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The concept of seasonal forests groups structural types of vegetation that are related to climatic seasonality in the tropics of South America. Consequently, this determines the physiognomy of the vegetation, from semi‐deciduous to strongly deciduous. The strongest link between seasonally dry tropical forests (SDTFs) is their floristic composition, where Leguminosae and Anacardiaceae dominate the woody flora. The fossil records of the Neogene of northwestern Argentina reveal a list of species found in various locations and formations of the Miocene–Lower Pleistocene obtained from studies of pollen, woods (logs), cuticles, impressions of leaves and fruits. The analysis of sediments and woody structures from the Tapebicuá, Toropí/Yupoí and El Palmar Formations (Upper Pleistocene) of the Mesopotamia region allowed us to identify several pollen taxa and silicified wood fragments (mineralized). The woody and shrubby association whose current relatives characterize the SDTF is composed of the 16 fossil species described here belonging to seven families. In our samples, Anadenanthera colubrina and Myracrodruon balansae are the most significant members of the families Leguminosae and Anacardiaceae, which are dominant in the SDTF. The paleobotanical species described in this study confirm the extension of the SDTF to the province of Corrientes, coinciding with various climatic events (dry subtropical, semi‐desert and warm‐humid climate) that would have favored the development of these forests during the Pleistocene in this region. The absolute dates obtained for the Toropí/Yupoí and Tapebicuá Formations confirm their synchronicity and correlation to Marine Isotope Stage 5. The palynological analysis, the presence of Menendoxylon and the sedimentological data allow us to infer the existence of a seasonally dry humid paleoclimate in northeastern Argentina during the Late Pleistocene favorable to the development of the SDTF. [ABSTRACT FROM AUTHOR]

Acute graft-versus-host disease (GVHD) is a significant complication following hematopoietic stem cell transplantation (HCT). Although recent advancements in GVHD prophylaxis have resulted in successful HCT across HLA barriers and expanded access to HCT for racial minorities, less is known about how race affects the severity and outcomes of acute GVHD. This study examines differences in the clinical course of acute GVHD and the prognostic value of GVHD biomarkers for Black and White recipients. We conducted a retrospective analysis of patients in the Mount Sinai Acute GVHD International Consortium (MAGIC) database who underwent HCT between 2014 and 2021 to describe the difference in clinical course of acute GVHD and significance of GVHD biomarkers between Black and White recipients. We used propensity score matching to generate a 1:3 matched cohort of 234 Black patients and 702 White patients with similar baseline characteristics. In the first year after HCT Black patients experienced a higher cumulative incidence of grade III-IV acute GVHD (17% versus 12%, P = 0.050), higher nonrelapse mortality (NRM; 18% versus 12%, P = .009), and lower overall survival that trended toward statistical significance (73% versus 79%, P = .071) compared to White patients. The difference in NRM in the first year was even greater among Black patients who developed GVHD than White patients (24% versus 14%, P = .041). The distribution of low, intermediate, and high MAGIC biomarker scores at the time of treatment was similar across racial groups (P = .847), however, Black patients with high biomarker scores experienced significantly worse NRM than White patients (71% versus 32%, P = .010). Our data indicate that Black patients are at a higher risk of NRM following HCT, primarily from a higher incidence of severe GVHD. Serum biomarkers at treatment initiation can stratify patients for risk of NRM across races, however Black patients with high biomarker scores had a significantly greater NRM risk. These results suggest a need for strategies that mitigate the higher risk for poor GVHD outcomes among Black patients., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Use of point-of-care ultrasound (POCUS) is integral to the practice of emergency medicine, and POCUS education is a required component of emergency medicine training. Developing POCUS skills requires iterative deliberate practice of image acquisition and interpretation. Providing feedback to learners regarding ultrasound image interpretation can be challenging for emergency medicine clinician educators. We present a framework called the directed image review technique. This framework guides learner ultrasound image interpretation and provides educators with a similar structured approach to evaluate a learner's ultrasound competency and provide targeted feedback regarding image acquisition and interpretation., Competing Interests: The authors declare no conflicts of interest., (© 2024 The Author(s). AEM Education and Training published by Wiley Periodicals LLC on behalf of Society for Academic Emergency Medicine.)

