Neurocircuitry underlying the actions of glucagon-like peptide 1 and peptide YY3-36 in the suppression of food, drug-seeking, and anxiogenesis.

Obesity is a critical health condition worldwide that increases the risks of comorbid chronic diseases, but it can be managed with weight loss. However, conventional interventions relying on diet and exercise are inadequate for achieving and maintaining weight loss, thus there is significant market interest for pharmaceutical anti-obesity agents. For decades, receptor agonists for the gut peptide glucagon-like peptide 1 (GLP-1) featured prominently in anti-obesity medications by suppressing appetite and food reward to elicit rapid weight loss. As the neurocircuitry underlying food motivation overlaps with that for drugs of abuse, GLP-1 receptor agonism has also been shown to decrease substance use and relapse, thus its therapeutic potential may extend beyond weight management to treat addictions. However, as prolonged use of anti-obesity drugs may increase the risk of mood-related disorders like anxiety and depression, and individuals taking GLP-1-based medication commonly report feeling demotivated, the long-term safety of such drugs is an ongoing concern. Interestingly, current research now focuses on dual agonist approaches that include GLP-1 receptor agonism to enable synergistic effects on weight loss or associated functions. GLP-1 is secreted from the same intestinal cells as the anorectic gut peptide, Peptide YY3-36 (PYY3-36), thus this review assessed the therapeutic potential and underlying neural circuits targeted by PYY3-36 when administered independently or in combination with GLP-1 to curb the appetite for food or drugs of abuse like opiates, alcohol, and nicotine. Additionally, we also reviewed animal and human studies to assess the impact, if any, for GLP-1 and/or PYY3-36 on mood-related behaviors in relation to anxiety and depression. As dual agonists targeting GLP-1 and PYY3-36 may produce synergistic effects, they can be effective at lower doses and offer an alternative approach for therapeutic benefits while mitigating undesirable side effects.

Empiric nasogastric decompression after pancreaticoduodenectomy is not necessary.

BACKGROUND: The aim of the present study was to evaluate the impact of routine NGT decompression after PD on postoperative outcomes in the era of an enhanced recovery after surgery (ERAS) protocol. MATERIALS AND METHODS: A retrospective review of all patients undergoing PD between January 2015 and October 2017 at our institution was performed comparing routine post-operative NGT decompression versus omission. The incidence of delayed gastric emptying, post-operative pancreatic fistula, hospital length of stay, operative time, 30-day readmission rate as well the time to first oral intake were evaluated. RESULTS: Out of 149 patients who underwent PD, 65 maintained post-operative NGT decompression while post-operative NGT decompression was omitted in 84 patients. No differences were noted in delayed gastric emptying rates (both p>0.05). The median length of stay (9 days for NGT group versus 8.5 days for no NGT group) and 30-day readmission rates (13.8% versus 15.5%, respectively) were similar (p=0.781). Compared with patients who had routine post-operative NGT placed, those who had omission of a post-operative NGT had a lower need for reinsertion, shorter time to PO intake, and a lower likelihood of extended length of stay. CONCLUSIONS: In the era of ERAS protocols, we observed no association between routine post-operative NGT decompression after PD and improved postoperative outcomes.

The diagnosis and management of intraductal papillary mucinous neoplasms of the pancreas: has progress been made?

Intraductal papillary mucinous neoplasms (IPMN) of the pancreas are premalignant mucin-producing epithelial tumors that arise from the pancreatic ductal system. These cystic tumors represent 15-30% of cystic lesions of the pancreas [Basturk et al. in Am J Surg Pathol 39(12):1730-1741, 1; Ferrone et al. in Arch Surg (Chicago, Ill: 1960) 144(5):448-454, 2, Kosmahl et al. in Virchows Arch Int J Pathol 445(2):168-178, 3; Spinelli et al. in Ann Surg. 239(5):651-657, 4]. It is believed that IPMN can progress from low-grade dysplasia to high-grade dysplasia to invasive cancer, and this pathway of progression accounts for 20-30% of pancreatic cancer [Adsay et al. in Am J Surg Pathol 28(7):839-848, 5; Tanaka et al. in J Gastroenterol 40(7):669-675, 6; Wu et al. in Sci Transl Med 3(92):92ra66, 7]. Furthermore, it is also widely believed that IPMN represent a field defect of the pancreas in which the entire ductal system is at risk of developing invasive carcinoma, not only in the area of radiographically detectable IPMN, and thus the remaining gland should undergo surveillance after partial pancreatectomy [Salvia et al. in Ann Surg 239(5):678-685, 8; Izawa et al. in Cancer 92(7):1807-1817, 9; Yamaguchi and Tanaka in Jpn J Clin Oncol 41(7):836-840, 10]. Increasingly, surgeons are faced with the dilemma between recommending highly complex resections-that have significant morbidity and mortality-in patients who may have low-risk IPMN (low-grade dysplasia), or alternatively, recommending observation for those who could possibly be harboring a radiographically occult malignancy. Given the complexity of the management decisions for patients with IPMN, the purpose of this paper is to review the current literature and to provide a summary of how accurate we are currently with the identification of high-grade dysplasia or progression to carcinoma in patients who present with IPMN.

