bluuebunny/crossref_metadata_2025 huggingface dataset:
A practical guide to combination advanced therapy in inflammatory bowel disease
Authors: Ray Christina M. , Panaccione Remo , Ma Christopher
Published: April 2024

Purpose of review

To provide an overview of the current literature regarding the use of advanced combination therapy (ACT) in patients with inflammatory bowel disease (IBD). Although the treatment of IBD has come a long way, many patients do not respond or will lose response to currently available treatments over time. ACT has been proposed as a model to create sustained remission in difficult-to-treat IBD patient populations. This review discusses the available literature supporting the use of ACT, followed by practical tips for applying this model of treatment to clinical practice.

Recent findings

Both observational and controlled evidence have demonstrated that there may be an increased benefit of ACT in specific IBD patient populations compared to advanced targeted immunomodulator (TIM) monotherapy. Additional data is required to understand how to best use combination TIMs and the long-term risks associated with this strategy.

While the literature has demonstrated the potential for benefit in both Crohn's disease and ulcerative colitis, the use of ACT is currently off-label and long-term controlled data is needed. The successful application of ACT requires careful consideration of both patient and disease profiles as well as close monitoring of treatment response and adverse events.
Ergonomic wellness for the trainee in gastrointestinal endoscopy
Authors: Gimpaya Nikko , Tran William T. , Grover Samir C.
Published: April 2024

Purpose of review

Endoscopy-related injuries (ERIs) are prevalent in gastrointestinal endoscopy. The aim of this review is to address the growing concern of ERIs by evaluating the ergonomic risk factors and the efficacy of interventions and educational strategies aimed at mitigating these risks, including novel approaches.

Recent findings

ERIs are highly prevalent, exacerbated by factors such as repetitive strain, nonneutral postures, suboptimal equipment design, and the procedural learning curve. Female sex and smaller hand sizes have been identified as specific risk factors. Recent guidelines underscore the importance of ergonomic education and the integration of ergonomic principles into the foundational training of gastroenterology fellows. Advances in equipment design focus on adaptability to different hand sizes and ergonomic positions. Furthermore, the incorporation of microbreaks and macrobreaks, along with neutral monitor and bed positioning, has shown promise in reducing the incidence of ERIs. Wearable sensors may be helpful in monitoring and promoting ergonomic practices among trainees.

Ergonomic wellness is paramount for gastroenterology trainees to prevent ERIs and ensure a sustainable career. Effective strategies include ergonomic education integrated into curricula, equipment design improvements, and procedural adaptations such as scheduled breaks and optimal positioning. Sensor-based and camera-based systems may allow for education and feedback to be provided regarding ergonomics to trainees in the future.
Changes in Partner-Seeking and Sexual Behavior Among US Adults During the First 2 Years of the COVID-19 Pandemic
Authors: Rushmore Julie , Copen Casey E. , Schneider John , Lamuda Phoebe , Taylor Bruce G. , Kirkcaldy Robert D. , Learner Emily R. , Bernstein Kyle T.
Published: April 2024

Background

The COVID-19 pandemic may have influenced partner-seeking and sexual behaviors of adults.

Methods

We examined cross-sectional survey data collected at the end of the first year (n = 1161) and second year (n = 1233) of the COVID-19 pandemic by the National Opinion Research Center's nationally representative, probability-based AmeriSpeak panel. Data were analyzed to (1) quantify behavioral changes across pandemic years, (2) examine changes of in-person dating prevalence during year 2, and (3) assess risk perception for acquiring COVID-19 or HIV/STIs through new partnerships during year 2. Weighted percentages were calculated for responses; univariate relationships between demographic characteristics and outcomes were assessed.

Results

Prevalence of new partners for dating remained stable across pandemic years (year 1: n = 1157 [10%]; year 2: n = 1225 [12%]). The prevalence of in-person sex with new partners was also stable (year 1: n = 1157 [7%], year 2: n = 1225 [6%]), marking a decline from a prepandemic estimate (2015–2016: 16%). Partner-seeking experiences varied by age and sexual identity in both years, and by race/ethnicity during year 2. Reports of in-person dating fluctuated throughout year 2, without clear relationship to viral variants. Respondents who met new partners in person during year 2 generally reported greater concern and preparedness for reducing risks associated with HIV/STIs than COVID-19.

Conclusions

The prevalence of US adults seeking new partners for dating or sex remained stable across pandemic years. During future public health emergencies, public health officials are encouraged to offer guidance for reducing disease risks in partnerships, while emphasizing sexual health and providing tailored messaging for persons more susceptible to infection.
Northern Nevada Public Health: Utilizing the Public Health Workforce Calculator and Workforce Capacity Self-assessment Tools to Develop a Framework for Workforce Investment
Authors: Beitsch Leslie M. , Stefanak Matthew , Moehrle Carol , Dick Kevin , Bialek Ron
Published: April 2024

Context:

Health departments nationally are critically understaffed and lack infrastructure support. By examining current staffing and allocations through a Foundational Public Health Services (FPHS) lens at the Northern Nevada Public Health (NNPH), there is an opportunity to make a strong case for greater investment if current dedicated full-time equivalents are inadequate and to guide which investments in public health workforce are prioritized.

Objective:

To assess the use of the Public Health Workforce Calculator (calculator) and other tools to identify and prioritize FPHS workforce needs in a field application.

