Predictors of increased risk for early treatment non-adherence to oral anti-estrogen therapies in early-stage breast cancer patients.

PURPOSE: Non-adherence to the oral anti-estrogen therapies (AET) tamoxifen and aromatase inhibitors in early-stage hormone receptor-positive breast cancer is associated with numerous negative clinical outcomes. Prior studies have identified that non-adherence is associated with psychological and menopause-related factors which are present during AET, but the presence of these characteristics prior to AET initiation has not been investigated. METHODS: Psychological and menopause symptoms (depression, generalized anxiety, insomnia, somatosensory amplification, hot flash frequency, and hot flash-related interference) were assessed pre-AET initiation as predictors of subsequent non-adherence in 73 participants (Mage = 55.0, SD = 10.1 years). Participants self-reported treatment adherence after three and 6 weeks on AET. Participants who did not initiate treatment were excluded from the analysis. RESULTS: Discriminant function analyses revealed that the hypothesized set of psychological and menopause symptoms at baseline (pre-AET) together statistically distinguished between those who were non-adherent (n = 19; 26.0%) from adherent (n = 54; 74.0%) at 6 weeks. Model classification accuracy was statistically significant (Wilks' ƛ = 0.782, χ2(6) = 15.50, p = 0.017) at the 6-week timepoint. Results were consistent at 3 weeks. Pre-AET psychological and menopause symptoms correctly classified 6-week treatment adherence 77.9% of the time. Depression contributed most to distinguishing between adherers and non-adherers. CONCLUSIONS: The presence of a composite profile of psychological and menopause symptoms prior to AET initiation may help to identify early treatment non-adherence. Results can be used to identify patients at risk for non-adherence and to guide psychological and symptom management interventions.

Colour bio-factories: Towards scale-up production of anthocyanins in plant cell cultures.

Anthocyanins are widely distributed, glycosylated, water-soluble plant pigments, which give many fruits and flowers their red, purple or blue colouration. Their beneficial effects in a dietary context have encouraged increasing use of anthocyanins as natural colourants in the food and cosmetic industries. However, the limited availability and diversity of anthocyanins commercially have initiated searches for alternative sources of these natural colourants. In plants, high-level production of secondary metabolites, such as anthocyanins, can be achieved by engineering of regulatory genes as well as genes encoding biosynthetic enzymes. We have used tobacco lines which constitutively produce high levels of cyanidin 3-O-rutinoside, delphinidin 3-O-rutinoside or a novel anthocyanin, acylated cyanidin 3-O-(coumaroyl) rutinoside to generate cell suspension cultures. The cell lines are stable in their production rates and superior to conventional plant cell cultures. Scale-up of anthocyanin production in small scale fermenters has been demonstrated. The cell cultures have also proven to be a suitable system for production of 13C-labelled anthocyanins. Our method for anthocyanin production is transferable to other plant species, such as Arabidopsis thaliana, demonstrating the potential of this approach for making a wide range of highly-decorated anthocyanins. The tobacco cell cultures represent a customisable and sustainable alternative to conventional anthocyanin production platforms and have considerable potential for use in industrial and medical applications of anthocyanins.

Adopting a 'community of practice' between palliative and dementia care nurses.

Dementia usually occurs as a result of brain disease and, while it is usually chronic or progressive in nature, it has not traditionally been conceptualised as a terminal or life-limiting syndrome. However, the median survival time for people with dementia is between 3.5 years and 4.5 years from symptom onset to death, although this varies depending at which stage the dementia is diagnosed and its cause. As such, it has long been recognised that people with dementia and their family carers have palliative care needs equal to those of patients with cancer. However, a palliative approach to dementia care requires both the dementia and palliative care workforces to fully understand the needs of people with dementia and their families towards the end of life. This article describes the development of a 'community of practice' where healthcare professionals from dementia and palliative care services shared their practice and learned from each other in a safe and supportive environment.

Screening for Comorbidity of Sleep Disorders in Career Firefighters.

