Unplanned readmissions within 30 days after discharge: improving quality through easy prediction.

OBJECTIVE: To propose an easy predictive model for the risk of rehospitalization, built from hospital administrative data, in order to prevent repeated admissions and to improve transitional care. DESIGN: Retrospective cohort study. SETTING: Azienda Ospedaliero Universitaria Pisana (Pisa University Hospital). PARTICIPANTS: Patients residing in the territory of the province of Pisa (Tuscany Region) with at least one unplanned hospital admission leading to a medical Diagnosis-Related Group (DRG) in the calendar year 2012. INTERVENTION: We compared two groups of patients: patients coded as 'RA30' (readmitted within 30 days after the previous discharge) and patients coded as 'NRA30' (either admitted only once or readmitted after 30 days since the latest discharge). MAIN OUTCOME MEASURES: The effect of age, sex, length of stay, number of diagnoses, normalized number of admissions and presence of diseases on the probability of rehospitalization within 30 days after discharge was evaluated. RESULTS: The significant variables included in the predictive model were: age, odds ratio (OR) = 1.018, 95% confidence interval (CI) = 1.011-1.026; normalized number of admissions, OR = 1.257, CI = 1.225-1.290; number of diagnoses, OR = 1.306, CI = 1.174-1.452 and presence of cancer diagnosis, OR = 1.479, CI = 1.088-2.011. CONCLUSIONS: The model can be easily applied when discharging patients who have been hospitalized after an access to the Emergency Department to predict the risk of rehospitalization within 30 days. The prediction can be used to activate focused hospital-primary care transitional interventions. The model has to be validated first in order to be implemented in clinical practice.

General medical conditions in 347 bipolar disorder patients: clinical correlates of metabolic and autoimmune-allergic diseases.

BACKGROUND: Patients with bipolar disorder (BD) suffer from greater physical morbidity and mortality than the general population. The aim of the present study is to explore the prevalence and clinical correlates of General Medical Conditions (GMC) in a large consecutive sample of patients with BD. METHOD: The study sample comprised of 347 patients who met DSM-IV-TR criteria for BD I (n=207, 59.7%), BD II or Cyclothymic Disorder (n=140, 40.3). Diagnostic information was collected by means of the Structured Clinical Interview for DSM-IV Axis I Disorders- Clinical Version (SCID-I), and information about personal and family history were collected by the Semi-Structured Interview for Mood Disorder-Revised (SIMD-R). Standardized procedure was used to assess the diagnosis of GMC, which was considered present only if a specific therapy to treat the condition was prescribed by a specialist or a general practitioner. In order to explore possible relationships between physical comorbidity and clinical features of BD, we compared patients with (MD) and without (No-MD) Metabolic Diseases (MD) and patients with (AAD) and without (No-AAD) Autoimmune-Allergic Diseases (AAD). RESULTS: The most commonly reported GMCs were: Headache, Hypercholesterolemia (>200mg/dl), Chronic Constipation, Obesity, Arterial Hypertension (BP >140/90 mmHg), Hypothyroidism, Allergic Rhino-Conjunctivitis, Irritable Bowel Syndrome, Hypertriglyceridemia (>150 mg/dl), Metabolic Syndrome, Hiatus Hernia, Dysmenorrhea, Urticaria, Atopic Dermatitis, Psoriasis, Seborrheic Dermatitis, Diabetes Mellitus, Bronchial Asthma, Cardiac Arrhythmias, Biliary Lithiasis, and COPD. In our sample, MD (n=148, 42.7%) and AAD (n=167, 48.1%) were the most common categories of GMCs. Interestingly, the lifetime prevalence of cancer and neoplastic diseases was very low: 1 patient (.3%) reported Lung Adenocarcinoma and 2 (.6%) patients Bowel Cancer. In the group comparisons, length of pharmacological treatment (OR=1.054; 95% CI=1.030-1.078), age at onset of first major episode (OR=1.043; 95% CI=1.019-1.067), length of the current episode (OR=1.025; 95% CI=1.020-1.533) and absence of lifetime comorbid substance abuse (OR=.373; 95% CI=.141-.989) were statistically associated with the presence of comorbid MD; while only AD-induced hypomania (OR=1.62; 95% CI=1.011-2.597), and cyclothymic temperament (OR=1.051; 95% CI=1.016-1.087) were statistically associated with the presence of comorbid AAD. LIMITATIONS: Possible referral and selection bias; retrospective, non-blind, cross-sectional evaluation. CONCLUSION: MD and AAD were highly represented in our sample, while cancer and neoplastic diseases were uncommon. The clinical correlates of different sub-groups of GMC suggest different interpretations. The presence of MD seems to be correlated with the progression of BD and the chronic medication exposure, while comorbid AAD seems to correlate with a specific clinical subtype of BD, characterized by mood reactivity and temperamental mood instability. If the link with autoimmune-allergic diathesis will be confirmed, it could provide an interesting new paradigm for the study of the "systemic" nature of mood disorders and a promising target for future treatment options.

