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Treatment-resistant schizophrenia, affecting approximately 20–30% of patients with schizophrenia, has a high burden both for patients and healthcare services. There is a need to identify treatment resistance earlier in the course of the illness, in order that effective treatment, such as clozapine, can be offered promptly. We conducted a systemic literature review of prospective longitudinal studies with the aim of identifying predictors of treatment-resistant schizophrenia from the first episode. From the 545 results screened, we identified 12 published studies where data at the first episode was used to predict treatment resistance. Younger age of onset was the most consistent predictor of treatment resistance. We discuss the gaps in the literature and how future prediction models can identify predictors of treatment response more robustly.
Pelvic internal organs change in volume and position during radiotherapy. This may compromise the efficacy of treatment or worsen its toxicity. There may be limitations to fully correcting these changes using online image guidance; therefore, effective and consistent patient preparation and positioning remain important. This review aims to provide an overview of the extent of pelvic organ motion and strategies to manage this motion.
Methods and Materials:
Given the breadth of this topic, a systematic review was not undertaken. Instead, existing systematic reviews and individual high-quality studies addressing strategies to manage pelvic organ motion have been discussed. Suggested levels of evidence and grades of recommendation for each strategy have been applied.
Various strategies to manage rectal changes have been investigated including diet and laxatives, enemas and rectal emptying tubes and rectal displacement with endorectal balloons (ERBs) and rectal spacers. Bladder-filling protocols and bladder ultrasound have been used to try to standardise bladder volume. Positioning the patient supine, using a full bladder and positioning prone with or without a belly board, has been examined in an attempt to reduce the volume of irradiated small bowel. Some randomised trials have been performed, with evidence to support the use of ERBs, rectal spacers, bladder-filling protocols and the supine over prone position in prostate radiotherapy. However, there was a lack of consistent high-quality evidence that would be applicable to different disease sites within the pelvis. Many studies included small numbers of patients were non-randomised, used less conformal radiotherapy techniques or did not report clinical outcomes such as toxicity.
There is uncertainty as to the clinical benefit of many of the commonly adopted interventions to minimise pelvic organ motion. Given this and the limitations in online image guidance compensation, further investigation of adaptive radiotherapy strategies is required.
We apply two methods to estimate the 21-cm bispectrum from data taken within the Epoch of Reionisation (EoR) project of the Murchison Widefield Array (MWA). Using data acquired with the Phase II compact array allows a direct bispectrum estimate to be undertaken on the multiple redundantly spaced triangles of antenna tiles, as well as an estimate based on data gridded to the uv-plane. The direct and gridded bispectrum estimators are applied to 21 h of high-band (167–197 MHz; z = 6.2–7.5) data from the 2016 and 2017 observing seasons. Analytic predictions for the bispectrum bias and variance for point-source foregrounds are derived. We compare the output of these approaches, the foreground contribution to the signal, and future prospects for measuring the bispectra with redundant and non-redundant arrays. We find that some triangle configurations yield bispectrum estimates that are consistent with the expected noise level after 10 h, while equilateral configurations are strongly foreground-dominated. Careful choice of triangle configurations may be made to reduce foreground bias that hinders power spectrum estimators, and the 21-cm bispectrum may be accessible in less time than the 21-cm power spectrum for some wave modes, with detections in hundreds of hours.
Item 9 of the Patient Health Questionnaire-9 (PHQ-9) queries about thoughts of death and self-harm, but not suicidality. Although it is sometimes used to assess suicide risk, most positive responses are not associated with suicidality. The PHQ-8, which omits Item 9, is thus increasingly used in research. We assessed equivalency of total score correlations and the diagnostic accuracy to detect major depression of the PHQ-8 and PHQ-9.
We conducted an individual patient data meta-analysis. We fit bivariate random-effects models to assess diagnostic accuracy.
