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Prior trials suggest that intravenous racemic ketamine is a highly effective for treatment-resistant depression (TRD), but phase 3 trials of racemic ketamine are needed.
To assess the acute efficacy and safety of a 4-week course of subcutaneous racemic ketamine in participants with TRD. Trial registration: ACTRN12616001096448 at www.anzctr.org.au.
This phase 3, double-blind, randomised, active-controlled multicentre trial was conducted at seven mood disorders centres in Australia and New Zealand. Participants received twice-weekly subcutaneous racemic ketamine or midazolam for 4 weeks. Initially, the trial tested fixed-dose ketamine 0.5 mg/kg versus midazolam 0.025 mg/kg (cohort 1). Dosing was revised, after a Data Safety Monitoring Board recommendation, to flexible-dose ketamine 0.5–0.9 mg/kg or midazolam 0.025–0.045 mg/kg, with response-guided dosing increments (cohort 2). The primary outcome was remission (Montgomery-Åsberg Rating Scale for Depression score ≤10) at the end of week 4.
The final analysis (those who received at least one treatment) comprised 68 in cohort 1 (fixed-dose), 106 in cohort 2 (flexible-dose). Ketamine was more efficacious than midazolam in cohort 2 (remission rate 19.6% v. 2.0%; OR = 12.1, 95% CI 2.1–69.2, P = 0.005), but not different in cohort 1 (remission rate 6.3% v. 8.8%; OR = 1.3, 95% CI 0.2–8.2, P = 0.76). Ketamine was well tolerated. Acute adverse effects (psychotomimetic, blood pressure increases) resolved within 2 h.
Adequately dosed subcutaneous racemic ketamine was efficacious and safe in treating TRD over a 4-week treatment period. The subcutaneous route is practical and feasible.
For a multi-vectored propeller aerostat with actuator faults, this study presents a fault-tolerant tracking control strategy, which includes fault modeling, observer, force estimation and tracking controller. Fault modeling considers the four types of faults of vectored propellers, namely, thrust offset, thrust efficiency loss, vectored angle offset and vectored angle stuck. Actuator faults can be determined from the fault observer, which identifies the thrust offset from the acceleration difference of the faulty aerostat with the ideal model. For tracking positions, a traditional PID controller is constructed with virtual control, compensated with the estimated fault force. The control allocation scheme is proposed to redistribute the available actuators in case faults occur. Simulation results of position tracking prove the effectiveness of the proposed strategy.
Mars exploration motivates the search for extraterrestrial life, the development of space technologies, and the design of human missions and habitations. Here, we seek new insights and pose unresolved questions relating to the natural history of Mars, habitability, robotic and human exploration, planetary protection, and the impacts on human society. Key observations and findings include:
– high escape rates of early Mars' atmosphere, including loss of water, impact present-day habitability;
– putative fossils on Mars will likely be ambiguous biomarkers for life;
– microbial contamination resulting from human habitation is unavoidable; and
– based on Mars' current planetary protection category, robotic payload(s) should characterize the local martian environment for any life-forms prior to human habitation.
Some of the outstanding questions are:
– which interpretation of the hemispheric dichotomy of the planet is correct;
– to what degree did deep-penetrating faults transport subsurface liquids to Mars' surface;
– in what abundance are carbonates formed by atmospheric processes;
– what properties of martian meteorites could be used to constrain their source locations;
– the origin(s) of organic macromolecules;
– was/is Mars inhabited;
– how can missions designed to uncover microbial activity in the subsurface eliminate potential false positives caused by microbial contaminants from Earth;
– how can we ensure that humans and microbes form a stable and benign biosphere; and
– should humans relate to putative extraterrestrial life from a biocentric viewpoint (preservation of all biology), or anthropocentric viewpoint of expanding habitation of space?
Studies of Mars' evolution can shed light on the habitability of extrasolar planets. In addition, Mars exploration can drive future policy developments and confirm (or put into question) the feasibility and/or extent of human habitability of space.
