Mobile Health Assessment of Traumatic Dental Injuries Using Smartphone-Acquired Photographs: A Multicenter Diagnostic Accuracy Study.

Background: Mobile health (mHealth) has an emerging potential for remote assessment of traumatic dental injuries (TDI) and support of emergency care. This study aimed to determine the diagnostic accuracy of TDI detection from smartphone-acquired photographs. Methods: The upper and lower anterior teeth of 153 individuals aged ≥ 6 years were photographed using a smartphone camera app. The photos of 148 eligible participants were reviewed independently by a dental specialist, two general dentists, and two dental therapists, using predetermined TDI classification and criteria. The sensitivity, specificity, accuracy, positive predictive value, negative predictive value, and inter-rater reliability were estimated to evaluate the diagnostic performance of the photographic method relative to the reference standard established by the dental specialist. Results: Of the 1,870 teeth screened, one-third showed TDI; and one-seventh of the participants had primary or mixed dentitions. Compared between the specialist's reference standard and four dental professionals' reviews, the diagnostic sensitivity and specificity for TDI versus non-TDI were 59-95% and 47-93%, respectively, with better performance for urgent types of TDI (78-89% and 99-100%, separately). The diagnostic consistency was also better for the primary/mixed dentitions than the permanent dentition. Conclusion: This study suggested a valid mHealth practice for remote assessment of TDI. A better diagnostic performance in the detection of urgent types of TDI and examination of the primary/mixed dentition was also reported. Future directions include professional development activities involving dental photography and photographic assessment, incorporation of a machine learning technology to aid photographic reviews, and randomized controlled trials in multiple clinical settings.

A Phase II, Open-Label, Randomized Trial of Durvalumab With Olaparib or Cediranib in Patients With Mismatch Repair-Proficient Colorectal or Pancreatic Cancer.

BACKGROUND: The use of immunotherapy in mismatch repair proficient colorectal cancer (pMMR-CRC) or pancreatic adenocarcinoma (PDAC) is associated with limited efficacy. DAPPER (NCT03851614) is a phase 2, basket study randomizing patients with pMMR CRC or PDAC to durvalumab with olaparib (durvalumab + olaparib) or durvalumab with cediranib (durvalumab + cediranib). METHODS: PDAC or pMMR-CRC patients were randomized to either durvalumab+olaparib (arm A), or durvalumab + cediranib (arm B). Co-primary endpoints included pharmacodynamic immune changes in the tumor microenvironment (TME) and safety. Objective response rate, progression-free survival (PFS) and overall survival (OS) were determined. Paired tumor samples were analyzed by multiplexed immunohistochemistry and RNA-sequencing. RESULTS: A total of 31 metastatic pMMR-CRC patients were randomized to arm A (n = 16) or B (n = 15). In 28 evaluable patients, 3 patients had stable disease (SD) (2 patients treated with durvalumab + olaparib and 1 patient treated with durvalumab + cediranib) while 25 had progressive disease (PD). Among patients with PDAC (n = 19), 9 patients were randomized to arm A and 10 patients were randomized to arm B. In 18 evaluable patients, 1 patient had a partial response (unconfirmed) with durvalumab + cediranib, 1 patient had SD with durvalumab + olaparib while 16 had PD. Safety profile was manageable and no grade 4-5 treatment-related adverse events were observed in either arm A or B. No significant changes were observed for CD3+/CD8+ immune infiltration in on-treatment biopsies as compared to baseline for pMMR-CRC and PDAC independent of treatment arms. Increased tumor-infiltrating lymphocytes at baseline, low baseline CD68+ cells and different immune gene expression signatures at baseline were associated with outcomes. CONCLUSIONS: In patients with pMMR-CRC or PDAC, durvalumab + olaparib and durvalumab + cediranib showed limited antitumor activity. Different immune components of the TME were associated with treatment outcomes.

