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Abstract Background African children with severe malaria are at increased risk of non-typhoidal salmonellae co-infection. Broad-spectrum antibiotics are recommended by guidelines but the optimal class and dose have not been established. We investigated the optimal dose of oral dispersible azithromycin and whether simple clinical criteria and point-of-care biomarkers could target antibiotics to those at greatest risk of bacterial co-infection. Methods We conducted a phase I/II trial in Ugandan children with severe malaria comparing a 5-day course of azithromycin: 10, 15 and 20 mg/kg of azithromycin (prescribed by weight bands) spanning the dose-range effective for other salmonellae infection. We generated relevant pharmacokinetic (PK) data by sparse sampling during dosing intervals and investigated associations between azithromycin exposure and potential mechanisms (PK-pharmacodynamics) using change in C-reactive protein (CRP), a putative marker of sepsis, at 72 h (continuous) and microbiological cure (7-day) (binary), alone and as a composite with 7-day and 90-day survival. To assess whether clinical or biomarkers could identify those at risk of sepsis, a non-severe malaria control was concurrently enrolled. Results Between January 2020 and January 2022, 105 cases were randomised azithromycin doses: 35 to 10 mg/kg, 35 to 15 mg/kg and 35 to 20 mg/kg. Fifty non-severe malaria controls were concurrently enrolled. CRP reduced in all arms by 72 h with a mean reduction of 65.8 mg/L (95% CI 57.1, 74.5) in the 10 mg/kg arm, 64.8 mg/L (95% CI 56.5, 73.1; p = 0.87) in the 20 mg/kg arm and a smaller reduction 51.2 mg/L (95% CI 42.9, 59.5; p = 0.02) in the 15 mg/kg arm. Microbiological cure alone outcome was not analysed as only one pathogen was found among cases. Three events contributed to the composite outcome of 7-day survival and microbiological cure, with no events in the 15 mg/kg arm. The odds ratio comparing 20 vs 10 mg/kg was 0.50 (95% CI 0.04, 5.79); p = 0.58. Due to the low number of pathogens identified, it was not possible to identify better methods for targeting antibiotics including both the cases and controls. Conclusions We found no evidence for an association between systemic azithromycin exposure and reduction in CRP. Further work is needed to better identify children at highest risk from bacterial co-infection. Trial registration ISRCTN49726849 (registered on 27th October 2017).

Abstract Background Workplace-based assessment (WBA) can facilitate evaluation of operative performance; however, implementation of WBA is sometimes unsuccessful. The American Board of Surgery Entrustable Professional Activities WBA project was launched in July 2023. Some programs will face the challenge of re-implementation of a WBA following previous failures. It is unknown what interventions are most effective for WBA re-implementation. Our goal is to identify barriers and facilitators to re-implementing SIMPL, an operative performance WBA. Methods The System for Improving and Measuring Procedural Learning (SIMPL) was implemented at our residency in 2018, but usage rates were low. We interviewed residents and faculty to identify barriers to usage and opportunities for improvement. Residents reported that SIMPL usage declined because of several factors, including a low faculty response rate, while some faculty reported not responding because they were unable to login to the app and because usage was not mandated. We then re-implemented SIMPL using a plan based on Kotter’s Model of Change. To evaluate impact, we analyzed rates of SIMPL usage when it was first implemented, as well as before and after the date of re-implementation. Results In September 2022, we re-implemented SIMPL at our program with measures addressing the identified barriers. We found that, in the six months after re-implementation, an average of 145.8 evaluations were submitted by residents per month, compared with 47 evaluations per month at the start of the original implementation and 5.8 evaluations per month just prior to re-implementation. Faculty completed 60.6% of evaluations and dictated feedback for 59.1% of these evaluations, compared with 69.1% at implementation (44% dictated) and 43% prior to re-implementation (53% dictated). Conclusions After identifying barriers to implementation of a WBA, we re-implemented it with significantly higher usage by faculty and residents. Future opportunities exist to implement or re-implement assessment tools within general surgery programs. These opportunities may have a significant impact in the setting of national standardization of workplace-based assessment among general surgery residencies.

