Structural and biochemical analysis of highly similar HLA-B allotypes differentially associated with type 1 diabetes.

Type 1 diabetes (T1D) is an autoimmune disease involving T cell-mediated destruction of the insulin-producing beta cells in the pancreatic islets of Langerhans. CD8+ T cells, responding to beta cell peptides presented by class I major histocompatibility complex (MHC) molecules, are important effectors leading to beta cell elimination. Human leukocyte antigen (HLA) B*39:06, B*39:01, and B*38:01 are closely related class I MHC allotypes that nonetheless show differential association with T1D. HLA-B*39:06 is the most predisposing of all HLA class I molecules and is associated with early age at disease onset. B*39:01 is also associated with susceptibility to T1D, but to a lesser extent, though differing from B*39:06 by only two amino acids. HLA-B*38:01, in contrast, is associated with protection from the disease. Upon identifying a peptide that binds to both HLA-B*39:06 and B*39:01, we determined the respective X-ray structures of the two allotypes presenting this peptide to 1.7 Å resolution. The peptide residues available for T cell receptor contact and those serving as anchors were identified. Analysis of the F pocket of HLA-B*39:06 and B*39:01 provided an explanation for the distinct peptide C-terminus preferences of the two allotypes. Structure-based modeling of the protective HLA-B*38:01 suggested a potential reason for its peptide preferences and its reduced propensity to present 8-mer peptides compared to B*39:06. Notably, the three allotypes showed differential binding to peptides derived from beta cell autoantigens. Taken together, our findings should facilitate identification of disease-relevant candidate T cell epitopes and structure-guided therapeutics to interfere with peptide binding.

Re-evaluating the impact and cost-effectiveness of pneumococcal conjugate vaccine introduction in 112 low-income and middle-income countries in children younger than 5 years: a modelling study.

BACKGROUND: Streptococcus pneumoniae has been estimated to cause 9·18 million cases of pneumococcal pneumonia, meningitis, and invasive non-pneumonia non-meningitis disease and 318 000 deaths among children younger than 5 years in 2015. We estimated the potential impact and cost-effectiveness of pneumococcal conjugate vaccine (PCV) introduction. METHODS: We updated our existing pseudodynamic model to estimate the impact of 13-valent PCV (PCV13) in 112 low-income and middle-income countries by adapting our previously published pseudodynamic model with new country-specific evidence on vaccine coverage, burden, and post-introduction vaccine impact from WHO-UNICEF estimates of national immunisation coverage and a global burden study. Deaths, disability-adjusted life-years (DALYs), and cases averted were estimated for children younger than 5 years born between 2000 and 2030. We used specific PCV coverage in each country and a hypothetical scenario in which coverage increased to diphtheria-tetanus-pertussis (DTP) levels. We conducted probabilistic uncertainty analyses. FINDINGS: Using specific vaccine coverage in countries, we estimated that PCV13 could prevent 697 000 (95% credibility interval 359 000-1 040 000) deaths, 46·0 (24·0-68·9) million DALYs, and 131 (89·0-172) million cases in 112 countries between 2000 and 2030. PCV was estimated to prevent 5·3% of pneumococcal deaths in children younger than 5 years during 2000-30. The incremental cost of vaccination would be I$851 (510-1530) per DALY averted. If PCV coverage were increased to DTP coverage in 2020, PCV13 could prevent an additional 146 000 (75 500-219 000) deaths. INTERPRETATION: The inclusion of real-world evidence from lower-income settings revealed that delays in PCV roll-out globally and low PCV coverage have cost many lives. Countries with delays in vaccine introduction or low vaccine coverage have experienced many PCV-preventable deaths. These findings underscore the importance of rapidly scaling up PCV to achieve high coverage and maximise vaccine impact. FUNDING: Bill & Melinda Gates Foundation and Gavi, the Vaccine Alliance.

Behavioral Animal Models and Neural-Circuit Framework of Depressive Disorder.