Real-World Treatment Patterns and Clinical Outcomes Among Patients with Metastatic or Unresectable EGFR-Mutated Non-Small Cell Lung Cancer Previously Treated with Osimertinib and Platinum-Based Chemotherapy.

INTRODUCTION: For patients with epidermal growth factor receptor-mutated (EGFRm) locally advanced/metastatic non-small cell lung cancer (mNSCLC) whose disease has progressed on or after osimertinib and platinum-based chemotherapy (PBC), no uniformly accepted standard of care exists. Moreover, limited efficacy of standard treatments indicates an unmet medical need, which is being addressed by ongoing clinical investigations, including the HERTHENA-Lung01 (NCT04619004) study of patritumab deruxtecan (HER3­DXd). However, because limited information is available on real-world clinical outcomes in such patients, early-phase trials of investigational therapies lack sufficient context for comparison. This study describes the real-world clinical characteristics, treatments, and outcomes for patients with EGFRm mNSCLC who initiated a new line of therapy following previous osimertinib and PBC, including a subset matched to the HERTHENA-Lung01 population. METHODS: This retrospective analysis used a US database derived from deidentified electronic health records. The reference cohort included patients with EGFRm mNSCLC who had initiated a new line of therapy between November 13, 2015 and June 30, 2021, following prior osimertinib and PBC. A subset of patients resembling the HERTHENA-Lung01 population was then extracted from the reference cohort; this matched subset was optimized using propensity score (PS) weighting. Endpoints were real-world overall survival (rwOS) and real-world progression-free survival (rwPFS). Confirmed real-world objective response rate (rwORR; partial/complete response confirmed ≥ 28 days later) was calculated for the response-evaluable subgroups of patients (with ≥ 2 response assessments spaced ≥ 28 days apart). RESULTS: In the reference cohort (N = 273), multiple treatment regimens were used, and none was predominant. Median rwPFS and rwOS were 3.3 and 8.6 months, respectively; confirmed rwORR (response evaluable, n = 123) was 13.0%. In the matched subset (n = 126), after PS weighting, median rwPFS and rwOS were 4.2 and 9.1 months, respectively; confirmed rwORR (response evaluable, n = 57) was 14.1%. CONCLUSION: The treatment landscape for this heavily pretreated population of patients with EGFRm mNSCLC is fragmented, with no uniformly accepted standard of care. A high unmet need exists for therapeutic options that provide meaningful improvements in clinical benefit.

Conditional frequency spectra as a tool for studying selection on complex traits in biobanks.

Natural selection on complex traits is difficult to study in part due to the ascertainment inherent to genome-wide association studies (GWAS). The power to detect a trait-associated variant in GWAS is a function of frequency and effect size - but for traits under selection, the effect size of a variant determines the strength of selection against it, constraining its frequency. To account for GWAS ascertainment, we propose studying the joint distribution of allele frequencies across populations, conditional on the frequencies in the GWAS cohort. Before considering these conditional frequency spectra, we first characterized the impact of selection and non-equilibrium demography on allele frequency dynamics forwards and backwards in time. We then used these results to understand conditional frequency spectra under realistic human demography. Finally, we investigated empirical conditional frequency spectra for GWAS variants associated with 106 complex traits, finding compelling evidence for either stabilizing or purifying selection. Our results provide insight into polygenic score portability and other properties of variants ascertained with GWAS, highlighting the utility of conditional frequency spectra.

2023 American College of Rheumatology (ACR)/American College of Chest Physicians (CHEST) Guideline for the Screening and Monitoring of Interstitial Lung Disease in People with Systemic Autoimmune Rheumatic Diseases.

