Publisher Correction: Whole-genome sequencing of a sporadic primary immunodeficiency cohort.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Whole-genome sequencing of a sporadic primary immunodeficiency cohort.

Primary immunodeficiency (PID) is characterized by recurrent and often life-threatening infections, autoimmunity and cancer, and it poses major diagnostic and therapeutic challenges. Although the most severe forms of PID are identified in early childhood, most patients present in adulthood, typically with no apparent family history and a variable clinical phenotype of widespread immune dysregulation: about 25% of patients have autoimmune disease, allergy is prevalent and up to 10% develop lymphoid malignancies1-3. Consequently, in sporadic (or non-familial) PID genetic diagnosis is difficult and the role of genetics is not well defined. Here we address these challenges by performing whole-genome sequencing in a large PID cohort of 1,318 participants. An analysis of the coding regions of the genome in 886 index cases of PID found that disease-causing mutations in known genes that are implicated in monogenic PID occurred in 10.3% of these patients, and a Bayesian approach (BeviMed4) identified multiple new candidate PID-associated genes, including IVNS1ABP. We also examined the noncoding genome, and found deletions in regulatory regions that contribute to disease causation. In addition, we used a genome-wide association study to identify loci that are associated with PID, and found evidence for the colocalization of-and interplay between-novel high-penetrance monogenic variants and common variants (at the PTPN2 and SOCS1 loci). This begins to explain the contribution of common variants to the variable penetrance and phenotypic complexity that are observed in PID. Thus, using a cohort-based whole-genome-sequencing approach in the diagnosis of PID can increase diagnostic yield and further our understanding of the key pathways that influence immune responsiveness in humans.

A novel mutation in EROS (CYBC1) causes chronic granulomatous disease.

Chronic Granulomatous Disease (CGD) is an inborn error of immunity characterised by opportunistic infection and sterile granulomatous inflammation. CGD is caused by a failure of reactive oxygen species (ROS) production by the phagocyte NADPH oxidase. Mutations in the genes encoding phagocyte NADPH oxidase subunits cause CGD. We and others have described a novel form of CGD (CGD5) secondary to lack of EROS (CYBC1), a highly selective chaperone for gp91phox. EROS-deficient cells express minimal levels of gp91phox and its binding partner p22phox, but EROS also controls the expression of other proteins such as P2X7. The full nature of CGD5 is currently unknown. We describe a homozygous frameshift mutation in CYBC1 leading to CGD. Individuals who are heterozygous for this mutation are found in South Asian populations (allele frequency = 0.00006545), thus it is not a private mutation. Therefore, it is likely to be the underlying cause of other cases of CGD.

Automated image quality assessment of mammography phantoms: a systematic review.

BACKGROUND: Computerized image analysis is a viable technique for evaluating image quality as a complement to human observers. PURPOSE: To systematically review the image analysis software used in the assessment of 2D image quality using mammography phantoms. MATERIAL AND METHODS: A systematic search of multiple databases was performed from inception to July 2020 for articles that incorporated computerized analysis of 2D images of physical mammography phantoms to determine image quality. RESULTS: A total of 26 studies were included, 12 were carried out using direct digital imaging and 14 using screen film mammography. The ACR phantom (model-156) was the most frequently evaluated phantom, possibly due to the lack of accepted standard software. In comparison to the inter-observer variations, the computerized image analysis was more consistent in scoring test objects. The template matching method was found to be one of the most reliable algorithms, especially for high-contrast test objects, while several algorithms found low-contrast test objects to be harder to distinguish due to the smaller contrast variations between test objects and their backgrounds. This was particularly true for small object sizes. CONCLUSION: Image analysis software was in agreement with human observers but demonstrated higher consistency and reproducibility of quality evaluation. Additionally, using computerized analysis, several quantitative metrics such as contrast-to-noise ratio (CNR) and the signal-to-noise ratio (SNR) could be used to complement the conventional scoring method. Implementing a computerized approach for monitoring image quality over time would be crucial to detect any deteriorating mammography system before clinical images are impacted.

Introducing a secondary segmentation to construct a radiomics model for pulmonary tuberculosis cavities.

