Prevalence of active infection by herpes simplex virus type 2 in patients with high-risk human papillomavirus infection: A cross-sectional study.

The aim is to determine the prevalence of active infection by herpes simplex virus type 2 (HSV-2) among Mexican women with high-risk human papillomavirus (HR-HPV) cervical infection, recruited from public gynecology and colposcopy services. In a cross-sectional study, HSV-2 antibodies, HSV-2 DNA, and HR-HPV DNA were quantified. Significant differences in HSV-2 seroprevalence and HSV-2 active infection rates were found between negative and positive HR-HPV cases. HSV-2 seroprevalence was 28.15% and 16.1% (P = .0001), while HSV-2 active infection rates were 6.83% and 0.62% (P = .001) for positive and negative HR-HPV groups, respectively. The risk of HSV-2 seropositivity was 1.7 times greater for HR-HPV-positive cases (P = .02). Similarly, HR-HPV-positive cases were nine times more likely to have an HSV-2 active infection than HR-HPV-negative cases (P = .03). High HSV-2/h-HPV coinfection rates were observed among women recruited from public gynecology and colposcopy services. The main factors related to an HSV-2 active infection are a history of risky sexual behavior and HR-HPV infection. The prevalence of HSV-2 active infection among positive HR-HPV subjects indicate that these infections constitute an important group of STIs in Mexico.

A prospective cohort study to evaluate immunosuppressive cytokines as predictors of viral persistence and progression to pre-malignant lesion in the cervix in women infected with HR-HPV: study protocol.

BACKGROUND: Cervical cancer (CC) is caused by a persistent infection of high-risk human papillomavirus (HR-HPV). While most HPV infections are transient, persistent HPV infections are a significant health problem in Mexico. With an estimated HPV prevalence of 10% among women in reproductive age, approximately 25% of these women present at least a positive result in triage test, which according to previous studies is expected to be confirmed as positive CIN-2/3. The immune system has a key role in the natural history of HPV infection; alterations in the cellular immune response are responsible for the failure to eliminate HPV. The objective of this project is to assess the prognostic value of detecting immune markers (IL-10, IL-4, TGFß1, IFNγ, IL-6, and TNFα), the expression of HPV-HR E6/E7 proteins, and the viral load at the cervical level with respect to the persistence or clearance of HR-HPV infection, and the regression or progression of a cervical premalignant lesion. METHODS: A dynamic cohort study is being conducted in women with colposcopic, cytological, and histopathological results negative for squamous intraepithelial lesion (SIL) in the cervix and a positive HPV test; the subjects will be followed-up for 5 years, period from which 3 years have already elapsed, with yearly studies (colposcopy, cytology, and histopathology diagnosis, along with molecular HPV test, quantification of viral load and of IL-10, IL-4, TGFß1, INFγ, IL-6, and TNFα levels, along with the expression of the HR-HPV E6/E7 proteins in the cervix as a viral marker. The outcome will be categorized as viral persistence or clearance; and as SIL persistence, progression, or regression. Binomial and/or multinomial regression models adjusted for potential confounders will be used, associating the relative risk of the outcome with the immune and viral markers evaluated. DISCUSSION: This research will generate knowledge about immune markers with predictive value for the persistence and clearance of HPV, which will improve the triage of positive HPV women and thus reduce the economic burden for the Mexican health system imposed by the management of high-grade SIL and CC cases, which are still detected in late stages.

Insulator-to-Semiconductor-to-Conductor Phase-Like Transition of DNA Chains.

Using a tight-binding model, we study the transport of charge carriers through DNA molecular wires. In double-stranded DNA chains, according to Chargaff's rules, only Adenine-Thymine (AT) and Cytosine-Guanine (CG) pairs are allowed. In our model, a decimation procedure allows us to represent each pair of bases by a single site with one localized electronic state. We consider chains of different lengths with only AT (CG) sites, and ordered and disordered chains with both types of sites. Disordered chains may include short range correlation. Additionally, hydration is considered in the form of a change of the site energy. We find a conductor-to-semiconductor-to-insulator transition as a function of the three effects taken into account: chain size, intrinsic disorder of CG and AT pairs, and hydration. This model predicts that an appropriate choice of chain size and concentration of AT pairs can be used to tailor the electrical behavior of DNA strands.