OBJECTIVE: We provide evidence-based recommendations regarding screening for interstitial lung disease (ILD) and the monitoring for ILD progression in people with systemic autoimmune rheumatic diseases (SARDs), specifically rheumatoid arthritis, systemic sclerosis, idiopathic inflammatory myopathies, mixed connective tissue disease, and Sjögren disease. METHODS: We developed clinically relevant population, intervention, comparator, and outcomes questions related to screening and monitoring for ILD in patients with SARDs. A systematic literature review was performed, and the available evidence was rated using the Grading of Recommendations, Assessment, Development, and Evaluation methodology. A Voting Panel of interdisciplinary clinician experts and patients achieved consensus on the direction and strength of each recommendation. RESULTS: Fifteen recommendations were developed. For screening people with these SARDs at risk for ILD, we conditionally recommend pulmonary function tests (PFTs) and high-resolution computed tomography of the chest (HRCT chest); conditionally recommend against screening with 6-minute walk test distance (6MWD), chest radiography, ambulatory desaturation testing, or bronchoscopy; and strongly recommend against screening with surgical lung biopsy. We conditionally recommend monitoring ILD with PFTs, HRCT chest, and ambulatory desaturation testing and conditionally recommend against monitoring with 6MWD, chest radiography, or bronchoscopy. We provide guidance on ILD risk factors and suggestions on frequency of testing to evaluate for the development of ILD in people with SARDs. CONCLUSION: This clinical practice guideline presents the first recommendations endorsed by the American College of Rheumatology and American College of Chest Physicians for the screening and monitoring of ILD in people with SARDs.

2023 American College of Rheumatology (ACR)/American College of Chest Physicians (CHEST) Guideline for the Screening and Monitoring of Interstitial Lung Disease in People with Systemic Autoimmune Rheumatic Diseases.

OBJECTIVE: We provide evidence-based recommendations regarding screening for interstitial lung disease (ILD) and the monitoring for ILD progression in people with systemic autoimmune rheumatic diseases (SARDs), specifically rheumatoid arthritis, systemic sclerosis, idiopathic inflammatory myopathies, mixed connective tissue disease, and Sjögren disease. METHODS: We developed clinically relevant population, intervention, comparator, and outcomes questions related to screening and monitoring for ILD in patients with SARDs. A systematic literature review was performed, and the available evidence was rated using the Grading of Recommendations, Assessment, Development, and Evaluation methodology. A Voting Panel of interdisciplinary clinician experts and patients achieved consensus on the direction and strength of each recommendation. RESULTS: Fifteen recommendations were developed. For screening people with these SARDs at risk for ILD, we conditionally recommend pulmonary function tests (PFTs) and high-resolution computed tomography of the chest (HRCT chest); conditionally recommend against screening with 6-minute walk test distance (6MWD), chest radiography, ambulatory desaturation testing, or bronchoscopy; and strongly recommend against screening with surgical lung biopsy. We conditionally recommend monitoring ILD with PFTs, HRCT chest, and ambulatory desaturation testing and conditionally recommend against monitoring with 6MWD, chest radiography, or bronchoscopy. We provide guidance on ILD risk factors and suggestions on frequency of testing to evaluate for the development of ILD in people with SARDs. CONCLUSION: This clinical practice guideline presents the first recommendations endorsed by the American College of Rheumatology and American College of Chest Physicians for the screening and monitoring of ILD in people with SARDs.

2023 American College of Rheumatology (ACR)/American College of Chest Physicians (CHEST) Guideline for the Treatment of Interstitial Lung Disease in People with Systemic Autoimmune Rheumatic Diseases.

OBJECTIVE: We provide evidence-based recommendations regarding the treatment of interstitial lung disease (ILD) in adults with systemic autoimmune rheumatic diseases (SARDs). METHODS: We developed clinically relevant population, intervention, comparator, and outcomes questions. A systematic literature review was then performed, and the available evidence was rated using the Grading of Recommendations, Assessment, Development, and Evaluation methodology. A panel of clinicians and patients reached consensus on the direction and strength of the recommendations. RESULTS: Thirty-five recommendations were generated (including two strong recommendations) for first-line SARD-ILD treatment, treatment of SARD-ILD progression despite first-line ILD therapy, and treatment of rapidly progressive ILD. The strong recommendations were against using glucocorticoids in systemic sclerosis-ILD as a first-line ILD therapy and after ILD progression. Otherwise, glucocorticoids are conditionally recommended for first-line ILD treatment in all other SARDs. CONCLUSION: This clinical practice guideline presents the first recommendations endorsed by the American College of Rheumatology and American College of Chest Physicians for the treatment of ILD in people with SARDs.

