Search

Prostate cancer treatment planning is largely dependent upon examination of core-needle biopsies. The microscopic architecture of the prostate glands forms the basis for prognostic grading by pathologists. Interpretation of these convoluted three-dimensional (3D) glandular structures via visual inspection of a limited number of two-dimensional (2D) histology sections is often unreliable, which contributes to the under- and overtreatment of patients. To improve risk assessment and treatment decisions, we have developed a workflow for nondestructive 3D pathology and computational analysis of whole prostate biopsies labeled with a rapid and inexpensive fluorescent analogue of standard hematoxylin and eosin (H&E) staining. This analysis is based on interpretable glandular features and is facilitated by the development of image translation–assisted segmentation in 3D (ITAS3D). ITAS3D is a generalizable deep learning–based strategy that enables tissue microstructures to be volumetrically segmented in an annotation-free and objective (biomarker-based) manner without requiring immunolabeling. As a preliminary demonstration of the translational value of a computational 3D versus a computational 2D pathology approach, we imaged 300 ex vivo biopsies extracted from 50 archived radical prostatectomy specimens, of which, 118 biopsies contained cancer. The 3D glandular features in cancer biopsies were superior to corresponding 2D features for risk stratification of patients with low- to intermediate-risk prostate cancer based on their clinical biochemical recurrence outcomes. The results of this study support the use of computational 3D pathology for guiding the clinical management of prostate cancer. Significance: An end-to-end pipeline for deep learning–assisted computational 3D histology analysis of whole prostate biopsies shows that nondestructive 3D pathology has the potential to enable superior prognostic stratification of patients with prostate cancer.

Objective To compare the relative value of 3 analgesic pathways for total knee arthroplasty (TKA). Patients and Methods Time-driven activity-based costing analyses were performed on 3 common analgesic pathways for patients undergoing TKA: periarticular infiltration (PAI) only, PAI and single-injection adductor canal blockade (SACB), and PAI and continuous adductor canal blockade (CACB). Additionally, adult patients who underwent elective primary TKA from November 1, 2017, to May 1, 2018, were retrospectively identified to analyze analgesic (pain score, opiate use) and hospital outcomes (distance walked, length of stay) after TKA based on analgesic pathway. Results There was no difference in patient demographic characteristics, specifically complexity (American Society of Anesthesiologists score) or preoperative opiate use, between groups. Compared with PAI, total cost (labor and material) was 1.4-times greater for PAI plus SACB and 2.3-times greater for PAI plus CACB. The addition of SACB to PAI resulted in lower average and maximum pain scores and opiate use on the day of operation compared with PAI alone. Average and maximum pain scores and opiate use between SACB and CACB were not significantly different. Walking distance and hospital length of stay were not significantly different between groups. Conclusion Perioperative care teams should consider the cost and relative value of pain management when selecting the optimal analgesic strategy for TKA. Despite slightly higher relative cost, the combination of SACB with PAI may offer short-term analgesic benefit compared with PAI alone, which could enhance its relative value in TKA.

Background Measles elimination (interruption of endemic measles virus transmission) in the United States was declared in 2000; however, the number of cases and outbreaks have increased in recent years. We characterized the epidemiology of measles outbreaks and measles transmission patterns after elimination to identify potential gaps in the US measles control program. Methods We analyzed national measles notification data from 1 January 2001 to 31 December 2019. We defined measles infection clusters as single cases (isolated cases not linked to additional cases), 2-case clusters, or outbreaks with ≥3 linked cases. We calculated the effective reproduction number (R) to assess changes in transmissibility and reviewed molecular epidemiology data. Results During 2001–2019, a total of 3873 measles cases, including 747 international importations, were reported in the United States; 29% of importations were associated with outbreaks. Among 871 clusters, 69% were single cases and 72% had no spread. Larger and longer clusters were reported since 2013, including 7 outbreaks with >50 cases lasting >2 months, 5 of which occurred in known underimmunized, close-knit communities. No measles lineage circulated in a single transmission chain for >12 months. Higher estimates of R were noted in recent years, although R remained below the epidemic threshold of 1. Conclusions Current epidemiology continues to support the interruption of endemic measles virus transmission in the United States. However, larger and longer outbreaks in recent postelimination years and emerging trends of increased transmission in underimmunized communities emphasize the need for targeted approaches to close existing immunity gaps and maintain measles elimination.

Neuroinflammation, particularly in the dorsolateral prefrontal cortex, is well-established in a subset of people with schizophrenia, with significant increases in inflammatory markers including several cytokines. Yet the cause(s) of cortical inflammation in schizophrenia remains unknown. Clues as to potential microenvironmental triggers and/or intracellular deficits in immunoregulation may be gleaned from looking further upstream of effector immune molecules to transcription factors that control inflammatory gene expression. Here, we focus on the ‘master immune regulator’ nuclear factor kappa B (NF-κB) and review evidence in support of NF-κB dysregulation causing or contributing to neuroinflammation in patients. We discuss the utility of ‘immune biotyping’ as a tool to analyse immune-related transcripts and proteins in patient tissue, and the insights into cortical NF-κB in schizophrenia revealed by immune biotyping compared to studies treating patients as a single, homogenous group. Though the ubiquitous nature of NF-κB presents several hurdles for drug development, targeting this key immunoregulator with novel or repurposed therapeutics in schizophrenia is a relatively underexplored area that could aid in reducing symptoms of patients with active neuroinflammation.

To assess the accuracy of radiographs in detecting the lateral plateau involvement of medial tibial plateau fractures as well as describe the impact of CT on preoperative planning for this specific fracture morphology. Radiograph and CT imaging of patients with a Schatzker type IV tibial plateau fractures (AO/OTA 41-B1.2, B1.3 h, B2.2. B3.2, and B3.3) between January 2013 and July 2017 were reviewed by three trauma fellowship-trained orthopedic surgeons to identify fractures of the medial condyle with an intact anterolateral articular surface. Lateral plateau involvement was identified in 16 (37%) radiographs and 26 (61%) CT images (p = 0.051). Radiographic detection of lateral plateau involvement demonstrated a sensitivity of 62% and specificity of 100%, and radiographs were able to predict the recommendation for surgical intervention for lateral plateau involvement with a positive predictive value (PPV) of 75% and a negative predictive value (NPV) of 60% compared to recommendations based on CT imaging. Radiographs predicted a need for a separate surgical approach with PPV of 63% and NPV of 70% when compared to recommendations based on CT images. Radiographs are reliable in ruling in lateral plateau involvement of medial plateau fractures, but occult lateral articular extension may only be identified in CT imaging for some cases. Surgical planning may be impacted by CT imaging for this fracture morphology, but further study is warranted to evaluate the correlation between preoperative planning and clinical outcomes. III.

