[Equality across ages : addressing gender discrimination among older patients]. / Égalité à tous les âges : aborder la discrimination de genre chez les patient-e-s âgé-e-s.

The aim of this article is to draw attention to sex- and gender-related differences in the management of elderly patients. This issue is illustrated with two diseases linked to gender and sex: osteoporosis and high blood pressure. On one hand, patients of the sex less affected by the disease may feel less concerned; on the other hand, these patients are at greater risk of being under-diagnosed by medical and nursing staff. In addition, studies tend to overlook patients of the less-affected sex, resulting in guidelines that do not take account of sex or gender specific characteristics. There is even less literature on gender-related disparities in care in the elderly population than in the young, but it can be assumed that this risk of disparities exists even more in relation to specificities in diagnosis and care of elderly patients.

Cet article vise à attirer l'attention sur le risque de différences de prise en charge des patient-e-s âgé-e-s liées au sexe et au genre, illustré par deux pathologies considérées l'une comme féminine, l'autre comme masculine : l'ostéoporose et l'hypertension artérielle. Dans ce type de pathologies, les patient-e-s du sexe le moins touché par la maladie peuvent se sentir moins concerné-e-s et ont un risque accru de sous-diagnostic de la part du corps médicosoignant. De plus, les études tendent à négliger les patient-e-s du sexe moins touché, aboutissant à des guidelines ne tenant pas compte de spécificités liées au sexe ou au genre. La littérature sur les disparités de prise en charge liées au genre dans la population âgée est encore très limitée. Néanmoins, il est important de prendre en compte les spécificités liées au genre au même titre que celles liées à l'âge avancé.

[Estimating renal function in older patients : which is the best formula?] / Estimation de la fonction rénale chez la personne âgée : quelle formule utiliser ?

An accurate assessment of renal function is crucial for the diagnosis and follow up of kidney diseases. However, there is currently no clear consensus on the optimal method on how to measure renal function in older individuals (>65 years of age). The Cockcroft-Gault formula, the MDRD equation, and the CKD-EPI equation are among the most used equations. However, they have several limitations when applied to the older population. Other formulas specifically developed for the older, such as the Berlin Initiative Study (BIS) and the Full Age Spectrum (FAS) equation, demonstrated conflicting results and require more external validation. This article provides an overview of the currently available methods to assess renal function in the older persons and summarizes their shortcomings.

Une évaluation correcte de la fonction rénale est essentielle pour diagnostiquer et prendre des décisions cliniques importantes. Cependant, il n'y a pas de consensus clair sur la meilleure méthode pour mesurer la fonction rénale chez les personnes âgées. Les équations les plus couramment utilisées sont la formule de Cockcroft-Gault et les équations MDRD et CKD-EPI, mais elles présentent des limitations dans cette population. D'autres formules spécifiquement développées pour les aînés, telles que l'étude de l'initiative de Berlin (BIS) et l'équation du spectre complet de l'âge (FAS), ont montré des résultats contradictoires et nécessitent des études de validation externe. En conclusion, les médecins doivent être conscients des différentes options disponibles et des limitations de chaque méthode pour prendre des décisions cliniques éclairées.

Fighting social isolation in times of pandemic COVID-19: the role of video calls for older hospitalized patients.

BACKGROUND: Loneliness and social isolation are associated with anxiety and psychological discomfort, especially amongst the oldest and fragile persons. AIMS: SILVER evaluates the acceptance of video calls by old hospitalized patients and their relatives during the ban on visits due to the COVID-19. Moreover, SILVER evaluates if the use of different communication technology is associated with different outcomes in terms of anxiety, fear of self and of others' death and mood. METHODS: SILVER is an observational multicentre study. Patients hospitalized in two geriatric units in Switzerland and in one orthogeriatric unit in Italy and their relatives were enrolled. Participants can freely choose to use phone or video calls and were evaluated over a week. We measured anxiety, fear of death and mood at baseline and at the end of the study with standard scales. The use of video or phone calls was associated to a change in these parameters by two-way ANOVA for repeated measures. RESULTS: Sixty-four patients and relatives were enrolled, 26.5% used phone calls and 73.5% video calls. The use of video calls was associated with a reduction in anxiety and fear of death in patients and relatives as compared to participants using phone calls. DISCUSSION: Old patients and their relatives accepted and appreciated the use of video calls during hospitalization; moreover, participant using video calls appears to be less anxious and less afraid of death. CONCLUSIONS: Video calls may be a useful communication tool for hospitalized older patients to keep social relationships with relatives and reduce their anxiety and fear of death. TRIAL REGISTRATION: Retrospectively registered on 1st September 2021 in ClinicalTrials.gov (NCT05000099).