Y-chromosome and mtDNA variation confirms independent domestications and directional hybridization in South American camelids.

Investigations of genetic diversity and domestication in South American camelids (SAC) have relied on autosomal microsatellite and maternally-inherited mitochondrial data. We present the first integrated analysis of domestic and wild SAC combining male and female sex-specific markers (male specific Y-chromosome and female-specific mtDNA sequence variation) to assess: (i) hypotheses about the origin of domestic camelids, (ii) directionality of introgression among domestic and/or wild taxa as evidence of hybridization and (iii) currently recognized subspecies patterns. Three male-specific Y-chromosome markers and control region sequences of mitochondrial DNA are studied here. Although no sequence variation was found in SRY and ZFY, there were seven variable sites in DBY generating five haplotypes on the Y-chromosome. The haplotype network showed clear separation between haplogroups of guanaco-llama and vicuña-alpaca, indicating two genetically distinct patrilineages with near absence of shared haplotypes between guanacos and vicuñas. Although we document some examples of directional hybridization, the patterns strongly support the hypothesis that llama (Lama glama) is derived from guanaco (Lama guanicoe) and the alpaca (Vicugna pacos) from vicuña (Vicugna vicugna). Within male guanacos we identified a haplogroup formed by three haplotypes with different geographical distributions, the northernmost of which (Peru and northern Chile) was also observed in llamas, supporting the commonly held hypothesis that llamas were domesticated from the northernmost populations of guanacos (L. g. cacilensis). Southern guanacos shared the other two haplotypes. A second haplogroup, consisting of two haplotypes, was mostly present in vicuñas and alpacas. However, Y-chromosome variation did not distinguish the two subspecies of vicuñas.

Risk allelic load in Th2 and Th3 cytokines genes as biomarker of susceptibility to HPV-16 positive cervical cancer: a case control study.

BACKGROUND: Alterations in the host cellular immune response allow persistent infections with High-Risk Human Papillomavirus (HR-HPV) and development of premalignant cervical lesions and cervical cancer (CC). Variations of immunosuppressive cytokine levels in cervix are associated with the natural history of CC. To assess the potential role of genetic host immunity and cytokines serum levels in the risk of developing CC, we conducted a case-control study paired by age. METHODS: Peripheral blood samples from patients with CC (n = 200) and hospital controls (n = 200), were used to evaluate nine biallelic SNPs of six cytokine genes of the adaptive immune system by allelic discrimination and cytokines serum levels by ELISA. RESULTS: After analyzing the SNP association by multivariate logistic regression adjusted by age, CC history and smoking history, three Th2 cytokines (IL-4, IL-6 and IL-10) and one Th3 (TGFB1) cytokine were significantly associated with CC. Individuals with at least one copy of the following risk alleles: T of SNP (-590C > T IL-4), C of SNP (-573G > C IL-6), A of SNP (-592C > A IL-10), T of SNP (-819C > T IL-10) and T of SNP (-509C > T TGFB1), had an adjusted odds ratio (OR) of 2.08 (95 % CI 1.475-2.934, p = 0.0001), an OR of 1.70 (95 % CI 1.208-2.404, p = 0.002), an OR of 1.87 (95 % CI 1.332-2.630, p = 0.0001), an OR of 1.67 (95 % CI 1.192-2.353, p = 0.003) and an OR of 1.91 (95 % CI 1.354-2.701, p = 0.0001), respectively, for CC. The burden of carrying two or more of these risk alleles was found to have an additive effect on the risk of CC (p trend = 0.0001). Finally, the serum levels of Th2 and Th3 cytokines were higher in CC cases than the controls; whereas IFNG levels, a Th1 cytokine, were higher in controls than CC cases. CONCLUSION: The significant associations of five SNPs with CC indicate that these polymorphisms are potential candidates for predicting the risk of development of CC, representing a risk allelic load for CC and can be used as a biomarker of susceptibility to this disease.

Plasma exosome profiles from dairy cows with divergent fertility phenotypes.

