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As more debates in American politics become constitutional questions, effective citizens must engage in constitutional interpretation. While most Americans venerate the Constitution as a part of a national, civil religion, levels of constitutional knowledge are also very low. In this paper, we analyze how ordinary Americans approach the task of constitutional interpretation. An analysis of two cross-sectional surveys indicates constitutional hermeneutics are a product of political factors, religious affiliation, and biblical interpretive preferences. We also present the results of a survey experiment where the manipulation of a clergy's interpretation of a biblical passage affects how respondents interpret both scripture and the Constitution, providing a potential causal mechanism for learning how to engage in hermeneutics.
Cognitive-behavioural therapy (CBT) is an effective treatment for depressed adults. CBT interventions are complex, as they include multiple content components and can be delivered in different ways. We compared the effectiveness of different types of therapy, different components and combinations of components and aspects of delivery used in CBT interventions for adult depression. We conducted a systematic review of randomised controlled trials in adults with a primary diagnosis of depression, which included a CBT intervention. Outcomes were pooled using a component-level network meta-analysis. Our primary analysis classified interventions according to the type of therapy and delivery mode. We also fitted more advanced models to examine the effectiveness of each content component or combination of components. We included 91 studies and found strong evidence that CBT interventions yielded a larger short-term decrease in depression scores compared to treatment-as-usual, with a standardised difference in mean change of −1.11 (95% credible interval −1.62 to −0.60) for face-to-face CBT, −1.06 (−2.05 to −0.08) for hybrid CBT, and −0.59 (−1.20 to 0.02) for multimedia CBT, whereas wait list control showed a detrimental effect of 0.72 (0.09 to 1.35). We found no evidence of specific effects of any content components or combinations of components. Technology is increasingly used in the context of CBT interventions for depression. Multimedia and hybrid CBT might be as effective as face-to-face CBT, although results need to be interpreted cautiously. The effectiveness of specific combinations of content components and delivery formats remain unclear. Wait list controls should be avoided if possible.
Background: Biallelic variants in POLR1C are associated with POLR3-related leukodystrophy (POLR3-HLD), or 4H leukodystrophy (Hypomyelination, Hypodontia, Hypogonadotropic Hypogonadism), and Treacher Collins syndrome (TCS). The clinical spectrum of POLR3-HLD caused by variants in this gene has not been described. Methods: A cross-sectional observational study involving 25 centers worldwide was conducted between 2016 and 2018. The clinical, radiologic and molecular features of 23 unreported and previously reported cases of POLR3-HLD caused by POLR1C variants were reviewed. Results: Most participants presented between birth and age 6 years with motor difficulties. Neurological deterioration was seen during childhood, suggesting a more severe phenotype than previously described. The dental, ocular and endocrine features often seen in POLR3-HLD were not invariably present. Five patients (22%) had a combination of hypomyelinating leukodystrophy and abnormal craniofacial development, including one individual with clear TCS features. Several cases did not exhibit all the typical radiologic characteristics of POLR3-HLD. A total of 29 different pathogenic variants in POLR1C were identified, including 13 new disease-causing variants. Conclusions: Based on the largest cohort of patients to date, these results suggest novel characteristics of POLR1C-related disorder, with a spectrum of clinical involvement characterized by hypomyelinating leukodystrophy with or without abnormal craniofacial development reminiscent of TCS.
