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The number of older patients is constantly growing, and early hospital readmissions in this population represent a major problem from a health, social and economic point of view. Furthermore, the early readmission rate is often used as an indicator of the quality of care. We performed a systematic review of the literature to better understand the risk factors of early readmission (30 and 90 days) in the geriatric population and to update the existing evidence on this subject. The search was carried out on the MEDLINE, EMBASE and PsycINFO databases. Three independent reviewers assessed the potential inclusion of the studies, and then each study was independently assessed by two reviewers using Joanna Briggs Institute critical appraisal tools; any discrepancies were resolved by the third reviewer. Studies that included inpatients in surgical wards were excluded. Twenty-nine studies were included in the review. Risk factors of early readmission can be classified into socio-economic factors, factors relating to the patient’s health characteristics, factors related to the use of the healthcare system and clinical factors. Among these risk factors, those linked to patient frailty play an important role, in particular malnutrition, reduced mobility, risk of falls, fatigue and functional dependence. The early identification of patients at higher risk of early readmission may allow for targeted interventions in view of discharge.

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.

Frailty syndrome severely burdens older age, and musculoskeletal diseases are of paramount importance in its development. The aim of this study is to unravel the contribution of musculoskeletal diseases to frailty syndrome. This is a case–control study, and we enrolled 55 robust community-dwelling age- and gender-matched patients, with 58 frail and pre-frail subjects. Frailty was diagnosed according to the Fried criteria (FP), and the Fragility Index (FI) was calculated. In all the subjects, a comprehensive geriatric assessment was carried out. Their nutritional status was evaluated by the Mini Nutritional Assessment and Bioelectrical Impedance Analyses. Their bone density (BMD), bone turnover, muscle mass, strength and performance were evaluated. Here, we show that the prevalence of frailty varies according to the diagnostic criteria used and that FP and FI showed a moderate to good agreement. Despite age and gender matching, frail subjects had lower muscle strength, performance and BMD. Their quality of life and cognitive performance were reduced in the frail subjects compared to the robust ones. Muscular strength and performance, together with mood, significantly predicted the diagnosis of frailty, whereas BMD and bone turnover did not. In conclusion, we show that sarcopenia plays a pivotal role in predicting the diagnosis of frailty, whereas osteoporosis does not.

Malnutrition often affects elderly patients and significantly contributes to the reduction in healthy life expectancy, causing high morbidity and mortality. In particular, protein malnutrition is one of the determinants of frailty and sarcopenia in elderly people.To investigate the role of amino acid supplementation in senior patients we performed an open-label randomized trial and administered a particular branched-chain amino acid enriched mixture (BCAAem) or provided diet advice in 155 elderly malnourished patients. They were followed for 2 months, assessing cognitive performance by Mini Mental State Examination (MMSE), muscle mass measured by anthropometry, strength measure by hand grip and performance measured by the Timed Up and Go (TUG) test, the 30 s Chair Sit to Stand (30-s CST) test and the 4 m gait speed test. Moreover we measured oxidative stress in plasma and mitochondrial production of ATP and electron flux in peripheral blood mononuclear cells.Both groups improved in nutritional status, general health and muscle mass, strength and performance; treatment with BCAAem supplementation was more effective than simple diet advice in increasing MMSE (1.2 increase versus 0.2, p = 0.0171), ATP production (0.43 increase versus -0.1, p = 0.0001), electron flux (0.50 increase versus 0.01, p 0.0001) and in maintaining low oxidative stress. The amelioration of clinical parameters as MMSE, balance, four meter walking test were associated to increased mitochondrial function.Overall, our findings show that sustaining nutritional support might be clinically relevant in increasing physical performance in elderly malnourished patients and that the use of specific BCAAem might ameliorate also cognitive performance thanks to an amelioration of mitochondria bioenergetics.

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).

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.

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 &lt, 0.01), with a statistically higher significance in fractured OP individuals vs. healthy subjects (p &lt, 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 &lt, 0.01) and in all OP males (p &lt, 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 &plusmn, 0.02 vs. 0.15 &plusmn, 0.01, ** p &lt, 0.01). Our results suggest circulating GAS5 as a putative biomarker for the diagnosis and prognosis of OP and OP-related fractures.

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.

Objective The sense of olfaction has been considered of minor importance in human communication. In recent years, evidence has emerged that humans might be influenced by unconscious messages sent through chemosignals in body odors. Data concerning the ability of humans to recognize fear, maybe related to the evolutionary role of these emotions in the fight‐or‐flight reactions, are well known. Methods To further understand the role of emotional chemosignals in mediating communication in humans and its influence on animal behaviors, we conducted a systematic literature review. Results Chemosignals derived from axillary odors collected under a variety of emotional stimuli and sad tears in humans affect receivers' social interactions, danger detection and risk‐taking behavior, social aspects of eating, and performance under stressing conditions. In addition, beyond the fight‐or‐flight response, even the body odors of happiness can be perceived by others. Furthermore, human chemosignals can influence behaviors and stressful responses in animals, particularly dogs and horses, which may partially explain their special relationship with humans. Conclusion Our review highlights the importance of chemosignaling in human intra‐ and interspecific interactions and suggests the need for further investigations, both in physiological conditions and in patients with psychiatric or neurodegenerative disorders., In recent years, evidence has emerged that humans might be influenced by unconscious messages sent through chemosignals in body odors. This is a systematic review of the studies on communication of emotions by chemosignals in humans and between humans and other species. Human chemosignals of fear and happiness can affect a variety of receivers' behaviors in humans. Furthermore, human chemosignals can influence behaviors and stressful responses in animals.

