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Persistent public misconceptions of plastic and reconstructive surgery (PRS), ambiguity between cosmetic versus reconstructive surgical procedures, and subjective interpretation of aesthetics can result in undervaluing of the field. Our study analyzes how patient context (cosmetic or reconstructive/restorative cues) affect public perception of outcomes and value of surgery.We distributed Qualtrics™ surveys to laypersons via Amazon Mechanical Turk. Demographics were self-reported. The survey presented a series of pre- and post-operative photographs of PRS surgeries alongside either a cosmetic or reconstructive/restorative cue, followed by questions on values of procedure. Survey responses were analyzed using two-tailed Student's t tests and chi square analyses, univariate and multivariate analysis, and linear regression.Of the 459 respondents, the mean age was 38.5 ± 12.1 years, and was 50.5% (232) male. The majority of respondents classified breast reconstruction as a cosmetic surgery (243, 66.8%), and was rated more attractive (p 0.0005), higher impact on self-esteem (p 0.001), and to be covered by health insurance (p 0.0001) compared to breast augmentation. Reconstructive cued breast and facial procedures were viewed more favorably; the exception was gynecomastia reduction. Reconstructive classification had significant positive correlation with support for insurance coverage (RThis study revealed more public support for reconstructive/restorative cued PRS cases over cosmetic cued PRS cases, and persistent misconceptions of breast reconstruction as a cosmetic procedure. Reconstructive or restorative cues can be used to educate the public and address skewed perceptions on the roles and value of PRS.

This study is the first to investigate pediatric craniomaxillofacial (CMF) trauma patients that present with concomitant burns. The authors aim to identify differing etiologies, presentations, facial fracture patterns, interventions, and outcomes between pediatric CMF trauma patients with versus without concomitant burns. In this retrospective cohort study of a tertiary care center between the years 1990 and 2010, concomitant burns were identified among pediatric patients presenting with CMF fractures. Patient charts were reviewed for demographics, presentation, burn characteristics (total body surface area %, location, and degree), imaging, interventions, involvement of child protective services, and long-term outcomes. Data were analyzed using two-tailed Student t tests and chi-square analysis. Of the identified 2966 pediatric CMF trauma patients (64.0% boys; age 7 ± 4.7 years), 10 (0.34%) patients presented with concomitant burns. Concomitant burn and CMF traumas were more likely to be due to penetrating injuries (P

BACKGROUND There is growing public concern surrounding breast implant safety. In fact, the U.S. Food and Drug Administration recently proposed changes to breast implant labeling, which include a boxed warning. Given such efforts to increase transparency on breast implant safety, this study assessed laywomen's perceptions of breast implant safety, and the impact of proposed changes to breast implant labeling on laywomen's decision-making regarding breast implants. METHODS This was a cross-sectional investigation of women recruited through Amazon Mechanical Turk. Discrete choice modeling was used to query opinions on breast implants after viewing proposed labeling changes. Chi-square and analysis of variance were used for subgroup analyses, and McNemar analyses were used to assess changes in participants' responses. RESULTS The authors received 500 survey responses. At baseline, 353 participants (70.6 percent) considered breast implants to be at least somewhat safe. After viewing the proposed boxed warning, 252 participants (50.4 percent) responded that they would be less likely to receive implants. In fact, a significantly greater proportion of participants considered breast implants to be either unsafe or very unsafe after viewing suggested changes to implant labeling than at baseline (58.4 percent versus 28.8 percent; p = 0.001). By the end of the survey, willingness to consider alternative options for breast augmentation/reconstruction increased significantly from baseline. CONCLUSIONS Improved labeling can enhance laywomen's understanding of breast implant safety and can impact decision-making. However, greater scrutiny of breast implants should not prevent women who need implants from receiving them. Transparency and objectivity in the surgeon-patient dialogue can ensure the appropriate use of medical devices such as breast implants.

Objectives Cause-of-death information, reported by frontline clinicians after a patient’s death, is an irreplaceable source of public health data. However, systematic bias in cause-of-death reporting can lead to over- or underestimation of deaths attributable to different causes. New York City consistently reports higher rates of deaths attributable to pneumonia and influenza than many other US cities and the country. We investigated systematic erroneous reporting as a possible explanation for this phenomenon. Methods We reviewed all deaths from 2 New York City hospitals during 2013-2014 in which pneumonia or influenza was reported as the underlying cause of death (n = 188), and we examined the association between erroneous reporting and multiple extrinsic factors that may influence cause-of-death reporting (patient demographic characteristics and medical comorbidities, time and hospital location of death, type of medical provider reporting the death, and availability of certain diagnostic information). Results Pneumonia was erroneously reported as the underlying cause of death in 163 (86.7%) reports. We identified heart disease and dementia as the more likely underlying cause of death in 21% and 17% of erroneously reported deaths attributable to pneumonia, respectively. We found no significant association between erroneous reporting and the multiple extrinsic factors examined. Conclusions Our results underscore how erroneous reporting of 1 condition can lead to underreporting of other causes of death. Misapplication or misunderstanding of procedures by medical providers, rather than extrinsic factors influencing the reporting process, are key drivers of erroneous cause-of-death reporting.

Purpose of Review Examining what older women know and perceive about mammography screening is critical for understanding patterns of under- and overuse, and concordance with screening mammography guidelines in the USA. This narrative review synthesizes qualitative and quantitative evidence around older women’s perspectives toward mammography screening. Recent Findings The majority of 43 identified studies focused on promoting mammography screening in women of different ages, with only four studies focusing on the overuse of mammography in women ≥ 70 years old. Older women hold positive attitudes around screening, perceive breast cancer as serious, believe the benefits outweigh the barriers, and are worried about undergoing treatment if diagnosed. Older women have limited knowledge of screening guidelines and potential harms of screening. Summary Efforts to address inequities in mammography access and underuse need to be supplemented by epidemiologic and interventional studies using mixed-methods approaches to improve awareness of benefits and harms of mammography screening in older racially and ethnically diverse women. As uncertainty around how best to approach mammography screening in older women remains, understanding women’s perspectives along with healthcare provider and system-level factors is critical for ensuring appropriate and equitable mammography screening use in older women.

Background Well-tolerated and commonly used medications are increasingly assessed for reducing breast cancer risk. These include metformin and statins, both linked to reduced hormone availability and cell proliferation or growth and sometimes prescribed concurrently. We investigated independent and joint associations of these medications with mammographic breast density (MBD), a useful biomarker for the effect of chemopreventive agents on breast cancer risk. Methods Using data from a cross-sectional study of 770 women (78% Hispanic, aged 40–61 years, in a mammography cohort with high cardiometabolic burden), we examined the association of self-reported “ever” use of statins and metformin with MBD measured via clinical Breast Imaging Reporting and Data System (BI-RADS) density classifications (relative risk regression) and continuous semi-automated percent and size of dense area (Cumulus) (linear regression), adjusted for age, body mass index, education, race, menopausal status, age at first birth, and insulin use. Results We observed high statin (27%), metformin (13%), and combination (9%) use, and most participants were overweight/obese (83%) and parous (87%). Statin use was associated with a lower likelihood of high density BI-RADS (RR = 0.60, 95% CI = 0.45 to 0.80), percent dense area (PD) (β = − 6.56, 95% CI = − 9.05 to − 4.06), and dense area (DA) (β = − 9.05, 95% CI = − 14.89 to − 3.22). Metformin use was associated with lower PD and higher non-dense area (NDA), but associations were attenuated by co-medication with statins. Compared to non-use of either medication, statin use alone or with metformin were associated with lower PD and DA (e.g., β = − 6.86, 95% CI: − 9.67, − 4.05 and β = − 7.07, 95% CI: − 10.97, − 3.17, respectively, for PD) and higher NDA (β = 25.05, 95% CI: 14.06, 36.03; β = 29.76, 95% CI: 14.55, 44.96, respectively). Conclusions Statin use was consistently associated with lower MBD, measured both through clinical radiologist assessment and continuous relative and absolute measures, including dense area. Metformin use was associated with lower PD and higher NDA, but this may be driven by co-medication with statins. These results support that statins may lower MBD but need confirmation with prospective and clinical data to distinguish the results of medication use from that of disease.

