Major Publications in the Critical Care Pharmacotherapy Literature: 2023.

OBJECTIVES: We aimed to summarize the most significant and impactful publications describing the pharmacotherapeutic care of critically ill patients in 2023. DATA SOURCES: PubMed/MEDLINE and the Clinical Pharmacy and Pharmacology Pharmacotherapy Literature Update. STUDY SELECTION: Randomized controlled trials and prospective studies of adult critically ill patients assessing a pharmacotherapeutic intervention and reporting clinical endpoints published between January 1, 2023, and December 31, 2023, were eligible for inclusion in this article. DATA EXTRACTION: Articles from a systematic search and the Clinical Pharmacy and Pharmacology Pharmacotherapy Literature Update were included. An a priori defined three-round modified Delphi process was employed to achieve consensus on the most impactful publications based on the following considerations: 1) overall contribution to scientific knowledge and 2) novelty to the literature. DATA SYNTHESIS: The systematic search and Clinical Pharmacy and Pharmacology Pharmacotherapy Literature Update returned a total of 1202 articles, of which 1164 were excluded. The remaining 38 articles underwent a three-round modified Delphi process. In each round, articles were independently scored based on overall contribution to scientific knowledge and novelty to the literature. Included articles are summarized and their impact discussed. Article topics included hydrocortisone for severe community-acquired pneumonia, inhaled amikacin for prevention of ventilator-associated pneumonia, methylene blue for septic shock, restrictive vs. liberal fluid management for sepsis-induced hypotension, andexanet alfa for major bleeding associated with factor Xa inhibitors, and early administration of four-factor prothrombin complex concentrate in patients with trauma at risk for massive transfusion. CONCLUSIONS: This review provides a summary and perspective on the potential impact of the most relevant articles in 2023 describing advances in the pharmacotherapeutic care of critically ill patients.

A prefrontal-periaqueductal gray pathway differentially engages autonomic, hormonal, and behavioral features of the stress coping response.

Activation of autonomic and hypothalamo-pituitary-adrenal (HPA) systems occur interdependently with behavioral adjustments under varying environmental demands. Nevertheless, laboratory rodent studies examining the neural bases of stress responses have generally attributed increments in these systems to be monolithic, regardless of whether an active or passive coping strategy is employed. Using the shock probe defensive burying test (SPDB) to measure stress-coping features naturalistically in male and female rats, we identify a neural pathway whereby activity changes may promote distinctive response patterns of hemodynamic and HPA indices typifying active and passive coping phenotypes. Optogenetic excitation of the rostral medial prefrontal cortex (mPFC) input to the ventrolateral periaqueductal gray (vlPAG) decreased passive behavior (immobility), attenuated the glucocorticoid hormone response, but did not prevent arterial pressure and heart rate increases associated with rats' active behavioral (defensive burying) engagement during the SPDB. By contrast, inhibition of the same pathway increased behavioral immobility and attenuated hemodynamic output but did not affect glucocorticoid increases. Correlational analyses confirmed that hemodynamic increments occurred preferentially during active behaviors, and decrements during immobility epochs, whereas pathway manipulations, regardless of the directionality of effect, weakened the correlational relationship. Finally, neuroanatomical evidence indicated that the influence of the rostral mPFC-vlPAG pathway on coping response patterns are mediated predominantly through GABAergic neurons within vlPAG. These data highlight the importance of this prefrontal-midbrain connection in organizing stress-coping responses, and in coordinating bodily systems with behavioral output for adaptation to aversive experiences.Significance statement Organisms maximize fitness by exhibiting distinct stress-coping responses that are specific to a particular challenge. However, the neurobiology underlying cortical control over coping styles is poorly understood. We reveal a novel role for a prefrontal-to-ventrolateral periaqueductal gray pathway in regulating active versus passive stress-coping response patterns in rats. Optogenetic excitation of this pathway decreased behavioral passivity, attenuated stress-induced glucocorticoid increases, but did not prevent associated increases in autonomic output. Pathway inhibition increased behavioral passivity, attenuated autonomic output, but did not affect glucocorticoid increases. These data highlight the importance of this prefrontal-midbrain connection in organizing stress-coping responses, and in coordinating bodily systems with behavioral output for adaptation to aversive experiences.

Effect of standardized ileal digestible arginine:lysine on growth performance of 6- to 13-kg nursery pigs.

