Household Severe Acute Respiratory Syndrome Coronavirus 2 Transmission and Children: A Network Prospective Study.

BACKGROUND: The role of children in household transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains unclear. We describe the epidemiological and clinical characteristics of children with coronavirus disease 2019 (COVID-19) in Catalonia, Spain, and investigate the household transmission dynamics. METHODS: A prospective, observational, multicenter study was performed during summer and school periods (1 July 2020-31 October 2020) to analyze epidemiological and clinical features and viral household transmission dynamics in COVID-19 patients aged <16 years. A pediatric index case was established when a child was the first individual infected. Secondary cases were defined when another household member tested positive for SARS-CoV-2 before the child. The secondary attack rate (SAR) was calculated, and logistic regression was used to assess associations between transmission risk factors and SARS-CoV-2 infection. RESULTS: The study included 1040 COVID-19 patients. Almost half (47.2%) were asymptomatic, 10.8% had comorbidities, and 2.6% required hospitalization. No deaths were reported. Viral transmission was common among household members (62.3%). More than 70% (756/1040) of pediatric cases were secondary to an adult, whereas 7.7% (80/1040) were index cases. The SAR was significantly lower in households with COVID-19 pediatric index cases during the school period relative to summer (P = .02) and compared to adults (P = .006). No individual or environmental risk factors associated with the SAR. CONCLUSIONS: Children are unlikely to cause household COVID-19 clusters or be major drivers of the pandemic, even if attending school. Interventions aimed at children are expected to have a small impact on reducing SARS-CoV-2 transmission.

Internet addiction and Facebook addiction in Spanish women with eating disorders.

AIM: We aim to investigate the association between the presence of eating disorders and both Internet addiction (IA) and Facebook addiction (FA) in women suffering from eating disorders. METHODS: A total of 124 women completed three instruments: the Internet Addiction Test (IAT), the Bergen Facebook Addiction Scale (BFAS) and a sociodemographic questionnaire. RESULTS: The proportion of FA was 37.9%. The distribution of risk of IA was 21.8%. When the risk of Internet or Facebook addiction was compared with respect to eating disorders, no significant differences were found between groups (P = 0.146 and P = 0.086, respectively). Age and Body Mass Index (BMI) were predictors of BFAS scores; the standardized beta coefficient (ß) for age was -0.463 (P ≤ 0.001), while for BMI it was 3.44; (P = 0.001) being a positive predictor of BFAS scores. For IAT scores, ß age (negatively) = -0.415; (P < 0.001) and ß for weight (positively) 3.657; (P < 0.001) were identified. CONCLUSIONS: The presence of an eating disorder does not seem to be a factor that characterizes the risk of Internet or Facebook addiction in our sample. As information regarding the potential association between Internet and Facebook addiction and the presence of eating disorders is limited, we encourage further studies on this topic.

Antioxidant and Photoprotective Activity of Apigenin and its Potassium Salt Derivative in Human Keratinocytes and Absorption in Caco-2 Cell Monolayers.

Ultraviolet (UV) radiation, especially types A (UVA) and B (UVB), is one of the main causes of skin disorders, including photoaging and skin cancer. Ultraviolent radiation causes oxidative stress, inflammation, p53 induction, DNA damage, mutagenesis, and oxidation of various molecules such as lipids and proteins. In recent decades, the use of polyphenols as molecules with an antioxidant and anti-inflammatory capacity has increased. However, some of these compounds are poorly soluble, and information regarding their absorption and bioavailability is scarce. The main objective of this study was to compare the intestinal absorption and biological activity of apigenin and its more soluble potassium salt (apigenin-K) in terms of antioxidant and photoprotective capacity. Photoprotective effects against UVA and UVB radiation were studied in human keratinocytes, and antioxidant capacity was determined by different methods, including trolox equivalent antioxidant capacity (TEAC), ferric reducing antioxidant power (FRAP) and oxygen radical absorbance capacity (ORAC) assays. Finally, the intestinal absorption of both apigenins was determined using an in vitro Caco-2 cell model. Apigenin showed a slightly higher antioxidant capacity in antioxidant activity assays when compared with apigenin-K. However, no significant differences were obtained for their photoprotective capacities against UVA or UVB. Results indicated that both apigenins protected cell viability in approximately 50% at 5 J/m2 of UVA and 90% at 500 J/m2 of UVB radiation. Regarding intestinal absorption, both apigenins showed similar apparent permeabilities (Papp), 1.81 × 10-5 cm/s and 1.78 × 10-5 cm/s, respectively. Taken together, these results suggest that both apigenins may be interesting candidates for the development of oral (nutraceutical) and topical photoprotective ingredients against UVA and UVB-induced skin damage, but the increased water solubility of apigenin-K makes it the best candidate for further development.

