Gut Analysis Toolbox: Automating quantitative analysis of enteric neurons.

The enteric nervous system (ENS) consists of an extensive network of neurons and glial cells embedded within the wall of the gastrointestinal (GI) tract. Alterations in neuronal distribution and function are strongly associated with GI dysfunction. Current methods for assessing neuronal distribution suffer from undersampling, partly due to challenges associated with imaging and analyzing large tissue areas, and operator bias due to manual analysis. We present the Gut Analysis Toolbox (GAT), an image analysis tool designed for characterization of enteric neurons and their neurochemical coding using 2D images of GI wholemount preparations. It is developed in Fiji, has a user-friendly interface and offers rapid and accurate segmentation via custom deep learning (DL) based cell segmentation models developed using StarDist, and a ganglion segmentation model in deepImageJ. We use proximal neighbor-based spatial analysis to reveal differences in cellular distribution across gut regions using a public dataset. In summary, GAT provides an easy-to-use toolbox to streamline routine image analysis tasks in ENS research. GAT enhances throughput allowing unbiased analysis of larger tissue areas, multiple neuronal markers and numerous samples rapidly.

Smoking exposure and Parkinson's disease: A UK Brain Bank pathology-validated case-control study.

INTRODUCTION: Epidemiological studies have consistently shown an inverse association between cigarette smoking and Parkinson's disease. Literature indicates that both current and former smokers have a reduced risk of developing PD compared to non-smokers. If smoking protects against Parkinson's disease risk or, conversely, smoking habit is abated due to the disease itself, according to the reverse causation, is still an unsolved question. METHODS: 118 patients from the UK Brain Bank with an alive clinical diagnosis of Parkinson's disease were enrolled. Post-mortem validation served as the gold standard for diagnosis to divide the population into true positive and false positive groups. Patient charts were reviewed to extract smoking exposure information and statistical analyses were conducted to determine the odds associated with smoking in the two diagnostic groups. RESULTS: Among alive clinically diagnosed patients with Parkinson's disease, 53 % had no smoking exposure. In the True Positive group, 58 % had no smoking exposure, while this proportion was lower in the False Positive group at 46 %. The Odds Ratio for the association between smoking exposure and the two groups was 0.63 (95 % CI: 0.32-1.37). The Chi-square test yielded a p-value of 0.2804. CONCLUSIONS: Our findings emphasize the role of smoking exposure in Parkinson's diagnosis. The results indicate that the observed association is not specific to idiopathic Parkinson's disease but rather a broader phenomenon encompassing various parkinsonian disorders. This suggests a potential common neuroprotective effect of smoking, shared risk factors, or supports the reverse causation hypothesis where parkinsonian symptoms reduce smoking exposure.

Stroke Alters the Function of Enteric Neurons to Impair Smooth Muscle Relaxation and Dysregulates Gut Transit.

BACKGROUND: Gut dysmotility is common after ischemic stroke, but the mechanism underlying this response is unknown. Under homeostasis, gut motility is regulated by the neurons of the enteric nervous system that control contractile/relaxation activity of muscle cells in the gut wall. More recently, studies of gut inflammation revealed interactions of macrophages with enteric neurons are also involved in modulating gut motility. However, whether poststroke gut dysmotility is mediated by direct signaling to the enteric nervous system or indirectly via inflammatory macrophages is unknown. METHODS AND RESULTS: We examined these hypotheses by using a clinically relevant permanent intraluminal midcerebral artery occlusion experimental model of stroke. At 24 hours after stroke, we performed in vivo and ex vivo gut motility assays, flow cytometry, immunofluorescence, and transcriptomic analysis. Stroke-induced gut dysmotility was associated with recruitment of muscularis macrophages into the gastrointestinal tract and redistribution of muscularis macrophages away from myenteric ganglia. The permanent intraluminal midcerebral artery occlusion model caused changes in gene expression in muscularis macrophages consistent with an altered phenotype. While the size of myenteric ganglia after stroke was not altered, myenteric neurons from post-permanent intraluminal midcerebral artery occlusion mice showed a reduction in neuronal nitric oxide synthase expression, and this response was associated with enhanced intestinal smooth muscle contraction ex vivo. Finally, chemical sympathectomy with 6-hydroxydopamine prevented the loss of myenteric neuronal nitric oxide synthase expression and stroke-induced slowed gut transit. CONCLUSIONS: Our findings demonstrate that activation of the sympathetic nervous system after stroke is associated with reduced neuronal nitric oxide synthase expression in myenteric neurons, resulting in impaired smooth muscle relaxation and dysregulation of gut transit.

