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Purpose: Recent research explores using neural networks to reconstruct undersampled magnetic resonance imaging. Because of the complexity of the artifacts in the reconstructed images, there is a need to develop task-based approaches to image quality. We compared conventional global quantitative metrics to evaluate image quality in undersampled images generated by a neural network with human observer performance in a detection task. The purpose is to study which acceleration (2×, 3×, 4×, 5×) would be chosen with the conventional metrics and compare it to the acceleration chosen by human observer performance., Approach: We used common global metrics for evaluating image quality: the normalized root mean squared error (NRMSE) and structural similarity (SSIM). These metrics are compared with a measure of image quality that incorporates a subtle signal for a specific task to allow for image quality assessment that locally evaluates the effect of undersampling on a signal. We used a U-Net to reconstruct under-sampled images with 2×, 3×, 4×, and 5× one-dimensional undersampling rates. Cross-validation was performed for a 500- and a 4000-image training set with both SSIM and MSE losses. A two-alternative forced choice (2-AFC) observer study was carried out for detecting a subtle signal (small blurred disk) from images with the 4000-image training set., Results: We found that for both loss functions, the human observer performance on the 2-AFC studies led to a choice of a 2× undersampling, but the SSIM and NRMSE led to a choice of a 3× undersampling., Conclusions: For this detection task using a subtle small signal at the edge of detectability, SSIM and NRMSE led to an overestimate of the achievable undersampling using a U-Net before a steep loss of image quality between 2×, 3×, 4×, 5× undersampling rates when compared to the performance of human observers in the detection task., (© 2024 Society of Photo-Optical Instrumentation Engineers (SPIE).)

The treatment for COVID-19 has evolved rapidly since the start of the pandemic and now consists mainly of antiviral and immunomodulatory agents. Antivirals, such as remdesivir and nirmatrelvir-ritonavir, have proved to be most useful earlier in illness (e.g., as outpatient therapy) and for less severe disease. Immunomodulatory therapies, such as dexamethasone and interleukin-6 or Janus kinase inhibitors, are most useful in severe disease or critical illness. The role of anti-SARS-CoV-2 monoclonal antibodies has diminished because of the emergence of viral variants that are not anticipated to be susceptible to these treatments, and there still is not a consensus on the use of convalescent plasma. COVID-19 has been associated with increased rates of venous thromboembolism, but the role of antithrombotic therapy is limited. Multiple investigational agents continue to be studied, which will alter current treatment paradigms as new data are released.

BACKGROUNDSanaria PfSPZ Vaccine, composed of attenuated Plasmodium falciparum (Pf) sporozoites (SPZ), protects against malaria. We conducted this clinical trial to assess the safety and efficacy of PfSPZ Vaccine in HIV-positive (HIV+) individuals, since the HIV-infection status of participants in mass vaccination programs may be unknown.METHODSThis randomized, double-blind, placebo-controlled trial enrolled 18- to 45-year-old HIV-negative (HIV-) and well-controlled HIV+ Tanzanians (HIV viral load <40 copies/mL, CD4 counts >500 cells/μL). Participants received 5 doses of PfSPZ Vaccine or normal saline (NS) over 28 days, followed by controlled human malaria infection (CHMI) 3 weeks later.RESULTSThere were no solicited adverse events in the 9 HIV- and 12 HIV+ participants. After CHMI, 6 of 6 NS controls, 1 of 5 HIV- vaccinees, and 4 of 4 HIV+ vaccinees were Pf positive by quantitative PCR (qPCR). After immunization, anti-Pf circumsporozoite protein (anti-PfCSP) (isotype and IgG subclass) and anti-PfSPZ antibodies, anti-PfSPZ CD4+ T cell responses, and Vδ2+ γδ CD3+ T cells were nonsignificantly higher in HIV- than in HIV+ vaccinees. Sera from HIV- vaccinees had significantly higher inhibition of PfSPZ invasion of hepatocytes in vitro and antibody-dependent complement deposition (ADCD) and Fcγ3B binding by anti-PfCSP and ADCD by anti-cell-traversal protein for ookinetes and SPZ (anti-PfCelTOS) antibodies.CONCLUSIONSPfSPZ Vaccine was safe and well tolerated in HIV+ vaccinees, but not protective. Vaccine efficacy was 80% in HIV- vaccinees (P = 0.012), whose sera had significantly higher inhibition of PfSPZ invasion of hepatocytes and enrichment of multifunctional PfCSP antibodies. A more potent PfSPZ vaccine or regimen is needed to protect those living with HIV against Pf infection in Africa.TRIAL REGISTRATIONClinicalTrials.gov NCT03420053.FUNDINGEquatorial Guinea Malaria Vaccine Initiative (EGMVI), made up of the Government of Equatorial Guinea Ministries of Mines and Hydrocarbons, and Health and Social Welfare, Marathon Equatorial Guinea Production Limited, Noble Energy, Atlantic Methanol Production Company, and EG LNG; Swiss government, through ESKAS scholarship grant no. 2016.0056; Intramural Research Program of the National Institute of Allergy and Infectious Diseases, NIH; NIH grant 1U01AI155354-01.

