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Background Intracardiac foreign bodies have been described in the literature, however, they are rare entities, particularly in pediatric patients. We present a case of a teenage boy diagnosed with perimyocarditis who was found to have an unexpected underlying etiology: an unknowingly swallowed sewing pin. Case Report A 17-year-old boy presented to the Emergency Department with 3 days of chest pain suggestive of perimyocarditis, in the absence of prodromal symptoms or trauma. Electrocardiogram at the time of presentation demonstrated diffuse ST-segment elevation consistent with perimyocarditis. A chest radiograph was significant for a linear density in the anterior mid chest, concerning for foreign body. Chest computed tomography confirmed the presence of a 3.5-cm linear metallic foreign body within the right ventricle. Why Should an Emergency Physician Be Aware of This? This case demonstrates the need to consider alternative etiologies for perimyocarditis, especially in the absence of the typical prodromal symptoms. In addition, it highlights the potential devastating complications of foreign body ingestion and challenges the paradigm that ingested sharp linear foreign bodies

PRIS is a potentially fatal syndrome characterized by various clinical symptoms and abnormalities. Experts suggest that propofol treatment duration ≥48 h or dose ≥83 μg/kg/min is associated with developing PRIS. We hypothesized PRIS might be underdiagnosed due to the overlap of PRIS clinical manifestations with critical illnesses.Multihospital, retrospective study of adult patients who received continuous propofol infusion ≥48 h or dose ≥60μg/kg/min for24 h since admission were assessed for the development of PRIS.The incidence of PRIS was 2.9% with a PRIS-associated mortality rate of 36.8%. In PRIS patients, propofol was administered at a median dose of 36.4 μg/kg/min and over a median duration of 147.0 h. The development of PRIS was observed at a median of 125.0 h post-propofol initiation and a cumulative dose of 276.5 mg/kg. The development of metabolic acidosis (78.9%), cardiac dysfunction (52.6%), hypertriglyceridemia (100%), and rhabdomyolysis (26.3%) were observed in our PRIS patients.PRIS can often be overlooked and underdiagnosed. It is important to monitor for early signs of PRIS in patients who are on prolonged propofol infusion. Prompt recognition and interventions can minimize the dangers resulting from PRIS.

Using companies listed in China’s Shanghai Exchange and Shenzhen Exchange in 2010–2015 as a sample, we test the impact of managerial overconfidence on choice of internal financing and investment efficiency (investment scale; overinvestment and underinvestment). We show that internal financing can fund business opportunities and alleviate capital shortages but may also cause excessive investment, especially in firms with managerial overconfidence. This overinvestment problem is more significantly related to managerial overconfidence in state-owned than non-state enterprises.

SUMMARY The emergence of influenza A viruses (IAVs) from zoonotic reservoirs poses a great threat to human health. As seasonal vaccines are ineffective against zoonotic strains, and newly transmitted viruses can quickly acquire drug resistance, there remains a need for host-directed therapeutics against IAVs. Here, we performed a genome-scale CRISPR/Cas9 knockout screen in human lung epithelial cells with a human isolate of an avian H5N1 strain. Several genes involved in sialic acid biosynthesis and related glycosylation pathways were highly enriched post-H5N1 selection, including SLC35A1, a sialic acid transporter essential for IAV receptor expression and thus viral entry. Importantly, we have identified capicua (CIC) as a negative regulator of cell-intrinsic immunity, as loss of CIC resulted in heightened antiviral responses and restricted replication of multiple viruses. Therefore, our study demonstrates that the CRISPR/Cas9 system can be utilized for the discovery of host factors critical for the replication of intracellular pathogens., In Brief Using a genome-wide CRISPR/Cas9 screen, Han et al. demonstrate that the major hit, the sialic acid transporter SLC35A1, is an essential host factor for IAV entry. In addition, they identify the DNA-binding transcriptional repressor CIC as a negative regulator of cell-intrinsic immunity.