Oxygenated organic molecules (OOMs) play an important role in the formation of atmospheric aerosols. Due to various analytical challenges with respect to measuring organic vapors, uncertainties remain regarding the formation and fate of OOMs. The chemical ionization Orbitrap (CI-Orbitrap) mass spectrometer has recently been shown to be a powerful technique that is able to accurately identify gaseous organic compounds due to its greater mass resolution. Here, we present the ammonium-ion-based CI-Orbitrap (NH4+-Orbitrap) as a technique capable of measuring a wide range of gaseous OOMs. The performance of the NH4+-Orbitrap is compared with that of state-of-the-art mass spectrometers, including a nitrate-ion-based chemical ionization atmospheric pressure interface coupled to a time-of-flight mass spectrometer (NO3--LTOF), a new generation of proton transfer reaction-TOF mass spectrometer (PTR3-TOF), and an iodide-based CI-TOF mass spectrometer equipped with a Filter Inlet for Gases and AEROsols (I−-CIMS). The instruments were deployed simultaneously in the Cosmic Leaving OUtdoors Droplets (CLOUD) chamber at the European Organization for Nuclear Research (CERN) during the CLOUD14 campaign in 2019. Products generated from α-pinene ozonolysis under various experimental conditions were simultaneously measured by the mass spectrometers. The NH4+-Orbitrap was able to identify the widest range of OOMs (i.e., O ≥ 2), from less-oxidized species to highly oxygenated organic molecules (HOMs). Excellent agreement was found between the NH4+-Orbitrap and the NO3--LTOF with respect to characterizing HOMs and with the PTR3-TOF for the less-oxidized monomeric species. OOM concentrations measured by NH4+-Orbitrap were estimated using calibration factors derived from the OOMs with high time-series correlations during the side-by-side measurements. As with the other mass spectrometry techniques used during this campaign, the detection sensitivity of the NH4+-Orbitrap to OOMs is greatly affected by relative humidity, which may be related to changes in ionization efficiency and/or multiphase chemistry. Overall, this study shows that NH4+-ion-based chemistry associated with the high mass resolution of the Orbitrap mass analyzer can measure almost all inclusive compounds. As a result, it is now possible to cover the entire range of compounds, which can lead to a better understanding of the oxidation processes.

Zinc fingers represent a highly diverse structural domain, with P53 being a notable example among zinc-dependent transcription factors. The folding patterns of proteins in the cell are heavily influenced by the concentration of zinc. The potential for zinc loss arises due to its dysregulation and the frequent occurrence of tumorigenic P53 mutations. This could lead to significant consequences such as protein misfolding and a reduction in tumor-suppressing capabilities. To gain deeper insights into the structural conformation, stability, flexibility, and compactness of the zinc-binding mutation C176F, a comprehensive comparative computational analysis was conducted on the wildtype (WT) and mutant (MT) P53 in the presence (Holo) and absence (Apo) of zinc. This analysis was performed using molecular dynamic simulation. The overall observation was that the mutation in C176F reduces the metal binding affinity and results in less stability in the Apo and Holo P53 MT protein.

Background Even on the best antimalarial treatments (injectable artesunate) African children with severe malaria have poor outcomes with most deaths occurring early in the course of hospital admission ( 2mmol/l). Three intravenous doses will be given at admission (0 hours), 8 and 16 hours. APPT will be measured 1 hour after each dose (to assess maximum toxicity). Studying 20 children will allow sufficient data on safety to be generated across a range of doses to identify the maximum tolerated dose (MTD) using the Continual Reassessment Method, which adapts or informs subsequent doses for each child based on the data from previously enrolled children. The MTD will be identified based on the dose-toxicity model updated by each previous patient’s APTT results using standard methods. Conclusions The results of the Phase I trial will identify the final dose to be tested in a Phase II trial in terms of both efficacy and safety outcomes. Registration PACTR number: 202007890194806 (date 20/07/2020) ISRCTN32271864 (date 28/07/2021)

