The Impact of Exercise and Cognitive Stimulation Therapy on Intrinsic Capacity Composite Score in Pre-Frail Older Adults: A Pre-Post Intervention Study.

Intrinsic capacity(IC) is a measure of physical, cognitive, vitality, psychological, and sensory abilities which determines functional ability. Decline in IC has been shown to accelerate the trajectory of frailty. We aim to show the impact of exercise (Ex) and cognitive stimulation therapy (CST) on (i) IC domains and composite score (ii) frailty and functional ability in pre-frail older adults. Secondary analysis of data from a pre-post intervention study of pre-frail older adults ≥ 65 years attending primary care clinic. Control (CON) and 2 intervention groups ((i) Ex 6 months (ii) CST 3 months with Ex 6 months (Ex+CST)) were recruited. Pre-frailty was determined using the FRAIL scale. Questionnaires (on demographics, functional ability, and depression) were administered and physical function assessment (gait speed (GS), short physical performance battery (SPPB) test, handgrip strength, five times sit-to-stand (5x-STS)) was conducted at 0, 3, 6 and 12 months. Four domains of IC were evaluated: locomotion (GS and 5x-STS), vitality (nutrition and muscle mass), cognition (MoCA and subjective cognitive decline) and psychological (depression and anxiety). Each domain was scored from 0 to 2 (no decline) with total IC score ranging from 0 to 8. 187 participants completed baseline and 3 months assessments, 109 (58.3%) were allocated to CON, 37 (19.8%) to Ex and 41 (21.9%) to Ex + CST groups. At 3 months, both Ex and Ex +CST showed improvement in IC composite scores, locomotion, and psychological domain scores but improvement in cognition domain only in Ex + CST group. At 6 months, there were improvements in total IC score, locomotion, vitality, and psychological domain in both Ex and Ex + CST groups. At 12 months, significant improvement was evident in total IC score for Ex and Ex+CST groups, vitality when fatigue (in addition to muscle mass and nutrition) was added and instrumental activities of daily living. Multidomain intervention incorporating exercise and CST resulted in significant improvement in IC composite scores, locomotion, vitality, cognition, and psychological domains.

FLASH radiotherapy for the treatment of symptomatic bone metastases in the thorax (FAST-02): protocol for a prospective study of a novel radiotherapy approach.

BACKGROUND: FLASH therapy is a treatment technique in which radiation is delivered at ultra-high dose rates (≥ 40 Gy/s). The first-in-human FAST-01 clinical trial demonstrated the clinical feasibility of proton FLASH in the treatment of extremity bone metastases. The objectives of this investigation are to assess the toxicities of treatment and pain relief in study participants with painful thoracic bone metastases treated with FLASH radiotherapy, as well as workflow metrics in a clinical setting. METHODS: This single-arm clinical trial is being conducted under an FDA investigational device exemption (IDE) approved for 10 patients with 1-3 painful bone metastases in the thorax, excluding bone metastases in the spine. Treatment will be 8 Gy in a single fraction administered at ≥ 40 Gy/s on a FLASH-enabled proton therapy system delivering a single transmission proton beam. Primary study endpoints are efficacy (pain relief) and safety. Patient questionnaires evaluating pain flare at the treatment site will be completed for 10 consecutive days post-RT. Pain response and adverse events (AEs) will be evaluated on the day of treatment and on day 7, day 15, months 1, 2, 3, 6, 9, and 12, and every 6 months thereafter. The outcomes for clinical workflow feasibility are the occurrence of any device issues as well as time on the treatment table. DISCUSSION: This prospective clinical trial will provide clinical data for evaluating the efficacy and safety of proton FLASH for palliation of bony metastases in the thorax. Positive findings will support the further exploration of FLASH radiation for other clinical indications including patient populations treated with curative intent. REGISTRATION: ClinicalTrials.gov NCT05524064.

Dissociable Contributions of Basolateral Amygdala and Ventrolateral Orbitofrontal Cortex to Flexible Learning Under Uncertainty.

