Linear Boltzmann equation solver for voxel-level dosimetry in radiopharmaceutical therapy: Comparison with Monte Carlo and kernel convolution.

BACKGROUND: With recent interest in patient-specific dosimetry for radiopharmaceutical therapy (RPT) and selective internal radiation therapy (SIRT), an increasing number of voxel-based algorithms are being evaluated. Monte Carlo (MC) radiation transport, generally considered to be the most accurate among different methods for voxel-level absorbed dose estimation, can be computationally inefficient for routine clinical use. PURPOSE: This work demonstrates a recently implemented grid-based linear Boltzmann transport equation (LBTE) solver for fast and accurate voxel-based dosimetry in RPT and SIRT and benchmarks it against MC. METHODS: A deterministic LBTE solver (Acuros MRT) was implemented within a commercial RPT dosimetry package (Velocity 4.1). The LBTE is directly discretized using an adaptive mesh refined grid and then the coupled photon-electron radiation transport is iteratively solved inside specified volumes to estimate radiation doses from both photons and charged particles in heterogeneous media. To evaluate the performance of the LBTE solver for RPT and SIRT applications, 177 Lu SPECT/CT, 90 Y PET/CT, and 131 I SPECT/CT images of phantoms and patients were used. Multiple lesions (2-1052 mL) and normal organs were delineated for each study. Voxel dosimetry was performed with the LBTE solver, dose voxel kernel (DVK) convolution with density correction, and a validated in-house MC code using the same time-integrated activity and density maps as input to the different dose engines. The resulting dose maps, difference maps, and dose-volume-histogram (DVH) metrics were compared, to assess the voxel-level agreement. Evaluation of mean absorbed dose included comparison with structure-level estimates from OLINDA. RESULTS: In the phantom inserts/compartments, the LBTE solver versus MC and DVK convolution demonstrated good agreement with mean absorbed dose and DVH metrics agreeing to within 5% except for the D90 and D70 metrics of a very low activity concentration insert of 90 Y where the agreement was within 15%. In the patient studies (five patients imaged after 177 Lu DOTATATE RPT, five after 90 Y SIRT, and two after 131 I radioimmunotherapy), in general, there was better agreement between the LBTE solver and MC than between LBTE solver and DVK convolution for mean absorbed dose and voxel-level evaluations. Across all patients for all three radionuclides, for soft tissue structures (kidney, liver, lesions), the mean absorbed dose estimates from the LBTE solver were in good agreement with those from MC (median difference < 1%, maximum 9%) and those from DVK (median difference < 5%, maximum 9%). The LBTE and OLINDA estimates for mean absorbed dose in kidneys and liver agreed to within 10%, but differences for lesions were larger with a maximum 14% for 177 Lu, 23% for 90 Y, and 26% for 131 I. For bone regions, the agreement in mean absorbed doses between LBTE and both MC and DVK were similar (median < 11%, max 11%) while for lung the agreement between LBTE and MC (median < 1%, max 8%) was substantially better than between LBTE and DVK (median < 16%, max 33%). Voxel level estimates for soft tissue structures also showed good agreement between the LBTE solver and both MC and DVK with a median difference < 5% (maximum < 13%) for the DVH metrics with all three radionuclides. The largest difference in DVH metrics was for the D90 and D70 metric in lung and bone where the uptake was low. Here, the difference between LBTE and MC had a median value < 14% (maximum 23%) for bone and < 4% (maximum 37%) for lung, while the corresponding differences between LBTE and DVK were < 23% (maximum 31%) and < 67% (maximum 313%), respectively. For a typical patient with a matrix size of 166 × 166 × 129 (voxel size 3 × 3 × 3 mm3 ), voxel dosimetry using the LBTE solver was as fast as ∼2 min on a desktop computer. CONCLUSION: Having established good agreement between the LBTE solver and MC for RPT and SIRT applications, the LBTE solver is a viable option for voxel dosimetry that can be faster than MC. Further analysis is being performed to encompass the broad range of radionuclides and conditions encountered clinically.

Trends in the Main Residency Match From 2007 to 2020.