A total of 480 newly weaned pigs (PIC 337 × 1050; Genus, Hendersonville, TN) with an initial body weight (BW) of 6.20 ±â€…0.61 kg were used in a dose-response study to investigate the impact of increasing standardized ileal digestible (SID) Arg:Lys on nursery pig growth performance. At weaning, pigs were placed into 48 pens with 5 barrows and 5 gilts per pen. Pens were randomly assigned to 1 of 6 dietary treatments. The experimental diets were formulated with increasing SID Arg:Lys, achieved by substituting corn starch, glycine, and l-alanine with l-arginine, resulting in SID Arg:Lys ranging from 45% to 145%. Diets were sublimiting in SID Lys and exceeded all other essential amino acid requirements. The experimental diets were fed across two feeding phases from days 0 to 10 and 10 to 27, with adjustments made to account for the Lys requirement of the pigs. All pens were placed on a common diet for the remaining 14 d of the study to evaluate carryover effects. Pigs and feeders were weighed at the start and end of each phase to calculate average daily gain (ADG), average daily feed intake (ADFI), and feed efficiency (G:F). Data were analyzed according to a linear regression model, which included the linear and quadratic effects of SID Arg:Lys and initial BW. Pen was the experimental unit, and results were considered significant at P ≤ 0.05 and a tendency at 0.50 < P ≤ 0.10. From days 0 to 27, Arg:Lys tended to have a quadratic effect on ADFI (P = 0.058), where 97.00 ±â€…7.631% SID Arg:Lys maximized feed intake. Similarly, Arg:Lys had a quadratic impact on ADG (P = 0.046), where ADG was maximized at a SID Arg:Lys of 95.65 ±â€…7.165. Correspondingly, Arg:Lys had a quadratic effect on pig BW on day 27 (P = 0.014). These effects were carried through the end of the study, where Arg:Lys quadratically impacted days 0 to 41 ADFI (P = 0.006), ADG (P = 0.077), and day 41 BW (P = 0.028). There was no evidence of an effect of SID Arg:Lys on G:F throughout the study (P ≥ 0.315). In conclusion, SID Arg:Lys quadratically impacted ADFI and ADG in 6- to 13-kg nursery pigs, where ADFI was maximized at a SID Arg:Lys of 97.00% (95% CI [81.6%, 112.4%]), and ADG was maximized at a SID Arg:Lys of 95.65% (95% CI [81.2%, 110.1%]). Together, these data suggest that the SID Arg:Lys requirement of nursery pigs is at least 81%, based on the lower bounds of the 95% CI for maximum ADG and ADFI, and excessive Arg supplementation may negatively affect growth performance.

Arginine is considered a conditionally essential amino acid (EAA) in swine, meaning that under certain circumstances, the rate of Arg utilization is greater than endogenous synthesis, resulting in a dietary Arg requirement to meet the pig's needs for growth and other biological functions. Our group and others have shown benefits to feeding Arg levels above the NRC (2012) estimated requirement; however, there has been a lack of research to determine the SID Arg requirement relative to lysine in young pigs. Therefore, the objective of this study was to determine the optimal dietary SID Arg:Lys to maximize growth performance in 6- to 13-kg nursery pigs. In the current trial, average daily gain (ADG) and average daily feed intake (ADFI) responded quadratically to increasing SID Arg:Lys from 45% to 145%, where ADFI was maximized at a SID Arg:Lys of 97.00% (95% CI [81.6%, 112.4%]) and ADG was maximized at 95.65% (95% CI [81.2%, 110.1%]). Together, the results of this study suggest the SID Arg:Lys requirement of 6- to 13-kg nursery pigs is at least 81%, based on the lower bounds of the 95% confidence intervals for maximum ADG and ADFI, but excess supplementation may reduce performance.

Oebalus pugnax (Hemiptera: Pentatomidae) resistance to lambda-cyhalothrin in Texas and efficacy of 2 alternative insecticides in grain sorghum.

Along the Coastal Bend of Texas, the rice stink bug, Oebalus pugnax (F.), is a major pest of grain sorghum and rice that is primarily managed by insecticide applications. Reports of rice stink bug resistance to pyrethroids in Texas first surfaced in 2015 and continued to spread. To determine the status of pyrethroid resistance, rice stink bug populations across Texas and Louisiana were evaluated from 2021 to 2023. Mortality was assessed through glass vial exposures to eight concentrations (0, 0.03, 0.1, 0.3, 1, 3, 10, and 30 µg/vial) of a pyrethroid, lambda-cyhalothrin. The concentration of lambda-cyhalothrin required to kill 50% (LC50) of each population was estimated by probit analysis. Furthermore, the efficacy of insecticides, including lambda-cyhalothrin, dimethoate, and dinotefuran, were evaluated in field experiments conducted in 2021. Our results indicated that 14 of the 21 rice stink bug populations sampled were resistant to lambda-cyhalothrin, with LC50 values ranging from 42 to 1,600 times higher than a susceptible population. In the field trial, lambda-cyhalothrin did not control rice stink bugs. Dinotefuran provided excellent control of nymphs, but dimethoate provided greater control of adult rice stink bugs. To our knowledge, this is the first study to thoroughly evaluate the extent or geographic range of pyrethroid resistance in Texas for rice stink bugs.