Reversal learning measures the ability to form flexible associations between choice outcomes with stimuli and actions that precede them. This type of learning is thought to rely on several cortical and subcortical areas, including the highly interconnected orbitofrontal cortex (OFC) and basolateral amygdala (BLA), and is often impaired in various neuropsychiatric and substance use disorders. However, the unique contributions of these regions to stimulus- and action-based reversal learning have not been systematically compared using a chemogenetic approach particularly before and after the first reversal that introduces new uncertainty. Here, we examined the roles of ventrolateral OFC (vlOFC) and BLA during reversal learning. Male and female rats were prepared with inhibitory designer receptors exclusively activated by designer drugs targeting projection neurons in these regions and tested on a series of deterministic and probabilistic reversals during which they learned about stimulus identity or side (left or right) associated with different reward probabilities. Using a counterbalanced within-subject design, we inhibited these regions prior to reversal sessions. We assessed initial and pre-/post-reversal changes in performance to measure learning and adjustments to reversals, respectively. We found that inhibition of the ventrolateral orbitofrontal cortex (vlOFC), but not BLA, eliminated adjustments to stimulus-based reversals. Inhibition of BLA, but not vlOFC, selectively impaired action-based probabilistic reversal learning, leaving deterministic reversal learning intact. vlOFC exhibited a sex-dependent role in early adjustment to action-based reversals, but not in overall learning. These results reveal dissociable roles for BLA and vlOFC in flexible learning and highlight a more crucial role for BLA in learning meaningful changes in the reward environment.

Quantum spin nematic phase in a square-lattice iridate.

Spin nematic is a magnetic analogue of classical liquid crystals, a fourth state of matter exhibiting characteristics of both liquid and solid1,2. Particularly intriguing is a valence-bond spin nematic3-5, in which spins are quantum entangled to form a multipolar order without breaking time-reversal symmetry, but its unambiguous experimental realization remains elusive. Here we establish a spin nematic phase in the square-lattice iridate Sr2IrO4, which approximately realizes a pseudospin one-half Heisenberg antiferromagnet in the strong spin-orbit coupling limit6-9. Upon cooling, the transition into the spin nematic phase at TC ≈ 263 K is marked by a divergence in the static spin quadrupole susceptibility extracted from our Raman spectra and concomitant emergence of a collective mode associated with the spontaneous breaking of rotational symmetries. The quadrupolar order persists in the antiferromagnetic phase below TN ≈ 230 K and becomes directly observable through its interference with the antiferromagnetic order in resonant X-ray diffraction, which allows us to uniquely determine its spatial structure. Further, we find using resonant inelastic X-ray scattering a complete breakdown of coherent magnon excitations at short-wavelength scales, suggesting a many-body quantum entanglement in the antiferromagnetic state10,11. Taken together, our results reveal a quantum order underlying the Néel antiferromagnet that is widely believed to be intimately connected to the mechanism of high-temperature superconductivity12,13.

Moving towards the ICOPE Approach: Evaluation of Community-Based Intervention Activities on Improving Intrinsic Capacity.

OBJECTIVES: Different types of community-based intervention activities may have differential effects in improving the intrinsic capacity (IC) of older people. This study aims to (i) identify subgroups of older people based on their IC impairments, (ii) examine the differential associations between different types of activity participations and change in IC across subgroups, and (iii) assess whether the activity participation patterns of older people align with the way that would benefit them the most. METHODS: Participants were community-dwelling older people aged 60 years or above. They were screened for IC impairments at baseline, and their participation records of different types (cognitive, physical, nutritional, mental, and social) of intervention activities were collected for one year. An aggregated IC score was created based on four IC domains including cognitive (self-rated memory), locomotor (self-rated difficulties in walking), vitality (self-rated weight loss), and psychological (subjective well-being). Cluster analysis was used to group homogenous participants. Mixed-effects regression was used to examine the associations between activity counts (i.e., number of sessions participated) and change in IC. Activity participation patterns were also compared across subgroups. RESULTS: Data were obtained from 7,357 participants (mean age = 74.72 years). Four clusters were identified, including those who were relatively robust (cluster 1, N = 4,380, 59.5%), those who had cognitive decline (cluster 2, N = 2,134, 29.0%), those who had impaired mobility and vitality (cluster 3, N = 319, 4.3%), and those with poor psychological well-being (cluster 4, N = 524, 7.1%). Overall, activity count was associated with IC improvement (ß = 0.073, 95% CI [0.037, 0.108]). However, as regards the cluster-specific results, different types of activities were associated with IC improvement for different specific clusters. For instance, cognitive activity count was associated with IC improvement only for cluster 2 (ß = 0.491, 95% CI [0.258, 0.732]). Notably, none of the activity types were associated with IC improvement for cluster 1. Regarding the activity participation patterns, there were no significant differences across the four clusters (Wilk's Λ = 0.997, F = 1.400, p = .138). CONCLUSIONS AND IMPLICATIONS: IC improvement depended on the activity types and IC status of older people. In view of this, a people-centred and targeted approach should be adopted to maximize the overall benefits of intervention activities.

Comparison of the Physical Function Trajectories in Three Birth Cohorts of Chinese Older Adults: A 14-Year Longitudinal Study.