Design:

Field application of the calculator in conjunction with the use of FPHS workforce capacity self-assessment tools.

Setting:

NNPH.

Participants:

NNPH and Public Health Foundation (PHF).

Intervention:

From June 2022 through April 2023, PHF collaborated with NNPH, serving Washoe County, to provide expertise and assistance as NNPH undertook an assessment of its workforce needs based upon the FPHS model.

Main Outcome Measure(s):

Comparison of the calculator output with FPHS workforce capacity self-assessment tools.

Results:

The calculator and the FPHS capacity self-assessment process yielded complementary FPHS workforce capacity gap data. The use of a structured and transparent process, coupled with additional tools that included prioritizing needs, provided a viable and sustainable process for public health workforce investment planning. NNPH successfully utilized the results to bolster a supplemental funding request and a state public health appropriation.

Conclusions:

The use of the calculator and an FPHS workforce capacity self-assessment in a facilitated and structured process such as that used by NNPH to identify staffing priorities may hold promise as an approach that could be used to support decision-making and justification for infrastructure resources when funding for public health increases in the future.
Needs for Community-Based Rehabilitation Services and Support 12 Months After Moderate and Severe Physical Traumatic Injuries
Authors: Andelic Nada , Moksnes Håkon , Rasmussen Mari S. , Schäfer Christoph , Hellstrøm Torgeir , Howe Emilie I. , Sveen Unni , Perrin Paul B. , Røe Cecilie , Anke Audny , Soberg Helene L.
Published: April 2024

Patients with physical traumatic injuries frequently require long-term rehabilitation services. To strengthen rehabilitation services in the postacute phase, we need to assess characteristics of this population and their healthcare and rehabilitation needs in the community. This brief report summarizes the frequency of unmet rehabilitation needs in community-based rehabilitation during the first year after moderate and severe trauma. Additionally, the associations between sociodemographic, injury severity factors and unmet needs were examined. Data from a prospective multicenter cohort study of patients with moderate and severe trauma (New Injury Severity Score > 9) of all ages, discharged alive from two regional trauma centers in 2020 were used. Needs were estimated using the Needs and Provision Complexity Scale. Overall, 46% of patients had unmet needs at 12-mo postinjury, particularly related to the provision of rehabilitation services, specialist follow-ups, and social and family support. The probability of unmet needs was associated with age, preinjury comorbidities, and impaired functioning. Our findings support strategies targeting younger patients, those with preinjury comorbidities, and those with higher levels of disability and provide a starting point for the development of standardized rehabilitation needs assessment and guidelines after injury.
Partner-based HIV treatment for seroconcordant couples attending antenatal and postnatal care in rural Mozambique: A cluster randomized controlled trial
Authors: Audet Carolyn M. , Graves Erin , Shepherd Bryan E. , Prigmore Heather L. , Brooks Hannah L. , Emílio Almiro , Matino Ariano , Paulo Paula , Diemer Matthew A. , Frisby Michael , Sack Daniel E. , Aboobacar Arifo , Barreto Ezequiel , Van Rompaey Sara , De Schacht Caroline
Published: April 2024

Introduction:

There is evidence that a supportive male partner facilitates maternal HIV testing during pregnancy, increases maternal ART initiation and adherence, and increases HIV-free infant survival. Most male partner engagement clinical strategies have focused on increasing uptake of couple-based HIV testing and counseling. We delivered a couple-based care and treatment intervention to improve of ART adherence in expectant couples living with HIV.

Methods:

We implemented a cluster randomized controlled trial for seroconcordant couples living with HIV, comparing retention (patient’s medication possession ratio) in HIV care for a couple-based care and treatment intervention versus standard of care services in rural Mozambique. The intervention included couple-based treatment, couple-based education and skills building, and couple-peer educator support.

Results:

We recruited 1080 couples to participate in the study. Using a linear mixed effect model with a random effect for clinic, the intervention had no impact on the medication possession ratio among women at 12 months. However, the intervention increased men’s medication ratio by 8.77%. Our unadjusted logistic regression model found the odds of an infant seroconverting in the intervention group was 30% less than in the control group, but the results were not statistically significant.

Discussion:

Our intervention resulted in no difference in maternal outcomes, but improved medication possession ratio among male partners. We provide a community/clinic-based treatment framework that can improve outcomes among male partners. Further work needs to be done to improve social support for pregnant women and to facilitate prevention of vertical transmission to infants among couples living with HIV.
Development of a Better Nomogram for Prediction of Preoperative Microvascular Invasion and Postoperative Prognosis in Hepatocellular Carcinoma Patients: A Comparison Study
Authors: Pei Jinxia , Wang Longsheng , Li Huan
Published: April 2024

Objective

Personalized precision medicine can be facilitated by clinically available preoperative microvascular invasion (MVI) prediction models that are reliable and postoperative MVI pathological grade-related recurrence prediction models that are accurate. In this study, we aimed to compare different mathematical models to derive the best preoperative prediction and postoperative recurrence prediction models for MVI.

Methods

A total of 143 patients with hepatocellular carcinoma (HCC) whose clinical, laboratory, imaging, and pathological data were available were included in the analysis. Logistic regression, Cox proportional hazards regression, LASSO regression with 10-fold cross-validation, stepwise regression, and random forest methods were used for variable screening and predictive modeling. The accuracy and validity of seven preoperative MVI prediction models and five postoperative recurrence prediction models were compared in terms of C-index, net reclassification improvement, and integrated discrimination improvement.