Silvopasture is the intentional integration of trees, forages, and livestock. Benefits of this agroforestry practice include shade for livestock, nutritious forage, and reduced wind speed in pastures, as well as ecosystem services and tree products. The literature indicate that some livestock producers are interested in silvopasture, but little is known about their establishment preferences and if they vary by demographics or operation type. This study hypothesized that producers are equally interested in planting trees in pastures (planting) and reducing forest canopy and planting forages (thinning) to establish silvopasture, and that the effects of the potential benefits of silvopasture on their preferences are similar. To test these hypotheses, 307 livestock producers in Virginia, United States of America were surveyed about whether they prefer planting or thinning. Producers also were asked about the extent to which potential benefits of silvopasture affect their preferences. Nearly 25% of the 139 respondents (response rate = 45%) were 'very interested' in thinning, compared to 8% for planting. Animal performance and welfare was their primary goal, but forest management and whole-farm productivity also were important. Guidelines are needed for maintaining stand health and productivity when thinning and for improving tree protection and growth in pastures when planting to establish silvopasture. Published version Public domain – authored by a U.S. government employee

Vaccination represents the best line of defense against infectious diseases and is crucial in curtailing pandemic spread of emerging pathogens to which a population has limited immunity. In recent years, mRNA vaccines have been proposed as the new frontier in vaccination, owing to their facile and rapid development while providing a safer alternative to traditional vaccine technologies such as live or attenuated viruses. Recent breakthroughs in mRNA vaccination have been through formulation with lipid nanoparticles (LNPs), which provide both protection and enhanced delivery of mRNA vaccines in vivo. In this review, current paradigms and state-of-the-art in mRNA-LNP vaccine development are explored through first highlighting advantages posed by mRNA vaccines, establishing LNPs as a biocompatible delivery system, and finally exploring the use of mRNA-LNP vaccines in vivo against infectious disease towards translation to the clinic. Furthermore, we highlight the progress of mRNA-LNP vaccine candidates against COVID-19 currently in clinical trials, with the current status and approval timelines, before discussing their future outlook and challenges that need to be overcome towards establishing mRNA-LNPs as next-generation vaccines. Statement of significance With the recent success of mRNA vaccines developed by Moderna and BioNTech/Pfizer against COVID-19, mRNA technology and lipid nanoparticles (LNP) have never received more attention. This manuscript timely reviews the most advanced mRNA-LNP vaccines that have just been approved for emergency use and are in clinical trials, with a focus on the remarkable development of several COVID-19 vaccines, faster than any other vaccine in history. We aim to give a comprehensive introduction of mRNA and LNP technology to the field of biomaterials science and increase accessibility to readers with a new interest in mRNA-LNP vaccines. We also highlight current limitations and future outlook of the mRNA vaccine technology that need further efforts of biomaterials scientists to address., Graphical abstract Image, graphical abstract

Cell-free fetal DNA (cfDNA) analyzes maternal and fetoplacental DNA, generating highly personal genetic information for both mother and fetus. This study aimed to determine how laboratories retain, use, and share genetic information from cfDNA. Other outcomes included laboratories’ adherence to American Society of Human Genetics (ASHG) privacy principles, and the readability of privacy policies. Laboratories offering cfDNA aneuploidy screening were identified from online searches, curated databases, and a genomics news website. Of 124 laboratories identified, 13 were commercial laboratories offering cfDNA aneuploidy screening in the United States, and were included. Genetic privacy policies from eligible laboratories were identified by reviewing requisition and consent forms, which were obtained online or by direct contact. Most laboratories use prenatal genetic information for research (n = 10, 77%), and more than half (n = 7, 54%) shared genetic information with others. Overall, laboratories inadequately disclosed privacy risks. In a readability analysis, 9 of 11 (82%) laboratories’ genetic privacy policies were written at or above a 12th grade reading level. Most laboratories allowed for prolonged use and sharing of cfDNA data, demonstrated incomplete adherence to ASHG privacy recommendations, and provided consents written in college-level language. Laboratories should revise their consent forms, and providers should help patients understand these forms.

INTRODUCTION: Kaposi’s sarcoma (KS) is a multifocal low-grade vascular neoplasm that can affect the skin, mucus membranes, visceral organs, and lymph nodes. KS can also affect the ocular surface and adnexa and can masquerade as other entities, delaying prompt diagnosis. AREAS COVERED: In this review, the manifestations of ocular KS are discussed along with theories for pathogenesis, common risk factors, and management options. EXPERT OPINION: KS is caused by the oncogenic human herpesvirus 8 (HHV8). Immunosuppression in patients with HIV and AIDS contributes to the development of KS but conjunctival and ocular adnexal KS lesions are now uncommon in the era of anti-retroviral therapy. A high index of suspicion is required to diagnose ocular KS as these lesions can be mistaken for alternative entities. Prompt diagnosis can reduce significant morbidity and mortality by prompting a multidisciplinary systemic evaluation, particularly in immunosuppressed individuals. While surgical excision, cryotherapy, intralesional or systemic chemotherapy, and radiation are all viable treatment options, ongoing research to identify novel therapies and molecular treatment targets will help expand the armamentarium of therapeutics available for this disease.

Educational technologies have captured the attention of researchers, policy makers, and parents. Each year, considerable effort and money are invested into new technologies, hoping to find the next effective learning tool. However, technology changes rapidly and little attention is paid to the changes after they occur. This paper provides an overall picture of the changing trends in educational technology by analyzing the Horizon Reports’ predictions of the most influential educational technologies from 2011 to 2021, identifying larger trends across these yearly predictions, and by using bibliometric analysis to evaluate the accuracy of the identified trends. The results suggest that mobile and analytics technologies trended consistently across the period, there was a trend towards maker technologies and games in the early part of the decade, and emerging technologies (e.g., VR, AI) are predicted to trend in the future. Overall, the specific technologies focused on by the HRs’ predictions and by educational researchers’ publications seem to coincide with the availability of consumer grade technologies, suggesting that the marketplace and technology industry is driving trends (cf., pedagogy or theory).

