A Survey of Availability and Affordability of Polypills for Cardiovascular Disease in Selected Countries.

Background: The recent inclusion of polypills-fixed-dose combinations of antihypertensive medicines and a statin with or without aspirin-in the World Health Organization's Essential Medicines List (EML) reiterates the potential of this approach to improve global treatment coverage for cardiovascular diseases (CVDs). Although there exists extensive evidence on the effectiveness, safety and acceptability of polypills, there has been no research to date assessing the real-world availability and affordability of polypills globally. Methods: We conducted a cross-sectional survey, based on the WHO/Health Action International methodology, in 13 countries around the world. In the surveyed countries, we first ascertained whether any polypill was authorised for marketing and/or included in EMLs and clinical guidelines. In each country, we collected retail and price data for polypills from at least one public-sector facility and three private pharmacies using convenience sampling. Polypills were considered unaffordable if the lowest-paid worker spent more than a day's wage to purchase a monthly supply. Results: Polypills were approved for marketing in four of the 13 surveyed countries: Spain, India, Mauritius and Argentina. None of these countries included polypills in national guidelines, formularies, or EMLs. In the four countries, no surveyed public pharmacies stocked polypills. In the private sector, we identified seven unique polypill combinations, marketed by eight different companies. Private sector availability was 100% in Argentina and Spain. Most combinations (n = 5) identified were in India. Combinations found in India and Spain were affordable in the local context. A lowest-paid government worker would spend between 0.2 (India) and 2.8 (Mauritius) days' wages to pay the price for one month's supply of the polypills. Polypills were likely to be affordable if they were manufactured in the same country. Conclusion: Low availability and affordability of polypills in the public sector suggest that implementation remains poor globally. Context-specific multi-disciplinary health system research is required to understand factors affecting polypill implementation and to design and evaluate appropriate implementation strategies.

Growth and Cognitive Development in Tanzanian Children are Associated with Timing of Birth in Relation to Seasonal Malnutrition.

OBJECTIVE: To evaluate in a rural Tanzanian birth cohort the association between birth timing in relation to the preharvest lean season and early-life growth and cognitive development. STUDY DESIGN: Children were enrolled within 14 days of birth and followed up for 18 months. Child anthropometry was measured every 3 months. The Malawi Developmental Assessment Test was administered at the end of follow-up. We estimated the association between timing of birth in the context of other early childhood risk factors and both growth and Malawi Developmental Assessment Test scores. RESULTS: Children born in the preharvest months September and October had the lowest cognitive scores at 18 months, compared with birth in July and August (-1.05 change in overall Malawi Developmental Assessment Test development-for-age Z score, 95% CI: -1.23, -0.86). This association was observed for the language (-1.67 change in development-for-age Z score; 95% CI: -1.93, -1.40) and fine motor subcomponent scores (-1.67; 95% CI: -1.96, -1.38) but not for gross motor (-0.07; 95% CI: -0.23, 0.10) or social subcomponents (-0.07; 95% CI: -0.23, 0.10). Children born in September and October were the longest at birth but had the largest declines in growth Z scores during the first 6 months. CONCLUSIONS: There was a strong association between birth at the beginning of the preharvest season and poor growth and cognitive development. If these associations were mediated by the preharvest postnatal environment, targeted maternal and child interventions for children born during high-risk periods may improve these outcomes. TRIAL REGISTRATION: NCT03268902 (https://clinicaltrials.gov/study/NCT03268902).

Implementing integrated hypertension and diabetes management using the World Health Organization's HEARTS model: protocol for a pilot study in the Guatemalan national primary care system.

