Modular design of synthetic receptors for programmed gene regulation in cell therapies.

Synthetic biology has established powerful tools to precisely control cell function. Engineering these systems to meet clinical requirements has enormous medical implications. Here, we adopted a clinically driven design process to build receptors for the autonomous control of therapeutic cells. We examined the function of key domains involved in regulated intramembrane proteolysis and showed that systematic modular engineering can generate a class of receptors that we call synthetic intramembrane proteolysis receptors (SNIPRs) that have tunable sensing and transcriptional response abilities. We demonstrate the therapeutic potential of the receptor platform by engineering human primary T cells for multi-antigen recognition and production of dosed, bioactive payloads relevant to the treatment of disease. Our design framework enables the development of fully humanized and customizable transcriptional receptors for the programming of therapeutic cells suitable for clinical translation.

Trends in chemotherapy use for early-stage breast cancer from 2006 to 2019.

BACKGROUND: Little is known about how use of chemotherapy has evolved in breast cancer patients. We therefore describe chemotherapy patterns for women with stage I-IIIA breast cancer in the Optimal Breast Cancer Chemotherapy Dosing (OBCD) Study using data from KPNC (Kaiser Permanente Northern California) and KPWA (Kaiser Permanente Washington). FINDINGS: Among 33,670 women, aged 18 + y, diagnosed with primary stage I-IIIA breast cancer at KPNC and KPWA from 2006 to 2019, we explored patterns of intravenous chemotherapy use, defined here as receipt of intravenous cytotoxic drugs and/or anti-HER2 therapies. We evaluated trends in chemotherapy receipt, duration over which chemotherapy was received, and number of associated infusion visits. In secondary analyses, we stratified by receipt of anti-HER2 therapies (trastuzumab and/or pertuzumab), given their longer duration. 38.9% received chemotherapy intravenously, declining from 40.2% in 2006 to 35.6% in 2019 (p-trend < 0.001). Among 13,089 women receiving chemotherapy, neoadjuvant treatment increased (4.1-14.7%; p-trend < 0.001), as did receipt of anti-HER2 therapies (20.8-30.9%) (p-trend < 0.001). The average treatment duration increased (5.3 to 6.0 months; p-trend < 0.001), as did the number of infusion visits (10.8 to 12.5; p-trend < 0.001). For those receiving anti-HER2 therapies, treatment duration and average number of visits decreased; among those not receiving anti-HER2 therapies, number of visits increased, with no change in duration. CONCLUSIONS: While the prevalence of chemotherapy receipt has decreased over time, the use of neoadjuvant chemotherapy has increased, as has use of anti-HER2 therapies; duration and number of administration visits have also increased. Understanding these trends is useful to inform clinical and administrative planning.

Patient characteristics associated with delayed time to adjuvant chemotherapy among women treated for stage I-IIIA breast cancer.

For patients with breast cancer, delays in chemotherapy initiation have been adversely associated with recurrence and survival. We evaluated patient-level factors associated with delayed chemotherapy initiation, from both diagnosis and surgery, in a community-based cohort of women with early-stage breast cancer. For the Optimal Breast Cancer Chemotherapy Dosing study, we identified a cohort of 34,109 women diagnosed with stage I-IIIA breast cancer at two U.S. integrated healthcare delivery systems between 2004 and 2019. We used logistic regression to calculate odds ratios (OR) and 95% confidence intervals (CI) to identify patient factors associated with delays in chemotherapy initiation after diagnosis (≥90 days) and surgery (≥60 days). Among 10,968 women receiving adjuvant chemotherapy, 21.1% experienced delays in chemotherapy initiation after diagnosis and 21.3% after surgery. Older age, non-Hispanic Black and Hispanic race and ethnicity, and ER+ and/or PR+ disease were associated with increased likelihood of delays to chemotherapy initiation after diagnosis and surgery. People diagnosed in 2012-2019 (vs. 2005-2011), with a higher grade and larger tumor size were less likely to experience delays. Other factors were associated with a higher likelihood of delays specifically from diagnosis (earlier stage, mastectomy vs. breast-conserving surgery), or surgery (higher comorbidity, increased nodal number). Women diagnosed with breast cancer who were at highest risk of progression and recurrence were less likely to experience delays in chemotherapy initiation after diagnosis and surgery. Understanding reasons for chemotherapy delays beyond patient factors may be potentially important to reduce risk of breast cancer recurrence and progression.

The landscape of use of NCCN-guideline chemotherapy regimens in stage I-IIIA breast cancer in an integrated healthcare delivery system.