Abstract: Acute graft-versus-host disease (GVHD) grading systems that use only clinical symptoms at treatment initiation such as the Minnesota risk identify standard and high-risk categories but lack a low-risk category suitable to minimize immunosuppressive strategies. We developed a new grading system that includes a low-risk stratum based on clinical symptoms alone and determined whether the incorporation of biomarkers would improve the model's prognostic accuracy. We randomly divided 1863 patients in the Mount Sinai Acute GVHD International Consortium (MAGIC) who were treated for GVHD into training and validation cohorts. Patients in the training cohort were divided into 14 groups based on similarity of clinical symptoms and similar nonrelapse mortality (NRM); we used a classification and regression tree (CART) algorithm to create three Manhattan risk groups that produced a significantly higher area under the receiver operating characteristic curve (AUC) for 6-month NRM than the Minnesota risk classification (0.69 vs 0.64, P = .009) in the validation cohort. We integrated serum GVHD biomarker scores with Manhattan risk using patients with available serum samples and again used a CART algorithm to establish 3 MAGIC composite scores that significantly improved prediction of NRM compared to Manhattan risk (AUC, 0.76 vs 0.70, P = .010). Each increase in MAGIC composite score also corresponded to a significant decrease in day 28 treatment response (80% vs 63% vs 30%, P < .001). We conclude that the MAGIC composite score more accurately predicts response to therapy and long-term outcomes than systems based on clinical symptoms alone and may help guide clinical decisions and trial design., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Abstract: The significance of biomarkers in second-line treatment for acute graft-versus-host disease (GVHD) has not been well characterized. We analyzed clinical data and serum samples at the initiation of second-line systemic treatment of acute GVHD from 167 patients from 17 centers of the Mount Sinai Acute GVHD International Consortium (MAGIC) between 2016 and 2021. Sixty-two patients received ruxolitinib-based therapy, whereas 102 received other systemic agents. In agreement with prospective trials, ruxolitinib resulted in a higher day 28 (D28) overall response Frate than nonruxolitinib therapies (55% vs 31%, P = .003) and patients who received ruxolitinib had significantly lower nonrelapse mortality (NRM) than those who received nonruxolitinib therapies (point estimates at 2-year: 35% vs 61%, P = .002). Biomarker analyses demonstrated that the benefit from ruxolitinib was observed only in patients with low MAGIC algorithm probabilities (MAPs) at the start of second-line treatment. Among patients with a low MAP, those who received ruxolitinib experienced significantly lower NRM than those who received nonruxolitinib therapies (point estimates at 2-year: 12% vs 41%, P = .016). However, patients with high MAP experienced high NRM regardless of treatment with ruxolitinib or nonruxolitinib therapies (point estimates at 2-year: 67% vs 80%, P = .65). A landmark analysis demonstrated that the relationship between the D28 response and NRM largely depends on the MAP level at the initiation of second-line therapy. In conclusion, MAP measured at second-line systemic treatment for acute GVHD predicts treatment response and NRM. The outcomes of patients with high MAP are poor regardless of treatment choice, and ruxolitinib appears to primarily benefit patients with low MAP., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Abstract: Graft-versus-host disease (GVHD) is a major cause of nonrelapse mortality (NRM) after allogeneic hematopoietic cell transplantation. Algorithms containing either the gastrointestinal (GI) GVHD biomarker amphiregulin (AREG) or a combination of 2 GI GVHD biomarkers (suppressor of tumorigenicity-2 [ST2] + regenerating family member 3 alpha [REG3α]) when measured at GVHD diagnosis are validated predictors of NRM risk but have never been assessed in the same patients using identical statistical methods. We measured the serum concentrations of ST2, REG3α, and AREG by enzyme-linked immunosorbent assay at the time of GVHD diagnosis in 715 patients divided by the date of transplantation into training (2004-2015) and validation (2015-2017) cohorts. The training cohort (n = 341) was used to develop algorithms for predicting the probability of 12-month NRM that contained all possible combinations of 1 to 3 biomarkers and a threshold corresponding to the concordance probability was used to stratify patients for the risk of NRM. Algorithms were compared with each other based on several metrics, including the area under the receiver operating characteristics curve, proportion of patients correctly classified, sensitivity, and specificity using only the validation cohort (n = 374). All algorithms were strong discriminators of 12-month NRM, whether or not patients were systemically treated (n = 321). An algorithm containing only ST2 + REG3α had the highest area under the receiver operating characteristics curve (0.757), correctly classified the most patients (75%), and more accurately risk-stratified those who developed Minnesota standard-risk GVHD and for patients who received posttransplant cyclophosphamide-based prophylaxis. An algorithm containing only AREG more accurately risk-stratified patients with Minnesota high-risk GVHD. Combining ST2, REG3α, and AREG into a single algorithm did not improve performance., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Acute graft versus host disease (GVHD) is a common and serious complication of allogeneic hematopoietic cell transplantation (HCT) in children but overall clinical grade at onset only modestly predicts response to treatment and survival outcomes. Two tools to assess risk at initiation of treatment were recently developed. The Minnesota risk system stratifies children for risk of nonrelapse mortality (NRM) according to the pattern of GVHD target organ severity. The Mount Sinai Acute GVHD International Consortium (MAGIC) algorithm of 2 serum biomarkers (ST2 and REG3α) predicts NRM in adult patients but has not been validated in a pediatric population. We aimed to develop and validate a system that stratifies children at the onset of GVHD for risk of 6-month NRM. We determined the MAGIC algorithm probabilities (MAPs) and Minnesota risk for a multicenter cohort of 315 pediatric patients who developed GVHD requiring treatment with systemic corticosteroids. MAPs created 3 risk groups with distinct outcomes at the start of treatment and were more accurate than Minnesota risk stratification for prediction of NRM (area