Synthesis and Properties of the Helium Clathrate and Defect Perovskite [He2-x □ x ][CaNb]F6.

The defect double perovskite [He2-x □ x ][CaNb]F6, with helium on its A-site, can be prepared by the insertion of helium into ReO3-type CaNbF6 at high pressure. Upon cooling from 300 to 100 K under 0.4 GPa helium, ∼60% of the A-sites become occupied. Helium uptake was quantified by both neutron powder diffraction and gas insertion and release measurements. After the conversion of gauge pressure to fugacity, the uptake of helium by CaNbF6 can be described by a Langmuir isotherm. The enthalpy of absorption for helium in [He2-x □ x ][CaNb]F6 is estimated to be ∼+3(1) kJ mol-1, implying that its formation is entropically favored. Helium is able to diffuse through the material on a time scale of minutes at temperatures down to ∼150 K but is trapped at 100 K and below. The insertion of helium into CaNbF6 reduces the magnitude of its negative thermal expansion, increases the bulk modulus, and modifies its phase behavior. On compressing pristine CaNbF6, at 50 and 100 K, a cubic (Fm3̅m) to rhombohedral (R3̅) phase transition was observed at <0.20 GPa. However, a helium-containing sample remained cubic at 0.4 GPa and 50 K. CaNbF6, compressed in helium at room temperature, remained cubic to >3.7 GPa, the limit of our X-ray diffraction measurements, in contrast to prior reports that upon compression in a nonpenetrating medium, a phase transition is detected at ∼0.4 GPa.

Effects of volume-matched once-weekly and thrice-weekly high-intensity interval training (HIIT) on body adiposity in adults with central obesity: Study protocol for a randomized controlled trial.

Objective: This study aims to examine the comparative effects of 75 min of volume-matched once-weekly and thrice-weekly high-intensity interval training (HIIT) on body adiposity in adults with central obesity. Methods: This assessor-blinded, three-arm, randomized controlled trial will recruit 315 physically inactive adults with central obesity (aged ≥18 years, body mass index ≥23, waist circumference ≥90 cm for men and ≥80 cm for women). Participants will be randomly allocated to the once-weekly HIIT, thrice-weekly HIIT or usual care control group. Participants in the HIIT groups will receive weekly exercise training sessions for 16 weeks, prescribed either once or three times weekly. Each HIIT session will consist of a supervised program of four 4-min high-intensity intervals at 85%-95% peak heart rate (HRpeak) interspersed with 3-min active recovery intervals at 50%-70% HRpeak. Participants in the once-weekly HIIT group will perform the 25-min HIIT bout three times with a break between each 25-min HIIT bout. The usual care control group will receive bi-weekly health education classes. The outcome assessments will be conducted at baseline, 16 weeks (post-intervention) and 32 weeks (follow-up). The primary outcome will be total body adiposity assessed by dual-energy X-ray absorptiometry (DXA). The secondary outcome measures will include markers of cardiovascular and metabolic health (body composition, cardiorespiratory fitness, blood pressure, and blood lipids), mental health, cognitive performance, health-related quality of life, sleep quality, habitual physical activity, diet, medication, adverse events and adherence to the intervention. Impact of the project: The findings from this study are expected to consolidate the therapeutic efficacy of HIIT for the management of central obesity and inform the comparative compliance, feasibility and suitability of once-weekly and thrice-weekly HIIT as exercise strategies to manage obesity. In particular, the present study is expected to provide a novel perspective on the utility of low-frequency HIIT (i.e., once-weekly) as an effective and sustainable exercise strategy to tackle the obesity pandemic. The anticipated findings will hold substantial translational value by informing public health policies and enhancing exercise compliance in the physically inactive obese population. Trial registration: ClinicalTrials.gov (NCT04887454).

The therapeutic effect of GAS6 in remyelination is dependent upon Tyro3.

