Influence of repeated effort induced by a 6-min walk test on postural response in older sedentary women.

According to the latest recommendations, adults should exercise regularly at moderate intensity to improve aerobic fitness and body composition. However, it is unknown whether aerobic exercise at submaximal intensity has detrimental effects on balance in older sedentary adults. We explored the effects of two 6-min walk tests (6MWTs) on the postural responses in 49 sedentary women between 60 and 76 years old. We assumed that an increase in the center of pressure (COP) fluctuations or a loss in the complexity of the COP time series would be a sign of a deleterious effect on balance. We used kinematic stabilometric parameters, recurrence quantification analysis (RQA) and the central tendency measure (CTM). We refer to the measures obtained through RQA and CTM methods by dynamical measures. Repeated-measures analysis of variance showed no significant differences between the three sets of postural kinematic measures (before vs. after the first vs. after the second 6MWT). However, we observed significant differences between the three sets for the CTM measure in the antero-posterior direction (p < 0.002), RQA determinism in the medio-lateral (ML) direction (p < 0.0001), and RQA entropy in the ML direction (F = 5.93; p < 0.004).Our results indicate that the effects of moderate-intensity walking exercise on posture are not revealed by classical postural kinematic measures but only by dynamical measures. The loss of complexity in the COP time series observed after both the first and second 6MWTs may indicate presymptomatic deterioration in the postural adaptive capabilities of sedentary older women.

The impact of exercise on Alzheimer's disease progression.

INTRODUCTION: The preventive effects of chronic physical exercise (CPE) on Alzheimer's disease (AD) are now admitted by the scientific community. Curative effects of CPE are more disputed, but they deserve to be investigated, since CPE is a natural non-pharmacological alternative for the treatment of AD. AREAS COVERED: In this perspective, the authors discuss the impact of CPE on AD based on an exhaustive literature search using the electronic databases PubMed, ScienceDirect and Google Scholar. EXPERT OPINION: Aerobic exercise alone is probably not the unique solution and needs to be complemented by other exercises (physical activities) to optimize the slowing down of AD. Anaerobic, muscle strength and power, balance/coordination and meditative exercises may also help to slow down the AD progression. However, the scientific evidence does not allow a precise description of the best training program for patients with AD. Influential environmental conditions (e.g. social relations, outdoor or indoor exercise) should also be studied to optimize training programs aimed at slowing down the AD progression.

DOK1 and DOK2 regulate CD8 T cell signaling and memory formation without affecting tumor cell killing.

Targeting intracellular inhibiting proteins has been revealed to be a promising strategy to improve CD8+ T cell anti-tumor efficacy. Here, we are focusing on intracellular inhibiting proteins specific to TCR signaling: DOK1 and DOK2 expressed in T cells. We hypothesized that depletion of intracellular inhibition checkpoint DOK1 and DOK2 could improve CD8+ T-cell based cancer therapies. To evaluate the role of DOK1 and DOK2 depletion in physiology and effector function of CD8+ T lymphocytes and in cancer progression, we established a transgenic T cell receptor mouse model specific to melanoma antigen hgp100 (pmel-1 TCR Tg) in WT and Dok1/Dok2 DKO (double KO) mice. We showed that both DOK1 and DOK2 depletion in CD8+ T cells after an in vitro pre-stimulation induced a higher percentage of effector memory T cells as well as an up regulation of TCR signaling cascade- induced by CD3 mAbs, including the increased levels of pAKT and pERK, two major phosphoproteins involved in T cell functions. Interestingly, this improved TCR signaling was not observed in naïve CD8+ T cells. Despite this enhanced TCR signaling essentially shown upon stimulation via CD3 mAbs, pre-stimulated Dok1/Dok2 DKO CD8+ T cells did not show any increase in their activation or cytotoxic capacities against melanoma cell line expressing hgp100 in vitro. Altogether we demonstrate here a novel aspect of the negative regulation by DOK1 and DOK2 proteins in CD8+ T cells. Indeed, our results allow us to conclude that DOK1 and DOK2 have an inhibitory role following long term T cell stimulations.

