Incidence, Predictors, and Outcomes of Clinically Significant Post-ERCP Bleeding: a Contemporary Multi-center Study.

BACKGROUND AIMS: Clinically significant post-endoscopic retrograde cholangiopancreatography (ERCP) bleeding (CSPEB) is common. Contemporary estimates of risk are lacking. We aimed to identify risk factors for and outcomes following CSPEB. METHODS: We analyzed multi-center prospective ERCP data between 2018-2023 with 30-day follow-up. The primary outcome was CSPEB, defined as hematemesis, melena, or hematochezia resulting in: hemoglobin drop ≥20 g/L or transfusion and/or endoscopy to evaluate suspected bleeding, and/or unplanned healthcare visitation and/or prolongation of existing admission. Firth logistic regression was employed. P-values <0.05 were significant, with odds ratios (ORs) and 95% confidence intervals reported. RESULTS: CSPEB occurred following 129 (1.5%) of 8,517 ERCPs (mean onset 3.2 days), with 110 of 4,849 events (2.3%) occurring following higher-risk interventions (sphincterotomy, sphincteroplasty, pre-cut sphincterotomy, and/or needle-knife access). CSPEB patients required endoscopy and transfusion in 86.0% and 53.5% of cases, respectively, with three cases (2.3%) being fatal. P2Y12 inhibitors were held for a median of 4 days (IQR 4) prior to higher-risk ERCP. Following higher-risk interventions, P2Y12 inhibitors (OR 3.33, 1.26-7.74), warfarin (OR 8.54, 3.32-19.81), dabigatran (OR 13.40, 2.06-59.96), rivaroxaban (OR 7.42, 3.43-15.24) and apixaban (OR 4.16, 1.99-8.20) were associated with CSPEB. Significant intraprocedural bleeding post sphincterotomy (OR 2.32, 1.06-4.60), but not post sphincteroplasty, was also associated. Concomitant cardiorespiratory events occurred more frequently within 30 days following CSPEB (OR 12.71, 4.75-32.54). CONCLUSIONS: Risks of antiplatelet-related CSPEB may be underestimated by endoscopists based on observations of suboptimal holding before higher-risk ERCP. Appropriate periprocedural antithrombotic management is essential and could represent novel quality initiative targets.

Glutathione synthesis in the mouse liver supports lipid abundance through NRF2 repression.

Cells rely on antioxidants to survive. The most abundant antioxidant is glutathione (GSH). The synthesis of GSH is non-redundantly controlled by the glutamate-cysteine ligase catalytic subunit (GCLC). GSH imbalance is implicated in many diseases, but the requirement for GSH in adult tissues is unclear. To interrogate this, we have developed a series of in vivo models to induce Gclc deletion in adult animals. We find that GSH is essential to lipid abundance in vivo. GSH levels are highest in liver tissue, which is also a hub for lipid production. While the loss of GSH does not cause liver failure, it decreases lipogenic enzyme expression, circulating triglyceride levels, and fat stores. Mechanistically, we find that GSH promotes lipid abundance by repressing NRF2, a transcription factor induced by oxidative stress. These studies identify GSH as a fulcrum in the liver's balance of redox buffering and triglyceride production.

Neurovascular coupling, functional connectivity, and cerebrovascular endothelial extracellular vesicles as biomarkers of mild cognitive impairment.

INTRODUCTION: Mild cognitive impairment (MCI) is a prodromal stage of dementia. Understanding the mechanistic changes from healthy aging to MCI is critical for comprehending disease progression and enabling preventative intervention. METHODS: Patients with MCI and age-matched controls (CN) were administered cognitive tasks during functional near-infrared spectroscopy (fNIRS) recording, and changes in plasma levels of extracellular vesicles (EVs) were assessed using small-particle flow cytometry. RESULTS: Neurovascular coupling (NVC) and functional connectivity (FC) were decreased in MCI compared to CN, prominently in the left-dorsolateral prefrontal cortex (LDLPFC). We observed an increased ratio of cerebrovascular endothelial EVs (CEEVs) to total endothelial EVs in patients with MCI compared to CN, correlating with structural MRI small vessel ischemic damage in MCI. LDLPFC NVC, CEEV ratio, and LDLPFC FC had the highest feature importance in the random Forest group classification. DISCUSSION: NVC, CEEVs, and FC predict MCI diagnosis, indicating their potential as markers for MCI cerebrovascular pathology. HIGHLIGHTS: Neurovascular coupling (NVC) is impaired in mild cognitive impairment (MCI). Functional connectivity (FC) compensation mechanism is lost in MCI. Cerebrovascular endothelial extracellular vesicles (CEEVs) are increased in MCI. CEEV load strongly associates with cerebral small vessel ischemic lesions in MCI. NVC, CEEVs, and FC predict MCI diagnosis over demographic and comorbidity factors.

