Low baseline ribosome-related gene expression and resistance training-induced declines in ribosome-related gene expression are associated with skeletal muscle hypertrophy in young men and women.

Ribosomes are essential cellular machinery for protein synthesis. It is hypothesised that ribosome content supports muscle growth and that individuals with more ribosomes have greater increases in muscle size following resistance training (RT). Aerobic conditioning (AC) also elicits distinct physiological adaptations; however, no measures of ribosome content following AC have been conducted. We used ribosome-related gene expression as a proxy measure for ribosome content and hypothesised that AC and RT would increase ribosome-related gene expression. Fourteen young men and women performed 6 weeks of single-legged AC followed by 10 weeks of double-legged RT. Muscle biopsies were taken following AC and following RT in the aerobically conditioned (AC+RT) and unconditioned (RT) legs. No differences in regulatory genes (Ubf, Cyclin D1, Tif-1a and Polr-1b) involved in ribosomal biogenesis or ribosomal RNA (45S, 5.8S, 18S and 28S rRNAs) expression were observed following AC and RT, except for c-Myc (RT > AC+RT) and 5S rRNA (RT < AC+RT at pre-RT) with 18S external transcribed spacer and 5.8S internal transcribed spacer expression decreasing from pre-RT to post-RT in the RT leg only. When divided for change in leg-lean soft tissue mass (ΔLLSTM) following RT, legs with the greatest ΔLLSTM had lower expression in 11/13 measured ribosome-related genes before RT and decreased expression in 9/13 genes following RT. These results indicate that AC and RT did not increase ribosome-related gene expression. Contrary to previous research, the greatest increase in muscle mass was associated with lower changes in ribosome-related gene expression over the course of the 10-week training programme. This may point to the importance of translational efficiency rather than translational capacity (i.e. ribosome content) in mediating long-term exercise-induced adaptations in skeletal muscle.

Sex-Specific Effect of CARM1 in Skeletal Muscle Adaptations to Exercise.

PURPOSE: The purpose of this study was to determine how the intersection of coactivator-associated arginine methyltransferase 1 (CARM1) and biological sex affects skeletal muscle adaptations to chronic physical activity. METHODS: Twelve-week-old female (F) and male (M) wild-type (WT) and CARM1 skeletal muscle-specific knockout (mKO) mice were randomly assigned to sedentary (SED) or voluntary wheel running (VWR) experimental groups. For 8 wk, the animals in the VWR cohort had volitional access to running wheels. Subsequently, we performed whole-body functional tests, and 48 h later muscles were harvested for molecular analysis. Western blotting, enzyme activity assays, as well as confocal and transmission electron microscopy were used to examine skeletal muscle biology. RESULTS: Our data reveal a sex-dependent reduction in VWR volume caused by muscle-specific ablation of CARM1, as F CARM1 mKO mice performed less chronic, volitional exercise than their WT counterparts. Regardless of VWR output, exercise-induced adaptations in physiological function were similar between experimental groups. A broad panel of protein arginine methyltransferase (PRMT) biology measurements, including markers of arginine methyltransferase expression and activity, were unaffected by VWR, except for CARM1 and PRMT7 protein levels, which decreased and increased with VWR, respectively. Changes in myofiber morphology and mitochondrial protein content showed similar trends among animals. However, a closer examination of transmission electron microscopy images revealed contrasting responses to VWR in CARM1 mKO mice compared with WT littermates, particularly in mitochondrial size and fractional area. CONCLUSIONS: The present findings demonstrate that CARM1 mKO reduces daily running volume in F mice, as well as exercise-evoked skeletal muscle mitochondrial plasticity, which indicates that this enzyme plays an essential role in sex-dependent differences in exercise performance and mitochondrial health.

CARM1 drives mitophagy and autophagy flux during fasting-induced skeletal muscle atrophy.

