Syrian hamster convalescence from prototype SARS-CoV-2 confers measurable protection against the attenuated disease caused by the Omicron variant.

The mutation profile of the SARS-CoV-2 Omicron (lineage BA.1) variant posed a concern for naturally acquired and vaccine-induced immunity. We investigated the ability of prior infection with an early SARS-CoV-2 ancestral isolate (Australia/VIC01/2020, VIC01) to protect against disease caused by BA.1. We established that BA.1 infection in naïve Syrian hamsters resulted in a less severe disease than a comparable dose of the ancestral virus, with fewer clinical signs including less weight loss. We present data to show that these clinical observations were almost absent in convalescent hamsters challenged with the same dose of BA.1 50 days after an initial infection with ancestral virus. These data provide evidence that convalescent immunity against ancestral SARS-CoV-2 is protective against BA.1 in the Syrian hamster model of infection. Comparison with published pre-clinical and clinical data supports consistency of the model and its predictive value for the outcome in humans. Further, the ability to detect protection against the less severe disease caused by BA.1 demonstrates continued value of the Syrian hamster model for evaluation of BA.1-specific countermeasures.

Mycobacterium tuberculosis modifies cell wall carbohydrates during biofilm growth with a concomitant reduction in complement activation.

The development of new vaccines for TB needs to be underpinned by an understanding of both the molecular and cellular mechanisms of host-pathogen interactions and how the immune response can be modulated to achieve protection from disease. Complement orchestrates many aspects of the innate and adaptive immune responses. However, little is known about the contribution of the complement pathways during TB disease, particularly with respect to mycobacterial phenotype. Extracellular communities (biofilms) of M. tuberculosis are found in the acellular rim of granulomas, during disease, and these are likely to be present in post-primary TB episodes, in necrotic lesions. Our study aimed to determine which mycobacterial cell wall components were altered during biofilm growth and how these cell wall alterations modified the complement response. We have shown that M. tuberculosis biofilms modified their cell wall carbohydrates and elicited reduced classical and lectin pathway activation. Consistent with this finding was the reduction of C3b/iC3b deposition on biofilm cell wall carbohydrate extracts. Here, we have highlighted the role of cell wall carbohydrate alterations during biofilm growth of M. tuberculosis and subsequent modulation of complement activation.

Development of flow cytometric opsonophagocytosis and antibody-mediated complement deposition assays for non-typeable Haemophilus influenzae.

BACKGROUND: Haemophilus influenzae is found in the nasopharynx of 80% of the human population. While colonisation with non-typeable Haemophilus influenzae (NTHi) is usually asymptomatic, it is capable of causing acute and chronic otitis media (OM) in infants, invasive disease in susceptible groups and is the leading cause of exacerbations of patients with chronic obstructive pulmonary disease (COPD). Current methods for assessing functional antibody immunity to NTHi are limited and labour intensive. Flow cytometric assays could provide an attractive alternative to evaluate immune responses to candidate vaccines in clinical trials. RESULTS: We have developed a duplexed flow-cytometric uptake and oxidative burst opsonophagocytosis assay (fOPA). We have also developed a duplexed antibody-mediated complement C3b/iC3b and C5b-9 deposition assay (CDA). Antibody-mediated C3b/iC3b deposition correlated with opsonophagocytic uptake (r = 0.65) and with opsonophagocytic oxidative burst (r = 0.69). Both fOPA and CDA were reproducible, with the majority of samples giving a coefficient of variation (CV) of < 20% and overall assay CVs of 14% and 16% respectively. CONCLUSIONS: The high-throughput flow cytometric assays developed here were successfully optimised for use with NTHi. Assays proved to be sensitive and highly reproducible for the measurement of bacterial uptake and oxidative burst opsonophagocytosis and antibody-mediated deposition of C3b/iC3b and C5b-9. These assays are useful tools for use in large scale epidemiological studies and to assist in the assessment of functional antibody induced by NTHi candidate vaccines.

Restrictive lung defects: parenchymal, chest wall and neuromuscular.

