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Background Cytomegalovirus (CMV) can manifest as corneal endotheliitis in immunocompetent individuals. Early diagnosis is prudent to prevent endothelial cell loss, which could ultimately lead to corneal decompensation. CMV DNA was first detected in an eye with corneal endotheliitis in 2006; since then, clinical evidence from numerous case reports and case series have accumulated. Main text In this narrative review, we identified several drugs, including ganciclovir, valganciclovir, and their combination in oral, intravenous, intravitreal, and topical forms in different concentrations, together with the judicious use of topical steroids, have reported variable success. There has yet to be any prospective comparative study evaluating the efficacy and safety of these assorted forms of treatment; clinical evidence is based on case reports and case series. CMV endotheliitis presenting with corneal edema can masquerade as other corneal diseases and thus poses a great challenge especially in post-keratoplasty eyes. Heightened awareness is needed before and after keratoplasty to start prompt prophylaxis and treatment. Conclusion There is no consensus on the management of CMV endotheliitis. Further studies are much needed to elucidate the optimal treatment modality, regime, and duration in the treatment and prophylaxis of CMV endotheliitis.

Dry eyes is one of the most common complications after laser vision correction. Small incision lenticule extraction (SMILE) is a flapless procedure with a smaller corneal incision, less corneal nerves are transected during, making it theoretically less prone to dry eyes. Both SMILE and femtosecond-laser-assisted in situ keratomileusis (FS-LASIK) induce a transient worsening in dry eye parameters, but there is evidence showing that SMILE holds promises to have fewer negative impacts on the ocular surface parameters and allow an earlier recovery. SMILE-treated eyes may also have shown less corneal denervation and better corneal sensitivity compared with FS-LASIK eyes. This review summarizes the mechanisms of dry eyes after laser vision correction, the short-term (≤6 months) and long-term (>6 months) results in changes to dry eyes signs and symptoms, and corneal sensitivity of SMILE, as compared with FS-LASIK. Limitation of the studies and reasons accounting for their discrepancies will be discussed. Future randomized controlled trials with standardized postoperative regime are needed for better evaluation of dry eyes after SMILE.

BACKGROUND: Treatments for Barrett's oesophagus, the precursor lesion of adenocarcinoma, are available but whether these therapies effectively prevent the development of adenocarcinoma, and in some cases eradicate the Barrett's oesophagus segment, remains unclear. OBJECTIVES: To summarise, quantify and compare the efficacy of pharmacological, surgical and endoscopic treatments for the eradication of dysplastic and non‐dysplastic Barrett's oesophagus and prevention of these states from progression to adenocarcinoma. SEARCH METHODS: We searched CENTRAL (The Cochrane Library 2004, issue 4), MEDLINE (1966 to June 2008) and EMBASE (1980 to June 2008). SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing medical, endoscopic or non‐resectional surgical treatments for Barrett's oesophagus. The primary outcome measures were complete eradication of Barrett's and dysplasia at 12 months, and reduction in the number of patients progressing to cancer at five years or latest time point. DATA COLLECTION AND ANALYSIS: Three authors independently extracted data and assessed the quality of the trials included in the analysis. MAIN RESULTS: Sixteen studies, including 1074 patients, were included. The mean number of participants in the studies was small (n = 49; range 8 to 208). Most studies did not report on the primary outcomes. Medical and surgical interventions to reduce symptoms and sequelae of gastro‐oesophageal reflux disease (GORD) did not induce significant eradication of Barrett's oesophagus or dysplasia. Endoscopic therapies (photodynamic therapy (PDT with aminolevulinic acid or porfimer sodium), argon plasma coagulation (APC) and radiofrequency ablation (RFA)) all induced regression of Barrett's oesophagus and dysplasia. The data for photodynamic therapy were heterogeneous with a mean eradication rate of 51% for Barrett's oesophagus and between 56% and 100% for dysplasia, depending on the treatment regimens. The variation in photodynamic therapy eradication rates for dysplasia was dependent on the drug, source and dose of light. Radiofrequency ablation resulted in eradication rates of 77% and 86% for Barrett's oesophagus and dysplasia, while those rates were 2% and 21% in the sham treatment group respectively. Endoscopic treatments were generally well tolerated, however all were associated with some buried glands, particularly following argon plasma coagulation and photodynamic therapy, as well as photosensitivity and strictures induced by porfimer sodium based photodynamic therapy in particular. AUTHORS' CONCLUSIONS: Despite their failure to eradicate Barrett's oesophagus, the role of medical and surgical interventions to reduce the troubling symptoms and sequelae of GORD is not questioned. Whether therapies for GORD reduce the cancer risk is not yet known. Ablative therapies have an increasing role in the management of dysplasia within Barrett's and current data would favour the use of radiofrequency ablation compared with photodynamic therapy. Radiofrequency ablation has been shown to yield significantly fewer complications than photodynamic therapy and is very efficacious at eradicating both dysplasia and Barrett's itself. However, long‐term follow‐up data are still needed before radiofrequency ablation can be used in routine clinical care without the need for very careful post‐treatment surveillance. More clinical trial data and in particular randomised controlled trials are required to assess whether or not the cancer risk is reduced in routine clinical practice.

Context The coronavirus disease 2019 (COVID-19) pandemic created a rapid and unprecedented shift in our medical system. Medical providers, teams, and organizations have needed to shift their visits away from face-to-face visits and toward telehealth (both by phone and through video). Palliative care teams who practice in the community setting are faced with a difficult task: How do we actively triage the most urgent visits while keeping our vulnerable patients safe from the pandemic? Measures The following are recommendations created by the Palo Alto Medical Foundation Palliative Care and Support Services team to help triage and coordinate for timely, safe, and effective palliative care in the community and outpatient setting during the ongoing COVID-19 pandemic. Patients are initially triaged based on location followed by acuity. Interdisciplinary care is implemented using strict infection control guidelines in the setting of limited personal protective equipment resources. We implement thorough screening for COVID-19 symptoms at multiple levels before a patient is seen by a designated provider. Conclusions/Lessons Learned We recommend active triaging, communication, and frequent screening for COVID-19 symptoms for palliative care patients been evaluated in the community setting. An understanding of infection risk, mutual consent between designated providers, patients, and their families are crucial to maintaining safety while delivering community-based palliative care during the COVID-19 pandemic.