Depressive disorder is a chronic, recurring, and potentially life-endangering neuropsychiatric disease. According to a report by the World Health Organization, the global population suffering from depression is experiencing a significant annual increase. Despite its prevalence and considerable impact on people, little is known about its pathogenesis. One major reason is the scarcity of reliable animal models due to the absence of consensus on the pathology and etiology of depression. Furthermore, the neural circuit mechanism of depression induced by various factors is particularly complex. Considering the variability in depressive behavior patterns and neurobiological mechanisms among different animal models of depression, a comparison between the neural circuits of depression induced by various factors is essential for its treatment. In this review, we mainly summarize the most widely used behavioral animal models and neural circuits under different triggers of depression, aiming to provide a theoretical basis for depression prevention.

Comparison of Minimally Invasive Chevron Akin and Open Lapidus Surgery in Older Patients at a Minimum 1-Year Follow-Up.

Background: Hallux valgus deformity affects more than 35% of people aged ≥65 years. Surgical correction in this population can be more complicated because of poor bone quality, worse deformity, and postoperative recovery challenges. The purpose of this study was to compare the radiographic and clinical outcomes of patients aged ≥65 years who underwent either open Lapidus or minimally invasive chevron Akin osteotomy for bunion correction. Methods: A retrospective review identified 62 patients aged ≥65 years who were treated surgically for hallux valgus with at least 1-year postoperative Patient-Reported Outcomes Measurement Information System (PROMIS) scores (physical function and pain interference). Preoperative and at least 6-month postoperative radiographs were measured for the hallux valgus angle and intermetatarsal angle. PROMIS scores were obtained preoperatively and at 1 and/or 2 years postoperatively. Differences in demographic, clinical, and radiographic outcomes were assessed using the Mann Whitney U test and P values were adjusted for a false discovery rate of 5%. Results: There was no difference between the MIS and open cohorts in pre- or postoperative radiographic measurements or clinical outcomes at any time point. At 1 year postoperatively, both groups had statistically significant improvements in the PROMIS pain interference domain but only the MIS group had a statistically significant improvement in the PROMIS physical function domain. Clinical significance was equivocal. At 2 years postoperatively, there were clinically and statistically significant improvements in the PROMIS pain interference and physical function domains for the open and MIS groups. Conclusion: Patients in both surgical groups had improvement in radiographic measurements and 2-year PROMIS scores, although there was no clinical or statistical difference found between groups. MIS and open surgical techniques appear to be safe and effective in correcting hallux valgus in older patients; however, patients may need to be counseled that maximum improvement after surgery may take more than 1 year. Level of Evidence: Level III, retrospective cohort study.

Complications of Hardware Removal in Pediatric Orthopaedic Surgery.

BACKGROUND: Hardware removal (HR) is one of the most common surgical procedures in pediatric orthopaedics. Surgeons advocate for HR for a variety of reasons, including to limit peri-implant fracture risk, restore native anatomy for adult reconstruction surgery, permit bone growth and development, and mitigate implant-related pain/irritation. To our knowledge, no recent study has investigated the characteristics and complications of HR in pediatric orthopaedics. The goal of this study is to report the prevalence and complications of hardware removals across all of pediatric orthopaedic surgery. METHODS: A retrospective case series was conducted of all hardware removals from 2012 to 2023 performed at a single urban tertiary-care children's hospital. Cases were identified using CPT codes/billing records. Spinal hardware and cases for which hardware was either implanted or explanted at an outside hospital were excluded. Patient demographic and clinical data were recorded. For patients with multiple hardware removals, each case was recorded independently. RESULTS: A total of 2585 HR cases for 2176 children met study criteria (57.7% male; mean age 12.3±4.4 y). The median postoperative follow-up time was 1.7 months (interquartile range: 0.6 to 6.9). The most common sites of hardware removal were the femur/knee (32.7%), tibia/fibula/ankle (19.3%), and pelvis/hip (18.5%). The most common complications included sustained, new-onset postoperative pain (2.6%), incomplete hardware removal (1.6%), and perioperative fracture (1.4%). The overall complication rate of hardware removal was 9.5%. Eighty-eight percent of patients who underwent hardware removal for pain experienced pain relief postoperatively. HR >18 months after insertion had a 1.2x higher odds of overall complication (P=0.002) and 3x higher odds of incomplete removal/breakage (P<0.001) than hardware removed 9 to 18 months after insertion. CONCLUSIONS: The overall complication rate of hardware removal across a large series in the pediatric population was 9.5%. Despite hardware removal being one of the most common and often routine procedures in pediatric orthopaedics, the complication rate is not benign. Surgeons should inform patients and families about the likelihood of success and the risks of incomplete removal during the informed consent process. LEVEL OF EVIDENCE: IV.