Introduction: Post-traumatic stress symptoms (PTSS) have been shown to negatively impact treatment outcomes in outpatient settings, but few have investigated in acute settings, such as partial hospital programs (PHP). The present study examined how PTSS may influence treatment outcomes– depression, anxiety, overall functioning– among patients attending a PHP. Methods: 1298 (Female n = 728) adults underwent standard transdiagnostic treatment at a PHP in which patients attend the day-long program for approximately 2 weeks for stabilization primarily focused on mood and anxiety symptoms. We utilized previously validated questionnaires to measure PTSD severity (PCL-5), anxiety (GAD-7), depression (PHQ-9), and overall functioning (WSAS). Linear regression analyses were conducted to determine the degree of improved symptoms and functioning across three trauma groups: patients with no trauma history, patients with trauma exposure, and patients who had severe PTSS. Results: Patients in the PTSS group were more likely to endorse higher depression and anxiety symptoms, as well as functional impairment at admission. Severe PTSS, not trauma exposure, predicted less improvement of depression, anxiety, and overall functioning at discharge. Limitations: Due to the nature of the private hospital, results may not generalize to a wider clinical population. Further, we were unable to test any potential mechanisms because the current naturalistic treatment study relied on a deidentified clinical database that was not designed with these research questions. Conclusions: Severe PTSS above and beyond anxiety and depression symptoms potentially serve as predictors of treatment outcomes in acute psychiatric settings such as PHPs, further emphasizing the need for enhanced trauma-informed care.

Assessing B cell affinity to pathogen‐specific antigens prior to or following exposure could facilitate the assessment of immune status. Current standard tools to assess antigen‐specific B cell responses focus on equilibrium binding of the secreted antibody in serum. These methods are costly, time‐consuming, and assess antibody affinity under zero force. Recent findings indicate that force may influence BCR‐antigen binding interactions and thus immune status. Herein, a simple laminar flow microfluidic chamber in which the antigen (hemagglutinin of influenza A) is bound to the chamber surface to assess antigen‐specific BCR binding affinity of five hemagglutinin‐specific hybridomas from 65 to 650 pN force range is designed. The results demonstrate that both increasing shear force and bound lifetime can be used to enrich antigen‐specific high‐affinity B cells. The affinity of the membrane‐bound BCR in the flow chamber correlates well with the affinity of the matched antibodies measured in solution. These findings demonstrate that a microfluidic strategy can rapidly assess BCR‐antigen‐binding properties and identify antigen‐specific high‐affinity B cells. This strategy has the potential to both assess functional immune status from peripheral B cells and be a cost‐effective way of identifying individual B cells as antibody sources for a range of clinical applications.

Through employing critical race theory, seen-invisibility, and circuits of dispossession as theoretical frames, this article complicates discourses around equity and Black student achievement by examining the underexplored experiences of high-achieving Black Canadian students in the Greater Toronto Area (GTA). Drawing on focus group data with four adolescent participants, the study finds that they experienced violent forms of racialization in their educational environments through a lack of physical, social, and intellectual space to exist as both Black and high-achieving. This rendered them persistently present due to their race, yet invisible in the perceptions of their intellect. Central to this article is an articulation, unpacking, and thus granular analysis of the particular ways that racialization can operate within education systems to "still" marginalize Black students and erect complex barriers--"even when" they demonstrate strong academic performance. These emerging insights inform a need for a broader and more holistic understanding of Black Canadian student experiences and a rethinking of intervention and resistance strategies.

Background African children with cerebral malaria and seizures caused Plasmodium falciparum are at greater risk of poor outcomes including death and neurological sequelae. The agonal events are severe hypoventilation and respiratory arrest often triggered by seizures. We hypothesised that prophylactic anti-seizure medication (ASM) could avert ‘spikes’ of intracranial pressure during or following seizures and that adequate ventilation could be supported by biphasic Cuirass Ventilation (BCV) which requires no intubation. Methods A Phase I trial conducted in Kilifi, Kenya designed to provide data on safety, feasibility and preliminary data on seizure control using prophylactic ASM (levetiracetam) and BCV as non-invasive ventilatory support in children with cerebral malaria. Children aged 3 months to 12-years hospitalised with P falciparum malaria (positive rapid diagnostic test or a malaria slide), a Blantyre Coma Score ≤2 and a history of acute seizures in this illness are eligible for the trial. In a phased evaluation we will study i) BCV alone for respiratory support (n=10); ii) prophylactic LVT: 40mg/kg loading dose then 30mg/kg every 12 hours given via nasogastric tube for 72 hours (or until fully conscious) plus BCV support (n=10) and; iii) prophylactic LVT: 60mg/kg loading dose then 45mg/kg every 12 hours given via nasogastric tube for 72 hours (or until fully conscious) plus BCV support (n=10). Primary outcome measure: cumulative time with a clinically detected seizures or number of observed seizures over 36 hours. Secondary outcomes will be assessed by feasibility or ability to implement BCV, and recovery from coma within 36 hours. Safety endpoints include: aspiration during admission; death at 28 days and 180 days; and de-novo neurological impairments at 180 days. Conclusions This is a Phase I trial largely designed to test the feasibility, tolerability and safety of using non-invasive ventilatory support and LVT prophylaxis in cerebral malaria. Registration ISRCTN76942974 (5.02.2019); PACTR202112749708968 (20.12.2021).

