-surgery recovery. However, due to limited access provided by a single incision, the miniaturization and maneuverability of these robots still needs to be improved. In this paper, we propose the design of a single-port, dual-arm robotically steerable endoscope containing one steerable major cannula and two steerable minor cannulas. By integrating the proposed nine degrees-of-freedom (DoFs) robotically steerable endoscope with an industrial robotic arm and a joystick controller, this robotic system can potentially achieve intuitive, and remote multi-arm manipulation capability. We present the design of the robotically steerable endoscope consisting of tendon-driven joints controlled by a compact actuation system and derive the kinematic and static models. We validate the derived models using different kinematic trajectories with an average RMSE value of 0.98 mm and 0.66 mm for the distal tip position errors of the two steerable minor cannulas., Competing Interests: Competing interestsGeorgia Tech Research Corporation and Emory University have submitted a U.S. Provisional Application for Patent titled ‘Systems and Methods for Teleoperated Control of a Robotic Endoscopic System’. J.P.D., R.Q., N.M., and K.H. are inventors on the provisional patent application (Application No. 63/674,030)., (© The Author(s) 2025.)

Umbrella reviews are systematic reviews of all systematic reviews on a given question and can provide a higher-level view of current available evidence on broad research topics. Given the importance and possible consequences of the insights derived from umbrella reviews, it is fundamental to ensure accurate, comprehensive reporting and methodological rigor in these papers. Here, we present the potential and limitations of these evolving evidence synthesis tools by looking at umbrella reviews published on vaccine research. Vaccines are essential tools in modern medicine for preventing disease and promoting public health. The scientific literature on vaccines grows rapidly as researchers work to improve existing vaccines and develop new ones. More than half a million scientific papers on vaccines have already been published, including several thousands of systematic reviews that aim to appraise and summarize this growing literature. However, as the published systematic reviews are only able to cover a small proportion of the literature it is important to also provide higher-level evidence syntheses. and discuss further improvements that could be made to integrate evidence on vaccines., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Antimicrobial resistance is due to genetic changes that allow bacteria to evade antibiotic treatment. Antimicrobial susceptibility testing is critical for the detection of antibiotic-resistant strains, the selection of effective therapeutic strategies against bacterial infections, and the evaluation of the efficacy of novel antimicrobials. Among the variety of clinical microbiology methods used for antibiotic susceptibility testing, minimum inhibitory concentration (MIC) assays have become the gold standard in clinical practice. MIC assays determine the lowest concentration of an antimicrobial agent that is required to inhibit visible bacterial growth in vitro. Here, we outline MIC assay protocols, in strict accordance with European Committee on Antimicrobial Susceptibility Testing (EUCAST) guidelines that aim to assess the susceptibility of non-fastidious organisms to antimicrobial agents. The protocols described in this methods paper are intended to aid the performance of reliable and informative MIC assays for research purposes that are in line with clinical microbiology practices., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Persistent bacterial lung infections in children lead to significant morbidity and mortality due to antibiotic resistance. In this paper, we describe how phage therapy has shown remarkable efficacy in preclinical and clinical studies, demonstrating significant therapeutic benefits through various administration routes. Ongoing trials are evaluating its safety and effectiveness against different pathogens. Advancing phage therapy through systematic studies and international collaboration could provide a viable alternative to traditional antibiotics for persistent infections., Competing Interests: Competing interests: A.M.S.S., P.H., A.K., P.P., K.M., L.C., K.S., M.A., P.M, A.Ki., T.C., P.G.H., and S.A. declare no financial or non-financial competing interests. D.L.W. serves as an editorial board member of this journal and had no role in the peer-review or decision to publish this manuscript. D.L.W. declares no financial competing interests., (© 2024. The Author(s).)