CARM1 (coactivator associated arginine methyltransferase 1) has recently emerged as a powerful regulator of skeletal muscle biology. However, the molecular mechanisms by which the methyltransferase remodels muscle remain to be fully understood. In this study, carm1 skeletal muscle-specific knockout (mKO) mice exhibited lower muscle mass with dysregulated macroautophagic/autophagic and atrophic signaling, including depressed AMP-activated protein kinase (AMPK) site-specific phosphorylation of ULK1 (unc-51 like autophagy activating kinase 1; Ser555) and FOXO3 (forkhead box O3; Ser588), as well as MTOR (mechanistic target of rapamycin kinase)-induced inhibition of ULK1 (Ser757), along with AKT/protein kinase B site-specific suppression of FOXO1 (Ser256) and FOXO3 (Ser253). In addition to lower mitophagy and autophagy flux in skeletal muscle, carm1 mKO led to increased mitochondrial PRKN/parkin accumulation, which suggests that CARM1 is required for basal mitochondrial turnover and autophagic clearance. carm1 deletion also elicited PPARGC1A (PPARG coactivator 1 alpha) activity and a slower, more oxidative muscle phenotype. As such, these carm1 mKO-evoked adaptations disrupted mitophagy and autophagy induction during food deprivation and collectively served to mitigate fasting-induced muscle atrophy. Furthermore, at the threshold of muscle atrophy during food deprivation experiments in humans, skeletal muscle CARM1 activity decreased similarly to our observations in mice, and was accompanied by site-specific activation of ULK1 (Ser757), highlighting the translational impact of the methyltransferase in human skeletal muscle. Taken together, our results indicate that CARM1 governs mitophagic, autophagic, and atrophic processes fundamental to the maintenance and remodeling of muscle mass. Targeting the enzyme may provide new therapeutic approaches for mitigating skeletal muscle atrophy.

Trade-Offs between Vaccine Effectiveness and Vaccine Safety: Personal versus Policy Decisions.

OBJECTIVE: We aimed to investigate whether individuals' trade-offs between vaccine effectiveness and vaccine safety vary if they are asked to consider the perspective of a policymaker making decisions for others compared with the decisions they would make for themselves. METHOD: A web-enabled discrete choice experiment survey was administered between 1 April and 1 May 2022 to participants recruited from the general population of two Southeast Asian countries (Indonesia and Vietnam). In each country, 500 participants were randomly assigned to make decisions regarding coronavirus disease 2019 (COVID-19) vaccines for others as a policymaker or in a personal capacity for their own use. Vaccines were characterized by three attributes: (1) effectiveness of the vaccine in reducing infection rate; (2) effectiveness of the vaccine in reducing hospitalization among those infected; and (3) risk of death from vaccine-related serious adverse events. A mixed logit model was utilized for analyses. RESULTS: Based on the attributes and levels used in this study, the most important vaccine attribute was the risk of death from vaccine-related adverse events, followed by effectiveness in reducing infection rate and hospitalizations. Compared with personal decisions, the mean probability of choosing a vaccine was (1) lower, and (2) more sensitive to the changes in risk of death from adverse events in policy decisions (p ≤ 0.01). CONCLUSIONS AND RELEVANCE: Our results suggest that, in the face of an infectious disease pandemic, individuals are likely to be more risk-averse to vaccine-related deaths when making decisions for others as a policymaker than they would for themselves.

Impact of short-term, pharmacological CARM1 inhibition on skeletal muscle mass, function, and atrophy in mice.