Introduction: Although use of point of care ultrasound (PoCUS) protocols for patients with undifferentiated hypotension in the Emergency Department (ED) is widespread, our previously reported SHoC-ED study showed no clear survival or length of stay benefit for patients assessed with PoCUS. In this analysis, we examine if the use of PoCUS changed fluid administration and rates of other emergency interventions between patients with different shock types. The primary comparison was between cardiogenic and non-cardiogenic shock types. Methods: A post-hoc analysis was completed on the database from an RCT of 273 patients who presented to the ED with undifferentiated hypotension (SBP <100 or shock index > 1) and who had been randomized to receive standard care with or without PoCUS in 6 centres in Canada and South Africa. PoCUS-trained physicians performed scans after initial assessment. Shock categories and diagnoses recorded at 60 minutes after ED presentation, were used to allocate patients into subcategories of shock for analysis of treatment. We analyzed actual care delivered including initial IV fluid bolus volumes (mL), rates of inotrope use and major procedures. Standard statistical tests were employed. Sample size was powered at 0.80 (α:0.05) for a moderate difference. Results: Although there were expected differences in the mean fluid bolus volume between patients with non-cardiogenic and cardiogenic shock, there was no difference in fluid bolus volume between the control and PoCUS groups (non-cardiogenic control 1878 mL (95% CI 1550 – 2206 mL) vs. non-cardiogenic PoCUS 1687 mL (1458 – 1916 mL); and cardiogenic control 768 mL (194 – 1341 mL) vs. cardiogenic PoCUS 981 mL (341 – 1620 mL). Likewise there were no differences in rates of inotrope administration, or major procedures for any of the subcategories of shock between the control group and PoCUS group patients. The most common subcategory of shock was distributive. Conclusion: Despite differences in care delivered by subcategory of shock, we did not find any significant difference in actual care delivered between patients who were examined using PoCUS and those who were not. This may help to explain the previously reported lack of outcome difference between groups.
Introduction: Point of care ultrasound has been reported to improve diagnosis in non-traumatic hypotensive ED patients. We compared diagnostic performance of physicians with and without PoCUS in undifferentiated hypotensive patients as part of an international prospective randomized controlled study. The primary outcome was diagnostic performance of PoCUS for cardiogenic vs. non-cardiogenic shock. Methods: SHoC-ED recruited hypotensive patients (SBP < 100 mmHg or shock index > 1) in 6 centres in Canada and South Africa. We describe previously unreported secondary outcomes relating to diagnostic accuracy. Patients were randomized to standard clinical assessment (No PoCUS) or PoCUS groups. PoCUS-trained physicians performed scans after initial assessment. Demographics, clinical details and findings were collected prospectively. Initial and secondary diagnoses including shock category were recorded at 0 and 60 minutes. Final diagnosis was determined by independent blinded chart review. Standard statistical tests were employed. Sample size was powered at 0.80 (α:0.05) for a moderate difference. Results: 273 patients were enrolled with follow-up for primary outcome completed for 270. Baseline demographics and perceived category of shock were similar between groups. 11% of patients were determined to have cardiogenic shock. PoCUS had a sensitivity of 80.0% (95% CI 54.8 to 93.0%), specificity 95.5% (90.0 to 98.1%), LR+ve 17.9 (7.34 to 43.8), LR-ve 0.21 (0.08 to 0.58), Diagnostic OR 85.6 (18.2 to 403.6) and accuracy 93.7% (88.0 to 97.2%) for cardiogenic shock. Standard assessment without PoCUS had a sensitivity of 91.7% (64.6 to 98.5%), specificity 93.8% (87.8 to 97.0%), LR+ve 14.8 (7.1 to 30.9), LR- of 0.09 (0.01 to 0.58), Diagnostic OR 166.6 (18.7 to 1481) and accuracy of 93.6% (87.8 to 97.2%). There was no significant difference in sensitivity (-11.7% (-37.8 to 18.3%)) or specificity (1.73% (-4.67 to 8.29%)). Diagnostic performance was also similar between other shock subcategories. Conclusion: As reported in other studies, PoCUS based assessment performed well diagnostically in undifferentiated hypotensive patients, especially as a rule-in test. However performance was similar to standard (non-PoCUS) assessment, which was excellent in this study.
Despite established clinical associations among major depression (MD), alcohol dependence (AD), and alcohol consumption (AC), the nature of the causal relationship between them is not completely understood. We leveraged genome-wide data from the Psychiatric Genomics Consortium (PGC) and UK Biobank to test for the presence of shared genetic mechanisms and causal relationships among MD, AD, and AC.
Linkage disequilibrium score regression and Mendelian randomization (MR) were performed using genome-wide data from the PGC (MD: 135 458 cases and 344 901 controls; AD: 10 206 cases and 28 480 controls) and UK Biobank (AC-frequency: 438 308 individuals; AC-quantity: 307 098 individuals).