TRPV4 is expressed by enteric glia and muscularis macrophages of the colon but does not play a prominent role in colonic motility.

Background: Mechanosensation is an important trigger of physiological processes in the gastrointestinal tract. Aberrant responses to mechanical input are associated with digestive disorders, including visceral hypersensitivity. Transient Receptor Potential Vanilloid 4 (TRPV4) is a mechanosensory ion channel with proposed roles in visceral afferent signaling, intestinal inflammation, and gut motility. While TRPV4 is a potential therapeutic target for digestive disease, current mechanistic understanding of how TRPV4 may influence gut function is limited by inconsistent reports of TRPV4 expression and distribution. Methods: In this study we profiled functional expression of TRPV4 using Ca2+ imaging of wholemount preparations of the mouse, monkey, and human intestine in combination with immunofluorescent labeling for established cellular markers. The involvement of TRPV4 in colonic motility was assessed in vitro using videomapping and contraction assays. Results: The TRPV4 agonist GSK1016790A evoked Ca2+ signaling in muscularis macrophages, enteric glia, and endothelial cells. TRPV4 specificity was confirmed using TRPV4 KO mouse tissue or antagonist pre-treatment. Calcium responses were not detected in other cell types required for neuromuscular signaling including enteric neurons, interstitial cells of Cajal, PDGFRα+ cells, and intestinal smooth muscle. TRPV4 activation led to rapid Ca2+ responses by a subpopulation of glial cells, followed by sustained Ca2+ signaling throughout the enteric glial network. Propagation of these waves was suppressed by inhibition of gap junctions or Ca2+ release from intracellular stores. Coordinated glial signaling in response to GSK1016790A was also disrupted in acute TNBS colitis. The involvement of TRPV4 in the initiation and propagation of colonic motility patterns was examined in vitro. Conclusions: We reveal a previously unappreciated role for TRPV4 in the initiation of distension-evoked colonic motility. These observations provide new insights into the functional role of TRPV4 activation in the gut, with important implications for how TRPV4 may influence critical processes including inflammatory signaling and motility.

Levodopa-Induced Dyskinesias in Parkinson's Disease: An Overview on Pathophysiology, Clinical Manifestations, Therapy Management Strategies and Future Directions.

Since its first introduction, levodopa has become the cornerstone for the treatment of Parkinson's disease and remains the leading therapeutic choice for motor control therapy so far. Unfortunately, the subsequent appearance of abnormal involuntary movements, known as dyskinesias, is a frequent drawback. Despite the deep knowledge of this complication, in terms of clinical phenomenology and the temporal relationship during a levodopa regimen, less is clear about the pathophysiological mechanisms underpinning it. As the disease progresses, specific oscillatory activities of both motor cortical and basal ganglia neurons and variation in levodopa metabolism, in terms of the dopamine receptor stimulation pattern and turnover rate, underlie dyskinesia onset. This review aims to provide a global overview on levodopa-induced dyskinesias, focusing on pathophysiology, clinical manifestations, therapy management strategies and future directions.

Identifying the Drivers of Inter-Regional Patients' Mobility: An Analysis on Hospital Beds Endowment.