BACKGROUND: The HEARTS technical package was developed by the World Health Organization to address the implementation gap in cardiovascular disease prevention in low- and middle-income countries. Guatemala is a middle-income country that is currently implementing HEARTS. National authorities in Guatemala are interested in exploring how hypertension and diabetes management can be integrated in HEARTS implementation. The objective of this study is to conduct a feasibility and acceptability pilot trial of integrated hypertension and diabetes management based on HEARTS in the publicly funded primary care system in Guatemala. METHODS: A single-arm pilot trial for 6 months will be carried out in 11 Ministry of Health primary care facilities starting in September 2023. A planned sample of 100 adult patients diagnosed with diabetes (n = 45), hypertension (n = 45), or both (n = 10) will be enrolled. The intervention will consist of HEARTS-aligned components: Training health workers on healthy-lifestyle counseling and evidence-based treatment protocols, strengthening access to medications and diagnostics, training on risk-based cardiovascular disease management, team-based care and task sharing, and systems monitoring and feedback, including implementation of a facility-based electronic monitoring tool at the individual level. Co-primary outcomes of feasibility and acceptability will be assessed using an explanatory sequential mixed-methods design. Secondary outcomes include clinical effectiveness (treatment with medication, glycemic control, and blood pressure control), key implementation outcomes (adoption, fidelity, usability, and sustainability), and patient-reported outcome measures (diabetes distress, disability, and treatment burden). Using an implementation mapping approach, a Technical Advisory Committee will develop implementation strategies for subsequent scale-up planning. DISCUSSION: This trial will produce evidence on implementing HEARTS-aligned hypertension and diabetes care in the MOH primary care system in Guatemala. Results also will inform future HEARTS projects in Guatemala and other low- and middle-income countries. TRIAL REGISTRATION: ClinicalTrials.gov ID NCT06080451. The trial was prospectively registered on October 12, 2023.

Treatment outcomes for ARUBA-eligible brain arteriovenous malformations: a comparison of real-world data from the NVQI-QOD AVM registry with the ARUBA trial.

BACKGROUND: Significant controversy exists about the management of unruptured cerebral arteriovenous malformations (AVMs). Results from A Randomized Trial of Unruptured Brain Arteriovenous Malformations (ARUBA) suggested that intervention increases the risk of stroke/death compared with medical management. However, numerous study limitations raised concerns about the trial's generalizability. OBJECTIVE: To assess the rate of stroke/death and functional outcomes in ARUBA-eligible patients from a multicenter database, the Neurovascular Quality Initiative-Quality Outcomes Database (NVQI-QOD). METHODS: We performed a retrospective analysis of prospectively collected data of ARUBA-eligible patients who underwent intervention at 18 participating centers. The primary endpoint was stroke/death from any cause. Secondary endpoints included neurologic, systemic, radiographic, and functional outcomes. RESULTS: 173 ARUBA-eligible patients underwent intervention with median follow-up of 269 (25-722.5) days. Seventy-five patients received microsurgery±embolization, 37 received radiosurgery, and 61 received embolization. Baseline demographics, risk factors, and general AVM characteristics were similar between groups. A total of 15 (8.7%) patients experienced stroke/death with no significant difference in primary outcome between treatment modalities. Microsurgery±embolization was more likely to achieve AVM obliteration (P<0.001). Kaplan-Meier survival curves demonstrated no difference in overall death/stroke outcomes between the different treatment modalities' 5-year period (P=0.087). Additionally, when compared with the ARUBA interventional arm, our patients were significantly less likely to experience death/stroke (8.7% vs 30.7%; P<0.001) and functional impairment (mRS score ≥2 25.4% vs 46.2%; P<0.01). CONCLUSION: Our results suggest that intervention for unruptured brain AVMs at comprehensive stroke centers across the United States is safe.

Costs of Care for Operative and Nonoperative Management of Emergency General Surgery Conditions.