Sarcoidosis is a multisystem condition which may affect a number of organs and, within the cardiopulmonary system, most commonly manifests as parenchymal, airway-centred, nodal, vascular or cardiac disease. Pleural involvement is rare, but well described, and often presents as pleural effusions or pleural thickening. Here, we present the first case of active sarcoidosis manifesting as bilateral pleural calcification. We highlight the importance of a nuanced understanding of pulmonary physiology when dissecting coexistent extrathoracic and intrathoracic pulmonary restriction. We demonstrate the value of positron emission tomography scanning for identification of sites of sarcoid activity, in this case the pleura, to ensure tissue confirmation of this rare but functionally important manifestation of disease. Sarcoidosis should be considered within the differential diagnosis for patients with pleural calcification, not explained by more common causes.

A Flow Cytometry Method for Assessing M. tuberculosis Responses to Antibiotics.

Traditional drug susceptibility methods can take several days or weeks of incubation between drug exposure and confirmation of sensitivity or resistance. In addition, these methods do not capture information about viable organisms that are not immediately culturable after drug exposure. Here, we present a rapid fluorescence detection method for assessing the susceptibility of M. tuberculosis to antibiotics. Fluorescent markers Calcein violet-AM and SYTOX-green are used for measuring cell viability or cell death and to capture information about the susceptibility of the whole population and not just those bacteria that can grow in media postexposure. Postexposure to the antibiotic, the method gives a rapid readout of drug susceptibility, as well as insights into the concentration and time-dependent drug activity following antibiotic exposure.

Improved nuclear medicine uniformity assessment with noise texture analysis.

UNLABELLED: Because γ cameras are generally susceptible to environmental conditions and system vulnerabilities, they require routine evaluation of uniformity performance. The metrics for such evaluations are commonly pixel value-based. Although these metrics are typically successful at identifying regional nonuniformities, they often do not adequately reflect subtle periodic structures; therefore, additional visual inspections are required. The goal of this project was to develop, test, and validate a new uniformity analysis metric capable of accurately identifying structures and patterns present in nuclear medicine flood-field uniformity images. METHODS: A new uniformity assessment metric, termed the structured noise index (SNI), was based on the 2-dimensional noise power spectrum (NPS). The contribution of quantum noise was subtracted from the NPS of a flood-field uniformity image, resulting in an NPS representing image artifacts. A visual response filter function was then applied to both the original NPS and the artifact NPS. A single quantitative score was calculated on the basis of the magnitude of the artifact. To verify the validity of the SNI, an observer study was performed with 5 expert nuclear medicine physicists. The correlation between the SNI and the visual score was assessed with Spearman rank correlation analysis. The SNI was also compared with pixel value-based assessment metrics modeled on the National Electrical Manufacturers Association standard for integral uniformity in both the useful field of view (UFOV) and the central field of view (CFOV). RESULTS: The SNI outperformed the pixel value-based metrics in terms of its correlation with the visual score (ρ values for the SNI, integral UFOV, and integral CFOV were 0.86, 0.59, and 0.58, respectively). The SNI had 100% sensitivity for identifying both structured and nonstructured nonuniformities; for the integral UFOV and CFOV metrics, the sensitivities were only 62% and 54%, respectively. The overall positive predictive value of the SNI was 87%; for the integral UFOV and CFOV metrics, the positive predictive values were only 67% and 50%, respectively. CONCLUSION: The SNI accurately identified both structured and nonstructured flood-field nonuniformities and correlated closely with expert visual assessment. Compared with traditional pixel value-based analysis, the SNI showed superior performance in terms of its correlation with visual perception. The SNI method is effective for detecting and quantifying visually apparent nonuniformities and may reduce the need for more subjective visual analyses.

Quantitative characterization of the imaging limits of diffuse low-grade oligodendrogliomas.