Cell-to-cell communication in physiological and pathological conditions may be influenced by neighboring cells, distant tissues, or local environmental factors. Exosomes are specific subsets of extracellular vesicles that internalize and deliver their content to near and distant sites. Exosomes may play a role in the maternal-embryo crosstalk vital for the recognition and maintenance of a pregnancy; however, their role in dairy cow reproduction has not been established. This study aimed to characterize the exosome profile in the plasma of 2 strains of dairy cow with divergent fertility phenotypes. Plasma was obtained and characterized on the basis of genetic ancestry as fertile (FERT; <23% North American genetics, New Zealand Holstein-Friesian strain, n=8) or subfertile (SUBFERT; >92% North American genetics, North American Holstein-Friesian strain, n=8). Exosomes were isolated by differential and buoyant density centrifugation and characterized by size distribution (nanoparticle tracking analysis, NanoSight NS500, NanoSight Ltd., Amesbury, UK), the presence of CD63 (Western blot), and their morphology (electron microscopy). The total number of exosomes was determined by quantifying the immunoreactive CD63 (ExoELISA kit, System Biosciences), and the protein content established by mass spectrometry. Enriched exosome fractions were identified as cup-shape vesicles with diameters around 100 nm and positive for the CD63 marker. The concentration of exosomes was 50% greater in FERT cows. Mass spectrometry identified 104 and 117 proteins in FERT and SUBFERT cows, of which 23 and 36 were unique, respectively. Gene ontology analysis revealed enrichment for proteins involved in immunomodulatory processes and cell-to-cell communication. Although the role of exosomes in dairy cow reproduction remains to be elucidated, their quantification and content in models with divergent fertility phenotypes could provide novel information to support both physiological and genetic approaches to improving dairy cow fertility.

Prevalence and risk factors for allergic rhinitis in two resource-limited settings in Peru with disparate degrees of urbanization.

BACKGROUND: Allergic rhinitis is a disease with a high global disease burden, but risk factors that contribute to this condition are not well understood. OBJECTIVE: To assess the prevalence and risk factors of allergic rhinitis in two Peruvian populations with disparate degrees of urbanization. METHODS: We conducted a population-based, cross-sectional study on 1441 children aged 13-15 years at enrollment (mean age 14.9 years, 51% boys) to investigate the prevalence of allergic disease. We used a standardized, Spanish validated questionnaire to determine the prevalence of allergic rhinitis and asked about sociodemographics and family history of allergies. Children also underwent spirometry, exhaled nitric oxide, allergy skin testing to 10 common household allergens and provided a blood sample for measurement of 25OH vitamin D and total serum IgE. RESULTS: Overall prevalence of allergic rhinitis was 18% (95% CI 16% to 20%). When stratified by site, the prevalence of allergic rhinitis was 23% Lima vs. 13% in Tumbes (P < 0.001); however, this difference was no longer significant after controlling for subject-specific factors (P = 0.95). There was a strong association with other allergic diseases: 53% of children with asthma had allergic rhinitis vs. 15% in those without asthma (P < 0.001) and 42% of children with eczema vs. 17% of those without eczema (P < 0.001). Important risk factors for allergic rhinitis were parental rhinitis (adjusted OR = 3.0, 95% CI 1.9-4.7 for 1 parent and adjusted OR = 4.4, 95% CI 1.5-13.7 for 2 parents); allergic sensitization to common household aeroallergens (1.6, 1.1-2.3); being overweight (1.5, 1.0-2.3); exhaled nitric oxide ≥ 20 ppb (1.9, 1.3-2.7); and total serum IgE ≥ 95th percentile (2.4, 1.2-4.8). Population attributable risk of important factors for allergic rhinitis were 25% for high exhaled nitric oxide, 22% for allergic sensitization to common household aeroallergens, 22% for paternal rhinitis, 10% for being overweight and 7% for an elevated total serum IgE. CONCLUSION AND CLINICAL RELEVANCE: Allergic rhinitis was prevalent in both settings, and important risk factors include elevated exhaled nitric oxide, allergic sensitization to common household aeroallergens, parental rhinitis, being overweight and high total serum IgE. When considering subject-specific factors, the difference in prevalence between the urban and rural settings became non-important.

25-hydroxy vitamin D levels are associated with childhood asthma in a population-based study in Peru.