Results

Multivariate logistic regression analysis revealed that a preoperative nomogram model with the variables cirrhosis diagnosis, alpha-fetoprotein > 400, and diameter, shape, and number of lesions can predict MVI in patients with HCC reliably. Postoperatively, a nomogram model with MVI grade, number of lesions, capsule involvement status, macrovascular invasion, and shape as the variables was selected after LASSO regression and 10-fold cross-validation analysis to accurately predict the prognosis for different MVI grades. The number and shape of the lesions were the most common predictors of MVI preoperatively and recurrence postoperatively.

Conclusions

Our study identified the best statistical approach for the prediction of preoperative MVI as well as postoperative recurrence in patients with HCC based on clinical, imaging, and laboratory tests results. This could expedite preoperative treatment decisions and facilitate postoperative management.
Keeping Up With ChatGPT
Authors: Rogasch Julian M.M. , Jochens Hans V. , Metzger Giulia , Wetz Christoph , Kaufmann Jonas , Furth Christian , Amthauer Holger , Schatka Imke
Published: April 2024

Purpose

The latest iteration of GPT4 (generative pretrained transformer) is a large multimodal model that can integrate both text and image input, but its performance with medical images has not been systematically evaluated. We studied whether ChatGPT with GPT-4V(ision) can recognize images from common nuclear medicine examinations and interpret them.

Patients and Methods

Fifteen representative images (scintigraphy, 11; PET, 4) were submitted to ChatGPT with GPT-4V(ision), both in its Default and “Advanced Data Analysis (beta)” version. ChatGPT was asked to name the type of examination and tracer, explain the findings and whether there are abnormalities. ChatGPT should also mark anatomical structures or pathological findings. The appropriateness of the responses was rated by 3 nuclear medicine physicians.

Results

The Default version identified the examination and the tracer correctly in the majority of the 15 cases (60% or 53%) and gave an “appropriate” description of the findings or abnormalities in 47% or 33% of cases, respectively. The Default version cannot manipulate images. “Advanced Data Analysis (beta)” failed in all tasks in >90% of cases. A “major” or “incompatible” inconsistency between 3 trials of the same prompt was observed in 73% (Default version) or 87% of cases (“Advanced Data Analysis (beta)” version).

Conclusions

Although GPT-4V(ision) demonstrates preliminary capabilities in analyzing nuclear medicine images, it exhibits significant limitations, particularly in its reliability (ie, correctness, predictability, and consistency).
PROACTIVE SCREENING ALGORITHM FOR EARLY-ONSET PNEUMONIA IN PATIENTS WITH OUT-OF-HOSPITAL CARDIAC ARREST: A BEFORE-AFTER IMPLEMENTATION STUDY
Authors: Lemée Pauline , Chapalain Xavier , Bailly Pierre , Sparrow Rosemary L. , Jean-Michel Vanessa , Prat Gwenael , Renault Anne , Tonnelier Jean-Marie , Aubron Cécile
Published: April 2024

Introduction: Early-onset pneumonia (EOP) occurs in around 50% of critically ill patients with out-of-hospital cardiac arrest (OHCA) and is associated with increased morbidity. Prompt diagnosis of EOP in these patients is difficult because of targeted temperature management and the postcardiac arrest syndrome. We hypothesized that an algorithm for proactive screening of EOP would improve patient outcomes. Methods: We conducted a single-center observational study comparing the outcomes of mechanically ventilated adult patients with OHCA, before (study period 1) and after (study period 2) implementation of an algorithm for proactive diagnosis of EOP, including an early distal pulmonary specimen. An inverse probability treatment weighted multivariable regression was performed to identify independent parameters associated with duration of mechanical ventilation. A subgroup analysis was conducted in patients alive on day 5 after intensive care unit admission. Results: Over the 4-year study period, 190 patients (99 and 91 for study periods 1 and 2, respectively) were enrolled. The overall incidence of EOP was 57.4% and was similar between both study periods. Although there was no difference in the time interval to antibiotic initiation, study period 2 was independently associated with higher SpO2/FiO2 ratios on days 3 and 4. We also observed a decrease in mechanical ventilation time in study period 2 (4.5 [1–11.3] vs. 3 [2–5.8] days; P = 0.07), and this reached statistical significance in the subgroup analysis of patients alive at day 5 (10 [5–17] vs. 5 [3–9] days, P = 0.01). Conclusion: In critically ill patients with OHCA, proactive diagnosis of EOP was not associated with a significant change in the time to antibiotic initiation. Further research is warranted to better define optimal diagnosis and management of EOP in this setting.
BONE MARROW MESENCHYMAL STROMAL CELL-DERIVED EXOSOMAL NRF2 AMELIORATES CEREBRAL ISCHEMIA-REPERFUSION INJURY BY TRANSCRIPTIONALLY ACTIVATING LIN28A
Authors: Liu Dongwen , Song Chunyan , Lv Cuiling , Zhang Aihua
Published: April 2024