Enhancing natural killer cells proliferation and cytotoxicity using imidazole-based lipid nanoparticles encapsulating interleukin-2 mRNA.

mRNA applications have undergone unprecedented applications-from vaccination to cell therapy. Natural killer (NK) cells are recognized to have a significant potential in immunotherapy. NK-based cell therapy has drawn attention as allogenic graft with a minimal graft-versus-host risk leading to easier off-the-shelf production. NK cells can be engineered with either viral vectors or electroporation, involving high costs, risks, and toxicity, emphasizing the need for alternative way as mRNA technology. We successfully developed, screened, and optimized novel lipid-based platforms based on imidazole lipids. Formulations are produced by microfluidic mixing and exhibit a size of approximately 100 nm with a polydispersity index of less than 0.2. They are able to transfect NK-92 cells, KHYG-1 cells, and primary NK cells with high efficiency without cytotoxicity, while Lipofectamine Messenger Max and D-Lin-MC3 lipid nanoparticle-based formulations do not. Moreover, the translation of non-modified mRNA was higher and more stable in time compared with a modified one. Remarkably, the delivery of therapeutically relevant interleukin 2 mRNA resulted in extended viability together with preserved activation markers and cytotoxic ability of both NK cell lines and primary NK cells. Altogether, our platforms feature all prerequisites needed for the successful deployment of NK-based therapeutic strategies.

Negative intracellular regulators of T-cell receptor (TCR) signaling as potential antitumor immunotherapy targets.

Immunotherapy strategies aim to mobilize immune defenses against tumor cells by targeting mainly T cells. Co-inhibitory receptors or immune checkpoints (ICPs) (such as PD-1 and CTLA4) can limit T cell receptor (TCR) signal propagation in T cells. Antibody-based blocking of immune checkpoints (immune checkpoint inhibitors, ICIs) enable escape from ICP inhibition of TCR signaling. ICI therapies have significantly impacted the prognosis and survival of patients with cancer. However, many patients remain refractory to these treatments. Thus, alternative approaches for cancer immunotherapy are needed. In addition to membrane-associated inhibitory molecules, a growing number of intracellular molecules may also serve to downregulate signaling cascades triggered by TCR engagement. These molecules are known as intracellular immune checkpoints (iICPs). Blocking the expression or the activity of these intracellular negative signaling molecules is a novel field of action to boost T cell-mediated antitumor responses. This area is rapidly expanding. Indeed, more than 30 different potential iICPs have been identified. Over the past 5 years, several phase I/II clinical trials targeting iICPs in T cells have been registered. In this study, we summarize recent preclinical and clinical data demonstrating that immunotherapies targeting T cell iICPs can mediate regression of solid tumors including (membrane associated) immune-checkpoint inhibitor refractory cancers. Finally, we discuss how these iICPs are targeted and controlled. Thereby, iICP inhibition is a promising strategy opening new avenues for future cancer immunotherapy treatments.

[Anti-fall plan for the elderly in France 2022-2024: objectives and methodology]. / Plan antichute des personnes âgées France 2022-2024 : objectifs et méthodologie1.

BACKGROUND: Falls and fall-related injuries are a major public health problem in industrialized countries. Faced with this challenge, a French national plan was launched in 2022 aiming to reduce by 20% the incidence of falls-related hospitalizations or deaths. OBJECTIVES: To describe the main pillars of the 2022-2024 French national plan against falls in older persons. Methods and assessment: The six pillars of the plan are: 1) screening and monitoring risks of falls and alert health and care workers; 2) home safety assessment and getting out safely; 3) developing technical aids for mobility and the use of assistive technologies at home; 4) appropriate physical activity, best weapon against falls; 5) tele-assistance devices for all older persons; 6) a cross-cutting pillar: Informing, raising awareness, training, and involving local actors. The plan, deployed in the 18 French regions, will provide a unique opportunity to determine the best strategies to achieve the objectives and the barriers encountered. CONCLUSIONS: The deployment of the French national plan will bring useful data for considering a long-term strategy in France and helping countries or regions wishing to implement a fall prevention plan on their territory.

