Cardiac Myosin Inhibitors: Expanding the Horizon for Hypertrophic Cardiomyopathy Management.

OBJECTIVE: To review the current literature on the efficacy and safety of cardiac myosin inhibitors (CMIs) for the treatment of hypertrophic cardiomyopathy (HCM). DATA SOURCES: A literature search was conducted on PubMed from origin to April 2023, using the search terms "MYK-461," "mavacamten," "CK-3773274," and "aficamten." Studies were limited to English-based literature, human subjects, and clinical trials resulting in the inclusion of 13 articles. ClinicalTrials.gov was also used with the same search terms for ongoing and completed trials. STUDY SELECTION AND DATA EXTRACTION: Only phase II and III studies were included in this review except for pharmacokinetic studies that were used to describe drug properties. DATA SYNTHESIS: CMIs enable cardiac muscle relaxation by decreasing the number of myosin heads that can bind to actin and form cross-bridges. Mavacamten, the first Food and Drug Administration (FDA)-approved drug in this class, has been shown to improve hemodynamic, functional, and quality of life measures in HCM with obstruction. In addition, aficamten is likely to become the next FDA-approved CMI with promising phase II data and an ongoing phase III trial expected to release results in the next year. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE IN COMPARISON WITH EXISTING DRUGS: CMIs provide a novel option for obstructive hypertrophic cardiomyopathy, particularly in those not suitable for septal reduction therapy. Utilization of these agents requires knowledge of drug interactions, dose titration schemes, and monitoring parameters for safety and efficacy. CONCLUSIONS: CMIs represent a new class of disease-specific drugs for treatment of HCM. Cost-effectiveness studies are needed to delineate the role of these agents in patient therapy.

Coping Strategies and Associated Symptom Burden Among Patients With Advanced Cancer.

BACKGROUND: Few studies examine how patients with advanced cancer cope with stress. The objective of our study was to evaluate coping strategies adopted by patients with cancer and their relationship with symptom burden. METHODS: A secondary data analysis of a prospective cross-sectional survey of patients with cancer and tobacco use was conducted, which examined demographics, symptom burden (Edmonton Symptom Assessment System), and coping strategies (the Brief COPE Questionnaire). Demographic characteristics were summarized by standard summary statistics; we also examined associations between patient characteristics and coping strategies using t-test, rank-sum test, chi-squared test, or Fisher's exact test depending on the distribution of data. RESULTS: Among 399 patients, the majority were female (60%), Caucasian (70%), the mean age was 56.5 (±12.0) years, and the most common malignancies were gastrointestinal (21%) and breast (19%). Patients with cancer adopted multiple adaptive coping strategies, most frequently acceptance (86.7%) and emotional support (79.9%), with humor (18.5%) being the least. Common maladaptive strategies included venting (14.5%) and self-distraction (36.6%), while substance use (1.0%) was infrequently reported. Of the adaptive strategies, female gender was significantly associated with higher engagement with emotional and instrumental support, positive reframing, religious coping, and acceptance (P < .05 for all). College educated patients reported significantly higher implementation of humor, planning, and acceptance. Maladaptive coping strategies such as denial were associated with increased pain and depression, while patients adopting emotional-focused strategies rated decreased emotional distress. CONCLUSIONS: The majority of patients with advanced cancer reported adopting multiple, adaptive coping strategies, and a minority utilized maladaptive or avoidant strategies, rarely substance use, and may need additional psychological support.

Self-incompatibility and the genetic architecture of inbreeding depression.

Inbreeding depression plays a fundamental role in evolution. To help detect and characterize the loci that underlie inbreeding depression, we used bud pollination and salt treatments to circumvent self-incompatibility (SI) in plants from populations of Leavenworthia alabamica and produced families of progeny that were then genotyped at genetically mapped single-nucleotide polymorphism (SNP) loci. Using Bayesian inference, the segregation patterns for each SNP were used to explore support for different dominance and selection coefficients at linked viability loci in different genomic regions. There was support for several partially recessive viability loci in one of the populations, and one such locus mapped to the genomic region of the novel SI locus in L. alabamica. These results are consistent with earlier findings that showed purging of inbreeding depression for germination rate in L. alabamica. They are also consistent with expectations from evolutionary genetic theory that recessive, deleterious alleles linked to loci under balancing selection can be sheltered from selection.