Background The United States Medical Licensing Exam (USMLE) Step 1 was recently changed from a numerically scored grading system to a pass/fail grading system. Until late 2024, there will be no formal studies about the impact that the grading change will have on the match process. To thoroughly assess the impact that this change will have on the overall match process, it is important to look at what the trends in applicants' objective measures have been in the years before the change. We aim to systematically evaluate the rates of change and mean trend of objective metrics found in residency applications in the main residency match.  Methods Objective medical student data of matched and unmatched applicants were queried from the National Matching Program's Charting Outcomes in the Match Reports for the 2007 to 2020 application cycles. Data were used to create linear regression analyses and statistical tests were performed to evaluate trends over time. Results For matched applicants, there were statistically significant positive trends for the mean number of contiguous ranks (m=0.33, p<0.01), having another non-doctoral graduate degree (m=0.67, p<0.01), membership to Alpha Omega Alpha (AOA) honor society (m=0.22, p<0.01), mean USMLE Step 1 score (m=1.01, p<0.01), mean USMLE Step 2 score (m=1.68, p<0.01), mean number of research experiences (m=0.12, p<0.01), and mean number of abstracts, presentations, and publications (m=0.34, p<0.01). Additionally, there was a statistically significant negative trend for the percentage who graduated from a top 40 National Institutes of Health-funded medical school (m=-0.41, p<0.01). For unmatched applicants, there were statistically significant positive trends for having another non-doctoral graduate degree (m=0.83, p<0.01), mean USMLE Step 1 score (m=1.26, p<0.01), mean USMLE Step 2 score (m=2.27, p<0.01), mean number of research experiences (m=0.13, p<0.01), and mean number of abstracts, presentations, and publications (m=0.33, p<0.01). Conclusion Our study shows that there have been statistically significant increases in almost all objective measures in the residency application. Recent changes to the abstracts, presentations, and publications on the Step 1 scoring system will force almost all residency programs to overhaul their application process and potentially increase reliance on Step 2, research, and other nonobjective factors. For students early in their medical education, emphasis on Step 2 and research will yield increased chances of matching into residency in the future.

Laminoplasty versus laminectomy with fusion for treating multilevel degenerative cervical myelopathy.

Background: Laminectomy with fusion (LF) and laminoplasty (LP) are common posterior decompression procedures used to treat multilevel degenerative cervical myelopathy (DCM). There is debate on their relative efficacy and safety for treatment of DCM. The goal of this study is to examine outcomes and costs of LF and LP procedures for DCM. Methods: This is a retrospective review of adult patients (<18) at a single center who underwent elective LP and LF of at least 3 levels from C3-C7. Outcome measures included operative characteristics, inpatient mobility status, length of stay, complications, revision surgery, VAS neck pain scores, and changes in radiographic alignment. Oral opioid analgesic needs and hospital cost comparison were also assessed. Results: LP cohort (n=76) and LF cohort (n=59) reported no difference in neck pain at baseline, 1, 6, 12, and 24 months postoperatively (p>.05). Patients were successfully weaned off opioids at similar rates (LF: 88%, LP: 86%). Fixed and variable costs respectively with LF cases hospital were higher, 15.7% and 25.7% compared to LP cases (p=.03 and p<.001). LF has a longer length of stay (4.2 vs. 3.1 days, p=.001). Wound-related complications were 5 times more likely after LF (13.6% vs. 5.9%, RR: 5.15) and C5 palsy rates were similar across the groups (LF: 11.9% LP: 5.6% RR: 1.8). Ground-level falls requiring an emergency department visit were more likely after LF (11.9% vs. 2.6%, p=.04). Conclusions: When treating multilevel DCM, LP has similar rates of new or increasing axial neck pain compared to LF. LF was associated with greater hospital costs, length of stay, and complications compared to LP. LP may in fact be a less morbid and more cost-effective alternative to LF for patients without cervical deformity.

Experimental validation of Monte Carlo dosimetry for therapeutic beta emitters with radiochromic film in a 3D-printed phantom.

