Gated CT imaging using a free-breathing respiration signal from flow-volume spirometry

Respiration-induced tumor motion is known to cause artifacts on free-breathing spiral CT images used in treatment planning. This leads to inaccurate delineation of target volumes on planning CT images. Flow-volume spirometry has been used previously for breath-holds during CT scans and radiation treatments using the active breathing control (ABC) system. We have developed a prototype by extending the flow-volume spirometer device to obtain gated CT scans using a PQ 5000 single-slice CT scanner. To test our prototype, we designed motion phantoms to compare image quality obtained with and without gated CT scan acquisition. Spiral and axial (nongated and gated) CT scans were obtained of phantoms with motion periods of 3-5 s and amplitudes of 0.5-2 cm. Errors observed in the volume estimate of these structures were as much as 30% with moving phantoms during CT simulation. Application of motion-gated CT with active breathing control reduced these errors to within 5%. Motion-gated CT was then implemented in patients and the results are presented for two clinical cases: lung and abdomen. In each case, gated scans were acquired at end-inhalation, end-exhalation in addition to a conventional free-breathing (nongated) scan. The gated CT scans revealed reduced artifacts compared with the conventional free-breathing scan. Differences of up to 20% in the volume of the structures were observed between gated and free-breathing scans. A comparison of the overlap of structures between the gated and free-breathing scans revealed misalignment of the structures. These results demonstrate the ability of flow-volume spirometry to reduce errors in target volumes via gating during CT imaging.     

Immune function in congenital osteopetrosis: Defective lymphocyte function in microphthalmic mice

Osteopetrosis is a prominent feature of a congenital mutation described in microphthalmic mice and is thought to be due to defective osteoclast function which causes a generalized lack of bone resorption. Reversal of defective bone resorption in osteopetrotic mutants has been achieved by hematopoietic cell trans-plantations; and conversely, defective bone resorption has been transferred to normals by hematopoietic cells from osteopetrotic littermates. This suggested that osteopetrotic mutants might also demonstrate defective immune functions which could in turn be related to the lack of normal bone resorption. To that end, aspects of $\text{in}$$\text{vitro}$ lymphocyte function in microphthalmic mice were compared to those of their phenotypically normal littermates. There was a significant diminution in the proliferative response of splenocytes to mitogens in microphthalmic mice. Microphthalmic splenocytes also were less responsive in an $\text{in}$$\text{vitro}$ assay which measured the capacity to form antibody forming cells.     

Diverse Effects of Combinations of Maternal-Neonatal VDR Polymorphisms and 25-Hydroxyvitamin D Concentrations on Neonatal Birth Anthropometry: Functional Phenocopy Variability Dependence,Highlights the Need for Targeted Maternal 25-Hydroxyvitamin D Cut-Offs during Pregnancy

