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.

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.

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

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

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.

Which Application Factors Are Associated With Outstanding Performance in Orthopaedic Surgery Residency?

BACKGROUND: Identifying ideal candidates for orthopaedic surgery residency is difficult. Data available for applicant selection are evolving; preclinical grades and the Alpha Omega Alpha (AOA) honors society are being phased out at some medical schools. Similarly, three-digit United States Medical Licensing Examination (USMLE) Step 1 scores have been eliminated. There is renewed interest in improving resident selection to provide a diverse, comprehensive educational opportunity that produces orthopaedic surgeons who are prepared for practice. QUESTIONS/PURPOSES: We sought to identify whether (1) academic achievements, (2) letters of recommendation, (3) research activity, and (4) miscellaneous factors available on Electronic Residency Application Service (ERAS) applications were associated with outstanding residency performance. METHODS: Ten faculty members (22% of all full-time faculty) with extensive educational involvement for at least 7 years, whose expertise covered all subspecialty departments at an urban, academic orthopaedic surgery residency program, were given an anonymous survey on the performance of the four most recent classes of residency graduates (24 residents). This survey was developed due to the lack of a validated residency outcomes tool or objective metrics for residency performance. The evaluated criteria were decided upon after discussion by a relatively large group of academic orthopaedic surgeons considering the factors most important for graduating orthopaedic residents. The faculty were selected based on their long-term knowledge of the residency, along with their diversity of specialty and backgrounds; there were no nonresponders. Faculty graded each resident on a scale from 1 to 10 (higher is better) on six criteria: surgical technical skills, research productivity, clinical knowledge, professionalism, personality, and fellowship match. The mean of the faculty ratings made by all faculty for all six criteria was calculated, producing the overall residency performance score. Factors available on each resident's ERAS application were then correlated with their overall residency performance score. Categorical ERAS factors, including AOA status, five or more honors in core clerkships, at least three exceptional letters of recommendation, collegiate athletics participation, expertise with a musical instrument, and research (6-year) track residents, were correlated with overall residency performance score via point biserial analysis. Continuous ERAS factors including USMLE Step 1 and Step 2 scores, number of publications before residency, number of research years before residency, medical school ranking, and number of volunteer experiences were correlated with overall residency performance score via Pearson correlation. USMLE Step 1 three-digit scores were evaluated despite their recent elimination because of their historic importance as a screening tool for residency interviews and for comparison to USMLE Step 2, which retains a three-digit score. Application factors with a p < 0.2 on univariate analysis (five or more honors in core clerkships, at least three exceptional letters of recommendation, research track residents) were included in a stepwise linear regression model with "overall residency performance score" as the outcome variable. All p values < 0.05 were considered significant. RESULTS: The mean overall residency performance score was 7.9 ± 1.2. Applicants with at least five honors grades in core clerkships had overall residency performance scores 1.2 points greater than those of their peers (95% confidence interval (CI) 0.3 to 2.0; p = 0.01, Cohen ƒ 2 = 0.2, representing a small effect size). ERAS applications including at least three exceptional letters of recommendation were associated with a 0.9-point increase in residency performance (95% CI 0.02 to 1.7; p = 0.046, Cohen ƒ 2 = 0.1, representing a small effect size). Participation in the residency research (6-year) track was associated with a 1-point improvement in residency performance (95% CI 0.1 to 1.9; p = 0.03, Cohen ƒ 2 = 0.2, again, representing a small effect size). Together, these three factors accounted for 53% of the variance in overall residency performance score observed in this study. CONCLUSION: Past clinical excellence, measured by core clerkship grades and exceptional letters of recommendation, is associated with slightly improved overall orthopaedic residency performance scores. Applicants meeting both criteria who also complete a research track residency may perform substantially better in residency than their counterparts, as these three factors accounted for half of all the variance observed in the current study. Although minimum requirements are necessary, traditionally used screening factors (such as USMLE scores, AOA status, medical school rank, and number of publications) may be of less utility in identifying successful future residents than previously thought. LEVEL OF EVIDENCE: Level III, therapeutic study.

Autocrine insulin pathway signaling regulates actin dynamics in cell wound repair.

Cells are exposed to frequent mechanical and/or chemical stressors that can compromise the integrity of the plasma membrane and underlying cortical cytoskeleton. The molecular mechanisms driving the immediate repair response launched to restore the cell cortex and circumvent cell death are largely unknown. Using microarrays and drug-inhibition studies to assess gene expression, we find that initiation of cell wound repair in the Drosophila model is dependent on translation, whereas transcription is required for subsequent steps. We identified 253 genes whose expression is up-regulated (80) or down-regulated (173) in response to laser wounding. A subset of these genes were validated using RNAi knockdowns and exhibit aberrant actomyosin ring assembly and/or actin remodeling defects. Strikingly, we find that the canonical insulin signaling pathway controls actin dynamics through the actin regulators Girdin and Chickadee (profilin), and its disruption leads to abnormal wound repair. Our results provide new insight for understanding how cell wound repair proceeds in healthy individuals and those with diseases involving wound healing deficiencies.