Background: Studies have demonstrated the protective role of antibodies against malaria. Young children are known to be particularly vulnerable to malaria, pointing to the evolution of naturally acquired clinical immunity over time. However, whether changes in antibody functionality track with the acquisition of naturally acquired malaria immunity remains incompletely understood., Methods: Using systems serology, we characterized sporozoite- and merozoite-specific antibody profiles of uninfected Malian children before the malaria season who differed in their ability to control parasitemia and fever following Plasmodium falciparum (Pf) infection. We then assessed the contributions of individual traits to overall clinical outcomes, focusing on the immunodominant sporozoite CSP and merozoite AMA1 and MSP1 antigens., Results: Humoral immunity evolved with age, with an expansion of both magnitude and functional quality, particularly within blood-stage phagocytic antibody activity. Moreover, concerning clinical outcomes postinfection, protected children had higher antibody-dependent neutrophil activity along with higher levels of MSP1-specific IgG3 and IgA and CSP-specific IgG3 and IgG4 prior to the malaria season., Conclusions: These data point to the natural evolution of functional humoral immunity to Pf with age and highlight particular antibody Fc-effector profiles associated with the control of malaria in children, providing clues for the design of next-generation vaccines or therapeutics., Competing Interests: Potential conflicts of interest. G. A. is the founder of Seromyx Inc and Leyden Labs. G. A.’s interests were reviewed and managed by MGH and Partners HealthCare in accordance with their conflict-of-interest policies. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts 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. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Beyond the acute illness caused by severe acute respiratory coronavirus 2 (SARS-CoV-2) infection, about one-fifth of infections result in long-term persistence of symptoms despite the apparent clearance of infection. Insights into the mechanisms that underlie postacute sequelae of COVID-19 (PASC) will be critical for the prevention and clinical management of long-term complications of COVID-19. Several hypotheses have been proposed that may account for the development of PASC, including persistence of virus and dysregulation of immune responses. Among the immunological changes noted in PASC, alterations in humoral immunity have been observed in some patient subsets. To begin to determine whether SARS-CoV-2- or other pathogen-specific humoral immune responses evolve uniquely in PASC, we performed comprehensive antibody profiling against SARS-CoV-2, a panel of endemic pathogens, and a panel of routine vaccine antigens using systems serology in two cohorts of patients with preexisting systemic autoimmune rheumatic disease (SARD) who either developed or did not develop PASC. A distinct qualitative shift observed in Fcγ receptor (FcγR) binding was observed in individuals with PASC. Specifically, individuals with PASC harbored weaker FcγR-binding anti-SARS-CoV-2 antibodies and stronger FcγR-binding antibody responses against the endemic coronavirus OC43. Individuals with PASC developed an OC43 S2-specific antibody response with stronger FcγR binding, linked to cross-reactivity across SARS-CoV-2 and common coronaviruses. These findings identify previous coronavirus imprinting as a potential marker for the development of PASC in individuals with SARDs.