With extended life expectancy, the older population is constantly increasing, and consequently, so too is the prevalence of age-related disorders. Sarcopenia, the pathological age-related loss of muscle mass and function; and malnutrition, the imbalance in nutrient intake and resultant energy production, are both commonly occurring conditions in old adults. Altered nutrition plays a crucial role in the onset of sarcopenia, and both these disorders are associated with detrimental consequences for patients (e.g., frailty, morbidity, and mortality) and society (e.g., healthcare costs). Importantly, sarcopenia and malnutrition also share critical molecular alterations, such as mitochondrial dysfunction, increased oxidative stress, and a chronic state of low grade and sterile inflammation, defined as inflammageing. Given the connection between malnutrition and sarcopenia, nutritional interventions capable of affecting mitochondrial health and correcting inflammageing are emerging as possible strategies to target sarcopenia. Here, we discuss mitochondrial dysfunction, oxidative stress, and inflammageing as key features leading to sarcopenia. Moreover, we examine the effects of some branched amino acids, omega-3 PUFA, and selected micronutrients on these pathways, and their potential role in modulating sarcopenia, warranting further clinical investigation.

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.

INTRODUCTION The rising prevalence of Diabetes mellitus (DM) in high TB-endemic countries may adversely affect sustainability of TB control since DM constitutes a risk factor for development of active tuberculosis (TB). The impact of DM on TB specific adaptive immune responses remains poorly addressed, particularly in people living in Sub-Saharan countries. We performed a functional characterization of TB specific cellular immune response in Tanzanian subjects with active or latent Mycobacterium tuberculosis (Mtb) infection stratified by their diabetic status. METHODS HIV negative active TB patients (≥18 years) with Xpert MTB/RIF positive pulmonary TB were included before starting TB treatment in Dar es Salaam, Tanzania between April and December 2013. HIV negative healthy controls latently infected with TB but without past TB history were also included. Active and latent TB patients were stratified in two groups according to their diabetic status. Peripheral Blood Mononuclear cells were stimulated with either live M. bovis BCG or Mtb-specific peptide pools and analyzed by intracellular cytokine staining and polychromatic flow cytometry. RESULTS Our results show a lower frequency of IFN-γ CD4+ T cells in patients with active TB and DM compared to patients with active TB only after live M. bovis BCG (p = 0.04) but not after Mtb peptide pools re-stimulation. Irrespective of TB status, level of glycaemia is selectively inversely correlated with IFN-γ and TNF-α CD4+ T cell production (p = 0.02 and p = 0.03) after live M. bovis BCG stimulation. CONCLUSIONS These results support the hypothesis that hyperglycaemia negatively impacts antigen processing and/or presentation of whole mycobacteria delaying secretion of key cytokines involved in TB immunity.

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. 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. 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

