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Although Androgen Deprivation Therapy (ADT) is effective in controlling prostate cancer (PCa) and increasing survival, it is associated with a myriad of side effects that cause significant morbidity. Previous research has shown that PCa patients starting on ADT are neither fully informed nor well-equipped to manage the breadth of ADT’s side effects. The ADT Educational Program (a 1.5 h interactive class plus a book) was developed as an evidence-based resource for patients dealing with ADT. Our aim here was to compare the efficacy of an online version of the class with a previously assessed in-person version of the class. Using mixed MANOVAs within a non-randomized comparison design, we assessed: (1) changes in patients’ experiences of self-efficacy to manage and bother associated with side effects approximately 10 weeks after attending a class, and (2) potential differences in these variables between online and in-person class formats. Side effect bother decreased from pre- to post-class but did not differ between in-person (n = 94) and online (n = 137) class cohorts. While self-efficacy to manage side effects was slightly higher post-class in both cohorts, the increase was not statistically significant. Average self-efficacy ratings were significantly higher among in-person versus online class participants (p < 0.05; ηp2 = 0.128). Both online and in-person classes are associated with a significant reduction in the severity of side effect bother reported by PCa patients, suggesting non-inferiority of online versus in-person formats. Online classes offer greater accessibility to the program for patients outside the reach of in-person classes, increasing the availability of the program to more PCa patients and family members across Canada.

Abstract Our current understanding of the spread and neurodegenerative effects of tau neurofibrillary tangles (NFTs) within the medial temporal lobe (MTL) during the early stages of Alzheimer’s Disease (AD) is limited by the presence of confounding non-AD pathologies and the two-dimensional (2-D) nature of conventional histology studies. Here, we combine ex vivo MRI and serial histological imaging from 25 human MTL specimens to present a detailed, 3-D characterization of quantitative NFT burden measures in the space of a high-resolution, ex vivo atlas with cytoarchitecturally-defined subregion labels, that can be used to inform future in vivo neuroimaging studies. Average maps show a clear anterior to poster gradient in NFT distribution and a precise, spatial pattern with highest levels of NFTs found not just within the transentorhinal region but also the cornu ammonis (CA1) subfield. Additionally, we identify granular MTL regions where measures of neurodegeneration are likely to be linked to NFTs specifically, and thus potentially more sensitive as early AD biomarkers.

ABSTRACT The establishment and spread of invasive species are directly related to intersexual interactions as dispersal and reproductive success are related to distribution, effective population size, and population growth. Accordingly, populations established by r‐selected species are particularly difficult to suppress or eradicate. One such species, the red swamp crayfish (Procambarus clarkii) is established globally at considerable ecological and financial costs to natural and human communities. Here, we develop a single nucleotide polymorphism (SNP) loci panel for P. clarkii using restriction‐associated DNA‐sequencing data. We use the SNP panel to successfully genotype 1800 individuals at 930 SNPs in southeastern Michigan, USA. Genotypic data were used to reconstruct pedigrees, which enabled the characterization of P. clarkii's mating system and statistical tests for associations among environmental, demographic, and phenotypic predictors and adult reproductive success estimates. We identified juvenile cohorts using genotype‐based pedigrees, body size, and sampling timing, which elucidated the breeding phenology of multiple introduced populations. We report a high prevalence of multiple paternity in each surveyed waterbody, indicating polyandry in this species. We highlight the use of newly developed rapid genomic assessment tools for monitoring population reproductive responses, effective population sizes, and dispersal during ongoing control efforts.

The last decade has seen unprecedented policy emphasis on the Less Commonly Taught Languages (LCTLs) – whether broadly, as indicated by the regular publication of lists of languages critical to the national interest, such as that of the US Department of Education (2010), or in the particular languages included in the multiple new Federal programs that comprise the National Security Language Initiative (NSLI), such as the National Language Service Corps, STARTALK, the Language Flagship, the English for Heritage Language Speakers program, or the NSLI for Youth, to cite several examples. The LCTLs predominate in these lists, reflecting a national level policy emphasis on the LCTLs. This emphasis derives from perceived and actual needs for specific LCTLs required for the common weal – for national security, economic well being, and social justice (Brecht et al., 2007; Brecht & Rivers, 2000). This emphasis, consisting in its entirety of programs promulgated, funded, and directed by the Federal government, stands in contrast to the ongoing perception in our professional fields that Foreign Languages (FLs), and the LCTLs among them, are under increasing and unprecedented stress in the educational system, and that furthermore, that the teaching of LCTLs lacks public support, or is even actively opposed in the broader US society (Wiley, 2007).