We summarize some of the past year's most important findings within climate change-related research. New research has improved our understanding about the remaining options to achieve the Paris Agreement goals, through overcoming political barriers to carbon pricing, taking into account non-CO2 factors, a well-designed implementation of demand-side and nature-based solutions, resilience building of ecosystems and the recognition that climate change mitigation costs can be justified by benefits to the health of humans and nature alone. We consider new insights about what to expect if we fail to include a new dimension of fire extremes and the prospect of cascading climate tipping elements.
A synthesis is made of 10 topics within climate research, where there have been significant advances since January 2020. The insights are based on input from an international open call with broad disciplinary scope. Findings include: (1) the options to still keep global warming below 1.5 °C; (2) the impact of non-CO2 factors in global warming; (3) a new dimension of fire extremes forced by climate change; (4) the increasing pressure on interconnected climate tipping elements; (5) the dimensions of climate justice; (6) political challenges impeding the effectiveness of carbon pricing; (7) demand-side solutions as vehicles of climate mitigation; (8) the potentials and caveats of nature-based solutions; (9) how building resilience of marine ecosystems is possible; and (10) that the costs of climate change mitigation policies can be more than justified by the benefits to the health of humans and nature.
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How do we limit global warming to 1.5 °C and why is it crucial? See highlights of latest climate science.
In China, the indications of paliperidone extended in schizophrenia adolescents (12-17 years) was approved by National Medical Products Administration (NMPA) in 2017. But, the utilization of paliperidone in this group needs to be further investigated.
To assess paliperidone utilization in schizophrenia adolescents.
The study employed the electronic medical records (EMRs) database from a psychiatry specialized hospital (PH) and a general hospital (GH), respectively. General information, including birth date, gender, visit date, diagnosis (inpatient and outpatient) with ICD-10 coding, drug characterize, prescription date and dosage, was de-identified and standardized for analysis. Schizophrenia adolescents (ICD-10: F20.x) received at least one prescription of paliperidone between 2018 and 2019 were included in this study. Index date was defined as the date of first identified paliperidone prescription. The patients were followed up until the end of 2019 with the last record, or upon reaching 18 years. The database was analyzed based on days of supply, administration frequency, and daily dose.
Overall, 112 and 117 eligible patients were included in the present study from PH and GH, respectively. The median drug supply was 179.0 days and 44.0 days, respectively, during which median number of prescriptions patients received was 6.0 and 3.0. Paliperidone was mostly initiated alone (57.1% and 88.9%) with frequency of once daily (97.3% and 88.9%), and the median of average daily dose during follow-up was 5.7 mg/day and 6.0 mg/day, respectively.
The duration of paliperidone usage was very different in two hospitals, but the dosages in both hospitals were generally agreed with prescribing information.
An acute gastroenteritis (AGE) outbreak caused by a norovirus occurred at a hospital in Shanghai, China, was studied for molecular epidemiology, host susceptibility and serological roles. Rectal and environmental swabs, paired serum samples and saliva specimens were collected. Pathogens were detected by real-time polymerase chain reaction and DNA sequencing. Histo-blood group antigens (HBGA) phenotypes of saliva samples and their binding to norovirus protruding proteins were determined by enzyme-linked immunosorbent assay. The HBGA-binding interfaces and the surrounding region were analysed by the MegAlign program of DNAstar 7.1. Twenty-seven individuals in two care units were attacked with AGE at attack rates of 9.02 and 11.68%. Eighteen (78.2%) symptomatic and five (38.4%) asymptomatic individuals were GII.6/b norovirus positive. Saliva-based HBGA phenotyping showed that all symptomatic and asymptomatic cases belonged to A, B, AB or O secretors. Only four (16.7%) out of the 24 tested serum samples showed low blockade activity against HBGA-norovirus binding at the acute phase, whereas 11 (45.8%) samples at the convalescence stage showed seroconversion of such blockade. Specific blockade antibody in the population played an essential role in this norovirus epidemic. A wide HBGA-binding spectrum of GII.6 supports a need for continuous health attention and surveillance in different settings.
