Tonsils at Telethon: developing a standardised collection of tonsil photographs for group A streptococcal (GAS) research.

Introduction: Group A streptococcus (GAS) infections, such as pharyngitis and impetigo, can lead to rheumatic fever and rheumatic heart disease (RHD). Australian Aboriginal and Torres Strait Islander populations experience high rates of RHD and GAS skin infection, yet rates of GAS pharyngitis are unclear. Anecdotally, clinical presentations of pharyngitis, including tonsillar hypertrophy and sore throat, are uncommon. This study aimed to develop a standardised set of tonsil photographs and determine tonsil size distribution from an urban paediatric population. Methods: A prospective cohort of children aged 3-15 years were recruited at the public events "Discover Day" and "Telethon Weekend" (October 2017) in Perth, Western Australia, Australia. Tonsil photographs, symptomatology, and GAS rapid antigen detection tests (RADT) were collected. Tonsil size was graded from the photographs using the Brodsky Grading Scale of tonsillar hypertrophy (Brodsky) by two independent clinicians, and inter-rater reliability calculated. Pharyngitis symptoms and GAS RADT were correlated, and immediate results provided. Results: Four hundred and twenty-six healthy children participated in the study over three days. The median age was seven years [interquartile range (IQR) 5.9-9.7 years]. Tonsil photographs were collected for 92% of participants, of which 62% were rated as good-quality photographs and 79% were deemed of adequate quality for assessment by both clinicians. When scored by two independent clinicians, 57% received the same grade. Average Brodsky grades (between clinicians) were 11%, 35%, 28%, 22% and 5% of grades 0,1,2,3 and 4, respectively. There was moderate agreement in grading using photographs, and minimal to weak agreement for signs of infection. Of 394 participants, 8% reported a sore throat. Of 334 GAS RADT performed, <1% were positive. Discussion: We report the first standardised use of paediatric tonsil photographs to assess tonsil size in urban-living Australian children. This provides a proof of concept from an urban-living cohort that could be compared with children in other settings with high risk of GAS pharyngitis or rheumatic fever such as remote-living Australian Indigenous populations.

Use of a Six-Item Modified Frailty Index to Predict 30-day Adverse Events, Readmission, and Mortality in Older Patients Undergoing Surgical Fixation of Lower Extremity, Pelvic, and Acetabular Fractures.

INTRODUCTION: This is a retrospective study evaluating the use of a new six-item modified frailty index (MF-6) to predict short-term outcomes of patients receiving surgery for lower extremity fractures. METHODS: Patients older than 65 years undergoing open reduction and internal fixation for lower extremity, pelvic, and acetabulum fractures were identified from the American College of Surgeons National Surgical Quality Improvement Program. The MF-6 was calculated by assigning one point for each of six common conditions. Multivariable analysis was used to compare patients with an MF-6 of <3 and ≥3. Outcome measures included complications, mortality, readmission, revision surgery, and length of stay. An area under the curve receiver operator analysis was conducted to compare the MF-6 with MF-5, an existing five-item frailty index. RESULTS: Nine thousand four hundred sixty-three patients were included. Patients with an MF-6 of ≥3 were at markedly higher risk of discharge destination other than home (Exp[B] = 2.09), mortality (Exp[B] = 2.48), major adverse events (Exp[B] = 2.16), and readmission (Exp[B] = 1.82). Receiver-operating curve analysis demonstrated an area under the curve of 0.65 for mortality, 0.62 for major adverse events, and 0.62 for discharge destination other than home, all of which outperformed the MF-5. DISCUSSION: The MF-6 was correlated with a 30-day postoperative incidence of infectious complications, readmission, and discharge destination. MF-6 scores can be used to risk-stratify patient populations as shifts to value-based care continue to develop.

The role of geographic disparities in outcomes after orthopaedic trauma surgery.

