Neutralization of Staphylococcus aureus Protein A Prevents Exacerbated Osteoclast Activity and Bone Loss during Osteomyelitis.

Osteomyelitis caused by Staphylococcus aureus is an important and current health care problem worldwide. Treatment of this infection frequently fails not only due to the increasing incidence of antimicrobial-resistant isolates but also because of the ability of S. aureus to evade the immune system, adapt to the bone microenvironment, and persist within this tissue for decades. We have previously demonstrated the role of staphylococcal protein A (SpA) in the induction of exacerbated osteoclastogenesis and increased bone matrix degradation during osteomyelitis. The aim of this study was to evaluate the potential of using anti-SpA antibodies as an adjunctive therapy to control inflammation and bone damage. By using an experimental in vivo model of osteomyelitis, we demonstrated that the administration of an anti-SpA antibody by the intraperitoneal route prevented excessive inflammatory responses in the bone upon challenge with S. aureus. Ex vivo assays indicated that blocking SpA reduced the priming of osteoclast precursors and their response to RANKL. Moreover, the neutralization of SpA was able to prevent the differentiation and activation of osteoclasts in vivo, leading to reduced expression levels of cathepsin K, reduced expression of markers associated with abnormal bone formation, and decreased trabecular bone loss during osteomyelitis. Taken together, these results demonstrate the feasibility of using anti-SpA antibodies as an antivirulence adjunctive therapy that may prevent the development of pathological conditions that not only damage the bone but also favor bacterial escape from antimicrobials and the immune system.

A small regulatory RNA alters Staphylococcus aureus virulence by titrating RNAIII activity.

Staphylococcus aureus is an opportunistic human and animal pathogen with an arsenal of virulence factors that are tightly regulated during bacterial infection. The latter is achieved through a sophisticated network of regulatory proteins and regulatory RNAs. Here, we describe the involvement of a novel prophage-carried small regulatory S. aureus RNA, SprY, in the control of virulence genes. An MS2-affinity purification assay reveals that SprY forms a complex in vivo with RNAIII, a major regulator of S. aureus virulence genes. SprY binds to the 13th stem-loop of RNAIII, a key functional region involved in the repression of multiple mRNA targets. mRNAs encoding the repressor of toxins Rot and the extracellular complement binding protein Ecb are among the targets whose expression is increased by SprY binding to RNAIII. Moreover, SprY decreases S. aureus hemolytic activity and virulence. Our results indicate that SprY titrates RNAIII activity by targeting a specific stem loop. Thus, we demonstrate that a prophage-encoded sRNA reduces the pathogenicity of S. aureus through RNA sponge activity.

Daily very low UV dose exposure enhances adaptive immunity, compared with a single high-dose exposure. Consequences for the control of a skin infection.

Ultraviolet radiation (UVr) promotes several well-known molecular changes, which may ultimately impact on health. Some of these effects are detrimental, like inflammation, carcinogenesis and immunosuppression. On the other hand, UVr also promotes vitamin D synthesis and other beneficial effects. We recently demonstrated that exposure to very low doses of UVr on four consecutive days [repetitive low UVd (rlUVd)] does not promote an inflammatory state, nor the recruitment of neutrophils or lymphocytes, as the exposure to a single high UV dose (shUVd) does. Moreover, rlUVd reinforce the epithelium by increasing antimicrobial peptides transcription and epidermal thickness. The aim of this study was to evaluate the adaptive immune response after shUVd and rlUVd, determining T-cell and B-cell responses. Finally, we challenged animals exposed to both irradiation procedures with Staphylococcus aureus to study the overall effects of both innate and adaptive immunity during a cutaneous infection. We observed, as expected, a marked suppression of T-cell and B-cell responses after exposure to an shUVd but a novel and significant increase in both specific responses after exposure to rlUVd. However, the control of the cutaneous S. aureus infection was defective in this last group, suggesting that responses against pathogens cannot be ruled out from isolated stimuli.