Children who are deaf or hard of hearing (DHH) are likely to exhibit difficulties in development of psychosocial skills, pragmatic language skills, and use of hearing for social communication in real-world environments. Some evidence suggests that pragmatic language use affects peer-relationships and school engagement in these children. However, no studies have investigated the influence of functional auditory performance and use of language and speech in real-world environments on children’s behavior and emotion, and on their health-related quality of life. This study explored the relationship in DHH children at 9 years of age. Data from 144 participants of the Longitudinal Outcomes of Children with Hearing Impairment study were analyzed. Parent reports were obtained on quality of life, behavior and emotion, pragmatic language skills, and auditory functional performance of children in real life. Children’s spoken language abilities and speech intelligibility were assessed by research speech pathologists. On average, performance of children in all domains was within the range of typically developing peers. There were significant associations among functional auditory performance, use of speech and language skills, psychosocial skills, and quality of life. Multiple linear regression analyses revealed that better auditory functional performance and pragmatic language skills, rather than structural language abilities, were associated with better psychosocial abilities and quality of life. The novel findings highlight the importance of targeted intervention for improving functional hearing skills and social communication abilities in DHH children, and emphasize the importance of collaborative approaches among medical, audiology, allied health, and educational professionals to identify those at risk so that timely referral and intervention can be implemented for improving psychosocial health and well-being in DHH children.

BACKGROUND: Barrett's esophagus (BE) occurs as consequence of reflux and is a risk factor for esophageal adenocarcinoma. The current "gold-standard" for diagnosing BE is endoscopy which remains prohibitively expensive and impractical as a population screening tool. We aimed to develop a pre-screening tool to aid decision making for diagnostic referrals. METHODOLOGY/PRINCIPAL FINDINGS: A prospective (training) cohort of 1603 patients attending for endoscopy was used for identification of risk factors to develop a risk prediction model. Factors associated with BE in the univariate analysis were selected to develop prediction models that were validated in an independent, external cohort of 477 non-BE patients referred for endoscopy with symptoms of reflux or dyspepsia. Two prediction models were developed separately for columnar lined epithelium (CLE) of any length and using a stricter definition of intestinal metaplasia (IM) with segments ≥ 2 cm with areas under the ROC curves (AUC) of 0.72 (95%CI: 0.67-0.77) and 0.81 (95%CI: 0.76-0.86), respectively. The two prediction models included demographics (age, sex), symptoms (heartburn, acid reflux, chest pain, abdominal pain) and medication for "stomach" symptoms. These two models were validated in the independent cohort with AUCs of 0.61 (95%CI: 0.54-0.68) and 0.64 (95%CI: 0.52-0.77) for CLE and IM ≥ 2 cm, respectively. CONCLUSIONS: We have identified and validated two prediction models for CLE and IM ≥ 2 cm. Both models have fair prediction accuracies and can select out around 20% of individuals unlikely to benefit from investigation for Barrett's esophagus. Such prediction models have the potential to generate useful cost-savings for BE screening among the symptomatic population.

Background Contemporary perioperative fasting guidelines aim to alleviate patient discomfort before surgery and enhance postoperative recovery whilst seeking to reduce the risk of pulmonary aspiration during anesthesia. The impact of a short message service (SMS) reminder on fasting guideline compliance is unknown. Therefore, we performed a retrospective observational study and quality improvement project aiming to quantify the extent of excessive and prolonged fasting, and then assessed the impact of a SMS reminder in reducing fasting times. Methods After ethics committee approval we performed a retrospective observational study investigating preoperative fasting times of adult patients undergoing elective surgery. First, we assessed whether the fasting guideline times were adhered to (Standard Care group). All patients received internationally recommended fasting guidelines in the form of a written hospital policy document. We then implemented an additional prompt via a mobile phone SMS 1 day prior to surgery containing a reminder of fasting guideline times (SMS group). The primary aims were to compare fasting times between the Standard Care group and the SMS group. Results The fasting times of 160 patients in the Standard Care group and 110 patients in the SMS group were evaluated. Adherence to the fasting guidelines for solids occurred in 14 patients (8.8%) in the Standard Care group vs. Twenty-two patients (13.6%) in the SMS group (p=0.01). Adherence to the fasting guidelines for fluids occurred in 4 patients (2.5%) in the Standard Care group vs. Ten patients (6.3%) in the SMS group (p=0.023). Patients in the Standard Care group had a longer median (inter-quartile range (IQR)) fasting time for fluids compared the SMS group [6.5 h (IQR 4.5:11) vs 3.5 h (IQR 3:8.5), pp=0.756). Conclusion Adherence to internationally recommended fasting guidelines for patients undergoing elective surgery is poor. The introduction of a fasting guideline reminder via a mobile phone SMS in addition to a written hospital policy improved adherence to fasting advice and reduced the fasting times for fluids but not for solids. The use of an SMS reminder of fasting guidelines is a simple, feasible, low-cost, and effective tool in minimising excessive fasting for fluids among elective surgical patients. Trial registration ACTRN12619001232123 (Australia New Zealand Clinical Trials Registry). Registered 6th September 2019 (retrospectively registered).