[Synthesis in French of the 2022 global recommendations for the management and prevention of falls in the elderly]. / Synthèse en langue française des recommandations mondiales 2022 pour la prise en charge et la prévention des chutes chez les personnes âgées.

BACKGROUND: Falls and fall-related injuries are common in older adults, have negative effects on functional independence and quality of life and are associated with increased morbidity, mortality and health related costs. OBJECTIVE: To synthesize evidence-based and expert consensus-based 2022 world guidelines for the management and prevention of falls in older adults. These recommendations consider a person-centred approach that includes the preferences of the patient, caregivers and other stakeholders, gaps in previous guidelines, recent developments in e-health and both local context and resources. RECOMMENDATIONS: All older adults should be advised on falls prevention and physical activity. Opportunistic case finding for falls risk is recommended for communitydwelling older adults. An algorithm is proposed to stratify falls risk and interventions for persons at low, moderate or high risk. Those considered at high risk should be offered a comprehensive multifactorial falls risk assessment with a view to co-design and implement personalised multidomain interventions. Other recommendations cover details of assessment and intervention components and combinations, and recommendations for specific settings and populations. CONCLUSIONS: The core set of recommendations provided will require flexible implementation strategies that consider both local context and resources.

Transition from persistent to anti-persistent correlations in postural sway indicates velocity-based control.

The displacement of the center-of-pressure (COP) during quiet stance has often been accounted for by the control of COP position dynamics. In this paper, we discuss the conclusions drawn from previous analyses of COP dynamics using fractal-related methods. On the basis of some methodological clarification and the analysis of experimental data using stabilogram diffusion analysis, detrended fluctuation analysis, and an improved version of spectral analysis, we show that COP velocity is typically bounded between upper and lower limits. We argue that the hypothesis of an intermittent velocity-based control of posture is more relevant than position-based control. A simple model for COP velocity dynamics, based on a bounded correlated random walk, reproduces the main statistical signatures evidenced in the experimental series. The implications of these results are discussed.

[Falls prévention in older persons]. / Comment évaluer le risque de chute chez le sujet âgé ?

"Falls prévention in older persons Falls in persons aged 65 or older are a major public health problem. Some simple questions (have you experienced any fall in the previous year ? Do you have a fear of falling when walking ?) And a few simple examinations (one-leg stance, timed up and go, chair-rising, stop walking when talking test) allow to differentiate between patients at low risk of falling, for whom education and risk reassessment at 12 months are offered, patients at moderate risk of falling, for whom a physical examination and a prescription review to modify the cause of instability, and referral to a adapted physical exercise program are offered, the effect of which will be evaluated at 3-6months, and patients at high risk of falls, for whom a standardized geriatric assessment shoud be offered, at best carried out by a geriatric team, allowing the establishment of an individualized program targeting all risk factors for falls, the effectiveness of which will be reassessed at 1-3 months."

"Prévention des chutes chez le sujet âgé Les chutes après 65ans constituent un important problème de santé publique. L'entretien médical (à la recherche d'antécédents de chute, d'une peur de tomber) et quelques examens simples (temps d'appui unipodal, timed up and go test, test de relever de chaise, stop walking when talking test) permettent au médecin de distinguer trois types de profils de risque. Pour les patients à risque faible, une éducation thérapeutique et une réévaluation du risque à 12mois sont proposées. Les patients à risque modéré sont examinés (et leur ordonnance révisée) à la recherche de causes d'instabilité, puis orientés vers un programme d'activités physiques adaptées dont l'effet sera évalué à 3-6mois. Les patients à haut risque de chute doivent bénéficier d'une évaluation gérontologique standardisée, dans l'idéal effectuée par une équipe gériatrique, pour mettre en place un programme individualisé ciblant tous les facteurs de risque de chute, dont l'efficacité doit être réévaluée à 1-3mois."