OBJECTIVE: Many emergency general surgery (EGS) conditions can be managed operatively or nonoperatively, with outcomes that vary by diagnosis. We hypothesized that operative management would lead to higher in-hospital costs but to cost savings over time. BACKGROUND: EGS conditions account for $28 billion in health care costs in the United States annually. Compared with scheduled surgery, patients who undergo emergency surgery are at increased risk of complications, readmissions, and death, with accompanying costs of care that are up to 50% higher than elective surgery. Our prior work demonstrated that operative management had variable impacts on clinical outcomes depending on the EGS condition. METHODS: This was a nationwide, retrospective study using fee-for-service Medicare claims data. We included patients 65.5 years of age or older with a principal diagnosis for an EGS condition 7/1/2015-6/30/2018. EGS conditions were categorized as: colorectal, general abdominal, hepatopancreaticobiliary (HPB), intestinal obstruction, and upper gastrointestinal. We used near-far matching with a preference-based instrumental variable to adjust for confounding and selection bias. Outcomes included Medicare payments for the index hospitalization and at 30, 90, and 180 days. RESULTS: Of 507,677 patients, 30.6% received an operation. For HPB conditions, costs for operative management were initially higher but became equivalent at 90 and 180 days. For all others, operative management was associated with higher inpatient costs, which persisted, though narrowed, over time. Out-of-pocket costs were nearly equivalent for operative and nonoperative management. CONCLUSIONS: Compared with nonoperative management, costs were higher or equivalent for operative management of EGS conditions through 180 days, which could impact decision-making for clinicians, patients, and health systems in situations where clinical outcomes are similar.

Seeing Through the Blind: Belief about Treatment Randomization and Smoking Cessation Outcome among People with Current or Past Major Depressive Disorder who Smoke in a Placebo-Controlled Trial of Varenicline.

INTRODUCTION: Blinding participants to randomization is a cornerstone of science. However, participant beliefs about their allocation can influence outcomes. We examined blind integrity, the association between trial arm belief and cessation, and potential mechanisms linking treatment arm and treatment arm belief among people with major depressive disorder (MDD) who smoke receiving varenicline in a placebo-controlled trial. METHODS: 175 participants were asked at the end of treatment (EOT) if they thought they received placebo, varenicline, or were not sure. We assessed the relationship between treatment arm belief and actual treatment allocation, examined the association between treatment arm belief and EOT cessation, and evaluated changes in craving, withdrawal, side effects, depression symptoms, and smoking reward as mediators through which treatment arm was believed. RESULTS: Treatment arm belief was significantly associated with actual arm assignment (χ2(2)=13.0, p=0.002). Participants in the varenicline arm were >3 times as likely to believe they were taking varenicline, vs. "not sure" (RR=3.05 [1.41-6.60], p=0.005). Participants in the placebo arm were just as likely to believe they were taking placebo vs. "not sure" (χ2[2]=0.75, p=0.69). Controlling for treatment arm, belief that one received varenicline was significantly associated with an increase in cessation rate (OR=5.91 [2.06-16.92], p=0.001). Change in the rewarding experience of smoking may mediate participant ability to discern getting varenicline B=0.077 [0.002-0.192], p <0.05). CONCLUSIONS: Participants receiving varenicline can discern that they received varenicline and this belief is associated with higher cessation rates. Research is needed to continue to examine how participants correctly identify their allocation to varenicline.

Evaluation of Vector-Enabled Xenosurveillance in Rural Guatemala.

Surveillance methods that permit rapid detection of circulating pathogens in low-resource settings are desperately needed. In this study, we evaluated a mosquito bloodmeal-based surveillance method ("xenosurveillance") in rural Guatemala. Twenty households from two villages (Los Encuentros and Chiquirines) in rural southwest Guatemala were enrolled and underwent weekly prospective surveillance from August 2019 to December 2019 (16 weeks). When febrile illness was reported in a household, recently blood-fed mosquitoes were collected from within dwellings and blood samples taken from each member of the household. Mosquitoes were identified to species and blood sources identified by sequencing. Shotgun metagenomic sequencing was used to identify circulating viruses. Culex pipiens (60.9%) and Aedes aegypti (18.6%) were the most abundant mosquitoes collected. Bloodmeal sources were most commonly human (32.6%) and chicken (31.6%), with various other mammal and avian hosts detected. Several mosquito-specific viruses were detected, including Culex orthophasma virus. Human pathogens were not detected. Therefore, xenosurveillance may require more intensive sampling to detect human pathogens in Guatemala and ecologically similar localities in Central America.

