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Early in the COVID-19 pandemic, the World Health Organization stressed the importance of daily clinical assessments of infected patients, yet current approaches frequently consider cross-sectional timepoints, cumulative summary measures, or time-to-event analyses. Statistical methods are available that make use of the rich information content of longitudinal assessments. We demonstrate the use of a multistate transition model to assess the dynamic nature of COVID-19-associated critical illness using daily evaluations of COVID-19 patients from 9 academic hospitals. We describe the accessibility and utility of methods that consider the clinical trajectory of critically ill COVID-19 patients.
Rigorous scientific review of research protocols is critical to making funding decisions, and to the protection of both human and non-human research participants. Given the increasing complexity of research designs and data analysis methods, quantitative experts, such as biostatisticians, play an essential role in evaluating the rigor and reproducibility of proposed methods. However, there is a common misconception that a statistician’s input is relevant only to sample size/power and statistical analysis sections of a protocol. The comprehensive nature of a biostatistical review coupled with limited guidance on key components of protocol review motived this work. Members of the Biostatistics, Epidemiology, and Research Design Special Interest Group of the Association for Clinical and Translational Science used a consensus approach to identify the elements of research protocols that a biostatistician should consider in a review, and provide specific guidance on how each element should be reviewed. We present the resulting review framework as an educational tool and guideline for biostatisticians navigating review boards and panels. We briefly describe the approach to developing the framework, and we provide a comprehensive checklist and guidance on review of each protocol element. We posit that the biostatistical reviewer, through their breadth of engagement across multiple disciplines and experience with a range of research designs, can and should contribute significantly beyond review of the statistical analysis plan and sample size justification. Through careful scientific review, we hope to prevent excess resource expenditure and risk to humans and animals on poorly planned studies.
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.
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: Choosing Wisely Canada has identified blood transfusions as a priority area for improving clinical appropriateness. Relevant recommendations include Dont transfuse blood if other non-transfusion therapies or observation would be just as effective. In parallel with this recommendation, the Alberta division of Towards Optimized Practice (ToP) has developed guidelines for the treatment of iron deficiency anemia (IDA) that emphasize the use of non-transfusion therapies (i.e. parenteral or oral iron, in appropriate patients). Choosing Wisely also emphasizes strategies to better engage patients in shared decision making. Methods: In order to better engage patients in shared decision making about their treatment options, both physician and patient handouts were developed using an iterative process. The development of the patient-facing documents began with a synthesis of educational materials currently available to patients with IDA. Clinical leaders from nine different specialties (Emergency Medicine, Family Medicine, Day Medicine, Hematology, and others) were continually engaged in the development of content using a consensus model. A focus group of ESCN patient advisors was assembled to review materials with an emphasis on: (1) Are the patient materials easily understood? (2) Are intended messages resonating while avoiding unintended messaging? (3) What information do patients require that has not been included? Following the focus group, revisions were made to patient materials and a subsequent online survey confirmed that the final version addressed any issues they had raised. Results: A four-page patient handout/infographic was developed utilizing best practices in information design, and in physician and patient engagement. Content includes the causes and symptoms of IDA, progressive treatment options from dietary changes to transfusion, and the four Choosing Wisely questions to discuss with your doctor. Conclusion: Patient education materials can be developed according to best practices in information design and stakeholder engagement. Patient focus groups demonstrate that such materials are easier to understand, and better equip patients to engage in shared decision making.
Introduction: Within Alberta, 30% of patients presenting to emergency with minor traumatic brain injury (mTBI) will receive a CT scan before being sent home, regardless of whether it was clinically indicated. Choosing Wisely (CW) Canada recommends using validated clinical decision support to determine whether a CT scan is necessary for patients presenting with a mTBI. In order to provide patients with information on the risks and benefits of CT scans in mTBI and to encourage discussions between patients and their doctor, the Emergency StrategicClinical Network (ESCN) designed a patient focused information visualization on CT scans for head injuries. Methods: The ESCN, Physician Learning Program and CW Alberta partnered with the Mount Royal University Department of Information Design to develop a patient information visualization (infographic) intervention. Students spent a semester developing these infographics on Choosing Wisely recommendations, which were then presented to stakeholders. A student was then selected to develop a final design. Refinement of the design took place in consultation with clinical experts and tested in two patient focus groups. The final design was evaluated against the International Patient Decision Aid Standards checklist. The infographic was posted in 2 local emergency department waiting rooms. A survey was administered to any patients in the waiting room when volunteers were available. The survey was designed to evaluate whether the tool influenced patient beliefs about the risks and benefits of CT scans, and their willingness to engage in a discussion with their doctor. Results: In a 26 day period, 90 patients consented and completed the survey. Before reading the infographic, 33% of patients thought that after a head injury a CT was always a good idea and 63% thought it was sometimes a good idea. 82% and 91% of patients stated the poster helped them understand the indications and risks of CT imaging for mTBI. After viewing the poster, only 15% of patients felt that a CT was always a good idea after a mTBI. Conclusion: The mTBI patient infographic significantly changed patient perceptions regarding the need for CT scans in the setting of mTBI. This study demonstrates that targeted patient education materials can help support CW recommendations.