16 742 participants (2097 major depression cases) from 54 studies were included. The correlation between PHQ-8 and PHQ-9 scores was 0.996 (95% confidence interval 0.996 to 0.996). The standard cutoff score of 10 for the PHQ-9 maximized sensitivity + specificity for the PHQ-8 among studies that used a semi-structured diagnostic interview reference standard (N = 27). At cutoff 10, the PHQ-8 was less sensitive by 0.02 (−0.06 to 0.00) and more specific by 0.01 (0.00 to 0.01) among those studies (N = 27), with similar results for studies that used other types of interviews (N = 27). For all 54 primary studies combined, across all cutoffs, the PHQ-8 was less sensitive than the PHQ-9 by 0.00 to 0.05 (0.03 at cutoff 10), and specificity was within 0.01 for all cutoffs (0.00 to 0.01).
PHQ-8 and PHQ-9 total scores were similar. Sensitivity may be minimally reduced with the PHQ-8, but specificity is similar.
Background: Spinal muscular atrophy (SMA) is a children’s neuromuscular disorder. Although motor neuron loss is a major feature of the disease, we have identified fatty acid abnormalities in SMA patients and in preclinical animal models, suggesting metabolic perturbation is also an important component of SMA. Methods: Biochemical, histological, proteomic, and high resolution respirometry were used. Results: SMA patients are more susceptible to dyslipidemia than the average population as determined by a standard lipid profile in a cohort of 72 pediatric patients. As well, we observed a non-alcoholic liver disease phenotype in apreclinical mouse model. Denervation alone was not sufficient to induce liver steatosis, as a mouse model of ALS, did not develop fatty liver. Hyperglucagonemia in Smn2B/-mice could explain the hepatic steatosis by increasing plasma substrate availability via glycogen depletion and peripheral lipolysis. Proteomic analysis identified mitochondrion and lipid metabolism as major clusters. Alterations in mitochondrial function were revealed by high-resolution respirometry. Finally, low-fat diets led to increased survival in Smn2B/-mice. Conclusions: These results provide strong evidence for lipid metabolism defects in SMA. Further investigation will be required to establish the primary mechanism of these alterations and understand how they lead to additional co-morbidities in SMA patients.
Objectives: The Addenbrooke’s Cognitive Examination (ACE) is a common cognitive screening test for dementia. Here, we examined the relationship between the most recent version (ACE-III) and its predecessor (ACE-R), determined ACE-III cutoff scores for the detection of dementia, and explored its relationship with functional ability. Methods: Study 1 included 199 dementia patients and 52 healthy controls who completed the ACE-III and ACE-R. ACE-III total and domain scores were regressed on their corresponding ACE-R values to obtain conversion formulae. Study 2 included 331 mixed dementia patients and 87 controls to establish the optimal ACE-III cutoff scores for the detection of dementia using receiver operator curve analysis. Study 3 included 194 dementia patients and their carers to investigate the relationship between ACE-III total score and functional ability. Results: Study 1: ACE-III and ACE-R scores differed by ≤1 point overall, the magnitude varying according to dementia type. Study 2: a new lower bound cutoff ACE-III score of 84/100 to detect dementia was identified (compared with 82 for the ACE-R). The upper bound cutoff score of 88/100 was retained. Study 3: ACE-III scores were significantly related to functional ability on the Clinical Dementia Rating Scale across all dementia syndromes, except for semantic dementia. Conclusions: This study represents one of the largest and most clinically diverse investigations of the ACE-III. Our results demonstrate that the ACE-III is an acceptable alternative to the ACE-R. In addition, ACE-III performance has broader clinical implications in that it relates to carer reports of functional impairment in most common dementias. (JINS, 2018, 24, 854–863)
At the QEII Health Sciences Centre Emergency Department (ED) in Halifax, Nova Scotia, advanced care paramedics (ACPs) perform procedural sedation and analgesia (PSA) for many indications, including orthopedic procedures. We have begun using ACPs as sedationists for emergent upper gastrointestinal (UGI) endoscopy. This study compares ACP-performed ED PSA for UGI endoscopy and orthopedic procedures in terms of adverse events, airway intervention, vasopressor requirement, and PSA medication use.
