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IntroductionLocal e-cigarette sales restrictions (ESRs) may impact e-cigarette use. This study examined the associations between living in localities with various ESR policies and changes in e-cigarette use among young adults in Los Angeles (LA) County, California, USA.MethodsData were from a cohort of LA County young adults (18–21 years; n=2100) who completed two waves of surveys (Fall 2018–Summer 2019 and Summer–Fall 2020). Local flavoured (n=9) and comprehensive (n=2) ESRs in LA County implemented between June 2019 and May 2020 were identified, coded and merged with the baseline data. Multivariable logistic regressions were used to examine the associations between living in ESR localities and e-cigarette use at follow-up, controlling for covariates and stratified by cigarette smoking at baseline.ResultsOverall, 20.9% and 14.3% of participants lived in localities with flavoured and comprehensive ESRs, respectively. Participants who were non-Hispanic, had higher socioeconomic statuses and were currently using e-cigarettes were generally more likely to live in ESR localities than their counterparts. The associations between living in ESR localities and e-cigarette use at follow-up were not found among baseline non-e-cigarette users regardless of their cigarette smoking status; a positive relationship was found among baseline e-cigarette users who also smoked cigarettes but not among non-smokers.DiscussionParticipants who lived in localities with various ESR policies were different in their baseline e-cigarette use and socioeconomic backgrounds. Future research examining the potential impact of ESRs on e-cigarette use change should consider the localities’ overall sociodemographic and tobacco-using characteristics and individuals’ cigarette smoking histories.

Younger age of initiating cigar smoking is associated with greater nicotine dependence and current use. Age of initiating cigarette smoking has increased over time, whereas trends in age of initiating cigar smoking remain understudied. These trends were examined by race/ethnicity, by education, and at their intersection.The analytic sample included U.S. Hispanic, Black, and White cigar-ever-smokers aged 24‒25 years (n=29,715) from the 2002‒2019 National Survey on Drug Use and Health. Participants reported their age, race/ethnicity, sex, education (≤high school; some college; ≥bachelor's degree), age of initiating cannabis use, and cigar smoking. Weighted multivariable linear regressions adjusted for sex and age of cannabis use initiation were used to examine trends in age of initiating cigar smoking by race/ethnicity, education, and education Χ year interactions within racial/ethnic groups. Age of initiating cigar smoking comparisons across race/ethnicity and education were examined using the most recent 2019 data.During 2002‒2019, across education, White cigar-ever-smokers started smoking cigars at an older age, whereas it remained unchanged among Hispanic cigar-ever-smokers. Among Black cigar-ever-smokers, age of initiating cigar smoking did not change among those with ≤high school and some college, and was older among those with ≥bachelor's degree. In 2019, age of initiating cigar smoking did not vary by educational level among Hispanic and White cigar-ever-smokers. Black cigar-ever-smokers with ≥bachelor's degree initiated cigar smoking at older ages than their White counterparts.Black individuals experienced widening education-related disparities, and Hispanic individuals had no progress in delaying age of initiating cigar smoking. Regulatory action banning cigar flavors may impact these trends.

Advances in human epidermal growth factor receptor 2 (HER2)-directed therapies have revolutionised the care of patients with HER2-positive breast cancer. While adjuvant trastuzumab in combination with chemotherapy has dramatically improved the prognosis for patients with early-stage disease, up to a quarter of patients will develop recurrent disease. The standard-of-care treatment paradigm has evolved with the introduction of newer HER2-directed therapies and increasing use of neoadjuvant systemic therapy, the latter providing us with important functional data to HER2-directed therapies and impacting subsequent adjuvant therapy decisions. However, these new strategies come at a cost of increased toxicity and economic burden, and only a subset of patients benefit from such approaches. Thus, ongoing work is required to identify predictive biomarkers of response, to de-escalate treatment in patients who may do just as well with less therapy, and new therapeutic approaches for patients who do not respond to currently used therapies. In this review, we will examine the current therapeutic landscape, summarise the latest evidence, and list the current treatment algorithms for early stage HER2-positive breast cancer.

OBJECTIVES: To investigate functional outcomes and state of consciousness at 1 year and ≥2 years postinjury in children who sustained a traumatic brain injury and were in a disorder of consciousness (DOC), either vegetative state (VS) or minimally conscious state (MCS), upon admission to inpatient rehabilitation. DESIGN: Retrospective chart review. SETTING: Pediatric inpatient rehabilitation unit. PARTICIPANTS: Children aged 2–18 years (N=37) who were admitted to inpatient rehabilitation with admission scores