BACKGROUND: Vitamin D deficiency may be associated with an increased risk of asthma. OBJECTIVE: We studied the association between 25-hydroxy (25-OH) vitamin D deficiency and asthma prevalence in two Peruvian populations close to the equator but with disparate degrees of urbanization. METHODS: We conducted a population-based study in 1441 children in two communities in Peru, of which 1134 (79%) provided a blood sample for 25-OH vitamin D analysis. RESULTS: In these 1134 children, mean age was 14.8 years; 52% were boys; asthma and atopy prevalence was 12% in Lima vs. 3% in Tumbes (P < 0.001) and 59% in Lima vs. 41% in Tumbes (P < 0.001), respectively; and, mean 25-OH vitamin D level was 20.8 ng/mL in Lima vs. 30.1 ng/mL in Tumbes (P < 0.001). Prevalence of 25-OH vitamin D deficiency (< 20 ng/mL) was 47% in Lima vs. 7% in Tumbes (P < 0.001). In multi-variable logistic regression, we found that lower 25-OH vitamin D levels were associated with an increased odds of asthma (OR = 1.7 per each 10 ng/mL decrease in 25-OH vitamin D levels, 95% CI 1.2-2.6; P < 0.01). In stratified analyses, the association between lower 25-OH vitamin D levels and asthma was limited to children with atopy (OR = 2.2, 95% CI 1.3-3.6) and not in those without atopy (OR = 0.9, 95% CI 0.5-2.0). We did not find associations between 25-OH vitamin D levels and other clinical biomarkers for asthma, including exhaled nitric oxide, total serum IgE and pulmonary function. CONCLUSION AND CLINICAL RELEVANCE: Both asthma and 25-OH vitamin D deficiency were common among children living in Lima (latitude = 12.0 °S) but not among those in Tumbes (3.6 °S). The relationship between 25-OH vitamin D deficiency and asthma was similar in both sites and was limited among children with atopy. Future supplementation trials may need to consider stratification by atopy at the time of design.

Current laboratory practices in the diagnosis and management of haemophilia: a global assessment.

Haemophilia management is complicated by the extreme variability in laboratory practices. Lack of consistency or comparability in testing makes it difficult to establish diagnostic criteria or disease severity, and complicates response assessment. A global survey was conducted to document current practices. A 35-min survey was completed by 30 laboratory scientists in each of seven countries (France, Germany, Italy, Japan, Spain, UK, USA; 210 in total); results were weighted by average country testing volume in haemophilia. Eighty-three per cent of participants reported participation in a Quality Assurance scheme. Ninety per cent reported using clotting tests in haemophilia A and 88% in haemophilia B (55% and 53% frequent use respectively). Sixty-eight per cent reported chromogenic assays were used in haemophilia A, with only 23% reporting frequent use, compared to only 11% reporting any use in haemophilia B. Twenty-nine separate activated partial thromboplastin time (aPTT) reagents were reported for haemophilia A and 27 aPTT reagents were reported for haemophilia B, with one-quarter or less obtaining reagents or kits from any single manufacturer. Fifty-four per cent run a calibration curve with every factor VIII (FVIII) assay. The mean number of plasma dilutions varied from 2 to 4 for FVIII assays and from 1 to 3 for FIX assays. Results indicate very low consistency in materials and practices used to test for factor activity in haemophilia. A number of responses suggest that some laboratory scientists' understanding of best practices or guidelines in haemophilia could be improved. More education and broader understanding is recommended regarding assay types, assay components, test material and instrument features and capabilities.

Cross-amplification of nonspecific microsatellites markers: a useful tool to study endangered/vulnerable species of southern Andes deer.

Thirty-nine microsatellite loci that are highly conserved in red deer, sika deer, reindeer, Soay sheep, and other artiodactyls were tested in two vulnerable and endangered Neotropical deer (pudu: Pudu puda and huemul: Hippocamelus bisulcus) with the aim of producing a standardized set of markers that can be used successfully in noninvasive samples from these species. We also compared these nonspecific loci against eight polymorphic loci that were recently developed for huemul to determine whether the nonspecific markers could reflect the huemul's genetic variation that was observed with the specific loci. We identified 10 suitable loci, six of which constitute a standardized set for the two species and can be used to identify them in the absence of phenotypic data. The expected heterozygosity per locus for the panel of six loci ranged from 0.461 to 0.889 (average 0.665), and the maximum probability of identity value was 6.9x10(-6) and 3.2x10(-4) in pudu and huemul, respectively. This set of loci has potential applications in evolutionary, ecological, forensic, and conservation studies in pudu and huemul.