Utilization and timing of surgical intervention for central cord syndrome in the United States.

STUDY DESIGN: Retrospective cohort analysis. OBJECTIVE: CCS is the most common type of incomplete spinal cord injury and can occur without or with bony injury. Surgical intervention and its timing for patients diagnosed with CCS has been controversial. The current study assessed utilization of and factors associated with operative intervention and its timing in patients diagnosed with central cord syndrome (CCS) in the absence of bony injury. METHODS: Adult patients diagnosed with CCS in the absence of vertebral fracture were queried from the national, multi-insurance, administrative 2015-2020 M151 PearlDiver database. The incidence, trends, and timing of operative intervention following CCS were assessed. Patient characteristics associated with surgical intervention and its timing were determined. RESULTS: From 2015 to 2020, 11,653 patients meeting inclusion criteria were identified, of which surgical intervention was identified for 2,003 (17.2%) and thus nonsurgical intervention for 9,650 (82.8%). The proportion of patients undergoing operative intervention evolved from 11.5% in 2015 to 19.7% in 2020 (p < 0.0001). Of those undergoing surgical intervention, the greatest increase was seen for those undergoing surgery within two days of diagnosis (5.5% in 2015 to 12.3% in 2020, p < 0.0001). On multivariable analysis, more recent year of service, region of service, younger age, and higher comorbidity burden were independent predictors of operative management (p < 0.05 for all). CONCLUSION: The majority of a large cohort of patients with first diagnosis CCS in the absence of bony injury were managed non-operatively. Operative management increased over the years of study, were performed earlier after diagnosis, and varied based on patient characteristic and geographic region.

Dihydrothiazolo ring-fused 2-pyridone antimicrobial compounds treat Streptococcus pyogenes skin and soft tissue infection.

We have developed GmPcides from a peptidomimetic dihydrothiazolo ring-fused 2-pyridone scaffold that has antimicrobial activities against a broad spectrum of Gram-positive pathogens. Here, we examine the treatment efficacy of GmPcides using skin and soft tissue infection (SSTI) and biofilm formation models by Streptococcus pyogenes. Screening our compound library for minimal inhibitory (MIC) and minimal bactericidal (MBC) concentrations identified GmPcide PS757 as highly active against S. pyogenes. Treatment of S. pyogenes biofilm with PS757 revealed robust efficacy against all phases of biofilm formation by preventing initial biofilm development, ceasing biofilm maturation and eradicating mature biofilm. In a murine model of S. pyogenes SSTI, subcutaneous delivery of PS757 resulted in reduced levels of tissue damage, decreased bacterial burdens, and accelerated rates of wound healing, which were associated with down-regulation of key virulence factors, including M protein and the SpeB cysteine protease. These data demonstrate that GmPcides show considerable promise for treating S. pyogenes infections.

Technical Feasibility and Safety of Image-Guided Biphasic Monopolar Pulsed Electric Field Ablation of Metastatic and Primary Malignancies.