Abstract Bulk composition of kidney stones, often analyzed with infrared spectroscopy, plays an essential role in determining the course of treatment for kidney stone disease. Though bulk analysis of kidney stones can hint at the general causes of stone formation, it is necessary to understand kidney stone microstructure to further advance potential treatments that rely on in vivo dissolution of stones rather than surgery. The utility of Raman microscopy is demonstrated for the purpose of studying kidney stone microstructure with chemical maps at ≤ 1 µm scales collected for calcium oxalate, calcium phosphate, uric acid, and struvite stones. Observed microstructures are discussed with respect to kidney stone growth and dissolution with emphasis placed on

Even though they have fewer children than in the past, North-American parents still devote almost as much time to their offspring – mothers a little less, fathers a little more. This is particularly true of young Quebec fathers. However, all in all, less time is spent in the physical company of the children, whatever the activity, though young Quebec fathers are once again the exception. The drop in maternal contact time is due mainly to women’s increased presence on the labour market. The fact of having young children at home, rather than age, gender or educational level, is one of the main factors impacting the parents’ daily schedules, more particularly as concerns the number of working hours and the amount of free time. When the children are grown up, parents tend to plan out their days like childless parents.

The skin, the largest external organ, serves as the primary defensive barrier against various environmental factors such as ultraviolet exposure, pollution, dietary habits, pathogens, and chemical compounds. Consequently, the skin reflects our age through visible signs of aging, such as wrinkles, age spots, dullness, and sagging. This review explores the gender-related aspects of cutaneous aging and the associated dermatological conditions. It highlights the different manifestations of aging in females and males that become evident after the age of 12, emphasizing the susceptibility to conditions such as seborrheic eczema, acne, and rosacea. Treatment strategies often vary between genders due to these disparities. While men tend to experience accelerated skin aging, most anti-aging products and strategies primarily target females. However, there has been a recent shift in men’s priorities, leading to increased interest in maintaining a youthful appearance and seeking cosmetic treatments. The manuscript covers a comprehensive range of modern dermal anti-aging and rejuvenation procedures, including plastic surgery, bio-revitalization methods, lasers, microneedling, and topical treatments. Additionally, it explores promising natural and synthetic therapeutics for combating age-related skin changes. The focus is on understanding the physiological aspects of gender-related cutaneous structure and aging to guide effective and tailored approaches in dermatological practice.

The purpose of this retrospective case series was to review the demographics of alpine skiers who sustain tibial plateau fractures, evaluate the inter-observer reliability of the Schatzker classification for fractures sustained while alpine skiing, and to evaluate patient-reported outcomes. We hypothesized that most tibial plateau fractures would be low-energy fracture patterns (Schatzker I–III) and occur in women and less-experienced skiers. Charts and radiographs of patients treated surgically for tibial plateau fractures caused by alpine skiing were evaluated. Patients treated less than two years prior to review were excluded. Patients who qualified were contacted to complete a questionnaire regarding their skiing experience, their pain levels experienced following their accident, the weather conditions during the accident, and their return to sport. Forty-seven patients met the inclusion criteria. The mean age was 49, and 60% of the participants were male. There were 28 low-energy fracture patterns (Schatzker I–III) and 19 high-energy patterns (Schatzker IV–VI) with a 95.7% inter-observer reliability. Contrary to the hypothesis, tibial plateau fractures sustained while alpine skiing occurred in older, experienced riders. Approximately 40% were high-energy fractures. Although over 75% of patients reported having no pain or occasional pain at their final follow-ups, less than half of the patients returned to alpine skiing.

Abstract Sea lamprey (Petromyzon marinus) is an invasive species that is a significant source of mortality for populations of valued fish species across the North American Great Lakes. Large annual control programs are needed to reduce the species' impacts; however, the number of successfully spawning adults cannot currently be accurately assessed. In this study, effective breeding size (Nb) and the minimum number of spawning adults (Ns) were estimated for larval cohorts from 17 tributaries across all five Great Lakes using single nucleotide polymorphisms (SNP) genotyped via RAD‐capture sequencing. Reconstructed larval pedigrees showed substantial variability in the size and number of full‐ and half‐sibling groups, Nb (

Loss of large-bodied wildlife, typically from hunting, degrades the ecological processes in tropical forests that sequester and store carbon. Carbon-based markets that incentivize wildlife conservation can generate revenues to support necessary forest and hunting management.

Thermodynamically induced length fluctuations of high-reflectivity mirror coatings put a fundamental limit on sensitivity and stability of precision optical interferometers like gravitational-wave detectors and ultrastable lasers. The main contribution—Brownian thermal noise—is related to the mechanical loss of the coating material. Al_{0.92}Ga_{0.08}As/GaAs crystalline mirror coatings are expected to reduce this limit. The first measurements of cryogenic silicon cavities revealed the existence of additional noise contributions exceeding the expected Brownian thermal noise. We describe a novel, nonthermal, photoinduced effect in birefringence that is most likely related to the recently discovered birefringence noise. Our studies of the dynamics and power dependence are an important step toward uncovering the underlying mechanisms. Averaging the anticorrelated birefringent noise results in a residual noise that is shown to be substantially different from Brownian thermal noise. To this end, we develop a new method for analyzing the coating noise in higher-order transverse-cavity modes, which makes it possible for the first time to determine the contribution of Brownian thermal noise to the total cavity noise. The new noise contributions must be considered carefully in precision interferometry experiments using similar coatings based on semiconductor materials.