Coactivator-associated arginine methyltransferase 1 (CARM1) catalyzes the methylation of arginine residues on target proteins critical for health and disease. The purpose of this study was to characterize the effects of short-term, pharmacological CARM1 inhibition on skeletal muscle size, function, and atrophy. Adult mice (n = 10 or 11/sex) were treated with either a CARM1 inhibitor (150 mg/kg EZM2302; EZM) or vehicle (Veh) via oral gavage for 11-13 days and muscle mass, function, and exercise capacity were assessed. In addition, we investigated the effect of CARM1 suppression on unilateral hindlimb denervation (DEN)-induced muscle atrophy (n = 8/sex). We report that CARM1 inhibition caused significant reductions in the asymmetric dimethylation of known CARM1 substrates but no change in CARM1 protein or mRNA content in skeletal muscle. Reduced CARM1 activity did not affect body or muscle mass, however, we observed a decrease in exercise capacity and muscular endurance in male mice. CARM1 methyltransferase activity increased in the muscle of Veh-treated mice following 7 days of DEN, and this response was blunted in EZM-dosed mice. Skeletal muscle mass and myofiber cross-sectional area were significantly reduced in DEN compared with contralateral, non-DEN limbs to a similar degree in both treatment groups. Furthermore, skeletal muscle atrophy and autophagy gene expression programs were elevated in response to DEN independent of CARM1 suppression. Collectively, these results suggest that short-term, pharmacological CARM1 inhibition in adult animals affects muscle performance in a sex-specific manner but does not impact the maintenance and remodeling of skeletal muscle mass during conditions of neurogenic muscle atrophy.NEW & NOTEWORTHY Short-term pharmacological inhibition of coactivator-associated arginine methyltransferase 1 (CARM1) was effective at significantly reducing CARM1 methyltransferase function in skeletal muscle. CARM1 inhibition did not impact muscle mass, but exercise capacity was impaired, particularly in male mice, whereas morphological and molecular signatures of denervation-induced muscle atrophy were largely maintained in animals administered the inhibitor. Altogether, the role of CARM1 in neuromuscular biology remains complex and requires further investigation of its therapeutic potential in muscle-wasting conditions.

Fortetropin supplementation prevents the rise in circulating myostatin but not disuse-induced muscle atrophy in young men with limb immobilization: A randomized controlled trial.

Supplementation with Fortetropin® (FOR), a naturally occurring component from fertilized egg yolks, reduces circulating myostatin concentration. We hypothesized that FOR would mitigate muscle atrophy during immobilization. We examined the effect of FOR supplementation on muscle size and strength during 2-wk of single-leg immobilization and recovery. Twenty-four healthy young men (22 ± 2 yrs; BMI = 24.3 ± 2.9 kg/m2) were randomly allocated to either a Fortetropin® supplement (FOR-SUPP, n = 12) group consuming 19.8 g/d of FOR or placebo (PLA-SUPP, n = 12) group consuming energy- and macronutrient-matched cheese powder for 6-wk. The 6-wk period consisted of 2-wk run-in, 2-wk single-leg immobilization, and 2-wk recovery phase returning to habitual physical activities. Ultrasonography, dual-energy X-ray absorptiometry, muscle biopsies and isometric peak torque assessments were performed prior to and following each phase (days 1, 14, 28, and 42) to measure vastus lateralis and muscle fiber cross-section area (CSA), leg lean mass (LM), and muscular strength. Blood samples were taken on days 1 and 42 for measurement of plasma myostatin concentration, which increased in PLA-SUPP (4221 ± 541 pg/mL to 6721 ± 864 pg/mL, P = 0.013) but not in FOR-SUPP (5487 ± 489 pg/mL to 5383 ± 781 pg/mL, P = 0.900). After the immobilization phase, vastus lateralis CSA, LM, and isometric peak torque were decreased by 7.9 ± 1.7% (P < 0.001), -1.6 ± 0.6% (P = 0.037), and -18.7 ± 2.7% (P < 0.001) respectively, with no difference between groups. The decreased peak torque was recovered after 2-wk of normal activity (vs. day 1, P = 0.129); however, CSA and LM were not recovered (vs. day 1, P < 0.001 and P = 0.003, respectively), with no differences between groups. Supplementation with FOR prevented the rise in circulating myostatin but not disuse-induced muscle atrophy in young men after 2-wk of single-leg immobilization.

The associations between prognostic awareness and health-related quality of life among patients with advanced cancer: A systematic review.