PURPOSE: To assess the technical feasibility and safety of image-guided percutaneous biphasic monopolar pulsed electric field (PEF) ablation of primary and metastatic tumors. METHODS AND METHODS: With IRB approval and HIPAA compliance, this retrospective, single-institution study cohort of 17 patients (mean age: 53.5 years, range: 20 - 94 years) with overall progressive disease underwent 26 PEF ablation procedures for 30 metastatic (90%) and primary (10%) target lesions in the thorax (n=20), abdomen (n=7), and head and neck (n=3). Concurrent systemic therapy was used in 14/17 patients (82%). Follow-up imaging was scheduled for 1, 3, and 6 months after PEF ablation, and target and off-target lesion sizes were recorded. The overall response was assessed by the RECIST 1.1 criteria with imaging immediately before PEF serving as baseline. Adverse events (AEs) were determined by the Society of Interventional Radiology classification. RESULTS: PEF ablation procedures were well tolerated and technically feasible for all 17 of 17 patients. The mean initial size of the target and off-target tumors were 2.6±1.5 cm (range: 0.4 - 6.9cm) and 2.2±1.1 cm (range: 1.0 - 5.2cm), respectively. Overall, 15/30 (50%) target lesions and 12/24 (50%) off-target lesions were unchanged or decreased in size at the patient's last follow-up. Eight patients had overall stable disease (47%) at the last follow-up. There were nine mild (9/26, 35%) and one moderate (1/26, 4%) AE. CONCLUSION: All PEF procedures were technically feasible with one moderate AE and stable disease for 47% of patients with a median follow-up period of three months.

Correction: Hyporheic hydraulic geometry: Conceptualizing relationships among hyporheic exchange, storage, and water age.

[This corrects the article DOI: 10.1371/journal.pone.0262080.].

Shape memory cycle conditions impact human bone marrow stromal cell binding to RGD- and YIGSR-conjugated poly (glycerol dodecanedioate).

Bioresorbable shape memory polymers (SMP) are an emerging class of polymers that can help address several challenges associated with minimally invasive surgery by providing a solution for structural tissue repair. Like most synthetic polymer networks, SMPs require additional biorelevance and modification for biomedical applications. Methodologies used to incorporate bioactive ligands must preserve SMP thermomechanics and ensure biofunctionality following in vivo delivery. We have previously described the development of a novel thermoresponsive bioresorbable SMP, poly (glycerol dodecanedioate) (PGD). In this study, cell-adhesive peptide sequences RGD and YIGSR were conjugated with PGD. We investigated 1) the impact of conjugated peptides on the fixity (Rf), recovery (Rr), and recovery rate (dRr/dT), 2) the impact of conjugated peptides on cell binding, and 3) the impact of the shape memory cycle (Tprog) on conjugated peptide functionality towards binding human bone marrow stromal cells (BMSC). Peptide conjugation conditions impact fixity but not the recovery or recovery rate (p < 0.01). Peptide-conjugated substrates increased cell attachment and proliferation compared with controls (p < 0.001). Using complementary integrin binding cell-adhesive peptides increased proliferation compared with using single peptides (p < 0.05). Peptides bound to PGD substrates exhibited specificity to their respective integrin targets. Following the shape memory cycle, peptides maintained functionality and specificity depending on the shape memory cycle conditions (p < 0.001). The dissipation of strain energy during recovery can drive differential arrangement of conjugated sequences impacting functionality, an important design consideration for functionalized SMPs. STATEMENT OF SIGNIFICANCE: Shape memory elastomers are an emerging class of polymers that are well-suited for minimally invasive repair of soft tissues. Tissue engineering approaches commonly utilize biodegradable scaffolds to deliver instructive cues, including cells and bioactive signals. Delivering these instructive cues on biodegradable shape memory elastomers requires modification with bioactive ligands. Furthermore, it is necessary to ensure the specificity of the ligands to their biological targets when conjugated to the polymer. Moreover, the bioactive ligand functionality must be conserved after completing the shape memory cycle, for applications in tissue engineering.

Manufacture Dependent Differential Biodegradation of 3D Printed Shape Memory Polymers.