Purpose: Improved graft reinnervation and functional recovery would greatly enhance the utility of vascularized composite allotransplantation (VCA). Pre-implantation of nerve grafts in a limb transplant recipient prior to transplantation to increase the length of the severed nerves in the amputation stump offers a novel, readily translatable approach to this problem. At the time of transplantation a pre-implanted nerve graft (PING) would be elevated from its wound bed in the amputated stump and unfurled distally into the transplanted limb, allowing for a more distal nerve coaptation. Methods: We used a reversed sciatic-tibial nerve isograft coapted end-to-end to a median nerve in a rat to: (1) determine viability of distal axons after elevating PINGs; and (2) assess for ischemic injury to axons in the distal PING following elevation from the wound bed. For axonal viability, grafts of varying lengths (2cm,3cm,4cm, n≥5/group) were left to regenerate for 8 weeks. The distal ends were then biopsied prior to elevation, and again one week after elevation. For ischemia assessment, blood flow along 4cm long PINGs was measured with laser doppler at multiple timepoints: baseline (at time of grafting), 8 weeks after grafting (before elevation), immediately after elevation, and 3 and 7 days post-elevation (n=8/timepoint). Means were compared with t-tests and ANOVA. A pig forelimb model was used to assess the functional impact of PINGs. A 6cm long reversed ulnar-PING was coapted to the proximally transected ulnar nerve. After 12 weeks of regeneration, the distal PING was transferred end-to-end to the median nerve just proximal to the elbow. A control group underwent ulnar-to-median nerve transfer 6cm proximal to the elbow (n=4 limbs/group). Hoof flexion force was measured every three weeks. Results Axonal viability: after 8 weeks, axons had regenerated into the distal grafts in all lengths: mean myelinated axon counts (±SD): 7043 (±790), 6066 (±1838), 6491 (±983) in 2cm,3cm,4cm grafts, with no differences between graft lengths (p=0.48). One week after elevation and unfurling, the number of myelinated axons was significantly decreased in all groups (p

BACKGROUND In 2018, the Northeastern Society of Plastic Surgeons first Women in Plastic Surgery was established, reflecting the national trend to address the gender gap between men and women in surgery. Conferences, such as the annual NESPS, are important opportunities to increase visibility of female role models and resources to address deterrents to surgical careers. We thus sought to examine the participation and visibility of women in the NESPS over the last decade. METHODS Abstracts and programs from the NESPS regional conferences between 2013 and 2019 were accessed via the publicly available past meetings archives, and registration lists were provided by the NESPS. Registrants, panelists, speakers, moderators, and first author and senior author listed for each poster presentation, podium presentation was listed, sex was determined (male or female), and sex were aggregated by category of participation. Significance was set at a P value of less than 0.05. RESULTS Registration of women for the NESPS annual conferences was constant for 5 years (2013-2017), followed by an increase in female registrants from 27.1% in 2017 to 42.3% in 2019. Female representation among poster and podium presentations also increased from 2017 to 2019 (7.7%-23.3% poster presentations and 11.1%-23.4% podium presentations). Invited positions (speakers, panelists, and moderators) had a peak of 32.2% in 2017, but otherwise, there is no clear evidence of improved representation of women. CONCLUSIONS We found an increase in the proportion of female registrants at the annual NESPS conferences from 2013 to 2019. However, visibility of female participants fluctuated over the same period; addressing this represents one opportunity for closing the gender gap at the NESPS. As the percentage of female trainees continues to rise, we look to female faculty to continue to participate in educational events, such as the NESPS meeting, and to be present as role models for the growing new generation of female plastic surgeons.

Trisomy 20 is a genetic abnormality in which individuals have an extra copy of chromosome 20. Complete trisomy 20 is rare and believed to be incompatible with life. A mosaic form of trisomy 20, in which only some cells or tissues contain the extra chromosome, is a relatively commonly encountered chromosomal abnormality found during prenatal testing, and c. 90% result in a normal phenotype. However, despite the absence of a consistent phenotype, certain findings have been reported across multiple cases of mosaic trisomy 20. These include an array of morphological findings, developmental delays, and learning disabilities. Beyond physical manifestations, a wide range of developmental and learning delays have also been reported. In this work, we provide an overview of the trisomy 20 literature and a case report of a young adult male with mosaic trisomy 20 who committed homicide. His developmental and life history, eventual diagnosis of mosaic trisomy 20, similarities and differences in his condition compared with prior research findings, and potentially new phenotypic findings associated with trisomy 20 that he manifested (childhood visual hallucinations, self-injury, polydactyly) are presented. Additionally, the potential role of this genetic diagnosis in his neuropsychiatric history and its successful application as a mitigating factor at his capital sentencing trial are described. We did not identify other similar cases during our search of major scientific and legal databases. As a backdrop, the use of genetics in criminal trials is on the rise, and courts are increasingly likely to accept behavioral genetics evidence; therefore, it is crucial that the legal system is well acquainted with the opportunities and limitations of these approaches.

The American Academy of Pediatrics recommends that pediatricians be trained to collaborate with school personnel and has stated that inadequate collaboration across systems is a contributor to suboptimal health care. Mail-based surveys were used to target chief residents of all pediatric residency programs in the United States (N = 214). Participants completed a 25-item survey inquiring about training, attitudes, and practices in collaborating with schools. A 68.6% response rate was obtained. The majority of respondents (73.5%) view collaboration with school personnel as important or very important and believe it improves overall patient care. However, 30.7% of respondents reported to never have collaborated with school personnel, and 47.8% reported doing so only once or twice a year. Further, 41.3% of respondents felt that school collaboration is not feasible for most pediatricians due to barriers including limited time, scheduling issues, and knowing how to contact relevant school personnel. Most respondents reported that school collaboration was rarely addressed in residency training.

Childhood adversities (CAs) and infections may affect the timing of reproductive development. We examined the associations of indicators of CAs and exposure to tonsillitis and infectious mononucleosis (mono) with age at menarche. A multiethnic cohort of 400 women (ages 40–64 years) reported exposure to parental maltreatment and maladjustment during childhood and any diagnosis of tonsillitis and/or mono, infections primarily acquired in early life and adolescence, respectively. We used linear and relative risk regression models to examine the associations of indicators of CAs individually and cumulatively, and history of tonsillitis/mono with an average age at menarche and early onset of menarche (&lt, 12 years of age). In multivariable models, histories of mental illness in the household (RR = 1.44, 95% CI: 1.01–2.06), and tonsillitis diagnosis (RR = 1.67, 95% CI: 1.20–2.33) were associated with early menarche (&lt, 12 years), and with an earlier average age at menarche by 7.1 months (95% CI: −1.15, −0.02) and 8.8 months (95% CI: −1.26, −0.20), respectively. Other adversities indicators, cumulative adversities, and mono were not statistically associated with menarcheal timing. These findings provided some support for the growing evidence that early life experiences may influence the reproductive development in girls.

Category: Ankle Arthritis Introduction/Purpose: Total ankle replacement (TAR) is common tool used by the foot and ankle specialist to treat end stage ankle arthritis. Current data about ankle motion following TAR is derived from gait analysis utilizing external markers. Utilizing Xray Reconstruction of Moving Morphology (XROMM), which combines 3-D mapping technology with biplanar fluoroscopy in vivo to visualize true skeletal motion, we can evaluate true motion of TAR implants. Current TAR replacement systems are either mobile bearing or fixed bearing. We hypothesized that subjects implanted with a fixed bearing prosthesis would exhibit less tibiotalar rotation and translation than subjects implanted with a mobile bearing prosthesis. Methods: Six subjects with total ankle replacement at least one-year post implantation gave informed consent before participating (IRB #H16496). Three subjects with a mobile bearing prosthesis with an average age 63.3+-11.1 yrs were compared to three matched subjects with a fixed bearing prosthesis with an average age of 64.7+-1.5 yrs. Utilizing 3D slicer software, lower body CT scans for each subject were evaluated to create 3D models of the foot and ankle bones and implant components. All subjects walked for several trials at a self-selected pace along a walkway while their foot and ankle motions were captured by a high-speed biplanar fluoroscopic x-ray motion analysis (XMA) system. The 3D models were combined with the x-ray images within a 3D animation platform and rotoscoped to resolve accurate kinematic motions at the tibiotalar joint during stance phase of gait. We examined for differences between the two groups using a two-sample t-test (pResults: Subjects with a mobile-bearing prosthesis demonstrated mean ROM’s of 7.4+-1.1°, 5.3+-2.3° and 7.1+-4.3° for dorsiflexion/plantarflexion, inversion/eversion, and internal/external rotation, respectively. Subjects with a fixed bearing ankle prosthesis did not exhibit significantly different mean ROM’s for dorsiflexion/plantarflexion (9.1+-4.0°, p=0.35), inversion/eversion (4.4+-2.1°, p=0.42), and internal/external rotation (9.0+-3.4°, p=0.35), respectively. Subjects with a fixed bearing prosthesis displayed significantly more translation along the anteroposterior (3.6+-1.2mm, pConclusion: Our preliminary results indicate that mobile and fixed bearing prosthesis provides similar angular motion at the tibiotalar joint, however, the fixed bearing prosthesis exhibits greater translational motion during walking. Further, there is the same amount of internal and external translation with both component designs. The implications of this work on success or failure of current implant designs is beyond the scope of this study but this work will provide the basis for future studies to help determine optimal future total ankle replacement designs.