BACKGROUND: The purpose of this study was to assess the prevalence and sequelae of insomnia, obstructive sleep apnea (OSA), and comorbid OSA and insomnia (COMISA). METHOD: In the morning, after a shift end, Midwest career firefighters ( N = 89) in a midsized city completed an electronic battery of questionnaire to screen for OSA, daytime sleepiness, insomnia, presleep arousal, nightmares, mental and physical health symptoms, and a one-night sleep diary. RESULTS: Prevalence of firefighters exceeding screening thresholds: OSA: 54%; insomnia: 30%; COMISA: 17%; four or more nightmares per month: 15%. Firefighters who met criteria for COMISA had shorter total sleep time, less restful and worse sleep quality, higher depression and anxiety symptoms, and presleep arousal symptoms than firefighters without self-reported sleep problems. CONCLUSIONS: Many firefighters are at elevated risk of individual behavioral sleep disorders, COMISA, and daytime dysfunction.

Cognitive behavioral therapy for insomnia treatment attrition in patients with weekly nightmares.

STUDY OBJECTIVES: This study's objective was to evaluate the effect of nightmares (NMs) on attrition and symptom change following cognitive behavioral therapy for insomnia (CBT-I) treatment using data from a successful CBT-I randomized controlled trial delivered to participants with recent interpersonal violence exposure. METHODS: The study randomized 110 participants (107 women; mean age: 35.5 years) to CBT-I or to an attention-control group. Participants were assessed at 3 time periods: baseline, post-CBT-I (or attention control), and at time 3 (T3) post-cognitive processing therapy received by all participants. NM reports were extracted from the Fear of Sleep Inventory. Participants with weekly NMs were compared with those with fewer than weekly NMs on outcomes including attrition, insomnia, posttraumatic stress disorder, and depression. Change in NM frequency was examined. RESULTS: Participants with weekly NMs (55%) were significantly more likely to be lost to follow-up post-CBT-I (37%) compared with participants with infrequent NMs (15.6%) and were less likely to complete T3 (43%) than patients with less frequent NMs (62.5%). NMs were unrelated to differential treatment response in insomnia, depression, or posttraumatic stress disorder. Treatment with CBT-I was not associated with reduced NM frequency; however, change in sleep-onset latency from post-CBT-I to T3 predicted fewer NMs at T3. CONCLUSIONS: Weekly NMs were associated with attrition but not a reduced change in insomnia symptoms following CBT-I. NM symptoms did not change as a function of CBT-I, but change in sleep-onset latency predicted lower NM frequency. CBT-I trials should screen for NMs and consider augmenting CBT-I to specifically address NMs. CITATION: Hamilton NA, Russell JA, Youngren WA, et al. Cognitive behavioral therapy for insomnia treatment attrition in patients with weekly nightmares. J Clin Sleep Med. 2023;19(11):1913-1921.

The homeodomain transcriptional regulator DVE-1 directs a program for synapse elimination during circuit remodeling.

The elimination of synapses during circuit remodeling is critical for brain maturation; however, the molecular mechanisms directing synapse elimination and its timing remain elusive. We show that the transcriptional regulator DVE-1, which shares homology with special AT-rich sequence-binding (SATB) family members previously implicated in human neurodevelopmental disorders, directs the elimination of juvenile synaptic inputs onto remodeling C. elegans GABAergic neurons. Juvenile acetylcholine receptor clusters and apposing presynaptic sites are eliminated during the maturation of wild-type GABAergic neurons but persist into adulthood in dve-1 mutants, producing heightened motor connectivity. DVE-1 localization to GABAergic nuclei is required for synapse elimination, consistent with DVE-1 regulation of transcription. Pathway analysis of putative DVE-1 target genes, proteasome inhibitor, and genetic experiments implicate the ubiquitin-proteasome system in synapse elimination. Together, our findings define a previously unappreciated role for a SATB family member in directing synapse elimination during circuit remodeling, likely through transcriptional regulation of protein degradation processes.

Sleep Fragmentation and Estradiol Suppression Decrease Fat Oxidation in Premenopausal Women.

