The role of laboratory medicine in a value-based healthcare system: the example of heart failure patient management in the Italian context.

OBJECTIVE: As of today, healthcare systems worldwide face severe challenges that undermine their sustainability. The value-based healthcare (VBHC) approach has been proposed as a strategic and methodological framework to ensure the delivery of the best patient outcomes with economic efficiency. Through the illustrative example of B-type natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP) for heart failure (HF) patient management in the context of the Italian National Healthcare system, this article explores the role that in vitro diagnostics (IVDs) can play in enabling value-based care models. SUBJECTS AND METHODS: 14 healthcare professionals representing the relevant professional figures involved in HF patient management met to revise the current HF patient journey and design a new care pathway that, leveraging on BNP/NT-proBNP, reflects the VBHC principles. RESULTS: The literature recognizes the dosage of BNP/NT-proBNP as the gold stan-dard for diagnosing HF. However, as of today, these IVDs are not employed at their full potential regarding HF patient management. A new patient journey is proposed so that patients are diagnosed early and properly monitored in the aftermath of hospitalization, improving outcomes at contained costs. CONCLUSIONS: As testified by the example of HF patient management in Italy, laboratory medicine can represent a lever for adopting value-based care models. Still, large-scale adoption of VBHC will call for structural reforms that revise how healthcare delivery is organized, measured, and reimbursed.

Acute changes in free and extracellular vesicle-associated circulating miRNAs and myokine profile in professional sky-runners during the Gran Sasso d'Italia vertical run.

The modification of gene expression profile, a first step in adaptation to exercise, leads to changes in the level of molecules associated with skeletal muscle activity and energy metabolism-such as myokines-as well as those involved in their transcriptional regulation, like microRNA. This study aimed to investigate the influence of strenuous exercise on circulating microRNAs and their possible association with myokine response. Pre-competition and post-competition plasma samples were collected from 14 male athletes participating in a vertical run (+1,000 m gain, 3,600 m length). Circulating total (t-miRNA) and extracellular vesicle-associated (EV-miRNA) miRNAs were extracted from the pooled plasma. Nanoparticle tracking analysis was performed to investigate pre- and post-competition EV concentration and size distribution. A panel of 179 miRNAs was assayed by qPCR and analyzed by Exiqon GenEx v6 normalized on the global mean. t-miRNA and EV-miRNAs whose level was ≥5-fold up- or down-regulated were validated for each single subject. Target prediction on MirWalk v3.0, Gene-Ontology, and pathway enrichment analysis on Panther v17.0 were performed to define the potential biological role of the identified miRNAs. A panel of 14 myokines was assayed in each sample by a multiplex immunoassay. In whole plasma, five miRNAs were upregulated and two were downregulated; in the EV fraction, five miRNAs were upregulated and three were downregulated. Nanoparticle tracking analysis revealed a similar EV size distribution in pre- and post-competition samples and a decreased concentration in post-competition samples related to pre-competition samples. Gene-Ontology and pathway enrichment analysis revealed that the identified t-miRNAs and EV-miRNAs were potentially involved in metabolism regulation in response to exercise. Correlation between fold-change of the post-competition relative to pre-competition plasma level of both t-miRNAs and EV-miRNAs and myokines further confirmed these results. This study provides an example of a systemic response to acute endurance exercise, in which circulating miRNAs play a pivotal role.

Are clinical practice guidelines for low back pain interventions of high quality and updated? A systematic review using the AGREE II instrument.

