The relationship between hot temperatures and hospital admissions for psychosis in adults diagnosed with schizophrenia: A case-crossover study in Quebec, Canada.

INTRODUCTION: Some studies have found hot temperatures to be associated with exacerbations of schizophrenia, namely psychoses. As climate changes faster in Northern countries, our understanding of the association between temperature and hospital admissions (HA) for psychosis needs to be deepened. OBJECTIVES: 1) Among adults diagnosed with schizophrenia, measure the relationship between mean temperatures and HAs for psychosis during summer. 2) Determine the influence of individual and ecological characteristics on this relationship. METHODS: A cohort of adults diagnosed with schizophrenia (n = 30,649) was assembled using Quebec's Integrated Chronic Disease Surveillance System (QICDSS). The follow-up spanned summers from 2001 to 2019, using hospital data from the QICDSS and meteorological data from the National Aeronautics and Space Administration's (NASA) Daymet database. In four geographic regions of the province of Quebec, a conditional logistic regression was used for the case-crossover analysis of the relationship between mean temperatures (at lags up to 6 days) and HAs for psychosis using a distributed lag non-linear model (DLNM). The analyses were adjusted for relative humidity, stratified according to individual (age, sex, and comorbidities) and ecological (material and social deprivation index and exposure to green space) factors, and then pooled through a meta-regression. RESULTS: The statistical analyses revealed a statistically significant increase in HAs three days (lag 3) after elevated mean temperatures corresponding to the 90th percentile relative to a minimum morbidity temperature (MMT) (OR 1.040; 95% CI 1.008-1.074), while the cumulative effect over six days was not statistically significant (OR 1.052; 95% IC 0.993-1.114). Stratified analyses revealed non statistically significant gradients of increasing HAs relative to increasing material deprivation and decreasing green space levels. CONCLUSIONS: The statistical analyses conducted in this project showed the pattern of admissions for psychosis after hot days. This finding could be useful to better plan health services in a rapidly changing climate.

Surgery, innovation, research and sustainable development.

In the healthcare sector, surgery (especially in the operating theatre) is responsible for emission of greenhouse gases, which is a source of global warming. The goal of this largely quantitative assessment is to address three questions on carbon footprint associated with surgery, the role of primary and secondary prevention prior to surgical procedures, and incorporation of the carbon footprint into judgment criteria in research and surgical innovations. It appears that while the impact of surgery on global warming is undeniable, its extent depends on means of treatment and geographical location. Before and after an operation, primary, secondary and tertiary prevention accompanied by surgical sobriety (avoiding unnecessary or unjustified actions) can be virtuous in terms of sustainable development. However, the sanitary benefits of these actions are often opposed to environmental benefit, which has yet to be satisfactorily assessed. Lastly, the carbon footprint has yet to be incorporated into research protocols or the innovations under development. This should impel us not only to sensitize the different healthcare actors to relevant issues, but also to improve working conditions.

Standardised handover process with checklist improves quality and safety of care in the postanaesthesia care unit: the Postanaesthesia Team Handover trial.

BACKGROUND: Miscommunication is a leading cause of preventable incidents in healthcare. A number of checklists have been created in an attempt to improve patient outcomes with only a small impact. However, the 2009 WHO Surgical Safety Checklist demonstrated benefits in terms of reduced morbidity and mortality. Our aim was to determine whether use of a Postanaesthesia Team Handover (PATH) checklist would reduce hypoxaemic events in the postanaesthesia care unit (PACU). METHODS: This single-centre, prospective, pre-/post-implementation study was conducted between February 2019 and July 2020 in the PACU of Versailles Private Hospital, Paris, France. Pre-PATH implementation data were collected for 294 consecutive adult patients (≥18 yr old) admitted to the PACU and post-PATH implementation data were collected for 293 consecutive patients. The primary outcome was the rate of hypoxaemic events post-surgery during PACU stay. RESULTS: The rates of hypoxaemic events were 4.1% (11/267 [95% confidence interval {CI}: 2.3-7.2%]) before the PATH checklist was introduced and 0.8% (2/266 [95% CI: 0.2-2.7%]) after. Patients in the PATH group were 5.6 times (odds ratio [OR] [95% CI: 1.3-33.6], P=0.041) less likely to have a hypoxaemic event than those in the control group. The handover process in the PATH checklist group also had significantly less interruptions (38.6% control vs 20.7% PATH; OR=2.5 [95% CI: 1.7-3.7]; P<0.0001). CONCLUSIONS: Implementation of the PATH checklist in adult patients post-surgery was associated with a reduction in the rate of hypoxaemic events in the PACU. These findings support standardisation of the handover process with checklists following anaesthesia and surgery. CLINICAL TRIAL REGISTRATION: NCT03972423.

