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1.
Gastroenterol Hepatol ; 46(1): 69-79, 2023 Jan.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-36179947

RESUMO

Endoscopic retrograde cholangiopancreatography (ERCP) is the technique of choice for the treatment of biliopancreatic pathology. However, fluoroscopic imaging does not always allow an adequate diagnosis. On the other hand, some large stones cannot be removed by the usual methods. In these situations, cholangioscopy has proven to be an essential tool for the diagnosis of biliary strictures and the treatment of large stones. Its role in pancreatic pathology is also increasing. The development of a single-operator, disposable cholangioscope has made it possible to expand the technique to a large number of hospitals that perform ERCP. For this reason, the Spanish Society of Digestive Endoscopy has developed this consensus document on the use of the Spyglass-DS cholangioscope. The document has been prepared by a group of endoscopists with expertise in cholangioscopy, reviewing the scientific evidence on the main current indications for cholangiopancreatoscopy.


Assuntos
Colangiopancreatografia Retrógrada Endoscópica , Colestase , Humanos , Consenso , Colangiopancreatografia Retrógrada Endoscópica/métodos , Endoscopia Gastrointestinal , Pâncreas
2.
J Public Health (Oxf) ; 43(2): 261-269, 2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-33458758

RESUMO

BACKGROUND: Disparities in cross-regional coronavirus disease 2019 (Covid-19) mortality remain poorly understood. The association between pre-epidemic health and epidemic mortality can inform a policy response to future outbreaks. METHOD: We conducted an ecological study of the association between the cumulative deaths attributed to Covid-19 epidemic in the 20 Italian regions and nine determinants of population health derived from a systematic review of the literature. We used a multiple least square regression to predict the cross-regional variation in mortality observed from the onset of the epidemic to 23 September 2020. RESULTS: Four independent variables best explained the cross-regional differences in the number of deaths attributed to Covid-19: the force of infection, population density, number of elderly living in assisted facilities and the standard rate of diabetes. The semi-partial correlation coefficients suggest that the force of infection and the number of elderly residents in nursing homes were the dominant predictors of the number of deaths attributed to Covid-19. Statistical controls and validation confirmed the generalizability of the predictive model. CONCLUSIONS: Our findings indicate that a significant reduction of social contacts in main metropolitan areas and the timely isolation of elderly and diabetic residents could significantly reduce the death toll of the next wave of Covid-19 infection in Italy.


Assuntos
COVID-19 , Idoso , Surtos de Doenças , Humanos , Itália/epidemiologia , Mortalidade , Casas de Saúde , SARS-CoV-2
3.
Phys Chem Chem Phys ; 22(43): 25165-25176, 2020 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-33124623

RESUMO

This work reports the experimental measurements of solvent acidity (SA), basicity (SB), and solvent dipolarity and polarizability (SPP) for water solutions with urea (U) and its molecular derivatives, monomethyl-urea (MU), 1,3-dimethyl-urea (DMU) and tetramethyl-urea (TMU). These solvatochromic parameters are applied to understanding the variation of indexes of refraction and densities and other physico-chemical properties reported for these solutions. These properties are well correlated to the SA, SB, and SPP solvent parameters of these solutions. As a result, from the characterization of the physico-chemical properties, one can infer that urea and its molecular derivatives are mainly modifiers in the structure of liquid water. The solvatochromic parameters indicate the possible existence of different mechanisms in the denaturation process of proteins in these urea/water solutions.


Assuntos
Desnaturação Proteica , Solventes/química , Ureia/química , Água/química , Concentração de Íons de Hidrogênio , Ureia/análogos & derivados
4.
Nucleic Acids Res ; 45(15): 9030-9045, 2017 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-28911117

RESUMO

Mitochondrial endonuclease G from Leishmania infantum (LiEndoG) participates in the degradation of double-stranded DNA (dsDNA) during parasite cell death and is catalytically inactive at a pH of 8.0 or above. The presence, in the primary sequence, of an acidic amino acid-rich insertion exclusive to trypanosomatids and its spatial position in a homology-built model of LiEndoG led us to postulate that this peptide stretch might act as a pH sensor for self-inhibition. We found that a LiEndoG variant lacking residues 145-180 is indeed far more active than its wild-type counterpart at pH values >7.0. In addition, we discovered that (i) LiEndoG exists as a homodimer, (ii) replacement of Ser211 in the active-site SRGH motif with the canonical aspartate from the DRGH motif of other nucleases leads to a catalytically deficient enzyme, (iii) the activity of the S211D variant can be restored upon the concomitant replacement of Ala247 with Arg and (iv) a C-terminal extension is responsible for the observed preferential cleavage of single-stranded DNA (ssDNA) and ssDNA-dsDNA junctions. Taken together, our results support the view that LiEndoG is a multidomain molecular machine whose nuclease activity can be subtly modulated or even abrogated through architectural changes brought about by environmental conditions and interaction with other binding partners.