ABSTRACT Biogenic methane in subsurface coal seam environments is produced by diverse consortia of microbes. Although this methane is useful for global energy security, it remains unclear which microbes can liberate carbon from the coal. Most of this carbon is relatively resistant to biodegradation, as it is contained within aromatic rings. Thus, to explore for coal-degrading taxa in the subsurface, this study reconstructed relevant metagenome-assembled genomes (MAGs) from coal seams by using a key genomic marker for the anaerobic degradation of monoaromatic compounds as a guide: the benzoyl-CoA reductase gene (bcrABCD). Three MAGs were identified with this genetic potential. The first represented a novel taxon from the Krumholzibacteriota phylum, which this study is the first to describe. This Krumholzibacteriota MAG contained a full set of genes for benzoyl-CoA dearomatization, in addition to other genes for anaerobic catabolism of monoaromatics. Analysis of Krumholzibacteriota MAGs from other environments revealed that this genetic potential may be common, and thus, Krumholzibacteriota may be important organisms for the liberation of recalcitrant carbon in a broad range of environments. Moreover, the assembly and characterization of two Syntrophorhabdus aromaticivorans MAGs from different continents and a Syntrophaceae sp. MAG implicate the Deltaproteobacteria class in coal seam monoaromatic degradation. Each of these taxa are potential rate-limiting organisms for subsurface coal-to-methane biodegradation. Their description here provides some understanding of their function within the coal seam microbiome and will help inform future efforts in coal bed methane stimulation, anoxic bioremediation of organic pollutants, and assessments of anoxic, subsurface carbon cycling and emissions.IMPORTANCESubsurface coal seams are highly anoxic, oligotrophic environments, where the main source of carbon is “locked away” within aromatic rings. Despite these challenges, many coal seams accumulate biogenic methane, implying that the coal seam microbiome is “unlocking” this carbon source in situ. For over two decades, researchers have endeavored to understand which organisms perform these processes. This study provides the first descriptions of organisms with this genetic potential from the coal seam environment. Here, we report metagenomic insights into carbon liberation from aromatic molecules and the degradation pathways involved and describe a Krumholzibacteriota, two Syntrophorhabdus aromaticivorans, and a Syntrophaceae MAG that contain this genetic potential. This is also the first time that the Krumholzibacteriota phylum has been implicated in anaerobic dearomatization of aromatic hydrocarbons. This potential is identified here in numerous MAGs from other terrestrial and marine subsurface habitats, implicating the Krumholzibacteriota in carbon-cycling processes across a broad range of environments.

Background and purposeImplementing any radiopharmaceutical therapy (RPT) program requires a comprehensive review of system readiness, appropriate workflows, and training to ensure safe and efficient treatment delivery. A quantitative assessment of the dose delivered to targets and organs at risk (OAR) using RPT is possible by correlating the absorbed doses with the delivered radioactivity. Integrating dosimetry into an established RPT program demands a thorough analysis of the necessary components and system fine-tuning. This study aims to report an optimized workflow for molecular radiation therapy using 177Lu with a primary focus on integrating patient-specific dosimetry into an established radiopharmaceutical program in a radiation oncology setting.Materials and methodsWe comprehensively reviewed using the Plan–Do–Check–Act (PDCA) cycle, including efficacy and accuracy of delivery and all aspects of radiation safety of the RPT program. The GE Discovery SPECT/CT 670DR™ system was calibrated per MIM protocol for dose calculation on MIM SurePlan™ MRT software. Jaszcak Phantom with 15–20 mCi of 177Lu DOTATATE with 2.5 µM EDTA solution was used, with the main energy window defined as 208 keV ±10% (187.6 to 229.2 keV); the upper scatter energy window was set to 240 keV ±5% (228 to 252 keV), while the lower scatter energy window was 177.8 keV ±5% (168.9 to 186.7 keV). Volumetric quality control tests and adjustments were performed to ensure the correct alignment of the table, NM, and CT gantry on SPECT/CT. A comprehensive end-to-end (E2E) test was performed to ensure workflow, functionality, and quantitative dose accuracy.ResultsWorkflow improvements and checklists are presented after systematically analyzing over 400 administrations of 177Lu-based RPT. Injected activity to each sphere in the NEMA Phantom scan was quantified, and the MIM Sureplan MRT reconstruction images calculated activities within ±12% of the injected activity. Image alignment tests on the SPECT/CT showed a discrepancy of more than the maximum tolerance of 2.2 mm on any individual axis. As a result of servicing the machine and updating the VQC and COR corrections, the hybrid imaging system was adjusted to achieve an accuracy of