Intestinal Permeability Study of Clinically Relevant Formulations of Silibinin in Caco-2 Cell Monolayers.

An ever-growing number of preclinical studies have investigated the tumoricidal activity of the milk thistle flavonolignan silibinin. The clinical value of silibinin as a bona fide anti-cancer therapy, however, remains uncertain with respect to its bioavailability and blood⁻brain barrier (BBB) permeability. To shed some light on the absorption and bioavailability of silibinin, we utilized the Caco-2 cell monolayer model of human intestinal absorption to evaluate the permeation properties of three different formulations of silibinin: silibinin-meglumine, a water-soluble form of silibinin complexed with the amino-sugar meglumine; silibinin-phosphatidylcholine, the phytolipid delivery system Siliphos; and Eurosil85/Euromed, a milk thistle extract that is the active component of the nutraceutical Legasil with enhanced bioavailability. Our approach predicted differential mechanisms of transport and blood⁻brain barrier permeabilities between the silibinin formulations tested. Our assessment might provide valuable information about an idoneous silibinin formulation capable of reaching target cancer tissues and accounting for the observed clinical effects of silibinin, including a recently reported meaningful central nervous system activity against brain metastases.

[Behaviour and attitudes towards the sexuality of the pregnant woman during the last trimester. Phenomenological study]. / Comportamiento y actitud frente a la sexualidad de la mujer embarazada durante el último trimestre. Estudio fenomenológico.

OBJECTIVE: To explore the life experiences on sexual relationships in the third trimester of pregnancy in primiparous women. DESIGN: Phenomenological qualitative study, SITE: Cáceres (Extremadura). PARTICIPANTS: Primiparous women in the third trimester of their pregnancy. METHODS: We use theoretical sampling, was conducted on pregnant primiparous. The study included 15 participants. The data was collected using in-depth interviews, that were voiced recorded and later transcribed. The analysis was made using Giorgi's proposal. RESULTS: The results show three main points. Fear of doing damage, mediated by the obstetric history and the desire to have the long-awaited child. Exploring new routes: forms of sexual expression are modified by the physical changes, the fears, and the mobility. Highlighting the importance of other displays of affection and love (kisses and caresses). The Sex Taboo: lack of information against sexuality during pregnancy is still common. CONCLUSIONS: Women in the third trimester of their pregnancy put aside their sexual appetite and that of their partners, and concentrate in the wellbeing of their new born baby. It highlights the role of the mother before the couple. The more desired and difficult the pregnancy has been, the more the sexual life is reduced. The Health Professionals must advise and inform the couples with an open-minded attitude.

An Updated Review on Marine Anticancer Compounds: The Use of Virtual Screening for the Discovery of Small-Molecule Cancer Drugs.

Marine secondary metabolites are a promising source of unexploited drugs that have a wide structural diversity and have shown a variety of biological activities. These compounds are produced in response to the harsh and competitive conditions that occur in the marine environment. Invertebrates are considered to be among the groups with the richest biodiversity. To date, a significant number of marine natural products (MNPs) have been established as antineoplastic drugs. This review gives an overview of MNPs, both in research or clinical stages, from diverse organisms that were reported as being active or potentially active in cancer treatment in the past seventeen years (from January 2000 until April 2017) and describes their putative mechanisms of action. The structural diversity of MNPs is also highlighted and compared with the small-molecule anticancer drugs in clinical use. In addition, this review examines the use of virtual screening for MNP-based drug discovery and reveals that classical approaches for the selection of drug candidates based on ADMET (absorption, distribution, metabolism, excretion, and toxicity) filtering may miss potential anticancer lead compounds. Finally, we introduce a novel and publically accessible chemical library of MNPs for virtual screening purposes.