Highlights With their predominantly coastal geographies, rapidly growing populations, and emissions-intensive activities, cities are highly vulnerable and major contributors to climate change. Their role as cultural centers, and commerce and innovation hubs, means they are also promising sources of solutions. Taken together, these factors demand a closer examination of the progress and solutions that cities are making to mitigate climate change and adapt to its impacts. However, research on the extent and effectiveness of cities’ implementation efforts is underdeveloped. There is a need to better understand if and how cities are rolling out effective implementation measures, what effects (intended and unintended) such measures are having, and whether their implementation efforts are achieving the transformational changes needed to realize a low carbon, climate-resilient future. This editorial introduces the special issue by exploring these issues and reflecting perspectives from a variety of disciplines both within and outside academia, and in relation to diverse cities in the Global North and South. To better understand the practical dimensions of implementation, and the various obstacles and opportunities faced by public and private sector actors in progressing climate action targets and goals, the editors invited submissions reflective of co-produced research. Though not all took this form, some did and helped to foreground the experiences of those actors who arguably have the most power and responsibility to advance implementation measures, and seed the very institutional arrangements needed for deeper, multisectoral climate action. Collectively, the content of the special issue points to a need for significant investment, policy change, social innovation, and cooperation across societal scales.

The spatial organization of cell surface receptors is critical for cell signaling and drug action. Here, the authors develop an optoproteomic method for mapping surface protein interactions, revealing cellular responses to antibodies, drugs and viral particles as well as immunosynapse signaling events.

The Canadian City of Toronto’s progress is evaluated for the implementation of its climate action plan, TransformTO, and its effectiveness in reducing sectoral emissions. Following a brief history of climate action in Toronto, the key climate policies and programs are subjected to a content analysis and assessed using an aggregate evaluation framework composed of qualitative indicators commonly used to track municipal climate action. The results of this assessment reveal that the city has made steady progress in reducing emissions, surpassing its 2020 greenhouse gas emissions reduction target of 30% reduction below 1990 levels. However, Toronto is not on track to meet its 2030 target of a 65% emissions reduction from 1990 levels. Without transformational action across all sectors, it is unlikely to meet the 2030 and 2040 targets. The results are intended to strengthen implementation and evaluation efforts in Toronto. The discussion will be of interest to decision-makers and practitioners who seek to accelerate implementation of municipal climate action plans. Policy relevance This paper is intended to support and strengthen the City of Toronto’s implementation of its climate action plan, TransformTO, and supporting Net Zero Strategies. Of potential relevance to policymakers in other Canadian cities is the role of ambitious top-down target-setting of the municipal organization and city at large for pursuing bold climate action, even in the face of significant constraints (e.g. provincial building code and energy grid, difficulties in accessing utilities energy use data). Policymakers may also draw insights from the Toronto context for leveraging staff and community commitment to climate action by involving them in planning and implementation of emissions reductions strategies. Useful recommendations are provided for overcoming modeling deficiencies and data limitations, while advancing transformative climate action through multi-sectoral partnerships, policies that support market transformation, the scale-up of low carbon programs and investments in low carbon infrastructure.

The V3-crown of the HIV-1 envelope protein largely elicits non-neutralizing antibodies. Here, the authors show that the V3-crown can be targeted by broadly neutralizing designed ankyrin repeat proteins recognizing two conformations one of which resembles CCR5- bound V3.

Abstract Tau neurofibrillary tangle (NFT) pathology in the medial temporal lobe (MTL) is closely linked to neurodegeneration, and is the early pathological change associated with Alzheimer’s disease (AD). To elucidate patterns of structural change in the MTL specifically associated with tau pathology, we compared high-resolution ex vivo MRI scans of human postmortem MTL specimens with histology-based pathological assessments of the MTL. MTL specimens were obtained from twenty-nine brain donors, including patients with AD, other dementias, and individuals with no known history of neurological disease. Ex vivo MRI scans were combined using a customized groupwise diffeomorphic registration approach to construct a 3D probabilistic atlas that captures the anatomical variability of the MTL. Using serial histology imaging in eleven specimens, we labelled the MTL subregions in the atlas based on cytoarchitecture. Leveraging the atlas and neuropathological ratings of tau and TAR DNA-binding protein 43 (TDP-43) pathology severity, morphometric analysis was performed to correlate regional MTL thickness with the severity of tau pathology, after correcting for age and TDP-43 pathology. We found significant correlations between tau pathology and thickness in the entorhinal cortex (ERC) and stratum radiatum lacunosum moleculare (SRLM). When focusing on cases with low levels of TDP-43 pathology, we found strong associations between tau pathology and thickness in the ERC, SRLM and the subiculum/cornu ammonis 1 (CA1) subfields of the hippocampus, consistent with early Braak stages.