Assuntos
Sequência de Aminoácidos , DNA de Protozoário/química , DNA de Cadeia Simples/química , Endodesoxirribonucleases/química , Leishmania infantum/enzimologia , Proteínas de Protozoários/química , Deleção de Sequência , Substituição de Aminoácidos , Domínio Catalítico , Clonagem Molecular , Clivagem do DNA , DNA de Protozoário/genética , DNA de Protozoário/metabolismo , DNA de Cadeia Simples/genética , DNA de Cadeia Simples/metabolismo , Endodesoxirribonucleases/genética , Endodesoxirribonucleases/metabolismo , Escherichia coli/genética , Escherichia coli/metabolismo , Expressão Gênica , Concentração de Íons de Hidrogênio , Cinética , Leishmania infantum/química , Modelos Moleculares , Conformação de Ácido Nucleico , Ligação Proteica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Domínios e Motivos de Interação entre Proteínas , Multimerização Proteica , Proteínas de Protozoários/genética , Proteínas de Protozoários/metabolismo , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Relação Estrutura-Atividade , Especificidade por Substrato
5.
Endoscopy ; 46(10): 851-6, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24977398

RESUMO

BACKGROUND AND STUDY AIMS: Meta-analyses suggest that an intravenous bolus or a high dose continuous infusion of somatostatin reduces the incidence of acute pancreatitis after endoscopic retrograde cholangiopancreatography (ERCP). Clinical guidelines, however, do not recommend this prophylaxis. The aim of this randomized, double-blind clinical trial was to evaluate the effect of somatostatin on the incidence of post-ERCP pancreatitis. PATIENTS AND METHODS: Patients undergoing ERCP at a single center were randomized to either intravenous bolus of somatostatin followed by a short (4-hour) continuous infusion, or to a similar placebo regimen. The primary outcome was post-ERCP pancreatitis, defined as abdominal pain with an amylase level at least three times higher than the upper limit of normality 24 hours after the ERCP and requiring admission for at least 2 days. RESULTS: A total of 510 patients were enrolled (255 patients per group) and all completed follow-up. The main indications for ERCP were choledocholithiasis (62 %), and biliary malignant stricture (31 %). Post-ERCP pancreatitis occurred in 19 patients (7.5 %) in the somatostatin group and 17 patients (6.7 %) in the placebo group (relative risk [RR] 1.12, 95 % confidence interval [95 %CI] 0.59 - 2.1; P = 0.73). The number of cases of moderate or severe acute pancreatitis was similar in the somatostatin (2.4 %) and the placebo (3.5 %) groups (RR 0.67, 95 %CI 0.24 - 1.85, P = 0.43). No side effects were observed related to the use of somatostatin. CONCLUSIONS: Administration of an intravenous bolus of somatostatin followed by a short continuous infusion does not reduce the incidence of post-ERCP pancreatitis. Clinical Trials.gov number: NCT01060826.


Assuntos
Colangiopancreatografia Retrógrada Endoscópica/efeitos adversos , Hormônios/uso terapêutico , Pancreatite/prevenção & controle , Somatostatina/uso terapêutico , Dor Abdominal/etiologia , Idoso , Idoso de 80 Anos ou mais , Método Duplo-Cego , Feminino , Humanos , Hiperamilassemia/etiologia , Análise de Intenção de Tratamento , Masculino , Pessoa de Meia-Idade , Pancreatite/sangue , Pancreatite/etiologia , Índice de Gravidade de Doença
6.
Br J Clin Pharmacol ; 77(6): 986-97, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24134181

RESUMO

AIMS: To evaluate the pharmacokinetics and pharmacodynamics following a single dose of liposomal mifamurtide (L-MTP-PE, MEPACT(®)) in adult subjects with mild (calculated creatinine clearance [CLcr ] of 50-80 ml min(-1)) or moderate (CLcr 30-50 ml min(-1)) renal impairment in comparison with age-, weight- and gender-matched healthy subjects with normal renal function (CLcr >80 ml min(-1)). METHODS: Subjects received a 4 mg dose of liposomal mifamurtide via 1 h intravenous infusion. Blood samples were collected over 72 h for analysis of plasma pharmacokinetics of total and non-liposome-associated (free) mifamurtide and assessment of pharmacodynamics (changes in serum interleukin-6 [IL-6], tumour necrosis factor-α [TNF-α], C-reactive protein [CRP]). RESULTS: Thirty-three subjects were enrolled: nine with mild renal impairment, eight with moderate renal impairment and 16 healthy subjects. Geometric mean (%CV) AUCinf for total mifamurtide was 89.5 (58.1), 94.8 (27.8), 85.1 (29.0), 95.4 (18.1) nM h in the mild renal impairment, mild-matched healthy subject, moderate renal impairment and moderate-matched healthy subject groups, respectively. Mifamurtide clearance was not correlated with CLcr, estimated glomerular filtration rate or iohexol clearance (all r(2) < 0.01). AUCinf of free mifamurtide was similar across the renal function groups. There were no readily apparent differences in serum pharmacodynamic effect parameters (baseline-adjusted AUEClast for IL-6 and TNF-α and Emax for CRP) between the renal function groups. No subjects reported grade ≥3 or serious adverse events. CONCLUSIONS: Mild or moderate renal impairment does not alter the clinical pharmacokinetics or pharmacodynamics of mifamurtide. No dose modifications appear necessary for these patients based on clinical pharmacologic considerations.