Cervical Spinal Cord Morphometrics in Degenerative Cervical Myelopathy: Quantification using Semi-automated Normalized Technique and Correlation with Neurological Dysfunctions.

BACKGROUND CONTEXT: Degenerative cervical myelopathy (DCM) is characterized by spinal cord atrophy. Accurate estimation of spinal cord atrophy is key to the understanding of neurological diseases, including DCM. However, its clinical application is hampered by difficulties in its precise and consistent estimation due to significant variability in spinal cord morphometry along the cervical spine, both within and between individuals. PURPOSE: To characterize morphometrics of the compressed spinal cord in DCM patients. We employed our semi-automated analysis framework that incorporates the Spinal Cord Toolbox (SCT) and a normalization approach to effectively address the challenges posed by cord compression in these patients. Additionally, we examined the clinical relevance of these morphometric measures to enhance our understanding of DCM pathophysiology. STUDY DESIGN: Prospective study. PATIENT SAMPLE: This study investigated 36 DCM patients and 31 healthy controls (HCs). OUTCOME MEASURES: Clinical scores including 9-hole peg test for hand dexterity, hand grip strength, balance, gait speed, modified Japanese Orthopaedic Association (mJOA) score, and imaging-based spinal cord morphometrics. METHOD: Using the generic spine acquisition protocol and our semi-automated analysis pipeline, spinal cord morphometrics, including cross-sectional area (CSA), anterior-posterior (AP) and transverse (RL) diameters, eccentricity, and solidity, were estimated from sagittal T2w magnetic resonance imaging (MRI) images using the Spinal Cord Toolbox (SCT). Normalized metrics were extracted from the C1 to C7 vertebral levels and compared between DCM patients and HC. Morphometric data at regions of maximum spinal cord compression (MSCC) were correlated with the clinical scores. A subset of participants underwent follow-up scans at six months to monitor longitudinal changes in spinal cord atrophy. RESULTS: Spinal cord morphometric data were normalized against the healthy population morphometry (PAM50 database) and extracted for all participants. DCM patients showed a notable reduction in CSA, AP, and RL diameter across all vertebral levels compared to HC. MSCC metrics correlated significantly with clinical scores like dexterity, grip strength, and mJOA scores. Longitudinal analysis indicated a decrease in CSA and worsening clinical scores in DCM patients. CONCLUSION: Our processing pipeline offers a reliable method for assessing spinal cord compression in DCM patients. Normalized spinal cord morphometrics, particularly the CSA could have potential for monitoring DCM disease severity and progression, guiding treatment decisions. Furthermore, to our knowledge our study is the first to apply the generic spinal cord acquisition protocol, ensuring consistent imaging across different MRI scanners and settings. Coupled with our semi-automated analysis pipeline, this protocol is key for the detailed morphometric characterization of compressed spinal cords in patients with DCM, a disease that is both complex and heterogenous. This study was funded by the National Institute of Neurological Disorders and Stroke (NINDS) (K23:NS091430) and (R01: NS129852-01A1).

Influence of long-term supplementation of a formulated botanical blend on growth performance and carcass traits in feedlot steers.