Electronic consultations (eConsultations) are increasingly used to obtain specialist guidance, avoiding unnecessary face-to-face patient visits for certain clinical questions. During the COVID-19 pandemic, when in-person care was limited, eConsultations may have helped clinicians obtain specialist input to guide patient care.To understand how the use of eConsultations changed during the COVID-19 pandemic and whether trends in eConsultation utilization differed based on patient's payer and primary language.This retrospective cohort study was conducted at 6 academic medical centers in the United States, all participating in the Association of American Colleges Coordinating Optimal Referral Experiences program. Participants included adult patients who had an outpatient visit, referral, or eConsultation during the study period. Data were analyzed from June 4, 2019, to July 28, 2020.The primary outcome was the eConsultation proportion of specialty contact, defined as the number of completed eConsultations divided by the sum of the number of completed eConsultations and specialty referrals, expressed as a percentage. eConsultation percentages of specialty contact were further stratified by payer type and language. Payers included commercial, Medicare, Medicaid, self-pay or uninsured, and other. Primary language included English and non-English languages.A total of 14 545 completed eConsultations and 189 776 referrals were included. More eConsultations were completed for English-speaking patients (11 363 eConsultations [95.0%]) than non-English-speaking patients (597 eConsultations [5.0%]). Patients with commercial insurance represented the highest number of completed eConsultations (8848 eConsultations [60.8%]) followed by Medicare (3891 eConsultations [26.8%]), Medicaid (930 eConsultations [6.4%]), other insurance (745 eConsultations [5.1%]), and self-pay or no insurance (131 eConsultations [0.9%]). At the start of the pandemic, across all academic medical centers, the percentage of specialty contact conducted via eConsultation significantly increased by 6.21% (95% CI, 4.97%-7.44%; P .001). When stratified by payer and language, the percentage of specialty contact conducted via eConsultation significantly increased at the beginning of the pandemic for both English-speaking patients (change, 6.09% (95% CI, 4.82% to 7.37%; P .001) and non-English-speaking patients (change, 8.48% [95% CI, 5.79% to 11.16%]; P .001) and for all payers, except self-pay and uninsured patients (change, -0.21% [95% CI, [-1.35% to 0.92%]; P = .70).This retrospective cohort study found that eConsultations provided an accessible mechanism for clinicians to receive specialist input when in-person care was limited.

An eVisit is a form of asynchronous telehealth whereby the patient submits an online request for medical advice and receives a written response from a health care provider. While thought to be an efficient way to resolve low-acuity medical issues, there is limited information on whether eVisits lead the avoidance of in-person care. We reviewed 8627 eVisits that occurred at our institution from July 2017 to March 2020 and found that 23.1% of eVisits required follow-up medical care within 14 days (22.6% with primary care physician, 0.3% with emergency department, 0.2% both). Our results indicate that eVisits are a feasible alternative to in-person care for low-complexity medical issues.

The 2021 National Youth Tobacco Survey (NYTS) was completed by youth online during class time, either in school or at home due to the COVID-19 pandemic. Given the role of NYTS data in tobacco regulatory science, it is vital to understand the effect of survey settings (home, school) on tobacco-use estimates. We used a series of multivariable logistic regressions to examine whether survey settings (home vs. school) predicted current e-cigarette use among high school students, controlling for other known predictors of e-cigarette use as well as the pandemic learning model that was dominant in students’ counties (e.g., nearly all at-home, majority in school). We observed a significant survey setting effect. Those who completed the survey in school had higher odds of current e-cigarette use than those who completed the same survey at home (AOR = 1.74); this effect was attenuated when we controlled for the pandemic learning model (AOR = 1.38). Moreover, e-cigarette use was independently associated with students’ learning model; students whose schools were nearly entirely in-person had the highest odds of e-cigarette use compared to students whose learning model was nearly all at-home (AOR = 1.65). Survey setting is a methodological artifact in the 2021 NYTS. Perceived privacy and peer effects can potentially explain this artifact.

Black young adults have the highest prevalence of cigar smoking in the U.S. Little is known about how this population perceives addiction to cigar smoking, which may influence long-term smoking and cessation outcomes. This study used semi-structured in-depth interviews to understand cravings, triggers, and perceived addiction from cigar smoking among a purposive sample of Black young adult cigar smokers (N = 40; 21–29 years). An iterative process was used to develop the codebook, and thematic analysis was used to capture findings based on the products predominantly used: cigarillos, large cigars, or blunts. Results suggest that while participants may share similar types of cravings and triggers (e.g., stress) across the use of these products, predominant blunt smokers reported more unique triggers related to relieving physical discomforts. While most participants reported cigars could be addictive to people in general, only a few perceived that they themselves were addicted. Participants who predominantly smoked cigarillos reported high perceived addiction to cigars, while those who predominantly smoked blunts reported low addiction. Education messages are needed to inform young Black adult cigar smokers about the risks and health symptoms of cigar addiction. These efforts may help increase cigar cessation seeking and reduce cigar addiction-related health consequences and disparities among Black populations.

Black young adults experience disparately high rates of cigar use and its health consequences. Little research has explored community-level influences on cigar smoking in this population, especially concerning product-specific influences and cigar smokers’ perceptions. We conducted in-depth interviews with 40 Black young adult (ages 21–29) cigar smokers in the Washington, D.C. area and analyzed themes regarding physical and sociocultural community-level factors perceived to influence cigar use. Themes were further analyzed based on participants’ predominant cigar products (cigarillos, large cigars, blunts). Participants reported easy access to affordable cigarillos, widespread cigarillo sales and targeted marketing, norms of cigar and blunt smoking for stress relief, socialization, and cultural participation, and ubiquitous cigar and blunt smoking cues, all of which promoted cigar use in their communities. Future research should further explore how community-level influences contribute to disproportionate cigar use among Black young adults. Our findings suggest that programs and policies addressing physical and sociocultural community-level pro-smoking influences may help mitigate cigar smoking disparities.