under the receiver operating curve (AUC), .79 versus .62, P = .001). A novel model that combined Minnesota risk and biomarker scores created from a training cohort was more accurate than either biomarkers or clinical systems in a validation cohort (AUC .87) and stratified patients into 2 groups with highly different 6-month NRM (5% versus 38%, P < .001). In summary, we validated the MAP as a prognostic biomarker in pediatric patients with GVHD, and a novel risk stratification that combines Minnesota risk and biomarker risk performed best. Biomarker-based risk stratification can be used in clinical trials to develop more tailored approaches for children who require treatment for GVHD., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Abstract: The absence of a standardized definition for graft-versus-host disease (GVHD) flares and data on its clinical course are significant concerns. We retrospectively evaluated 968 patients across 23 Mount Sinai Acute GVHD International Consortium (MAGIC) transplant centers who achieved complete response (CR) or very good partial response (VGPR) within 4 weeks of treatment. The cumulative incidence of flares within 6 months was 22%, and flares were associated with a higher risk of nonrelapse mortality (NRM; adjusted hazard ratio [aHR], 4.84; 95% confidence interval [CI], 3.19-7.36; P < .001). Flares were more severe (grades 3/4, 41% vs 16%; P < .001) and had more frequent lower gastrointestinal (LGI) involvement (55% vs 32%; P < .001) than the initial GVHD. At CR/VGPR, elevated MAGIC biomarkers predicted the future occurrence of a flare, along with its severity and LGI involvement. In multivariate analyses, higher Ann Arbor (AA) biomarker scores at CR/VGPR were significant risk factors for flares (AA2 vs AA1: aHR, 1.81 [95% CI, 1.32-2.48; P = .001]; AA3 vs AA1: aHR, 3.14 [95% CI, 1.98-4.98; P < .001]), as were early response to initial treatment (aHR, 1.84; 95% CI, 1.21-2.80; P = .004) and HLA-mismatched unrelated donor (aHR, 1.74; 95% CI, 1.00-3.02; P = .049). MAGIC biomarkers also stratified the risk of NRM both at CR/VGPR and at the time of flare. We conclude that GVHD flares are common and carry a significant mortality risk. The occurrence of future flares can be predicted by serum biomarkers that may serve to guide adjustment and discontinuation of immunosuppression., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

The overall response rate (ORR) 28 days after treatment has been adopted as the primary endpoint for clinical trials of acute graft versus host disease (GVHD). However, physicians often need to modify immunosuppression earlier than day (D) 28, and non-relapse mortality (NRM) does not always correlate with ORR at D28. We studied 1144 patients that received systemic treatment for GVHD in the Mount Sinai Acute GVHD International Consortium (MAGIC) and divided them into a training set (n=764) and a validation set (n=380). We used a recursive partitioning algorithm to create a Mount Sinai model that classifies patients into favorable or unfavorable groups that predicted 12 month NRM according to overall GVHD grade at both onset and D14. In the Mount Sinai model grade II GVHD at D14 was unfavorable for grade III/IV GVHD at onset and predicted NRM as well as the D28 standard response model. The MAGIC algorithm probability (MAP) is a validated score that combines the serum concentrations of suppression of tumorigenicity 2 (ST2) and regenerating islet-derived 3-alpha (REG3α) to predict NRM. Inclusion of the D14 MAP biomarker score with the D14 Mount Sinai model created three distinct groups (good, intermediate, poor) with strikingly different NRM (8%, 35%, 76% respectively). This D14 MAGIC model displayed better AUC, sensitivity, positive and negative predictive value, and net benefit in decision curve analysis compared to the D28 standard response model. We conclude that this D14 MAGIC model could be useful in therapeutic decisions and may offer an improved endpoint for clinical trials of acute GVHD treatment., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Introduction: American Indian and Alaska Native (AIAN) communities continue to flourish and innovate in the face of the COVID-19 pandemic. Storytelling is an important tradition for AIAN communities that can function as an intervention modality. To support the needs of AIAN children and caregivers, we (a collaborative workgroup of Indigenous health researchers) developed a culturally grounded storybook that provides pandemic-related public health guidance and mental health coping strategies woven with Inter-Tribal values and teachings., Methods: A collaborative workgroup, representing diverse tribal affiliations, met via four virtual meetings in early 2021 to discuss evolving COVID-19 pandemic public health guidance, community experiences and responses to emerging challenges, and how to ground the story in shared AIAN cultural strengths. We developed and distributed a brief survey for caregivers to evaluate the resulting book., Results: The workgroup iteratively reviewed versions of the storyline until reaching a consensus on the final text. An AI artist from the workgroup created illustrations to accompany the text. The resulting book, titled Our Smallest Warriors, Our Strongest Medicine: Honoring Our Teachings during COVID-19 contains 46 pages of text and full-color illustrations. An online toolkit including coloring pages, traditional language activities, and caregiver resources accompanies the book. We printed and distributed 50,024 physical copies of the book and a free online version remains available. An online survey completed by N  = 34 caregivers who read the book with their child(ren) showed strong satisfaction with the book and interest in future books., Discussion: The development of this storybook provides insights for creative dissemination of future public health initiatives, especially those geared toward AIAN communities. The positive reception and widespread interest in the storybook illustrate how braiding AIAN cultural teachings with public health guidance can be an effective way to disseminate health information. This storybook highlights the importance of storytelling as an immersive learning experience through which caregivers and children connect to family, community, culture, and public health guidance. Culturally grounded public health interventions can be effective and powerful in uplifting AIAN cultural values and promoting health and well-being for present and future generations., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Maudrie, Grubin, Conrad, Velasquez Baez, Saniguq Ullrich, Allison-Burbank, Martin, Austin, Joyner, Ronyak, Masten, Ingalls, Haroz and O’Keefe.)