Background In the randomized, double-blind, phase 3 trial SOLO1, olaparib (OLA) in the maintenance setting demonstrated a 70% lower risk of disease progression or death than placebo in women with newly diagnosed advanced ovarian cancer and a BRCA1/2 mutation. This study aimed to evaluate the cost-effectiveness of OLA maintenance therapy versus routine surveillance (RS) after response to first-line platinum-based chemotherapy in this population in Singapore. Methods A three-state partitioned survival model was developed to simulate the lifetime (50 years) incremental cost-effectiveness ratio (ICER) of OLA versus RS from a healthcare payer perspective. Progression-free and overall survival curves were estimated using data from SOLO1 and extrapolated beyond the trial period using parametric survival models. Any patient who remained progression-free at year 7 was assumed to be a long-term survivor and no longer at risk of progression. Mortality rates for this group were modelled on all-cause mortality from the general population adjusted for BRCA1/2 mutation status. These assumptions were validated with local clinicians. Health state utilities and adverse event frequencies were obtained from SOLO1. Drug costs were sourced from local public healthcare institutions. Healthcare resource usage and costs were based on local clinician input and publications. A 3% discount rate was applied to costs and outcomes. Deterministic and probabilistic sensitivity analyses (PSA) were performed to assess the robustness of results. Results The base-case analysis of OLA maintenance therapy versus RS resulted in an ICER of SGD17,326 per quality-adjusted life year (QALY) gained. The ICER was most sensitive to variations in the discount rate and mortality risk in long-term survivors. PSA demonstrated that OLA was associated with an 81% probability of being cost-effective at a willingness-to-pay threshold of SGD50,000 per QALY gained. Conclusions OLA has a high potential of being a cost-effective maintenance therapy versus RS for patients with BRCA1/2 mutated advanced ovarian cancer after response to first-line chemotherapy in Singapore. Legal entity responsible for the study AstraZeneca Singapore Pte Ltd. Funding AstraZeneca Singapore Pte Ltd. Disclosure D.S. Tan: Honoraria (self): AstraZeneca; Honoraria (self): Novartis; Honoraria (self): Roche; Honoraria (self): MSD; Honoraria (self): Bayer; Honoraria (self): Genmab; Honoraria (self): Tessa Therapeutics; Honoraria (self): Merck Serono ; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Karyopharm Therapeutics; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Roche (Foundation Medicine); Research grant / Funding (self): National Medical Research Council Singapore Clinician Scientist Award; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Roche; Advisory / Consultancy: Bayer; Advisory / Consultancy: ETC/D3 Singapore; Advisory / Consultancy: Tessa Therapeutics; Advisory / Consultancy: Genmab. J.J. Chan: Honoraria (self): Novartis; Honoraria (self): AstraZeneca; Honoraria (self): Merck Sharp & Dohme; Advisory / Consultancy: Eisai; Advisory / Consultancy: Pfizer; Research grant / Funding (institution): OncoQuest Inc; Research grant / Funding (institution): Pfizer; Travel / Accommodation / Expenses: Synthon; Travel / Accommodation / Expenses: Novartis; Travel / Accommodation / Expenses: AstraZeneca; Travel / Accommodation / Expenses: Celgene. J.K. Loke: Full / Part-time employment: AstraZeneca. R. Hettle: Full / Part-time employment: AstraZeneca. C.C. Yu: Full / Part-time employment: AstraZeneca. All other authors have declared no conflicts of interest.