Background Physicians are at the forefront of identifying innovative targets to address current medical needs. 3D printing technology has emerged as a state-of-the-art method of prototyping medical devices or producing patient-specific models that is more cost-efficient, with faster turnaround time, in comparison to traditional prototype manufacturing. However, initiating 3D printing projects can be daunting due to the engineering learning curve, including the number of methodologies, variables, and techniques for printing from which to choose. To help address these challenges, we sought to create a guide for physicians interested in venturing into 3D printing. Study Design All commercially available, plug-and-play, material and stereolithography printers costing less than $15,000 were identified via web search. Companies were contacted to obtain quotes and information sheets for all printer models. The qualifying printers’ manufacturer specification sheets were reviewed, and pertinent variables were extracted. Results We reviewed 309 commercially available printers and materials and identified 118 printers appropriate for clinicians desiring plug-and-play models for accelerated device production. We synthesized this information into a decision-making tool to choose the appropriate parameters based on project goals. Conclusions There is a growing clinical need for medical devices to reduce costs of care and increase access to personalized treatments; however, the learning curve may be daunting for surgeons. In this review paper, we introduce the “3Ms of 3D printing” for medical professionals and provide tools and data sheets for selection of commercially available, affordable, plug-and-play 3D printers appropriate for surgeons interested in innovation.

Background A growing number of transgender women present to plastic surgeons seeking breast augmentation. Despite some advocating their technical similarity, the authors have found substantially different planning and techniques are needed to obtain aesthetic results in transgender patients versus cosmetic breast augmentation. The authors sought to develop an approach for operative planning and technique to elucidate these differences and obtain consistent results. Methods All patients who underwent breast augmentation at the Johns Hopkins Center for Transgender Health were included in this study. Anthropometric assessments were obtained and comparative statistics between operative and nonoperative cohorts were calculated. Outcomes were analyzed and a patient-reported survey was performed to evaluate patient satisfaction. Results Fifty-nine consecutive transfemale patients presented for evaluation. Anthropometric measurements included base width (median, 15.0 ± 2.1 cm), notch-to-nipple distance (median, 22.0 cm), nipple-to-midline distance (median, 12.0 cm), areolar diameter (median, 3.5 ± 1.5 cm), and upper pole pinch (mean, 1.8 ± 1.1 cm). Thirty-six patients underwent augmentation mammaplasty. Postoperative complications (8.3 percent) included a minor hematoma and grade III capsular contracture in two patients. Patients were asked to complete a brief outcomes survey and reported an improvement in psychosocial well-being and high satisfaction rate (100 percent) with the overall cosmetic result. Conclusions Transgender female patients represent a unique patient population requiring special consideration of anatomical differences in key planning decisions. The authors delineate the first systematic algorithm that addresses these differences, emphasizing maneuvers such as routine inframammary fold lowering. This can allow experienced augmentation surgeons to obtain excellent aesthetic and patient-reported outcomes in this population. As with cosmetic breast augmentation, patient satisfaction rates are high. Clinical question/level of evidence Therapeutic, IV.

Objective This study aimed to determine whether children's headache drawings can distinguish between pseudotumor cerebri and migraine. Background Headache features associated with pseudotumor cerebri (pseudotumor; idiopathic intracranial hypertension) are nonspecific and are difficult to distinguish clinically from migraines. Children's headache drawings have a high predictive value for migraine versus nonmigraine headaches. We hypothesized that drawings could help to differentiate pediatric headaches due to pseudotumor cerebri from those associated with migraines. Methods Children aged six to 18 years old attending university hospital pediatric neurology clinics were asked to draw a picture of how their headache feels. From our database of children's headache drawings, pictures by children with clinically diagnosed pseudotumor were compared with migraine drawings. Results Headache drawings of 21 children (16 females) with pseudotumor were compared with those of 518 children with migraine. Pseudotumor drawings depicted a variety of symptoms including pounding pain (n = 11), pressure-like pain (n = 3), photophobia (3), dizziness (1), and recumbency (1). Severe pain indicators included hammers, bombs, anvil, and vise grip. Positive visual phenomena included scintillations, scotomata, or blurring (n = 8). Negative visual phenomena included field defects (n = 2). Pseudotumor drawings were similar to migraine drawings except that 6 of 21 pseudotumor drawings (28.6%) depicted diplopia (crossed eyes, double images), whereas only three of 518 migraine drawings (0.6%) depicted diplopia ( P Conclusions Diplopia was depicted in a significantly higher percentage of pseudotumor drawings than migraine drawings. In all other respects, headache drawings by children with pseudotumor cerebri were similar to those drawn by children with migraine.

Purpose: There is poor functional recovery following delayed peripheral nerve repair since both muscle and Schwann cells (SC) undergo denervation atrophy. We investigated the specific temporal effect of nerve/SC denervation on recovery as well as changes in RNA expression in the nerves that may elucidate changes in recovery potential. We hypothesized that functional recovery would be worse after prolonged nerve/SC denervation and that the expression profiles would differ. Methods: Our study was conducted using a forelimb model in adult Lewis rats. Each animal underwent unilateral forelimb denervation of 8, 12, 16, or 24 weeks duration. In the functional recovery arm of the study, the ulnar nerve was denervated proximally or a sham surgery was performed. After the denervation period had elapsed, an in situ nerve transfer of median to ulnar to median nerve was performed. Functional recovery was then measured by stimulated grip strength weekly for 12 weeks. In the RNA expression arm, median and ulnar nerves were denervated. The same time points were used with the addition of a 1-week denervation group. After the denervation period, the median and ulnar nerves were harvested bilaterally. To create a comprehensive RNA-Seq dataset, the median nerve, with an average length of 3 cm, was homogenized and RNA was purified. RNA-sequencing was carried out using TrueSeq RiboZero gold kit. Samples were analyzed through FastQC, aligned to reference genome using STAR and quantified as transcripts per million (TPM) using Salmon. Principle component analysis was performed, followed by differential gene analysis using a linear mixed effects model to control for the control nerves being from the same animals. Results: Functional recovery was statistically significantly different depending on the duration of nerve/SC denervation (P0.05, we identified 1624 genes differentially expressed, of which 327 genes were upregulated and rest (1297 genes) downregulated with denervation. Conclusions: Prolonged nerve/SC denervation of more than 12 weeks resulted in significantly worse functional recovery. RNA sequencing demonstrated that not only were there many genes differentially expressed, but these appear to vary with duration of denervation as well. Further investigation into the specific genes and their changes over time will allow us to know why recovery potential is decreased and targets for interventions to improve recovery.