Background Children hospitalised with severe acute malnutrition (SAM) are frequently complicated (>50%) by diarrhoea ( ≥3 watery stools/day) which is accompanied by poor outcomes. Rehydration guidelines for SAM are exceptionally conservative and controversial, based upon expert opinion. The guidelines only permit use of intravenous fluids for cases with advanced shock and exclusive use of low sodium intravenous and oral rehydration solutions (ORS) for fear of fluid and/or sodium overload. Children managed in accordance to these guidelines have a very high mortality. The proposed GASTROSAM trial will reappraise current recommendations with mortality as the primary outcome. We hypothesize that liberal rehydration strategies for both intravenous and oral rehydration in SAM children with diarrhoea may reduce adverse outcomes. Methods An open Phase II trial, with a partial factorial design, enrolling children in Uganda, Kenya, Nigeria and Niger aged 6 months to 12 years with SAM hospitalised with gastroenteritis (>3 loose stools/day) and signs of moderate and severe dehydration. In Stratum A (severe dehydration) children will be randomised (1:1:2) to WHO plan C (100mls/kg Ringers Lactate (RL) with intravenous rehydration (IV) given over 3-6 hours according to age including boluses for shock), slow rehydration (100 mls/kg RL over 8 hours (no boluses)) or WHO SAM rehydration regime (ORS only (boluses for shock (standard of care)). Stratum B incorporates all children with moderate dehydration and severe dehydration post-intravenous rehydration and compares (1:1 ratio) standard WHO ORS given for non-SAM (experimental) versus WHO SAM-recommended low-sodium ReSoMal. The primary outcome for intravenous rehydration is mortality to 96 hours and for oral rehydration a change in sodium levels at 24 hours post-randomisation. Secondary outcomes include measures assessing safety (evidence of pulmonary oedema or heart failure); change in sodium from post-iv levels for those in Stratum A; perturbations of electrolyte abnormalities (severe hyponatraemia

Over the past decade, medical education has shifted from a time-based approach to a competency-based approach for surgical training. This transition presents many new systemic challenges. The Society for Improving Medical Professional Learning (SIMPL) was created to respond to these challenges through coordinated collaboration across an international network of medical educators. The primary goal of the SIMPL network was to implement a workplace-based assessment and feedback platform. To date, SIMPL has developed, implemented, and sustained a platform that represents the earliest and largest effort to support workplace-based assessment at scale. The SIMPL model for collaborative improvement demonstrates a potential approach to addressing other complex systemic problems in medical education.

In this study, we fabricated a divergent strategy to enhance the electrochemical capacitive properties of electrodes via the cost-effective multistep green and facile electrodeposition and brush coating technique of PEDOT-TiO2/GO/PEDOT-TiO2 composite. The synthesised composite showed both EDLCs and pseudocapacitive behaviour with a good specific capacitance of 501 Fg−1 for sandwiched structure at 1 Ag−1. From the results, synthesized composite has a better ion transportation mechanism which leads to a fast charge–discharge cycle as well as a very high value of power density (500 kW/ kg) suitable for supercapacitor applications. The substance demonstrated excellent electrochemical stability, retaining 94 % of capacitance after 2000 cycles. The obtained nanocomposites were examined by FTIR, XRD, Raman, SEM-EDX and electrochemical analyses such as CV, GCD and EIS analyses. We consider that the highly stable PEDOT-TiO2/GO/PEDOT-TiO2 nanocomposite with super-capacitive behaviours is a very promising material for high-performance electrochemical storage.