Neuroendocrine carcinomas of the gallbladder: Lessons learnt from cases at opposite ends of the spectrum.

Neuroendocrine tumors are the rarest tumors of gallbladder. The most aggressive variant is neuroendocrine carcinoma which represents about 0.5% of all gallbladder carcinomas and 0.2% of all neuroendocrine tumors. It seems possible that survival rates can be improved by utilizing wide surgical resection combined with chemotherapy. We report on two cases of extreme presentation, including age, extend of disease and treatment modalities.

Vinylation of Aryl Ether (Lignin ß-O-4 Linkage) and Epoxides with Calcium Carbide through C-O Bond Cleavage.

Calcium carbide has been increasingly used as a sustainable, easy-to-handle, and low-cost feedstock in organic synthesis. Currently, methodologies of using calcium carbide as "solid acetylene" in synthesis are strictly limited to activation and reaction with X-H (X=C, N, O, S) bonds. Herein, a mild and transition-metal-free protocol was developed for the vinylation of epoxides and aryl ether linkage (ß-O-4 lignin model compound) with calcium carbide through C-O bond cleavage, forming valuable vinyl ether products. Calcium carbide plays a vital role in the C-O bond activation and cleavage, and in providing acetylide source for the formation of vinylated products. These exciting results may provide new methodologies for organic synthesis and new insights toward lignin- or biomassrelated degradation to useful products.

Transcranial random noise stimulation and cognitive training to improve learning and cognition of the atypically developing brain: A pilot study.

Learning disabilities that affect about 10% of human population are linked to atypical neurodevelopment, but predominantly treated by behavioural interventions. Behavioural interventions alone have shown little efficacy, indicating limited success in modulating neuroplasticity, especially in brains with neural atypicalities. Even in healthy adults, weeks of cognitive training alone led to inconsistent generalisable training gains, or "transfer effects" to non-trained materials. Meanwhile, transcranial random noise stimulation (tRNS), a painless and more direct neuromodulation method was shown to further promote cognitive training and transfer effects in healthy adults without harmful effects. It is unknown whether tRNS on the atypically developing brain might promote greater learning and transfer outcomes than training alone. Here, we show that tRNS over the bilateral dorsolateral prefrontal cortices (dlPFCs) improved learning and performance of children with mathematical learning disabilities (MLD) during arithmetic training compared to those who received sham (placebo) tRNS. Training gains correlated positively with improvement on a standardized mathematical diagnostic test, and this effect was strengthened by tRNS. These findings mirror those in healthy adults, and encourage replications using larger cohorts. Overall, this study offers insights into the concept of combining tRNS and cognitive training for improving learning and cognition of children with learning disabilities.

Distinct microenvironmental cues stimulate divergent TLR4-mediated signaling pathways in macrophages.

Macrophages exhibit a phenotypic plasticity that enables them to orchestrate specific immune responses to distinct threats. The microbial product lipopolysaccharide (LPS) and the extracellular matrix glycoprotein tenascin-C are released during bacterial infection and tissue injury, respectively, and both activate Toll-like receptor 4 (TLR4). We found that these two TLR4 ligands stimulated distinct signaling pathways in macrophages, resulting in cells with divergent phenotypes. Although macrophages activated by LPS or tenascin-C displayed some common features, including activation of nuclear factor κB and mitogen-activated protein kinase signaling and cytokine synthesis, each ligand stimulated the production of different subsets of cytokines and generated different phosphoproteomic signatures. Moreover, tenascin-C promoted the generation of macrophages that exhibited increased synthesis and phosphorylation of extracellular matrix components, whereas LPS stimulated the production of macrophages that exhibited an enhanced capacity to degrade the matrix. These data reveal how the activation of one pattern recognition receptor by different microenvironmental cues generates macrophage with distinct phenotypes.

Isolation and Reactivity of 1,4,2-Diazaborole.

An isolable 1,4,2-diazaborole derivative was synthesized and structurally characterized. X-ray diffraction analysis and computational studies revealed a delocalization of 6π-electrons over the BC2N2 five-membered ring, which thus indicates the aromatic property. The reactivity toward electrophiles such as MeOTf and selectfluor was also investigated.

Endoscopy training in Canadian general surgery residency programs.