A data set was built from an ED PSA quality control database matching 61 UGI endoscopy PSAs to 183 orthopedic PSAs by propensity scores calculated using age, gender, and the American Society of Anesthesiologists (ASA) classification. Outcomes assessed were hypotension (systolic BP<100 mm Hg or a 15% decrease from baseline), hypoxia (SaO2<90%), apnea (>30 sec), vomiting, arrhythmias, death, airway intervention, vasopressor requirement, and PSA medication use.
UGI endoscopy patients experienced hypotension more frequently than orthopedic patients (OR=4.11, CI: 2.05-8.22) and required airway repositioning less often (OR=0.24, CI: 0.10-0.59). They received ketamine more frequently (OR=15.7, CI: 4.75-67.7) and fentanyl less often (OR=0.30, CI: 0.15-0.63) than orthopedic patients. Four endoscopy patients received phenylephrine, and one required intubation. No patient died in either group.
In ACP-led sedation for UGI endoscopy and orthopedic procedures, adverse events were rare with the notable exception of hypotension, which was more frequent in the endoscopy group. Only endoscopy patients required vasopressor treatment and intubation. We provide preliminary evidence that ACPs can manage ED PSA for emergent UGI endoscopy, although priorities must shift from pain control to hemodynamic optimization.
Different diagnostic interviews are used as reference standards for major depression classification in research. Semi-structured interviews involve clinical judgement, whereas fully structured interviews are completely scripted. The Mini International Neuropsychiatric Interview (MINI), a brief fully structured interview, is also sometimes used. It is not known whether interview method is associated with probability of major depression classification.
To evaluate the association between interview method and odds of major depression classification, controlling for depressive symptom scores and participant characteristics.
Data collected for an individual participant data meta-analysis of Patient Health Questionnaire-9 (PHQ-9) diagnostic accuracy were analysed and binomial generalised linear mixed models were fit.
A total of 17 158 participants (2287 with major depression) from 57 primary studies were analysed. Among fully structured interviews, odds of major depression were higher for the MINI compared with the Composite International Diagnostic Interview (CIDI) (odds ratio (OR) = 2.10; 95% CI = 1.15–3.87). Compared with semi-structured interviews, fully structured interviews (MINI excluded) were non-significantly more likely to classify participants with low-level depressive symptoms (PHQ-9 scores ≤6) as having major depression (OR = 3.13; 95% CI = 0.98–10.00), similarly likely for moderate-level symptoms (PHQ-9 scores 7–15) (OR = 0.96; 95% CI = 0.56–1.66) and significantly less likely for high-level symptoms (PHQ-9 scores ≥16) (OR = 0.50; 95% CI = 0.26–0.97).
The MINI may identify more people as depressed than the CIDI, and semi-structured and fully structured interviews may not be interchangeable methods, but these results should be replicated.
Declaration of interest
Drs Jetté and Patten declare that they received a grant, outside the submitted work, from the Hotchkiss Brain Institute, which was jointly funded by the Institute and Pfizer. Pfizer was the original sponsor of the development of the PHQ-9, which is now in the public domain. Dr Chan is a steering committee member or consultant of Astra Zeneca, Bayer, Lilly, MSD and Pfizer. She has received sponsorships and honorarium for giving lectures and providing consultancy and her affiliated institution has received research grants from these companies. Dr Hegerl declares that within the past 3 years, he was an advisory board member for Lundbeck, Servier and Otsuka Pharma; a consultant for Bayer Pharma; and a speaker for Medice Arzneimittel, Novartis, and Roche Pharma, all outside the submitted work. Dr Inagaki declares that he has received grants from Novartis Pharma, lecture fees from Pfizer, Mochida, Shionogi, Sumitomo Dainippon Pharma, Daiichi-Sankyo, Meiji Seika and Takeda, and royalties from Nippon Hyoron Sha, Nanzando, Seiwa Shoten, Igaku-shoin and Technomics, all outside of the submitted work. Dr Yamada reports personal fees from Meiji Seika Pharma Co., Ltd., MSD K.K., Asahi Kasei Pharma Corporation, Seishin Shobo, Seiwa Shoten Co., Ltd., Igaku-shoin Ltd., Chugai Igakusha and Sentan Igakusha, all outside the submitted work. All other authors declare no competing interests. No funder had any role in the design and conduct of the study; collection, management, analysis and interpretation of the data; preparation, review or approval of the manuscript; and decision to submit the manuscript for publication.
