Comparative Population Pharmacokinetics of Darunavir in SARS-CoV-2 Patients vs. HIV Patients: The Role of Interleukin-6

Background: Darunavir is an anti-HIV protease inhibitor repurposed for SARS-CoV-2 treatment. Objective: The aim of this study was to assess the population pharmacokinetics of darunavir in SARS-CoV-2 patients compared with HIV patients. Methods: Two separate models were created by means of a nonlinear mixed-effect approach. The influence of clinical covariates on each basic model was tested and the association of significant covariates with darunavir parameters was assessed at multivariate regression and classification and regression tree (CART) analyses. Monte Carlo simulation assessed the influence of covariates on the darunavir concentration versus time profile. Results: A one-compartment model well-described darunavir concentrations in both groups. In SARS-CoV-2 patients (n = 30), interleukin (IL)-6 and body surface area were covariates associated with darunavir oral clearance (CL/F) and volume of distribution (Vd), respectively; no covariates were identified in HIV patients (n = 25). Darunavir CL/F was significantly lower in SARS-CoV-2 patients compared with HIV patients (4.1 vs. 10.3\ua0L/h; p < 0.001). CART analysis found that an IL-6 level of 18\ua0pg/mL may split the SARS-CoV-2 population in patients with low versus high darunavir CL/F (mean \ub1 standard deviation 3.47 \ub1 1.90 vs. 8.03 \ub1 3.24\ua0L/h; proportion of reduction in error = 0.46). Median (interquartile range) darunavir CL/F was significantly lower in SARS-CoV-2 patients with IL-6 levels 65 18\ua0pg/mL than in SARS-CoV-2 patients with IL-6 levels < 18\ua0pg/mL or HIV patients (2.78 [2.16\u20134.47] vs. 7.24 [5.88\u201310.38] vs. 9.75 [8.45\u201313.79]\ua0L/h, respectively; p < 0.0001). Increasing IL-6 levels affected darunavir concentration versus time simulated profiles. We hypothesized that increases in IL-6 levels associated with severe SARS-CoV-2 disease may downregulate the cytochrome P450 (CYP)\ua03A4-mediated metabolism of darunavir. Conclusions: This is a proof-of-concept of SARS-CoV-2 disease\u2013drug interactions, and may support the need for optimal dose selection of sensitive CYP3A4 substrates in severe SARS-CoV-2 patients

Produção de forragem e grãos de variedades de feijão-miúdo em consórcio com milho.

Espécies leguminosas tropicais são melhoradoras de solos, pela capacidade de fixação biológica de nitrogênio e pelo residual de fertilidade que permitem aos cultivos subsequentes. O feijãomiúdo é uma espécie que tem se destacado na região Sul do Brasil devido à sua multiplicidade de uso. Seu cultivo vem se difundindo rapidamente, principalmente nas bacias leiteiras, mas informações sobre seu cultivo e potencial de uso são escassos. Um experimento foi conduzido com o objetivo de avaliar a produção de forragem e grãos de quatro variedades de feijão-miúdo em cultivo consorciado com milho. Foram determinadas a densidade real de plantas e as produções de massa verde e seca totais e de massa seca de lâminas foliares, colmos e de grãos (kg ha-1) de feijão-miúdo, na ocasião da colheita do milho. Não foram verificadas diferenças estatísticas nas variáveis analisadas, devido, provavelmente, aos altos coeficientes de variação obtidos. Contudo, verificam-se diferenças numéricas expressivas entre os tratamentos. As produções podem ser consideradas satisfatórias para o sistema e região de cultivo, mas outros estudos deverão ser realizados para que sejam possíveis conclusões mais pontuais sobre as características das variedades de feijão-miúdo e seu cultivo consorciado com milho. Mesmo sem respaldo estatístico, podem ser destacadas as produções de massa seca total, de lâminas foliares e de grãos obtidas pela variedade Amendoim

Incidence and Risk Factors for Venous Thromboembolism in Female Patients Undergoing Breast Surgery

Albeit it does not have the highest venous thromboembolism (VTE) incidence compared to other neoplasms, breast cancer contributes to many VTE events because it is the most diagnosed tumor in women. We aim to analyze the occurrence and timing of VTE during the follow-up of patients who underwent breast surgery, the possible correlated factors, and the overall survival. This retrospective study included all female patients diagnosed with mammary pathology and surgically treated in our clinic between January 2002 and January 2012. Of 5039 women who underwent breast surgery, 1056 were found to have no evidence of malignancy, whereas 3983 were diagnosed with breast cancer. VTE rate resulted significantly higher in patients with invasive breast cancer than in women with benign breast disease or carcinoma in situ. Invasive cancers other than lobular or ductal were associated with a higher VTE rate. In addition, chronic hypertension, high BMI, cancer type, and evidence of metastasis turned out to be the most significant risk factors for VTE in women who underwent breast surgery. Moreover, VTE occurrence significantly impacted survival in invasive breast cancer patients. Compared to women with benign mammary pathology, VTE prevalence in women with breast cancer is significantly higher. The knowledge about the risk factors of VTE could be helpful as prognostic information, but also to eventually target preventive treatment strategies for VTE, as far as the co-existence of invasive breast cancer and VTE has a significantly negative impact on survival