Treatment in vitro with PPARα and PPARγ ligands drives M1-to-M2 polarization of macrophages from T. cruzi-infected mice.

Trypanosoma cruzi, the etiological agent of Chagas' disease, induces a persistent inflammatory response. Macrophages are a first line cell phenotype involved in the clearance of infection. Upon parasite uptake, these cells increase inflammatory mediators like NO, TNF-α, IL-1ß and IL-6, leading to parasite killing. Although desired, inflammatory response perpetuation and exacerbation may lead to tissue damage. Peroxisome proliferator-activated receptors (PPARs) are ligand-dependent nuclear transcription factors that, besides regulating lipid and carbohydrate metabolism, have a significant anti-inflammatory effect. This is mediated through the interaction of the receptors with their ligands. PPARγ, one of the PPAR isoforms, has been implicated in macrophage polarization from M1, the classically activated phenotype, to M2, the alternatively activated phenotype, in different models of metabolic disorders and infection. In this study, we show for the first time that, besides PPARγ, PPARα is also involved in the in vitro polarization of macrophages isolated from T. cruzi-infected mice. Polarization was evidenced by a decrease in the expression of NOS2 and proinflammatory cytokines and the increase in M2 markers like Arginase I, Ym1, mannose receptor and TGF-ß. Besides, macrophage phagocytic activity was significantly enhanced, leading to increased parasite load. We suggest that modulation of the inflammatory response by both PPARs might be due, at least in part, to a change in the profile of inflammatory macrophages. The potential use of PPAR agonists as modulators of overt inflammatory response during the course of Chagas' disease deserves further investigation.

Efficacy of a hyperglycemia treatment program in a Vascular Surgery Department supervised by Endocrinology. / Eficacia de un programa de tratamiento de la hiperglucemia en un Servicio de Cirugía Vascular supervisado por Endocrinología.

BACKGROUND: The aim of this study was to evaluate the strategy and efficacy of a hyperglycemia treatment program supervised by Endocrinology. METHODS: All patients with type 2 diabetes hospitalized at the vascular surgery department over a 12 month period were retrospectively reviewed. Clinical characteristics and hyperglycemia treatment during hospitalization, at discharge and 2-6 month after discharge were collected. Glycemic control was assessed using capillary blood glucose profiles and HbA1c at admission and 2-6 months post-discharge. RESULTS: A total of 140 hospitalizations of 123 patients were included. The protocol to choose the insulin regimen was applied in 96.4% of patients (22.8% correction dose, 23.6% basal-correction dose and 50% basal-bolus-correction dose [BBC]). Patients with BBC had higher HbA1c (7.7±1.5% vs. 6.7 ±0.8%; P<.001) and mean glycemia on the first day of hospitalization (184.4±59.2 vs. 140.5±31.4mg/dl; P<.001). Mean blood glucose was reduced to 162.1±41.8mg/dl in the middle and 160.8±43.3mg/dl in the last 24h of hospitalization in patients with BBC (P=.007), but did not change in the remaining patients. In 22.1% patients with treatment changes performed at discharge, HbA1c decreased from 8.2±1.6 to 6.8±1.6% at 2-6 months post-discharge (P=.019). CONCLUSIONS: The hyperglycemia treatment protocol applied by an endocrinologist in the hospital, allows the identification of the appropriate therapy and the improvement of the glycemic control during hospitalization and discharge, supporting its efficacy in clinical practice.

Thyroglobulin as early prognostic marker to predict remission at 18-24 months in differentiated thyroid carcinoma.

