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Several life-threatening diseases of the kidney have their origins in mutational events that occur during embryonic development. In this study, we investigate the role of the Wolffian duct (WD), the earliest embryonic epithelial progenitor of renal tubules, in the etiology of autosomal dominant polycystic kidney disease (ADPKD). ADPKD is associated with a germline mutation of one of the two Pkd1 alleles. For the disease to occur, a second event that disrupts the expression of the other inherited Pkd1 allele must occur. We postulated that this secondary event can occur in the pronephric WD. Using Cre-Lox recombination, mice with WD-specific deletion of one or both Pkd1 alleles were generated. Homozygous Pkd1-targeted deletion in WD-derived tissues resulted in mice with large cystic kidneys and serologic evidence of renal failure. In contrast, heterozygous deletion of Pkd1 in the WD led to kidneys that were phenotypically indistinguishable from control in the early postnatal period. High-throughput sequencing, however, revealed underlying gene and microRNA (miRNA) changes in these heterozygous mutant kidneys that suggest a strong predisposition toward developing ADPKD. Bioinformatic analysis of this data demonstrated an upregulation of several miRNAs that have been previously associated with PKD; pathway analysis further demonstrated that the differentially expressed genes in the heterozygous mutant kidneys were overrepresented in signaling pathways associated with maintenance and function of the renal tubular epithelium. These results suggest that the WD may be an early epithelial target for the genetic or molecular signals that can lead to cyst formation in ADPKD.
The COllaborative project of Development of Anthropometrical measures in Twins (CODATwins) project is a large international collaborative effort to analyze individual-level phenotype data from twins in multiple cohorts from different environments. The main objective is to study factors that modify genetic and environmental variation of height, body mass index (BMI, kg/m2) and size at birth, and additionally to address other research questions such as long-term consequences of birth size. The project started in 2013 and is open to all twin projects in the world having height and weight measures on twins with information on zygosity. Thus far, 54 twin projects from 24 countries have provided individual-level data. The CODATwins database includes 489,981 twin individuals (228,635 complete twin pairs). Since many twin cohorts have collected longitudinal data, there is a total of 1,049,785 height and weight observations. For many cohorts, we also have information on birth weight and length, own smoking behavior and own or parental education. We found that the heritability estimates of height and BMI systematically changed from infancy to old age. Remarkably, only minor differences in the heritability estimates were found across cultural–geographic regions, measurement time and birth cohort for height and BMI. In addition to genetic epidemiological studies, we looked at associations of height and BMI with education, birth weight and smoking status. Within-family analyses examined differences within same-sex and opposite-sex dizygotic twins in birth size and later development. The CODATwins project demonstrates the feasibility and value of international collaboration to address gene-by-exposure interactions that require large sample sizes and address the effects of different exposures across time, geographical regions and socioeconomic status.
We sought to assess the presence and reporting quality of peer-reviewed literature concerning the accuracy, precision, and reliability of home monitoring technologies for vital signs and glucose determinations in older adult populations.
A narrative literature review was undertaken searching the databases Medline, Embase, and Compendex. Peer-reviewed publications with keywords related to vital signs, monitoring devices and technologies, independent living, and older adults were searched. Publications between the years 2012 and 2018 were included. Two reviewers independently conducted title and abstract screening, and four reviewers independently undertook full-text screening and data extraction with all disagreements resolved through discussion and consensus.
Two hundred nine articles were included. Our review showed limited assessment and low-quality reporting of evidence concerning the accuracy, precision, and reliability of home monitoring technologies. Of 209 articles describing a relevant device, only 45 percent (n = 95) provided a citation or some evidence to support their validation claim. Of forty-eight articles that described the use of a comparator device, 65 percent (n = 31) used low-quality statistical methods, 23 percent (n = 11) used moderate-quality statistical methods, and only 12 percent (n = 6) used high-quality statistical methods.
Our review found that current validity claims were based on low-quality assessments that do not provide the necessary confidence needed by clinicians for medical decision-making purposes. This narrative review highlights the need for standardized health technology reporting to increase health practitioner confidence in these devices, support the appropriate adoption of such devices within the healthcare system, and improve health outcomes.