High-throughput mass cytometry staining for deep phenotyping of human natural killer cells.

This protocol details the step-by-step procedure for in-depth immune phenotyping of peripheral blood natural killer (NK) cells from clinical samples by mass cytometry. The protocol consists of three main steps: PBMC incubation with a mix of metal-conjugated antibodies for extracellular phenotyping followed by fixation, permeabilization and incubation with a mix of metal-conjugated antibodies for staining of intracellular proteins, and sample acquisition on a mass cytometer. High-dimensional analysis enables the visualization of NK cell subsets and their phenotypical characteristics. For complete details on the use and execution of this protocol, please refer to Chretien et al. (2021).

Targeting CISH enhances natural cytotoxicity receptor signaling and reduces NK cell exhaustion to improve solid tumor immunity.

BACKGROUND: The success and limitations of current immunotherapies have pushed research toward the development of alternative approaches and the possibility to manipulate other cytotoxic immune cells such as natural killer (NK) cells. Here, we targeted an intracellular inhibiting protein 'cytokine inducible SH2-containing protein' (CISH) in NK cells to evaluate the impact on their functions and antitumor properties. METHODS: To further understand CISH functions in NK cells, we developed a conditional Cish-deficient mouse model in NK cells (Cishfl/flNcr1Ki/+ ). NK cells cytokine expression, signaling and cytotoxicity has been evaluated in vitro. Using intravenous injection of B16F10 melanoma cell line and EO711 triple negative breast cancer cell line, metastasis evaluation was performed. Then, orthotopic implantation of breast tumors was performed and tumor growth was followed using bioluminescence. Infiltration and phenotype of NK cells in the tumor was evaluated. Finally, we targeted CISH in human NK-92 or primary NK cells, using a technology combining the CRISPR(i)-dCas9 tool with a new lentiviral pseudotype. We then tested human NK cells functions. RESULTS: In Cishfl/flNcr1Ki/+ mice, we detected no developmental or homeostatic difference in NK cells. Global gene expression of Cishfl/flNcr1Ki/+ NK cells compared with Cish+/+Ncr1Ki/+ NK cells revealed upregulation of pathways and genes associated with NK cell cycling and activation. We show that CISH does not only regulate interleukin-15 (IL-15) signaling pathways but also natural cytotoxicity receptors (NCR) pathways, triggering CISH protein expression. Primed Cishfl/flNcr1Ki/+ NK cells display increased activation upon NCR stimulation. Cishfl/flNcr1Ki/+ NK cells display lower activation thresholds and Cishfl/flNcr1Ki/+ mice are more resistant to tumor metastasis and to primary breast cancer growth. CISH deletion favors NK cell accumulation to the primary tumor, optimizes NK cell killing properties and decreases TIGIT immune checkpoint receptor expression, limiting NK cell exhaustion. Finally, using CRISPRi, we then targeted CISH in human NK-92 or primary NK cells. In human NK cells, CISH deletion also favors NCR signaling and antitumor functions. CONCLUSION: This study represents a crucial step in the mechanistic understanding and safety of Cish targeting to unleash NK cell antitumor function in solid tumors. Our results validate CISH as an emerging therapeutic target to enhance NK cell immunotherapy.

Role of non-pharmacological interventions for healthy ageing.

The range of non-pharmacological interventions (NPIs) available for people over 60 years of age is continuously expanding, both in terms of prevention and therapy. They have been empirically selected for centuries and more recently developed through epigenetic studies, clinical trials and technological innovations, and their development has increased and diversified around the world. Residual questions concern: 1) the scope of such treatments which appears to overlap with alternative medicines, 2) their evaluation, which some researchers say is impossible, and 3) their implementation in the elderly, which appears to be overly complicated. This article addresses these three questions and presents digital tools developed by the CEPS University Platform facilitating the evaluation of NPIs in the field of healthy aging. The transformation of the health system, which has become necessary to meet the needs of baby boomers, will widen the arsenal of health-related solutions. The combination of approaches to medicine and health has become personalised, comprehensive and integrative. NPIs will play a major role in the coming century. These practices differ from alternative medicines, general public health messages and socio-cultural approaches through continuous research, a quality approach and traceability of use. NPIs today constitute a complementary ecosystem for biomedical treatments which are increasingly becoming economically and legally consolidated.