Background: Complete resection of malignant gliomas is hampered by the difficulty in distinguishing tumor cells at the infiltration zone. Fluorescence guidance with 5-ALA assists in reaching this goal. Using hyperspectral imaging, previous work characterized five fluorophores' emission spectra in most human brain tumors., Methods: In this paper, the effectiveness of these five spectra was explored for different tumor and tissue classification tasks in 184 patients (891 hyperspectral measurements) harboring low- (n = 30) and high-grade gliomas (n = 115), non-glial primary brain tumors (n = 19), radiation necrosis (n = 2), miscellaneous (n = 10) and metastases (n = 8). Four machine-learning models were trained to classify tumor type, grade, glioma margins, and IDH mutation., Results: Using random forests and multilayer perceptrons, the classifiers achieve average test accuracies of 84-87%, 96.1%, 86%, and 91% respectively. All five fluorophore abundances vary between tumor margin types and tumor grades (p < 0.01). For tissue type, at least four of the five fluorophore abundances are significantly different (p < 0.01) between all classes., Conclusions: These results demonstrate the fluorophores' differing abundances in different tissue classes and the value of the five fluorophores as potential optical biomarkers, opening new opportunities for intraoperative classification systems in fluorescence-guided neurosurgery., (© 2024. The Author(s).)

Antimicrobial resistance is a global threat to public health. Without proactive intervention, common infections may become untreatable, restricting the types of clinical intervention that can be undertaken and reversing improvements in mortality rates. Effective antimicrobial stewardship represents one approach to restrict the spread of antimicrobial resistance but relies on rapid and accurate diagnostics that minimise the unnecessary use of antibiotics. This is increasingly a key unmet clinical need. In this paper, we describe existing techniques for the detection of antimicrobial resistance, while examining their drawbacks and limitations. We also discuss emerging diagnostic technologies in the field, and the need for standardisation to allow for swifter and more widespread clinical adoption., Competing Interests: Competing interests: The Medicines and Healthcare product Regulatory Authority laboratories at South Mimms is part of an Arms Length Body of the UK Government. The laboratories prepare, curate and distribute globally, reference materials including WHO International Standards. The distribution of reference materials is undertaken on a cost-recovery basis. Further information is available at www.nibsc.org All authors declare no financial or non-financial competing interests., (© 2024. Crown.)

Background: Opioid use in the United States and abroad is an endemic part of society with yearly increases in overdose rates and deaths. In response, the use of the safe and effective reversal agent, naloxone, is being fielded and used by emergency medical technicians at a greater rate. There is evidence that repeated dosing of a naloxone nasal spray is becoming more common. Despite this we lack repeated dosing guidelines as a function of the amount of opiate the patient has taken., Methods: To measure repeat dosing guidelines, we construct a whole-body model of the pharmacokinetics and dynamics of an opiate, fentanyl on respiratory depression. We then construct a model of nasal deposition and administration of naloxone to investigate repeat dosing requirements for large overdose scenarios. We run a single patient through multiple goal directed resuscitation protocols and measure total naloxone administered., Results: Here we show that naloxone is highly effective at reversing the respiratory symptoms of the patient and recommend dosing requirements as a function of the fentanyl amount administered. We show that for increasing doses of fentanyl, naloxone requirements also increase. The rescue dose displays a nonlinear response to the initial opioid dose. This nonlinear response is largely logistic with three distinct phases: onset, rapid acceleration, and a plateau period for doses above 1.2 mg., Conclusions: This paper investigates the total naloxone dose needed to properly reverse respiratory depression associated with fentanyl overdose. We show that the current guidelines for a rescue dose may be much lower than required., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: A clear understanding of public perceptions of the social determinants of health remains lacking. This paper aimed to describe the relationship between income and urbanicity levels and public views of the determinants of health in eight middle-and high-income countries that varied across multiple characteristics., Methods: We conducted a cross-sectional online survey in Brazil, China, Germany, Egypt, India, Indonesia, Nigeria, and the United States. Respondents were asked to select what they considered to be most important for health out of a list of ten determinants. We stratified the results by income and urbanicity levels and tested significance of differences between groups using two-tailed χ 2 tests. Multivariable logistic regression models tested associations between demographic factors and the likelihood of respondents selecting the genetics, healthcare, income and wealth, or social support determinants., Results: Here we show 8753 respondents across eight countries. Rankings of determinants are similar across income groups, except for two determinants. Respondents in the highest income group rank genetics in higher proportions (32.4%, 95%CI: 29.0%,35.8%) compared to other income groups. Conversely, those in lowest income group rank social support more frequently (27.9%, 95%CI: 25.3%,30.7%) than other income groups. Those living in urban settings rank healthcare in higher proportions (61.2%, 95%CI: 59.0%,63.4%) compared to non-urban respondents; meanwhile, higher proportions (26.6%, 95%CI: 24.9%,28.3%) of non-urban respondents rank social support as important for health compared to urban respondents., Conclusion: Demographic factors play a role in shaping public views of what affects health. Advancing public understanding about determinants of health requires tailoring public health messaging to account for socioeconomic position within a population., (© 2024. The Author(s).)

