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Vitamin D, Ca and dairy products are negatively associated with colorectal cancer (CRC) incidence, but little is known of their influence on CRC survival. To investigate prediagnostic intakes of vitamin D, Ca and dairy products for their relevance to CRC prognosis, we analysed 504 CRC patients enrolled in the Newfoundland Colorectal Cancer Registry Cohort Study who were diagnosed for the first time with CRC between 1999 and 2003. Follow-up for mortality and cancer recurrence was through April 2010. Data on diet and lifestyle factors were gathered via a validated, semi-quantitative FFQ and a Personal History Questionnaire. Multivariate Cox models estimated hazard ratios (HR) and 95 % CI for the relationship of prediagnostic intakes of vitamin D, Ca and dairy products with all-cause mortality (overall survival, OS) and disease-free survival (DFS) among CRC patients. We found that prediagnostic Ca intake from foods, but not total Ca intake, was negatively associated with all-cause mortality (HR for Q2 v. Q1, 0·44; 95 % CI, 0·26, 0·75). An inverse relationship was also seen in a dose–response fashion for prediagnostic cheese intake (HR for Q4 v. Q1, 0·57, 95 % CI, 0·34, 0·95, Ptrend = 0·029). No evidence for modification by sex, physical activity, alcohol drinking and cigarette smoking was observed. In summary, high prediagnostic intakes of cheese and Ca from foods may be associated with increased survival among CRC patients. By manipulating diet, this study may contribute to the development of novel therapies that add to the armamentarium against CRC. Replication studies are required before any nutritional interventions are made available.
Major depressive disorder (MDD) is a clinically and biologically heterogeneous syndrome. Identifying discrete subtypes of illness with distinguishing neurobiological substrates and clinical features is a promising strategy for guiding personalised therapeutics.
This study aimed to identify depression subtypes with correlated patterns of functional network connectivity and clinical symptoms by clustering patients according to a weighted linear combination of both features in a relatively large, medication-naïve depression sample.
We recruited 115 medication-naïve adults with MDD and 129 matched healthy controls, and evaluated all participants with magnetic resonance imaging. We used regularised canonical correlation analysis to identify component mapping relationships between functional network connectivity and symptom profiles, and K-means clustering was used to define distinct subtypes of patients.
Two subtypes of MDD were identified: insomnia-dominated subtype 1 and anhedonia-dominated subtype 2. Subtype 1 was characterised by abnormal hyperconnectivity within the ventral attention network and sleep maintenance insomnia. Subtype 2 was characterised by abnormal hypoconnectivity in the subcortical and dorsal attention networks, and prominent anhedonia symptoms.
Our study identified two distinct subtypes of patients with specific neurobiological and clinical symptom profiles. These findings advance understanding of the biological and clinical heterogeneity of MDD, offering a pathway for defining categorical subtypes of illness via consideration of both biological and clinical features.
Background: Antibiotics targeted against Clostridioides difficile bacteria are necessary, but insufficient, to achieve a durable clinical response because they have no effect on C. difficile spores that germinate within a disrupted microbiome. ECOSPOR-III evaluated SER-109, an investigational, biologically derived microbiome therapeutic of purified Firmicute spores for treatment of rCDI. Herein, we present the interim analysis in the ITT population at 8 and 12 weeks. Methods: Adults ≥18 years with rCDI (≥3 episodes in 12 months) were screened at 75 US and CAN sites. CDI was defined as ≥3 unformed stools per day for <48 hours with a positive C. difficile assay. After completion of 10–21 days of vancomycin or fidaxomicin, adults with symptom resolution were randomized 1:1 to SER-109 (4 capsules × 3 days) or matching placebo and stratified by age (≥ or <65 years) and antibiotic received. Primary objectives were safety and efficacy at 8 weeks. Primary efficacy endpoint was rCDI (recurrent toxin+ diarrhea requiring treatment); secondary endpoints included efficacy at 12 weeks after dosing. Results: Overall, 287 participants were screened and 182 were randomized (59.9% female; mean age, 65.5 years). The most common reason for screen failure was a negative C. difficile toxin assay. A significantly lower proportion of SER-109 participants had rCDI after dosing compared to placebo at week 8 (11.1% vs 41.3%, respectively; relative risk [RR], 0.27; 95% confidence interval [CI], 0.15–0.51; p-value <0.001). Efficacy rates were significantly higher with SER-109 vs placebo in both stratified age groups (Figure 1). SER-109 was well-tolerated with a safety profile similar to placebo. The most common treatment-emergent adverse events (TEAEs) were gastrointestinal and were mainly mild to moderate. No serious TEAEs, infections, deaths, or drug discontinuations were deemed related to study drug. Conclusions: SER-109, an oral live microbiome therapeutic, achieved high rates of sustained clinical response with a favorable safety profile. By enriching for Firmicute spores, SER-109 achieves high efficacy while mitigating risk of transmitting infectious agents, beyond donor screening alone. SER-109 represents a major paradigm shift in the clinical management of patients with recurrent CDI. Clinicaltrials.gov Identifier NCT03183128. These data were previously presented as a late breaker at American College of Gastroenterology 2020.