Objective: The objective of this study was to determine if a formulated blend of capsicum oleoresin, clove essential oil, and garlic essential oil (Fytera® Advance - Selko® USA, Indianapolis IN; CCG) influences measures of cattle growth, efficiency, or carcass traits, during the finishing phase in steers fed a concentrate-based diet. Methods: Charolais × Angus steers (n = 96; initial shrunk BW = 391± 34.0 kg) were used in a 144-d (16 February 2023 to 9 July 2023) finishing feedlot experiment in Brookings, SD. Steers were individually weighed and allotted to one of 14 pens (6 to 7 steers; 7 pens/treatment) in a randomized complete block design and randomly assigned to 1 of 2 treatments: control diet without the test product (CON) or a diet including CCG at 500 mg/steer daily (CCG). Steers were fed twice daily, and bunks were managed according to a slick bunk system. Results: There were no differences (P ≥ 0.10) in any growth performance outcomes from d 1 to 35, 36 to 70, or 71 to 98. From d 99 to 144 steers from CCG tended to have 5% greater ADG (P = 0.09) and 8% improved G:F (P = 0.01). No differences (P ≥ 0.15) were noted for cumulative growth performance measures. No differences were noted for any carcass measurements or categorical carcass outcomes, nor lung or liver health outcomes (P ≥ 0.15). Conclusion: The use of CCG had no influence on cumulative growth performance responses. However, the use of CCG improved G:F during the late feeding period.

Evaluating the Implementation of the Pediatric Acute Care Education (PACE) Program in Northwestern Tanzania: A Mixed-Methods Study Guided by Normalization Process Theory.

Background: In low- and -middle-income countries (LMICs) like Tanzania, the competency of healthcare providers critically influences the quality of pediatric care. To address this, we introduced PACE (Pediatric Acute Care Education), an adaptive e-learning program tailored to enhance provider competency in line with Tanzania's national guidelines for managing seriously ill children. Adaptive e-learning presents a promising alternative to traditional in-service education, yet optimal strategies for its implementation in LMIC settings remain to be fully elucidated. Objectives: This study aimed to (1) evaluate the initial implementation of PACE in Mwanza, Tanzania, using the constructs of Normalization Process Theory (NPT), and (2) provide insights into its feasibility, acceptability, and scalability potential. Methods: A mixed-methods approach was employed across three healthcare settings in Mwanza: a zonal hospital and two health centers. NPT was utilized to navigate the complexities of implementing PACE. Data collection involved a customized NoMAD survey, focus groups and in-depth interviews with healthcare providers. Results: The study engaged 82 healthcare providers through the NoMAD survey and 79 in focus groups and interviews. Findings indicated high levels of coherence and cognitive participation, demonstrating that PACE is well-understood and resonates with existing healthcare goals. Providers expressed a willingness to integrate PACE into their practice, distinguishing it from existing educational methods. However, challenges related to resources and infrastructure, particularly affecting collective action, were noted. The short duration of the study limited the assessment of reflexive monitoring, though early indicators point towards the potential for PACE's long-term sustainability. Conclusion: This study offers vital insights into the feasibility and acceptability of implementing PACE in a Tanzanian context. While PACE aligns well with healthcare objectives, addressing resource and infrastructure challenges is crucial for its successful and sustainable implementation. Furthermore, the study underscores the value of NPT as a framework in guiding implementation processes, with broader implications for implementation science and pediatric acute care in LMICs.

Critical care pharmacist perspectives on optimal practice models and prioritization of professional activities: A cross-sectional survey.

DISCLAIMER: In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. PURPOSE: Critical care pharmacists (CCPs) are essential members of the multidisciplinary critical care team. Professional activities of the CCP are outlined in a 2020 position paper on critical care pharmacy services. This study looks to characterize CCP perspectives for priorities in optimizing pharmacy practice models and professional activities. METHODS: This was a cross-sectional survey conducted from July 24 to September 20, 2023. A 41-question survey instrument was developed to assess 7 domains: demographics, CCP resource utilization, patient care, quality improvement, research and scholarship, training and education, and professional development. This voluntary survey was sent to members of the American College of Clinical Pharmacy's Critical Care Practice and Research Network. The survey was open for a total of 6 weeks. RESULTS: There was a response rate of 20.7% (332 of 1,605 invitees), with 66.6% of respondents (n = 221) completing at least 90% of the survey questions. Most respondents were clinical specialists (58.2%) and/or practiced at an academic medical center (58.5%). Direct patient care, quality improvement and medication safety, and teaching and precepting were identified as the CCP activities of highest importance to CCPs. The CCP-to-patient ratios considered ideal were 1:11-15 (selected by 49.8% of respondents) and 1:16-20 (33.9% of respondents). The ideal percentage of time dedicated to direct patient care activities, as identified by survey respondents, was 50% (interquartile range, 40-50). CONCLUSION: These findings highlight the professional activities viewed as having the highest priority by CCPs. Future research is needed to define optimal CCP practice models for the delivery of patient care in real-world settings.