Coronavirus disease 2019 (COVID-19) convalescent plasma (CCP), a passive polyclonal antibody therapeutic agent, has had mixed clinical results. Although antibody neutralization is the predominant approach to benchmarking CCP efficacy, CCP may also influence the evolution of the endogenous antibody response. Using systems serology to comprehensively profile severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) functional antibodies of hospitalized people with COVID-19 enrolled in a randomized controlled trial of CCP (ClinicalTrials.gov: NCT04397757), we find that the clinical benefits of CCP are associated with a shift toward reduced inflammatory Spike (S) responses and enhanced nucleocapsid (N) humoral responses. We find that CCP has the greatest clinical benefit in participants with low pre-existing anti-SARS-CoV-2 antibody function and that CCP-induced immunomodulatory Fc glycan profiles and N immunodominant profiles persist for at least 2 months. We highlight a potential mechanism of action of CCP associated with durable immunomodulation, outline optimal patient characteristics for CCP treatment, and provide guidance for development of a different class of COVID-19 hyperinflammation-targeting antibody therapeutic agents., Competing Interests: Declaration of interests G.A. is a founder of SeromYx Systems, Inc., an equity holder in Leyden Labs, and a member of the scientific advisory board of Sanofi Pasteur., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Transfer of convalescent plasma (CP) had been proposed early during the SARS-CoV-2 pandemic as an accessible therapy, yet trial results worldwide have been mixed, potentially due to the heterogeneous nature of CP. Here we perform deep profiling of SARS-CoV-2-specific antibody titer, Fc-receptor binding, and Fc-mediated functional assays in CP units, as well as in plasma from hospitalized COVID-19 patients before and after CP administration. The profiling results show that, although all recipients exhibit expanded SARS-CoV-2-specific humoral immune responses, CP units contain more functional antibodies than recipient plasma. Meanwhile, CP functional profiles influence the evolution of recipient humoral immunity in conjuncture with the recipient's pre-existing SARS-CoV2-specific antibody titers: CP-derived SARS-CoV-2 nucleocapsid-specific antibody functions are associated with muted humoral immune evolution in patients with high titer anti-spike IgG. Our data thus provide insights into the unexpected impact of CP-derived functional anti-spike and anti-nucleocapsid antibodies on the evolution of SARS-CoV-2-specific response following severe infection., (© 2021. The Author(s).)

Mountain regions in arid and semi-arid climates, such as California, are considered particularly sensitive to climate change because global warming is expected to alter snowpack storage and related surface water supply. It is therefore important to accurately capture snowmelt processes in watershed models for climate change impact assessment. In this study we use the Soil and Water Assessment Tool (SWAT) to estimate projected changes in snowpack and streamflow in four alpine tributaries to the agriculturally important but less studied southern Central Valley, California. Watershed responses are evaluated for four CMIP5 climate models (HadGEM&#95;ES, CNRM-CM5, CanESM2 and MIROC5) and two emission scenarios (RCP 4.5 and RCP 8.5) for 2020-2099. SWAT models are calibrated following a dual-objective, lumped calibration approach with an automatic calibration against observed streamflow (stage 1) and a manual calibration against reconstructed Parallel Energy Balance (ParBal) snow water equivalent (SWE) data (stage 2). Results indicate that under a warming climate, peak streamflow is expected to increase 0.5-4 times in magnitude in the coming decades and to arrive 2-4 months earlier in the year because of earlier snowmelt. In the foreseeable future, snow cover will reduce gradually in the lower elevations and diminish at higher rates at higher elevation towards the end of the 21st century. Surface water supply is predicted to increase in the southern Central Valley under the evaluated scenarios but increased temporal variability (wetter wet seasons and drier dry seasons) will create new challenges for managing supply. The study further highlights that the use of remote sensing based, reconstructed SWE data could fill the current gap of limited in-situ SWE observations to improve the snow calibration of SWAT to better predict climate change impacts in semi-arid, snow-dominated watersheds., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Satellite services are fundamental to the global economy, and their design reflects a tradeoff between coverage and cost. Here, we report the discovery of two alternative 4-satellite constellations with 24- and 48-hour periods, both of which attain nearly continuous global coverage. The 4-satellite constellations harness energy from nonlinear orbital perturbation forces (e.g., Earth's geopotential, gravitational effects of the sun and moon, and solar radiation pressure) to reduce their propellant and maintenance costs. Our findings demonstrate that small sacrifices in global coverage at user-specified longitudes allow operationally viable constellations with significantly reduced mass-to-orbit costs and increased design life. The 24-hour period constellation reduces the overall required vehicle mass budget for propellant by approximately 60% compared to a geostationary Earth orbit constellation with similar coverage over typical satellite lifetimes. Mass savings of this magnitude permit the use of less expensive launch vehicles, installation of additional instruments, and substantially improved mission life.

