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AIM: To investigate ophthalmologic findings in children with thalassemia major (TM) and compare the findings with healthy controls. METHODS: In a cross-sectional study, 43 children with thalassemia major from pediatric hematology outpatient clinics from two university hospitals and age/sex matched 47 healthy children were included in the study. After a complete ophthalmic examination, tear function tests including the Schirmer test, fluorescein tear break-up time (BUT), ultrasound pachymetry, and axial length measurement were performed. Obtained data was recorded for statistical analysis and the values of right eyes were compared between groups. RESULTS: The mean best corrected visual acuity was 1.34±0.75 in TM and 1.08±0.28 in controls. It was found lower than 0.1 logMAR unit in 10 (23.2%) children with TM and 2 (4.2%) in controls, and the difference was statistically significant (P＜0.05). The mean central corneal thickness was 540±26.95 in children with TM and 536.98±20.45µm in controls (P＞0.05). The mean axial length was 22.53±0.50 in TM and 22.57±0.43mm in the control group. The mean Schirmer test score was 19.94±6.91 in TM and 24.22±3.95mm in the control group (P＜0.01). The mean BUT score was 9.62±1.28 in TM and 9.73±0.6s in the control group (P＞0.05). CONCLUSION: In TM, while corneal thickness, axial length, and BUT are close to controls, the Schirmer scores are less than normal. The study revealed that TM may be affected by the tear function and visual acuity.

Introduction: Cypermethrin causes its neurotoxic effect through voltage-dependent sodium channels and integral protein ATPases in the neuronal membrane. Brain and nerve damage are often associated with low residual level of pesticides. In vitro and in vivo studies have also shown that pesticides cause free radical-mediated tissue damage in brain. Propolis has antioxidant properties. The main chemical classes found in propolis are flavonoids and phenolics. Bioflavonoids are antioxidant molecules that play important roles in scavenging free radicals, which are produced in neurodegenerative diseases and aging. Methods: To determine the protective role of propolis, rainbow trouts were treated with cypermethrin, followed by biochemical analyses of brain tissue. Fish were divided into four groups: control, propolis-treated, cypermethrin-treated, and cypermethrin+propolis-treated. Results: In fish brains, catalase (CAT) activity decreased (P≤0.001) and malondialdehyde (MDA) level increased (P≤0.001) in cypermethrin-treated group compared to control group. In cypermethrin + propolis-treated group CAT activity increased (P≤0.001) and MDA level decreased (P≤0.001) compared to cypermethrin group. Discussion: The results demonstrated that the negative effects, observed as a result of cypermethrin treatment, could be reversed by adding supplementary propolis. Propolis may improve some biochemical markers associated with oxidative stress in fish brain, after exposure to cypermethrin.

OBJECTIVE: Multiple myeloma (MM) is characterized by the accumulation and proliferation of malignant plasma cells, secreting monoclonal immunoglobulins and genetic abnormalities in MM have implications for disease progression and survival. In the present study, we investigated the frequency of chromosomal abnormalities (CA) in Turkish patients with MM, using interphase FISH and CC and evaluated the relationship between the rearrangements detected, prognosis and stage of disease. METHODS: We performed conventional cytogenetic and FISH studies in 50 patients to detect chromosome anomalies associated with MM. FISH probes were used to detect 13q14, 13q34, 17p13 deletions, IGH rearrangements, and monosomy and/or trisomy of chromosomes 5, 9, and 15. RESULTS: CC studies could be performed in 32 of 50 cases and five patients (15.6%) showed chromosomal aberrations while 27 (84.3%) had normal karyotypes. By FISH, eighteen percent (9/50) of cases were found to be normal for all parameters evaluated. Eighty-two percent (41/50) of the patients were positive for at least one abnormality. Chromosome 13 anomalies were detected in 54% (27/50) of cases. The second most common aberration observed is chromosome 15 aberrations (50%). CONCLUSION: Median survival rate was shorter in patients with one of the abnormalities including chromosome 13 aberrations, IGH rearrangements or P53 deletions. Chromosome 15 aberrations were significantly higher in patients with stage III disease (p=0.02). We conclude that FISH studies should be performed in conjunction with conventional cytogenetic analysis for prognosis in multiple myeloma patients.