INTRODUCTION: Healthcare disparities linked to patient rurality and socioeconomic status are known to exist, but few studies have examined the effect of urban versus rural status on outcomes after orthopedic trauma surgery. The aim of this study was to examine the correlation between patient rurality, socioeconomic status, and outcomes after orthopedic trauma. MATERIALS AND METHODS: This is a retrospective cohort study of patients diagnosed with a hip or long bone fracture between January 2016 and December 2017. Data were collected from the Nationwide Inpatient Sample (NIS), a 20% weighted sample of 95% of the U.S. inpatient population. Patients were stratified into 3 groups: isolated hip fracture, isolated long bone fracture, and polytrauma. Bivariate analysis was completed using chi-squared tests for categorical variables and t-tests for continuous variables. Multivariable analysis was completed using population-weighted logistic regression models, based on a conceptual model derived selection of covariates. RESULTS: We included 235,393 patients diagnosed with a hip or extremity fracture. These were weighted to represent 1,176,965 patients nationally. In the hip fracture group, rural patient status was associated with higher odds of mortality (OR 1.32, P < 0.001) but not complications (OR 0.95, P = 0.082). In the extremity fracture and polytrauma groups, rural patient status was not associated with significantly higher odds of mortality or complications. In the urban polytrauma group, zip code with below-median income was associated with increased odds of mortality (OR 1.23, P = 0.002) but not complications. In the rural polytrauma group, zip code with below-median income was not associated with significantly increased odds of mortality or complications. In the hip fracture and extremity fracture groups, below-median income was not associated with significantly higher odds of mortality. CONCLUSION: We found that rural patients with hip fracture have higher mortality compared to urban patients and that socioeconomic disparities in mortality after a polytrauma exist in urban settings. These results speak to the ongoing need to develop objective measures of disparity-sensitive healthcare and optimize trauma systems to better serve low-income patients and patients in rural areas.

Radiation and immune checkpoint inhibitor-mediated pneumonitis risk stratification in patients with locally advanced non-small cell lung cancer: role of functional lung radiomics?

BACKGROUND: Patients undergoing chemoradiation and immune checkpoint inhibitor (ICI) therapy for locally advanced non-small cell lung cancer (NSCLC) experience pulmonary toxicity at higher rates than historical reports. Identifying biomarkers beyond conventional clinical factors and radiation dosimetry is especially relevant in the modern cancer immunotherapy era. We investigated the role of novel functional lung radiomics, relative to functional lung dosimetry and clinical characteristics, for pneumonitis risk stratification in locally advanced NSCLC. METHODS: Patients with locally advanced NSCLC were prospectively enrolled on the FLARE-RT trial (NCT02773238). All received concurrent chemoradiation using functional lung avoidance planning, while approximately half received consolidation durvalumab ICI. Within tumour-subtracted lung regions, 110 radiomics features (size, shape, intensity, texture) were extracted on pre-treatment [99mTc]MAA SPECT/CT perfusion images using fixed-bin-width discretization. The performance of functional lung radiomics for pneumonitis (CTCAE v4 grade 2 or higher) risk stratification was benchmarked against previously reported lung dosimetric parameters and clinical risk factors. Multivariate least absolute shrinkage and selection operator Cox models of time-varying pneumonitis risk were constructed, and prediction performance was evaluated using optimism-adjusted concordance index (c-index) with 95% confidence interval reporting throughout. RESULTS: Thirty-nine patients were included in the study and pneumonitis occurred in 16/39 (41%) patients. Among clinical characteristics and anatomic/functional lung dosimetry variables, only the presence of baseline chronic obstructive pulmonary disease (COPD) was significantly associated with the development of pneumonitis (HR 4.59 [1.69-12.49]) and served as the primary prediction benchmark model (c-index 0.69 [0.59-0.80]). Discrimination of time-varying pneumonitis risk was numerically higher when combining COPD with perfused lung radiomics size (c-index 0.77 [0.65-0.88]) or shape feature classes (c-index 0.79 [0.66-0.91]) but did not reach statistical significance compared to benchmark models (p > 0.26). COPD was associated with perfused lung radiomics size features, including patients with larger lung volumes (AUC 0.75 [0.59-0.91]). Perfused lung radiomic texture features were correlated with lung volume (adj R2 = 0.84-1.00), representing surrogates rather than independent predictors of pneumonitis risk. CONCLUSIONS: In patients undergoing chemoradiation with functional lung avoidance therapy and optional consolidative immune checkpoint inhibitor therapy for locally advanced NSCLC, the strongest predictor of pneumonitis was the presence of baseline chronic obstructive pulmonary disease. Results from this novel functional lung radiomics exploratory study can inform future validation studies to refine pneumonitis risk models following combinations of radiation and immunotherapy. Our results support functional lung radiomics as surrogates of COPD for non-invasive monitoring during and after treatment. Further study of clinical, dosimetric, and radiomic feature combinations for radiation and immune-mediated pneumonitis risk stratification in a larger patient population is warranted.