BACKGROUND: In a Beveridgean decentralized healthcare system, like the Italian one, where regions are responsible for their own health planning and financing, the analysis of patients' mobility appears very interesting as it has economic and social implications. The study aims to analyze both patients' mobility for hospital rehabilitation and if the beds endowment is a driver for these flows; Methods: From 2011 to 2019, admissions data were collected from the Hospital Discharge Cards database of the Italian Ministry of Health, population data from the Italian National Institute of Statistics and data on beds endowment from the Italian Ministry of Health website. To evaluate patients' mobility, we used Gandy's Nomogram, while to assess if beds endowments are mobility drivers, we created two matrices, one with attraction indexes (AI) and one with escape indexes (EI). The beds endowment, for each Italian region, was correlated with AI and EI. Spearman's test was carried out through STATA software; Results: Gandy's Nomogram showed that only some northern regions had good hospital planning for rehabilitation. A statistically significant correlation between beds endowment and AI was found for four regions and with EI for eight regions; Conclusions: Only some northern regions appear able to satisfy the care needs of their residents, with a positive attractions minus escapes epidemiological balance. The beds endowment seems to be a driver of patients' mobility, mainly for escapes. Certainly, the search for mobility drivers needs further investigation given the situation in Molise and Basilicata.

Unlocking the Potential of Stroke Blood Biomarkers: Early Diagnosis, Ischemic vs. Haemorrhagic Differentiation and Haemorrhagic Transformation Risk: A Comprehensive Review.

Stroke, a complex and heterogeneous disease, is a leading cause of morbidity and mortality worldwide. The timely therapeutic intervention significantly impacts patient outcomes, but early stroke diagnosis is challenging due to the lack of specific diagnostic biomarkers. This review critically examines the literature for potential biomarkers that may aid in early diagnosis, differentiation between ischemic and hemorrhagic stroke, and prediction of hemorrhagic transformation in ischemic stroke. After a thorough analysis, four promising biomarkers were identified: Antithrombin III (ATIII), fibrinogen, and ischemia-modified albumin (IMA) for diagnostic purposes; glial fibrillary acidic protein (GFAP), micro RNA 124-3p, and a panel of 11 metabolites for distinguishing between ischemic and hemorrhagic stroke; and matrix metalloproteinase-9 (MMP-9), s100b, and interleukin 33 for predicting hemorrhagic transformation. We propose a biomarker panel integrating these markers, each reflecting different pathophysiological stages of stroke, that could significantly improve stroke patients' early detection and treatment. Despite promising results, further research and validation are needed to demonstrate the clinical utility of this proposed panel for routine stroke treatment.

Quantitative High Density EEG Brain Connectivity Evaluation in Parkinson's Disease: The Phase Locking Value (PLV).

INTRODUCTION: The present study explores brain connectivity in Parkinson's disease (PD) and in age matched healthy controls (HC), using quantitative EEG analysis, at rest and during a motor tasks. We also evaluated the diagnostic performance of the phase locking value (PLV), a measure of functional connectivity, in differentiating PD patients from HCs. METHODS: High-density, 64-channels, EEG data from 26 PD patients and 13 HC were analyzed. EEG signals were recorded at rest and during a motor task. Phase locking value (PLV), as a measure of functional connectivity, was evaluated for each group in a resting state and during a motor task for the following frequency bands: (i) delta: 2-4 Hz; (ii) theta: 5-7 Hz; (iii) alpha: 8-12 Hz; beta: 13-29 Hz; and gamma: 30-60 Hz. The diagnostic performance in PD vs. HC discrimination was evaluated. RESULTS: Results showed no significant differences in PLV connectivity between the two groups during the resting state, but a higher PLV connectivity in the delta band during the motor task, in HC compared to PD. Comparing the resting state versus the motor task for each group, only HCs showed a higher PLV connectivity in the delta band during motor task. A ROC curve analysis for HC vs. PD discrimination, showed an area under the ROC curve (AUC) of 0.75, a sensitivity of 100%, and a negative predictive value (NPV) of 100%. CONCLUSIONS: The present study evaluated the brain connectivity through quantitative EEG analysis in Parkinson's disease versus healthy controls, showing a higher PLV connectivity in the delta band during the motor task, in HC compared to PD. This neurophysiology biomarkers showed the potentiality to be explored in future studies as a potential screening biomarker for PD patients.

Neurons, Macrophages, and Glia: The Role of Intercellular Communication in the Enteric Nervous System.