Objective: Ischemia and reperfusion injury due to tourniquet application during arthroscopy is a well known problem. This study aimed to compare the effects of dexmedetomidine and ketamine on hemodynamic and respiratory variables and on total anti-oxidant status (TAS), total oxidant status (TOS) and malondialdehyde (MDA) as markers of ischemia-reperfusion injury. Materials and Methods: This study was approved by a local ethics committee. The study was performed on patients undergoing arthroscopic operation under spinal anesthesia. Thirty patients were randomized into two groups: Group D (dexmedetomidine; n=15) and Group K (Ketamine; n=15). Spinal anesthesia at the L2-4 level was achieved using a 25G spinal needle with hyperbaric bupivacaine at a dose of 12-15 mg in all patients. In Group D, patients were sedated with dexmedetomidine at a dose of 0.3-0.5 µg/kg/h, while Group K received ketamine at a dose of 1-1.5 mg/kg/h. Hemodynamic parameters, oxygen saturation, Ramsey sedation scale (RSS), and TAS, TOS, and MDA levels were recorded. Results: Demographic parameters, TAS, TOS and MDA levels were similar between groups. In Group K, the TOS levels after tourniquet removal were significantly lower than at baseline and during the use of the tourniquet. Preoperative hemodynamic and respiratory variables were similar in both groups. Blood pressure values were decreased compared to baseline but these decreases were not statistically significant. Conclusion: In patients undergoing arthroscopy under spinal anesthesia, dexmedetomidine had effects similar to ketamine, led to insignificant alterations in hemodynamic and respiratory variables during surgery and had comparable effects on ischemia-reperfusion injury. Thus, we think that dexmedetomidine can be a safe alternative to ketamine as an intraoperative sedative.

Hydrogels are an interesting class of materials used in extrusion-based 3D printing, e.g., for drug delivery or tissue engineering. However, new hydrogel formulations for 3D printing as well as a detailed understanding of crucial formulation properties for 3D printing are needed. In this contribution, hydrogels based on poly(ethylene glycol) diacrylate (PEG-DA) and the charged monomers 3-sulfopropyl acrylate and [2-(acryloyloxy)ethyl]trimethylammonium chloride are formulated for 3D printing, together with Poloxamer 407 (P407). Chemical curing of formulations with PEG-DA and up to 5% (w/w) of the charged monomers was possible without difficulty. Through careful examination of the rheological properties of the non-cured formulations, it was found that flow properties of formulations with a high P407 concentration of 22.5% (w/w) possessed yield stresses well above 100 Pa together with pronounced shear thinning behavior. Thus, those formulations could be processed by 3D printing, as demonstrated by the generation of pyramidal objects. Modelling of the flow profile during 3D printing suggests that a plug-like laminar flow is prevalent inside the printer capillary. Under such circumstances, fast recovery of a high vicosity after material deposition might not be necessary to guarantee shape fidelity because the majority of the 3D printed volume does not face any relevant shear stress during printing.

Background: The blocking of nitric oxide synthase (NOS) activity may reason vasoconstriction with formation of reactive oxygen species. Propolis has biological and pharmacological properties, such as antioxidant. The aim of this study was to examine the antioxidant effects of propolis which natural product on biochemical parameters in brain and lung tissues of acute nitric oxide synthase inhibited rats by Nω-nitro-L-arginine methyl ester (L-NAME). Methods: Rats have been received L-NAME (40 mg/kg, intraperitoneally), NOS inhibitor for 15 days to produce hypertension and propolis (200mg/kg, by gavage) the lastest 5 of 15 days. Results: There were the increase (P

This study was carried out at the Yenice Irrigation Pond between October 1999 and October 2000. For this study 368 roach (Rutilus rutilus) were examined and 37 parasites and 93 Ligula intestinalis were found in the abdominal cavity of the host (prevalence 10.1%, mean intensity 2.51 specimens/fish). Based on season, the highest number of infected fish occurred during summer (33.3%, 4 parasite/fish), and during the other season the mean intensity of infection was relatively low (prevalence 3.3%, 1 specimens/fish). On the other hand, the parasite species was determined especially on small and medium host fish sizes (2.17-100%). Basic criteria for the assessment of the parasite species of host fish were the general parameters related to parasite populations, which are prevalence, mean intensity, seasonal variation, and relationship between host size and infection.

Tenosynovial chondromatosis is a very rare disease. The most common symptom is a slowly enlarging soft tissue mass, which may be painful or cause limitation of joint motion. Plain radiograph may appear normal during early phases of the disease, but subsequent imaging may be necessary to exclude other pathologies. Nonoperative treatment may be elected for some patients, but a synovectomy and the removal of loose bodies are indicated for persistent symptoms. This report describe a case with a multinodular cartilaginous proliferation and rice body in the first web space of the hand, similar to synovial chondromatosis, but arising in the tenosynovial membranes.