Results After review of the pre-specified IA, the IDMC recommended full analysis and disclosure of the results. With 256 IDFS events reported, administration of T-DM1 significantly improved IDFS compared with trastuzumab (unstratified HR = 0.50; 95% CI: 0.39 to 0.64; p

It is widely accepted that some firms' attributes or characteristics, such as a firm's size or book-to-market ratio, attract premiums in terms of average returns, which is a pervasive phenomenon not restricted to just a few individual markets. However, the way to derive these premiums by sorting firms based on their characteristics that are known to be associated with share returns, is not without controversy. This study takes a totally different approach by adopting a novel Self-Organizing Maps approach to cluster share returns first and identify the attributable factors afterwards. It finds eminent presence of the value effect in the Chinese A-shares market. It also finds that two other firm attributes, ROA and cash-flow-to-price, also have explanatory power over share returns. Liquidity and the ratio of tradable to total shares, which are often used to proxy corporate governance, show little evidence of explaining share return dispersion. Surprisingly, a “reversed” size effect is reported in this study.

Here, we present the case of a female infant, the firstchild of a 32-year-old woman and a 45-year-old man,who were healthy and non-consanguineous. The familyhistory was unremarkable. The infant was delivered at37 weeks’ gestation with a birth weight of 2,834g. Shehad midface hypoplasia, cleft palate, low-set ears, andbilateral syndactyly of the hands and feet (Figures 1–3).She had a 46,XX karyotype. DNA testing for Apert syn-drome revealed a heterozygous c.755 C >G, TCG >TGGtransversion leading to a Ser252Trp (S252W) mutationin the fibroblast growth factor receptor 2 (

124 A 40-year-old, gravida 2, para 1, woman underwent amniocentesis at 16 weeks of gestation because of advanced maternal age. Her husband was 43 years of age. Both parents were healthy, and there was no family history of congenital malformations. Amniocentesis revealed mosaicism for a supernumerary isochromosome consisting of two entire short arms of chromosome 12 or i(12)(p10). The karyotype was 47,XX,+i(12p)[16]/ 46,XX[9] derived from 25 colonies of amniocytes, with 64% (16/25) of the amniocytes being +i(12p). The parental karyotypes were normal. Prenatal ultrasound at 19+4 weeks of gestation revealed a normal volume of amniotic fluid, macrocephaly with a biparietal diameter of 5.01 cm (21.72 weeks), hypertelorism, an abdominal circumference of 15.27 cm (20.48 weeks), a femur length of 3 cm (19.26 weeks), and a flat face with a very small nose and protruding lips (Figures 1 and 2). A diagnosis of Pallister-Killian syndrome (PKS) was made. The pregnancy was subsequently terminated, and a 399-g fetus, with macrocephaly, a large coarse face, a long philtrum, retrognathia, a Cupid’s bow mouth with thin lips, a flattened nose with a low nasal bridge, anteverted nostrils, upslanting palpebral fissures and low-set ears, was delivered (Figures 3 and 4). Postnatal ABNORMALLY FLAT FACIAL PROFILE ON TWOAND THREE-DIMENSIONAL ULTRASOUND AND ARRAY COMPARATIVE GENOMIC HYBRIDIZATION FOR THE DIAGNOSIS OF PALLISTER-KILLIAN SYNDROME