BACKGROUND: Prognostic awareness among patients with advanced cancer is important for better palliative and end-of-life care. However, the relationships between prognostic awareness and patient health-related quality of life outcomes remain inconsistent across studies. Critically synthesizing empirical literature will allow for a better understanding of these associations. AIM: To investigate the associations between prognostic awareness and health-related quality of life outcomes among patients with advanced cancer. DESIGN: This study was a systematic review, prospectively registered on PROSPERO (CRD42020177228). DATA SOURCES: Seven databases (PubMed/Medline, Embase, Scopus, Cochrane Central, PsycINFO, CINAHL, and Web of Science) were searched in March 2022. Cross-sectional and longitudinal empirical studies in English were included regardless of cancer type or publication date. RESULTS: We identified 1338 articles and included 36 for review. A substantial proportion of patients remained prognostically unaware (50%). Prognostic awareness was either not significantly associated (48%) or associated with worsened (40%) outcomes. These associations were found to vary (e.g., be differently associated with improved, worsened, or non-significant health-related quality of life outcomes) based on the definition of prognostic awareness used and the population sampled (Asian vs Western). Few structured, validated questionnaires were used and only three studies investigated how the associations evolved over time. CONCLUSIONS: To facilitate better understanding of the relationships between prognostic awareness and health-related quality of life, future research must focus on developing a standardized, "gold standard" measurement of prognostic awareness. Research should also examine the influence of culture and the evolution of these relationships longitudinally.

Acute, next-generation AMPK activation initiates a disease-resistant gene expression program in dystrophic skeletal muscle.

Duchenne muscular dystrophy (DMD) is a life-limiting neuromuscular disorder characterized by muscle weakness and wasting. Previous proof-of-concept studies demonstrate that the dystrophic phenotype can be mitigated with the pharmacological stimulation of AMP-activated protein kinase (AMPK). However, first-generation AMPK activators have failed to translate from bench to bedside due to either their lack of potency or toxic, off-target effects. The identification of safe and efficacious molecules that stimulate AMPK in dystrophic muscle is of particular importance as it may broaden the therapeutic landscape for DMD patients regardless of their specific dystrophin mutation. Here, we demonstrate that a single dose of the next generation, orally-bioactive AMPK agonist MK-8722 (MK) to mdx mice evoked skeletal muscle AMPK and extensive downstream stimulation within 12 h post-treatment. Specifically, MK elicited a gene expression profile indicative of a more disease-resistant slow, oxidative phenotype including increased peroxisome proliferator-activated receptor É£ coactivator-1⍺ activity and utrophin levels. In addition, we observed augmented autophagy signaling downstream of AMPK, as well as elevations in critical autophagic genes such as Map1lc3 and Sqstm1 subsequent to the myonuclear accumulation of the master regulator of the autophagy gene program, transcription factor EB. Lastly, we show that pharmacological AMPK stimulation normalizes the expression of myogenic regulatory factors and amends activated muscle stem cell content in mdx muscle. Our results indicate that AMPK activation via MK enhances disease-mitigating mechanisms in dystrophic muscle and prefaces further investigation on the chronic effects of novel small molecule AMPK agonists.

AMPK is mitochondrial medicine for neuromuscular disorders.

Duchenne muscular dystrophy (DMD), myotonic dystrophy type 1 (DM1), and spinal muscular atrophy (SMA) are the most prevalent neuromuscular disorders (NMDs) in children and adults. Central to a healthy neuromuscular system are the processes that govern mitochondrial turnover and dynamics, which are regulated by AMP-activated protein kinase (AMPK). Here, we survey mitochondrial stresses that are common between, as well as unique to, DMD, DM1, and SMA, and which may serve as potential therapeutic targets to mitigate neuromuscular disease. We also highlight recent advances that leverage a mutation-agnostic strategy featuring physiological or pharmacological AMPK activation to enhance mitochondrial health in these conditions, as well as identify outstanding questions and opportunities for future pursuit.

