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Overeating can be compulsive, resembling drug addiction. This paper reports that in rats, developing diet-induced obesity correlates with decreasing sensitivity of the brain's reward system. Knockdown of the striatal dopamine receptor D2 led to rapid loss of reward function and to compulsive overeating undeterred by conditioned aversive foot shocks. We found that development of obesity was coupled with emergence of a progressively worsening deficit in neural reward responses. Similar changes in reward homeostasis induced by cocaine or heroin are considered to be crucial in triggering the transition from casual to compulsive drug-taking. Accordingly, we detected compulsive-like feeding behavior in obese but not lean rats, measured as palatable food consumption that was resistant to disruption by an aversive conditioned stimulus. Striatal dopamine D2 receptors (D2Rs) were downregulated in obese rats, as has been reported in humans addicted to drugs. Moreover, lentivirus-mediated knockdown of striatal D2Rs rapidly accelerated the development of addiction-like reward deficits and the onset of compulsive-like food seeking in rats with extended access to palatable high-fat food. These data demonstrate that overconsumption of palatable food triggers addiction-like neuroadaptive responses in brain reward circuits and drives the development of compulsive eating. Common hedonic mechanisms may therefore underlie obesity and drug addiction.

Non-invasive, molecularly-specific, focal modulation of brain circuits with low off-target effects can lead to breakthroughs in treatments of brain disorders. We systemically inject engineered ultrasound-controllable drug carriers and subsequently apply a novel two-component Aggregation and Uncaging Focused Ultrasound Sequence (AU-FUS) at the desired targets inside the brain. The first sequence aggregates drug carriers with millimeter-precision by orders of magnitude. The second sequence uncages the carrier’s cargo locally to achieve high target specificity without compromising the blood-brain barrier (BBB). Upon release from the carriers, drugs locally cross the intact BBB. We show circuit-specific manipulation of sensory signaling in motor cortex in rats by locally concentrating and releasing a GABA A receptor agonist from ultrasound-controlled carriers. Our approach uses orders of magnitude (1300x) less drug than is otherwise required by systemic injection and requires very low ultrasound pressures (20-fold below FDA safety limits for diagnostic imaging). We show that the BBB remains intact using passive cavitation detection (PCD), MRI-contrast agents and, importantly, also by sensitive fluorescent dye extravasation and immunohistochemistry. Non-invasive manipulation of brain circuits with molecular and spatial specificity could revolutionize the treatment of brain disorders. Here, the authors remotely concentrate and deliver drugs to focal brain regions without compromising the blood-brain barrier using novel ultrasound sequences and drug carriers.

Tropical cyclones are the leading cause of major power outages in the U.S., and their effects can be devastating for communities. However, few studies have holistically examined the degree to which socio-economic variables can explain spatial variations in disruptions and reveal potential inequities thereof. Here, we apply machine learning techniques to analyze 20 tropical cyclones and predict county-level outage duration and percentage of customers losing power using a comprehensive set of weather, environmental, and socio-economic factors. Our models are able to accurately predict these outage response variables, but after controlling for the effects of weather conditions and environmental factors in the models, we find the effects of socio-economic variables to be largely immaterial. However, county-level data could be overlooking effects of socio-economic disparities taking place at more granular spatial scales, and we must remain aware of the fact that when faced with similar outage events, socio-economically vulnerable communities will still find it more difficult to cope with disruptions compared to less vulnerable ones.

Background The purpose of this research was to examine the self-reported practice patterns of Canadian general surgeons regarding the elective repair of incisional hernias. Methods A mail survey was sent to all general surgeons in Canada. Data were collected regarding surgeon training, years in practice, practice setting and management of incisional hernias. Surgeons were asked to describe their usual surgical approach for a patient with a midline incisional hernia and a 10 × 6 cm fascial defect. Results Of the 1876 surveys mailed out 555 (30%) were returned and 483 surgeons indicated that they perform incisional hernia repair. The majority (62%) have been in practice > 10 years and 73% regularly repair incisional hernias. In response to the clinical scenario of a patient with an incisional hernia, 74% indicated that they would perform an open repair and 18% would perform a laparoscopic repair. Ninety eight percent of surgeons would use mesh, 73% would perform primary fascial closure and 47% would perform a component separation. The most common locations for mesh placement were intraperitoneal (46%) and retrorectus/preperitoneal (48%). The most common repair, which was reported by 37% of surgeons, was an open operation, with mesh, with primary fascial closure and a component separation. Conclusions While almost all surgeons who perform incisional hernia repairs would use permanent mesh, there was substantial variation reported in surgical approach, mesh location, fascial closure and use of component separation techniques. It is unclear how this variability may impact healthcare resources and patient outcomes.