Objectives To assess agreement among experts in pelvic fracture management regarding stability and need for operative repair of lateral compression (LC) type pelvic fractures with static radiographs compared to static radiographs and exam under anesthesia (EUA). Setting Online surveyPatients/Participants: Ten patients who presented to our level-1 trauma center with a pelvic ring injury were selected. Vignettes were distributed to 11 experienced pelvic surgeons. Intervention Exam under anesthesia MAIN OUTCOME MEASUREMENTS:: Agreement regarding pelvic fracture stability, need for surgical fixation. Results Agreement on stability was achieved in 4 (40%) cases without EUA compared to 8 (80%) cases with EUA. Inter-reviewer reliability was poor without EUA and moderate with EUA (0.207 vs. 0.592). Agreement on need to perform surgery was achieved in 5 (50%) cases compared to 6 (60%) cases with EUA. Inter-reviewer reliability was poor without EUA and moderate with EUA (0.250 vs. 0.432). For reference cases with agreement, surgeons were able to predict stability or instability using standard imaging in 57 of a possible 88 reviewer choices (64.8%) compared to 82 of 88 choices (93.2%) with the addition of EUA (p Conclusions EUA increased agreement among experienced pelvic surgeons regarding the assessment of pelvic ring stability and the need for operative intervention. Further research is necessary to define specific indications for which patients may benefit from EUA. Level of evidence Diagnostic Level V. See Instructions for authors for a complete description of levels of evidence.

To determine the relationship between maternal age and labor induction duration among nulliparous women.This retrospective cohort study included nulliparous women with non-anomalous, term, singleton pregnancies undergoing labor induction with intact membranes at a tertiary-care academic hospital from January 2015 to April 2017. Maternal age was stratified as follows:25 years, 25-29 years, 30-34 years, 35-39 years, and ≥ 40 years. The primary outcome was induction duration, defined as the time the first induction agent was administered to time of birth. Secondary outcomes were cesarean delivery, cesarean indication, hemorrhage, blood transfusion, peripartum infection, composite neonatal morbidity, and induction duration among the subset of women who ultimately underwent cesarean. The data were analyzed using chi-squared and Fisher exact tests. Multivariable regression was used to adjust for maternal race/ethnicity, maternal body mass index, gestational age at start of induction, and induction indication. Hazard ratios were used to calculate induction duration among women who underwent cesarean delivery, stratified by age and adjusted by the same variables.Among the 955 patients included, the median induction duration was 32.3 h (interquartile range (IQR) 20.4-41.0 h). Women 40 years and older had a slight increase in induction duration (adjusted odds ratio (aOR) 1.03, 95% confidence interval (CI) 1.01-1.05) and a seven-fold increased risk of induction lasting 60 h or longer (adjusted relative risk (aRR) 7.3, CI 1.8-29.9) when compared to those under 25 years of age; otherwise, there was no association between maternal age and labor induction duration. There was no association between age and cesarean delivery, cesarean indication, hemorrhage, transfusion, peripartum infection, or adverse neonatal outcomes. Furthermore, there was no association between maternal age and induction duration even among women who ultimately underwent cesarean.We found no association between maternal age and induction duration for women under 40 years of age. For women 40 years of age and older, these was an increased risk of labor induction lasting 60 h or longer. Despite this, we found no association between maternal age and cesarean delivery or other adverse maternal or fetal outcomes.

In view of reported discrepancies concerning antioxidant activity of dehydroepiandrosterone (DHEA), a widely used dietary supplement, the current investigation was undertaken to evaluate the antioxidant properties of DHEA in both kidney-cortex and liver of alloxan (ALX)-induced diabetic rabbits, as this diabetogenic compound exhibits the ROS-dependent action. ALX was injected to animals following 7 days of DHEA administration. Four groups of rabbits were used in the experiments: control, DHEA-treated control, diabetic and DHEA-treated diabetic. Our results show for the first time, that in kidney-cortex DHEA resulted in normalization of hydroxyl free radicals (HFR) levels and restoration of catalase (CAT) and glutathione peroxidase (GPx) activities to near the control values, while in liver DHEA prevented the malondialdehyde (MDA) accumulation and normalized glutathione reductase (GR) and glucose-6-phosphate dehydrogenase (G6PDH) activities. Moreover, in both kidney-cortex and liver DHEA supplementation prevented GSSG elevation accompanied by a decrease in GSH/GSSG ratio. Although DHEA attenuated oxidative stress in both kidney-cortex and liver of ALX-induced diabetic rabbits and significantly delayed the onset of diabetes in time, it did not protect against the final development of diabetes. In conclusion, the current investigation underscores the complexity of the antioxidant action of DHEA. The data are of clinical interest since DHEA supplementation could prevent the deleterious effects of ROS and delay, or even prevent the onset of many diseases. However, in view of the reported pro-oxidant effects of high DHEA doses, the potential use of this agent as a supplement needs a careful evaluation.

Modern prenatal genetic screening techniques such as cell-free fetal DNA and expanded carrier screening genotype substantial amounts of maternal and fetoplacental DNA. Although DNA can be deidentified by stripping protected health information from genetic data, anonymized DNA can be reidentified using genetic databases, raising long-term genetic privacy concerns for both mother and fetus. In this commentary, we explore the evolution of prenatal genetic screening and how modern screening techniques may pose unanticipated privacy risks. We highlight knowledge gaps and outline steps to improve patient awareness of and control over their genetic privacy, including specific recommendations for laboratories and prenatal care practitioners who offer screening. We also encourage our colleagues who provide prenatal care to be well informed about the privacy implications of the genetic tests we order and to be vocal advocates for our patients' genetic privacy, both with the laboratories that perform these tests and in the public sphere.

The hallmarks of COVID-19 are higher pathogenicity and mortality in the elderly compared to children. Examining baseline SARS-CoV-2 cross-reactive immunological responses, induced by circulating human coronaviruses (hCoVs), is needed to understand such divergent clinical outcomes. Here we show analysis of coronavirus antibody responses of pre-pandemic healthy children (n = 89), adults (n = 98), elderly (n = 57), and COVID-19 patients (n = 50) by systems serology. Moderate levels of cross-reactive, but non-neutralizing, SARS-CoV-2 antibodies are detected in pre-pandemic healthy individuals. SARS-CoV-2 antigen-specific Fcγ receptor binding accurately distinguishes COVID-19 patients from healthy individuals, suggesting that SARS-CoV-2 infection induces qualitative changes to antibody Fc, enhancing Fcγ receptor engagement. Higher cross-reactive SARS-CoV-2 IgA and IgG are observed in healthy elderly, while healthy children display elevated SARS-CoV-2 IgM, suggesting that children have fewer hCoV exposures, resulting in less-experienced but more polyreactive humoral immunity. Age-dependent analysis of COVID-19 patients, confirms elevated class-switched antibodies in elderly, while children have stronger Fc responses which we demonstrate are functionally different. These insights will inform COVID-19 vaccination strategies, improved serological diagnostics and therapeutics., Antibody responses to SARS-CoV-2 are critical in the immune response to infection, but the potential cross-reactivity to other human corona viruses is poorly appreciated. Here the authors apply a systems based approach to characterise the antibody response in pre-pandemic cohorts and assess heterotypic reactivity to SARS-CoV-2.