Multiple sclerosis is an autoimmune disease of the central nervous system (CNS) characterized by demyelination, axonal damage and, for the majority of people, a decline in neurological function in the long-term. Remyelination could assist in the protection of axons and their functional recovery, but such therapies are not, as yet, available. The TAM (Tyro3, Axl, and MERTK) receptor ligand GAS6 potentiates myelination in vitro and promotes recovery in pre-clinical models of MS. However, it has remained unclear which TAM receptor is responsible for transducing this effect and whether post-translational modification of GAS6 is required. In this study, we show that the promotion of myelination requires post-translational modification of the GLA domain of GAS6 via vitamin K-dependent γ-carboxylation. We also confirmed that the intracerebroventricular provision of GAS6 for 2 weeks to demyelinated wild-type (WT) mice challenged with cuprizone increased the density of myelinated axons in the corpus callosum by over 2-fold compared with vehicle control. Conversely, the provision of GAS6 to Tyro3 KO mice did not significantly improve the density of myelinated axons. The improvement in remyelination following the provision of GAS6 to WT mice was also accompanied by an increased density of CC1+ve mature oligodendrocytes compared with vehicle control, whereas this improvement was not observed in the absence of Tyro3. This effect occurs independent of any influence on microglial activation. This work therefore establishes that the remyelinative activity of GAS6 is dependent on Tyro3 and includes potentiation of oligodendrocyte numbers.

Study protocol for a comparative randomized controlled trial of Tai Chi and conventional exercise training on alleviating depression in older insomniacs.

Background: Insomnia and depression are prevalent mental disorders that are often comorbid among older adults. Lifestyle intervention strategies incorporating Tai Chi or conventional exercise have been shown to alleviate symptoms of insomnia and depression. However, the comparative efficacy of these exercise modalities in individuals with both disorders has yet to be determined. Therefore, the aim of this study is to examine the efficacy of Tai Chi and conventional exercise for reducing depressive symptoms in older adults with chronic insomnia and depressive symptoms, when compared to a health education control. Methods: This study is a prospective, assessor-blinded, three-arm, parallel group, randomized controlled trial. Older adults aged ≥60 years with a diagnosis of chronic insomnia and depressive symptoms will be randomly assigned to a Tai Chi, conventional exercise or health education control condition on a 1:1:1 basis. Interventions will last for 3 months, with a 6-month follow-up period. The primary outcome is depressive symptoms, assessed using the Hospital Anxiety and Depression Scale. Secondary outcomes include subjective sleep quality, 7-day actigraphy, 7-day sleep diary, anxiety symptoms, quality of life, medication usage and physical function. All measurements will be conducted at baseline, 3 months and 9 months by outcome assessors who are blinded to group allocation. Discussion: This study will compare the efficacy of Tai Chi and conventional exercise in improving depression outcomes in older adults with chronic insomnia and depressive symptoms. Our results will shed light on the clinical potential of these interventions for combating insomnia and depression in older adults.

Length-Dependent Cellular Internalization of Nanobody-Functionalized Poly(2-oxazoline) Nanorods.

The ability to target specific tissues and to be internalized by cells is critical for successful nanoparticle-based targeted drug delivery. Here, we combined "stealthy" rod-shaped poly(2-oxazoline) (POx) nanoparticles of different lengths with a cancer marker targeting nanobody and a fluorescent cell internalization sensor via a heat-induced living crystallization-driven self-assembly (CDSA) strategy. A significant increase in association and uptake driven by nanobody-receptor interactions was observed alongside nanorod-length-dependent kinetics. Importantly, the incorporation of the internalization sensor allowed for quantitative differentiation between cell surface association and internalization of the targeted nanorods, revealing unprecedented length-dependent cellular interactions of CDSA nanorods. This study highlights the modularity and versatility of the heat-induced CDSA process and further demonstrates the potential of POx nanorods as a modular nanomedicine platform.

Self-Immolative Polymer Nanoparticles with Precise and Controllable pH-Dependent Degradation.