Summary: Papillary thyroid carcinoma (PTC) is the most common and well-differentiated cancer of the thyroid. Unlike most cancers, spread to local lymph node does not worsen the survival rate of PTC, and complete resection of the metastases seems to be important and may have favorable effects on the prognosis. A 33-year-old woman was referred to our clinic with a mass involving the right angulus mandible. Incisional biopsy of the mass diagnosed follicular variant of papillary thyroid carcinoma. Right hemimandibulectomy was performed and reconstructed with costochondral rib graft. The patient survived for 5 years after the hemimandibulectomy. Metastases to the oral cavity indicate a grave prognosis, but PTC has relatively indolent biological behavior; long-term survival is usually possible even in patients with metastatic disease.

Background. Nonclassic congenital adrenal hyperplasia (NCAH), caused by mutations in the gene encoding 21-hydroxylase, is a common autosomal recessive disorder. In the present work, our aim was to determine the prevalence of NCAH presenting as premature pubarche (PP), hirsutism, or polycystic ovarian syndrome (PCOS) and to evaluate the molecular spectrum of CYP21A2 mutations in NCAH patients. Methods. A total of 126 patients (122 females, 4 males) with PP, hirsutism, or PCOS were included in the present study. All patients underwent an ACTH stimulation test. NCAH was considered to be present when the stimulated 17-hydroxyprogesterone plasma level was >10 ng/mL. Results. Seventy-one of the 126 patients (56%) presented with PP, 29 (23%) with PCOS, and 26 (21%) with hirsutism. Six patients (4,7%) were diagnosed with NCAH based on mutational analysis. Four different mutations (Q318X, P30L, V281L, and P453S) were found in six NCAH patients. One patient with NCAH was a compound heterozygote for this mutation, and five were heterozygous. Conclusion. NCAH should be considered as a differential diagnosis in patients presenting with PP, hirsutism, and PCOS, especially in countries in which consanguineous marriages are prevalent.

Abstract Background The arterial switch operation (ASO) has become the surgical approach of choice for d-transposition of the great arteries (d-TGA). There is, however an increased incidence of midterm and longterm adverse sequelae in some survivors. In order to evaluate operative risk and midterm outcome in this population, we reviewed patients who underwent ASO for TGA at our centre. Methods In this retrospective study 52 consecutive patients with TGA who underwent ASO between 04/1991 and 12/1999 were included. To analyze the predictors for mortality and adverse events (coronary stenoses, distortion of the pulmonary arteries, dilatation of the neoaortic root, and aortic regurgitation), a multivariate analysis was performed. The follow-up time was ranged from 1–10 years (mean 5 years, cumulative 260 patient-years). Results All over mortality rate was 15.4% and was only observed in the early postoperative period till 1994. The predictors for poor operative survival were low APGAR-score, older age at surgery, and necessity of associated surgical procedures. Late re-operations were necessary in 6 patients (13.6%) and included a pulmonary artery patch enlargement due to supravalvular stenosis (n = 3), coronary revascularisation due to coronary stenosis in a coronary anatomy type E, aortic valve replacement due to neoaortic valve regurgitation (n = 2), and patch-plasty of a pulmonary vein due to obstruction (n = 1). The dilatation of neoaortic root was not observed in the follow up. Conclusions ASO remains the procedure of choice for TGA with acceptable early and late outcome in terms of overall survival and freedom of reoperation. Although ASO is often complex and may be associated with morbidity, most patients survived without major complications even in a small centre.

• The proposed method was designed for pulmonary CT image registration. • Adding one-shot learning improves population learning image registration. • Intensity changes between inspiration-expiration lung CT images are accommodated. • The vesselness constraint improves pulmonary image registration accuracy. • The proposed method achieved sub-voxel accuracy on DIR-LAB and SPIROMICS data sets. [Display omitted] This paper presents the Population Learning followed by One Shot Learning (PLOSL) pulmonary image registration method. PLOSL is a fast unsupervised learning-based framework for 3D-CT pulmonary image registration algorithm based on combining population learning (PL) and one-shot learning (OSL). The PLOSL image registration has the advantages of the PL and OSL approaches while reducing their respective drawbacks. The advantages of PLOSL include improved performance over PL, substantially reducing OSL training time and reducing the likelihood of OSL getting stuck in local minima. PLOSL pulmonary image registration uses tissue volume preserving and vesselness constraints for registration of inspiration-to-expiration and expiration-to-inspiration pulmonary CT images. A coarse-to-fine convolution encoder-decoder CNN architecture is used to register large and small shape features. During training, the sum of squared tissue volume difference (SSTVD) compensates for intensity differences between inspiration and expiration computed tomography (CT) images and the sum of squared vesselness measure difference (SSVMD) helps match the lung vessel tree. Results show that the PLOSL (SSTVD+SSVMD) algorithm achieved subvoxel landmark error while preserving pulmonary topology on the SPIROMICS data set, the public DIR-LAB COPDGene and 4DCT data sets. [ABSTRACT FROM AUTHOR]