Prevalence, Clinical Characteristics and Risk Factors of Post-COVID-19 Condition in a Multicenter Pediatric Primary and Hospital Care Cohort.

The prevalence of post-COVID-19 condition is not well defined. We describe a cohort of 244 children diagnosed with COVID-19 and followed up for 6 months, in which 4.9% of patients had persistent symptoms at 12 weeks. Anosmia was the most frequent symptom. Being female and having more than 3 symptoms in acute infection were associated with an increased risk of post-COVID.

A Prospective Observational Study of Frailty in Geriatric Revitalization Aimed at Community-Dwelling Elderly.

(1) Background: The increasing life expectancy brings an increase in geriatric syndromes, specifically frailty. The literature shows that exercise is a key to preventing, or even reversing, frailty in community-dwelling populations. The main objective is to demonstrate how an intervention based on multicomponent exercise produces an improvement in frailty and pre-frailty in a community-dwelling population. (2) Methods: a prospective observational study of a multicomponent exercise program for geriatric revitalization with people aged over 65 holding Barthel Index scores equal to, or beyond, 90. The program was developed over 30 weeks, three times a week, in sessions lasting 45-50 min each. Frailty levels were registered by the Short Physical Performance Battery, FRAIL Questionnaire Screening Tool, and Timed "Up & Go" at the beginning of the program, 30 weeks later (at the end of the program), and following 13 weeks without training; (3) Results: 360 participants completed the program; a greater risk of frailty was found before the program started among older women living in urban areas, with a more elevated fat percentage, more baseline pathologies, and wider baseline medication use. Furthermore, heterogeneous results were observed both in training periods and in periods without physical activity. However, they are consistent over time and show improvement after training. They show a good correlation between TUG and SPPB; (4) Conclusions: A thirty-week multicomponent exercise program improves frailty and pre-frailty status in a community-dwelling population with no functional decline. Nevertheless, a lack of homogeneity is evident among the various tools used for measuring frailty over training periods and inactivity periods.

Evaluating the influence of sleep quality and quantity on glycemic control in adults with type 1 diabetes.

Background: Sleep quality disturbances are frequent in adults with type 1 diabetes. However, the possible influence of sleep problems on glycemic variability has yet to be studied in depth. This study aims to assess the influence of sleep quality on glycemic control. Materials and methods: An observational study of 25 adults with type 1 diabetes, with simultaneous recording, for 14 days, of continuous glucose monitoring (Abbott FreeStyle Libre system) and a sleep study by wrist actigraphy (Fitbit Ionic device). The study analyzes, using artificial intelligence techniques, the relationship between the quality and structure of sleep with time in normo-, hypo-, and hyperglycemia ranges and with glycemic variability. The patients were also studied as a group, comparing patients with good and poor sleep quality. Results: A total of 243 days/nights were analyzed, of which 77% (n = 189) were categorized as poor quality and 33% (n = 54) as good quality. Linear regression methods were used to find a correlation (r =0.8) between the variability of sleep efficiency and the variability of mean blood glucose. With clustering techniques, patients were grouped according to their sleep structure (characterizing this structure by the number of transitions between the different sleep phases). These clusters showed a relationship between time in range and sleep structure. Conclusions: This study suggests that poor sleep quality is associated with lower time in range and greater glycemic variability, so improving sleep quality in patients with type 1 diabetes could improve their glycemic control.

Impact of preoperative pharmaceutical care consultation on medication errors in surgical patients: a comprehensive analysis.