PURPOSE: Accurate segmentation (separating diseased portions of the lung from normal appearing lung) is a challenge in radiomic studies of non-neoplastic diseases, such as pulmonary tuberculosis (PTB). In this study, we developed a segmentation method, applicable to chest X-rays (CXR), that can eliminate the need for precise disease delineation, and that is effective for constructing radiomic models for automatic PTB cavity classification. METHODS: This retrospective study used a dataset of 266 posteroanterior CXR of patients diagnosed with laboratory confirmed PTB. The lungs were segmented using a U-net-based in-house automatic segmentation model. A secondary segmentation was developed using a sliding window, superimposed on the primary lung segmentation. Pyradiomics was used for feature extraction from every window which increased the dimensionality of the data, but this allowed us to accurately capture the spread of the features across the lung. Two separate measures (standard-deviation and variance) were used to consolidate the features. Pearson's correlation analysis (with a 0.8 cut-off value) was then applied for dimensionality reduction followed by the construction of Random Forest radiomic models. RESULTS: Two almost identical radiomic signatures consisting of 10 texture features each (9 were the same plus 1 other feature) were identified using the two separate consolidation measures. Two well performing random forest models were constructed from these signatures. The standard-deviation model (AUC = 0.9444 (95% CI, 0.8762; 0.9814)) performed marginally better than the variance model (AUC = 0.9288 (95% CI, 0.9046; 0.9843)). CONCLUSION: The introduction of the secondary sliding window segmentation on CXR could eliminate the need for disease delineation in pulmonary radiomic studies, and it could improve the accuracy of CXR reporting currently regaining prominence as a high-volume screening tool as the developed radiomic models correctly classify cavities from normal CXR.

The First Iranian Cohort of Pediatric Patients with Activated Phosphoinositide 3-Kinase-δ (PI3Kδ) Syndrome (APDS).

BACKGROUND: Activated phosphoinositide 3-kinase δ syndrome (APDS) is a recently defined combined primary immunodeficiency disease (PID) characterized by recurrent respiratory tract infections, lymphoproliferation, autoimmunity and lymphoma. Gain-of-function mutations in PIK3CD and loss-of-function of PIK3R1 genes lead to APDS1 and APDS2, respectively. METHODS: Demographic, clinical, immunological and genetic data were collected from medical records of 15 pediatric patients, who were genetically identified using the whole-exome sequencing method. RESULTS: Fifteen patients (6 APDS1 and 9 APDS2) were enrolled in this study. Recurrent respiratory tract infections followed by lymphoproliferation and autoimmunity were the most common manifestations (86.7%, 53.3% and 26.7%, respectively). Five patients (33.3%) had a Hyper-IgM-syndrome-like immunoglobulin profile. In the APDS1 group, splice site and missense mutations were found in half of the patients and the C-lobe domain of PIK3CD was the most affected region (50%). In the APDS2 group, splice site mutation was the most frequent mutation (77.8%) and the inter-SH2 domain was the most affected region of PIK3R1 (66.7%). Mortality rate was significantly higher in APDS2 group (P = .02) mainly due to chronic lung infections. CONCLUSION: Respiratory tract infections and humoral immunodeficiency are commonly the most important complication in pediatric APDS patients, and they can be fatal by ultimately causing catastrophic damage to the structure of lungs. Hence, physicians should be aware of its significance and further work-up of patients with recurrent respiratory tract infections especially in patients with lymphoproliferation. Moreover, delineation of genotype-phenotype associations with disease severity could be helpful in the timely application of appropriate management and patients' survival.

Variable Abnormalities in T and B Cell Subsets in Ataxia Telangiectasia.