Background: Cerebral ischemia-reperfusion (I/R) injury (CIRI) have severe consequences on brain function, and the exciting evidence has revealed protective role of acyl-CoA synthetase long chain family member 4 (Lin28a) against cerebral ischemia-reperfusion injury. The present work aims to reveal its molecular mechanism in regulating CIRI, with the hope of providing a therapeutic method for cerebral I/R injury. We hypothesized that the exosomal nuclear factor erythroid 2-related factor 2 (NRF2) derived from bone marrow mesenchymal stromal cells could transcriptionally activate Lin28a and thereby alleviate cerebral ischemia-reperfusion injury. This hypothesis was validated in the present work. Methods: Middle cerebral artery occlusion (MCAO) model was established using C57BL/6J mice, and the neurological deficit, infarct volume, and brain water content were assessed to evaluate neuron injury. Human glioblastoma cells (A172) were subjected to oxygen-glucose deprivation and reoxygenation (OGD/R) treatment to mimic a cerebral I/R injury cell model. Exosome isolation reagent was used to isolate exosomes from cell supernatant of bone marrow mesenchymal stromal cells through sequential centrifugation and filtration steps. mRNA expression level of Lin28a was detected by quantitative real-time polymerase chain reaction. Protein expression was analyzed by western blotting assay. TUNEL cell apoptosis detection kit was used to analyze cell apoptosis in brain tissues. Enzyme-linked immunosorbent assays and commercial kits were used to detect levels of inflammatory markers and oxidative stress markers. Ferrous Iron Colorimetric Assay Kit and Fe2+ colorimetric assay kit were used to analyze Fe2+ level. The association of Lin28a and NRF2 was identified by chromatin immunoprecipitation assay and dual-luciferase reporter assay. Results: The treatment of MCAO substantially augmented infarct volume in mice, impaired neurological function, and elevated brain water content. Lin28a was lowly expressed in brain tissues of mice with CIRI, and its overexpression protected against cerebral I/R injury of MCAO mice. Moreover, Lin28a overexpression protected A172 cells against OGD/R treatment-induced injury. Additionally, NRF2 transcriptionally activated Lin28a in A172 cells. Bone marrow mesenchymal stromal cell-derived exosomes increased Lin28a expression in a NRF2-dependent manner. Bone marrow mesenchymal stromal cell-derived exosomal NRF2 improved OGD/R-induced A172 cell injury by inducing Lin28a production. Conclusion: Bone marrow mesenchymal stromal cell-derived exosomal NRF2 improved CIRI by transcriptionally activating Lin28a.
NOVEL ECHOCARDIOGRAM ANALYSIS OF CARDIAC DYSFUNCTION IS ASSOCIATED WITH MORTALITY IN PEDIATRIC SEPSIS
Authors: Cater Daniel T. , Meyers Brett A. , Mitra Shailee , Bhattacharya Sayantan , Machado Roberto F. , Serrano Ryan , Rowan Courtney M. , Gaston Benjamin , Vlachos Pavlos
Published: April 2024

Objectives: The objective of our study was to semiautomatically generate echocardiogram indices in pediatric sepsis using novel algorithms and determine which indices were associated with mortality. We hypothesized that strain and diastolic indices would be most associated with mortality. Design: Retrospective cohort study of children with sepsis from 2017 to 2022. Survivors and nonsurvivors were compared for echocardiogram indices. Multivariate Cox proportional hazard models were constructed for our primary outcome of in-hospital mortality. Linear regression was performed for secondary outcomes, which included multiple composite 28-day outcomes. Results: Of the 54 patients in the study, 9 (17%) died. Multiple echocardiogram indices of both right (RV) and left ventricles (LV) were associated with in-hospital mortality [RV GLS adjusted hazard ratio (aHR): 1.16 (1.03–1.29), P = 0.011; RV global longitudinal early diastolic strain rate (GLSre) aHR: 0.24 (0.07 to 0.75), P = 0.014; LV GLSre aHR: 0.33 (0.11–0.97), P = 0.044]. Impairment in GLS was associated with fewer ventilator-free days [RV GLS β-coefficient: −0.47 (−0.84 to −0.10), P = 0.013; LV GLS β-coefficient −0.62 (−1.07 to −0.17), P = 0.008], organ-support free days [RV GLS β-coefficient: −0.49 (−0.87 to −0.11), P = 0.013; LV GLS β-coefficient: −0.64 (−1.10 to −0.17), P = 0.008], and days free from ICU [RV GLS β-coefficient: −0.42 (−0.79 to −0.05), P = 0.026; LV GLS β-coefficient: −0.58 (−1.03 to −0.13), P = 0.012]. Systolic indices were not associated with mortality in this cohort. Conclusion: Our study demonstrates the feasibility of obtaining echocardiogram indices in a semiautomatic method using our algorithms. We showed that abnormal strain is associated with worse outcomes in a cohort of children with sepsis.
VASOPRESSOR REDUCTION EFFECT OF POLYMYXIN B HEMOPERFUSION IN PATIENTS WITH PERITONITIS-INDUCED SEPTIC SHOCK: A PROPENSITY SCORE-MATCHED ANALYSIS
Authors: Cho Ara , Oh Seung-Young , Lee Hannah , Ryu Ho Geol
Published: April 2024

