Sublithospheric diamond ages and the supercontinent cycle.

Subduction related to the ancient supercontinent cycle is poorly constrained by mantle samples. Sublithospheric diamond crystallization records the release of melts from subducting oceanic lithosphere at 300-700 km depths1,2 and is especially suited to tracking the timing and effects of deep mantle processes on supercontinents. Here we show that four isotope systems (Rb-Sr, Sm-Nd, U-Pb and Re-Os) applied to Fe-sulfide and CaSiO3 inclusions within 13 sublithospheric diamonds from Juína (Brazil) and Kankan (Guinea) give broadly overlapping crystallization ages from around 450 to 650 million years ago. The intracratonic location of the diamond deposits on Gondwana and the ages, initial isotopic ratios, and trace element content of the inclusions indicate formation from a peri-Gondwanan subduction system. Preservation of these Neoproterozoic-Palaeozoic sublithospheric diamonds beneath Gondwana until its Cretaceous breakup, coupled with majorite geobarometry3,4, suggests that they accreted to and were retained in the lithospheric keel for more than 300 Myr during supercontinent migration. We propose that this process of lithosphere growth-with diamonds attached to the supercontinent keel by the diapiric uprise of depleted buoyant material and pieces of slab crust-could have enhanced supercontinent stability.

Ultrasensitive Raman Detection of Biomolecular Conformation at the Attomole Scale using Chiral Nanophotonics.

Understanding the function of a biomolecule hinges on its 3D conformation or secondary structure. Chirally sensitive, optically active techniques based on the differential absorption of UV-vis circularly polarized light excel at rapid characterisation of secondary structures. However, Raman spectroscopy, a powerful method for determining the structure of simple molecules, has limited capacity for structural analysis of biomolecules because of intrinsically weak optical activity, necessitating millimolar (mM) sample quantities. A breakthrough is presented for utilising Raman spectroscopy in ultrasensitive biomolecular conformation detection, surpassing conventional Raman optical activity by 15 orders of magnitude. This strategy combines chiral plasmonic metasurfaces with achiral molecular Raman reporters and enables the detection of different conformations (α-helix and random coil) of a model peptide (poly-L/D-lysine) at the ≤attomole level (monolayer). This exceptional sensitivity stems from the ability to detect local, molecular-scale changes in the electromagnetic (EM) environment of a chiral nanocavity induced by the presence of biomolecules using molecular Raman reporters. Further signal enhancement is achieved by incorporating achiral Au nanoparticles. The introduction of the nanoparticles creates highly localized regions of extreme optical chirality. This approach, which exploits Raman, a generic phenomenon, paves the way for next-generation technologies for the ultrasensitive detection of diverse biomolecular structures.

Comparison of In-person VS remote learning modalities for ultrasound-guided knee arthrocentesis training using formalin-embalmed cadavers.

OBJECTIVES: This study aims to compare the efficacy of remote versus in-person training strategies to teach ultrasound guided knee arthrocentesis using formalin embalmed cadavers. METHODS: 30 first-year medical student participants were randomly assigned to remote or in-person training groups. Pre- and post- training surveys were used to evaluate participant's self-confidence in their ability to perform the procedure. Participants were asked to watch a 30-minute training video and then attend a skills training workshop. The workshops consisted of 20 min of hands-on instruction followed by a skills assessment. RESULTS: Following training, participant self-confidence increased significantly across all survey items in both groups (p = 0.0001). No significant changes in participant self-confidence were detected between the groups. Skills and knowledge-related metrics did not differ significantly between the groups with the exception of the "knowledge of instruments" variable. CONCLUSIONS: Our data suggests that remote ultrasound-guided procedure training, although logistically complex, is a viable alternative to traditional in-person learning techniques even for a notoriously hands on skill like ultrasound guided knee arthrocentesis. Novice first-year medical student operators in the remote-training group were able to significantly increase their confidence and demonstrate competency in a manner statistically indistinguishable from those trained in-person. These results support the pedagogical validity of using remote training to teach ultrasound guided procedures which could have implications in rural and global health initiatives where educational resources are more limited.

Teaching medical students ultrasound-guided needle aspiration of synthetic cysts: effect of a formalin-embalmed cadaver simulation model.

