A mutation associated with resistance to synthetic pyrethroids is widespread in US populations of the tropical lineage of Rhipicephalus sanguineus s.l.

The brown dog tick, Rhipicephalus sanguineus sensu lato (s.l.), is an important vector for Rickettsia rickettsii, causative agent of Rocky Mountain spotted fever. Current public health prevention and control efforts to protect people involve preventing tick infestations on domestic animals and in and around houses. Primary prevention tools rely on acaricides, often synthetic pyrethroids (SPs); resistance to this chemical class is widespread in ticks and other arthropods. Rhipicephalus sanguineus s.l. is a complex that likely contains multiple unique species and although the distribution of this complex is global, there are differences in morphology, ecology, and perhaps vector competence among these major lineages. Two major lineages within Rh. sanguineus s.l., commonly referred to as temperate and tropical, have been documented from multiple locations in North America, but are thought to occupy different ecological niches. To evaluate potential acaricide resistance and better define the distributions of the tropical and temperate lineages throughout the US and in northern Mexico, we employed a highly multiplexed amplicon sequencing approach to characterize sequence diversity at: 1) three loci within the voltage-gated sodium channel (VGSC) gene, which contains numerous genetic mutations associated with resistance to SPs; 2) a region of the gamma-aminobutyric acid-gated chloride channel gene (GABA-Cl) containing several mutations associated with dieldrin/fipronil resistance in other species; and 3) three mitochondrial genes (COI, 12S, and 16S). We utilized a geographically diverse set of Rh sanguineus s.l. collected from domestic pets in the US in 2013 and a smaller set of ticks collected from canines in Baja California, Mexico in 2021. We determined that a single nucleotide polymorphism (T2134C) in domain III segment 6 of the VGSC, which has previously been associated with SP resistance in Rh. sanguineus s.l., was widespread and abundant in tropical lineage ticks (>50 %) but absent from the temperate lineage, suggesting that resistance to SPs may be common in the tropical lineage. We found evidence of multiple copies of GABA-Cl in ticks from both lineages, with some copies containing mutations associated with fipronil resistance in other species, but the effects of these patterns on fipronil resistance in Rh. sanguineus s.l. are currently unknown. The tropical lineage was abundant and geographically widespread, accounting for 79 % of analyzed ticks and present at 13/14 collection sites. The temperate and tropical lineages co-occurred in four US states, and as far north as New York. None of the ticks we examined were positive for Rickettsia rickettsii or Rickettsia massiliae.

Dissection of a CTCF topological boundary uncovers principles of enhancer-oncogene regulation.

Enhancer-gene communication is dependent on topologically associating domains (TADs) and boundaries enforced by the CCCTC-binding factor (CTCF) insulator, but the underlying structures and mechanisms remain controversial. Here, we investigate a boundary that typically insulates fibroblast growth factor (FGF) oncogenes but is disrupted by DNA hypermethylation in gastrointestinal stromal tumors (GISTs). The boundary contains an array of CTCF sites that enforce adjacent TADs, one containing FGF genes and the other containing ANO1 and its putative enhancers, which are specifically active in GIST and its likely cell of origin. We show that coordinate disruption of four CTCF motifs in the boundary fuses the adjacent TADs, allows the ANO1 enhancer to contact FGF3, and causes its robust induction. High-resolution micro-C maps reveal specific contact between transcription initiation sites in the ANO1 enhancer and FGF3 promoter that quantitatively scales with FGF3 induction such that modest changes in contact frequency result in strong changes in expression, consistent with a causal relationship.

Prevalence and risk factors for Q fever, spotted fever group rickettsioses, and typhus group rickettsioses in a pastoralist community of northern Tanzania, 2016-2017.