CONTEXT: Body fat gain associated with menopause has been attributed to estradiol (E2) withdrawal. Hypoestrogenism is unlikely to be the only contributing factor, however. OBJECTIVE: Given the links between sleep and metabolic health, we examined the effects of an experimental menopausal model of sleep fragmentation on energy metabolism. METHODS: Twenty premenopausal women (age 21-45 years) underwent a 5-night inpatient study during the mid-to-late follicular phase (estrogenized; n = 20) and the same protocol was repeated in a subset of the participants (n = 9) following leuprolide-induced E2 suppression (hypo-estrogenized). During each 5-night study, there were 2 nights of unfragmented sleep followed by 3 nights of fragmented sleep. Indirect calorimetry was used to assess fasted resting energy expenditure (REE) and substrate oxidation. RESULTS: Sleep fragmentation in the estrogenized state increased the respiratory exchange ratio (RER) and carbohydrate oxidation while decreasing fat oxidation (all P < 0.01). Similarly, in the hypo-estrogenized state without sleep fragmentation, RER and carbohydrate oxidation increased and fat oxidation decreased (all P < 0.01); addition of sleep fragmentation to the hypo-estrogenized state did not produce further effects beyond that observed for either intervention alone (P < 0.05). There were no effects of either sleep fragmentation or E2 state on REE. CONCLUSION: Sleep fragmentation and hypoestrogenism each independently alter fasting substrate oxidation in a manner that may contribute to body fat gain. These findings are important for understanding mechanisms underlying propensity to body fat gain in women across the menopause transition.

Living in your own home and being socially connected at 95 years and beyond: a qualitative study.

BACKGROUND: Being socially connected is linked to positively influencing older people's ability to remain living in their own homes and has shown to support independence and enhance well-being. AIM: To explore how individuals aged 95 years and older living in their own home remain socially connected. METHODS: Informed by a critical gerontological approach, semi-structured interviews with eight women and two men aged between 96 and 100 years were undertaken. Following transcription, data were thematically analysed. RESULTS: Three main themes illuminating social connectedness were identified: "Keeping company: staying connected with family and friends", "Doing things together: engaging with paid and unpaid helpers" and "Having pride and enjoyment: continuing with hobbies and interests". CONCLUSION: It is important that health professionals and social service providers recognise the importance of social connectedness, and provide a range of options to support continuing social connectedness and community engagement for older people.

Quantitation of gene expression in formaldehyde-fixed and fluorescence-activated sorted cells.

Fluorescence-activated cell sorting (FACS) is a sensitive and valuable technique to characterize cellular subpopulations and great advances have been made using this approach. Cells are often fixed with formaldehyde prior to the sorting process to preserve cell morphology and maintain the expression of surface molecules, as well as to ensure safety in the sorting of infected cells. It is widely recognized that formaldehyde fixation alters RNA and DNA structure and integrity, thus analyzing gene expression in these cells has been difficult. We therefore examined the effects of formaldehyde fixation on the stability and quantitation of nucleic acids in cell lines, primary leukocytes and also cells isolated from SIV-infected pigtailed macaques. We developed a method to extract RNA from fixed cells that yielded the same amount of RNA as our common method of RNA isolation from fresh cells. Quantitation of RNA by RT-qPCR in fixed cells was not always comparable with that in unfixed cells. In comparison, when RNA was measured by the probe-based NanoString system, there was no significant difference in RNA quantitation. In addition, we demonstrated that quantitation of proviral DNA in fixed cells by qPCR is comparable to that in unfixed cells when normalized by a single-copy cellular gene. These results provide a systematic procedure to quantitate gene expression in cells that have been fixed with formaldehyde and sorted by FACS.

Expansion of a subset of CD14highCD16negCCR2low/neg monocytes functionally similar to myeloid-derived suppressor cells during SIV and HIV infection.