OBJECTIVES: It remains uncertain whether the favorable trend of reduction in physical disabilities has become reversed in the recent-born cohorts of older adults. This study aimed to compare the rate of decline with time in self-reported Instrumental Activity of Daily Living (IADL) difficulties, objective measurement of gait speed and grip strength, in three birth cohorts of Chinese older adults. DESIGN: A prospective cohort study. SETTING AND PARTICIPANTS: Four thousand Chinese older adults aged 65 years or above in three birth cohorts (1934-1938, 1929-1933, 1905-1928) were recruited from the community in Hong Kong. MEASUREMENTS: Grip strength, gait speed and IADL difficulties were measured between 2001 to 2017. Joint models were used to examine the trajectories of grip strength, gait speed and IADL difficulties over time, and the interaction effect of age-by-cohort (or also age2-by-cohort) was also examined. RESULTS: The recently born cohort (1934 - 1938) had worse grip strength and more IADL difficulties at the same age than the earlier two cohorts (1929 - 1933; 1905 - 1928). Furthermore, the most recently born cohort also followed a more rapid decline longitudinally with a greater decline observed in gait speed, grip strength and IADL difficulties for women whereas a greater decline in grip strength and IADL difficulties for men. CONCLUSIONS: The continuous improvement of physical limitations in old age may have halted and there appears to be a reversal of this favourable trend in the recent born cohort of older adults living in Hong Kong.

A Dyadic Cooking-Based Intervention for Improving Subjective Health and Well-Being of Older Adults with Subjective Cognitive Decline and Their Caregivers: A Randomized Controlled Trial.

OBJECTIVES: Evidence on the effectiveness of cooking activities as a well-being promotion intervention for older adults with subjective cognitive decline (SCD) and their caregivers is scarce. In view of this, a randomized controlled trial was conducted to examine whether a dyadic cooking-based intervention can improve the subjective health and well-being of older adults with SCD and their caregivers, as well as the cooking competence of the former group. DESIGN: Randomized controlled trial. SETTING: Community. PARTICIPANTS: Sixty pairs of community-dwelling older adults aged 60 years or above with SCD (mean age = 78.4 years) and their caregivers (mean age = 65.3 years) were randomly assigned to the intervention group (N = 30 pairs) and the wait-list control group (N = 30 pairs). INTERVENTION: The intervention was an innovative 5-week (two hours per week) dyadic cooking-based intervention employing procedural learning methods specifically adapted for older adults with SCD. MEASUREMENTS: The outcome measures included 1) a well-being index composed by four indicators: life satisfaction, feeling of happiness, sense of purpose and meaning in life, and perceived health, and 2) cooking competence. RESULTS: For both older adults with SCD and their caregivers, the increases in the well-being index were significantly greater in the intervention group than in the control group (ß = 0.508, 95% CI [0.036, 0.980]). For older adults with SCD, the increases in the cooking competence score were significantly greater in the intervention group than in the control group (ß = 1.629, 95% CI [0.165, 3.071]). CONCLUSION: The dyadic cooking-based intervention resulted in improvements in the cooking competence and well-being of older adults with SCD, as well as the well-being of caregivers.

Telehealth for a better service delivery in orthopaedic surgery.

Telehealth has the potential to change the way we approach patient care. From virtual consenting to reducing carbon emissions, costs, and waiting times, it is a powerful tool in our clinical armamentarium. There is mounting evidence that remote diagnostic evaluation and decision-making have reached an acceptable level of accuracy and can safely be adopted in orthopaedic surgery. Furthermore, patients' and surgeons' satisfaction with virtual appointments are comparable to in-person consultations. Challenges to the widespread use of telehealth should, however, be acknowledged and include the cost of installation, training, maintenance, and accessibility. It is also vital that clinicians are conscious of the medicolegal and ethical considerations surrounding the medium and adhere strictly to the relevant data protection legislation and storage framework. It remains to be seen how organizations harness the full spectrum of the technology to facilitate effective patient care.

The impact of the menstrual cycle on orthopaedic sports injuries in female athletes.

There is a disparity in sport-related injuries between sexes, with females sustaining non-contact musculoskeletal injuries at a higher rate. Anterior cruciate ligament ruptures are between two and eight times more common than in males, and females also have a higher incidence of ankle sprains, patellofemoral pain, and bone stress injuries. The sequelae of such injuries can be devastating to an athlete, resulting in time out of sport, surgery, and the early onset of osteoarthritis. It is important to identify the causes of this disparity and introduce prevention programmes to reduce the incidence of these injuries. A natural difference reflects the effect of reproductive hormones in females, which have receptors in certain musculoskeletal tissues. Relaxin increases ligamentous laxity. Oestrogen decreases the synthesis of collagen and progesterone does the opposite. Insufficient diet and intensive training can lead to menstrual irregularities, which are common in female athletes and result in injury, whereas oral contraception may have a protective effect against certain injuries. It is important for coaches, physiotherapists, nutritionists, doctors, and athletes to be aware of these issues and to implement preventive measures. This annotation explores the relationship between the menstrual cycle and orthopaedic sports injuries in pre-menopausal females, and proposes recommendations to mitigate the risk of sustaining these injuries.