Positive genetic correlation was observed between MD and AD (rgMD−AD = + 0.47, P = 6.6 × 10−10). AC-quantity showed positive genetic correlation with both AD (rgAD−AC quantity = + 0.75, P = 1.8 × 10−14) and MD (rgMD−AC quantity = + 0.14, P = 2.9 × 10−7), while there was negative correlation of AC-frequency with MD (rgMD−AC frequency = −0.17, P = 1.5 × 10−10) and a non-significant result with AD. MR analyses confirmed the presence of pleiotropy among these four traits. However, the MD-AD results reflect a mediated-pleiotropy mechanism (i.e. causal relationship) with an effect of MD on AD (beta = 0.28, P = 1.29 × 10−6). There was no evidence for reverse causation.
This study supports a causal role for genetic liability of MD on AD based on genetic datasets including thousands of individuals. Understanding mechanisms underlying MD-AD comorbidity addresses important public health concerns and has the potential to facilitate prevention and intervention efforts.
Postmortem human brain studies provide the molecular, cellular, and circuitry levels of resolution essential for the development of mechanistically-novel interventions for cognitive deficits in schizophrenia. However, the absence of measures of premortem cognitive aptitude in postmortem subjects has presented a major challenge to interpreting the relationship between the severity of neural alterations and cognitive deficits within the same subjects.
To begin addressing this challenge, proxy measures of cognitive aptitude were evaluated in postmortem subjects (N = 507) meeting criteria for schizophrenia, major depressive or bipolar disorder, and unaffected comparison subjects. Specifically, highest levels of educational and occupational attainment of the decedent and their parents were obtained during postmortem psychological autopsies.
Consistent with prior findings in living subjects, subjects with schizophrenia had the lowest educational and occupational attainment relative to all other subject groups, and they also failed to show the generational improvement in attainment observed in all other subject groups.
Educational and occupational attainment data obtained during postmortem psychological autopsies can be used as proxy measures of premortem cognitive function to interrogate the neural substrate of cognitive dysfunction in schizophrenia.
The days of Debye-Scherrer film as a recording medium for X-ray powder patterns are all but gone with the development of precise, high sensitivity diffractometer systems. However, film does present some advantages over diffractometry (digital positioning and recording) for certain applications, A scanning densitometer system is described which totally automates the analysis of Debye-Scherrer film. It is much more precise and more capable than the simple line readers available in the past and can reduce the analysis time of complicated patterns from hours to minutes.
OBJECTIVES/SPECIFIC AIMS: In an effort to elucidate the role of potentially cancer chemopreventive drugs, we leveraged the Mayo Clinic-Karolinska Institute collaboration to create a multidisciplinary team that included an epidemiologist, statisticians, and physicians. We performed a population-based cohort study to examine the association between low dose aspirin, non-aspirin NSAIDs, statins, metformin, other risk factors and the risk of biliary tract cancer (BTC), while assessing confounding by sex. METHODS/STUDY POPULATION: We conducted a nationwide Swedish population-based cohort study using the Swedish Prescribed Drug Registry, which virtually completely enumerates use of prescribed medications nationwide since 2005. BTC diagnosis (intrahepatic cholangiocarcinoma [iCCA], extrahepatic cholangiocarcinoma [eCCA] or gallbladder cancer [GBC]) was ascertained from the Swedish Cancer Registry. Age-scaled Cox models, with exposure as time-varying covariates, were used to calculate hazard ratios (HRs), separately for men and women. RESULTS/ANTICIPATED RESULTS: In the 5.7 million person cohort, the risk of iCCA was significantly lower in men using statins (HR 0.62,95%CI 0.39-1.00, p = 0.05), with a non-significant reduction in women. Statin use was associated with a significantly decreased risk of eCCA in both women (HR 0.60,0.38-0.94, p = 0.03) and men (HR 0.47,0.28-0.80, p = 0.01). Low dose aspirin (HR 0.76,0.60-0.97, p = 0.03) was associated with a lower risk of GBC only in women, while statins (HR 0.72,0.55-0.93, p = 0.01) showed a significantly decreased risk of GBC in women and a non-significant reduction in men. For all BTC subtypes, combined use of low dose aspirin and statins did not confer additional risk reductions beyond those achieved by statins alone. Male and female users of non-aspirin NSAIDs appeared to be at increased risk of BTC and its subtypes. Metformin did not significantly affect risk of BTC. DISCUSSION/SIGNIFICANCE OF IMPACT: Our collaborative efforts allowed us to develop the largest population-based cohort evaluating risk and protective factors for BTC. Our results provide strong evidence in favor of the chemopreventive roles of low dose aspirin and statins in a subtype- and sex-specific manner. Individual risk factors contribute to development of BTC subtypes in different magnitudes. The next steps to translate these findings into clinical practice require randomized clinical trials that validate our results and provide a more complete picture of the risk-benefit ratio.