Experimental Set-up for FLASH Proton Irradiation of Small Animals Using a Clinical System.

PURPOSE: Recent in vivo investigations have shown that short pulses of electrons at very high dose rates (FLASH) are less harmful to healthy tissues but just as efficient as conventional dose-rate radiation to inhibit tumor growth. In view of the potential clinical value of FLASH and the availability of modern proton therapy infrastructures to achieve this goal, we herein describe a series of technological developments required to investigate the biology of FLASH irradiation using a commercially available clinical proton therapy system. METHODS AND MATERIALS: Numerical simulations and experimental dosimetric characterization of a modified clinical proton beamline, upstream from the isocenter, were performed with a Monte Carlo toolkit and different detectors. A single scattering system was optimized with a ridge filter and a high current monitoring system. In addition, a submillimetric set-up protocol based on image guidance using a digital camera and an animal positioning system was also developed. RESULTS: The dosimetric properties of the resulting beam and monitoring system were characterized; linearity with dose rate and homogeneity for a 12 × 12 mm2 field size were assessed. Dose rates exceeding 40 Gy/s at energies between 138 and 198 MeV were obtained, enabling uniform irradiation for radiobiology investigations of small animals in a modified clinical proton beam line. CONCLUSIONS: This approach will enable us to conduct FLASH proton therapy experiments on small animals, specifically for mouse lung irradiation. Dose rates exceeding 40 Gy/s were achieved, which was not possible with the conventional clinical mode of the existing beamline.

Vitamin B12 (cyanocobalamin) in Infant Formula Adult/Pediatric Nutritional Formula by Liquid Chromatography with Ultraviolet Detection: Collaborative Study, Final Action 2014.02.

To determine the repeatability and reproducibility figures of the AOAC First Action Official MethodSM 2014.02 (Vitamin B12 in Infant Formula and Adult/Pediatric Formula by Liquid Chromatography with UV Detection), a collaborative study was organized. Twenty-one laboratories located in 13 different countries agreed to participate. The study was divided into two parts. During the first part, the laboratories analyzed two samples in duplicate by using the method described in the protocol. The laboratories that provided results within the expected range were qualified for part two, during which they analyzed 10 samples in blind duplicates. Eighteen laboratories managed to provide results on time for reporting. The results were compared with the Standard Method Performance Requirement (SMPR® 2011.005) established for vitamin B12. The precision results met the requirements stated in the SMPR except for one sample. Repeatability and reproducibility relative standard deviation ranged from 1.1 to 6.5% and from 6.0 to 23.8%, respectively, with only one matrix showing reproducibility values higher than the required 11%. Horwitz ratio values were all well below 2 (0.17-0.78). The AOAC Expert Review Panel (Stakeholder Panel for Infant Formula and Adult Nutritional Expert Review Panel) determined that the data presented met the SMPR and, hence, recommended the method to be granted Final Action status in September 2016.

Application of supercritical fluid chromatography coupled to mass spectrometry to the determination of fat-soluble vitamins in selected food products.

In the present manuscript, we describe a fully optimized and validated method suitable to analyse nine compounds (retinyl acetate, retinyl palmitate, retinol, α-tocopherol, α-tocopheryl acetate, cholecalciferol, ergocalciferol, phylloquinone, menaquinone-4) representing the major contributors to the fat-soluble vitamin activity of selected food products (infant formulas, adult nutritionals, infant cereals and mixed meals). Sample preparation involves direct solvent extraction using enzyme-assisted matrix disintegration and methanolic protein precipitation. Direct injection of the extract allows quantification of vitamins A, E and K in only 7 min, while vitamin D is determined after fast derivatization of the extract. Separation is achieved by supercritical fluid chromatography and detection performed by tandem mass spectrometry in positive Atmospheric Pressure Chemical Ionization mode. Results on a Standard Reference Material (SRM 1849a Infant/Adult Nutritional) were not statistically different from reference values. Full validation of the method showed excellent overall performance. Average recovery rate was between 90 and 110% for all vitamins and matrixes. The methodology shows enhanced safety and reduced cost as compared with previously published methods, together with potential for application to more complex matrixes. The full procedure can be easily applied in control laboratories dramatically increasing sample throughput and reducing solvent consumption.