Neurons of the enteric nervous system (ENS) are the primary controllers of gastrointestinal functions. Although the ENS has been the central focus of research areas such as motility, this has now expanded to include the modulatory roles that non-neuronal cells have on neuronal function. This review discusses how enteric glia (EGC) and resident muscularis macrophages (mMacs) influence ENS communication. It highlights how the understanding of neuroglia interactions has extended beyond EGCs responding to exogenously applied neurotransmitters. Proposed mechanisms for neuron-EGC and glio-glia communication are discussed. The significance of these interactions is evidenced by gut functions that rely on these processes. mMacs are commonly known for their roles as immune cells which sample and respond to changes in the tissue environment. However, a more recent theory suggests that mMacs and enteric neurons are mutually dependent for their maintenance and function. This review summarizes the supportive and contradictory evidence for this theory, including potential mechanisms for mMac-neuron interaction. The need for a more thorough classification scheme to define how the "state" of mMacs relates to neuron loss or impaired function in disease is discussed. Despite the growing literature suggesting EGCs and mMacs have supportive or modulatory roles in ENS communication and gut function, conflicting evidence from different groups suggests more investigation is required. A broader understanding of why enteric neurons may need assistance from EGCs and mMacs in neurotransmission is still missing.

Therapeutic potential of allosteric modulators for the treatment of gastrointestinal motility disorders.

Gastrointestinal motility is tightly regulated by the enteric nervous system (ENS). Disruption of coordinated enteric nervous system activity can result in dysmotility. Pharmacological treatment options for dysmotility include targeting of G protein-coupled receptors (GPCRs) expressed by neurons of the enteric nervous system. Current GPCR-targeting drugs for motility disorders bind to the highly conserved endogenous ligand-binding site and promote indiscriminate activation or inhibition of the target receptor throughout the body. This can be associated with significant side-effect liability and a loss of physiological tone. Allosteric modulators of GPCRs bind to a distinct site from the endogenous ligand, which is typically less conserved across multiple receptor subtypes and can modulate endogenous ligand signalling. Allosteric modulation of GPCRs that are important for enteric nervous system function may provide effective relief from motility disorders while limiting side-effects. This review will focus on how allosteric modulators of GPCRs may influence gastrointestinal motility, using 5-hydroxytryptamine (5-HT), acetylcholine (ACh) and opioid receptors as examples.

From contact coverage to effective coverage of community care for patients with severe mental disorders: A real-world investigation from Italy.

Objectives: To measure the gap between contact and effective coverage of mental healthcare (MHC). Materials and methods: 45,761 newly referred cases of depression, schizophrenia, bipolar disorder, and personality disorder from four Italian regions were included. A variant of the self-controlled case series method was adopted to estimate the incidence rate ratio (IRR) for the relationship between exposure (i.e., use of different types of MHC such as pharmacotherapy, generic contact with the outpatient services, psychosocial intervention, and psychotherapy) and relapse (emergency hospital admissions for mental illness). Results: 11,500 relapses occurred. Relapse risk was reduced during periods covered by (i) psychotherapy for patients with depression (IRR 0.67; 95% CI: 0.49 to 0.91) and bipolar disorder (0.64; 0.29 to 0.99); (ii) psychosocial interventions for those with depression (0.74; 0.56 to 0.98), schizophrenia (0.83; 0.68 to 0.99), and bipolar disorder (0.55; 0.36 to 0.84), (iii) pharmacotherapy for patients with schizophrenia (0.58; 0.49 to 0.69), and bipolar disorder (0.59; 0.44 to 0.78). Coverage with generic care, in absence of psychosocial/psychotherapeutic interventions, did not affect risk of relapse. Conclusion: This study ascertained the gap between contact and effective coverage of MHC and showed that administrative data can usefully contribute to assess the effectiveness of a mental health system.

Inter-Regional Patients' Migration for Hospital Orthopedic Intensive Rehabilitation: The Italian Experience.