Background:Asynchronous virtual patient care is increasingly used; however, the effectiveness of virtually delivering guideline-concordant care in conjunction with antibiotic stewardship initiatives remains uncertain. We developed a bundled stewardship intervention to improve antibiotic use in E-visits for upper respiratory tract infections (URTIs).Methods:In this before-and-after study, adult patients who completed E-visits for “cough,” “flu,” or “sinus symptoms” at Michigan Medicine between January 1, 2018, and September 30, 2020, were included. Patient demographics, diagnoses, and antibiotic details were collected. The multifaceted intervention occurred over 6 months. Segmented linear regression was performed to estimate the effect of the intervention on appropriate antibiotic use for URTI diagnoses (defined as no antibiotic prescribed) and sinusitis (defined as guideline-concordant antibiotic selection and duration). Regression lines were fit to data before the bundled intervention (January 2019) and after the bundled intervention (May 2019).Results:In total, 5,151 E-visits were included. The intervention decreased the number of visits for flu, cough, or sinus symptoms prescribed antibiotics from 43.2% to 28.9% (P < .001). Guideline concordance of antibiotic prescriptions improved following the intervention: first-line amoxicillin-clavulanate rose from 37.9% of prescriptions to 66.1% of prescriptions (P < .001), second-line doxycycline rose from 13.8% to 22.7% (P < .001); and median duration of antibiotics decreased from 10 days to 5 days (P < .001).Conclusions:A multifaceted stewardship bundle for E-visits involving both changes in the EMR and audit and feedback improved guideline-concordant antibiotic use for URTIs. This approach can aid stewardship efforts in the ambulatory care setting with regard to telemedicine.

E-cigarette marketing tactics to reach and appeal to youth are rapidly changing. This study examined to what extent youth e-cigarette marketing exposure was associated with e-cigarette use behavior change one year later, during a time when youth e-cigarette use was starting to surge in the U.S. Using nationally representative longitudinal public-use data from the Population Assessment of Tobacco and Health (PATH) Study, we examined associations between recalled e-cigarette marketing exposure (2016-2018) at Wave (W) 4 and e-cigarette use harm perception and behavior change (ever, current, and regular use) one year later (W4.5; 2017-2018) among W4 never tobacco users (n = 9405). Recall of exposure to e-cigarette marketing through different channels was also examined in multivariable models controlling for socio-demographic factors and established e-cigarette use risk factors. Results show that the most frequently recalled channels of e-cigarette marketing exposure were retail stores (50.3%), television (22.2%), and websites/social media (20.2%). Over one year, 21.2%, 7.8%, 3.4%, and 1.2% of respondents reported reduced harm perceptions, and ever, current, and regular use of e-cigarettes, respectively, at follow-up. Recalled exposure to e-cigarette marketing was associated with reduced e-cigarette harm perception (AOR = 1.20; 95% CI = 1.05-1.37) and ever (AOR = 1.26; 95% CI = 1.01-1.56) and current use (AOR = 1.40; 95% CI = 1.02-1.92) at follow-up. E-cigarette marketing exposure through websites/social media was associated with reduced harm perceptions and all stages of e-cigarette use change, including regular use. Identifying marketing techniques and channels that change youth e-cigarette harm perceptions and influence e-cigarette use progression is essential to inform e-cigarette regulatory policies and prevention campaigns.

Background Most health insurance organizations reimbursed both video and audio-only (i.e., phone) visits during the COVID-19 pandemic, but may discontinue phone visit coverage after the pandemic. The impact of discontinuing phone visit coverage on various patient subgroups is uncertain. Objective Identify patient subgroups that are more probable to access telehealth through phone versus video. Design Retrospective cohort. Patients All patients at a U.S. academic medical center who had an outpatient visit that was eligible for telehealth from April through June 2020. Main Measures The marginal and cumulative effect of patient demographic, socioeconomic, and geographic characteristics on the probability of using video versus phone visits. Key Results A total of 104,204 patients had at least one telehealth visit and 45.4% received care through phone visits only. Patient characteristics associated with lower probability of using video visits included age (average marginal effect [AME] −6.9% for every 10 years of age increase, 95%CI −7.8, −4.5), African-American (AME −10.2%, 95%CI −11.4, −7.6), need an interpreter (AME −19.3%, 95%CI −21.8, −14.4), Medicaid as primary insurance (AME −12.1%, 95%CI −13.7, −9.0), and live in a zip code with low broadband access (AME −7.2%, 95%CI −8.1, −4.8). Most patients had more than one factor which further reduced their probability of using video visits. Conclusions Patients who are older, are African-American, require an interpreter, use Medicaid, and live in areas with low broadband access are less likely to use video visits as compared to phone. Post-pandemic policies that eliminate insurance coverage for phone visits may decrease telehealth access for patients who have one or more of these characteristics. Supplementary Information The online version contains supplementary material available at 10.1007/s11606-021-07172-y.

Background. Query a single institution computed tomography (CT) database to assess the prevalence of aortic arch anomalies in general adult population and their potential association with thoracic aortopathies. Methods. CT chest scan reports of patients aged 50-85 years old performed for any indication at a single health system between 2013 and 2016 were included in the analysis. Characteristics of patients with and without aortic arch anomalies were compared by t-test and Fisher exact tests. Logistic regression analysis was performed to assess for independent risk factors of thoracic aortic aneurysm. Results. Of 21,336 CT scans, 603 (2.8%) described arch anomalies. Bovine arch (n=354, 58.7%) was the most common diagnosis. Patients with arch anomalies were more likely to be female (p

Patients with clinically progressive metastatic ERTen women (mean age 57 years) underwent imaging. 8/10 demonstrated disease on both DOTA and FDG. 2/10 positive on conventional imaging, but DOTAWhilst we have not demonstrated DOTA to be superior to FDG in staging of ER