Oxygenated organic molecules (OOMs) are dominated by the N-containing species in polluted urban environments. As N-containing OOMs, especially those with more than one nitrogen atom, prevail in the high m/z (mass-to-charge) range (m/z> 350 Th), unambiguous identification of N-containing OOMs is highly desirable for understanding of their formation processes, precursors and influencing factors. To achieve this, we applied an ultra-high-resolution chemical-ionization Orbitrap (CI-Orbitrap) in a field campaign and found that OOMs contain one (1N-OOMs), two (2N-OOMs) and three (3N-OOMs) nitrogen atoms comprised 50 %, 26 % and 4 %, respectively, of total OOMs. More interestingly, the fraction of 2N-OOMs increased with the increase in carbon number (nC) and was dominated by the ones derived from aliphatic precursors (2N-OOMAli, 64.2 %), indicating the importance of multistep oxidation. Plausible precursors of 2N-OOMs were aliphatics (2N-OOMAli, 64.2 %), aromatics (2N-OOMAro, 16 %) and monoterpenes (2N-OOMMT, 15.4 %). The absolute concentrations of 2N-OOMs were greatly affected by the pollution level for most cases. The 2N-OOMAli was the most abundant 2N-OOM, and its fraction even increased on the polluted day with an enhanced proportion of the ones with nC >10. While 2N-OOMAli and 2N-OOMAro were dominated by daytime photochemical production, nighttime NO3-initiated oxidation played a comparable role to the daytime photochemistry in the formation of 2N-OOMMT. The 2N-OOMAro species were of the highest oxygenation level, followed by 2N-OOMMT and 2N-OOMAli, which were affected by photochemistry and NOx concentrations. These results highlight the significant formation of 2N-OOMs and the influencing factors on their formation in polluted urban environments, where various volatile organic compound (VOC) precursors and atmospheric oxidants are present.

To align with climate initiatives, multiple reporting programs are transitioning from generic activity-based emission factors to site-specific measured emissions data to estimate greenhouse gas emissions at oil and gas facilities. This study contemporaneously deployed two top-down (TD) aerial methods across 14 midstream facilities, building upon previous research in the field. The methods produced multiple whole-facility estimates at each facility, resulting in 773 individual paired estimates (same facility, same day), and robust mean estimates for each facility. Mean estimates for each facility, aggregated across all facilities, differed by nearly 2:1 (49% [32% to 69%]). At 6 of 14 facilities, the methods produced mean estimates that differed by more than a factor of two. These data suggest that one or both methods did not produce accurate facility-level estimates at a majority of facilities and in aggregate across all facilities. The overall results are augmented with two case studies where TD estimates at two pre-selected facilities were coupled with comprehensive onsite measurements to understand the factors driving the divergence between TD and bottom-up (BU) emissions estimates. In 3 of 4 paired comparisons between the intensive onsite estimates and one of the TD methods, the intensive onsite surveys did not conclusively diagnose the difference in estimates. In these cases, our work suggests that the TD methods mis-estimate emissions an unknown fraction of the time, for unknown reasons. While two methods were selected for this study, it is unlikely that the issues identified here are confined to these two methods; similar issues may exist for other similar whole-facility methods on midstream and/or other facility types. These findings have important implications for the construction of voluntary and regulatory reporting programs that rely on emission estimates for reporting fees or penalties, or for studies using whole-facility estimates to aggregate TD emissions to basin or regional estimates.