BACKGROUND: Ataxia-telangiectasia (AT) is a rare genetic condition, caused by biallelic deleterious variants in the ATM gene, and has variable immunological abnormalities. This study aimed to examine immunologic parameters reflecting cell development, activation, proliferation, and class switch recombination (CSR) and determine their relationship to the clinical phenotype in AT patients. METHODS: In this study, 40 patients with a confirmed diagnosis of AT from the Iranian immunodeficiency registry center and 28 age-sex matched healthy controls were enrolled. We compared peripheral B and T cell subsets and T cell proliferation response to CD3/CD28 stimulation in AT patients with and without CSR defects using flow cytometry. RESULTS: A significant decrease in naïve, transitional, switched memory, and IgM only memory B cells, along with a sharp increase in the marginal zone-like and CD21low B cells was observed in the patients. We also found CD4+ and CD8+ naïve, central memory, and terminally differentiated effector memory CD4+ (TEMRA) T cells were decreased. CD4+ and CD8+ effector memory, CD8+ TEMRA, and CD4+ regulatory T cells were significantly elevated in our patients. CD4+ T cell proliferation was markedly impaired compared to the healthy controls. Moreover, immunological investigations of 15 AT patients with CSR defect revealed a significant reduction in the marginal zone, switched memory, and more intense defects in IgM only memory B cells, CD4+ naïve and central memory T cells. CONCLUSION: The present study revealed that patients with AT have a broad spectrum of cellular and humoral deficiencies. Therefore, a detailed evaluation of T and B cell subsets increases understanding of the disease in patients and the risk of infection.

Oral Plasma Kallikrein Inhibitor for Prophylaxis in Hereditary Angioedema.

BACKGROUND: Hereditary angioedema is a life-threatening illness caused by mutations in the gene encoding C1 inhibitor (also called C1 esterase inhibitor) that lead to overactivation of the kallikrein-bradykinin cascade. BCX7353 is a potent oral small-molecule inhibitor of plasma kallikrein with a pharmacokinetic and pharmacodynamic profile that may help prevent angioedema attacks. METHODS: In this international, three-part, dose-ranging, placebo-controlled trial, we evaluated four doses of BCX7353 (62.5 mg, 125 mg, 250 mg, and 350 mg once daily) for the prevention of angioedema attacks over a 28-day period. Patients with type I or II hereditary angioedema with a history of at least two angioedema attacks per month were randomly assigned to BCX7353 or placebo. The primary efficacy end point was the number of confirmed angioedema attacks. Key secondary end points included angioedema attacks according to anatomical location and quality of life. RESULTS: A total of 77 patients underwent randomization, 75 received BCX7353 or placebo, and 72 completed the trial. The rate of confirmed angioedema attacks was significantly lower among patients who received BCX7353 at daily doses of 125 mg or more than among those who received placebo, with a 73.8% difference at 125 mg (P<0.001). Significant benefits with respect to quality-of-life scores were observed in the 125-mg and 250-mg dose groups (P<0.05). Gastrointestinal adverse events, predominantly of grade 1, were the most commonly reported adverse events, particularly in the two highest BCX7353 dose groups. CONCLUSIONS: Once-daily oral administration of BCX7353 at a dose of 125 mg or more resulted in a significantly lower rate of attacks of hereditary angioedema than placebo. Mild gastrointestinal symptoms were the principal side effect. (Funded by BioCryst Pharmaceuticals; APeX-1 ClinicalTrials.gov number, NCT02870972 .).

The Prevalence of Atopic Manifestations in 313 Iranian Patients with Inborn Errors of Immunity.

INTRODUCTION: Inborn errors of immunity (IEIs) are rare inherited disorders with a broad spectrum of manifestations. Here, we aimed to delineate the atopy burden in a cohort of patients with IEIs. METHODS: 313 patients with IEIs were enrolled in the study within a 9-years period, and data were collected via a questionnaire. All statistical analyses were performed using SPSS software (v. 25.0, Chicago, IL, USA). The statistical significance level was set at p < 0.05. RESULTS: Overall, 51 out of 313 (16.3%) patients were identified to have atopic manifestations. Food allergy was detected in 34 (10.2%), atopic dermatitis in 21 (6.7%), as well as allergic asthma and allergic rhinitis each in 4 (1.3%) patients. The allergic disorders were reported as initial manifestations among 14 out of 35 (40.0%) atopic patients. Most of these 51 patients fell within the category of combined immunodeficiency (CID) (n = 38, 74.5%), followed by, severe CID (SCID) (n = 5, 9.8%), common variable immunodeficiency (n = 3, 5.9%), chronic granulomatous disease (n = 3, 5.9%), selective IgA deficiency (n = 1, 2.0%), and leukocyte adhesion defect (n = 1, 2.0%). No patient with Mendelian susceptibility to mycobacteria was found to have atopic manifestation. Atopic dermatitis (p = 0.001) and food allergy (p < 0.001) were both significantly higher in patients with CID than in other IEI groups. Among atopic patients with CID and SCID, food allergy and atopic dermatitis were the most prevalent comorbidities. DISCUSSION/CONCLUSION: Atopic diseases may contribute to the clinical picture of IEIs, particularly in patients with CID. Atopy in association with other warning signs of IEIs increases the possibility of an underlying IEI.