Encapsulated Butyric Acid and Zinc as a Feed Additive for Lambs Abruptly Transitioned to a Grain-Based Diet.

Butyric acid is attributed to gastrointestinal epithelial development and health and two studies were conducted to determine if supplementing encapsulated butyric acid and zinc (BZ) in lambs abruptly transitioned to a finishing diet has effects on growth performance, efficiency of dietary net energy utilization, rumen morphometrics, small intestinal histology, and carcass traits. Polypay wethers (n = 84; initial shrunk body weight = 38.8 kg ± 4.8 kg) were used in a randomized complete block design study. Wethers were abruptly transitioned from a high roughage-based diet to a 100% concentrate-based diet and dietary treatments were 0 or 2 g BZ/kg of diet dry matter. Study 1 evaluated growth performance and carcass traits of lambs over a 59.5 d feeding period, and Study 2 evaluated changes in rumen morphometrics and small intestine histology in serial harvested lambs. Wethers supplemented with BZ had increased body wall thickness, decreased calculated boneless closely trimmed retail cuts, and decreased red meat yield (p ≤ 0.03) compared to non-supplemented wethers. Linear effects (p ≤ 0.01) for harvest date were observed for most rumen and small intestine measurements. Supplementing wethers with BZ did not improve growth performance, carcass traits, or rumen and small intestine measurements. The effects of BZ supplementation on fat deposition in ruminants should be further investigated.

Evaluation of long-term supplementation of a Bacillus subtilis direct-fed microbial and enzymatically hydrolyzed yeast cell culture product used alone or in combination on Clostridia, Clostridium perfringens, Escherichia coli, and Salmonella prevalence in beef steers.

The objective was to determine the influence of long-term supplementation (258 d) of a direct-fed microbial (DFM) and/or yeast cell wall (YCW) product on bacterial populations in beef steers. Single-sourced Charolais × Red Angus steers (n = 256; body weight = 246 ±â€…1.68 kg) were used in a randomized complete block design and blocked by location into one of four treatments: 1) fed no DFM and no YCW (Control); 2) fed only the DFM (DFM; Certillus CP B1801 Dry, 28 g/steer d-1 ); 3) fed only the YCW (YCW; Celmanax; 18 g/steer d-1 ); and 4) fed the DFM and the YCW (DFM+YCW). Steers were vaccinated for respiratory and clostridial diseases and treated for internal and external parasites at processing and individually weighed on days 1, 14, 42, 77, 105, 133, 161, 182, 230, and 258. To determine bacterial prevalence, fecal samples were collected on days 1, 14, 77, 133, 182, and 230 and environmental (pen area, feed, and water) samples were collected at the beginning of the week when cattle were weighed. No treatment × day interactions or treatment effects (P > 0.05) were observed between treatment groups at any sampling days for the bacterial populations. Samples on days 1, 133, and 182 had greater (P < 0.05) Clostridia levels compared to the other sampling points but were not different from each other. Clostridia levels were also greater (P < 0.05) on day 77 compared to days 14 and 230. Samples on days 77 and 230 had greater (P < 0.05) Clostridium perfringens levels compared to the other sampling points but were not different (P > 0.05) from each other. Samples on days 1 and 14 had lower (P < 0.05) total Escherichia coli levels compared to the other sampling points but were not different (P > 0.05) from each other. Escherichia coli levels on day 77 were higher (P < 0.05) compared to days 133, 182, and 230. Little Salmonella prevalence (1.5%) was observed throughout the study. This study had greater levels of Clostridia compared to small and large commercial feedlots in the Church and Dwight research database, but C. perfringens, total and pathogenic E. coli, and Salmonella prevalence were notably lower. Collectively, there were no appreciable treatment influences on bacterial populations. These data further indicate a low pathogenic bacterial challenge at the trial site, which could partially explain the lack of differences with DFM or YCW supplementation. The DFM and YCW used alone or in combination cannot be expected to show additional benefits when animals are relatively unstressed with a low pathogenic bacterial challenge.