A prospective study of psychological distress among patients with advanced cancer and their caregivers.

BACKGROUND: Cancer can impact the psychological well-being of both patients and their informal caregivers. We investigated the joint trajectories of psychological distress among Singaporean advanced cancer patients-caregiver dyads. We also examined predictors of trajectory group membership. METHODS: This study utilised data from 299 patients with advanced solid cancer and their caregivers over 33 months (12 times points). Group-based trajectory modelling was used to examine the joint trajectories of patient anxiety, patient depression, caregiver anxiety and caregiver depression scores using the Hospital Anxiety and Depression Scale. RESULTS: Four joint trajectory groups were found: (1) Patient-caregiver low distress (27%), (2) patient-caregiver increasing distress (28.5%), (3) patient low- caregiver borderline distress (25%), (4) patient-caregiver high distress (19.5%). Dyads where the patient is below 50 years of age were more likely to be in Group 4. Dyads where caregiver-patient emotional closeness was low were more likely to be in Groups 2 or 4 where dyads reported increasing/high distress. Dyads that reported financial inadequacy were more likely to be in Groups 2, 3 and 4, while dyads with caregivers who were employed were more likely to be in group 3. CONCLUSIONS: A substantial proportion of patients and caregivers reported anxiety and/or depression that lasted or increased throughout the study duration. We found significant heterogeneity in how dyads experienced psychological distress, suggesting that efforts should consider dyadic differences when providing psychological support. Particular focus should be placed on identifying dyads that are at risk and who require additional support.

Quality of life and psychological distress of patients with advanced cancer in the Philippines.

PURPOSE: This study aimed to describe the quality of life (QOL) and psychological distress (anxiety and depression) of Filipino patients with advanced solid cancers and identify sociodemographic and clinical-related factors associated with them. METHODS: 195 patients with advanced cancer were recruited from a major hospital treating cancer patients in the Philippines. Participants completed self-reported surveys on Quality-of-life (QOL-FACT-G) and psychological distress (HADS-D, HADS-A). Multi-variable OLS regression models were performed where sociodemographic, health history and clinical characteristics were included as predictors. RESULTS: The average total FACT-G score was 65.39/108 (Standard deviation (SD) = 13.76), with the physical well-being scale having the lowest scores (M = 14.14/28, SD = 5.92). The two most common symptoms reported were fatigue (88%) and pain (86.5%). Physical symptom burden was significantly negatively associated with QOL and psychological distress. The average HADS-total score was 14.46/21 (SD = 5.77), with 8% with probable anxiety and 27% with probable depression. Participants who reported greater reliance on their spiritual faith for strength in coping with illness reported lower depression scores. CONCLUSIONS: Our findings underline the importance of understanding the multi-dimensional outcomes of Filipino advanced cancer patients. Results may be used to improve QOL and reduce the psychological distress of advanced cancer patients.

The role of a multicentre data repository in ocular inflammation: The Ocular Autoimmune Systemic Inflammatory Infectious Study (OASIS).

In the current literature, clinical registry cohorts related to ocular inflammation are few and far between, and there are none involving multi-continental international data. Many existing registries comprise administrative databases, data related to specific uveitic diseases, or are designed to address a particular clinical problem. The existing data, although useful and serving their intended purposes, are segmented and may not be sufficiently robust to design prognostication tools or draw epidemiological conclusions in the field of uveitis and ocular inflammation. To solve this, we have developed the Ocular Autoimmune Systemic Inflammatory Infectious Study (OASIS) Clinical Registry. OASIS collects prospective and retrospective data on patients with all types of ocular inflammatory conditions from centers all around the world. It is a primarily web-based platform with alternative offline modes of access. A comprehensive set of clinical data ranging from demographics, past medical history, clinical presentation, working diagnosis to visual outcomes are collected over a range of time points. Additionally, clinical images such as optical coherence tomography, fundus fluorescein angiography and indocyanine green angiography studies may be uploaded. Through the capturing of diverse, well-structured, and clinically meaningful data in a simplified and consistent fashion, OASIS will deliver a comprehensive and well organized data set ripe for data analysis. The applications of the registry are numerous, and include performing epidemiological analysis, monitoring drug side effects, and studying treatment safety efficacy. Furthermore, the data compiled in OASIS will be used to develop new classification and diagnostic systems, as well as treatment and prognostication guidelines for uveitis.