Evaluation of altered cell-cell communication between glia and neurons in the hippocampus of 3xTg-AD mice at two time points.

Alzheimer's disease (AD) is the most common form of dementia and is characterized by progressive memory loss and cognitive decline, affecting behavior, speech, and motor abilities. The neuropathology of AD includes the formation of extracellular amyloid-ß plaque and intracellular neurofibrillary tangles of phosphorylated tau, along with neuronal loss. While neuronal loss is an AD hallmark, cell-cell communication between neuronal and non-neuronal cell populations maintains neuronal health and brain homeostasis. To study changes in cellcell communication during disease progression, we performed snRNA-sequencing of the hippocampus from female 3xTg-AD and wild-type littermates at 6 and 12 months. We inferred differential cell-cell communication between 3xTg-AD and wild-type mice across time points and between senders (astrocytes, microglia, oligodendrocytes, and OPCs) and receivers (excitatory and inhibitory neurons) of interest. We also assessed the downstream effects of altered glia-neuron communication using pseudobulk differential gene expression, functional enrichment, and gene regulatory analyses. We found that glia-neuron communication is increasingly dysregulated in 12-month 3xTg-AD mice. We also identified 23 AD-associated ligand-receptor pairs that are upregulated in the 12-month-old 3xTg-AD hippocampus. Our results suggest increased AD association of interactions originating from microglia. Signaling mediators were not significantly differentially expressed but showed altered gene regulation and TF activity. Our findings indicate that altered glia-neuron communication is increasingly dysregulated and affects the gene regulatory mechanisms in neurons of 12-month-old 3xTg-AD mice.

The Role of Maternal Secretor Status and Human Milk Oligosaccharides on Early Childhood Development: A Systematic Review and Meta-Analysis.

Background: Breast milk is the gold standard of infant nutrition, delivering nutrients and bioactive molecules as needed to support optimal infant growth and cognitive development. Increasing evidence links human milk oligosaccharides (HMOs) to these early childhood development milestones. Aims: To summarize and synthesize the evidence relating to HMOs and infant brain development, physical growth, and cognitive development. In addition, HMO concentrations in secretor and nonsecretor mothers were compared via a meta-analysis. Study Design: A systematic review and meta-analysis were carried out in accordance with the PRISMA statement. This review used three databases (PubMed, Scopus, and Web of Science) and was limited to English-language articles published between 2000 and June 30, 2023. Results: The initial searches yielded 245 articles, 27 of which were included in the systematic review and 12 in the meta-analysis. The meta-analysis revealed a substantial between-study heterogeneity, I2 = 97.3%. The pooled effect was 0.21 (95% CI: -0.41 to 0.83; p = 0.484), indicating that secretors had higher HMO concentrations, although this difference was not statistically significant. At one month of age, 2'FL, 3FL, and 3'SL play an important role in brain maturation and thus play a critical role in cognitive development. Secretors produce higher concentrations of 2'FL and 3'SL, explaining the benefits to infants of secretor mothers. Growth velocity was correlated to fucosylated and sialylated HMO concentrations, with lower concentrations linked to stunting. Conclusions: According to evidence from the systematically reviewed articles, HMOs are essential for a child's early development, but the extent to which they have an impact depends on maternal secretor status.

Factors associated with viral load non-suppression among treatment-experienced pre-teenage children living with HIV in Kenya: a nationwide population-based cohort study, 2015-2021.

Background: Viral load non-suppression (VLNS) in children is a major public health concern because of attendant HIV disease progression and risk of morbidity and mortality. Based on a nationally representative database we present estimates of the prevalence, trends and factors associated with VLNS in Kenyan pre-teenage children between 2015 and 2021. Methods: Kenya National AIDS & STI Control Program's (NASCOP) maintains an early infant diagnosis and viral load (EID/VL) database for all persons living with HIV who are enrolled in the country's primary care clinics for purposes of monitoring progress towards achievement of the 95% viral suppression goals. Participants were eligible if they were children living with HIV (CLHIV), on combination ART (cART) treatment, and ≤12 years old. The modified Mann-Kendall trend test for serially correlated data was used to identify VLNS trends. Generalized estimating equations (GEE) with a logit link was used to assess the effects of covariates on the odds of VLNS (VL ≥1,000 copies/mL) over repeated points in time, allowing for the correlation among the repeated measures. Findings: Between January 2015 and December 2021, 508,743 viral load tests were performed on samples collected from 109,682 pre-teenage children. The prevalence of VLNS decreased from 22.9% (95% CI 22.4-23.3) to 12.5% (95% CI 12.1-12.9), p < 0.0001, and mean age increased from 3.1 (4.2) to 8.0 (3.2) years in 2015 and 2021 respectively. A modified Mann-Kendall trend test for serially correlated data denotes a statistically significant decreasing trend (τ = -0.300, p < 0.0001) over the study period. In the multivariable GEE analysis adjusted for covariates, the odds of VLNS decreased by 11% per year during the study period, (GEE-aOR 0.89, 95% CI 0.88-0.90; p < 0.0001). Factors positively associated with VLNS were EFV/NVP-based first-line cART regimen (GEE-aOR 1.74, 95% CI 1.65-1.84, p < 0.0001), PI-based cART regimen (GEE-aOR 1.82, 95% CI 1.72-1.92, p < 0.0001), and children aged 1-3 years (toddlers) (GEE-aOR: 1.84, 95% CI 1.79-1.90, p < 0.0001). On the contrary, DTG-based cART regimen, were negatively associated with VLNS (GEE-aOR 0.70, 95% CI 0.65-0.75, p < 0.0001). Interpretation: There is a strong evidence of decreasing viremia between 2015 and 2021. To sustain the decreasing trend, accelerating the switch from the suboptimal EVP/NVP first-line regimen to optimised DTG regimen is warranted. Funding: U.S. President's Emergency Plan for AIDS Relief (PEPFAR) and Clinton Health Access Initiative (CHAI).

