Be present now, sleep well later: Mindfulness promotes sleep health via emotion regulation.

OBJECTIVE: Despite the popularity of mindfulness in research and interventions, information is missing about how and why mindfulness may benefit employee sleep health. Drawing from emotion regulation theory, we evaluate affective rumination, negative affect, and positive affect as potential mechanisms. We also explore differential effects of trait and state attentional mindfulness on both subjective (e.g., quality and sufficiency) and actigraphy-measured aspects (e.g., duration and wake after sleep onset) of sleep health. METHOD: Ecological momentary assessment and sleep actigraphy data were collected across two independent samples of health care workers (N1 = 60, N2 = 84). Ecological momentary assessment was also used to collect daily information on state mindfulness, affect, and rumination. RESULTS: Our results support rumination and, to a less consistent extent, negative affect as mediators of the association between mindfulness and sleep health but not positive affect. Trait and state mindfulness demonstrate comparable benefits for employee sleep health, but these benefits largely emerge for subjective sleep dimensions than actigraphy-measured. CONCLUSIONS: These findings support emotion regulation as a sound theoretical framework for sleep and mindfulness research and may support more informed workplace mindfulness interventions. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Biallelic variants in Plexin B2 (PLXNB2) cause amelogenesis imperfecta, hearing loss and intellectual disability.

BACKGROUND: Plexins are large transmembrane receptors for the semaphorin family of signalling proteins. Semaphorin-plexin signalling controls cellular interactions that are critical during development as well as in adult life stages. Nine plexin genes have been identified in humans, but despite the apparent importance of plexins in development, only biallelic PLXND1 and PLXNA1 variants have so far been associated with Mendelian genetic disease. METHODS: Eight individuals from six families presented with a recessively inherited variable clinical condition, with core features of amelogenesis imperfecta (AI) and sensorineural hearing loss (SNHL), with variable intellectual disability. Probands were investigated by exome or genome sequencing. Common variants and those unlikely to affect function were excluded. Variants consistent with autosomal recessive inheritance were prioritised. Variant segregation analysis was performed by Sanger sequencing. RNA expression analysis was conducted in C57Bl6 mice. RESULTS: Rare biallelic pathogenic variants in plexin B2 (PLXNB2), a large transmembrane semaphorin receptor protein, were found to segregate with disease in all six families. The variants identified include missense, nonsense, splicing changes and a multiexon deletion. Plxnb2 expression was detected in differentiating ameloblasts. CONCLUSION: We identify rare biallelic pathogenic variants in PLXNB2 as a cause of a new autosomal recessive, phenotypically diverse syndrome with AI and SNHL as core features. Intellectual disability, ocular disease, ear developmental abnormalities and lymphoedema were also present in multiple cases. The variable syndromic human phenotype overlaps with that seen in Plxnb2 knockout mice, and, together with the rarity of human PLXNB2 variants, may explain why pathogenic variants in PLXNB2 have not been reported previously.

Ten-Year Stability of an Insomnia Sleeper Phenotype and Its Association With Chronic Conditions.

OBJECTIVE: To identify distinct sleep health phenotypes in adults, examine transitions in sleep health phenotypes over time, and subsequently relate these to the risk of chronic conditions. METHODS: A national sample of adults from the Midlife in the United States study ( N = 3683) provided longitudinal data with two time points (T1: 2004-2006, T2: 2013-2017). Participants self-reported on sleep health (regularity, satisfaction, alertness, efficiency, duration) and the number and type of chronic conditions. Covariates included age, sex, race, education, education, partnered status, number of children, work status, smoking, alcohol, and physical activity. RESULTS: Latent transition analysis identified four sleep health phenotypes across both time points: good sleepers, insomnia sleepers, weekend catch-up sleepers, and nappers. Between T1 and T2, the majority (77%) maintained their phenotype, with the nappers and insomnia sleepers being the most stable. In fully adjusted models with good sleepers at both time points as the reference, being an insomnia sleeper at either time point was related to having an increased number of total chronic conditions by 28%-81% at T2, adjusting for T1 conditions. Insomnia sleepers at both time points were at 72%-188% higher risk for cardiovascular disease, diabetes, depression, and frailty. Being a napper at any time point related to increased risks for diabetes, cancer, and frailty. Being a weekend catch-up sleeper was not associated with chronic conditions. Those with lower education and unemployed were more likely to be insomnia sleepers; older adults and retirees were more likely to be nappers. CONCLUSION: Findings indicate a heightened risk of chronic conditions involved in suboptimal sleep health phenotypes, mainly insomnia sleepers.