Self-reported fatigue: A significant risk factor for falling in older women and men.

OBJECTIVE: To determine whether fatigue may be a risk factor for falling in older men and women, independent of other components of the frailty phenotype, fear of falling, and physical performance. DESIGN: Among 986 women and 485 men visiting a health resort (mean age 72.3 and 72.7, respectively), subjects with at least one fall in the previous year were compared with non-fallers using a multivariate logistic regression analysis. Age, fatigue and fear of falling over the previous month were assessed by visual analogue scale (VAS), and the past 7 days of activity were assessed using the International Physical Activity Questionnaire. The following parameters were also assessed: weight loss in the past year, maximum grip strength measured with a hand dynamometer, time to perform the 5-chair stand and the up and go tests, time to walk 4 m, time held on one leg, feet together, as well as in the semi-tandem and tandem positions. RESULTS: A feeling of fatigue (VAS score ≥ 5/10 in women or ≥4/10 in men), a fear of falling (VAS score ≥ 4/10 in women or ≥2 in men), and poor balance (time held in semi-tandem position < 10 s in women and time held on one leg < 6.5 s in men) were the 3 independent parameters distinguishing fallers from non-fallers. CONCLUSION: The present study suggests the interest of adding a VAS score of fatigue to that of fear of falling and balance measurements for screening men and women aged 65 or older who are at risk of falls.

[Role of non-pharmacological interventions for healthy aging]. / Rôle des interventions non médicamenteuses pour vieillir en bonne santé.

Non-pharmacological interventions (NPIs) are continuously expanding for people over 60, both in terms of prevention and therapy. Selected empirically for centuries or recently appeared with the help of epigenetic studies, clinical trials and technological innovations, their development increase and are diversified around the world. Residual questions concern 1) their perimeter which seems to overlap with alternative medicines, 2) their evaluation which seems impossible according to some researchers, and 3) their implementation in the elderly which seems too fastidious. This article answers these three questions and then presents digital tools developed by the CEPS University Platform facilitating the evaluation of NPIs in the field of successful aging. The transformation of the health system, which has become necessary to meet the needs of baby-boomers, will widen the arsenal of solutions relevant to health, their combination of medicine and health approach that have become personalized, comprehensive and integrative. NPIs will play a major role there during the century. These practices are distinguished from alternative medicines, general public health messages and socio-cultural offers by continuous research, a quality approach and traceability of use. NPIs today constitute a complementary ecosystem for biomedical treatments whose economic and legal consolidation is increasing.

Effectiveness of a programme delivered in a falls clinic in preventing serious injuries in high-risk older adults: A pre- and post-intervention study.

OBJECTIVE: To evaluate whether a multifactorial programme delivered in a real practice setting would help prevent serious fall-related injuries in high-risk older patients. DESIGN: A 6-month pre-post intervention study in 134 fallers (81.6 ± 7.2 years) consecutively referred to a fall prevention clinic after repeated falls in the previous year or after a fall associated with balance, gait, or strength disorders. The programme was delivered by a physiotherapist, an occupational therapist, a podiatrist, and a geriatrician based on a 3-hour fall risk assessment. RESULTS: The proportion of patients with serious and moderate fall-related injuries was significantly lower in the 6 months after than in the 6-months preceding clinic attendance [8 (6.1%) vs 40 (30.5%), and 11 (8.2%) vs 19 (14.2%), respectively; p < 0.0001], as were the overall proportion of fallers (32.1% vs 95.4%; p < 0.0001) and the number of falls per patient (-5.2 ± -20.4; p < 0.0001). When compared with baseline, fear of falling at 6 months was reduced (p < 0.05), mobility was maintained, and the proportion of patients with an ADL score ≤ 2 was increased (5.6% vs 9.7% respectively; p < 0.001). Adherence to the main recommendations and satisfaction with the programme were > 75% at 6 months post-clinic. CONCLUSIONS: A multifactorial fall prevention programme delivered by a multidisciplinary geriatric team in older patients at high risk of falling helps to reduce over a 6-month period the risk of serious and moderate injuries related to falls, the risk of falling, and the fear of falling, and helps to maintain mobility and improve functional status.

