Separate Cohort Research Articles

Retrolabyrinthine Bone Thickness as a Radiologic Marker for the Hypoplastic Endotype in Menière Disease.

Menière disease (MD) manifests in 2 major endotypes: one with a hypoplastic, underdeveloped endolymphatic sac (MD-hp) and the other with a normally developed sac that degenerates over time (MD-dg). Determining the specific endotype in patients is important for predicting disease progression, tailoring patient counseling, and optimizing treatment strategies. Endotype diagnosis involves measuring an angular trajectory of the vestibular aqueduct (ATVA), with an ATVA ≥140° indicative of MD-hp and an ATVA ≤120° of MD-dg. However, assessing the ATVA can be challenging. This study aimed to explore the link between ATVA and the thickness of the retrolabyrinthine bone as an alternative diagnostic measure that could provide differentiation between MD endotypes using CT and MR imaging. Retrospective review of CT temporal bone imaging from 32 adult patients with definite MD (60 ears) and 33 age-matched controls without MD or other inner ear symptoms (61 ears) was performed. The ATVA and retrolabyrinthine bone thickness were measured using uniform methodology on standardized axial CT images. Comparative analyses were performed to determine the correlation between ATVA and retrolabyrinthine bone thickness. Additionally, from a separate cohort of 11 patients (22 ears), CT and MR examinations of the temporal bone were retrospectively reviewed for retrolabyrinthine bone thickness measurements, to verify the correlation across the 2 modalities. The average retrolabyrinthine bone thickness was statistically significantly different between MD endotypes, being a mean of 0.8 (SD, 0.3) mm in patients with MD-hp (ATVA ≥140°) and 2.0 (SD, 0.9) mm in patients with MD-dg (ATVA ≤120°), with a consistent pattern of thin retrolabyrinthine bone in MD-hp and variable thickness in MD-dg. Receiver operating characteristic curve analysis within the MD cohort revealed that a retrolabyrinthine bone thickness ≥1.2 mm effectively rules out MD-hp. Excellent interrater reliability was noted for the retrolabyrinthine measurement, and there was near-perfect correlation between CT and MR measurements. Retrolabyrinthine bone thickness proved to be a useful and straightforward alternative marker for distinguishing MD endotypes, being particularly useful for excluding MD-hp. Including information on retrolabyrinthine bone thickness should be considered a routine part of reporting in the context of MD imaging.

Second opinion machine learning for fast-track pathway assignment in hip and knee replacement surgery: the use of patient-reported outcome measures

BackgroundThe frequency of hip and knee arthroplasty surgeries has been rising steadily in recent decades. This trend is attributed to an aging population, leading to increased demands on healthcare systems. Fast Track (FT) surgical protocols, perioperative procedures designed to expedite patient recovery and early mobilization, have demonstrated efficacy in reducing hospital stays, convalescence periods, and associated costs. However, the criteria for selecting patients for FT procedures have not fully capitalized on the available patient data, including patient-reported outcome measures (PROMs).MethodsOur study focused on developing machine learning (ML) models to support decision making in assigning patients to FT procedures, utilizing data from patients’ self-reported health status. These models are specifically designed to predict the potential health status improvement in patients initially selected for FT. Our approach focused on techniques inspired by the concept of controllable AI. This includes eXplainable AI (XAI), which aims to make the model’s recommendations comprehensible to clinicians, and cautious prediction, a method used to alert clinicians about potential control losses, thereby enhancing the models’ trustworthiness and reliability.ResultsOur models were trained and tested using a dataset comprising 899 records from individual patients admitted to the FT program at IRCCS Ospedale Galeazzi-Sant’Ambrogio. After training and selecting hyper-parameters, the models were assessed using a separate internal test set. The interpretable models demonstrated performance on par or even better than the most effective ‘black-box’ model (Random Forest). These models achieved sensitivity, specificity, and positive predictive value (PPV) exceeding 70%, with an area under the curve (AUC) greater than 80%. The cautious prediction models exhibited enhanced performance while maintaining satisfactory coverage (over 50%). Further, when externally validated on a separate cohort from the same hospital-comprising patients from a subsequent time period-the models showed no pragmatically notable decline in performance.ConclusionsOur results demonstrate the effectiveness of utilizing PROMs as basis to develop ML models for planning assignments to FT procedures. Notably, the application of controllable AI techniques, particularly those based on XAI and cautious prediction, emerges as a promising approach. These techniques provide reliable and interpretable support, essential for informed decision-making in clinical processes.

Educational perspectives in cardiothoracic anesthesia in the United States using a survey of educators and learners.

Cardiothoracic anesthesiology training presents learners with unique challenges, procedural skills, and the management of high-intensity critical scenarios. An effective relationship between educator and learner can serve as the backbone for effective learning, which is crucial for the development of budding anesthesiologists. Strengthening this educational alliance between teachers and trainees involves understanding the educational values educators and learners find most important to their learning experiences. This study aimed to identify the key educational values related to cardiothoracic anesthesia for both learners and educators. By identifying these values in separate cohorts (learners and educators), the importance of various educational values can be examined and compared between the trainees and teachers. Two separate surveys (one for learners and one for teachers) were adapted from the Pratt and Collins Teaching Perspectives Inventory to establish the importance of various educational values related to cardiothoracic anesthesia. Surveys were sent to 165 Accreditation Council for Graduate Medical Education-accredited anesthesiology residency training programs in the United States to trainees (residents and cardiothoracic anesthesiology fellows) and educators (board-certified cardiothoracic anesthesiologists). Analysis of survey results from 19 educators and 57 learners revealed no statistical differences across the two groups, except Q15: "Let trainee perform critical technical steps" (P value = 0.02). While learners and educators in cardiothoracic anesthesia hold similar values regarding cardiac anesthesia education, they differ in the degree to which critical technical steps should be performed by learners.