Adult child socio-economic status and older parents' psychosocial outcomes during the COVID-19 pandemic.

Purpose: Older adults' psychosocial outcomes during the COVID-19 pandemic have been inequitable by socio-economic status (SES). However, studies have focused solely on own SES, ignoring emerging evidence of the relationship between adult child SES and late-life health. We evaluated whether adult child educational attainment - a core marker of SES - is associated with older parents' psychosocial outcomes during the pandemic. Methods: We used data from the Survey of Health, Aging, and Retirement in Europe (SHARE; 2004-2018) and the SHARE Corona Surveys (2020 and 2021). We included 15,553 respondents > 65 years who had pre-pandemic information on adult child educational attainment, self-reported mental health, and worsened mental health compared to the pre-pandemic period. We used generalized estimating equations adjusted for respondent and family-level characteristics, including respondents' own SES. Results: Older adults whose adult children averaged levels of educational attainment at or above (vs. below) their country-specific mean had a lower prevalence of nervousness (Prevalence Ratio [PR]: 0.95, 95% Confidence Interval [CI]: 0.91, 0.99), depression (PR: 0.96, 95% CI: 0.92, 1.00), and trouble sleeping (PR: 0.96, 95% CI: 0.92, 1.00) during the pandemic; associations with loneliness were null. Overall associations with worsened mental health as compared to the pre-pandemic period were null. Protective associations were stronger in countries experiencing "high" levels of COVID-19 intensity. Conclusions: Adult child SES may be an important driver of inequities in older adults' mental health during the COVID-19 pandemic. Policies aimed at improving adult child SES may buffer the adverse psychosocial impacts of societal stressors.

Diversity of gut Bifidobacterium species is not altered between allergic and non-allergic French infants.

Some clinical studies have suggested a relationship between allergic diseases and gut microbiota. We aimed to study bifidobacterial colonization at species and strain levels in ten allergic French infants included at their first clinical consultation and 20 controls matching for age at sampling, mode of delivery, per partum antibiotics, type of feeding and antibiotics in the first weeks of life. The faecal microbiota was analyzed by culture methods and TTGE. Bifidobacterial species and strains were identified using multiplex PCR and Box-PCR fingerprinting. No differences were observed between groups in the number of colonized infants or in the levels of colonization by the main aerobic and anaerobic genera. All infants were colonized with high levels of Bifidobacterium except for one in each group. One to 5 Bifidobacterium species and 1 to 7 strains were observed per subject independently of allergic status and age at sampling. Our study showed the infants to be colonized by several species and strains, including several strains from the same species. This diversity in Bifidobacterium colonization was not related with the allergic status and showed that the link between Bifidobacterium colonization and allergic diseases is complex and cannot be restricted to the role attributed to Bifidobacterium species.

Effect of protamine in obesity induced by high-fat diets in rats.

OBJECTIVE: Protamine has been shown to have an inhibitory effect on protein lipase in vitro; the objective of this study was to evaluate the antiobesity activity effect of protamine in obese induced rats, and to evaluate the effect of protamine on postprandial hypertriacylglyceridemia in rats by intragastric administration of a lipid emulsion containing corn oil. DESIGN: Two experiments were carried out: (1) In a parallel study in rats, we administered a lipid emulsion containing corn oil plus 0, 200 or 500 mg kg(-1) of protamine intragastrically. (2) In a randomized parallel prospective rats experiment, rats were fed with a high-fat diet and 0, 200 or 500 mg of protamine per kg of animal weight during 5 weeks. SUBJECTS: Male Sprague-Dawley rats. MEASUREMENTS: In experiment 1, plasma triacylglycerol levels after oral administration of lipid emulsion were determined. In experiment 2, weight gain, concentrations of plasma triacylglycerol, plasma total cholesterol and albumin were determined, and the subcutaneous and visceral adipose tissues were weighed. RESULTS: Plasma triacylglycerol concentration in rats administered with 200 or 500 mg kg(-1) of protamine was significantly lower than that in rats in the control group (200 mg kg(-1) of protamine, P<0.05 at 1, 2, 3 and 4 h; 500 mg kg(-1) of protamine P<0.05 at 2, 3 and 4 h). In rats fed with a high-fat diet, and 200 and 500 mg kg(-1) of protamine, there was a decreased body weight gain by 52 and 66 g, respectively, reduced visceral fat by 5 and 8 g, respectively and subcutaneous tissue weights by 12 and 15 g, respectively. Plasma triacylglycerol was 17 and 45 mg per 100 ml lower in rats fed with high-fat diet plus 200 and 500 mg kg(-1) of protamine, respectively. And cholesterol concentrations were 18 and 22 mg per 100 ml lower in both protamine groups, respectively. CONCLUSION: Our study demonstrates that protamine reduce weight gain and body fat accumulation through the inhibition of dietary fat absorption.