Study of the binding interaction between fluorinated matrix metalloproteinase inhibitors and Human Serum Albumin.

Fluorinated, arylsulfone-based inhibitors of Matrix Metalloproteinases (MMP) have been used, in the [(18)F]-radiolabelled version, as radiotracers targeted to MMP-2/9 for Positron Emission Tomography (PET). Although they showed acceptable tumour uptake, specificity was rather low. To get further insights into the reason of low specificity, the binding interaction of these compounds with Human Serum Albumin (HSA) has been investigated. (19)F NMR spectroscopy showed that all compounds considered partition between multiple HSA binding sites, being characterized by either slow-exchange kinetics (with Ka in the order of 10(5) M(-1)) and fast-exchange kinetics (with Ka in the order of 10(4) M(-1)). For 2-(2-(4'-(2-fluoroethoxy)biphenyl-4-ylsulfonyl)phenyl)acetic acid (1a) and 2-(2-(4'-(2-fluoroacetamido)biphenyl-4-ylsulfonyl)phenyl)acetic acid (1c), these slow and fast-exchanging binding sites could be mapped to Sudlow's site I and II, respectively. It is shown that high affinity albumin binding constitutes a theoretical limitation for the specificity achievable by MMP-inhibitors as MMP-targeted PET tracers in cancer imaging, because albumin accumulating aspecifically in tumours lowers the binding potential of radiotracers.

Selective arylsulfonamide inhibitors of ADAM-17: hit optimization and activity in ovarian cancer cell models.

Activated leukocyte cell adhesion molecule (ALCAM) is expressed at the surface of epithelial ovarian cancer (EOC) cells and is released in a soluble form (sALCAM) by ADAM-17-mediated shedding. This process is relevant to EOC cell motility and invasiveness, which is reduced by inhibitors of ADAM-17. In addition, ADAM-17 plays a key role in EGFR signaling and thus may represent a useful target in anticancer therapy. Herein we report our hit optimization effort to identify potent and selective ADAM-17 inhibitors, starting with previously identified inhibitor 1. A new series of secondary sulfonamido-based hydroxamates was designed and synthesized. The biological activity of the newly synthesized compounds was tested in vitro on isolated enzymes and human EOC cell lines. The optimization process led to compound 21, which showed an IC50 of 1.9 nM on ADAM-17 with greatly increased selectivity. This compound maintained good inhibitory properties on sALCAM shedding in several in vitro assays.

Synthesis and preliminary evaluation in tumor bearing mice of new (18)F-labeled arylsulfone matrix metalloproteinase inhibitors as tracers for positron emission tomography.

New fluorinated, arylsulfone-based matrix metalloproteinase (MMP) inhibitors containing carboxylate as the zinc binding group were synthesized as radiotracers for positron emission tomography. Inhibitors were characterized by Ki for MMP-2 in the nanomolar range and by a fair selectivity for MMP-2/9/12/13 over MMP-1/3/14. Two of these compounds were obtained in the (18)F-radiolabeled form, with radiochemical purity and yield suitable for preliminary studies in mice xenografted with a human U-87 MG glioblastoma. Target density in xenografts was assessed by Western blot, yielding Bmax/Kd = 14. The biodistribution of the tracer was dominated by liver uptake and hepatobiliary clearance. Tumor uptake of (18)F-labeled MMP inhibitors was about 30% that of [(18)F]fluorodeoxyglucose. Accumulation of radioactivity within the tumor periphery colocalized with MMP-2 activity (evaluated by in situ zimography). However, specific tumor uptake accounted for only 18% of total uptake. The aspecific uptake was ascribed to the high binding affinity between the radiotracer and serum albumin.

Arylsulfonamide inhibitors of aggrecanases as potential therapeutic agents for osteoarthritis: synthesis and biological evaluation.

Aggrecanases, in particular aggrecanase-2 (ADAMTS-5), are considered the principal proteases responsible for aggrecan degradation in osteoarthritis. For this reason, considerable effort has been put on the discovery and development of aggrecanase inhibitors able to slow down or halt the progression of osteoarthritis. We report herein the synthesis and biological evaluation of a series of arylsulfonamido-based hydroxamates as aggrecanase inhibitors. Compound 18 was found to have a nanomolar activity for ADAMTS-5, ADAMTS-4 and MMP-13 and high selectivity over MMP-1 and MMP-14. Furthermore, this compound proved to be effective in blocking ex vivo cartilage degradation without having effect on cell cytotoxicity.

Identification of novel molecular scaffolds for the design of MMP-13 inhibitors: a first round of lead optimization.