BACKGROUND: In northern Tanzania, Q fever, spotted fever group (SFG) rickettsioses, and typhus group (TG) rickettsioses are common causes of febrile illness. We sought to describe the prevalence and risk factors for these zoonoses in a pastoralist community. METHODS: Febrile patients ≥2 years old presenting to Endulen Hospital in the Ngorongoro Conservation Area were enrolled from August 2016 through October 2017. Acute and convalescent blood samples were collected, and a questionnaire was administered. Sera were tested by immunofluorescent antibody (IFA) IgG assays using Coxiella burnetii (Phase II), Rickettsia africae, and Rickettsia typhi antigens. Serologic evidence of exposure was defined by an IFA titre ≥1:64; probable cases by an acute IFA titre ≥1:128; and confirmed cases by a ≥4-fold rise in titre between samples. Risk factors for exposure and acute case status were evaluated. RESULTS: Of 228 participants, 99 (43.4%) were male and the median (interquartile range) age was 27 (16-41) years. Among these, 117 (51.3%) had C. burnetii exposure, 74 (32.5%) had probable Q fever, 176 (77.2%) had SFG Rickettsia exposure, 134 (58.8%) had probable SFG rickettsioses, 11 (4.8%) had TG Rickettsia exposure, and 4 (1.8%) had probable TG rickettsioses. Of 146 participants with paired sera, 1 (0.5%) had confirmed Q fever, 8 (5.5%) had confirmed SFG rickettsioses, and none had confirmed TG rickettsioses. Livestock slaughter was associated with acute Q fever (adjusted odds ratio [OR] 2.54, 95% confidence interval [CI] 1.38-4.76) and sheep slaughter with SFG rickettsioses case (OR 4.63, 95% CI 1.08-23.50). DISCUSSION: Acute Q fever and SFG rickettsioses were detected in participants with febrile illness. Exposures to C. burnetii and to SFG Rickettsia were highly prevalent, and interactions with livestock were associated with increased odds of illness with both pathogens. Further characterisation of the burden and risks for these diseases is warranted.

Assessment of Dosing Strategies for Pediatric Drug Products.

Pediatric drug dosing is challenged by the heterogeneity of developing physiology and ethical considerations surrounding a vulnerable population. Often, pediatric drug dosing leverages findings from the adult population; however, recent regulatory efforts have motivated drug sponsors to pursue pediatric-specific programs to meet an unmet medical need and improve pediatric drug labeling. This paradigm is further complicated by the pathophysiological implications of obesity on drug distribution and metabolism and the roles that body composition and body size play in drug dosing. Therefore, we sought to understand the landscape of pediatric drug dosing by characterizing the dosing strategies from drug products recently approved for pediatric indications identified using FDA Drug Databases and analyze the impact of body size descriptors (age, body surface area, weight) on drug pharmacokinetics for several selected antipsychotics approved in pediatric patients. Our review of these pediatric databases revealed a dependence on body size-guided dosing, with 68% of dosing in pediatric drug labelings being dependent on knowing either the age, body surface area, or weight of the patient to guide dosing for pediatric patients. This dependence on body size-guided dosing drives the need for special consideration when dosing a drug in overweight and obese patients. Exploratory pharmacokinetic analyses in antipsychotics illustrate possible effects of drug exposure when applying different dosing strategies for this class of drugs. Future efforts should aim to further understand the pediatric drug dosing and obesity paradigm across pediatric age ranges and drug classes to optimize drug development and clinical care for this patient population.

Intrinsic risk factors for alpha-gal syndrome in a case-control study, 2019 to 2020.

BACKGROUND: Alpha-gal syndrome (AGS) is an allergy to galactose-α-1,3-galactose (alpha-gal), a carbohydrate found in most mammals. Evidence indicates that AGS develops after a tick bite, and in the United States, AGS is most associated with bites from Amblyomma americanum (lone star tick); however, not all persons bitten by ticks develop clinical AGS. OBJECTIVE: To investigate intrinsic risk factors associated with the development of AGS. METHODS: We performed a case-control study among adults presenting for diagnosis or management of AGS at an allergy clinic in North Carolina during 2019 to 2020 and compared them with controls enrolled from 2 nearby internal medicine clinics. A questionnaire gathered epidemiologic and tick exposure data, and blood was obtained for alpha-gal-specific IgE and other testing. RESULTS: The 82 enrolled case patients and 191 controls did not differ significantly by age or sex. Case patients were more likely than controls to have A or O blood types (non B-antigen), have experienced childhood allergies, and have a family history of AGS and other food allergies. Case patients were also more likely to report experiencing long healing times for insect bites or stings and a family history of allergy to stinging or biting insects. CONCLUSION: This study suggested that intrinsic factors contribute to risk of developing AGS. Some traits are genetic, but common behaviors among households and family units likely also contribute. Identification of these risk factors can inform personal risk, aid health care providers in understanding susceptible populations, and contribute to ongoing understanding of AGS epidemiology.