BACKGROUND: Clinical practice guidelines (CPGs) provide recommendations for practice, but the proliferation of CPGs issued by multiple organisations in recent years has raised concern about their quality. The aim of this study was to systematically appraise CPGs quality for low back pain (LBP) interventions and to explore inter-rater reliability (IRR) between quality appraisers. The time between systematic review search and publication of CPGs was recorded. METHODS: Electronic databases (PubMed, Embase, PEDro, TRIP), guideline organisation databases, websites, and grey literature were searched from January 2016 to January 2020 to identify GPCs on rehabilitative, pharmacological or surgical intervention for LBP management. Four independent reviewers used the Appraisal of Guidelines for Research and Evaluation II (AGREE II) tool to evaluate CPGs quality and record the year the CPGs were published and the year the search strategies were conducted. RESULTS: A total of 21 CPGs met the inclusion criteria and were appraised. Seven (33%) were broad in scope and involved surgery, rehabilitation or pharmacological intervention. The score for each AGREE II item was: Editorial Independence (median 67%, interquartile range [IQR] 31-84%), Scope and Purpose (median 64%, IQR 22-83%), Rigour of Development (median 50%, IQR 21-72%), Clarity and Presentation (median 50%, IQR 28-79%), Stakeholder Involvement (median 36%, IQR 10-74%), and Applicability (median 11%, IQR 0-46%). The IRR between the assessors was nearly perfect (interclass correlation 0.90; 95% confidence interval 0.88-0.91). The median time span was 2 years (range, 1-4), however, 38% of the CPGs did not report the coverage dates for systematic searches. CONCLUSIONS: We found methodological limitations that affect CPGs quality. In our opinion, a universal database is needed in which guidelines can be registered and recommendations dynamically developed through a living systematic reviews approach to ensure that guidelines are based on updated evidence. LEVEL OF EVIDENCE: 1 TRIAL REGISTRATION: REGISTRATION PROSPERO DETAILS: CRD42019127619 .

How the effects of actions become our own.

Every day, we do things that cause effects in the outside world with little doubt about who caused what. To some, this sense of agency derives from a post hoc reconstruction of a likely causal relationship between an event and our preceding movements; others propose that the sense of agency originates from prospective comparisons of motor programs and their effects. Using functional magnetic resonance imaging, we found that the sense of agency is associated with a brain network including the pre-supplementary motor area (SMA) and dorsal parietal cortex. Transcranial magnetic stimulation affected the sense of agency only when delivered over the pre-SMA and specifically when time-locked to action planning, rather than when the physical consequences of the actions appeared. These findings make a prospective theory of the sense of agency more likely.

Evidence-Based Medicine (EBM) is properly perceived but its application is still limited in the orthopedic clinical practice: an online survey among the European Society of Sports Traumatology, Knee Surgery and Arthroscopy (ESSKA) members.

PURPOSE: To evaluate the knowledge and awareness of Evidence-Based Medicine (EBM) among members of the European Society of Sports Traumatology, Knee Surgery and Arthroscopy (ESSKA). METHODS: A questionnaire was developed that explored the following areas: (i) respondents' attitudes to EBM; (ii) their motivation to implement EBM in daily practice; (iii) their educational background, knowledge and skills related to accessing and interpreting information; (iv) their level of attention to, and use of, scientific literature; (v) access to and availability of evidence; (vi) perceived barriers in using EBM in clinical practice. The resulting data were analyzed using descriptive statistics, and the correlation between age, educational background and country was further investigated. RESULTS: Two-hundred and eighty-eight ESSKA members (11% of the total population) compiled the questionnaire. The participants covered all the five continents and an expected prevalence of European professionals (77%) was observed. The vast majority of participants were medical doctors (91%), mainly specialized in knee surgery with minimal involvement in research. 97% of the participants declared having some knowledge of EBM, acquired mainly during their professional education, with some geographical differences. The youngest clinicians and those from Eastern Europe reported the greatest difficulty in using EBM in daily practice. The application of EBM in clinical practice is positively affected by the time dedicated to research and negatively correlates with the time dedicated to patient care. CONCLUSIONS: The results of this survey highlight the need for further investigation into the main reasons behind the limited diffusion of the EBM approach, despite the medical community's knowledge and interest in the concept. A wider application of EMB would upgrade clinical practice, linking medical knowledge and scientific evidence to patients' needs which would result of benefit to patients, but also more in general to the health system.

How Task Interactivity Shapes Action Observation.