Hereditary angioedema (HAE) is a disease manifested by repeated episodes of localized submucosal or subcutaneous edematous episodes, potentially triggered by emotional stress, mechanical trauma, or intake of estrogens. We present our experience managing two parturients with HAE. Multidisciplinary care is essential for planning and executing the specialized care of these patients, and management included extensive planning among obstetric, anesthesiology, and allergy and immunology teams. Pregnancy has been shown to have a variable effect on triggering HAE episodes. First-line treatment includes C1 esterase inhibitor concentrate, which can also be used for prophylaxis in high-risk patients. Neuraxial analgesia is recommended to avoid general anesthesia and was established early in both individuals. Vaginal delivery was well tolerated without need for emergent treatment for angioedema symptoms.

Recent technological advances have demonstrated the feasibility of achieving high-throughput slide-free three-dimensional (3D) pathology of biopsy and surgical specimens. In comparison to conventional slide-based pathology, 3D pathology has the potential to provide a transformative improvement in diagnostic performance for a number of reasons: (1) vastly greater (multiple log orders) sampling of tissue specimens, (2) volumetric imaging of cell distributions and tissue structures that are prognostic and predictive, (3) nondestructive imaging, which allows valuable biopsy specimens to be used for downstream molecular assays, and (4) a simplified process with cost benefits for pathology laboratories. However, due to the immense size of these feature-rich datasets, new challenges exist in terms of data management and computer-aided interpretation. In this forward-looking Perspective, we first provide a brief overview of the imaging technologies that can enable nondestructive 3D pathology, including computational tools needed to support these 3D methods. We then provide a roadmap for how machine learning, which is already being developed within the context of 2D digital pathology, should be leveraged and refined for 3D pathology. Finally, we discuss future challenges and opportunities for the clinical validation, regulatory approval, and clinical adoption of this new paradigm for precision medicine, including for reducing health disparities across populations. This includes learning from, and integrating with, other diagnostic modalities such as radiology and genomics.

The purpose of this study was to describe the incidence of subsidence in patients with AO/OTA 41 (tibial plateau) fractures which were repaired with a novel fenestrated screw system to used to deliver CaPO4 bone substitute material to fill the subchondral void and support the articular reduction. Patients with unicondylar and bicondylar tibial plateau fractures were treated according to the usual technique of two surgeons. After fixation, the Zimmer Biomet N-Force Fixation System®, a fenestrated screw that allows for the injection of bone substitute was placed and used for injection of the proprietary calcium phosphate bone graft substitute into the subchondral void. For all included patients, demographic information, operative data, radiographs, and clinic notes were reviewed. Patients were considered to have articular subsidence if one or more of two observations were made when comparing post-operative to their most recent clinic radiographs: > 2 mm change in the distance between the screw and the lowest point of the tibial plateau, > 2 mm change in the distance between the screw and the most superior aspect of the plate. Data were analyzed to determine if there were any identifiable risk factors for complication, reoperation, or subsidence using logistic regression. Statistical significance was set at p

Background/aimAn objective marker is needed to detect when corneal nerve abnormalities underlie neuropathic corneal pain (NCP), as symptoms often overlap with those of dry eye (DE). This study evaluated microneuroma (MN) frequency in various populations and investigated relationships between MN presence and DE clinical features in individuals with DE symptoms but without a history of refractive surgery, in order to eliminate refractive surgery as a potential confounder of nerve abnormalities.MethodsThis was a retrospective study that included individuals with and without DE symptoms who underwent a clinical evaluation for DE (symptom surveys and ocular surface evaluation) and in vivo confocal microscopy imaging. DE clinical features (including those suggestive of neuropathic pain) were compared based on MN presence using t-tests, χ2 analyses and Pearson’s correlation coefficients with 0.05 alpha level.ResultsMN frequencies did not significantly differ between individuals with DE symptoms (Dry Eye Questionnaire 5 score ≥6) and a history of refractive surgery (n=1/16, 6%), individuals with DE symptoms without a history of refractive surgery (n=26/119, 22%) and individuals without DE symptoms (n=2/18, 11%, p=0.22). Among individuals with DE symptoms without a history of refractive surgery, DE clinical features, including those indicative of NCP (burning sensation and sensitivity to light, wind and extreme temperatures), did not significantly differ based on MN presence (p>0.05).ConclusionMN frequencies did not significantly differ between individuals with and without DE symptoms. Their presence alone could not distinguish between DE subtypes, including features of NCP in our study population.

In this paper, the safety and thermal comfort of protective clothing used by firefighters was analyzed. Three-dimensional geometry and morphology models of real multilayer assemblies used in thermal protective clothing were mapped by selected Computer-Aided Design (CAD) software. In the designed assembly models, different scales of the resolution were used for the particular layers – a homogenization for nonwoven fabrics model and designing the geometry of the individual yarns in the model of woven fabrics. Then, the finite volume method to simulate heat transfer through the assemblies caused by their exposure to the flame was applied. Finally, the simulation results with experimental measurements conducted according to the EN ISO 9151 were compared. Based on both the experimental and simulation results, parameters describing the tested clothing protective features directly affecting the firefighter’s safety were determined. As a result of the experiment and simulations, comparable values of these parameters were determined, which could show that used methods are an efficient tool in studying the thermal properties of multilayer protective clothing.

Antibody-based drugs and vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are being expedited through preclinical and clinical development. Data from the study of SARS-CoV and other respiratory viruses suggest that anti-SARS-CoV-2 antibodies could exacerbate COVID-19 through antibody-dependent enhancement (ADE). Previous respiratory syncytial virus and dengue virus vaccine studies revealed human clinical safety risks related to ADE, resulting in failed vaccine trials. Here, we describe key ADE mechanisms and discuss mitigation strategies for SARS-CoV-2 vaccines and therapies in development. We also outline recently published data to evaluate the risks and opportunities for antibody-based protection against SARS-CoV-2.

Objectives To assess agreement among pelvic surgeons regarding the interpretation of examination under anesthesia (EUA), the methodology by which EUA should be performed, and the definition of a positive examination. Design Survey. Patients/participants Ten patients who presented to our Level 1 trauma center with a pelvic ring injury were selected as clinical vignettes. Vignettes were distributed to 15 experienced pelvic surgeons. Intervention Examination under anesthesia. Main outcome measurements Agreement regarding pelvic fracture stability (defined as >80% similar responses), need for surgical fixation, definition of an unstable EUA, and method of performing EUA. Results There was agreement that a pelvic fracture was stable or unstable in 8 (80%) of 10 cases. There was agreement that fixation was required or not required in 6 (60.0%) of 10 cases. Seven (46.7%) surgeons endorsed performing a full 15-part EUA, whereas the other 8 (53.3%) used an abbreviated or alternative method. Eight (53.3%) surgeons provided a definition of what constitutes a positive EUA, whereas the remaining 7 did not endorse adhering to a strict definition. Conclusions Pelvic surgeons generally agree on what constitutes a positive or negative EUA but not necessarily the implications of a positive or negative examination. There is no clear consensus among surgeons regarding the method of performing EUA nor regarding the definition of a positive EUA. Level of evidence Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence.

