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As the pace of biomedical innovation rapidly evolves, there is a need to train researchers to understand regulatory science challenges associated with clinical translation. We describe a pilot course aimed at addressing this need delivered jointly through the Mayo Clinic Center for Clinical and Translational Science and the Yale-Mayo Center for Excellence in Regulatory Science and Innovation. Course design was informed by the Association for Clinical and Translational Science’s Regulatory Science Working Group’s competencies. The course used didactic, case-, and problem-based learning sessions to expose students to regulatory science concepts. Course evaluation focused on student satisfaction and learning. A total of 25 students enrolled in the first two course deliveries. Students represented several disciplines and career stages, from pre-doctoral to faculty. Students reported learning “an incredible amount” (7/19, 36.8%) or “a lot” (9/19, 47.4%); this was reflected in individual coursework and their course evaluations. Qualitative feedback indicated that assignments that challenged them to apply the content to their own research were appreciated. The heterogeneity of students enrolled, coupled with assessments and course evaluations, supports the statement that there is a growing need and desire for regulatory science-focused curricula. Future research will determine the long-term impact.
Places such as Poverty Point, Mound City, and Chaco Canyon remind us that the siting of ritual infrastructure in ancient North America was a matter of cosmological precedent. The cosmic gravity of these places gathered persons periodically in numbers that challenged routine production. Ritual economies intensified, but beyond the material demands of hosting people, the siting of these places and the timing of gatherings were cosmic work that preconfigured these outcomes. A first millennium AD civic-ceremonial center on the northern Gulf Coast of Florida illustrates the rationale for holding feasts on the end of a parabolic dune that it shared with an existing mortuary facility. Archaeofauna from large pits at Shell Mound support the inference that feasts were timed to summer solstices. Gatherings were large, judging from the infrastructure in support of feasts and efforts to intensify production through oyster mariculture and the construction of a large tidal fish trap. The 250-year history of summer solstice feasts at Shell Mound reinforces the premise that ritual economies were not simply the amplification of routine production. It also suggests that the ecological potential for intensification was secondary to the cosmic significance of solstice-oriented dunes and their connection to mortuary and world-renewal ceremonialism.
Apolipoprotein E (APOE) E4 is the main genetic risk factor for Alzheimer’s disease (AD). Due to the consistent association, there is interest as to whether E4 influences the risk of other neurodegenerative diseases. Further, there is a constant search for other genetic biomarkers contributing to these phenotypes, such as microtubule-associated protein tau (MAPT) haplotypes. Here, participants from the Ontario Neurodegenerative Disease Research Initiative were genotyped to investigate whether the APOE E4 allele or MAPT H1 haplotype are associated with five neurodegenerative diseases: (1) AD and mild cognitive impairment (MCI), (2) amyotrophic lateral sclerosis, (3) frontotemporal dementia (FTD), (4) Parkinson’s disease, and (5) vascular cognitive impairment.
Genotypes were defined for their respective APOE allele and MAPT haplotype calls for each participant, and logistic regression analyses were performed to identify the associations with the presentations of neurodegenerative diseases.
Our work confirmed the association of the E4 allele with a dose-dependent increased presentation of AD, and an association between the E4 allele alone and MCI; however, the other four diseases were not associated with E4. Further, the APOE E2 allele was associated with decreased presentation of both AD and MCI. No associations were identified between MAPT haplotype and the neurodegenerative disease cohorts; but following subtyping of the FTD cohort, the H1 haplotype was significantly associated with progressive supranuclear palsy.
This is the first study to concurrently analyze the association of APOE isoforms and MAPT haplotypes with five neurodegenerative diseases using consistent enrollment criteria and broad phenotypic analysis.
The authors report on strong exciton–photon coupling in all-metal microcavities containing functionalized anthradithiophene (ADT) in host poly(methyl methacrylate) matrices for a wide range of ADT concentrations. Angle-resolved reflectance of polycrystalline films revealed Rabi splittings up to 340 meV. Angle-resolved photoluminescence in films with low ADT concentrations (dominated by “isolated” ADT molecules) showed Rabi splittings which scaled with the square root of oscillator strength. When “aggregated” and “isolated” ADT molecules coexisted in film, cavities preferentially coupled to “isolated” molecules due to an anisotropic distribution of aggregates. As a solution-processable high-performance organic semiconductor, ADT shows promise as an (opto)electronic polaritonic material.
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.
Respiratory viral infections are a leading cause of disease worldwide. A variety of respiratory viruses produce infections in humans with effects ranging from asymptomatic to life-treathening. Standard surveillance systems typically only target severe infections (ED outpatients, hospitalisations, deaths) and fail to track asymptomatic or mild infections. Here we performed a large-scale community study across multiple age groups to assess the pathogenicity of 18 respiratory viruses. We enrolled 214 individuals at multiple New York City locations and tested weekly for respiratory viral pathogens, irrespective of symptom status, from fall 2016 to spring 2018. We combined these test results with participant-provided daily records of cold and flu symptoms and used this information to characterise symptom severity by virus and age category. Asymptomatic infection rates exceeded 70% for most viruses, excepting influenza and human metapneumovirus, which produced significantly more severe outcomes. Symptoms were negatively associated with infection frequency, with children displaying the lowest score among age groups. Upper respiratory manifestations were most common for all viruses, whereas systemic effects were less typical. These findings indicate a high burden of asymptomatic respiratory virus infection exists in the general population.