Trainee-perceived benefits of a virtual temporal bone competition.

OBJECTIVE: To assess the perceived benefits of a novel educational approach for otolaryngology trainees: a virtual reality temporal bone simulator drilling competition. METHODS: Regional otolaryngology trainees participated in the competition. Drilling activities using the Voxel-Man TempoSurg simulator were scored by experts. Questionnaires that contained questions covering motivators for attending, perceived learning and enjoyment were sent to participants. Agreement with statements was measured on a 10-point Likert scale (1 = strongly disagree, 10 = strongly agree). RESULTS: Eighteen trainees participated. The most cited reason for attending was for learning and/or education (61 per cent), with most attendees (72 per cent) believing that competition encourages more reading and/or practice. Seventeen attendees (94 per cent) believed Voxel-Man TempoSurg-based simulation would help to improve intra-operative performance in mastoidectomy (mean 7.83 ± 1.47, p < 0.001) and understanding of anatomy (mean 8.72 ± 1.13, p < 0.001). All participants rated the competition as 'fun' and 83 per cent believed the competitive element added to this. CONCLUSION: The virtual reality temporal bone competition is a novel educational approach within otolaryngology that was positively received by otolaryngology trainees.

Population Pharmacokinetics of Pediatric Lopinavir/Ritonavir Oral Pellets in Children Living with HIV in Africa.

Antiretroviral therapy for children living with HIV (CLHIV) under 3 years of age commonly includes lopinavir/ritonavir (LPV/r). However, the original liquid LPV/r formulation has taste and cold storage difficulties. To address these challenges, LPV/r oral pellets have been developed. These pellets can be mixed with milk or food for administration and do not require refrigeration. We developed the population pharmacokinetic (PK) model and assessed drug exposure of LPV/r oral pellets administered twice daily to CLHIV per World Health Organization (WHO) weight bands. The PK analysis included Kenyan and Ugandan children participating in the LIVING studies (NCT02346487) receiving LPV/r pellets (40/10 mg) and ABC/3TC (60/30 mg) dispersible tablets. Population PK models were developed for lopinavir (LPV) and ritonavir (RTV) to evaluate the impact of RTV on the oral clearance (CL/F) of LPV. The data obtained from the study were analyzed using nonlinear mixed-effects modeling approach. Data from 514 children, comprising a total of 2,998 plasma concentrations of LPV/r were included in the analysis. The LPV and RTV concentrations were accurately represented by a one-compartment model with first-order absorption (incorporating a lag-time) and elimination. Body weight influenced LPV and RTV PK parameters. The impact of RTV concentrations on the CL/F of LPV was characterized using a maximum effect model. Simulation-predicted target LPV exposures were achieved in children with this pellet formulation across the WHO weight bands. The LPV/r pellets dosed in accordance with WHO weight bands provide adequate LPV exposures in Kenyan and Ugandan children weighing 3.0 to 24.9 kg.

Adolescent experiences, perceptions, and preferences for the process of HIV status disclosure in Kenya.