Pediatric patients with medically refractory ulcerative colitis (UC) often undergo an initial subtotal colectomy end ileostomy (STC-I). The role of fecal diversion in the subsequent completion proctectomy/ileal-pouch anal anastomosis (CP-IPAA) remains controversial. A multi-institutional retrospective review was performed of pediatric UC patients who underwent an STC-I followed by CP-IPAA from 2008 to 2016. 37 patients were included [diverted (n = 20), undiverted (n = 17)]. Children who underwent undiverted CP-IPAA had a longer length of stay (days) compared to the diverted group (9, 6.5–13 vs. 6, 5–6, p = 0.002). The 30-day complication rate was significantly higher in the undiverted group (p = 0.003) although the difference in anastomotic leak, readmission rate, unplanned computer tomography use, and reoperation was not statistically significant. Three patients with undiverted CP-IPAA required additional surgery in the perioperative period for fecal diversion. The mean long-term follow-up was 25.68 ± 21.56 months. There were no significant differences in functional pouch outcomes. Patients who underwent an undiverted CP-IPAA after initial STC-I had significantly more complications in the immediate postoperative period compared to diverted patients, although this did not translate into long-term differences in functional outcomes. Questions remain regarding careful patient selection and counseling for undiverted pouches in the pediatric UC population.

The recent literature has shown that vulvar squamous cell carcinoma (VSCC) can be stratified into two prognostically relevant groups based on human papillomavirus (HPV) status. The prognostic value of p53 for further sub-stratification, particularly in the HPV-independent group, has not been agreed upon. This disagreement is likely due to tremendous variations in p53 immunohistochemical (IHC) interpretation. To address this problem, we sought to compare p53 IHC patterns with TP53 mutation status. We studied 61 VSCC (48 conventional VSCC, 2 VSCC with sarcomatoid features, and 11 verrucous carcinomas) and 42 in situ lesions (30 differentiated vulvar intraepithelial neoplasia [dVIN], 9 differentiated exophytic vulvar intraepithelial lesions [deVIL], and 3 high-grade squamous intraepithelial lesions or usual vulvar intraepithelial neoplasia [HSIL/uVIN]). IHC for p16 and p53, and sequencing of TP53 exons 4-9 were performed. HPV in situ hybridization (ISH) was performed in selected cases. We identified six major p53 IHC patterns, two wild-type patterns: (1) scattered, (2) mid-epithelial expression (with basal sparing), and four mutant patterns: (3) basal overexpression, (4) parabasal/diffuse overexpression, (5) absent, and (6) cytoplasmic expression. These IHC patterns were consistent with TP53 mutation status in 58/61 (95%) VSCC and 39/42 (93%) in situ lesions. Cases that exhibited strong scattered staining and those with a weak basal overexpression pattern could be easily confused. The mid-epithelial pattern was exclusively observed in p16-positive lesions; the basal and parabasal layers that had absent p53 staining, appeared to correlate with the cells that were positive for HPV-ISH. This study describes a pattern-based p53 IHC interpretation framework, which can be utilized as a surrogate marker for TP53 mutational status in both VSCC and vulvar in situ lesions.

The treatment of children with myelomeningocele (MMC) has improved over time, from supportive management to early postnatal closure to prenatal repair of the defect. The Management of Myelomeningocele Study (MOMS) showed that prenatal repair of MMC resulted in improved neurological outcomes compared to postnatal closure. Follow-up studies showed that prenatal repair was, as with any other fetal intervention, associated with higher rates of obstetrical complications. There was no significant difference in urological outcomes. Long-term follow-up of ambulatory status, executive functioning, and urological outcomes is needed to determine the durable effects of fetal MMC repair on mobility, functional independence, and the prevalence of renal insufficiency in patients with MMC who survive to adulthood. The future of fetal MMC repair consists of developing strategies to reduce maternal morbidity and improve infant outcomes. Fetoscopic MMC repair has been suggested as an alternative to open repair that may reduce obstetrical complications and the need for cesarean delivery in subsequent pregnancies. Translational research using mesenchymal stromal cells to augment fetal repair of ovine MMC has shown improvement in motor function.

We have recently encountered p53 immunohistochemical (IHC) patterns in human papillomavirus (HPV)-associated carcinomas of the gynecologic tract, which were confused with absent (null) or overexpression TP53 mutational staining. We therefore evaluated p53 and p16 IHC in 25 squamous cell carcinomas (SCC) (16 vulva, 4 Bartholin's gland, and 5 cervix), 20 endocervical adenocarcinomas (EDAC), 14 high-grade squamous intraepithelial lesions (HSIL), 2 adenocarcinoma in situ (AIS), all of which exhibited morphologic features of HPV. Only cases showing diffuse/strong block-like p16 staining were included for further study. All EDACs underwent TP53 sequencing and HPV in situ hybridization (ISH) was performed in selected cases. p53 IHC staining fell into two main patterns. The most common was designated as "markedly reduced (null-like)" (absence or significantly attenuated staining in70% of cells), which could be confused with true null mutational pattern. This was present in 14/25 (56%) SCCs, 7/14 (50%) HSILs, and 18/20 (90%) EDACs. The second notable pattern was "mid-epithelial (basal sparing)" (distinct absence of staining in basal cells juxtaposed with strong staining in parabasal cells), seen in 10/25 (40%) SCC, 7/14 (50%) HSIL, and none of the EDACs. There was scattered weak to moderate p53 staining (conventional wild type) in 1/25 (4%) SCC and 2/20 (10%) EDAC. No cases showed strong/diffuse overexpression. One EDAC had a TP53 missense mutation and exhibited "markedly reduced (null-like)" staining. HPV ISH revealed an inverse relationship with p53, cells positive for HPV mRNA were negative for p53. Knowledge of these patterns can help pathologists avoid misinterpreting p53 status in the setting of HPVA cancers.