Ion implantation is known to increase the lifetime of cutting tools. Current theories are the increase in lifetime is caused by an increase in the residual stress, or by work hardening of the surface associated with the implantation. In this work the effect of ion implantation on the residual stress in titanium nitride coatings made by the standard industrial methods of chemical and physical vapor deposition (CVD and PVD) is studied. It is found in the as-received condition (unimplanted), the residual stress levels are near zero for CVD materials and highly compressive, of the order of 6 GPa, for PVD materials. Ion implantation has no effect on the residual stress: in the coatings made by CVD. Nitrogen does increase the compressive residual stress by some 10% in the near surface regions of PVD coatings, while nickel-titanium dual metal ion implantation does not have any effect. It appears that the lifetime increase is not associated with residual stress effects.
To examine associations between maternal parenting style and pre-school children’s dietary intake and to test whether perceived maternal time pressures, parenting arrangements and employment status influence these relationships.
This cross-sectional study examined mothers’ reports of their child’s frequency of consumption of eight food and drink groups, including sugar-sweetened beverages (SSB), unhealthy snacks, takeaway foods, fruit and vegetables. Parenting styles were classified as authoritative, authoritarian, permissive or disengaged using two parenting dimensions (warmth and control). The moderating roles of parenting arrangements, indexed by number of parents in the home and maternal employment status, were assessed. Associations were examined using multinomial regression.
Data were from the infant and child cohorts in the Longitudinal Study of Australian Children.
Children aged 4–5 years from both cohorts (infant: n 3607; child: n 4661) were included.
Compared with children of disengaged mothers, children of authoritative mothers consumed most unhealthy foods less frequently, and fruit and vegetables more frequently. Results suggested parenting arrangements and mothers’ working status may moderate associations between parenting styles and SSB, takeaway foods, takeaway snacks and fruit consumption.
These findings suggest that authoritative parenting style is associated with a higher consumption of fruit and vegetables and a lower consumption of unhealthy foods among children. However, parenting arrangements and the mothers’ working status may influence these relationships. Further research is required to examine the influence of other potential moderators of parenting style/food consumption relationships such as household time and resource limitations.
Accurately dating when people first colonized new areas is vital for understanding the pace of past cultural and environmental changes, including questions of mobility, human impacts and human responses to climate change. Establishing effective chronologies of these events requires the synthesis of multiple radiocarbon (14C) dates. Various “chronometric hygiene” protocols have been used to refine 14C dating of island colonization, but they can discard up to 95% of available 14C dates leaving very small datasets for further analysis. Despite their foundation in sound theory, without independent tests we cannot know if these protocols are apt, too strict or too lax. In Iceland, an ice core-dated tephrochronology of the archaeology of first settlement enables us to evaluate the accuracy of 14C chronologies. This approach demonstrated that the inclusion of a wider range of 14C samples in Bayesian models improves the precision, but does not affect the model outcome. Therefore, based on our assessments, we advocate a new protocol that works with a much wider range of samples and where outlying 14C dates are systematically disqualified using Bayesian Outlier Models. We show that this approach can produce robust termini ante quos for colonization events and may be usefully applied elsewhere.
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.
A discordant twin gestation, in which one fetus is significantly growth restricted, compared to the other normal twin, is a unique model that can be used to elucidate the mechanism(s) by which the intrauterine environment affects fetal growth. In many model systems, placental transcription factor genes regulate fetal growth. Transcription factors regulate growth through their activation or repression of downstream target genes that mediate important cell functions. The objective of this study was to determine the expression of the placental HLX homeobox gene transcription factor and its downstream target genes in dizygotic twins with growth discordance. In this cross-sectional study, HLX and its downstream target genes’ retinoblastoma 1 (RB1) and cyclin kinase D (CDKN1C) expression levels were determined in placentae obtained from dichorionic diamniotic twin pregnancies (n = 23) where one of the twins was growth restricted. Fetal growth restriction (FGR) was defined as small for gestational age with abnormal umbilical artery Doppler indices when compared with the normal control co-twin. Homeobox gene HLX expression was significantly decreased at both the mRNA and protein levels in FGR twin placentae compared with the normal control co-twin placentae (p < .05). Downstream target genes CDKN1C and RB1 were also significantly decreased and increased, respectively, at both the mRNA and protein levels in FGR twin placentae compared with normal control co-twin placentae (p < .05). Together, these observations suggest an important association between HLX transcription factor expression and abnormal human placental development in discordant twin pregnancies.