Changes to physical activity behavior during the COVID-19 pandemic and their associated factors: a cross sectional survey of Mexican women.

BACKGROUND: On March 24, 2020, the Mexican Government established social distancing measures to address the outbreak of the COVID-19 pandemic. The resulting home confinement affected daily lifestyle habits such as eating, sleeping, and physical activity (PA). The objectives of this study were to determine changes in PA behaviors among Mexican women due to the COVID-19 pandemic and to assess potential factors associated with these changes. METHODS: This was a cross-sectional study based on an anonymous online questionnaire developed by the Task Force on Physical Activity for Persons with Disabilities (PAPD) within the International Society of Physical and Rehabilitation Medicine (ISPRM). Descriptive, quantitative statistics were used for data analysis. A Chi-squared (χ²) test was used to explore associations between dependent and independent variables. RESULTS: A total of 1882 surveys were completed. Among the respondents, 53.3% declared that their PA was reduced during the pandemic, 26.6% reported similar PA behavior, and 20.1% declared that their PA had increased during the pandemic. Lower PA behavior during the pandemic was associated with lower education levels, stricter pandemic constraints, obesity, and lower self-perceived functioning levels. A statistically significant association between poorer self-perceived mental health and decreased PA behaviors was also found. Respondents who were younger, self-perceived as unimpaired, not overweight, and whose income was not impacted by COVID-19 were associated with higher levels of reported physical and mental health. CONCLUSIONS: The study results identify disparities experienced in PA behavior during the COVID-19 pandemic among Mexican women and highlights the need for social support for PA participation.

New U-Pb geochronology for the Central Atlantic Magmatic Province, critical reevaluation of high-precision ages and their impact on the end-Triassic extinction event.

The end-Triassic extinction (ETE) event represents one of the 'big five' episodes of mass extinction. The leading hypothesis for the cause of the ETE is the intrusion of voluminous magmas of the Central Atlantic Magmatic Province (CAMP) into carbon-rich sediments of two South American sedimentary basins, around 201.5 Ma. The timing of dikes and sills emplacement, however, must be considered in light of age models from CAMP rocks occurring in North America. In this work, we present new high-precision ages for critical samples in NE Brazil (201.579 ± 0.057 Ma) and Canada (201.464 ± 0.017 Ma), in order to evaluate how the South and North American magmatic events compare at the 100-ka level, and to the ETE timing. We also discuss inter-laboratory reproducibility of high-precision CAMP ages, including the 230Th disequilibrium corrections that are made to zircon U-Pb dates. Our findings in this newly discovered extension of the CAMP large igneous province in NE Brazil support the hypothesis that the CAMP may be responsible for the ETE through the triggering of greenhouse gas release from magma-evaporite interactions (contact metamorphism) in the South American basins.

Healthcare provider's perspectives on home blood pressure management in Peru and Cameroon: Findings from the BPMONITOR study.

Home blood pressure management, including self-monitoring and medication self-titration, is an efficient and cost-effective tool. Although its use is increasing globally, little is known about the feasibility of such interventions in low and middle-income countries. Further, the perspectives and experiences of healthcare providers who play a big role in ensuring the success of home blood pressure management interventions have not been documented. This qualitative study was conducted with a total of 35 healthcare providers (60% female, mean [SD] age = 37.3 [6.9 years] years), through 4 in-depth interviews from Peru, and 8 in-depth interviews and 4 focus groups from Cameroon. Study participants (healthcare providers) include physicians (primary care physicians), specialists (cardiologists and geriatricians), and nurses that were purposively recruited from two hospitals in two of the largest cities in both countries. Results were thematically analyzed by two researchers. Themes derived were related to feasibility and acceptability, and largely reflected providers in both countries endorsing home blood pressure management. Providers' concerns were in three main areas; 1) safety of patients when they self-titrate medications, 2) resources such as healthcare financing, local hospital policies that support communications with patients for home blood pressure management, and 3) sustainability through patient adherence, incorporating home blood pressure management within clinical guidelines and hospital policies, and complementing with continued health education and lifestyle modifications. According to providers, home blood pressure management may be feasible and acceptable if tailored multi-faceted protocols were introduced bearing in mind local contexts.