PURPOSE: The National Comprehensive Cancer Network (NCCN) guidelines recommend a variety of drug combinations with specific administration schedules for the treatment of early-stage breast cancer, allowing physicians to deliver treatments recognizing individual patient complexities, including comorbidities, and patient-physician preference. While use of guideline regimens has shifted over time, there is little data to describe changes in how treatment for early-stage breast cancer has evolved over time. METHODS: In a cohort of 34,109 women treated for stage I-IIIA breast cancer between 2006-2019 at Kaiser Permanente Northern California and Kaiser Permanente Washington, we present the changes in chemotherapy regimens over time, and explore use of NCCN-guideline regimens (GR), guideline regimens used when said regimens were not included in guidelines, referred to as time-discordant regimens (TDR), and non-guideline regimens (NGR). Results are presented by drug combination and over time. RESULTS: Among 12,506 women receiving chemotherapy, 77.4% (n = 9681) received GRs, 9.1% (n = 1140) received TDRs, and 13.5% (n = 1685) received NGRs. In 2006, AC-T (cyclophosphamide-doxorubicin, paclitaxel) was the most common regimen, with TC (cyclophosphamide-docetaxel) becoming the most prevalent by 2019. NGRs were more common in cyclophosphamide-methotrexate-5-fluorouracil (CMF); cyclophosphamide-doxorubicin-paclitaxel-trastuzumab (ACTH); and paclitaxel-trastuzumab (TH). The use of GR has increased over time (p-trend < 0.001), while use of NGR (both in terms of administration schedule and drug combination) and TDR have decreased, although patterns vary by drug combination. CONCLUSION: Chemotherapy delivery has changed markedly over time, with a move toward more use of GR. These data are important for understanding the landscape of chemotherapy delivery in community healthcare settings.

Association of Postarrest Hypotension Burden With Unfavorable Neurologic Outcome After Pediatric Cardiac Arrest.

OBJECTIVE: Quantify hypotension burden using high-resolution continuous arterial blood pressure (ABP) data and determine its association with outcome after pediatric cardiac arrest. DESIGN: Retrospective observational study. SETTING: Academic PICU. PATIENTS: Children 18 years old or younger admitted with in-of-hospital or out-of-hospital cardiac arrest who had invasive ABP monitoring during postcardiac arrest care. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: High-resolution continuous ABP was analyzed up to 24 hours after the return of circulation (ROC). Hypotension burden was the time-normalized integral area between mean arterial pressure (MAP) and fifth percentile MAP for age. The primary outcome was unfavorable neurologic status (pediatric cerebral performance category ≥ 3 with change from baseline) at hospital discharge. Mann-Whitney U tests compared hypotension burden, duration, and magnitude between favorable and unfavorable patients. Multivariable logistic regression determined the association of unfavorable outcomes with hypotension burden, duration, and magnitude at various percentile thresholds from the 5th through 50th percentile for age. Of 140 patients (median age 53 [interquartile range 11-146] mo, 61% male); 63% had unfavorable outcomes. Monitoring duration was 21 (7-24) hours. Using a MAP threshold at the fifth percentile for age, the median hypotension burden was 0.01 (0-0.11) mm Hg-hours per hour, greater for patients with unfavorable compared with favorable outcomes (0 [0-0.02] vs. 0.02 [0-0.27] mm Hg-hr per hour, p < 0.001). Hypotension duration and magnitude were greater for unfavorable compared with favorable patients (0.03 [0-0.77] vs. 0.71 [0-5.01]%, p = 0.003; and 0.16 [0-1.99] vs. 2 [0-4.02] mm Hg, p = 0.001). On logistic regression, a 1-point increase in hypotension burden below the fifth percentile for age (equivalent to 1 mm Hg-hr of burden per hour of recording) was associated with increased odds of unfavorable outcome (adjusted odds ratio [aOR] 14.8; 95% CI, 1.1-200; p = 0.040). At MAP thresholds of 10th-50th percentiles for age, MAP burden below the threshold was greater in unfavorable compared with favorable patients in a dose-dependent manner. CONCLUSIONS: High-resolution continuous ABP data can be used to quantify hypotension burden after pediatric cardiac arrest. The burden, duration, and magnitude of hypotension are associated with unfavorable neurologic outcomes.

Revisiting the Association of ECOG Performance Status With Clinical Outcomes in Diverse Patients With Cancer.