The contribution of minor folates to the total vitamin B9 content of Infant formula and clinical nutrition products.

In the present study an optimization of trienzyme treatment combining α-amylase, protease and γ-carboxy peptidase allowing complete sample preparation within a working day for the analysis of vitamin B9 (folate) in infant formula and adult/pediatric nutritional products is presented. The optimized sample preparation was applied to a set of samples representing most of the products in the marketplace. Results on Standard Reference Material 1849a were well in agreement with certified values. The main contributor to total folate was folic acid, 5-methyl-tetrahydrofolate was the only minor contributor in milk-based products. Soy-based formulas contained polyglutamates of 5-formyl-tetrahydrofolate. The relative contribution of polyglutamates to the total folate content remained low in the types of product included in this study. The results suggest that a simple di-enzyme treatment could be enough for these products, nevertheless, this should be carefully evaluated prior to making a decision on the use of tri- or di-enzyme treatment.

Use of a collaborative tool to simplify the outsourcing of preclinical safety studies: an insight into the AstraZeneca-Charles River Laboratories strategic relationship.

In 2012, AstraZeneca entered into a strategic relationship with Charles River Laboratories whereby preclinical safety packages comprising safety pharmacology, toxicology, formulation analysis, in vivo ADME, bioanalysis and pharmacokinetics studies are outsourced. New processes were put in place to ensure seamless workflows with the aim of accelerating the delivery of new medicines to patients. Here, we describe in more detail the AstraZeneca preclinical safety outsourcing model and the way in which a collaborative tool has helped to translate the processes in AstraZeneca and Charles River Laboratories into simpler integrated workflows that are efficient and visible across the two companies.

An Improved Method for the Quantification of Thiamine (Vitamin B1) in Cocoa-Containing Beverage Powders.

The purpose of this work was to understand low recoveries of thiamine (vitamin B1) when extracted from cocoa-containing beverage powders fortified with water-soluble vitamin B1, and to develop and validate a new procedure to improve these results. Based on the literature, previous trials have focused on two main factors: pH value prior to paper filtration and the need for solid-phase extraction (SPE) clean up. We demonstrate that by following European Standard EN 14122, recovery of thiamine in cocoa-containing beverage powders is low and dependent on the test portion (86 and 72% for 0.5 and 1.5 g test portions, respectively). Our improved method resolved this problem by keeping the pH low (around 1) prior to paper filtration, leading to a 96.3% recovery and high precision (RSDr of 3.5%). The use of strong cation-exchange SPE cartridges for cleanup prior to the thiamine oxidation reaction proved to be essential. A comparison between our improved method and EN 14122 on nine cocoa-containing beverage samples available on local market from different manufacturers showed a systematic increase in thiamine content (up to 70%) when the improved method was applied. The highest difference was observed for the sample that contained the highest amount of cocoa. However, for beverage powders that contained both cocoa and milk, no difference was observed.

Vitamin C in Infant Formula and Adult/Pediatric Nutritional Formula by Liquid Chromatography with UV Detection: Collaborative Study, Final Action 2012.22.

To determine the repeatability and reproducibility values of the AOAC INTERNATIONAL First Action Method 2012.22, Vitamin C in Infant Formula and Adult/Pediatric Nutritional Formula by Liquid Chromatography with UV Detection, a collaborative study was organized. The study was divided into two parts: method setup and qualification of participants (part 1) and collaborative study participation (part 2). During part 1, each laboratory was asked to analyze two practice samples using the aforementioned method. Laboratories that provided results within a range of expected levels were qualified for part 2, where they analyzed 10 samples in blind duplicates. Two of the samples were suspected of spoilage during the test and new cans of the same type of product were analyzed by a subset of laboratories in part 3. The results were compared with Standard Method Performance Requirement (SMPR®) 2012.012 established for vitamin C. The precision results were within the requirements stated in the SMPR: 1.4-7.3% and 3.2-11.4% respectively, for repeatability and reproducibility. Finally, Horwitz ratio values were all <2 (0.5-1.7). The Expert Review Panel for Stakeholder Panel for Infant Formula and Adult Nutritionals Nutrient Methods determined that the data presented met the SMPR and therefore recommended the method be granted Final Action status.