Action observation triggers imitation, a powerful mechanism permitting interpersonal coordination. Coordination, however, also occurs when the partners' actions are nonimitative and physically incongruent. One influential theory postulates that this is achieved via top-down modulation of imitation exerted by prefrontal regions. Here, we rather argue that coordination depends on sharing a goal with the interacting partner: this shapes action observation, overriding involuntary imitation, through the predictive activity of the left ventral premotor cortex (lvPMc). During functional magnetic resonance imaging (fMRI), participants played music in turn with a virtual partner in interactive and noninteractive conditions requiring 50% of imitative/nonimitative responses. In a full-factorial design, both perceptual features and low-level motor requirements were kept constant throughout the experiment. Behaviorally, the interactive context minimized visuomotor interference due to the involuntary imitation of physically incongruent movements. This was paralleled by modulation of neural activity in the lvPMc, which was specifically recruited during the interactive task independently of the imitative/nonimitative nature of the social exchange. This lvPMc activity reflected the predictive decoding of the partner's actions, as revealed by multivariate pattern analysis. This demonstrates that, during interactions, we process our partners' behavior to prospectively infer their contribution to the shared goal achievement, generating motor predictions for cooperation beyond low-level imitation.

Modular implant design affects metal ion release following metal-on-metal hip arthroplasty: a retrospective study on 75 cases.

Metal-on-Metal (MoM) total hip arthroplasty (THA) has been associated to wear and metal-ions release, controversially related to a variety of clinical complications. Little is known about the relevant design-dependent parameters involved in this process. The present study investigated the correlation between metal ion release in blood and revision rate as a function of: (i) specific MoM implant modular design parameters, (i.e. acetabular cup and femoral head diameters, taper adapter material and size, femoral neck material and modularity and stem size); (ii) MoM bilaterality. Co and Cr ions concentration levels in blood of 75 patients were retrospectively-evaluated with a mean follow-up of 4.8 years (range: 1.8-6.3). Patients were divided in a unilateral and a bilateral group. Statistical analysis was performed to find any significant difference related to acetabular cup diameter, femoral head diameter, taper adapter material/size, neck material/size and stem size. The bilateral MoM group had 4-times higher metal ion levels in blood than the unilateral one (p=0.017 only Cr), related to a higher revision rate (30% vs 20%): differences were 10-times higher particularly with a 48 mm femoral head diameter (p=0.012) and a Ti-alloy neck (p=0.041). Within the monolateral group using a shorter taper adapter and a shorter neutrally-oriented neck demonstrated higher ion levels (p=0.038 only Cr and p=0.008 only Co, respectively). The aforementioned design-features and MoM bilaterality are important risk-factors for metal-ion release in modular MoM THA.

The effect of repeated whole-body cryostimulation on the HSP-70 and lipid metabolisms in healthy subjects.

The aim of this study was to evaluate the effects of exposure to 30 daily whole body cryostimulation (WBC) on lipid metabolic parameters and serum HSP-70 concentration. The study involved 45 volunteers, homogeneous in terms of diet and daily physical activity. Blood samples were collected before and after the 10(th), the 20(th), and the 30(th) session and one month after the intervention. Total cholesterol, HDL, TG concentrations and Apolipoprotein A-I, ApoB and HSP-70 protein levels were determined in serum. Additionally, the LI (Lipid Index) and the LDL level were calculated. During exposure, positive changes in the lipid profile that included a decrease in the TCh, initiated after the 20th WBC session with a simultaneous decrease in TG and LDL levels, and an increase in the HDL concentration were observed. These changes were accompanied by a downward trend in the ApoB concentration and a decrease in the ApoB:ApoA-I ratio after 30 sessions. The nature of these changes persisted for a month after the exposure. The obtained results indicate metabolic benefits that result from prolonged exposure to cryogenic temperatures, confirming the postulate of using WBC in the regulation of lipid metabolism and the prevention of cardiovascular diseases.

Hungry brains: A meta-analytical review of brain activation imaging studies on food perception and appetite in obese individuals.

The dysregulation of food intake in chronic obesity has been explained by different theories. To assess their explanatory power, we meta-analyzed 22 brain-activation imaging studies. We found that obese individuals exhibit hyper-responsivity of the brain regions involved in taste and reward for food-related stimuli. Consistent with a Reward Surfeit Hypothesis, obese individuals exhibit a ventral striatum hyper-responsivity in response to pure tastes, particularly when fasting. Furthermore, we found that obese subjects display more frequent ventral striatal activation for visual food cues when satiated: this continued processing within the reward system, together with the aforementioned evidence, is compatible with the Incentive Sensitization Theory. On the other hand, we did not find univocal evidence in favor of a Reward Deficit Hypothesis nor for a systematic deficit of inhibitory cognitive control. We conclude that the available brain activation data on the dysregulated food intake and food-related behavior in chronic obesity can be best framed within an Incentive Sensitization Theory. Implications of these findings for a brain-based therapy of obesity are briefly discussed.