Does Adding Single-Nucleotide Polymorphisms to Risk Algorithms Improve Cardiovascular Disease Risk Prediction in Rheumatoid Arthritis? An Internal and External Validation of a Clinical Risk Score.

Current risk algorithms do not accurately predict cardiovascular disease (CVD) risk in rheumatoid arthritis (RA). An area of interest is that of single-nucleotide polymorphisms (SNPs), of which several have been associated with CVD in the general population. We investigated whether these SNPs are associated with CVD in RA and whether SNPs could improve CVD risk prediction in RA. Sixty SNPs were genotyped in 353 patients with RA. Logistic and Cox regression analyses were performed to identify SNPs that were associated with CVD (n = 99). A prediction model with clinical variables was made. SNPs were added to investigate the additional predictive value. Both models were internally validated. External validation was done in a separate cohort (n = 297). rs3184504, rs4773144, rs12190287, and rs445925 were significantly associated with new CVD. The clinical prediction model consisted of age, sex, body mass index, systolic blood pressure, high-density lipoprotein cholesterol (HDLc), and creatinine, with an area under the curve (AUC) of 0.74 (P = 0.03). Internal validation resulted in an AUC of 0.76 (P < 0.01). A new model was made including SNPs and resulted in a model with rs17011666 and rs801426, age, total cholesterol, and HDLc, which performed slightly better with an AUC of 0.77 (P < 0.01). External validation resulted in a good fit for the clinical model, but a poor fit for the SNP model. Several SNPs were associated with CVD in RA. Risk prediction slightly improved after adding SNPs to the models, but the clinical relevance is debatable. However, larger studies are needed to determine more accurately the additional value of these SNPs to CVD risk prediction algorithms.

Short-term high fat diet impairs memory, exacerbates the neuroimmune response, and evokes synaptic degradation via a complement-dependent mechanism in a mouse model of Alzheimer’s disease

Alzheimer’s Disease (AD) is a neurodegenerative disease characterized by profound memory impairments, synaptic loss, neuroinflammation, and hallmark pathological markers. High-fat diet (HFD) consumption increases the risk of developing AD even after controlling for metabolic syndrome, pointing to a role of the diet itself in increasing risk. In AD, the complement system, an arm of the immune system which normally tags redundant or damaged synapses for pruning, becomes pathologically overactivated leading to tagging of healthy synapses. While the unhealthy diet to AD link is strong, the underlying mechanisms are not well understood in part due to confounding variables associated with long-term HFD which can independently influence the brain. Therefore, we experimented with a short-term diet regimen to isolate the diet’s impact on brain function without causing obesity. This project investigated the effect of short-term HFD on 1) memory, 2) neuroinflammation including complement, 3) AD pathology markers, 4) synaptic markers, and 5) in vitro microglial synaptic phagocytosis in the 3xTg-AD mouse model. Following the consumption of either standard chow or HFD, 3xTg-AD and non-Tg mice were tested for memory impairments. In a separate cohort of mice, levels of hippocampal inflammatory markers, complement proteins, AD pathology markers, and synaptic markers were measured. For the last set of experiments, BV2 microglial phagocytosis of synapses was evaluated. Synaptoneurosomes isolated from the hippocampus of 3xTg-AD mice fed chow or HFD were incubated with equal numbers of BV2 microglia. The number of BV2 microglia that phagocytosed synaptoneurosomes was tracked over time with a live-cell imaging assay. Finally, we incubated BV2 microglia with a complement receptor inhibitor (NIF) and repeated the assay. Behavioral analysis showed 3xTg-AD mice had significantly impaired long-term contextual and cued fear memory compared to non-Tg mice that was further impaired by HFD. HFD significantly increased inflammatory markers and complement expression while decreasing synaptic marker expression only in 3xTg-AD mice, without altering AD pathology markers. Synaptoneurosomes from HFD-fed 3xTg-AD mice were phagocytosed at a significantly higher rate than those from chow-fed mice, suggesting the synapses were altered by HFD. The complement receptor inhibitor blocked this effect in a dose-dependent manner, demonstrating the HFD-mediated increase in phagocytosis was complement dependent. This study indicates HFD consumption increases neuroinflammation and over-activates the complement cascade in 3xTg-AD mice, resulting in poorer memory. The in vitro data point to complement as a potential mechanistic culprit and therapeutic target underlying HFD’s influence in increasing cognitive vulnerability to AD.

Validation of the hotspot for dorsolateral subthalamic nucleus targeting in deep brain stimulation surgery for Parkinson’s disease: a post hoc analysis of a randomised controlled trial

BackgroundVisualisation of the dorsolateral subthalamic nucleus (STN) remains challenging on 1.5 and 3Tesla T2-weighted MRI. Our previously defined hotspot, relative to the well-visualised medial STN border, serves as an MRI...