Editorial: Social Determinants of Maintaining Nutrition in Older Adults with Advanced Dementia.

Dysphagia is recognised as part of the frailty syndrome, especially for those at the end of life. There is a tension in management between the need to optimize nutrition status as part of the management of oral frailty, and respecting the wishes of patients and/or family members in the form of advance care planning and advance directives regarding to artificial nutrition and hydration. Management will likely be influenced by many social determinants, rather than solely be based on evidence from clinical research.

Genome-wide gene expression responses to experimental manipulation of Saccharomyces cerevisiae repressor activator protein 1 (Rap1) expression level.

Precise regulation of transcription in gene expression is critical for all aspects of normal organism form, fitness, and function and even minor alterations in the level, location, and timing of gene expression can result in phenotypic variation within and between species including evolutionary innovations and human disease states. Eukaryotic transcription is regulated by a complex interplay of multiple factors working both at a physical and molecular levels influencing this process. In Saccharomyces cerevisiae, the TF with the greatest number of putative regulatory targets is the essential gene Repressor Activator Protein 1 (RAP1). While much is known about the roles of Rap1 in gene regulation and numerous cellular processes, the response of Rap1 target genes to systematic titration of RAP1 expression level remains unknown. To fill this knowledge gap, we used a strain with a tetracycline-titratable promoter replacing wild-type regulatory sequences of RAP1 to systematically reduce the expression level of RAP1 and followed this with RNA sequencing (RNA-seq) to measure genome-wide gene expression responses. Previous research indicated that Rap1 plays a significant regulatory role in particular groups of genes including telomere-proximal genes, homothallic mating (HM) loci, glycolytic genes, DNA repair genes, and ribosomal protein genes; therefore, we focused our analyses on these groups and downstream targets to determine how they respond to reductions in RAP1 expression level. Overall, despite being known as both an activator and as a repressor of its target genes, we found that Rap1 acts as an activator for more target genes than as a repressor. Additionally, we found that Rap1 functions as an activator of ribosomal protein genes and a repressor for HM loci genes consistent with predictions from the literature. Unexpectedly, we found that Rap1 functions as a repressor of glycolytic enzyme genes contrary to prior reports of it having the opposite effect. We also compared the expression of RAP1 to five different genes related to DNA repair pathway and found that decreasing RAP1 downregulated four of those five genes. Finally, we found no effect of RAP1 depletion on telomere-proximal genes despite its functioning to silence telomeric repeat-containing RNAs. Together our results enrich our understanding of this important transcriptional regulator.

Assessing the Readiness for Implementing the World Health Organization's ICOPE Approach in Hong Kong: Perspectives from Social Care and Policy Stakeholders.

Although integrated care has been considered a key strategy in reforming health systems around the world, it seems hard to realise in practice, particularly in the part of medical social integration. Worse still, little is known about the capacity of social care professionals who implement it, or their perceived roles and responsibilities, as well as the barriers and facilitators that stakeholders from the health and social sectors identify as factors affecting the ICOPE implementation process. Therefore, the present study was performed to probe into these issues. Data were collected from an online survey based on the WHO ICOPE scorecard (N = 34), and focus groups with policy makers, managers, health and social care professionals (N = 47). Inductive analyses were performed in accordance with the service and system levels within the WHO ICOPE implementation framework. While the findings from the scorecard survey highlight the gap in actualizing the ICOPE approach within the existing social services and care structures, we found support for a model of integrated care underpinned by the WHO ICOPE approach. Factors that may hinder and facilitate ICOPE implementation include workforce capacity-building, coordinated networks and partnerships, and financial mechanisms. This finding can help inform subsequent actions that further support health and social care advancement and collaboration, and the implementation of the ICOPE approach.

Resonant inelastic X-ray scattering endstation at the 1C beamline of Pohang Light Source II.