BACKGROUND: Following the introduction of administrative federalism in the Italian National Health Service, inter-regional patients' mobility has become increasingly relevant because, in addition to being an indirect index of the quality of care, it has important economic and financial implications. This study aimed to evaluate the fulfillment of the need for hospital orthopedic intensive rehabilitation on site and care-seeking patients' migration to other regions. METHODS: From 2011 to 2019, the data of intensive orthopedic rehabilitation extracts from the Hospital Discharge Cards provided by Italian Ministry of Health were analyzed. We studied the hospital networks of every Italian region (catchment areas). The epidemiological flows of inter-regional mobility were analyzed with Gandy's Nomogram, while the financial flows were analyzed through Attraction Absorption and Escape Production Indexes. RESULTS: Gandy's Nomogram showed that only Piedmont, Lombardy, A.P. of Trento, E. Romagna, Umbria and Abruzzo had good public hospital planning for intensive orthopedic rehabilitation, with a positive balance for all studied periods. Lombardy, E. Romagna, Piedmont, Veneto and Latium have absorbed approximately 70% of all financial flows (about EUR 60.5 million). CONCLUSIONS: Only six regions appear to be able to satisfy the care needs of their residents, with a positive epidemiological and financial balance for all studied periods.

Dystonia Diagnosis: Clinical Neurophysiology and Genetics.

Dystonia diagnosis is based on clinical examination performed by a neurologist with expertise in movement disorders. Clues that indicate the diagnosis of a movement disorder such as dystonia are dystonic movements, dystonic postures, and three additional physical signs (mirror dystonia, overflow dystonia, and geste antagonists/sensory tricks). Despite advances in research, there is no diagnostic test with a high level of accuracy for the dystonia diagnosis. Clinical neurophysiology and genetics might support the clinician in the diagnostic process. Neurophysiology played a role in untangling dystonia pathophysiology, demonstrating characteristic reduction in inhibition of central motor circuits and alterations in the somatosensory system. The neurophysiologic measure with the greatest evidence in identifying patients affected by dystonia is the somatosensory temporal discrimination threshold (STDT). Other parameters need further confirmations and more solid evidence to be considered as support for the dystonia diagnosis. Genetic testing should be guided by characteristics such as age at onset, body distribution, associated features, and coexistence of other movement disorders (parkinsonism, myoclonus, and other hyperkinesia). The aim of the present review is to summarize the state of the art regarding dystonia diagnosis focusing on the role of neurophysiology and genetic testing.

COVID-19 response: effectiveness of weekly rapid risk assessments, Italy.

PROBLEM: After Italy's first national restriction measures in 2020, a robust approach was needed to monitor the emerging epidemic of coronavirus disease 2019 (COVID-19) at subnational level and provide data to inform the strengthening or easing of epidemic control measures. APPROACH: We adapted the European Centre for Disease Prevention and Control rapid risk assessment tool by including quantitative and qualitative indicators from existing national surveillance systems. We defined COVID-19 risk as a combination of the probability of uncontrolled transmission of severe acute respiratory syndrome coronavirus 2 and of an unsustainable impact of COVID-19 cases on hospital services, adjusted in relation to the health system's resilience. The monitoring system was implemented with no additional cost in May 2020. LOCAL SETTING: The infectious diseases surveillance system in Italy uses consistent data collection methods across the country's decentralized regions and autonomous provinces. RELEVANT CHANGES: Weekly risk assessments using this approach were sustainable in monitoring the epidemic at regional level from 4 May 2020 to 24 September 2021. The tool provided reliable assessments of when and where a rapid increase in demand for health-care services would occur if control or mitigation measures were not increased in the following 3 weeks. LESSONS LEARNT: Although the system worked well, framing the risk assessment tool in a legal decree hampered its flexibility, as indicators could not be changed without changing the law. The relative complexity of the tool, the impossibility of real-time validation and its use for the definition of restrictions posed communication challenges.

The quality of mental health care delivered to patients with schizophrenia and related disorders in the Italian mental health system. The QUADIM project: a multi-regional Italian investigation based on healthcare utilisation databases.