INTRODUCTION: Thyroglobulin (Tg), the most common marker to determine remission of differentiated thyroid carcinoma (DTC), can take 18 months or longer to be undetectable. We hypothesized that Tg stimulated after surgery and immediately before radioiodine treatment (baseline-stimulated Tg) could be a good predictor of remission at 18-24 months. The aim of this study was to evaluate the role of baseline-stimulated Tg as early prognostic marker of DTC. PATIENTS AND METHODS: Retrospective study of 133 patients with DTC from 1998 to 2010 (age at diagnosis 47·4 ± 16·8, follow-up 5·09 ± 3·2 years). Initial subset analysis was performed after excluding patients with positive TgAb, who were later included in the second. Baseline-stimulated Tg was divided into tertiles. Multivariate logistic regression analysis included baseline Tg and other known prognostic markers and receiver operating characteristic (ROC) curve to identify the best cut-off level of baseline Tg were performed. RESULTS: Baseline-stimulated Tg in the highest tertile was the only predictive variable of persistence of disease at 18-24 months in the initial analysis (OR 45·3, P < 0·01). In the second analysis, the predictive variables were baseline-stimulated Tg (OR 39·6, P < 0·001), presence of TgAb (OR 23·4, P < 0·005) and uptake outside of the thyroid bed post-treatment whole body scan (WBS; OR 5·3, P < 0·05) were predictive of persistence of disease. The ROC curve showed that baseline-stimulated Tg below 8·55 µg/l identified 95% of disease-free patients at 18-24 months after initial treatment. CONCLUSIONS: Baseline-stimulated Tg is a good predictor of remission of disease at 18-24 months after initial treatment and could be a useful marker to stratify risk immediately after surgery.

Shedding of tumor necrosis factor receptor 1 induced by protein A decreases tumor necrosis factor alpha availability and inflammation during systemic Staphylococcus aureus infection.

Staphylococcus aureus infections are an important public health concern due to their increasing incidence and high rates of mortality. The success of S. aureus as a pathogen is highly related to its enormous capacity to evade the host immune response. The critical role of tumor necrosis factor alpha (TNF-α) in the initial host defense against systemic staphylococcal infection has been demonstrated in experimental models and may partially explain the lack of significant benefits observed in clinical trials attempting to neutralize this cytokine in septic patients. S. aureus protein A plays a key role in regulating inflammation through its ability to bind and signal through the TNF-α receptor 1 (TNFR1). In this study, we demonstrate that S. aureus, via protein A-mediated signaling, induces early shedding of TNFR1, which precedes the secretion of TNF-α in vitro and in vivo. The results obtained using a protein A-deficient mutant and tnfr1(-/-) mice strongly suggest that the increased levels of soluble TNFR1 present during experimental S. aureus infection may neutralize circulating TNF-α and impair the host inflammatory response. Early shedding of TNFR1 induced by protein A may constitute a novel mechanism by which S. aureus subverts the host immune response.

New Weapons to Fight against Staphylococcus aureus Skin Infections.

The treatment of Staphylococcus aureus skin and soft tissue infections faces several challenges, such as the increased incidence of antibiotic-resistant strains and the fact that the antibiotics available to treat methicillin-resistant S. aureus present low bioavailability, are not easily metabolized, and cause severe secondary effects. Moreover, besides the susceptibility pattern of the S. aureus isolates detected in vitro, during patient treatment, the antibiotics may never encounter the bacteria because S. aureus hides within biofilms or inside eukaryotic cells. In addition, vascular compromise as well as other comorbidities of the patient may impede proper arrival to the skin when the antibiotic is given parenterally. In this manuscript, we revise some of the more promising strategies to improve antibiotic sensitivity, bioavailability, and delivery, including the combination of antibiotics with bactericidal nanomaterials, chemical inhibitors, antisense oligonucleotides, and lytic enzymes, among others. In addition, alternative non-antibiotic-based experimental therapies, including the delivery of antimicrobial peptides, bioactive glass nanoparticles or nanocrystalline cellulose, phototherapies, and hyperthermia, are also reviewed.

Evaluation of the usefulness of and satisfaction with the flash glucose monitoring system (FreeStyle Libre®) guide for use in patients with type 1 diabetes⋆.