Objectives We evaluated how well phase II trials in locally advanced and metastatic pancreatic cancer (LAMPC) meet current recommendations for trial design. Methods We conducted a systematic review of phase II first-line treatment trial for LAMPC. We assessed baseline characteristics, type of comparison, and primary end point to examine adherence to the National Cancer Institute recommendations for trial design. Results We identified 148 studies (180 treatment arms, 7505 participants). Forty-seven (32%) studies adhered to none of the 5 evaluated National Cancer Institute recommendations, 62 (42%) followed 1, 31 (21%) followed 2, and 8 (5%) followed 3 recommendations. Studies varied with respect to the proportion of patients with good performance status (range, 0%-80%) and locally advanced disease (range, 14%-100%). Eighty-two (55%) studies concluded that investigational agents should progress to phase III testing; of these, 24 (16%) had documented phase III trials. Three (8%) phase III trials demonstrated clinically meaningful improvements for investigational agents. One of 38 phase II trials that investigated biological investigational agents was enriched for a biomarker. Conclusions Phase II trials do not conform well to current recommendations for trial design in LAMPC.

Window of opportunity therapies, which involve short-term administration of systemic therapy between cancer diagnosis and surgery, have raised significant interest in recent years as a mean of assessing the sensitivity of a patient's cancer to therapy prior to surgery. There is now compelling evidence that in patients with early stage hormone-receptor positive breast cancer, a 2-week preoperative treatment with standard hormone therapies in a preoperative window period provides important prognostic information, which in turn helps to aid decision-making regarding treatment options. Changes in short-term biomarker endpoints such as cell proliferation measured by Ki-67 can act as surrogate markers of long-term outcomes. Paired tissues obtained pre- and post-investigational treatment, without having to subject the patient to additional biopsies, can then be used to conduct translational research to investigate predictive biomarkers and pharmacodynamics. In this review, we will examine the utility and challenges of window of opportunities therapies in breast cancer in the current literature, and the current Australian and international trial landscape in this clinical space.

// Daniel Brungs 1, 2, 3, 4 , Julia Chen 5 , Morteza Aghmesheh 1, 3, 4 , Kara L. Vine 1, 2, 4 , Therese M. Becker 4, 6, 7, 8 , Martin G. Carolan 1, 3, 4 , Marie Ranson 1, 2, 4 1 Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, Australia 2 School of Biological Sciences, University of Wollongong, Wollongong, Australia 3 Illawarra Cancer Centre, Wollongong Hospital, Wollongong, Australia 4 CONCERT-Translational Cancer Research Centre, New South Wales, Australia 5 St George Cancer Centre, St George Hospital, Sydney, Australia 6 Ingham Institute for Applied Medical Research, Liverpool Hospital, Australia 7 School of Medicine, University of Western Sydney, Liverpool, Australia 8 South Western Medical School, University of New South Wales, Liverpool, Australia Correspondence to: Daniel Brungs, email: Daniel.brungs@health.nsw.gov.au Keywords: stomach neoplasms, gastrointestinal neoplasms, urokinase-type plasminogen activator, urokinase plasminogen activator Received: November 30, 2016 Accepted: February 07, 2017 Published: February 18, 2017 ABSTRACT Background: The urokinase plasminogen activation (uPA) system is a crucial pathway for tumour invasion and establishment of metastasis. Although there is good evidence that uPA system expression is a clinically relevant biomarker in some solid tumours, its role in gastroesophageal cancer is uncertain. Results: We identified 22 studies encompassing 1966 patients which fulfilled the inclusion criteria. uPA, uPAR, or PAI-1 expression is significantly associated with high risk clinicopathological features. High uPA expression is associated with a shorter RFS (HR 1.90 95% 1.16–3.11, p = 0.01) and OS (HR 2.21 95% CI 1.74–2.80, p < 0.0001). High uPAR expression is associated with poorer OS (HR 2.21 95%CI 1.82–2.69, p < 0.0001). High PAI-1 expression is associated with shorter RFS (HR 1.96 96% CI 1.07–3.58, p = 0.03) and OS (HR 1.84 95%CI 1.28–2.64, p < 0.0001). There was no significant association between PAI-2 expression and OS (HR 0.97 95%CI 0.48–1.94, p < 0.92) although data was limited. Materials and Methods: We undertook a systematic review evaluating expression of uPA, urokinase plasminogen activator receptor (uPAR), plasminogen activator inhibitor-1 (PAI-1/SerpinE1) and plasminogen activator inhibitor-2 (PAI-2/SerpinB2) on primary oesophageal, gastro-oesophageal junction, and gastric adenocarcinomas. We performed a meta-analysis of clinicopathological associations, overall survival (OS) and recurrence free survival (RFS). Conclusions: We conclude that the uPA system is a clinically relevant biomarker in primary gastroesophageal cancer, with higher expression of uPA, uPAR and PAI-1 associated with higher risk disease and poorer prognosis. This also highlights the potential utility of the uPA system as a therapeutic target for improved treatment strategies.

Background Multimodal pain management strategies are used for analgesia following pectus excavatum repair. However, the optimal regimen has not been identified. We describe our early experience with intercostal cryoablation for pain management in children undergoing the Nuss procedure and compare early cryoablation outcomes to our prior outcomes using thoracic epidural analgesia. Methods A multi-institutional, retrospective review of fifty-two patients undergoing Nuss bar placement with either intercostal cryoablation ( n =26) or thoracic epidural analgesia ( n =26) from March 2013 to January 2016 was conducted. The primary outcome was hospital length of stay. Secondary outcomes included telemetry unit monitoring time, total intravenous narcotic use, duration of intravenous narcotic use, and postoperative complications. Results Patients who underwent intercostal cryoablation had a significant reduction in the mean hospital length of stay, time in a monitored telemetry bed, total use of intravenous narcotics, and the duration of intravenous narcotic administration when compared to thoracic epidural patients. Cryoablation patients had a slightly higher rate of postoperative complications. Conclusion Intercostal cryoablation is a promising technique for postoperative pain management in children undergoing repair of pectus excavatum. This therapy results in reduced time to hospital discharge, decreased intravenous narcotic utilization, and has eliminated epidurals from our practice. Level of evidence Retrospective study – level III.