Polymer nanoparticles have generated significant interest as delivery systems for therapeutic cargo. Self-immolative polymers (SIPs) are an interesting category of materials for delivery applications, as the characteristic property of end-to-end depolymerization allows for the disintegration of the delivery system, facilitating a more effective release of the cargo and clearance from the body after use. In this work, nanoparticles based on a pH-responsive polymer poly(ethylene glycol)-b-(2-diisopropyl)amino ethyl methacrylate) and a self-immolative polymer poly[N,N-(diisopropylamino)ethyl glyoxylamide-r-N,N-(dibutylamino)ethyl glyoxylamide] (P(DPAEGAm-r-DBAEGAm)) were developed. Four particles were synthesized based on P(DPAEGAm-r-DBAEGAm) polymers with varied diisopropylamino to dibutylamino ratios of 4:1, 2:1, 2:3, and 0:1, termed 4:1, 2:1, 2:3, and 0:1 PGAm particles. The pH of particle disassembly was tuned from pH 7.0 to pH 5.0 by adjusting the ratio of diisopropylamino to dibutylamino substituents on the pendant tertiary amine. The P(DPAEGAm-r-DBAEGAm) polymers were observed to depolymerize (60-80%) below the particle disassembly pH after ∼2 h, compared to <10% at pH 7.4 and maintained reasonable stability at pH 7.4 (20-50% depolymerization) after 1 week. While all particles exhibited the ability to load a peptide cargo, only the 4:1 PGAm particles had higher endosomal escape efficiency (∼4%) compared to the 2:3 or 0:1 PGAm particles (<1%). The 4:1 PGAm particle is a promising candidate for further optimization as an intracellular drug delivery system with rapid and precisely controlled degradation.

Equation of state predictions for ScF3 and CaZrF6 with neural network-driven molecular dynamics.

In silico property prediction based on density functional theory (DFT) is increasingly performed for crystalline materials. Whether quantitative agreement with experiment can be achieved with current methods is often an unresolved question, and may require detailed examination of physical effects such as electron correlation, reciprocal space sampling, phonon anharmonicity, and nuclear quantum effects (NQE), among others. In this work, we attempt first-principles equation of state prediction for the crystalline materials ScF3 and CaZrF6, which are known to exhibit negative thermal expansion (NTE) over a broad temperature range. We develop neural network (NN) potentials for both ScF3 and CaZrF6 trained to extensive DFT data, and conduct direct molecular dynamics prediction of the equation(s) of state over a broad temperature/pressure range. The NN potentials serve as surrogates of the DFT Hamiltonian with enhanced computational efficiency allowing for simulations with larger supercells and inclusion of NQE utilizing path integral approaches. The conclusion of the study is mixed: while some equation of state behavior is predicted in semiquantitative agreement with experiment, the pressure-induced softening phenomenon observed for ScF3 is not captured in our simulations. We show that NQE have a moderate effect on NTE at low temperature but does not significantly contribute to equation of state predictions at increasing temperature. Overall, while the NN potentials are valuable for property prediction of these NTE (and related) materials, we infer that a higher level of electron correlation, beyond the generalized gradient approximation density functional employed here, is necessary for achieving quantitative agreement with experiment.

Effectiveness of Exercise, Cognitive Behavioral Therapy, and Pharmacotherapy on Improving Sleep in Adults with Chronic Insomnia: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials.

Despite the well-established treatment effectiveness of exercise, cognitive behavioral therapy for insomnia (CBT-I), and pharmacotherapy on improving sleep, there have been no studies to compare their long-term effectiveness, which is of clinical importance for sustainable management of chronic insomnia. This study compared the long-term effectiveness of these three interventions on improving sleep in adults with chronic insomnia. MEDLINE, PsycINFO, Embase, and SPORTDiscus were searched for eligible reports. Trials that investigated the long-term effectiveness of these three interventions on improving sleep were included. The post-intervention follow-up of the trial had to be ≥6 months to be eligible. The primary outcome was the long-term effectiveness of the three interventions on improving sleep. Treatment effectiveness was the secondary outcome. A random-effects network meta-analysis was carried out using a frequentist approach. Thirteen trials were included in the study. After an average post-intervention follow-up period of 10.3 months, both exercise (SMD, -0.29; 95% CI, -0.57 to -0.01) and CBT-I (-0.48; -0.68 to -0.28) showed superior long-term effectiveness on improving sleep compared with control. Temazepam was the only included pharmacotherapy, which demonstrated superior treatment effectiveness (-0.80; -1.25 to -0.36) but not long-term effectiveness (0.19; -0.32 to 0.69) compared with control. The findings support the use of both exercise and CBT-I for long-term management of chronic insomnia, while temazepam may be used for short-term treatment.