Monocytes have been categorized in three main subpopulations based on CD14 and CD16 surface expression. Classical monocytes express the CD14(++)CD16(-)CCR2(+) phenotype and migrate to inflammatory sites by quickly responding to CCL2 signaling. Here, we identified and characterized the expansion of a novel monocyte subset during HIV and SIV infection, which were undistinguishable from classical monocytes, based on CD14 and CD16 expression, but expressed significantly lower surface CCR2. Transcriptome analysis of sorted cells demonstrated that the CCR2(low/neg) cells are a distinct subpopulation and express lower levels of inflammatory cytokines and activation markers than their CCR2(high) counterparts. They exhibited impaired phagocytosis and greatly diminished chemotaxis in response to CCL2 and CCL7. In addition, these monocytes are refractory to SIV infection and suppress CD8(+) T cell proliferation in vitro. These cells express higher levels of STAT3 and NOS2, suggesting a phenotype similar to monocytic myeloid-derived cells, which suppress expansion of CD8(+) T cells in vivo. They may reflect an antiproliferative response against the extreme immune activation observed during HIV and SIV infections. In addition, they may suppress antiviral responses and thus, have a role in AIDS pathogenesis. Antiretroviral therapy in infected macaque and human subjects caused this population to decline, suggesting that this atypical phenotype is linked to viral replication.

Detection of microbial translocation in HIV and SIV infection using the Limulus amebocyte lysate assay is masked by serum and plasma.

OBJECTIVE: Microbial translocation (MT) is thought to be a major contributor to the pathogenesis of HIV-related immune activation, and circulating lipopolysaccharide (LPS) from gram-negative bacteria is the principle measurement of this process. However, related research has been impeded by inconsistent LPS test results. METHODS: Specimens were obtained from HIV-infected adults enrolled in the PEARLS study (ACTG A5175) and HIV-HCV co-infected participants enrolled in a study of liver disease staging using MRI elastography. Pig-tailed macaque specimens were obtained from SIV-infected and -uninfected animals. Samples were tested for LPS using the LAL assay with diazo-coupling modifications to improve sensitive detection. RESULTS: When exogenous LPS was added to macaque plasma, >25% inhibition of LPS detection was found in 10/10 (100%) samples at 20% plasma concentration compared to control; in contrast 5/10 (50%) samples at 2% plasma concentration (p = 0.07) and 0/10 (0%) at 0.1% plasma concentration (p = 0.004) showed >25% inhibition of LPS detection. Similarly, when LPS was added to human serum, >25% inhibition of LPS detection was found in 5/12 (42%) of samples at 2% serum concentration compared to control, while 0/12 (0%) of samples in 0.1% serum showed >25% inhibition of LPS detection (p = 0.07). Likewise, LPS detection in human sera without exogenous LPS was improved by dilution: LPS was detected in 2/12 (17%) human samples in 2% serum, ranging from 3,436-4,736 pg/mL, compared to 9/12 (75%) samples in 0.1% serum, ranging from 123 pg/mL -60,131 pg/mL (p = 0.016). In a separate validation cohort of HIV-HCV co-infected participants sampled at two different times on the same day, LPS measured in 0.2% plasma and with diazo-coupling was closely correlated between the first and second samples (R = 0.66, p<0.05). CONCLUSIONS: Undiluted serum and plasma mask LPS detection. The extent of MT may be substantially underestimated.

The liverwort Marchantia foliacea forms a specialized symbiosis with arbuscular mycorrhizal fungi in the genus Glomus.

Microscopic evidence suggests that fungi forming endosymbioses with liverworts in the Marchantiales are arbuscular mycorrhizal (AM) fungi from the Glomeromycota. Polymerase chain reaction amplification of ribosomal sequences confirmed that endophytes of the New Zealand liverwort, Marchantia foliacea, were members of the genus Glomus. Endophytes from two Glomus rDNA phylotypes were repeatedly isolated from geographically separated liverwort samples. Multiple phylotypes were present in the same liverwort patch. The colonizing Glomus species exhibited substantial internal transcribed spacer sequence variation within phylotypes. This work suggests that certain liverwort species may serve as a model for studying DNA sequence variation in colonizing AM phylotypes and specificity in AM-host relationships.