Introduction: Pelvic reirradiation (re-RT) presents challenges due to concerns for late toxicity to tissues-at-risk including pelvic bone marrow (PBM). We routinely utilize a hyperfractionated, accelerated re-RT for recurrent rectal or anal cancer in the setting of prior radiation. We hypothesized that proton beam radiation (PBR) is uniquely suited to limit doses to pelvic non-target tissues better than photon-based approaches., Materials and Methods: All patients who received hyperfractionated, accelerated PBR re-RT to the pelvis from 2007 to 2017 were identified. Re-RT was delivered twice daily with a 6 h minimum interfraction interval at 1.5 Gray Relative Biological Effectiveness (Gy(RBE)) per fraction to a total dose of 39-45 Gy(RBE). Concurrent chemotherapy was given to all patients. Comparison photon plans were generated for dosimetric analysis. Dosimetric parameters compared using a matched-pair analysis and the Wilcoxon signed-rank test. Survival analysis was performed Kaplan Meier curves., Results: Fifteen patients were identified, with a median prior pelvic RT dose of 50.4 Gy (range 25-80 Gy). Median time between the initial RT and PBRT re-RT was 4.7 years (range 1.0-36.1 years). In comparison to corresponding photon re-RT plans, PBR re-RT plans had lower mean PBM dose, and lower volume of PBM getting 5 Gy, 10 Gy, 20 Gy, and 30 Gy (p < 0.001, p < 0.001, p < 0.001, and p = 0.033, respectively).With median 13.9 months follow-up after PBR re-RT, five patients had developed local recurrences, and four patients had developed distant metastases. One-year overall survival following PBR re-RT was 67.5% and one-year progression free survival was 58.7%. No patients developed acute or late Grade 4 toxicity., Conclusion: PBR re-RT affords improved sparing of PBM compared with photon-based re-RT. Clinically, PBR re-RT is well-tolerated. However, given modest control rates with definitive re-RT without subsequent surgical resection, a multidisciplinary approach should be favored in this setting when feasible., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

We have previously identified the cytoplasmic prolyl tRNA synthetase in Plasmodium falciparum as the functional target of the natural product febrifugine and its synthetic analogue halofuginone (HFG), one of the most potent antimalarials discovered to date. However, our studies also discovered that short-term treatment of asexual blood stage P. falciparum with HFG analogues causes a 20-fold increase in intracellular proline, termed the adaptive proline response (APR), which renders parasites tolerant to HFG. This novel resistance phenotype lacks an apparent genetic basis but remains stable after drug withdrawal. On the basis of our findings that HFG treatment induces eIF2α phosphorylation, a sensitive marker and mediator of cellular stress, we here investigate if eIF2α-signaling is functionally linked to the APR. In our comparative studies using a parasite line lacking PfeIK1, the Plasmodium orthologue of the eIF2α-kinase GCN2 that mediates amino acid deprivation sensing, we show that HFG activity and the APR are independent from PfeIK1 and eIF2α signaling.

The emergence of drug resistance is a major limitation of current antimalarials. The discovery of new druggable targets and pathways including those that are critical for multiple life cycle stages of the malaria parasite is a major goal for developing next-generation antimalarial drugs. Using an integrated chemogenomics approach that combined drug resistance selection, whole-genome sequencing, and an orthogonal yeast model, we demonstrate that the cytoplasmic prolyl-tRNA (transfer RNA) synthetase (PfcPRS) of the malaria parasite Plasmodium falciparum is a biochemical and functional target of febrifugine and its synthetic derivative halofuginone. Febrifugine is the active principle of a traditional Chinese herbal remedy for malaria. We show that treatment with febrifugine derivatives activated the amino acid starvation response in both P. falciparum and a transgenic yeast strain expressing PfcPRS. We further demonstrate in the Plasmodium berghei mouse model of malaria that halofuginol, a new halofuginone analog that we developed, is active against both liver and asexual blood stages of the malaria parasite. Halofuginol, unlike halofuginone and febrifugine, is well tolerated at efficacious doses and represents a promising lead for the development of dual-stage next-generation antimalarials., (Copyright © 2015, American Association for the Advancement of Science.)