Ability of a multi-segment foot model to measure kinematic differences in cavus, neutrally aligned, asymptomatic planus, and symptomatic planus foot types

BackgroundMulti-segment foot models (MFMs) provide a better understanding of the intricate biomechanics of the foot, yet it is unclear if they accurately differentiate foot type function during locomotion. Research questionWe employed an MFM to detect subtle kinematic differences between foot types, including: pes cavus, neutrally aligned, and asymptomatic and symptomatic pes planus. The study investigates how variable the results of this MFM are and if it can detect kinematic differences between pathologic and non-pathologic foot types during the stance phase of gait. MethodsIndependently, three raters instrumented three subjects on three days to assess variability. In a separate cohort, each foot type was statically quantified for ten subjects per group. Each subject walked while instrumented with a four-segment foot model to assess static alignment and foot motion during the stance phase of gait. Statistical analysis performed with a linear mixed effects regression. ResultsModel variability was highest for between-day and lowest for between–rater, with all variability measures being within the true sample variance. Almost all static measures (radiographic, digital scan, and kinematic markers) differed significantly by foot type. Sagittal hindfoot to leg and forefoot to leg kinematics differed between foot types during late stance, as well as coronal hallux to forefoot range of motion. The MFM had low between-rater variability and may be suitable for multiple raters to apply to a single study sample without introducing significant error. The model, however, only detected a few dynamic differences, with the most dramatic being the hallux to forefoot coronal plane range of motion.Significance: Results only somewhat aligned with previous work. It remains unclear if the MFM is sensitive enough to accurately detect different motion between foot types (pathologic and non-pathologic). A more accurate method of tracking foot bone motion (e.g., biplane fluoroscopy) may be needed to address this question.

COVID-19 infection and severe clinical outcomes in patients with kidney disease by vaccination status: a nationwide cohort study in Korea.

Patients with kidney disease have been prioritized for coronavirus disease 2019 (COVID-19) vaccination due to their susceptibility to COVID-19 infection. However, little evidence exists regarding these patients' vulnerability to COVID-19 post-vaccination. Thus, we evaluated the risk of COVID-19 in patients with kidney disease compared to individuals without kidney disease according to vaccination status. A retrospective cohort study was conducted using the Korean nationwide COVID-19 registry linked with National Health Insurance Service claims data (2018-2021). Among individuals aged 12 years or older, 2 separate cohorts were constructed: a COVID-19-vaccinated cohort and an unvaccinated cohort. Within each cohort, the risk of COVID-19 infection and all-cause mortality, hospitalization, and emergency room visits within 30 days of COVID-19 infection were compared between patients with and without kidney disease. To adjust for potential confounding, we used propensity score matching. Hazard ratios (HRs) for each outcome were estimated using a Cox proportional hazard model. We identified 785,390 and 836,490 individuals in the vaccinated and unvaccinated cohorts, respectively. Compared to patients without kidney disease, patients with kidney disease were at a higher risk of COVID-19 infection in both the vaccinated cohort (HR, 1.08; 95% confidence interval [CI], 1.02 to 1.16) and the unvaccinated cohort (HR, 1.09; 95% CI, 0.99 to 1.20). Likewise, patients with kidney disease generally were at higher risk for severe clinical outcomes within 30 days of COVID-19 infection. Subgroup and sensitivity analyses showed generally consistent results. Our study observed excess risk of COVID-19 in patients with kidney disease, highlighting the importance of ongoing attention to these patients even post-vaccination.

The role of spinal cord neuroanatomy in the variances of epidural spinal recordings

BackgroundSpinal cord stimulation (SCS) has demonstrated multiple benefits in treating chronic pain and other clinical disorders related to sensorimotor dysfunctions. However, the underlying mechanisms are still not fully understood, including how electrode placement in relation to the spinal cord neuroanatomy influences epidural spinal recordings (ESRs). To characterize this relationship, this study utilized stimulation applied at various anatomical sections of the spinal column, including at levels of the intervertebral disc and regions correlating to the dorsal root entry zone.MethodTwo electrode arrays were surgically implanted into the dorsal epidural space of the swine. The stimulation leads were positioned such that the caudal-most electrode contact was at the level of a thoracic intervertebral segment. Intraoperative cone beam computed tomography (CBCT) images were utilized to precisely determine the location of the epidural leads relative to the spinal column. High-resolution microCT imaging and 3D-model reconstructions of the explanted spinal cord illustrated precise positioning and dimensions of the epidural leads in relation to the surrounding neuroanatomy, including the spinal rootlets of the dorsal and ventral columns of the spinal cord. In a separate swine cohort, implanted epidural leads were used for SCS and recording evoked ESRs.ResultsReconstructed 3D-models of the swine spinal cord with epidural lead implants demonstrated considerable distinctions in the dimensions of a single electrode contact on a standard industry epidural stimulation lead compared to dorsal rootlets at the dorsal root entry zone (DREZ). At the intervertebral segment, it was observed that a single electrode contact may cover 20-25% of the DREZ if positioned laterally. Electrode contacts were estimated to be ~0.75 mm from the margins of the DREZ when placed at the midline. Furthermore, ventral rootlets were observed to travel in proximity and parallel to dorsal rootlets at this level prior to separation into their respective sides of the spinal cord. Cathodic stimulation at the level of the intervertebral disc, compared to an ‘off-disc’ stimulation (7 mm rostral), demonstrated considerable variations in the features of recorded ESRs, such as amplitude and shape, and evoked unintended motor activation at lower stimulation thresholds. This substantial change may be due to the influence of nearby ventral roots. To further illustrate the influence of rootlet activation vs. dorsal column activation, the stimulation lead was displaced laterally at ~2.88 mm from the midline, resulting in variances in both evoked compound action potential (ECAP) components and electromyography (EMG) components in ESRs at lower stimulation thresholds.ConclusionThe results of this study suggest that the ECAP and EMG components of recorded ESRs can vary depending on small differences in the location of the stimulating electrodes within the spinal anatomy, such as at the level of the intervertebral segment. Furthermore, the effects of sub-centimeter lateral displacement of the stimulation lead from the midline, leading to significant changes in electrophysiological metrics. The results of this pilot study reveal the importance of the small displacement of the electrodes that can cause significant changes to evoked responses SCS. These results may provide further valuable insights into the underlying mechanisms and assist in optimizing future SCS-related applications.