Flightless I Negatively Regulates Macrophage Surface TLR4, Delays Early Inflammation, and Impedes Wound Healing.

TLR4 plays a pivotal role in orchestrating inflammation and tissue repair. Its expression has finally been balanced to initiate the early, robust immune response necessary for efficient repair without excessively amplifying and prolonging inflammation, which impairs healing. Studies show Flightless I (Flii) is an immunomodulator that negatively regulates macrophage TLR4 signalling. Using macrophages from Flii+/-, WT, and FliiTg/Tg mice, we have shown that elevated Flii reduces early TLR4 surface expression, delaying and reducing subsequent TNF secretions. In contrast, reduced Flii increases surface TLR4, leading to an earlier robust TNF peak. In Flii+/- mice, TLR4 levels peak earlier during wound repair, and overall healing is accelerated. Fewer neutrophils, monocytes and macrophages are recruited to Flii+/- wounds, leading to fewer TNF-positive macrophages, alongside an early peak and a robust shift to M2 anti-inflammatory, reparative Ym1+ and IL-10+ macrophages. Importantly, in diabetic mice, high Flii levels are found in plasma and unwounded skin, with further increases observed in their wounds, which have impaired healing. Lowering Flii in diabetic mice results in an earlier shift to M2 macrophages and improved healing. Overall, this suggests Flii regulation of TLR4 reduces early inflammation and decreases the M2 macrophage phenotype, leading to impaired healing.

Prognostic Value of Early Fluorodeoxyglucose-Positron Emission Tomography Response Imaging and Peripheral Immunologic Biomarkers: Substudy of a Phase II Trial of Risk-Adaptive Chemoradiation for Unresectable Non-Small Cell Lung Cancer.

Purpose: We sought to examine the prognostic value of fluorodeoxyglucose-positron emission tomography (PET) imaging during chemoradiation for unresectable non-small cell lung cancer for survival and hypothesized that tumor PET response is correlated with peripheral T-cell function. Methods and Materials: Forty-five patients with American Joint Committee on Cancer version 7 stage IIB-IIIB non-small cell lung cancer enrolled in a phase II trial and received platinum-doublet chemotherapy concurrent with 6 weeks of radiation (NCT02773238). Fluorodeoxyglucose-PET was performed before treatment start and after 24 Gy of radiation (week 3). PET response status was prospectively defined by multifactorial radiologic interpretation. PET responders received 60 Gy in 30 fractions, while nonresponders received concomitant boosts to 74 Gy in 30 fractions. Peripheral blood was drawn synchronously with PET imaging, from which germline DNA sequencing, T-cell receptor sequencing, and plasma cytokine analysis were performed. Results: Median follow-up was 18.8 months, 1-year overall survival (OS) 82%, 1-year progression-free survival 53%, and 1-year locoregional control 88%. Higher midtreatment PET total lesion glycolysis was detrimental to OS (1 year 87% vs 63%, P < .001), progression-free survival (1 year 60% vs 26%, P = .044), and locoregional control (1 year 94% vs 65%, P = .012), even after adjustment for clinical/treatment factors. Twenty-nine of 45 patients (64%) were classified as PET responders based on a priori definition. Higher tumor programmed death-ligand 1 expression was correlated with response on PET (P = .017). Higher T-cell receptor richness and clone distribution slope were associated with improved OS (P = .018-0.035); clone distribution slope was correlated with PET response (P = .031). Conclusions: Midchemoradiation PET imaging is prognostic for survival; PET response may be linked to tumor and peripheral T-cell biomarkers.

Reliability of Quantitative 18F-FDG PET/CT Imaging Biomarkers for Classifying Early Response to Chemoradiotherapy in Patients With Locally Advanced Non-Small Cell Lung Cancer.