The article presents the results of an attempt to use high-resolution X-ray micro-computed tomography (micro-CT) to model the thermal insulation of clothing as one of the most important parameters affecting the heat balance between a human and his/her surroundings. Cotton knitted fabric applied in functional clothing for newborns and aramid woven fabric used in multilayer protective clothing for firefighters were the tested materials. The 3D models of real textiles based on micro-CT images were developed. Next, the models were applied to heat transfer simulations using the finite volume method. The usefulness of the models was experimentally verified using thermography with real textiles. The simulation results were consistent with the measurement results and confirmed the relationship between the thermal insulation and geometry of the textiles on the one hand and the physical parameters of the raw materials from which they were made on the other hand.

Background and objectivesThoracic paravertebral blockade is often used as an anesthetic and/or analgesic technique for breast surgery. With ultrasound guidance, the rate of complications is speculated to be lower than when using landmark-based techniques. This investigation aimed to quantify the incidence of pleural puncture and pneumothorax following non-continuous ultrasound-guided thoracic paravertebral blockade for breast surgery.MethodsPatients who received thoracic paravertebral blockade for breast surgery were identified by retrospective query of our institution’s electronic database over a 5-year period. Data collected included patient demographics, level of block, type and volume of local anesthetic, occurrence of pleural puncture, occurrence of pneumothorax, evidence of local anesthetic toxicity, and patient vital signs. The incidence of block complications, including pleural puncture, pneumothorax, and local anesthetic toxicity, were ascertained.Results529 patients underwent 2163 thoracic paravertebral injections. Zero pleural punctures were identified during block performance; however, two patients were found to have a pneumothorax on postoperative chest X-ray (3.6 per 1000 surgeries, 95% CI 0.5 to 13.6; 0.9 per 1000 levels blocked, 95% CI 0.1 to 3.3). There were no cases of local anesthetic systemic toxicity or associated lipid emulsion therapy administration.ConclusionsPneumothorax following non-continuous ultrasound-guided thoracic paravertebral block using a parasagittal approach is an uncommon occurrence, with a similar rate to pneumothorax following breast surgery alone.

Background Intrathecal opioids are routinely administered during spinal anesthesia for postcesarean analgesia. The effectiveness of intrathecal morphine for postcesarean analgesia is well established, and the use of intrathecal hydromorphone is growing. No prospective studies have compared the effectiveness of equipotent doses of intrathecal morphine versus intrathecal hydromorphone as part of a multimodal analgesic regimen for postcesarean analgesia. The authors hypothesized that intrathecal morphine would result in superior analgesia compared with intrathecal hydromorphone 24 h after delivery. Methods In this single-center, double-blinded, randomized trial, 138 parturients undergoing scheduled cesarean delivery were randomized to receive 150 µg of intrathecal morphine or 75 µg of intrathecal hydromorphone as part of a primary spinal anesthetic and multimodal analgesic regimen; 134 parturients were included in the analysis. The primary outcome was the numerical rating scale score for pain with movement 24 h after delivery. Static and dynamic pain scores, nausea, pruritus, degree of sedation, and patient satisfaction were assessed every 6 h for 36 h postpartum. Total opioid consumption was recorded. Results There was no significant difference in pain scores with movement at 24 h (intrathecal hydromorphone median [25th, 75th] 4 [3, 5] and intrathecal morphine 3 [2, 4.5]) or at any time point (estimated difference, 0.5; 95% CI, 0 to 1; P = 0.139). Opioid received in the first 24 h did not differ between groups (median [25th, 75th] oral morphine milligram equivalents for intrathecal hydromorphone 30 [7.5, 45.06] vs. intrathecal morphine 22.5 [14.0, 37.5], P = 0.769). From Kaplan–Meier analysis, the median time to first opioid request was 5.4 h for hydromorphone and 12.1 h for morphine (log-rank test P = 0.200). Conclusions Although the hypothesis was that intrathecal morphine would provide superior analgesia to intrathecal hydromorphone, the results did not confirm this. At the doses studied, both intrathecal morphine and intrathecal hydromorphone provide effective postcesarean analgesia when combined with a multimodal analgesia regimen. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

It has long been observed that neonates born between 39 and 40 gestational weeks have the best perinatal outcomes. What has not been known, until recently, is whether these ideal perinatal outcomes would be achieved in neonates whose delivery was brought on intentionally in this window by labor induction. Recent randomized trials and large observational cohorts have answered this question: labor induction, as compared with expectant management, lowers the rate of cesarean delivery (without increasing other adverse maternal outcomes) and improves perinatal outcomes. For those women still pregnant, delivery at 39 weeks of gestation would simultaneously lower the number of cesarean deliveries and reduce the number of stillbirths and neonatal deaths in the United States.

We sought to determine hemodynamic mechanisms of exercise intolerance in a group of patients with the HeartWare ventricular assist device (VAD) compared to a group of heart failure patients. Twenty VAD and 22 heart failure patients underwent symptom-limited active straight leg raising exercise during right heart catheterization with thermodilution (TD), and upright cycling cardiopulmonary stress testing with cardiac output measurement by inert gas rebreathing (IGR) method. The TD and IGR exercise cardiac indexes were higher in VAD compared with heart failure group (both P < 0.05), although there was only a borderline increase in peak exercise oxygen consumption (VO2) (P = 0.06). Baseline and exercise right heart catheterization pressures were not significantly different between the two groups. The only significant independent predictors of peak VO2 in the heart failure group were exercise heart rate and cardiac index (both P < 0.05). In contrast, for the VAD group only, resting pulmonary arterial wedge and pulmonary arterial mean pressures were independently related to peak VO2 (both P < 0.05). Thus, in heart failure, exercise cardiac index is an important limitation to exercise capacity, and VADs increase exercise cardiac index. However, in VAD patients, this only produces limited benefits as increased pulmonary and pulmonary wedge pressures limit increases in exercise capacity.