OBJECTIVE: Assessing the impact of introducing preoperative pharmaceutical care consultations by analyzing the severity of prevented medication errors (MEs) and their potential effects on the surgical process. METHODS: Preoperative pharmaceutical care consultation was implemented in our hospital to assess the preoperative medication management of surgical patients between the pre-anesthesia consultation and the day of surgery. Pharmacists evaluated the appropriateness of medication management based on a consensus multidisciplinary institutional protocol. All errors identified between 2016 and 2020 were analyzed, and their severity and potential impact on surgery were standardized. A list of therapeutic groups was created to prioritize patients for consultations. RESULTS: During the study period, 3,105 patients attended the consultations and 1,179 MEs were prevented. According to severity, 30.6% of MEs were classified as category E and 26.2% as D. The Number Needed to Treat to prevent a category E or higher ME (indicating potential harm to patients) was 5 patients. About 14.84% of MEs belonged to the prioritized drug groups. One hundred and thirteen errors would have resulted in a surgery delay of more than 24 h, and 175 errors were classified as G-H (irreversible damage). CONCLUSIONS: This study highlights the effectiveness of pharmaceutical care consultations in preventing MEs and improving surgical outcomes.

Prehospital mSOFA Score for Quick Prediction of Life-Saving Interventions and Mortality in Trauma Patients: A Prospective, Multicenter, Ambulance-based, Cohort Study.

Background: Prehospital emergency medical services (EMS) are the main gateway for trauma patients. Recent advances in point-of-care testing and the development of early warning scores have allowed EMS to improve patient classification. We aimed to identify patients presenting with major trauma involving life-saving interventions (LSI) using the modified Sequential Organ Failure Assessment (mSOFA) score in the prehospital scenario, and to compare these results with those of other trauma scores. Methods: This was a prospective, ambulance-based, multicenter, training-validation study in trauma patients who were treated in a prehospital setting and subsequently transported to a hospital. The study involved six Advanced Life Support units, 38 Basic Life Support units, and four hospitals. The primary outcome was LSI performed at the scene or en route and intensive care unit (ICU) admission and all-cause two-day in-hospital mortality. We collected epidemiological variables, creatinine, lactate, base excess, international normalized ratio, and vital signs. Discriminative power (area under the receiver operating characteristic curve [AUC]), calibration (observed vs predicted outcome agreement), and decision-curve analysis (DCA, clinical utility) were used to assess the reliability of the mSOFA in comparison to other scores. Results: Between January 1, 2020-April 30, 2022, a total of 763 patients were selected. The mSOFA score's AUC was 0.927 (95% confidence interval [CI] 0.898-0.957) for LSI, 0.845 (95% CI 0.808-0.882) for ICU admission, and 0.979 (95% CI 0.966-0.991) for two-day mortality. Conclusion: The mSOFA score outperformed the other scores, allowing a quick identification of high-risk patients. The routine implementation in EMS of mSOFA could provide critical support in the decision-making process in time-dependent trauma injuries.

Engineering 3D-Printed Advanced Healthcare Materials for Periprosthetic Joint Infections.

The use of additive manufacturing or 3D printing in biomedicine has experienced fast growth in the last few years, becoming a promising tool in pharmaceutical development and manufacturing, especially in parenteral formulations and implantable drug delivery systems (IDDSs). Periprosthetic joint infections (PJIs) are a common complication in arthroplasties, with a prevalence of over 4%. There is still no treatment that fully covers the need for preventing and treating biofilm formation. However, 3D printing plays a major role in the development of novel therapies for PJIs. This review will provide a deep understanding of the different approaches based on 3D-printing techniques for the current management and prophylaxis of PJIs. The two main strategies are focused on IDDSs that are loaded or coated with antimicrobials, commonly in combination with bone regeneration agents and 3D-printed orthopedic implants with modified surfaces and antimicrobial properties. The wide variety of printing methods and materials have allowed for the manufacture of IDDSs that are perfectly adjusted to patients' physiognomy, with different drug release profiles, geometries, and inner and outer architectures, and are fully individualized, targeting specific pathogens. Although these novel treatments are demonstrating promising results, in vivo studies and clinical trials are required for their translation from the bench to the market.