The objectives of this paper are to: (1) identify contextual factors such as policy that impacted the implementation of community-based primary health care (CBPHC) innovations among 12 Canadian research teams and (2) describe strategies used by the teams to address contextual factors influencing implementation of CBPHC innovations. In primary care settings, consideration of contextual factors when implementing change has been recognized as critically important to success. However, contextual factors are rarely recorded, analyzed or considered when implementing change. The lack of consideration of contextual factors has negative implications not only for successfully implementing primary health care (PHC) innovations, but also for their sustainability and scalability. For this evaluation, data collection was conducted using self-administered questionnaires and follow-up telephone interviews with team representatives. We used a combination of directed and conventional content analysis approaches to analyze the questionnaire and interview data. Representatives from all 12 teams completed the questionnaire and 11 teams participated in the interviews; 40 individuals participated in this evaluation. Four themes representing contextual factors that impacted the implementation of CBPHC innovations were identified: (I) diversity of jurisdictions (II) complexity of interactions and collaborations (III) policy, and (IV) the multifaceted nature of PHC. The teams used six strategies to address these contextual factors including: (1) conduct an environmental scan at the beginning (2) maintaining engagement among partners and stakeholders by encouraging open and inclusive communication; (3) contextualizing the innovation for different settings; (4) anticipating and addressing changes, delays, and the need for additional resources; (5) fostering a culture of research and innovation among partners and stakeholders; and (6) ensuring information about the innovation is widely available. Implementing CBPHC innovations across jurisdictions is complex and involves navigating through multiple contextual factors. Awareness of the dynamic nature of context should be considered when implementing innovations.
Andrew Harding, in his excursus on ‘legal transplantation’, observed: ‘[W]e do live in a world of legal connectivity in which we share common problems which can only be addressed by a limited range of solutions which are unlikely not to have been tried before’. This prescient remark is apt in the context of the growing importance of the proportionality concept in the Australian public law arena. The proportionality concept attained particular prominence when the High Court of Australia found a freedom of political communication impliedly embedded in the Constitution. It was inevitable that with the establishment of such an implied fundamental constitutional guarantee, the High Court had to craft a principle to enable the saving or invalidation of legislation claimed to be in violation of the implied freedom.
Antipseudomonal carbapenems are an important target for antimicrobial stewardship programs. We evaluated the impact of formulary restriction and preauthorization on relative carbapenem use for medical and surgical intensive care units at a large, urban academic medical center using interrupted time-series analysis.
We used multivariable analyses to assess whether meeting core elements was associated with antibiotic utilization. Compliance with 7 elements versus not doing so was associated with higher use of broad-spectrum agents for community-acquired infections [days of therapy per 1,000 patient days: 155 (39) vs 133 (29), P = .02] and anti-methicillin-resistant S. aureus agents [days of therapy per 1,000 patient days: 145 (37) vs 124 (30), P = .03].
Background: Stimulation frequency has been considered a crucial determinant of efficacy in deep brain stimulation (DBS). DBS at frequencies over 250Hz is not currently employed and consensus in the field suggests that higher frequencies are not clinically effective. With the recent demonstration of clinically effective ultra-high frequency (UHF) spinal cord stimulation at 10kHz we tested whether UHF stimulation could also be clinically useful in movement disorder patients with DBS. Methods: We studied the effects of conventional (130Hz) and UHF stimulation in five patients with Parkinson’s disease (PD) with STN DBS and in one patient with essential tremor (ET) with VIM DBS. We compared the clinical benefit and adverse effects of stimulation at various amplitudes either intraoperatively or postoperatively with the electrodes externalized. Results: Motor performance improved in all six patients with UHF DBS. 10kHz stimulation at amplitudes ≥3.0mA appeared to be as effective as 130Hz in improving motor symptoms (46.2% vs 53.5% motor score reduction, p=0.110, N=90 trials). Interestingly, 10kHz stimulation resulted in fewer stimulation-induced paresthesiae and speech adverse effects than 130Hz stimulation. Conclusions: Our results indicate that DBS at 10kHz produces clinical benefits while possibly reducing stimulation-induced adverse effects in patients with movement disorders.
We investigated whether neurobehavioral markers of risk for emotion dysregulation were evident among newborns, as well as whether the identified markers were associated with prenatal exposure to maternal emotion dysregulation. Pregnant women (N = 162) reported on their emotion dysregulation prior to a laboratory assessment. The women were then invited to the laboratory to assess baseline respiratory sinus arrhythmia (RSA) and RSA in response to an infant cry. Newborns were assessed after birth via the NICU Network Neurobehavioral Scale. We identified two newborn neurobehavioral factors—arousal and attention—via exploratory factor analysis. Low arousal was characterized by less irritability, excitability, and motor agitation, while low attention was related to a lower threshold for auditory and visual stimulation, less sustained attention, and poorer visual tracking abilities. Pregnant women who reported higher levels of emotion dysregulation had newborns with low arousal levels and less attention. Larger decreases in maternal RSA in response to cry were also related to lower newborn arousal. We provide the first evidence that a woman's emotion dysregulation while pregnant is associated with risks for dysregulation in her newborn. Implications for intergenerational transmission of emotion dysregulation are discussed.