Purpose: Despite clinical concerns associated with traumatic brain injuries (TBIs), they remain grossly underreported: 46% of TBIs in adult craniomaxillofacial (CMF) trauma patients remained unrecorded at discharge. This has not been studied in the pediatric CMF trauma population. Consequently, this is the first retrospective study to characterize concomitant pediatric TBI and CMF trauma patients, including incidence, presentation, documentation, and outcomes. The authors hypothesize that TBI in pediatric CMF trauma is associated with worse prognosis and remains under-recorded. Methods: An IRB-approved retrospective cohort study was performed to identify all pediatric patients presenting with CMF fractures at a high volume, tertiary trauma center between January 1st, 1990 to December 31st, 2010. Patients were included if they were (1) age younger than 15 years and (2) confirmed presence of CMF injury by means of imaging, radiology report, and physical examination. Patient charts were reviewed for demographic information, dentition stage, CMF fracture patterns, mechanism of injury, presentation, need for operative management, length of stay, and mortality at 2 years. Charts were reviewed to identify concomitant TBIs, defined as intracranial injury, cerebral hemorrhage, brain concussion, epilepsy or seizures (post-traumatic), and traumatic brain injury (documented). Data was analyzed using two-tailed Student’s t-tests and chi square analysis. Point-biserial correlation coefficients were calculated between a continuous and dichotomous variable; Pearson correlation coefficients were calculated between continuous variables. A P value ≤ 0.05 was considered statistically significant. Results: Of the 2966 pediatric CMF trauma patients identified and included for analysis (mean age of 7 +/- 4.7 years old, predominantly white, 59.8%, and male, 64.0%), 809 had concomitant TBI (frequency of 27.3%). Only 13 of the 809 TBI cases were documented in charts (1.6%). Concomitant TBI with CMF trauma patients were more likely to be male (69.1% vs 62%, P < 0.05), and be caused by blunt injury (98.9% vs. 95.5%, P < 0.05), compared to CMF trauma patients without TBI. TBI patients had a higher mortality rate at two years (8.0% vs 4.8%, P < 0.05). Mortality at two years, length of stay in hospital, and time to follow up significantly increased from mild to severe TBIs. Concomitant TBI and CMF trauma patients were also more likely to present with skull & upper third fractures than CMF trauma without TBI (81.8% vs 61.1%, P < 0.05). Conclusion: In this 20-year retrospective review, concomitant TBI injuries were present in a significant number of pediatric CMF trauma cases (27.3%) but was not documented for most cases. Given the importance of initial management and long-term care in TBI patients, it is critical for clinicians to remain vigilant for and manage TBIs in pediatric CMF trauma patients in collaboration with appropriate neurology and/or neurosurgery teams. Future prospective studies are necessary to better characterize TBI patient injury patterns and outcomes to generate practice guiding recommendations for this patient population.

It is not clear if pre-existing anti-virus immunity or multicycle treatment of oncolytic virus (OV) can affect the treatment outcome. This study is to investigate the impact of pre-existing anti Herpes Simplex Virus type-1 (HSV-1) immunity or multicycle OV treatment on the efficacy of VG161, a novel HSV-1 OV armed with IL12, IL15 with its receptor α unit (IL15RA), and a PD-L1 peptide blocker (PDL1B). VG161 has entered phase I trial in Australia and China. Seventy Balb/c mice were divided into 2 groups. One group (35 mice) was subcutaneously immunized by mVG161 (a version of VG161 expresses mouse IL12, human IL15 and PDL1B) on day 1 (5x105 PFU/mouse) followed by a boost on day 7. The other group (35 mice) was non-immunized. On day 7 post-boost, the blood was collected from tail to determine anti-HSV antibody. At the same time, all 70 mice were subcutaneously implanted with CT26 mouse colon cancer cells. Once the tumors reached 100 mm3, 20 mice (10 from each group) were treated with intra-tumoral (IT) injection of either mVG161 at a dose of 5×106 PFU/mouse or Vehicle, once a day for 5 days. Hepatic cancer (HC) PDX tissues were dissected into pieces of 27 mm3 and subcutaneously implanted into humanized mice established by transplantation of 1×104 human CD34 stem cells (HLA matched with PDX). When the tumor reached 100-150 mm3, animals were divided into 4 groups (10 mice/group): vehicle control, positive control (oxaliplatin 5 mg/kg and gemcitabine 100 mg/kg), and 2 groups treated with VG161 at high dose (7.75×106 PFU) or low dose (3.10×105 PFU). The OV treatments were given for 3 cycles with IT injection of VG161 once a day for day 1-5 of each cycle. Tumor, spleen, and peripheral blood mononuclear cells were collected for further analysis. All HSV pre-immunized mice but not naïve mice were HSV-1 antibody positive. By day 19 post-treatment, mVG161 significantly inhibited CT26 tumor growth in both HSV-1 pre-immunized and non-immunized groups, while all control mice were euthanized due to tumor size reached 2000 mm3. Starting from day 27, tumors grew back in non-immunized group but not in pre-immunized group, resulting in a significant difference of tumor size between the 2 groups on day 31 to 39 (p As compared to the negative controls, HC PDX tumors in both treatment groups were significantly smaller with percentage of T/C less than 40% on day 72. The median time for 3-fold increase of tumor size is 41.5 days (95%CI: 32-58) in the vehicle control, 74 days (95%CI: 51-undefined) in high dose group, and not reached in low dose group (p The anti-cancer efficacy of VG161 can be enhanced by pre-immunization of HSV-1 or multicycle administration when the virus is given by IT, suggesting potential clinical benefits of HSV-1 based OV therapy in HSV sero-positive patients and multicycle administration of VG161 for long term maintenance treatment. Citation Format: Jun Ding, Jason Sun, Yana Murad, Erica Lee, Ismael Samudio, William Jia, Ronghua Zhao. Pre-existing HSV-1 Immunity enhances anti-cancer efficacy of a novel immune stimulating oncolytic virus - VG161 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1913.

Among non-melanoma skin cancers, cutaneous squamous cell carcinoma entails the highest morbidity and mortality, and yet there is little guidance on how to identify the subset of cutaneous squamous cell carcinomas that behave aggressively. The staging of non-melanoma skin cancers is meant to provide this guidance, by dividing patients into groups for which survival differs between groups, is similar within each group, and consistently decreases with each increasing stage group. In the present review, we explore the history of how the staging of non-melanoma skin cancers, focusing on cutaneous squamous cell carcinomas, has evolved over time. We describe the common criticisms leveled at the American Joint Committee on Cancer (AJCC) staging rubric. We discuss alternative staging systems that have recently been proposed, and how they have stood up to validation. Finally, we preview the AJCC staging changes that will go into effect next year and lay out some future directions for the improvement of skin cancer staging. How to cite this article Le MN, Lee E, Singh B. The Evolution of Staging of Cutaneous Squamous Cell Carcinomas: A Structured Review. Int J Head Neck Surg 2017;8(2):57-63.

Background Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) has entered the spotlight, as several high-profile media outlets have begun to relay the evolving science to the public. This study aimed to gauge the baseline knowledge and concern regarding BIA-ALCL among adult laywomen within the United States. Methods Mechanical Turk was used to survey 500 American women on self-reported demographics, prior experience with breast implants, and 11 questions regarding their knowledge and concern regarding BIA-ALCL. Responses were reviewed for quality control before study inclusion. Results Overall, 12 percent of respondents had received breast implants and 73 percent knew someone with implants; 13.6 percent of respondents (including 51.7 percent of respondents with implants) had previously heard of BIA-ALCL. After providing information about its risk, 58.4 percent of respondents were still willing to receive a reconstructive implant and 45.8 percent a cosmetic implant; 35.8 percent reported they would be less likely to receive an implant. Of the respondents with breast implants, 66.7 percent reported some degree of concern regarding BIA-ALCL and 35.0 percent are strongly considering removing their implants. Those who had heard of BIA-ALCL consumed information from several sources, predominantly health professionals or media/health care blogs. Different sources of information were not associated with a respondent's degree of concern. Conclusions Only a minority of American women have heard of BIA-ALCL and understand its association with breast implants. As plastic surgeons who perform breast reconstruction, we can promote the spread of information through the popular media and health care blogs to address this growing concern, particularly among women with existing breast implants.