Introduction: Immediate access to naloxone is needed to prevent fatal opioid-related overdoses in the presence of fentanyl analogs saturating the opioid supply. Peer models engage impacted populations who are not accessing naloxone through standard venues, yet compensating peers who utilize syringe service programs with cash stipends to distribute naloxone within networks of people who use drugs is not well described., Methods: As part of the HEALing Communities Study, syringe service program-based interventions were developed in Holyoke and Gloucester, MA, which paid people who use drugs ("peers") cash to distribute naloxone. Early program outcomes were evaluated for the time each program was funded within the HCS study period., Results: During 22 study-months of observation, peers in two communities distributed 1104 naloxone kits. The total cost of peer compensation for program delivery was $10,510. The rate of peer-distributed naloxone per 100 K population reached 109 kits/mo and 222 kits/mo in the two communities. Participating peers addressed gaps in harm reduction outreach and distributed naloxone and other harm reduction equipment to individuals who were not syringe service program participants, expanding organizational reach. Being compensated with unrestricted cash stipends supported dignity and acknowledged peers' work in overdose prevention., Conclusion: The underutilization of compensated peer models is often attributed to funding and organizational barriers. These programs demonstrate that providing cash stipends to peers is feasible and expanded naloxone distribution at two existing syringe service programs. Providing cash stipends for peers who engage in secondary naloxone distribution offers promise in delivering naloxone to people not accessing syringe services., (© 2024. The Author(s).)

This study is the second part of a two-part study whereby supersaturated solutions of calcium and phosphate ions generate well-defined hydroxyapatite coatings for orthopaedic implants. An 'ideal' process solution is selected from Part 1, and the detailed characterisation of films produced from this solution is undertaken here in Part 2. Analysis is presented on the hydroxyapatite produced, in both powder form and as a film upon titanium substrates representative of orthopaedic implants. From thermal analysis data, it is shown that there is bound and interstitial water present in the hydroxyapatite. Nuclear magnetic resonance data allow for the distinction between an amorphous and a crystalline component of the material. As hydroxyapatite coatings are generated, their growth mechanism is tracked across repeated process runs. A clear understanding of the growth mechanism is achieved though crystallinity and electron imaging data. Transmission electron imaging data support the proposed crystal growth and deposition mechanism. All of the data conclude that this process has a clear propensity to grow the hydroxyapatite phase of octacalcium phosphate. The investigation of the hydroxyapatite coating and its growth mechanism establish that a stable and reproducible process window has been identified. Precise control is achieved, leading to the successful formation of the desired hydroxyapatite films.

This study introduces and explores the use of supersaturated solutions of calcium and phosphate ions to generate well-defined hydroxyapatite coatings for orthopaedic implants. The deposition of hydroxyapatite is conducted via several solutions of metastable precursors that precipitate insoluble hydroxyapatite minerals at a substrate-solution interface. Solutions of this nature are intrinsically unstable, but this paper outlines process windows in terms of time, temperature, concentration and pH in which coating deposition is controlled via the stop/go reaction. To understand the kinetics of the deposition process, comparisons based on ionic strength, particle size, electron imaging, elemental analyses and mass of the formed coating for various deposition solutions are carried out. This comprehensive dataset enables the measurement of deposition kinetics and identification of an optimum solution and its reaction mechanism. This study has established stable and reproducible process windows, which are precisely controlled, leading to the successful formation of desired hydroxyapatite films. The data demonstrate that this process is a promising and highly repeatable method for forming hydroxyapatites with desirable thickness, morphology and chemical composition at low temperatures and low capital cost compared to the existing techniques., Competing Interests: The authors declare no conflict of interest.