The doll therapy as a first line treatment for behavioral and psychologic symptoms of dementia in nursing homes residents: a randomized, controlled study.

BACKGROUND: Patients living with dementia are severely affected by the development of behavioral and psychologic symptoms (BPSD) which represent a burden for patients and caregivers. The use of psychotropic drugs in the control of BPSD is widely diffused, however the use of a first line non-pharmacologic approach is highly recommended. Here we evaluate the effect of doll therapy (DT) in the management of BPSD, on the reduction of caregiver burden and delirium incidence in nursing home residents by a randomized controlled trial. METHODS: We enrolled fifty-two nursing homes residents living with dementia and BPSD. Subjects were randomized to DT (26) or standard treatment (ST, 26), we measured BPSD, caregiver burden and delirium with standard clinical scales at baseline, after 45 and 90 days. In order to evaluate the presence of BPSD we used Neuropsychiatric Inventory (NPI) scale and the A.Di.CO scale, the caregiver burden was measured by the Greutzner scale and delirium by the Confusion Assessment Method (CAM) scale. RESULTS: DT was more effective in reducing agitation and aggressiveness as respect to ST. Moreover DT globally reduced the presence of BPSD as dysphoria, wandering and apathy. We observed a significant reduction of the professional caregiver burden and the incidence of delirium was significantly reduced in subjects treated with DT. CONCLUSIONS: We show that DT is more effective that ST in the control of BSPD in patients affected by moderate to severe dementia. Moreover we suggest that DT may effective in reducing the incidence of delirium. TRIAL REGISTRATION: Retrospectively registered in ClinicalTrials.gov the 10th June 2, 2021 trial registration number NCT04920591.

[To D or not to D ? Why and how to treat vitamin D deficiency in older patients]. / « To D or not to D ¼ : pourquoi et comment traiter l'hypovitaminose D chez les personnes âgées.

Vitamin D deficiency is so frequent in older patients (aged 65 years and older) that the international consensus does not recommend routine vitamin D measurement. Assessment of overall health status is a cornerstone before considering vitamin D supplementation, as the effect of vitamin D supplementation has only been demonstrated in vulnerable or dependent but not for robust older patients. The effect of the different modalities of oral vitamin D supplementation are equivalent : 800-1'200 IU/day, 10'000 IU/week or 30'000-50'000 IU/month. Monitoring of vitamin D blood level monitoring is not necessary because of a large therapeutic margin. In the presence of osteoporosis, a dietary or supplementation intake of 1'200 mg per day of calcium should be added.

L'hypovitaminose D est très fréquente chez les personnes âgées (65 ans et plus), à tel point que le consensus international est de ne pas doser la vitamine D en routine. L'évaluation de l'état de santé global est primordiale avant d'envisager une supplémentation en vitamine D, son effet ayant été démontré seulement chez les personnes âgées vulnérables ou dépendantes, mais pas chez les robustes. L'efficacité des modalités de supplémentation en vitamine D per os sont équivalentes : 800-1200 UI/jour, 10 000 UI/semaine ou 30 000-50 000 UI/mois. Un monitoring du taux sanguin de vitamine D n'est pas nécessaire en raison d'une large marge thérapeutique. En présence d'une ostéoporose, cette supplémentation devrait être complétée par un apport alimentaire ou une supplémentation de 1200 mg de calcium par jour.

HIV Infection Functionally Impairs Mycobacterium tuberculosis-Specific CD4 and CD8 T-Cell Responses.

