Effect of the Ketogenic Diet on Behavioral Symptoms of Autism in the Poly(IC) Mouse Model

Autism spectrum disorder (ASD) is a neurological disorder characterized by decreased sociability, deficits in communication, and restricted and repetitive behaviors. The ketogenic diet (KD), a high-fat, low-carbohydrate, and moderate-protein diet has been shown to improve these three behavioral symptoms in the BTBR mouse model of autism. However, further research is required to strengthen the body of knowledge surrounding the potential of KD as diet therapy for autism. Epidemiological observations have shown that maternal immune activation (MIA) during pregnancy increases the risk of autism in offspring. Based on these observations, the polyinosinic:polycytidylic acid (poly(IC)) mouse model was developed as an animal model to study autism. Poly(IC) is a synthetic analog of double stranded RNA and acts as a viral mimic. It is injected into a pregnant dam, activating an immune response without causing an infection. The offspring of this protocol are the poly(IC) MIA mouse model. They have been shown to have the autistic symptoms of deficits in sociability and communication as well as increased repetitive behaviors. In this study, pregnant dams were injected with poly(IC) or the saline vehicle during the late first trimester. The offspring were separated into control and test groups. At 5 weeks of age, the test group was placed on a 6:1 fat:(carbohydrates + protein) KD while the control groups remained on standard chow. After three weeks on the diet, we assessed sociability, repetitive behavior, and communication. Our results showed that KD reversed increased self-grooming in poly(IC) mice. Results did not indicate autistic-like behavior in our poly(IC) mice for social contact, sociability, grooming during the 3-chamber test, or repetitive behavior in the marble-burying test. However, KD increased social contact in poly(IC) mice. It also increased sociability and decreased 3-chamber grooming in poly(IC) males. Poly(IC) mice did not have a deficit in the social transmission of food preference task, a previously unused assessment of the poly(IC) mouse model. While our study did not succeed in replicating several autistic behaviors in the poly(IC) mouse model, KD had influence on behavior in multiple measures, increasing sociability and decreasing grooming. This suggests that KD may be an effective diet therapy for autism

Ketogenic diet improves behaviors in a maternal immune activation model of autism spectrum disorder

Prenatal factors influence autism spectrum disorder (ASD) incidence in children and can increase ASD symptoms in offspring of animal models. These may include maternal immune activation (MIA) due to viral or bacterial infection during the first trimesters. Unfortunately, regardless of ASD etiology, existing drugs are poorly effective against core symptoms. For nearly a century a ketogenic diet (KD) has been used to treat seizures, and recent insights into mechanisms of ASD and a growing recognition that immune/inflammatory conditions exacerbate ASD risk has increased interest in KD as a treatment for ASD. Here we studied the effects of KD on core ASD symptoms in offspring exposed to MIA. To produce MIA, pregnant C57Bl/6 mice were injected with the viral mimic polyinosinic-polycytidylic acid; after weaning offspring were fed KD or control diet for three weeks. Consistent with an ASD phenotype of a higher incidence in males, control diet-fed MIA male offspring were not social and exhibited high levels of repetitive self-directed behaviors; female offspring were unaffected. However, KD feeding partially or completely reversed all MIA-induced behavioral abnormalities in males; it had no effect on behavior in females. KD-induced metabolic changes of reduced blood glucose and elevated blood ketones were quantified in offspring of both sexes. Prior work from our laboratory and others demonstrate KDs improve relevant behaviors in several ASD models, and here we demonstrate clear benefits of KD in the MIA model of ASD. Together these studies suggest a broad utility for metabolic therapy in improving core ASD symptoms, and support further research to develop and apply ketogenic and/or metabolic strategies in patients with ASD

Erratum to: 36th International Symposium on Intensive Care and Emergency Medicine

[This corrects the article DOI: 10.1186/s13054-016-1208-6.]

Laparoscopy in management of appendicitis in high-, middle-, and low-income countries: a multicenter, prospective, cohort study.