BACKGROUND: Standard training for ultrasound-guided cyst needle aspiration is currently performed on live patients during residency. This practice presents risk of iatrogenic injury to patients and provides a high-stress learning environment for medical trainees. Simulation training using synthetic cysts in a formalin-embalmed cadaver model may allow for realistic, practical, and effective training free from patient risk. METHODS: Thirty first-year medical students viewed an orientation video, then attended a skills workshop to perform cyst needle aspiration in formalin-embalmed cadaver tissue under ultrasound guidance. Participants were randomly assigned to one of three ultrasound-trained instructor-types which included a medical student, clinical anatomist, or an ultrasound fellowship trained emergency medicine physician. After training, participants underwent a 5-min skills test to assess their ability to drain a synthetic cyst independently. Pre- and post-training self-confidence surveys were administered. RESULTS: Ultrasound images of synthetic cysts in formalin-embalmed tissue were clear and realistic in appearance, and sonographic needle visualization was excellent. Participants took an average of 161.5 s and 1.9 attempts to complete the procedure. Two of the 30 participants could not complete the procedure within the time limit. Participants' self-reported confidence with respect to all aspects of the procedure significantly increased post-training. Mean confidence scores rose from 1.2 (95% CI 0.96 to 1.39) to 4.4 (95% CI 4.09 to 4.53) (P < 0.0001) Procedure time, number of attempts, performance scores, and self-confidence outcomes were not significantly affected by instructor type. CONCLUSIONS: The use of synthetic cysts in formalin-embalmed cadaveric tissue is feasible, realistic, and efficacious for the teaching of ultrasound-guided needle aspiration to novice medical trainees. This simulation training method can be delivered effectively by multiple instructor types and may allow medical trainees to increase their tactical skill and self-confidence prior to performing ultrasound-guided cyst needle aspiration on live patients.

A Delphi-method-based consensus guideline for definition of treatment-resistant depression for clinical trials.

Criteria for treatment-resistant depression (TRD) and partially responsive depression (PRD) as subtypes of major depressive disorder (MDD) are not unequivocally defined. In the present document we used a Delphi-method-based consensus approach to define TRD and PRD and to serve as operational criteria for future clinical studies, especially if conducted for regulatory purposes. We reviewed the literature and brought together a group of international experts (including clinicians, academics, researchers, employees of pharmaceutical companies, regulatory bodies representatives, and one person with lived experience) to evaluate the state-of-the-art and main controversies regarding the current classification. We then provided recommendations on how to design clinical trials, and on how to guide research in unmet needs and knowledge gaps. This report will feed into one of the main objectives of the EUropean Patient-cEntric clinicAl tRial pLatforms, Innovative Medicines Initiative (EU-PEARL, IMI) MDD project, to design a protocol for platform trials of new medications for TRD/PRD.

Structure and Functional Characterization of a Humanized Anti-CCL20 Antibody following Exposure to Serum Reveals the Formation of Immune Complex That Leads to Toxicity.

mAbs have revolutionized the treatment of autoimmune disorders. Even though mAbs have shown impressive efficacy in blocking T cell or B cell activation and/or recruitment to sites of inflammation, this group of biologicals are not devoid of adverse effects. The most serious adverse effects include infusion reactions, including the activation of the complement pathway. In this study, we present a detailed structure-function study of an anti-CCL20 humanized IgG1 mAb that neutralizes CCL20 chemokine and prevents the recruitment of Th17 cells to sites of inflammation. We demonstrate that the anti-CCL20 Ab changes significantly following administration to humans and monkeys and exposure to human serum. Analysis of the drug product revealed that the anti-CCL20 Ab has unexpectedly high C1q binding. This high binding was linked to immune complex formation in vivo but not during in vitro serum incubation. The immune complex contained multiple complement components. Anti-CCL20 Ab-mediated, complement-dependent cytotoxicity occurred when the Ab bound to CCL20 tethered to the cell membrane of target cells. Taken together, these results provide a likely cause for the animal toxicity observed. In addition, anti-CCL20 revealed progressive acidification because of N100 (located in CDR) deamidation over time, which did not directly impact Ag binding. Our study demonstrates that the safety profiling of mAbs should include the evaluation of effector functions in addition to typical stressed conditions.

Perspectives on informative Bayesian methods in pediatrics.

Bayesian methods have been proposed as a natural fit for pediatric extrapolation, as they allow the incorporation of relevant external data to reduce the required sample size and hence trial burden for the pediatric patient population. In this paper we will discuss our experience and perspectives with these methods in pediatric trials. We will present some of the background and thinking underlying pediatric extrapolation and discuss the use of Bayesian methods within this context. We will present two recent case examples illustrating the value of a Bayesian approach in this setting and present perspectives on some of the issues that we have encountered in these and other cases.

A longitudinal rat model for assessing postoperative recovery and bone healing following tibial osteotomy and plate fixation.