Statements about building walls, deportation and denying services to undocumented immigrants made during President Trump's presidential campaign and presidency may induce fear in Latino populations and create barriers to their health care access. To assess how these statements relate to undocumented Latino immigrants' (UDLI) and Latino legal residents/citizens' (LLRC) perceptions of safety and their presentations for emergency care, we conducted surveys of adult patients at three county emergency departments (EDs) in California from June 2017 to December 2018. Of 1,684 patients approached, 1,337 (79.4%) agreed to participate: 34.3% UDLI, 36.9% LLRC, and 29.8% non-Latino legal residents/citizens (NLRC). The vast majority of UDLI (95%), LLRC (94%) and NLRC (85%) had heard statements about immigrants. Most UDLI (89%), LLRC (88%) and NLRC (87%) either thought that these measures were being enacted now or will be enacted in the future. Most UDLI and half of LLRC reported that these statements made them feel unsafe living in the US, 75% (95% CI 70-80%) and 51% (95% CI 47-56%), respectively. More UDLI reported that these statements made them afraid to come to the ED (24%, 95% CI 20-28%) vs LLRC (4.4%, 95% CI 3-7%) and NLRC (3.5%, 95% CI 2-6%); 55% of UDLI with this fear stated it caused them to delay coming to the ED (median delay 2-3 days). The vast majority of patients in our California EDs have heard statements during the 2016 presidential campaign or from President Trump about measures against undocumented immigrants, which have induced worry and safety concerns in both UDLI and LLRC patients. Exposure to these statements was also associated with fear of accessing emergency care in some UDLIs. Given California's sanctuary state status, these safety concerns and ED access fears may be greater in a nationwide population of Latinos.

// Yubo Jiang 1 , Anthony W.I. Lo 2 , Angela Wong 3 , Wenfeng Chen 3 , Yan Wang 1 , Li Lin 1 , Jianming Xu 1 1 Department of Gastrointestinal Oncology, Affiliated Hospital Cancer Center, Academy of Military Medical Sciences, Beijing, P. R. China 2 Division of Anatomical Pathology, Department of Pathology & Clinical Biochemistry, Queen Mary Hospital, Hong Kong Special Administrative Region, P. R. China 3 Global Early Development, Merck Serono China, Beijing, P. R. China Correspondence to: Jianming Xu, email: jmxu2003@yahoo.com Keywords: esophageal squamous cell carcinoma, PD-L1, TILs, prognostic factor, tumor microenvironment Received: November 11, 2016 Accepted: January 11, 2017 Published: February 22, 2017 ABSTRACT Programmed death-1 receptor (PD-1) and its ligand (PD-L1) play an integral role in regulating the immune response against cancer. This study investigated the prognostic significance of PD-L1 expression on tumor cells and tumor-infiltrating immune cells (TILs) in the tumor microenvironment in Chinese patients with esophageal squamous cell carcinoma (ESCC). Archival formalin-fixed, paraffin-embedded ESCC samples from treatment-naive patients with ESCC after surgery or by diagnostic endoscopic biopsy were collected between 2004 and 2014. Expression of PD-L1 in ESCC tumor specimens was assessed by immunohistochemistry (IHC), and the degree of TIL infiltration was evaluated by examining hematoxylin and eosin-stained (H&E) specimens. PD-L1+ as defined as ≥1% of tumor cell membranes showing ≥1+ intensity. In 428 patients, specimens from 341 (79.7%) were PD-L1+. In the definitive treatment group (patients who received curative esophagectomy or definitive [chemo-]radiation therapy), PD-L1 positivity was associated with a significantly shorter DFS and OS. In the palliative chemotherapy group exhibited, neither PFS nor OS correlated significantly with PD-L1 expression. PD-L1 expression was positively associated with TIL density. In 17 paired tumor tissues collected before and after treatment, an increase in PD-L1 expression was associated with disease progression, whereas a decrease in PD-L1 expression was associated with response to chemotherapy or disease control. So, PD-L1 expression was associated with a significantly worse prognosis in patients with ESCC. These observations suggest that PD-L1 may play a critical role in ESCC cancer progression and provide a rationale for developing PD-L1 inhibitors for treatment of a subset of ESCC patients.

The development of children’s mealtime television (TV) habits has not been well studied. We assessed whether mealtime TV habits established in infancy will persist into early childhood. We analyzed data collected through parent surveys at birth and at 6-month intervals from a randomized controlled trial. We used t-tests, χ2 tests, and a multivariable logistic regression to determine if family characteristics were associated with mealtime TV. A McNemar test was used to assess whether mealtime TV exposure changed over time. College-educated fathers and families with an annual income >$50 000 were associated with less-frequent TV exposure during children’s mealtimes. It was found that 84% of children retained their level of exposure to TV during mealtimes from the first 24 months through 48 months of life. Clinicians should counsel families about mealtime TV use within the first 2 years of life because these habits seem to develop early and persist into at least early childhood.

Purpose The purpose of this clinical nurse specialist-led interprofessional quality improvement project was to reduce hospital-acquired pressure ulcers (HAPUs) using evidence-based practice. Background Hospital-acquired pressure ulcers (PUs) have been linked to morbidity, poor quality of life, and increasing costs. Pressure ulcer prevention and management remain a challenge for interprofessional teams in acute care settings. Rationale Hospital-acquired PU rate is a critical nursing quality indicator for healthcare organizations and ties directly with Mount Sinai Hospital's (MSH's) mission and vision, which mandates providing the highest quality care to patients and families. Description This quality improvement project, guided by the Donabedian model, was based on the Registered Nurses' Association of Ontario Best Practice Guideline Risk Assessment & Prevention of Pressure Ulcers. A working group was established to promote evidence-based practice for PU prevention. Initiatives such as documentation standardization, development of staff education and patient and family educational resources, initiation of a hospital-wide inventory for support surfaces, and procurement of equipment were implemented to improve PU prevention and management across the organization. Outcome An 80% decrease in HAPUs has been achieved since the implementation of best practices by the Best Practice Guideline Pressure Ulcer working group. Conclusion The implementation of PU prevention strategies led to a reduction in HAPU rates. The working group will continue to work on building interprofessional awareness and collaboration in order to prevent HAPUs and promote an organizational culture that supports staff development, teamwork and communication. Implications This quality improvement project is a successful example of an interprofessional clinical nurse specialist-led initiative that impacts patient/family and organization outcomes through the identification and implementation of evidence-based nursing practice.