Currently, general surgeons provide about 50% of endoscopy services across Canada and an even greater proportion outside large urban centres. It is essential that endoscopy remain a core component of general surgery practice and a core competency of general surgery residency training. The Canadian Association of General Surgeons Residents Committee supports the position that quality endoscopy training for all Canadian general surgery residents is in the best interest of the Canadian public. However, the means by which quality endoscopy training is achieved has not been defined at a national level. Endoscopy training in Canadian general surgery residency programs requires standardization across the country and improved measurement to ensure that competency and basic credentialing requirements are met.

Late preterm delivery in women with preterm prelabour rupture of membranes.

OBJECTIVE: To estimate maternal and neonatal outcomes in women with preterm prelabour rupture of membranes (PPROM) who delivered at 34+0 to 36+6 weeks' gestation, particularly in those who had an obstetrically indicated delivery. METHODS: We conducted a population-based study of late preterm singleton births complicated by PPROM, using data from the Nova Scotia Atlee Perinatal Database from 1988 to 2006. The study cohort was categorized by type of labour (spontaneous, induced, no labour), and each group's characteristics prior to delivery, and their outcomes were compared after accounting for potential confounding variables. RESULTS: From a total population of 164 384 pregnancies, 2618 deliveries were identified as having PPROM. Among these, 2180 (83.3%) delivered between 34+0 and 36+6 weeks' gestation. Adjusted analyses showed no differences in risk between those women entering labour spontaneously (n = 1296) and those with obstetrically indicated delivery (labour induction or Caesarean section without labour, n = 698). Additional adjusted analyses evaluating only women with obstetrically indicated delivery showed that rates of chorioamnionitis (OR 0.27; 95% CI 0.08 to 0.93), composite perinatal morbidity/mortality (OR 0.39; 95% CI 0.25 to 0.62), neonatal depression at birth (OR 0.22; 95% CI 0.06 to 0.86), and respiratory distress syndrome (OR 0.17; 95% CI 0.06 to 0.47) were significantly lower in those delivering at 36 weeks (n = 458) than in those delivering at 34 to 35 weeks (n = 240). CONCLUSIONS: This large population-based study suggests that in pregnancies complicated by PPROM rates of adverse maternal and perinatal outcomes at 36 weeks' gestational age are at least comparable to those in pregnancies delivering at 34 to 35 weeks, and these rates may be further reduced by delivery after 36 completed weeks if spontaneous labour has not occurred.

The effect of universal influenza immunization on mortality and health care use.

BACKGROUND: In 2000, Ontario, Canada, initiated a universal influenza immunization program (UIIP) to provide free influenza vaccines for the entire population aged 6 mo or older. Influenza immunization increased more rapidly in younger age groups in Ontario compared to other Canadian provinces, which all maintained targeted immunization programs. We evaluated the effect of Ontario's UIIP on influenza-associated mortality, hospitalizations, emergency department (ED) use, and visits to doctors' offices. METHODS AND FINDINGS: Mortality and hospitalization data from 1997 to 2004 for all ten Canadian provinces were obtained from national datasets. Physician billing claims for visits to EDs and doctors' offices were obtained from provincial administrative datasets for four provinces with comprehensive data. Since outcomes coded as influenza are known to underestimate the true burden of influenza, we studied more broadly defined conditions. Hospitalizations, ED use, doctors' office visits for pneumonia and influenza, and all-cause mortality from 1997 to 2004 were modelled using Poisson regression, controlling for age, sex, province, influenza surveillance data, and temporal trends, and used to estimate the expected baseline outcome rates in the absence of influenza activity. The primary outcome was then defined as influenza-associated events, or the difference between the observed events and the expected baseline events. Changes in influenza-associated outcome rates before and after UIIP introduction in Ontario were compared to the corresponding changes in other provinces. After UIIP introduction, influenza-associated mortality decreased more in Ontario (relative rate [RR] = 0.26) than in other provinces (RR = 0.43) (ratio of RRs = 0.61, p = 0.002). Similar differences between Ontario and other provinces were observed for influenza-associated hospitalizations (RR = 0.25 versus 0.44, ratio of RRs = 0.58, p < 0.001), ED use (RR = 0.31 versus 0.69, ratio of RRs = 0.45, p < 0.001), and doctors' office visits (RR = 0.21 versus 0.52, ratio of RRs = 0.41, p < 0.001). Sensitivity analyses were carried out to assess consistency, specificity, and the presence of a dose-response relationship. Limitations of this study include the ecological study design, the nonspecific outcomes, difficulty in modeling baseline events, data quality and availability, and the inability to control for potentially important confounders. CONCLUSIONS: Compared to targeted programs in other provinces, introduction of universal vaccination in Ontario in 2000 was associated with relative reductions in influenza-associated mortality and health care use. The results of this large-scale natural experiment suggest that universal vaccination may be an effective public health measure for reducing the annual burden of influenza.

How many people have had a myocardial infarction? Prevalence estimated using historical hospital data.