Heterozygous COL17A1 variants are a frequent cause of amelogenesis imperfecta.

BACKGROUND: Collagen XVII is most typically associated with human disease when biallelic COL17A1 variants (>230) cause junctional epidermolysis bullosa (JEB), a rare, genetically heterogeneous, mucocutaneous blistering disease with amelogenesis imperfecta (AI), a developmental enamel defect. Despite recognition that heterozygous carriers in JEB families can have AI, and that heterozygous COL17A1 variants also cause dominant corneal epithelial recurrent erosion dystrophy (ERED), the importance of heterozygous COL17A1 variants causing dominant non-syndromic AI is not widely recognised. METHODS: Probands from an AI cohort were screened by single molecule molecular inversion probes or targeted hybridisation capture (both a custom panel and whole exome sequencing) for COL17A1 variants. Patient phenotypes were assessed by clinical examination and analyses of affected teeth. RESULTS: Nineteen unrelated probands with isolated AI (no co-segregating features) had 17 heterozygous, potentially pathogenic COL17A1 variants, including missense, premature termination codons, frameshift and splice site variants in both the endo-domains and the ecto-domains of the protein. The AI phenotype was consistent with enamel of near normal thickness and variable focal hypoplasia with surface irregularities including pitting. CONCLUSION: These results indicate that COL17A1 variants are a frequent cause of dominantly inherited non-syndromic AI. Comparison of variants implicated in AI and JEB identifies similarities in type and distribution, with five identified in both conditions, one of which may also cause ERED. Increased availability of genetic testing means that more individuals will receive reports of heterozygous COL17A1 variants. We propose that patients with isolated AI or ERED, due to COL17A1 variants, should be considered as potential carriers for JEB and counselled accordingly, reflecting the importance of multidisciplinary care.

Quality of life in the adjuvant setting: A meta-analysis of US Food and Drug Administration approved anti-cancer drugs from 2018 to 2022.

BACKGROUND: In oncology, quality of life (QoL) questionnaires were historically designed to be used in the advanced or metastatic setting. We sought to determine the effects of contemporary treatments on QoL in the adjuvant setting and to determine if the QoL instruments used in these studies provide a relevant assessment. METHODS: We conducted a systematic identification of all anti-cancer drugs used in the adjuvant setting and approved by the US Food and Drug Administration from January 2018 to March 2022. We conducted a quality evaluation and a meta-analysis of reported QoL results. We used the global QoL results when multiple QoL outcomes were reported. RESULTS: There were 224 FDA approvals reviewed, of which 12 met the inclusion criteria. The placebo was the control arm in 10 out of 12 trials. Of those, 11 trials (92 %) assessed QoL, and ten (83 %) reported results. In reports with QoL results, a moderate-risk of bias was found in 3 out of 10 (30 %) and a high-risk of bias in 6 out of 10 (60 %) of reports, respectively. No trial reported a meaningful difference between arms. The meta-analysis found an overall detrimental effect on QoL in the experimental arm, though it was not statistically different. CONCLUSION: This study identified 12 FDA registration trials in the adjuvant setting between 2018 and 2022. We found a moderate- to high-risk of bias in 90 % of the ten trials reporting QoL data. Our meta-analysis suggested a detrimental effect on QoL in the experimental arm, questioning the relevancy, in the adjuvant setting, of thresholds that were mostly developed in the advanced or metastatic setting. POLICY SUMMARY: Future works should focus on specificities of the adjuvant setting when considering QoL evaluation.