Lactose drives Enterococcus expansion to promote graft-versus-host disease.

Disruption of intestinal microbial communities appears to underlie many human illnesses, but the mechanisms that promote this dysbiosis and its adverse consequences are poorly understood. In patients who received allogeneic hematopoietic cell transplantation (allo-HCT), we describe a high incidence of enterococcal expansion, which was associated with graft-versus-host disease (GVHD) and mortality. We found that Enterococcus also expands in the mouse gastrointestinal tract after allo-HCT and exacerbates disease severity in gnotobiotic models. Enterococcus growth is dependent on the disaccharide lactose, and dietary lactose depletion attenuates Enterococcus outgrowth and reduces the severity of GVHD in mice. Allo-HCT patients carrying lactose-nonabsorber genotypes showed compromised clearance of postantibiotic Enterococcus domination. We report lactose as a common nutrient that drives expansion of a commensal bacterium that exacerbates an intestinal and systemic inflammatory disease.

Extended embryo culture to increase implantation rate.

Multiple pregnancies are a serious adverse event of IVF treatment. Several strategies have been developed to improve embryo selection and embryo developmental potential to increase pregnancy rates without increasing the risk of multiple pregnancies. The only way to effectively solve this problem is to reduce the number of embryos transferred to one. The introduction of extended embryo culture has provided IVF programmes with a valuable tool to select more accurately those embryos with a higher implantation potential. The concept of single embryo transfer presents a clinical dilemma with seemingly opposing sides: one seeking to maintain acceptable pregnancy rates and the other seeking to reduce the number of twin births or high order multiple pregnancies. The present review addresses the potential benefits and drawbacks of blastocyst transfer.

[Factors involved in the burden of the primary caregiver of cancer patients]. / Factores que intervienen en la sobrecarga del cuidador primario del paciente con cáncer.

OBJECTIVE: The aim of the study was to identify the factors involved between burden in the primary caregiver of cancer patients and their quality of life. MATERIAL AND METHODS: A cross-sectional study was conducted in a secondary level hospital on 100 primary caregivers of cancer patients. The level of burden was determined using the Zarit scale and the perception of quality of life using the World Health Organisation Quality of Life questionnaire. Quality of life was categorised as high or low and compared between groups according to their level of burden. Descriptive statistics were performed on the study variables, and differences between groups were analysed according to their level of burden. RESULTS: In assessing the overload, it was found that 31% of caregivers had burden. A good quality of life was perceived by 76% of caregivers, while the remaining 24% perceived it as poor. To identify association between these two variables Chi squared (X2) was used to determine whether there was any association between quality of life and overloading of the primary caregiver, giving a P≤.05. A Spearman correlation was also performed, obtaining an r-value of .321 with a P≤.05, finding a slightly positive correlation. CONCLUSIONS: The factors that have a bearing on a good quality of life despite having burden were: being married, dedicated to the home, and kinship (to be immediate family: spouse, parents and children). Conversely, the type of cancer, sleep hours, and hours of care influence the perception of a poor quality of life.

Medical decision support systems and therapeutics: The role of autopilots.

For decades, medical practice has increasingly relied on prescription medicines to treat, cure, or prevent illness but their net benefit is reduced by prescribing errors that result in adverse drug reactions (ADRs) and tens of thousands of deaths each year. Optimal prescribing requires effective management of massive amounts of data. Clinical decision support systems (CDSS) can help manage information and support optimal therapeutic decisions before errors are made by operating as the prescribers' "autopilot."