Dose-response effects of exercise and caloric restriction on visceral adiposity in overweight and obese adults: a systematic review and meta-analysis of randomised controlled trials.

OBJECTIVE: To determine and compare the dose-response effects of exercise and caloric restriction on visceral adipose tissue in overweight and obese adults, while controlling for the weekly energy deficit induced by the interventions. METHODS: PubMed, Embase, CINAHL and Web of Science were searched for randomised controlled trials comparing exercise or caloric restriction against eucaloric controls in overweight or obese adults. The primary outcome was the change in visceral fat measured by CT or MRI. Meta-analyses and meta-regressions were performed to determine the overall effect size (ES) and the dose-dependent relationship of exercise and caloric restriction on visceral fat. Heterogeneity, risk of bias and the certainty of evidence were also assessed. RESULTS: Forty randomised controlled trials involving 2190 participants were included. Overall, exercise (ES -0.28 (-0.37 to -0.19); p<0.001; I2=25%) and caloric restriction (ES -0.53 (-0.71 to -0.35); p<0.001; I2=33%) reduced visceral fat compared with the controls. Exercise demonstrated a dose-response effect of -0.15 ((-0.23 to -0.07); p<0.001) per 1000 calories deficit per week, whereas the effect of caloric restriction was not dose-dependent (ES 0.03 (-0.12 to 0.18); p=0.64). Most of the studies showed a moderate risk of bias. CONCLUSIONS: These findings support the dose-dependent effects of exercise to reduce visceral fat in overweight and obese adults. Caloric restriction did not demonstrate a dose-response relationship, although this may be attributed to the smaller number of studies available for analysis, compared with exercise studies. PROSPERO REGISTRATION NUMBER: CRD42020210096.

Comparison of moderate and vigorous walking exercise on reducing depression in middle-aged and older adults: A pilot randomized controlled trial.

The optimal intensity of physical activity for alleviating depression in middle-aged and older adults remains unclear. The World Health Organization (WHO) physical activity guidelines recommend adults and older adults to accumulate at least 150-300 minutes of moderate or 75-150 minutes of vigorous aerobic-type physical activity weekly or an equivalent combination of both for health benefits including reduced risk of depression. This parallel, assessor-blinded, pilot randomized controlled trial preliminarily compared the effectiveness of the minimal volume of aerobic-type physical activity at different intensities as recommended by WHO (150 minutes of moderate walking exercise and 75 minutes of vigorous walking exercise weekly) on alleviating depression in middle-aged and older adults. Thirty-five participants were randomized to the control group (CON), moderate walking exercise group (MOD), or vigorous walking exercise group (VIG). The exercise frequency was three times a week and the intervention duration was 12 weeks. The primary outcome was the severity of depression assessed by Beck Depression Inventory. Secondary outcomes included severity of anxiety, sleep quality, quality of life, and cardiorespiratory fitness. Thirty participants completed the study (CON: n = 10, MOD: n = 10, VIG: n = 10). Participants in both MOD and VIG had significantly decreased depression severity after the intervention compared to CON (both p < 0.001). There was no significant difference between MOD and VIG (p = 0.92). Both MOD and VIG interventions also mitigated anxiety severity, improved quality of life and cardiorespiratory fitness. The minimum volume of walking exercise at either moderate or vigorous intensity was found to alleviate depression in middle-aged and older adults.Trial registration: ClinicalTrials.gov identifier: NCT04403373.HighlightsThe 12-week 150-minute moderate walking exercise and 75-minute vigorous walking exercise (the minimal weekly volumes of aerobic-type physical activity recommended by WHO guidelines) similarly reduced the severity of depression in middle-aged and older adults.The 12-week walking exercise interventions significantly reduced anxiety severity concomitant with improved quality of life and cardiorespiratory fitness in middle-aged and older adults with depression.

Effects of Tai Chi and cognitive behavioral therapy for insomnia on improving sleep in older adults: Study protocol for a non-inferiority trial.