The Flash Guide (FG) for insulin dosing (A. Chico, C. González) was the first document intended for FreeStyle Libre® (FSL) user patients to help with decision-making depending on glucose level and trend. The objective of the study was to evaluate the usefulness of and the level of satisfaction with the recommendations given by the FG in a group of patients with type 1 diabetes (DM1) who were FSL users. It included 31 subjects (54% women; age 41 ± 15 years; DM duration 21 ± 14 years; 22 with FSL > 12 months) who were provided with the FG. They completed a questionnaire on decision-making depending on glucose trend in different situations (before and three months after using the FG), and a satisfaction questionnaire (ad hoc). Demographic, clinical and glycaemic control data were collected. The percentage of subjects who used glucose trend in decision-making after receiving the FG increased: for adjusting insulin (51 vs. 83; p = 0.016), action without insulin (51 vs. 90%; p = 0.001), and in special circumstances. The FG was evaluated as very useful (4.19/5). There were no significant changes in glycaemic control, although the percentage of data gathered increased significantly (89.07 vs. 94.46%; p = 0.042). In conclusion, the FG was evaluated well for managing glucose trends with FSL by the patients with DM1 analysed, increasing their use of trend in decision-making, with no changes in glycaemic control, but with more data gathered.

Effects of a Digital Patient Empowerment and Communication Tool on Metabolic Control in People With Type 2 Diabetes: The DeMpower Multicenter Ambispective Study.

BACKGROUND: Diabetes is a major health care problem, reaching epidemic numbers worldwide. Reducing hemoglobin A1c (HbA1c) levels to recommended targets is associated with a marked decrease in the risk of type 2 diabetes mellitus (T2DM)-related complications. The implementation of new technologies, particularly telemedicine, may be helpful to facilitate self-care and empower people with T2DM, leading to improved metabolic control of the disease. OBJECTIVE: This study aimed to analyze the effect of a home digital patient empowerment and communication tool (DeMpower App) on metabolic control in people with inadequately controlled T2DM. METHODS: The DeMpower study was multicenter with a retrospective (observational: 52 weeks of follow-up) and prospective (interventional: 52 weeks of follow-up) design that included people with T2DM, aged ≥18 and ≤80 years, with HbA1c levels ≥7.5% to ≤9.5%, receiving treatment with noninsulin antihyperglycemic agents, and able to use a smartphone app. Individuals were randomly assigned (2:1) to the DeMpower app-empowered group or control group. We describe the effect of empowerment on the proportion of patients achieving the study glycemic target, defined as HbA1c≤7.5% with a ≥0.5% reduction in HbA1c at week 24. RESULTS: Due to the COVID-19 pandemic, the study was stopped prematurely, and 50 patients (33 in the DeMpower app-empowered group and 17 in the control group) were analyzed. There was a trend toward a higher proportion of patients achieving the study glycemic target (46% vs 18%; P=.07) in the DeMpower app group that was statistically significant when the target was HbA1c≤7.5% (64% vs 24%; P=.02) or HbA1c≤8% (85% vs 53%; P=.02). The mean HbA1c was significantly reduced at week 24 (-0.81, SD 0.89 vs -0.15, SD 1.03; P=.03); trends for improvement in other cardiovascular risk factors, medication adherence, and satisfaction were observed. CONCLUSIONS: The results suggest that patient empowerment through home digital tools has a potential effect on metabolic control, which might be even more relevant during the COVID-19 pandemic and in a digital health scenario.

Initial clinical and treatment patterns of advanced differentiated thyroid cancer: ERUDIT study.