The accelerated risk of cardiovascular disease (CVD) in Rheumatoid Arthritis (RA) requires further study of the underlying pathophysiology and determination of the at-risk RA phenotype. Our objectives were to describe the cardiac structure and function and arterial stiffness, and association with disease phenotype in patients with established) RA, in comparison to healthy controls, as measured by cardiovascular magnetic resonance imaging (CMR). 76 patients with established RA and no history of CVD/diabetes mellitus were assessed for RA and cardiovascular profile and underwent a non-contrast 3T-CMR, and compared to 26 healthy controls. A univariable analysis and multivariable linear regression model determined associations between baseline variables and CMR-measures. Ten-year cardiovascular risk scores were increased in RA compared with controls. Adjusting for age, sex and traditional cardiovascular risk factors, patients with RA had reduced left ventricular ejection fraction (mean difference − 2.86% (− 5.17, − 0.55) p = 0.016), reduced absolute values of mid systolic strain rate (p 2 (− 8.92, − 0.20), p = 0.041). CMR-measures predominantly associated with traditional cardiovascular risk factors; male sex and systolic blood pressure independently with increasing LVMI. Patients with established RA and no history of CVD have evidence of reduced LV systolic function and LVMI after adjustment for traditional cardiovascular risk factors; the latter suggesting cardiac pathology other than atherosclerosis in RA. Traditional cardiovascular risk factors, rather than RA disease phenotype, appear to be key determinants of subclinical CVD in RA potentially warranting more effective cardiovascular risk reduction programs.

Objective This study aimed to quantify the relative maternal and fetal risks and benefits of continuing labor induction. Study Design This retrospective cohort study included nulliparous women with nonanomalous, singleton, vertex, term pregnancies undergoing labor induction with intact membranes at a tertiary-care academic hospital from January 2015 to April 2017. The primary outcome was mode of delivery. Secondary outcomes included hemorrhage, transfusion, infection, and composite neonatal morbidity. The data were analyzed using chi-square and Fisher's exact tests. Multivariable regression was used to control for potential confounders. Results A total of 955 patients met the inclusion criteria. The median induction duration was 32.3 hours (interquartile range: 20.4–41 hours) and the vaginal delivery rate was 70.5% (n = 673). The chance of vaginal delivery at 12, 24, 36, 48, 60, and ≥60 hours was 76, 83, 77, 74, 72, and 48%, respectively. After controlling for confounders, there was a 20% decrease in chance of vaginal delivery with induction ≥ 24 hours compared with induction Conclusion In this cohort, the chance of vaginal delivery remained nearly 50% even when induction extended beyond 60 hours. Risks of hemorrhage and maternal infection rose modestly over time, but primarily in patients who underwent cesarean delivery. There was no difference in the risk of transfusion beyond 24 hours and no association between induction duration and neonatal morbidity. These findings may be useful when engaging patients in shared decision-making during labor induction.

Studies presented in this paper concern wide issue of thermal comfort of protective clothing. The Computer Aided Design (CAD) software tools to analyze thermal insulation of multilayer textile assembly used in thermal protective clothing were applied. First, 3D geometry and morphology of a real textile assembly was modeled. In the designed model different scales of resolution were used for individual layers, ranging from a homogenized nonwoven fabrics model to mapping the geometry of yarns in woven fabrics model. Next, the finite volume method to estimate thermal insulation properties of this assembly, when exposed to heat radiation, was used. Finally, the simulation results were verified experimentally using method described in EN ISO 6942. On the basis of both simulation and experimental results obtained for the multilayer textile assembly, protective clothing parameters directly affecting the ability to protect against heat, were determined. Correlating simulated and experimental values of these parameters were obtained, which may indicate that applied software can be an effective tool in analyzing thermal properties of newly designed multilayer functional clothing.

The Movement Disorder Society criteria for progressive supranuclear palsy introduced the category 'probable 4-repeat (4R)-tauopathy' for joint clinical diagnosis of progressive supranuclear palsy and corticobasal degeneration.To validate the accuracy of these clinical criteria for 'probable 4R-tauopathy' to predict underlying 4R-tauopathy pathology.Diagnostic accuracy for 4R-tauopathies according to the established criteria was estimated retrospectively in autopsy-confirmed patients with progressive supranuclear palsy and corticobasal degeneration (grouped as 4R-tauopathies), and Parkinson's disease, multiple system atrophy, and frontotemporal lobar degeneration (grouped as non-4R-tauopathies).We identified 250 cases with progressive supranuclear palsy (N = 195) and corticobasal degeneration (N = 55) and with and non-4R-tauopathies (N = 161). Sensitivity and specificity of 'probable 4R-tauopathy' was 10% and 99% in the first year and 59% and 88% at final record.The new diagnostic category 'probable 4R-tauopathy' showed high specificity and may be suitable for the recruitment of patients with progressive supranuclear palsy and corticobasal degeneration into therapeutic trials targeting 4R-tauopathy. The low sensitivity underpins the need for diagnostic biomarkers. © 2019 International Parkinson and Movement Disorder Society.

Background/Context The Individuals with Disabilities Education Act (IDEA, 2004) requires that all students with disabilities (SWD) receive a free, appropriate public education designed to meet their unique needs to prepare them for post-school education and employment (American Psychological Association, 2018). In the past two decades, momentum has grown for a supplementary idea: that schools be held accountable for SWD achieving grade-level standards. Thus standards-based reform for SWD is often caught between ideals of standardization and principles of differentiation. Purpose and Research Questions The purpose of this study was to examine the extent to which district administrators, principals, general educators, and special educators differ in their policy perceptions of the newest college- and career-readiness standards (CCRS) for SWD versus other learners. Our research questions were: To what extent do teachers of SWD report delivering similar or different instructional content compared to general education teachers? What types of instructional supports do teachers provide, what types of professional development do teachers receive, and how do these differ by teacher type? How do policy perceptions differ between teachers of SWD and general education teachers? How do district administrators, principals, and teachers differ in their policy perceptions of the CCRS as they relate to SWD? Research Design In three states (Texas, Ohio, and Kentucky), we surveyed a stratified sample of teachers, principals, and district administrators on the implementation of their state's standards and directed them to respond for SWD who participate in the regular accountability system. Conclusions/Recommendations Results indicate an environment where SWD continue to receive less grade-level content and, in Texas and Ohio, are served by personnel who do not believe that the standards are appropriate. Kentucky demonstrated greater consistencies between general education and SWD instruction and policy environments. Findings raise questions about whether CCRS are being implemented for all students.