Introduction: With the increasing volume of medical literature published each year, it is difficult for clinicians to translate the latest research into practice. Awareness is the first step of knowledge translation and journals have begun using social media to increase the dissemination and awareness of their publications. Infographics can describe research findings visually, are shared broadly on social media, and may be a more effective way to convey information. We hypothesized that infographic abstracts would increase the social media dissemination and online readership of research articles relative to traditional abstracts. Methods: In this randomized controlled trial, 24 original research articles were chosen from the six issues of the Canadian Journal of Emergency Medicine (CJEM) published between July 2016 and May 2017 (4 articles per issue). Half were randomized to the infographic and control groups within each issue. Infographic articles were promoted using a visual infographic outlining the findings of the article. Control articles were promoted using a screen capture image of each articles abstract. Both were disseminated through the journals social media accounts (Twitter and Facebook) along with the link to the selected article. Infographics were also published on CanadiEM.org. Abstract views, full text views, and the change in Altmetric score were tracked for 30 days and compared between groups. Unpaired two-tailed t-tests were used to detect significant differences. Results: Abstract views (mean, SD) were significantly higher for infographic articles (378.9, 162.0) than control articles (175.5, 69.2, p<0.001). Mean Altmetric scores were significantly higher for infographic articles (26.4, 13.8) than control articles (3.4, 1.7, p<0.0001). There was no statistically significant difference in full-text views between infographic (49.7, 90.4) and control articles (25.3, 12.3). Conclusion: CJEM articles promoted on social media using infographics had higher abstract viewership and Altmetric scores than those promoted with traditional abstracts. Although there was no difference in full-text readership, our results suggest that infographic abstracts may have a role in increasing the dissemination of medical literature.
For livestock production systems to play a positive role in global food security, the balance between their benefits and disbenefits to society must be appropriately managed. Based on the evidence provided by field-scale randomised controlled trials around the world, this debate has traditionally centred on the concept of economic-environmental trade-offs, of which existence is theoretically assured when resource allocation is perfect on the farm. Recent research conducted on commercial farms indicates, however, that the economic-environmental nexus is not nearly as straightforward in the real world, with environmental performances of enterprises often positively correlated with their economic profitability. Using high-resolution primary data from the North Wyke Farm Platform, an intensively instrumented farm-scale ruminant research facility located in southwest United Kingdom, this paper proposes a novel, information-driven approach to carry out comprehensive assessments of economic-environmental trade-offs inherent within pasture-based cattle and sheep production systems. The results of a data-mining exercise suggest that a potentially systematic interaction exists between ‘soil health’, ecological surroundings and livestock grazing, whereby a higher level of soil organic carbon (SOC) stock is associated with a better animal performance and less nutrient losses into watercourses, and a higher stocking density with greater botanical diversity and elevated SOC. We contend that a combination of farming system-wide trials and environmental instrumentation provides an ideal setting for enrolling scientifically sound and biologically informative metrics for agricultural sustainability, through which agricultural producers could obtain guidance to manage soils, water, pasture and livestock in an economically and environmentally acceptable manner. Priority areas for future farm-scale research to ensure long-term sustainability are also discussed.