Graft-versus-host disease (GVHD) of the gastrointestinal (GI) tract is the main cause of nonrelapse mortality (NRM) after allogeneic hematopoietic cell transplantation. Ann Arbor (AA) scores derived from serum biomarkers at onset of GVHD quantify GI crypt damage; AA2/3 scores correlate with resistance to treatment and higher NRM. We conducted a multicenter, phase 2 study using natalizumab, a humanized monoclonal antibody that blocks T-cell trafficking to the GI tract through the α4 subunit of α4β7 integrin, combined with corticosteroids as primary treatment for patients with new onset AA2/3 GVHD. Seventy-five patients who were evaluable were enrolled and treated; 81% received natalizumab within 2 days of starting corticosteroids. Therapy was well tolerated with no treatment emergent adverse events in >10% of patients. Outcomes for patients treated with natalizumab plus corticosteroids were compared with 150 well-matched controls from the MAGIC database whose primary treatment was corticosteroids alone. There were no significant differences in overall or complete response between patients treated with natalizumab plus corticosteroids and those treated with corticosteroids alone (60% vs 58%; P = .67% and 48% vs 48%; P = 1.0, respectively) including relevant subgroups. There were also no significant differences in NRM or overall survival at 12 months in patients treated with natalizumab plus corticosteroids compared with controls treated with corticosteroids alone (38% vs 39%; P = .80% and 46% vs 54%; P = .48, respectively). In this multicenter biomarker-based phase 2 study, natalizumab combined with corticosteroids failed to improve outcome of patients with newly diagnosed high-risk GVHD. This trial was registered at www.clinicaltrials.gov as # NCT02133924., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Whilst titanium, stainless steel, and cobalt-chrome alloys are the most common materials for use in orthopaedic implant devices, there are significant advantages in moving to alternative non-metallic substrates. Substrates such as polymers may have advantageous mechanical biological properties whilst other substrates may bring unique capability. A key challenge in the use of non-metal products is producing substrates which can be modified to allow the formation of well-adhered hydroxyapatite films which promote osteointegration and have other beneficial properties. In this work, we aim to develop methodology for the growth of hydroxyapatite films on surfaces other than bulk metallic parts using a wet chemical coating process, and we provide a detailed characterisation of the coatings. In this study, hydroxyapatite is grown from saturated solutions onto thin titanium films and silicon substrates and compared to results from titanium alloy substrates. The coating process efficacy is shown to be dependent on substrate roughness, hydrophilicity, and activation. The mechanism of the hydroxyapatite growth is investigated in terms of initial attachment and morphological development using SEM and XPS analysis. XPS analysis reveals the exact chemical state of the hydroxyapatite compositional elements of Ca, P, and O. The characterisation of grown hydroxyapatite layers by XRD reveals that the hydroxyapatite forms from amorphous phases, displaying preferential crystal growth along the [002] direction, with TEM imagery confirming polycrystalline pockets amid an amorphous matrix. SEM-EDX and FTIR confirmed the presence of hydroxyapatite phases through elemental atomic weight percentages and bond assignment. All data are collated and reviewed for the different substrates. The results demonstrate that once hydroxyapatite seeds, it crystallises in the same manner as bulk titanium whether that be on a titanium or silicon substrate. These data suggest that a range of substrates may be coated using this facile hydroxyapatite deposition technique, just broadening the choice of substrate for a particular function.

Late acute graft-versus-host disease (GVHD) is defined as de novo acute GVHD presenting beyond 100 days after allogeneic hematopoietic cell transplantation (HCT) without manifestations of chronic GVHD. Data are limited regarding its characteristics, clinical course, and risk factors because of underrecognition and changes in classification. We evaluated 3542 consecutive adult recipients of first HCTs at 24 Mount Sinai Acute GVHD International Consortium (MAGIC) centers between January 2014 and August 2021 to better describe the clinical evolution and outcomes of late acute GVHD. The cumulative incidence of classic acute GVHD that required systemic treatment was 35.2%, and an additional 5.7% of patients required treatment for late acute GVHD. At the onset of symptoms, late acute GVHD was more severe than classic acute GVHD based on both clinical and MAGIC algorithm probability biomarker parameters and showed a lower overall response rate on day 28. Both clinical and biomarker grading at the time of treatment stratified the risk of nonrelapse mortality (NRM) in patients with classic and late acute GVHD, respectively, but long-term NRM and overall survival did not differ between patients with classic and late acute GVHD. Advanced age, female-to-male sex mismatch, and the use of reduced intensity conditioning were associated with the development of late acute GVHD, whereas the use of posttransplant cyclophosphamide-based GVHD prevention was protective mainly because of shifts in GVHD timing. Because overall outcomes were comparable, our findings, although not definitive, suggest that similar treatment strategies, including eligibility for clinical trials, based solely on clinical presentation at onset are appropriate., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Objectives: Massive fetomaternal hemorrhage (FMH) is rare and reported to be the cause in approximately 3% of all fetal deaths. Maternal management of massive FMH includes prevention of Rh(D) alloimmunization in Rh(D)-negative mothers by administration of Rh(D) immune globulin (RhIG)., Methods: We describe a case of a 30-year-old O-negative, primigravida woman who presented at 38 weeks of gestation with decreased fetal movements. She underwent an emergency cesarean section and delivered an O-positive baby girl who died shortly after birth., Results: The patient's FMH screen was positive, with a Kleihauer-Betke test demonstrating 10.7% fetal blood in maternal circulation. The calculated dose of 6,300 µg RhIG was given prior to discharge over 2 days using an intravenous (IV) preparation. Antibody screening a week after discharge showed anti-D and anti-C. The anti-C was attributed to acquired passive immunity from the large dose of RhIG. Anti-C reactivity waned and was negative at 6 months, but the anti-D pattern persisted at 9 months postdelivery. Negative antibody screens were noted at 12 and 14 months., Conclusions: This case highlights the immunohematology challenges of IV RhIG as well as the success in preventing alloimmunization with IV RhIG given the patient's complete resolution of anti-C and no anti-D formation, with a subsequent healthy pregnancy., (© The Author(s) 2023. Published by Oxford University Press on behalf of American Society for Clinical Pathology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Balloon tamponade of esophagogastric variceal hemorrhage is a lifesaving but challenging procedure. One difficulty that often arises is coiling of the tube in the oropharynx. We describe a novel use of the bougie as an external stylet to help guide placement of the balloon to help overcome this challenge., Discussion: We describe four cases in which the bougie was successfully utilized as an external stylet to place a tamponade balloon (3 Minnesota tubes, 1 Sengstaken-Blakemore tube) without any apparent complication. The straight end of the bougie is inserted approximately 0.5 cm into the most proximal of the gastric aspiration ports. The tube is then inserted into the esophagus under direct or video laryngoscopic visualization using the bougie to help "push" the tube into place as an external stylet. Once the gastric balloon is fully inflated and withdrawn to the gastroesophageal junction, the bougie is gently removed., Conclusion: The bougie may be considered as an adjunct for placement of tamponade balloons for massive esophagogastric variceal hemorrhage when placement proves refractory to traditional techniques. We think this can be a valuable tool in the emergency physician's procedural repertoire., (Published by Elsevier Inc.)