Testing the stress gradient hypothesis in soil bacterial communities associated with vegetation belts in the Andean Atacama Desert.

BACKGROUND: Soil microorganisms are in constant interaction with plants, and these interactions shape the composition of soil bacterial communities by modifying their environment. However, little is known about the relationship between microorganisms and native plants present in extreme environments that are not affected by human intervention. Using high-throughput sequencing in combination with random forest and co-occurrence network analyses, we compared soil bacterial communities inhabiting the rhizosphere surrounding soil (RSS) and the corresponding bulk soil (BS) of 21 native plant species organized into three vegetation belts along the altitudinal gradient (2400-4500 m a.s.l.) of the Talabre-Lejía transect (TLT) in the slopes of the Andes in the Atacama Desert. We assessed how each plant community influenced the taxa, potential functions, and ecological interactions of the soil bacterial communities in this extreme natural ecosystem. We tested the ability of the stress gradient hypothesis, which predicts that positive species interactions become increasingly important as stressful conditions increase, to explain the interactions among members of TLT soil microbial communities. RESULTS: Our comparison of RSS and BS compartments along the TLT provided evidence of plant-specific microbial community composition in the RSS and showed that bacterial communities modify their ecological interactions, in particular, their positive:negative connection ratios in the presence of plant roots at each vegetation belt. We also identified the taxa driving the transition of the BS to the RSS, which appear to be indicators of key host-microbial relationships in the rhizosphere of plants in response to different abiotic conditions. Finally, the potential functions of the bacterial communities also diverge between the BS and the RSS compartments, particularly in the extreme and harshest belts of the TLT. CONCLUSIONS: In this study, we identified taxa of bacterial communities that establish species-specific relationships with native plants and showed that over a gradient of changing abiotic conditions, these relationships may also be plant community specific. These findings also reveal that the interactions among members of the soil microbial communities do not support the stress gradient hypothesis. However, through the RSS compartment, each plant community appears to moderate the abiotic stress gradient and increase the efficiency of the soil microbial community, suggesting that positive interactions may be context dependent.

COVID-19 contagious health care personnel 5-day early return-to-work program.

BACKGROUND: COVID-19 contagious health care personnel (HCP) who are self-isolating for a 10-day period increases burden to workforce shortages. Implementation of a 5-day early return-to-work (RTW) program may reduce self-isolation periods, without increasing transmission risk, during the COVID-19 pandemic. DESIGN AND METHODS: This observational cohort quality improvement study included newly diagnosed COVID-19 HCP at a multifacility health care system. The program allowed HCP to return to work 6 days after date of a positive test result if they were not immunocompromised, had mild and improving symptoms, and self-reported a SARS-CoV-2 antigen negative test on day 5. RESULTS: Between January 4 and April 3, 2022, 1,023 HCP self-enrolled and 344 (33.6%) self-reported negative test results. Among these, 161 (46.8%) self-reported negative test results on day 5 and were eligible for early RTW on day 6. A total of 714 days were saved from missed work in self-isolation. The number of tests purchased, dispensed, and reported per day of HCP time saved was 4.4. No transmission events were observed originating from HCP who participated in early RTW. CONCLUSION: Implementing a 5-day early RTW program that includes HCP self-reporting SARS-CoV-2 antigen test results can increase staffing availability, while maintaining a low risk of SARS-CoV-2 transmission.

UV Inactivation of Common Pathogens and Surrogates Under 222 nm Irradiation from KrCl* Excimer Lamps.