The objective of this research was to determine the influence of long-term supplementation (258 d) of a direct-fed microbial (DFM) and/or yeast cell wall (YCW) product on bacterial populations in beef steers. Collectively, there were no appreciable treatment influences on bacterial populations. These data further indicate a low pathogenic bacterial challenge at the trial site, which could further explain the reasons for little differences. The DFM and YCW used alone or in combination cannot be expected to show productive benefits when animals are relatively unstressed with a low pathogenic bacterial challenge.

Associations Among Tremor Amplitude, Activities of Daily Living, and Quality of Life in Patients with Essential Tremor.

Background: Essential tremor (ET) is a disabling syndrome consisting of tremor, primarily in the upper limbs. We assessed the correlation of The Essential Tremor Rating Assessment Scale (TETRAS) Performance Item 4 ratings of upper limb tremor with the TETRAS activities of daily living (ADL) subscale and with 2 quality of life (QoL) scales. Methods: This noninterventional, cross-sectional, point-in-time survey of neurologists(n = 60), primary care physicians (n = 38), and their patients with ET (n = 1,003) used real-world data collected through the Adelphi ET Disease Specific Programme™. Physician-reported measures (TETRAS Performance Item 4 and TETRAS ADL total) and patient-reported QoL measures (generic EuroQol-5 Dimension 5 Level [EQ-5D-5 L] and ET-specific Quality of Life in Essential Tremor Questionnaire (QUEST)) were assessed with bivariate and multivariable analyses. Sensitivity analyses were also conducted. Results: The bivariate association between TETRAS Performance Item 4 score and TETRAS ADL total score was high (Pearson r = 0.761, P < 0.001). The bivariate associations between TETRAS Performance Item 4 score and EQ-5D-5 L index score (r = -0.410, P < 0.001) and between TETRAS ADL total score and EQ-5D-5 L index score (r = -0.543, P < 0.001) were moderate. The bivariate associations between TETRAS Performance Item 4 score and QUEST total score (r = 0.457, P < 0.001), and between TETRAS ADL total score and QUEST total score (r = 0.630, P < 0.001) were also moderate. These associations were unaltered by the inclusion of covariates. Discussion: This study showed that greater tremor severity (TETRAS Performance Item 4) was positively correlated with ADL impairment (TETRAS ADL) and negatively associated with QoL (EQ-5D-5 L and QUEST). TETRAS Performance Item 4 score is a robust predictor of TETRAS ADL total score, and TETRAS Performance Item 4 and TETRAS ADL total scores were robust predictors of the 2 QoL scales. The results demonstrate the value of TETRAS scores as valid endpoints for future clinical trials. Highlights: This real-world study assessed TETRAS scores as predictors of impaired QoL in ET. TETRAS Performance Item 4 and ADL were associated with EQ-5D-5 L and QUEST. TETRAS scores may serve as valid endpoints for future clinical trials.

Evaluating osteoporosis and bone quality in the aging spine: modern considerations for surgical management in the geriatric population.

Surgical management paradigms of spinal pathologies in the aging population carry inherent substantial risks, with surgical complications being more prevalent among patients with osteoporosis compared to those with normal bone mineral density. In this narrative review, we aim to highlight important clinical understanding and considerations in perioperative evaluation and management of patients elected to undergo spinal surgery. Osteoporosis is a well-defined risk factor for mechanical complications following spinal surgery, and as such, perioperative optimization of bone health in the setting of surgery for geriatric patients remains a critical research area alongside intraoperative surgical augmentation techniques. Surgical techniques to circumvent challenges with instrumentation of poor bone mineral density have included augmentation of pedicle screw fixation, including segmental bicortical screw fixation techniques, cement augmentation with fenestrated screws, or use of expandable pedicle screws to improve bone-implant interface. Judicious selection of treatment modalities and subsequent perioperative optimization is paramount to minimize surgical complications. Contemporary guidelines and evolving paradigms in perioperative evaluation, optimization, and management of the aging spine include the advent of quantitatively evaluating computed tomography (CT) via assessment of the magnitude of Hounsfield units. Prescribing pharmacotherapeutic agents and monitoring bone health requires a multidisciplinary team approach, including endocrinologists and geriatricians to coordinate high-quality care for advanced-age patients who require surgical management of their spinal disorders.

Examining the Association Between DCT Solutions Use and Participant Diversity in Clinical Trials.