Food pantries provide free food to individuals at nutritional risk given lack of available foods. Frequent use of food pantries is associated with higher dietary quality; however, neither the nutrient contributions of food pantries to participant diets nor their relationship with household food security are known. This cross-sectional analysis used secondary data from rural food pantry participants, including sociodemographic characteristics, household food security and 24-h recalls. Mean intakes of selected food groups and nutrients from food pantries, supermarkets, other stores and restaurants, and other were compared by one-way ANCOVA. Interaction effects of household food security with food sources were evaluated by two-way ANCOVA. About 40 % of participants’ dietary intake came from food pantries. Mean intakes of fibre (P < 0·0001), Na (P < 0·0001), fruit (P < 0·0001), grains (P < 0·0001) and oils (P < 0·0001) were higher from food pantries compared with all other sources, as were Ca (P = 0·004), vitamin D (P < 0·0001) and K (P < 0·0001) from food pantries compared with two other sources. Percentage total energy intake (%TEI) from added sugars (P < 0·0001) and saturated fat (P < 0·0001) was higher from supermarkets than most other sources. Significant interaction effects were observed between food sources and household food security for vegetables (P = 0·01), Na (P = 0·01) and %TEI from saturated fat (P = 0·004), with food-insecure participants having significantly higher intakes from food pantries and/or supermarkets compared with all other sources. Future interventions may incorporate these findings by providing education on purchasing and preparing healthy meals on limited budgets, to complement foods received from pantries, and by reducing Na in pantry environments.
The dietary insulin index directly estimates the postprandial insulin secretion potential of foods, whereas the empirical dietary index for hyperinsulinaemia (EDIH) assesses the insulinaemic potential of usual diets based on fasting plasma C-peptide, and is primarily reflective of insulin resistance. It is unknown whether these insulin-related indices are predictive of an integrated measure of insulin secretion. We conducted a cross-sectional analysis that included 293 non-diabetic men with 24-h urinary C-peptide data from the Men’s Lifestyle Validation Study. EDIH, dietary insulin index and dietary insulin load were calculated using validated FFQ. We conducted multivariable-adjusted linear regression to estimate relative and absolute concentrations of 24-h urinary C-peptide. In multivariable-adjusted models, we found a significant positive association between all three insulin-related dietary indices and 24-h urinary C-peptide (P < 0·05). Relative concentrations of 24-h urinary C-peptide per 1-sd increase in insulin-related dietary indices were 1·12 (95 % CI 1·02, 1·23) for EDIH, 1·18 (95 % CI 1·07, 1·29) for dietary insulin index and 1·16 (95 % CI 1·06, 1·27) for dietary insulin load. When we further adjusted for BMI, the association was attenuated for EDIH, to 1·07 (95 % CI 0·98, 1·16), and remained unchanged for dietary insulin index and dietary insulin load. In conclusion, EDIH, dietary insulin index and dietary insulin load were predictive of integrated insulin secretion assessed by 24-h urinary C-peptide. Findings after adjustment for BMI appear to confirm the relation of EDIH to insulin resistance and dietary insulin index/load to insulin secretion; the respective constructs of the two dietary indices.
Introduction: Despite an overall decline in opioid prescriptions in Canada, healthcare visits, hospitalizations, and deaths due to opioid-related harms continue to rise for children. Clinicians urgently require high quality synthesized evidence to inform personalized decisions regarding opioid use for children. The objective of this systematic review was to examine the association between short-term therapeutic exposure to opioids and development of opioid use disorder. Methods: A medical librarian conducted a comprehensive search of 10 databases from inception to May 2019. Two authors independently assessed studies for inclusion. Studies were eligible if they reported primary research in English or French, and study participants had short (<14 days) or non-specific duration of therapeutic exposure to opioids before age 18 years. Primary outcome was the development of an opioid use disorder; secondary outcomes included opioid addiction, dependence, misuse, and abuse. Data extraction involved two independent reviewers utilizing a standardized form. Methodological quality was assessed using the NIH tools for observational studies. Results are described narratively. Results: The search identified 4,072 unique citations; 82 were selected for review, and 17 were included (3 retrospective cohort, 4 prospective cohort, and 10 cross-sectional). All studies took place in the USA. A total of 1,562,503 participants were analyzed. Nine studies were administered in schools, 3 used administrative data. While most settings were non-specific, 1 study examined opioid use in dentistry, 1 in trauma, and 1 in organized sports. One comparative study showed an association between short-term therapeutic use and opioid misuse. Two studies showed opioid related adverse events (e.g., overdose) among cohorts exposed to short-term use. The remaining 14 studies did not specify duration of exposure; therefore, confirming whether misuse was due to short-term therapeutic exposure was not possible. Conclusion: A small number of studies in this review suggest an association between short-term opioid use and opioid misuse; however, further analysis is underway with consideration of methodological limitations of the individual studies (final results pending). Careful consideration of the risk and benefits of short-term opioid use should be undertaken prior to prescribing opioids. PROSPERO Registration Number: 122681.