Face transplant: long-term follow-up and results of a prospective open study.

BACKGROUND: More than 30 face transplantations have been done worldwide since 2005 but no documented long-term follow-up has been reported in the literature. We aimed to answer remaining question about the long-term risks and benefits of face transplant. METHODS: In this single-centre, prospective, open study, we assessed 20 patients presenting with facial defects. Ten patients were selected, and, after three were secondarily excluded, seven were transplanted: two with neurofibromatosis 1, one with a burn, and four with self-inflicted facial gunshot injuries. We report the long-term outcomes of six face allotransplant recipients at an average of 6 years (range 3·4-9 years) after the transplantation. All admissions to hospital except for planned revisions and immunosuppressive follow-up therapy were reported as adverse events (safety endpoint). Predefined immunological, metabolic, surgical, and social integration endpoints were collected prospectively. Patients underwent quantitative health-related quality of life assessments through Short Form 36 health questionnaires. This study was registered with ClinicalTrials.gov, number NCT00527280. FINDINGS: Two of seven patients died: one at 65 days due to transplant destruction with concomitant pseudomonas infection and the second at 3·4 years after transplantation by suicide. The six patients alive at long-term follow-up presented with functional transplants. Safety endpoints were related to infection in the first month, acute rejection from 1 day to 7 years after transplantation, or side-effects of immunosuppressive therapy. Recurrent rejection episodes justified maintenance therapy with high-dose steroids at high levels in all patients at last follow-up, yet none of the patients developed diabetes. Three patients were found to have hypertension with one requiring therapy. All patients had a noticeable reduction in glomerular filtration rate. All recipients and their families accepted their transplant. Improvements in social integration and quality of life were highly variable among the patients and depended on baseline levels and psychiatric comorbidities. INTERPRETATION: These long-term results show the crucial effect of patients' social support and pre-existing psychiatric conditions on the risk-benefit ratio of facial transplantation. Careful preoperative patient selection and long-term postoperative follow-up programmes under strict institutional review board controls should be used for any future grafts of this type. FUNDING: Protocole Hospitalier de Recherche Clinique (PHRC) National.

New Methods for the Analysis of Water-Soluble Vitamins in Infant Formula and Adult/Pediatric Nutritionals.

Water-soluble vitamins (WSVs) are a group of organic compounds which are essential micronutrients. WSVs could be divided between the B complex group and vitamin C (l-ascorbic acid). Within the B complex group, eight vitamins are recognized: vitamins B1 (thiamin), B2 (riboflavin), B3 (niacin or niacinamide), B5 (pantothenic acid), B6 (pyridoxine, pyridoxal, or pyridoxamine), B7 (biotin), B9 (folic acid), and B12 (various cobalamins). This paper reviews the new methods for the analysis of these vitamins, with a focus on infant formula and adult nutritionals.

Determination of 18 water-soluble artificial dyes by LC-MS in selected matrices.

A multi-residue method based on two different extraction procedures was developed and compared with liquid chromatography electrospray ionization tandem mass spectrometry analysis of eighteen water-soluble artificial colours including Tartrazine (E102), Chrysoine (E103), Quinoline Yellow (E104), Yellow 2G (E107), Sunset Yellow (E110), Azorubine (E122), Amaranth (E123), Ponceau 4R (E124), Erythrosine (E127), Red 2G (E128), Allura Red (E129), Patent Blue V (E131), Indigo Carmine (E132), Brilliant Blue (E133), Green S (E142), Fast Green (E143), Brilliant Black (E151), and Black 7984 (E152) in sugar and gummy confectionary, ice-cream, and chocolate sweets. Sample preparation included SPE clean-up and liquid-liquid extraction for ice-cream and chocolate sweets. Accuracy was evaluated by recovery experiments. Correlation between response and concentration was obtained with R(2)>0.98 for all but six colours. Limits of quantification were within the 10-50 µg/kg range for E129; 20-200 µg/kg for E152; 10-250 µg/kg for E103; 10-500 µg/kg for E102, E104, E107, E110, E122, E123, E124, E127, E128, E131, E133; 20-800 µg/kg for E132, 142, 151; and 10-1000 µg/kg for E143. CV for repeatability ranged from 4.0% to 51.0%, while the CV for intermediate reproducibility ranged from 5.8% to 41.4%. Finally, recoveries varied from 84.3% to 166.0%. Together, these demonstrate that the method has been validated for complex matrices and is, thus, fit-for-purpose.