Apert syndrome (OMIM 101200) is a congenital disorder characterized by acrocephaly, craniosynostosis, midface hypoplasia, and syndactyly of the hands and feet [1]. The reported prevalence of Apert syndrome at birth has ranged from 1 in 160,000 [2] to 1 in 64,500 births [3]. The majority of cases of Apert syndrome arise sporadically as the result of a de novo mutation in the sperm, associated with a paternal age effect; only a few cases are inherited from affected parents in an autosomal dominant pattern [4,5]. Apert syndrome is caused by mutations in the fibroblast growth factor receptor 2 (FGFR2) gene (OMIM 176943) located at 10q26. Two mutations of Ser252Trp (S252W) and Pro253Arg (P253R) account for over 98% of cases of Apert syndrome [6,7]. Although cases of prenatally diagnosed Apert syndrome have been reported, many cases remain undiagnosed until delivery, or are diagnosed in late gestation when polyhydramnios and craniofacial deformities become evident. Syndromes involving craniosynostosis may be associated with abnormalities of the digits. Crouzon syndrome is associated with normal hands and feet. Jackson-Weiss syndrome is associated with normal hands, medially deviated broad great toes and cutaneous syndactyly of the second and the third toes. Apert syndrome is associated with symmetric syndactyly of the hands and feet. Pfeiffer syndrome is associated with broad abducted thumbs, broad great toes, and brachymesophalangy and partial syndactyly of the hands and feet. In cases with mild ventriculomegaly, a thorough examination of the hands in the second trimester may lead to a specific diagnosis of Apert syndrome, as in the current case. A 30-year-old, gravida 1, woman was referred to Mackay Memorial Hospital for amniocentesis at 21 weeks of gestation because of mild ventriculomegaly and clenched hands detected on prenatal ultrasound. Her husband was 32 years of age. She and her husband were both healthy and unrelated, and there was no family history of congenital malformations. Prenatal ultrasound at 18 weeks of gestation revealed a male fetus with fetal biometry equivalent to 18 weeks, a normal skull shape, mild ventriculomegaly, and clenched hands (Figures 1 and 2). Trisomy 18 was highly suspected. Amniocentesis was performed at 21 weeks of gestation. Conventional cytogenetic analysis revealed a 46,XY karyotype. Oligonucleotide-based array comparative genomic hybridization using uncultured amniocytes demonstrated no deletions or duplications. SECOND-TRIMESTER MOLECULAR PRENATAL DIAGNOSIS OF SPORADIC APERT SYNDROME FOLLOWING SONOGRAPHIC FINDINGS OF MILD VENTRICULOMEGALY AND CLENCHED HANDS MIMICKING TRISOMY 18

Ghrelin is known to enhance gastric motility and accelerate gastric emptying of liquid and solid food in rats. As solid gastric emptying is regulated by the coordinated motor pattern between the antrum and pylorus (antro-pyloric coordination), we studied the correlation between solid gastric emptying and antro-pyloric coordination in response to ghrelin. Rats were given 1.5 g of solid food after a 24-h fasting. Immediately after the ingestion, ghrelin (0.4-8.0 microg/kg) or saline was administered by intraperitoneal (i.p.) injection. Ninety minutes after the feeding, rats were euthanized and gastric content was removed to calculate gastric emptying. To evaluate the antro-pyloric coordination, strain gauge transducers were sutured on the antrum and pylorus. The incidence of postprandial antro-pyloric coordination was compared between ghrelin-and saline-injected rats. In saline-injected rats, gastric emptying was 58.3+/-3.7% (n=6). Ghrelin (4.0-8.0 microg/kg), accelerated gastric emptying. Maximum effect was obtained by ghrelin (4.0 microg/kg), which significantly accelerated gastric emptying to 77.4+/-3.7% (n=6, p0.05). The number of antro-pyloric coordination 20-40 min after feeding was significantly increased in ghrelin-injected rats, compared to that of saline-injected rats (n=4, p0.05). It is suggested that enhanced antro-pyloric coordination play an important role in accelerated solid gastric emptying induced by ghrelin.

To clarify the mechanism of site-specific effects of acupuncture on gastric motor function, we studied the simultaneous recording of gastric motility and electrocardiogram (ECG) for heart rate variability (HRV) analysis in conscious rats. Gastric motility and ECG were recorded before, during and after electroacupuncture (EA) at ST-36 (hind limb) or ST-25 (abdomen). EA at ST-36 significantly increased gastric motility and decreased the ratio of low frequency (LF)/high frequency (HF) of the HRV analysis. In contrast, EA at ST-25 significantly inhibited gastric motility and increased LF/HF ratio. There was a significant correlation observed between the changes of gastric motility and LF/HF ratio in response to EA. It is suggested that the stimulatory effect of EA at ST-36 on gastric motility is associated with its stimulatory effect on vagal activity. The inhibitory effect of EA at ST-25 on gastric motility is associated with its stimulatory effect on the sympathetic nerve activity.