[Translated article] Achieving excellence in the pharmaceutical care of the surgical patient.

The perioperative setting is one of the hospital areas with the highest prevalence of medication errors. Despite the wide experience of hospital pharmacists in developing medication safety programs and improvement initiatives, the perioperative setting has remained one of the areas in which there is less experience. Clinical pharmacist should be integrated into the multidisciplinary care team so that they can be involved in the different surgical phases of care, which include from the preoperative assessment to inpatient stay, and finally discharge from hospital. Their work will consist of coordinating and implementing strategies that have been demonstrated to reduce medication errors during the perioperative process. The aim of this paper is to introduce a specialized pharmaceutical care program to achieve excellence in the pharmaceutical care of surgical patients. This program is especially aimed at promoting the figure of the clinical pharmacist in the perioperative setting to guarantee the highest quality and safety in pharmacotherapeutic care throughout all the surgical phases of care.

Influence of Previous Mental State on Psychological Outcomes of Spanish Out-of-Hospital Professionals during the COVID-19 Pandemic.

This study aimed to describe factors relating to the psychological distress of healthcare workers (HCWs) in Spanish out-of-hospital emergency medical services (EMS), according to the previous or non-use of psychotropic drugs or psychotherapy. A multicentre, cross-sectional descriptive study was designed. The study population were all physicians, nurses, and emergency medical technicians (EMTs) working in any Spanish out-of-hospital EMS between February and April 2021. The main outcomes were the levels of stress, anxiety, depression, and self-efficacy, assessed by DASS-21 and G-SES. Differences in levels of stress, anxiety, depression, and self-efficacy, according to sex, age, previous use of psychotropic drug or psychotherapy, work experience, professional category, type of work, and modification of working conditions were measured using the Student's t-test for independent samples, one-way ANOVA, Pearson's correlation, or 2-factor analysis of covariance. A total of 1636 HCWs were included, of whom one in three had severe mental disorders because of the pandemic. The interaction of the previous or non-use of psychotropic drugs or psychotherapy with the rest of the factors considered did not modify the levels of stress, anxiety, depression, and self-efficacy. However, HCWs with a history of psychotropic drug or psychotherapy use had a more intense negative emotional response and lower self-efficacy, regardless of their sex, professional category, type of work, or change in the working conditions. These HCWs are considered particularly vulnerable to the development or recurrence of new disorders or other comorbidities; therefore, the implementation of monitoring and follow-up strategies should be a priority.

[Translated article] Analysis of the appropriateness of antibiotic prophylaxis in surgical procedures in Spain. Protocol for the "ProA-Q" study.

Surgical antibiotic prophylaxis is one of the most useful measures to prevent surgical wound infection. OBJECTIVE: The aim of this project is to evaluate the appropriateness of the use of antibiotic prophylaxis in surgical procedures performed in Spanish hospitals, both globally and according to the type of surgery performed. METHOD: For this purpose, an observational, retrospective, cross-sectional, and multicentre study has been designed to collect all the variables that allow the evaluation of the appropriateness of surgical antibiotic prophylaxis by comparing the prescribed treatment, the recommendations included in the local guidelines, and the consensus document of the Spanish Society of Infectious Diseases and Clinical Microbiology and the Spanish Association of Surgeons. Indication, choice of antimicrobial, dose, route and duration of administration, timing, re-dosing, and duration of the prophylaxis will be taken into account. The sample will consist of patients who underwent scheduled or emergency surgery, either as inpatients or outpatients, in hospitals in Spain. A sample size of 2335 patients has been established to estimate, with 95% confidence and 80% power, a percentage of appropriateness that is expected to be around 70%. Differences between variables will be analysed using Student's t-test, Mann-Whitney U test, Chi-square test, or Fisher's test, as appropriate. The degree of agreement between the antibiotic prophylaxis recommended by the guidelines of the different hospitals and that recommended in the literature will be analysed by calculating the Cohen's kappa indicator. Binary logistic regression analysis using generalised linear mixed models will be performed to identify possible factors associated with differences in the appropriateness of antibiotic prophylaxis. DISCUSSION: The results of this clinical study will allow us to focus on specific surgical areas with higher rates of inappropriateness, identify key points of action and guide future strategies for antimicrobial stewardship programs in the area of antibiotic prophylaxis.