BACKGROUND: Rodent models are commonly employed to validate preclinical disease models through the evaluation of postoperative behavior and allodynia. Our study investigates the dynamic interplay between pain and functional recovery in the context of traumatic osteotomy and surgical repair. Specifically, we established a rat model of tibial osteotomy, followed by internal fixation using a 5-hole Y-plate with 4 screws, to explore the hypothesis that histological bone healing is closely associated with functional recovery. OBJECTIVE: Our primary objective was to assess the correlation between bone healing and functional outcomes in a rat model of tibial osteotomy and plate fixation. METHODS: Seventeen male Sprague-Dawley rats underwent a metaphyseal transverse osteotomy of the proximal tibia, simulating a fracture-like injury. The resultant bone defect was meticulously repaired by realigning and stabilizing the bone surfaces with the Y-plate. To comprehensively assess recovery and healing, we performed quantitative and qualitative evaluations at 2, 4, 6, and 8 weeks post-surgery. Evaluation methods included micro-CT imaging, X-ray analysis, and histological examination to monitor bone defect healing. Concurrently, we employed video recording and gait analysis to evaluate functional recovery, encompassing parameters such as temporal symmetry, hindlimb duty factor imbalance, phase dispersion, and toe spread. RESULTS: Our findings revealed complete healing of the bone defect at 8 weeks, as confirmed by micro-CT and histological assessments. Specifically, micro-CT data showed a decline in fracture volume over time, indicating progressive healing. Histological examination demonstrated the formation of new trabecular bone and the resolution of inflammation. Importantly, specific gait analysis parameters exhibited longitudinal changes consistent with bone healing. Hindlimb duty factor imbalance, hindlimb temporal symmetry, and phase dispersion correlated strongly with the healing process, emphasizing the direct link between bone healing and functional outcomes. CONCLUSIONS: The establishment of this tibia osteotomy model underscores the association between bone healing and functional outcomes, emphasizing the feasibility of monitoring postoperative recovery using endpoint measurements. Our overarching objective is to employ this model for assessing the local efficacy of drug delivery devices in ameliorating post-surgical pain and enhancing functional recovery.

ERCP in patients with prior sphincterotomy has a 50% lower rate of post-ERCP pancreatitis and fewer unplanned hospital admissions.

OBJECTIVES: ERCP is essential in managing pancreaticobiliary disease, with well-documented complications. Rates of clinically significant complications are about 10%, approximately half of which is related to post-ERCP pancreatitis (PEP). We aimed to quantify the effect of previous sphincterotomy on post-endoiscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP). MATERIALS AND METHODS: Data were collated from a contemporaneously collected database of 2876 consecutive ERCP procedures of a single operator in a tertiary referral centre. Analysis was conducted using R software, and logistic regression models. RESULTS: Of 2876 procedures (mean age 63 years, 56% female), 120 (4.2%) developed PEP and 268 (9.3%) had prolonged/unplanned hospital admission. Univariate analysis showed patients with previous sphincterotomy 28/1054 (2.7%) had decreased risk of PEP compared with those without sphincterotomy 92/1822 (5.0%) (OR 0.52, p = .0021). This difference was not evident when multivariate analysis for age, sex and indication was undertaken due to a particularly low risk of PEP in stent change patients (1.4%), which were disproportionately represented in the previous sphincterotomy group. The rate of prolonged/unplanned hospital admission was recorded for a total of 2876 patients, occurring in 184/1802 (10.1%) in the native ampulla group, versus 84/1045 (8.0%) in the previous sphincterotomy group. CONCLUSIONS: The risk of PEP is halved by prior sphincterotomy. The presence of a biliary stent conferred an even lower risk of PEP (1.4%), but those without an in situ stent at the time of ERCP had a similar risk of PEP (4.6%) of prolonged/unplanned hospitalisation to those with a native ampulla.

Slab melting as a barrier to deep carbon subduction.

Interactions between crustal and mantle reservoirs dominate the surface inventory of volatile elements over geological time, moderating atmospheric composition and maintaining a life-supporting planet. While volcanoes expel volatile components into surface reservoirs, subduction of oceanic crust is responsible for replenishment of mantle reservoirs. Many natural, 'superdeep' diamonds originating in the deep upper mantle and transition zone host mineral inclusions, indicating an affinity to subducted oceanic crust. Here we show that the majority of slab geotherms will intersect a deep depression along the melting curve of carbonated oceanic crust at depths of approximately 300 to 700 kilometres, creating a barrier to direct carbonate recycling into the deep mantle. Low-degree partial melts are alkaline carbonatites that are highly reactive with reduced ambient mantle, producing diamond. Many inclusions in superdeep diamonds are best explained by carbonate melt-peridotite reaction. A deep carbon barrier may dominate the recycling of carbon in the mantle and contribute to chemical and isotopic heterogeneity of the mantle reservoir.