Anemia From Inflammation After Intracerebral Hemorrhage and Relationships With Outcome.

Baseline anemia is associated with poor intracerebral hemorrhage (ICH) outcomes. However, underlying drivers for anemia and whether anemia development after ICH impacts clinical outcomes are unknown. We hypothesized that inflammation drives anemia development after ICH and assessed their relationship to outcomes. Patients with serial hemoglobin and iron biomarker concentrations from the HIDEF (High-Dose Deferoxamine in Intracerebral Hemorrhage) trial were analyzed. Adjusted linear mixed models assessed laboratory changes over time. Of 42 patients, significant decrements in hemoglobin occurred with anemia increasing from 19% to 45% by day 5. Anemia of inflammation iron biomarker criteria was met in 88%. A separate cohort of 521 patients with ICH with more granular serial hemoglobin and long-term neurological outcome data was also investigated. Separate regression models assessed whether (1) systemic inflammatory response syndrome (SIRS) scores related to hemoglobin changes over time and (2) hemoglobin changes related to poor 90-day outcome. In this cohort, anemia prevalence increased from 30% to 71% within 2 days of admission yet persisted beyond this time. Elevated systemic inflammatory response syndrome was associated with greater hemoglobin decrements over time (adjusted parameter estimate: -0.27 [95% CI, -0.37 to -0.17]) and greater hemoglobin decrements were associated with poor outcomes (adjusted odds ratio per 1 g/dL increase, 0.76 [95% CI, 0.62-0.93]) independent to inflammation and ICH severity. We identified novel findings that acute anemia development after ICH is common, rapid, and related to inflammation. Because anemia development is associated with poor outcomes, further work is required to clarify if anemia, or its underlying drivers, are modifiable treatment targets that can improve ICH outcomes. https://www.clinicaltrials.gov Unique identifier: NCT01662895.

Response-Adapted Ultralow-Dose Radiation Therapy for Orbital Indolent B-Cell Lymphoma

Radiation therapy to doses of 24 to 36 Gy is currently used to treat indolent B-cell lymphoma of the ocular adnexa; however, ocular adverse effects are common. To determine if a response-adapted radiation therapy strategy will result in excellent disease outcomes while reducing orbital morbidity. This single-institution, phase 2 prospective nonrandomized controlled trial of a response-adapted strategy involved 50 evaluable patients with stage I to IV indolent B-cell lymphoma of the ocular adnexa enrolled between July 2015 and January 2021. This treatment approach was also retrospectively evaluated with a separate 55-patient cohort treated between March 2013 and October 2021. All data were analyzed between November 2021 and December 2023. Patients were treated with ultralow-dose radiation therapy to 4 Gy in 2 fractions and assessed for response at 3-month intervals. Patients with persistent orbital lymphoma were offered an additional 20 Gy in 10 fractions to complete the response-adapted treatment. The primary end point was 2-year local orbital control within the irradiated field after response-adapted therapy. Secondary end points included overall survival and complete response rate. The 50 prospective patients were a median (range) of 63 (29-88) years old, and 31 (62%) were female. Among the 50 patients, 32 (64%) had mucosa-associated lymphoid tissue lymphoma, 12 (24%) had follicular lymphoma, and 6 (12%) had unclassifiable low-grade B-cell lymphoma. Thirty-one patients (62%) had stage I disease, and 36 (72%) were newly diagnosed. At a median follow-up of 37.4 (95% CI, 33.7-52.5) months, the 2-year local control rate was 89.4% (95% CI, 81.0%-98.7%), and the 2-year overall survival rate was 98.0% (95% CI, 94.1%-100%); 45 patients (90.0%; 95% CI, 78.2%-96.7%) experienced a complete response to response-adapted radiation, including 44 patients with a complete response to ultralow-dose radiation and 1 patient with a complete response after an additional 20 Gy. No local recurrences were observed among patients with a complete response to response-adapted therapy. No grade 3 or higher toxic effects were observed. In a planned subset analysis of 22 patients with newly diagnosed, untreated stage I mucosa-associated lymphoid tissue lymphoma, the 2-year local control rate was 90.7% (95% CI, 79.2%-100%), and the 2-year freedom from distant relapse rate was 95.2% (95% CI, 86.6%-100%). In this nonrandomized controlled trial, response-adapted ultralow-dose therapy for indolent orbital B-cell lymphoma resulted in reduced radiation exposure, negligible toxic effects, and excellent disease outcomes. ClinicalTrials.gov Identifier: NCT02494700.