Assuntos
Acetilmuramil-Alanil-Isoglutamina/análogos & derivados , Adjuvantes Imunológicos/farmacocinética , Fosfatidiletanolaminas/farmacocinética , Insuficiência Renal/metabolismo , Acetilmuramil-Alanil-Isoglutamina/administração & dosagem , Acetilmuramil-Alanil-Isoglutamina/farmacocinética , Adulto , Idoso , Proteína C-Reativa/análise , Feminino , Humanos , Interleucina-6/sangue , Lipossomos , Masculino , Pessoa de Meia-Idade , Fosfatidiletanolaminas/administração & dosagem , Fator de Necrose Tumoral alfa/sangue
7.
Br J Clin Pharmacol ; 77(6): 998-1010, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24134216

RESUMO

AIMS: To evaluate the pharmacokinetics and pharmacodynamics after a single dose of liposomal mifamurtide (liposomal muramyl tripeptide phospatidyl ethanolamine; MEPACT(®)) in adult subjects with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment in comparison with age-, weight- and sex-matched healthy subjects with normal hepatic function. METHODS: Subjects received a 4 mg dose of liposomal mifamurtide via 1 h intravenous infusion. Blood samples were collected over 72 h for pharmacokinetic and pharmacodynamic assessments (changes in serum interleukin-6, tumour necrosis factor-α and C-reactive protein). RESULTS: Thirty-seven subjects were enrolled: nine with mild hepatic impairment, eight with moderate hepatic impairment and 20 matched healthy subjects. Geometric least-square mean ratios of total mifamurtide AUCinf for the mild hepatic impairment and moderate hepatic impairment groups vs. matched healthy subjects were 105% (90% confidence interval, 83.6-132%) and 119% (90% confidence interval, 94.1-151%), respectively, which are below the protocol-specified threshold (150%) to require development of dose-modification recommendations. Pharmacodynamic parameters for changes in serum interleukin-6 and tumour necrosis factor-α concentrations were generally similar across hepatic function groups. Mifamurtide-induced increases in serum C-reactive protein were attenuated in the moderate hepatic impairment group, consistent with the liver being the major organ of C-reactive protein synthesis. No grade ≥3 adverse events were seen in subjects administered mifamurtide (4 mg). CONCLUSIONS: These results support the conclusion that mild or moderate hepatic impairment does not produce clinically meaningful effects on the clinical pharmacokinetics or pharmacodynamics of mifamurtide; no dose modifications are needed in these special patient populations based on clinical pharmacological considerations.


Assuntos
Acetilmuramil-Alanil-Isoglutamina/análogos & derivados , Adjuvantes Imunológicos/farmacocinética , Insuficiência Hepática/metabolismo , Fosfatidiletanolaminas/farmacocinética , Acetilmuramil-Alanil-Isoglutamina/efeitos adversos , Acetilmuramil-Alanil-Isoglutamina/farmacocinética , Acetilmuramil-Alanil-Isoglutamina/farmacologia , Adulto , Área Sob a Curva , Proteína C-Reativa/análise , Feminino , Humanos , Interleucina-6/sangue , Lipossomos , Masculino , Pessoa de Meia-Idade , Fosfatidiletanolaminas/efeitos adversos , Fosfatidiletanolaminas/farmacologia , Fator de Necrose Tumoral alfa/sangue
8.
Front Public Health ; 12: 1345119, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38694983

RESUMO

Objectives: Amidst the second wave of the COVID-19 pandemic, Italian policymakers mandated to exhibit evidence of vaccination or immunity (the Green Pass) as a condition to access retail premises and public offices. This study aims to offer evidence, in a quasi-experimental setting, suggesting that an unintended consequence of this policy was the emergence of moral hazard. Methods: Google visit duration data measured the time customers typically spend on retail premises or public offices. A pairwise comparison of median visit time per premise was performed at a six-week interval before and after the introduction of the Green Pass. Results: This study is the first to provide evidence of "ex-post" moral hazard associated with introducing a domestic Green Pass policy. The median visiting time on premises that required digital immunity control significantly increased after introducing the domestic Green Pass policy, contrary to other public premises where access remained free of limitations. The increase in median visit time in premises with faster customer turnaround, such as coffee shops (+49%) and fast-food restaurants (+45%), was lower than the increase observed for fine-dining restaurants (+74%) and pizzerias (+163%). No significant increase in median visit time was observed in premises where the Green Pass was not required, such as food supermarkets, retail non-food shops, post offices, banks, pharmacies, and gas stations. Conclusion: The evidence of moral hazard highlights the critical issue of unintended consequences stemming from public health policies. This discovery is pivotal for policymakers, indicating that unforeseen behavioral adjustments could offset the intended benefits despite the intent to reduce risk through measures like the Green Pass.