The Protoplanetary Discussions conference—held in Edinburgh, UK, from 2016 March 7th–11th—included several open sessions led by participants. This paper reports on the discussions collectively concerned with the multi-physics modelling of protoplanetary discs, including the self-consistent calculation of gas and dust dynamics, radiative transfer, and chemistry. After a short introduction to each of these disciplines in isolation, we identify a series of burning questions and grand challenges associated with their continuing development and integration. We then discuss potential pathways towards solving these challenges, grouped by strategical, technical, and collaborative developments. This paper is not intended to be a review, but rather to motivate and direct future research and collaboration across typically distinct fields based on community-driven input, to encourage further progress in our understanding of circumstellar and protoplanetary discs.
Analysis of pelites with detrital white-micas in the Clew Bay–Galway Bay segment of the Irish Caledonides indicates that b0 data from whole-rock and < 2 μm fractions generally show differences smaller than the errors of the method, irrespective of (001) illite crystallinity values, probably due to metamorphic recrystallization. Intermediate pressure metamorphism of the Ordovician–Silurian Clew Bay Group indicates slow subduction, allowing partial thermal re-equilibration before exhumation. In contrast, the Croagh Patrick Group Laurentian shelf-sediments underwent high-pressure alteration, suggesting rapid subduction/exhumation, synchronous with strike-slip faulting. The Murrisk Group, which underwent high-intermediate pressure metamorphism in an Ordovician back-arc, forms a separate terrane to the Croagh Patrick Group to the north and also to the Ordovician Lough Nafooey and Tourmakeady groups and Rosroe Formation in the south, in which low-intermediate pressure alteration occurred. These, together with the Silurian North Galway Group, may have undergone heating due to movement over or deposition on the hot Gowlaun Detachment as the Connemara Dalradian was exhumed. The South Connemara Group also underwent a high-pressure alteration, consistent with its inferred subduction environment. Evidence of contact alteration, due to known or inferred buried late- to post-Caledonian granitoid plutons, has been found in the Clew Bay, Louisburg–Clare Island, Croagh Patrick, Murrisk and South Connemara groups. These show evidence of lower-pressure alteration than the surrounding country-rocks.
Escherichia coli O157.H7 was found in 10 of 3570 (0·28%) faecal samples from dairy cattle in 5 of 60 herds (8·3%). Several tentative associations with manure handling and feeding management practices on dairy farms were identified. Faecal/urine slurry samples, bulk milk samples, and milk filters from dairy herds were negative for E. coli 0157.H7. E. coli 0157.H7 was also isolated from 10 of 1412 (0·71 %) faecal samples from pastured beef cattle in 4 of 25 (16%) herds. The prevalence of E. coli 0157. H7 excretion in feedlot beef cattle was 2 of 600 (0·33 %). The identification of cattle management practices associated with colonization of cattle by E. coli 0157.H7 suggests the possibility that human E. coli O157.H7 exposure may be reduced by cattle management procedures.
Suicide is a leading cause of death and has been strongly associated with affective disorders. The influence of affective disorder polarity on subsequent suicide attempts or completions and any differential effect of suicide risk factors by polarity were assessed in a prospective cohort.
Participants with major affective disorders in the National Institute of Mental Health (NIMH) Collaborative Depression Study (CDS) were followed prospectively for up to 25 years. A total of 909 participants meeting prospective diagnostic criteria for major depressive and bipolar disorders were followed through 4204 mood cycles. Suicidal behavior was defined as suicide attempts or completions. Mixed-effects, grouped-time survival analysis assessed risk of suicidal behavior and differential effects of risk factors for suicidal behavior by polarity. In addition to polarity, the main effects of age, gender, hopelessness, married status, prior suicide attempts and active substance abuse were modeled, with mood cycle as the unit of analysis.
After controlling for age of onset, there were no differences in prior suicide attempts by polarity although bipolar participants had more prior severe attempts. During follow-up, 40 cycles ended in suicide and 384 cycles contained at least one suicide attempt. Age, hopelessness and active substance abuse but not polarity predicted suicidal behavior. The effects of risk factors did not differ by polarity.
Bipolarity does not independently influence risk of suicidal behavior or alter the influence of well-established suicide risk factors within affective disorders. Suicide risk assessment strategies may continue to appraise these common risk factors without regard to mood polarity.
Dolerite dykes in the East Finnmark Scandinavian Caledonides form three geochemical suites: Digermulhalvøya–Magerøya – WNW–ESE-trending, c. 337–332 Ma, possibly also c. 293 Ma, continental within-plate; East Varangerhalvøya – NE–SW and N–S, c. 376 Ma, continental plate-margin; Styret – NE–SW, also c. 376 Ma, chemically intermediate to the other two groups. New K–Ar data from metadolerites on Varangerhalvøya give a 7-point ‘lower envelope’ isochron of 577 ± 14 Ma (MSWD 1.04). This is concordant with a published upper intercept U–Pb zircon age (567+30−23 Ma) from an East Varangerhalvøya dolerite, here re-interpreted to reflect Neoproterozoic basement fracturing contemporaneous with the emplacement of the metadolerites. Intrusion of the younger dolerites at c. 376 Ma reactivated this trend, and may be responsible for the published zircon lower intercept age of 392+25−36 Ma. Clarification of the intrusion and structural chronology, integrated with extensive new geochemical data, enables a better understanding of the evolution of this part of the Scandinavian Caledonides.