BACKGROUND: The ECOG performance status (PS) scale was developed to support national clinical trials, but the degree to which ECOG PS predicts clinical outcomes in patient subgroups outside of clinical trials is relatively unknown. This study examined associations between ECOG PS and adverse outcomes in a diverse community oncology population. PATIENTS AND METHODS: In this retrospective cohort study, demographic and clinical characteristics, including the most recent ECOG PS between January 1, 2017, and December 31, 2019, were examined for patients receiving cancer treatment within Kaiser Permanente Northern California (KPNC). Proportional hazard models were used to evaluate the effect of ECOG PS on adverse outcomes. RESULTS: A total of 21,730 patients were identified. Overall, most patients had an ECOG PS of 0 (42.5%) or 1 (42.5%). In multivariable analysis, an ECOG PS of 3 or 4 was associated with higher risk of 30-day emergency department visits (adjusted hazard ratio [aHR], 3.85; 95% CI, 3.47-4.26), 30-day hospitalizations (aHR, 4.70; 95% CI, 4.12-5.36), and 6-month mortality (aHR, 7.34; 95% CI, 6.64-8.11) compared with an ECOG PS of 0. Additionally, we found that upper gastrointestinal and stage IV cancers were associated with a higher risk of adverse outcomes compared with breast and stage I cancers, respectively. When adjusted for ECOG PS, African American race, Asian race, and female sex were associated with a lower risk of mortality than White race and male sex. An ECOG PS of 3 or 4 was more predictive of mortality in younger patients and those with breast cancer (P<.001). CONCLUSIONS: ECOG PS and upper gastrointestinal and stage IV cancers were independently associated with increased risk of emergency department visits, hospitalizations, and mortality, whereas African American and Asian race and female sex were associated with decreased risk of mortality. An ECOG PS of 3 or 4 was more predictive of an increased risk of mortality in younger patients and patients with breast cancer. These findings can enhance the use of ECOG PS for clinical decision-making and defining eligibility for clinical trials.

A Claims-Based Method for Identification and Characterization of Practicing Interventional Radiologists.

PURPOSE: To propose a research method for identifying "practicing interventional radiologists" using 2 national claims data sets. MATERIALS AND METHODS: The 2015-2019 100% Medicare Part B data and 2015-2019 private insurance claims from Optum's Clinformatics Data Mart (CDM) database were used to rank-order radiologists' interventional radiology (IR)-related work as a percentage of total billed work relative value units (RVUs). Characteristics were analyzed at various threshold percentages. External validation used Medicare self-designated specialty with Society of Interventional Radiology (SIR) membership records; Youden index evaluated sensitivity and specificity. Multivariate logistic regression assessed practicing IR characteristics. RESULTS: In the Medicare data, above a 10% IR-related work threshold, only 23.8% of selected practicing interventional radiologists were designated as interventional radiologists; above 50% and 90% thresholds, this percentage increased to 42.0% and 47.5%, respectively. The mean percentage of IR-related work among practicing interventional radiologists was 45%, 84%, and 96% of total work RVUs for the 10%, 50%, and 90% thresholds, respectively. At these thresholds, the CDM practicing interventional radiologists included 21.2%, 35.2%, and 38.4% designated interventional radiologists, and evaluation and management services comprised relatively more total work RVUs. Practicing interventional radiologists were more likely to be males, metropolitan, and earlier in their careers than other radiologists at all thresholds. CONCLUSIONS: Most radiologists performing IR-related work are designated in claims data as diagnostic radiologists, indicating insufficiency of specialty designation for IR identification. The proposed method to identify practicing interventional radiologists by percent IR-related work effort could improve generalizability and comparability across claims-based IR studies.

Impact of pharmacist managed oral epidermal growth factor receptor inhibitors.

BACKGROUND: Pharmacists are an integral part of medication management, with the positive impact of their clinical services in patient outcomes previously studied and reported in literature. The roles and responsibilities of pharmacists continue to expand, including optimizing patient medication and health outcomes related to complex oral anticancer drugs. OBJECTIVE: To evaluate the impact of a pharmacist-managed oral chemotherapy clinic in patients with non-small cell lung cancer (NSCLC) taking oral epidermal growth factor receptor inhibitor (EGFRi) regimens within an integrated healthcare delivery system. METHODS: This was an observational cohort study using data from Kaiser Permanente Northern and Southern California regions on adult patients who received oncology pharmacist-managed care compared to patients with usual care. Patients were newly initiated with EGFRi therapy to treat NSCLC between 2017 and 2019. The follow-up period was defined as the time from index date (first sold date of EGFRi) to December 2020 or end of membership or death, whichever occurred first. Primary outcome measures included adherence to EGFRi, frequency of imaging during drug exposure, and presence of imaging prior to treatment change. Outcomes were analyzed with Chi-square test for categorical variables, and Student's t-test or Wilcoxon rank-sum test for continuous variables. RESULTS: There were 613 patients in the pharmacist-managed group and 714 patients in the usual care group. Overall, the mean age was 68.2 ± 11.3 years, and 65.1% were female. In the pharmacist-managed group, there was a significantly higher mean proportion of days covered (PDC) during the first three months of therapy (0.86 ± 0.24 vs 0.82 ± 0.36, p = 0.01) and a higher percentage of patients who were adherent to EGFRi therapy (with PDC ≥0.80) during the drug exposure period (95.8% vs 92.4%, p = 0.01). The rate of computed tomography (CT) and magnetic resonance imaging (MRI) during drug exposure was higher in the pharmacist-managed group compared to the usual care group (31.8% vs 20.7%, p < 0.01) with a higher number of mean scans completed per patient (1.15 ± 2.42 vs 0.62 ± 1.63, p < 0.01) and per patient-year (2.60 ± 7.27 vs 1.58 ± 5.95, p < 0.01). Overall, 66.2% of patients had a treatment change, with a higher percentage of patients in the pharmacist-managed group who completed a CT or MRI scan prior to treatment change (36.3% vs 26.3%, p < 0.01). Additionally, the median time between the scan and treatment change was shorter for patients with pharmacist-managed care (1.8 vs 4 months, p = 0.04). CONCLUSION: Clinical pharmacy services contributed to improved adherence, higher rates of imaging, and shorter time between imaging and treatment changes in NSCLC patients who were taking EGFRi regimens.