BACKGROUND: Health administrative data are increasingly used to examine disease occurrence. However, health administrative data are typically available for a limited number of years - posing challenges for estimating disease prevalence and incidence. The objective of this study is to estimate the prevalence of people previously hospitalized with an acute myocardial infarction (AMI) using 17 years of hospital data and to create a registry of people with myocardial infarction. METHODS: Myocardial infarction prevalence in Ontario 2004 was estimated using four methods: 1) observed hospital admissions from 1988 to 2004; 2) observed (1988 to 2004) and extrapolated unobserved events (prior to 1988) using a "back tracing" method using Poisson models; 3) DisMod incidence-prevalence-mortality model; 4) self-reported heart disease from the population-based Canadian Community Health Survey (CCHS) in 2000/2001. Individual respondents of the CCHS were individually linked to hospital discharge records to examine the agreement between self-report and hospital AMI admission. RESULTS: 170,061 Ontario residents who were alive on March 31, 2004, and over age 20 years survived an AMI hospital admission between 1988 to 2004 (cumulative incidence 1.8%). This estimate increased to 2.03% (95% CI 2.01 to 2.05) after adding extrapolated cases that likely occurred before 1988. The estimated prevalence appeared stable with 5 to 10 years of historic hospital data. All 17 years of data were needed to create a reasonably complete registry (90% of estimated prevalent cases). The estimated prevalence using both DisMod and self-reported "heart attack" was higher (2.5% and 2.7% respectively). There was poor agreement between self-reported "heart attack" and the likelihood of having an observed AMI admission (sensitivity = 63.5%, positive predictive value = 54.3%). CONCLUSION: Estimating myocardial infarction prevalence using a limited number of years of hospital data is feasible, and validity increases when unobserved events are added to observed events. The "back tracing" method is simple, reliable, and produces a myocardial infarction registry with high estimated "completeness" for jurisdictions with linked hospital data.

Effectiveness and efficiency of different guidelines on statin treatment for preventing deaths from coronary heart disease: modelling study.

OBJECTIVE: To examine the potential effectiveness and efficiency of different guidelines for statin treatment to reduce deaths from coronary heart disease in the Canadian population. DESIGN: Modelled outcomes of screening and treatment recommendations of six national or international guidelines--from Canada, Australia, New Zealand, the United States, joint British societies, and European societies. SETTING: Canada. DATA SOURCES: Details for 6760 men and women aged 20-74 years from the Canadian Heart Health Survey (weighted sample of 12,300,000 people) that included physical measurements including a lipid profile. MAIN OUTCOME MEASURES: The number of people recommended for treatment with statins, the potential number of deaths from coronary heart disease avoided, and the number needed to treat to avoid one coronary heart disease death with five years of statin treatment if the recommendations from each guideline were fully implemented. RESULTS: When applied to the Canadian population, the Australian and British guidelines were the most effective, potentially avoiding the most deaths over five years (> 15,000 deaths). The New Zealand guideline was the most efficient, potentially avoiding almost as many deaths (14,700) while recommending treatment to the fewest number of people (12.9% of people v 17.3% with the Australian and British guidelines). If their "optional" recommendations are included, the US guidelines recommended treating about twice as many people as the New Zealand guidelines (24.5% of the population, an additional 1.4 million people) with almost no increase in the number of deaths avoided. CONCLUSIONS: By focusing recommendations on people with the highest risk of coronary heart disease, the Canadian, US, and European societies guidelines could improve either their effectiveness (in terms of hundreds of avoided deaths) or efficiency (in terms of thousands of fewer people recommended treatment) in the Canadian population.

Gender differences in the blood volume of conscious Sprague-Dawley rats.

Reference values of blood volume (BV) and plasma volume (PV) of animal species are given as functions of body weight and gender specification generally is not given. Considering the common observation of a decreased hematocrit (Hct) in the females of many species, the BV, the PV, or both must differ between genders. The present study was performed to determine the magnitude of those differences. We measured Hct and PV in 24 female and 23 male Sprague-Dawley rats in their 12th week of life. The rats were surgically prepared with indwelling femoral arterial catheters 4 d prior to the determination of BV. Evan's Blue dye dilution was used to determine PV in conscious, quietly resting animals. BV was calculated as PV/(1-Hct). Mean Hct was 2% lower in female rats than males, and PV (mean +/- 1 standard deviation) was 4.86 +/- 0.54 ml/100 g in females compared with 4.12 +/- 0.32 ml/100 g in males. Calculated BV in female rats was 7.84 +/- 0.70 ml/100 g compared with 6.86 +/- 0.53 ml/100 g in males. When precise estimates of BV or PV are needed for research or dosing purposes, gender differences of 18% for PV and 14% for BV must be considered. In addition, species other than the rat may have similar discrepancies between sexes, and the prudent investigator must determine individual volume assessments of both sexes before assumptions of BV and PV for a species can be made.