Germicidal ultraviolet (UV) devices have been widely used for pathogen disinfection in water, air, and on food and surfaces. Emerging UV technologies, like the krypton chloride (KrCl*) excimer emitting at 222 nm, are rapidly gaining popularity due to their minimal adverse effects on skin and eyes compared with conventional UV lamps emitting at 254 nm, opening opportunities for UV disinfection in occupied public spaces. In this study, inactivation of seven bacteria and five viruses, including waterborne, foodborne and respiratory pathogens, was determined in a thin-film aqueous solution using a filtered KrCl* excimer emitting primarily at 222 nm. Our results show that the KrCl* excimer can effectively inactivate all tested bacteria and viruses, with most microorganisms achieving more than 4-log (99.99%) reduction with a UV dose of 10 mJ cm-2 . Compared with conventional UV lamps, the KrCl* excimer lamp exhibited better disinfection performance for viruses but was slightly less effective for bacteria. The relationships between UV sensitivities at 222 and 254 nm for bacteria and viruses were evaluated using regression analysis, resulting in factors that could be used to estimate the KrCl* excimer disinfection performance from well-documented UV kinetics using conventional 254 nm UV lamps. This study provides fundamental information for pathogen disinfection when employing KrCl* excimers.

Psychometric Properties of the Fear of COVID-19 Scale: a Response to Mercado-Lara et al. "Validity and Reliability of the Spanish Version of Fear of COVID-19 Scale in Colombian Physicians".

A paper reporting the psychometric properties of the Spanish Fear of COVID-19 Scale (FCV-19S) among Colombian physicians was recently published in the International Journal of Mental Health and Addiction. Although we welcome the translation and validation of our seven-item scale, this commentary outlines some major concerns we have with the study especially the removal of two items in developing a five-item FCV-19S. Based on these concerns, we strongly recommend that healthcare providers and researchers should use the five-item FCV-19S with caution.

A potential syndemic effect associated with symptoms of depression among men who have sex with men.

INTRODUCTION: Globally, depression rates are high among men who have sex with men (MSM). Multiple factors may interact synergistically to increase this risk. This analysis assessed the prevalence of symptoms of depression among MSM in Brazil and synergistic effects of several factors. METHODS: Cross-sectional study conducted in 12 cities using respondent-driven sampling. Sociodemographic and behavioral characteristics were collected. The PHQ-9 was used to screen for depression. Having moderate-severe depressive symptoms was compared to none-mild using logistic regression. The syndemic factor was a composite of hazardous alcohol use, sexual violence, and discrimination due to sexual orientation. Those with one to three of these factors were compared to those with none. RESULTS: The weighted prevalence of moderate-severe depressive symptoms was 24.9% (95%CI = 21.8-28.8) and 16.2%, 22.9%, 46.0% and 51.0% when none, one, two, or three syndemic factors were present, respectively, indicating a dose-response effect. Perception of HIV risk, high level of HIV knowledge, known HIV infection, and health self-rated as poor or very poor were also associated with depressive symptoms. CONCLUSION: The prevalence of moderate-severe depressive symptoms among MSM in Brazil is high, and selected factors act synergistically in increasing their prevalence. Public health policies should consider holistic depression prevention and treatment interventions for this population.

A potential syndemic effect associated with symptoms of depression among men who have sex with men

Introduction: Globally, depression rates are high among men who have sex with men (MSM). Multiple factors may interact synergistically to increase this risk. This analysis assessed the prevalence of symptoms of depression among MSM in Brazil and synergistic effects of several factors. Methods: Cross-sectional study conducted in 12 cities using respondent-driven sampling. Sociodemographic and behavioral characteristics were collected. The PHQ-9 was used to screen for depression. Having moderate-severe depressive symptoms was compared to none-mild using logistic regression. The syndemic factor was a composite of hazardous alcohol use, sexual violence, and discrimination due to sexual orientation. Those with one to three of these factors were compared to those with none. Results: The weighted prevalence of moderate-severe depressive symptoms was 24.9% (95%CI = 21.8-28.8) and 16.2%, 22.9%, 46.0% and 51.0% when none, one, two, or three syndemic factors were present, respectively, indicating a dose-response effect. Perception of HIV risk, high level of HIV knowledge, known HIV infection, and health self-rated as poor or very poor were also associated with depressive symptoms. Conclusion: The prevalence of moderate-severe depressive symptoms among MSM in Brazil is high, and selected factors act synergistically in increasing their prevalence. Public health policies should consider holistic depression prevention and treatment interventions for this population.