The present study identified the neural mechanism of risky decision-making in Internet gaming disorder (IGD) under a probability discounting task.
Independent component analysis was used on the functional magnetic resonance imaging data from 19 IGD subjects (22.2 ± 3.08 years) and 21 healthy controls (HC, 22.8 ± 3.5 years).
For the behavioral results, IGD subjects prefer the risky to the fixed options and showed shorter reaction time compared to HC. For the imaging results, the IGD subjects showed higher task-related activity in default mode network (DMN) and less engagement in the executive control network (ECN) than HC when making the risky decisions. Also, we found the activities of DMN correlate negatively with the reaction time and the ECN correlate positively with the probability discounting rates.
The results suggest that people with IGD show altered modulation in DMN and deficit in executive control function, which might be the reason for why the IGD subjects continue to play online games despite the potential negative consequences.
Although playing of Internet games may lead to Internet gaming disorder (IGD), most game-users do not develop problems and only a relatively small subset experiences IGD. Game playing may have positive health associations, whereas IGD has been repeatedly associated with negative health measures, and it is thus important to understand differences between individuals with IGD, recreational (non-problematic) game use (RGU) and non-/low-frequency game use (NLFGU). Individuals with IGD have shown differences in neural activations from non-gamers, yet few studies have examined neural differences between individuals with IGD, RGU and NLFGU. Eighteen individuals with IGD, 21 with RGU and 19 with NFLGU performed a color-word Stroop task and a guessing task assessing reward/loss processing. Behavioral and functional imaging data were collected and compared between groups. RGU and NLFGU subjects showed lower Stroop effects as compared with those with IGD. RGU subjects as compared to those with IGD demonstrated less frontal cortical activation brain activation during Stroop performance. During the guessing task, RGU subjects showed greater cortico-striatal activations than IGD subjects during processing of winning outcomes and greater frontal brain during processing of losing outcomes. Findings suggest that RGU as compared with IGD subjects show greater executive control and greater activations of brain regions implicated in motivational processes during reward processing and greater cortical activations during loss processing. These findings suggest neural and behavioral features distinguishing RGU from IGD and mechanisms by which RGU may be motivated to play online games frequently yet avoid developing IGD.
Competence committees play a key role in a competency-based system of assessment. These committees are tasked with reviewing and synthesizing clinical performance data to make judgments regarding residents’ competence. Canadian emergency medicine (EM) postgraduate training programs recently implemented competence committees; however, a paucity of literature guides their work.
The objective of this study was to develop consensus-based recommendations to optimize the function and decisions of competence committees in Canadian EM training programs.
Semi-structured interviews of EM competence committee chairs were conducted and analyzed. The interview guide was informed by a literature review of competence committee structure, processes, and best practices. Inductive thematic analysis of interview transcripts was conducted to identify emerging themes. Preliminary recommendations, based on themes, were drafted and presented at the 2019 CAEP Academic Symposium on Education. Through a live presentation and survey poll, symposium attendees representing the national EM community participated in a facilitated discussion of the recommendations. The authors incorporated this feedback and identified consensus among symposium attendees on a final set of nine high-yield recommendations.
The Canadian EM community used a structured process to develop nine best practice recommendations for competence committees addressing: committee membership, meeting processes, decision outcomes, use of high-quality performance data, and ongoing quality improvement. These recommendations can inform the structure and processes of competence committees in Canadian EM training programs.