An overview of different health indicators used in the European Health Systems.

INTRODUCTION: In the European Union three different health systems could be defined according to service delivery, financing, and economic policies: Beveridge, Bismarck and Mixed system. Although health systems are hardly to compare, various organizations are developing methods assessing performance. In the present work the performance of the three systems were evaluated using European Community Health Indicators according to Organization for Economic Cooperation and Development. METHODS: The study has been conducted among the 28 states of the European Union using the following indicators: Standardized death rate for diseases of the circulatory system, standardized death rate of malignant neoplasms, road traffic accidents with injury, life expectancy at birth, incidence of Human Immunodeficiency Virus (HIV), infant deaths, pure alcohol consumption, infants vaccinated against Diphtheria Tetanus Pertussis (DTP), public and total expenditure on health over the period 2001-2010. RESULTS: The variation of health indicators over the observational time shows similar trend of circulatory system diseases and malignant neoplasms death rates, road accidents with injury, infant deaths, life expectancy at birth, public and total health expenditure. Some differences in the trend of HIV incidence, alcohol intake and DTP vaccination rates arise among systems. Grouping countries by health system paradigm and geographical area, resulted in a relevant heterogeneity (I2 ≥ 90%, Pvalue < 0.0001). No clear superiority of a given health delivery system was found with respect to other paradigms. CONCLUSIONS: In accordance with the evidence of our study, it can be stated that best performances are more likely to be linked to country specific economic factors. In conclusion, it was not possible to identify the best health system model.

European cardiovascular mortality over the last three decades: evaluation of time trends, forecasts for 2016.

BACKGROUND: The circulatory diseases, in particular ischemic heart diseases and stroke, represent the main causes of death worldwide both in high income and in middle and low income countries. Our aim is to provide a comprehensive report to depict the circulatory disease mortality in Europe over the last 30 years and to address the sources of heterogeneity among different countries. METHODS: Our study was performed using the WHO statistical information system - mortality database - and was restricted to the 28 countries belonging to the European Union (EU-28). We evaluated gender and age time series of all circulatory disease mortality, ischemic heart diseases, cerebrovascular diseases, pulmonary and other circulatory diseases and than we performed forecast for 2016. Mortality heterogeneity was evaluated by countries using the Cochrane Q statistic and the I-squared index. RESULTS: Between 1985 and 2011 SDR for deaths attributable to all circulatory system diseases decreased from 440.9 to 212.0 x 100,000 in EU-28 and a clear uniform reduction was observed. Heterogeneity among countries was found to be consistent, therefore different analysis were carried out considering geographical area. CONCLUSIONS: We forecast a reduction in European cardiovascular mortality. Heterogeneity among countries could only in part be explained by both geographical and health expenditure factors.

The adult zebrafish as polyhedric model for skeletal studies.

In the last decade, several examples have been produced by scientific literature about zebrafish as a model to study human bone diseases. In fish, bone turnover, reparation and remodeling of the adult bone tissue cannot be studied in embryonic or juvenile stages. In addition, fins and scales represent unique anatomical features useful to study adult bone metabolism and diseases. For these reasons, the adult zebrafish represents an innovative and readily available resource for studying the bone metabolism at cellular and molecular level. Although the adult fish is less used than the embryo, several applications have been found in the last years with the production of innovative pathological models in adult zebrafish, helpful to understand the mechanisms of bone physiopathology. The use of mutants, regenerating organs, transgenic fish and scales have increased the power of this model in the last years.

Anti-adalimumab antibodies in psoriasis: lack of clinical utility and laboratory evidence.