Preoperative prediction of nodal status using clinical data and artificial intelligence derived mammogram features enabling abstention of sentinel lymph node biopsy in breast cancer.

Patients with clinically node-negative breast cancer have a negative sentinel lymph node status (pN0) in approximately 75% of cases and the necessity of routine surgical nodal staging by sentinel lymph node biopsy (SLNB) has been questioned. Previous prediction models for pN0 have included postoperative variables, thus defeating their purpose to spare patients non-beneficial axillary surgery. We aimed to develop a preoperative prediction model for pN0 and to evaluate the contribution of mammographic breast density and mammogram features derived by artificial intelligence for de-escalation of SLNB. This retrospective cohort study included 755 women with primary breast cancer. Mammograms were analyzed by commercially available artificial intelligence and automated systems. The additional predictive value of features was evaluated using logistic regression models including preoperative clinical variables and radiological tumor size. The final model was internally validated using bootstrap and externally validated in a separate cohort. A nomogram for prediction of pN0 was developed. The correlation between pathological tumor size and the preoperative radiological tumor size was calculated. Radiological tumor size was the strongest predictor of pN0 and included in a preoperative prediction model displaying an area under the curve of 0.68 (95% confidence interval: 0.63-0.72) in internal validation and 0.64 (95% confidence interval: 0.59-0.69) in external validation. Although the addition of mammographic features did not improve discrimination, the prediction model provided a 21% SLNB reduction rate when a false negative rate of 10% was accepted, reflecting the accepted false negative rate of SLNB. This study shows that the preoperatively available radiological tumor size might replace pathological tumor size as a key predictor in a preoperative prediction model for pN0. While the overall performance was not improved by mammographic features, one in five patients could be omitted from axillary surgery by applying the preoperative prediction model for nodal status. The nomogram visualizing the model could support preoperative patient-centered decision-making on the management of the axilla.

Anatomic Versus Reverse Total Shoulder Arthroplasty for Primary Osteoarthritis With an Intact Rotator Cuff: A Midterm Comparison of Early Top Performers.

Several surgeons state that their best anatomic total shoulder arthroplasty (aTSA) outperforms their best reverse total shoulder arthroplasty (rTSA) when performed for rotator cuff-intact glenohumeral osteoarthritis. We identified the top-performing aTSAs and rTSAs at short-term follow-up and compared their clinical performance at midterm follow-up to validate this common claim. A retrospective review of a multicenter shoulder arthroplasty database was conducted. All shoulders undergoing primary aTSA or rTSA for rotator cuff-intact glenohumeral osteoarthritis between 2007 and 2020 were reviewed. Shoulders with a follow-up clinical visit between 2 and 3 years and a clinical follow-up of minimum 5 years were included. Two separate cohorts were identified: patients with a top 20% (1) American Shoulder and Elbow Surgeons (ASES) score and (2) Shoulder Arthroplasty Smart (SAS) score at 2 to 3 years of follow-up. Clinical outcomes including range of motion, outcome scores, and rates of complications and revision surgeries were compared at minimum 5-year follow-up. The ASES score cohort comprised 185 aTSAs (mean age 67 years, 42% female) and 49 rTSAs (mean age 72 years, 45% female). The SAS score cohort comprised 145 aTSAs (mean age 67 years, 59% female) and 42 rTSAs (mean age 71 years, 57% female). Active external rotation (ER) was greater after aTSA at midterm follow-up in both ASES and SAS score cohorts; however, preoperative to postoperative improvement was equivalent. Postoperative ER and SAS scores were greater after aTSA in both cohorts ( P < 0.05); however, no other significant differences in any preoperative or postoperative clinical outcomes were present ( P > 0.05), and patients achieved the minimal clinically important difference and substantial clinical benefit at similar rates for all outcomes. No difference was found in the incidence of complications and revision surgeries between top-performing aTSAs and rTSAs. Among top-performing shoulder arthroplasties at early follow-up, aTSA does not appear to outperform rTSA, except superior ER at midterm follow-up. Retrospective comparative cohort study, Level Ⅲ.

Optimizing DCD Liver Grafts With Prolonged Warm Ischemic Time Using Stabilized Plasmin in a Static Cold Storage Orthotopic Rat Liver Transplant Model.