Human immunodeficiency virus (HIV) infection is the major risk factor predisposing for Mycobacterium tuberculosis progression from latent tuberculosis infection (LTBI) to tuberculosis disease (TB). Since long-term-treated aviremic HIV-infected individuals remained at higher risk of developing TB than HIV-uninfected individuals, we hypothesized that progression from LTBI to pulmonary TB (PTB) might be due not only to CD4 T-cell depletion but also to M. tuberculosis-specific CD4 T-cell functional impairment. To test this hypothesis, M. tuberculosis-specific T-cell frequencies and cytokine profiles were investigated in untreated Tanzanian individuals suffering from LTBI (n = 20) or PTB (n = 67) and compared to those of untreated M. tuberculosis/HIV-coinfected individuals suffering from LTBI (n = 15) or PTB (n = 10). We showed that HIV infection significantly reduced the proportion of Th2 (interleukin 4 [IL-4]/IL-5/IL-13) producing M. tuberculosis-specific CD4 T cells and IL-2-producing M. tuberculosis-specific CD4 and CD8 T cells in individuals with LTBI or PTB (P < 0.05). Interestingly, the loss of IL-2 production was associated with a significant increase of PD-1 expression on M. tuberculosis-specific CD4 and CD8 T cells (P < 0.05), while the loss of Th2 cytokine production was associated with a significant reduction of Gata-3 expression in memory CD4 T cells (P < 0.05). Finally, we showed that the serum levels of IL-1α, IL-6, C-reactive protein (CRP), IL-23, and IP-10 were significantly reduced in M. tuberculosis/HIV-coinfected individuals with PTB compared to those in HIV-negative individuals with PTB (P < 0.05), suggesting that HIV infection significantly suppresses M. tuberculosis-induced systemic proinflammatory cytokine responses. Taken together, this study suggests that in addition to depleting M. tuberculosis-specific CD4 T cells, HIV infection significantly impairs functionally favorable M. tuberculosis-specific CD4 T-cell responses in Tanzanian individuals with LTBI or PTB.IMPORTANCEMycobacterium tuberculosis and human immunodeficiency virus (HIV) infections are coendemic in several regions of the world, and M. tuberculosis/HIV-coinfected individuals are more susceptible to progression to tuberculosis disease. We therefore hypothesized that HIV infection would potentially impair M. tuberculosis-specific protective immunity in individuals suffering from latent tuberculosis infection (LTBI) or active pulmonary tuberculosis (PTB). In this study, we demonstrated that M. tuberculosis/HIV-coinfected individuals have fewer circulating M. tuberculosis-specific CD4 T cells and that those that remained were functionally impaired in both LTBI and PTB settings. In addition, we showed that HIV infection significantly interferes with M. tuberculosis-induced systemic proinflammatory cytokine/chemokine responses. Taken together, these data suggest that HIV infection impairs functionally favorable M. tuberculosis-specific immunity.

Humoral immune response to adenovirus induce tolerogenic bystander dendritic cells that promote generation of regulatory T cells.

Following repeated encounters with adenoviruses most of us develop robust humoral and cellular immune responses that are thought to act together to combat ongoing and subsequent infections. Yet in spite of robust immune responses, adenoviruses establish subclinical persistent infections that can last for decades. While adenovirus persistence pose minimal risk in B-cell compromised individuals, if T-cell immunity is severely compromised reactivation of latent adenoviruses can be life threatening. This dichotomy led us to ask how anti-adenovirus antibodies influence adenovirus T-cell immunity. Using primary human blood cells, transcriptome and secretome profiling, and pharmacological, biochemical, genetic, molecular, and cell biological approaches, we initially found that healthy adults harbor adenovirus-specific regulatory T cells (Tregs). As peripherally induced Tregs are generated by tolerogenic dendritic cells (DCs), we then addressed how tolerogenic DCs could be created. Here, we demonstrate that DCs that take up immunoglobulin-complexed (IC)-adenoviruses create an environment that causes bystander DCs to become tolerogenic. These adenovirus antigen loaded tolerogenic DCs can drive naïve T cells to mature into adenovirus-specific Tregs. Our study reveals a mechanism by which an antiviral humoral responses could, counterintuitively, favor virus persistence.