OBJECTIVE: Adalimumab has proven effective in psoriasis; however, secondary failure may result from the drug's immunogenicity. Prevalence data on the immunogenicity of biologicals, and of adalimumab in particular, are highly variable. We investigated the prevalence of anti-adalimumab antibodies and the association with clinical indexes and tumour necrosis factor α (TNFα) serum levels in psoriatic patients. DESIGN: Case-control, longitudinal. SETTING: Single centre. PARTICIPANTS: Patient groups: I (n=20) receiving biological therapies after switching from adalimumab; II (n=30) ongoing adalimumab therapy; III (n=30) novel adalimumab therapy; IV (n=15) biological therapies other than adalimumab.Healthy subjects: (group V; n=15) never treated with immunosuppressants or biologicals. INTERVENTIONS: All groups were tested at enrolment. Group II was also tested at 12 months, and group III at 1, 3, and 6 months. PRIMARY AND SECONDARY OUTCOME MEASURES: Standard clinical evaluations (Psoriasis Area Severity Index (PASI)), blood samples and two-site ELISA-based measurement of serum adalimumab trough levels, anti-adalimumab antibodies and TNFα. RESULTS: The false-positive rate was 23% for adalimumab detection and 22% for anti-adalimumab antibodies in patients naïve to adalimumab. Spurious positivity for anti-adalimumab antibodies (one-time-point positivity in group III during follow-up) accounted for 33% of the total. The prevalence of anti-drug antibodies was highest (87%) in group I patients. No correlations were found between the presence of anti-adalimumab antibodies or adalimumab levels and changes in PASI scores. CONCLUSIONS: High variability of results, high prevalence of false-positives and lack of association between anti-adalimumab antibodies and TNFα level/PASI score limit this assay's usefulness. Accurate clinical evaluation is key to early identification of treatment failures.

Wnt signaling pathway inhibitors as promising diagnostic serum markers of osteolytic bone metastasis.

Despite the clinical importance of bone metastases, we still know little about their onset and progression and current diagnostic tools lack the sensitivity and specificity required for clear early diagnosis. We therefore need to continue studying the pathogenesis of bone metastatic invasion in order to improve diagnosis. The Wnt pathway has been described as having an important role in bone carcinogenesis and metastatic progression. This study investigated the diagnostic potential of the two main Wnt inhibitors, sclerostin and DKK-1, to improve the detection of osteolytic bone metastases. We measured sclerostin and DKK-1, MMP-2 and MMP-9, the bone resorption marker TRAP5b and the metastatic marker survivin in a control group of healthy patients, in patients with primary tumors and in a group with metastasis. Sclerostin and DKK-1 were clearly high in primary tumor patients and even higher in metastatic patients, compared to controls. The close correlations with metastatic markers and bone resorption markers make sclerostin and DKK-1 promising as new biomarkers in the diagnosis of bone osteolytic metastases.

Plasma endocannabinoid behaviour in total knee and hip arthroplasty.

Endocannabinoids are a class of lipid mediators involved in a wide range of physiological pathways including pain perception, and immunological defences. In particular, the involvement of endocannabinoids in bone metabolism and bone resorption has recently been studied. Moreover, one study on total knee arthroplasty describes the probable role of endocannabinoids in pain perception after surgery. The aim of the present study was to evaluate variations of endocannabinoid concentrations in patients undergoing total hip or total knee arthroplasty before and after surgery. Sera from 23 patients were collected at three different times: before surgery and at two different times during rehabilitation, and endocannabinoids were quantified by HPLC-MS/MS analysis. Mean values of endocannabinoids in presurgical serum samples were: 6.11±0.5 ng/ml for N-palmitoylethanolamide, 1.39±0.08ng/ml for N-stearoylethanolamide, 4.84±0.04 ng/ml for N-oleoylethanolamide, 0.44±0.03ng/ml for N-arachidonoylethanolamide, 0.84±0.05ng/ml for N-linoleoylethanolamide, 0.17±0.01ng/ml for N-α-linolenoylethanolamide. Statistical analysis showed a significant decrease of all the endocannabinoids after surgery, while there were no remarkable differences between total hip and total knee arthroplasties or between genders. Moreover, the results show no significant correlation between endocannabinoid concentrations and C-reactive protein and Erythrocyte sedimentation rate. The present study shows for the first time a specific and univocal behaviour of six endocannabinoids and N-acylethanolamides in orthopaedic surgery, suggesting the endocannabinoid system as a possible pharmacological target for presurgical therapeutics.

Effects of bioactive fatty acid amide derivatives in zebrafish scale model of bone metabolism and disease.