Background: Insomnia is a prevailing health problem among older adults. Tai Chi, a popular mind-body exercise practiced by older people in various oriental communities, has been shown to improve sleep. However, Tai Chi has not been directly compared to cognitive behavioral therapy for insomnia (CBT-I), which is the first-line non-pharmacological treatment for insomnia in older adults. This study aims to examine whether Tai Chi is non-inferior to CBT-I as a treatment for insomnia in older adults. Methods: This is a single-center, assessor-blinded, non-inferiority randomized controlled trial comparing Tai Chi and CBT-I in 180 older adults aged ≥50 years with chronic insomnia according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Participants will be randomly assigned to either the Tai Chi or CBT-I group. Interventions will last for 3 months with a 12-month follow-up. The primary outcome is self-perceived insomnia severity measured by Insomnia Severity Index (ISI) at 3 months and at 15 months. The secondary outcomes include the remission rate of chronic insomnia, insomnia treatment response, subjective sleep quantity and quality, 7-day actigraphy, 7-day sleep diary, sleep medication, health-related quality of life, mental health, body balance and lower extremity function, adverse events, habitual physical activity, and dietary intake. Measurements will be conducted at baseline, 3 months, and 15 months by outcome assessors who are blinded to the group allocation. Discussion: This will be the first non-inferiority randomized controlled trial to compare the efficacy and long-term outcomes of Tai Chi versus CBT-I for treating insomnia in older adults. This study will be of clinical importance as it supports the use of Tai Chi as an alternative non-pharmacological approach for insomnia treatment and sustainable management.

Directional sensitivity of dynamic cerebral autoregulation during spontaneous fluctuations in arterial blood pressure at rest.

Directional sensitivity, the more efficient response of cerebral autoregulation to increases, compared to decreases, in mean arterial pressure (MAP), has been demonstrated with repeated squat-stand maneuvers (SSM). In 43 healthy subjects (26 male, 23.1 ± 4.2 years old), five min. recordings of cerebral blood velocity (bilateral Doppler ultrasound), MAP (Finometer), end-tidal CO2 (capnograph), and heart rate (ECG) were obtained during sitting (SIT), standing (STA) and SSM. A new analytical procedure, based on autoregressive-moving average models, allowed distinct estimates of the autoregulation index (ARI) by separating the MAP signal into its positive (MAP+D) and negative (MAP-D) derivatives. ARI+D was higher than ARI-D (p < 0.0001), SIT: 5.61 ± 1.58 vs 4.31 ± 2.16; STA: 5.70 ± 1.24 vs 4.63 ± 1.92; SSM: 4.70 ± 1.11 vs 3.31 ± 1.53, but the difference ARI+D-ARI-D was not influenced by the condition. A bootstrap procedure determined the critical number of subjects needed to identify a significant difference between ARI+D and ARI-D, corresponding to 24, 37 and 38 subjects, respectively, for SSM, STA and SIT. Further investigations are needed on the influences of sex, aging and other phenotypical characteristics on the phenomenon of directional sensitivity of dynamic autoregulation.

Nanoparticles for vaccine and gene therapy: Overcoming the barriers to nucleic acid delivery.

Nucleic acid therapeutics can be used to control virtually every aspect of cell behavior and therefore have significant potential to treat genetic disorders, infectious diseases, and cancer. However, while clinically approved to treat a small number of diseases, the full potential of nucleic acid therapeutics is hampered by inefficient delivery. Nucleic acids are large, highly charged biomolecules that are sensitive to degradation and so the approaches to deliver these molecules differ significantly from traditional small molecule drugs. Current studies suggest less than 1% of the injected nucleic acid dose is delivered to the target cell in an active form. This inefficient delivery increases costs and limits their use to applications where a small amount of nucleic acid is sufficient. In this review, we focus on two of the major barriers to efficient nucleic acid delivery: (1) delivery to the target cell and (2) transport to the subcellular compartment where the nucleic acids are therapeutically active. We explore how nanoparticles can be modified with targeting ligands to increase accumulation in specific cells, and how the composition of the nanoparticle can be engineered to manipulate or disrupt cellular membranes and facilitate delivery to the optimal subcellular compartments. Finally, we highlight how with intelligent material design, nanoparticle delivery systems have been developed to deliver nucleic acids that silence aberrant genes, correct genetic mutations, and act as both therapeutic and prophylactic vaccines. This article is categorized under: Nanotechnology Approaches to Biology > Cells at the Nanoscale Therapeutic Approaches and Drug Discovery > Nanomedicine for Infectious Disease Biology-Inspired Nanomaterials > Lipid-Based Structures.