Nimbolide, a ring seco-C limonoid natural product, was recently found to inhibit the poly(ADP)-ribosylation (PARylation)-dependent ubiquitin E3 ligase RNF114. In doing so, it induces the 'supertrapping' of both PARylated PARP1 and PAR-dependent DNA-repair factors. PARP1 inhibitors have reshaped the treatment of cancer patients with germline BRCA1 / 2 mutations partly through the PARP1 trapping mechanism. To this end, modular access to nimbolide analogues represents an opportunity to develop cancer therapeutics with enhanced PARP1 trapping capability. Here we report a convergent synthesis of nimbolide through a late-stage coupling strategy. Through a sulfonyl hydrazone-mediated etherification and a radical cyclization, this strategy uses a pharmacophore-containing building block and diversifiable hydrazone units to enable the modular synthesis of nimbolide and its analogues. The broad generality of our synthetic strategy allowed access to a variety of analogues with their preliminary cellular cytotoxicity and PARP1 trapping activity reported., Competing Interests: Competing interests Patent WO 2022/150667 ‘Nimbolide analogs and methods of use thereof’ has been filed on some aspects of the work in this paper, and H.D., H.D., C.K., P.L., Y.Y. and T.Q. are listed as inventors. Y.Y. and T.Q. are co-founders and shareholders of ProteoValent Therapeutics. The other authors declare no competing interests.