Hyponatremia, Hypokalemia, and Fragility Fractures in Old Patients: More than an Association?

PURPOSE: Hyponatremia and hypokalemia are common among elderly and have been associated with osteoporosis, we evaluate the role of these electrolytes as risk for fragility fractures. METHODS: This study is divided in two parts: one retrospective and one prospective. We retrospectively collected data on urgently admitted patients for femoral fragility fractures (Fx) or for acute myocardial infarction (AMI), and patients admitted for elective hip/knee replacement surgery for osteoarthrosis (OA). Age, sex, serum sodium, potassium, creatinine, and comorbidities were recorded. We enrolled prospectively in-patients from our unit: age, sex, comorbidities, drugs, and fragility fractures were recorded. Blood electrolytes were measured. Cognitive function, nutrition, muscular strength, and balance were evaluated by standard tests. The mortality rate was recorded with a follow-up after hospital discharge. RESULTS: The retrospective study included 2166 subjects: 702 Fx and 1464 controls (907 AMI, 557 OA): the prevalence of hyponatremia was similar in Fx and AMI, whereas it was higher in Fx with respect to OA (p < 0.001) as well as hypokalemia (p < 0.001). Sodium decrease was associated with higher fracture risk. Among the 284 subjects included in the prospective study, 50 patients were hyponatremic, more likely malnourished, and presented a higher prevalence of fragility fractures (p = 0.008). They had a higher mortality after hospital discharge (HR = 1.80, p = 0.005), however, this association disappears after correction for confounding variables. CONCLUSIONS: We suggest that hyponatremia and hypokalemia have to be considered as a marker of poor health more than an independent fracture risk.

Regulatory T cells are expanded by Teriparatide treatment in humans and mediate intermittent PTH-induced bone anabolism in mice.

Teriparatide is a bone anabolic treatment for osteoporosis, modeled in animals by intermittent PTH (iPTH) administration, but the cellular and molecular mechanisms of action of iPTH are largely unknown. Here, we show that Teriparatide and iPTH cause a ~two-threefold increase in the number of regulatory T cells (Tregs) in humans and mice. Attesting in vivo relevance, blockade of the Treg increase in mice prevents the increase in bone formation and trabecular bone volume and structure induced by iPTH Therefore, increasing the number of Tregs is a pivotal mechanism by which iPTH exerts its bone anabolic activity. Increasing Tregs pharmacologically may represent a novel bone anabolic therapy, while iPTH-induced Treg increase may find applications in inflammatory conditions and transplant medicine.

Circulating Long Non-Coding RNA GAS5 Is Overexpressed in Serum from Osteoporotic Patients and Is Associated with Increased Risk of Bone Fragility.

Osteoporosis (OP) is a multifactorial disorder in which environmental factors along with genetic variants and epigenetic mechanisms have been implicated. Long non-coding RNAs (lncRNAs) have recently emerged as important regulators of bone metabolism and OP aetiology. In this study, we analyzed the expression level and the genetic association of lncRNA GAS5 in OP patients compared to controls. Quantitative RT-PCR analysis of GAS5 was performed on the serum of 56 OP patients and 28 healthy individuals. OP subjects were divided into three groups of analysis: 29 with fragility fractures of lumbar spine (OP_VF), 14 with fragility fractures of femoral neck (OP_FF) and 13 without fractures (OP_WF). Genotyping of the rs145204276 insertion/deletion polymorphism has also been performed by Restriction fragment length polymorphism (RFLP) and direct sequencing analyses. Expression of circulating GAS5 is significantly increased in OP patients compared to controls (p < 0.01), with a statistically higher significance in fractured OP individuals vs. healthy subjects (p < 0.001). No statistically significant change was found in female OP patients; conversely, GAS5 is upregulated in the subgroup of fractured OP women sera (p < 0.01) and in all OP males (p < 0.05). Furthermore, a direct correlation between GAS5 expression level and parathyroid hormone (PTH) concentration was found in OP patients (r = 0.2930; p = 0.0389). Genetic analysis of rs145204276 revealed that the deletion allele was correlated with a higher expression of GAS5 in OP patients (0.22 ± 0.02 vs. 0.15 ± 0.01, ** p < 0.01). Our results suggest circulating GAS5 as a putative biomarker for the diagnosis and prognosis of OP and OP-related fractures.