Assuntos
COVID-19 , Humanos , Itália/epidemiologia , SARS-CoV-2 , Pandemias , Restaurantes , Política de Saúde , Princípios Morais , Vacinação/estatística & dados numéricos
9.
Br J Clin Pharmacol ; 75(2): 381-91, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22803642

RESUMO

AIMS: Two randomized, double-blind, placebo-controlled studies were performed to characterize the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of the investigational metastin analogue, TAK-683, in healthy men. METHODS: We first investigated a single subcutaneous (s.c.) dose of TAK-683 (0.01-2.0 mg) in 60 subjects (TAK-683, n = 42; placebo, n = 18). We then assessed a single s.c. bolus of 0.03-1.0 mg TAK-683 on day 1, followed by a 0.01-2.0 mg day(-1) continuous infusion on days 2-13, to simulate a depot formulation, in 30 subjects (TAK-683, n = 25; placebo, n = 5) for 14 days. RESULTS: TAK-683 was well tolerated up to a dose of 2.0 mg day(-1) by continuous s.c. infusion for 14 days. Adverse events were similar between TAK-683 and placebo subjects at all dose levels. TAK-683 plasma concentrations generally increased in proportion to dose with single and continuous dosing, with steady-state concentrations achieved by day 2 of continuous dosing. TAK-683 at 2.0 mg day(-1) suppressed testosterone below castration level (<50 ng dl(-1)) in four of five subjects by day 7 of continuous dosing. Luteinizing hormone and follicle stimulating hormone concentrations were suppressed with TAK-683 continuous dosing compared with placebo by up to 70 and 43%, respectively, but this was not consistently dose-dependent. CONCLUSIONS: In healthy men, s.c. administration of TAK-683 was well tolerated at all dose levels. The PK profile of TAK-683 was favourable, and TAK-683 suppressed testosterone profoundly during continuous dosing. Further investigation of metastin analogues is warranted for the treatment of castration-resistant prostate cancer.


Assuntos
Antineoplásicos , Kisspeptinas , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Relação Dose-Resposta a Droga , Método Duplo-Cego , Humanos , Injeções Subcutâneas , Kisspeptinas/efeitos adversos , Kisspeptinas/química , Kisspeptinas/farmacocinética , Kisspeptinas/farmacologia , Masculino , Pessoa de Meia-Idade , Testosterona/sangue
10.
Eur J Clin Pharmacol ; 68(10): 1347-55, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22460239

RESUMO

PURPOSE: This study evaluated the pharmacokinetics (PK), pharmacodynamics (PD), safety/tolerability, and cardiac safety of liposomal muramyl tripeptide phosphatidyl-ethanolamine [mifamurtide (L-MTP-PE)] in healthy adults. METHODS: L-MTP-PE 4 mg was administered intravenously over 30 min. Study participants were monitored from 24 h preinfusion until 72 h postinfusion. Blood samples were drawn over 0-72 h postdose to determine serum MTP-PE, interleukin (IL)-6, tumor necrosis factor (TNF)-α, and C-reactive protein (CRP) concentrations. Electrocardiograpic (ECG) data were collected via continuous Holter monitoring beginning 24 h predose through 24 h postdose. Changes from time-matched pretreatment baseline QTc and associated two-sided 90 % confidence intervals were calculated. RESULTS: Twenty-one participants received L-MTP-PE. Total serum MTP-PE declined rapidly with a terminal half-life of 2.05 ± 0.40 h. PK variability was low, with <30 % coefficient of variation in systemic exposure. Serum concentrations of IL-6, TNF-α, and CRP increased following L-MTP-PE infusion. Maximum observed increases in IL-6 and TNF-α occurred at 4 and 2 h, respectively, returning toward baseline by 8 h postdose. L-MTP-PE was generally well tolerated, with no adverse events greater than grade 3. Headache, chills, tachycardia, nausea, and pyrexia were the most frequent adverse events. L-MTP-PE infusion resulted in an increased heart rate without readily apparent QTc prolongation. CONCLUSIONS: MTP-PE PK following L-MTP-PE administration were characterized by a short serum half-life and low variability. Increases in IL-6, TNF-α, and CRP and the safety profile were consistent with the immunomodulatory mechanism of action. No clinically significant effect of L-MTP-PE on cardiovascular repolarization was observed based on analysis of ECG QTc intervals.