In the field of tissue engineering, 3D printed shape memory polymers (SMPs) are drawing increased interest. Understanding how these 3D printed SMPs degrade is critical for their use in the clinic, as small changes in material properties can significantly change how they behave after in vivo implantation. Degradation of 3D printed acrylated poly(glycerol-dodecanedioate) (APGD) was examined via in vitro hydrolytic, enzymatic, and in vivo subcutaneous implantation assays. Three APGD manufacturing modalities were assessed to determine differences in degradation. Material extrusion samples showed significantly larger mass and volume loss at 2 months, compared to lasercut and vat photopolymerization samples, under both enzymatic and in vivo degradation. Critically, melt transition temperatures of degraded PGD increased over time in vitro, but not in vivo. Histology of tissue surrounding APGD implants showed no significant signs of inflammation compared to controls, providing a promising outlook for use of 3D printed APGD devices in the clinic.

Age-related changes in ultrasound-assessed muscle composition and postural stability.

While the simultaneous degradation of muscle composition and postural stability in aging are independently highly investigated due to their association with fall risk, the interplay between the two has received little attention. Thus, the purpose of this study is to explore how age-related changes in muscle composition relate to postural stability. To that aim, we collected posturography measures and ultrasound images of the dominant Vastus Lateralis and Biceps Brachii from 32 young (18-35 year old) and 34 older (65-85 year old) participants. Muscle properties were quantified with echo-intensity and texture-based metrics derived from gray-level co-occurrence matrix analysis, and postural stability with the variability of the center of pressure during bipedal stance tasks. Ultrasound parameters revealed that young muscle possessed lower echo-intensity and higher homogeneity compared to the elderly. Echo-intensity and muscle thickness, and several texture-based parameters possessed outstanding young versus older classification performance. A canonical correlation analysis demonstrated a significant relationship between ultrasound and postural measures only within the young group (r = 0.53, p < 0.002), where those with 'better' muscle composition displayed larger postural sways. Our results indicate that, in older individuals, postural stability and muscle composition, two common fall risk factors, are unrelated. In view of this decoupling, both may contribute independently to fall risk. Furthermore, our data support the view that texture-based parameters provide a robust alternative to echo-intensity in providing markers of muscle composition.

A Comparison of PROMIS Scores of Metatarsophalangeal Joint Arthrodesis and Polyvinyl Alcohol Hydrogel Implant Hemiarthroplasty for Hallux Rigidus.

Background: The current literature shows similar clinical outcomes between first metatarsophalangeal (MTP) joint arthrodesis and synthetic cartilage implant (SCI) hemiarthroplasty in the treatment of hallux rigidus; however, prior studies have not reported validated patient-reported outcome measures (PROMs). To our knowledge, this is the first study to compare PROMs using 6 domains of the validated Patient-Reported Outcomes Measurement Information System (PROMIS) in patients treated for hallux rigidus with MTP joint arthrodesis and with SCI hemiarthroplasty. In addition, this novel study provides comparative data on the complication and revision rates for each procedure. Methods: A single-center, retrospective registry search identified all patients with preoperative PROMIS scores who underwent MTP joint arthrodesis or SCI hemiarthroplasty for hallux rigidus between February 2016 and June 2021. The study aimed to determine if the 2 procedures showed statistically or clinically equivalent PROMIS scores in 6 domains: physical function, pain interference, pain intensity, global physical health, global mental health, and depression. A multivariable linear regression analysis was performed to compare adjusted 1-year postoperative PROMIS scores between the 2 cohorts. Complication and revision rates were also compared. Results: The study included 82 patients who underwent SCI hemiarthroplasty and 101 who underwent MTP joint arthrodesis. Demographic data and preoperative hallux rigidus severity showed no significant differences between the cohorts. PROMIS scores were mostly comparable between the 2 groups, except for the pain intensity domain. The patients who underwent MTP joint arthrodesis exhibited significantly better pain relief at 1 and 2 years postoperatively, which was supported by adjusted postoperative PROMIS scores. At 2 years, the SCI group had worse pain intensity scores and lower global physical health scores. There were no differences between the cohorts in additional PROMIS scores or complication data. Conclusions: While outcomes in most of the domains were similar, MTP joint arthrodesis was more effective at mitigating pain intensity compared with SCI hemiarthroplasty. This information can guide patient counseling and decision-making when considering surgical intervention for hallux rigidus. Level of Evidence: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Confidence-Aware Severity Assessment of Lung Disease from Chest X-Rays Using Deep Neural Network on a Multi-Reader Dataset.