e14574 Background: Oncolytic virus (OV) can specifically replicate in cancer cells causing cell lysis. Together with the expression of immune stimulating payloads, OV can induce an anti-tumor immune response. The aim of this study is to assess the safety, tolerability, and PK profile of VG161, a novel HSV-1 OV armed with IL12, IL15 with its receptor α unit, and PD-L1 antagonist (Fc-fused 14 amino acid peptide), after single intra-tumoral injection (IT) in patients with advanced refractory solid tumors. Methods: This is an open label, single-arm, accelerated titration design pilot trial. Based on preclinical NOAEL, the first cohort dose level was calculated as 5×107/subject, followed with 2 cohorts (1×108 and 2×108 PFU), 1-3 patients per cohort. One patient was treated in each cohort and the subsequent cohorts were initiated only after the safety observation of the current cohort was completed (21 days) with no DLT and no > 2 moderate toxicity events deemed possibly, probably, or definitely related to VG161, otherwise, it would be expanded per the 3+3 design. DNA copy number of VG161 was measured with qPCR in the tumor biopsy and blood, in urine for virus shedding, as well as swabs of injection site and mouth. Immune cytokines were measured with MSD assay (electrochemiluminescence detection) in blood. Peripheral lymphocyte subsets were analyzed with flowcytometry. Results: Three patients (1 per cohort) were treated and completed safety observation. No DLT, and 10 AEs (fever, low neutrophils and lymphocytes, etc.) were possibly, probably, or definitely related. Grade 3 fever was the only related SAE, which recovered in 3 days. Dose dependent increase of VG161 DNA copy was detected in the tumor 2-3 days after treatment (C-max: 10, 1000, and 1000000 times increase from low to high dose), in contrast, it remained undetectable in blood, oral swab, and urine. Virus DNA was detected in injection site swab for the patient at the highest dose level but not for those treated at lower dose levels. After dosing, increases of IL-12 (C-max: 2.0, 2.4, and 21 times of baseline), IL-15 (C-max: 1.6, 3.2, and 2.5 times of baseline), IFN-γ (C-max: 49, 638, and 236 times of baseline) and TNF-α (C-max: 2.3, 3.7, and 2.2 times of baseline) from low to high dose were seen. Peripheral lymphocyte subset analysis and immune profiling of injected tumor are ongoing. Interestingly, partial regression of multiple visible non-injected lesions was observed in 1 patient shortly after dosing, however no durable direct or abscopal responses were seen to date. Conclusions: Single IT injection of VG161 up to 2×108 PFU/subject is safe and well tolerated, with no unexpected viral spread or shedding. The post-dose increase in cytokines and the transit regression of non-injected lesions imply the activation of anti-cancer immunity induced by VG161. This holds potential for further dose optimization to assess the safety and efficacy. Clinical trial information: ACTRN12620000244909.

Background Block scheduling optimizes utilization of valuable operating room (OR) resources. While most studies investigate block scheduling and surgical workloads from a systems perspective, surgeons’ perspectives have yet to be assessed. Such information could provide systems-level solutions to help mitigate prevalent issues such as surgeon burnout. This study surveyed attending surgeons on satisfaction with OR block scheduling and to assess the impact of surgeon characteristics on OR block allocation/satisfaction. Methods This was a cross-sectional investigation of attending surgeons at three academic/tertiary-care hospitals. Sensitivity analyses were completed to evaluate for nonresponse bias. Surgeons’ allocated block times versus their workloads, as well as surgeons’ satisfaction with their block times, were investigated. Associations between survey responses and surgeon characteristics were evaluated using univariable and multivariable analyses. Results Surveys were emailed to 264 surgeons, of whom 159 (60.2%) participated. Nonresponse bias was not found to impact study results. Senior faculty (odds ratio [OR]:2.4; 99.5% confidence interval [CI]:1.1-5.2; p=0.002) and fellowship-trained surgeons (OR:9.5; 99.5% CI:3.7-24.4; p Conclusions Surgical block time allocation and satisfaction at three academic centers varied by surgeons’ gender, position, and training. Furthermore, our results demonstrated that surgical block scheduling can substantially impact surgeons’ personal/career goals and burnout levels. Greater transparency and incorporation of surgeon input into block allocation may improve surgeons’ professional development and patient care.

Key Points Question Are incidence rates of US breast cancer molecular subtypes changing across age and racial/ethnic groups? Findings In this cross-sectional study including 320 124 women diagnosed with breast cancer from 2010 to 2016, incidence rates of luminal A breast cancer increased in non-Hispanic White and Asian/Pacific Islander women aged 40 to 69 years, and in non-Hispanic black women aged 55 to 69 years, for luminal B breast cancer in non-Hispanic White and Hispanic women of all ages, and for ERBB2-enriched breast cancer in non-Hispanic White women aged 25 to 39 years. Incidence rates for triple-negative breast cancer decreased in non-Hispanic Black and non-Hispanic White women aged 40 to 69 years. Meaning These findings of differing breast cancer molecular subtype–specific trends may suggest changes in the prevalence of breast cancer risk factors by race/ethnicity and age., This cross-sectional study examines the incidence of different molecular subtypes of breast cancers among different racial/ethnic and age groups., Importance Breast cancer incidence trends by age and race/ethnicity have been documented; it is less clear whether incidence trends of breast cancer molecular subtypes, which differ in risk factors and prognosis, also vary by age and race/ethnicity. Objective To estimate annual percentage changes and trends in breast cancer molecular subtype–specific incidence rates by age at diagnosis and race/ethnicity in the US. Design, Setting, and Participants This population-based cross-sectional study included data from 18 cancer registries in the Surveillance, Epidemiology and End Results database, capturing 27.8% of the US population. Hispanic and non-Hispanic White, Black, and Asian/Pacific Islander women aged 25 to 84 years who were diagnosed with invasive breast cancer from 2010 to 2016 were included. Data were analyzed from September 2019 to February 2020. Exposures Age and racial/ethnic groups. Main Outcomes and Measures Annual percentage change (APC) and 95% CIs for age-standardized breast cancer incidence rates stratified by 15-year age groups at diagnosis and race/ethnicity. Results Of 320 124 women diagnosed with breast cancer from 2010 to 2016, 232 558 (72.6%) had luminal A, 35 869 (11.2%) had luminal B, 15 472 (4.8%) had ERBB2-enriched, and 36 225 (11.3%) had triple-negative breast cancer subtypes. Luminal A breast cancer incidence rates increased in non-Hispanic White (APC from 2010-2014, 2.3%; 95% CI, 0.3% to 4.2%) and non-Hispanic Asian/Pacific Islander (APC from 2010-2016, 2.5%; 95% CI, 0.6% to 4.5%) women aged 40 to 54 years, and in non-Hispanic Black women aged 55 to 69 years women (APC from 2010-2012, 4.9%; 95% CI, 4.0% to 5.7%). Luminal B breast cancer incidence rates increased in all age groups for non-Hispanic White women (age 25-39 years: APC, 4.3%; 95% CI, 1.5% to 7.%2; age 40-54 years: APC, 3.5%; 95% CI, 1.4% to 5.6%; age 55-69 years: APC, 3.3%; 95% CI, 1.6% to 5.0%; age 70-84 years: APC, 3.9%; 95% CI, 1.9% to 6.0%) and Hispanic women (age 25-39 years: APC, 8.4%; 95% CI, 5.8% to 11.2%; age 40-54 years: APC, 6.1%; 95% CI, 4.2% to 8.0%; age 55-69 years: APC, 5.1%; 95% CI, 1.5% to 8.8%; age 70-84 years: APC, 7.1%; 95% CI, 4.6% to 9.6%) and in non-Hispanic Asian/Pacific Islander women aged 55 to 69 years (APC, 6.1%; 95% CI, 3.2% to 9.0%). ERBB2-enriched breast cancer incidence rates increased in non-Hispanic White women aged 25 to 39 years (APC, 4.7%; 95% CI, 1.5% to 8.0%). Triple-negative breast cancer incidence rates decreased in non-Hispanic White women aged 40 to 54 years (APC, –2.3%; 95% CI, –3.8% to –0.7%) and 55 to 69 years (APC, –3.6%; 95% CI, –5.1% to –2.1%) and in non-Hispanic Black women aged 55 to 69 years (APC, –1.4%; 95% CI, –2.2% to –0.7%). Conclusions and Relevance The findings of this cross-sectional study suggest that between 2010 and 2016, luminal A and luminal B breast cancer incidence rates increased for many racial/ethnic and age groups, with the largest increases observed for luminal B breast cancer. ERBB2-enriched breast cancer incidence rates increased for young non-Hispanic White women, while triple-negative breast cancer incidence rates decreased for midlife non-Hispanic White and non-Hispanic Black women. These trends may suggest changes in breast cancer risk factor profiles across age and racial/ethnic groups.