Background: Recruiting participants who are representative of the population as a whole is essential to ensure the development of treatments that benefit all rather than a select few. Understanding the reasons patients accept or decline participation, and then making adjustments to the recruiting process based on these findings, is one way to encourage study participation. Aim: To better understand what factors influence a potential participant's decision to either accept or decline participation in breast cancer trials. Methods: These are preliminary data from a pilot study that uses a short questionnaire to investigate which factors influence a woman's consent or decline to study participation. Women are approached for this study after being asked to participate in one of three other breast cancer trials targeting women who either have breast cancer or are at high risk for breast cancer. Women are approached for this study regardless of their decision to participate in the previous study. Participants are asked a set of questions about 1. the specific interaction they had with the consenter from the previous study, 2. general characteristics of a consenter, and 3. research in general. Demographic information is also collected for future analysis of responses based on race/ethnicity, income, education level, and primary language. Results: A total of 24 participants have completed the questionnaire so far, with an accrual rate of approximately 25 patients per month. Participants ranked the importance of the various factors on a 4-point scale with 1 being “not important at all” and 4 being “very important.” Factors that participants indicated were the least important to their decision to participate were: financial compensation (xÌ… 1.07), racial/ethnic parity between consenter and consentee (\bar x $ 1.19), consenter looking like someone from their community (\bar x $ 1.19), gender parity (\bar x $ 1.19), religious beliefs (\bar x $ 1.38), pleasing their doctor (\bar x $ 1.56), and feeling overwhelmed (\bar x $ 1.85). Factors participants indicated were the most important to them were: the desire to benefit others in the future (\bar x $ 3.63), to benefit their family (\bar x $ 3.56), to acknowledge the contributions of past generations (\bar x $ 3.20), the feeling participation was “the right thing to do” (\bar x $ 3.15), presence or lack of potential side effects associated with participation ((\bar x $ 3.15), feeling empowered by the consenter (\bar x $ 3.15), feeling the consenter was listening (\bar x $ 3.11), and trust in research (\bar x $ 3.07). Conclusions: Concerning the consenter, physical characteristics such as race/ethnicity and gender parity were less important than the actual interaction with the consenter, including their flexibility, listening skills, and ability to make the patient feel empowered. For research in general, the idea of contributing to the “greater good” emerged as a powerful motivation to participate. An emphasis on this, as well as well-trained consenters, may help studies attract more participants. Note: This abstract was not presented at the conference. Citation Format: Ellen Rippberger, Noe Chavez, Tanya Chavez, Christine Thai, Angelica Sanchez, Angela Wong, Karen Herold, Alan Nenez, Krista Rounds, Victoria Seewaldt. Factors influencing women's attitudes toward participation in breast cancer clinical research [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr A086.

The therapeutic value of inhibiting translation of the amyloid precursor protein (APP) offers the possibility to reduce neurotoxic amyloid formation, particularly in cases of familial Alzheimer’s disease (AD) caused by APP gene duplications (Dup⁻APP) and in aging Down syndrome individuals. APP mRNA translation inhibitors such as the anticholinesterase phenserine, and high throughput screened molecules, selectively inhibited the uniquely folded iron-response element (IRE) sequences in the 5’untranslated region (5’UTR) of APP mRNA and this class of drug continues to be tested in a clinical trial as an anti-amyloid treatment for AD. By contrast, in younger age groups, APP expression is not associated with amyloidosis, instead it acts solely as a neuroprotectant while facilitating cellular ferroportin-dependent iron efflux. We have reported that the environmental metallotoxins Lead (Pb) and manganese (Mn) cause neuronal death by interfering with IRE dependent translation of APP and ferritin. The loss of these iron homeostatic neuroprotectants thereby caused an embargo of iron (Fe) export from neurons as associated with excess unstored intracellular iron and the formation of toxic reactive oxidative species (ROS). We propose that APP 5’UTR directed translation activators can be employed therapeutically to protect neurons exposed to high acute Pb and/or Mn exposure. Certainly, high potency APP translation activators, exemplified by the Food and Drug Administration (FDA) pre-approved M1 muscarinic agonist AF102B and high throughput-screened APP 5’UTR translation activators, are available for drug development to treat acute toxicity caused by Pb/Mn exposure to neurons. We conclude that APP translation activators can be predicted to prevent acute metal toxicity to neurons by a mechanism related to the 5’UTR specific yohimbine which binds and targets the canonical IRE RNA stem loop as an H-ferritin translation activator.

The two isoforms of the nuclear estrogen receptor, ERα and ERβ are widely expressed in the central nervous system. Although they were first described as nuclear receptors, both isoforms have also been found at the cell membrane where they mediate cell signaling. Surface biotinylation studies using neuronal and glial primary cultures label an alternatively spliced form of ERα. The 52 kDa protein, ERαΔ4, is missing exon 4 and is highly expressed in membrane fractions derived from cultured cells. In vivo, both full-length (66 kDa) ERα and ERαΔ4 are present in membrane fractions. In response to estradiol, full-length ERα and ERαΔ4 are initially trafficked to the membrane, and then internalized in parallel. Previous studies determined that only the full-length ERα associates with metabotropic glutamate receptor-1a (mGluR1a), initiating cellular signaling. The role of ERαΔ4, remained to be elucidated. Here, we report ERαΔ4 trafficking, association with mGluR2/3, and downstream signaling in female rat arcuate nucleus (ARH). Caveolin (CAV) proteins are needed for ER transport to the cell membrane, and using co-immunoprecipitation CAV-3 was shown to associate with ERαΔ4. CAV-3 was necessary for ERαΔ4 trafficking to the membrane: in the ARH, microinjection of CAV-3 siRNA reduced CAV-3 and ERαΔ4a in membrane fractions by 50%, and 60%, respectively. Moreover, co-immunoprecipitation revealed that ERαΔ4 associated with inhibitory mGluRs, mGluR2/3. Estrogen benzoate (EB) treatment (5 μg; s.c.; every 4 days; three cycles) reduced levels of cAMP, an effect attenuated by antagonizing mGluR2/3. Following EB treatment, membrane levels of ERαΔ4 and mGluR2/3 were reduced implying ligand-induced internalization. These results implicate ERαΔ4 in an estradiol-induced inhibitory cell signaling in the ARH.