Effects of exercise intensity and frequency on improving cognitive performance in middle-aged and older adults with mild cognitive impairment: A pilot randomized controlled trial on the minimum physical activity recommendation from WHO.

Background: The World Health Organization physical activity guidelines recommend adults and older adults to accumulate at least 150-300 min of moderate or 75-150 min of vigorous aerobic-type physical activity weekly for health benefits including improvements of cognitive performance. However, the optimal exercise intensity and frequency for maximizing the cognitive benefits remain unclear. Purpose: We conducted a parallel, assessor-blinded, pilot randomized controlled trial to evaluate the effectiveness of different intensities and frequencies of the WHO-recommended minimal volume of aerobic-type physical activity on improving cognitive performance in middle-aged and older adults with mild cognitive impairment (MCI). Methods: Participants were randomly allocated to the stretching exercise control group (CON), once-a-week and thrice-a-week moderate-intensity walking groups (M1 and M3), and once-a-week and thrice-a-week vigorous-intensity walking groups (V1 and V3). Intervention duration was 12 weeks. The primary outcome was global cognitive performance assessed by the Hong Kong version of Montreal Cognitive Assessment. Secondary outcomes were self-report and objective cognitive performances, mental health, sleep quality, and cardiorespiratory fitness. Results: Thirty-seven participants completed the study (CON: n = 7, M1: n = 7, M3: n = 7, V1: n = 8, V3: n = 8). Participants in all four walking exercise groups demonstrated significant improvements in global cognitive performance assessed by the Hong Kong version of the Montreal Cognitive Assessment after the intervention when compared to CON (p < 0.001). The walking exercise interventions also significantly mitigated the anxiety severity (p < 0.005) and improved the cardiorespiratory fitness (p < 0.05) of the participants in the walking exercise groups. Conclusion: 150-min moderate- or 75-min vigorous-intensity walking exercise performed once- or thrice-weekly showed similar effects on improving cognitive performance in middle-aged and older adults with MCI. The 12-week walking exercise interventions also reduced anxiety severity and improved cardiorespiratory fitness of the participants. Clinical Trial Registration: clinicaltrials.gov, identifier NCT04515563.

Resolving subcellular pH with a quantitative fluorescent lifetime biosensor.

Changes in sub-cellular pH play a key role in metabolism, membrane transport, and triggering cargo release from therapeutic delivery systems. Most methods to measure pH rely on intensity changes of pH sensitive fluorophores, however, these measurements are hampered by high uncertainty in the inferred pH and the need for multiple fluorophores. To address this, here we combine pH dependant fluorescent lifetime imaging microscopy (pHLIM) with deep learning to accurately quantify sub-cellular pH in individual vesicles. We engineer the pH sensitive protein mApple to localise in the cytosol, endosomes, and lysosomes, and demonstrate that pHLIM can rapidly detect pH changes induced by drugs such as bafilomycin A1 and chloroquine. We also demonstrate that polyethylenimine (a common transfection reagent) does not exhibit a proton sponge effect and had no measurable impact on the pH of endocytic vesicles. pHLIM is a simple and quantitative method that will help to understand drug action and disease progression.

Identifying cell-to-cell variability in internalization using flow cytometry.

Biological heterogeneity is a primary contributor to the variation observed in experiments that probe dynamical processes, such as the internalization of material by cells. Given that internalization is a critical process by which many therapeutics and viruses reach their intracellular site of action, quantifying cell-to-cell variability in internalization is of high biological interest. Yet, it is common for studies of internalization to neglect cell-to-cell variability. We develop a simple mathematical model of internalization that captures the dynamical behaviour, cell-to-cell variation, and extrinsic noise introduced by flow cytometry. We calibrate our model through a novel distribution-matching approximate Bayesian computation algorithm to flow cytometry data of internalization of anti-transferrin receptor antibody in a human B-cell lymphoblastoid cell line. This approach provides information relating to the region of the parameter space, and consequentially the nature of cell-to-cell variability, that produces model realizations consistent with the experimental data. Given that our approach is agnostic to sample size and signal-to-noise ratio, our modelling framework is broadly applicable to identify biological variability in single-cell data from internalization assays and similar experiments that probe cellular dynamical processes.