• This paper presents a novel geodesic density registration (GDR) algorithm to remove motion artifacts in 4DCT pulmonary imaging that occur during breathing. • The GDR algorithm uses binary artifact masks to exclude artifact regions from the regression and accommodates image intensity change associated with breathing by using a tissue density deformation action. • This paper provides experimental evidence that not every artifact needs to be masked for the GDR approach to reduce the effects of motion artifacts. Thus, artifact masks can be quickly identified by hand. • We demonstrate that the GDR method is able to remove artifacts in treatment planning 4DCT images in regions with and without artifact masks. [Display omitted] Pulmonary respiratory motion artifacts are common in four-dimensional computed tomography (4DCT) of lungs and are caused by missing, duplicated, and misaligned image data. This paper presents a geodesic density regression (GDR) algorithm to correct motion artifacts in 4DCT by correcting artifacts in one breathing phase with artifact-free data from corresponding regions of other breathing phases. The GDR algorithm estimates an artifact-free lung template image and a smooth, dense, 4D (space plus time) vector field that deforms the template image to each breathing phase to produce an artifact-free 4DCT scan. Correspondences are estimated by accounting for the local tissue density change associated with air entering and leaving the lungs, and using binary artifact masks to exclude regions with artifacts from image regression. The artifact-free lung template image is generated by mapping the artifact-free regions of each phase volume to a common reference coordinate system using the estimated correspondences and then averaging. This procedure generates a fixed view of the lung with an improved signal-to-noise ratio. The GDR algorithm was evaluated and compared to a state-of-the-art geodesic intensity regression (GIR) algorithm using simulated CT time-series and 4DCT scans with clinically observed motion artifacts. The simulation shows that the GDR algorithm has achieved significantly more accurate Jacobian images and sharper template images, and is less sensitive to data dropout than the GIR algorithm. We also demonstrate that the GDR algorithm is more effective than the GIR algorithm for removing clinically observed motion artifacts in treatment planning 4DCT scans. Our code is freely available at https://github.com/Wei-Shao-Reg/GDR. [ABSTRACT FROM AUTHOR]

Out-of-phase ventilation occurs when local regions of the lung reach their maximum or minimum volumes at breathing phases other than the global end inhalation or exhalation phases. This paper presents the N-phase local expansion ratio (LER $_{N}$) as a surrogate for lung ventilation. A common approach to estimate lung ventilation is to use image registration to align the end exhalation and inhalation 3DCT images and then analyze the resulting correspondence map. This 2-phase local expansion ratio (LER2) is limited because it ignores out-of-phase ventilation and thus may underestimate local lung ventilation. To overcome this limitation, LER $_{N}$ measures the maximum ratio of local expansion and contraction over the entire breathing cycle. Comparing LER2 to LER $_{N}$ provides a means for detecting and characterizing locations of the lung that experience out-of-phase ventilation. We present a novel in-phase/out-of-phase ventilation (IOV) function plot to visualize and measure the amount of high-function IOV that occurs during a breathing cycle. Treatment planning 4DCT scans collected during coached breathing from 32 human subjects with lung cancer were analyzed in this study. Results show that out-of-phase breathing occurred in all subjects and that the spatial distribution of out-of-phase ventilation varied from subject to subject. For the 32 subjects analyzed, 50% of the out-of-phase regions on average were mislabeled as low-function by LER2 (high-function threshold of 1.1, IOV threshold of 1.05). 4DCT and Xenon-enhanced CT of four sheep showed that LER8 is more accurate than LER2 for measuring lung ventilation. [ABSTRACT FROM AUTHOR]