A major focus for improving the diets in many less developed countries (LDCS) is the provision of rumen fermentable nitrogen (N) using protein supplements to complement N-deficient foods. However, in vitro digestibility methods usually use N-rich environments for the degradation of single foods. This conventional approach may give data which do not reflect the nutritive value of the N-deficient diets often on offer in LDCS, neither is it appropriate for using in vitro gas production to study protein supplementation. Our earlier study indicated that, by using a N-free medium, the gas production technique responded to added ammonium sulphate and urea. The ADAS standardized methodology, which used 10 ml of inoculum instead of the 5 ml used in the earlier study, was found not to be very responsive to N supplementation. The ADAS methodology was therefore investigated in order to develop a modified protocol for fermenting foods in an N-limited environment. The study involved using inocula diluted to different extents in N-free medium for fermenting N-deficient substrates in N-free and N-rich media. The modified protocol was then used for investigating the interactions between N-rich and N-deficient foods from north-west India.
In the proceedings of this, and of several recent close binary conferences, there have been several contributions describing smoothed particle hydrodynamics simulations of accretion disks. It is opposite therefore to review the numerical scheme itself with emphasis on its advantages for disk modelling, and the methods used for modelling viscous processes.
Enteric pathogens are commonly known to be transmitted through food or water; however, contact with animals is another important transmission route. This study estimated the annual burden of illness attributable to animal contact for eight enteric pathogens in Canada. Using data from a Canadian expert elicitation on transmission routes, the proportion of enteric illnesses attributable to animal contact was estimated for each pathogen to estimate the annual number of illnesses, hospitalizations and deaths in Canada. For each estimate, a mean and probability intervals were generated. Of all illnesses caused by these eight pathogens, 16% were estimated attributable to animal contact. This estimate translates to 86 000 (31 000–166 000) illnesses, 488 (186–890) hospitalizations and 12 (2–28) deaths annually for the eight pathogens combined. Campylobacter spp. is the leading cause of illnesses annually, with an estimated 38 000 (14 000–71 000) illnesses occurring each year, followed by non-typhoidal Salmonella spp. (17 000, 6000–32 000). The majority of hospitalizations were attributable to non-typhoidal Salmonella spp. (36%) and Campylobacter spp. (31%). Non-typhoidal Salmonella spp. (28%) and Listeria monocytogenes (31%) were responsible for the majority of the estimated deaths. These results identify farm animal and pet/pet food exposure as key pathways of transmission for several pathogens. The estimated burden of illness associated with animal contact is substantial.
A range of endophenotypes characterise psychosis, however there has been limited work understanding if and how they are inter-related.
This multi-centre study includes 8754 participants: 2212 people with a psychotic disorder, 1487 unaffected relatives of probands, and 5055 healthy controls. We investigated cognition [digit span (N = 3127), block design (N = 5491), and the Rey Auditory Verbal Learning Test (N = 3543)], electrophysiology [P300 amplitude and latency (N = 1102)], and neuroanatomy [lateral ventricular volume (N = 1721)]. We used linear regression to assess the interrelationships between endophenotypes.
The P300 amplitude and latency were not associated (regression coef. −0.06, 95% CI −0.12 to 0.01, p = 0.060), and P300 amplitude was positively associated with block design (coef. 0.19, 95% CI 0.10–0.28, p < 0.001). There was no evidence of associations between lateral ventricular volume and the other measures (all p > 0.38). All the cognitive endophenotypes were associated with each other in the expected directions (all p < 0.001). Lastly, the relationships between pairs of endophenotypes were consistent in all three participant groups, differing for some of the cognitive pairings only in the strengths of the relationships.
The P300 amplitude and latency are independent endophenotypes; the former indexing spatial visualisation and working memory, and the latter is hypothesised to index basic processing speed. Individuals with psychotic illnesses, their unaffected relatives, and healthy controls all show similar patterns of associations between endophenotypes, endorsing the theory of a continuum of psychosis liability across the population.
In continuation of a long term programme of measurement of parallaxes and proper motions in the South Galactic Cap from plates taken with the UK Schmidt Telescope and measured in GALAXY at RGO, data for some 800 red stars brighter than B = 17.5 have been derived from two independent plate series. The parallaxes obtained from unfiltered IIaO plates show a large systematic error depending on magnitude compared with those obtained from IIaD plates with GG 495 filter. After correction, the combined trigonometric parallaxes show very satisfactory agreement with photometric parallaxes, and the average r.m.s. error of a combined parallax is found to be about ±0″.012 both from internal and external evidence.