Measuring diet choice in grazing animals is challenging, complicating the assessment of feed efficiency in pasture-based systems. Furthermore, animals may modify their intake of a forage species depending on its nutritive value and on their own physiological status. Various fecal markers have been used to estimate feed intake in grazing animals. However, plant-wax markers such as n-alkanes (ALK) and long-chain alcohols may provide reliable estimates of both dietary choices and intakes. Still, their use in beef cattle has been relatively limited. The present study was designed to test the reliability of the ALK technique to estimate diet choices in beef heifers. Twenty-two Angus-cross heifers were evaluated at both post-weaning and yearling age. At each age, they were offered both red clover and fescue hay as cubes. Following 3-week acclimation periods, daily intake of each forage species was assessed daily for 10 days. During the final 5 days, fecal grab samples were collected twice daily. The ALK fecal concentrations were adjusted using recovery fractions compiled from literature. Diet composition was estimated using two statistical methods. Post-weaning, dietary choices were reliably estimated, with low residual error, regardless of the statistical approach adopted. The regression of observed on estimated red clover proportion ranged from 0.85±0.08 to 1.01±0.09 for fecal samples collected in the p.m. and for daily proportions once averaged, respectively. However, at yearling age, the estimates were less reliable. There was a tendency to overestimate the red clover proportion in diets of heifers preferring fescue, and vice versa. This was due to greater variability in ALK fecal concentrations in the yearling heifers. Overall, the ALK technique provided a reliable tool for estimating diet choice in animals fed a simple forage diet. Although further refinements in the application of this methodology are needed, plant-wax markers provide opportunities for evaluating diet composition in grazing systems in cattle.
The link between circulating glucocorticoids and leptin in beef calves has not been explored but has been noted in several studies. The aim of this study is to determine the effects of exogenous glucocorticoids given at birth and 1 day of age on serum leptin concentrations in beef calves. Ruminant animals secrete leptin, which is thought to be important for the programming of the hypothalamic appetite centers. Angus crossbred cows (n = 31) bred via natural service were utilized for this experiment. At parturition (day 0), calf BW was recorded and each calf was infused intravenously with either a hydrocortisol sodium succinate solution (HC, 8 males and 8 females) at a dosage of 3.5 μg/kg of BW or a similar volume of saline solution (CONT, 7 males and 8 females). Each calf was given a second infusion of its respective treatment 24 h postpartum at 1.5 μg/kg of BW for HC treatment. Calf treatment was blocked by sex, dam body condition score (BCS), and dam age. Blood samples were taken via jugular venipuncture before infusion, daily from days 0 to 5, then every other day up to day 17. Serum leptin and cortisol concentrations were analyzed via radioimmunoassay. Dam age, dam BCS, calf BW, and serum leptin and cortisol concentrations were analyzed using MIXED procedure of SAS. Dam age was not different (P = 0.81) among HC and CONT calves (4.9±0.5 and 4.7±0.5, respectively). Dam BCS was not different between treatments (5.7±0.2 and 5.6±0.2 HC and CONT, respectively; P = 0.66). There was no difference in calf birth BW between treatments (P = 0.87) and averaged 38.3±1.4 kg. Cortisol concentrations were not different between both treatments (P = 0.23) from birth to day 4 of age. Calves that received the HC treatment showed significantly reduced (P = 0.03) leptin concentrations on days 1 to 13. Calf BW from 60 to 150 days of age was not different between CONT and HC treated calves (P = 0.65). These data indicate that exogenous glucocorticoids can be used to suppress neonatal leptin levels in calves. This could lead to changes in voluntary feed intake of treated calves.