Existing reinforced concrete (RC) buildings designed according to outdated codes may lack sufficient strength, stiffness or ductility to meet the seismic performance criteria of current codes. To enhance the system stiffness and re-centering capability, an elastically designed supplementary steel frame (SF) is installed in parallel with the BRBs. Near full-scale cyclic tests are conducted on such retrofit schemes for performance evaluation. The retrofitted specimens showed stable hysteretic behavior up to the retrofit target story drift of 1/150 as proposed in the Japanese seismic regulations. Tests demonstrate that the proposed system is feasible and increases both strength, ductility, and damping to an adequate seismic performance level while the elastic steel frame is effective in providing post-yield stiffness and re-centering capability even when the RC frame is subjected to moderate inelasticity. Special emphasis is placed on the composite behavior of RC members and SF. A simplified composite interaction model is proposed and results from the developed model show good agreement with the experimental data. Ductility demands are shown to concentrate in the BRBs as per the design intent. [ABSTRACT FROM AUTHOR]

This paper presents an experimental investigation into possible variations of mechanical properties of structural steel and concrete in composite cellular beams exposed to ISO 834 fire and cooled down phases. Four full-scale fire tests were performed on protected and unprotected beams under assumed service loads. Tensile stress-strain behavior of steel coupons taken from the beams and compressive strengths of concrete cores taken from the reinforced concrete slabs are studied. Material coupon tests for steel are carried out as per TS EN ISO 6892-1. As for the concrete, compression tests were conducted. Coupon test results reveal that, after fire testing, a maximum reduction ratio of 65% in ultimate strain is obtained for the unprotected beam samples. This indicates that the reductions in the mechanical properties of steel in the protected beams are much less when compared to those of the unprotected beams. It is also found that the maximum increase in post-fire strength/pre-fire strength ratios for concrete is 11% for the unprotected beam, while a 20 % decrease is recorded for water based protected cellular beam. For the protected specimens, the RC slabs were exposed to higher temperatures, and the compressive strength of concrete after testing was lower than that of the unprotected beam slabs.

Both experimental and numerical investigations are performed to determine complete inelastic behavior of circular concrete filled double skin steel tubes (CFDSTs) with different compositions. In the experimental part, 8 circular tubes including 2 DSTs (double skin steel tubes without infill) and 6 CFDSTs are tested under concentric axial compression to failure. Presence/absence of infill concrete, hollow ratio (χ = 0.47 ∼ 0.70), and concrete type (plain, polypropylene and steel fibers added) are the parameters. To cover more parameters such as further hollow ratios, inner and outer tube thicknesses, a numerical work is added. AISC 360–16 and Eurocode 4 (EC4) are employed to evaluate their applicability for CFDSTs. Results show that the hollow ratio and outer/inner tube slendernesses (D/t) have a significant impact on the behavior. Experimental and numerical results reveal that, independent of the concrete composition (i.e. with or without any fibers) and hollow section ratio, concrete infill has significantly improved axial strength (up to 86 %) and ductility (up to 314 %) by delaying local buckling. Polypropylene and steel fibers improve the overall behavior with an enhanced displacement ductility and energy absorbtion. CFDSTs with smaller hollow ratios (say 0.47 or smaller) present much better inelastic behavior mainly from the enhanced confinement effect. [ABSTRACT FROM AUTHOR]

• Investigation of composite behavior in RC buildings retrofitted using BRBs with steel frame (SF). • Proposed retrofit method can avoid damage concentration and secure self-centering function. • Development of a detailed numerical model to simulate the composite behavior between RC and SF. • Development of a simple design method without iteration incorporating the composite behavior. • Application of the proposed retrofit method to an existing RC school building. Seismically retrofitting reinforced concrete (RC) building with a combination of buckling-restrained braces (BRBs) and elastic steel frames offers a practical solution that provides additional lateral stiffness and energy dissipation capacity. However, the available methods to vertically distribute the BRB sizes based on equivalent linearization do not consider the additional stiffness due to the composite behavior between the RC frame and the elastic steel frame, which may lead to an overly conservative estimate of the BRB stiffness demands. This study proposes a retrofit design method incorporating the composite behavior. Numerical models considering the detailed composite behavior are developed and calibrated against quasi-static cyclic loading tests, and a simplified evaluation method is proposed. A four-story RC school building is used as a benchmark model, and the proposed retrofit design method is validated using nonlinear response history analysis. The analysis results suggest that taking the composite behavior into account by using the proposed retrofit design method more accurately estimates the lateral stiffness of the retrofitted structure and leads to a more economic retrofit. [ABSTRACT FROM AUTHOR]

Human recombination-activating gene (RAG) deficiency can manifest with distinct clinical and immunological phenotypes. By applying a multiomics approach to a large group of RAG -mutated patients, we aimed at characterizing the immunopathology associated with each phenotype. Although defective T and B cell development is common to all phenotypes, patients with hypomorphic RAG variants can generate T and B cells with signatures of immune dysregulation and produce autoantibodies to a broad range of self-antigens, including type I interferons. T helper 2 (T H 2) cell skewing and a prominent inflammatory signature characterize Omenn syndrome, whereas more hypomorphic forms of RAG deficiency are associated with a type 1 immune profile both in blood and tissues. We used cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) analysis to define the cell lineage-specific contribution to the immunopathology of the distinct RAG phenotypes. These insights may help improve the diagnosis and clinical management of the various forms of the disease.