Hedgehog-interacting protein (HHIP) sequesters Hedgehog ligands to repress Smoothened (SMO)-mediated recruitment of the GLI family of transcription factors. Allelic variation in HHIP confers risk of chronic obstructive pulmonary disease and other smoking-related lung diseases, but underlying mechanisms are unclear. Using single-cell and cell-type-specific translational profiling, we show that HHIP expression is highly enriched in medial habenula (MHb) neurons, particularly MHb cholinergic neurons that regulate aversive behavioral responses to nicotine. HHIP deficiency dysregulated the expression of genes involved in cholinergic signaling in the MHb and disrupted the function of nicotinic acetylcholine receptors (nAChRs) through a PTCH-1/cholesteroldependent mechanism. Further, CRISPR/Cas9-mediated genomic cleavage of the Hhip gene in MHb neurons enhanced the motivational properties of nicotine in mice. These findings suggest that HHIP influences vulnerability to smoking-related lung diseases in part by regulating the actions of nicotine on habenular aversion circuits.

Transanal endoscopic microsurgery (TEM) is widely used for the excision of rectal adenomas and early rectal adenocarcinoma. Few recommendations currently exist for surveillance of lesions excised by TEM. The purpose of this study was to review the surveillance practices and the patterns of recurrence among TEM resected lesions at a tertiary care hospital. A retrospective chart review was performed on all patients who underwent TEM for rectal adenoma or adenocarcinoma before June 2017. In our study population of 114 patients, the final pathology included 78 (68%) adenomas and 36 (32%) adenocarcinomas. Of the adenocarcinomas 23, 9, and 4 were T1, T2, T3 lesions, respectively. Of those, 25 patients opted for surveillance instead of further treatment. The most commonly recommended endoscopic surveillance strategy by our group for both adenomas and adenocarcinomas excised by TEM was flexible sigmoidoscopy every 6 months for 2 years. Recurrences occurred in 4/78 (5.1%) adenoma patients, all found within 16.9 months of surgery, and in 4/25 (16%) adenocarcinoma patients, found between 7.4 and 38.5 months post-surgery. Our data highlights the fact that the timing of recurrences post TEM surgery is variable. Further studies looking at recurrence patterns are needed in order to create comprehensive guidelines for surveillance of these patients.

Background The purpose of this research was to examine the morbidity, mortality and rate of recurrent bowel obstruction associated with the treatment of small bowel obstruction (SBO) in older adults. Methods We prospectively enrolled all patients 70 years or older with an SBO who were admitted to a tertiary care teaching centre between Jul. 1, 2011, and Sept. 30, 2012. Data regarding presentation, investigations, treatment and outcomes were collected. Results Of the 104 patients admitted with an SBO, 49% were managed nonoperatively and 51% underwent surgery. Patients who underwent surgery experienced more complications (64% v. 27%, p = 0.002) and stayed in hospital longer (10 v. 3 d, p < 0.001) than patients managed nonoperatively. Nonoperative management was associated with a high rate of recurrent SBO: 31% after a median follow-up of 17 months. Of the patients managed operatively, 60% underwent immediate surgery and 40% underwent surgery after attempted nonoperative management. Patients in whom nonoperative management failed underwent surgery after a median of 2 days, and 89% underwent surgery within 5 days. The rate of bowel resection was high (29%) among those who underwent delayed surgery. Surgery after failed nonoperative management was associated with a mortality of 14% versus 3% for those who underwent immediate surgery; however, this difference was not significant. Conclusion These data suggest that some elderly patients with SBO may be waiting too long for surgery.