Personal dosimeter utilisation among South African interventionalists.

Ionising radiation (IR) is increasingly being used in diagnostic and therapeutic procedures and offers increased benefits to patients but poses an increased occupational health risk to operators. The consistent use and monitoring of radiation health care workers' dosimeters is an important part of the process for ensuring adequate monitoring and control of IR in the workplace. There is however often inconsistent dosimeter utilisation among these workers. The aim of this study was to report on the dosimeter utilisation and dosimetry practices in South African interventionalists. We conducted a survey and did in-depth and group interviews to evaluate dosimetry practices and the factors influencing these practices. We used STATA 15 to do a descriptive analysis of the quantitative data. A thematic analysis of the qualitative data was done using a deductive and inductive approach. There were 108 respondents (35 radiologists, 41 adult cardiologists, 32 paediatric cardiologists). The majority overall (65.8%), and in each category were males. The median age was 44 (interquartile range (IQR) 31-66)) and the median years worked with fluoroscopy was 10 years (IQR 1-32). Overall interventionalists (55%) ranked their perceived occupation risk as 2/10. Thirteen per cent of all interventionalists reported never using a personal dosimeter (PD), 58% reported wearing it >70% of the time. Inconsistent and inappropriate use of PDs emerged strongly from the qualitative data. There was poor dosimeter utilisation in this study. Participants were not aware of the role of medical physics departments. Evaluation of dosimetry practices as a means of monitoring and improving radiation safety in the catheterisation laboratory must be improved to create an improved culture of radiation safety and protection.

Mutations in RPSA and NKX2-3 link development of the spleen and intestinal vasculature.

Idiopathic intestinal varicosis is a developmental disorder defined by dilated and convoluted submucosal veins in the colon or small bowel. A limited number of families with idiopathic intestinal varices has been reported, but the genetic cause has not yet been identified. We performed whole-exome and targeted Sanger sequencing of candidate genes in five intestinal varicosis families. In four families, mutations in the RPSA gene were found, a gene previously linked to congenital asplenia. Individuals in these pedigrees had intestinal varicose veins and angiodysplasia, often in combination with asplenia. In a further four-generation pedigree that only showed intestinal varicosities, the RPSA gene was normal. Instead, a nonsense mutation in the homeobox gene NKX2-3 was detected which cosegregated with the disease in this large family with a LOD (logarithm of the odds) score of 3.3. NKX2-3 is a component of a molecular pathway underlying spleen and gut vasculature development in mice. Our results provide a molecular basis for familial idiopathic intestinal varices. We provide evidence for a relationship between the molecular pathways underlying the development of the spleen and intestinal mucosal vasculature that is conserved between humans and mice. We propose that clinical management of intestinal varices, should include assessment of a functional spleen.

Is mammographic density a marker of breast cancer phenotypes?