Subcutaneous delivery of a dendrimer-BH3 mimetic improves lymphatic uptake and survival in lymphoma.

As a malignant tumour of lymphatic origin, B-cell lymphoma represents a significant challenge for drug delivery, where effective therapies must access malignant cells in the blood, organs and lymphatics while avoiding off-target toxicity. Subcutaneous (SC) administration of nanomedicines allows preferential access to both the lymphatic and blood systems and may therefore provide a route to enhanced drug exposure to lymphomas. Here we examine the impact of SC dosing on lymphatic exposure, pharmacokinetics (PK), and efficacy of AZD0466, a small molecule dual Bcl-2/Bcl-xL inhibitor conjugated to a 'DEP®' G5 poly-l-lysine dendrimer. PK studies reveal that the plasma half-life of the dendrimer-drug conjugate is 8-times longer than that of drug alone, providing evidence of slow release from the circulating dendrimer nanocarrier. The SC dosed construct also shows preferential lymphatic transport, with over 50% of the bioavailable dose recovered in thoracic lymph. Increases in dose (up to 400 mg/kg) are well tolerated after SC administration and studies in a model of disseminated lymphoma in mice show that high dose SC treatment outperforms IV administration using doses that lead to similar total plasma exposure (lower peak concentrations but extended exposure after SC). These data show that the DEP® dendrimer can act as a circulating drug depot accessing both the lymphatic and blood circulatory systems. SC administration improves lymphatic exposure and facilitates higher dose administration due to improved tolerability. Higher dose SC administration also results in improved efficacy, suggesting that drug delivery systems that access both plasma and lymph hold significant potential for the treatment of haematological cancers where lymphatic and extranodal dissemination are poor prognostic factors.

Tai Chi versus conventional exercise for improving cognitive function in older adults: a pilot randomized controlled trial.

Studies have shown that Tai Chi and conventional exercise can modify the brain through distinct mechanisms, resulting in different brain adaptations. Therefore, it is conceivable to speculate that these two exercise modalities may have different effects on improving cognitive function. This study was a parallel group, assessor-blinded, pilot randomized controlled trial comparing the effects of Tai Chi and conventional exercise on improving cognitive function in older persons with mild cognitive impairment (MCI). A total of 34 adults aged ≥ 50 years with MCI were randomized (1:1:1) to the Tai Chi group (TC, n = 10, 3 sessions of 60-min Yang-style Tai Chi training per week for 24 weeks), conventional exercise group (EX: n = 12, 3 sessions of 60-min fitness training per week for 24 weeks), or control group (CON: n = 12, no intervention). Global cognitive function assessed by the Hong Kong version of the Montreal Cognitive Assessment (MoCA-HK) and performance in various cognitive domains were examined at baseline, and 12 and 24 weeks of the intervention. Both exercise groups showed improved global cognitive function as measured by MoCA-HK compared with the control group after 12 and 24 weeks of the intervention, (all P < 0.001). Only TC achieved clinically relevant improvement on global cognitive function at week 12. Both exercise groups achieved clinically relevant improvements at the end of the interventions at week 24. Compared with EX, TC exhibited greater improvements on global cognitive function indicated by MoCA-HK after 12 weeks of the intervention (P < 0.001) and cognitive flexibility indicated by part B/A ratio score of the Trail Making Test throughout the study (all P < 0.05). Both interventions were equally effective in improving the other examined cognitive domains. Further studies are needed to substantiate the superior long-term benefits of Tai Chi on global cognitive function compared with conventional exercise, and dissect the underlying mechanisms of the two exercises on improving cognitive domains and the corresponding brain adaptations. Trial registration: This study was registered at clinicaltrials.gov (Trial registration number: NCT04248400; first registration date: 30/01/2020).

Effects of Exercise Frequency and Intensity on Reducing Depressive Symptoms in Older Adults With Insomnia: A Pilot Randomized Controlled Trial.