Lecithodendrium linstowi is one of the most prevalent and abundant trematodes of bats, but the larval stages and intermediate hosts have not been identified. We present the first molecular and morphological characterization of the cercariae of L. linstowi based on a phylogenetic analysis of partial fragments of LSU and ITS2 rDNA. The first intermediate host was incriminated as Radix balthica by DNA barcoding using cox1 and ITS2 sequences, although the snail morphologically resembled Radix peregra, emphasizing the requirement for molecular identification of lymnaeids as important intermediate hosts of medical and veterinary impact. The application of molecular data in this study has enabled linkage of life cycle stages and accurate incrimination of the first intermediate host.
A field study was conducted for the 2014 and 2015 growing season in Arkansas, Indiana, Illinois, Missouri, Ohio, and Tennessee to determine the effect of cereal rye and either oats, radish, or annual ryegrass on the control of Amaranthus spp. when integrated with comprehensive herbicide programs in glyphosate-resistant and glufosinate-resistant soybean. Amaranthus species included redroot pigweed, waterhemp, and Palmer amaranth. The two herbicide programs included were: a PRE residual herbicide followed by POST application of foliar and residual herbicide (PRE/POST); or PRE residual herbicide followed by POST application of foliar and residual herbicide, followed by another POST application of residual herbicide (PRE/POST/POST). Control was not affected by type of soybean resistance trait. At the end of the season, herbicides controlled 100 and 96% of the redroot pigweed and Palmer amaranth, respectively, versus 49 and 29% in the absence of herbicides, averaged over sites and other factors. The PRE/POST and PRE/POST/POST herbicide treatments controlled 83 and 90% of waterhemp at the end of the season, respectively, versus 14% without herbicide. Cover crop treatments affected control of waterhemp and Palmer amaranth and soybean yield, only in the absence of herbicides. The rye cover crop consistently reduced Amaranthus spp. density in the absence of herbicides compared to no cover treatment.
Risk adjustment is needed to fairly compare central-line–associated bloodstream infection (CLABSI) rates between hospitals. Until 2017, the Centers for Disease Control and Prevention (CDC) methodology adjusted CLABSI rates only by type of intensive care unit (ICU). The 2017 CDC models also adjust for hospital size and medical school affiliation. We hypothesized that risk adjustment would be improved by including patient demographics and comorbidities from electronically available hospital discharge codes.
Using a cohort design across 22 hospitals, we analyzed data from ICU patients admitted between January 2012 and December 2013. Demographics and International Classification of Diseases, Ninth Edition, Clinical Modification (ICD-9-CM) discharge codes were obtained for each patient, and CLABSIs were identified by trained infection preventionists. Models adjusting only for ICU type and for ICU type plus patient case mix were built and compared using discrimination and standardized infection ratio (SIR). Hospitals were ranked by SIR for each model to examine and compare the changes in rank.
Overall, 85,849 ICU patients were analyzed and 162 (0.2%) developed CLABSI. The significant variables added to the ICU model were coagulopathy, paralysis, renal failure, malnutrition, and age. The C statistics were 0.55 (95% CI, 0.51–0.59) for the ICU-type model and 0.64 (95% CI, 0.60–0.69) for the ICU-type plus patient case-mix model. When the hospitals were ranked by adjusted SIRs, 10 hospitals (45%) changed rank when comorbidity was added to the ICU-type model.
Our risk-adjustment model for CLABSI using electronically available comorbidities demonstrated better discrimination than did the CDC model. The CDC should strongly consider comorbidity-based risk adjustment to more accurately compare CLABSI rates across hospitals.
Antibiotic resistance is a major threat to public health. Resistance is largely driven by antibiotic usage, which in many cases is unnecessary and can be improved. The impact of decreasing overall antibiotic usage on resistance is unknown and difficult to assess using standard study designs. The objective of this study was to explore the potential impact of reducing antibiotic usage on the transmission of multidrug-resistant organisms (MDROs).
We used agent-based modeling to simulate interactions between patients and healthcare workers (HCWs) using model inputs informed by the literature. We modeled the effect of antibiotic usage as (1) a microbiome effect, for which antibiotic usage decreases competing bacteria and increases the MDRO transmission probability between patients and HCWs and (2) a mutation effect that designates a proportion of patients who receive antibiotics to subsequently develop a MDRO via genetic mutation.
Intensive care unit
Absolute reduction in overall antibiotic usage by experimental values of 10% and 25%
Reducing antibiotic usage absolutely by 10% (from 75% to 65%) and 25% (from 75% to 50%) reduced acquisition rates of high-prevalence MDROs by 11.2% (P<.001) and 28.3% (P<.001), respectively. We observed similar effect sizes for low-prevalence MDROs.
In a critical care setting, where up to 50% of antibiotic courses may be inappropriate, even a moderate reduction in antibiotic usage can reduce MDRO transmission.