How Prominent Are Gender Bias, Racial Bias, and Score Inflation in Orthopaedic Surgery Residency Recommendation Letters? A Systematic Review.

INTRODUCTION: Letters of recommendation are considered an important factor in the holistic ranking of orthopaedic residency applications. The standardized letter of recommendation (SLOR) was introduced in 2017 in response to the inherent bias and limited comparative value of traditional LORs. It includes standardized questions about an applicant's orthopaedic qualifications, designed to enable fair comparisons among candidates. However, disparate and inconsistent findings have made it difficult to draw meaningful conclusions from individual studies on the SLOR and narrative letter of recommendation. QUESTION/PURPOSES: In this systematic review we asked: (1) What is the distribution of applicant SLOR rating among nine domains and summative scores? (2) Are there applicant characteristics associated with SLOR ratings? (3) Is there gender and racial bias in the SLOR and narrative letter of recommendation? METHODS: PubMed, EBSCO, and Google Scholar electronic databases were queried on March 20, 2023, to identify all studies evaluating SLOR and narrative letter of recommendations between January 1, 2017, and March 20, 2023. Articles that evaluated orthopaedic SLOR or narrative LORs were included. Systematic reviews, case reports, duplicate studies between databases, and grey literature such as abstracts and articles on preprint servers were excluded. Eight studies including 6179 applicants and 18,987 letters of recommendation were included in the final analysis. The applicant classes ranged from years 2014 to 2020. Two reviewers independently evaluated the quality of the included studies using the Joanna Briggs Institute (JBI) tool for cross-sectional studies. The mean JBI score of included studies was 7.4 out of a maximum of 8, with higher scores indicating better quality. The primary outcome was to determine the distribution of applicant SLOR rankings in their summative score. Summative scores were separated into ranked to match, top one-third, middle one-third, lower one-third, and not a fit. Four studies reported the summative SLOR scores of applicants. Our secondary study goal was to assess applicant characteristics associated with SLOR summative scores and assess any bias present in the SLOR or narrative recommendation. Five studies compared SLOR ratings across applicant characteristics including gender, race, USMLE Step 1 score, USMLE Step 2 score, Alpha Omega Alpha (AΩA) membership, clerkship grades, and publications. Gender and racial bias were also assessed across five studies. Four studies utilized a linguistic analysis software to search letters of recommendation for differences in word category use by gender and race. RESULTS: Studies consistently found that a higher percentage of candidates were identified in the top percentile blocks than is mathematically possible. For example, the two studies that tallied the proportion of candidates ranking in the top 10% of applicants found that 36% and 42% were rated as being in the top 10%. Similarly, articles found more than 87% of applicants scored in the top one-third. Studies had mixed results, but in general, they suggested that AΩA status, higher Step 1 scores, and more research publications have a slightly positive association with increased SLOR scores. We found no evidence of gender bias against women, and in fact, most studies evaluating word choices found word choices for women candidates generally were stronger. Similarly, no consistent disparities were identified in word categories utilized in SLORs based on applicant race. CONCLUSION: Most notably, a mathematically impossible proportion of applicants were counted in the top percentiles in letters of recommendation. This compromises readers' abilities to differentiate candidates. Factors like AOA status and research publications displayed a modest positive correlation with SLOR scores. Gender bias against women or candidates from racial minority groups was not evident. CLINICAL RELEVANCE: We suggest that group SLOR authorship, with a consensus assessment by clerkship or residency directors, should be considered. We also recommend the incorporation of mean and SD scores for each letter writer (or group) alongside their letters. Furthermore, studies indicate that submitting all four SLOR letters can substantially improve an applicant's chances of success. We advise students to choose strategically and submit the maximum allowable number of SLORs.

Correction: Correlation Between Remote Symptom Reporting by Caregivers and Adverse Clinical Outcomes: Mixed Methods Study.

[This corrects the article DOI: 10.2196/49100.].

Alpha angle and anterior femoral neck offset identify different cohorts of cam morphology: an osteologic study.