The clinical success of liver transplantation has led to increased demand, requiring further expansion of the donor pool. Therapeutic interventions to optimize organs from donation after circulatory death (DCD) have significant potential to mitigate the organ shortage. Dysfunction in DCD liver grafts is mediated by microvascular thrombosis during the warm ischemic period, and strategies that reduce this thrombotic burden may improve graft function. We hypothesized that the administration of the fibrinolytic enzyme plasmin to the donor organ during the cold storage period would reduce the thrombotic burden and improve DCD liver graft function. In 2 separate cohorts, 32 syngeneic orthotopic rat liver transplants were performed in Lewis rats. Livers were procured from donors with 45 min of warm ischemic injury. Liver grafts were flushed with histidine-tryptophan-ketoglutarate preservation solution mixed with either plasmin (experimental group) or albumin (control group). All investigators were blinded to treatment group. After preparing the liver for implant using a modified cuff technique, the liver was stored for 1 h by static cold storage at 4 °C. Immediately before implantation, the liver graft was flushed, and this effluent was analyzed for fibrin degradation products to determine graft clot burden. Twenty-four hours following transplantation, animals were euthanized, and samples were collected. Recipient survival was significantly higher for DCD liver grafts treated with plasmin compared with control. Moreover, histology of liver graft tissue immediately before implant reflected significantly reduced congestion in plasmin-treated livers (score, mean ± SD: 0.73 ± 0.59 versus 1.12 ± 0.48; P = 0.0456). The concentration of fibrin degradation products in the final flush before implantation was significantly reduced in plasmin-treated livers (743 ± 136 versus 10 919 ± 4642 pg/mL; P = 0.0001), reflecting decreased clot burden in the graft. The present study demonstrates that plasmin improves survival and may reduce thrombotic burden in DCD liver grafts with prolonged warm ischemic injury, meriting further study.

Dynamic properties in functional connectivity changes and striatal dopamine deficiency in Parkinson's disease.

Recent studies in Parkinson's disease (PD) patients reported disruptions in dynamic functional connectivity (dFC, i.e., a characterization of spontaneous fluctuations in functional connectivity over time). Here, we assessed whether the integrity of striatal dopamine terminals directly modulates dFC metrics in two separate PD cohorts, indexing dopamine-related changes in large-scale brain network dynamics and its implications in clinical features. We pooled data from two disease-control cohorts reflecting early PD. From the Parkinson's Progression Marker Initiative (PPMI) cohort, resting-state functional magnetic resonance imaging (rsfMRI) and dopamine transporter (DaT) single-photon emission computed tomography (SPECT) were available for 63 PD patients and 16 age- and sex-matched healthy controls. From the clinical research group 219 (KFO) cohort, rsfMRI imaging was available for 52 PD patients and 17 age- and sex-matched healthy controls. A subset of 41 PD patients and 13 healthy control subjects additionally underwent 18F-DOPA-positron emission tomography (PET) imaging. The striatal synthesis capacity of 18F-DOPA PET and dopamine terminal quantity of DaT SPECT images were extracted for the putamen and the caudate. After rsfMRI pre-processing, an independent component analysis was performed on both cohorts simultaneously. Based on the derived components, an individual sliding window approach (44 s window) and a subsequent k-means clustering were conducted separately for each cohort to derive dFC states (reemerging intra- and interindividual connectivity patterns). From these states, we derived temporal metrics, such as average dwell time per state, state attendance, and number of transitions and compared them between groups and cohorts. Further, we correlated these with the respective measures for local dopaminergic impairment and clinical severity. The cohorts did not differ regarding age and sex. Between cohorts, PD groups differed regarding disease duration, education, cognitive scores and L-dopa equivalent daily dose. In both cohorts, the dFC analysis resulted in three distinct states, varying in connectivity patterns and strength. In the PPMI cohort, PD patients showed a lower state attendance for the globally integrated (GI) state and a lower number of transitions than controls. Significantly, worse motor scores (Unified Parkinson's Disease Rating Scale Part III) and dopaminergic impairment in the putamen and the caudate were associated with low average dwell time in the GI state and a low total number of transitions. These results were not observed in the KFO cohort: No group differences in dFC measures or associations between dFC variables and dopamine synthesis capacity were observed. Notably, worse motor performance was associated with a low number of bidirectional transitions between the GI and the lesser connected (LC) state across the PD groups of both cohorts. Hence, in early PD, relative preservation of motor performance may be linked to a more dynamic engagement of an interconnected brain state. Specifically, those large-scale network dynamics seem to relate to striatal dopamine availability. Notably, most of these results were obtained only for one cohort, suggesting that dFC is impacted by certain cohort features like educational level, or disease severity. As we could not pinpoint these features with the data at hand, we suspect that other, in our case untracked, demographical features drive connectivity dynamics in PD. PRACTITIONER POINTS: Exploring dopamine's role in brain network dynamics in two Parkinson's disease (PD) cohorts, we unraveled PD-specific changes in dynamic functional connectivity. Results in the Parkinson's Progression Marker Initiative (PPMI) and the KFO cohort suggest motor performance may be linked to a more dynamic engagement and disengagement of an interconnected brain state. Results only in the PPMI cohort suggest striatal dopamine availability influences large-scale network dynamics that are relevant in motor control.