Background: Small (30-150nm) extracellular vesicles (sEV), also known as exosomes, play a key role in cell-to-cell signaling. They are produced by all cells, circulate freely and are present in all body fluids. Evidence indicates that cytokines are present on the surface and/or in the lumen of sEV. The contribution of intravesicular cytokines to cytokine levels in plasma are unknown., Methods: sEV were isolated by ultrafiltration/size exclusion chromatography from pre-cleared plasma obtained from patients with head and neck squamous cell carcinoma (HNSCC) and healthy donors (HDs). Multiplex immunoassays were used to measure cytokine levels in paired untreated and detergent-treated (0.5% Triton X-100) plasma and plasma-derived detergent-treated sEV. Non-parametric tests were used to assess differences in cytokine levels., Results: The presence of cytokines in sEV isolated from patients' and HDs' plasma was confirmed by immunoblots and on-bead flow cytometry. sEV-associated cytokines were functional in various in vitro assays. Levels of cytokines in sEV varied among the HNSCC patients and were generally significantly higher than the levels observed in sEV from HDs. Compared to untreated plasma, levels for the majority (40/51) of the evaluated proteins were significantly higher in detergent-treated plasma ( P <0.0001-0.03). In addition, levels of 24/51 proteins in sEV, including IL6, TNFRII, IL-17a, IFNa and IFNg, were significantly positively correlated with the difference between levels detected in detergent-treated plasma and untreated plasma., Discussion: The data indicate that sEV-associated cytokines account for the differences in cytokine levels measured in detergent-treated versus untreated plasma. Ab-based assays using untreated plasma detect only soluble cytokines and miss cytokines carried in the lumen of sEV. Permeabilization of sEV with a mild detergent allows for Ab-based detection of sEV-associated and soluble cytokines in plasma. The failure to detect cytokines carried in the sEV lumen leads to inaccurate estimates of cytokine levels in body fluids., Competing Interests: Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Alzheimer's disease (AD) is influenced by a variety of modifiable risk factors, including a person's dietary habits. While the ketogenic diet (KD) holds promise in reducing metabolic risks and potentially affecting AD progression, only a few studies have explored KD's metabolic impact, especially on blood and cerebrospinal fluid (CSF). Our study involved participants at risk for AD, either cognitively normal or with mild cognitive impairment. The participants consumed both a modified Mediterranean Ketogenic Diet (MMKD) and the American Heart Association diet (AHAD) for 6 weeks each, separated by a 6-week washout period. We employed nuclear magnetic resonance (NMR)-based metabolomics to profile serum and CSF and metagenomics profiling on fecal samples. While the AHAD induced no notable metabolic changes, MMKD led to significant alterations in both serum and CSF. These changes included improved modifiable risk factors, like increased HDL-C and reduced BMI, reversed serum metabolic disturbances linked to AD such as a microbiome-mediated increase in valine levels, and a reduction in systemic inflammation. Additionally, the MMKD was linked to increased amino acid levels in the CSF, a breakdown of branched-chain amino acids (BCAAs), and decreased valine levels. Importantly, we observed a strong correlation between metabolic changes in the CSF and serum, suggesting a systemic regulation of metabolism. Our findings highlight that MMKD can improve AD-related risk factors, reverse some metabolic disturbances associated with AD, and align metabolic changes across the blood-CSF barrier., Competing Interests: Competing interestsP.C.D. consulted for DSM animal health in 2023, is an advisor and holds equity in Cybele, bileOmix and Sirenas, and a Scientific co-founder, advisor and holds equity in Ometa, Enveda, and Arome with prior approval by UC San Diego. K.B. has served as a consultant and on advisory boards for Abbvie, AC Immune, ALZPath, AriBio, BioArctic, Biogen, Eisai, Lilly, Moleac Pte. Ltd, Neurimmune, Novartis, Ono Pharma, Prothena, Roche Diagnostics, and Siemens Healthineers; has served on data monitoring committees for Julius Clinical and Novartis; has given lectures, produced educational materials and participated in educational programs for AC Immune, Biogen, Celdara Medical, Eisai and Roche Diagnostics; and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program, outside the work presented in this paper., (© The Author(s) 2024.)

Background: A precision medicine approach in type 2 diabetes requires the identification of clinical and biological features that are reproducibly associated with differences in clinical outcomes with specific anti-hyperglycaemic therapies. Robust evidence of such treatment effect heterogeneity could support more individualized clinical decisions on optimal type 2 diabetes therapy., Methods: We performed a pre-registered systematic review of meta-analysis studies, randomized control trials, and observational studies evaluating clinical and biological features associated with heterogenous treatment effects for SGLT2-inhibitor and GLP1-receptor agonist therapies, considering glycaemic, cardiovascular, and renal outcomes. After screening 5,686 studies, we included 101 studies of SGLT2-inhibitors and 75 studies of GLP1-receptor agonists in the final systematic review., Results: Here we show that the majority of included papers have methodological limitations precluding robust assessment of treatment effect heterogeneity. For SGLT2-inhibitors, multiple observational studies suggest lower renal function as a predictor of lesser glycaemic response, while markers of reduced insulin secretion predict lesser glycaemic response with GLP1-receptor agonists. For both therapies, multiple post-hoc analyses of randomized control trials (including trial meta-analysis) identify minimal clinically relevant treatment effect heterogeneity for cardiovascular and renal outcomes., Conclusions: Current evidence on treatment effect heterogeneity for SGLT2-inhibitor and GLP1-receptor agonist therapies is limited, likely reflecting the methodological limitations of published studies. Robust and appropriately powered studies are required to understand type 2 diabetes treatment effect heterogeneity and evaluate the potential for precision medicine to inform future clinical care., (© 2023. Springer Nature Limited.)