Introduction: Disclosure of HIV status to adolescents living with HIV has been associated with improved treatment outcomes. However, there are limited data regarding the experiences of, perceptions of, and preferences for the process of disclosure of HIV status among adolescents and young adults living with HIV (AYLH), especially in sub-Saharan Africa. Methods: Young adults living with HIV from 20 HIV clinics in Kenya who participated in a clinical trial evaluating the effectiveness of a disclosure and transition package completed an anonymous survey in 2019. We described their experiences and preferences using counts and proportions and assessed factors associated with satisfaction with the disclosure process using linear regression, reporting age-adjusted mean differences (aMD), and 95% confidence intervals (95%CIs). Results: Of the 375 enrolled AYLH, 265 (71%) had perinatally acquired HIV, of whom 162 (61%) were female. The median age of the enrolled AYLH was 16 years (IQR: 14-19 years), and all of them were on antiretroviral therapy (ART). For over half (55%) of the participants, caregivers disclosed their HIV status, and 57% preferred that their caregivers disclose the status to them. Most (78%) of the participants preferred full disclosure by 12 years of age. The majority (69%) believed the disclosure was planned, and 11% suspected being HIV positive before the disclosure. Overall, 198 (75%) AYLH reported that they were ready for disclosure when it happened, and 86% were satisfied with the process. During both pre-disclosure (67 and 70%, respectively) and post-disclosure (>75% for each), AYLH felt supported by the clinic and caregivers. Factors associated with higher satisfaction with the disclosure process were pre-disclosure clinic support (aMD: 0.19 [95%CI: 0.05-0.33]) and pre-disclosure (aMD: 0.19 [0.06-0.31]) and post-disclosure (aMD: 0.17 [0.03-0.31]) caregiver support. AYLH who suspected they were HIV positive before they were disclosed to tended to have lower satisfaction when compared to those who never suspected (aMD: -0.37 [-0.74-(-0.01)]). Overall, they reported that disclosure positively influenced their ART adherence (78%), clinic attendance (45%), and communication with caregivers (20%), and 40% reported being happier after disclosure. Conclusion: Young adults living with HIV advocated for an appropriately timed disclosure process with the involvement of caregivers and healthcare workers (HCWs). Support from caregivers and HCWs before and during disclosure is key to improving their disclosure experience.

Skeletal muscle TFEB signaling promotes central nervous system function and reduces neuroinflammation during aging and neurodegenerative disease.

Skeletal muscle has recently arisen as a regulator of central nervous system (CNS) function and aging, secreting bioactive molecules known as myokines with metabolism-modifying functions in targeted tissues, including the CNS. Here, we report the generation of a transgenic mouse with enhanced skeletal muscle lysosomal and mitochondrial function via targeted overexpression of transcription factor E-B (TFEB). We discovered that the resulting geroprotective effects in skeletal muscle reduce neuroinflammation and the accumulation of tau-associated pathological hallmarks in a mouse model of tauopathy. Muscle-specific TFEB overexpression significantly ameliorates proteotoxicity, reduces neuroinflammation, and promotes transcriptional remodeling of the aged CNS, preserving cognition and memory in aged mice. Our results implicate the maintenance of skeletal muscle function throughout aging in direct regulation of CNS health and disease and suggest that skeletal muscle originating factors may act as therapeutic targets against age-associated neurodegenerative disorders.

Host search behaviors of specialist and generalist root feeding herbivores (Diabrotica spp.) on host and non-host plants.

Western, northern, Mexican, and southern corn rootworms (WCR, NCR, MCR, and SCR) are serious corn pests. We evaluated host search behavior of these pests on six plant species using a video tracking system. After a 5-min exposure to plant roots, behavioral parameters were automatically recorded and used to quantify the search behavior. The search behavior was not observed for sorghum since no neonates survived after contacting sorghum roots. After exposures to corn roots, all neonates exhibited the localized search behaviors (i.e., shortening total distance traveled, lowering movement speed, increasing turn angle, moving farther from origin) which are used to stay in and search within root systems. When larvae contacted roots of wheat, barley, oats, soybean, or controls, they expanded the search area by extending the travel path, increasing velocity, and reducing turn angles and total distance moved. The intensity of the search expansion is highly associated with the host preferences known for the four rootworm species and subspecies. Neonates of each corn rootworm exhibited distinct search behaviors. In fact, NCR larvae had the highest speed, the greatest travel path, and the lowest turn angle, whereas MCR larvae had the highest turn angle and moved faster than WCR and SCR larvae.

Race and Ethnicity and Prehospital Use of Opioid or Ketamine Analgesia in Acute Traumatic Injury.