Working and working out: Decision-making inputs connect daily work demands to physical exercise.

Work demands can undermine engagement in physical exercise, posing a threat to employee health and well-being. Integrating resource theories and a novel decision-making theory called the decision triangle, we propose that this effect may emerge because work stress changes the energetic and emotional processes people engage in when making decisions about exercise after work. Using diary-style data across two workweeks (N = 83 workers, 783 days), we used multilevel latent profile analysis to extract common decision input profiles, or daily configurations of energy and affect as key decision-making resources. Consistent with the decision triangle, three profiles emerged: visceral inputs (low energy/high negative affect), automatic inputs (low energy/low negative affect), and logical inputs (high energy/low negative affect). Daily job demands were highest among the visceral profile. In turn, the daily visceral profile related to the lowest likelihood of and intensity of physical exercise after work, especially relative to the daily logical profile. Whether or not those in the daily automatic profile exercised depended on their health orientation, or trait-level value of maintaining personal health. Our results support decision-making as a promising mechanism explaining the link between work demands and healthy leisure choices. Organizational interventions can target work stress, health orientation, or logical decision-making to promote frequent and vigorous employee physical exercise. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Targeted nanopore sequencing enables complete characterisation of structural deletions initially identified using exon-based short-read sequencing strategies.

BACKGROUND: The widespread adoption of exome sequencing has greatly increased the rate of genetic diagnosis for inherited conditions. However, the detection and validation of large deletions remains challenging. While numerous bioinformatics approaches have been developed to detect deletions from whole - exome sequencing and targeted panels, further work is typically required to define the physical breakpoints or integration sites. Accurate characterisation requires either expensive follow - up whole - genome sequencing or the time - consuming, laborious process of PCR walking, both of which are challenging when dealing with the repeat sequences which frequently intersect deletion breakpoints. The aim of this study was to develop a cost-effective, long-range sequencing method to characterise deletions. METHODS: Genomic DNA was amplified with primers spanning the deletion using long-range PCR and the products purified. Sequencing was performed on MinION flongle flowcells. The resulting fast5 files were basecalled using Guppy, trimmed using Porechop and aligned using Minimap2. Filtering was performed using NanoFilt. Nanopore sequencing results were verified by Sanger sequencing. RESULTS: Four cases with deletions detected following comparative read-depth analysis of targeted short-read sequencing were analysed. Nanopore sequencing defined breakpoints at the molecular level in all cases including homozygous breakpoints in EYS, CNGA1 and CNGB1 and a heterozygous deletion in PRPF31. All breakpoints were verified by Sanger sequencing. CONCLUSIONS: In this study, a quick, accurate and cost - effective method is described to characterise deletions identified from exome, and similar data, using nanopore sequencing.

Late-Onset Autosomal Dominant Macular Degeneration Caused by Deletion of the CRX Gene.

PURPOSE: To characterize the phenotype observed in a case series with macular disease and determine the cause. DESIGN: Multicenter case series. PARTICIPANTS: Six families (7 patients) with sporadic or multiplex macular disease with onset at 20 to 78 years, and 1 patient with age-related macular degeneration. METHODS: Patients underwent ophthalmic examination; exome, genome, or targeted sequencing; and/or polymerase chain reaction (PCR) amplification of the breakpoint, followed by cloning and Sanger sequencing or direct Sanger sequencing. MAIN OUTCOME MEASURES: Clinical phenotypes, genomic findings, and a hypothesis explaining the mechanism underlying disease in these patients. RESULTS: All 8 cases carried the same deletion encompassing the genes TPRX1, CRX, and SULT2A1, which was absent from 382 control individuals screened by breakpoint PCR and 13 096 Clinical Genetics patients with a range of other inherited conditions screened by array comparative genomic hybridization. Microsatellite genotypes showed that these 7 families are not closely related, but genotypes immediately adjacent to the deletion breakpoints suggest they may share a distant common ancestor. CONCLUSIONS: Previous studies had found that carriers for a single defective CRX allele that was predicted to produce no functional CRX protein had a normal ocular phenotype. Here, we show that CRX whole-gene deletion in fact does cause a dominant late-onset macular disease.