Introduction: Many drugs, including cannabis and alcohol, cause impairment and contribute to motor vehicle collisions (MVCs). Policy makers require knowledge of the prevalence of drug use in crash-involved drivers, and types of drugs used in order to develop effective prevention programs. This issue is particularly relevant with the recent legalization of cannabis. We aim to study the prevalence of alcohol, cannabis, sedating medications, and other drugs in injured drivers from 4 Canadian Provinces. Methods: This prospective cohort study obtained excess clinical blood samples from consecutive injured drivers who attended a participating Canadian trauma centre following a MVC. Blood samples were analyzed using a broad spectrum toxicology screen capable of detecting cannabinoids, cocaine, amphetamines (including their major analogues), and opioids as well as psychotropic pharmaceuticals (including antihistamines, benzodiazepines, other hypnotics, and sedating antidepressants). Alcohol and cannabinoids were quantified. Health records were reviewed to extract demographic, medical, and MVC information using a standardized data collection tool. Results: This study has been collecting data in 4 trauma centres in British Columbia (BC) since 2011 and was launched in 2 trauma centres in Alberta (AB), 1 in Saskatchewan (SK), and 2 in Ontario (ON) in 2018. In preliminary results from BC (n = 2412), 8% of injured drivers tested positive for THC and 13% for alcohol. Preliminary results from other provinces (n = 301) suggest a regional variation in prevalence of drivers testing positive for THC (10% - 27%), alcohol (17% - 29%), and other drugs. By May 2018, an estimated 4500 cases from BC, 600 from AB, 150 from SK, and 650 from ON will have been analyzed. We will report the prevalence of positive tests for alcohol, THC, other recreational drugs, and sedating medications, pre and post cannabis legalization. The number of cases with alcohol and/or THC levels above Canadian per se limits will also be reported. Results will be reported according to province, driver sex, age, single vs. multi vehicle crashes, and requirement for hospital admission. Conclusion: This will be among the largest international datasets on drug use by injured drivers. Our findings will provide patterns of drug and alcohol impairment in 4 Canadian provinces pre and post cannabis legalization. The significance of these findings and implication for impaired driving policy and prevention programs in Canada will be discussed.
Introduction: It is recommended that seniors consulting to the Emergency Department (ED) undergo a comprehensive geriatric screening, which is difficult for most EDs. Patient self-assessment using electronic tablet could be an interesting solution to this issue. However, the acceptability of self-assessment by older ED patients remains unknown. Assessing acceptability is a fundamental step in evaluating new interventions. The main objective of this project is to compare the acceptability of older patient self-assessment in the ED to that of a standard assessment made by a professional, according to seniors and their caregivers. Methods: Design: This randomized crossover design cohort study took place between May and July 2018. Participants: 1) Patients aged ≥65 years consulting to the ED, 2) their caregiver, when present. Measurements: Patients performed self-assessment of their frailty, cognitive and functional status using an electronic tablet. Acceptability was measured using the Treatment Acceptability and Preferences (TAP) questionnaires. Analyses: Descriptive analyses were performed for sociodemographic variables. Scores were adjusted for confounding variables using multivariate linear regression. Thematic content analysis was performed by two independent analysts for qualitative data collected in the TAP's open-ended question. Results: A total of 67 patients were included in this study. Mean age was 75.5 ± 8.0 and 55.2% of participants were women. Adjusted mean TAP scores for RA evaluation and patient self-assessment were 2.36 and 2.20, respectively. We found no difference between the two types of evaluations (p = 0.0831). When patients are stratified by age groups, patients aged 85 and over (n = 11) showed a difference between the TAPs scores, 2.27 for RA evaluation and 1.72 for patient self-assessment (p = 0.0053). Our qualitative data shows that this might be attributed to the use of technology, rather than to the self-assessment itself. Data from 9 caregivers showed a 2.42 mean TAP score for RA evaluation and 2.44 for self-assessment. However, this relatively small sample size prevented us to perform statistical tests. Conclusion: Our results show that older patients find self-assessment in the ED using an electronic tablet just as acceptable as a standard evaluation by a professional.