Background: Drug resistance remains a major public health challenge for malaria treatment and eradication. Individual loci associated with drug resistance to many antimalarials have been identified, but their epistasis with other resistance mechanisms has not yet been elucidated., Results: We previously described two mutations in the cytoplasmic prolyl-tRNA synthetase (cPRS) gene that confer resistance to halofuginone. We describe here the evolutionary trajectory of halofuginone resistance of two independent drug resistance selections in Plasmodium falciparum. Using this novel methodology, we discover an unexpected non-genetic drug resistance mechanism that P. falciparum utilizes before genetic modification of the cPRS. P. falciparum first upregulates its proline amino acid homeostasis in response to halofuginone pressure. We show that this non-genetic adaptation to halofuginone is not likely mediated by differential RNA expression and precedes mutation or amplification of the cPRS gene. By tracking the evolution of the two drug resistance selections with whole genome sequencing, we further demonstrate that the cPRS locus accounts for the majority of genetic adaptation to halofuginone in P. falciparum. We further validate that copy-number variations at the cPRS locus also contribute to halofuginone resistance., Conclusions: We provide a three-step model for multi-locus evolution of halofuginone drug resistance in P. falciparum. Informed by genomic approaches, our results provide the first comprehensive view of the evolutionary trajectory malaria parasites take to achieve drug resistance. Our understanding of the multiple genetic and non-genetic mechanisms of drug resistance informs how we will design and pair future anti-malarials for clinical use.

Objective: To examine the effect of various clinical tracks within the veterinary medical clinical curriculum at Texas A&M University on clinical diagnostic proficiency as determined by pre- and post-training assessment. We expected that the clinical track chosen by the student would impact their measured outcome with bias toward higher scores in their chosen field., Design: Prospective cohort study., Study Population: 32 students from the College of Veterinary Medicine and Biomedical Sciences at Texas A&M University., Procedures: By use of standardized, written case scenarios, clinical reasoning was assessed twice: once prior to the clinical (fourth) year of the curriculum and again at completion of the clinical year. Students demonstrated their abilities to collect and organize appropriate clinical data (history, physical examination, and laboratory findings), determine clinical diagnoses, and formulate and implement acceptable treatment modalities. Data from clinical assessments were compared for a given cohort and correlated with other measures (eg, grades, standardized test scores, and species-specific curricular track)., Results: Differences were detected in clinical diagnostic proficiency among students in different clinical tracks and for different species groups in the case scenarios. Tracking by species group in the clinical veterinary curriculum appeared to affect development of clinical reasoning and resulted in differential proficiency among cases for differing species groups., Conclusions and Clinical Relevance: Differences in clinical experiences between small animal tracks and all other track opportunities (large animal, mixed animal, and alternative) influenced the development of clinical proficiency in fourth-year veterinary students during their clinical training period.

Objective: To evaluate chemotactic, phagocytic, and bactericidal activities of bovine and porcine alveolar macrophages (AM) exposed to tilmicosin., Animals: 12 healthy calves and 12 healthy pigs., Procedures: Lungs were obtained immediately after euthanasia; AM were collected by means of bronchoalveolar lavage and density gradient centrifugation. Chemotactic activity was evaluated by exposing AM to lipopolysaccharide or macrophage inhibitory peptide during incubation with tilmicosin. Phagocytic activity was evaluated by incubating AM with tilmicosin for 24 hours and then with tilmicosin-resistant Salmonella serotype Typhimurium. Bactericidal activity was evaluated by incubating AM with tilmicosin (0, 10, or 20 microg/ml for bovine AM; 0 or 10 microg/ml or 10 microg/ml but washed free of tilmicosin for porcine AM) and then with Mannheimia haemolytica (bovine AM) or with Actinobacillus pleuropneumoniae or Pasteurella multocida (porcine AM)., Results: Tilmicosin had no significant effects on chemotactic or phagocytic activities of bovine or porcine AM. The time-course of bactericidal activity was best described by polynomial equations. Time to cessation of bacterial growth and area under the time versus bacterial number curve were significantly affected by incubation of AM with tilmicosin., Conclusions and Clinical Relevance: Results show that bactericidal activity of bovine and porcine AM was enhanced by tilmicosin, but not in proportion to the reported ability of AM to concentrate tilmicosin intracellularly. With or without exposure to tilmicosin, the time-course of bactericidal activity of bovine AM against M haemolytica and of porcine AM against A pleuropneumoniae or P multocida was too complex to be reduced to a simple linear equation.

Five years or more after receiving cardiac radiation, 41 patients with Hodgkin's disease and seminoma in remission were subjected to echocardiography. The abnormalities detected included pericardial thickening in 70%, thickening of the aortic and/or mitral valves in 28%, right ventricular dilatation or hypokinesis in 39%, and left ventricular dysfunction in 39%. In the 23 patients treated by an upper mantle technique with shielding, the incidence of right ventricular abnormalities and valvular thickening was significantly lower than in patients treated with modified techniques. Although no symptoms were attributable to the observed abnormalities, longer follow-up time may reveal important functional implications.