The endocannabinoid system (which includes fatty acid derivatives, receptors, and metabolizing enzymes) is involved in a variety of physiological processes, including bone metabolism in which it regulates the function of osteoblasts and osteoclasts, as well as differentiation of their precursors. The zebrafish (Danio rerio) provides a useful animal model for bone research since zebrafish bones develop rapidly and are anatomically similar to mammalian bones. Putative orthologues and paralogs of endocannabinoid genes have recently been identified in zebrafish, demonstrating the presence of cannabinoid type 1 (CB1) and type 2 (CB2) receptors with affinity to endocannabinoid ligands. To identify therapeutic molecules potentially useful in bone-related diseases, we evaluated the in vivo effects of exposure to long-chain fatty acid amides in adult zebrafish. Using a well-established zebrafish scale model, we found that anandamide and N-linoleoylethanolamine are able to stimulate bone formation by increasing alkaline phosphatase activity in physiological conditions. In addition, they prevent the alteration of bone markers in a prednisolone-induced osteoporosis model in adult zebrafish scales, whereas their esterified forms do not. These data suggest that long-chain fatty acid amides are involved in regulating bone metabolism in zebrafish scales and that the CB2 receptor is a key mediator in this process.

Predictors of renal survival in ANCA-associated vasculitis. Validation of a histopatological classification schema and review of the literature.

OBJECTIVES: In 2010 a histopathological classification of ANCA-associated glomerulonephritis was proposed to predict the outcomes at diagnosis. Our aim was to validate the proposed classification in our cohort of patients and to compare the studies already published. METHODS: The data of 93 patients who underwent kidney biopsy in a single Italian centre within 15 years were retrospectively collected. RESULTS: The 10-year renal and patients' survival were 60% and 81%, respectively. Biopsies were classified as 21% focal, 30% crescentic, 39% mixed and 10% sclerotic. Survival without ESRD at 5 years was 82% in focal, 37% in crescentic, 81% in mixed and 51% in sclerotic group. The Kaplan-Meier analysis highlights that renal survival was not different between sclerotic and crescentic groups (p=0.9) but both had a significantly worse prognosis than focal (p=0.04 and 0.015 respectively) and mixed groups (p=0.05 and 0.03 respectively). Focal and mixed groups had the same renal survival (p=0.7). At multivariate analysis the independent predictors of end-stage renal disease were less than 20% of normal glomeruli at kidney biopsy (p=0.022), high serum creatinine (p=0.009) and arterial hypertension at presentation (p= 0.006). CONCLUSIONS: In our cohort, the proposed histological classification was not predictive of renal prognosis. The focal and the mixed classes had the same prognosis and a significantly better renal outcome than both the crescentic and the sclerotic classes. At multivariate analysis among the histological features only less than 20% of normal glomeruli defines the renal prognosis together with renal function and arterial hypertension at baseline.

Perisurgical and intra-rehabilitative salivary steroid hormone profiles in bicompartmental arthroplasty.

Sex hormones play a role in pain perception, a key variable in evaluating the progression and treatment of osteoarthritis. The aim of this study was to determine the relationship between salivary concentrations of four steroid hormones and functional/clinical outcomes after hip and knee arthroplasty. Saliva samples were collected from 24 otherwise healthy patients with osteoarthritis before surgery, on admission to rehabilitation, and at hospital discharge. Salivary concentrations of testosterone, 17ß-estradiol, dehydroepiandrosterone (DHEA), and cortisol were immunoassayed. Changes in hormone levels were compared with clinical outcomes, as assessed by functional independence measure (FIM®), Barthel Index (BI), and visual analog scale for pain (VAS) scores. Changes in testosterone levels were significantly inversely correlated with VAS (r= -0.53, p=0.043) and FIM® and BI scores in all patients (r= -0.30, p= 0.043, and r= -0.35, p=0.031, respectively). The testosterone to cortisol ratio was inversely correlated with BI scores in all patients (r= -0.30, p=0.040), and in the men (r= -0.55, p=0.005) and the women (r= -0.28, p=0.042) when analyzed separately. Changes in salivary testosterone concentrations closely correlated with clinical outcome measurements for total hip and knee arthroplasty. Clinical outcome after arthroplasty was generally better among the men.