BACKGROUND: Supratentorial diffuse low-grade gliomas in adults extend beyond maximal visible MRI-defined abnormalities, and a gap exists between the imaging signal changes and the actual tumor margins. Direct quantitative comparisons between imaging and histological analyses are lacking to date. However, they are of the utmost importance if one wishes to develop realistic models for diffuse glioma growth. METHODS: In this study, we quantitatively compared the cell concentration and the edema fraction from human histological biopsy samples (BSs) performed inside and outside imaging abnormalities during serial imaging-based stereotactic biopsy of diffuse low-grade gliomas. RESULTS: The cell concentration was significantly higher in BSs located inside (1189 ± 378 cell/mm(2)) than outside (740 ± 124 cell/mm(2)) MRI-defined abnormalities (P = .0003). The edema fraction was significantly higher in BSs located inside (mean, 45% ± 23%) than outside (mean, 5 %± 9%) MRI-defined abnormalities (P < .0001). At borders of the MRI-defined abnormalities, 20% of the tissue surface area was occupied by edema and only 3% by tumor cells. The cycling cell concentration was significantly higher in BSs located inside (10 ± 12 cell/mm(2)), compared with outside (0.5 ± 0.9 cell/mm(2)), MRI-defined abnormalities (P = .0001). CONCLUSIONS: We showed that the margins of T2-weighted signal changes are mainly correlated with the edema fraction. In 62.5% of patients, the cycling tumor cell fraction (defined as the ratio of the cycling tumor cell concentration to the total number of tumor cells) was higher at the limits of the MRI-defined abnormalities than closer to the center of the tumor. In the remaining patients, the cycling tumor cell fraction increased towards the center of the tumor.

MIRD pamphlet No. 21: a generalized schema for radiopharmaceutical dosimetry--standardization of nomenclature.

The internal dosimetry schema of the Medical Internal Radiation Dose (MIRD) Committee of the Society of Nuclear Medicine has provided a broad framework for assessment of the absorbed dose to whole organs, tissue subregions, voxelized tissue structures, and individual cellular compartments for use in both diagnostic and therapeutic nuclear medicine. The schema was originally published in 1968, revised in 1976, and republished in didactic form with comprehensive examples as the MIRD primer in 1988 and 1991. The International Commission on Radiological Protection (ICRP) is an organization that also supplies dosimetric models and technical data, for use in providing recommendations for limits on ionizing radiation exposure to workers and members of the general public. The ICRP has developed a dosimetry schema similar to that of the MIRD Committee but has used different terminology and symbols for fundamental quantities such as the absorbed fraction, specific absorbed fraction, and various dose coefficients. The MIRD Committee objectives for this pamphlet are 3-fold: to restate its schema for assessment of absorbed dose in a manner consistent with the needs of both the nuclear medicine and the radiation protection communities, with the goal of standardizing nomenclature; to formally adopt the dosimetry quantities equivalent dose and effective dose for use in comparative evaluations of potential risks of radiation-induced stochastic effects to patients after nuclear medicine procedures; and to discuss the need to identify dosimetry quantities based on absorbed dose that address deterministic effects relevant to targeted radionuclide therapy.

MIRD pamphlet No. 20: the effect of model assumptions on kidney dosimetry and response--implications for radionuclide therapy.

UNLABELLED: Renal toxicity associated with small-molecule radionuclide therapy has been shown to be dose-limiting for many clinical studies. Strategies for maximizing dose to the target tissues while sparing normal critical organs based on absorbed dose and biologic response parameters are commonly used in external-beam therapy. However, radiopharmaceuticals passing though the kidneys result in a differential dose rate to suborgan elements, presenting a significant challenge in assessing an accurate dose-response relationship that is predictive of toxicity in future patients. We have modeled the multiregional internal dosimetry of the kidneys combined with the biologic response parameters based on experience with brachytherapy and external-beam radiation therapy to provide an approach for predicting radiation toxicity to the kidneys. METHODS: The multiregion kidney dosimetry model of MIRD pamphlet no. 19 has been used to calculate absorbed dose to regional structures based on preclinical and clinical data. Using the linear quadratic model for radiobiologic response, we computed regionally based surviving fractions for the kidney cortex and medulla in terms of their concentration ratios for several examples of radiopharmaceutical uptake and clearance. We used past experience to illustrate the relationship between absorbed dose and calculated biologically effective dose (BED) with radionuclide-induced nephrotoxicity. RESULTS: Parametric analysis for the examples showed that high dose rates associated with regions of high activity concentration resulted in the greatest decrease in tissue survival. Higher dose rates from short-lived radionuclides or increased localization of radiopharmaceuticals in radiosensitive kidney subregions can potentially lead to greater whole-organ toxicity. This finding is consistent with reports of kidney toxicity associated with early peptide receptor radionuclide therapy and (166)Ho-phosphonate clinical investigations. CONCLUSION: Radionuclide therapy dose-response data, when expressed in terms of biologically effective dose, have been found to be consistent with external-beam experience for predicting kidney toxicity. Model predictions using both the multiregion kidney and linear quadratic models may serve to guide the investigator in planning and optimizing future clinical trials of radionuclide therapy.