BACKGROUND: Appendicitis is the most common abdominal surgical emergency worldwide. Differences between high- and low-income settings in the availability of laparoscopic appendectomy, alternative management choices, and outcomes are poorly described. The aim was to identify variation in surgical management and outcomes of appendicitis within low-, middle-, and high-Human Development Index (HDI) countries worldwide. METHODS: This is a multicenter, international prospective cohort study. Consecutive sampling of patients undergoing emergency appendectomy over 6 months was conducted. Follow-up lasted 30 days. RESULTS: 4546 patients from 52 countries underwent appendectomy (2499 high-, 1540 middle-, and 507 low-HDI groups). Surgical site infection (SSI) rates were higher in low-HDI (OR 2.57, 95% CI 1.33-4.99, p = 0.005) but not middle-HDI countries (OR 1.38, 95% CI 0.76-2.52, p = 0.291), compared with high-HDI countries after adjustment. A laparoscopic approach was common in high-HDI countries (1693/2499, 67.7%), but infrequent in low-HDI (41/507, 8.1%) and middle-HDI (132/1540, 8.6%) groups. After accounting for case-mix, laparoscopy was still associated with fewer overall complications (OR 0.55, 95% CI 0.42-0.71, p < 0.001) and SSIs (OR 0.22, 95% CI 0.14-0.33, p < 0.001). In propensity-score matched groups within low-/middle-HDI countries, laparoscopy was still associated with fewer overall complications (OR 0.23 95% CI 0.11-0.44) and SSI (OR 0.21 95% CI 0.09-0.45). CONCLUSION: A laparoscopic approach is associated with better outcomes and availability appears to differ by country HDI. Despite the profound clinical, operational, and financial barriers to its widespread introduction, laparoscopy could significantly improve outcomes for patients in low-resource environments. TRIAL REGISTRATION: NCT02179112

Pooled analysis of WHO Surgical Safety Checklist use and mortality after emergency laparotomy

Background The World Health Organization (WHO) Surgical Safety Checklist has fostered safe practice for 10 years, yet its place in emergency surgery has not been assessed on a global scale. The aim of this study was to evaluate reported checklist use in emergency settings and examine the relationship with perioperative mortality in patients who had emergency laparotomy. Methods In two multinational cohort studies, adults undergoing emergency laparotomy were compared with those having elective gastrointestinal surgery. Relationships between reported checklist use and mortality were determined using multivariable logistic regression and bootstrapped simulation. Results Of 12 296 patients included from 76 countries, 4843 underwent emergency laparotomy. After adjusting for patient and disease factors, checklist use before emergency laparotomy was more common in countries with a high Human Development Index (HDI) (2455 of 2741, 89.6 per cent) compared with that in countries with a middle (753 of 1242, 60.6 per cent; odds ratio (OR) 0.17, 95 per cent c.i. 0.14 to 0.21, P <0001) or low (363 of 860, 422 per cent; OR 008, 007 to 010, P <0.001) HDI. Checklist use was less common in elective surgery than for emergency laparotomy in high-HDI countries (risk difference -94 (95 per cent c.i. -11.9 to -6.9) per cent; P <0001), but the relationship was reversed in low-HDI countries (+121 (+7.0 to +173) per cent; P <0001). In multivariable models, checklist use was associated with a lower 30-day perioperative mortality (OR 0.60, 0.50 to 073; P <0.001). The greatest absolute benefit was seen for emergency surgery in low- and middle-HDI countries. Conclusion Checklist use in emergency laparotomy was associated with a significantly lower perioperative mortality rate. Checklist use in low-HDI countries was half that in high-HDI countries.Peer reviewe

Mortality of emergency abdominal surgery in high-, middle- and low-income countries

Background: Surgical mortality data are collected routinely in high-income countries, yet virtually no low- or middle-income countries have outcome surveillance in place. The aim was prospectively to collect worldwide mortality data following emergency abdominal surgery, comparing findings across countries with a low, middle or high Human Development Index (HDI). Methods: This was a prospective, multicentre, cohort study. Self-selected hospitals performing emergency surgery submitted prespecified data for consecutive patients from at least one 2-week interval during July to December 2014. Postoperative mortality was analysed by hierarchical multivariable logistic regression. Results: Data were obtained for 10 745 patients from 357 centres in 58 countries; 6538 were from high-, 2889 from middle- and 1318 from low-HDI settings. The overall mortality rate was 1⋅6 per cent at 24 h (high 1⋅1 per cent, middle 1⋅9 per cent, low 3⋅4 per cent; P < 0⋅001), increasing to 5⋅4 per cent by 30 days (high 4⋅5 per cent, middle 6⋅0 per cent, low 8⋅6 per cent; P < 0⋅001). Of the 578 patients who died, 404 (69⋅9 per cent) did so between 24 h and 30 days following surgery (high 74⋅2 per cent, middle 68⋅8 per cent, low 60⋅5 per cent). After adjustment, 30-day mortality remained higher in middle-income (odds ratio (OR) 2⋅78, 95 per cent c.i. 1⋅84 to 4⋅20) and low-income (OR 2⋅97, 1⋅84 to 4⋅81) countries. Surgical safety checklist use was less frequent in low- and middle-income countries, but when used was associated with reduced mortality at 30 days. Conclusion: Mortality is three times higher in low- compared with high-HDI countries even when adjusted for prognostic factors. Patient safety factors may have an important role. Registration number: NCT02179112 (http://www.clinicaltrials.gov)