Background: This study aimed to evaluate the effect of polymyxin B hemoperfusion (PMX-HP) in patients with peritonitis-induced septic shock who still required high-dose vasopressors after surgical source control. Methods: This retrospective study included adult patients admitted to the surgical intensive care unit (ICU) at Seoul National University Hospital between July 2014 and February 2021 who underwent major abdominal surgery to control the source of sepsis. Patients were divided into two groups based on whether PMX-HP was applied after surgery or not. The primary and secondary endpoints were the vasopressor reduction effect, and in-ICU mortality, respectively. Propensity score matching was performed to compare the vasopressor reduction effect. Results: A total of 338 patients met the inclusion criteria, of which 23 patients underwent PMX-HP postoperatively, whereas 315 patients did not during the study period. Serum norepinephrine concentration decreased over time regardless of whether PMX-HP was applied. However, it decreased more rapidly in the PMX-HP(+) group than in the PMX-HP(−) group. There were no significant differences in demographics including age, sex, body mass index, and most underlying comorbidities between the two groups. Risk factors for in-ICU mortality were identified by comparing patient characteristics and perioperative factors between the two groups using multivariate analysis. Conclusion: For patients with peritonitis-induced septic shock, PMX-HP rapidly reduces the requirement of vasopressors immediately after surgery but does not reduce in-ICU mortality. This effect could potentially accelerate recovery from shock, reduce sequelae from vasopressors, and ultimately improve quality of life after discharge.
Safety of Non-invasive Brain Stimulation in Patients with Implants: A Computational Study
Authors: Karimi Fariba , Cassarà Antonino M. , Capstick Myles , Kuster Niels , Neufeld Esra
Published: April 2024

Objective

Non-invasive brain stimulation (NIBS) methodologies, such as transcranial electric (tES) and magnetic stimulation are increasingly employed for therapeutic, diagnostic, or research purposes. The concurrent presence of active or passive implants can pose safety risks, affect the NIBS delivery, or generate confounding signals. A systematic investigation is required to understand the interaction mechanisms, quantify exposure, assess safety, and establish guidance for NIBS applications.

Approach

We used measurements, simplified generic, and detailed anatomical modeling to: (i) systematically analyze exposure conditions with passive and active implants, considering local field enhancement, exposure dosimetry, tissue heating and neuromodulation, capacitive lead current injection, low-impedance pathways between electrode contacts, and insulation damage; (ii) identify safety metrics and efficient prediction strategies; (iii) quantify these metrics in relevant exposure cases and (iv) identify worst case conditions. Various aspects including implant design, positioning, scar tissue formation, anisotropy, and frequency were investigated.

Results

At typical tES frequencies, local enhancement of dosimetric exposure quantities can reach up to one order of magnitude for DBS and SEEG implants (more for elongated passive implants), potentially resulting in unwanted neuromodulation that can confound results but is still 2-3 orders of magnitude lower than active DBS. Under worst-case conditions, capacitive current injection in the lead of active implants can produce local exposures of similar magnitude as the passive field enhancement, while capacitive pathways between contacts are negligible. Above 10 kHz, applied current magnitudes increase, necessitating consideration of tissue heating. Furthermore, capacitive effects become more prominent, leading to current injection that can reach DBS-like levels. Adverse effects from abandoned/damaged leads in direct electrode vicinity cannot be excluded.

Significance

Safety related concerns of tES application in the presence of implants are systematically identified and explored, resulting in specific and quantitative guidance and establishing a basis for safety standards. Furthermore, several methods for reducing risks are suggested.
Defect-Engineered Metal-Organic Frameworks as Nanocarriers for Pharmacotherapy: Insights into Intracellular Dynamics at The Single Particle Level
Authors: Huang Ge , Dreisler Marcus Winther , Kæstel-Hansen Jacob , Nielsen Annette Juma , Zhang Min , Hatzakis Nikos S.
Published: April 2024

NanoMOFs are widely implemented in a host of assays involving drug delivery, biosensing catalysis, and bioimaging. Despite their wide use, the cell entry pathways and cell fate remain poorly understood. Here we have synthesized a new fluorescent nanoMOF integrating ATTO 655 into surface defects of colloidal nano UiO-66 that allowed us to track the spatiotemporal localization of Single nanoMOF in live cells. Density Functional Theory(DFT) reveals the stronger binding of ATTO 655 to the uncoordinated saturated Zr6cluster nodes compared with phosphate and Alendronate Sodium (AL). Parallelized tracking of the spatiotemporal localization of tens of thousands of nanoMOFs and analysis using machine learning platforms revealed whether nanoMOFs remain outside as well as their cellular internalization pathways. To quantitatively assess their colocalization with endo/lysosomal compartments, we developed a colocalization proxy approach relying on the nanoMOF detection of particles in one channel to the signal in the corresponding endo/lysosomal compartments channel, considering signal vs local background intensity ratio (S/B) and signal-to-noise ratio (SNR). This strategy effectively mitigates the potential inflation of colocalization values arising from the heightened expression of signals originating from endo/lysosomal compartments, it also overcomes limitations of low SNRs in the endo/lysosomal compartments marker channel, which incapacitates any trajectory-trajectory colocalization assessment. The results accurately measure the amount of nanoMOFs’ colocalization in real-time from early (EE) to late endosomes(LE) and lysosomes(LY) and emphasize the importance of understanding their intracellular dynamics based on single-particle tracking (SPT) for optimal and safe drug delivery.
A morphing map model for place field organization in large environments
Authors: Naim Michelangelo , Khona Mikail , Cueva Christopher J.
Published: April 2024