The microbiota colonizes each barrier site and broadly controls host physiology 1 . However, when uncontrolled, microbial colonists can also promote inflammation and induce systemic infection 2 . The unique strategies employed at each barrier tissue to control the coexistence of the host with its microbiota remain largely elusive. Here we uncover that, within the skin, host-microbiota symbiosis depends on the remarkable ability of the skin to act as an autonomous lymphoid organ. Notably, an encounter with a new skin commensal promotes two parallel responses, both under the control of Langerhans cells. On one hand, skin commensals induce the formation of classical germinal centers within the lymph node associated with IgG1 and IgG3 antibody responses. On the other hand, microbial colonization also leads to the development of tertiary lymphoid organs within the skin that can locally sustain IgG2b and IgG2c responses. These phenomena are supported by the ability of regulatory T cells to convert into T follicular helper cells. Skin autonomous production of antibodies is sufficient to control local microbial biomass, as well as subsequent systemic infection with the same microbe. Collectively, these results reveal a striking compartmentalization of humoral responses to the microbiota allowing for control of both microbial symbiosis and potential pathogenesis., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: The study of rodent malaria parasites has significantly advanced our understanding of malaria parasite biology and host responses to parasite infections. There are four well-characterized rodent malaria parasite species (Plasmodium yoelii, P. chabaudi, P. berghei, and P. vinckei). Each species also has multiple strains that cause different disease phenotypes. P. yoelii nigeriensis N67C and N67, two isogenic parasites, are particularly intriguing as they differ in virulence and incite different immune responses in mice. The genome of the N67 parasite has been assembled recently, but not that of N67C. This study used PacBio HiFi sequencing data to assemble the N67C genome, compared the two genomes, and performed RNA sequencing to identify polymorphisms and differentially expressed genes (DEGs)., Results: The assembled N67C parasite genome consisted of 16 scaffolds and three contigs of approximately 22.5 Mb with 100% and 96.6% completeness based on well-characterized single-copy orthologs specific to the Apicomplexa phylum and the Plasmodium genus, respectively. A comparison between the annotated N67C and N67 genomes revealed 133 single nucleotide polymorphisms (SNPs) and 75 indels. Among the polymorphic sites, an S (N67) to N (N67C) amino acid substitution at position 114 (S114N) in the dihydrofolate reductase-thymidylate synthase (DHFR-TS) confers resistance to pyrimethamine in mice. Additionally, 60 differentially expressed single-copy genes (DEGs) were detected after comparing mRNA levels between the two parasites. Starting with the predicted and annotated 5,681 N67C and 5,749 N67 genes, we identified 4,641 orthogroups that included at least one gene from the four P. yoelii parasites (N67, N67C, 17X, and YM), whereas 758 orthogroups showed subspecies or strain-specific patterns., Conclusion: The identification of polymorphic sites between the N67 and N67C genomes, along with the detection of the DEGs, may provide crucial insights into the variations in parasite drug responses and disease severity between these two isogenic parasites. The functional characterization of these genetic differences and candidate genes will deepen our understanding of disease mechanisms and pave the way for developing more effective control measures against malaria., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: A better understanding of the dynamics of human immunodeficiency virus (HIV) reservoirs in CD4+ T cells of people with HIV (PWH) receiving antiretroviral therapy (ART) is crucial for developing therapies to eradicate the virus., Methods: We conducted a study involving 28 aviremic PWH receiving ART with high and low levels of HIV DNA. We analyzed immunologic and virologic parameters and their association with the HIV reservoir size., Results: The frequency of CD4+ T cells carrying HIV DNA was associated with higher pre-ART plasma viremia, lower pre-ART CD4+ T-cell counts, and lower pre-ART CD4/CD8 ratios. During ART, the High group maintained elevated levels of intact HIV proviral DNA, cell-associated HIV RNA, and inducible virion-associated HIV RNA. HIV sequence analysis showed no evidence for preferential accumulation of defective proviruses nor higher frequencies of clonal expansion in the High versus Low group. Phenotypic and functional T-cell analyses did not show enhanced immune-mediated virologic control in the Low versus High group. Of considerable interest, pre-ART innate immunity was significantly higher in the Low versus High group., Conclusions: Our data suggest that innate immunity at the time of ART initiation may play an important role in modulating the dynamics and persistence of viral reservoirs in PWH., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts of interest. 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., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2023.)