A single dose of exercise stimulates skeletal muscle mitochondrial plasticity in myotonic dystrophy type 1.

AIM: Myotonic dystrophy type 1 (DM1) is the second most common muscular dystrophy after Duchenne and is the most prevalent muscular dystrophy in adults. DM1 patients that participate in aerobic exercise training experience several physiological benefits concomitant with improved muscle mitochondrial function without alterations in typical DM1-specific disease mechanisms, which suggests that correcting organelle health is key to ameliorate the DM1 pathology. However, our understanding of the molecular mechanisms of mitochondrial turnover and dynamics in DM1 skeletal muscle is lacking. METHODS: Skeletal muscle tissue was sampled from healthy and DM1 mice under sedentary conditions and at several recovery time points following an exhaustive treadmill run. RESULTS: We demonstrate that DM1 patients exhibit an imbalance in the transcriptional apparatus for mitochondrial turnover and dynamics in skeletal muscle. Additionally, DM1 mice displayed elevated expression of autophagy and mitophagy regulators. A single dose of exercise successfully enhanced canonical exercise molecular pathways and skeletal muscle mitochondrial biogenesis despite failing to alter the cellular pathology in DM1 mice. However, treadmill running stimulated coordinated organelle fusion and fission signaling, as well as improved alternative splicing of Optic atrophy 1. Exercise also evoked autophagy and mitophagy pathways in DM1 skeletal muscle resulting in the normalized expression of autophagy- and lysosome-related machinery responsible for the clearance of dysfunctional organelles. CONCLUSION: Collectively, our data indicate that mitochondrial dynamics and turnover processes in DM1 skeletal muscle are initiated with a single dose of exercise, which may underlie the adaptive benefits previously documented in DM1 mice and patients.

A prospective cohort study of decision-making role preferences of patients with advanced cancer and their family caregivers.

BACKGROUND: This study aimed to examine (1) the evolution of patients-caregiver dyad decision-making role preferences over 3 years and the predictors of these preferences; and (2) discordance in decision-making role preferences among dyads. METHODS: A total of 311 patients with advanced solid cancer and their caregivers in Singapore reported their preferences for decision-making roles every 3 months. The predictors for decision-making role preferences among dyads were identified via the actor-partner interdependence framework using a mixed-effect ordered logistic model. RESULTS: The proportion of patients and caregivers preferring patient-led decision-making was higher at the end of third year compared to baseline (patients: 40% vs. 20%, p value <.01; caregivers: 33% vs. 21%, p value = .03). Patients with female (odds ratio [OR], 1.74; p value <.01) and older (1-year OR, 1.02; p value <.01) caregivers and younger patients (1-year OR, 0.97; p value <.01) preferred higher involvement in decision-making. Caregivers with tertiary education (vs. lower education) (OR, 1.59; p value = .02) and those who accurately understood patients' treatment goals (OR, 1.37; p value = .01) preferred greater patient involvement in decision-making. Conversely, caregivers of female patients (OR, 0.68; p value = .03) and younger patients (1-year OR, 0.98; p value <.01) preferred lesser patient involvement in decision-making. The proportion of patient-caregiver dyads with discordance in preferred decision-making was lower at the end of the third year (51%) compared to baseline (68%) (p value <.01). CONCLUSION: Despite a reduction in the proportion of dyads with discordance toward the end-of-life, the percentage with discordance remained high throughout the illness trajectory. Interventions facilitating open communication between dyads should be pursued in efforts to decrease dyadic discordance.