Restoring L4-S1 Lordosis Shape in Severe Sagittal Deformity: Impact of Correction Techniques on Alignment and Complication Profile.

BACKGROUND: Severe sagittal plane deformity with loss of L4-S1 lordosis is disabling and can be improved through various surgical techniques. However, data are limited on the differing ability of anterior lumbar interbody fusion (ALIF), pedicle subtraction osteotomy (PSO), and transforaminal lumbar interbody fusion (TLIF) to achieve alignment goals in severely malaligned patients. METHODS: Severe adult spinal deformity patients with preoperative PI-LL >20°, L4-S1 lordosis <30°, and full body radiographs and PROMs at baseline and 6-week postoperative visit were included. Patients were grouped into ALIF (1-2 level ALIF at L4-S1), PSO (L4/L5 PSO), and TLIF (1-2 level TLIF at L4-S1). Comparative analyses were performed on demographics, radiographic spinopelvic parameters, complications, and PROMs. RESULTS: Among the 96 included patients, 40 underwent ALIF, 27 underwent PSO, and 29 underwent TLIF. At baseline, cohorts had comparable age, sex, race, Edmonton frailty scores, and radiographic spinopelvic parameters (P > 0.05). However, PSO was performed more often in revision cases (P < 0.001). Following surgery, L4-S1 lordosis correction (P = 0.001) was comparable among ALIF and PSO patients and caudal lordotic apex migration (P = 0.044) was highest among ALIF patients. PSO patients had higher intraoperative estimated blood loss (P < 0.001) and motor deficits (P = 0.049), and in-hospital ICU admission (P = 0.022) and blood products given (P = 0.004), but were otherwise comparable in terms of length of stay, blood transfusion given, and postoperative admission to rehab. Likewise, 90-day postoperative complication profiles and 6-week PROMs were comparable as well. CONCLUSIONS: ALIF can restore L4-S1 sagittal alignment as powerfully as PSO, with fewer intraoperative and in-hospital complications. When feasible, ALIF is a suitable alternative to PSO and likely superior to TLIF for correcting L4-S1 lordosis among patients with severe sagittal malalignment.

Leveraging a clinical emergency department dataset to estimate two-dose COVID-19 vaccine effectiveness and duration of protection in Canada.

BACKGROUND: During the COVID-19 pandemic, clinical care shifted toward virtual and Emergency Department care. We explored the feasibility of mRNA vaccine effectiveness (VE) estimation against SARS-CoV-2-related Emergency Department visits and hospitalizations using prospectively collected Emergency Department data. METHODS: We estimated two-dose VE using a test-negative design and data from 10 participating sites of the Canadian COVID-19 Emergency Department Rapid Response Network (CCEDRRN). We included Emergency Department patients presenting with COVID-19 symptoms and nucleic acid amplification testing for SARS-CoV-2 between July 19 and December 31, 2021. We excluded patients with unclear vaccination and one or more than 2 vaccine doses by their Emergency Department visit. RESULTS: Among 3,405 eligible patients, adjusted two-dose mRNA VE against SARS-CoV-2-related Emergency Department visits was 93.3 % (95 % CI 87.9-96.3 %) between 7-55 days, sustained over 80 % through 139 days post-vaccination. In stratified analyses, VE was similar among patients with select immune-compromising conditions, chronic kidney disease, lung disease, unstable housing, and reported illicit substance use. CONCLUSIONS: Two-dose mRNA VE against SARS-CoV-2-related Emergency Department visit was high and sustained, including among vulnerable subgroups. Compared to administrative datasets, active Emergency Department enrolment enables standardization for testing access and indication and supports separate VE assessment among special population subgroups. Compared to other active enrolment settings, Emergency Departments more consistently function during crises when alternate healthcare sectors become variably closed. TRIAL REGISTRATION: Clinicaltrials.gov, NCT0470294.