[COVID-19 infection in the elderly in French-speaking Switzerland: an inventory of beliefs, convictions and certainties]. / Infection COVID-19 chez les personnes âgées en Suisse Romande - Un état des lieux entre croyances, convictions et certitudes.

Most patients hospitalized for COVID-19 are aged over 70 years old, and half of those who die are over 83 years old. Older patients do not always present with typical symptoms (fever, cough and dyspnoea) but sometimes are and remain asymptomatic (contact screening), or have aspecific presentations (altered general condition, falls, delirium, unusual fatigue). Rectal swab, which minimizes exposition risk, appears useful in long-term care patients with diarrhea. Older age is associated with worse prognosis, but the analysis should be refined by means of prognostic indexes that account for the heterogeneous health, functional, and cognitive status of the elderly population. Gathering elderly patients' wishes and assessing their remaining life expectancy allows to anticipate care decisions according to the level of tension in the health system.

La majorité des patients COVID-19 hospitalisés ont plus de 70 ans et 50 % de ceux qui en décèdent ont plus de 83 ans. La clinique typique n'est pas toujours présente chez les personnes très âgées qui peuvent être et rester totalement asymptomatiques (dépistage contact) ou avoir des manifestations aspécifiques (baisse de l'état général, chutes, delirium, fatigue). Le frottis anal, qui minimise le risque d'exposition, peut s'avérer très utile en EMS lors de diarrhées. L'âge avancé est un marqueur de mauvais pronostic, mais devrait être pondéré à l'aide d'index pronostiques pour tenir compte de l'hétérogénéité de l'état de santé, fonctionnel et cognitif à l'âge avancé. Recueillir les souhaits de la personne et évaluer son espérance de vie restante permet d'anticiper les décisions de soins selon le niveau de tension du système de santé.

Identification of a novel locus on chromosome 2q13, which predisposes to clinical vertebral fractures independently of bone density.

OBJECTIVES: To identify genetic determinants of susceptibility to clinical vertebral fractures, which is an important complication of osteoporosis. METHODS: Here we conduct a genome-wide association study in 1553 postmenopausal women with clinical vertebral fractures and 4340 controls, with a two-stage replication involving 1028 cases and 3762 controls. Potentially causal variants were identified using expression quantitative trait loci (eQTL) data from transiliac bone biopsies and bioinformatic studies. RESULTS: A locus tagged by rs10190845 was identified on chromosome 2q13, which was significantly associated with clinical vertebral fracture (P=1.04×10-9) with a large effect size (OR 1.74, 95% CI 1.06 to 2.6). Bioinformatic analysis of this locus identified several potentially functional SNPs that are associated with expression of the positional candidate genes TTL (tubulin tyrosine ligase) and SLC20A1 (solute carrier family 20 member 1). Three other suggestive loci were identified on chromosomes 1p31, 11q12 and 15q11. All these loci were novel and had not previously been associated with bone mineral density or clinical fractures. CONCLUSION: We have identified a novel genetic variant that is associated with clinical vertebral fractures by mechanisms that are independent of BMD. Further studies are now in progress to validate this association and evaluate the underlying mechanism.

ICOS-Ligand Triggering Impairs Osteoclast Differentiation and Function In Vitro and In Vivo.