Seasonal climate variability is an important component of Earth's climate system, and has a significant impact on ecosystems and social systems. However, the temporal resolution of most proxy-based paleoclimate records is limiting to fully understand the past seasonal changes. Here, we used high-precision monthly resolution Sr/Ca records of three Tridacna squamosa specimens from the northern South China Sea (SCS) to reconstruct the sea surface temperature (SST) seasonality during three time periods from the middle Holocene. The results suggested that SST seasonality in the northern SCS during the middle Holocene (3.21 ± 0.98°C) was smaller than that for recent decades (AD 1994–2004, 4.32 ± 0.59°C). Analysis of modern instrumental data showed that the SST seasonality in the northern SCS was dominated by the winter SST, which was deeply influenced by the intensity of East Asian winter monsoon (EAWM). A strong EAWM usually resulted in cooler winter SST and a larger SST seasonality in the northern SCS. The reconstructed Holocene EAWM records showed that the EAWM strengthened from the middle to late Holocene, which was seen in our reconstruction of less SST seasonality changes during the middle Holocene in the northern SCS. This study highlighted that the Sr/Ca ratios from Tridacna shells can be used as a potential high-resolution indicator of past seasonal climate changes.
The Dayao Paleolithic site, located in Inner Mongolia on the eastern margin of China's vast northwestern drylands, was a lithic quarry-workshop utilized by Pleistocene human migrants through the region. Determining the age of this activity has previously yielded controversial results. Our magnetostratigraphic and OSL dating results suggest the two artifact-bearing paleosols are correlated with MIS 5 and 7, respectively. Correlating paleoclimatic data with marine δ18O records leads us to conclude that two sandy gravel layers containing many artifacts in the lower part of the Dayao sequence were formed during MIS 9 and 11, if not earlier. Our results reveal that the earliest human occupation at the Dayao site occurred before ca. 400 ka during a relatively warm and moist interglacial period, similar to several subsequent occupations, documenting the earliest and northernmost archaeological assemblage yet reported in China's arid northwest. We conclude that the northward and southward displacements of the East Asian summer monsoon rain belt during past interglacial-glacial cycles were responsible for the discontinuous human occupation detected at the Dayao site. The penetration of this precipitation regime into dryland ecologies via the Huanghe (Yellow River) Valley effectively created a corridor for hominin migration into China's arid northwest.
To evaluate broad-spectrum intravenous antibiotic use before and after the implementation of a revised febrile neutropenia management algorithm in a population of adults with hematologic malignancies.
Setting and population:
Patients admitted between 2014 and 2018 to the Adult Malignant Hematology service of an acute-care hospital in the United States.
Aggregate data for adult malignant hematology service were obtained for population-level antibiotic use: days of therapy (DOT), C. difficile infections, bacterial bloodstream infections, intensive care unit (ICU) length of stay, and in-hospital mortality. All rates are reported per 1,000 patient days before the implementation of an febrile neutropenia management algorithm (July 2014–May 2016) and after the intervention (June 2016–December 2018). These data were compared using interrupted time series analysis.