Wellbeing in buildings is often approached by practitioners and researchers as the aggregate result of individual interactions between building occupants and building features. This sum-of-the-parts approach, however, ignores the ways in which broader social ('i.e'. sense of ownership and belonging) and symbolic ('i.e'. what it means to be ‘well’ in a specific culture at a particular place and time) components of wellbeing influence occupant experience of the built environment. A social practice perspective on wellbeing in buildings is proposed that accounts for these elements. Beginning with discussions of how wellbeing has been assessed and the foundations of social practice theory, it is suggested that occupant wellbeing is emergent not just from individual interactions with building features but also from broader social and symbolic elements. 'Policy relevance' A social practice perspective on wellbeing in buildings has implications for both the assessment of wellbeing and the role of wellbeing in the building design process. Integrating social and symbolic elements into measures of wellbeing pushes assessment beyond the typical focus on comfort and spatial experience (indoor environmental quality). These more nuanced assessments may in turn shape how wellbeing is addressed in building design, construction, and management.

Abstract Respiratory syncytial virus (RSV) can cause severe respiratory disease in humans, particularly in infants and the elderly. However, attempts to develop a safe and effective vaccine have so far been unsuccessful. Atomic-level structures of epitopes targeted by RSV-neutralizing antibodies are now known, including that bound by Motavizumab and its clinically used progenitor Palivizumab. We developed a chemically defined approach to RSV vaccine design, that allows control of both immunogenicity and safety features of the vaccine. Structure-guided antigen design and a synthetic nanoparticle delivery platform led to a vaccine candidate that elicits high titers of palivizumab-like, epitope-specific neutralizing antibodies. The vaccine protects preclinical animal models from RSV infection and lung pathology typical of vaccine-derived disease enhancement. The results suggest that the development of a safe and effective synthetic epitope-specific RSV vaccine may be feasible by combining this conformationally stabilized peptide and synthetic nanoparticle delivery system.

Abstract Background Prostate cancer predisposes patients and caregivers to a wide range of complex physical and psychosocial challenges, and interventions must incorporate a wide range of self-management strategies to help patients and their caregivers effectively cope with cancer challenges. To palliate this need, our team recently developed and evaluated the initial acceptability of a dyadic, Tailored, wEb-based, psychosocial, and physical activity self-Management PrOgram (TEMPO). TEMPO is a 10-week, interactive, web-based intervention consisting of five modules designed to help dyads manage their physical and psychosocial needs. It aims to teach dyads new self-management strategies and encourages them to increase their physical activity (PA) levels, mainly through walking and strength-based exercises. Initial acceptability evaluation of TEMPO revealed high user satisfaction, in addition to having a number of potential benefits for participants. After integrating suggested changes to TEMPO, the proposed pilot study aims to further test the acceptability and feasibility of TEMPO. Methods This study is a multicenter, stratified, parallel, two-group, pilot randomized control trial (RCT), where patient–caregiver dyads are randomized (stratified by anxiety level) to receive (a) TEMPO or (b) usual care. Participants (n goal = 40) are recruited across Canada at participating cancer centers and through self-referral (e.g., online recruitment). Patient inclusion criteria are (a) having received prostate cancer treatment within the past 2 years or scheduled to receive treatment, (b) identified a primary caregiver willing to participate in the study, and (c) has access to the Internet. Eligible caregivers are those identified by the patient as his primary source of support. Dyads complete a baseline questionnaire (T1) and another one 3 months later (T2) assessing various aspects of physical and emotional functioning (e.g., the Medical Outcomes Study (MOS) 12-item Short Form Health Survey (SF-12), the Hospital Anxiety and Depression Scale (HADS), and the Perceived Stress Scale (PSS)), self-management behaviors (e.g., the Health Education Impact Questionnaire (heiQ)), physical activity (the International Physical Activity Questionnaires (IPAQ) and the Multidimensional Self-efficacy for Exercise Scale (MSES)), and dyadic coping (the Dyadic Coping Inventory (DCI)). Dyads that used TEMPO are also asked to participate in a semi-structured exit interview exploring their overall experience with the program. Discussion This feasibility analysis will begin to develop the knowledge base on TEMPO’s value for men with prostate cancer and their caregivers to inform a larger trial. Trial registration NCT04304196