A series of 2,4,5-tri-substituted imidazoles has proven to be highly potent in inhibiting mammalian 15-lipoxygenase (15-LO) with excellent selectivity over human isozymes 5- and P-12-LO. Non-symmetrical sulfamides (e.g., 21a–n) were found to be suitable replacements for the earlier arylsulfonamide-containing members of this series (e.g., 2, 14a–p). Several members of these series also demonstrated potent inhibition of human 15-LO in a cell-based assay.

Background Post-operative ileus (POI) is a transient bowel dysmotility after operation. We have previously shown that laparotomy alone significantly delayed gastrointestinal (GI) transit, compared to anesthesia alone. The GI transit was further delayed after laparotomy plus intestinal manipulation. Dai-Kenchu-to (DKT), an herbal medicine, has been used for treating adhesive bowel obstruction in Japan. We studied whether DKT improves delayed GI transit after the operation, with or without morphine administration in rats. Materials and methods Under isoflurane anesthesia, POI was induced by laparotomy with intestinal manipulation. Immediately after the operation, the rats received 51Cr by gavage. Three hours after the operation, the rats were sacrificed and GI transit was estimated by calculating the geometric center (GC). DKT (120, 360, and 1,200 mg/kg) were administered by gavage after the operation, with or without morphine administration (1 mg/kg s.c.). A muscarinic receptor antagonist (atropine; 50 μg/kg), a 5HT3 receptor antagonist (ondansetron; 1 mg/kg) and a 5HT4 receptor antagonist (GR113,808; 3 mg/kg) were administered before the operation. Truncal vagotomy was performed preceding the operation. Results Laparotomy with intestinal manipulation produced a significant delay in GI transit (GC = 2.93 ± 0.16), compared to that of anesthesia alone (9.51 ± 0.45). DKT at the dose of 360 mg/kg (GC = 3.77 ± 0.10, P < 0.01) and 1,200 mg/kg (GC = 3.77 ± 0.20, P < 0.01) significantly accelerated delayed GI transit induced by operation. Ondansetron, GR113,808, atropine, and truncal vagotomy abolished the stimulatory effect of DKT (360 mg/kg). When morphine was administered, GI transit was further reduced (GC = 1.97 ± 0.10). DKT at the dose of 360 mg/kg (GC = 2.81 ± 0.22, P < 0.05) and 1,200 mg/kg (GC = 2.87 ± 0.23, P < 0.05) significantly improved delayed GI transit in morphine treated rats. Conclusions DKT accelerates delayed GI transit induced by intestinal manipulation with and without concomitant morphine administration. DKT treatment may be useful for the patients with POI.

A high throughput method with ultra-low level quantification limit (10 pg/ml) was developed and validated for the quantitative determination of LAG078, a lipid modulator, in human plasma to support clinical studies employing low doses of the compound. The method consisted of reverse phase chromatographic separation of the analyte from plasma extract followed by electrospray ionization (ESI) in the negative ion mode and tandem mass spectrometry in the multiple reaction monitoring mode (MRM). Extraction was performed using a combination of protein precipitation and liquid–liquid extraction in the 96-well plate format to increase the throughput of the method. Optimised chromatographic separation in a short and high-resolution column (50 mm × 2.0 mm i.d., 3 μm particle size) coupled with MRM mode of detection yielded clean chromatograms with minimal signal suppression. The standard curve was linear ( r = 0.996) within the concentration range of 0.01 (lower limit of quantification) to 50 ng/ml using 0.5 ml of human plasma. The accuracy of the method varied from 95–101% with a precision (CV) of 5.29–13.2% over the concentration range. The method was simple and rapid.