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

BACKGROUND: Timely collection of patient-reported outcomes (PROs) decreases emergency department visits and hospitalizations and increases survival. However, little is known about the outcome predictivity of unpaid informal caregivers' reporting using similar clinical outcome assessments. OBJECTIVE: The aim of this study is to assess whether caregivers and adults with cancer adhered to a planned schedule for electronically collecting patient-reported outcomes (PROs) and if PROs were associated with future clinical events. METHODS: We developed 2 iPhone apps to collect PROs, one for patients with cancer and another for caregivers. We enrolled 52 patient-caregiver dyads from Kaiser Permanente Northern California in a nonrandomized study. Participants used the apps independently for 4 weeks. Specific clinical events were obtained from the patients' electronic health records up to 6 months following the study. We used logistic and quasi-Poisson regression analyses to test associations between PROs and clinical events. RESULTS: Participants completed 97% (251/260) of the planned Patient-Reported Outcomes Common Terminology Criteria for Adverse Events (PRO-CTCAE) surveys and 98% (254/260) of the Patient-Reported Outcomes Measurement Information System (PROMIS) surveys. PRO-CTCAE surveys completed by caregivers were associated with patients' hospitalizations or emergency department visits, grade 3-4 treatment-related adverse events, dose reductions (P<.05), and hospice referrals (P=.03). PROMIS surveys completed by caregivers were associated with hospice referrals (P=.02). PRO-CTCAE surveys completed by patients were not associated with any clinical events, but their baseline PROMIS surveys were associated with mortality (P=.03), while their antecedent or final PROMIS surveys were associated with all clinical events examined except for total days of treatment breaks. CONCLUSIONS: In this study, caregivers and patients completed PROs using smartphone apps as requested. The association of caregiver PRO-CTCAE surveys with patient clinical events suggests that this is a feasible approach to reducing patient burden in clinical trial data collection and may help provide early information about increasing symptom severity.

Applicability of Shoulder, Olecranon, and Wrist-based Skeletal Maturity Estimation Systems to the Modern Pediatric Population.

BACKGROUND: The proximal humerus ossification system (PHOS), olecranon apophyseal ossification system (OAOS), and modified Fels wrist skeletal maturity system (mFWS) were recently developed or updated using a historical, mostly White, pediatric population. These upper extremity skeletal maturity systems have demonstrated skeletal age estimation performance superior or equivalent to Greulich and Pyle in historical patients. Their applicability to modern pediatric populations has not yet been evaluated. METHODS: We reviewed anteroposterior shoulder, lateral elbow, and anteroposterior hand and wrist x-rays of 4 pediatric cohorts: White males, Black males, White females, and Black females. Peripubertal x-rays were evaluated: males 9 to17 years and females 7 to 15 years. Five nonpathologic radiographs for each age and joint were randomly selected from each group. Skeletal age estimates made by each of the 3 skeletal maturity systems were plotted against the chronological age associated with each radiograph and compared between cohorts, and with the historical patients. RESULTS: Five hundred forty modern radiographs were evaluated (180 shoulders, 180 elbows, and 180 wrists). All radiographic parameters had inter- and intra-rater reliability coefficients at or above 0.79, indicating very good reliability. For PHOS, White males had delayed skeletal age compared with Black males (Δ-0.12 y, P =0.02) and historical males (Δ-0.17 y, P <0.001). Black females were skeletally advanced compared with historical females (Δ0.11 y, P =0.01). For OAOS, White males (Δ-0.31 y, P <0.001) and Black males (Δ-0.24 y, P <0.001) had delayed skeletal age compared with historical males. For mFWS, White males (Δ0.29 y, P =0.024), Black males (Δ0.58 y, P <0.001), and Black females (Δ0.44 y, P <0.001) had advanced skeletal age compared with historical counterparts of the same sex. All other comparisons were not significant ( P >0.05). CONCLUSIONS: The PHOS, OAOS, and mFWS have mild discrepancies in skeletal age estimates when applied to modern pediatric populations depending on the race and sex of the patient. LEVEL OF EVIDENCE: Level III - retrospective chart review.

Applicability of the Modified Fels and Optimized Oxford Skeletal Maturity Estimation Systems to the Modern Pediatric Population.

BACKGROUND: The recently developed modified Fels knee and optimized Oxford hip skeletal maturity systems (SMS) have demonstrated impressive performance compared with the Greulich and Pyle skeletal age atlas when applied to the same historical, mostly white, pediatric population. We sought to determine whether these 2 systems require modification before being used in modern children. METHODS: We collected knee and hip radiographs between January 2015 and September 2020 from our electronic medical record from 4 groups of children: (1) white males, (2) black males, (3) white females, and (4) black females. Males between 9 and 17 years and females between 7 and 15 years were included. After reliability analyses, 5 nonpathologic radiographs for each age and joint were randomly selected from each group and evaluated with the appropriate SMS. The mean discrepancy between each group's chronological age at the time of radiograph and estimated skeletal age was compared between our modern cohort and the historical Bolton-Brush children. After normality testing, paired t tests or Wilcoxon signed-rank tests were performed, as appropriate. A Bonferroni correction was applied to address multiple testing. RESULTS: Three hundred sixty modern radiographs were evaluated (180 knees and 180 hips). All 7 modified Fels knee parameters and all 5 optimized Oxford hip parameters had inter and intrarater reliability coefficients ≥0.7, indicating good to very good reliability. For the modified Fels knee SMS, white males (Δ0.74 y, P <0.001), black males (Δ0.69 y, P <0.001), and black females (Δ0.4 y, P =0.04) had advanced skeletal age compared with their historical counterparts of the same sex. No differences were found between historical and modern patients for the optimized Oxford hip SMS. No differences were found for either SMS comparing modern patients along racial lines ( P >0.05 for all). CONCLUSIONS: Discrepancies in skeletal age estimates made by the modified Fels knee SMS exist between modern pediatric white males, black males, and black females and their historic counterparts. No differences were found when using optimized Oxford hip SMS. Future studies should evaluate how these translate to clinical decision-making. LEVEL OF EVIDENCE: Level III; retrospective chart review.