BACKGROUND: Whereas anecdotal reports suggest that the use of decentralized clinical trial (DCT) solutions can improve participant diversity in clinical trials there is no quantitative evidence to support such reports. METHODS: Tufts CSDD conducted this initial study based on data collected from prior research and publicly available data drawn from Clinicaltrials.gov to compare and contrast participant diversity in trials which included various DCT solutions - virtual visits or televisits, home visits, devices or wearables, and the use of local labs. RESULTS: The results of this analysis indicate that the use of local labs is associated with a lower percentage of white participants; the use of virtual visits or televisits is associated with a lower percentage of Black participants; and the use of devices or wearables was not associated with any significant change in participant demographics. The use of home visits could not be tested for significant differences.

New Estimates on the Cost of a Delay Day in Drug Development.

Two frequently cited figures by clinical research insiders and observers - the cost of missing a day to generate prescription drug sales and the cost of a day to conduct a clinical trial - are outdated and based on anecdotal evidence. In late 2023, the Tufts Center for the Study of Drug Development conducted empirical research to gather more accurate and granular estimates and to test whether average sales per day have changed over time. 645 drugs launched since 2000, and 409 clinical trial budgets were drawn from commercially available and proprietary data sets and analyzed. The results indicate that a single day equals approximately $500,000 in lost prescription drug or biologic sales, with daily prescription sales for infectious, hematologic, cardiovascular, and gastrointestinal diseases among the highest. The results also show that each year, the average sales per day of prescription drugs and biologics has decreased by approximately $80,000-$100,000. The estimated direct daily cost to conduct a clinical trial is approximately $40,000 per day for phase II and III clinical trials, with those in respiratory, rheumatology, and dermatology having the highest relative daily direct costs.

Single Layer Silk and Cotton Woven Fabrics for Acoustic Emission and Active Sound Suppression.

Whether intentionally generating acoustic waves or attempting to mitigate unwanted noise, sound control is an area of challenge and opportunity. This study investigates traditional fabrics as emitters and suppressors of sound. When attached to a single strand of a piezoelectric fiber actuator, a silk fabric emits up to 70 dB of sound. Despite the complex fabric structure, vibrometer measurements reveal behavior reminiscent of a classical thin plate. Fabric pore size relative to the viscous boundary layer thickness is found-through comparative fabric analysis-to influence acoustic-emission efficiency. Sound suppression is demonstrated using two distinct mechanisms. In the first, direct acoustic interference is shown to reduce sound by up to 37 dB. The second relies on pacifying the fabric vibrations by the piezoelectric fiber, reducing the amplitude of vibration waves by 95% and attenuating the transmitted sound by up to 75%. Interestingly, this vibration-mediated suppression in principle reduces sound in an unlimited volume. It also allows the acoustic reflectivity of the fabric to be dynamically controlled, increasing by up to 68%. The sound emission and suppression efficiency of a 130 µm silk fabric presents opportunities for sound control in a variety of applications ranging from apparel to transportation to architecture.

Reconstructing axial progenitor field dynamics in mouse stem cell-derived embryoids.

Embryogenesis requires substantial coordination to translate genetic programs to the collective behavior of differentiating cells, but understanding how cellular decisions control tissue morphology remains conceptually and technically challenging. Here, we combine continuous Cas9-based molecular recording with a mouse embryonic stem cell-based model of the embryonic trunk to build single-cell phylogenies that describe the behavior of transient, multipotent neuro-mesodermal progenitors (NMPs) as they commit into neural and somitic cell types. We find that NMPs show subtle transcriptional signatures related to their recent differentiation and contribute to downstream lineages through a surprisingly broad distribution of individual fate outcomes. Although decision-making can be heavily influenced by environmental cues to induce morphological phenotypes, axial progenitors intrinsically mature over developmental time to favor the neural lineage. Using these data, we present an experimental and analytical framework for exploring the non-homeostatic dynamics of transient progenitor populations as they shape complex tissues during critical developmental windows.

Prohibitin Expression in Antigen-Presenting Cells: Implications for Inciting Trigger in CNS IgG4-Related Disease.