Potential clinical applications of current and future oral forms of desmopressin (Review).

Desmopressin is a synthetic analogue of vasopressin and a selective vasopressin receptor 2 agonist. It was first synthesised in 1967 and utilised for its antidiuretic properties. It is also used in bleeding disorders to enhance clotting. Other potential uses of the drug have been reported. The present review aims to provide a broad overview of the literature on potential further uses of oral forms of desmopressin. Key therapeutic areas of interest were identified based on known physiological activities/targets of desmopressin or reports of an effect of desmopressin in the literature. The feasibility of adequate dosing with oral forms of the drug was also considered. Systematic literature searches were carried out using the silvi.ai software for the identified areas, and summaries of available papers were included in tables and discussed. The results of the searches showed that desmopressin has been investigated for its efficacy in a number of areas, including bleeding control, renal colic, the central nervous system and oncology. Evidence suggests that oral desmopressin may have the potential to be of clinical benefit for renal colic and bleeding control in particular. However, further research is needed to clarify its effect in these areas, including randomised controlled studies and studies specifically of oral formulations (and doses). Further research may also yield findings for cancer, cognition and overactive bladder.

Comparative analysis of patient demographics, perioperative outcomes, and adverse events after lumbar spinal fusion between urban and rural hospitals: an analysis of the National Inpatient Sample (NIS) database.

OBJECTIVE: Rural location of a patient's primary residence has been associated with worse clinical and surgical outcomes due to limited resource availability in these parts of the US. However, there is a paucity of literature investigating the effect that a rural hospital location may have on these outcomes specific to lumbar spine fusions. METHODS: Using the National Inpatient Sample (NIS) database, we identified all patients who underwent primary lumbar spinal fusion in the years between 2009 and 2020. Patients were separated according to whether the operative hospital was considered rural or urban. Univariable and multivariable regression models were used for data analysis. RESULTS: Of 2,863,816 patients identified, 120,298 (4.2 %) had their operation at a rural hospital, with the remaining in an urban hospital. Patients in the urban cohort were younger (P < .001), more likely to have private insurance (39.81 % vs 31.95 %, P < .001), and fewer of them were in the first (22.52 % vs 43.00 %, P < .001) and second (25.96 % vs 38.90 %, P < .001) quartiles of median household income compared to the rural cohort. The urban cohort had significantly increased rates of respiratory (4.49 % vs 3.37 %), urinary (5.25 % vs 4.15 %), infectious (0.49 % vs 0.32 %), venous thrombotic (0.57 % vs 0.24 %, P < .001), and neurological (0.79 % vs 0.36 %) (all P < .001) perioperative complications. On multivariable analysis, the urban cohort had significantly increased odds of the same perioperative complications: respiratory (odds ratio[OR] = 1.48; 95 % confidence interval [CI], 1.26-1.74), urinary (OR = 1.34; 95 %CI, 1.20-1.50), infection (OR = 1.63; 95 %CI, 1.23-2.17), venous thrombotic (OR = 1.79; 95 %CI, 1.32-2.41), neurological injury (OR = 1.92; 95 %CI, 1.46-2.53), and localized infection (OR = 1.65; 95 %CI, 1.25-2.17) (all P < .001). CONCLUSIONS: Patients undergoing lumbar fusions experience significantly different outcomes based on the rural or urban location of the operative hospital.

Rearing density and food variety impact growth, development, and survival of larvae in the declining amphibian, Pseudacris maculata.