Attachment and compassion-threat: Influence of a secure attachment-prime.

OBJECTIVES: The present paper proposed and tested a methodology for reducing individual's threat response to compassion-imagery, by increasing their levels of state attachment-security. DESIGN: A total of 68 University students (63% female, mean age = 25) completed an experimental study, where they were randomly assigned to either a 10-min attachment-prime (to enhance attachment-security) or an interpersonal skills module (control condition). METHODS: Participants completed a compassion-focused imagery exercise before and after the manipulation, to determine the effects of the attachment-prime. To measure the effects of the manipulation on individual's threat response, heart rate variability data were collected at baseline and during both compassion exercises. RESULTS: As predicted, individuals who reported higher levels of anxious and avoidant attachment styles were more likely to display a threat response (decreases in heart rate variability), to the first compassion-focused imagery. After receiving an attachment-prime, heart rate variability increased suggesting that individual's experienced greater self-soothing responses and decreased threat responses to the second compassion-focused imagery. CONCLUSIONS: The present findings suggest that individuals with insecure attachments are likely to require additional support increasing their attachment-security, before they can successfully engage in compassion-based exercises or therapies. PRACTITIONER POINTS: Compassion-based exercises may result in fear and consequently avoidance in some populations of individuals. Threat responses to compassion can be reduced by using attachment-based techniques. Research findings will help inform and broaden the clinical applicability of compassion-based therapies.

Inbreeding depression is difficult to purge in self-incompatible populations of Leavenworthia alabamica.

The extent to which inbreeding depression can be purged is a major determinant of mating system evolution and is important to conservation and crop improvement. Studies of inbreeding depression purging have not been conducted in self-incompatible plants before. An experimental ('ancestral') treatment was first created from self-incompatible plants of Leavenworthia alabamica. Lines derived from this population were maintained by self-pollination for three generations in the attempt to create a 'purged' population with fewer recessive, deleterious mutations of large effect. Fitness components and the frequency of malformed phenotypes were monitored in progeny derived from selfing and outcrossing in the ancestral and purged treatments. Fitness component means and inbreeding depression were largely unchanged by three generations of forced self-pollination, and there was no reduction in the frequency of plants exhibiting malformed phenotypes. Our findings indicate that inbreeding depression in this species is largely a result of mutations of mild effect, consistent with the observation that self-incompatibility is maintained in most populations of L. alabamica, despite the presence of genetic variants with weaker self-incompatibility. Moreover, although population theory suggests that deleterious mutations of large effect should be sheltered from selection in the region of self-incompatibility locus, our results do not support this prediction.

Using stepped-care approaches within internet-based interventions for youth anxiety: Three case studies.

BACKGROUND: There are a lack of clear guidelines for the dissemination of Internet-based cognitive behaviour therapy (ICBT) for childhood and adolescent anxiety in routine care. While self-guided ICBT has greater reach than therapist-guided ICBT, it is plagued by problems of low program adherence and many young people are not successfully treated. It is important that we identify models of ICBT that are accessible, but provide the right support, at the right time to those who need it. Stepped-care models of ICBT offer one potential solution. OBJECTIVE: This case study examined the application of stepped-care within an ICBT intervention for childhood and adolescent anxiety, in which young people were stepped up from self-guided to therapist-guided ICBT. METHODS: Three case studies are presented and include young males (aged 11-12 years) who participated in BRAVE Stepped-Care, a new ICBT program incorporating two treatment steps: Step 1 - five sessions of self-guided ICBT and Step 2 - five sessions of therapist-guided ICBT. Participants completed diagnostic assessments at pre- and post-treatment, along with a battery of self-report questionnaires. Step-up requirements were determined at a mid-treatment assessment. Treatment response was determined by change on diagnostic severity and presence of diagnosis and changes in self-reported anxiety symptoms (through T-scores and Reliable Change Indices). RESULTS: In-depth examination of the three case studies showed that decisions to step-up from Step 1 to Step 2 were complex and required consideration of program engagement and adherence, as well as changes on self-reported anxiety, behavioural indicators of anxiety and parent perspectives. Results showed that non-responders at mid-treatment who were stepped-up to therapist-guided ICBT after Step 1 were able to increase engagement and response to treatment in Step 2, such that they were free of their primary anxiety diagnosis at post-treatment. CONCLUSIONS: The findings highlight the importance of early assessment of engagement and non-response within self-guided ICBT programs for youth anxiety and the positive changes that can subsequently occur when therapist-guidance is introduced mid-treatment for non-responders. The efficacy of stepped-care ICBT models needs to be confirmed in larger randomised controlled trials.