Cerebral amyloid angiopathy (CAA), a common comorbidity of Alzheimer’s disease (AD), is a cerebral small vessel disease (CSVD) characterized by deposition of fibrillar amyloid β (Aβ) in blood vessels of the brain and promotes neuroinflammation and vascular cognitive impairment and dementia (VCID). Hypertension, a prominent non-amyloidal CSVD, has been found to increase risk of dementia, but clinical data regarding its effects in CAA patients is controversial. To understand the effects of hypertension on CAA, we bred rTg-DI transgenic rats, a model of CAA, with spontaneously hypertensive, stroke prone (SHR-SP) rats producing bigenic rTg-DI/SHR-SP and non-transgenic SHR-SP littermates. At 7 months (M) of age, cohorts of both rTg-DI/SHR-SP and SHR-SP littermates exhibit elevated systolic blood pressures. However, transgene human amyloid β-protein (Aβ) precursor and Aβ peptide levels, as well as behavioral testing showed no changes between bigenic rTg-DI/SHR-SP and rTg-DI rats. Subsequent cohorts of rats were aged further to 10 M where bigenic rTg-DI/SHR-SP and SHR-SP littermates exhibit elevated systolic and diastolic blood pressures. Vascular amyloid load in hippocampus and thalamus was significantly decreased, whereas pial surface vessel amyloid increased, in bigenic rTg-DI/SHR-SP rats compared to rTg-DI rats suggesting a redistribution of vascular amyloid in bigenic animals. There was activation of both astrocytes and microglia in rTg-DI rats and bigenic rTg-DI/SHR-SP rats not observed in SHR-SP rats indicating that glial activation was likely in response to the presence of vascular amyloid. Thalamic microbleeds were present in both rTg-DI rats and bigenic rTg-DI/SHR-SP rats. Although the number of thalamic small vessel occlusions were not different between rTg-DI and bigenic rTg-DI/SHR-SP rats, a significant difference in occlusion size and distribution in the thalamus was found. Proteomic analysis of cortical tissue indicated that bigenic rTg-DI/SHR-SP rats largely adopt features of the rTg-DI rats with enhancement of certain changes. Our findings indicate that at 10 M of age non-pharmacological hypertension in rTg-DI rats causes a redistribution of vascular amyloid and significantly alters the size and distribution of thalamic occluded vessels. In addition, our findings indicate that bigenic rTg-DI/SHR-SP rats provide a non-pharmacological model to further study hypertension and CAA as co-morbidities for CSVD and VCID.

Abstract Background In 2013, our laboratory designed a targeted sequencing panel, “LipidSeq”, to study the genetic determinants of dyslipidemia and metabolic disorders. Over the last 6 years, we have analyzed 3262 patient samples obtained from our own Lipid Genetics Clinic and international colleagues. Here, we highlight our findings and discuss research benefits and clinical implications of our panel. Methods LipidSeq targets 69 genes and 185 single-nucleotide polymorphisms (SNPs) either causally related or associated with dyslipidemia and metabolic disorders. This design allows us to simultaneously evaluate monogenic—caused by rare single-nucleotide variants (SNVs) or copy-number variants (CNVs)—and polygenic forms of dyslipidemia. Polygenic determinants were assessed using three polygenic scores, one each for low-density lipoprotein cholesterol, triglyceride, and high-density lipoprotein cholesterol. Results Among 3262 patient samples evaluated, the majority had hypertriglyceridemia (40.1%) and familial hypercholesterolemia (28.3%). Across all samples, we identified 24,931 unique SNVs, including 2205 rare variants predicted disruptive to protein function, and 77 unique CNVs. Considering our own 1466 clinic patients, LipidSeq results have helped in diagnosis and improving treatment options. Conclusions Our LipidSeq design based on ontology of lipid disorders has enabled robust detection of variants underlying monogenic and polygenic dyslipidemias. In more than 50 publications related to LipidSeq, we have described novel variants, the polygenic nature of many dyslipidemias—some previously thought to be primarily monogenic—and have uncovered novel mechanisms of disease. We further demonstrate several tangible clinical benefits of its use.

Summary: Lipopolysaccharides (LPSs) cause lethal endotoxemia if not rapidly cleared from blood circulation. Liver sinusoidal endothelial cells (LSEC) systemically clear LPS by unknown mechanisms. We discovered that LPS clearance through LSEC involves endocytosis and lysosomal inactivation via Stabilin-1 and 2 (Stab1 and Stab2) but does not involve TLR4. Cytokine production was inversely related to clearance/endocytosis of LPS by LSEC. When exposed to LPS, Stabilin double knockout mice (Stab DK) and Stab1 KO, but not Stab2 KO, showed significantly enhanced systemic inflammatory cytokine production and early death compared with WT mice. Stab1 KO is not significantly different from Stab DK in circulatory LPS clearance, LPS uptake and endocytosis by LSEC, and cytokine production. These data indicate that (1) Stab1 receptor primarily facilitates the proactive clearance of LPS and limits TLR4-mediated inflammation and (2) TLR4 and Stab1 are functionally opposing LPS receptors. These findings suggest that endotoxemia can be controlled by optimizing LPS clearance by Stab1.

The causative agent of anthrax, Bacillus anthracis, evades the host immune response and establishes infection through the production of binary exotoxins composed of Protective Antigen (PA) and one of two subunits, lethal factor (LF) or edema factor (EF). The majority of vaccination strategies have focused upon the antibody response to the PA subunit. We have used a panel of humanised HLA class II transgenic mouse strains to define HLA-DR-restricted and HLA-DQ-restricted CD4+ T cell responses to the immunodominant epitopes of PA. This was correlated with the binding affinities of epitopes to HLA class II molecules, as well as the responses of two human cohorts: individuals vaccinated with the Anthrax Vaccine Precipitated (AVP) vaccine (which contains PA and trace amounts of LF), and patients recovering from cutaneous anthrax infections. The infected and vaccinated cohorts expressing different HLA types were found to make CD4+ T cell responses to multiple and diverse epitopes of PA. The effects of HLA polymorphism were explored using transgenic mouse lines, which demonstrated differential susceptibility, indicating that HLA-DR1 and HLA-DQ8 alleles conferred protective immunity relative to HLA-DR15, HLA-DR4 and HLA-DQ6. The HLA transgenics enabled a reductionist approach, allowing us to better define CD4+ T cell epitopes. Appreciating the effects of HLA polymorphism on the variability of responses to natural infection and vaccination is vital in planning protective strategies against anthrax.