Assuntos
Acetilmuramil-Alanil-Isoglutamina/análogos & derivados , Coração/efeitos dos fármacos , Fosfatidiletanolaminas/administração & dosagem , Fosfatidiletanolaminas/farmacocinética , Acetilmuramil-Alanil-Isoglutamina/administração & dosagem , Acetilmuramil-Alanil-Isoglutamina/efeitos adversos , Acetilmuramil-Alanil-Isoglutamina/farmacocinética , Adulto , Área Sob a Curva , Proteína C-Reativa/metabolismo , Eletrocardiografia/métodos , Feminino , Coração/fisiologia , Humanos , Interleucina-6/sangue , Interleucina-6/metabolismo , Lipossomos/administração & dosagem , Masculino , Pessoa de Meia-Idade , Fosfatidiletanolaminas/efeitos adversos , Estudos Prospectivos , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/metabolismo , Adulto Jovem
11.
Surg Endosc ; 26(1): 222-9, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21858574

RESUMO

BACKGROUND: Endoscopic biliary stenting is a well-established palliative treatment in patients with unresectable malignant biliary strictures. Obstruction of uncovered self-expanding metal stent (SEMS) due to tumor ingrowth is the most frequent complication. Partially covered SEMS might increase stent patency but could favor complications related to stent covering, such as pancreatitis, cholecystitis, and migration. The aim of this study was to evaluate the efficacy and safety of partially covered SEMS in patients with an unresectable malignant biliary stricture. METHODS: Patients with malignant extrahepatic biliary obstruction treated endoscopically with partially covered SEMS were included in this multicenter, prospective, nonrandomized study. RESULTS: One hundred ninety-nine patients were endoscopically treated with partially covered SEMS in 32 Spanish hospitals. Clinical success after deep cannulation was 96%. Early complications occurred in 4% (3 pancreatitis, 2 cholangitis, 1 hemorrhage, 1 perforation, and 1 cholecystitis). Late complications occurred in 19.5% (18 obstructions, 10 migrations, 6 cholangitis without obstruction, 3 acute cholecystitis, and 2 pancreatitis), with no tumor ingrowth in any case. Median stent patency was 138.9 ± 112.6 days. One-year actuarial probability of stent patency was 70% and that of nonmigration was 86%. Multivariate analysis showed adjuvant radio- or chemotherapy as the only independent predictive factor of stent patency and previous insertion of a biliary stent was the only predictive factor of migration. CONCLUSIONS: The partially covered SEMS was easily inserted, had a high clinical success rate, and prevented tumor ingrowth. The incidence of possible complications related to stent coverage, namely, migration, pancreatitis, and cholecystitis, was lower than in previously published series.


Assuntos
Neoplasias do Sistema Biliar/cirurgia , Colestase Extra-Hepática/cirurgia , Stents , Idoso , Idoso de 80 Anos ou mais , Neoplasias do Sistema Biliar/complicações , Neoplasias do Sistema Biliar/mortalidade , Colangiopancreatografia Retrógrada Endoscópica , Colestase Extra-Hepática/etiologia , Colestase Extra-Hepática/mortalidade , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Cuidados Paliativos/métodos , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/mortalidade , Estudos Prospectivos , Falha de Prótese/efeitos adversos
12.
Front Public Health ; 10: 872698, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35865252

RESUMO

The Delta variant became dominant during the second wave of the Covid-19 pandemic due to its competitive advantage, the ability to reduce close contact duration from minutes to seconds, and, consequently, increase the risk of exposure to COVID-19. We used game theory to model the most effective public health response to this new threat. We compared the absolute and relative risk of exposure to COVID-19 before and after the emergence of the Delta variant. The absolute risk of exposure was defined as the product of crowding (people within a six feet distance) and visit duration. Our epidemiological investigation used aggregated and anonymized mobility data from Google Maps to estimate the visit duration for 808 premises in the metropolitan area of Genoa, Italy, in June 2021. The relative risk of exposure was obtained by dividing the risk of exposure of each activity by the lowest value (gas stations = 1). The median absolute risk of exposure to COVID-19 increased by sixty-fold in the first semester of 2021, while the relative risk did not significantly differ from the risk of exposure to the ancestral form of Covid-19 (5.9 in 2021 vs. 2.5 in 2021). The Delta variant represents an evolution of the game against COVID-19, but it is not a game-changer. The best response is to commit to our original strategy based on population-wide vaccination and social distancing. Unilateral deviations from the dominant strategy could offer COVID-19 a fighting chance against humanity.


Assuntos
COVID-19 , COVID-19/epidemiologia , Humanos , Pandemias , Distanciamento Físico , SARS-CoV-2
13.
Artigo em Inglês | MEDLINE | ID: mdl-33925428

RESUMO

COVID-19 spreads mainly among people who are in close contact. Policymakers mostly resorted to normative measures to limit close contacts and impose social distancing. Our study aimed to estimate the risk of exposure to COVID-19 by location and activity in crowded metropolitan areas. The risk of exposure to COVID-19 was defined as the product of crowding (people within a six feet distance) and exposure duration (fraction of 15 min). Our epidemiological investigation used aggregated and anonymized mobility data from Google Maps to estimate the visit duration. We collected visit duration data for 561 premises in the metropolitan area of Genoa, Italy from October 2020 to January 2021. The sample was then clustered into 14 everyday activities, from grocery shopping to the post office. Crowding data by activity were obtained from pre-existing building norms and new government measures to contain the pandemic. The study found significant variance in the risk of exposure to COVID-19 among activities and, for the same activity, among locations. The empirical determination of the risk of exposure to COVID-19 can inform national and local public health policies to contain the pandemic's diffusion. Its simple numerical form can help policymakers effectively communicate difficult decisions affecting our daily lives. Most importantly, risk data by location can help us rethink our daily routine and make informed, responsible choices when we decide to go out.