Introduction: Lung cancer in never smokers (LCINS) accounts for 15% of lung cancers diagnosed in the UK, making it the 8th most common cancer. There are few robust studies specific to the LCINS population making data surrounding the incidence and mortality of LCINS incomplete, leaving many gaps in our understanding of the needs of this population., Methods: To address a lack of research in this important area, the UK National Cancer Research Institute Lung Study Group (NCRI-LSG) undertook a national survey and hosted a research strategy day to define key research priorities. A wide cross section of stakeholders, including patient advocates, the charitable sector, basic and translational researchers, and multi-disciplinary healthcare professionals contributed highlighting their research priorities., Results: One-hundred twenty-seven surveys were completed (52 by patients/patient advocates) prior to the strategy day. These identified themes for expert review presentations and subsequent workshop discussions at the national research strategy day, which registered 190 attendees (50 patients/patient advocates). The four key themes that emerged to form the basis of a research strategy for LCINS are (1) Raising awareness, (2) Risk assessment and early detection, (3) Disease biology, (4) Living with and beyond., Conclusion: This paper summarises current evidence and important gaps in our knowledge related to LCINS. We present recommendations for a national research strategy aimed at improving outcomes for patients., (© 2023. The Author(s).)

Background: Unlike linear models which are traditionally used to study all-cause mortality, complex machine learning models can capture non-linear interrelations and provide opportunities to identify unexplored risk factors. Explainable artificial intelligence can improve prediction accuracy over linear models and reveal great insights into outcomes like mortality. This paper comprehensively analyzes all-cause mortality by explaining complex machine learning models., Methods: We propose the IMPACT framework that uses XAI technique to explain a state-of-the-art tree ensemble mortality prediction model. We apply IMPACT to understand all-cause mortality for 1-, 3-, 5-, and 10-year follow-up times within the NHANES dataset, which contains 47,261 samples and 151 features., Results: We show that IMPACT models achieve higher accuracy than linear models and neural networks. Using IMPACT, we identify several overlooked risk factors and interaction effects. Furthermore, we identify relationships between laboratory features and mortality that may suggest adjusting established reference intervals. Finally, we develop highly accurate, efficient and interpretable mortality risk scores that can be used by medical professionals and individuals without medical expertise. We ensure generalizability by performing temporal validation of the mortality risk scores and external validation of important findings with the UK Biobank dataset., Conclusions: IMPACT's unique strength is the explainable prediction, which provides insights into the complex, non-linear relationships between mortality and features, while maintaining high accuracy. Our explainable risk scores could help individuals improve self-awareness of their health status and help clinicians identify patients with high risk. IMPACT takes a consequential step towards bringing contemporary developments in XAI to epidemiology., Competing Interests: Competing interestsThe authors declare no competing interests., (© The Author(s) 2022.)

Background: The COVID-19 pandemic exit strategies depend on widespread acceptance of COVID-19 vaccines. We aim to estimate the global acceptance and uptake of COVID-19 vaccination, and their variations across populations, countries, time, and sociodemographic subgroups., Methods: We searched four peer-reviewed databases (PubMed, EMBASE, Web of Science, and EBSCO) for papers published in English from December 1, 2019 to February 27, 2022. This review included original survey studies which investigated acceptance or uptake of COVID-19 vaccination, and study quality was assessed using the Appraisal tool for Cross-Sectional Studies. We reported the pooled acceptance or uptake rates and 95% confidence interval (CI) using meta-analysis with a random-effects model., Results: Among 15690 identified studies, 519 articles with 7,990,117 participants are eligible for meta-analysis. The global acceptance and uptake rate of COVID-19 vaccination are 67.8% (95% CI: 67.1-68.6) and 42.3% (95% CI: 38.2-46.5), respectively. Among all population groups, pregnant/breastfeeding women have the lowest acceptance (54.0%, 46.3-61.7) and uptake rates (7.3%, 1.7-12.8). The acceptance rate varies across countries, ranging from 35.9% (34.3-37.5) to 86.9% (81.4-92.5) for adults, and the lowest acceptance is found in Russia, Ghana, Jordan, Lebanon, and Syria (below 50%). The acceptance rate declines globally in 2020, then recovers from December 2020 to June 2021, and further drops in late 2021. Females, those aged < 60 years old, Black individuals, those with lower education or income have the lower acceptance than their counterparts. There are large gaps (around 20%) between acceptance and uptake rates for populations with low education or income., Conclusion: COVID-19 vaccine acceptance needs to be improved globally. Continuous vaccine acceptance monitoring is necessary to inform public health decision making., Competing Interests: Competing interestsThe authors declare no competing interests., (© The Author(s) 2022.)