Insecticide resistance is an increasing problem in citrus production. The Asian citrus psyllid, Diaphornia citri Kuwayama, is recognized as one of the most important citrus pests worldwide and it has developed resistance in areas where insecticides have been overused. The development of insecticide resistance is often associated with fitness costs that only become apparent in the absence of selection pressure. Here, the fitness costs associated with resistance to thiamethoxam and imidacloprid were investigated in three agricultural populations of D. citri as compared with susceptible laboratory colonies. Results showed that all field populations had greater resistance than laboratory susceptible colonies. For both thiamethoxam and imidacloprid, a Candidatus Liberibacter asiaticus-positive (CLas+) colony was more susceptible than the CLas− colony. Resistance ratios ranged from 7.65–16.11 for imidacloprid and 26.79–49.09 for thiamethoxam in field populations as compared with a susceptible, CLas− laboratory strain. Among three resistant field populations, a significantly reduced net reproductive rate and finite rate of population increase were observed in a population from Lake Wales, FL as compared to both susceptible strains. The fecundity of field populations from Lake Wales, FL was statistically lower than both laboratory susceptible populations. Certain changes in morphological characteristics were observed among resistant, as compared, with susceptible strains. Our data suggest fitness disadvantages associated with insecticide resistance in D. citri are related to both development and reproduction. The lower fitness of D. citri populations that exhibit resistance to neonicotinoid insecticides should promote recovery of sensitivity when those populations are no longer exposed to thiamethoxam and/or imidacloprid in the field. The results are congruent with a strategy of insecticide rotation for resistance management.
Predicting the magnitude of the annual seasonal peak in influenza-like illness (ILI)-related emergency department (ED) visit volumes can inform the decision to open influenza care clinics (ICCs), which can mitigate pressure at the ED. Using ILI-related ED visit data from the Alberta Real Time Syndromic Surveillance Net for Edmonton, Alberta, Canada, we developed (training data, 1 August 2004–31 July 2008) and tested (testing data, 1 August 2008–19 February 2014) spatio-temporal statistical prediction models of daily ILI-related ED visits to estimate high visit volumes 3 days in advance. Our Main Model, based on a generalised linear mixed model with random intercept, incorporated prediction residuals over 14 days and captured increases in observed volume ahead of peaks. During seasonal influenza periods, our Main Model predicted volumes within ±30% of observed volumes for 67%–82% of high-volume days and within 0.3%–21% of observed seasonal peak volumes. Model predictions were not as successful during the 2009 H1N1 pandemic. Our model can provide early warning of increases in ILI-related ED visit volumes during seasonal influenza periods of differing intensities. These predictions may be used to support public health decisions, such as if and when to open ICCs, during seasonal influenza epidemics.
Rumen-protected betaine (RPB) can enhance betaine absorption in the small intestine of ruminants, while betaine can alter fat distribution and has the potential to affect the meat quality of livestock. Hence, we hypothesized that RPB might also affect the meat quality of lambs. Sixty male Hu sheep of similar weight (30.47 ± 2.04 kg) were selected and randomly subjected to five different treatments. The sheep were fed a control diet (control treatment, CTL); 1.1 g/day unprotected-betaine supplemented diet (UPB); or doses of 1.1 g/day (low RPB treatment; L-PB), 2.2 g/day (middle RPB treatment; M-PB) or 3.3 g/day (high RPB treatment; H-PB) RPB-supplemented diet for 70 days. Slaughter performance, meat quality, fatty acid and amino acid content in the longissimus dorsi (LD) muscle, shoulder muscle (SM) and gluteus muscle (GM) were measured. Compared with CTL, betaine (including UPB and RPB) supplementation increased the average daily weight gain (ADG) (P < 0.05) and average daily feed intake (P < 0.01) of lambs. Rumen-protected betaine increased ADG (P < 0.05) compared with UPB. With increasing RPB doses, the eye muscle area of the lambs linearly increased (P < 0.05). Compared with CTL, betaine supplementation decreased water loss (P < 0.05) in SM and increased pH24 in the SM (P < 0.05) and GM (P < 0.05). Compared with UPB, RPB decreased water loss in the GM (P < 0.01), decreased shear force (P < 0.05) in the LD and SM and increased the pH of the meat 24 h after slaughter (pH24). With increasing RPB doses, the shear force and b* value in the LD linearly decreased (P < 0.05), and the pH24 of the meat quadratically increased (P < 0.05). Compared with CTL, betaine supplementation increased the polyunsaturated fatty acid in the GM (P < 0.05). Compared with UPB, RPB supplementation decreased the saturated fatty acid (SFA) content in the LD (P < 0.05) and increased the unsaturated fatty acids (UFA), mono-unsaturated fatty acids and UFA/SFA ratio in the LD (P < 0.05). Compared with CTL, the content of histidine in the LD increased with betaine supplementation. Compared with UPB, RPB supplementation increased the content of total free amino acids and flavor amino acids in the LD of lambs (P < 0.05). With increasing RPB, the isoleucine and phenylalanine contents in the LD linearly increased (P < 0.05). Overall, the data collected indicated that the meat quality of lambs (especially in the LD) improved as a result of betaine supplementation, and RPB showed better effects than those of UPB.