PURPOSE: The purpose of this study was to explore differences in cam morphology defined by alpha angle and anterior femoral neck offset, in the context of other anthropometric parameters in an osteologic collection to further elucidate whether each measurement tool is identifying the same underlying pathology. METHODS: Anthropometric measurements of 992 cadaveric hips from the Hamann-Todd Osteological Collection were analyzed. Femurs with cam morphology were identified by AA >55° or AFNO <7mm. Anthropometric parameters stratified by cam morphology were assessed with Wilcoxon rank-sum and Pearson's chi-squared tests. Multivariate logistic regressions were performed on significant variables in univariate analysis to examine the predictive ability of anthropometric variables to cam morphology. RESULTS: Cam morphology was identified in 242 hips via AA, 344 hips via AFNO, and 123 hips via both measures. Multivariate logarithmic regression analysis demonstrated that sex negatively predicted AA (females with less pathology, ß= -0.14, p= 0.04), race negatively predicted AA (blacks with less pathology, ß= -0.21, p<0.01), and proximal femoral osteoarthritis was positively associated with AA (ß= 0.16, p= 0.02), while none of these were associated with AFNO. On the other hand, right side specimens were associated with AA (ß= 0.15, p= 0.02) and AFNO (ß= 0.25, p= <0.01), whereas combined version was unassociated with both measures. CONCLUSION: In conclusion, cam morphology was identified in a modest percentage of osteological specimens by both AA and AFNO in our study. Further, associations of multiple demographic, anthropometric and anatomical parameters to alpha angle and anterior femoral neck offset suggest they may identify different subsets of cam morphology.

The Addition of Hand-specific Skeletal Maturity Parameters Does Not Improve Skeletal Maturity Estimation Accuracy of the Modified Fels Wrist System.

BACKGROUND: The Modified Fels Wrist system is potentially the most accurate clinically accessible skeletal maturity system utilizing hand or wrist radiographs. During development, parameters distal to the metacarpals were excluded. We attempted to further optimize the Modified Fels wrist system through the inclusion of hand parameters distal to the metacarpals. METHODS: Forty-three new anteroposterior (AP) hand radiographic parameters were identified from the Fels and Greulich and Pyle (GP) skeletal maturity systems. Twelve parameters were eliminated from further evaluation for poor correlation with skeletal maturity, poor reliability, and lack of relevance in the peripubertal years. In addition to the 8 previously described Modified Fels Wrist parameters, 31 hand radiographic parameters were evaluated on serial peripubertal AP hand radiographs to identify the ones most important for accurately estimating skeletal age. This process produced a "Modified Fels hand-wrist" model; its performance was compared with (1) GP only; (2) Sanders Hand (SH) only; (3) age, sex, and GP; (4) age, sex, and SH; and (5) Modified Fels Wrist system. RESULTS: Three hundred seventy-two radiographs from 42 girls and 38 boys were included. Of the 39 radiographic parameters that underwent full evaluation, 9 remained in the combined Modified Fels Hand-Wrist system in addition to chronological age and sex. Four parameters are wrist specific, and the remaining 5 are hand specific. The Hand-Wrist system outperformed both GP and SH in estimating skeletal maturity ( P <0.001). When compared with the Modified Fels Wrist system, the Modified Fels Hand-Wrist system performed similarly regarding skeletal maturity estimation (0.36±0.32 vs. 0.34±0.26, P =0.59) but had an increased (worse) rate of outlier predictions >1 year discrepant from true skeletal maturity (4.9% vs. 1.9%, P =0.01). CONCLUSIONS: The addition of hand parameters to the existing Modified Fels Wrist system did not improve skeletal maturity estimation accuracy and worsened the rate of outlier estimations. When an AP hand-wrist radiograph is available, the existing Modified Fels wrist system is best for skeletal maturity estimation. LEVEL OF EVIDENCE: Level III.

Prospective Multicenter Preliminary Validation of Limb Deformity-modified Scoliosis Instruments in Pediatric Patients With Limb Deformity.

INTRODUCTION: There are few disease-specific patient-reported outcome measures (PROMs) for use in pediatric limb deformity (LD), with authors instead relying on generic PROMs such as the Pediatric Outcomes Data Collection Instrument (PODCI) to assess treatment outcomes from the patient's perspective. The purpose of this study was to perform preliminary validation of 2 disease-specific PROMs in pediatric patients with LD. METHODS: LD modifications were created by substituting the word "limb" for "back" in the Early Onset Scoliosis Questionnaire (EOSQ, ages 10 and younger) and the Scoliosis Research Society (SRS, ages 11 to 18) survey, creating the LD-EOSQ and LD-SRS instruments. Children were preoperatively administered the age-appropriate LD-PROMs (n=34 LD-EOSQ; n=30 LD-SRS) and PODCI questionnaires. LD-PROMs were assessed for construct (convergent and discriminant) validity, floor and ceiling effects, content validity, and minimal clinically important difference. RESULTS: Both LD-EOSQ and LD-SRS demonstrated excellent preliminary convergent validity with similar PODCI domains and discriminant validity with demographic information, deformity data, and LLRS-AIM scores. There were minimal floor or ceiling effects. Content validity was achieved in 100% of LD-EOSQ surveys and more than 80% of LD-SRS surveys. Minimal clinically important difference was 0.4 for LD-EOSQ and 0.3 for LD-SRS. CONCLUSIONS: The LD-EOSQ for patients aged 10 and under and LD-SRS for patients aged 11 to 18 demonstrated preliminary validity and reliability in the pediatric LD population. These measures provide more information specifically related to familial impact in younger children and self-image and mental health in adolescents compared to the PODCI and should be further evaluated for use in these patients. LEVEL OF EVIDENCE: Level II-diagnostic. Prospective cross-sectional cohort design.