Oncolytic viruses (OVs) are the wild-type or genomic modified viruses, which can specifically replicate in cancer cells but not in normal cells. They cause cancer cell lysis and more importantly, their replication in tumor cells induces an antitumor immune response from the host. As synergistic stimulation of antitumor immune response requires multiple immune-regulatory factors, OVs armed with multiple immune-modulating factors are of high potential in cancer immunotherapy. We have constructed a novel herpes simplex virus type-1 virus (HSV-1), VG161, that is armed with IL12, IL15, and a unique PDL-1 peptide blocker. The aim of this study is to investigate the anticancer efficacy of VG161 in gastrointestinal (GI) cancers including gastric, hepatic, and colorectal cancers. The immune-stimulating activities in tumor-bearing immune competent mice were also demonstrated. VG161 was given to the tumor-bearing animals by intratumor injection (5 × 106-5 × 107 PFU/animal, once a day for 3-5 days). Antitumor activity of VG161 was tested in both immune-deficient mice as well as in immune-competent mice. Oncolytic activity of VG161 was demonstrated in human gastric (SGC-7901), hepatic (patient-derived xenograft, PDX), and colorectal (LS174T) cancer-bearing nude mice as the human tumors are susceptible to HSV infection and the immune system is compromised in those models. To determine the antitumor immune response activated by VG161, colorectal cancer (CT26) syngeneic model was used in immune competent animals and T cell subpopulation analysis, ELISPOT, and tumor rechallenge assay was applied to measure specific antitumor immunity. VG161 caused complete tumor eradication in PDX and CT26 tumor models and significantly inhibited tumor growth in SGC-7901 and LS174T models. All animals treated with VG161 survived for many months till sacrificed. In the CT26 model, no tumor could be found after rechallenging with the same tumor cells. The number of CD8+ tumor infiltrated T cells was significantly increased, and systemic specific anticancer immunity was confirmed by ELISPOT assay on T cells isolated from spleen. VG161 is a novel oncolytic virus that is both strong in oncolysis and stimulating antitumor immunity for GI cancers. Intratumorally expressing multiple immune-regulatory factors by an oncolytic virus may significantly change the GI tumor immune microenvironment and stimulate anticancer immunity, to further enhance the efficacy of the oncolytic virus. Citation Format: Ronghua Zhao, Jun Ding, Tianchi Liu, Shuyun Liu, Dmitry Chouljenko, Yanal Murad, Erica Lee, Guoyu Liu, Luke Bu, William Jia. Anticancer efficacy of a novel immune-stimulating oncolytic virus: VG161 in gastrointestinal cancers [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr B85.

The 2003 revision of the US Standard Certificate of Live Birth (birth certificate) and Pregnancy Risk Assessment Monitoring System (PRAMS) are important for maternal weight research and surveillance. We examined quality of prepregnancy body mass index (BMI), gestational weight gain, and component variables from these sources.Data are from a PRAMS data quality improvement study among a subset of New York City and Vermont respondents in 2009. We calculated mean differences comparing prepregnancy BMI data from the birth certificate and PRAMS (n = 734), and gestational weight gain data from the birth certificate (n = 678) to the medical record, considered the gold standard. We compared BMI categories (underweight, normal weight, overweight, obese) and gestational weight gain categories (below, within, above recommendations), classified by different sources, using percent agreement and the simple κ statistic.For most maternal weight variables, mean differences between the birth certificate and PRAMS compared with the medical record were less than 1 kg. Compared with the medical record, the birth certificate classified similar proportions into prepregnancy BMI categories (agreement = 89%, κ = 0.83); PRAMS slightly underestimated overweight and obesity (agreement = 84%, κ = 0.73). Compared with the medical record, the birth certificate overestimated gestational weight gain below recommendations and underestimated weight gain within recommendations (agreement = 81%, κ = 0.69). Agreement varied by maternal and pregnancy-related characteristics.Classification of prepregnancy BMI and gestational weight gain from the birth certificate or PRAMS was mostly similar to the medical record but varied by maternal and pregnancy-related characteristics. Efforts to understand how misclassification influences epidemiologic associations are needed.

Graphical abstract, Recently, some polysaccharides showed therapeutic potentials for the treatment of neurodegenerative diseases while the most important property, their permeability to the blood brain barrier (BBB) that sheathes the brain and spinal cord, is not yet determined. The determination has been delayed by the difficulty in tracking a target polysaccharide among endogenous polysaccharides in animal. We developed an easy way to examine the BBB-permeability and, possibly, tissue distribution of a target polysaccharide in animal. We tagged a polysaccharide with fluorescent 8-aminonaphthalene-1,3,6-trisulfonic acid disodium salt (ANTS) for tracking. We also developed a simple method to separate ANTS-tagged polysaccharide from unconjugated free ANTS using 75% ethanol. After ANTS-polysaccharide was intra-nasally administered into animals, we could quantify the amounts of ANTS-polysaccharide in the brain and the serum by fluorocytometry. We could also separate free ANTS-polysaccharide from serum proteins using trichloroacetic acid (TCA) and 75% ethanol. Our method will help to track a polysaccharide in animal easily. • ANTS-labeling is less tedious than but as powerful as radiolabeling for tracking a target polysaccharide in animal. • Our simple method can separate structurally intact ANTS-polysaccharide from animal serum and tissues. • This method is good for the fluorometry-based measurement of ANTS-conjugated macromolecules in tissues.

Oncolytic viruses (OVs) are among the most powerful approaches in cancer immunotherapy. OVs not only cause cancer cell lysis but more importantly, their infection in tumors induces anti-tumor immune response from the host, resulting in lasting anti-tumor immunity. It has been recognized that anti-tumor immune response requires multiple immune regulatory factors that act synergistically and tumor microenvironment is critical for tumor to grow. Herpes simplex virus type-1 (HSV-1) has been approved by FDA as an oncolytic viral drug to treat melanoma. One advantage of HSV-1 is its large genomic capacity for carrying multiple exogenous genes.A HSV-1 oncolytic viral vector (VG161) was constructed to simultaneously express IL12, IL15 with its receptor alpha unit and a PDL-1 blocking peptide. Antitumor activity of VG161 was tested in both immune competent mice (CT26 and A20 tumor models) and nude mice for human tumor models (LNCaP and U87). Since CT26 and A20 are poorly permissive for HSV-1 replication, the mouse tumor models were able to demonstrate the antitumor immune response induced by VG161 while oncolytic activity of VG161 was demonstrated in LNCaP and U87 models since the immune system is compromised in those models.VG161 completely inhibited tumors in all the models tested and the animals survived tumor-free for many months till sacrificed. VG161 induced tumor oncolysis in both LNCaP and U87 tumors. In the CT26 model, animals were protected from the second challenging with CT26 cells following previous virally induced tumor regression. Furthermore, in a A20 double tumor model, intratumoral injection into the tumor on one side caused tumor regression on both sides. Transcriptome analysis showed significant change in tumor microenvironment. Finally, tumor specific memory T-cells were evident in the treated animals. The anti-tumor immune response by VG161 was significantly stronger than similar viruses that did not express any immune stimulating gene or only express GM-CSF. These results showed that intratumorally expressed multiple immune regulatory factors by an oncolytic virus may significantly change the tumor immune microenvironment to enhance efficacy of the oncolytic virus. Citation Format: Ronghua Zhao, Jun Ding, Dmitry Choujenko, Yanal Murad, Erica Lee, Guoyu Liu, Luke Bu, William Jia. Synergistic activation of antitumor immunity by an oncolytic virus VG161 armed with multiple immune-stimulating genes [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B059.

Objective: Public, consumer and professional views about attention deficit hyperactivity disorder, its assessment and treatment – especially with medication – remain a highly contested domain. Parents in particular express disquiet with services. One response to this tension is a multidisciplinary evaluation. Parental and education perceptions of this process have not been evaluated previously. A community multidisciplinary approach was assessed in terms of diagnostic outcomes and client satisfaction. Method: A comprehensive multidisciplinary structured assessment of the first 50 referred children with severe attentional problems was documented. Demographic and symptom/behavioural profiles, developmental history and indicated multi-disciplinary evaluation were recorded. A team consensus process arrived at diagnostic classification. Post-assessment satisfaction of parents and school staff was surveyed. Results: Thirteen children (26%) were diagnosed with attention deficit hyperactivity disorder and three commenced stimulants. The majority of parents and educators were satisfied with the service. Conclusions: A multidisciplinary assessment clinic for children presenting with attention problems resulted in minimal prescribing. Overall, education staff and parents were satisfied with the service. The model may be a suitable response to the multiple concerns in the community.