In this study, we present a method based on Monte Carlo Dropout (MCD) as Bayesian neural network (BNN) approximation for confidence-aware severity classification of lung diseases in COVID-19 patients using chest X-rays (CXRs). Trained and tested on 1208 CXRs from Hospital 1 in the USA, the model categorizes severity into four levels (i.e., normal, mild, moderate, and severe) based on lung consolidation and opacity. Severity labels, determined by the median consensus of five radiologists, serve as the reference standard. The model's performance is internally validated against evaluations from an additional radiologist and two residents that were excluded from the median. The performance of the model is further evaluated on additional internal and external datasets comprising 2200 CXRs from the same hospital and 1300 CXRs from Hospital 2 in South Korea. The model achieves an average area under the curve (AUC) of 0.94 ± 0.01 across all classes in the primary dataset, surpassing human readers in each severity class and achieves a higher Kendall correlation coefficient (KCC) of 0.80 ± 0.03. The performance of the model is consistent across varied datasets, highlighting its generalization. A key aspect of the model is its predictive uncertainty (PU), which is inversely related to the level of agreement among radiologists, particularly in mild and moderate cases. The study concludes that the model outperforms human readers in severity assessment and maintains consistent accuracy across diverse datasets. Its ability to provide confidence measures in predictions is pivotal for potential clinical use, underscoring the BNN's role in enhancing diagnostic precision in lung disease analysis through CXR.

Biokinetics of Americium-241 in the euryhaline diamond sturgeon Acipenser gueldenstaedtii following its uptake from water or food.

Americium-241 whole body and internal biokinetics were experimentally investigated in the euryhaline diamond sturgeon Acipenser gueldenstaedtii during its uptake from water and food, in fresh (FW) and brackish water (BW; 9 psu). Whole-body uptake rates of 241Am from water and subsequent depuration rates were quantified over 14 and 28 days, respectively, and assimilation efficiency (AE) of 241Am from diet (chironomid) was determined over 28 days. FW reduced the biological half-life of 241Am following aqueous uptake by an order of magnitude. In contrast BW greatly reduced 241Am assimilation efficiency (AE) from diet (chironomid) by several orders of magnitude (from an AE of 8.5% (FW) down to 0.003% (BW)). Hence, salinity per se is indicated as a major environmental variable in determining the radiological exposure of A. gueldenstaedtii to 241Am. During aqueous exposure BW appreciably increased 241Am activity concentrations in most body components, but aqueous or dietary exposure pathway at either salinity did not determine marked differences in how 241Am was distributed among six body components. The highly mineralized skin of A. gueldenstaedtii recurred as a major repository of 241Am in all experimental treatments, as high as 50% among body components, due to its internal transfer from diet, surface adsorption and/or active absorption from water. The indicated prominence of the aqueous, compared to the dietary, exposure pathway for 241Am accumulation by A. gueldenstaedtii suggests its radiological exposure would be enhanced by BW as it leads to its greater long-term retention, due to a much longer biological half-life.

Synonymous codon substitutions modulate transcription and translation of a divergent upstream gene by modulating antisense RNA production.