Developmental Anatomy of the Radial Bow in Pediatric Patients Using 3D Imaging.

BACKGROUND: While radial bow shape is well characterized in adults, its development in children is not well understood. Previous studies on the radial bow use radiographs, thus, rotational positioning of the forearm could alter bowing measurements. This study used 3D imaging to better assess the pediatric radial bow. METHODS: Computed tomography scans from the New Mexico Decedent Image Database were obtained for ages 2 to 16 (females) and 18 (males) (n=152). 3D models were generated using Slicer and Rhino software. Length of the entire radial bow (bicipital tuberosity to sigmoid notch), maximum radial bow, location of the maximum radial bow (bicipital tuberosity to the point of maximum bowing), and distal, middle, and proximal third radial bows were measured. RESULTS: The length of the entire bow increased with age, with a strong correlation with age ( r =0.90, P <0.01). The maximum bow increased with age, with a strong correlation with age ( r =0.78, P <0.01). The maximum bow normalized to the length of the entire bow increased mildly with age, mean 0.059 ± 0.012 ( r =0.24, P =0.0024), but seems to plateau around age 8. The location of the maximum bow increased with age ( r =0.85, P <0.01). The normalized location of the maximum bow remained constant between ages, with a mean of 0.41 ± 0.10 ( r =0.12, P =0.14). The normalized distal third bow mildly increased with age ( r =0.34, P <0.01), the normalized middle third bow mildly increased with age ( r =0.25, P <0.01), and the normalized proximal third bow remained constant between ages ( r =0.096, P =0.24). CONCLUSIONS: Normalized values for maximum, distal third, and middle third radial bow increase with age, while normalized values for location and proximal third radial bow remain relatively constant, suggesting the proportional shape of the radius changes during development, although qualitatively plateaus after age 8. LEVEL OF EVIDENCE: Retrospective comparative study, Level-III.

Correlations Between Eight Comprehensive Skeletal Maturity Systems in a Modern Peripubertal Pediatric Population.

BACKGROUND: Several skeletal maturity systems allow for accurate skeletal age assessment from a wide variety of joints. However, discrepancies in estimates have been noted when applying systems concurrently. The aims of our study were to (1) compare the agreement among 8 different skeletal maturity systems in modern pediatric patients and (2) compare these discrepancy trends qbetween modern and historic children. METHODS: We performed a retrospective (January 2000 to May 2022) query of our picture archiving and communication systems and included peripubertal patients who had at least two radiographs of different anatomic regions obtained ≤3 months apart for 8 systems: (1) proximal humerus ossification system (PHOS), (2) olecranon apophysis ossification staging system (OAOSS), (3) lateral elbow system, (4) modified Fels wrist system, (5) Sanders Hand Classification, (6) optimized oxford hip system, (7) modified Fels knee system, and (8) calcaneal apophysis ossification staging system (CAOSS). Any abnormal (ie, evidence of fracture or congenital deformity) or low-quality radiographs were excluded. These were compared with a cohort from a historic longitudinal study. SEM skeletal age, representing the variance of skeletal age estimates, was calculated for each system and used to compare system precision. RESULTS: A total of 700 radiographs from 350 modern patients and 954 radiographs from 66 historic patients were evaluated. In the modern cohort, the greatest variance was seen in PHOS (SEM: 0.28 y), Sanders Hand (0.26 y), and CAOSS (0.25 y). The modified Fels knee system demonstrated the smallest variance (0.20 y). For historic children, the PHOS, OAOSS, and CAOSS were the least precise (0.20 y for all). All other systems performed similarly in historic children with lower SEMs (range: 0.18 to 0.19 y). The lateral elbow system was more precise than the OAOSS in both cohorts. CONCLUSIONS: The precision of skeletal maturity systems varies across anatomic regions. Staged, single-parameter systems (eg, PHOS, Sanders Hand, OAOSS, and CAOSS) may correlate less with other systems than those with more parameters. LEVEL OF EVIDENCE: Level III-retrospective study.