AIMS: To evaluate the quality of mental health care delivered to patients with schizophrenia and related disorders taken-in-care by mental health services in four Italian regions (Lombardy, Emilia-Romagna, Lazio, Sicily). METHODS: Thirty-one clinical indicators concerning accessibility, appropriateness, continuity and safety were defined and estimated using healthcare utilisation (HCU) databases, containing data on mental health treatments, hospital admissions, outpatient interventions, lab tests and drug prescriptions. RESULTS: A total of 70 586 prevalent patients with schizophrenia and related disorders treated in 2015 were identified, of whom 1752 were newly taken-in-care by the facilities of regional mental health services. For most patients community care was accessible and moderately intensive. However, care pathways were not implemented based on a structured assessment and only half of the patients received psychosocial treatments. One patient out of ten had access to psychological interventions and psychoeducation. Activities specifically addressed to families involved a third of prevalent patients and less than half of new patients. One patient out of six was admitted to a community residential facility, and one out of ten to a General Hospital Psychiatric Ward (GHPW); higher values were identified in new cases. In general hospitals, few patients had a length of stay (LoS) of more than 30 days, while one-fifth of the admissions were followed by readmission within 30 days of discharge. For two-thirds of patients, continuity of community care was met, and six times out of ten a discharge from a GHPW was followed by an outpatient contact within 2 weeks. For cases newly taken-in-care, the continuity of community care was uncommon, while the readiness of outpatient contacts after discharge was slightly more frequent. Most of the patients received antipsychotic medication, but their adherence to long-term treatment was low. Antipsychotic polytherapy was frequent and the control of metabolic side effects was poor. The variability between regions was high and consistent in all the quality domains. CONCLUSIONS: The Italian mental health system could be improved by increasing the accessibility to psychosocial interventions, improving the quality of care for newly taken-in-care patients, focusing on somatic health and mortality, and reducing regional variability. Clinical indicators demonstrate the strengths and weaknesses of the mental health system in these regions, and, as HCU databases, they could be useful tools in the routine assessment of mental healthcare quality at regional and national levels.

Positive allosteric modulation of endogenous delta opioid receptor signaling in the enteric nervous system is a potential treatment for gastrointestinal motility disorders.

Allosteric modulators (AMs) are molecules that can fine-tune signaling by G protein-coupled receptors (GPCRs). Although they are a promising therapeutic approach for treating a range of disorders, allosteric modulation of GPCRs in the context of the enteric nervous system (ENS) and digestive dysfunction remains largely unexplored. This study examined allosteric modulation of the delta opioid receptor (DOR) in the ENS and assessed the suitability of DOR AMs for the treatment of irritable bowel syndrome (IBS) symptoms using mouse models. The effects of the positive allosteric modulator (PAM) of DOR, BMS-986187, on neurogenic contractions of the mouse colon and on DOR internalization in enteric neurons were quantified. The ability of BMS-986187 to influence colonic motility was assessed both in vitro and in vivo. BMS-986187 displayed DOR-selective PAM-agonist activity and orthosteric agonist probe dependence in the mouse colon. BMS-986187 augmented the inhibitory effects of DOR agonists on neurogenic contractions and enhanced reflex-evoked DOR internalization in myenteric neurons. BMS-986187 significantly increased DOR endocytosis in myenteric neurons in response to the weakly internalizing agonist ARM390. BMS-986187 reduced the generation of complex motor patterns in the isolated intact colon. BMS-986187 reduced fecal output and diarrhea onset in the novel environment stress and castor oil models of IBS symptoms, respectively. DOR PAMs enhance DOR-mediated signaling in the ENS and have potential benefit for the treatment of dysmotility. This study provides proof of concept to support the use of GPCR AMs for the treatment of gastrointestinal motility disorders.NEW & NOTEWORTHY This study assesses the use of positive allosteric modulation as a pharmacological approach to enhance opioid receptor signaling in the enteric nervous system. We demonstrate that selective modulation of endogenous delta opioid receptor signaling can suppress colonic motility without causing constipation. We propose that allosteric modulation of opioid receptor signaling may be a therapeutic strategy to normalize gastrointestinal motility in conditions such as irritable bowel syndrome.

Contributions of bile acids to gastrointestinal physiology as receptor agonists and modifiers of ion channels.