One-Year Review of the SCREEN (Skin Cancer Post-Transplant) Clinic.

The Skin Cancer Post-Transplant (SCREEN) Clinic is a skin-cancer screening clinic that is fully integrated into the renal transplantation clinic at St Paul's Hospital in Vancouver, British Columbia. The purpose of this review was to determine characteristics of patients most at risk for skin cancer, to specify types and locations of skin cancers diagnosed, and to identify areas for patient and physician education. Transplant patients (91% renal; 5% heart) screened by a dermatologist during a 12-month period were stratified into low-, medium-, and high-risk groups based on detailed history and skin examination. In total, 118 skin cancers were diagnosed. White males were found to be most at risk. Squamous cell carcinoma accounted for the majority of tumours, over 25% of which demonstrated invasion. Forty-two percent of patients used only 1 to 2 bottles of sunscreen per year, and sun-protective practices were limited. With this information, we have identified potential target areas for patient and physician education.

Post-Discharge Survival Outcomes of Patients with Advanced Cancer from the University of Texas MD Anderson Cancer Center Investigational Cancer Therapeutics (Phase I Trials) Inpatient Unit.

BACKGROUND: Patients with advanced cancer who progress on standard therapy are potential candidates for phase I clinical trials. Due to their aggressive disease and complex comorbid conditions, these patients often need inpatient admission. This study assessed the outcomes of such patients after they were discharged to hospice care. PATIENTS AND METHODS: We performed a retrospective analysis of patients with solid tumor malignancies who were discharged to hospice care from the inpatient service. RESULTS: One hundred thirty-three patients were included in the study cohort. All patients had metastatic disease and an Eastern Cooperative Oncology Group performance status ≥3. The median survival after discharge to hospice from an inpatient setting was 16 days, with a survival rate of 5% at 3 months after discharge. The median survival after the last cancer treatment was 46 days, with survival of 17% at 3 months, and 5% at 6 months. Patients with lactate dehydrogenase (LDH) >618 IU/L had a median post-discharge survival of 11 days versus 20 days for patients with LDH ≤618 IU/L. CONCLUSIONS: Patients with metastatic cancer participating in phase I trials who have poor performance status and require inpatient admission have a very short survival after discharge to hospice. A high LDH level predicts an even shorter survival.

Genetic variation for pseudo-self-compatibility in self-incompatible populations of Leavenworthia alabamica (Brassicaceae).

Self-incompatibility (SI) promotes outcrossing, but transitions to self-compatibility (SC) are frequent. Population genetic theory describing the breakdown of SI to SC suggests that, under most conditions, populations should be composed of either SI or SC individuals. Under a narrow range of conditions, theory suggests that SI may persist alongside reduced expression of SI (pseudo-SI, PSI) in mixed-mating populations. We studied genetic variation for PSI segregating in four SI populations of Leavenworthia alabamica by measurement of the heritability of pollen tube number after self-pollination. We tested for the role of the S-locus in this variation by sequencing seven S-alleles from plants with high pseudo-SC (PSC) and testing for the co-segregation of these alleles with PSC. We found a continuous distribution of PSC in all populations and 90% of plants exhibited PSC. The heritability ranged from 0.39 to 0.57. All seven S-alleles from plants with high PSC exhibited trans-specific polymorphism, and no stop codons were observed within the c. 600-bp region sequenced. One of these S-alleles was directly associated with the inheritance of PSC. We conclude that heritable variation in PSC is largely a result of genetic variation in the signaling cascade downstream of the S-locus reaction, together with the presence of one leaky S-allele.