Navigation and spatial memory, essential for animal survival, are founded on the hippocampal formation’s ability to host spatial neurons marking an animal’s position. Within controlled settings, the place cells of the hippocampus are activated in specific regions, the ‘place fields’. In this paper, we introduce a “morphing map algorithm” based on bat data from a 200-meter tunnel, highlighting a multifield, multiscale spatial representation of place fields. This algorithm posits that in vast environments, bats opt to select landmarks or ‘anchors’ for spatial representation. The method introduces a hyperbolic geometry in spatial representation, aligning with bat data from vast areas. We apply Procrustes distance to evaluate similarities between neural maps of bats and model-generated maps, revealing shared structure across bat maps, which might be dictated by common anchor points. Further explorations into anchor point ablation provide insights into their crucial role in map stability. The results present an evolved neural navigation strategy in expansive habitats and guide future spatial representation research across species.
An aortic hemodynamic fingerprint reduced order modeling analysis reveals traits associated with vascular disease in a medical biobank
Authors: Sokolow Ryan , Kissas Georgios , Beeche Cameron , Swago Sophia , Thompson Elizabeth W. , Viswanadha Mukund , Chirinos Julio , Damrauer Scott , Perdakaris Paris , Rader Daniel J. , Witschey Walter R.
Published: April 2024

Purpose

To determine the clinical relevance of reduced order model (ROM) aortic hemodynamic imaging-derived phenotypes (IDPs) for a range of flow conditions applied to computed tomography (CT) scan data in the Penn Medicine Biobank (PMBB).

Methods

The human thoracic aorta was automatically segmented in 3,204 chest CT scans from patients in the Penn Medicine Biobank (PMBB) patients using deep learning. Thoracic aorta anatomic IDPs such as aortic diameter and length were computed. Resistance, and flow boundary conditions, were varied, resulting in 125,000 ROM simulations, producing a fingerprint of aortic hemodynamics IDPs for a range of flow conditions. To determine the clinical relevance of the aortic hemodynamic fingerprint, untargeted phenome wide association studies (PheWAS) for disease conditions were performed using aortic geometries and pulse pressure as IDPs.

Results

By utilizing patient metadata from the PMBB, the human aortic radius for different age groups over a normalized radius was visualized, showing how the vessel deforms with age, as well as other characteristic geometric information. The average radius of the ascending thoracic aortic data set was 26.6 ± 3.1 mm, with an average length of 310 ± 37 mm. A combination of pathology codes (phecodes) and hemodynamic simulations were utilized to develop a relationship between them, showing a strong relationship between the resulting pulse pressure and diseases relating to aortic aneurysms and heart valve disorders. The average pulse pressure calculated by the model was 22.5 ± 8.5 mmHg, with the maximum pressure modeled by the system being 201 mmHg, with the minimum being 63.6 mmHg. The pulse pressures of the most significant phecodes were examined for patients with and without the condition, showing a slight separation between the two cases. The pulse pressure was also slightly negatively correlated with the calculated tapering angle of the ascending thoracic aorta.

Conclusions

ROM hemodynamic simulations can be applied to aortic imaging traits from thoracic imaging data in a medical biobank. The derived hemodynamic fingerprint, describing the response of the aorta to a range of flow conditions, shows clinically relevant associations with disease.
Mapping polarization sensitive optical coherence tomography and ultra-high-field diffusion MRI in the macaque brain
Authors: Pisharady Pramod K , Yeatts Marilyn , Farooq Hamza , Johnson Matthew , Harel Noam , Moeller Steen , Zimmermann Jan , Yacoub Essa , Ugurbil Kamil , Heilbronner Sarah R. , Lenglet Christophe , Akkin Taner
Published: April 2024

This paper provides comparisons between microstructure and two-dimensional fiber orientations measured optically using polarization sensitive optical coherence tomography (PS-OCT) and those estimated from ultra-high-field diffusion MRI (dMRI) at 10.5T in the macaque brain. The PS-OCT imaging is done at an in-plane resolution of ∼10 microns in and around the thalamus. Whole brain dMRI is acquired at an isotropic resolution of 0.75 mm. We provide comparisons between cross-polarization and optical orientation from PS-OCT with the fractional anisotropy and two-dimensional orientations extracted from dMRI using a diffusion tensor model. The orientations from PS-OCT are also extracted computationally using a structure tensor. Additionally, we demonstrate the utility of mesoscale, PS-OCT imaging in improving the MRI resolution by learning the mapping between these contrasts using a super-resolution Generative Adversarial Network.
A deep intronic variant inMMEcauses autosomal recessive Charcot-Marie-Tooth neuropathy through aberrant splicing
Authors: Grosz Bianca R , Parmar Jevin M , Ellis Melina , Bryen Samantha , Simons Cas , Reis Andre L.M. , Stevanovski Igor , Deveson Ira W. , Nicholson Garth , Laing Nigel , Wallis Mathew , Ravenscroft Gianina , Kumar Kishore R. , Vucic Steve , Kennerson Marina L
Published: April 2024

Background

Loss-of-function variants inMME(membrane metalloendopeptidase) are a known cause of recessive Charcot-Marie-Tooth Neuropathy (CMT). A deep intronic variant,MMEc.1188+428A>G (NM_000902.5), was identified through whole genome sequencing (WGS) of two Australian families with recessive inheritance of axonal CMT using the seqr platform.MMEc.1188+428A>G was detected in a homozygous state in Family 1, and in a compound heterozygous state with a known pathogenicMMEvariant (c.467del; p.Pro156Leufs*14) in Family 2.