Bile acids (BAs) are known to be important regulators of intestinal motility and epithelial fluid and electrolyte transport. Over the past two decades, significant advances in identifying and characterizing the receptors, transporters, and ion channels targeted by BAs have led to exciting new insights into the molecular mechanisms involved in these processes. Our appreciation of BAs, their receptors, and BA-modulated ion channels as potential targets for the development of new approaches to treat intestinal motility and transport disorders is increasing. In the current review, we aim to summarize recent advances in our knowledge of the different BA receptors and BA-modulated ion channels present in the gastrointestinal system. We discuss how they regulate motility and epithelial transport, their roles in pathogenesis, and their therapeutic potential in a range of gastrointestinal diseases.

Stratification of the risk of developing severe or lethal Covid-19 using a new score from a large Italian population: a population-based cohort study.

OBJECTIVES: To develop a population-based risk stratification model (COVID-19 Vulnerability Score) for predicting severe/fatal clinical manifestations of SARS-CoV-2 infection, using the multiple source information provided by the healthcare utilisation databases of the Italian National Health Service. DESIGN: Retrospective observational cohort study. SETTING: Population-based study using the healthcare utilisation database from five Italian regions. PARTICIPANTS: Beneficiaries of the National Health Service, aged 18-79 years, who had the residentship in the five participating regions. Residents in a nursing home were not included. The model was built from the 7 655 502 residents of Lombardy region. MAIN OUTCOME MEASURE: The score included gender, age and 29 conditions/diseases selected from a list of 61 conditions which independently predicted the primary outcome, that is, severe (intensive care unit admission) or fatal manifestation of COVID-19 experienced during the first epidemic wave (until June 2020). The score performance was validated by applying the model to several validation sets, that is, Lombardy population (second epidemic wave), and the other four Italian regions (entire 2020) for a total of about 15.4 million individuals and 7031 outcomes. Predictive performance was assessed by discrimination (areas under the receiver operating characteristic curve) and calibration (plot of observed vs predicted outcomes). RESULTS: We observed a clear positive trend towards increasing outcome incidence as the score increased. The areas under the receiver operating characteristic curve of the COVID-19 Vulnerability Score ranged from 0.85 to 0.88, which compared favourably with the areas of generic scores such as the Charlson Comorbidity Score (0.60). A remarkable performance of the score on the calibration of observed and predicted outcome probability was also observed. CONCLUSIONS: A score based on data used for public health management accurately predicted the occurrence of severe/fatal manifestations of COVID-19. Use of this score may help health decision-makers to more accurately identify high-risk citizens who need early preventive or treatment interventions.

Cost-effectiveness of the adherence with recommendations for clinical monitoring of patients with diabetes.

BACKGROUND AND AIMS: To validate a set of indicators for monitoring the quality of care of patients with diabetes in 'real-life' practice through its relationship with measurable clinical outcomes and healthcare costs. METHODS AND RESULTS: A population-based cohort study was carried out by including the 20,635 patients, residents in the Lombardy Region (Italy), who in the year 2012 were newly taken-in-care for diabetes. Adherence with clinical recommendations (i.e., controls for glycated haemoglobin, lipid profile, urine albumin excretion and serum creatinine) was recorded during the first year after the patient was taken-in-care, and categorized according whether he/she complied with none or almost none (0 or 1), just some (2) or all or almost all (3 or 4) the recommendations, respectively denoted as poor, intermediate and high adherence. Short- and long-term complications of diabetes, and healthcare cost incurred by the National Health Service, were assessed during follow-up. Compared with patients with poor adherence, those with intermediate and high adherence respectively showed (i) a delay in outcome occurrence of 13 days (95% CI, -2 to 27) and 23 days (9-38), and (ii) a lower healthcare cost of 54 € and 77 €. In average, a gain of 18 Euros and 15 Euros for each day free from diabetic complication by increasing adherence respectively from poor to intermediate and from poor to high were observed. CONCLUSION: Close control of patients with diabetes through regular clinical examinations must be considered the cornerstone of national guidance, national audits, and quality improvement incentive schemes.