C-Reactive Protein Level: A Key Predictive Marker of Cachexia in Lymphoma and Myeloma Patients.

BACKGROUND: Cachexia is defined as an involuntary loss of weight, characterized by a loss of skeletal muscle mass with or without fat mass loss. It increases mortality risk and decreases quality of life in patients with lymphoma or myeloma. Early markers of cachexia are not identified. The objective of this work was to identify risk factor of cachexia in a cohort of patients with hematological malignancies to develop strategies to prevent cachexia and its consequences. METHODS: Clinical and biological parameters were collected before and at the end of the treatment. Quantification of weight loss during cachexia was performed by the method of Martin. Clinical responses to treatment of patients with lymphoma or myeloma were monitored. RESULTS: Thirty-eight percent of the 145 patients enrolled were cachectic at the end of treatment. Classical prognostic disease scores at the time of diagnosis seemed to be not associated with cachexia observed at the end of treatment. Only C-reactive protein (CRP) > 54 mg/L seemed to be a risk factor of cachexia (P = 0.023, odds ratio (OR): 5.94 (1.55 - 39.14), confidence interval (CI): 1.55 - 39.14). Those results were confirmed by bootstrap analysis. CONCLUSION: This study highlights that high CRP level at diagnosis seems to be a risk factor for cachexia during treatment, permitting to identify patients at risk and in future to implement preventive strategies.

Relationship between a three-month physical conditioning "posture-balance-motricity and health education" (PBM-HE) program on postural and balance capacities of sedentary older adults: influence of initial motor profile.

BACKGROUND: The aims of this study were (i) to define the relationship between a physical reconditioning cycle using balance exercises and muscular-articular stress and the balance capabilities of sedentary older adults and (ii) to assess whether older adults with weaker equilibrium abilities have a significantly limited progression. Our sample consisted of 338 people (263 women, 75 men) with an age, weight and height of 74.4 years (+/- 8.6), 67 kg (+/- 13.6) and 161.4 cm (+/- 8) and with a body mass index of 25.6 (+/- 4.3). The functional evaluations consisted of individual motor profile tests, monopodal eyes open and eyes closed for 30 s, a Timed Up and Go test (TUG) and stabilometric measurements on hard ground with eyes open for a duration of 25.6 s. The physical repackaging protocol was based on the 12-week Posture-Balance-Motricity and Health Education (PBM-ES) method with two 90-min weekly group sessions. RESULTS: The evolution of the "posture" and "balance" variables was significantly associated with the equilibration capacities (p < 0.001). For unipedal stance with open eyes on the dominant and non-dominant sides, respectively, the progressions were significant for the profiles of middle (OR: 4.78 and 2.42) and low levels (OR: 4.34 and 1.66). Eyes-closed progressions were non-significant for the low-level balance profiles. For the COP Surface and Length variables, compared to those with high levels of balance, respectively, the progressions were significant for the middle- (OR: 1.41 and 2.98) and low-level (OR: 2.91 and 3.28) profiles. CONCLUSIONS: After a 3-month bi-weekly PBM-HE program, we observed that sedentary older adults with the lowest initial level of balance progressed significantly more than high-level individuals, but only for basic motor abilities. It turns out that even among the most deconditioned people and older adults, very significant progress can be made. This increase requires an individualized training content focused on initial mobilizable capacities.