Risk-Reducing Breast and Gynecological Surgery for BRCA Mutation Carriers: A Narrative Review

This narrative review aims to clarify the role of breast and gynecological risk-reduction surgery in BRCA mutation carriers. We examine the indications, contraindications, complications, technical aspects, timing, economic impact, ethical issues, and prognostic benefits of the most common prophylactic surgical options from the perspectives of a breast surgeon and a gynecologist. A comprehensive literature review was conducted using the PubMed/Medline, Scopus, and EMBASE databases. The databases were explored from their inceptions to August 2022. Three independent reviewers screened the items and selected those most relevant to this review’s scope. BRCA1/2 mutation carriers are significantly more likely to develop breast, ovarian, and serous endometrial cancer. Because of the Angelina effect, there has been a significant increase in bilateral risk-reducing mastectomy (BRRM) since 2013. BRRM and risk-reducing salpingo-oophorectomy (RRSO) significantly reduce the risk of developing breast and ovarian cancer. RRSO has significant side effects, including an impact on fertility and early menopause (i.e., vasomotor symptoms, cardiovascular disease, osteoporosis, cognitive impairment, and sexual dysfunction). Hormonal therapy can help with these symptoms. Because of the lower risk of developing breast cancer in the residual mammary gland tissue after BRRM, estrogen-only treatments have an advantage over an estrogen/progesterone combined treatment. Risk-reducing hysterectomy allows for estrogen-only treatments and lowers the risk of endometrial cancer. Although prophylactic surgery reduces the cancer risk, it has disadvantages associated with early menopause. A multidisciplinary team must carefully inform the woman who chooses this path of the broad spectrum of implications, from cancer risk reduction to hormonal therapies

Mismatch repair system in endometriotic tissue and eutopic endometrium of unaffected women

9Objective: To test the immunohistochemical staining pattern of some mismatch repair (MMR) system proteins in endometriotic tissue (ET) and eutopic endometrium. Methods: This was a retrospective study conducted at the Pathology and Obstetrics and Gynecology Departments of the Udine University Hospital. We analyzed 528 samples obtained from 246 patients affected by endometriosis and 71 samples from 71 patients with normal endometrium. A tissue microarray model was used to analyze the immunohistochemical expression of MMR system proteins. Results: Significant loss of MMR proteins was found in the stromal component of ETs. We found MSH2 to be expressed at a higher level than any other MMR system proteins in eutopic endometrium and ETs, to be significantly correlated to Ki-67 expression in both stromal and glandular components of ETs, and to be expressed at a significantly higher level in ETs than in eutopic endometrium. When considering the subgroup of endometriosis with high recurrence rate and glandular cytoplasmic staining for aurora A kinase, we found MMR proteins expressed at a significantly higher level in these ETs than in other ETs and eutopic endometrium of unaffected women. Conclusions: We found significant loss of MMR proteins (known to be associated with microsatellite instability) in the stromal component of ETs. The group of ETs with glandular cytoplasmic staining for aurora A kinase had higher MMR protein expression, suggesting an increased activity of this system. Our result suggests a novel role of increased MSH2 expression in cellular proliferation of endometriosis.openopenGrassi, T.; Calcagno, A.; Marzinotto, S.; Londero, A.P.; Orsaria, M.; Canciani, G.N.; Beltrami, C.A.; Marchesoni, D.; Mariuzzi, L.Grassi, T.; Calcagno, A.; Marzinotto, S.; Londero, Ambrogio P.; Orsaria, M.; Canciani, G. N.; Beltrami, Carlo Alberto; Marchesoni, Diego; Mariuzzi, Laur

Impact of social determinants on antiretroviral therapy access and outcomes entering the era of universal treatment for people living with HIV in Italy