Immunoglobulin G4-related disease (IgG4-RD) is a rare autoimmune disorder with an unknown etiology. Using orthogonal immune profiling and automated sequential multiplexing, we found an enhanced frequency of activated circulating B cells, antigen-presenting myeloid cells in peripheral blood, and a distinct distribution of immune cells within the CNS lesions. Prohibitin-expressing CD138+ plasma B cells and CD11c+ dendritic cells have been found interacting with T cells resulting in irmnune cell activation within the lesion. The data implicate prohibitin as a potential triggering antigen in the pathogenesis of IgG4-RD and shed light on the cellular dynamics and interactions driving IgG4-RD in the central nervous system, emphasizing the need for further studies corroborating these findings.

Distinct Time-Resolved Brain-Wide Coactivations in Oxygenated and Deoxygenated Hemoglobin.

OBJECTIVE: Human resting-state networks (RSNs) estimated from oxygenated (HbO) and deoxygenated hemoglobin (HbR) data exhibit strong similarities, while task-based studies show different dynamics in HbR and HbO responses. Such a discrepancy might be explained due to time-averaged estimations of RSNs. Our study investigated differences between HbO and HbR on time-resolved brain-wide coactivation patterns (CAPs). METHODS: Diffuse optical tomography was reconstructed from resting-state whole-head functional near-infrared spectroscopy data of HbR and HbO in individual healthy participants. Time-averaged RSNs were obtained using the group-level independent component analysis. Time-resolved CAPs were estimated using a clustering approach on the time courses of all obtained RSNs. Characteristics of the RSNs and CAPs from HbR and HbO were compared. RESULTS: Spatial patterns of HbR and HbO RSNs exhibited significant similarities. Meanwhile, HbR CAPs revealed much more organized spatial and dynamic characteristics than HbO CAPs. The entire set of HbR CAPs suggests a superstructure resulted from brain-wide neuronal dynamics, which is less evident in the set of HbO CAPs. These differences between HbO and HbR CAPs were consistently replicated in individual session data. CONCLUSION: Our results suggest that human resting brain-wide neuronal activations are preserved better in time-resolved brain-wide patterns, i.e., CAPs, from HbR than those from HbO, while such a difference is lost between time-averaged HbR and HbO RSNs. SIGNIFICANCE: Our results reveal, for the first time, HbR concentration fluctuations are more directly coupled with resting dynamics of brain-wide neuronal activations in human brains.

Graph Attention Site Prediction (GrASP): Identifying Druggable Binding Sites Using Graph Neural Networks with Attention.

Identifying and discovering druggable protein binding sites is an important early step in computer-aided drug discovery, but it remains a difficult task where most campaigns rely on a priori knowledge of binding sites from experiments. Here, we present a binding site prediction method called Graph Attention Site Prediction (GrASP) and re-evaluate assumptions in nearly every step in the site prediction workflow from data set preparation to model evaluation. GrASP is able to achieve state-of-the-art performance at recovering binding sites in PDB structures while maintaining a high degree of precision which will minimize wasted computation in downstream tasks such as docking and free energy perturbation.

New Benchmarks on Protocol Amendment Experience in Oncology Clinical Trials.

BACKGROUND: The drug development industry's focus on cancer-related treatments continues to rise, with narrow patient populations and complex procedures increasing the complexity of oncology protocols at an accelerated rate compared to non-oncology drugs. Tufts Center for the Study of Drug Development utilized data from a study investigating the impact of protocol amendments to compare how oncology clinical trials differ from non-oncology and identify opportunities to optimize performance in oncology clinical trials. METHODS: Sixteen drug development industry companies contributed data from 950 protocols and 2,188 amendments to a study conducted in 2022 investigating protocol amendments. Analysis compared differences in amendment impact and causes between 249 oncology and 701 non-oncology protocols. RESULTS: Compared to non-oncology, oncology protocols had a significantly higher prevalence (72.1% and 91.1%, respectively) and number (3.0 and 4.0, respectively) of protocol amendments. Oncology protocols with amendments had significantly lower participant completion rates compared to oncology protocols without amendments, while no significant differences were found among non-oncology. During the COVID-19 pandemic, the study found an increased number of substantial amendments, lower completion rates, and higher dropout rates among oncology protocols compared to before the pandemic. CONCLUSIONS: Efforts to prevent avoidable protocol amendments in the industry have not been effective in oncology, where increasingly complex designs are reflected in difficult to predict cycle times, barriers to recruitment and retention and an increase in protocol amendments.