Oncolytic HSV-1 (oHSV-1) are among the most promising therapies for cancer. Besides the oncolytic activity delivered by the virus against tumor cells, this treatment can also induce a potent immune response against tumor antigens (whether classic TAA, or neoantigens specific to the tumor being targeted). We have constructed an oncolytic HSV-1 virus (VG161) to deliver 2 immunomodulator cytokines, IL12 and IL15, to the tumor micro-environment. These two cytokines can work synergistically to trigger an efficient anti-tumor immune response. A PD-L1 mimic peptide capable of blocking PD-1/PD-L1 interaction is also delivered as a Fc fusion peptide (TF-Fc) to help in maintaining an effective immune response against the tumor. For the construction of the recombinant virus, the exogenous components were cloned under CMV promoter control. The ICP34.5 gene was deleted as a safety measure for the recombinant virus. The expression of Il12, IL15 and TF-Fc were confirmed, in vitro and in vivo, by qRT-PCR, ELISA and Western blot. Upon intra-tumoral injection of VG161, expressed IL12, IL15 and TF-Fc were detected only in the injected tumor mass, but not in the animals' blood or other organs. The bio-distribution of the virus was tested by qPCR after injecting VG161 intratumorally, and most of the injected virus were concentrated in the tumor mass. Minimal amounts of the virus were detected in the liver and spleen for short periods after virus injection. We have demonstrated the superior activity of the VG161 virus, compared to the back-bone virus (with no payloads) using immune-competent mouse models (CT26) and nude mice implanted with human tumor cells lines (LNCaP and U87). VG161 induced tumor oncolysis resulting in complete tumor regression in nude mice. In the CT26 model, the tumor regressed to undetectable limits upon intra-tumoral injection with VG161. When the treated mice were challenged with the same tumor, the tumor cells did not grow. The added efficacy in CT26 tumor model can be attributed to the immune response generated by the modified virus, as demonstrated by a higher number of tumor-infiltrating CD8 T cells. The specific activity of T cells against the tumor cells was also demonstrated by ELISpot assay. Finally, memory T-cells were evident in the treated animals demonstrated by multiple assays. Conclusions This work has demonstrated the safety and efficacy of VG161, a novel oncolytic virus which can induce a strong anti-tumor immunity and oncolytic activity. We have also demonstrated that the Intra-tumoral expression of multiple immune regulatory factors may significantly change the tumor immune microenvironment to enhance the efficacy of the oncolytic virus. Citation Format: Yanal M. Murad, Jun Ding, Dmitry Chouljenko , Erica Lee, Luke Bu, Guoyu Liu, Ronghua Zhao, Zahid Delwar, Will Liu, William Jia. Synergy of immunomodulators delivered by an HSV-1 oncolytic virus can enhance its therapeutic effects in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5641.

Objective: This paper examines the concept of consumer participation in the context of developmental changes in parent/child relationships and associated differences in the utilization of child and adolescent mental health services. Method: Existing definitions and characteristics of mental health service delivery for children and young people are examined to answer the question ,“Who is the consumer in the context of clinical services for young clients and their parents, and does this change with the child or young person's developmental stage?”. Results: As children, young people and parents utilize services in this area of mental health, the roles of consumer and carer need redefinition to accommodate both young clients and parents as consumers, and parents also as carers. Conclusion: The proposed framework addresses the changing roles of parents and young clients from infancy to early adulthood to guide consumer and carer participation strategies. If child and adolescent mental health services are to apply a developmental perspective and engage both young clients and parents as ‘consumers’, they need to address challenges related to the differences in expectations and capacities of young clients and parents, to the complexity associated with dual roles, and to promoting meaningful participation.

Objectives Perinatal mortality prevention strategies that target fetal deaths often utilize vital records data sets shown to contain critical quality deficiencies. To understand the causes of deficient data, we linked survey responses of fetal death reporters with facility fetal death data quality indicators. Methods In 2011, we surveyed the person most responsible for fetal death reporting at New York City healthcare facilities on their attitudes, barriers, and practices regarding reporting. We compared responses by 2 facility data quality indicators (data completeness and ill-defined cause of fetal death) for third trimester fetal death registrations using Chi squared tests. Results Thirty-nine of 50 facilities completed full questionnaires (78 % response rate); responding facilities reported 84 % (n = 11,891) of all 2011 fetal deaths, including 329 third trimester fetal deaths. Facilities citing ≥1 reporting barrier were approximately five times more likely to have incomplete third trimester registrations than facilities citing no substantial barriers (37.5 vs 7.9 %; RR 4.7; 95 % CI [1.6–14.2]). Reported barriers included onerous reporting requirements (n = 10; 26 %) and competing physician priorities (n = 11; 28 %). Facilities citing difficulty involving physicians in reporting were more likely to report fetal deaths with nonspecific cause-of-death information (70.9 vs 56.6 %; RR 1.3; 95 % CI [1.1–1.5]). Conclusions Self-reported challenges correlate with completeness and accuracy of reported fetal death data, suggesting that such barriers are likely contributing to low quality data. We identified several improvement opportunities, including in-depth training and reducing the information collected, especially for early fetal deaths (

Te Whiringa Ora is an evidence-based integrated care service based in the community that facilitates an interdisciplinary web of care around patients (and their whanau) who are identified as having complex, long term health needs and are high users of hospital services. The aim of the service is to improve self management. _“As far as my condition goes, that really hasn’t changed, the condition hasn’t changed, it will never go away. Its just that now I’ve got it more under control, its not so scary. I feel quite confident for the future”[patient]_ The team consists of registered nurses as case managers, and kaitautoko (health coaches) as navigators. Self-management is enabled through patient-centred goal plans, ongoing ‘navigator’ support and in some patients reinforced by the smart use of telemonitor technology. This service was based in the Eastern Bay of Plenty in New Zealand, a predominantly low socioeconomic area where 50% of the population are Maori, a population with a higher burden of chronic disease. An evaluation framework was designed in the development phase. Three years later we are able to report on the outcomes aligned with the Triple Aim framework. As positive as these were, we are now exploring measurement tools that might show improvements in domains such as selfmanagement and self-efficacy, and shared decision making. We discuss the service model, the outcomes, what we believe enabled self-management success, and what measurement tools we are now exploring in the next iteration of the service.

Objective: To identify services supporting the well-being of infants and their families in an area of South Brisbane, Australia, highlight problems of accessing these services and recommend strategies to make them more readily available. Method: Semistructured interviews were conducted with staff from 18 service providers offering antenatal services, or programmes primarily focused on children under the age of 2 years and/or their families. The interview aimed to identify the precise nature of the services offered, problems encountered in providing those services, perceived gaps in services and potential strategies for improvement. Results: Services were diverse, provided by a range of different professionals, in varying locations (home, community, hospital) and with funding from various sources. The major findings were:(i) the fragmentation of services, lack of communication between them, and lack of continuity in services from one stage of family formation to another; (ii) the shortage of services working with the parents and infant together; and (iii) the difficulty ofproviding services for some at-risk populations. Conclusions: Recommendations included: (i) maintaining a range of different services networked through a centralized resource/referral centre; (ii) expandingjoint mother–infant services and providing training for such services; and (iii) supporting outreach services for difficult to engage populations.

Objective: To review the origins, processes, clientele and outcomes of a child and youth interagency forum, a collaborative response to children and youth with severe and complex presentations. Methods: After a description of the Forum origins, membership and processes, both qualitative and quantitative information is provided on the Forum clientele. The Forum's effectiveness is considered in terms of changes in services provided to this group, as well as changes in agency and interagency work practices. Results: Forum clients were predominantly boys aged 12 years, with an overrepresentation of indigenous and intellectually disabled children. Few lived with biological parents, and on average had experienced five schools, 11 or more residential placements and were involved with six agencies. Disruptive behaviour symptoms were common, as were suicidal thoughts or actions (43%), history of physical (50%) or sexual abuse (21%), alcohol (29%) and drug use (14%). On average Forum clients were taking three psychotropic medications. Forum client impairment ranged from major impairment to gross impairment across several domains. Conclusions: While this is not a formal outcome study, evidence suggesting Forum usefulness included qualitative feedback from agencies, altered clinical and interagency practices, and decreased client impairment. Practical interventions for clients with chronic, complex multidomain impairments are discussed in the context of current Australian child and adolescent mental health services.

Objectives: Our aim is to critique Australian child maltreatment policy, outline abuse trends and provide data on family risk factors. Method: We identified policy gaps and reviewed family profiles within selective child maltreatment databases. Data sources included international and Australian literature, Queensland Department of Child Safety reports and a research clinical database. Results: Data reviewed suggest that a pattern of co-occurring complex multiple system family problems characterize substantiated abuse cases. Conclusions: The presence of multiple family problems suggests the need for a new treatment paradigm. Multisystemic Therapy for child physical abuse and neglect is an evidence-based intervention that matches the therapeutic needs of such families.