PURPOSE OF THE REPORT: We evaluated the reliability of 18F-FDG PET imaging biomarkers to classify early response status across observers, scanners, and reconstruction algorithms in support of biologically adaptive radiation therapy for locally advanced non-small cell lung cancer. PATIENTS AND METHODS: Thirty-one patients with unresectable locally advanced non-small cell lung cancer were prospectively enrolled on a phase 2 trial (NCT02773238) and underwent 18F-FDG PET on GE Discovery STE (DSTE) or GE Discovery MI (DMI) PET/CT systems at baseline and during the third week external beam radiation therapy regimens. All PET scans were reconstructed using OSEM; GE-DMI scans were also reconstructed with BSREM-TOF (block sequential regularized expectation maximization reconstruction algorithm incorporating time of flight). Primary tumors were contoured by 3 observers using semiautomatic gradient-based segmentation. SUVmax, SUVmean, SUVpeak, MTV (metabolic tumor volume), and total lesion glycolysis were correlated with midtherapy multidisciplinary clinical response assessment. Dice similarity of contours and response classification areas under the curve were evaluated across observers, scanners, and reconstruction algorithms. LASSO logistic regression models were trained on DSTE PET patient data and independently tested on DMI PET patient data. RESULTS: Interobserver variability of PET contours was low for both OSEM and BSREM-TOF reconstructions; intraobserver variability between reconstructions was slightly higher. ΔSUVpeak was the most robust response predictor across observers and image reconstructions. LASSO models consistently selected ΔSUVpeak and ΔMTV as response predictors. Response classification models achieved high cross-validated performance on the DSTE cohort and more variable testing performance on the DMI cohort. CONCLUSIONS: The variability FDG PET lesion contours and imaging biomarkers was relatively low across observers, scanners, and reconstructions. Objective midtreatment PET response assessment may lead to improved precision of biologically adaptive radiation therapy.

Treatment and outcomes of basicervical femoral neck fractures: A systematic review.

PURPOSE: This study aims to systematically review the literature comparing surgical treatments options and respective failure rates for basicervical hip fractures. METHODS: A comprehensive search of databases, including MEDLINE, Embase, Web of Science, and Cochrane Central for studies published in English on or before June 21, 2019 was performed. Selected search terms included "basicervical," "basi cervical," "AO/OTA type 31-B," "femoral neck fracture" AND "bone nails," "bone screws," "fracture fixation," "internal fixation," "arthroplasty," "cephalomedullary," "sliding hip screw," "ORIF," and "treatment outcome." We included studies that assessed outcomes of basicervical fracture fixation using open reduction internal fixation or arthroplasty. Two authors extracted the following data from each paper: study design, country, cohort year, definition of basicervical, intervention type, sample size, patient demographics, follow-up length, percent of fractures that required revision, and the percent of implants that failed. RESULTS: Sixteen articles encompassing 910 patients were included. The main outcome was the percent of implants that required revision. The total revision rates were 8% (8 studies, 157 patients, range 0%-55%) for cephalomedullary nails, 7% (10 studies, 584 patients, range 0%-18%) for sliding hip screws, 23% (3 studies, 40 patients, range 16%-50%) for cannulated screws, 0% (1 study, 6 patients) for total hip arthroplasty, and 8% (2 studies, 13 patients, range 0%-11%) for hemiarthroplasty. CONCLUSION: Management of basicervical fractures with SHS and CMN produces similar failure and re-operation rates. Limited evidence is available on the use of cannulated screws and arthroplasty, but available studies suggest that cannulated screws have an unacceptable revision rate (23%) while arthroplasty may be acceptable. Future studies examining the comparative efficacy of various fixation methods would benefit from strict definition of fracture type as well as consistent reporting of functional outcomes, re-operation rates, and mortality.

Attenuation of Flightless I Increases Human Pericyte Proliferation, Migration and Angiogenic Functions and Improves Healing in Murine Diabetic Wounds.

Pericytes are peri-vascular mural cells which have an important role in the homeostatic regulation of inflammatory and angiogenic processes. Flightless I (Flii) is a cytoskeletal protein involved in regulating cellular functions, but its involvement in pericyte activities during wound healing is unknown. Exacerbated inflammation and reduced angiogenesis are hallmarks of impaired diabetic healing responses, and strategies aimed at regulating these processes are vital for improving healing outcomes. To determine the effect of altering Flii expression on pericyte function, in vitro and in vivo studies were performed to assess the effect on healing, inflammation and angiogenesis in diabetic wounds. Here, we demonstrated that human diabetic wounds display upregulated expression of the Flii protein in conjunction with a depletion in the number of platelet derived growth factor receptor ß (PDGFRß) +/ neural glial antigen 2 (NG2) + pericytes present in the dermis. Human pericytes were found to be positive for Flii and attenuating its expression in vitro through siRNA knockdown led to enhanced proliferation, migration and angiogenic functions. Genetic knockdown of Flii in a streptozotocin-induced murine model of diabetes led to increased numbers of pericytes within the wound. This was associated with dampened inflammation, an increased rate of angiogenic repair and improved wound healing. Our findings show that Flii expression directly impacts pericyte functions, including proliferation, motility and angiogenic responses. This suggests that Flii regulation of pericyte function may be in part responsible for the changes in pericyte-related processes observed in diabetic wounds.