Postoperative complications have been identified as an important and potentially preventable cause of increased hospital costs. While older adults are at increased risk of experiencing complications and other adverse events, very little research has specifically examined how these events impact inpatient costs. We sought to examine the association between postoperative complications, hospital mortality and loss of independence and direct inpatient health care costs in patients 70 years or older who underwent nonelective abdominal surgery. We prospectively enrolled consecutive patients 70 years or older who underwent nonelective abdominal surgery between July 1, 2011, and Sept. 30, 2012. Detailed patient-level data were collected regarding demographics, diagnosis, treatment and outcomes. Patient-level resource tracking was used to calculate direct hospital costs (2012 $CDN). We examined the association between complications, hospital mortality and loss of independence cost using multiple linear regression. During the study period 212 patients underwent surgery. Overall, 51.9% of patients experienced a nonfatal complication (32.5% minor and 19.4% major), 6.6% died in hospital and 22.6% experienced a loss of independence. On multivariate analysis nonfatal complications (p < 0.001), hospital mortality (p = 0.021) and loss of independence at discharge (p < 0.001) were independently associated with health care costs. These adverse events respectively accounted for 30%, 4% and 10% of the total costs of hospital care. Adverse events were common after abdominal surgery in older adults and accounted for 44% of overall costs. This represents a substantial opportunity for better patient outcomes and cost savings with quality improvement strategies tailored to the needs of this high-risk surgical population. Les complications postopératoires sont une cause évitable qui contribue grandement aux coûts hospitaliers élevés. Malgré le fait que les personnes âgées courent un risque accru de subir des complications ou des événements indésirables, peu de recherches ont étudié l’incidence de ces éléments sur les coûts d’hospitalisation. Nous nous sommes penchés sur la relation entre les coûts des soins de santé assumés par les malades hospitalisés et les complications postopératoires, la mortalité hospitalière et la perte d’autonomie auprès d’une population de patients de 70 ans et plus ayant subi une intervention chirurgicale abdominale non facultative. La cohorte prospective a été formée de patients consécutifs âgés de 70 ans et plus ayant subi une intervention chirurgicale abdominale non facultative entre le 1er juillet 2011 et le 30 septembre 2012. Des données détaillées concernant leur profil démographique, leur diagnostic, leur traitement et leurs résultats ont été recueillies. Le calcul des coûts hospitaliers directs est basé sur un suivi des ressources utilisées par les patients (en dollars canadiens, 2012). Au moyen d’une régression linéaire multiple, nous avons analysé la relation entre les complications, la mortalité hospitalière et la perte d’autonomie. Pendant la période à l’étude, 212 patients ont subi une intervention chirurgicale. Parmi eux, 51,9 % ont subi une complication non mortelle (mineure dans 32,5 % des cas; majeure dans 19,4 % des cas), 6,6 % sont décédés à l’hôpital, et 22,6 % ont subi une perte d’autonomie. Une analyse multivariable a permis de conclure que les complications non mortelles (p < 0,001), la mortalité hospitalière (p = 0,021) et la perte d’autonomie à la sortie de l’hôpital (p < 0,001) étaient indépendamment associées aux coûts des soins de santé et qu’elles représentaient respectivement 30 %, 4 % et 10 % des coûts d’hospitalisation totaux. Les événements indésirables étaient fréquents dans le contexte des interventions chirurgicales abdominales réalisées sur des personnes âgées et représentaient 44 % des coûts totaux. Nous devons saisir cette occasion et nous doter de stratégies d’amélioration de la qualité adaptées aux besoins de cette population, à risque élevé sur le plan chirurgical, afin d’améliorer les résultats pour les patients et de diminuer les coûts.

Genetic variation in CHRNA5, the gene encoding the α5 nicotinic acetylcholine receptor subunit, increases vulnerability to tobacco addiction and lung cancer, but the underlying mechanisms are unknown. Here we report markedly increased nicotine intake in mice with a null mutation in Chrna5 . This effect was ‘rescued’ in knockout mice by re-expressing α5 subunits in the medial habenula (MHb), and recapitulated in rats through α5 subunit knockdown in MHb. Remarkably, α5 subunit knockdown in MHb did not alter the rewarding effects of nicotine but abolished the inhibitory effects of higher nicotine doses on brain reward systems. The MHb extends projections almost exclusively to the interpeduncular nucleus (IPN). We found diminished IPN activation in response to nicotine in α5 knockout mice. Further, disruption of IPN signalling increased nicotine intake in rats. Our findings indicate that nicotine activates the habenulo-interpeduncular pathway through α5-containing nAChRs, triggering an inhibitory motivational signal that acts to limit nicotine intake. Anti-smoking drug target Genetic association studies implicate variation in CHRNA5 , the gene for the α5 neuronal nicotinic acetylcholine receptor (nAChR) subunit, in susceptibility to tobacco dependence, lung cancer and chronic obstructive pulmonary disease. The mechanisms linking this gene to behaviour are unknown. Using knockout mice, lentiviral rescue and RNAi knockdown in rats, Fowler et al . show that manipulating the levels of this subunit alters the drive to obtain nicotine, particularly at high doses. Altering activity levels in the habenulo-interpeduncular tract of the brain, where this subunit is highly expressed, changes the amount of nicotine the animals consume. This work identifies α5-containing nAChRs as potential targets for smoking-cessation therapies. In humans, vulnerability to tobacco addiction has been linked to variations in the gene encoding the α5 nicotinic acetylcholine receptor subunit, but the functional mechanisms linking gene to behaviour are unknown. Using a combination of knockout mice, lentiviral rescue, and RNAi knockdown in rats, this study shows that manipulating the levels of this subunit alters the drive to obtain nicotine, particularly at high doses that are aversive to wild-type animals. Furthermore, these subunits are implicated in the projection between medial habenula and interpeduncular nucleus in integrating negative side effects of high doses of nicotine and reward signals. It is proposed that this projection provides a negative motivational signal that limits nicotine consumption.