Introduction: In recent years, there has been increasing awareness of the lack of diversity among clinical trial participants. Equitable representation is key when testing novel therapeutic and non-therapeutic interventions to ensure safety and efficacy across populations. Unfortunately, in the United States (US), racial and ethnic minority populations continue to be underrepresented in clinical trials compared to their White counterparts., Methods: Two webinars in a four-part series, titled "Health Equity through Diversity," were held to discuss solutions for advancing health equity through diversifying clinical trials and addressing medical mistrust in communities. Each webinar was 1.5 hours long, beginning with panelist discussions followed by breakout rooms where moderators led discussions related to health equity and scribes recorded each room's conversations. The diverse groups of panelists included community members, civic representatives, clinician-scientists, and biopharmaceutical representatives. Scribe notes from discussions were collected and thematically analyzed to uncover the central themes., Results: The first two webinars were attended by 242 and 205 individuals, respectively. The attendees represented 25 US states, four countries outside the US, and shared various backgrounds including community members, clinician/researchers, government organizations, biotechnology/biopharmaceutical professionals, and others. Barriers to clinical trial participation are broadly grouped into the themes of access, awareness, discrimination and racism, and workforce diversity. Participants noted that innovative, community-engaged, co-designed solutions are essential., Conclusions: Despite racial and ethnic minority groups making up nearly half of the US population, underrepresentation in clinical trials remains a critical challenge. The community engaged co-developed solutions detailed in this report to address access, awareness, discrimination and racism, and workforce diversity are critical to advancing clinical trial diversity., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Reopell et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: A continuing nationwide vaccination campaign began in the Dominican Republic on February 16, 2021 to prevent severe consequences of acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Estimates of vaccine effectiveness under real-world conditions are needed to support policy decision making and inform further vaccine selection., Methods: We conducted a test-negative case-control study to assess the real-world effectiveness of nationwide coronavirus disease 2019 (COVID-19) vaccination program using an inactivated vaccine (CoronaVac) on preventing symptomatic SARS-CoV-2 infections and hospitalizations from August to November 2021 in the Dominican Republic. Participants were recruited from 10 hospitals in 5 provinces to estimate the effectiveness of full immunization (≥14 days after receipt of the second dose) and partial immunization (otherwise with at least 1 dose ≥14 days after receipt of the first dose)., Results: Of 1078 adult participants seeking medical care for COVID-19-related symptoms, 395 (36.6%) had positive polymerase chain reaction (PCR) tests for SARS-CoV-2; 142 (13.2%) were hospitalized during 15 days of follow up, including 91 (23%) among 395 PCR-positive and 51 (7.5%) among 683 PCR-negative participants. Full vaccination was associated with 31% lower odds of symptomatic infection (odds ratio [OR], 0.69; 95% confidence interval [CI], 0.52-0.93) and partial vaccination was associated with 49% lower odds (OR, 0.51; CI, 0.30-0.86). Among 395 PCR-positive participants, full vaccination reduced the odds of COVID-19-related hospitalization by 85% (OR, 0.15; 95% CI, 0.08-0.25) and partial vaccination reduced it by 75% (OR, 0.25; 95% CI, 0.08-0.80); full vaccination was associated with reduced use of assisted ventilation by 73% (OR, 0.27; 95% CI, 0.15-0.49)., Conclusions: Given the ancestral and delta viral variants circulating during this study period, our results suggest that the inactivated COVID-19 vaccine offered moderate protection against symptomatic SARS-CoV-2 infections and high protection against COVID-19-related hospitalizations and assisted ventilation. This is reassuring given that, as of August 2022, an estimated 2.6 billion inactivated CoronaVac vaccine doses had been administered worldwide. This vaccine will become a basis for developing multivalent vaccine against the currently circulating omicron variant., Competing Interests: Potential conflicts of interest. Four authors serve on a Sinovac scientific advisory board: YQC, XW, YS, and SHV. H-ZQ is currently affiliated with GSK plc, and he conducted this study as a faculty member in his former employer Yale University. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

The standard primary treatment for acute graft-versus-host disease (GVHD) requires prolonged, high-dose systemic corticosteroids (SCSs) that delay reconstitution of the immune system. We used validated clinical and biomarker staging criteria to identify a group of patients with low-risk (LR) GVHD that is very likely to respond to SCS. We hypothesized that itacitinib, a selective JAK1 inhibitor, would effectively treat LR GVHD without SCS. We treated 70 patients with LR GVHD in a multicenter, phase 2 trial (NCT03846479) with 28 days of itacitinib 200 mg/d (responders could receive a second 28-day cycle), and we compared their outcomes to those of 140 contemporaneous, matched control patients treated with SCSs. More patients responded to itacitinib within 7 days (81% vs 66%, P = .02), and response rates at day 28 were very high for both groups (89% vs 86%, P = .67), with few symptomatic flares (11% vs 12%, P = .88). Fewer itacitinib-treated patients developed a serious infection within 90 days (27% vs 42%, P = .04) due to fewer viral and fungal infections. Grade ≥3 cytopenias were similar between groups except for less severe leukopenia with itacitinib (16% vs 31%, P = .02). No other grade ≥3 adverse events occurred in >10% of itacitinib-treated patients. There were no significant differences between groups at 1 year for nonrelapse mortality (4% vs 11%, P = .21), relapse (18% vs 21%, P = .64), chronic GVHD (28% vs 33%, P = .33), or survival (88% vs 80%, P = .11). Itacitinib monotherapy seems to be a safe and effective alternative to SCS treatment for LR GVHD and deserves further investigation., (© 2023 by The American Society of Hematology.)