Direct vs. indirect effects of whole-genome duplication on prezygotic isolation in Chamerion angustifolium: Implications for rapid speciation.

PREMISE OF THE STUDY: The depiction of polyploid speciation as instantaneous implies that strong prezygotic and postzygotic isolation form as a direct result of whole-genome duplication. However, the direct vs. indirect contributions of genome duplication to phenotypic divergence and prezygotic isolation are rarely quantified across multiple reproductive barriers. METHODS: We compared the phenotypic differences between diploid and both naturally occurring and synthesized tetraploids (neotetraploids) of the plant Chamerion angustifolium. Using this information and additional published values for this species, we compared the magnitude of isolation (ecological, flowering, pollinator, and gametic) between diploids and natural-occurring tetraploids to that between diploids and neotetraploids. KEY RESULTS: Differences among ploidy cytotypes were observed for eight of 12 vegetative and reproductive traits measured. Neotetraploids resembled diploids but differed from natural tetraploids with respect to four traits, including flowering time and plant height. Diploid-neotetraploid (2x-4xneo) experimental arrays exhibited lower pollinator fidelity to cytotype and seed set compared with 2x-4xnat arrays. Based on these results and published evidence, reproductive isolation between diploids and neotetraploids across all four life stages averaged 0.48 and deviated significantly from that between diploids and natural tetraploids (RI = 0.96). CONCLUSIONS: Genome duplication causes phenotypic shifts and contributes directly to prezygotic isolation for some barriers (gametic isolation) but cannot account for the cumulative isolation from diploids observed in natural tetraploids. Therefore, conditions for species formation through genome duplication are not necessarily instantaneous and selection to strengthen prezygotic barriers in young polyploids is critical for the establishment of polyploid species in sympatry.

Cutaneous Metastasis of a Mucoepidermoid Carcinoma of the Pancreas: First Reported Case.

BACKGROUND: Mucoepidermoid pancreatic cancer is a rare entity with only 8 cases reported in the literature. On review of the literature, the authors found that cutaneous metastases in pancreatic cancer are rare and have not been associated with the mucoepidermoid subtype. The authors present the first reported case of cutaneous metastasis in a patient with mucoepidermoid carcinoma of the pancreas. CASE PRESENTATION: A 50-year old white male with a metastatic invasive poorly differentiated mucoepidermoid carcinoma of the pancreas was found to have a slow growing lesion in the skin over his left upper quadrant while undergoing active therapy. The lesion was biopsied and the pathology was consistent with pancreatic origin sharing similar morphologic features when compared with the primary pancreactectomy specimen. CONCLUSIONS: Mucoepidermoid pancreatic cancer is an exceedingly rare subtype of pancreatic cancer, with very little information regarding its diagnosis, treatment, and patterns of metastases. Here, the authors present the first reported case of cutaneous metastases of mucoepidermoid pancreatic cancer.

Primary care hypnotic and anxiolytic prescription: Reviewing prescribing practice over 8 years.

INTRODUCTION: Over the last few years, hypnotic and anxiolytic medications have had their clinical efficacy questioned in the context of concerns regarding dependence, tolerance alongside other adverse effects. It remains unclear how these concerns have impacted clinical prescribing practice. MATERIALS AND METHODS: This is a study reviewing community-dispensed prescribing data for patients on the East Practice Medical Center list in Arbroath, Scotland, in 2007, 2011 and 2015. Anxiolytic and hypnotic medications were defined in accordance with the British National Formulary chapter 4.1.1 and chapter 4.1.2. All patients receiving a drug within this class in any of the study years were collated and anonymized using primary care prescribing data. The patients' age, gender, name of the prescribed drug(s), and total number of prescriptions in this class over the year were extracted. RESULTS: The proportion of patients prescribed a benzodiazepine medication decreased between 2007 and 2015: 83.8% (n = 109) in 2007, 70.5% (n = 122) in 2011, and 51.7% (n = 138) in 2015 (P = 0.006). The proportion of these patients prescribed a nonbenzodiazepine drug increased between 2007 and 2015: 30% (n = 39) in 2007, 46.2% (n = 80) in 2011, and 52.4% (n = 140) in 2015 (P = 0.001). There was a significant increase in the number of patients prescribed melatonin (P = 0.020). DISCUSSION: This study reports a reduction in benzodiazepine prescriptions in primary care alongside increases in nonbenzodiazepine and melatonin prescribing, with an increase in prescribing rates of this drug class overall. CONCLUSION: Changes in this prescribing practice may reflect the medicalization of insomnia, local changes in prescribing practice and alongside national recommendations.