PURPOSE: Validation of dosimetry software, such as Monte Carlo (MC) radiation transport codes used for patient-specific absorbed dose estimation, is critical prior to their use in clinical decision making. However, direct experimental validation in the clinic is generally not performed for low/medium-energy beta emitters used in radiopharmaceutical therapy (RPT) due to the challenges of measuring energy deposited by short-range particles. Our objective was to design a practical phantom geometry for radiochromic film (RF)-based absorbed dose measurements of beta-emitting radionuclides and perform experiments to directly validate our in-house developed Dose Planning Method (DPM) MC code dedicated to internal dosimetry. METHODS: The experimental setup was designed for measuring absorbed dose from beta emitters that have a range sufficiently penetrating to ∼200 µm in water as well as to capture any photon contributions to absorbed dose. Assayed 177 Lu and 90 Y liquid sources, 13-450 MBq estimated to deliver 0.5-10 Gy to the sensitive layer of the RF, were injected into the cavity of two 3D-printed half-cylinders that had been sealed with 12.7 µm or 25.4 µm thick Kapton Tape. A 3.8 × 6 cm strip of GafChromic EBT3 RF was sandwiched between the two taped half-cylinders. After 2-48 h exposures, films were retrieved and wipe tested for contamination. Absorbed dose to the RF was measured using a commercial triple-channel dosimetry optimization method and a calibration generated via 6 MV photon beam. Profiles were analyzed across the central 1 cm2 area of the RF for validation. Eleven experiments were completed with 177 Lu and nine with 90 Y both in saline and a bone equivalent solution. Depth dose curves were generated for 177 Lu and 90 Y stacking multiple RF strips between a single filled half-cylinder and an acrylic backing. All experiments were modeled in DPM to generate voxelized MC absorbed dose estimates. We extended our study to benchmark general purpose MC codes MCNP6 and EGSnrc against the experimental results as well. RESULTS: A total of 20 experiments showed that both the 3D-printed phantoms and the final absorbed dose values were reproducible. The agreement between the absorbed dose estimates from the RF measurements and DPM was on average -4.0% (range -10.9% to 3.2%) for all single film 177 Lu experiments and was on average -1.0% (range -2.7% to 0.7%) for all single film 90 Y experiments. Absorbed depth dose estimates by DPM agreed with RF on average 1.2% (range -8.0% to 15.2%) across all depths for 177 Lu and on average 4.0% (range -5.0% to 9.3%) across all depths for 90 Y. DPM absorbed dose estimates agreed with estimates from EGSnrc and MCNP across the board, within 4.7% and within 3.4% for 177 Lu and 90 Y respectively, for all geometries and across all depths. MC showed that absorbed dose to RF from betas was greater than 92% of the total (betas + other radiations) for 177 Lu, indicating measurement of dominant beta contribution with our design. CONCLUSIONS: The reproducible results with a RF insert in a simple phantom designed for liquid sources demonstrate that this is a reliable setup for experimentally validating dosimetry algorithms used in therapies with beta-emitting unsealed sources. Absorbed doses estimated with the DPM MC code showed close agreement with RF measurement and with results from two general purpose MC codes, thereby validating the use of this algorithms for clinical RPT dosimetry.

Comparing Fusion Rates Between Fresh-Frozen and Freeze-Dried Allografts in Anterior Cervical Discectomy and Fusion.

Objective: The objective of this retrospective study is to compare the fusion rates in anterior cervical discectomy and fusion surgery using freeze-dried versus fresh-frozen allografts. Methods: The study comprised 79 patients. Fifty-one patients received freeze-dried allograft (106 total spinal levels) and 28 patients received fresh-frozen allograft (50 total spinal levels). Fusion was assessed through trabecular bridging on follow-up anterior-posterior/lateral radiographs. Trabecular bridging was assessed on the superior and inferior borders of each spinal level and given a fusion grade. Complete fusion is defined as >50% bridging between superior and inferior borders of the bone graft; union is complete fusion in <26 weeks; delayed union is complete fusion after 26 weeks; and fibrous union is <50% bridging at ≥1 borders over 52 weeks. Results: All spinal levels reached complete fusion for both graft types. Of the freeze-dried treated cervical spinal levels, 77.35% (82/106) reached union (adequate trabecular bridging within 6 months) without delay compared with 80% (35/50) for the fresh-frozen bone graft group (P = 0.85). There was no significant difference in time-to-fusion analysis and no significant association between delayed union and any patient factors. In assessing Neck Disability Index (NDI), freeze-dried allografts did show a significantly greater decrease in NDI scores at 6 months (P = 0.03). At the 1 year follow-up, improvements in NDI were consistent in both allografts (P = 0.9647). Conclusions: From this study, freeze-dried and fresh-frozen allografts showed comparable rates of union, and both allografts can be used interchangeably for anterior cervical discectomy and fusion.