An insect trap constructed using three-dimensional (3D) printing technology was tested in potato (Solanum tuberosum Linnaeus; Solanaceae) fields to determine whether it could substitute for the standard yellow sticky card used to monitor Bactericera cockerelli (Šulc) (Hemiptera: Psylloidea: Triozidae). Sticky cards have shortcomings that prompted search for a replacement: cards are messy, require weekly replacement, are expensive to purchase, and accumulate large numbers of nontarget insects. Bactericera cockerelli on sticky cards also deteriorate enough that specimens cannot be tested reliably for the presence of vectored plant pathogens. A prototype trap constructed using 3D printing technology for monitoring Diaphorina citri Kuwayama (Hemiptera: Psylloidea: Liviidae) was tested for monitoring B. cockerelli. The trap was designed to attract B. cockerelli visually to the trap and then funnel specimens into preservative-filled vials at the trap bottom. Prototype traps were paired against yellow sticky cards at multiple fields to compare the captures of B. cockerelli between cards and traps. The prototype trap was competitive with sticky cards early in the growing season when B. cockerelli numbers were low. We estimated that two or three prototype traps would collect as many B. cockerelli as one sticky card under these conditions. Efficacy of the prototype declined as B. cockerelli numbers increased seasonally. The prototype trap accumulated nontarget taxa that are common on sticky cards (especially Thysanoptera and Diptera), and was also found to capture taxa of possible interest in integrated pest management research, including predatory insects, parasitic Hymenoptera, and winged Aphididae (Hemiptera), suggesting that the traps could be useful outside of the purpose targeted here. We believe that 3D printing technology has substantial promise for developing monitoring tools that exploit behavioural traits of the targeted insect. Ongoing work includes the use of this technology to modify the prototype, with a focus on making it more effective at capturing psyllids and less susceptible to capture of nontarget species.
The role that vitamin D plays in pulmonary function remains uncertain. Epidemiological studies reported mixed findings for serum 25-hydroxyvitamin D (25(OH)D)–pulmonary function association. We conducted the largest cross-sectional meta-analysis of the 25(OH)D–pulmonary function association to date, based on nine European ancestry (EA) cohorts (n 22 838) and five African ancestry (AA) cohorts (n 4290) in the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium. Data were analysed using linear models by cohort and ancestry. Effect modification by smoking status (current/former/never) was tested. Results were combined using fixed-effects meta-analysis. Mean serum 25(OH)D was 68 (sd 29) nmol/l for EA and 49 (sd 21) nmol/l for AA. For each 1 nmol/l higher 25(OH)D, forced expiratory volume in the 1st second (FEV1) was higher by 1·1 ml in EA (95 % CI 0·9, 1·3; P<0·0001) and 1·8 ml (95 % CI 1·1, 2·5; P<0·0001) in AA (Prace difference=0·06), and forced vital capacity (FVC) was higher by 1·3 ml in EA (95 % CI 1·0, 1·6; P<0·0001) and 1·5 ml (95 % CI 0·8, 2·3; P=0·0001) in AA (Prace difference=0·56). Among EA, the 25(OH)D–FVC association was stronger in smokers: per 1 nmol/l higher 25(OH)D, FVC was higher by 1·7 ml (95 % CI 1·1, 2·3) for current smokers and 1·7 ml (95 % CI 1·2, 2·1) for former smokers, compared with 0·8 ml (95 % CI 0·4, 1·2) for never smokers. In summary, the 25(OH)D associations with FEV1 and FVC were positive in both ancestries. In EA, a stronger association was observed for smokers compared with never smokers, which supports the importance of vitamin D in vulnerable populations.