Predictors of long-term durable response in de novo HER2-positive metastatic breast cancer and the real-world treatment experience at two institutions.

PURPOSE: HER2-directed therapies enable some patients with de novo HER2+ metastatic breast cancer (MBC) to achieve long-term, durable responses (DR). Expert opinion dictates indefinite HER2-directed therapies for patients who achieve DRs, but real-world examples of this practice are lacking in the literature. Patient factors that predict DR continue to be elucidated. METHODS: This is a retrospective study of patients with de novo HER2 + MBC. DR is defined as absence of progression/death at any point after diagnosis. Controls are patients with evidence of progression/death. Age, ER/PR status, sites of metastasis, surgical resection of primary tumor, and initial treatment were analyzed. RESULTS: 96 patients with de novo HER2 + MBC, 28 with DR, and 68 with progression were identified. 75% of patients with DR had a single metastatic site, compared with 47% of patients with progression (OR 3.7, p = 0.01). 64% of patients with DR received a regimen containing trastuzumab, pertuzumab, and a taxane, while 28% of patients who progressed did (OR 4.5, p < 0.001). 57% of patients with DR underwent surgical removal of breast primary, compared with 24% of patients who progressed (OR 4.3, p = 0.002.) Among patients with DR, nine patients have been receiving trastuzumab for over ten years with no evidence of disease and one patient opted to discontinue trastuzumab. CONCLUSION: Nearly a third of patients with de novo HER2 + MBC achieved DR. Factors that correlate with DR include single metastatic site, initial trastuzumab, pertuzumab and taxane therapy, and surgical resection of primary tumor. Among patients with DR, indefinite trastuzumab administration is the norm.

Insights on recent innovations in bladder cancer immunotherapy.

Bladder carcinoma is the most common genitourinary cancer, with a high prevalence and global incidence. In addition to early detection by cytology, the management of bladder cancer has recently advanced, not only by improvements in conventional treatments such as surgery and chemotherapy, but also through the introduction of immunotherapeutic strategies. The number of approved immunotherapeutic agents has dramatically increased, with various preclinical and clinical applications in cancer drug discovery. Some bladder cancer immunotherapies include immune checkpoint inhibitors, adoptive cell therapy, cytokine-based therapy, bispecific antibodies, and antibody-drug conjugates. This review provides an overview of some of the innovative immunotherapeutic agents approved and in development that can potentially be used in the treatment of bladder cancer.

Can incivility be informative? Client incivility as a signal for provider creativity.

Workplace incivility is generally viewed as a deleterious interpersonal stressor. Yet, alternative theories suggest that incivility may have instrumental implications for some targets. Applying signaling theory, we study client-provider relationships in a health care context to unpack linkages between incivility enacted by organizational outsiders and work creativity responses by employee targets. We argue that providers leverage information from client incivility to provide more creative care over time. In Study 1 (N = 186), results suggest that clients may use incivility to signal perceptions of poor treatment quality to providers. In Study 2 (N = 416), results from topic modeling of qualitative data show that providers observe client incivility and believe it can contain valuable information about client satisfaction. In Study 3 (N = 503), providers reported their experiences of client incivility and creativity (incremental and radical) in client care over five waves of data to capture the incubation time that providers may need to reflect on instances of incivility. Employing trait-state-occasion modeling, our findings show that episodic (i.e., higher than normal) client incivility had positive lagged relationships with incremental and radical provider creativity, suggesting that time is needed for providers to process the information contained in the client incivility signal and creatively modify treatment plans. Theoretical and practical implications for workplace incivility and creativity are discussed. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Cardiovascular risks and sociodemographic correlates of multidimensional sleep phenotypes in two samples of US adults.