Choroidal Microvascular Alterations in COVID-19 Patients.

OBJECTIVE: To evaluate alterations in the choroidal angioarchitecture of COVID-19 patients using optical Coherence Tomography (OCT) based surrogate markers. METHODS: This prospective case-control study recruited 56 COVID-19 patients (111 eyes) and 61 healthy individuals (120 eyes). Choroidal thickness (CT) and Choroidal vascularity index (CVI) were derived from OCT images using a purpose-built automated software for choroidal image segmentation. A linear mixed model with age and gender as covariates was employed to compare CVI and CT between groups. RESULTS: COVID-19 patients had significantly higher subfoveal (81.3um vs 86.8um, p = .02), temporal (78.8um vs 84.3um, p = .005), nasal (87.5um vs 95.1um, p = .001) and average CT (82.5um vs 88.7um, p = .001). COVID-19 patients had significantly lower subfoveal (64.0 vs 63.5, p = .02) and average CVI (63.5 vs 63.1, p = .02). CONCLUSION: COVID-19 results in significantly thicker choroid with reduced relative vascularity. This may be attributable to increased vascular permeability secondary to inflammation, resulting in choroidal stromal edema.

Evaluation of Retinal Vascularity Index in Patients with COVID-19: A Case-Control Study.

INTRODUCTION: The purpose of this study was to evaluate the impact of COVID-19 infection on retinal microvasculature by topographically mapping the retinal arteriole-to-venule ratio (AVR). METHODS: In a comparative cross-sectional case-control study, fundus photos were obtained in COVID-19-infected patients and healthy controls. AVT was measured over 16 points across the retina using retinal vascularity index (RVI)-a novel semi-automated computerized parameter based on retinal vasculature. RESULTS: A total of 51 COVID-19-positive patients and 65 healthy controls were enrolled in the study. Overall, the mean RVI of all 16 points across the retina was 0.34 ± 0.02 in patients with COVID-19 and 0.33 ± 0.02 in control subjects (p = 0.64). Out of the 16 points being measured, three points had a statistically significant greater value in patients with COVID compared to normal controls. CONCLUSION: Localised greater RVI values were found in some of the points in COVID-19-positive patients, which likely indicates a more focal change of the vasculature.

Caregiver-Reported Roles in Treatment Decision Making in Advanced Cancer and Associated Caregiving Burden and Psychological Distress: A Longitudinal Study.

OBJECTIVE: To longitudinally examine caregiver-reported treatment decision-making roles and to investigate the associations of these roles with caregiver burden, caregiving esteem, caregiver anxiety, and depression. METHODS: 281 caregivers of patients with stage IV solid cancers were recruited from outpatient clinics in Singapore. Caregivers were eligible if they were aged ≥21 y, primary informal caregiver, and involved in treatment decision making. We used 3 y of longitudinal data. The decision-making roles were grouped into 4 categories: no family involvement, patient/physician-led, joint, and family-led/alone decision making. Mixed-effects linear regressions were used to assess associations between decision-making roles and caregiver outcomes. RESULTS: On average, 72% of caregivers reported family involvement in decision making. Compared with baseline, a higher proportion of caregivers at the 36-mo follow-up reported no family involvement (from 23% to 34%, P = 0.05) and patient/physician-led decision making (from 22% to 34%, P = 0.02), while a lower proportion reported family-led/alone (from 19% to 7%, P = 0.01) decision making. Compared with family-led/alone decision making, caregivers reporting no family involvement reported lower impact on finances (-0.15 [-0.28, -0.01], P = 0.03) while caregivers who reported patient/physician-led decision making reported lower impact on schedule and health (-0.12 [-0.20, -0.03], P = 0.01), and finances (-0.15 [-0.28, -0.03], P = 0.02), and lower anxiety (-0.69 [-1.17, -0.22], P < 0.01), and depressive symptoms (-0.69 [-1.12, -0.26], P < 0.01). Caregivers who reported joint decision making reported higher caregiving esteem (0.07 [0.01, 0.14], P = 0.02). CONCLUSIONS: Higher family involvement in decision making was associated with higher caregiver burden and psychological distress. Help should be given so that family caregivers can support patient decision-making in a meaningful way. HIGHLIGHTS: Compared with baseline, a lower proportion of caregivers at the 36-mo follow-up reported family-led or family-alone decision making, and a higher proportion of caregivers reported patient-led or physician-led decision making.Higher levels of family involvement in decision making were associated with burdens on caregivers' daily life, health, and finances and increased caregiver anxiety and depression.Support must be given so that family members can contribute to making medical decisions in a rewarding manner.