Early-Life Social Determinants of SCA6 Age at Onset, Severity, and Progression.

SCA6 patients with the same size CAG repeat allele can vary significantly in age at onset (AAO) and clinical progression. The specific external factors affecting SCA6 have yet to be investigated. We assessed the effect of early life events on AAO, severity, and progression in SCA6 patients using a social determinant of health approach. We performed a survey of biological and social factors in SCA6 patients enrolled in the SCA6 Network at the University of Chicago. AAO of ataxia symptoms and patient-reported outcome measure (PROM) of ataxia were used as primary outcome measures. Least absolute shrinkage and selection operation (LASSO) regressions were used to identify which early life factors are predictive of SCA6 AAO, severity, and progression. Multiple linear regression models were then used to assess the degree to which these determinants influence SCA6 health outcomes. A total of 105 participants with genetically confirmed SCA6 completed the assessments. SCA6 participants with maternal difficulty during pregnancy, active participation in school sports, and/or longer CAG repeats were determined to have earlier AAO. We found a 13.44-year earlier AAO for those with maternal difficulty in pregnancy than those without (p = 0.008) and a 12.31-year earlier AAO for those active in school sports than those who were not (p < 0.001). Higher education attainment was associated with decreased SCA6 severity and slower progression. Early life biological and social factors can have a strong influence on the SCA6 disease course, indicating that non-genetic factors can contribute significantly to SCA6 health outcomes.

The microstratigraphy and depositional environments of Lida Ajer and Ngalau Gupin, two fossil-bearing tropical limestone caves of west Sumatra.

Lida Ajer and Ngalau Gupin are karstic caves situated in the Padang Highlands, western Sumatra, Indonesia. Lida Ajer is best known for yielding fossil evidence that places the arrival of Homo sapiens in Southeast Asia during Marine Isotope Stage 4, one of the earliest records for the region. Ngalau Gupin recently produced the first record of hippopotamid Hexaprotodon on the island, representing the only globally extinct taxon in Pleistocene deposits from Sumatra. Microstratigraphic (micromorphological) analyses were applied to unconsolidated fossil-bearing cave sediments from these two sites. We use micromorphology as part of a micro-contextualised taphonomic approach to identify the diagenetic processes affecting fossils and sediments within these caves, through phases of their depositional history. The fossil-bearing sediments in Lida Ajer have been subjected to a suite of natural sedimentation processes ranging from water action to carnivore occupation, which would indicate the fossils underwent significant reworking prior to lithification of the deposit. The results demonstrate that the base of the unconsolidated fossil-bearing sediments in Ngalau Gupin were derived from the interior of the cave, where the matrix was partially phosphatized as a result of guano-driven diagenesis. These observations can be used to test hypotheses about the integrity of incorporated vertebrate remains and to aid in local palaeoenvironmental reconstructions. The methods employed in this research have not previously been applied to cave sediments from sites in the Padang Highlands and provide key new insights into the palaeontological and natural history of the western region of Sumatra.

Food-Drug Effects and Pediatric Drug Development Studies Submitted to the US Food and Drug Administration, 2012-2022.

Food effect (FE) studies characterize food-drug interactions that may alter the efficacy or safety of a drug, but these studies are not conducted in pediatric patients. Pediatric patients have substantial physiologic, anatomic, and dietary differences from adults, which may result in differences in their FE considerations. Therefore, the objective of this study was to identify oral drug products approved for use in pediatric patients aged <6 years with an FE observed in adults. Additional objectives were to summarize the therapeutic areas, pharmacokinetic effects, and labeling instructions that resulted from these studies. Publicly available data were searched for products studied in pediatric patients and approved for use by the United States Food and Drug Administration (FDA) from 2012 to 2022. Of the 102 oral drug products approved for use in patients aged <6 years, 43 recommended the consideration of food intake in the drug labeling. These included drug products recommended to be taken with food (n = 21, 49%) or without food (n = 14, 33%). Each of the 14 drug products recommended to be taken without food are approved for use in pediatric patients aged <2 years. The products approved for use in pediatric patients aged <2 years comprised the highest proportion with area under the plasma concentration-time curve extrapolated to infinity (AUCinf , n = 35, 75%) and maximum serum concentration (Cmax , n = 45, 80%) affected by food. Close monitoring is warranted during the postapproval period for products identified as having a significant FE in adults and that are approved for use in pediatric patients aged <6 years. Promising tools for predicting pediatric FE may include physiologically based pharmacokinetic absorption modeling.