Vitamin D receptor (VDR) polymorphisms have been associated with a plethora of adverse pregnancy and offspring outcomes. The aim of this study was to evaluate the combined effect of maternal and neonatal VDR polymorphisms (ApaI, TaqI, BsmI, FokI, Tru9I) and different maternal and neonatal 25(OH)D cut-offs on neonatal birth anthropometry. This cross-sectional study included data and samples from a cohort of mother–child pairs at birth. A detailed neonatal anthropometry analysis at birth was also conducted. Different 25(OH)D cut-offs for neonates and mothers were included, according to their vitamin D status at birth: for neonates, cut-offs of [25(OH)D ≤ 25 and > 25 nmol/L] and [25(OH)D ≤ 50 nmol/L] were adopted, whereas for mothers, a 25(OH)D cut-off of [25(OH)D ≤ 50 and > 50 nmol/L)] was investigated. Following this classification, maternal and neonatal VDR polymorphisms were evaluated to investigate the potential different effects of different neonatal and maternal 25(OH)D cut-offs on neonatal birth anthropometry. A total of 69 maternal-neonatal dyads were included in final analysis. Weight, neck rump length, chest circumference, abdominal circumference, abdominal circumference (iliac), high thigh circumference, middle thigh circumference, lower arm radial circumference, and lower leg calf circumference of neonates who had the TAQl SNP TT genotype and maternal 25(OH)D < 50 nmol/L were significantly higher than that of neonates who had the Tt or tt genotypes (p = 0.001, Hg = 1.341, p = 0.036, Hg = 0.976, p = 0.004, Hg = 1.381, p = 0.001, Hg = 1.554, p = 0.001, Hg = 1.351, p = 0.028, Hg = 0.918, p = 0.008, Hg = 1.090, p = 0.002, Hg = 1.217, and p = 0.020, Hg = 1.263, respectively). Skin fold high anterior was significantly lower in neonates who had the BSMI SNP BB genotype compared to that of neonates with Bb or bb genotypes (p = 0.041, Hg = 0.950), whereas neck rump length was significantly higher in neonates who had the FOKI SNP FF genotype compared to that of neonates who had Ff or ff genotypes (p = 0.042, Hg = 1.228). Regarding neonatal VDR polymorphisms and cut-offs, the abdominal circumference (cm) of neonates who had the TAQI SNP TT genotype and 25(OH)D < 25 nmol/L were significantly higher than that of neonates who had the Tt or tt genotypes (p = 0.038, Hg = 1.138). In conclusion, these results indicate that the maternal TAQI VDR polymorphism significantly affected neonatal birth anthropometry when maternal 25(OH) concentrations were <50 nmol/L, but not for a higher cut-off of >50 nmol/L, whereas this effect is minimally evident in the presence of neonatal TAQI polymorphism with neonatal 25(OH)D values <25 nmol/L. The implication of these findings could be incorporated in daily clinical practice by targeting a maternal 25(OH)D cut-off >50 nmol/L, which could be protective against any effect of genetic VDR variance polymorphism on birth anthropometry.     

Safety and immunogenicity of adjuvanted recombinant subunit herpes zoster vaccine in lung transplant recipients

Lung transplant recipients are at high risk for herpes zoster and preventive measures are a significant unmet need. We investigated the safety and immunogenicity of two doses of a recombinant zoster vaccine (RZV) in lung transplant recipients (≥50 years). We enrolled 50 patients of which 49 received at least one vaccine dose. Anti-glycoprotein E (gE) antibody levels (n = 43) increased significantly compared to baseline (median optical density [OD] 1.96; interquartile range [IQR]: 1.17–2.89) after the first (median OD 3.41, IQR 2.54–3.81, p < .0001) and second vaccine dose (median OD 3.63, IQR 3.39–3.86, p < .0001). gE-specific polyfunctional CD4+ T cell frequencies (n = 38) also increased from baseline (median 85 per 10⁶ CD4+ T cells; IQR: 46–180) to the first (median 128 per 10⁶ CD4+ T cells; IQR: 82–353; p = .023) and after the second dose (median 361 per 10⁶ CD4+ T cells; IQR: 146–848; p < .0001). Tenderness (83.0%; 95%CI: 69.2–92.4%) and redness (31.9%; 95%CI: 19.1–47.1%) at injection site were common. One rejection episode within 3 weeks of vaccination was observed. This is the first study demonstrating that RZV was safe and elicited significant humoral and cell-mediated immunity in lung transplant recipients. RZV is a new option for the prevention of shingles in this population.     