Prognostic awareness and its association with health outcomes in the last year of life.

BACKGROUND: Little research has examined changes in prognostic awareness (PA) in the last year of life and the extent PA change was associated with anxiety, depression, and spiritual well-being among metastatic cancer patients. METHODS: Two surveys were administered in the last year of life to 176 conveniently sampled Singaporean patients with stage 4 solid cancers. PA was assessed by asking patients whether they were aware that their treatments were unlikely to cure their cancer. Multivariable linear regression models were used to investigate the association of PA change with anxiety, depression, and spiritual well-being. RESULTS: The proportion of patients with accurate PA increased (39.2%-45.5%; p < 0.05) from the second-last assessment to the last assessment before death. Those with inaccurate PA decreased (26.1%-20.4%; p < 0.05) while a third of patients remained uncertain at both assessments (34.7% and 34.1%). Compared to patients with inaccurate PA at both assessments, patients who reported accurate PA at both assessments reported worsened anxiety (ß = 2.08), depression (ß = 3.87), and spiritual well-being (ß = -4.45) while patients who reported being uncertain about their prognosis at both assessments reported worsened spiritual well-being (ß = - 6.30) at the last assessment before death (p < 0.05 for all). CONCLUSIONS: Interventions should dually focus on decreasing prognostic uncertainty at the end-of-life while minimising the psychological and spiritual sequelae associated with being prognostically aware. More research is needed to clarify the causes of prognostic uncertainty.

Machine Learning-Enabled NIR Spectroscopy in Assessing Powder Blend Uniformity: Clear-Up Disparities and Biases Induced by Physical Artefacts.

NIR spectroscopy is a non-destructive characterization tool for the blend uniformity (BU) assessment. However, NIR spectra of powder blends often contain overlapping physical and chemical information of the samples. Deconvoluting the information related to chemical properties from that associated with the physical effects is one of the major objectives of this work. We achieve this aim in two ways. Firstly, we identified various sources of variability that might affect the BU results. Secondly, we leverage the machine learning-based sophisticated data analytics processes. To accomplish the aforementioned objectives, calibration samples of amlodipine as an active pharmaceutical ingredient (API) with the concentrations ranging between 67 and 133% w/w (dose ~ 3.6% w/w), in powder blends containing excipients, were prepared using a gravimetric approach and assessed using NIR spectroscopic analysis, followed by HPLC measurements. The bias in NIR results was investigated by employing data quality metrics (DQM) and bias-variance decomposition (BVD). To overcome the bias, the clustered regression (non-parametric and linear) was applied. We assessed the model's performance by employing the hold-out and k-fold internal cross-validation (CV). NIR-based blend homogeneity with low mean absolute error and an interval estimates of 0.674 (mean) ± 0.218 (standard deviation) w/w was established. Additionally, bootstrapping-based CV was leveraged as part of the NIR method lifecycle management that demonstrated the mean absolute error (MAE) of BU ± 3.5% w/w and BU ± 1.5% w/w for model generalizability and model transferability, respectively. A workflow integrating machine learning to NIR spectral analysis was established and implemented. Impact of various data learning approaches on NIR spectral data.