Study Objectives: Sleep is a modifiable risk factor for cardiovascular conditions. Holistic examination of within-person, multidimensional sleep patterns may offer more detailed information about the sleep-cardiovascular condition link, including who is more vulnerable to both. This study aimed to identify common sleep phenotypes in adulthood, establish the validity of the phenotypes in relation to cardiovascular conditions, and explore sociodemographic and background characteristics of the phenotypes. Methods: Across two independent samples of adults (N 1 = 4600; N 2 = 2598) from the Midlife in the United States Study, latent class analysis (LCA) extracted sleep phenotypes using five key self-reported sleep dimensions. Log-binomial regression was used to determine whether sleep phenotypes differentially predicted cardiovascular conditions, adjusting for known risk factors. LCA with covariates was used to compare sociodemographic characteristics of the identified sleep phenotypes. Results: Four sleep phenotypes were identified consistently across the two samples: good sleepers, nappers, dissatisfied/inefficient sleepers, and irregular sleepers. Compared to good sleepers (reference), dissatisfied/inefficient sleepers exhibited a higher risk of cardiovascular conditions in both samples (RR Sample1: 29%, RR Sample2: 53%) and consisted of relatively more racial/ethnic minorities. Nappers exhibited a higher risk of cardiovascular conditions in one sample (RR Sample1: 38%) and consisted of more women and older adults. Irregular sleepers exhibited no significantly different cardiovascular risk and were relatively younger. Conclusions: Common sleep phenotypes in adulthood exhibit differential risks for cardiovascular conditions. Cooccurring sleep dissatisfaction and inefficiency, in particular, may relate to increased risk of cardiovascular conditions. Certain sociodemographic groups (racial minorities, women, older adults) disproportionately fit within high-risk sleep phenotypes.

Identifying diverse forms of (un)healthy sleep: Sleep profiles differentiate adults' psychological and physical well-being.

RATIONALE: Sleep health is best described by the co-occurrence of various dimensions (e.g., regularity, daytime alertness, satisfaction, efficiency, duration) but is rarely measured this way. Information is needed regarding common within-person patterns of sleep characteristics among adults and their relative healthiness. OBJECTIVE: To deepen understanding of healthy and unhealthy sleep, the present study aimed to uncover multidimensional sleep profiles in adults and their associations with a variety of psychological and physical well-being outcomes. METHODS: Survey data from 4622 adults who participated in the Midlife in the United States (MIDUS) project was used to identify latent sleep profiles across five core sleep dimensions. Adjusting for individual sleep dimensions and sociodemographic covariates, General Linear Models were used to test the associations of sleep profile membership with hedonic and eudemonic well-being and chronic physical conditions. RESULTS: Four latent sleep profiles were revealed, good sleepers, sufficient but irregular sleepers, nappers, and short, dissatisfied, and inefficient sleepers. The profiles differentially related to well-being outcomes above and beyond individual sleep dimensions and sociodemographic covariates. Good sleepers generally reported the best outcomes, and short, dissatisfied, and inefficient sleepers generally reported the worst outcomes. CONCLUSION: Four common sleep profiles describe adults' holistic sleep experiences and predict a variety of well-being outcomes beyond other known predictors. In adulthood, healthy sleep may involve sufficient sleep across all dimensions whereas unhealthy sleep may involve insufficient sleep across three key dimensions: duration, satisfaction, and efficiency.

The "What", "Why" and "Whom" of Interrole Interference Among Home-Based Teleworkers.

Many employees are drawn to work-from-home arrangements based on expectations that such arrangements will help them manage both work and home life more effectively. Yet, mixed empirical findings suggest that telework arrangements do not uniformly result in less interrole interference (i.e., work-home and home-work interference). Applying and extending a border theory perspective, the present research offers insight into what factors may predict interrole interference, mediating mechanisms that may explain why such interference occurs, and a moderator that tests for whom interference is most damaging when employees work from home. Specifically, we test cross-role interruption behaviors as a predictor of interrole interference, with recovery experiences as a mediator of this relation and work-life border segmentation preference as a moderator. A sample of 504 home-based teleworkers recruited through Amazon's Mechanical Turk participated in a three-wave survey. Results from a structural equation modeling approach support our overall model. However, the extent and valence of the impact of cross-role interruption behaviors had on teleworkers' interrole interference depended on the direction of the interruption, type of recovery experience, and personal work-life border preference. These findings provide theoretical and practical insights that may help explain the gap between expected and actual occurrence of interrole interference in home-based telework arrangements.