Background: Up to 30% of differentiated thyroid cancer (DTC) will develop advanced-stage disease (aDTC) with reduced overall survival (OS). Objective: The aim of this study is to characterize initial diagnosis of aDTC, its therapeutic management, and prognosis in Spain and Portugal. Methods: A multicentre, longitudinal, retrospective study of adult patients diagnosed with aDTC in the Iberian Peninsula was conducted between January 2007 and December 2012. Analyses of baseline characteristics and results of initial treatments, relapse- or progression-free survival ((RP)FS) from first DTC diagnosis, OS, and prognostic factors impacting the evolution of advanced disease were evaluated. Results: Two hundred and thirteen patients (median age: 63 years; 57% female) were eligible from 23 hospitals. Advanced disease presented at first diagnosis (de novo aDTC) included 54% of patients, while 46% had relapsed from early disease (recurrent/progressive eDTC). At initial stage, most patients received surgery (98%) and/or radioiodine (RAI) (89%), with no differences seen between median OS (95% CI) (10.4 (7.3-15.3) years) and median disease-specific-survival (95% CI) (11.1 (8.7-16.2) years; log-rank test P = 0.4737). Age at diagnosis being <55 years was associated with a lower risk of death (Wald chi-square (Wc-s) P < 0.0001), while a poor response to RAI to a higher risk of death ((Wc-s) P < 0.05). In the eDTC cohort, median (RP)FS (95% CI) was of 1.7 (1.0-2.0) years after RAI, with R0/R1 surgeries being the only common significant favourable factor for longer (RP)FS and time to aDTC ((Wc-s) P < 0.05). Conclusion: Identification of early treatment-dependent prognostic factors for an unfavourable course of advanced disease is possible. An intensified therapeutic attitude may reverse this trend and should be considered in poor-performing patients. Prospective studies are required to confirm these findings.

Evaluation of the usefulness of and satisfaction with the flash glucose monitoring system (FreeStyle Libre®) guide for use in patients with type 1 diabetes. / Evaluación de la utilidad y satisfacción con la guía de uso del sistema flash de monitorización de glucosa (FreeStyle Libre®) en pacientes con diabetes tipo 1.

The Flash Guide (FG) for insulin dosing (A. Chico, C. González) was the first document intended for FreeStyle Libre® (FSL) user patients to help with decision-making depending on glucose level and trend. The objective of the study was to evaluate the usefulness of and the level of satisfaction with the recommendations given by the FG in a group of patients with type 1 diabetes (DM1) who were FSL users. It included 31 subjects (54% women; age 41±15 years; DM duration 21±14 years; 22 with FSL>12 months) who were provided with the FG. They completed a questionnaire on decision-making depending on glucose trend in different situations (before and three months after using the FG), and a satisfaction questionnaire (ad hoc). Demographic, clinical and glycaemic control data were collected. The percentage of subjects who used glucose trend in decision-making after receiving the FG increased: for adjusting insulin (51 vs. 83; P=.016), action without insulin (51 vs. 90%; P=.001), and in special circumstances. The FG was evaluated as very useful (4.19/5). There were no significant changes in glycaemic control, although the percentage of data gathered increased significantly (89.07 vs. 94.46%; P=.042). In conclusion, the FG was evaluated well for managing glucose trends with FSL by the patients with DM1 analysed, increasing their use of trend in decision-making, with no changes in glycaemic control, but with more data gathered.

Protein A Modulates Neutrophil and Keratinocyte Signaling and Survival in Response to Staphylococcus aureus.

The type 1 TNF-α receptor (TNFR1) has a central role in initiating both pro-inflammatory and pro-apoptotic signaling cascades in neutrophils. Considering that TNFR1 signals Staphylococcus aureus protein A (SpA), the aim of this study was to explore the interaction of this bacterial surface protein with neutrophils and keratinocytes to underscore the signaling pathways that may determine the fate of these innate immune cells in the infected tissue during staphylococcal skin infections. Using human neutrophils cultured in vitro and isogenic staphylococcal strains expressing or not protein A, we demonstrated that SpA is a potent inducer of IL-8 in neutrophils and that the induction of this chemokine is dependent on the SpA-TNFR1 interaction and p38 activation. In addition to IL-8, protein A induced the expression of TNF-α and MIP-1α highlighting the importance of SpA in the amplification of the inflammatory response. Protein A contributed to reduce neutrophil mortality prolonging their lifespan upon the encounter with S. aureus. Signaling initiated by SpA modulated the type of neutrophil cell death in vitro and during skin and soft tissue infections (SSTI) in vivo triggering the apoptotic pathway instead of necrosis. Moreover, SpA induced pro-inflammatory cytokines in keratinocytes, modulating their survival in vitro and preventing the exacerbated necrosis and ulceration of the epithelium during SSTI in vivo. Taken together, these results highlight the importance of the inflammatory signaling induced by protein A in neutrophils and skin epithelial cells. The ability of protein A to modulate the neutrophil/epithelial cell death program in the skin is of clinical relevance considering that lysis of neutrophils and epithelial cells will promote an intense inflammatory response and contribute to tissue damage, a non-desirable feature of complicated SSTI.