Importance: Racial and ethnic disparities in pain management have been characterized in many hospital-based settings. Painful traumatic injuries are a common reason for 911 activations of the EMS (emergency medical services) system. Objective: To evaluate whether, among patients treated by EMS with traumatic injuries, race and ethnicity are associated with either disparate recording of pain scores or disparate administration of analgesia when a high pain score is recorded. Design, Settings, and Participants: This cohort study included interactions from 2019 to 2021 for US patients ages 14 to 99 years who had experienced painful acute traumatic injuries and were treated and transported by an advanced life support unit following the activation of the 911 EMS system. The data were analyzed in January 2023. Exposures: Acute painful traumatic injuries including burns. Main Outcomes and Measures: Outcomes were the recording of a pain score and the administration of a nonoral opioid or ketamine. Results: The study cohort included 4 781 396 EMS activations for acute traumatic injury, with a median (IQR) patient age of 59 (35-78) years (2 497 053 female [52.2%]; 31 266 American Indian or Alaskan Native [0.7%]; 59 713 Asian [1.2%]; 742 931 Black [15.5%], 411 934 Hispanic or Latino [8.6%], 10 747 Native Hawaiian or other Pacific Islander [0.2%]; 2 764 499 White [57.8%]; 16 161 multiple races [0.3%]). The analysis showed that race and ethnicity was associated with the likelihood of having a pain score recorded. Compared with White patients, American Indian and Alaskan Native patients had the lowest adjusted odds ratio (AOR) of having a pain score recorded (AOR, 0.74; 95% CI, 0.71-0.76). Among patients for whom a high pain score was recorded (between 7 and 10 out of 10), Black patients were about half as likely to receive opioid or ketamine analgesia as White patients (AOR, 0.53; 95% CI, 0.52-0.54) despite having a pain score recorded almost as frequently as White patients. Conclusions and Relevance: In this nationwide study of patients treated by EMS for acute traumatic injuries, patients from racial or ethnic minority groups were less likely to have a pain score recorded, with Native American and Alaskan Natives the least likely to have a pain score recorded. Among patients with a high pain score, patients from racial and ethnic minority groups were also significantly less likely to receive opioid or ketamine analgesia treatment, with Black patients having the lowest adjusted odds of receiving these treatments.

Abacavir Drug Exposures in African Children Under 14 kg Using Pediatric Solid Fixed Dose Combinations According to World Health Organization Weight Bands.

BACKGROUND: The pharmacokinetics of abacavir (ABC) in African children living with HIV (CLHIV) weighing <14 kg and receiving pediatric fixed dose combinations (FDC) according to WHO weight bands dosing are limited. An ABC population pharmacokinetic model was developed to evaluate ABC exposure across different World Health Organization (WHO) weight bands. METHODS: Children enrolled in the LIVING study in Kenya and Uganda receiving ABC/lamivudine (3TC) dispersible tablets (60/30 mg) according to WHO weight bands. A population approach was used to determine the pharmacokinetic parameters. Monte Carlo simulations were conducted using an in silico population with demographic characteristics associated with African CLHIV. ABC exposures (AUC0-24) of 6.4-50.4 mg h/L were used as targets. RESULTS: Plasma samples were obtained from 387 children. A 1-compartment model with allometric scaling of clearance (CL/F) and volume of distribution (V/F) according to body weight best characterized the pharmacokinetic data of ABC. The maturation of ABC CL/F was characterized using a sigmoidal Emax model dependent on postnatal age (50% of adult CL/F reached by 0.48 years of age). Exposures to ABC were within the target range for children weighing 6.0-24.9 kg, but children weighing 3-5.9 kg were predicted to be overexposed. CONCLUSIONS: Lowering the ABC dosage to 30 mg twice daily or 60 mg once daily for children weighing 3-5.9 kg increased the proportion of children within the target and provided comparable exposures. Further clinical study is required to investigate clinical implications and safety of the proposed alternative ABC doses.

FBXO21 mediated degradation of p85α regulates proliferation and survival of acute myeloid leukemia.

Acute myeloid leukemia (AML) is a heterogeneous disease characterized by clonal expansion of myeloid blasts in the bone marrow (BM). Despite advances in therapy, the prognosis for AML patients remains poor, and there is a need to identify novel molecular pathways regulating tumor cell survival and proliferation. F-box ubiquitin E3 ligase, FBXO21, has low expression in AML, but expression correlates with survival in AML patients and patients with higher expression have poorer outcomes. Silencing FBXO21 in human-derived AML cell lines and primary patient samples leads to differentiation, inhibition of tumor progression, and sensitization to chemotherapy agents. Additionally, knockdown of FBXO21 leads to up-regulation of cytokine signaling pathways. Through a mass spectrometry-based proteomic analysis of FBXO21 in AML, we identified that FBXO21 ubiquitylates p85α, a regulatory subunit of the phosphoinositide 3-kinase (PI3K) pathway, for degradation resulting in decreased PI3K signaling, dimerization of free p85α and ERK activation. These findings reveal the ubiquitin E3 ligase, FBXO21, plays a critical role in regulating AML pathogenesis, specifically through alterations in PI3K via regulation of p85α protein stability.

The effects of dietary essential fatty acid ratios and linoleic acid level in grow-finish pigs.