Osteoblasts, osteocytes, and osteoclasts (OCs) are involved in the bone production and resorption, which are crucial in bone homeostasis. OC hyperactivation plays a role in the exaggerated bone resorption of diseases such as osteoporosis, rheumatoid arthritis, and osteolytic tumor metastases. This work stems from the finding that OCs can express B7h (ICOS-Ligand), which is the ligand of the ICOS T cell costimulatory molecule. Because recent reports have shown that, in endothelial, dendritic, and tumor cells, B7h triggering modulates several activities of these cells, we analyzed the effect of B7h triggering by recombinant ICOS-Fc on OC differentiation and function. The results showed that ICOS-Fc inhibits RANKL-mediated differentiation of human monocyte-derived OC-like cells (MDOCs) by inhibiting the acquirement of the OC morphology, the CD14- cathepsin K+ phenotype, and the expression of tartrate-resistant acid phosphatase, OSCAR, NFATc1, and DC-STAMP. Moreover, ICOS-Fc induces a reversible decrease in the sizes of cells and nuclei and cathepsin K expression in mature MDOCs. Finally, ICOS-Fc inhibits the osteolytic activities of MDOCs in vitro and the development of bone loss in ovariectomized or soluble RANKL-treated mice. These findings open a novel field in the pharmacological use of agonists and antagonists of the ICOS-B7h system.

Type 2 diabetes affects bone cells precursors and bone turnover.

BACKGROUND: Here we study the effect of type 2 diabetes (T2DM) on bone cell precursors, turnover and cytokines involved in the control of bone cell formation and activity. METHODS: We enrolled in the study 21 T2DM women and 21 non diabetic controls matched for age and body mass index (BMI). In each subject we measured bone cell precursors, Receptor Activator of Nuclear Factor κB (RANKL), Osteoprotegerin (OPG), Sclerostin (SCL) and Dickoppf-1 (DKK-1) as cytokines involved in the control of osteoblast and osteoclast formation and activity, bone density (BMD) and quality trough trabecular bone score (TBS) and bone turnover. T2DM patients and controls were compared for the analyzed variables by one way ANOVA for Gaussian ones and by Mann-Whitney or Kruskal-Wallis test for non-Gaussian variables. RESULTS: RANKL was decreased and DKK-1 increased in T2DM. Accordingly, patients with T2DM have lower bone turnover compared to controls. BMD and TBS were not significantly different from healthy controls. Bone precursor cells were more immature in T2DM. However the number of osteoclast precursors was increased and that of osteoblasts decreased. CONCLUSIONS: Patients with T2DM have more immature bone cells precursors, with increased number of osteoclasts and decreased osteoblasts, confirming low bone turnover and reduced cytokines such as RANKL and DKK-1. BMD and TBS are not significantly altered in T2DM although, in contrast with other studies, this may be due to the match of patients and controls for BMI rather than age.

DKK-1 in prostate cancer diagnosis and follow up.

BACKGROUND: Dickoppf-1 (DKK-1) is a negative regulator of bone formation with tumorigenic potential. The up-regulation of DKK-1 is an early event in prostate cancer (PCa) development, thus we investigated its role as a marker in the diagnosis and prognosis of PCa. METHODS: We retrospectively enrolled 159 patients who underwent prostate biopsy, either for elevated PSA or suspect digital rectal examination, between 2003 and 2010. During the biopsy, one serum sample was collected from all patients; PSA and DKK-1 were measured by ELISA technique. Amongst the biopsy of 159 patients 75 were affected by PCa and 84 were not the mean period of follow-up for these patients was 5 years; a new biopsy was performed in case of PCa suspicion. RESULTS: PSA performed better than DKK-1 in detecting PCa (0.63 vs 0.51 respectively). Differently from PSA DKK-1 was significantly higher in patients who developed PCa during follow-up than in cancer-free ones, thus DKK-1 performed better than PSA in detecting these patients (0.67 vs 0.55). DKK-1 was significantly lower in patients with bone metastases, whereas PSA was not significantly different in patients with different outcomes. CONCLUSIONS: DKK-1 might be predictive for patients negative at first biopsy who will develop PCa and in the prognosis of bone metastases. It performed worse than PSA in the early diagnosis of Pca.

A contribution to the French validation of the clinical anxiety scale amongst health care workers in Switzerland.