Boreal chorus frogs (Pseudacris maculata Agassiz 1850) are a widespread amphibian in North America, but several populations are in decline. Specifically, we are developing captive breeding and reintroduction methods for the Great Lakes/St. Lawrence-Canadian Shield population. Here we present the effects of tadpole density, food variety, and addition of supplemental minerals to rearing water on the growth, development, and survival during the larval and metamorph/juvenile stages. We conducted two experiments using a factorial design. We found that low tadpole density (1 vs. 2 tadpoles/L) and high food variety (five food items vs. three food items) significantly increased tadpole body length and Gosner stage after 2 weeks (p < .001), increased survival to metamorphosis (p < .001), decreased time to metamorphosis (p < .001), and increased weight after metamorphosis (p < .001). On average, tadpoles in the high density/low food treatment, compared to the low density/high food, were 25% smaller after 2 weeks, had 3.9× lower survival to metamorphosis, took 1.25× longer to reach metamorphosis, and weighed 1.5× less after metamorphosis. In contrast, neither density (0.5 vs. 1 tadpole/L) nor mineral supplemented water affected growth and development, but tadpole survival was higher at 1 tadpole/L. Our findings demonstrate the feasibility of rearing boreal chorus frogs in captivity and provide guidelines for rearing this and similar species in a laboratory environment.

The Society of Thoracic Surgeons Clinical Practice Guidelines on the Management of Neonates and Infants with Coarctation.

BACKGROUND: Although coarctation of the aorta without concomitant intracardiac pathology is relatively common, there is lack of guidance regarding aspects of its management in neonates and infants. METHODS: A panel of experienced congenital cardiac surgeons, cardiologists, and intensivists was created, and key questions related to the management of isolated coarctation in neonates and infants were formed using the PICO (Patients/Population, Intervention, Comparison/Control, Outcome) Framework. A literature search was then performed for each question. Practice guidelines were developed with classification of recommendation and level of evidence using a modified Delphi method. RESULTS: For neonates and infants with isolated coarctation, surgery is indicated in the absence of obvious surgical contraindications. For patients with risk factors for surgery, medical management before intervention is reasonable. For those stable off prostaglandin E1, the threshold for intervention remains unclear. Thoracotomy is indicated when arch hypoplasia is not present. Sternotomy is preferable when arch hypoplasia is present that cannot be adequately addressed through a thoracotomy. Sternotomy may also be considered in the presence of a bovine aortic arch. Antegrade cerebral perfusion may be reasonable when the repair is performed through a sternotomy. Extended end-to-end, arch advancement, and patch augmentation are all reasonable techniques. CONCLUSIONS: Surgery remains the standard of care for the management of isolated coarctation in neonates and infants. Depending on degree and location, arch hypoplasia may require a sternotomy approach as opposed to a thoracotomy approach. Significant opportunities remain to better delineate management in these patients.

Association of Diagnostic Discrepancy with Length of Stay and Mortality in Congestive Heart Failure Patients Admitted to the Emergency Department.

The goal of this study was to analyze diagnostic discrepancies between emergency department (ED) and hospital discharge diagnoses in patients with congestive heart failure admitted to the ED. Using a synthetic dataset from the Department of Veterans Affairs, the patients' primary diagnoses were compared at two levels: diagnostic category and body system. With 12,621 patients and 24,235 admission cases, the study found a 58% mismatch rate at the category level, which was reduced to 30% at the body system level. Diagnostic categories associated with higher levels of mismatch included aplastic anemia, pneumonia, and bacterial infections. In contrast, diagnostic categories associated with lower levels of mismatch included alcohol-related disorders, COVID-19, cardiac dysrhythmias, and gastrointestinal hemorrhage. Further investigation revealed that diagnostic mismatches are associated with longer hospital stays and higher mortality rates. These findings highlight the importance of reducing diagnostic uncertainty, particularly in specific diagnostic categories and body systems, to improve patient care following ED admission.

High levels of immunoglobulin G against cow's milk proteins and frequency of cow milk consumption are associated with the development of islet autoimmunity and type 1 diabetes - the TRIGR study.