MK-0869 (aprepitant), a potent substance P antagonist, is the active ingredient of EMEND which has recently been approved by the FDA for the prevention of chemotherapy-induced nausea and vomiting. Early clinical tablet formulations of MK-0869 showed significant food effects on absorption, suggesting that formulation could have a significant role in improving bioavailability. A Beagle dog model was developed in an effort to guide novel formulation development. Using the suspension of the micronized bulk drug used for the tablet formulations, the food effect on absorption was confirmed in the dog at a similar magnitude to that observed in humans. Further dog studies demonstrated a clear correlation between particle size and in vivo exposures, with the nanoparticle (NanoCrystal) colloidal dispersion formulation providing the highest exposure, suggesting dissolution-limited absorption. The NanoCrystal dispersion also eliminated the food effect on oral absorption in the dog at a dose of 2mg/kg. Regional absorption studies using triport dogs indicated that the absorption of MK-0869 was limited to the upper gastrointestinal tract. These results provided strong evidence that the large increase in surface areas of the drug nanoparticles could overcome the narrow absorption window and lead to rapid in vivo dissolution, fast absorption, and increased bioavailability. In addition, the dog model was used for optimizing formulation processes in which the nanoparticles were incorporated into solid dosage forms, and for selecting excipients to effectively re-disperse the nanoparticles from the dosage units. The human pharmacokinetic data using the nanoparticle formulation showed excellent correlations with those generated in the dog.

The life span of patients with Fanconi Anemia (FA) is severely shortened by bone marrow failure and malignancies. Currently, the only efficient therapy is bone-marrow transplantation from a matched sibling donor. Therefore, FA is considered a good candidate disease for hematopoietic gene therapy. Our previous preclinical gene therapy experiments with Fancc knock-out mice have shown that wild-type hematopoietic stem cells (introduced by transplantation or generated by gene transfer) have a strong selective growth advantage in vivo. However, despite the successful modeling of FA gene therapy in the mouse, application of the same approach to humans is complicated by the requirement for ex vivo manipulation and scarcity of HSCs in FA patients. Consequently, the development of new gene transfer methods that support stable integration of therapeutic transgenes in vivo are greatly desired. Here, we have utilized the Sleeping Beauty (SB) transposon system to facilitate stable, transposase-mediated gene transfer of the human FANCC cDNA in vivo from a plasmid-based system. The transposase and FANCC transposon plasmid constructs were co-transfected into bone-marrow cells of Fancc mutant mice by two different methods: 1) via electroporation into enriched hematopoietic cells; 2) via direct injection into the femur cavity. In each case, the presence of the transgene was followed in treated animals by semi-quantitative PCR. Although no transgene was detectable in peripheral blood DNA 2 weeks after injection, 2/4 mice injected into the femur cavity were PCR positive 4 weeks after injection, even in the absence of selective pressure. At this time, a single low dose of cyclophosphamide (CPA) was given to provide a selective advantage for FANCC corrected cells. Four weeks after CPA administration, all the experimental electroporated animals (N=2) and femur injected animals (N=8) were strongly PCR positive in their peripheral blood and have remained stably positive for at least 9 months. Furthermore, upon transplantation of bone marrow from these mice into wild-type lethally irradiated recipients, we observed that 81/110 (74%) of day 12 CFU-S colonies were transgene positive. Similarly, 64/110 (64%) of the 12-day CFU-S colonies were transgene positive from the femur-injected donors, thus confirming that transgene integration had occurred in bona fide stem cells. Collectively, these studies demonstrate that a) hematopoietic stem cells from Fancc mutant mice are proficient in taking up plasmid DNA; b) stable integration of plasmid DNA into the genome of hematopoietic stem cells is possible and c) the efficiency of stable gene transfer using these nonviral approaches compares favorably to that achieved by alternative viral-based methods. We are in the process of analyzing transposon host cellular DNA junctions to determine the mechanism of transgene persistence in each experimental group. The above experiments have been repeated independently with more animals: N=5 for electroporated and N=6 for femur injected. Details of all these results will be discussed.