Background: Functional T-cell responses are essential for virus clearance and long-term protection after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, whereas certain clinical factors, such as older age and immunocompromise, are associated with worse outcome., Objective: We sought to study the breadth and magnitude of T-cell responses in patients with coronavirus disease 2019 (COVID-19) and in individuals with inborn errors of immunity (IEIs) who had received COVID-19 mRNA vaccine., Methods: Using high-throughput sequencing and bioinformatics tools to characterize the T-cell receptor β repertoire signatures in 540 individuals after SARS-CoV-2 infection, 31 IEI recipients of COVID-19 mRNA vaccine, and healthy controls, we quantified HLA class I- and class II-restricted SARS-CoV-2-specific responses and also identified several HLA allele-clonotype motif associations in patients with COVID-19, including a subcohort of anti-type 1 interferon (IFN-1)-positive patients., Results: Our analysis revealed that elderly patients with COVID-19 with critical disease manifested lower SARS-CoV-2 T-cell clonotype diversity as well as T-cell responses with reduced magnitude, whereas the SARS-CoV-2-specific clonotypes targeted a broad range of HLA class I- and class II-restricted epitopes across the viral proteome. The presence of anti-IFN-I antibodies was associated with certain HLA alleles. Finally, COVID-19 mRNA immunization induced an increase in the breadth of SARS-CoV-2-specific clonotypes in patients with IEIs, including those who had failed to seroconvert., Conclusions: Elderly individuals have impaired capacity to develop broad and sustained T-cell responses after SARS-CoV-2 infection. Genetic factors may play a role in the production of anti-IFN-1 antibodies. COVID-19 mRNA vaccines are effective in inducing T-cell responses in patients with IEIs., (Published by Elsevier Inc.)

Background: The immunogenicity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccines is variable in individuals with different inborn errors of immunity or acquired immune deficiencies and is yet unknown in people with idiopathic CD4 lymphopenia (ICL)., Objective: We sought to determine the immunogenicity of mRNA vaccines in patients with ICL with a broad range of CD4 T-cell counts., Methods: Samples were collected from 25 patients with ICL and 23 age- and sex-matched healthy volunteers (HVs) after their second or third SARS-CoV-2 mRNA vaccine dose. Anti-spike and anti-receptor binding domain antibodies were measured. T-cell receptor sequencing and stimulation assays were performed to quantify SARS-CoV-2-specific T-cell responses., Results: The median age of ICL participants was 51 years, and their median CD4 count was 150 cells/μL; 11 participants had CD4 counts ≤100 cells/μL. Anti-spike IgG antibody levels were greater in HVs than in patients with ICL after 2 and 3 doses of mRNA vaccine. There was no detectable significant difference, however, in anti-S IgG between HVs and participants with ICL and CD4 counts >100 cells/μL. The depth of spike-specific T-cell responses by T-cell receptor sequencing was lower in individuals with ICL. Activation-induced markers and cytokine production of spike-specific CD4 T cells in participants with ICL did not differ significantly compared with HVs after 2 or 3 vaccine doses., Conclusions: Patients with ICL and CD4 counts >100 cells/μL can mount vigorous humoral and cellular immune responses to SARS-CoV-2 vaccination; however, patients with more severe CD4 lymphopenia have blunted vaccine-induced immunity and may require additional vaccine doses and other risk mitigation strategies., (Copyright © 2023. Published by Elsevier Inc.)