Vitamin A degradation in triglycerides varying by their saturation levels.

Vitamin A deficiency has a widespread occurrence globally and is considered as one of the world's most serious health risk factors. Potential solutions to address this deficiency include dietary diversification or supplementation, but food fortification is generally accepted as the most cost-effective solution. The main issue with food fortification of this vitamin is related to its high instability in food matrices. Dilution of vitamin A in triglycerides is a natural and appropriate way to stabilize this compound. We show here that vitamin A palmitate stability increases with increasing concentration of triglycerides. Moreover, we found that vitamin A palmitate displays improved stability in more saturated oils. Using various temperatures, and Arrhenius plots of experiments performed at storage temperatures between 30°C and 60°C for oils varying by their saturation and crystallinity, we demonstrate that crystallization is not responsible for this phenomenon. Additionally, we show by centrifugation that vitamin A is preferably solubilized in the liquid phase compared to the crystalline phase, explaining that triglyceride crystallization does not stabilize vitamin A palmitate. It is proposed that unsaturated fats generate more oxidation products such as radicals and peroxides, leading to a quicker degradation of vitamin A.

Pantothenic Acid (Vitamin B5) in Infant Formula and Adult/ Pediatric Nutritional Formula by Ultra-High Pressure Liquid Chromatography/Tandem Mass Spectrometry Method: Collaborative Study, Final Action 2012.16.

In order to determine repeatability and reproducibility of AOAC First Action Method 2012.16 [Pantothenic Acid (Vitamin B5) in Infant Formula and Adult/Pediatric Nutritional Formula by Ultra-High Pressure Liquid Chromatography/Tandem Mass Spectrometry], a collaborative study was organized. The study was divided in two parts: method setup and qualification of participants (part 1) and collaborative study participation (part 2). For part 1, each participating laboratory was asked to analyze two practice samples using the aforementioned method. Laboratories that provided results within a range of expected levels were qualified for part 2, during which each laboratory received 10 samples in blind duplicates. Results have been compared to the Standard Method Performance Requirement (SMPR®) 2012.009 established for pantothenic acid. Precision results (repeatability and reproducibility) were within the limits stated in the SMPR. Repeatability ranged from 1.3 to 3.3%, and reproducibility ranged from 4.1 to 7.0%. Horwitz ratio (HorRat) values were all <1, ranging from 0.33 to 0.69. The AOAC Expert Review Panel on Stakeholder Panel on Infant Formula and Adult Nutritionals Nutrient Methods determined that the data presented met the SMPR and recommended the method for Final Action status, which was then granted by the AOAC Official Methods Board.

Experimental Investigation of Pressure Applied on the Lower Leg by Elastic Compression Bandage.

Compression therapy with stockings or bandages is the most common treatment for venous or lymphatic disorders. The objective of this study was to investigate the influence of bandage mechanical properties, application technique and subject morphology on the interface pressure, which is the key of this treatment. Bandage stretch and interface pressure measurements (between the bandage and the leg) were performed on 30 healthy subjects (15 men and 15 women) at two different heights on the lower leg and in two positions (supine and standing). Two bandages were applied with two application techniques by a single operator. The statistical analysis of the results revealed: no significant difference in pressure between men and women, except for the pressure variation between supine and standing positions; a very strong correlation between pressure and bandage mechanical properties (p < 0.00001) and between pressure and bandage overlapping (p < 0.00001); a significant pressure increase from supine to standing positions (p < 0.0001). Also, it showed that pressure tended to decrease when leg circumference increased. Overall, pressure applied by elastic compression bandages varies with subject morphology, bandage mechanical properties and application technique. A better knowledge of the impact of these parameters on the applied pressure may lead to a more effective treatment.