Streamlit is an open-source Python coding framework for building web-applications or "web-apps" and is now being used by researchers to share large data sets from published studies and other resources. Here we present Stmol, an easy-to-use component for rendering interactive 3D molecular visualizations of protein and ligand structures within Streamlit web-apps. Stmol can render protein and ligand structures with just a few lines of Python code by utilizing popular visualization libraries, currently Py3DMol and Speck. On the user-end, Stmol does not require expertise to interactively navigate. On the developer-end, Stmol can be easily integrated within structural bioinformatic and cheminformatic pipelines to provide a simple means for user-end researchers to advance biological studies and drug discovery efforts. In this paper, we highlight a few examples of how Stmol has already been utilized by scientific communities to share interactive molecular visualizations of protein and ligand structures from known open databases. We hope Stmol will be used by researchers to build additional open-sourced web-apps to benefit current and future generations of scientists., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Nápoles-Duarte, Biswas, Parker, Palomares-Baez, Chávez-Rojo and Rodríguez-Valdez.)

Most often, IgM-mediated autoimmune hemolytic anemia (AIHA) presents as cold agglutinin disease in the pediatric population. The IgM warm agglutinins are rare, with few reports in the literature. This case study describes a 5 year old girl with nausea, abdominal pain and jaundice, and a hemoglobin of 5.5 g/dL who was diagnosed with a warm reactive IgM AIHA. The laboratory workup revealed a pan-reactive antibody and a direct antiglobulin test negative for IgG and C3. A thermal amplitude assay revealed reactive IgM antibodies at 37°C, 30°C, 25°C, and 4°C and an antibody titer of 1:8. An adsorption for IgM-specific autoantibodies exposed underlying anti-E and anti-Cw alloantibodies. Transfusion of phenotypically matched red blood cell units supported ongoing hemolysis. The AIHA treatment included steroids followed by rituximab with complete resolution. A literature review shows variable outcomes for warm AIHA in the pediatric population and often describes the presence of warm reactive IgM-mediated AIHA as an indicator for poor prognosis., (© American Society for Clinical Pathology, 2021. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

We used a rigorous PRoBE (prospective-specimen collection, retrospective-blinded-evaluation) study design to compare the ability of biomarkers of systemic inflammation and biomarkers of gastrointestinal (GI) tissue damage to predict response to corticosteroid treatment, the incidence of clinically severe disease, 6-month nonrelapse mortality (NRM), and overall survival in patients with acute graft-versus-host disease (GVHD). We prospectively collected serum samples of newly diagnosed GVHD patients (n = 730) from 19 centers, divided them into training (n = 352) and validation (n = 378) cohorts, and measured TNFR1, TIM3, IL6, ST2, and REG3α via enzyme-linked immunosorbent assay. Performances of the 4 strongest algorithms from the training cohort (TNFR1 + TIM3, TNFR1 + ST2, TNFR1 + REG3α, and ST2 + REG3α) were evaluated in the validation cohort. The algorithm that included only biomarkers of systemic inflammation (TNFR1 + TIM3) had a significantly smaller area under the curve (AUC; 0.57) than the AUCs of algorithms that contained ≥1 GI damage biomarker (TNFR1 + ST2, 0.70; TNFR1 + REG3α, 0.73; ST2 + REG3α, 0.79; all P < .001). All 4 algorithms were able to predict short-term outcomes such as response to systemic corticosteroids and severe GVHD, but the inclusion of a GI damage biomarker was needed to predict long-term outcomes such as 6-month NRM and survival. The algorithm that included 2 GI damage biomarkers was the most accurate of the 4 algorithms for all endpoints., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Typical enteroaggregative Escherichia coli (tEAEC) is a diarrheagenic E. coli pathotype associated with pediatric and traveler's diarrhea. Even without diarrhea, EAEC infections in children also lead to increased gut inflammation and growth shortfalls. EAEC strain's defining phenotype is the aggregative adherence pattern on epithelial cells attributable to the aggregative adherence fimbriae (AAF). EAEC only causes diarrhea in humans; therefore, not much is known of the exact intestinal region of infection and damage or its interactions with intestinal enterocytes in vivo and in situ . This study aimed to develop a new tEAEC mouse model of infection, characterize the microbiota of infected mice, and evaluate in situ the expression of host adherence and surface molecules triggering EAEC infection and the role of the EAEC AAF-II in adherence. Six-week-old C57BL/6 mice, without previous antibiotic