BACKGROUND: Anxiety disorders are frequent but remain often underdiagnosed and undertreated. Hence, valid screening instruments are needed to enhance the diagnostic process. The Clinical Anxiety Scale (CAS) is a 25-item anxiety screening tool derived from the Hamilton Anxiety Scale (HAM-A). However, this scale is not available in French. The General anxiety disorder - 7 (GAD-7) scale, which has been validated in French, is a 7-item instrument with good psychometric properties. This study contributes to the validation of an adapted French version of the CAS, using the GAD-7 as the reference. METHODS: A forward-backward English-French-English translation of the CAS was performed according to standard practice. The French versions of the CAS and GAD-7 were completed by 127 French speaking healthcare professionals. CAS internal consistency was assessed using Crohnbach's alpha, and test-retest reliability was tested after 15 days in a subsample of 30 subjects. Convergent validity with GAD-7 was assessed using Pearson's correlation coefficient. Test-retest reliability was explored using one-way random effects model to calculate the intra-class correlation coefficient (ICC). RESULTS: French CAS showed excellent internal consistency (Cronbach's alpha 0.97), high convergent validity with GAD-7 (Pearson's R 0.81, p < 0.001), and very good test-retest reliability (ICC = 0.97, 95% CI 0.93-0.98). CONCLUSION: The proposed French version of the CAS showed high reliability and validity that need to be further investigated in different populations.

Dickkopf-1 (DKK1) drives growth and metastases in castration-resistant prostate cancer.

Metastatic castration-resistant prostate cancer (mCRPC) is associated with a poor prognosis and remains an incurable fatal disease. Therefore, the identification of molecular markers involved in cancer progression is urgently needed to develop more-effective therapies. The present study investigated the role of the Wnt signaling modulator Dickkopf-1 (DKK1) in the growth and metastatic progression of mCRPC. DKK1 silencing through siRNA and deletion via CRISPR/Cas9 editing were performed in two different metastatic castration-resistant prostate cancer cell lines (PC3 and DU145). A xenograft tumor model was used to assess tumor growth and metastases. In in vitro experiments, both DKK1 silencing and deletion reduced cell growth and migration of both cell lines. DKK1 knockout clones (DKK1-KO) exhibited cell cycle arrest, tubulin reorganization, and modulation of tumor metastasis-associated genes. Furthermore, in DKK1-KO cells, E-cadherin re-expression and its membrane co-localization with ß-catenin were observed, contributing to reduced migration; Cadherin-11, known to increase during epithelial-mesenchymal transition, was down-regulated in DKK1-KO cells. In the xenograft mouse model, DKK1 deletion not only reduced tumor growth but also inhibited the formation of lung metastases. In conclusion, our findings support the key role of DKK1 in the growth and metastatic dissemination of mCRPC, both in vitro and in vivo.

The science of micronutrients in clinical practice - Report on the ESPEN symposium.

BACKGROUND & AIMS: The European Society for Clinical Nutrition and Metabolism published its first clinical guidelines for use of micronutrients (MNs) in 2022. A two-day web symposium was organized in November 2022 discussing how to apply the guidelines in clinical practice. The present paper reports the main findings of this symposium. METHODS: Current evidence was discussed, the first day being devoted to clarifying the biology underlying the guidelines, especially regarding the definition of deficiency, the impact of inflammation, and the roles in antioxidant defences and immunity. The second day focused on clinical situations with high prevalence of MN depletion and deficiency. RESULTS: The importance of the determination of MN status in patients at risk and diagnosis of deficiencies is still insufficiently perceived, considering the essential role of MNs in immune and antioxidant defences. Epidemiological data show that deficiencies of several MNs (iron, iodine, vitamin D) are a global problem that affects human health and well-being including immune responses such as to vaccination. Clinical conditions frequently associated with MN deficiencies were discussed including cancer, obesity with impact of bariatric surgery, diseases of the gastrointestinal tract, critical illness, and aging. In all these conditions, MN deficiency is associated with worsening of outcomes. The recurrent problem of shortage of MN products, but also lack of individual MN-products is a worldwide problem. CONCLUSION: Despite important progress in epidemiology and clinical nutrition, numerous gaps in practice persist. MN depletion and deficiency are frequently insufficiently searched for in clinical conditions, leading to inadequate treatment. The symposium concluded that more research and continued education are required to improve patient outcome.