An endstation for resonant inelastic X-ray scattering (RIXS), dedicated to operations in the hard X-ray regime, has been constructed at the 1C beamline of Pohang Light Source II. At the Ir L3-edge, a total energy resolution of 34.2 meV was achieved, close to the theoretical estimation of 34.0 meV, which considers factors such as the incident energy bandpass, intrinsic analyzer resolution, geometrical broadening of the spectrometer, finite beam-size effect and Johann aberration. The performance of the RIXS instrument is demonstrated by measuring the RIXS spectra of Sr2IrO4. The endstation can be easily reconfigured to measure energy-integrated intensities with very low background for diffuse scattering and diffraction experiments.

Trajectories of Intrinsic Capacity: Determinants and Associations with Disability.

OBJECTIVES: Intrinsic capacity (IC) declines progressively with age, thereby increasing the risk of disability. However, it is less known whether IC trajectories are associated with disability. This study aims to identify the different patterns of IC trajectories in older people, and examine their determinants and associations with Instrumental Activities of Daily Living (IADL). DESIGN: Cohort study. SETTING: Community centres in different regions in Hong Kong. PARTICIPANTS AND MEASUREMENTS: Longitudinal data from community-dwelling older people aged 60 years or above (n = 1371) collected between 2016 and 2021 was analysed. Their mean age was 74.5 years, and 78.7% of them were female. Repeated measurements of a set of 14 self-reported items were used to generate IC scores at four time points using a bi-factor model. Latent class growth analysis was performed to identify classes with distinct IC trajectories. The association between class membership and IADL disability was then examined using logistic regression. RESULTS: Three distinct IC trajectories were identified. The 1st class included those with the highest level of baseline IC and the least declining trajectory, whereas the 3rd class was composed by those with the lowest level of baseline IC and the most declining trajectory. Older age, female gender, lower perceived financial adequacy, living in public or subsidized housing, and chronic diseases were associated with the 3rd class. After adjusting for demographic factors, socioeconomic status, and the number of chronic diseases, the 1st class was more likely to preserve IADL when compared against the 2nd class, with OR being 3.179 (95% CI: 2.152-4.793), whereas for the 3rd class, the OR was 0.253 (95% CI: 0.178-0.359). CONCLUSION: Monitoring IC trajectories is of relevance to clinical practice, as it helps shift the focus from treating acute episodes of illness to preserving the functional ability of older people.

Cold Plasma Treatment Promotes Full-thickness Healing of Skin Wounds in Murine Models.

Cold plasma can be beneficial for promoting skin wound healing and has a high potential of being effectively used in treating various wounds. Our aim was to verify the effect of cold plasma in accelerating wound healing and investigate its underlying mechanism in vitro and in vivo. For the in vivo experiments, 2 full-thickness dermal wounds were created in each mouse (n = 30). While one wound was exposed to 2 daily plasma treatments for 3 min, the other wound served as a control. The wounds were evaluated by imaging and histological analyses at 4, 7, and 11 days post the wound infliction process. Immunohistochemical studies were also performed at the same time points. In vitro proliferation and scratch assay using HaCaT keratinocytes and fibroblasts were performed. The expression levels of wound healing-related genes were analyzed by real-time polymerase chain reaction and western blot analysis. On day 7, the wound healing rates were 53.94% and 63.58% for the control group and the plasma-treated group, respectively. On day 11, these rates were 76.05% and 93.44% for the control and plasma-treated groups, respectively, and the difference between them was significant (P = .039). Histological analysis demonstrated that plasma treatment promotes the formation of epidermal keratin and granular layers. Immunohistochemical studies also revealed that collagen 1, collagen 3, and alpha-smooth muscle actin appeared more abundantly in the plasma-treated group than in the control group. In vitro, the proliferation of keratinocytes was promoted by plasma exposure. Scratch assay showed that fibroblast exposure to plasma increased their migration. The expression levels of collagen 1, collagen 3, and alpha-smooth muscle actin were elevated upon plasma treatment. In conclusion, cold plasma can accelerate skin wound healing and is well tolerated.

The Effect of Counterfactual Potency on Behavioral Intentions.

This research examines how counterfactual potency (CP), the multiplicative effect of the likelihoods of the "if" and "then" clauses of counterfactuals, determines the effects of counterfactuals on behavioral intentions. In Study 1, we found that participants who read highly (vs. minimally) mutable vignettes perceived the counterfactuals as more likely and endorsed relevant intentions more. However, CP did not mediate the effect of mutability on intentions. In Studies 2 and 3, we found that CP directly affected intentions and also mediated the effects of mutability on intentions when mutability was specifically manipulated via controllability (Study 2) or norm violation (Study 3). Finally, Study 4 used archival reaction time data to show that more concrete counterfactuals were perceived as more likely and subsequently facilitated intentions. Taken together, the current research provides evidence that more likely counterfactuals facilitate behavioral intentions.