Summary This letter addresses the controversial issue of the use of oral corticosteroids during wheezing exacerbations in preschool-aged children by demonstrating findings of a prematurely terminated multi-center clinical trial, discussing lessons learned, and suggesting future directions.

Aim: To compare outcomes of continuous subcutaneous infusion of local anesthetic and epidural analgesia following the Nuss procedure. Patients & methods: A retrospective chart review compared patients managed with subcutaneous local anesthetic infusion (n = 12) versus thoracic epidural (n = 19) following the Nuss procedure from March 2013 to June 2015. Results: There was no difference in hospital length of stay or days on intravenous narcotics. Epidural catheter placement prolonged operating room time (146.58 ± 28.30 vs 121.42 ± 21.98 min, p = 0.01). Average pain scores were slightly higher in the subcutaneous infusion group (3.72 ± 1.62 vs 2.35 ± 0.95, p = 0.02), but of negligible clinical significance. Conclusion: Continuous subcutaneous infusion of local anesthetic could eliminate the need for thoracic epidural for pain management after the Nuss procedure.

Purpose The purpose of this study was to demonstrate a method of isolating myogenic progenitor cells from human placenta chorionic villi and to confirm the myogenic characteristics of the isolated cells. Methods Cells were isolated from chorionic villi of a second trimester male placenta via a combined enzymatic digestion and explant culture. A morphologically distinct subpopulation of elongated and multinucleated cells was identified. This subpopulation was manually passaged from the explant culture, expanded, and analyzed by fluorescence in situ hybridization (FISH) assay, immunocytochemistry, and flow cytometry. Myogenic characteristics including alignment and fusion were tested by growing these cells on aligned polylactic acid microfibrous scaffold in a fusion media composed of 2% horse serum in Dulbecco's modified Eagle medium/high glucose. Results The expanded subpopulation was uniformly positive for integrin α-7. Presence of Y-chromosome by FISH analysis confirmed chorionic villus origin rather than maternal cell contamination. Isolated cells grew, aligned, and fused on the microfibrous scaffold, and they expressed myogenin, desmin, and MHC confirming their myogenic identity. Conclusion Myogenic progenitor cells can be isolated from human chorionic villi. This opens the possibility for translational and clinical applications using autologous myogenic cells for possible engraftment in treatment of chest and abdominal wall defects.

Background/Objectives: The Management of Myelomeningocele (MMC) Study (MOMS) showed that prenatal repair of MMC resulted in improved neurological outcomes but was associated with high rates of obstetrical complications. This study compares outcomes of open and fetoscopic MMC repair. Data Sources: PubMed and Embase studies reporting outcomes of fetal MMC repair published since the completion of the MOMS. Results: We analyzed 11 studies and found no difference in mortality or the rate of shunt placement for hydrocephalus. Percutaneous fetoscopic repair was associated with higher rates of premature rupture of membranes (91 vs. 36%, p < 0.01) and preterm birth (96 vs. 81%, p = 0.04) compared to open repair, whereas fetoscopic repair via maternal laparotomy reduced preterm birth. The rate of dehiscence and leakage from the MMC repair site was higher after both types of fetoscopic surgery (30 vs. 7%, p < 0.01), while the rate of uterine dehiscence was higher after open repair (11 vs. 0%, p < 0.01). Discussion: Fetoscopic repair is a promising alternative to open fetal MMC repair with a lower risk of uterine dehiscence; however, fetoscopic techniques should be optimized to overcome the high rate of dehiscence and leakage at the MMC repair site. A fetoscopic approach via maternal laparotomy reduces the risk of preterm birth.

Leptomeningeal carcinomatosis (LMC) is a terminal event in advanced cancer, its incidence in epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) is increasing due to recent advances in systemic therapy and prolongation of survival. Osimertinib is a third generation EGFR-tyrosine kinase inhibitor (TKI) with preclinical and early clinical studies showing activity against LMC resistant to previous TKI treatments and acquired T790M mutation. We report a case of osimertinib in the treatment of LMC in a T790M-negative, EGFR-mutated NSCLC with significant clinical benefit and no toxicity. Osimertinib is a potentially effective treatment for LMC associated with EGFR-mutated NSCLC regardless of T790M status and a well-tolerated treatment for poor performance status patients.

Purpose Determine the effect of 2-octylcyanoacrylate on placenta derived mesenchymal stromal cells (PMSCs) seeded onto extracellular matrix (ECM) in order to assess its biocompatibility as a potential adhesive for in-vivo fetal cell delivery. Methods PMSCs isolated from chorionic villus tissue were seeded onto ECM. A MTS proliferation assay assessed cellular metabolic activity at various time points in PMSC-ECM with direct, indirect, and no glue contact. Conditioned media collected prior to and 24 hours after glue exposure was analyzed for secretion of human brain-derived neurotrophic factor, hepatocyte growth factor, and vascular endothelial growth factor. Results Direct and indirect contact with 2-octylcyanoacrylate results in progressively decreased cellular metabolic activity over 24 hours compared to no glue controls. Cells with direct contact are less metabolically active than cells with indirect contact. 24 hours of glue exposure resulted in suppression of growth factor secretion that is near complete with direct contact. Discussion Exposure to 2-octylcyanoacrylate results in decreased metabolic activity and decreased measurable secretion of growth factors by PMSCs seeded onto ECM. Thus, the application of 2-octylcyanoacrylate glue should be limited when working with cell-engineered scaffolds as its inhibitory effects on cell growth and secretory function can limit the therapeutic potential of cell-based interventions.