In total, 2,014 patients comprised 6,788 encounters and 89,612 patient days during the study period. Broad-spectrum intravenous (IV) antibiotic use decreased by 5.7% with immediate reductions in meropenem and vancomycin use by 22 (P = .02) and 15 (P = .001) DOT per 1,000 patient days, respectively. Bacterial bloodstream infection rates significantly increased following algorithm implementation. No differences were observed in the use of other antibiotics or safety outcomes including C. difficile infection, ICU length of stay, and in-hospital mortality.
Reductions in vancomycin and meropenem were observed following the implementation of a more stringent febrile neutropenia management algorithm, without evidence of adverse outcomes. Successful implementation occurred through a collaborative effort and continues to be a core reinforcement strategy at our institution. Future studies evaluating patient-level data may identify further stewardship opportunities in this population.
Cysticercosis caused by the metacestode larval stage of Taenia hydatigena formerly referred to as Cysticercus tenuicollis is a disease of veterinary importance that constitutes a significant threat to livestock production worldwide, especially in endemic regions due to condemnation of visceral organs and mortality rate of infected young animals. While the genetic diversity among parasites is found to be potentially useful in many areas of research including molecular diagnostics, epidemiology and control, that of T. hydatigena across the globe remains poorly understood. In this study, analysis of the mitochondrial DNA (mtDNA) of adult worms and larval stages of T. hydatigena isolated from dogs, sheep and a wild boar in China showed that the population structure consists of two major haplogroups with very high nucleotide substitutions involving synonymous and non-synonymous changes. Compared with other cestodes such as Echinococcus spp., the genetic variation observed between the haplogroups is sufficient for the assignment of major haplotype or genotype division as both groups showed a total of 166 point-mutation differences between the 12 mitochondrial protein-coding gene sequences. Preliminary analysis of a nuclear protein-coding gene (pepck) did not reveal any peculiar changes between both groups which suggests that these variants may only differ in their mitochondrial makeup.
Vibration-based methods can be used effectively to characterize the physical properties of biological materials, with an increasing interest focused on the mechanics of individual, living cells. Real-time measurements of cell properties, such as mass and Young's modulus, can yield important insights into many aspects of cell growth and metabolism as well as the interaction of cells with external stimuli (e.g., drugs). Vibrational test structures designed for the study of such cell properties often use fixed configurations and operational modes, with associated limitations in determining multiple characteristics of the cell, simultaneously. Recent development of mechanics-guided techniques for deterministic assembly of three-dimensional (3D) microstructures provides a route to vibrational frameworks that offer tunable configurations, vibration modes, and resonant frequencies. Here we propose a method that exploits such tunable vibrational structures to simultaneously determine the mass and modulus of a single adherent cell, or of other biological materials or small-scale living systems (e.g., organoids), through theoretical modeling and finite element analysis. The idea involves a 3D architecture that supports two different vibrational structures and can be converted from one to the other through application of strain to an elastomeric substrate. Specifically, tailored designs for serpentine ribbons in these systems enable a decoupling of the dependence of the resonant frequencies of the two structures to the cell mass and modulus, with an associated ability to measure these two properties accurately and independently. These same concepts can be scaled to apply to various types of cells, as well as to organoids (3D clusters of cells) and other biological materials with small geometries, across a range of values of mass and modulus. This method could serve as the foundation for microelectromechanical systems capable of monitoring mass and modulus in real time for use in research in biomechanics and dynamic biological processes.