The good side of inflammation: Staphylococcus aureus proteins SpA and Sbi contribute to proper abscess formation and wound healing during skin and soft tissue infections.

Staphylococcus aureus is the most prominent cause of skin and soft tissue infections (SSTI) worldwide. Mortality associated with invasive SSTI is a major threat to public health considering the incidence of antibiotic resistant isolates in particular methicillin resistant S. aureus both in the hospital (HA-MRSA) and in the community (CA-MRSA). To overcome the increasing difficulties in the clinical management of SSTI due to MRSA, new prophylactic and therapeutic approaches are urgently needed and a preventive vaccine would be welcome. The rational design of an anti-S. aureus vaccine requires a deep knowledge of the role that the different bacterial virulence factors play according to the type of infection. In the present study, using a set of isogenic deficient mutants and their complemented strains we determined that the staphylococcal surface proteins SpA and Sbi play an important role in the induction of inflammatory cytokines and chemokines in the skin during SSTI. SpA and Sbi initiate signaling cascades that lead to the early recruitment of neutrophils, modulate their lifespan in the skin milieu and contribute to proper abscess formation and bacterial eradication. Moreover, the expression of SpA and Sbi appear critical for skin repair and wound healing. Thus, these results indicate that SpA and Sbi can promote immune responses in the skin that are beneficial for the host and therefore, should not be neutralized with vaccine formulations designed to prevent SSTI.

Cholesterol and 27-hydroxycholesterol promote thyroid carcinoma aggressiveness.

Cholesterol mediates its proliferative and metastatic effects via the metabolite 27-hydroxycholesterol (27-HC), at least in breast and endometrial cancer. We determined the serum lipoprotein profile, intratumoral cholesterol and 27-HC levels in a cohort of patients with well-differentiated papillary thyroid carcinoma (PTC; low/intermediate and high risk), advanced thyroid cancers (poorly differentiated, PDTC and anaplastic thyroid carcinoma, ATC) and benign thyroid tumors, as well as the expression of genes involved in cholesterol metabolism. We investigated the gene expression profile, cellular proliferation, and migration in Nthy-ori 3.1 and CAL-62 cell lines loaded with human low-density lipoprotein (LDL). Patients with more aggressive tumors (high-risk PTC and PDTC/ATC) showed a decrease in blood LDL cholesterol and apolipoprotein B. These changes were associated with an increase in the expression of the thyroid's LDL receptor, whereas 3-hydroxy-3-methylglutaryl-CoA reductase and 25-hydroxycholesterol 7-alpha-hydroxylase were downregulated, with an intratumoral increase of the 27-HC metabolite. Furthermore, LDL promoted proliferation in both the Nthy-ori 3.1 and CAL-62 thyroid cellular models, but only in ATC cells was its cellular migration increased significantly. We conclude that cholesterol and intratumoral accumulation of 27-HC promote the aggressive behavior process of PTC. Targeting cholesterol metabolism could be a new therapeutic strategy in thyroid tumors with poor prognosis.

TNFR1 Signaling Contributes to T Cell Anergy During Staphylococcus aureus Sepsis.