Summary Background Several SARS-CoV-2 variants of concern have been identified that partly escape serum neutralisation elicited by current vaccines. Studies have also shown that vaccines demonstrate reduced protection against symptomatic infection with SARS-CoV-2 variants. We explored whether in-vitro neutralisation titres remain predictive of vaccine protection from infection with SARS-CoV-2 variants. Methods In this meta-analysis, we analysed published data from 24 identified studies on in-vitro neutralisation and clinical protection to understand the loss of neutralisation to existing SARS-CoV-2 variants of concern. We integrated the results of this analysis into our existing statistical model relating in-vitro neutralisation to protection (parameterised on data from ancestral virus infection) to estimate vaccine efficacy against SARS-CoV-2 variants. We also analysed data on boosting of vaccine responses and use the model to predict the impact of booster vaccination on protection against SARS-CoV-2 variants. Findings The neutralising activity against the ancestral SARS-CoV-2 was highly predictive of neutralisation of variants of concern. Decreases in neutralisation titre to the alpha (1·6-fold), beta (8·8-fold), gamma (3·5-fold), and delta (3·9-fold) variants (compared to the ancestral virus) were not significantly different between different vaccines. Neutralisation remained strongly correlated with protection from symptomatic infection with SARS-CoV-2 variants of concern (rS=0·81, p=0·0005) and the existing model remained predictive of vaccine efficacy against variants of concern once decreases in neutralisation to the variants of concern were incorporated. Modelling of predicted vaccine efficacy against variants over time suggested that protection against symptomatic infection might decrease below 50% within the first year after vaccination for some vaccines. Boosting of previously infected individuals with existing vaccines (which target ancestral virus) is predicted to provide a higher degree of protection from infection with variants of concern than primary vaccination schedules alone. Interpretation In-vitro neutralisation titres remain a correlate of protection from SARS-CoV-2 variants and modelling of the effects of waning immunity predicts a loss of protection to the variants after vaccination. However, booster vaccination with current vaccines should enable higher neutralisation to SARS-CoV-2 variants than is achieved with primary vaccination, which is predicted to provide robust protection from severe infection outcomes with the current SARS-CoV-2 variants of concern, at least in the medium term. Funding The National Health and Medical Research Council (Australia), the Medical Research Future Fund (Australia), and the Victorian Government.

Skeletal muscle dysfunction may contribute to the progression and severity of amyotrophic lateral sclerosis (ALS). In the present study, we characterized the skeletal muscle pathophysiology in an inducible transgenic mouse model (rNLS8) that develops a TAR-DNA binding protein (TDP-43) proteinopathy and ALS-like neuropathology and disease progression; representative of >90% of all familial and sporadic ALS cases. As we previously observed elevated levels of miR-23a in skeletal muscle of patients with familial and sporadic ALS, we also investigated the effect of miR-23a suppression on skeletal muscle pathophysiology and disease severity in rNLS8 mice. Five weeks after disease onset TDP-43 protein accumulation was observed in tibialis anterior (TA), quadriceps (QUAD) and diaphragm muscle lysates and associated with skeletal muscle atrophy. In the TA muscle TDP-43 was detected in muscle fibres that appeared atrophied and angular in appearance and that also contained β-amyloid aggregates. These fibres were also positive for neural cell adhesion molecule (NCAM), but not embryonic myosin heavy chain (eMHC), indicating TDP-43/ β-amyloid localization in denervated muscle fibres. There was an upregulation of genes associated with myogenesis and NMJ degeneration and a decrease in the MURF1 atrophy-related protein in skeletal muscle. Suppression of miR-23a impaired rotarod performance and grip strength and accelerated body weight loss during early stages of disease progression. This was associated with increased AchRα mRNA expression and decreased protein levels of PGC-1α. The TDP-43 proteinopathy-induced impairment of whole body and skeletal muscle functional performance is associated with muscle wasting and elevated myogenic and NMJ stress markers. Suppressing miR-23a in the rNLS8 mouse model of ALS contributes to an early acceleration of disease progression as measured by decline in motor function.

OBJECTIVE The objective of this study was to assess the relevance of shunted hydrocephalus in regard to participation by young patients in physical education (PE) classes. Students diagnosed with this condition are very often restricted in PE classes owing to the lack of official and well-defined guidelines. However, the medical literature suggests that there is no relationship between the disease and risk of sport-related injuries. In this study, the authors intended to evaluate not only the accuracy of this statement, but also to explore the factors that delay or foreclose return to exercise. METHODS The analysis was conducted on patients aged < 18 years with a diagnosis of shunt-treated hydrocephalus who received follow-up for a minimum of 1 year. Collected medical data were examined for factors limiting participation in PE at school. Indicators of both sport-related injuries and conditions acceptable for return to exercise were gathered during follow-up visits. RESULTS In this study, 72.72% of patients attended sport activities in schools. The group based on return to PE class differed significantly in the occurrence of neurological deficits, as well as presence of comorbidities. In univariate analysis, the authors identified these parameters as risk factors limiting participation in PE. On the contrary, etiology of hydrocephalus, type of shunting device, number of shunt malfunctions, and presence of epilepsy did not significantly influence sport engagement. CONCLUSIONS This study shows that many patients with shunt-treated hydrocephalus can safely participate in PE. Presence of neurological deficits before and after neurosurgical treatment, as well as presence of comorbidities, are factors that negatively impact the possibility of a patient returning to physical activity. Sport-related injuries do occur, but at a low incidence.

Background Posthemorrhagic hydrocephalus of prematurity (PHHP) is a result of intraventricular hemorrhage (IVH). IVH occurs in 6 to 23% of the preterms in countries with advanced medical health care. Most of these patients will eventually require the use of ventriculoperitoneal shunt (VPS). The purpose of this study is to assess the risk factors of VPS implantation in patients with PHHP who have been treated with ventricular catheter with subcutaneous reservoir (VCSR). Methods The retrospective study was conducted evaluating 35 premature patients who suffered from severe IVH. Their mean gestational age was 28 weeks. The assessment included antenatal factors such as gestational age, birth weight, and intrauterine and perinatal infection. Postparturient period factors such as the IVH grade, time between diagnosis, and VCSR implantation and body weight on VCSR implantation were also considered in the study. Postprocedural complications, such as bacterial cerebrospinal fluid (CSF) infection, sepsis, and skin lesions, were evaluated. Data were calculated with R program, version 4.04. Results From among 35 evaluated patients, 23 (65.71%) required a VPS. Median of birth weight was 1,190 g. Infections were observed in 11 (31.43%) cases. Mean time between IVH diagnosis and VCSR implantation was 2.6 weeks. Postprocedural complications occurred in 19 (54.29%) patients. None of the evaluated factors has proven its statistical significance (p > 0.05) for being a potential risk factor for VPS implantation. Conclusion External factors seem to not affect the necessity of VPS implantation in patients after the severe IVH. Ostensibly, there seems to be no difference between the grades III and the IV of Papile's IVH scale regarding VPS implantation necessity.