Evidence from epidemiological and molecular studies of bovine Escherichia coli O157[ratio ]H7 suggests that strains are frequently transmitted across wide geographic distances. To test this hypothesis, we compared the geographic and genetic distance of a set of international bovine Escherichia coli O157[ratio ]H7 isolates using the Mantel correlation. For a measure of genetic relatedness, pulsed-field gel electrophoresis of six different restriction enzyme digests was used to generate an average Dice similarity coefficient for each isolate pair. Geographic distance was calculated using latitude and longitude data for isolate source locations. The Mantel correlation between genetic similarity and the logarithm of geographic distance in kilometers was −0·21 (P<0·001). The low magnitude of the Mantel correlation indicates that transmission over long distances is common. The occurrence of isolates from different continents on the same cluster of the dendrogram also supports the idea that Escherichia coli O157[ratio ]H7 strains can be transferred with considerable frequency over global distances.
Cattle are considered to be a reservoir host of Escherichia coli O157[ratio ]H7 and contaminated foods of bovine origin are important vehicles of human infection. In this study, the susceptibility of calves to experimental E. coli O157[ratio ]H7 infection following low oral exposures was determined. Two of 17 calves exposed to very low (<300 c.f.u.) doses, and 3 of 4 calves exposed to low (<10000 c.f.u.) doses, subsequently excreted the challenge strains in their faeces. All calves (n = 12) sharing isolation rooms with calves that excreted the challenge strain in their faeces similarly began faecal excretion of the same strains within 21 days or less. The identity between the challenge strains and the strains excreted in calf faeces was confirmed by restriction digestion electrophoretic patterns using pulsed field gel electrophoresis. Calves shed E. coli O157[ratio ]H7 in their faeces after very low dose exposures at concentrations ranging from <30 to >107 c.f.u./g, and for durations similar to the values previously reported for calves challenged by larger doses. The susceptibility of calves to infection following very low exposures or direct contact with infected calves has important implications for programmes for pre-harvest control of this agent.
Escherichia coli O157 isolates from cattle in Japan (n = 91)
and in the USA (n = 415) were compared by pulsed-field gel electrophoresis of endonuclease-cleaved genomic DNA,
location of the stx genes and bacteriophage typing. Three isolates from cattle in Japan with high
similarity to isolates from cattle in the USA were found. Isolates from cattle farms in Japan
and the USA may share a common source.
Salmonella Typhimurium definitive type 104 with chromosomally encoded resistance to five or
more antimicrobial drugs (R-type ACSSuT+) has been reported increasingly frequently as the
cause of human and animal salmonellosis since 1990. Among animal isolates from the
northwestern United States (NWUS), R-type ACSSuT+ Typhimurium isolates increased
through the early 1990s to comprise 73% of Typhimurium isolates by 1995, but subsequently
decreased to comprise only 30% of isolates during 1998. NWUS S. Typhimurium R-type
ACSSuT+ were consistently (99%) phage typed as DT104 or the closely related DTu302. S.
Typhimurium isolates from cattle with primary salmonellosis, randomly selected from a
national repository, from NWUS were more likely to exhibit R-type ACSSuT+ (19/24, 79%)
compared to isolates from other quadrants (17/71, 24%; P < 0.01). Human patients infected
with R-type ACSSuT+ resided in postal zip code polygons of above average cattle farm
density (P < 0.05), while patients infected with other R-types showed no similar tendency.
Furthermore, humans infected with R-type ACSSuT+ Typhimurium were more likely to
report direct contact with livestock (P < 0.01) than humans infected with other R-types.
Escherichia coli O157 (n = 376) from 41 cattle farms were subtyped using pulsed field gel
electrophoresis of endonuclease cleaved chromosomal DNA. Cleavage with XbaI resulted in 81
subtypes. Fifty-one isolates from subtypes found in more than one herd, or in herds on
multiple sample collection dates were compared using the endonuclease NotI, resulting in 23
additional subtypes. Up to 11 XbaI subtypes were found per farm with up to 7 subtypes/farm
identified from a single date. Indistinguishable subtypes (both XbaI and NotI) were found to
persist on 4 farms for 6–24 months. Five subtypes were found on more than one farm
separated by up to 640 km. Dairy farms where cattle had moved onto the farm had a similar
number of subtypes as farms with no movement of cattle, and feedlots had more subtypes than
dairy farms. These data indicate that there is a mechanism for multiple herd exposure to
specific subtypes, there are multiple sources of exposure for cattle on farms, and on-farm
reservoirs other than cattle may exist.