Background: Targeted antibiotic stewardship interventions are needed to reduce unnecessary treatment of asymptomatic bacteriuria (ASB). Organizational readiness for change is a precursor to successful change implementation. The Organizational Readiness to Change Assessment (ORCA) is a validated survey instrument that has been used to detect potential obstacles and tailor interventions. In an outpatient stewardship study, primary care practices with high readiness to change trended toward greater improvements in antibiotic prescribing. We used the ORCA to assess barriers to change before implementing a multicenter inpatient stewardship intervention for ASB. Methods: Surveys were self-administered by healthcare professionals in inpatient medicine and long-term care units at 4 geographically diverse Veterans’ Affairs facilities during January–December 2018. Participants included providers (physicians, physician assistants, and nurse practitioners), nurses, pharmacists, infection preventionists, and quality managers. The survey included 7 subscales: evidence (perceived evidence strength) and 6 context subscales (favorability of the organizational context to support change). Responses were scored on a 5-point Likert scale, with 1 meaning very weak or strongly disagree. Scores were compared between professional types and sites. We also measured allocated employee effort for stewardship at each site. Results: Overall, 104 surveys were completed, with an overall response rate of 69.3%. For all sites combined, the evidence subscale had the highest score of the 7 subscales (mean, 4; SD, 0.9); the resources subscale was significantly lower than other subscales (mean, 2.8; SD, 0.9; P < .001). Scores for budget and staffing resources were lower than scores for training and facility resources (P < .001 for both comparisons). Pharmacists had lower scores than providers for the staff culture subscale (P = .04). Comparing subscales between sites, ORCA scores were significantly different for leadership behavior (communication and management), measurement (goal setting and accountability), and general resources (Fig. 1). The site with the lowest scores for resources (mean, 2.4) also had lower scores for leadership behavior and measurement, and lower pharmacist effort devoted to antibiotic stewardship. Conclusions: Although healthcare professionals endorsed the evidence about nontreatment of ASB, perceived barriers to antibiotic stewardship included inadequate resources and lack of leadership support. These findings provide targets for tailoring the intervention to maximize the success of our stewardship program. Our support to sites with lower leadership scores includes training of local champions who are dedicated to supporting the intervention. For sites with low scores for resources, our targeted implementation strategies include analyzing local needs and avoiding increased workload for existing personnel.
Calcifying pseudoneoplasm of the neuraxis (CAPNON) is a rare tumor-like lesion with unknown pathogenesis. It is likely under-reported due to diagnostic challenges including the nonspecific radiographic features, lack of diagnostic markers, and often asymptomatic nature of the lesions.
We performed detailed examination of 11 CAPNON specimens diagnosed by histopathology, with the help of electron microscopy and immunohistochemistry.
Electron microscopy revealed the presence of fibrillary materials consistent with neurofilaments. In addition to some entrapped axons at the periphery of CAPNONs, we discovered that all specimens stained positive for neurofilament-light (NF-L) within the granular amorphous cores, but not neurofilament-phosphorylated (NF-p). CAPNONs also showed variable infiltration of CD8+ T-cells and a decreased ratio of CD4/CD8+ T-cells, suggesting an immune-mediated process in the pathogenesis of CAPNON.
NF-L and CD4/CD8 immunostains may serve as diagnostic markers for CAPNON and shed light on its pathogenesis.
To slow down the transmission of coronavirus disease 2019 (COVID-19), it is important to identify specific symptoms for effective screening. While anosmia/hyposmia and dysgeusia/ageusia have been identified as highly prevalent symptoms, there are wide geographic variations, necessitating the regional evaluation of the prevalence of the symptoms.
A cross-sectional study was performed to evaluate the self-reported symptoms among adults (over 18 years old) who underwent COVID-19 tests at an ambulatory assessment centre. We identified 1,345 patients (102 positive and 1,243 negative) who visited the assessment centre between March 16 and April 15, 2020. We randomly sampled negative patients in a 1:3 ratio. The primary outcome was the prevalence of self-reported anosmia/hyposmia and dysgeusia/ageusia. Logistic regression was performed to evaluate the association between COVID-19 positivity and loss of smell and taste.
Fifty-six of 102 (50%) positive patients and 72 of 306 (23.5%) negative patients completed the survey. Anosmia/hyposmia and dysgeusia/ageusia were more prevalent among COVID-19 positive patients (41.1% v. 4.2%, p < 0.001 for smell and 46.4% v. 5.6%, p < 0.001 for taste). Anosmia/hyposmia and dysgeusia/ageusia were independently highly associated with COVID-19 positivity (adjusted odds ratios 14.4 and 11.4 for smell and taste, respectively).
In this Canadian study, smell and taste loss may be key symptoms of COVID-19. This evidence can be helpful in the clinical diagnosis of COVID-19, particularly settings of limited testing capacity.