Early research on sepsis has focused on the initial hyper-inflammatory, cytokine mediated phase of the disorder whereas the events that govern the concomitant and subsequent anti-inflammatory compensatory response are not completely understood. In this context, the putative participation of TNFR1-mediated signaling in the immunosuppressive phase of Staphylococcus aureus sepsis has not been elucidated. The aim of this study was to determine the role of TNFR1 in directing the immune dysfunction during S. aureus sepsis and the potential contribution of MDSC to this process. Using a model of sepsis of peritoneal origin and tnfr1-/- mice, we demonstrated that during staphylococcal sepsis CD4+ T cell anergy is significantly dependent on TNFR1 expression and that signaling through this receptor has an impact on bacterial clearance in the spleen. MDSC played a major role in the generation of anergic CD4+ T cells and their accumulation in the spleen during S. aureus sepsis correlated with IL-6 induction. Although TNFR1 signaling was not required for MDSC accumulation and expansion in the spleen, it determined the in vivo expression of Arginase 1 and iNOS, enzymes known to participate in the suppressive function of this population. Moreover, our data indicate that TNFR1-mediated IL-10 production may modulate MDSC function during staphylococcal sepsis. Taken together these results indicate that TNFR1 plays a critical role on T cell dysfunction during S. aureus sepsis by regulating immunomodulatory mediators in MDSC. The role of TNFR1-mediated signaling during the immunosuppressive phase of staphylococcal sepsis should be considered when designing novel alternative therapeutic approaches.

Mutation of Agr Is Associated with the Adaptation of Staphylococcus aureus to the Host during Chronic Osteomyelitis.

Selection pressures exerted on Staphylococcus aureus by host factors may lead to the emergence of mutants better adapted to the evolving conditions at the infection site. This study was aimed at identifying the changes that occur in S. aureus exposed to the host defense mechanisms during chronic osteomyelitis and evaluating whether these changes affect the virulence of the organism. Genome assessment of two S. aureus isolates collected 13 months apart (HU-85a and HU-85c) from a host with chronic osteomyelitis was made by whole genome sequencing. Agr functionality was assessed by qRT-PCR. Isolates were tested in a rat model of osteomyelitis and the bacterial load (CFU/tibia) and the morphometric osteomyelitic index (OI) were determined. The ability of the isolates to trigger the release of proinflammatory cytokines was determined on macrophages in culture. Persistence of S. aureus within the host resulted in an agrC frameshift mutation that likely led to the observed phenotype. The capacity to cause bone tissue damage and trigger proinflammatory cytokines by macrophages of the agr-deficient, unencapsulated derivative (HU-85c) was decreased when compared with those of the isogenic CP8-capsulated parental strain (HU-85a). By comparison, no significant differences were found in the bacterial load or the OI from rats challenged with isogenic Reynolds strains [CP5, CP8, and non-typeable (NT)], indicating that lack of CP expression alone was not likely responsible for the reduced capacity to cause tissue damage in HU-85c compared with HU-85a. The production of biofilm was significantly increased in the isogenic derivative HU-85c. Lack of agr-dependent factors makes S. aureus less virulent during chronic osteomyelitis and alteration of the agr functionality seems to permit better adaptation of S. aureus to the chronically infected host.

Web Support for Weight-Loss Interventions: PREDIRCAM2 Clinical Trial Baseline Characteristics and Preliminary Results.

An ongoing clinical trial is testing the efficacy of web telematic support in a structured program for obesity treatment and diabetes prevention. Participants were recruited from two tertiary-care hospitals and randomized to receive either a telematic intervention (TI) supported by PREDIRCAM2 web platform or a non-telematic intervention (NTI). All receive 1-year follow-up. Both interventions consist of tailored dietary and exercise prescriptions, based on a Mediterranean dietary pattern and general WHO exercise recommendations for adults. At 6 months, both groups have received 7 contacts, 3 exclusively telematic for the TI group. This is a preliminary result intention-to-treat analysis. One hundred eighty-three participants were recruited, with a mean body mass index of 34.75 ± 2.75 kg/m2. General dropout rate at 6 months was 26.8%. Weight changes were statistically significant at months 3 and 6 compared to baseline, -2.915 ± 0.24 kg, -3.29 ± 0.36 kg, respectively (P < 0.001), but not statistically significant between the 3- and 6-month time points -0.37 ± 0.21 kg (P = 0.24). Mean group differences showed that the TI group lost 1.61 ± 1.88 kg more than the NTI group (P = 0.39). Waist, waist/hip ratio, resting heart rate, blood pressure, HbA1c, and low-density lipoprotein cholesterol also showed statistically significant changes at 6 months, with no significant differences between groups. Weight loss in the TI group shows similar results as the usual care NTI group for weight loss and control of obesity comorbidities. At completion of the clinical trial, these results will be reevaluated to assess the potential role of web support in weight-loss maintenance and its cost-effectiveness.