ObjectiveMost of the work in terms of liquid biopsies in patients with solid tumors is focused on circulating tumor DNA (ctDNA). Our aim was to evaluate the feasibility of using circulating tumor cells (CTCs) in peripheral blood samples from patients with advanced or metastatic gastrointestinal (GI) cancers.MethodsIn this prospective study, blood samples were collected from each patient in 2 AccuCyte® blood collection tubes and each tube underwent CTC analysis performed utilizing the RareCyte® platform. The results from both tubes were averaged and a total of 150 draws were done, with 281 unique reported results. The cadence of sampling was based on convenience sampling and piggybacked onto days of actual clinical follow-ups and treatment visits. The CTC results were correlated with patient- and tumor-related variables.ResultsData from a total of 59 unique patients were included in this study. Patients had a median age of 58 years, with males representing 69% of the study population. More than 57% had received treatment prior to taking blood samples. The type of GI malignancy varied, with more than half the patients having colorectal cancer (CRC, 54%) followed by esophageal/gastric cancer (17%). The least common cancer was cholangiocarcinoma (9%). The greatest number of CTCs were found in patients with colorectal cancer (Mean: 15.8 per 7.5 ml; Median: 7.5 per 7.5 ml). In comparison, patients with pancreatic cancer (PC) had considerably fewer CTCs (Mean: 4.2 per 7.5 ml; Median: 3 per 7.5 ml). Additionally, we found that patients receiving treatment had significantly fewer CTCs than patients who were not receiving treatment (Median 2.7 versus 0.7). CTC numbers showed noteworthy disparities between patients with responding/stable disease in comparison to those with untreated/progressive disease (Median of 2.7 versus 0). When CTCs were present, biomarker analyses of the four markers human epidermal growth factor receptor 2 (HER2)/programmed death-ligand 1 (PD-L1)/Kiel 67 (Ki-67)/epidermal growth factor receptor (EGFR) was feasible. Single cell sequencing confirmed the tumor of origin.ConclusionOur study is one of the first prospective real-time studies evaluating CTCs in patients with GI malignancies. While ctDNA-based analyses are more common in clinical trials and practice, CTC analysis provides complementary information from a liquid biopsy perspective that is of value and worthy of continued research.

Background Even on the best antimalarial treatments (injectable artesunate) African children with severe malaria have poor outcomes with most deaths occurring early in the course of hospital admission ( 2mmol/l). Three intravenous doses will be given at admission (0 hours), 8 and 16 hours. APPT will be measured 1 hour after each dose (to assess maximum toxicity). Studying 20 children will allow sufficient data on safety to be generated across a range of doses to identify the maximum tolerated dose (MTD) using the Continual Reassessment Method, which adapts or informs subsequent doses for each child based on the data from previously enrolled children. The MTD will be identified based on the dose-toxicity model updated by each previous patient’s APTT results using standard methods. Conclusions The results of the Phase I trial will identify the final dose to be tested in a Phase II trial in terms of both efficacy and safety outcomes. Registration PACTR number: 202007890194806 (date 20/07/2020) ISRCTN32271864 (date 28/07/2021)

Abstract Background Common bile duct exploration (CBDE) is safe and effective for managing choledocholithiasis, but most US general surgeons have limited experience with CBDE and are uncomfortable performing this procedure in practice. Surgical trainee exposure to CBDE is limited, and their learning curve for achieving autonomous, practice-ready performance has not been previously described. This study tests the hypothesis that receipt of one or more prior CBDE operative performance assessments, combined with formative feedback, is associated with greater resident operative performance and autonomy. Methods Resident and attending assessments of resident operative performance and autonomy were obtained for 189 laparoscopic or open CBDEs performed at 28 institutions. Performance and autonomy were graded along validated ordinal scales. Cases in which the resident had one or more prior CBDE case evaluations (n = 48) were compared with cases in which the resident had no prior evaluations (n = 141). Results Compared with cases in which the resident had no prior CBDE case evaluations, cases with a prior evaluation had greater proportions of practice-ready or exceptional performance ratings according to both residents (27% vs. 11%, p = .009) and attendings (58% vs. 19%, p

Abstract Endothelial cells line all major blood vessels and serve as integral regulators of many functions including vessel diameter, cellular trafficking, and transport of soluble mediators. Despite similar functions, the phenotype of endothelial cells is highly organ-specific, yet our understanding of the mechanisms leading to organ-level differentiation is incomplete. We generated 3D microvessel networks by combining a common naïve endothelial cell with six different stromal cells derived from the lung, skin, heart, bone marrow, pancreas, and pancreatic cancer. Single cell RNA-Seq analysis of the microvessel networks reveals five distinct endothelial cell populations, for which the relative proportion depends on the stromal cell population. Morphologic features of the organotypic vessel networks inversely correlate with a cluster of endothelial cells associated with protein synthesis. The organotypic stromal cells were each characterized by a unique subpopulation of cells dedicated to extracellular matrix organization and assembly. Finally, compared to cells in 2D monolayer, the endothelial cell transcriptome from the 3D in vitro heart, skin, lung, and pancreas microvessel networks are more similar to the in vivo endothelial cells from the respective organs. We conclude that stromal cells contribute to endothelial cell and microvessel network organ tropism, and create an endothelial cell phenotype that more closely resembles that present in vivo.