Focal segmental glomerulosclerosis (FSGS) is a pattern of kidney damage that can occur in individuals at any age, including children. Pediatric patients with FSGS require medication monitoring, growth, and psychological health. This article discusses the NP's role in the clinical presentation, diagnostic workup, and treatment of FSGS in pediatric patients.

Objective. To describe the timing of introduction and type of food introduced to infants with a family history of atopy. Methods. We conducted a secondary analysis of foods introduced each month to an interventional birth cohort of 149 infants at risk for atopy. Results. Seven percent of infants received solid food prior to 4 months of age; 13% after 6 months of age. Hyperallergenic foods were introduced on average in the following order: wheat (8.7 months); eggs (11.2 months); soy (13.0 months); fish (13.4 months); peanut (20.2 months); tree nuts (21.8 months); and other seafood (21.8 months). Asian race (odds ratio 3.94; 95% CI 1.14-13.58) and maternal history of food allergy (odds ratio 3.86; 95% CI 1.29-11.56) were associated with late food introduction. Conclusion. Variation in timing of food introduction may reflect cultural preferences and/or previous experience with food allergy, as well as the ambiguous state of current recommendations.

Positive feedback on gonadotropin release requires not only estrogen but also progesterone to activate neural circuits. In rodents, ovarian estradiol (E2) stimulates progesterone synthesis in hypothalamic astrocytes (neuroP), needed for the luteinizing hormone (LH) surge. Kisspeptin (kiss) neurons are the principal stimulators of gonadotropin-releasing hormone neurons, and disruption of kiss signaling abrogates the LH surge. Similarly, blocking steroid synthesis in the hypothalamus or deleting classical progesterone receptor (PGR) selectively in kiss neurons prevents the LH surge. These results suggest a synergistic action of E2 and progesterone in kiss neurons to affect gonadotropin release. The mHypoA51, immortalized kiss-expressing neuronal cell line derived from adult female mice, is a tractable model for examining integration of steroid signaling underlying estrogen positive feedback. Here, we report that kiss neurons in vitro integrate E2 and progesterone signaling to increase levels of kiss translation and release. mHypoA51 neurons expressed nonclassical membrane progesterone receptors (mPRα and mPRβ) and E2-inducible PGR, required for progesterone-augmentation of E2-induced kiss expression. With astrocyte-conditioned media or in mHypoA51-astrocyte co-culture, neuroP augmented stimulatory effects of E2 on kiss protein. Progesterone activation of classical, membrane-localized PGR led to activation of MAPK and Src kinases. Importantly, progesterone or Src activation induced release of kiss from E2-primed mHypoA51 neurons. Consistent with previous studies, the present results provide compelling evidence that the interaction of E2 and progesterone stimulates kiss expression and release. Further, these results demonstrate a mechanism though which peripheral E2 may prime kiss neurons to respond to neuroP, mediating estrogen positive feedback.

OBJECTIVES: To determine if probiotic administration during the first 6 months of life decreases childhood asthma and eczema. METHODS: We conducted a randomized, double-blind controlled trial of Lactobacillus rhamnosus GG (LGG) supplementation on the cumulative incidence of eczema (primary end point) and asthma and rhinitis (secondary end points) in high-risk infants. For the first 6 months of life, intervention infants (n = 92) received a daily dose of 10 billion colony-forming units of LGG and 225 mg of inulin (Amerifit Brands, Cromwell, CT), and control infants (n = 92) received 325 mg of inulin alone. We used survival analysis methods to estimate disease incidences in the presence or absence of LGG and to estimate the efficacy of LGG in delaying or preventing these diseases. RESULTS: Infants were accrued over a 6-year period (median follow-up: 4.6 years; 95% retention rate at 2 years). At 2 years of age, the estimated cumulative incidence of eczema was 30.9% (95% confidence interval [CI], 21.4%–40.4%) in the control arm and 28.7% (95% CI, 19.4%–38.0%) in the LGG arm, for a hazard ratio of 0.95 (95% CI, 0.59–1.53) (log-rank P = .83). At 5 years of age, the cumulative incidence of asthma was 17.4% (95% CI, 7.6%–27.1%) in the control arm and 9.7% (95% CI, 2.7%–16.6%) in the LGG arm, for a hazard ratio of 0.88 (95% CI, 0.41–1.87) (log-rank P = .25). CONCLUSIONS: For high-risk infants, early LGG supplementation for the first 6 months of life does not appear to prevent the development of eczema or asthma at 2 years of age.