Evaluation of a New Digital Automated Glycemic Pattern Detection Tool.

BACKGROUND: Blood glucose meters are reliable devices for data collection, providing electronic logs of historical data easier to interpret than handwritten logbooks. Automated tools to analyze these data are necessary to facilitate glucose pattern detection and support treatment adjustment. These tools emerge in a broad variety in a more or less nonevaluated manner. The aim of this study was to compare eDetecta, a new automated pattern detection tool, to nonautomated pattern analysis in terms of time investment, data interpretation, and clinical utility, with the overarching goal to identify early in development and implementation of tool areas of improvement and potential safety risks. METHODS: Multicenter web-based evaluation in which 37 endocrinologists were asked to assess glycemic patterns of 4 real reports (2 continuous subcutaneous insulin infusion [CSII] and 2 multiple daily injection [MDI]). Endocrinologist and eDetecta analyses were compared on time spent to analyze each report and agreement on the presence or absence of defined patterns. RESULTS: eDetecta module markedly reduced the time taken to analyze each case on the basis of the emminens eConecta reports (CSII: 18 min; MDI: 12.5), compared to the automatic eDetecta analysis. Agreement between endocrinologists and eDetecta varied depending on the patterns, with high level of agreement in patterns of glycemic variability. Further analysis of low level of agreement led to identifying areas where algorithms used could be improved to optimize trend pattern identification. CONCLUSION: eDetecta was a useful tool for glycemic pattern detection, helping clinicians to reduce time required to review emminens eConecta glycemic reports. No safety risks were identified during the study.

Expert Study: Utility of an Automated Bolus Advisor System in Patients with Type 1 Diabetes Treated with Multiple Daily Injections of Insulin-A Crossover Study.

OBJECTIVE: This study was designed to assess the impact of the use of an automated bolus advisor (ABA) on glycemic control, quality of life, and satisfaction in adult patients with type 1 diabetes mellitus treated with multiple daily injections of insulin. MATERIALS AND METHODS: A crossover, prospective, randomized, controlled, multicenter study of 36 weeks duration was conducted. Patients were randomized to start in either control phase (CP) using a traditional blood glucose meter to calculate insulin doses (Accu-Chek(®) Aviva Nano; Roche Diagnostics, Indianapolis, IN) or intervention phase (IP) using an ABA meter (Accu-Chek Aviva Expert; Roche Diagnostics) and switched to the other phase after a washout period. Each phase was 12 weeks in duration. RESULTS: Significant glycated hemoglobin (HbA1c) reduction was observed in both phases (CP, initial HbA1c of 8.05 ± 0.7%, final HbA1c of 7.59 ± 0.7% [P < 0.001]; IP, initial HbA1c of 8.13 ± 1%, final HbA1c of 7.61 ± 0.8% [P < 0.001]). Although the trend was to a higher HbA1c reduction in IP, no statistically significant differences were observed between phases (CP, HbA1c -0.39%; IP, HbA1c -0.52% [P = 0.8]). During IP, the number of daily glucose measurements was greater (4.28 ± 1.2 vs. 4.01 ± 1.1 [P < 0.006]), the rate of postprandial hypoglycemia was lower, and an improvement in quality of life and higher satisfaction were observed. CONCLUSIONS: In this first crossover study comparing the use of an ABA with the standard usual care, the use of an ABA was effective and well accepted. Furthermore, reduction in hypoglycemic events, improvement in adherence and quality of life, and higher treatment satisfaction were observed.