The objective of this study was to investigate the effects of dietary linoleic acid level and the ratio of linoleic acid:linolenic acid (LA:ALA) on the growth performance, expression of genes associated with lipid metabolism, and inflammatory status of grow-finish pigs. A total of 300 growing pigs (body weight [BW] = 41.1 ±â€…6.3 kg) were randomly assigned to either a high (30 g/kg; HLA) or low (15 g/kg; LLA) dietary linoleic acid level with a high (23:1; HR), moderate (13:1; MR) or low (4:1; LR) dietary LA:ALA in a 2 × 3 factorial design. Diets were fed across three 28-d phases and were balanced for dietary metabolizable energy. Pigs were housed five pigs per pen in single-sex pens. Blood samples were collected on days 0, 21, 42, and 84, and synovial fluid was collected from the hock joint on days 0 and 84 for inflammatory marker analysis. Data were analyzed as repeated measures using PROC MIXED (SAS 9.4) with initial BW as a covariate, pen as the experimental unit, and LA level, LA:ALA, sex, phases, and their interactions as fixed effects. Compared to HLA, LLA pigs tended to have increased BW at days 56 and 84 (P = 0.088). There was no effect of LA × LA:ALA for growth performance. For the overall days 0 to 84 growth period, pigs fed HR had increased ADG compared to MR, with pigs receiving LR performing intermediate of MR and HR. Gilts receiving HR diets had increased day 84 BW compared to gilts receiving the low and moderate LA:ALA (P = 0.006), which was a result of improved overall days 0 to 84 ADG compared to gilts receiving the MR diets (P = 0.023). Barrows fed LR had improved BW on day 56 compared to MR and HR and higher final BW compared to HR, with MR performing intermediately (P = 0.006). This was a result of greater days 0 to 84 ADG (P = 0.023). Overall, C-reactive protein (CRP), tumor necrosis factor-α (TNFα), and interleukin-6 were reduced in the plasma of pigs over time (P ≤ 0.037). Across all treatments, CRP and TNFα were reduced in the hock and carpus synovial fluid on day 84 vs. day 0 (P ≤ 0.049). In conclusion, LA:ALA ratios utilized in this study can be fed at varying linoleic acid levels without impacting growth or inflammation. Additionally, LA:ALA ratios can differentially impact the growth of gilts and barrows.

Previous research in lactating sows has reported that dietary inclusion of the essential fatty acids linoleic acid and linolenic acid is important for performance. Research in grow­finish pigs has shown an improvement in gilt growth performance when fed differing linoleic:linolenic acid ratios (LA:ALA); however, further research evaluating LA:ALA in diets with similar metabolizable energy is needed in growing pigs. In the present research, a 23:1 dietary essential fatty acid ratio increased the final body weight of gilts compared to a 13:1 or 4:1 LA:ALA, while barrows fed a 4:1 dietary essential fatty acid ratio had increased gain and final body weight compared to a 23:1 LA:ALA. Plasma and synovial fluid inflammatory markers were also reduced with time and were unaffected by dietary LA:ALA or linoleic acid inclusion. Dietary essential fatty acid ratio can differentially impact the growth of barrows and gilts, with no impact on systemic or joint inflammation.

Evaluation of branched-chain amino acid interactions in 10 to 20 kg nursery pigs using a central composite design.

Two groups of 240 pigs (PIC 337 × 1050, PIC Genus, Hendersonville, TN) were used to investigate the interactions between leucine, isoleucine, and valine on the growth performance of approximately 10 to 20 kg nursery pigs. At weaning, pigs were placed into 40 pens with three barrows and three gilts per pen and fed a common diet for 3 wk. On day 21 postweaning, pens were randomly assigned to 1 of 15 dietary treatments in a central composite design. Diets were formulated to various levels of standardized ileal digestible (SID) Leu, Ile, and Val by supplementing L-Leu, L-Ile, and L-Val. Levels of the branched-chain amino acids, expressed as ratios to SID Lys, ranged from 98% to 180%, 46% to 64%, and 51% to 78% for Leu, Ile, and Val, respectively. Diets were formulated to be iso-Lys, isonitrogenous, and isocaloric. Pig weights and feed intake were measured for the 21-d experiment to calculate average daily gain (ADG), average daily feed intake (ADFI), and feed efficiency (G:F). Growth performance data were analyzed using the lm() function in R version 4.2.2 (R Core Team, 2022). The second-order polynomial model included the linear and quadratic effects of Leu, Ile, and Val, their three two-way interactions, and initial body weight. Pen was the experimental unit, and parameters were considered significant at P ≤ 0.10. A linear and quadratic effect of Val was observed for ADG and G:F (P < 0.001). There was an interaction between Leu and Ile for ADG (P = 0.069) and G:F (P = 0.032), where increasing Leu and decreasing Ile, and the inverse, improved ADG and G:F. However, growth and efficiency were negatively impacted as Leu and Ile increased in the diet. There was an interaction between Leu and Val for ADFI (P = 0.060), where Leu negatively impacted feed intake at low levels of Val but had little impact as Val increased above NRC (2012) recommendations. In conclusion, Val linearly and quadratically impacted ADG and G:F, regardless of Leu and Ile levels in the diet, while ADG and G:F were reduced with high levels of Leu and Ile, which was resolved as either Leu or Ile was reduced. Furthermore, ADFI was negatively impacted by increased Leu when Val was below NRC (2012) recommendations but was not affected by Leu at higher Val levels. Together, the results of this experiment emphasize the complexity of amino acid metabolism in nursery pigs and the importance of considering potential interactions among amino acids when conducting requirement studies.