Achieving excellence in the pharmaceutical care of the surgical patient. / Hacia la excelencia en la atención farmacéutica al paciente quirúrgico.

The perioperative setting is one of the hospital areas with the highest prevalence of medication errors. Despite the wide experience of hospital pharmacists in developing medication safety programs and improvement initiatives, the surgical environment has remained one of the areas in which there is less experience. Clinical pharmacist should be integrated into the multidisciplinary care teams so that they can be involved in the different surgical phases of care, which include from the preoperative assessment to inpatient stay, and finally discharge from hospital. Their work will consist of coordinating and implementing strategies that have been demonstrated to reduce medication errors throughout the perioperative process. The aim of this paper is to introduce a specialized pharmaceutical care program to achieve excellence in the pharmaceutical care of surgical patients. This program is especially aimed at promoting the figure of the clinical pharmacist in the perioperative setting to guarantee the highest quality and safety in pharmacotherapeutic care throughout all the surgical phases of care.

Analysis of the appropriateness of antibiotic prophylaxis in surgical procedures in Spain. Protocol for the "ProA-Q" study. / Análisis de la adecuación de la profilaxis antibiótica en procedimientos quirúrgicos en España. Protocolo del estudio ProA-Q.

Surgical antibiotic prophylaxis is one of the most useful measures to prevent surgical wound infection. OBJECTIVE: The aim of this project is to evaluate the appropriateness of the use of antibiotic prophylaxis in surgical procedures performed in Spanish hospitals, both globally and according to the type of surgery performed. METHOD: For this purpose, an observational, retrospective, cross-sectional and multicenter study has been designed to collect all the variables that allow the evaluation of the appropriateness of surgical antibiotic prophylaxis by comparing the prescribed treatment, the recommendations included in the local guidelines and the consensus document of the Spanish Society of Infectious Diseases and Clinical Microbiology and the Spanish Association of Surgeons. Indication, choice of antimicrobial, dose, route and duration of administration, timing, re-dosing and duration of the prophylaxis will be taken into account. The sample will consist of patients who underwent scheduled or emergency surgery, either as inpatients or outpatients, in hospitals in Spain. A sample size of 2,335 patients has been established to estimate, with 95% confidence and 80% power, a percentage of appropriateness that is expected to be around 70%. Differences between variables will be analyzed using Student's t-test, Mann-Whitney U test, Chi-square test, or Fisher's test, as appropriate. The degree of agreement between the antibiotic prophylaxis recommended by the guidelines of the different hospitals and that recommended in the literature will be analyzed by calculating the Cohen's kappa indicator. Binary logistic regression analysis using generalized linear mixed models will be performed to identify possible factors associated with differences in the appropriateness of antibiotic prophylaxis. DISCUSSION: The results of this clinical study will allow us to focus on specific surgical areas with higher rates of inappropriateness, identify key points of action and guide future strategies for antimicrobial stewardship programs in the area of antibiotic prophylaxis.

Factors influencing HPV knowledge and vaccine acceptability in parents of adolescent children: results from a survey-based study (KAPPAS study).

Human Papillomavirus (HPV) is one of the most common sexually transmitted infections associated with a wide range of diseases and cancers that may affect both genders. Since 2007, the Spanish National Immunization Program includes HPV vaccination, and currently it only targets 12-year-old girls. The objective of our study is to assess differences in the knowledge of HPV and HPV vaccine acceptability according to different factors, and to identify the role of different sources of information. A cross-sectional, multicenter survey research was carried out in twenty-four pediatric offices in Spain, and included parents of children aged 9 to 14 years old. 1,405 valid survey-responses were considered for the analysis. Parental awareness of HPV and HPV vaccine, as well as vaccine acceptability, are still strongly associated with child gender (girls) and age (12-14 years old). HPV knowledge and HPV vaccine acceptability are related to parental gender, HPV vaccination status and having at least one daughter. Parents who consulted a healthcare source to obtain further information about HPV had greater HPV and HPV vaccine knowledge and acceptability. HPV and HPV vaccine awareness and acceptability are strongly associated with child gender and age, which correlates with the current immunization program.