treatment, were orally challenged with EAEC 042 strain or EAEC 042 AAF-II mutant (ΔAAF/II) strain, or DAEC-MXR strain (diffusely adherent E. coli clinical isolate), and with saline solution (control group). Paraffin sections of the colon and ileum were stained with H&E and periodic acid-Schiff. ZO-1, β-catenin, MUC1, and bacteria were analyzed by immunofluorescence. EAEC-infected mice, in comparison with DAEC-MXR-infected and control mice, significantly lost weight during the first 3 days. After 7 days post-infection, mucus production was increased in the colon and ileum, ZO-1 localization remained unaltered, and morphological alterations were more pronounced in the ileum since increased expression and apical localization of β-catenin in ileal enterocytes were observed. EAEC-infected mice developed dysbiosis 21 days post-infection. At 4 days post-infection, EAEC strain 042 formed a biofilm on ileal villi and increased the expression and apical localization of β-catenin in ileal enterocytes; these effects were not seen in animals infected with the 042 ΔAAF/II strain. At 3 days post-infection, MUC1 expression on ileal enterocytes was mainly detectable among infected mice and colocalized with 042 strains on the enterocyte surface. We developed a novel mouse model of EAEC infection, which mimics human infection, not an illness, revealing that EAEC 042 exerts its pathogenic effects in the mouse ileum and causes dysbiosis. This model is a unique tool to unveil early molecular mechanisms of EAEC infection in vivo and in situ ., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Moran-Garcia, Lopez-Saucedo, Becerra, Meza-Segura, Hernandez-Cazares, Guerrero-Baez, Galindo-Gómez, Tsutsumi, Schnoor, Méndez-Tenorio, Nataro and Estrada-Garcia.)

Acute graft-versus-host disease (GVHD) is a major cause of mortality in patients undergoing hematopoietic cell transplantation (HCT) for hematologic malignancies. The skin is the most commonly involved organ in GVHD. Elafin, a protease inhibitor overexpressed in inflamed epidermis, was previously identified as a diagnostic biomarker of skin GVHD; however, this finding was restricted to a subset of patients with isolated skin GVHD. The main driver of nonrelapse mortality (NRM) in HCT recipients is gastrointestinal (GI) GVHD. Two biomarkers, Regenerating islet-derived 3a (REG3α) and Suppressor of tumorigenesis 2 (ST2), have been validated as biomarkers of GI GVHD that predict long-term outcomes in patients treated for GVHD. We undertook this study to determine the utility of elafin as a prognostic biomarker in the general population of acute GVHD patients in whom GVHD may develop in multiple organs. We analyzed serum elafin concentrations as a predictive biomarker of acute GVHD outcomes and compared it with ST2 and REG3α in a large group of patients treated at multiple centers. A total of 526 patients from the Mount Sinai Acute GVHD International Consortium (MAGIC) who had received corticosteroid treatment for skin GVHD and who had not been previously studied were analyzed. Serum concentrations of elafin, ST2, and REG3α were measured by ELISA in all patients. The patients were divided at random into equal training and validation sets, and a competing-risk regression model was developed to model 6-month NRM using elafin concentration in the training set. Additional models were developed using concentrations of ST2 and REG3α or the combination of all 3 biomarkers as predictors. Receiver operating characteristic (ROC) curves were constructed using the validation set to evaluate the predictive accuracy of each model and to stratify patients into high- and low-risk biomarker groups. The cumulative incidence of 6-month NRM, overall survival (OS), and 4-week treatment response were compared between the risk groups. Unexpectedly, patients in the low-risk elafin group demonstrated a higher incidence of 6-month NRM, although the difference was not statistically significant (17% versus 11%; P = .19). OS at 6 months (68% versus 68%; P > .99) and 4-week response (78% versus 78%; P = .98) were similar in the low-risk and high-risk elafin groups. The area under the ROC curve (AUC) was 0.55 for elafin and 0.75 for the combination of ST2 and REG3α. The addition of elafin to the other 2 biomarkers did not improve the AUC. Our data indicate that serum elafin concentrations measured at the initiation of systemic treatment for acute GVHD did not predict 6-month NRM, OS, or treatment response in a multicenter population of patients treated systemically for acute GVHD. As seen in previous studies, serum concentrations of the GI GVHD biomarkers ST2 and REG3α were significant predictors of NRM, and the addition of elafin levels did not improve their accuracy. These results underscore the importance of GI disease in driving NRM in patients who develop acute GVHD., (Copyright © 2021 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)