Severe hypertriglyceridemia (HTG) is a relatively common form of dyslipidemia with a complex pathophysiology and serious health complications. HTG can develop in the presence of rare genetic factors disrupting genes involved in the triglyceride (TG) metabolic pathway, including large-scale copy-number variants (CNVs). Improvements in next-generation sequencing technologies and bioinformatic analyses have better allowed assessment of CNVs as possible causes of or contributors to severe HTG. We screened targeted sequencing data of 632 patients with severe HTG and identified partial deletions of the LPL gene, encoding the central enzyme involved in the metabolism of TG-rich lipoproteins, in four individuals (0.63%). We confirmed the genomic breakpoints in each patient with Sanger sequencing. Three patients carried an identical heterozygous deletion spanning the 5′ untranslated region (UTR) to LPL exon 2, and one patient carried a heterozygous deletion spanning the 5′UTR to LPL exon 1. All four heterozygous CNV carriers were determined to have multifactorial severe HTG. The predicted null nature of our identified LPL deletions may contribute to relatively higher TG levels and a more severe clinical phenotype than other forms of genetic variation associated with the disease, particularly in the polygenic state. The identification of novel CNVs in patients with severe HTG suggests that methods for CNV detection should be included in the diagnostic workup and molecular genetic evaluation of patients with high TG levels.

This essay is a direct application of the five language codes described in Roland Barthes’ essay “Style and its image”. The language codes consist of the Actional (Proairetic) code; the literal action of subjects or characters within the dramatic plot of the poetry; the Referential, or the cultural worldview of the work’s subject or theme; the Semantic, those suggestive details which describe characters or the setting of the work; the Hermeneutic, considering language units which conceal unknown aspects of the work or facts about character, setting or other qualities of the writing, though also those qualities traditionally considered literary conventions; and the Symbolic, or those aspects of language which suggest ideas beyond the literal text itself. The writer takes a fresh look at an earlier example of Contemporary American poetry using Structuralist discourse as a tool with which to explicate Donald Hall’s poem “The Town of Hill”, first published in 1975.

Abstract Background Targeted next-generation sequencing (NGS) enables rapid identification of common and rare genetic variation. The detection of variants contributing to therapeutic drug response or adverse effects is essential for implementation of individualized pharmacotherapy. Successful application of short-read based NGS to pharmacogenes with high sequence homology, nearby pseudogenes and complex structure has been previously shown despite anticipated technical challenges. However, little is known regarding the utility of such panels to detect copy number variation (CNV) in the highly polymorphic cytochrome P450 (CYP) 2D6 gene, or to identify the promoter (TA)7 TAA repeat polymorphism UDP glucuronosyltransferase (UGT) 1A1*28. Here we developed and validated PGxSeq, a targeted exome panel for pharmacogenes pertinent to drug disposition and/or response. Methods A panel of capture probes was generated to assess 422 kb of total coding region in 100 pharmacogenes. NGS was carried out in 235 subjects, and sequencing performance and accuracy of variant discovery validated in clinically relevant pharmacogenes. CYP2D6 CNV was determined using the bioinformatics tool CNV caller (VarSeq). Identified SNVs were assessed in terms of population allele frequency and predicted functional effects through in silico algorithms. Results Adequate performance of the PGxSeq panel was demonstrated with a depth-of-coverage (DOC) ≥ 20× for at least 94% of the target sequence. We showed accurate detection of 39 clinically relevant gene variants compared to standard genotyping techniques (99.9% concordance), including CYP2D6 CNV and UGT1A1*28. Allele frequency of rare or novel variants and predicted function in 235 subjects mirrored findings from large genomic datasets. A large proportion of patients (78%, 183 out of 235) were identified as homozygous carriers of at least one variant necessitating altered pharmacotherapy. Conclusions PGxSeq can serve as a comprehensive, rapid, and reliable approach for the detection of common and novel SNVs in pharmacogenes benefiting the emerging field of precision medicine.

HDL cholesterol (HDL-C) remains a superior biochemical predictor of CVD risk, but its genetic basis is incompletely defined. In patients with extreme HDL-C concentrations, we concurrently evaluated the contributions of multiple large- and small-effect genetic variants. In a discovery cohort of 255 unrelated lipid clinic patients with extreme HDL-C levels, we used a targeted next-generation sequencing panel to evaluate rare variants in known HDL metabolism genes, simultaneously with common variants bundled into a polygenic trait score. Two additional cohorts were used for validation and included 1,746 individuals from the Montréal Heart Institute Biobank and 1,048 individuals from the University of Pennsylvania. Findings were consistent between cohorts: we found rare heterozygous large-effect variants in 18.7% and 10.9% of low- and high-HDL-C patients, respectively. We also found common variant accumulation, indicated by extreme polygenic trait scores, in an additional 12.8% and 19.3% of overall cases of low- and high-HDL-C extremes, respectively. Thus, the genetic basis of extreme HDL-C concentrations encountered clinically is frequently polygenic, with contributions from both rare large-effect and common small-effect variants. Multiple types of genetic variants should be considered as contributing factors in patients with extreme dyslipidemia.