Ossification of the Posterior Longitudinal Ligament: Pathophysiology, Diagnosis, and Management.

Ossification of the posterior longitudinal ligament (OPLL) occurs as heterotopic bone forms in the posterior longitudinal ligament, resulting in neural compression, myelopathy, and radiculopathy. OPLL is most commonly observed in East Asian populations, with prevalence rates of 1.9% to 4.3% reported in Japan. OPLL rates are lower in North American and European patients, with reported prevalence of 0.1% to 1.7%. Patients typically develop symptoms due to OPLL in their cervical spines. The etiology of OPLL is multifactorial, including genetic, metabolic, and anatomic factors. Asymptomatic or symptomatic patients with OPLL can be managed nonsurgically, whereas patients with neurologic symptoms may require surgical decompression from an anterior, posterior, or combined approach. Surgical treatment can provide notable improvement in neurologic function. Surgical decision making accounts for multiple factors, including patient comorbidities, neurologic status, disease morphology, radiographic findings, and procedure complication profiles. In this study, we review OPLL epidemiology and pathophysiology, clinical features, radiographic evaluation, management, and complications.

An International Study of Factors Affecting Variability of Dosimetry Calculations, Part 1: Design and Early Results of the SNMMI Dosimetry Challenge.

In this work, we present details and initial results from a 177Lu dosimetry challenge that has been designed to collect data from the global nuclear medicine community aiming at identifying, understanding, and quantitatively characterizing the consequences of the various sources of variability in dosimetry. Methods: The challenge covers different approaches to performing dosimetry: planar, hybrid, and pure SPECT. It consists of 5 different and independent tasks to measure the variability of each step in the dosimetry workflow. Each task involves the calculation of absorbed doses to organs and tumors and was meant to be performed in sequential order. The order of the tasks is such that results from a previous one would not affect subsequent ones. Different sources of variability are removed as the participants advance through the challenge by giving them the data required to begin the calculations at different steps of the dosimetry workflow. Data from 2 patients after a therapeutic administration of 177Lu-DOTATATE were used for this study. The data are hosted in Deep Blue Data, a data repository service run by the University of Michigan. Participants submit results in standardized spreadsheets and with a short description summarizing their methods. Results: In total, 178 participants have signed up for the challenge, and 119 submissions have been received. Sixty percent of submissions have used voxelized dose methods, with 47% of those using commercial software. In initial analysis, the volume of organs showed a variability of up to 49.8% whereas for lesions this was up to 176%. Variability in time-integrated activity was up to 192%. Mean absorbed doses varied up to 57.7%. Segmentation is the step that required the longest time to complete, with a median of 43 min. The median total time to perform the full calculation was 89 min. Conclusion: To advance dosimetry and encourage its routine use in radiopharmaceutical therapy applications, it is critical that dosimetry results be reproducible across centers. Our initial results provide insights into the variability associated with performing dose calculations. It is expected that this dataset, including results from future stages, will result in efforts to standardize and harmonize methods and procedures.

Diffuse Idiopathic Skeletal Hyperostosis of the Spine: Pathophysiology, Diagnosis, and Management.

Diffuse idiopathic skeletal hyperostosis (DISH) is an ankylosing condition affecting up to 32.5% of the general cohort. Although often asymptomatic, affected individuals may present with back pain, stiffness, dysphagia, functional decline, and neurologic deficits. Radiographically, DISH is characterized by flowing ossifications along the anterior spine spanning ≥4 vertebral bodies. Although the etiology of DISH remains unknown, diabetes mellitus and other metabolic derangements are strongly associated with DISH. Importantly, spinal ankylosis in DISH predisposes patients to unstable spine fractures from low-energy trauma, and careful consideration must be taken in managing these patients. This article reviews the epidemiology and pathophysiology of DISH, and its clinical findings, diagnostic criteria, and management.