Leucine, isoleucine, and valine are known as the branched-chain amino acids (BCAA). Aside from being essential for protein synthesis, BCAA play signaling roles, stimulating pathways of muscle protein synthesis. The first two steps in the BCAA catabolic pathway are shared amongst the three amino acids; consequently, excess consumption of one BCAA may increase the catabolism of the other two, hindering growth performance. Therefore, the objective of this trial was to investigate the interactions of BCAA and their impact on the growth performance of approximately 10 to 20 kg nursery pigs. In the current trial, valine linearly and quadratically impacted average daily gain and feed efficiency, regardless of leucine and isoleucine levels in the diet, but high levels of both leucine and isoleucine negatively impacted growth and efficiency. Furthermore, increasing leucine in the diet reduced feed intake when accompanied by low levels of valine, which was resolved as valine increased. Using a central composite design allowed for the description of the complex interactions between BCAA in nursery pigs and demonstrated the utility and application of this design in swine nutrition research. Together, the results of this study highlight the importance of considering the balance of BCAA in the diet of nursery pigs.

Extended Sentinel Monitoring of Helicoverpa zea Resistance to Cry and Vip3Aa Toxins in Bt Sweet Corn: Assessing Changes in Phenotypic and Allele Frequencies of Resistance.

Transgenic corn and cotton that produce Cry and Vip3Aa toxins derived from Bacillus thuringiensis (Bt) are widely planted in the United States to control lepidopteran pests. The sustainability of these Bt crops is threatened because the corn earworm/bollworm, Helicoverpa zea (Boddie), is evolving a resistance to these toxins. Using Bt sweet corn as a sentinel plant to monitor the evolution of resistance, collaborators established 146 trials in twenty-five states and five Canadian provinces during 2020-2022. The study evaluated overall changes in the phenotypic frequency of resistance (the ratio of larval densities in Bt ears relative to densities in non-Bt ears) in H. zea populations and the range of resistance allele frequencies for Cry1Ab and Vip3Aa. The results revealed a widespread resistance to Cry1Ab, Cry2Ab2, and Cry1A.105 Cry toxins, with higher numbers of larvae surviving in Bt ears than in non-Bt ears at many trial locations. Depending on assumptions about the inheritance of resistance, allele frequencies for Cry1Ab ranged from 0.465 (dominant resistance) to 0.995 (recessive resistance). Although Vip3Aa provided high control efficacy against H. zea, the results show a notable increase in ear damage and a number of surviving older larvae, particularly at southern locations. Assuming recessive resistance, the estimated resistance allele frequencies for Vip3Aa ranged from 0.115 in the Gulf states to 0.032 at more northern locations. These findings indicate that better resistance management practices are urgently needed to sustain efficacy the of corn and cotton that produce Vip3Aa.

Disruptions to in-person medical visits across the United States during the COVID-19 pandemic: evolving disparities by medical specialty and socio-economic status.

OBJECTIVES: This study aimed to investigate how people's health-seeking behaviors evolve in the COVID-19 pandemic by community and medical service category. STUDY DESIGN: This is a longitudinal study using mobility data from 19 million mobile devices of visits to all types of health facility locations for all US states. METHODS: We examine the variations in weekly in-person medical visits across county, neighborhood, and specialty levels. Different regression models are used for each level to investigate factors that influence the disparities in medical visits. County-level analysis explores associations between county medical visit patterns, political orientation, and COVID-19 infection rate. Neighborhood-level analysis focuses on neighborhood socio-economic compositions as potential determinants of medical visit levels. Specialty-level analysis compares the evolution of visit disruptions in different specialties. RESULTS: A more left-leaning political orientation and a higher local infection rate were associated with larger decreases in in-person medical visits, and these associations became stronger, moving from the initial period of stay-at-home orders into the post-lockdown period. Initial reactions were strongest for seniors and those of high socio-economic status, but this reversed in post-lockdown period where socio-economically disadvantaged communities stabilized at a lower level of medical visits. Neighborhoods with more female and young people exhibited larger decreases in in-person medical visits throughout the initial and post-lockdown periods. The evolution of disruptions diverges across medical specialties, from only short-term disruption in specialties such as dentistry to increasing disruption, as in cardiology. CONCLUSIONS: Given distinct patterns in visit between communities, medical service categories, and between different periods in the pandemic, policy makers, and providers should concentrate on monitoring patients in disrupted specialties who overlap with the at-risk contexts and socio-economic factors in future health emergencies.