PURPOSE: To investigate the association between mammographic density (MD) phenotypes and both clinicopathologic features of breast cancer (BC) and tumor location. METHODS: MD was measured for 297 BC-affected females using qualitative (visual method) and quantitative (fully automated area-based method) approaches. Radiologists' description, visible external markers, and surgical scar were used to establish the location of tumors. Binary logistic regression models were used to assess the association between MD phenotypes and BC clinicopathologic features. RESULTS: Categorical and numerical MD measures showed no association with clinicopathologic features of BC (p > 0.05). Participants with higher BI-RADS scores [(51-75% glandular) and (> 75% glandular)] (p < 0.001), and percent density (PD) categories [PD (21-49%) and PD ≥ 50%] (p = 0.01) were more likely to have tumors emanating from dense areas. Additionally, tumors were commonly found in dense regions of the breast among patients with higher medians of PD (p = 0.001), dense area (DA) (p = 0.02), and lower medians of non-dense area (NDA) (p < 0.001). Adjusted logistic regression models showed that high BI-RADS density (> 75% glandular) has an almost fivefold increased odds of tumors developing within dense areas (OR 4.99, 95% CI 0.93-25.9; p = 0.05. PD (OR 1.02, 95% CI 1-1.03, p = 0.002) and NDA (OR 0.99, 95% CI 0.991-0.997, p < 0.001) had very small effect on tumor location. Compared to tumors within non-dense areas, tumors in dense areas tended to exhibit human epidermal growth factor receptor 2 positive (p = 0.05) and carcinoma in situ (p = 0.01) characteristics. CONCLUSION: MD shows no significant association with clinicopathologic features of BC. However, BC was more likely to originate from dense tissue, with tumors in dense regions having human epidermal growth receptor 2 positive and carcinoma in situ characteristics.

Comparison of central, peripheral, and weighted size-specific dose in CT.

The objective of this study is to determine X-ray dose distribution and the correlation between central, peripheral and weighted-centre peripheral doses for various phantom sizes and tube voltages in computed tomography (CT). We used phantoms developed in-house, with various water-equivalent diameters (Dw) from 8.5 up to 42.1 cm. The phantoms have one hole in the centre and four holes at the periphery. By using these five holes, it is possible to measure the size-specific central dose (Ds,c), peripheral dose (Ds,p), and weighted dose (Ds,w).The phantoms are scanned using a CT scanner (Siemens Somatom Definition AS), with the tube voltage varied from 80 up to 140 kVps. The doses are measured using a pencil ionization chamber (Ray safe X2 CT Sensor) in every hole for all phantoms. The relationships between Ds,c, Ds,p, and Ds,w, and the water-equivalent diameter are established. The size-conversion factors are calculated. Comparisons between Ds,c, Ds,p, and Ds,ware also established. We observe that the dose is relatively homogeneous over the phantom for water-equivalent diameters of 12-14 cm. For water-equivalent diameters less than 12 cm, the dose in the centre is higher than at the periphery, whereas for water-equivalent diameters greater than 14 cm, the dose at the centre is lower than that at the periphery. We also find that the distribution of the doses is influenced by the tube voltage. These dose distributions may be useful for calculating organ doses for specific patients using their CT images in future clinical practice.

Biodistribution (as determined by the radiolabelled equivalent) of a gold(III) bis(pyrrolide-imine) Schiff base complex: a potential chemotherapeutic.

The biodistribution of an N2 N2 ' tetradentate gold(III) chelate, which is known to be cytotoxic towards a range of human cancer cell lines, was determined by a radiolabelled equivalent of the compound. The (198) Au-labelled gold(III) chelate of a bis(pyrrolide-imine) Schiff base ligand with a three-carbon di(azomethine) linkage was successfully synthesised with a high radiochemical yield of 73% and radiochemical purity of >95%. The high energy γ-ray emitted by the (198) Au nucleus was used to follow the biodistribution of the compound in vivo in six male Sprague Dawley rats on a gamma camera. The log Po/w value of the (nat) Au analogue, -1.92(2), showed that the compound is hydrophilic and therefore likely to largely remain in the blood pool. This was confirmed by the biodistribution study, which showed 21% of the injected dose (ID) remained in the blood pool 4.5 h after injection. This decreased to 10.8% over a 24-h period. The activity measured in the lungs, 1.48%ID/g, remained relatively constant over a 24-h period suggesting that the complex had accumulated in the lungs in the form of particulates, and could not be cleared by the test subjects. The t½ for the heart and lungs was greater than 24 h. Excretion of the test compound is seemingly via the kidneys, but is slow with approximately 30% of the ID excreted within 24 h.

The Optic Nerve Compartment Syndrome in Cryptococcus-Induced Visual Loss.