Y-90 SIRT: evaluation of TCP variation across dosimetric models.

INTRODUCTION: Much progress has been made in implementing selective internal radiation therapy (SIRT) as a viable treatment option for hepatic malignancies. However, there is still much need for improved options for calculating the amount of activity to be administered. To make advances towards this goal, this study examines the relationship between predicted biological outcomes of liver tumors via tumor control probabilities (TCP) and parenchyma via normal tissue complication probabilities (NTCP) given variations in absorbed dose prescription methodologies. METHODS: Thirty-nine glass microsphere treatments in 35 patients with hepatocellular carcinoma or metastatic liver disease were analyzed using 99mTc-MAA SPECT/CT and 90Y PET/CT scans. Predicted biological outcomes corresponding to the single compartment (standard) model and multi-compartment (partition) dosimetry model were compared using our previously derived TCP dose-response curves over a range of 80-150 Gy prescribed absorbed dose to the perfused volume, recommended in the package insert for glass microspheres. Retrospective planning dosimetry was performed on the MAA SPECT/CT; changes from the planned infused activity due to selection of absorbed dose level and dosimetry model (standard or partition) were used to scale absorbed doses reported from 90Y PET/CT including liver parenchyma and lesions (N = 120) > 2 ml. A parameterized charting system was developed across all potential prescription options to enable a clear relationship between standard prescription vs. the partition model-based prescription. Using a previously proposed NTCP model, the change in prescribed dose from a standard model prescription of 120 Gy to the perfused volume to a 15% NTCP prescription to the normal liver was explored. RESULTS: Average TCP predictions for the partition model compared with the standard model varied from a 13% decrease to a 32% increase when the prescribed dose was varied across the range of 80-150 Gy. In the parametrized chart comparing absorbed dose prescription ranges across the standard model and partition models, a line of equivalent absorbed dose to a tumor was identified. TCP predictions on a per lesion basis varied between a 26% decrease and a 81% increase for the most commonly chosen prescription options when comparing the partition model with the standard model. NTCP model was only applicable to a subset of patients because of the small volume fraction of the liver that was targeted in most cases. CONCLUSION: Our retrospective analysis of patient imaging data shows that the choice of prescribed dose and which model to prescribe potentially contribute to a wide variation in average tumor efficacy. Biological response data should be included as one factor when looking to improve patient care in the clinic. The use of parameterized charting, such as presented here, will help direct physicians when transitioning to newer prescription methods.

What is the Trend in Representation of Women and Under-represented Minorities in Orthopaedic Surgery Residency?