BACKGROUND: The Trial to Reduce IDDM in the Genetically at Risk (TRIGR) (NCT00179777) found no difference type 1 diabetes risk between hydrolyzed and regular infant formula. However, cow's milk consumption during childhood is consistently linked to type 1 diabetes risk in prospective cohort studies. OBJECTIVE: Our primary aim was to study whether humoral immune responses to cow's milk and cow's milk consumption are associated with type 1 diabetes in TRIGR children. METHODS: TRIGR comprised 2159 children with genetic susceptibility to type 1 diabetes born between 2002-2007 in 15 countries. Children were randomized into groups receiving extensively hydrolyzed casein or a regular cow's milk formula and followed until age 10. Type 1 diabetes related autoantibodies and antibodies to cow's milk proteins were analyzed. Infant formula intake was measured by structured dietary interviews and milk consumption with a food frequency questionnaire. Associations of milk antibodies and milk consumption with the risk to develop type 1 diabetes were analysed by Cox survival model. RESULTS: Cow's milk antibody levels both in cord blood [HR for islet autoimmunity 1.30 (95% CI 1.05-1.61); type 1 diabetes 1.32 (1.02-1.71)] and longitudinally from birth to 3 years [islet autoimmunity 1.39 (1.07-1.81); type 1 diabetes 1.43 (1.04-1.96)] were associated with increased risk of developing type 1 diabetes. The amount of regular infant formula was associated with a reduced islet autoimmunity risk in the regular infant formula group [0.92 (0.85-0.99)]. Furthermore, frequent liquid milk consumption after infancy was associated with an increased risk of islet autoimmunity or type 1 diabetes. CONCLUSIONS: Elevated cow's milk antibody levels and high consumption of liquid milk after infancy are related to type 1 diabetes development in children with an increased genetic susceptibility to type 1 diabetes. Enhanced antibody levels to cow's milk may provide a biomarker of immune system prone to develop islet autoimmunity. TRIAL REGISTRY NUMBER: NCT00179777.

Perioperative Modified FOLFIRINOX for Resectable Pancreatic Cancer: A Nonrandomized Controlled Trial.

Importance: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignant tumor, and durable disease control is rare with the current standard of care, even for patients who undergo surgical resection. Objective: To assess whether neoadjuvant modified 5-fluorouracil, leucovorin, oxaliplatin, and irinotecan (mFOLFIRINOX) leads to early control of micrometastasis and improves survival. Design, Setting, and Participants: This open-label, single-arm, phase 2 nonrandomized controlled trial for resectable PDAC was conducted at the Yale Smilow Cancer Hospital from April 3, 2014, to August 16, 2021. Pancreatic protocol computed tomography was performed at diagnosis to assess surgical candidacy. Data were analyzed from January to July 2023. Interventions: Patients received 6 cycles of neoadjuvant mFOLFIRINOX before surgery and 6 cycles of adjuvant mFOLFIRINOX. Whole blood was collected and processed to stored plasma for analysis of circulating tumor DNA (ctDNA) levels. Tumors were evaluated for treatment response and keratin 17 (K17) expression. Main Outcomes and Measures: The primary end point was 12-month progression-free survival (PFS) rate. Additional end points included overall survival (OS), ctDNA level, tumor molecular features, and K17 tumor levels. Survival curves were summarized using Kaplan-Meier estimator. Results: Of 46 patients who received mFOLFIRINOX, 31 (67%) were male, and the median (range) age was 65 (46-80) years. A total of 37 (80%) completed 6 preoperative cycles and 33 (72%) underwent surgery. A total of 27 patients (59%) underwent resection per protocol (25 with R0 disease and 2 with R1 disease); metastatic or unresectable disease was identified in 6 patients during exploration. Ten patients underwent surgery off protocol. The 12-month PFS was 67% (90% CI, 56.9-100); the median PFS and OS were 16.6 months (95% CI, 13.3-40.6) and 37.2 months (95% CI, 17.5-not reached), respectively. Baseline ctDNA levels were detected in 16 of 22 patients (73%) and in 3 of 17 (18%) after 6 cycles of mFOLFIRINOX. Those with detectable ctDNA levels 4 weeks postresection had worse PFS (hazard ratio [HR], 34.0; 95% CI, 2.6-4758.6; P = .006) and OS (HR, 11.7; 95% CI, 1.5-129.9; P = .02) compared with those with undetectable levels. Patients with high K17 expression had nonsignificantly worse PFS (HR, 2.7; 95% CI, 0.7-10.9; P = .09) and OS (HR, 3.2; 95% CI, 0.8-13.6; P = .07). Conclusions and Relevance: This nonrandomized controlled trial met its primary end point, and perioperative mFOLFIRINOX warrants further evaluation in randomized clinical trials. Postoperative ctDNA positivity was strongly associated with recurrence. K17 and ctDNA are promising biomarkers that require additional validation in future prospective studies. Trial Registration: ClinicalTrials.gov Identifier: NCT02047474.