O-314 Investigating the embryonic contribution to recurrent pregnancy loss: a retrospective analysis of embryo quality, chromosomal status and morphokinetics in 11,169 embryos

Abstract Study question What is the embryonic contribution, in terms of embryo quality, chromosomal status and morphokinetics, to the reproductive success of recurrent pregnancy loss (RPL) patients? Summary answer RPL patients undergoing PGT-A had significantly fewer embryos available for biopsy, higher aneuploidy rates and showed morphokinetic alterations around the time of blastulation. What is known already RPL is diagnosed following the loss of two or more pregnancies before the 24th week of gestation. RPL has a multifactorial etiology encompassing both maternal and embryonic factors, such as uterine malformations, the presence of anti-phospholipid antibodies, maternal obesity or embryo aneuploidy, among others. While some studies have shown increased rates of chromosomal abnormalities in blastocysts from idiopathic RPL patients, a comprehensive characterization of the embryonic contribution to the disorder remains limited, and the role of embryo morphokinetics is still underexplored. Study design, size, duration This retrospective cohort study analyzed 11,169 embryos from 3,005 PGT-A cycles performed across 9 European fertility clinics between January 2017 and July 2023. Differences in the number of biopsied embryos, aneuploidy rates and embryo quality were compared between RPL and non-RPL patients. Morphokinetic timings were evaluated in a subset of 704 RPL embryos from 2 fertility centers, which was then compared to a separate cohort of embryos (n = 952) derived from double gamete donation cycles (n = 134). Participants/materials, setting, methods Genetic and clinical outcomes were assessed by multivariate analyses adjusting for maternal age, paternal age, the presence of male factor and embryo grade, as appropriate. Kaplan-Meier survival curves were constructed for each morphokinetic parameter (tPNf, t2, t3, t4, t5, t8, tSB and tB) and analyzed by Cox regression using maternal age and male factor as adjusting variables. P-values &amp;lt;0.05 were considered statistically significant. Main results and the role of chance RPL patients undergoing PGT-A represented 15.47% (n = 465/3,005) of the cohort and were significantly younger than the rest of the patients (34,97±6.6 vs 36.38±6.6, p &amp;lt; 0.0001). RPL patients obtained significantly fewer blastocysts available for biopsy (coefficient -0.39, 95%CI: -0.703- -0.076, p = 0.01) and had significantly higher aneuploidy rates (OR = 1.19, 95%CI: 1.06-1.35, p = 0.004). However, embryo quality (excellent vs. rest, p &amp;gt; 0.05) was comparable between the two groups (n = 11,169 embryos). As anticipated, biochemical and clinical pregnancy rates were comparable between RPL patients and non-RPL patients (OR = 0.94, 95%CI:0.72-1.24, p = 0.68; OR = 0.95, 95%CI: 0.72-1.24, p = 0.71, respectively), however patients with RPL presented with significantly higher miscarriage rates (OR = 1.66, 95% CI:1.03-2.74, p = 0.04). Compared to double donation embryos, RPL embryos exhibited significant delays in all analyzed times (tPNf: 23.7±3.1 vs. 22.7±3.1; t2: 26.5±4.1 vs. 25.6±3.4; t3: 37.1±5.4 vs. 36.0±4.7; t4: 39.2±6.3 vs. 37.9±5.3; t5: 50.2±7.9 vs. 49.3±7.4; tsB: 99.4±10.3 vs. 97.9±9.7; tB: 110.3±11.5 vs. 106.4±11.8; p &amp;lt; 0.05). Notably, delays in blastocyst formation were also observed when adjusting for maternal age and male factor (Hazard Ratio=0.38, 95% CI: 0.18-0.79, p = 0.009). Significantly, morphokinetic alterations persisted even when exclusively comparing euploid RPL embryos to the double donation group (n = 41, t8: Hazard Ratio=1.78, 95% CI: 1.22-2.57, p = 0.002; tsB: Hazard Ratio=1.70, 95% CI: 1.17-2.48, p = 0.006). Limitations, reasons for caution The main limitation of the study is its retrospective design, where known RPL risk factors leading to the selection of a PGT-A cycle were not considered, potentially introducing biases. Wider implications of the findings These findings highlight the intricate interplay between embryo quality, aneuploidy, and morphokinetics in RPL, guiding personalized patient management. Higher embryo aneuploidy and morphokinetic alterations observed even in euploid RPL embryos suggest an embryonic role, underscoring the condition’s multifactorial nature and urging exploration of molecular mechanisms linking embryonic factors to RPL. Trial registration number not applicable

Upregulation and epigenetic modification of the creatine transporter SLC6A8 in non-small cell lung cancer.

Lung cancer is a major cause of cancer-related death worldwide and effective therapies, besides surgery, are available only for a small proportion of patients. Since cellular respiration is known to be broadly altered in malignant tumors, the cellular processes of respiration can be a potential therapeutic target. One important element of cellular respiration is creatine and its transport by the creatine transporter SLC6A8. Here we describe the expression of SLC6A8 at the RNA and protein level, epigenetic modifications as well as survival analysis in NSCLC tissues and matched controls. We analyzed epigenetic modifications of the SLC68A gene in 32 patients, of which 18 were additionally analyzed by transcriptome analysis. The expression of SLC6A8 at the protein level was assessed by immunohistochemistry using an independent cohort and correlated with clinicopathological data including survival. Kaplan-Meier analysis was performed to analyze the possible effects of the transcriptional levels of SLC6A8 in another separate cohort (n=1925). SLC6A8 loci are epigenetically modified in NSCLC compared with tumor-free controls. SLC6A8 is upregulated in NSCLC at the RNA and protein level. High mRNA expression of SLC6A8 was associated with an overall poor prognosis in lung adenocarcinoma patients and displayed the strongest adverse prognostic effect in male smokers with adenocarcinomas. Results of transcriptome analysis were partially confirmed at the protein level. Our results suggest an important role of creatine and its transport via SLC6A8 in NSCLC.