Familial hypercholesterolemia (FH) is a heritable condition of severely elevated LDL cholesterol, caused predominantly by autosomal codominant mutations in the LDL receptor gene (LDLR). In providing a molecular diagnosis for FH, the current procedure often includes targeted next-generation sequencing (NGS) panels for the detection of small-scale DNA variants, followed by multiplex ligation-dependent probe amplification (MLPA) in LDLR for the detection of whole-exon copy number variants (CNVs). The latter is essential because ∼10% of FH cases are attributed to CNVs in LDLR; accounting for them decreases false negative findings. Here, we determined the potential of replacing MLPA with bioinformatic analysis applied to NGS data, which uses depth-of-coverage analysis as its principal method to identify whole-exon CNV events. In analysis of 388 FH patient samples, there was 100% concordance in LDLR CNV detection between these two methods: 38 reported CNVs identified by MLPA were also successfully detected by our NGS method, while 350 samples negative for CNVs by MLPA were also negative by NGS. This result suggests that MLPA can be removed from the routine diagnostic screening for FH, significantly reducing associated costs, resources, and analysis time, while promoting more widespread assessment of this important class of mutations across diagnostic laboratories.

Abstract Frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) is associated with the accumulation of pathological neuronal and glial intracytoplasmic inclusions as well as accompanying neuron loss. We explored if cortical neurons detected by NeuN decreased with increasing TDP-43 inclusion pathology in the postmortem brains of 63 patients with sporadic and familial FTLD-TDP. Semi-automated quantitative algorithms to quantify histology in tissue sections stained with antibodies specific for pathological or phosphorylated TDP-43 (pTDP-43) and NeuN were developed and validated in affected (cerebral cortex) and minimally affected (cerebellar cortex) brain regions of FTLD-TDP cases. Immunohistochemistry (IHC) for NeuN and other neuronal markers found numerous neurons lacking reactivity, suggesting NeuN may reflect neuron health rather than neuron loss in FTLD. We found three patterns of NeuN and pTDP-43 reactivity in our sample of cortical tissue representing three intracortical region-specific stages of FTLD-TDP progression: Group 1 showed low levels of pathological pTDP-43 and high levels NeuN, while Group 2 showed increased levels of pTDP-43, and Group 3 tissues were characterized by reduced staining for both pTDP-43 and NeuN. Comparison of non-C9orf72/GRN FTLD-TDP with cases linked to both GRN mutations and C9orf72 expansions showed a significantly increased frequency of Group 3 histopathology in the latter cases, suggesting more advanced cortical disease. Hence, we propose that IHC profiles of pTDP-43 and NeuN reflect the burden of pTDP-43 and its deleterious effects on neuron health.

We use frequency-comb-based optical two-way time-frequency transfer (O-TWTFT) to measure the optical frequency ratio of state-of-the-art ytterbium and strontium optical atomic clocks separated by a 1.5-km open-air link. Our free-space measurement is compared to a simultaneous measurement acquired via a noise-cancelled fiber link. Despite nonstationary, ps-level time-of-flight variations in the free-space link, ratio measurements obtained from the two links, averaged over 30.5 hours across six days, agree to 6×10^{−19}, showing that O-TWTFT can support free-space atomic clock comparisons below the 10^{−18} level.