Background Scientific interest in the clinical aspects surrounding vitamin D has increased exponentially in recent years. Unfortunately, this interest is not currently associated with a proportional level of consensus. Indeed, the large number of studies in this field, which are often of low quality and secondary importance has confused even experts and driven them towards controversial positions. Objectives To shed light on this topic, we arranged a meeting with the aim of collecting the opinions of 50 experts in different specialties (“D..Battito Group”), including internists, endocrinologists, rheumatologists, pediatricians, geriatricians, dermatologists, gynecologists and nephrologists. This meeting dealt with specific questions regarding the management of hypovitaminosis D and aimed to investigate the opinions of Italian experts on this topic. Six key questions were addressed in the meeting. Methods After a short lecture and a 30 minutes discussion, all the experts expressed their opinions, which were recorded together with any specific commentary. Results The results of the meeting demonstrated the presence of insufficient agreement on many key questions regarding the management of vitamin D deficiency, even among clinical experts. Conclusion We hope that the various scientific societies will recognize and analyze the inconsistencies in their own positions and reach adequate consensus, especially on the tenets required for conducting proper and useful investigations on the topic, and that the results of these future new studies will be able to shed the needed light. Acknowledgement Abdel Jaber M, Benini C, Boner A, Bortolotti R, Brigo M, Catalano A, Ferlin A, Girasole G, Idolazzi L, Lello S, Maestri E, Martinis F, Muratore M, Olivari F, Peroni D, Romagnoli E, Ruggiero C, Saviola G, Sella S, Sfrappini M, Silveri F, Vantaggiato E, Venturin A, Zuccaro C. Disclosure of Interests Alessandro Giollo: None declared, Ombretta Viapiana Speakers bureau: Novartis, Abbvie, Eli-Lilly, Sanofi Genzyme, Angelo Fassio Speakers bureau: Abiogen Pharma, Francesco Bertoldo: None declared, Vania Teresa Braga: None declared, Maria Luisa Brandi: None declared, Stefano Calvieri: None declared, Luisella Cianferotti Speakers bureau: Abiogen Pharma, Bruno Farmaceutici, Shire, Annamaria Colao: None declared, Patrizia D’Amelio: None declared, Giovanni Mario D’Avola: None declared, Luca Degli Esposti: None declared, Bruno Frediani: None declared, Sandro Giannini: None declared, Andrea Giusti Grant/research support from: Abiogen Pharma, Consultant for: EffRx, Speakers bureau: Abiogen Pharma, Eli Lilly, AMGEN, Andrea Giustina: None declared, Stefano Gonnelli: None declared, Nazzarena Malavolta: None declared, Claudio Marcocci Grant/research support from: Shire, Speakers bureau: Shire and AbiogenPharma, Salvatore Minisola: None declared, Nicola Napoli: None declared, Ranuccio Nuti: None declared, Giovanni Passeri Grant/research support from: Abiogen Pharma and Chiesi Farmaceutici, Speakers bureau: Abiogen Pharma and Chiesi Farmaceutici, Maurizio Rossini: None declared, Luigi Sinigaglia: None declared, Francesco Vierucci: None declared, Davide Gatti Speakers bureau: Abiogen, Amgen, Janssen-Cilag, Mundipharma, Pfeizer

Local priming of osteoclast precursors (OCp) has long been considered the main and obvious pathway that takes place in the human body, where local bone lining cells and RANKL-expressing osteocytes may facilitate the differentiation of OCp. However, priming of OCp away from bone, such as in inflammatory tissues, as revealed in peripheral blood, may represent a second pathway, particularly relevant in individuals who suffer from systemic bone loss such as prevalent in inflammatory diseases. In this review, we used a systematic approach to review the literature on osteoclast formation in peripheral blood in patients with inflammatory diseases associated with bone loss. Only studies that compared inflammatory (bone) disease with healthy controls in the same study were included. Using this core collection, it becomes clear that experimental osteoclastogenesis using peripheral blood from patients with bone loss diseases in prevalent diseases such as rheumatoid arthritis, osteoporosis, periodontitis and cancer-related osteopenia unequivocally point towards an intrinsically increased osteoclast formation and activation. In particular, such increased osteoclastogenesis already takes place without the addition of the classical osteoclastogenesis cytokines M-CSF and RANKL in vitro. We show that T-cells and monocytes as OCp are the minimal demands for such unstimulated osteoclast formation. In search for common and disease-specific denominators of the diseases with inflammation-driven bone loss, we demonstrate that altered T-cell activity and a different composition - such as the CD14+CD16+ versus CD14+CD16- monocytes - and priming of OCp as seen in peripheral blood play a role in increased osteoclast formation and activity. The putative common denominators, skewness of monocyte subtypes, T-lymphocytes and the contribution of inflammatory cytokines such as TNF-α and M-CSF that are released in osteoclast cultures or that are present in peripheral blood are discussed.

Mycobacterium 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., 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

The classical functions of vitamin D are to regulate calcium-phosphorus homeostasis and control bone metabolism. However, vitamin D deficiency has been reported in several chronic conditions associated with increased inflammation and deregulation of the immune system, such as diabetes, asthma, and rheumatoid arthritis. These observations, together with experimental studies, suggest a critical role for vitamin D in the modulation of immune function. This leads to the hypothesis of a disease-specific alteration of vitamin D metabolism and reinforces the role of vitamin D in maintaining a healthy immune system. Two key observations validate this important non-classical action of vitamin D: first, vitamin D receptor (VDR) is expressed by the majority of immune cells, including B and T lymphocytes, monocytes, macrophages, and dendritic cells; second, there is an active vitamin D metabolism by immune cells that is able to locally convert 25(OH)D3 into 1,25(OH)2D3, its active form. Vitamin D and VDR signaling together have a suppressive role on autoimmunity and an anti-inflammatory effect, promoting dendritic cell and regulatory T-cell differentiation and reducing T helper Th 17 cell response and inflammatory cytokines secretion. This review summarizes experimental data and clinical observations on the potential immunomodulating properties of vitamin D.

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., Author summary While numerous studies have addressed the cellular and humoral response to primary virus encounters, relatively little is known about the interplay between persistent infections, neutralizing antibodies, antigen-presenting cells, and T-cell responses. Our studies suggests that if adenovirus–antibody complexes are taken up by professional antigen-presenting cells (e.g. dendritic cells), the DCs can generate an environment that causes bystander dendritic cells to become tolerogenic. These tolerogenic dendritic cells favors the creation of adenovirus-specific regulatory T cells. While this pathway likely favors pathogen survival, there may be advantages for the host also.