We describe 14 yr of public data from the Parkes Pulsar Timing Array (PPTA), an ongoing project that is producing precise measurements of pulse times of arrival from 26 millisecond pulsars using the 64-m Parkes radio telescope with a cadence of approximately 3 weeks in three observing bands. A comprehensive description of the pulsar observing systems employed at the telescope since 2004 is provided, including the calibration methodology and an analysis of the stability of system components. We attempt to provide full accounting of the reduction from the raw measured Stokes parameters to pulse times of arrival to aid third parties in reproducing our results. This conversion is encapsulated in a processing pipeline designed to track provenance. Our data products include pulse times of arrival for each of the pulsars along with an initial set of pulsar parameters and noise models. The calibrated pulse profiles and timing template profiles are also available. These data represent almost 21 000 h of recorded data spanning over 14 yr. After accounting for processes that induce time-correlated noise, 22 of the pulsars have weighted root-mean-square timing residuals of
in at least one radio band. The data should allow end users to quickly undertake their own gravitational wave analyses, for example, without having to understand the intricacies of pulsar polarisation calibration or attain a mastery of radio frequency interference mitigation as is required when analysing raw data files.
We describe an ultra-wide-bandwidth, low-frequency receiver recently installed on the Parkes radio telescope. The receiver system provides continuous frequency coverage from 704 to 4032 MHz. For much of the band (
), the system temperature is approximately 22 K and the receiver system remains in a linear regime even in the presence of strong mobile phone transmissions. We discuss the scientific and technical aspects of the new receiver, including its astronomical objectives, as well as the feed, receiver, digitiser, and signal processor design. We describe the pipeline routines that form the archive-ready data products and how those data files can be accessed from the archives. The system performance is quantified, including the system noise and linearity, beam shape, antenna efficiency, polarisation calibration, and timing stability.
Scholars and policy makers need systematic assessments of the validity of the measures produced by V-Dem. In Chapter 6, we present our approach to comparative data validation – the set of steps we take to evaluate the precision, accuracy, and reliability of our measures, both in isolation and compared to extant measures of the same concepts. Our approach assesses the degree to which measures align with shared concepts (content validation), shared rules of translation (data generation assessment), and shared realities (convergent validation). Within convergent validity, we execute two convergent validity tests. First, we examine convergent validity as it is typically conceived – examining convergence between V-Dem measures and extant measures. Second, we evaluate the level of convergence across coders, considering the individual coder and country traits that predict coder convergence. Throughout the chapter, we focus on three indices included in the V-Dem data set: polyarchy, corruption, and core civil society. These three concepts collectively provide a “hard test” for the validity of our data, representing a range of existing measurement approaches, challenges, and solutions.
This chapter sets forth the conceptual scheme for the V–Dem project. We begin by discussing the concept of democracy. Next, we lay out seven principles by which this key concept may be understood – electoral, liberal, majoritarian, consensual, participatory, deliberative, and egalitarian. Each defines a “variety“ of democracy, and together they offer a fairly comprehensive accounting of the concept as used in the world today. Next, we show how this seven-part framework fits into our overall thinking about democracy, including multiple levels of disaggregation – to components, subcomponents, and indicators. The final section of the chapter discusses several important caveats and clarifications pertaining to this ambitious taxonomic exercise.
This chapter recounts how a project of this scale came together and why it has succeeded. Five main factors were responsible for V–Dem’s success: timing, inclusion, deliberation, administrative centralization, and fund–raising. First, planning for V-Dem began at a time when both social scientists and practitioners were realizing that they needed better democracy measures. This made it possible to recruit collaborators and find funding. Second, the leaders of the project were always eager to expand the team to acquire whatever expertise they lacked and share credit with everyone who contributed. Third, the project leaders practiced an intensely deliberative decision–making style to ensure that all points of view were consulted and only decisions that won wide acceptance were adopted. Fourth, centralizing the execution of the agreed–upon tasks helped tremendously by streamlining processes and promoting standardization, documentation, professionalization, and coordination of a large number of intricate steps. Finally, successful fund–raising from a mix of both research foundations and bilateral and multilateral organizations has been critical.