Assuntos
COVID-19 , Humanos , Itália/epidemiologia , Pandemias , Distanciamento Físico , SARS-CoV-2
14.
Korean J Anesthesiol ; 74(1): 45-52, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-32434292

RESUMO

BACKGROUND: Cytoreductive surgery was developed as a treatment for peritoneal carcinomatosis. However, this surgery is associated with important complications. The present study aimed to assess the relationship between lactacidemia and the rate of associated complications during the immediate postoperative period in the intensive care unit (ICU) in patients undergoing cytoreductive surgery. METHODS: This was a retrospective observational study. A total of 57 patients underwent cytoreductive surgery. All patients were admitted to the ICU immediately after the surgery. Data on lactic acid levels at the time of admission and discharge from the ICU were collected. Postsurgical complications that occurred during the ICU stay were recorded according to failure-to-rescue analysis and their severity stratified according to the Clavien-Dindo classification. RESULTS: The lactic acid levels at admission to the ICU were significantly higher in patients who developed complications, with an almost tripled unadjusted relative risk (2.9, 95% CI: 1.6, 5.3), than in those who did not develop complications for the lactacidemia threshold established in the cumulative sum curve graphs. After adjustment for confounding effects, the relative risk became even higher (3.1, 95% CI: 1.8, 3.6). Lactic acid levels were still significantly higher in this group at the time of discharge from the ICU. CONCLUSIONS: Serum lactate level is a risk factor for postoperative complications in patients undergoing cytoreductive surgery for peritoneal carcinomatosis. This study suggests that the risk of developing severe complications almost triples with a lactic acid level of 2.5 mmol/L or higher at the time of admission in the ICU.


Assuntos
Neoplasias Peritoneais , Procedimentos Cirúrgicos de Citorredução , Humanos , Unidades de Terapia Intensiva , Neoplasias Peritoneais/epidemiologia , Neoplasias Peritoneais/cirurgia , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Estudos Retrospectivos
15.
Oncologist ; 15(9): 924-34, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20736298

RESUMO

OBJECTIVES: A planned interim analysis of study EGF100151 prompted early termination of enrollment based on a longer time to progression with lapatinib and capecitabine than with capecitabine alone in patients with human epidermal growth factor receptor (HER)-2(+) previously treated advanced breast cancer or metastatic breast cancer (MBC). Here, we report final analyses of overall survival. PATIENTS AND METHODS: Women with HER-2(+) MBC who progressed after regimens that included, but were not limited to, anthracyclines, taxanes, and trastuzumab, were randomized to lapatinib (1,250 mg/day) plus capecitabine (2,000 mg/m(2)) or capecitabine monotherapy (2,500 mg/m(2)) on days 1-14 of a 21-day cycle. RESULTS: At enrollment termination, 399 patients were randomized, and nine were being screened and were offered combination treatment. In total, 207 and 201 patients were enrolled to combination therapy and monotherapy, respectively. Thirty-six patients receiving monotherapy crossed over to combination therapy following enrollment termination. The median overall survival times were 75.0 weeks for the combination arm and 64.7 weeks for the monotherapy arm (hazard ratio [HR], 0.87; 95% confidence interval [CI], 0.71-1.08; p = .210). A Cox regression analysis considering crossover as a time-dependent covariate suggested a 20% lower risk for death for patients treated with combination therapy (HR, 0.80; 95% CI, 0.64-0.99; p = .043). The low incidence of serious adverse events was consistent with previously reported rates. CONCLUSIONS: Although premature enrollment termination and subsequent crossover resulted in insufficient power to detect differences in overall survival, exploratory analyses demonstrate a trend toward a survival advantage with lapatinib plus capecitabine. These data continue to support the efficacy of lapatinib in patients with HER-2(+) MBC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Receptor ErbB-2/análise , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/química , Neoplasias da Mama/mortalidade , Capecitabina , Estudos Cross-Over , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Desoxicitidina/análogos & derivados , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Fluoruracila/análogos & derivados , Humanos , Lapatinib , Fígado/efeitos dos fármacos , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Quinazolinas/administração & dosagem , Quinazolinas/efeitos adversos , Função Ventricular Esquerda/efeitos dos fármacos
16.
Clin Cancer Res ; 15(10): 3530-9, 2009 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-19417026