To address the question of whether, on a population level, early detection and amplification improve outcomes of children with hearing impairment.All families of children who were born between 2002 and 2007, and who presented for hearing services below 3 years of age at Australian Hearing pediatric centers in New South Wales, Victoria, and Southern Queensland were invited to participate in a prospective study on outcomes. Children's speech, language, functional, and social outcomes were assessed at 3 years of age, using a battery of age-appropriate tests. Demographic information relating to the child, family, and educational intervention was solicited through the use of custom-designed questionnaires. Audiological data were collected from the national database of Australian Hearing and records held at educational intervention agencies for children. Regression analysis was used to investigate the effects of each of 15 predictor variables, including age of amplification, on outcomes.Four hundred and fifty-one children enrolled in the study, 56% of whom received their first hearing aid fitting before 6 months of age. On the basis of clinical records, 44 children (10%) were diagnosed with auditory neuropathy spectrum disorder. There were 107 children (24%) reported to have additional disabilities. At 3 years of age, 317 children (70%) were hearing aid users and 134 children (30%) used cochlear implants. On the basis of parent reports, about 71% used an aural/oral mode of communication, and about 79% used English as the spoken language at home. Children's performance scores on standardized tests administered at 3 years of age were used in a factor analysis to derive a global development factor score. On average, the global score of hearing-impaired children was more than 1 SD below the mean of normal-hearing children at the same age. Regression analysis revealed that five factors, including female gender, absence of additional disabilities, less severe hearing loss, higher maternal education, and (for children with cochlear implants) earlier age of switch-on were associated with better outcomes at the 5% significance level. Whereas the effect of age of hearing aid fitting on child outcomes was weak, a younger age at cochlear implant switch-on was significantly associated with better outcomes for children with cochlear implants at 3 years of age.Fifty-six percent of the 451 children were fitted with hearing aids before 6 months of age. At 3 years of age, 134 children used cochlear implants and the remaining children used hearing aids. On average, outcomes were well below population norms. Significant predictors of child outcomes include: presence/absence of additional disabilities, severity of hearing loss, gender, maternal education, together with age of switch-on for children with cochlear implants.

We describe herein a novel series of 3-amino-4-hydrazine-cyclobut-3-ene-1,2-diones as potent and selective inhibitors against the CXCR2 chemokine receptor and IL-8-mediated chemotaxis of a CXCR2-expressing cell line. Furthermore, these alkyl-hydrazine series inhibitors such as 5b demonstrated acceptable metabolic stability when incubated in human and rat microsomes.

Background Over-use and misuse of antibiotics are major causes of antibiotic resistance. This study explored the understanding and reported use of antibiotics amongst three ethnic groups in New Zealand. Methods Questionnaire survey of 300 Indian, Egyptian, and Korean people. Results Most people (73.3%) knew that antibiotics killed bacteria, but other incorrect responses were also common. A range of medicines were mistakenly identified as antibiotics. Nearly half the sample (43.3%) believed colds and flu were caused by bacteria. Only 45.4% were sure that antibiotics were not useful for colds and flu. A minority of participants knew about antibiotic resistance. There were significant differences between groups, with Koreans having lower levels of understanding. Discussion Interventions to improve use of antibiotics need to be pitched at a very basic level of knowledge, and need to be targeted towards particular ethnic groups, particularly those in whose home countries antibiotics are widely available without prescription.

The purpose of this study was to identify the inherent educational qualities of nutrition labeling and those qualities that require consumer education to enhance their usefulness. The population was women, ages 25 to 45, who either were familiar with Nutrition Facts labels or had never before seen such a label. The study instrument assessed the ability to locate and manipulate Nutrition Facts label data and assess nutrient-content claim accuracy. All study participants could skillfully locate label data, thereby indicating that the label format is easy to read. Those who had never before seen a Nutrition Facts label were significantly less able to manipulate label data than those familiar with these labels. Both groups performed similarly when asked to assess nutrient content claim accuracy. For Nutrition Facts labels to have the greatest impact, education continues to be key. The findings provide insight into directions nutrition labeling education should take.

This study evaluated and compared the abilities of women (n = 50) between the ages of 25 and 45 residing in the UK to locate and manipulate information on nutrition labels prepared in accordance with US regulations (i.e. Nutrition Facts labels) and those prepared in accordance with the EU Directive and UK Food Labelling Regulations 1996. It also assessed their ability to assess the accuracy of nutrient content claims. Study findings indicate that the women could locate and manipulate information on both labels equally well. However, they were significantly more able to assess nutrient content claims using the Nutrition Facts label. The research findings suggest EU labelling changes that may facilitate consumer use of labels in making dietary planning decisions.

The effects of pH of conventional lactate-based peritoneal dialysis solutions (LPDS) on the net ultrafiltration and solute removal in intermittent peritoneal dialysis (IPD) were studied. Conventional LPDS is rendered acidic to minimize the caramelization of glucose. Fifteen stable uremic patients were put on weekly IPD with a conventional 1.5% LPDS (hourly 2 L cycle for 60 L). pH of the LPDS was raised to around 7.4 by the addition of 1.4 mmol sodium hydroxide (1 M solution) to each litre of LPDS under an aseptic condition before the commencement of dialysis. A similar study was performed with the same 15 patients but the sodium hydroxide was replaced by a similar amount of sodium chloride. The net ultrafiltration, removal of urea, creatinine, sodium, and potassium were determined and compared. Serum levels of urea, creatinine, sodium, and potassium were also measured before and after the IPD. No peritonitis was encountered during the study. The net ultrafiltration volume in the euvolemic LPDS group was greater than the acidic LPDS group although this was not statistically significant [(mean ±SD) 2526 ±910 mL and 2186 ±750 mL, respectively, p = 0.21]. The clearances of urea, creatinine, sodium, and potassium showed no differences in both groups. We concluded that the ultrafiltration, clearances of urea, creatinine, sodium, and potassium in IPD were not affected by the pH of a LPDS from our results and a larger study is warranted to see the effect of dialysate pH on the peritoneal membrane.

To determine the effect of nonlinear frequency compression (NLFC) on children's development of speech and language at three years of age.A randomized controlled trial was conducted as part of the population-based longitudinal study on outcomes of children with hearing impairment (LOCHI). Participants were randomly assigned to fitting with NLFC (Phonak Naida V SP or UP) or with conventional processing in hearing aids, prescribed by using either the NAL or the DSL formula. Standardized tests of speech production, receptive and expressive language were administered, and parent ratings were collected. All assessments were double-blinded.Participants were 44 of the 450 children in the LOCHI cohort.Compared to children using conventional processing, receptive and expressive language was higher but receptive vocabulary and consonant articulation scores were lower for children who use NLFC. There was increased substitution of affricates by fricatives for children using NLFC, compared to children using conventional amplification. After allowing for the effect of multiple demographic variables, the difference in global language scores between groups was not significant (effect: 0.8 [95% confidence interval: - 6.7, 8.3]).There is insufficient evidence to indicate a difference in language ability between children using NLFC and those using conventional amplification.