With complements: C3 inhibition in the clinic

C3 is a key complement protein, located at the nexus of all complement activation pathways. Extracellular, tissue, cell-derived, and intracellular C3 plays critical roles in the immune response that is dysregulated in many diseases, making it an attractive therapeutic target. However, challenges such as very high concentration in blood, increased acute expression, and the elevated risk of infections have historically posed significant challenges in the development of C3-targeted therapeutics. This is further complicated because C3 activation fragments and their receptors trigger a complex network of downstream effects; therefore, a clear understanding of these is needed to provide context for a better understanding of the mechanism of action (MoA) of C3 inhibitors, such as pegcetacoplan. Because of C3's differential upstream position to C5 in the complement cascade, there are mechanistic differences between pegcetacoplan and eculizumab that determine their efficacy in patients with paroxysmal nocturnal hemoglobinuria. In this review, we compare the MoA of pegcetacoplan and eculizumab in paroxysmal nocturnal hemoglobinuria and discuss the complement-mediated disease that might be amenable to C3 inhibition. We further discuss the current state and outlook for C3-targeted therapeutics and provide our perspective on which diseases might be the next success stories in the C3 therapeutics journey.     

1p36 deletion syndrome: Review and mapping with further characterization of the phenotype,a new cohort of 86 patients

Chromosome 1p36 deletion syndrome (1p36DS) is one of the most common terminal deletion syndromes (incidence between 1/5000 and 1/10,000 live births in the American population), due to a heterozygous deletion of part of the short arm of chromosome 1. The 1p36DS is characterized by typical craniofacial features, developmental delay/intellectual disability, hypotonia, epilepsy, cardiomyopathy/congenital heart defect, brain abnormalities, hearing loss, eyes/vision problem, and short stature. The aim of our study was to (1) evaluate the incidence of the 1p36DS in the French population compared to 22q11.2 deletion syndrome and trisomy 21; (2) review the postnatal phenotype related to microarray data, compared to previously publish prenatal data. Thanks to a collaboration with the ACLF (Association des Cytogénéticiens de Langue Française), we have collected data of 86 patients constituting, to the best of our knowledge, the second-largest cohort of 1p36DS patients in the literature. We estimated an average of at least 10 cases per year in France. 1p36DS seems to be much less frequent than 22q11.2 deletion syndrome and trisomy 21. Patients presented mainly dysmorphism, microcephaly, developmental delay/intellectual disability, hypotonia, epilepsy, brain malformations, behavioral disorders, cardiomyopathy, or cardiovascular malformations and, pre and/or postnatal growth retardation. Cardiac abnormalities, brain malformations, and epilepsy were more frequent in distal deletions, whereas microcephaly was more common in proximal deletions. Mapping and genotype–phenotype correlation allowed us to identify four critical regions responsible for intellectual disability. This study highlights some phenotypic variability, according to the deletion position, and helps to refine the phenotype of 1p36DS, allowing improved management and follow-up of patients.     

Neuroaxonal dystrophy in HTLV-1-associated myelopathy/tropical spastic paraparesis: neuropathologic and neuroimmunologic correlations

Summary Detailed neuropathologic and immunohistologic analysis of a case of serologically and polymerase chain reaction-confirmed human immunodeficiency virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is reported in a 73-year-old North American black woman. In addition to the usual neuropathologic features of HAM/TSP, including tractal degeneration of the spinal cord, leptomeningeal and perivascular fibrosis, perivascular demyelination and chronic inflammation, neuroaxonal spheroids were prominent in the spinal cord. Neuroaxonal dystrophy was characterized by neurofilamentous masses that were immunoreactive for phosphorylated neurofilament epitopes, but not ubiquitin. Neuroimmunologic analysis of the inflammatory reaction revealed a prevalence of CD8⁺ T cells and class I major histocompatibility molecules (MHC) (HLA-ABC and 2-microglobulin), but very few CD4⁺ T cells. Microglia were highly reactive for class II MHC (HLA-DR) and this was attributed to activation, rather than CD4 interaction, since CD4 presence was minimal. Inflammatory cytokine immunoreactivity was also detected in glia. It is concluded that the cumulative effects of cytotoxic T cell (CD8) infiltration and the possible involvement of cytokines were responsible for the unusual degree of neuroaxonal dystrophy and vascular fibrosis, as well as the observed demyelination in this case.Supported in part by grants NS 07098, NS 08952, NS 11920 and MH 47667 from the NIH; and RG 1001-G-7 from the National Multiple Sclerosis Society.