The association between cigarette smoking and psychosis remains unexplained, but could relate to causal effects in both directions, confounding by socioeconomic factors, such as ethnicity, or use of other substances, including cannabis. Few studies have evaluated the association between cigarettes and psychotic experiences (PEs) in diverse, inner-city populations, or relationships with number of cigarettes consumed.
We assessed associations and dose–response relationships between cigarette smoking and PEs in a cross-sectional survey of household residents (n = 1680) in South East London, using logistic regression to adjust for cannabis use, other illicit substances, and socioeconomic factors, including ethnicity.
We found association between any PEs and daily cigarette smoking, which remained following adjustment for age, gender, ethnicity, cannabis and use of illicit stimulant drugs (fully adjusted odds ratio 1.47, 95% confidence interval 1.01–2.15). Fully adjusted estimates for the association, and with number of PEs, increased with number of cigarettes smoked daily, implying a dose–response effect (p = 0.001 and <0.001, respectively). Odds of reporting any PEs in ex-smokers were similar to never-smokers.
In this diverse epidemiological sample, association between smoking and PEs was not explained by confounders such as cannabis or illicit drugs. Daily cigarette consumption showed a dose–response relationship with the odds of reporting PEs, and of reporting a greater number of PEs. There was no difference in odds of reporting PEs between ex-smokers and never-smokers, raising the possibility that the increase in PEs associated with smoking may be reversible.
A considerable body of evidence suggests that early caregiving may affect the short-term functioning and longer term development of the hypothalamic–pituitary–adrenocortical axis. Despite this, most research to date has been cross-sectional in nature or restricted to relatively short-term longitudinal follow-ups. More important, there is a paucity of research on the role of caregiving in low- and middle-income countries, where the protective effects of high-quality care in buffering the child's developing stress regulation systems may be crucial. In this paper, we report findings from a longitudinal study (N = 232) conducted in an impoverished periurban settlement in Cape Town, South Africa. We measured caregiving sensitivity and security of attachment in infancy and followed children up at age 13 years, when we conducted assessments of hypothalamus–pituitary–adrenocortical axis reactivity, as indexed by salivary cortisol during the Trier Social Stress Test. The findings indicated that insecure attachment was predictive of reduced cortisol responses to social stress, particularly in boys, and that attachment status moderated the impact of contextual adversity on stress responses: secure children in highly adverse circumstances did not show the blunted cortisol response shown by their insecure counterparts. Some evidence was found that sensitivity of care in infancy was also associated with cortisol reactivity, but in this case, insensitivity was associated with heightened cortisol reactivity, and only for girls. The discussion focuses on the potentially important role of caregiving in the long-term calibration of the stress system and the need to better understand the social and biological mechanisms shaping the stress response across development in low- and middle-income countries.
We examined longitudinally the course and predictors of treatment resistance in a large cohort of first-episode psychosis (FEP) patients from initiation of antipsychotic treatment. We hypothesized that antipsychotic treatment resistance is: (a) present at illness onset; and (b) differentially associated with clinical and demographic factors.
The study sample comprised 323 FEP patients who were studied at first contact and at 10-year follow-up. We collated clinical information on severity of symptoms, antipsychotic medication and treatment adherence during the follow-up period to determine the presence, course and predictors of treatment resistance.
From the 23% of the patients, who were treatment resistant, 84% were treatment resistant from illness onset. Multivariable regression analysis revealed that diagnosis of schizophrenia, negative symptoms, younger age at onset, and longer duration of untreated psychosis predicted treatment resistance from illness onset.
The striking majority of treatment-resistant patients do not respond to first-line antipsychotic treatment even at time of FEP. Clinicians must be alert to this subgroup of patients and consider clozapine treatment as early as possible during the first presentation of psychosis.