OBJECTIVE:To test the hypothesis that a longer length of time between diagnosis of hypertensive disorders of pregnancy and delivery is associated with increased risk of cardiovascular morbidity in the years after delivery.METHODS:This is a retrospective cohort study based in the New York State Inpat

COVID-19 has become a major cause of global mortality and driven massive health and economic disruptions. Mass global vaccination offers the most efficient pathway towards ending the pandemic. The development and deployment of first-generation COVID-19 vaccines, encompassing mRNA or viral vectors, has proceeded at a phenomenal pace. Going forward, nanoparticle-based vaccines which deliver SARS-CoV-2 antigens will play an increasing role in extending or improving vaccination outcomes against COVID-19. At present, over 26 nanoparticle vaccine candidates have advanced into clinical testing, with ∼60 more in pre-clinical development. Here, we discuss the emerging promise of nanotechnology in vaccine design and manufacturing to combat SARS-CoV-2, and highlight opportunities and challenges presented by these novel vaccine platforms.

We present the results for CAPRI Round 50, the fourth joint CASP-CAPRI protein assembly prediction challenge. The Round comprised a total of twelve targets, including six dimers, three trimers, and three higher-order oligomers. Four of these were easy targets, for which good structural templates were available either for the full assembly, or for the main interfaces (of the higher-order oligomers). Eight were difficult targets for which only distantly related templates were found for the individual subunits. Twenty-five CAPRI groups including eight automatic servers submitted ~1250 models per target. Twenty groups including six servers participated in the CAPRI scoring challenge submitted ~190 models per target. The accuracy of the predicted models was evaluated using the classical CAPRI criteria. The prediction performance was measured by a weighted scoring scheme that takes into account the number of models of acceptable quality or higher submitted by each group as part of their five top-ranking models. Compared to the previous CASP-CAPRI challenge, top performing groups submitted such models for a larger fraction (70–75%) of the targets in this Round, but fewer of these models were of high accuracy. Scorer groups achieved stronger performance with more groups submitting correct models for 70–80% of the targets or achieving high accuracy predictions. Servers performed less well in general, except for the MDOCKPP and LZERD servers, who performed on par with human groups. In addition to these results, major advances in methodology are discussed, providing an informative overview of where the prediction of protein assemblies currently stands., Cancer Research UK, Grant/Award Number: FC001003; Changzhou Science and Technology Bureau, Grant/Award Number: CE20200503; Department of Energy and Climate Change, Grant/Award Numbers: DE-AR001213, DE-SC0020400, DE-SC0021303; H2020 European Institute of Innovation and Technology, Grant/Award Numbers: 675728, 777536, 823830; Institut national de recherche en informatique et en automatique (INRIA), Grant/Award Number: Cordi-S; Lietuvos Mokslo Taryba, Grant/Award Numbers: S-MIP-17-60, S-MIP-21-35; Medical Research Council, Grant/Award Number: FC001003; Japan Society for the Promotion of Science KAKENHI, Grant/Award Number: JP19J00950; Ministerio de Ciencia e Innovación, Grant/Award Number: PID2019-110167RB-I00; Narodowe Centrum Nauki, Grant/Award Numbers: UMO-2017/25/B/ST4/01026, UMO-2017/26/M/ST4/00044, UMO-2017/27/B/ST4/00926; National Institute of General Medical Sciences, Grant/Award Numbers: R21GM127952, R35GM118078, RM1135136, T32GM132024; National Institutes of Health, Grant/Award Numbers: R01GM074255, R01GM078221, R01GM093123, R01GM109980, R01GM133840, R01GN123055, R01HL142301, R35GM124952, R35GM136409; National Natural Science Foundation of China, Grant/Award Number: 81603152; National Science Foundation, Grant/Award Numbers: AF1645512, CCF1943008, CMMI1825941, DBI1759277, DBI1759934, DBI1917263, DBI20036350, IIS1763246, MCB1925643; NWO, Grant/Award Number: TOP-PUNT 718.015.001; Wellcome Trust, Grant/Award Number: FC001003

OBJECTIVE Iron-deficiency anemia (IDA) can have serious consequences for mothers and babies. Iron supplementation is recommended, but the administration route is controversial. We sought to conduct a randomized controlled trial (RCT) testing the effectiveness and safety of intravenous (IV) iron compared with oral iron on perinatal outcomes in pregnant women with IDA. STUDY DESIGN This open-label RCT randomized patients with IDA (hemoglobin [hgb]

Significance Indigenous populations worldwide are highly susceptible to influenza virus infections. Vaccination with inactivated virus is highly recommended to protect Indigenous populations, including Indigenous Australians. There is no study to date that assessed immune responses induced by the inactivated seasonal influenza vaccine in the Indigenous population. Vaccine recommendations are thus based on data generated for non-Indigenous populations and might not be representative for Indigenous people. We found robust antibody responses to influenza vaccination induced in Indigenous Australians, with activation profiles of cTFH1 cells at the acute response strongly correlating with total change of antibody vaccine titers induced by vaccination. Our work strongly supports the recommendation of influenza vaccination to protect Indigenous populations from severe seasonal influenza virus infections and subsequent complications., Morbidity and mortality rates from seasonal and pandemic influenza occur disproportionately in high-risk groups, including Indigenous people globally. Although vaccination against influenza is recommended for those most at risk, studies on immune responses elicited by seasonal vaccines in Indigenous populations are largely missing, with no data available for Indigenous Australians and only one report published on antibody responses in Indigenous Canadians. We recruited 78 Indigenous and 84 non-Indigenous Australians vaccinated with the quadrivalent influenza vaccine into the Looking into InFluenza T cell immunity - Vaccination cohort study and collected blood to define baseline, early (day 7), and memory (day 28) immune responses. We performed in-depth analyses of T and B cell activation, formation of memory B cells, and antibody profiles and investigated host factors that could contribute to vaccine responses. We found activation profiles of circulating T follicular helper type-1 cells at the early stage correlated strongly with the total change in antibody titers induced by vaccination. Formation of influenza-specific hemagglutinin-binding memory B cells was significantly higher in seroconverters compared with nonseroconverters. In-depth antibody characterization revealed a reduction in immunoglobulin G3 before and after vaccination in the Indigenous Australian population, potentially linked to the increased frequency of the G3m21* allotype. Overall, our data provide evidence that Indigenous populations elicit robust, broad, and prototypical immune responses following immunization with seasonal inactivated influenza vaccines. Our work strongly supports the recommendation of influenza vaccination to protect Indigenous populations from severe seasonal influenza virus infections and their subsequent complications.