Introduction: According to WHO, one third of patients aged ≥65 fall every year. Those falls account for 25% of all geriatric emergency department (ED) visits. Fear of falling (FOF) is common in older patients who sustained a fall and is associated with a decline in mobility and health issues for patients. We hypothesized that there is an association between FOF and return to ED (RTED) and future falls. Objective: To assess the relation between FOF and RTED and subsequent falls in older ED patients Methods: This research was conducted as part of the Canadian Emergency Team Initiative in elderly (CETIe) multicenter prospective cohort study from 2011 to 2016. Participants: Patients 65 years or older were assessed and discharged from ED following a minor trauma. They had to be independent in all basic activities of daily living and being able to communicate in English or French. Measures: Primary outcome was RTED and secondary outcome was subsequent falls. Both were self-reported at 3 and 6 months. Patients were stratified according to Short Falls Efficacy Scale International (SFES-I) score, assessing FOF in different situations. A total score is calculated to determine the mild, moderate or severe level of FOF. Previous falls and TUG were used to evaluate patients’ mobility. OARS, ISAR and SOF were used to evaluated patient frailty. Descriptive statistical were performed and multiple regression were performed to show the association between SFES-1 score and outcomes. Results: FOF was measured in 2899 participants, of which 2214 participated at the 3 months follow-up and 2009 participated at the 6 months follow-up. Odds Ratio (OR) of return to ED at 3 months was 1.10 for moderate FOF and 1.52 for severe FOF (Type 3 test p = 0.11). At 6 months, OR was 1.03 for moderate FOF and 1.25 for severe FOF (Type 3 test p = 0.63). OR of subsequent fall at 3 months was 1.80 for moderate FOF and 2.18 for severe FOF (Type 3 test p < 0.001). At 6 months, OR of subsequent fall was 1.63 for moderate FOF and 2.37 for severe FOF (Type 3 test p < 0.001). Conclusion: The multicenter cohort study showed that severe fear of falling is strongly associated with subsequent falls over the next 6 months following ED discharge, but not significantly associated with return to ED episodes. Further research should be done to analyze the association between severe FOF and RTED.
We have developed a novel strategy for elaborating composite plasmonic nanomaterials in a well controlled manner. Combining several techniques commonly used in microelectronic engineering, namely sputtering deposition, thermal oxidation, ultra low energy ion implantation, focused ion beam lithography, thermal or laser annealing, we have obtained 3D patterned optical layers. Their spatial and spectral responses take benefit of optical interference, plasmonic resonance effects and coupling between excitations in both near and far field regime. Moreover these structures show high level of uniformity, reproducibility and stability, and they preserve flat and chemically uniform surfaces.
We assessed self-reported drives for alcohol use and their impact on clinical features of alcohol use disorder (AUD) patients. Our prediction was that, in contrast to “affectively” (reward or fear) driven drinking, “habitual” drinking would be associated with worse clinical features in relation to alcohol use and higher occurrence of associated psychiatric symptoms.
Fifty-eight Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) alcohol abuse patients were assessed with a comprehensive battery of reward- and fear-based behavioral tendencies. An 18-item self-report instrument (the Habit, Reward and Fear Scale; HRFS) was employed to quantify affective (fear or reward) and non-affective (habitual) motivations for alcohol use. To characterize clinical and demographic measures associated with habit, reward, and fear, we conducted a partial least squares analysis.
Habitual alcohol use was significantly associated with the severity of alcohol dependence reflected across a range of domains and with lower number of detoxifications across multiple settings. In contrast, reward-driven alcohol use was associated with a single domain of alcohol dependence, reward-related behavioral tendencies, and lower number of detoxifications.
These results seem to be consistent with a shift from goal-directed to habit-driven alcohol use with severity and progression of addiction, complementing preclinical work and informing biological models of addiction. Both reward-related and habit-driven alcohol use were associated with lower number of detoxifications, perhaps stemming from more benign course for the reward-related and lack of treatment engagement for the habit-related alcohol abuse group. Future work should further explore the role of habit in this and other addictive disorders, and in obsessive-compulsive related disorders.
Production electrolytic chromium coatings suffer from cracks, which result from high internal stresses generated during the electrolytic crystallization process. This paper characterizes the anisotropy, texture and residual stress state in high contraction chromium coatings on steel-Strong <111> fiber texture, almost perfect in-plane azimuthal symmetry, and high surface residual stresses were observed. Anisotropy factor and aggregate elastic moduli were calculated from single crystal elastic constants. A matrix inversion method was developed to solve for biaxial residual stress and unstrained lattice parameter in textured chromium coatings. Assuming an isotropic elastic Hill-Neerfeld model, residual stress was also evaluated using the sin2ψ method adapted to multiple families of reflections.
Reciprocal space mapping can be efficiently carried out using a position-sensitive x-ray detector (PSD) coupled to a traditional double-axis diffractometer. The PSD offers parallel measurement of the total scattering angle of all diffracted x-rays during a single rocking-curve scan. As a result, a two-dimensional reciprocal space map can be made in a very short time similar to that of a one-dimensional rocking-curve scan. Fast, efficient reciprocal space mapping offers numerous routine advantages to the x-ray diffraction analyst. Some of these advantages arc the explicit differentiation of lattice strain from crystal orientation effects in strain-relaxed heteroepitaxial layers; the nondestructive characterization of the size, shape and orientation of nanocrystalline domains in ordered-alloy epilayers; and the ability to measure the average size and shape of voids in porous epilayers. Here, the PSD-based diffractometer is described, and specific examples clearly illustrating the advantages of complete reciprocal space analysis are presented.