Background: Over five million joint replacements are performed across the world each year. Cobalt chrome (CoCr) components are used in most of these procedures. Some patients develop delayed-type hypersensitivity (DTH) responses to CoCr implants, resulting in tissue damage and revision surgery. DTH is unpredictable and genetic links have yet to be definitively established., Methods: At a single site, we carried out an initial investigation to identify HLA alleles associated with development of DTH following metal-on-metal hip arthroplasty. We then recruited patients from other centres to train and validate an algorithm incorporating patient age, gender, HLA genotype, and blood metal concentrations to predict the development of DTH. Accuracy of the modelling was assessed using performance metrics including time-dependent receiver operator curves., Results: Using next-generation sequencing, here we determine the HLA genotypes of 606 patients. 176 of these patients had experienced failure of their prostheses; the remaining 430 remain asymptomatic at a mean follow up of twelve years. We demonstrate that the development of DTH is associated with patient age, gender, the magnitude of metal exposure, and the presence of certain HLA class II alleles. We show that the predictive algorithm developed from this investigation performs to an accuracy suitable for clinical use, with weighted mean survival probability errors of 1.8% and 3.1% for pre-operative and post-operative models respectively., Conclusions: The development of DTH following joint replacement appears to be determined by the interaction between implant wear and a patient's genotype. The algorithm described in this paper may improve implant selection and help direct patient surveillance following surgery. Further consideration should be given towards understanding patient-specific responses to different biomaterials., Competing Interests: Competing interestsThe authors declare the following competing interests: the algorithm described in this study has been developed into software to be used as a commercial medical device (Orthotype). Orthotype has been patented, and is owned by the company PXD Ltd, trading as ExplantLab. David Langton, the lead author, is director of this company. Matthew Nargol is an employee of ExplantLab. All other authors have no competing interests to declare., (© The Author(s) 2022.)

Background: The Centers for Disease Control and Prevention identify antibiotic prescribing stewardship as the most important action to combat increasing antibiotic resistance. Clinicians balance broad empiric antibiotic coverage vs. precision coverage targeting only the most likely pathogens. We investigate the utility of machine learning-based clinical decision support for antibiotic prescribing stewardship., Methods: In this retrospective multi-site study, we developed machine learning models that predict antibiotic susceptibility patterns (personalized antibiograms) using electronic health record data of 8342 infections from Stanford emergency departments and 15,806 uncomplicated urinary tract infections from Massachusetts General Hospital and Brigham & Women's Hospital in Boston. We assessed the trade-off between broad-spectrum and precise antibiotic prescribing using linear programming., Results: We find in Stanford data that personalized antibiograms reallocate clinician antibiotic selections with a coverage rate (fraction of infections covered by treatment) of 85.9%; similar to clinician performance (84.3% p  = 0.11). In the Boston dataset, the personalized antibiograms coverage rate is 90.4%; a significant improvement over clinicians (88.1% p  < 0.0001). Personalized antibiograms achieve similar coverage to the clinician benchmark with narrower antibiotics. With Stanford data, personalized antibiograms maintain clinician coverage rates while narrowing 69% of empiric vancomycin+piperacillin/tazobactam prescriptions to piperacillin/tazobactam. In the Boston dataset, personalized antibiograms maintain clinician coverage rates while narrowing 48% of ciprofloxacin to trimethoprim/sulfamethoxazole., Conclusions: Precision empiric antibiotic prescribing with personalized antibiograms could improve patient safety and antibiotic stewardship by reducing unnecessary use of broad-spectrum antibiotics that breed a growing tide of resistant organisms., Competing Interests: Competing interestsThe authors declare the following competing interests. C.K.C. receives consultation payment from Fountain Therapeutics, Inc. C.K.C. was an intern at Verily Life Sciences while drafting the paper. J.H.C. co-founded of Reaction Explorer LLC that develops and licenses organic chemistry education software and receives consultation payment from the National Institute of Drug Abuse Clinical Trials Network, Tuolc Inc., Roche Inc., and Younker Hyde MacFarlane PLLC. M.N. receives consultation payment from Vida Health. All other authors declare no competing interests., (© The Author(s) 2022.)