Background: A genetically engineered pig cardiac xenotransplantation was done on Jan 7, 2022, in a non-ambulatory male patient, aged 57 years, with end-stage heart failure, and on veno-arterial extracorporeal membrane oxygenation support, who was ineligible for an allograft. This report details our current understanding of factors important to the xenotransplantation outcome., Methods: Physiological and biochemical parameters critical for the care of all heart transplant recipients were collected in extensive clinical monitoring in an intensive care unit. To ascertain the cause of xenograft dysfunction, we did extensive immunological and histopathological studies, including electron microscopy and quantification of porcine cytomegalovirus or porcine roseolovirus (PCMV/PRV) in the xenograft, recipient cells, and tissue by DNA PCR and RNA transcription. We performed intravenous immunoglobulin (IVIG) binding to donor cells and single-cell RNA sequencing of peripheral blood mononuclear cells., Findings: After successful xenotransplantation, the graft functioned well on echocardiography and sustained cardiovascular and other organ systems functions until postoperative day 47 when diastolic heart failure occurred. At postoperative day 50, the endomyocardial biopsy revealed damaged capillaries with interstitial oedema, red cell extravasation, rare thrombotic microangiopathy, and complement deposition. Increased anti-pig xenoantibodies, mainly IgG, were detected after IVIG administration for hypogammaglobulinaemia and during the first plasma exchange. Endomyocardial biopsy on postoperative day 56 showed fibrotic changes consistent with progressive myocardial stiffness. Microbial cell-free DNA testing indicated increasing titres of PCMV/PRV cell-free DNA. Post-mortem single-cell RNA sequencing showed overlapping causes., Interpretation: Hyperacute rejection was avoided. We identified potential mediators of the observed endothelial injury. First, widespread endothelial injury indicates antibody-mediated rejection. Second, IVIG bound strongly to donor endothelium, possibly causing immune activation. Finally, reactivation and replication of latent PCMV/PRV in the xenograft possibly initiated a damaging inflammatory response. The findings point to specific measures to improve xenotransplant outcomes in the future., Funding: The University of Maryland School of Medicine, and the University of Maryland Medical Center., Competing Interests: Declaration of interests DA, AD, TV, LS, and KK are employees of Revivicor, a subsidy of United Therapeutics. KB is an employee of Kiniksa Pharmaceuticals. Members of Program in Cardiac Xenotransplantation received research funding from United Therapeutics. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Foxp3 is regarded as the major transcription factor for T regulatory (T reg ) cells and expression of Foxp3 is used to identify and quantitate Treg cells in mouse models. However, several studies have demonstrated that human CD4 + T conventional (T conv ) cells activated in vitro by T cell receptor (TCR) stimulation can express Foxp3. This observation has raised doubt as to the suitability of Foxp3 as a T reg marker in man. Helios, a member of the Ikaros gene family, has been shown to be expressed by 80-90% of human Foxp3 + T reg cells and can potentially serve as a marker of human T reg . Here, we confirm that Foxp3 expression is readily upregulated by T conv upon TCR stimulation in vitro , while Helios expression is not altered. More importantly, we show that Foxp3 expression is not elevated by stimulation of hT conv in a humanized mouse model of graft versus host disease (GVHD) and in patients with a wide variety of acute and chronic inflammatory diseases including sickle cell disease, acute and chronic GVHD, systemic lupus erythematosus, as well as critical COVID-19. In all patients studied, an excellent correlation was observed between the percentage of CD4 + T cells expressing Foxp3 and the percentage expressing Helios. Taken together, these studies demonstrate that Foxp3 is not induced upon T conv cell activation in vivo and that Foxp3 expression alone can be used to quantitate T reg cells in humans. Nevertheless, the combined use of Foxp3 and Helios expression provides a more reliable approach for the characterization of T reg in humans., Competing Interests: MB is employed by the company Janssen Pharmaceuticals. AG is employed by the company Miltenyi Biotech. CO is employed by Axle Informatics. Studies unrelated to the present manuscript in the Shevach Laboratory (LM, MJ, ES, and MB) are supported by CRADAs from Janssen Pharmaceuticals and Boehringer Ingelheim Pharmaceuticals. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Morina, Jones, Oguz, Kaplan, Gangaplara, Fitzhugh, Kanakry, Shevach and Buszko.)

Competing Interests: Competing interests: None declared.

Most studies of adaptive immunity to SARS-CoV-2 infection focus on peripheral blood, which may not fully reflect immune responses at the site of infection. Using samples from 110 children undergoing tonsillectomy and adenoidectomy during the COVID-19 pandemic, we identified 24 samples with evidence of previous SARS-CoV-2 infection, including neutralizing antibodies in serum and SARS-CoV-2-specific germinal center and memory B cells in the tonsils and adenoids. Single-cell B cell receptor (BCR) sequencing indicated virus-specific BCRs were class-switched and somatically hypermutated, with overlapping clones in the two tissues. Expanded T cell clonotypes were found in tonsils, adenoids and blood post-COVID-19, some with CDR3 sequences identical to previously reported SARS-CoV-2-reactive T cell receptors (TCRs). Pharyngeal tissues from COVID-19-convalescent children showed persistent expansion of germinal center and antiviral lymphocyte populations associated with interferon (IFN)-γ-type responses, particularly in the adenoids, and viral RNA in both tissues. Our results provide evidence for persistent tissue-specific immunity to SARS-CoV-2 in the upper respiratory tract of children after infection., (© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)