Scanning Beam Proton Therapy versus Photon IMRT for Stage III Lung Cancer: Comparison of Dosimetry, Toxicity, and Outcomes.

PURPOSE: There are limited clinical data on scanning-beam proton therapy (SPT) in treating locally advanced lung cancer, as most published studies have used passive-scatter technology. There is increasing interest in whether the dosimetric advantages of SPT compared with photon therapy can translate into superior clinical outcomes. We present our experience of SPT and photon intensity modulated radiation therapy (IMRT) with clinical dosimetry and outcomes in patients with stage III lung cancer. METHODS AND MATERIALS: Patients with stage III lung cancer treated at our center between 2013 and May 2018 were identified in compliance with our institutional review board (64 patients = 34 SPT + 30 IMRT). Most proton patients were treated with pencil beam scanning (28 of 34), and 6 of 34 were treated with uniform scanning. Fisher exact test, χ2 test, and Mann-Whitney test were used to compare groups. All tests were 2-sided. RESULTS: Patient characteristics were similar between the IMRT and SPT patients, except for worse lung function in the IMRT group. Mean dose to lung, heart, and esophagus was lower in the SPT group, with most benefit in the low-dose region (lungs, 9.7 Gy vs 15.7 Gy for SPT vs IMRT, respectively [P = .004]; heart, 7 Gy vs 14 Gy [P = .001]; esophagus, 28.2 Gy vs 30.9 Gy [P = .023]). Esophagitis and dermatitis grades were not different between the 2 groups. Grade 2+ pneumonitis was 21% in the SPT group and 40% in the IMRT group (P = .107). Changes in blood counts were not different between the 2 groups. Overall survival and progression-free survival were not different between SPT and IMRT (median overall survival, 41.6 vs 30.7 months, respectively [P = .52]; median progression-free survival, 19.5 vs 14.6 months [P = .50]). CONCLUSIONS: We report our experience with SPT and IMRT in stage III lung cancer. Our cohort of patients treated with SPT had lower doses to normal organs (lungs, heart, esophagus) than our IMRT cohort. There was no statistically significant difference in toxicity rates or survival, although there may have been a trend toward lower rates of pneumonitis.

Relapse Rates in Patients with Clubfoot Treated Using the Ponseti Method Increase with Time: A Systematic Review.

BACKGROUND: The Ponseti method is the preferred technique to manage idiopathic clubfoot deformity; however, there is no consensus on the expected relapse rate or the percentage of patients who will ultimately require a corrective surgical procedure. The objective of the present systematic review was to determine how reported rates of relapsed deformity and rates of a secondary surgical procedure are influenced by each study's length of follow-up. METHODS: A comprehensive literature search using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines was performed to identify relevant articles. The definition of relapse, the percentage of patients who relapsed, the percentage of feet that required a surgical procedure, and the mean duration of follow-up of each study were extracted. Pearson correlations were performed to determine associations among the following variables: mean follow-up duration, percentage of patients who relapsed, percentage of feet that required a joint-sparing surgical procedure, and percentage of feet that required a joint-invasive surgical procedure. Logarithmic curve fit regressions were used to model the relapse rate, the rate of joint-sparing surgical procedures, and the rate of joint-invasive surgical procedures as a function of follow-up time. RESULTS: Forty-six studies met the inclusion criteria. Four distinct definitions of relapse were identified. The reported relapse rates varied from 3.7% to 67.3% of patients. The mean duration of follow-up was strongly correlated with the relapse rate (Pearson correlation coefficient = 0.44; p < 0.01) and the percentage of feet that required a joint-sparing surgical procedure (Pearson correlation coefficient = 0.59; p < 0.01). Studies with longer follow-up showed significantly larger percentages of relapse and joint-sparing surgical procedures than studies with shorter follow-up (p < 0.05). CONCLUSIONS: Relapses have been reported to occur at as late as 10 years of age; however, very few studies follow patients for at least 8 years. Notwithstanding that, the results indicated that the rate of relapse and percentage of feet requiring a joint-sparing surgical procedure increased as the duration of follow-up increased. Longer-term follow-up studies are required to accurately predict the ultimate risk of relapsed deformity. Patients and their parents should be aware of the possibility of relapse during middle and late childhood, and, thus, follow-up of these patients until skeletal maturity may be warranted. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.