Background: Functional recovery of arm movement typically plateaus following a stroke, leaving chronic motor deficits. Brain-computer interfaces (BCI) may be a potential treatment for post-stroke deficits., Methods: In this n-of-1 trial (NCT03913286), a person with chronic subcortical stroke with upper-limb motor impairment used a powered elbow-wrist-hand orthosis that opened and closed the affected hand using cortical activity, recorded from a percutaneous BCI comprised of four microelectrode arrays implanted in the ipsilesional precentral gyrus, based on decoding of spiking patterns and high frequency field potentials generated by imagined hand movements. The system was evaluated in a home setting for 12 weeks., Results: Robust single unit activity, modulating with attempted or imagined movement, was present throughout the precentral gyrus. The participant acquired voluntary control over a hand-orthosis, achieving 10 points on the Action Research Arm Test using the BCI, compared to 0 without any device, and 5 using myoelectric control. Strength, spasticity, the Fugl-Meyer scores improved., Conclusions: We demonstrate in a human being that ensembles of individual neurons in the cortex overlying a chronic supratentorial, subcortical stroke remain active and engaged in motor representation and planning and can be used to electrically bypass the stroke and promote limb function. The participant's ability to rapidly acquire control over otherwise paralyzed hand opening, more than 18 months after a stroke, may justify development of a fully implanted movement restoration system to expand the utility of fully implantable BCI to a clinical population that numbers in the tens of millions worldwide., Competing Interests: Competing interestsDrs. M.D.S. and A.N. are inventors on a US provisional patent application that has been filed by Thomas Jefferson University on the methods described in this paper. All other authors report that they do not have any conflicts of interest with the research described., (© The Author(s) 2022.)

Background: Neuro-axonal brain damage releases neurofilament light chain (NfL) proteins, which enter the blood. Serum NfL has recently emerged as a promising biomarker for grading axonal damage, monitoring treatment responses, and prognosis in neurological diseases. Importantly, serum NfL levels also increase with aging, and the interpretation of serum NfL levels in neurological diseases is incomplete due to lack of a reliable model for age-related variation in serum NfL levels in healthy subjects., Methods: Graph signal processing (GSP) provides analytical tools, such as graph Fourier transform (GFT), to produce measures from functional dynamics of brain activity constrained by white matter anatomy. Here, we leveraged a set of features using GFT that quantified the coupling between blood oxygen level dependent signals and structural connectome to investigate their associations with serum NfL levels collected from healthy subjects and former athletes with history of concussions., Results: Here we show that GSP feature from isthmus cingulate in the right hemisphere (r-iCg) is strongly linked with serum NfL in healthy controls. In contrast, GSP features from temporal lobe and lingual areas in the left hemisphere and posterior cingulate in the right hemisphere are the most associated with serum NfL in former athletes. Additional analysis reveals that the GSP feature from r-iCg is associated with behavioral and structural measures that predict aggressive behavior in healthy controls and former athletes., Conclusions: Our results suggest that GSP-derived brain features may be included in models of baseline variance when evaluating NfL as a biomarker of neurological diseases and studying their impact on personality traits., Competing Interests: Competing interestsThe authors declare the following competing interests: MCT has served as at advisory board for Biogen, Denali, and Roche. KB has served as a consultant, at advisory boards, or at data monitoring committees for Abcam, Axon, Biogen, JOMDD/Shimadzu, Julius Clinical, Lilly, MagQu, Novartis, Roche Diagnostics, and Siemens Healthineers, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (all outside the present paper). HZ has served at scientific advisory boards for Denali, Roche Diagnostics, Wave, Samumed, Siemens Healthineers, Pinteon Therapeutics and CogRx, has given lectures in symposia sponsored by Fujirebio, Alzecure and Biogen, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). All other authors do not have any competing interests to declare., (© The Author(s) 2022.)