The search for life in the Universe is a fundamental problem of astrobiology and modern science. The current progress in the detection of terrestrial-type exoplanets has opened a new avenue in the characterization of exoplanetary atmospheres and in the search for biosignatures of life with the upcoming ground-based and space missions. To specify the conditions favourable for the origin, development and sustainment of life as we know it in other worlds, we need to understand the nature of global (astrospheric), and local (atmospheric and surface) environments of exoplanets in the habitable zones (HZs) around G-K-M dwarf stars including our young Sun. Global environment is formed by propagated disturbances from the planet-hosting stars in the form of stellar flares, coronal mass ejections, energetic particles and winds collectively known as astrospheric space weather. Its characterization will help in understanding how an exoplanetary ecosystem interacts with its host star, as well as in the specification of the physical, chemical and biochemical conditions that can create favourable and/or detrimental conditions for planetary climate and habitability along with evolution of planetary internal dynamics over geological timescales. A key linkage of (astro)physical, chemical and geological processes can only be understood in the framework of interdisciplinary studies with the incorporation of progress in heliophysics, astrophysics, planetary and Earth sciences. The assessment of the impacts of host stars on the climate and habitability of terrestrial (exo)planets will significantly expand the current definition of the HZ to the biogenic zone and provide new observational strategies for searching for signatures of life. The major goal of this paper is to describe and discuss the current status and recent progress in this interdisciplinary field in light of presentations and discussions during the NASA Nexus for Exoplanetary System Science funded workshop ‘Exoplanetary Space Weather, Climate and Habitability’ and to provide a new roadmap for the future development of the emerging field of exoplanetary science and astrobiology.
Dietary fibre is believed to provide important health benefits including protection from colorectal cancer. However, the evidence on the relationships with different dietary fibre sources is mixed and little is known about which fibre source provides the greatest benefits. We conducted a dose–response meta-analysis of prospective cohorts to summarise the relationships of different fibre sources with colorectal cancer and adenoma risks. Analyses were restricted to publications that reported all fibre sources (cereals, vegetables, fruits, legumes) to increase comparability between results. PubMed and Embase were searched through August 2018 to identify relevant studies. The summary relative risks (RR) and 95 % CI were estimated using a random-effects model. This analysis included a total of ten prospective studies. The summary RR of colorectal cancer associated with each 10 g/d increase in fibre intake were 0·91 (95 % CI 0·82, 1·00; I2 = 0 %) for cereal fibre, 0·95 (95 % CI 0·87, 1·03, I2 = 0 %) for vegetable fibre, 0·91 (95 % CI 0·78, 1·06, I2 = 43 %) for fruit fibre and 0·84 (95 % CI 0·63, 1·13, I2 = 45 %) for legume fibre. For cereal fibre, the association with colorectal cancer risk remained statistically significant after adjustment for folate intake (RR 0·89, 95 % CI 0·80, 0·99, I2 = 2 %). For vegetable and fruit fibres, the dose–response curve suggested evidence of non-linearity. All fibre sources were inversely associated with incident adenoma (per 10 g/d increase: RR 0·81 (95 % CI 0·54, 1·21) cereals, 0·84 (95 % CI 0·71, 0·98) for vegetables, 0·78 (95 % CI 0·65, 0·93) for fruits) but not associated with recurrent adenoma. Our data suggest that, although all fibre sources may provide some benefits, the evidence for colorectal cancer prevention is strongest for fibre from cereals/grains.