The TAM family receptor tyrosine kinases, consisting of Tyro3, Axl and Mer, are implicated in a diverse range of cellular processes such as cell survival, proliferation, migration, angiogenesis, and inflammatory response. Despite the debates over their role as a driver in carcinogenesis owing to some recent findings, their link to human cancer is strongly supported by direct correlation of the level of expression/activity with tumor grade and prognosis. In particular, Axl was found to underlie metastasis as an essential regulator of the epithelial-mesenchymal transition (EMT) process and also to confer acquired resistance to the TKI-mediated targeted therapies by up-regulation of associated kinases. Currently, none of FDA-approved kinase drugs were developed for the TAM family kinases. In our effort to develop such small-molecule inhibitors targeting the TAM kinases for oncology indications, we uncovered a series of novel potent compounds with low nM potency against Axl and Tyro3. Effect of these compounds in human cancer cell lines of different tissue origins was mediated mainly through the Axl-dependent signaling pathways. Detailed analysis of signaling proteins downstream of Axl revealed different mechanisms of action for these compounds. In addition to suppression of cell proliferation, these compounds inhibited anchorage-independent colony formation, cell migration and invasion. Four compounds were selected to be evaluated in pharmacokinetic studies in mice and the results indicated that these compounds possess reasonable PK properties with high exposure, reasonably long half-life, and good bioavailability. The results of the efficacy studies in suppressing tumor growth in a xenograft and an orthotropic mouse models will be discussed. Citation Format: Hong Zhang, Zaihui Zhang, Xiaoqing Shi, Erica Lee, Rick Li, Yuxiang Hu, Jun Yan, Jasbinder Sanghera. Evaluation of compounds developed against the TAM family kinases. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5393. doi:10.1158/1538-7445.AM2015-5393

This study was undertaken to determine whether overexpression of the oncogene HER-2 is associated with an increase in local recurrence in women with early stage breast cancer treated with breast-conserving therapy (BCT). A retrospective review of the medical records of all women treated with stage I-II invasive breast cancer from 1991 through 2001 was performed. Of 596 eligible patients treated in that time period, immunohistochemical testing for HER-2 expression was performed in 352 patients (59%): 266 patients (76%) were HER-2 negative and 86 patients (24%) were HER-2 positive. Median follow-up was 5.4 years. The patient characteristics for the two groups were compared for age, pathologic T and N stage, number of positive nodes, estrogen receptor (ER) and progesterone receptor (PR) status, radiation treatment, and use of hormonal therapy or chemotherapy. There were no significant differences in any of these parameters between the two groups (all p > or = 0.10). Local recurrence at 5 years was 2% in the HER-2-negative group and 0% in the HER-2-positive group (p = 0.15). There was no difference in local recurrence after BCT between HER-2-positive and negative breast cancers at 5 years. Therefore HER-2 overexpression does not appear to be a contraindication to BCT.

Commentary on: Sourander A, Multimaki P, Santalahti P, et al. Mental health service use among 18-year-old adolescent boys: a prospective 10-year follow-up study. J Am Acad Child Adolesc Psychiatry 2004; 43:1250–8. [Extract] Sourander et al replicate findings from other epidemiological studies that report mental health service utilisation by adolescent males is very low (approximately 2%). Further analysis identified a range of psychopathological symptoms (anxious–depressive and withdrawn symptoms) and other variables (health problems; not living with parents; illicit drug, alcohol, and cigarette use) that were independently associated with mental health service use in a multivariate model. These findings concur with identification of comorbidity and multidomain impairment in clinical child and adolescent mental health samples1 and highlight the need for an inclusive service response, such as the multisystemic therapy model,2 rather than fragmentation across different providers.

TAM family (Tyro3, Axl, and Mer) of receptor tyrosine kinases mediated signaling is involved in cell survival, proliferation, migration and adhesion, vascular smooth muscle homeostasis, platelet function and erythropoiesis, and regulation of inflammatory cytokine release. These RTKs are frequently co-expressed in vascular, reproductive, nervous, and immune system in adults. TAM family kinases can be activated by vitamin K-dependent ligands GAS6 and Protein S. Tyro3, Axl, and Mer also display ectopic or overexpression in numerous cancers, including myeloid and lymphoblastic leukemias, melanoma, breast, lung, colon, liver, gastric, kidney, ovarian, uterine, and brain cancers. Therefore, they represent another class of kinase targets for development of cancer therapy. In this study, we report the discovery of a new class of potent and selective inhibitors of TAM family. These new compounds have demonstrated in vitro potency in nM range against these kinases and selectivity against other kinases in a selected panel. Many of these new compounds can dramatically reduce the pAkt levels in several cancer cell lines in a dose dependent manner. In thymidine incorporation assay, some compounds showed inhibition of cell proliferation at sub-micromolar concentrations. Furthermore, some compounds have demonstrated efficacy in colony formation assays. The most promising compounds are now being selected for in vivo proof-of-concept studies. The pharmaceutical properties of these compounds together with ADME profile were also evaluated. Taken together, the data generated so far indicates that these new inhibitors of TAM family kinases represent a new approach for cancer therapy. Citation Format: Zaihui Zhang, Rick Li, Erica Lee, Yuxiang Hu, Jun Yan, Jasbinder Sanghera. Discovery of novel TAM family kinase inhibitors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2716. doi:10.1158/1538-7445.AM2014-2716

Axl is a member of the TAM tyrosine kinase family and is activated by products of Gas6 and Protein S genes. Axl is overexpressed or overactive in breast, renal, endometrial, ovarian, thyroid, non-small cell lung carcinoma, uveal melanoma as well as in myeloid leukemias. It has also been demonstrated that Axl expression is upregulated in drug-resistant cancer cells. Knock-down of Axl by RNAi repressed tumor formation in MDA-231 breast carcinoma model. Downregulation of Axl expression by RNAi led to a decrease of K562/ADR and MCF-7/ADR cells invasion, proliferation, and increased cell chemosensitivity in vitro. In a xenograft model of MDR cells, downregulation of Axl enhanced the anticancer activity of chemotherapeutic drugs. Therefore, Axl is a potential target for the development of chemotherapeutic agents for cancer therapy. During our endeavor of discovering and developing Axl kinase inhibitors for cancer therapy, we have discovered a series of potent and selective Axl inhibitors. These new compounds have demonstrated nM potency against Axl and good selectivity against other kinases in a selected panel of kinases. Many of these new compounds can reduce the pAkt levels in several cancer cell lines in a dose dependent manner and demonstrated inhibition of cell proliferation at sub-micromolar concentration in thymidine incorporation assay. Several selected compounds have demonstrated efficacy in colony formation assays. The most promising compounds are now being selected for in vivo proof-of-concept studies. The pharmaceutical properties of these compounds together with ADME profile were also evaluated and will be reported. These new Axl inhibitors represent a new approach for cancer therapy. Citation Format: Zaihui Zhang, Rick Li, Erica Lee, Yuxiang Hu, Jun Yan, Jasbinder Sanghera. Novel and selective Axl inhibitors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1746. doi:10.1158/1538-7445.AM2014-1746

Summary Broadly neutralizing antibodies (bNAbs) against HIV-1 envelope (Env) inform vaccine design and are potential therapeutic agents. We identified SF12 and related bNAbs with up to 62% neutralization breadth from an HIV-infected donor. SF12 recognized a glycan-dominated epitope on Env’s silent face and was potent against clade AE viruses, which are poorly covered by V3-glycan bNAbs. A 3.3Å cryo-EM structure of a SF12-Env trimer complex showed additional contacts to Env protein residues by SF12 compared with VRC-PG05, the only other known donor-derived silentface antibody, explaining SF12's increased neutralization breadth, potency, and resistance to Env mutation routes. Asymmetric binding of SF12 was associated with distinct N-glycan conformations across Env protomers, demonstrating intra-Env glycan heterogeneity. Administrating SF12 to HIV-1-infected humanized mice suppressed viremia and selected for viruses lacking the N448gp120 glycan. Effective bNAbs can therefore be raised against HIV-1 Env’s silent face, suggesting their potential for HIV-1 prevention, therapy, and vaccine development., Graphical Abstract, Highlights • Silentface (SF) bNAbs can reach substantial neutralization breadth and potency • Defined structure of a SF bNAb bound to an Env trimer • Binding of SF bNAb resulted in trimer asymmetry in the V3 region • SF antibodies have in vivo activity and potential for clinical use, VRC-PG05 was the only donor-derived antibody against the silentface (SF) of HIV-1 envelope described to date. Schoofs et al. identify the antibody SF12 and its relatives, which recognize the center of the SF with a different angle and more extensive protein recognition than VRC-PG05, thereby achieving substantial neutralizing ability and potential for clinical use.