Background: The coronavirus disease (COVID-19) caused by SARS-CoV-2 has swept through the globe at an unprecedented rate. CRISPR-based detection technologies have emerged as a rapid and affordable platform that can shape the future of diagnostics., Methods: We developed ENHANCEv2 that is composed of a chimeric guide RNA, a modified LbCas12a enzyme, and a dual reporter construct to improve the previously reported ENHANCE system. We validated both ENHANCE and ENHANCEv2 using 62 nasopharyngeal swabs and compared the results to RT-qPCR. We created a lyophilized version of ENHANCEv2 and characterized its detection capability and stability., Results: Here we demonstrate that when coupled with an RT-LAMP step, ENHANCE detects COVID-19 samples down to a few copies with 95% accuracy while maintaining a high specificity towards various isolates of SARS-CoV-2 against 31 highly similar and common respiratory pathogens. ENHANCE works robustly in a wide range of magnesium concentrations (3 mM-13 mM), allowing for further assay optimization. Our clinical validation results for both ENHANCE and ENHANCEv2 show 60/62 (96.7%) sample agreement with RT-qPCR results while only using 5 µL of sample and 20 minutes of CRISPR reaction. We show that the lateral flow assay using paper-based strips displays 100% agreement with the fluorescence-based reporter assay during clinical validation. Finally, we demonstrate that a lyophilized version of ENHANCEv2 shows high sensitivity and specificity for SARS-CoV-2 detection while reducing the CRISPR reaction time to as low as 3 minutes while maintaining its detection capability for several weeks upon storage at room temperature., Conclusions: CRISPR-based diagnostic platforms offer many advantages as compared to conventional qPCR-based detection methods. Our work here provides clinical validation of ENHANCE and its improved form ENHANCEv2 for the detection of COVID-19., Competing Interests: Competing interestsP.K.J. and L.T.N. are listed as inventors on the multiple patent applications related to the content of this work. P.K.J. is a co-founder of Genable Biosciences, LLC. The remaining authors declare no competing interests., (© This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply 2022, corrected publication 2022.)

Background: Neutralizing antibodies (NAbs) prevent pathogens from infecting host cells. Detection of SARS-CoV-2 NAbs is critical to evaluate herd immunity and monitor vaccine efficacy against SARS-CoV-2, the virus that causes COVID-19. All currently available NAb tests are lab-based and time-intensive., Method: We develop a 10 min cellulose pull-down test to detect NAbs against SARS-CoV-2 from human plasma. The test evaluates the ability of antibodies to disrupt ACE2 receptor-RBD complex formation. The simple, portable, and rapid testing process relies on two key technologies: (i) the vertical-flow paper-based assay format and (ii) the rapid interaction of cellulose binding domain to cellulose paper., Results: Here we show the construction of a cellulose-based vertical-flow test. The developed test gives above 80% sensitivity and specificity and up to 93% accuracy as compared to two current lab-based methods using COVID-19 convalescent plasma., Conclusions: A rapid 10 min cellulose based test has been developed for detection of NAb against SARS-CoV-2. The test demonstrates comparable performance to the lab-based tests and can be used at Point-of-Care. Importantly, the approach used for this test can be easily extended to test RBD variants or to evaluate NAbs against other pathogens., Competing Interests: Competing interestsMIT (H.D.S. and S.K.) and SMART (P.K., H.J., and H.D.S.) declare patents and submitted patent applications in relation to this work. P.R.P., P.K., H.J., M.E.M., H.D.S. are co-founder of Thrixen Pte. Ltd a company that aims to explore technology described in this manuscript. All other authors have no competing interests., (© The Author(s) 2021.)