Spectrum of pathogenic variants and founder effects in amelogenesis imperfecta associated with MMP20.

Amelogenesis imperfecta (AI) describes a heterogeneous group of developmental enamel defects that typically have Mendelian inheritance. Exome sequencing of 10 families with recessive hypomaturation AI revealed four novel and one known variants in the matrix metallopeptidase 20 (MMP20) gene that were predicted to be pathogenic. MMP20 encodes a protease that cleaves the developing extracellular enamel matrix and is necessary for normal enamel crystal growth during amelogenesis. New homozygous missense changes were shared between four families of Pakistani heritage (c.625G>C; p.(Glu209Gln)) and two of Omani origin (c.710C>A; p.(Ser237Tyr)). In two families of UK origin and one from Costa Rica, affected individuals were homozygous for the previously reported c.954-2A>T; p.(Ile319Phefs*19) variant. For each of these variants, microsatellite haplotypes appeared to exclude a recent founder effect, but elements of haplotype were conserved, suggesting more distant founding ancestors. New compound heterozygous changes were identified in one family of the European heritage: c.809_811+12delinsCCAG; p.(?) and c.1122A>C; p.(Gln374His). This report further elucidates the mutation spectrum of MMP20 and the probable impact on protein function, confirms a consistent hypomaturation phenotype and shows that mutations in MMP20 are a common cause of autosomal recessive AI in some communities.

CDK 4/6 inhibitors are associated with a high incidence of thrombotic events in women with breast cancer in real-world practice.

PURPOSE: Cyclin-dependent kinase (CDK) 4/6 inhibitors are integral treatment for advanced hormone receptor positive breast cancer; however, venous thromboembolic events (VTE) occurred in 1%-5% of clinical trial patients. Thrombosis rates in the real-world setting remain unclear. We aimed to define the rate of thromboembolic events, risk factors for thrombosis on CDK 4/6 inhibitors and evaluate the Khorana VTE risk score as a predictive tool for VTE in patients on CDK 4/6 therapy. METHODS: Multicenter retrospective analysis of adult breast cancer patients prescribed palbociclib, ribociclib, or abemaciclib. The primary endpoint was thrombosis during treatment or within 30 days of CDK inhibitor discontinuation. Cox regression was used to model time-to-thrombosis, starting from a patient's initiation of CDK 4/6 therapy. The extended Kaplan-Meier method and Cox modeling were used to assess the effect of time-varying thrombosis status on overall survival. RESULTS: Two hundred and sixty-six patients were included (89% on palbociclib, 14% on abemaciclib, 7% on ribociclib). Twenty-nine thrombotic events occurred in 26 (9.8%) women. Of these events, 72% were venous and 34% were arterial. The 1-year incidence of thrombosis was 10.4% overall, 10.9% on palbociclib, 8.3% on ribociclib, and 4.8% on abemaciclib. Hemoglobin less than 10 g/dL was a statistically significant predictor of thrombosis (HR 3.53, P: .014). Khorana score ranged from 0-3, with the majority between 0 and 1 and was not predictive of VTE. Thrombosis was associated with reduced overall survival (HR 1.28, P: .128, median 7.3 months) compared to not having a CDK-associated clot (median 35.7 months). DISCUSSION: VTE in our analysis is higher than reported in clinical trials and arterial thrombosis comprised over one-third of events. The highest incidence was with palbociclib, followed by ribociclib. Khorana score did not predict VTE risk. Larger, real-world studies are needed. The role for prophylactic anticoagulation is yet to be defined in this patient population.