Global variation in anastomosis and end colostomy formation following left-sided colorectal resection

Background End colostomy rates following colorectal resection vary across institutions in high-income settings, being influenced by patient, disease, surgeon and system factors. This study aimed to assess global variation in end colostomy rates after left-sided colorectal resection. Methods This study comprised an analysis of GlobalSurg-1 and -2 international, prospective, observational cohort studies (2014, 2016), including consecutive adult patients undergoing elective or emergency left-sided colorectal resection within discrete 2-week windows. Countries were grouped into high-, middle- and low-income tertiles according to the United Nations Human Development Index (HDI). Factors associated with colostomy formation versus primary anastomosis were explored using a multilevel, multivariable logistic regression model. Results In total, 1635 patients from 242 hospitals in 57 countries undergoing left-sided colorectal resection were included: 113 (6·9 per cent) from low-HDI, 254 (15·5 per cent) from middle-HDI and 1268 (77·6 per cent) from high-HDI countries. There was a higher proportion of patients with perforated disease (57·5, 40·9 and 35·4 per cent; P < 0·001) and subsequent use of end colostomy (52·2, 24·8 and 18·9 per cent; P < 0·001) in low- compared with middle- and high-HDI settings. The association with colostomy use in low-HDI settings persisted (odds ratio (OR) 3·20, 95 per cent c.i. 1·35 to 7·57; P = 0·008) after risk adjustment for malignant disease (OR 2·34, 1·65 to 3·32; P < 0·001), emergency surgery (OR 4·08, 2·73 to 6·10; P < 0·001), time to operation at least 48 h (OR 1·99, 1·28 to 3·09; P = 0·002) and disease perforation (OR 4·00, 2·81 to 5·69; P < 0·001). Conclusion Global differences existed in the proportion of patients receiving end stomas after left-sided colorectal resection based on income, which went beyond case mix alone

Hallmarks of KD therapy confirmed in MIA mice.

<p><i>Left</i>: Blood β-hydroxybutyrate was elevated by KD feeding. <i>Middle</i>: Blood glucose was reduced by KD feeding. ***p<0.001 compared to CD-fed control offspring; n = 20–23. There were no sex differences in either measure (in initial analysis, sex-by-treatment interaction: F = 1.7, p = 0.19 for ketones; F = 1.8, p = 0.18 for glucose); male and female data are combined. <i>Right</i>: CD-fed female mice gained significant weight during diet treatment; KD-fed mice did not. §§§p<0.001 compared to baseline; n = 11–12. Available data from male mice showed a similar pattern (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0171643#pone.0171643.s001" target="_blank">S1 File</a>).</p

KD effects on social behavior in male and female MIA offspring.

<p><i>Top panels</i>: male mice. <i>Top left</i>: Chamber time in the three-chamber test. CD-fed MIA offspring were not social in phase 2. This effect was reversed by KD feeding. Control offspring were social, as expected. Mice in all treatment groups showed significant preference for social novelty in phase 3. <i>Top right</i>: Social contact in the three-chamber test. Social contact time was decreased in male MIA offspring, and elevated by KD feeding to levels above control offspring. §p<0.05, §§p<0.01, §§§p<0.001 compared to phase 1 within the same treatment group. *p<0.05 compared to control mice. ###p<0.001 compared to CD-fed MIA offspring; n = 8–12. <i>Bottom panels</i>: female mice. <i>Bottom left</i>: Sociability expressed as time in chamber with a mouse was not impaired by MIA treatment and not affected by KD feeding. §§§p<0.001 overall phase 2 compared to phase 1; n = 10–12. <i>Bottom right</i>: Sociability expressed as social contact was not impaired by MIA treatment; however KD-feeding elevated social contact. ***p<0.001 overall compared to CD-fed control and MIA offspring; n = 11 all groups.</p