Background In this study we describe the development of a Current Good Manufacturing Practice (CGMP)-compliant process to isolate, expand and bank placenta-derived mesenchymal stromal cells (PMSCs) for use as stem cell therapy. We characterize the viability, proliferation and neuroprotective secretory profile of PMSCs seeded on clinical-grade porcine small intestine submucosa extracellular matrix (SIS-ECM; Cook Biotech). Methods PMSCs were isolated from early gestation placenta chorionic villus tissue via explant culture. Cells were expanded, banked and screened. Purity and expression of markers of pluripotency were determined using flow cytometry. Optimal loading density and viability of PMSCs on SIS-ECM were determined using 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) cell proliferation and fluorescent live/dead assays, respectively. Growth factors secretion was analyzed using enzyme-linked immunosorbent assays (ELISA). Results PMSCs were rapidly expanded and banked. Viable Master and Working Cell Banks were stable with minimal decrease in viability at 6 months. All PMSCs were sterile, free from Mycoplasma species, karyotypically normal and had low endotoxin levels. PMSCs were homogeneous by immunophenotyping and expressed little to no pluripotency markers. Optimal loading density on SIS-ECM was 3–5 × 10 5 cells/cm 2 , and seeded cells were >95% viable. Neurotrophic factor secretion was detectable from PMSCs seeded on plastic and SIS-ECM with variability between donor lots. Discussion PMSCs from early gestation placental tissues can be rapidly expanded and banked in stable, viable cell banks that are free from contaminating agents, genetically normal and pure. PMSC delivery can be accomplished by using SIS-ECM, which maintains cell viability and protein secretion. Future work in vivo is necessary to optimize cell seeding and transplantation to maximize therapeutic capabilities.

The aim of the study is to investigate the outcomes of the da Vinci robot-assisted laparoscopic hernia repair of small-sized ventral hernias with circumferential suturing of the mesh compared to the traditional laparoscopic repair with trans-fascial suturing. A retrospective review was conducted of all robot-assisted umbilical, epigastric and incisional hernia repairs performed at our institution between 2013 and 2015 compared to laparoscopic umbilical or epigastric hernia repairs. Patient characteristics, operative details and postoperative complications were collected and analyzed using univariate analysis. Three primary minimally invasive fellowship trained surgeons performed all of the procedures included in the analysis. 72 patients were identified during the study period. 39 patients underwent robot- assisted repair (21 umbilical, 14 epigastric, 4 incisional), and 33 patients laparoscopic repair (27 umbilical, 6 epigastric). Seven had recurrent hernias (robot: 4, laparoscopic: 3). There were no significant differences in preoperative characteristics between the two groups. Average operative time was 156 min for robot-assisted repair and 65 min for laparoscopic repair (p

This study provides new evidence of deficient auditory cortical processing of speech in noise in autism spectrum disorders (ASD). Speech-evoked responses (approximately 100-300 ms) in quiet and background noise were evaluated in typically-developing (TD) children and children with ASD. ASD responses showed delayed timing (both conditions) and reduced amplitudes (quiet) compared to TD responses. As expected, TD responses in noise were delayed and reduced compared to quiet responses. However, minimal quiet-to-noise response differences were found in children with ASD, presumably because quiet responses were already severely degraded. Moreover, ASD quiet responses resembled TD noise responses, implying that children with ASD process speech in quiet only as well as TD children do in background noise.

Aim This study determined the influence of prematurity on the manifestation and treatment of neonatal abstinence syndrome (NAS). Methods This was a medical record review of Australian infants exposed to opiates in 2004 and 2007. Finnegan scores were obtained for 215 of 361 (59%) preterm infants under 37-week gestation and 694 of 1178 (59%) term infants. Results The mean and standard deviation (SD) gestational ages were 34 (3) and 38 (3) weeks for preterm and term infants, respectively. Maternal daily methadone doses were similar for the preterm and term infants with a mean (SD) of 79 mg (39) versus 72 mg (38) (p = 0.06). Maximum Finnegan scores were significantly lower in preterm infants (10 versus 11, p = 0.01), scores were positively correlated with gestation and fewer preterm infants were medicated for NAS (40% versus 48% p = 0.05). Maximum median daily and interquartile range morphine doses were lower for preterm than term infants (0.5 mg/kg/day (0.3–0.6) versus 0.5 mg/kg/day (0.4–0.7), p = 0.02). Conclusion Preterm infants were just as likely to be monitored for withdrawal as term infants, but their Finnegan scores were lower and fewer preterm infants were treated for NAS. Whether this indicates decreased NAS severity or physiological immaturity is uncertain. Other means of evaluating NAS in preterm infants are warranted, especially long-term outcomes.