RESUMO

PURPOSE: Mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP-1) dephosphorylates mitogen-activated protein kinase [extracellular signal-regulated kinase (ERK), c-Jun NH(2)-terminal kinase (JNK), and p38], mediates breast cancer chemoresistance, and is repressible by doxorubicin in breast cancer cells. We aimed to characterize doxorubicin effects on MKP-1 and phospho-MAPKs in human breast cancers and to further study the clinical relevance of MKP-1 expression in this disease. EXPERIMENTAL DESIGN: Doxorubicin effects on MKP-1, phospho-ERK1/2 (p-ERK1/2), phospho-JNK (p-JNK), and phospho-p38 were assayed in a panel of human breast cancer cells by Western blot and in human breast cancer were assayed ex vivo by immunohistochemistry (n = 50). MKP-1 expression was also assayed in a range of normal to malignant breast lesions (n = 30) and in a series of patients (n = 96) with breast cancer and clinical follow-up. RESULTS: MKP-1 was expressed at low levels in normal breast and in usual ductal hyperplasia and at high levels in in situ carcinoma. MKP-1 was overexpressed in approximately 50% of infiltrating breast carcinomas. Similar to what was observed in breast cancer cell lines, ex vivo exposure of breast tumors to doxorubicin down-regulated MKP-1, and up-regulated p-ERK1/2 and p-JNK, in the majority of cases. However, in a proportion of tumors overexpressing MKP-1, doxorubicin did not significantly affect MKP-1 or phospho-MAPKs. With regard to patient outcome, MKP-1 overexpression was an adverse prognostic factor for relapse both by univariate (P < 0.001) and multivariate analysis (P = 0.002). CONCLUSIONS: MKP-1 is overexpressed during the malignant transformation of the breast and independently predicts poor prognosis. Furthermore, MKP-1 is repressed by doxorubicin in many human breast cancers.


Assuntos
Neoplasias da Mama/patologia , Doxorrubicina/farmacologia , Fosfatase 1 de Especificidade Dupla/metabolismo , Antibióticos Antineoplásicos/farmacologia , Western Blotting , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Análise por Conglomerados , Fosfatase 1 de Especificidade Dupla/genética , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Imuno-Histoquímica , Técnicas In Vitro , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Estimativa de Kaplan-Meier , Recidiva Local de Neoplasia , Fosforilação/efeitos dos fármacos , Valor Preditivo dos Testes , Prognóstico , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
17.
Clin Cancer Res ; 15(4): 1452-9, 2009 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-19228746

RESUMO

PURPOSE: Brain metastases develop in one third of patients with advanced HER2+ breast cancer. Effective therapy for patients with central nervous system (CNS) progression after cranial radiation is extremely limited and represents a major clinical challenge. Lapatinib, an epidermal growth factor receptor/HER2 inhibitor, was associated with regressions of CNS lesions in a small phase 2 trial. The current study was done to further evaluate the CNS activity of lapatinib. The study was later amended to allow patients who progressed on lapatinib the option of receiving lapatinib plus capecitabine. EXPERIMENTAL DESIGN: Eligible patients had HER2+ breast cancer, progressive brain metastases, prior trastuzumab, and cranial radiotherapy. The primary end point was CNS objective response, defined as >or=50% volumetric reduction of CNS lesion(s) in the absence of increasing steroid use, progressive neurologic signs and symptoms, or progressive extra-CNS disease. RESULTS: Two-hundred and forty-two patients entered the study. CNS objective responses to lapatinib were observed in 6% of patients. In an exploratory analysis, 21% of patients experienced a >or=20% volumetric reduction in their CNS lesions. An association was observed between volumetric reduction and improvement in progression-free survival and neurologic signs and symptoms. Of the 50 evaluable patients who entered the lapatinib plus capecitabine extension, 20% experienced a CNS objective response and 40% experienced a >or=20% volumetric reduction in their CNS lesions. CONCLUSIONS: This study confirms the modest CNS antitumor activity of lapatinib. Additional responses were observed with the combination of lapatinib and capecitabine. Further studies of lapatinib-based regimens for CNS metastases from HER2+ breast cancer are warranted.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/secundário , Neoplasias da Mama/patologia , Inibidores de Proteínas Quinases/uso terapêutico , Quinazolinas/uso terapêutico , Receptor ErbB-2/análise , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/mortalidade , Capecitabina , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/análogos & derivados , Humanos , Lapatinib , Pessoa de Meia-Idade , Estudos Prospectivos , Quinazolinas/administração & dosagem , Quinazolinas/efeitos adversos , Receptor ErbB-2/antagonistas & inibidores
18.
N Engl J Med ; 355(26): 2733-43, 2006 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-17192538