To examine the impact of prescription on predicted speech intelligibility and loudness for children.A between-group comparison of speech intelligibility index (SII) and loudness, based on hearing aids fitted according to NAL-NL1, DSL v4.1, or DSL m[i/o] prescriptions. A within-group comparison of gains prescribed by DSL m[i/o] and NAL-NL2 for children in terms of SII and loudness.Participants were 200 children, who were randomly assigned to first hearing-aid fitting with either NAL-NL1, DSL v4.1, or DSL m[i/o]. Audiometric data and hearing-aid data at 3 years of age were used.On average, SII calculated on the basis of hearing-aid gains were higher for DSL than for NAL-NL1 at low input level, equivalent at medium input level, and higher for NAL-NL1 than DSL at high input level. Greater loudness was associated with DSL than with NAL-NL1, across a range of input levels. Comparing NAL-NL2 and DSL m[i/o] target gains revealed higher SII for the latter at low input level. SII was higher for NAL-NL2 than for DSL m[i/o] at medium- and high-input levels despite greater loudness for gains prescribed by DSL m[i/o] than by NAL-NL2.The choice of prescription has minimal effects on speech intelligibility predictions but marked effects on loudness predictions.

13 Background: Programmed death-1 receptor (PD-1) and its ligand (PD-L1) play an integral role in the immune response against cancer. This study investigated the prognostic significance of PD-L1 expression and tumor-infiltrating immune cells (TILs) in tumor microenvironment in Chinese patients with esophageal squamous cell carcinoma (ESCC). Methods: A total of 428 archival formalin-fixed, paraffin-embedded (FFPE) ESCC samples were collected between 2004 and 2014 from treatment naïve patients with ESCC after surgery or by diagnostic endoscopic biopsy. Expression of PD-L1 was assessed by IHC. The degree of TILs infiltration was evaluated by examining the H&E-stained specimens. Associations of PD-L1 expression and TILs with clinicopathological features were evaluated by non-zero correlation test. Survival distribution was compared by Kaplan-Meier and a log-rank test. The median follow-up time was 34.4 months(0.3-147.1 m). Changes of PD-L1 expression between paired tumor samples, which were collected before and after chemotherapy (2 cycles and 4 cycles or more), were also evaluated. Results: In the entire cohort, 79.7% (341/428) of specimens were PD-L1+ (defined as having ≥ 1% of tumor cell membranes showing ≥ 1+ intensity). In the intent-to-treat group (patients received curative esophagectomy or definitive chemoradiation therapy), PD-L1 positivity was associated with a significantly poorer DFS and OS. Neither PFS nor OS in palliative chemotherapy group presented a significant difference corresponding to PD-L1 expression. Furthermore, PD-L1 expression was positively associated with TIL density. Changes in PD-L1 expression was examined in 17 paired tumor tissues collected before and after treatments. Results showed that an increase in PD-L1 expression was associated with disease progression, a decrease in PD-L1 expression was associated with satisfactory chemotherapy treatment response. Conclusions: PositivePD-L1 expression was associated with a significantly worse prognosis in ESCC. These observations suggest that PD-L1 may play a critical role in ESCC cancer progression and provide a rationale for developing PD-L1 inhibitors for treatment of a subset of ESCC patients.

4042 Background: Programmed death-1 receptor (PD-1) and its ligand (PD-L1) play an integral role in the immune response against cancer. This study in Chinese patients (pts) with gastric carcinoma (...

An investigation into the structure–activity relationship of a lead compound, prolyl-5-aminopentanoic acid 4 , led to the identification of a novel series of 4-piperidinylacetic acid, 1-piperazinylacetic acid, and 4-aminobenzoic acid derivatives as potent VLA-4 antagonists with low nanomolar IC 50 values. A representative compound morpholinyl-4-piperidinylacetic acid derivative ( 13d : IC 50 = 4.4 nM) showed efficacy in the Ascaris -antigen sensitized murine airway inflammation model by oral administration.

Introduction Barrett’s oesophagus (BO) occurs as consequence of reflux and is a risk factor for oesophageal adenocarcinoma (OAC). The current “gold-standard” for diagnosing BO is endoscopy which remains prohibitively expensive and impractical as a population screening tool. Therefore, we aimed to investigate the epidemiological factors and symptoms associated with BO in order to develop a pre-screening tool to aid decision making for diagnostic referrals. Methods A prospective (training) cohort of 1603 patients attending for gastroscopy was used for identification of risk factors to develop a risk prediction model. Factors significantly associated with BO in the univariate analysis were selected to develop a prediction model that was validated in an independent, external cohort of 504 patients in primary care. We used two definitions of BO in the current study: 1) columnar lined epithelium of oesophagus (CLE) of any length reported in the endoscopy report with columnar epithelium on biopsy 2) an intestinal metaplasia confirmed on histopathological assessment with endoscopic length of BO ≥2 cm (IM ≥ 2 cm). Results An eight-factor panel, including age, sex, smoking status, heartburn, acid reflux, chest pain, abdominal pain, anti-reflux medication, was identified from the training cohort with an area under the ROC curve (AUC) of 0.74 (95%CI: 0.70–0.77) for CLE, and 0.80 (95% CI: 0.75–0.84) for IM ≥ 2cm. This panel was significantly associated with BO in the external cohort, and the odds ratios for each factor increase were 1.43 (95%CI: 1.02–2.01) and 1.30 (95%CI: 1.04–1.62) for CLE and IM ≥ 2cm, respectively. The AUCs of the 8-factor panel for CLE and IM ≥ 2cm in the external cohorts were 0.85 (95%CI: 0.77–0.92) and 0.78 (95%CI: 0.71–0.84), respectively. After controlling for over-fitting, the AUCs dropped to 0.65 (95% CI: 0.54–0.77) and 0.67 (95%CI: 0.60–0.74), respectively. Conclusion An eight-factor panel can help predict the presence of BO and has the potential to be applied in the general population with GORD symptoms as a pre-screening tool to help select patients for further investigation. Disclosure of Interest None Declared.