Physiologically Based Pharmacokinetic Modeling of Nilotinib for Drug-Drug Interactions, Pediatric Patients, and Pregnancy and Lactation.

Nilotinib is a second-generation BCR-ABL tyrosine kinase inhibitor for the treatment of Philadelphia chromosome-positive chronic myeloid leukemia in both adult and pediatric patients. The pharmacokinetics (PK) of nilotinib in specific populations such as pregnant and lactating people remain poorly understood. Therefore, the objectives of the current study were to develop a physiologically based pharmacokinetic (PBPK) model to predict nilotinib PK in virtual drug-drug interaction (DDI) studies, as well as in pediatric, pregnant, and lactating populations. The nilotinib PBPK model was built in PK-Sim, which is part of the free and open-source software Open Systems Pharmacology. The observed clinical data for the validation of the nilotinib models were obtained from the literature. The model reasonably predicted nilotinib concentrations in the adult population; the DDIs between nilotinib and rifampin or ketoconazole in the adult population; and the PK in the pediatric, pregnant, and lactating populations, although in the latter 2 populations plasma concentrations were slightly underestimated. The ratio of predicted versus observed PK parameters for the adult model ranged from 0.71 to 1.11 for area under the concentration-time curve and 0.55 to 0.95 for maximum concentration. For the DDI, the predicted area under the concentration-time curve ratio and maximum concentration ratio fell within the Guest criterion. The current study demonstrated the utility of using PBPK modeling to understand the mechanistic basis of PK differences between adults and specific populations, such as pediatrics, and pregnant and lactating individuals, indicating that this technology can potentially inform or optimize dosing conditions in specific populations.

Analysis of Monosynaptic Inputs to Thalamic Paraventricular Nucleus Neurons Innervating the Shell of the Nucleus Accumbens and Central Extended Amygdala.

The paraventricular nucleus of the thalamus (PVT) sends dense projections to the shell of the nucleus accumbens (NAcSh), dorsolateral region of the bed nucleus of the stria terminalis (BSTDL) and the lateral region of central nucleus of the amygdala (CeL). Projection specific modulation of these pathways has been shown to regulate appetitive and aversive behavioral responses. The present investigation applied an intersectional monosynaptic rabies tracing approach to quantify the brain-wide sources of afferent input to PVT neurons that primarily project to the NAcSh, BSTDL and CeL. The results demonstrate that these projection neurons receive monosynaptic input from similar brain regions. The prefrontal cortex and the ventral subiculum of the hippocampus were major sources of input to the PVT projection neurons. In addition, the lateral septal nucleus, thalamic reticular nucleus and the hypothalamic medial preoptic area, dorsomedial, ventromedial, and arcuate nuclei were sources of input. The subfornical organ, parasubthalamic nucleus, periaqueductal gray matter, lateral parabrachial nucleus, and nucleus of the solitary tract were consistent but lesser sources of input. This input-output relationship is consistent with recent observations that PVT neurons have axons that bifurcate extensively to divergently innervate the NAcSh, BSTDL and CeL.

Development of a Generic Fetal Physiologically Based Pharmacokinetic Model and Prediction of Human Maternal and Fetal Organ Concentrations of Cefuroxime.