The Reliability of the Modified Fels Knee Skeletal Maturity System.

BACKGROUND: The recently described Modified Fels knee skeletal maturity system (mFels) has proven utility in prediction of ultimate lower extremity length in modern pediatric patients. mFels users evaluate chronological age, sex, and 7 anteroposterior knee radiographic parameters to produce a skeletal age estimate. We developed a free mobile application to minimize the learning curve of mFels radiographic parameter evaluation. We sought to identify the reliability of mFels for new users. METHODS: Five pediatric orthopaedic surgeons, 5 orthopaedic surgery residents, 3 pediatric orthopaedic nurse practitioners, and 5 medical students completely naïve to mFels each evaluated a set of 20 pediatric anteroposterior knee radiographs with the assistance of the (What's the Skeletal Maturity?) mobile application. They were not provided any guidance beyond the instructions and examples embedded in the app. The results of their radiographic evaluations and skeletal age estimates were compared with those of the mFels app developers. RESULTS: Averaging across participant groups, inter-rater reliability for each mFels parameter ranged from 0.73 to 0.91. Inter-rater reliability of skeletal age estimates was 0.98. Regardless of group, steady proficiency was reached by the seventh radiograph measured. CONCLUSIONS: mFels is a reliable means of skeletal maturity evaluation. No special instruction is necessary for first time users at any level to utilize the (What's the Skeletal Maturity?) mobile application, and proficiency in skeletal age estimation is obtained by the seventh radiograph. LEVEL OF EVIDENCE: Level II.

Early Treatment of High-Risk Hospitalized Coronavirus Disease 2019 (COVID-19) Patients With a Combination of Interferon Beta-1b and Remdesivir: A Phase 2 Open-label Randomized Controlled Trial.

BACKGROUND: Early antiviral therapy was effective in the treatment of coronavirus disease 2019 (COVID-19). We assessed the efficacy and safety of combined interferon beta-1b and remdesivir treatment in hospitalized COVID-19 patients. METHODS: We conducted a multicentre, prospective open-label, randomized-controlled trial involving high-risk adults hospitalized for COVID-19. Patients were randomly assigned to a 5-day interferon beta-1b 16 million units daily and remdesivir 200 mg loading on day 1 followed by 100 mg daily on day 2 to 5 (combination group), or to remdesivir only of similar regimen (control group) (1:1). The primary endpoint was the time to complete alleviation of symptoms (NEWS2 = 0). RESULTS: Two-hundred and twelve patients were enrolled. The median days of starting treatment from symptom onset was 3 days. The median age was 65 years, and 159 patients (75%) had chronic disease. The baseline demographics were similar. There was no mortality. For the primary endpoint, the combination group was significantly quicker to NEWS2 = 0 (4 vs 6.5 days; hazard ratio [HR], 6.59; 95% confidence interval [CI], 6.1-7.09; P < .0001) when compared to the control group. For the secondary endpoints, the combination group was quicker to negative nasopharyngeal swab (NPS) viral load (VL) (6 vs 8 days; HR, 8.16; 95% CI, 7.79-8.52; P < .0001) and to develop seropositive immunoglobulin G (IgG) (8 vs 10 days; HR, 10.78; 95% CI, 9.98-11.58; P < .0001). All adverse events resolved upon follow-up. Combination group (HR, 4.1 95% CI, 1.9-8.6, P < .0001) was the most significant independent factor associated with NEWS2 = 0 on day 4. CONCLUSIONS: Early treatment with interferon beta-1b and remdesivir was safe and better than remdesivir only in alleviating symptoms, and in shortening viral shedding and hospitalization with earlier seropositivity in high-risk COVID-19 patients. CLINICAL TRIALS REGISTRATION: NCT04647695.

Mode of Detection of Second Breast Cancers in Patients Undergoing Surveillance After Treatment of Ductal Carcinoma in Situ.