Reoperations in Adolescents and Adults after Prior Arterial Switch Operation: STS Congenital Database Analysis.

BACKGROUND: Arterial switch operation (ASO) has supplanted physiologic repairs for transposition of the great arteries and related anomalies. As survival rates have increased, so has the potential need for cardiac reoperations to address ASO-related complications arising later in life. METHODS: The STS-CHSD (2010-2021) was reviewed to assess prevalence and types of cardiac reoperations among patients aged ≥10 years with prior ASO for TGA or DORV/TGA-type. A hierarchical stratification designating 13 Procedure Categories was established a priori by investigators. Each eligible surgical hospitalization was assigned to the single highest applicable hierarchical category. Outcomes were compared across Procedure Categories, excluding hospitalizations limited to pacemaker-only and/or mechanical circulatory support-only procedures. Variation over the study period in relative proportions of Left Heart vs Non-Left Heart Procedure Category encounters was assessed. RESULTS: There were 698 cardiac surgical hospitalizations among patients aged 10-35 years at 100 centers. The most common Left Heart Procedure Categories were Aortic Valve procedures (n=146), Aortic Root procedures (n=117), and Coronary Artery procedures (n=40). Of 619 hospitalizations eligible for outcomes analysis, Major Complications occurred in 11% (67/619). Discharge mortality was 2.3% (14/619). Year-by-year analysis of surgical hospitalizations reveals substantial growth in numbers for the aggregate of all Procedure Categories. Growth in relative proportions of Left Heart vs Non-Left Heart Procedures was significant, p=0.0029 (Cochran-Armitage trend test). CONCLUSIONS: This largest multicenter study of post-ASO reoperations beyond early childhood documents year-over-year growth in total reoperations. Recently, left heart procedures had the highest rate of rise. These observations have implications for counseling, surveillance, and management.

Full Hill-type muscle model of the I1/I3 retractor muscle complex in Aplysia californica.

The coordination of complex behavior requires knowledge of both neural dynamics and the mechanics of the periphery. The feeding system of Aplysia californica is an excellent model for investigating questions in soft body systems' neuromechanics because of its experimental tractability. Prior work has attempted to elucidate the mechanical properties of the periphery by using a Hill-type muscle model to characterize the force generation capabilities of the key protractor muscle responsible for moving Aplysia's grasper anteriorly, the I2 muscle. However, the I1/I3 muscle, which is the main driver of retractions of Aplysia's grasper, has not been characterized. Because of the importance of the musculature's properties in generating functional behavior, understanding the properties of muscles like the I1/I3 complex may help to create more realistic simulations of the feeding behavior of Aplysia, which can aid in greater understanding of the neuromechanics of soft-bodied systems. To bridge this gap, in this work, the I1/I3 muscle complex was characterized using force-frequency, length-tension, and force-velocity experiments and showed that a Hill-type model can accurately predict its force-generation properties. Furthermore, the muscle's peak isometric force and stiffness were found to exceed those of the I2 muscle, and these results were analyzed in the context of prior studies on the I1/I3 complex's kinematics in vivo.