Aims

We aimed to determine the pathogenicity of theMMEc.1188+428A>G variant through segregation and splicing analysis.

Methods

The splicing impact of the deep intronicMMEvariant c.1188+428A>G was assessed using anin vitroexon-trapping assay.

Results

The exon-trapping assay demonstrated that theMMEc.1188+428A>G variant created a novel splice donor site resulting in the inclusion of an 83 bp pseudoexon betweenMMEexons 12 and 13. The incorporation of the pseudoexon intoMMEtranscript is predicted to lead to a coding frameshift and premature termination codon (PTC) inMMEexon 14 (p.Ala397ProfsTer47). This PTC is likely to result in nonsense mediated decay (NMD) ofMMEtranscript leading to a pathogenic loss-of-function.

Interpretation

To our knowledge, this is the first report of a pathogenic deep intronicMMEvariant causing CMT. This is of significance as deep intronic variants are missed using whole exome sequencing screening methods. Individuals with CMT should be reassessed for deep intronic variants, with splicing impacts being considered in relation to the potential pathogenicity of variants.
Characterization of age-associated inflammasome activation reveals tissue specific differences in transcriptional and post-translational inflammatory responses
Authors: Talley Sarah , Nguyen Tyler , Van Ye Lily , Valiauga Rasa , DeCarlo Jake , Mustafa Jabra , Cook Benjamin , White Fletcher A , Campbell Edward M.
Published: April 2024

Aging is associated with systemic chronic, low-grade inflammation, termed ‘inflammaging’. This pattern of inflammation is multifactorial and is driven by numerous inflammatory pathways, including the inflammasome. However, most studies to date have examined changes in the transcriptomes that are associated with aging and inflammaging, despite the fact that inflammasome activation is driven by a series of post-translational activation steps, culminating in the cleavage and activation of caspase-1. Here, we utilized transgenic mice expressing a caspase-1 biosensor to examine age-associated inflammasome activation in various organs and tissues to define these post-translational manifestations of inflammaging. Consistent with other studies, we observe increased inflammation, including inflammasome activation, in tissues. However, we note that the degree of inflammasome activation is not uniformly correlated with transcriptional changes commonly used as a surrogate for inflammasome activation in tissues. Furthermore, we used a skull thinning technique to monitor central nervous system inflammasome activationin vivoin aged mice and found that neuroinflammation is significantly amplified in aged mice in response to endotoxin challenge. Together, these data reveal that inflammaging is associated with both transcriptional and post-translational inflammatory pathways that are not uniform between tissues and establish new methodologies for measuring age-associated inflammasome activationin vivoandex vivo.
Holistic AI analysis of hybrid cardiac perfusion images for mortality prediction
Authors: Michalowska Anna M , Zhang Wenhao , Shanbhag Aakash , Miller Robert JH , Lemley Mark , Ramirez Giselle , Buchwald Mikolaj , Killekar Aditya , Kavanagh Paul B , Feher Attila , Miller Edward J , Einstein Andrew J , Ruddy Terrence D , Liang Joanna X , Builoff Valerie , Ouyang David , Berman Daniel S , Dey Damini , Slomka Piotr J
Published: April 2024

Background

While low-dose computed tomography scans are traditionally used for attenuation correction in hybrid myocardial perfusion imaging (MPI), they also contain additional anatomic and pathologic information not utilized in clinical assessment. We seek to uncover the full potential of these scans utilizing a holistic artificial intelligence (AI)-driven image framework for image assessment.

Methods

Patients with SPECT/CT MPI from 4 REFINE SPECT registry sites were studied. A multi-structure model segmented 33 structures and quantified 15 radiomics features for each on CT attenuation correction (CTAC) scans. Coronary artery calcium and epicardial adipose tissue scores were obtained from separate deep-learning models. Normal standard quantitative MPI features were derived by clinical software. Extreme Gradient Boosting derived all-cause mortality risk scores from SPECT, CT, stress test, and clinical features utilizing a 10-fold cross-validation regimen to separate training from testing data. The performance of the models for the prediction of all-cause mortality was evaluated using area under the receiver-operating characteristic curves (AUCs).

Results

Of 10,480 patients, 5,745 (54.8%) were male, and median age was 65 (interquartile range [IQR] 57-73) years. During the median follow-up of 2.9 years (1.6-4.0), 651 (6.2%) patients died. The AUC for mortality prediction of the model (combining CTAC, MPI, and clinical data) was 0.80 (95% confidence interval [0.74-0.87]), which was higher than that of an AI CTAC model (0.78 [0.71-0.85]), and AI hybrid model (0.79 [0.72-0.86]) incorporating CTAC and MPI data (p<0.001 for all).

Conclusion

In patients with normal perfusion, the comprehensive model (0.76 [0.65-0.86]) had significantly better performance than the AI CTAC (0.72 [0.61-0.83]) and AI hybrid (0.73 [0.62-0.84]) models (p<0.001, for all).CTAC significantly enhances AI risk stratification with MPI SPECT/CT beyond its primary role - attenuation correction. A comprehensive multimodality approach can significantly improve mortality prediction compared to MPI information alone in patients undergoing cardiac SPECT/CT.
A Generative Model For Evaluating Missing Data Methods in Large Epidemiological Cohorts
Authors: Radosavljević Lav , Smith Stephen M. , Nichols Thomas E.
Published: April 2024

Background

The potential value of large scale datasets is constrained by the ubiquitous problem of missing data, arising in either a structured or unstructured fashion. When imputation methods are proposed for large scale data, one limitation is the simplicity of existing evaluation methods. Specifically, most evaluations create synthetic data with only a simple, unstructured missing data mechanism which does not resemble the missing data patterns found in real data. For example, in the UK Biobank missing data tends to appear in blocks, because non-participation in one of the sub-studies leads to missingness for all sub-study variables.