Development and validation of a machine learning-based interpretable model for predicting sepsis by complete blood cell parameters

BackgroundSepsis, a severe infectious disease, carries a high mortality rate. Early detection and prompt treatment are crucial for reducing mortality and improving prognosis. The aim of this research is to develop a clinical prediction model using machine learning algorithms, leveraging complete blood cell (CBC) parameters, to detect sepsis at an early stage. MethodsThe study involved 572 patients admitted to West China Hospital of Sichuan University between July 2020 and September 2021. Among them, 215 were diagnosed with sepsis, while 357 had local infections. Demographic information was collected, and 57 CBC parameters were analyzed to identify potential predictors using techniques such as the Least Absolute Shrinkage and Selection Operator (LASSO), Random Forest (RF), Support Vector Machine (SVM), and eXtreme Gradient Boosting (XGBoost). The prediction model was built using Logistic Regression and evaluated for diagnostic specificity, discrimination, and clinical applicability including metrics such as the area under the curve (AUC), calibration curve, clinical impact curve, and clinical decision curve. Additionally, the model's diagnostic performance was assessed on a separate validation cohort. Shapley's additive explanations (SHAP), and breakdown (BD) profiles were used to explain the contribution of each variable in predicting the outcome. ResultsAmong all the machine learning methods' prediction models, the LASSO-based model (λ = min) demonstrated the highest diagnostic performance in both the discovery cohort (AUC = 0.9446, P < 0.001) and the validation cohort (AUC = 0.9001, P < 0.001). Furthermore, upon local analysis and interpretation of the model, we demonstrated that LY-Z, MO-Z, and PLT-I had the most significant impact on the outcome. ConclusionsThe predictive model based on CBC parameters can be utilized as an effective approach for the early detection of sepsis.

Taste sensitivities mediate differential snack choices across BMI groups: a study with New Zealand young male individuals.

This study aimed to: 1) test for the link between snack choices and BMI using a novel sensory-based classification method; and 2) elucidate the role of gustatory sensitivity in orienting snack choices. The study employed a dual approach involving sensory and nutritional assessments. Ninety-eight European male individuals were tested for gustatory sensitivities to sweetness, saltiness, umami, and lipid perception. Participant food intake was measured over 4 days. A separate cohort of 327 participants categorized the recorded snacks based on taste patterns, enabling profiling of snack choices across body-weight groups. Results showed clear differentiations in snack choices across the BMI groups: Individuals with a higher BMI consumed more "Sweet" and "Sweet+Fat" snacks and less "Savory" snacks compared with the lower-BMI group (p < 0.05). Mediation analyses confirmed a significant effect of gustatory sensitivity, showing that the greater choice for "Sweet" and "Sweet+Fat" snacks among those with a higher BMI was mediated by sensitivities to sweetness and lipid perception (p = 0.008-0.044). Our study revealed that gustatory sensitivity can mediate the relationship between BMI and energy consumption from different snacks. These findings highlight the significance of taste perception in shaping snack choice, suggesting potential strategies for interventions aimed at addressing gustatory sensitivityto promote healthier dietary preferences.

A phase I thorough QT/QTc study evaluating therapeutic and supratherapeutic doses of avacopan in healthy participants.

This phase I thorough QTc, double-blind, randomized, placebo- and positive-controlled, parallel group, multiple-dose study evaluated avacopan's effect on cardiac repolarization using concentration-QTc (C-QTc) as the primary analysis. Avacopan 30 mg b.i.d. (therapeutic dose) was administered orally on days 1 through 7 followed by avacopan 100 mg b.i.d. (supratherapeutic dose) on days 8 through 14 in 29 healthy participants. Moxifloxacin 400 mg and placebo were administered on days 1 and 15 in a nested crossover design for assay sensitivity in separate cohorts to 28 participants. Time-matched plasma concentrations and up to 10 replicate ECGs were obtained on prespecified days at baseline and postdose on days 1, 7, 14, and 15. The mean change from baseline on QTcF for avacopan (-5.5 to 3.5 ms) was similar to placebo (-6.9 to 1.4 ms) across days 1, 7, and 14. The mean effect on ΔΔQTcF (90% CI) was estimated as 1.5 ms (-0.17 to 3.09) and 0.8 ms (-2.41 to 4.05) for 30 and 100 mg avacopan b.i.d. treatments, respectively. Based on the C-QTc analysis, avacopan's effect on ΔΔQTcF >10 ms can be excluded within the observed plasma concentration range of up to ~1220 and ~335 ng/mL for avacopan and active major metabolite, M1, respectively. The estimated population slopes showed a shallow relationship, which was not statistically significant. There was no clinically meaningful effect of avacopan on heart rate or cardiac conduction (PR and QRS intervals). Avacopan appeared to be generally well tolerated in this study population.