The American Board of Radiology Perspective on Maintenance of Certification: Part IV: Practice quality improvement in radiologic physics.

Recent initiatives of the American Board of Medical Specialties (ABMS) in the area of maintenance of certification (MOC) have been reflective of the response of the medical community to address public concerns regarding quality of care, medical error reduction, and patient safety. In March 2000, the 24 member boards of the ABMS representing all medical subspecialties in the USA agreed to initiate specialty-specific maintenance of certification (MOC) programs. The American Board of Radiology (ABR) MOC program for diagnostic radiology, radiation oncology, and radiologic physics has been developed, approved by the ABMS, and initiated with full implementation for all three disciplines beginning in 2007. The overriding objective of MOC is to improve the quality of health care through diplomate-initiated learning and quality improvement. The four component parts to the MOC process are: Part I: Professional standing, Part II: Evidence of life long learning and periodic self-assessment, Part III: Cognitive expertise, and Part IV: Evaluation of performance in practice (with the latter being the focus of this paper). The key components of Part IV require a physicist-based response to demonstrate commitment to practice quality improvement (PQI) and progress in continuing individual competence in practice. Diplomates of radiologic physics must select a project to be completed over the ten-year cycle that potentially can improve the quality of the diplomate's individual or systems practice and enhance the quality of care. Five categories have been created from which an individual radiologic physics diplomate can select one required PQI project: (1) Safety for patients, employees, and the public, (2) accuracy of analyses and calculations, (3) report turnaround time and communication issues, (4) practice guidelines and technical standards, and (5) surveys (including peer review of self-assessment reports). Each diplomate may select a project appropriate for an individual, participate in a project within a clinical department, participate in a peer review of a self-assessment report, or choose a qualified national project sponsored by a society. Once a project has been selected, the steps are: (1) Collect baseline data relevant to the chosen project, (2) review and analyze the data, (3) create and implement an improvement plan, (4) remeasure and track, and (5) report participation to the ABR, using the template provided by the ABR. These steps begin in Year 2, following training in Year 1. Specific examples of individual PQI projects for each of the three disciplines of radiologic physics are provided. Now, through the MOC programs, the relationship between the radiologic physicist and the ABR will be continuous through the diplomate's professional career. The ABR is committed to providing an effective infrastructure that will promote and assist the process of continuing professional development including the enhancement of practice quality improvement for radiologic physicists.

Iodine biokinetics and dosimetry in radioiodine therapy of thyroid cancer: procedures and results of a prospective international controlled study of ablation after rhTSH or hormone withdrawal.

UNLABELLED: Technical aspects and results of the dosimetric assessments of postoperative radioiodine ablation in the framework of an international, prospective, controlled, randomized, comparative study of the effectiveness of ablation therapy with 3.7 GBq (131)I in differentiated thyroid cancer after stimulation with recombinant human TSH (rhTSH) or by thyroid hormone withdrawal (THW) are presented. METHODS: Sixty-three patients were randomized after thyroidectomy to either the THW or the rhTSH group. Scintigraphic neck images were acquired starting 48 h after radioiodine administration to assess biokinetics in the thyroid remnant. The activity in blood samples was quantified and data from whole-body probe measurements and scintigraphic whole-body scans were combined to deduce retention curves in blood and whole body, respectively. The absorbed dose to the blood was calculated using a modified approach based on the formalism of the MIRD Committee of the Society of Nuclear Medicine. RESULTS: The effective half-time in the remnant thyroid tissue was significantly longer after rhTSH than THW (67.6 +/- 48.8 vs. 48.0 +/- 52.6 h, respectively; P = 0.01), whereas the observed differences of the mean 48-h (131)I uptakes (0.5% +/- 0.7% vs. 0.9% +/- 1.0% after THW; P = 0.1) and residence times (0.9 +/- 1.3 vs. 1.4 +/- 1.5 h after THW; P = 0.1) between the rhTSH and THW groups were not statistically significant. The specific absorbed dose to the blood was significantly (P <0.0001) lower after administration of rhTSH (mean, 0.109 +/- 0.028 mGy/MBq; maximum, 0.18 mGy/MBq) than after THW (mean, 0.167 +/- 0.061 mGy/MBq; maximum, 0.35 mGy/MBq), indicating that higher activities of radioiodine might be safely administered after exogenous stimulation with rhTSH. CONCLUSION: Indication of an influence of the residence time of radioiodine in the blood on the fractional uptake into thyroid remnant was found. A novel regimen is proposed in which therapeutic activities to be administered are determined from the individual specific blood dose.