Methods

We propose a method for generating mixed type missing data mimicking key properties of a given real large scale epidemiological data set with both structured and unstructured missingness while accounting for informative missingness. The process involves identifying sub-studies using hierarchical clustering of missingness patterns and modelling the dependence of inter-variable correlation and co-missingness patterns.

Results

On the UK Biobank brain imaging cohort, we identify several large blocks of missing data. We demonstrate the use of our method for evaluating several imputation methods, showing modest accuracy of imputation overall, with iterative imputation having the best performance. We compare our evaluations based on synthetic data to an exemplar study which includes variable selection on a single real imputed dataset, finding only small differences between the imputation methods though with iterative imputation leading to the most informative selection of variables.

Conclusions

We have created a framework for simulating large scale data with that captures the complexities of the inter-variable dependence as well as structured and unstructured informative missingness. Evaluations using this framework highlight the immense challenge of data imputation in this setting and the need for improved missing data methods.
A Qualitative Interview Study of General Practitioners’ Experiences of Managing Post-COVID-19 Syndrome
Authors: Schulze Josefine , Lind Lennart , Rojas Alina , Lüdtke Laura , Hensen Jens , Bergelt Corinna , Härter Martin , Pohontsch Nadine Janis
Published: April 2024

Background

The management of the long-term sequelae of COVID-19 infection, known as post-COVID-19 syndrome (PCS), continues to challenge the medical community, largely due to a significant gap in the understanding of its aetiology, diagnosis and effective treatment.

Aim

To examine general practitioners’ (GPs) experiences of caring for patients with PCS and to identify unmet care needs and opportunities for improvement.

Design and setting

This study follows a qualitative design, using in-depth semi-structured telephone interviews with GPs (N=31) from across Germany.

Method

Interviews were audio-recorded, transcribed verbatim and analysed using qualitative content analysis.

Results

Patients with persistent symptoms after SARS-CoV-2 infection often consult their GPs as the first point of contact, with symptoms typically resolving within weeks. While ongoing symptomatic COVID-19 is perceived to be more common, the relevance of PCS to GP practices is considerable given its severe impact on patients’ functioning, social participation, and the substantial time required for patient care. GPs coordinate diagnosis and treatment, but face difficulties because of the unclear definition of PCS and difficulties in attributing symptoms, resulting in a cautious approach to ICD-10 coding. Interviewees highlight lengthy diagnostic pathways and barriers to accessing specialist care.

Conclusion

The findings confirm the high functional limitations and psychosocial burden of PCS on patients and the central role of GPs in their care. The study suggests a need for further research and health policy measures to support GPs in navigating diagnostic uncertainty, interprofessional communication and the limited evidence on effective treatments.

How this fits in

Post-COVID-19 syndrome has garnered attention in research and healthcare, but limited evidence on its causes and effective treatment challenges clinicians. This study illustrates the symptom-driven approaches to diagnosis and treatment adopted by general practitioners and their concerns about referring patients to specialist clinics. Greater collaboration and communication across sectors and disciplines is needed to meet the identified need for interprofessional care. Research should also focus on developing comprehensive differential diagnostic protocols, and health policy should address barriers to accessing specific outpatient services.
Mitochondrial genome variants associated with Amyotrophic Lateral Sclerosis and their haplogroup distribution
Authors: Briones Marcelo R. S. , Campos João H. , Ferreira Renata C. , Schneper Lisa , Santos Ilda M. , Antoneli Fernando M. ,   NYGC ALS Consortium, Broach James R.
Published: April 2024

Introduction/Aims

Amyotrophic lateral sclerosis (ALS) may be familial or sporadic, and twin studies have revealed that even sporadic forms have a significant genetic component. Variants in 55 nuclear genes have been associated with ALS and although mitochondrial disfunction is observed in ALS, variants in mitochondrial genomes (mitogenomes) have not yet been tested for association with ALS.

Methods

Here we conducted a genome wide association study (GWAS) in mitogenomes of 1,965 ALS patients and 2,547 controls to test the hypothesis that mitogenome variants are associated with ALS.

Results

We identified 51 mitogenome variants withp-values <10−7of which 13 variants have odds ratios (OR)>1, in genesRNR1,ND1,CO1,CO3,ND5,ND6andCYB, while 38 variants have OR<1 in genesRNR1,RNA2,ND1,ND2,CO2,ATP8,ATP6,CO3,ND3,ND4,ND5,ND6andCYB. The frequencies of haplogroups H, U and L, the most frequent in our ALS dataset, are the same in different onset sites (bulbar, limb, spinal and axial). Also, intra-haplogroup GWAS revealed unique ALS-associated variants in haplogroups L and U.

Discussion

Our study shows that mitogenome variants (SNVs) are associated with ALS and suggests that these SNVs could be included in routine genetic testing for ALS and that mitochondrial replacement therapy would have a potential basis for ALS treatment.