Conditioned enhancement of the rat eyeblink reflex was studied using as a response measure the electromyogram (EMG) in the orbicularis oculi (oo) muscle, which is responsible for the active force generating eyelid closure. During a reflex eyeblink, the EMG evidences both a short-latency (R1) and a long-latency (R2) component, mediated by different circuits. The R2 response exhibits several experience- or use-dependent modifications. We were interested in the modifiability of the neurophysiologically simpler R1 response. Experiments were designed to determine whether the R1 response can be enhanced by a conditioned stimulus (CS) that has been explicitly paired with an aversive unconditioned stimulus (US). The R1 response was elicited by electrical stimulation of the supraorbital branch of the trigeminal nerve. Following long-delay conditioning, the CS produced a significant R1 enhancement and latency decrease that were dependent upon explicit CS-US pairings. The CS by itself produced no significant EMG response, consistent with a modulatory rather than additive effect. This is the first demonstration that the R1 response can be associatively modulated. Based on other evidence, we hypothesize that the CS-produced enhancement results from a relatively direct projection from the amygdala to the R1 circuit. As an index of aversive conditioning, R1 enhancement may prove to be a useful expression system because it offers high temporal resolution and the underlying circuitry is relatively simple-the shortest path from the fifth nerve to the muscle consisting of only two central synapses.

Introduction: The effects of cold ischemic preservation and degree of donor-recipient histoincompatibility on graft coronary arteriosclerosis(GCA)were examined using a rat heterotopic cardiac transplant model. Methods: Three donor-recipient rat strain combinations were utilized. Lewis-F344 rats which vary slightly in class I Major Histocompatibility (MHC) Loci genes, ACI-Lewis which vary significantly in MHC class I and II genes, and Lewis-Lewis (control), donor-recipient strain combinations were subjected to varying lengths of cold ischemic preservation prior to transplantation(0, 4, and 24h in University-of-Wisconsin solution at 4’C).There were 9 rats per group.Grafts were harvested at 90 days post-op. and sections of the epicardial arteries were examined (H&E and van Gieson elastin stains).Intimal area ratio (IAR = intimal area/area within internal elastic lamina), intimal thickness score (ITS-based on % luminal compromise, perimeter of involvement), and rejection score (RS) were determined for each specimen using computerized image morphometry. Results: IAR, ITS and RS were significantly higher at 24hrs vs. 0hrs (p ∗ . IAR (hr) LEW-LEW (%) LEW-F344 ∗ (%) LEW-ACI ∗ (%) 0 0.38 ± 0.15 0.33 ± 0.16 0.57 ± 0.16 4 0.34 ± 0.11 0.42 ± 0.21 0.72 ± 0.29 24 0.41 ± 0.18 0.63 ± 0.14 ITS (hr) 0 0.36 ± 1.00 0.67 ± 0.84 2.00 ± 1.40 4 0.14 ± 0.29 0.82 ± 0.94 2.80 ± 2.10 24 0.91 ± 0.91 1.90 ± 0.87 RS (hr) 0 0.11 ± .33 3.30 ± 0.89 3.10 ± 1.4 4 0.56 ± .88 3.80 ± 0.71 5.00 ± 0.0 24 1.10 ± 1.4 4.50 ± 0.53 4.40 ± .71 ∗ p Conclusions: GCA is significantly increased by greater MHC disparity and longer cold ischemic times. GCA may be caused by an Immune-mediated antigen dependent vasculopathy secondary to histoincompatability. In the control group, longer cold ischemic times did not have a significant effect on GCA, suggesting that better histocompatibility may mitigate the adverse effects of longer ischemic times.

This article reports two outbreaks of gastroenteritis which occurred in nursing homes in South Eastern Sydney during November 1998 in which an assay, developed by the South Eastern Area Laboratory Services (SEALS) Enteric and Virology Laboratories, was used to confirm the aetiological agent as Norwalk-like viruses (NLVs).

4′-(9-Acridinylamino)methanesulfon- m -anisidide (mAMSA) interacts with red cell membranes, resulting in the formation of fluorescent protein adducts. The mAMSA-membrane protein adducts exhibited an emission fluorescence maximum at 445 nm, with two shoulders at approximately 425 and 470 nm. The major labeled proteins were identified as spectrins 1 and 2 and bands 3, 4.1, 4.2 and 5. The fluorescence intensity increased with increasing mAMSA concentrations (0.03 to 1.5 mM), time (15–120 min), and temperature of the reaction. Results from sodium dodecyl sulfate gel electrophoresis show that mAMSA caused no detectable change in the molecular weight of membrane proteins. This indicates that mAMSA is a monofunctional, noncrosslinking agent. Other acridine analogs, 9-aminoacridine and acridine, did not fluorescently label membrane proteins, suggesting that the presence of the acridine nucleus is not sufficient for labeling. Addition of 2-mercaptoethanol to the mAMSA-membrane reaction mixtures reversed the fluorescence labeling. Furthermore, pretreatment of membrane proteins with N -ethylmaleimide or iodoacetamide prevented the formation of fluorescent mAMSA-membrane protein adducts. These data suggest that mAMSA interacts with sulfhydryl groups of the membrane proteins. When the membrane sulfhydryl groups were assayed by labeling with N -[ ethyl -2- 3 H ]ethylmaleimide, it was shown that the accessible membrane sulfhydryl groups were reduced after the mAMSA treatment. The above results suggest that mAMSA covalently binds to the sulfhydryl groups in the red cell membrane, with the production of fluorescent mAMSA-protein adducts.