Effective dose of dual-energy X-ray absorptiometry scans in children as a function of age.

Effective dose, a parameter utilized to assess biological risk related to radiation exposure, may be used to evaluate risk associated with dual-energy X-ray absorptiometry (DXA). We estimated the effective dose from DXA (Hologic QDR 4500A) scans of the lumbar spine (fast array mode), total body, hip (fast array mode), and forearm for children ages 1, 5, 10, and 15 yr and for adults. Entrance dose incorporating backscatter was determined for each scan type. Depth-dose curves were derived using Plexiglas slabs simulating tissue attenuation. Organ depth was estimated using pediatric phantom models. For all scan types, the effective dose decreased as age increased. The effective dose values for a 1-yr-old and an adult, respectively, were 4.7 microSv and 2.2 microSv for a lumbar spine scan performed in fast array mode, 3.4/3.5 microSv and 1.8/2.1 microSv (male/female) for a total body scan, and 0.14 microSv and 0.03 microSv for a forearm scan. There were marked sex differences in the effective dose associated with hip scans (fast array mode) ranging from 15.2 microSv for a 1-yr-old male to 4.6 microSv for an adult female. A comprehensive uncertainty analysis indicated that the effective dose values were reliable within a factor of 3. With the exception of the hip scans in 1- and 5-yr-olds, the effective doses were below the negligible individual dose limit of 10 microSv/yr.

Radiation-absorbed dose from 201Tl-thallous chloride.

UNLABELLED: Revised radiation dosimetry estimates for 201Tl-thallous chloride have been developed using new data specifically acquired to address the issue of testicular uptake of this agent and through reevaluation of extant data for biodistribution in other organs. METHODS: Quantitative testicular scintigraphy data of sequestered testes (body-background shielded) were obtained from 28 patients (56 studies) injected with 201Tl-thallous chloride at peak exercise. Previously published data for 15 patients injected at maximal exercise were reanalyzed to obtain updated biodistribution parameters for designated organs. Radiation dose was calculated according to the MIRD schema. Radiation dose to testes as a function of age was determined. Comparisons are made between organ dose estimates derived in this study and those previously published. The dose contributions of possible contaminants (200Tl, 202Tl, 203Pb) have been included. Estimates are provided of the dose component from these contaminants if injected at the time of the maximum recommended 5-d shelf life (as opposed to at the designated calibration time). RESULTS: The radiation dose per unit administered activity to adult testes calculated in this study of 0.21 mGy/MBq (0.77 rad/mCi) is approximately a factor of 2 less than the value of 0.45 mGy/MBq (1.7 rad/mCi) previously accepted. The revised dose estimates for other organs show less variation from published values. The effective dose determined in this work is approximately 0.16 mSv/MBq (0.60 rem/mCi). Under the assumption of similar biokinetics as for the adult, the testes dose for children increases significantly as age decreases with a value of 7.5 mGy/MBq (28 rad/mCi) for a newborn. Contributions from radiocontaminants that may be encountered in the preparation of 201Tl-thallous chloride are shown to range from a fraction of a percent up to approximately 20% of the total dose for some organs, with the higher values arising from the long half-life contaminant 202Tl after a 5-d shelf life. CONCLUSION: It is recommended that the dose values determined in this study be used when estimating the radiation dose to the adult testes from intravenous administration of 201Tl-thallous chloride. The potential for increased radiation dose per administered activity to the testes at younger ages should be evaluated before performing procedures on children. The presence of radiocontaminants in the product should be considered when estimating radiation dose and may add a significant contribution to dose dependent on the specific radionuclide and concentration at the time of administration.