BACKGROUND: Orthopaedic surgery training programs have lagged behind other surgical specialties in increasing their representation of women and people from under-represented minority (URM) groups. Comparative data between orthopaedic surgery and other specialties are needed to help identify solutions to closing the diversity gap. QUESTIONS/PURPOSES: (1) Which surgical specialties have the greatest representation of women residents and residents from URM groups? (2) How have the proportions of women residents and residents from URM groups changed across the surgical specialties during the past decade? METHODS: This was a retrospective evaluation of a large, longitudinally maintained survey database. Resident data by gender and ethnicity were retrieved from the Accreditation Council for Graduate Medical Education Data Resource Books for the 2011 to 2012 through 2019 to 2020 academic years. The Accreditation Council for Graduate Medical Education database is updated annually; thus, it is the most up-to-date and complete database available for gender and ethnicity data for all surgical residents. Data were obtained and analyzed for seven different surgical specialties: orthopaedic surgery, neurosurgery, ophthalmology, otolaryngology, plastic surgery, general surgery, and urology. No sampling was necessary, and thus descriptive statistics of the data were completed. Because the entire population of residents was included for the period of time in question, no statistical comparisons were made, and the reported differences represent absolute differences between the groups for these periods. Linear regression analyses were performed to estimate the annual growth rates of women residents and residents from URM groups in each specialty. RESULTS: Among the seven surgical specialties, representation of women residents increased from 28% (4640 of 16,854) of residents in 2012 to 33% (6879 of 20,788) in 2020. Orthopaedic surgery had the lowest representation of women residents every year, with women residents comprising 16% of residents (700 of 4342) in 2020. Among the seven surgical specialties, representation of residents from URM groups increased from 8.1% (1362 of 16,854) in 2012 to 9.7% (2013 of 20,788) in 2020. In 2020, the representation of residents from URM groups in orthopaedic surgery was 7.7% (333 of 4342). In 2020, general surgery had the highest representation of women residents (42%; 3696 of 8809) as well as residents from URM groups (12%; 1065 of 8809). Plastic surgery (1.46% per year) and general surgery (0.95% per year) had larger annual growth rates of women residents than the other specialties did. In each surgical specialty, the annual growth rate of residents from URM groups was insignificant. CONCLUSION: During the past decade, there was only a small increase in the representation of women in orthopaedic surgery, while the representation of people from URM groups did not change. In contrast, by 2020, general surgery had become the most diverse among the seven surgical specialties. To increase diversity in our field, we need to evaluate and implement some of the effective interventions that have helped general surgery become the diverse surgical specialty that it is today. CLINICAL RELEVANCE: General surgery has substantially reduced gender and ethnic disparities that existed in the past, while those in orthopaedic surgery still persist. General surgery residencies have implemented a holistic review of resident applications and longitudinal mentoring programs to successfully address these disparities. Orthopaedic surgery programs should consider placing less emphasis on United States Medical Licensing Examination score thresholds and more weight on applicants' non-academic attributes, and put more efforts into targeted longitudinal mentorship programs, some of which should be led by non-minority faculty.

CaMKII Serine 280 O-GlcNAcylation Links Diabetic Hyperglycemia to Proarrhythmia.

[Figure: see text].

Impeding DNA Break Repair Enables Oocyte Quality Control.

Oocyte quality control culls eggs with defects in meiosis. In mouse, oocyte death can be triggered by defects in chromosome synapsis and recombination, which involve repair of DNA double-strand breaks (DSBs) between homologous chromosomes. We show that RNF212, a SUMO ligase required for crossing over, also mediates oocyte quality control. Both physiological apoptosis and wholesale oocyte elimination in meiotic mutants require RNF212. RNF212 sensitizes oocytes to DSB-induced apoptosis within a narrow window as chromosomes desynapse and cells transition into quiescence. Analysis of DNA damage during this transition implies that RNF212 impedes DSB repair. Consistently, RNF212 is required for HORMAD1, a negative regulator of inter-sister recombination, to associate with desynapsing chromosomes. We infer that oocytes impede repair of residual DSBs to retain a "memory" of meiotic defects that enables quality-control processes. These results define the logic of oocyte quality control and suggest RNF212 variants may influence transmission of defective genomes.

Scalable gamma-ray camera for wide-area search based on silicon photomultipliers array.

Portable coded-aperture imaging systems based on scintillators and semiconductors have found use in a variety of radiological applications. For stand-off detection of weakly emitting materials, large volume detectors can facilitate the rapid localization of emitting materials. We describe a scalable coded-aperture imaging system based on 5.02 × 5.02 cm2 CsI(Tl) scintillator modules, each partitioned into 4 × 4 × 20 mm3 pixels that are optically coupled to 12 × 12 pixel silicon photo-multiplier (SiPM) arrays. The 144 pixels per module are read-out with a resistor-based charge-division circuit that reduces the readout outputs from 144 to four signals per module, from which the interaction position and total deposited energy can be extracted. All 144 CsI(Tl) pixels are readily distinguishable with an average energy resolution, at 662 keV, of 13.7% FWHM, a peak-to-valley ratio of 8.2, and a peak-to-Compton ratio of 2.9. The detector module is composed of a SiPM array coupled with a 2 cm thick scintillator and modified uniformly redundant array mask. For the image reconstruction, cross correlation and maximum likelihood expectation maximization methods are used. The system shows a field of view of 45° and an angular resolution of 4.7° FWHM.