Effects of Essential Amino Acid Deficiency on General Control Nonderepressible 2/Eukaryotic Initiation Factor 2 Signaling and Proteomic Changes in Primary Bovine Mammary Epithelial Cells.

We hypothesized that the general control nonderepressible 2 (GCN2)/eukaryotic initiation factor 2 (eIF2) signaling pathway and intracellular protein synthesis (PS) are regulated to maintain milk PS in primary bovine mammary epithelial cells (MECs) under essential amino acid (EAA) starvation conditions. We cultured MECs with 0%, 2% (depletion), and 100% (control) EAA for two exposure times (8 and 24 h), followed by three refeeding (RF) times with 100% EAA (0, 8, and 24 h). Subsequently, we measured cell viability, total protein concentration, and proliferation. Western blotting was used to quantify the levels of casein and the expression of total GCN2 and eIF2, as well as phosphorylated GCN2 (GCN2P) and eIF2 (eIF2P). The ISOQuant method was used to assess MEC proteomes, and the resultant data were analyzed using the Kruskal−Wallis test, nonpaired Wilcoxon rank post-hoc test, and ANOVA−Tukey test, as well as principal component analyses and multiple regressions models. Differences in cell viability were observed between the control versus the depleted and repleted MECs, respectively, where 97.2−99.8% viability indicated low cell death rates. Proliferation (range, 1.02−1.55 arbitrary units (AU)) was affected by starvation for 12 and 24 h and repletion for 24 h, but it was not increased compared with the control. Total protein expression was unaffected by both depletion and repletion treatments (median 3158 µg/mL). eIF2P expression was significantly increased (p < 0.05) after treatment with 2% EAA for 8 and 24 h compared with 2% EAA with 8 h + 24 h RF and 2% EAA with 24 h + 8 h RF. GCN2P also showed significantly increased expression (p < 0.05) after treatment with 2% EAA for 24 h compared with the control and 2% EAA with 24 h + 8 h RF. Intracellular casein/α-tubulin expression was unaffected by 2% EAA compared with control (0.073 ± 0.01 AU versus 0.086 ± 0.02 AU, respectively). We studied 30 of the detected 1180 proteins, 16 of which were differentially expressed in starved and refed MECs. Cells faced with EAA deficiency activated the GCN2P/eIF2P pathway, and the lack of change in the levels of casein and other milk proteins suggested that the EAA deficit was mitigated by metabolic flexibility to maintain homeostasis.

Population Pharmacokinetic Model of Piperacillin in Critically Ill Patients and Describing Interethnic Variation Using External Validation.

Objectives: This study aimed to develop a piperacillin population PK model for critically ill Brazil-ian patients and describe interethnic variation using an external validation. Methods: Plasma samples were obtained from 24 ICU patients during the fifth day of piperacillin treatment and assayed by HPLC-UV. Population pharmacokinetic modelling was conducted using Pmetrics. Empiric dose of 4 g IV 6- and 8-hourly were simulated for 50 and 100% fT > MIC and the probabil-ity of target attainment (PTA) and the fractional target attainment (FTA) determined. Results: A two-compartment model was designed to describe the pharmacokinetics of critically ill Brazillian patients. Clearance and volume of distribution were (mean ± SD) 3.33 ± 1.24 L h−1 and 10.69 ± 4.50 L, respectively. Creatinine clearance was positively correlated with piperacillin clearance and a high creatinine clearance was associated with lower values of PTA and FTA. An external vali-dation was performed using data from two different ethnic ICU populations (n = 30), resulting in acceptable bias and precision. Conclusion: The primary pharmacokinetic parameters obtained from critically ill Brazilian patients were similar to those observed in studies performed in critically ill patients of other ethnicities. Based on our results, the use of dose adjustment based on creati-nine clearance is required in Brazilian patients.