Hydroxypropyl-ß-cyclodextrin impacts renal and systemic hemodynamics in the anesthetized dog.

Hydroxypropyl-ß-cyclodextrin (HPßCD) is a complexation agent used to enhance drug solubilization and formulation stability. Although its toxicity is well characterized, its cardiovascular effects are less known. To investigate them, HPßCD was infused intravenously over 10 min in anesthetized dogs (10-40% (w/v, i.e. 200-800 mg/kg) in non-denervated animals and at 40% in denervated animals). HPßCD increased renal arteriolar resistance and decreased renal blood flow at all doses, almost immediately after infusion start, more drastically in females. A less pronounced increase in total peripheral resistance occurred in females only due to sex difference in sympathetic tone. Pulmonary hemodynamic parameters remained unaffected, suggesting that the renal effect was rather selective. As a consequence of the increased systemic blood pressure, heart rate decreased in normal animals without direct effect on cardiac conductance. This effect was abolished in denervated animals. This suggests that autonomous nervous feedback loops are functional in normal animals and that HPßCD has no direct chronotropic effect. In conclusion, systemic and renal hemodynamic changes should be considered as potential background effects at 200-400 mg/kg. At higher doses (800 mg/kg), changes are more pronounced and could mask/exacerbate hemodynamic response of drug candidate; such doses should be avoided in nonclinical safety studies.

The efficacy of a glial inhibitor, minocycline, for preventing persistent pain after lumbar discectomy: a randomized, double-blind, controlled study.

Minocycline strongly inhibits microglial activation, which contributes to central sensitization, a major mechanism underlying chronic pain development. We hypothesized that the perioperative administration of minocycline might decrease persistent pain after lumbar discectomy. We randomly assigned 100 patients undergoing scheduled lumbar discectomy to placebo and minocycline groups. The minocycline group received 100mg minocycline orally, twice daily, beginning the evening before surgery and continuing for 8 days. The primary outcome was the change in lower limb pain intensity at rest between baseline and 3 months. Secondary outcomes were pain intensity on movement, the incidence of persistent pain and chronic neuropathic pain, back pain intensity at rest and on movement, and changes in Neuropathic Pain Symptom Inventory, Brief Pain Inventory, and Roland-Morris scores at 3 months. An intention-to-treat analysis was performed for patients assessed from the day before surgery to 3 months. The decrease in lower limb pain intensity was similar in the placebo and minocycline groups, both at rest -1.7 ± 1.6 vs -2.3 ± 2.4 and on movement -2.5 ± 2.1 vs -3.4 ± 2.9. The incidence and intensity of neuropathic pain and functional scores did not differ between the minocycline and placebo groups. Exploratory analysis suggested that minocycline might be effective in a subgroup of patients with predominantly deep spontaneous pain at baseline. Perioperative minocycline administration for 8 days does not improve persistent pain after lumbar discectomy.

Pyridocoumarin, aristolactam and aporphine alkaloids from the Australian rainforest plant Goniothalamus australis.

Chemical investigation of the CH(2)Cl(2)/CH(3)OH extracts from aerial parts of the Australian plant Goniothalamus australis has resulted in the isolation of two pyridocoumarin alkaloids, goniothalines A (1) and B (2) as well as eight known natural products, aristolactam AII (3), enterocarpam II (4), caldensine (5), sauristolactam (6), (-)-anonaine (7), asimilobine (8), altholactone (9) and (+)-goniofufurone (10). The chemical structures of all compounds were determined by extensive spectroscopic and spectrometric analysis. Methylation of 2 using TMS-diazomethane afforded 1, which unequivocally established that both 1 and 2 possessed a 10-methyl-2H-pyrano[2,3-f]quinolin-2-one skeleton. These pyridocoumarin alkaloids are putatively proposed to arise biosynthetically from an aporphinoid precursor. Compounds 1-10 were evaluated for in vitro antimalarial activity against a chloroquine-sensitive Plasmodium falciparum line (3D7). Sauristolactam (6) and (-)-anonaine (7) exhibited the most potent antiparasitic activity with IC(50) values of 9 and 7 µM, respectively.