Visual loss in cryptococcal meningitis has been postulated to be due to papilloedema and/or optic neuritis. A 28-year-old human immunodeficiency virus (HIV)-positive female presented with visual loss, swollen optic discs, and elevated intracranial pressure due to cryptococcal meningitis. Computerised tomographic cisternography and T2-weighted magnetic resonance imaging showed occlusion of the peri-optic subarachnoid space and its reopening after serial lumbar punctures. Presumably lowering of the intracranial pressure resulted in equalisation of pressure across the pressure gradient created by the fungal block. This case supports a third mechanism of visual loss in cryptococcal meningitis, namely, an optic nerve compartment syndrome, that seems more plausible as the principal mechanism.

FACTORS INFLUENCING SIZE-SPECIFIC DOSE ESTIMATES OF SELECTED COMPUTED TOMOGRAPHY PROTOCOLS AT TWO CLINICAL PRACTICES IN SOUTH AFRICA.

The study aimed to determine the factors that impact the size-specific dose estimate (SSDE) for computed tomography (CT) examinations of the chest-abdomen-pelvis and abdomen-pelvis protocols in two clinical radiology practices and evaluate the image quality of these protocols. Imaging parameters, protocols, dose metrics from the CT units and size-related parameters to calculate the SSDE were documented. The image quality of the CT images was assessed using an image subtraction algorithm. The SSDE increased as the volumetric CT dose index (CTDIvol), and the patient's body mass index increased, respectively. Significant differences (p < 0.001) occurred between the two hospitals regarding image quality. However, these differences were not indicative of differences in the diagnostic performances for task-based imaging protocols. Different clinical protocols should be reviewed to optimise dose. The inclusion of the pre-monitoring sequence, age of the machine and the scan requisition parameters impacted the SSDEs. Image quality should be assessed to evaluate the consistency of image quality between protocols applied by different CT units when assessing SSDEs.

The potential advantages and workflow challenges of long axial field of view PET/CT.

Recently developed Long (≥100 cm) axial field of view (AFOV) PET/CT scanners are capable of producing images with higher signal-to-noise ratio, or performing faster whole-body acquisitions, or scanning with lower radiation dose to the patient, compared with conventional PET/CT scanners. These benefits, which arise due to their substantially higher, by more than an order of magnitude, geometric efficiency, have been well described in the recent literature. The introduction of Long AFOV PET/CT technology into the clinic also has important implications for the design and workflow of PET/CT facilities and their effects on radiation exposure to staff and patients. Maximising the considerable benefits of this technology requires a thorough understanding of the relationships between these factors to optimise workflows while appropriately managing radiation exposure. This article reviews current knowledge on PET/CT facility design, workflows and their effects on radiation exposure, identifies gaps in the literature and discusses the challenges that need to be considered with the introduction of Long AFOV PET/CT into the clinic.

Quantitative Chest X-ray Radiomics for Therapy Response Monitoring in Patients with Pulmonary Tuberculosis.

Tuberculosis (TB) remains the second leading cause of death globally from a single infectious agent, and there is a critical need to develop improved imaging biomarkers and aid rapid assessments of responses to therapy. We aimed to utilize radiomics, a rapidly developing image analysis tool, to develop a scoring system for this purpose. A chest X-ray radiomics score (RadScore) was developed by implementing a unique segmentation method, followed by feature extraction and parameter map construction. Signature parameter maps that showed a high correlation to lung pathology were consolidated into four frequency bins to obtain the RadScore. A clinical score (TBscore) and a radiological score (RLscore) were also developed based on existing scoring algorithms. The correlation between the change in the three scores, calculated from serial X-rays taken while patients received TB therapy, was evaluated using Spearman's correlation. Poor correlations were observed between the changes in the TBscore and the RLscore (0.09 (p-value = 0.36)) and the TBscore and the RadScore (0.02 (p-value = 0.86)). The changes in the RLscore and the RadScore had a much stronger correlation of 0.22, which is statistically significant (p-value = 0.02). This shows that the developed RadScore has the potential to be a quantitative monitoring tool for responses to therapy.