The association between polyploidy and clonal reproduction in diploid and tetraploid Chamerion angustifolium.

Clonal reproduction is associated with the incidence of polyploidy in flowering plants. This pattern may arise through selection for increased clonality in polyploids compared to diploids to reduce mixed-ploidy mating. Here, we test whether clonal reproduction is greater in tetraploid than diploid populations of the mixed-ploidy plant, Chamerion angustifolium, through an analysis of the size and spatial distribution of clones in natural populations using AFLP genotyping and a comparison of root bud production in a greenhouse study. Natural tetraploid populations (N = 5) had significantly more AFLP genotypes (x¯ = 10.8) than diploid populations (x¯ = 6.0). Tetraploid populations tended to have fewer ramets per genotype and fewer genotypes with >1 ramet. In a spatial autocorrelation analysis, ramets within genotypes were more spatially aggregated in diploid populations than in tetraploid populations. In the greenhouse, tetraploids allocated 90.4% more dry mass to root buds than diploids, but tetraploids produced no more root buds and 44% fewer root buds per unit root mass than diploids. Our results indicate that clonal reproduction is significant in most populations, but tetraploid populations are not more clonal than diploids, nor are their clones more spatially aggregated. As a result, tetraploids may be less sheltered from mixed-ploidy mating and diploids more exposed to inbreeding, the balance of which could influence the establishment of tetraploids in diploid populations.

The effects of rapid desiccation on estimates of plant genome size.

Flow cytometry has become the dominant method for estimating nuclear DNA content in plants, either for ploidy determination or quantification of absolute genome size. Current best practices for flow cytometry involve the analysis of fresh tissue, however, this imposes significant limitations on the geographic scope and taxonomic diversity of plants that can be included in large-scale genome size studies. Dried tissue has been used increasingly in recent years, but largely in the context of ploidy analysis. Here we test rapid tissue drying with silica gel as a method for use in genome size studies, potentially enabling broader geographic sampling of plants when fresh tissue collection is not feasible. Our results indicate that rapid drying introduces comparatively minor error (<10%), which is similar to the error introduced by other common methodological variations such as instrument. Additionally, the relative effect of drying on genome size and data quality varied between species and buffers. Tissue desiccation provides a promising approach for expanding our knowledge of plant genome size diversity.

Genome duplication and the evolution of conspecific pollen precedence.

Conspecific pollen precedence can be a strong reproductive barrier between polyploid and diploid species, but the role of genome multiplication in the evolution of this barrier has not been investigated. Here, we examine the direct effect of genome duplication on the evolution of pollen siring success in tetraploid Chamerion angustifolium. To separate the effects of genome duplication from selection after duplication, we compared pollen siring success of synthesized tetraploids (neotetraploids) with that of naturally occurring tetraploids by applying 2x, 4x (neo or established) or 2x + 4x pollen to diploid and tetraploid flowers. Seed set increased in diploids and decreased in both types of tetraploids as the proportion of pollen from diploid plants increased. Based on offspring ploidy from mixed-ploidy pollinations, pollen of the maternal ploidy always sired the majority of offspring but was strongest in established tetraploids and weakest in neotetraploids. Pollen from established tetraploids had significantly higher siring rates than neotetraploids when deposited on diploid (4x(est) = 47.2%, 4x(neo) = 27.1%) and on tetraploid recipients (4x(est) = 91.9%, 4x(neo) = 56.0%). Siring success of established tetraploids exceeded that of neotetraploids despite having similar pollen production per anther and pollen diameter. Our results suggest that, while pollen precedence can arise in association with the duplication event, the strength of polyploid siring success evolves after the duplication event.