Background: The effects of exercise frequency and intensity on alleviating depressive symptoms in older adults with insomnia are unclear. Purpose: The purpose of this study was to investigate the influence of different exercise frequencies and intensities on prescribed aerobic-type physical activity (i.e., 75 min of vigorous-intensity exercise or 150 min of moderate-intensity exercise weekly) for reducing depressive symptoms in older adults living with insomnia, as recommended by the WHO. Design: This study is a randomized, controlled, assessor-blinded trial. Setting: This study is conducted at a single research site in Hong Kong. Participants: This study includes older adults aged 50 years or above with depressive symptoms and insomnia. Intervention: Participants were randomly assigned in a 1:1:1:1:1 ratio to the following groups: attention control (CON), moderate walking once weekly (MOD × 1/week), moderate walking thrice weekly (MOD × 3/week), vigorous walking once weekly (VIG × 1/week), and vigorous walking thrice weekly (VIG × 3/week). The total weekly exercise volumes among the walking groups were matched to the minimum recommended physical activity volume. Measurements: Depression, anxiety, self-perceived sleep quality, insomnia severity, actigraphy-assessed 7-day sleep data, 7-day sleep diary, cardiorespiratory fitness, adherence, and habitual physical activity were examined at baseline and after 12 weeks of intervention. Results: Both MOD × 3/week and VIG × 3/week groups demonstrated reduced depression (Hospital Anxiety and Depression Scale [HADS] - Depression: MOD × 3/wk: -68.6%; VIG × 3/week: -67.4%) and anxiety levels (HADS - Anxiety: MOD × 3/week: -54.3%; VIG × 3/week: -59.8%) compared with CON (both p < 0.01). Self-perceived sleep quality was improved in MOD × 3/week (-31.4% of the Pittsburgh Sleep Quality Index [PSQI]), VIG × 1/week (-34.1% of PSQI), and VIG × 3/week (-38.3% of PSQI), but not in MOD × 1/week, when compared with CON (p < 0.05). No serious adverse events were observed in this study. Conclusion: The effects of walking training on reducing depressive symptoms appeared to be dependent on exercise frequency. Our findings suggest that three sessions of walking per week at either moderate or vigorous-intensity effectively alleviate depressive symptoms in older adults with insomnia. Additional research is needed to further verify the effects of exercise frequency on depression. Clinical Trial Registration: [ClinicalTrials.gov], identifier [NCT04354922].

Effects of one-year once-weekly high-intensity interval training on body adiposity and liver fat in adults with central obesity: Study protocol for a randomized controlled trial.

Objective: This study aims to examine the effects of one-year, once-weekly high-intensity interval training (HIIT) on body adiposity and liver fat in adults with central obesity. Methods: One-hundred and twenty adults aged 18-60 years with central obesity (body mass index ≥25, waist circumference ≥90 cm for men and ≥80 cm for women). This is an assessor-blinded randomized controlled trial. Participants will be randomly assigned to the HIIT group or the usual care control group. Each HIIT session will consist of 4 × 4-min bouts at 85%-95% maximal heart rate, interspersed with 3-min bouts at 50%-70% maximal heart rate. The HIIT group will complete one session per week for 12 months, whereas the usual care control group will receive health education. The primary outcomes of this study are total body adiposity and intrahepatic triglyceride content. The secondary outcomes include abdominal visceral adipose tissue, subcutaneous adipose tissue, body mass index, waist circumference, hip circumference, cardiorespiratory fitness, lean body mass, bone mineral density, blood pressure, fasting blood glucose, insulin, triglycerides, glycated hemoglobin, cholesterol profile, liver function enzymes, medications, adherence to exercise, adverse events, quality of life, and mental health. Outcome measure will be conducted at baseline, 12 months (post-intervention), and 24 months (one-year follow-up). Impact of the project: This study will explore the benefits of long-term once-weekly HIIT with a follow-up period to assess its effectiveness, adherence, and sustainability. We expect this intervention will enhance the practical suitability of HIIT in inactive adults with central obesity, and provide insights on low-frequency HIIT as a novel exercise option for the management of patients with central obesity and liver fat. Trial registration: ClinicalTrials.gov (NCT03912272) registered on 11 April 2019.