BACKGROUND: For patients undergoing posttreatment surveillance after ductal carcinoma in situ (DCIS), the NCCN Guidelines for Breast Cancer recommend annual breast imaging and physical examination every 6 to 12 months for 5 years, and then annually. The aim of our study was to evaluate the modes of detection (imaging, patient reported, or physical examination) of second cancers in a cohort of patients undergoing surveillance after primary DCIS treatment to better inform surveillance recommendations. METHODS: We performed a retrospective cohort study of patients with DCIS treated between January 1, 2008, and December 31, 2011, within a large integrated health care system. Information on patient demographics, index DCIS treatment, tumor characteristics, and mode of detection of second breast cancer was obtained from the electronic health record or chart review. RESULTS: Our study cohort consisted of 1,550 women, with a median age of 59 years at diagnosis. Surgical treatment of DCIS included lumpectomy (75.0%; n=1,162), unilateral mastectomy (21.1%; n=327), or bilateral mastectomy (3.9%; n=61), with or without sentinel lymph node biopsy. Additionally, 44.4% (n=688) and 28.3% (n=438) received radiation and endocrine therapies, respectively. Median follow-up was 10 years, during which 179 (11.5%) women were diagnosed with a second breast cancer. Of the second cancers, 43.0% (n=77) were ipsilateral and 54.8% (n=98) contralateral, and 2.2% (n=4) presented with distant metastases; 61.5% (n=110) were invasive, 36.3% (n=65) were DCIS, and 2.2% (n=4) were Paget's disease. Second breast cancers were imaging-detected in 74.3% (n=133) of cases, patient-detected in 20.1% (n=36), physician-detected in 2.2% (n=4), and detected incidentally on imaging or pathology from procedures unrelated to oncologic care in 3.4% (n=6). CONCLUSIONS: In our cohort of patients undergoing surveillance following diagnosis and treatment of DCIS, 2% of second breast cancers were detected by a clinical breast examination. This suggests that survivorship care should prioritize mammography and patient education regarding breast self-examination and symptoms that warrant evaluation to detect second breast cancers.

Research Consensus Panel Follow-Up: A Systematic Review and Update on Cost Research in IR.

PURPOSE: To systematically review cost research in interventional radiology (IR) published since the Society of Interventional Radiology Research Consensus Panel on Cost in December 2016. MATERIALS AND METHODS: A retrospective assessment of cost research in adult and pediatric IR since December 2016 to July 2022 was conducted. All cost methodologies, service lines, and IR modalities were screened. Analyses were reported in a standardized fashion to include service lines, comparators, cost variables, analytical processes, and databases used. RESULTS: There were 62 studies published, with most from the United States (58%). Incremental cost-effectiveness ratio, quality-adjusted life-years, and time-driven activity-based costing (TDABC) analyses were performed in 50%, 48%, and 10%, respectively. The most frequently reported service line was interventional oncology (21%). No studies on venous thromboembolism, biliary, or IR endocrine therapies were found. Cost reporting was heterogeneous owing to varying cost variables, databases, time horizons, and willingness-to-pay (WTP) thresholds. IR therapies were more cost-effective than their non-IR counterparts for treating hepatocellular carcinoma ($55,925 vs $211,286), renal tumors ($12,435 vs $19,399), benign prostatic hyperplasia ($6,464 vs $9,221), uterine fibroids ($3,772 vs $6,318), subarachnoid hemorrhage ($1,923 vs $4,343), and stroke ($551,159 vs $577,181). TDABC identified disposable costs contributing most to total IR costs: thoracic duct embolization (68%), ablation (42%), chemoembolization (30%), radioembolization (80%), and venous malformations (75%). CONCLUSIONS: Although much of the contemporary cost-based research in IR aligned with the recommendations by the Research Consensus Panel, gaps remained in service lines, standardization of methodology, and addressing high disposable costs. Future steps include tailoring WTP thresholds to nation and health systems, cost-effective pricing for disposables, and standardizing cost sourcing methodology.

Leisure-time physical activity, daily sitting time, and mortality among US skin cancer survivors.

PURPOSE: To investigate the long-term effect of sitting time and physical activity after a skin cancer diagnosis. METHODS: A cohort of a nationally representative sample of skin cancer survivors (n=862) and non-cancer adults (n=13691) ≥50 years from the US National Health and Nutrition Examination Survey. Mortality data were linked through December 31, 2019. RESULTS: During up to 13.2 years of follow-up (median, 6.3 years; 94,093 person-years), 207 deaths (cancer: 53) occurred in skin cancer survivors and 1970 (cancer: 414) in non-cancer adults. After adjusting for covariates and skin cancer type, being active was associated with lower risks of all-cause (HR=0.69; 95% CI: 0.47 to 1.00) and non-cancer (HR=0.59; 95% CI: 0.36 to 0.97) mortality compared to being inactive among skin cancer survivors. Meanwhile, sitting 8 h/d was associated with higher risks of all-cause (HR=1.72; 95% CI: 1.11 to 2.67) and non-cancer (HR=1.76; 95% CI: 1.07 to 2.92) mortality compared to sitting <6 h/d. In the joint analysis, inactive skin cancer survivors sitting >8 h/d had the highest mortality risks from all-cause (HR=2.26; 95% CI: 1.28 to 4.00) and non-cancer (HR=2.11; 95% CI,1.10 to 4.17). Additionally, the associations of LTPA and sitting time with all-cause and cause-specific mortality did not differ between skin cancer survivors and non-cancer adults (all P for interaction>0.05) CONCLUSION: The combination of prolonged sitting and lack of physical activity was associated with elevated risks of all-cause and non-cancer deaths among US skin cancer survivors. Skin cancer survivors could benefit from maintaining a physically active lifestyle.