Background: Social determinants are known to be a driving force of health inequalities, even in high income countries. Aim of our study was to determine if these factors can limit antiretroviral therapy (ART) access, outcome and retention in care of people living with HIV (PLHIV) in Italy. Methods: All ART naïve HIV+ patients (pts) of Italian nationality enrolled in the ICONA Cohort from 2002 to 2016 were included. The association of socio-demographic characteristics (age, sex, risk factor for HIV infection, educational level, occupational status and residency area) with time to: ART initiation (from the first positive anti-HIV test), ART regimen discontinuation, and first HIV-RNA &lt; 50 cp/mL, were evaluated by Cox regression analysis, Kaplan Meier method and log-rank test. Results: A total of 8023 HIV+ pts (82% males, median age at first pos anti-HIV test 36 years, IQR: 29-44) were included: 6214 (77.5%) started ART during the study period. Women, people who inject drugs (PWID) and residents in Southern Italy presented the lowest levels of education and the highest rate of unemployment compared to other groups. Females, pts aged &gt; 50 yrs., unemployed vs employed, and people with lower educational levels presented the lowest CD4 count at ART initiation compared to other groups. The overall median time to ART initiation was 0.6 years (yrs) (IQR 0.1-3.7), with a significant decrease over time [2002-2006 = 3.3 yrs. (0.2-9.4); 2007-2011 = 1.0 yrs. (0.1-3.9); 2012-2016 = 0.2 yrs. (0.1-2.1), p &lt; 0.001]. By multivariate analysis, females (p &lt; 0.01) and PWID (p &lt; 0.001), presented a longer time to ART initiation, while older people (p &lt; 0.001), people with higher educational levels (p &lt; 0.001), unemployed (p = 0.02) and students (p &lt; 0.001) were more likely to initiate ART. Moreover, PWID, unemployed vs stable employed, and pts. with lower educational levels showed a lower 1-year probability of achieving HIV-RNA suppression, while females, older patients, men who have sex with men (MSM), unemployed had higher 1-year risk of first-line ART discontinuation. Conclusions: Despite median time to ART start decreased from 2002 to 2016, socio-demographic factors still contribute to disparities in ART initiation, outcome and durability

La completezza della documentazione sanitaria: ruolo dei Link Professional nel miglioramento continuo

INTRODUZIONE \u2013 premesse e scopo dello studio: La completezza della Cartella Clinica (CC) \ue8 un indicatore della qualit\ue0 delle cure erogate, per questo la valutazione regolare del contenuto rientra nelle attivit\ue0 di miglioramento continuo. Scopo di questo studio \ue8 valutare se il coinvolgimento e la formazione specifica di professionisti gi\ue0 impegnati nell\u2019attivit\ue0 assistenziale e clinica abbia un effetto sulla completezza della CC introdotta presso le due Strutture Operative Complesse (Medicina Fisica e Unit\ue0 Spinale, Medicina Fisica e Unit\ue0 delle Gravi Cerebro-lesioni acquisite) del Dipartimento Medicina Fisica e Riabilitazione (IMFR) di Udine. MATERIALI E METODI: Nel dicembre 2017 \ue8 stata adottata dall\u2019IMFR una nuova CC integrata multidisciplinare e ne \ue8 stato valutato l\u2019impatto in termini di completezza a gennaio 2018 (T0). Contestualmente sono stati formati sulla corretta compilazione della CC 17 link professional che, fungendo da raccordo tra i colleghi operatori e direzione ospedaliera, nelle settimane successive hanno promosso incontri periodici di formazione e approfondimento sul tema coinvolgendo tutto il personale sanitario. La completezza della CC \ue8 stata rivalutata a maggio 2018 (T1), a valle degli incontri formativi. Le misurazioni sono state effettuate mediante valutazione da parte dei link professional su 38 CC (20 a T0 ed 18 a T1) di pazienti in ricovero ordinario, utilizzando la medesima griglia composta da 10 sezioni, articolate in 59 voci. Per valutare l\u2019eventuale miglioramento \ue8 stata calcolata la completezza complessiva e la differenza tra T0 e T1 (\uf044T1-T0) in termini percentuali ed \ue8 stata effettuata una verifica del test d\u2019ipotesi con \uf0632. RISULTATI: La completezza complessiva della CC delle due strutture \ue8 aumentata significativamente (p<0,01), passando dal 62% (T0) all\u201980% (T1). A T1 \ue8 stata raggiunta, con un miglioramento significativo (p<0,01), una completezza pari al 100% nella sezione consensi (\uf044=29%), al 98% nella valutazione riabilitativa (\uf044=20%), al 92% nella lettera di dimissione (\uf044=29%), all\u201985% nella valutazione infermieristica (\uf044=13%), all\u201982% nel progetto riabilitativo individuale (\uf044=24%), al 74% nel piano integrato di cura (\uf044=15%) e al 77% nella grafica e scheda terapia (\uf044=34%). Un miglioramento, anche se non significativo, \ue8 stato registrato nelle rimanenti sezioni: valutazione medica (completezza: 82%, \uf044=6%), diario integrato (65%, \uf044=17%) e varie (64%, \uf044=8%). CONCLUSIONI: Il modello adottato si \ue8 dimostrato efficace nel supportare il processo di miglioramento della completezza della cartella clinica