Au cours des dix dernières années, de nombreuses nouvelles études ont fait surface sur l’impact, sur les relations intimes, du dysfonctionnement érectile (DE) induit par le traitement du cancer de la prostate (CP). Malgré les importants progrès dans le traitement du DE—grâce aux inhibiteurs de phosphodiestérase, aux pompes à vide pour pénis et aux injections intracaverneuses—les patients et leurs partenaires continuent d’avoir des difficultés à maintenir une vie sexuelle gratifiante. Seuls la moitié des patients atteints d’un CP sont disposés à tenter un traitement contre le DE, et moins de la moitié des patients qui constatent des résultats positifs à la suite d’un tel traitement continuent de l’utiliser à long terme. Bien qu’il existe des stratégies efficaces qui s’enseignent aux patients pour surmonter les obstacles associés à l’application des traitements contre le DE, la plupart des patients, s’ils sont laissés à eux-mêmes, se découragent et abandonnent rapidement. Les infirmières jouent un rôle important dans l’éducation et le counselling aux patients, tant en ce qui concerne leur préparation avant le traitement du CP qu’à l’étape du suivi. Elles sont donc bien placées pour promouvoir le rétablissement sexuel des patients atteints de CP et pour ainsi accroître le taux de réussite parmi les patients et leurs partenaires en matière de sexualité. Les infirmières sont formées pour dispenser des soins biopsychosociaux holistiques, une approche qui complète les traitements biomédicaux contre le DE et qui répond à un besoin bien réel. Dans un premier temps, nous offrons aux infirmières des suggestions qui visent à renforcer leur capacité de discuter, d’évaluer et d’intervenir dans le domaine des difficultés d’ordre sexuel. S’ensuivent des recommandations précises—basées sur la documentation scientifique sur le CP—visant à aider les infirmières à soutenir les patients qui reçoivent un traitement contre le DE. Nous offrons en outre des conseils sur des méthodes d’éducation des patients qui favorisent le développement d’attentes réalistes face aux traitements. Non seulement ces suggestions devraient-elles aider à améliorer l’adhésion aux traitements contre le DE, mais encore elles devraient aider les patients à réfléchir de façon plus globale au processus de rétablissement sexuel et à élaborer des objectifs de rétablissement au-delà de la simple restauration du fonctionnement érectile. La souplesse dans les pratiques sexuelles semble être importante pour la renégociation fructueuse du fonctionnement sexuel. Par conséquent, on devrait suggérer aux patients des stratégies sexuelles sans pénétration—qui ne requièrent donc pas d’érections—dans le cadre de la pratique clinique de routine. Outre les stratégies visant à surmonter les obstacles particuliers comme la perte de libido et de moral liée à l’échec du traitement, il convient d’offrir des recommandations concernant la communication de couple, la persistance dans le processus thérapeutique et le travail de deuil par rapport à la perte de fonctionnement sexuel.Mots clés : cancer de la prostate, dysfonctionnement érectile, adaptation sexuelle, counselling, éducation du patient

In the past decade there has been a surge of literature documenting the impact of prostate cancer (PCa) treatment-induced erectile dysfunction (ED) on intimate relationships. While there have been significant advances in the treatment of ED, with phosphodiesterase inhibitors, vacuum erection devices and intracavernous injections, patients and their partners continue to struggle to finds ways to maintain enjoyable sexual activity. Only half of PCa patients are willing to try ED treatments, and less than half of those patients, who find ED treatments helpful in improving erectile function, will continue to use them long-term.While there are effective strategies that can be taught to patients for overcoming the barriers associated with the use of ED treatments, many patients struggle on their own with these challenges, become discouraged, and quickly give up. Nurses play a large role in patient education and counselling, both in preparing patients for PCa treatment, and in follow-up. Consequently, they are well positioned to play a significant part in promoting sexual recovery among PCa patients and, thus, increasing patients’ and partners’ experiences of success. Nurses are well versed in providing holistic biopsychosocial care, which is a much-needed approach to complement the use of biomedical ED treatments. We begin by providing suggestions for nurses to increase their competence in discussing, assessing and intervening in the area of sexual difficulties. We follow with specific suggestions, based on the PCa literature, to guide nurses in supporting patients receiving ED treatment. Guidance is offered regarding approaches to patient education that fosters the development of realistic treatment expectations. Not only should these suggestions help improve adherence to ED treatments, but they should also help patients think more broadly about the sexual recovery process, encouraging the development of goals in sexual recovery beyond restoration of erectile function. Flexibility in sexual practice is found to be a key in successful sexual renegotiation, therefore, non-penetrative sexual strategies—that are not dependent on erections—should be offered to patients, as a routine part of clinical practice. Additional suggestions regarding couple communication, persistence in the treatment process, and working through grief associated with sexual losses are also offered in addition to strategies for overcoming specific barriers such as loss of libido and demoralization associated with treatment failures.Key words: prostate cancer, erectile dysfunction, sexual adaptation, counselling, patient education

Prostate cancer (PCa) treatments result in a wide range of short- and long-term survivorship issues not only for men, but also their partners. The effects of treatment vary from urinary incontinence and sexual dysfunction, to psychological, relational and social challenges. Androgen-deprivation therapy contributes as well to serious health risks (e.g., cardiovascular disease and osteoporosis), which must be effectively managed. Although there are a myriad of survivorship issues to manage, there are few survivorship programs in Canada to help patients and partners address the outcomes of PCa diagnosis and treatment. However, this is starting to change. Several sites across Canada are participating in developing a range of programs to address the supportive care needs of men with PCa and their partners. In this article, we discuss the issues and the programs that are now emerging to address them. Prostate cancer (PCa) patients face a myriad of issues associated with treatment that significantly impact quality of life. The primary localized and potentially curative PCa treatments are radical prostatectomy and radiation treatment (in the form of brachytherapy or external beam radiation). Systemic therapies such as androgen deprivation therapy (ADT) are also common. Although patients and their partners experience significant physical and psychosocial impacts from such treatments, support to address these issues is limited and inconsistently in Canadian cancer centres.A number of Canadian cancer centres have been working diligently over the past six years to improve the supportive care offered to PCa patients and their partners. Two examples of these programs will be discussed, one focusing on sexual dysfunction arising from localized treatment for PCa and the second, addressing adaptation to androgen deprivation therapy.