RESUMO

BACKGROUND: Lapatinib, a tyrosine kinase inhibitor of human epidermal growth factor receptor type 2 (HER2, also referred to as HER2/neu) and epidermal growth factor receptor (EGFR), is active in combination with capecitabine in women with HER2-positive metastatic breast cancer that has progressed after trastuzumab-based therapy. In this trial, we compared lapatinib plus capecitabine with capecitabine alone in such patients. METHODS: Women with HER2-positive, locally advanced or metastatic breast cancer that had progressed after treatment with regimens that included an anthracycline, a taxane, and trastuzumab were randomly assigned to receive either combination therapy (lapatinib at a dose of 1250 mg per day continuously plus capecitabine at a dose of 2000 mg per square meter of body-surface area on days 1 through 14 of a 21-day cycle) or monotherapy (capecitabine alone at a dose of 2500 mg per square meter on days 1 through 14 of a 21-day cycle). The primary end point was time to progression, based on an evaluation by independent reviewers under blinded conditions. RESULTS: The interim analysis of time to progression met specified criteria for early reporting on the basis of superiority in the combination-therapy group. The hazard ratio for the independently assessed time to progression was 0.49 (95% confidence interval, 0.34 to 0.71; P<0.001), with 49 events in the combination-therapy group and 72 events in the monotherapy group. The median time to progression was 8.4 months in the combination-therapy group as compared with 4.4 months in the monotherapy group. This improvement was achieved without an increase in serious toxic effects or symptomatic cardiac events. CONCLUSIONS: Lapatinib plus capecitabine is superior to capecitabine alone in women with HER2-positive advanced breast cancer that has progressed after treatment with regimens that included an anthracycline, a taxane, and trastuzumab. (ClinicalTrials.gov number, NCT00078572 [ClinicalTrials.gov].).


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Desoxicitidina/análogos & derivados , Fluoruracila/análogos & derivados , Inibidores de Proteínas Quinases/uso terapêutico , Quinazolinas/uso terapêutico , Receptor ErbB-2/antagonistas & inibidores , Adulto , Idoso , Idoso de 80 Anos ou mais , Antimetabólitos Antineoplásicos/efeitos adversos , Antimetabólitos Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/química , Neoplasias da Mama/mortalidade , Capecitabina , Desoxicitidina/efeitos adversos , Desoxicitidina/uso terapêutico , Progressão da Doença , Feminino , Fluoruracila/efeitos adversos , Fluoruracila/uso terapêutico , Cardiopatias/induzido quimicamente , Humanos , Lapatinib , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Inibidores de Proteínas Quinases/efeitos adversos , Quinazolinas/efeitos adversos , Receptor ErbB-2/análise , Análise de Sobrevida
19.
Clin Cancer Res ; 14(23): 7861-70, 2008 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-19047115

RESUMO

PURPOSE: Biomarkers from two randomized phase III trials were analyzed to optimize selection of patients for lapatinib therapy. EXPERIMENTAL DESIGN: In available breast cancer tissue from EGF30001 (paclitaxel +/- lapatinib in HER-2-negative/unknown metastatic breast cancer, n = 579) and EGF100151 (capecitabine +/- lapatinib in HER-2-positive metastatic breast cancer, n = 399), HER-2 gene amplification by fluorescence in situ hybridization (FISH), HER-2 mRNA by reverse transcription-PCR (RT-PCR), HER-2 protein expression by HercepTest immunohistochemistry (IHC), epidermal growth factor receptor (EGFR) mRNA level by RT-PCR, and EGFR protein by IHC were analyzed and compared with clinical outcome. HER-2 was determined by FISH in an academic reference/research laboratory and in a large, high-volume commercial reference laboratory. RESULTS: The HER-2 gene was amplified in 47% (344 of 733) and IHC was 3+ in 35% (279 of 798), with significant correlation (P < 0.01) between FISH and IHC. Positive EGFR immunostaining (IHC 1+, 2+, or 3+) in 28% (213 of 761) correlated with EGFR mRNA levels by RT-PCR (r = 0.59; P < 0.01). HER-2 gene amplification/overexpression was associated with improved clinical outcomes (progression-free survival; P < 0.001) in both trials. A significant improvement in outcome was seen in FISH-positive and IHC 0, 1+, or 2+ patients. HER-2 mRNA expression correlated with HER-2 FISH (r = 0.83) and IHC status (r = 0.72; n = 138). No correlation was found between EGFR expression (IHC or mRNA) and responsiveness to lapatinib regardless of HER-2 status. Although a significant correlation with lapatinib responsiveness was observed among "HER-2-negative" breast cancer patients in the large, high-volume commercial reference laboratory, this was not confirmed in the academic reference/research laboratory. CONCLUSIONS: Women with HER-2-positive metastatic breast cancer benefit from lapatinib, whereas women with HER-2-negative metastatic breast cancer derive no incremental benefit from lapatinib.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias da Mama/genética , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/biossíntese , Quinazolinas/uso terapêutico , Receptor ErbB-2/biossíntese , Biomarcadores Tumorais/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/mortalidade , Ensaios Clínicos Fase III como Assunto , Intervalo Livre de Doença , Receptores ErbB/genética , Feminino , Amplificação de Genes , Genes erbB-2 , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente/normas , Estimativa de Kaplan-Meier , Laboratórios Hospitalares/normas , Lapatinib , Pessoal de Laboratório Médico , Patologia Clínica/normas , Médicos , RNA Mensageiro/análise , Receptor ErbB-2/genética , Reprodutibilidade dos Testes , Reação em Cadeia da Polimerase Via Transcriptase Reversa
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