Synonymous codons were originally viewed as interchangeable, with no phenotypic consequences. However, substantial evidence has now demonstrated that synonymous substitutions can perturb a variety of gene expression and protein homeostasis mechanisms, including translational efficiency, translational fidelity, and cotranslational folding of the encoded protein. To date, most studies of synonymous codon-derived perturbations have focused on effects within a single gene. Here, we show that synonymous codon substitutions made far within the coding sequence of Escherichia coli plasmid-encoded chloramphenicol acetyltransferase (cat) can significantly increase expression of the divergent upstream tetracycline resistance gene, tetR. In four out of nine synonymously recoded cat sequences tested, expression of the upstream tetR gene was significantly elevated due to transcription of a long antisense RNA (asRNA) originating from a transcription start site within cat. Surprisingly, transcription of this asRNA readily bypassed the native tet transcriptional repression mechanism. Even more surprisingly, accumulation of the TetR protein correlated with the level of asRNA, rather than total tetR RNA. These effects of synonymous codon substitutions on transcription and translation of a neighboring gene suggest that synonymous codon usage in bacteria may be under selection to both preserve the amino acid sequence of the encoded gene and avoid DNA sequence elements that can significantly perturb expression of neighboring genes. Avoiding such sequences may be especially important in plasmids and prokaryotic genomes, where genes and regulatory elements are often densely packed. Similar considerations may apply to the design of genetic circuits for synthetic biology applications.

Interferon alpha induces a stronger antiviral effect than interferon lambda in HBV/HDV infected humanized mice.

Recent studies indicate that treatment of chronic hepatitis D virus (HDV) with either pegylated interferon (IFN)λ or pegylated IFNα monotherapy leads to a dramatic decline in HDV RNA. Herein, we investigated the innate antiviral efficacy of IFNλ and IFNα in humanized mice that lack an adaptive immune response. Humanized mice were either co-infected with hepatitis B virus (HBV) and HDV simultaneously, or HDV infection was performed subsequent to HBV infection (i.e., superinfected). After steady viral replication was achieved, mice received either IFNλ (n = 6) or IFNα (n = 7) for 12 (or 13) weeks. Pretreatment median levels of serum HBV DNA (8.8 [IQR:0.2] log IU/ml), HDV RNA (9.8 [0.5] log IU/ml), HBsAg (4.0 [0.4] log IU/ml) and human albumin, hAlb (6.9 [0.1] log ng/mL) were similar between mice treated with IFNα or IFNλ and between those coinfected versus superinfected. Compared to mice treated with IFNλ, mice treated with IFNα had a significantly greater decline in HBV, HDV, and HBsAg levels. In conclusion, IFNα induces stronger inhibition of HBV and HDV than IFNλ in humanized mice that lack an adaptive immune response. Further studies are needed to assess the respective role of the combined innate-and adaptive-immune systems in the treatment of HBV and HDV with IFNα and IFNλ.

A multidimensional analysis reveals distinct immune phenotypes and the composition of immune aggregates in pediatric acute myeloid leukemia.

Because of the low mutational burden and consequently, fewer potential neoantigens, children with acute myeloid leukemia (AML) are thought to have a T cell-depleted or 'cold' tumor microenvironment and may have a low likelihood of response to T cell-directed immunotherapies. Understanding the composition, phenotype, and spatial organization of T cells and other microenvironmental populations in the pediatric AML bone marrow (BM) is essential for informing future immunotherapeutic trials about targetable immune-evasion mechanisms specific to pediatric AML. Here, we conducted a multidimensional analysis of the tumor immune microenvironment in pediatric AML and non-leukemic controls. We demonstrated that nearly one-third of pediatric AML cases has an immune-infiltrated BM, which is characterized by a decreased ratio of M2- to M1-like macrophages. Furthermore, we detected the presence of large T cell networks, both with and without colocalizing B cells, in the BM and dissected the cellular composition of T- and B cell-rich aggregates using spatial transcriptomics. These analyses revealed that these aggregates are hotspots of CD8+ T cells, memory B cells, plasma cells and/or plasmablasts, and M1-like macrophages. Collectively, our study provides a multidimensional characterization of the BM immune microenvironment in pediatric AML and indicates starting points for further investigations into immunomodulatory mechanisms in this devastating disease.