Comprehensive Approach to Genomic and Immune Profiling: Insights of a Real-World Experience in Gynecological Tumors.

Gynecological cancer accounts for an elevated incidence worldwide requiring responsiveness regarding its care. The comprehensive genomic approach agrees with the classification of certain tumor types. We evaluated 49 patients with gynecological tumors undergoing high-throughput sequencing to explore whether identifying alterations in cancer-associated genes could characterize concrete histological subtypes. We performed immune examination and analyzed subsequent clinical impact. We found 220 genomic aberrations mostly distributed as single nucleotide variants (SNV, 77%). Only 3% were classified as variants of strong clinical significance in BRCA1 and BRCA2 of ovarian high-grade serous (HGSC) and uterine endometrioid carcinoma. TP53 and BRCA1 occurred in 72% and 28% of HGSC. Cervical squamous cell carcinoma was entirely HPV-associated and mutations occurred in PIK3CA (60%), as well as in uterine serous carcinoma (80%). Alterations were seen in PTEN (71%) and PIK3CA (60%) of uterine endometrioid carcinoma. Elevated programmed death-ligand 1 (PD-L1) was associated with high TILs. Either PD-L1 augmented in deficient mis-matched repair (MMR) proteins or POLE mutated cases when compared to a proficient MMR state. An 18% received genotype-guided therapy and a 4% immunotherapy. The description of tumor subtypes is plausible through high-throughput sequencing by recognizing clinically relevant alterations. Additional concomitant assessment of immune biomarkers identifies candidates for immunotherapy.

Population pharmacokinetic/pharmacogenetic model for optimization of efavirenz therapy in Caucasian HIV-infected patients.

Despite extensive clinical experience with efavirenz (EFV), unpredictable interindividual variabilities in efficacy and toxicity remain important limitations associated with the use of this antiretroviral. The purpose of this study was to determine the factors affecting EFV pharmacokinetics and to develop a pharmacokinetic/pharmacogenetic (PK/PG) model in a Caucasian population of HIV-infected patients. In total, 869 EFV plasma concentrations from 128 HIV-infected patients treated with EFV were quantitatively assessed using a validated high-performance liquid chromatography technique. All patients were genotyped for 90 single nucleotide polymorphisms (SNPs) in genes coding for proteins involved in the metabolism and transport of EFV, using a MassArray platform provided by Sequenom. The influence of these polymorphisms on EFV pharmacokinetics and the effects of demographic, clinical, biochemical, lifestyle, and concurrent drug covariates were evaluated. Plasma concentrations were fitted by a one-compartment model, with first-order absorption and elimination using nonlinear mixed-effect modeling (NONMEM program). The CYP2B6*6 allele, multidrug resistance-associated protein 4 (MRP4) 1497C → T, and gamma-glutamyltranspeptidase (GGT) were identified as major factors influencing the apparent EFV oral clearance (CL/F), reducing the initial interindividual variability by 54.8%, according to the model CL/F = (12.2 - 0.00279 · GGT) · 0.602(CYP2B6*6 [G/T]) · 0.354(CYP2B6*6 [T/T]) · 0.793(MRP4 1497C → T), where CYP2B6*6 [G/T], CYP2B6*6 [T/T], and MRP4 1497C → T take values of 0 or 1 to indicate the absence or presence of polymorphisms. The detailed genetic analysis conducted in this study identified two of 90 SNPs that significantly impacted CL/F, which might indicate that the remaining SNPs analyzed do not influence this PK parameter, at least in Caucasian populations with characteristics similar to those of our study population.