Development of a Multicompartment Permeability-Limited Lung PBPK Model and Its Application in Predicting Pulmonary Pharmacokinetics of Antituberculosis Drugs.

Achieving sufficient concentrations of antituberculosis (TB) drugs in pulmonary tissue at the optimum time is still a challenge in developing therapeutic regimens for TB. A physiologically based pharmacokinetic model incorporating a multicompartment permeability-limited lung model was developed and used to simulate plasma and pulmonary concentrations of seven drugs. Passive permeability of drugs within the lung was predicted using an in vitro-in vivo extrapolation approach. Simulated epithelial lining fluid (ELF):plasma concentration ratios showed reasonable agreement with observed clinical data for rifampicin, isoniazid, ethambutol, and erythromycin. For clarithromycin, itraconazole and pyrazinamide the observed ELF:plasma ratios were significantly underpredicted. Sensitivity analyses showed that changing ELF pH or introducing efflux transporter activity between lung tissue and ELF can alter the ELF:plasma concentration ratios. The described model has shown utility in predicting the lung pharmacokinetics of anti-TB drugs and provides a framework for predicting pulmonary concentrations of novel anti-TB drugs.

Análisis Biomecánico de una Prótesis de Cadera mediante Elementos Finitos / Biomechanical Analysis of a Hip Prosthesis Using a Finite Element

Resumen En el presente trabajo se plantea un análisis biomecánico de una prótesis de cadera bajo condiciones de cargas estáticas asociadas a actividades cotidianas, en el cual se comparan tres materiales metálicos para la fabricación de una prótesis personalizada a partir de imágenes médicas. Se utilizaron plataformas en la nube de diseño asistido por computadora y de análisis por elementos finitos. Se diseñaron dos modelos de la prótesis a analizar, uno hueco y otro sólido mediante curvas spline paramétricas. Para el análisis biomecánico se requirió un tamaño de malla de 2,537,684 de elementos tetraédricos y 471,335 nodos para estudiar siete casos de posturas para una persona de 75 kg de peso, mismos que se analizaron tomando como materiales base acero inoxidable 316L, aleación Ti-6AL-4V y L-605. Se observó que con actividades tales como trotar, subir y bajar escaleras los materiales 316L y L-605, presentan el riesgo de deformación plástica e inclusive fractura. Los resultados mostraron que el material más idóneo para la fabricación de este tipo de prótesis es el Ti-6Al-4V, además de que este nos permite realizar modelos tanto sólidos como huecos, suponiendo este último, un ahorro de material y proporcionando mayor ligereza en la prótesis.

Abstract This paper shows a biomechanical analysis of a hip prosthesis under conditions of static loads associated with daily activities. For which it compared three metallic materials for the manufacture of a customized prosthesis from medical images, it was used cloud platforms with computer-aided design and finite element analysis. Two models of prosthesis one hollow and the other one solid using parametric spline curves were designed and analyzed. The biomechanical analysis required a mesh size consisting of 2,537,684 tetrahedral elements and 471,335 nodes to study seven cases of postures for a person weighing 75 kg. These cases were analyzed based on 316L stainless steel, Ti-6AL-4V alloy, and another L-605 alloy. It was observed that with activities such as jogging, climbing and descending stairs, materials 316L, and L-605 present the risk of plastic deformation and even fracture. The results show that the most suitable material for the manufacture of this type of prosthesis is the Ti-6Al-4V, which allows us to make both solid and hollow models. Assuming this last material is saved and improves the prosthesis lightness.

The future is now: model-based clinical trial design for Alzheimer's disease.

Failures in trials for Alzheimer's disease (AD) may be attributable to inadequate dosing, population selection, drug inefficacy, or insufficient design optimization. The Coalition Against Major Diseases (CAMD) was formed in 2008 to develop drug development tools (DDT) to expedite drug development for AD and Parkinson's disease. CAMD led a process that successfully advanced a clinical trial simulation (CTS) tool for AD through the formal regulatory review process at the US Food and Drug Administration (FDA) and European Medicines Agency (EMA).