To determine the short-term outcomes of Australian buprenorphine-exposed mother/infant dyads.Retrospective record review of drug-exposed mothers and infants in Australia. Groups were based on drug exposure: buprenorphine (55, 3.8%), non-buprenorphine opiates (O, 686, 48.6%) and non-opiates (NO, 671, 47.5%).More than 30% of buprenorphine mothers continued to use heroin (21, 38%) and benzodiazepines (16, 29%). They were more likely to have child at risk concerns (29, 52.7%, P = 0.019) and have previous children placed in out-of-home care (9, 16.3%, P = 049). Buprenorphine babies were less likely to be preterm (16% vs. 25% (O), P = 0.001 and 23% (NO), P = 0.004) and had higher birthweights (median: 3165 g vs. 2842.5 g (O), P0.001 and 2900 g (NO), P = 0.004). Buprenorphine and non-buprenorphine opioid babies had similar maximum Finnegan scores (median 10 vs. 11(O), P = 0.144). The number of babies needing abstinence treatment (45% vs. 51% (O), P = 0.411) and length of hospital stay (median days 9 vs. 11(O), P = 0.067) were similar, but buprenorphine infants required lower maximum morphine doses (mg/kg/day) (median 0.4 mg vs. 0.5 mg (O), P = 0.009).Short-term medical outcomes of infants of buprenorphine-using mothers are similar to those of non-buprenorphine opiate-using mothers, but interpretation of these results is confounded by the high rates of polydrug exposure in the buprenorphine group. This and other social concerns noted in buprenorphine mothers and infants warrant further study.

Although computed tomography (CT) scans play an important role in the diagnosis and management of anastomotic leaks (AL), there is no consensus on what radiographic findings are associated with AL. The purpose of this study is to identify the most common CT scan findings associated with AL and whether the amount of extraluminal air or the density of extraluminal fluid can be correlated with the presence of an AL. A retrospective chart review of 210 patients with anastomotic leaks from 2003 to 2010 at Mount Sinai Medical Center was performed. Eighty-six patients fit our criteria and were included. All CT scans were reread by an independent radiologist not involved with patient care. Our study included 59 per cent men and 41 per cent women with a mean age of 51 years. Diagnoses included inflammatory bowel disease (53%), malignancy (21%), and diverticulitis (12%). One hundred per cent of the patients had one of three findings: extraluminal air (92%), extraluminal fluid (88%), or extravasation of contrast (32%). Eighty-one per cent (70/86) had both fluid and air simultaneously. Extraluminal air was seen in 79 patients. The estimated amounts of extraluminal air were as follows: 0 to 25 mL (49%), 26 to 500 mL (41%), 500 to 1000 mL (5%), and more than 1000 mL (5%). The Hounsfield unit (HU) measurements of the fluid ranged from 3 to 633 HUs. The most common CT findings associated with AL are pneumoperitoneum and extraluminal fluid, including extravasation of contrast, which can be seen in up to 100 per cent of patients. The amount of estimated extraluminal air and density of fluid collection have no prognostic value in predicting AL.

A better understanding of bone growth will benefit efforts to reduce fracture incidence, because variation in elderly bone traits is determined primarily by adulthood. The natural variation in robustness was used as a model to understand how variable growth patterns define adult bone morphology. Longitudinally acquired hand radiographs of 29 boys and 30 girls were obtained from the Bolton–Brush study for 6 time points spanning 8 to 18 years of age. Segregating individuals into tertiles based on robustness revealed that the biological activity underlying bone growth varied significantly with the natural variation in robustness. For boys, slender metacarpals used an osteoblast-dependent growth pattern to establish function, whereas robust metacarpals used an osteoclast-dependent growth pattern. In contrast, differences in biological activity between girls with slender and robust metacarpals were largely based on the age at which the marrow surface changed from expansion to infilling. Importantly, cortical area for slender metacarpals was as much as 19.7% and 32.2% lower than robust metacarpals for boys and girls, respectively, indicating that robustness was a major determinant of adult cortical area. Finally, after accounting for robustness and body weight effects, we found that the inter-individual variation in cortical area was established as early as 8 years of age. While variation in the amount of bone acquired during growth has primarily been attributed to factors like nutrition, exercise, and genetic background, we showed that the natural variation in robustness was also a major determinant of cortical area, which is an important determinant of bone mass. This predictable relationship between robustness and cortical area should be incorporated into clinical diagnostic measures and experimental studies.

Rosacea is a common, chronic skin disease that is currently incurable. Although environmental factors influence rosacea, the genetic basis of rosacea is not established. In this genome-wide association study, a discovery group of 22,952 individuals (2,618 rosacea cases and 20,334 controls) was analyzed, leading to identification of two significant single-nucleotide polymorphisms (SNPs) associated with rosacea, one of which replicated in a new group of 29,481 individuals (3,205 rosacea cases and 26,262 controls). The confirmed SNP, rs763035 (P=8.0 × 10(-11) discovery group; P=0.00031 replication group), is intergenic between HLA-DRA and BTNL2. Exploratory immunohistochemical analysis of HLA-DRA and BTNL2 expression in papulopustular rosacea lesions from six individuals, including one with the rs763035 variant, revealed staining in the perifollicular inflammatory infiltrate of rosacea for both proteins. In addition, three HLA alleles, all MHC class II proteins, were significantly associated with rosacea in the discovery group and confirmed in the replication group: HLA-DRB1*03:01 (P=1.0 × 10(-8) discovery group; P=4.4 × 10(-6) replication group), HLA-DQB1*02:01 (P=1.3 × 10(-8) discovery group; P=7.2 × 10(-6) replication group), and HLA-DQA1*05:01 (P=1.4 × 10(-8) discovery group; P=7.6 × 10(-6) replication group). Collectively, the gene variants identified in this study support the concept of a genetic component for rosacea, and provide candidate targets for future studies to better understand and treat rosacea.