Osteoarthritis (OA) is the leading cause of joint pain and disability in middle-aged and elderly patients, and is characterized by progressive loss of articular cartilage. Among the various matrix metalloproteinases (MMPs), MMP-13 is specifically expressed in the cartilage of human OA patients and is not present in normal adult cartilage. Thus, MMP-13-selective inhibitors are promising candidates in osteoarthritis therapy. Recently, we designed an N-isopropoxy-arylsulfonamide-based hydroxamate inhibitor, which showed low nanomolar activity and high selectivity for MMP-13. In parallel to further studies aiming to assess the in vivo activity of our compound, we screened the Life Chemicals database through computational docking to seek for novel scaffolds as zinc-chelating non-hydroxamate inhibitors. Experimental evaluation of 20 selected candidate compounds verified five novel leads with IC(50) in the low µM range. These newly discovered inhibitors are structurally unrelated to the ones known so far and provide useful scaffolds to develop compounds with more desirable properties. Finally, a first round of structure-based optimization on lead 1 was accomplished and led to an increase in potency of more than 5 fold.

Synthesis and biological evaluation in U87MG glioma cells of (ethynylthiophene)sulfonamido-based hydroxamates as matrix metalloproteinase inhibitors.

Matrix metalloproteinases (MMPs) are important factors in gliomas since these enzymes facilitate invasion into the surrounding brain and participate in neovascularization. In particular, the gelatinases (MMP-2 and MMP-9), and more recently MMP-25, have been shown to be highly expressed in gliomas and have been associated with disease progression. Thus, inhibition of these MMPs may represent a promising non-cytotoxic approach to glioma treatment. We report herein the synthesis and biological evaluation of a series of 4-butylphenyl(ethynylthiophene)sulfonamido-based hydroxamates. Among the new compounds tested, a promising derivative, 5a, was identified, which exhibits nanomolar inhibition of MMP-2, MMP-9, and MMP-25, but weak inhibitory activity toward other members of the MMP family. This compound also exhibited anti-invasive activity of U87MG glioblastoma cells at nanomolar concentrations, without affecting cell viability.

Potent arylsulfonamide inhibitors of tumor necrosis factor-alpha converting enzyme able to reduce activated leukocyte cell adhesion molecule shedding in cancer cell models.

Activated leukocyte cell adhesion molecule (ALCAM) plays a relevant role in tumor biology and progression. Our previous studies showed that ALCAM is expressed at the surface of epithelial ovarian cancer (EOC) cells and is released in a soluble form by ADAM-17-mediated shedding. This process is relevant to EOC cell motility and invasiveness, which is reduced by nonspecific inhibitors of ADAM-17. For this reason, ADAM-17 may represent a new useful target in anticancer therapy. Herein, we report the synthesis and biological evaluation of new ADAM-17 inhibitors containing an arylsulfonamidic scaffold. Among the new potential inhibitors, two very promising compounds 17 and 18 were discovered, with a nanomolar activity for ADAM-17 isolated enzyme. These compounds proved to be also the most potent in inhibiting soluble ALCAM release in cancer cells, showing a nanomolar activity on A2774 and SKOV3 cell lines.

Design, synthesis, biological evaluation, and NMR studies of a new series of arylsulfones as selective and potent matrix metalloproteinase-12 inhibitors.

Overexpression of macrophage elastase (MMP-12), a member of the matrix metalloproteinases family, can be linked to tissue remodeling and degradation in some inflammatory processes, such as chronic obstructive pulmonary disease (COPD), emphysema, rheumatoid arthritis (RA), and atherosclerosis. On this basis, MMP-12 can be considered an attractive target for studying selective inhibitors that are useful in the development of new therapies for COPD and other inflammatory diseases. We report herein the design, synthesis, and in vitro evaluation of a new series of compounds, possessing an arylsulfonyl scaffold, for their potential as selective inhibitors of MMP-12. The best compound in the series showed an IC50 value of 0.2 nM, with good selectivity over MMP-1 and MMP-14. A docking study was carried out on this compound in order to investigate its binding interactions with MMP-12, and NMR studies on the complex with the MMP-12 catalytic domain were able to validate the proposed binding mode.

N-O-isopropyl sulfonamido-based hydroxamates: design, synthesis and biological evaluation of selective matrix metalloproteinase-13 inhibitors as potential therapeutic agents for osteoarthritis.

Matrix metalloproteinase-13 (MMP-13) is a key enzyme implicated in the degradation of the extracellular matrix in osteoarthritis (OA). For this reason, MMP-13 synthetic inhibitors are being sought as potential therapeutic agents to prevent cartilage degradation and to halt the progression of OA. Herein, we report the synthesis and in vitro evaluation of a new series of selective MMP-13 inhibitors possessing an arylsulfonamidic scaffold. Among these potential inhibitors, a very promising compound was discovered exhibiting nanomolar activity for MMP-13 and was highly selective for this enzyme compared to MMP-1, -14, and TACE. This compound acted as a slow-binding inhibitor of MMP-13 and was demonstrated to be effective in an in vitro collagen assay and in a model of cartilage degradation. Furthermore, a docking study was conducted for this compound in order to investigate its binding interactions with MMP-13 and the reasons for its selectivity toward MMP-13 versus other MMPs.