BACKGROUND AND OBJECTIVE: Physiologically based pharmacokinetic (PBPK) models for pregnant women have recently been successfully used to predict maternal and umbilical cord pharmacokinetics (PK). Because there is very limited opportunity for conducting clinical and PK investigations for fetal drug exposure, PBPK models may provide further insights. The objectives of this study were to extend a whole-body pregnancy PBPK model by multiple compartments representing fetal organs, and to predict the PK of cefuroxime in the maternal and fetal plasma, the amniotic fluid, and several fetal organs. METHODS: To this end, a previously developed pregnancy PBPK model for cefuroxime was updated using the open-source software Open Systems Pharmacology (PK-Sim®/MoBi®). Multiple compartments were implemented to represent fetal organs including brain, heart, liver, lungs, kidneys, the gastrointestinal tract (GI), muscles, and fat tissue, as well as another compartment lumping organs and tissues not explicitly represented. RESULTS: This novel PBPK model successfully predicted cefuroxime concentrations in maternal blood, umbilical cord, amniotic fluid, and several fetal organs including heart, liver, and lungs. Further model validation with additional clinical PK data is needed to build confidence in the model. CONCLUSIONS: Being developed with an open-source software, the presented generic model can be freely re-used and tailored to address specific questions at hand, e.g., to assist the design of clinical studies in the context of drug research or to predict fetal organ concentrations of chemicals in the context of fetal health risk assessment.

Antibiotic Use in Hospital Urinary Tract Infections After FDA Regulation.

BACKGROUND: The FDA issued a "black box" warning regarding risks of fluoroquinolones in 2008 with updates in 2011, 2013, and 2016. OBJECTIVE: To examine antimicrobial use in hospital-treated UTIs from 2000 to 2020. DESIGN: Cross-sectional study with interrupted time series analysis. PARTICIPANTS: Patient encounters with a diagnosis of UTI from January 2000 to March 2020, excluding diagnoses of renal abscess, chronic cystitis, and infection of the gastrointestinal tract, lungs, or prostate. MAIN MEASURES: Monthly use of fluoroquinolone and non-fluoroquinolone antibiotics were assessed. Fluoroquinolone resistance was assessed in available cultures. Interrupted time series analysis examined level and trend changes of antimicrobial use with each FDA label change. KEY RESULTS: A total of 9,950,790 patient encounters were included. From July 2008 to March 2020, fluoroquinolone use declined from 61.7% to 11.7%, with similar negative trends observed in inpatients and outpatients, age ≥ 60 and < 60 years, males and females, patients with and without pyelonephritis, and across physician specialties. Ceftriaxone use increased from 26.4% encounters in July 2008 to 63.6% of encounters in March 2020. Among encounters with available culture data, fluoroquinolone resistance declined by 28.9% from 2009 to 2020. On interrupted time series analysis, the July 2008 FDA warning was associated with a trend change (-0.32%, < 0.001) and level change (-5.02%, p < 0.001) in monthly fluoroquinolone use. CONCLUSIONS: During this era of "black box" warnings, there was a decline in fluoroquinolone use for hospital-treated UTI with a concomitant decline in fluoroquinolone resistance and rise in ceftriaxone use. Efforts to restrict use of a medication class may lead to compensatory increases in use of a single alternative agent with changes in antimicrobial resistance profiles.

Effect of Obesity on the Pharmacokinetics and Pharmacodynamics of Anticancer Agents.

An objective of the Precision Medicine Initiative, launched in 2015 by the US Food and Drug Administration and National Institutes of Health, is to optimize and individualize dosing of drugs, especially anticancer agents, with high pharmacokinetic and pharmacodynamic variability. The American Society of Clinical Oncology recently reported that 40% of obese patients receive insufficient chemotherapy doses and exposures, which may lead to reduced efficacy, and recommended pharmacokinetic studies to guide appropriate dosing in these patients. These issues will only increase in importance as the incidence of obesity in the population increases. This publication reviews the effects of obesity on (1) tumor biology, development of cancer, and antitumor response; (2) pharmacokinetics and pharmacodynamics of small-molecule anticancer drugs; and (3) pharmacokinetics and pharmacodynamics of complex anticancer drugs, such as carrier-mediated agents and biologics. These topics are not only important from a scientific research perspective but also from a drug development and regulator perspective. Thus, it is important to evaluate the effects of obesity on the pharmacokinetics and pharmacodynamics of anticancer agents in all categories of body habitus and especially in patients who are obese and morbidly obese. As the effects of obesity on the pharmacokinetics and pharmacodynamics of anticancer agents may be highly variable across drug types, the optimal dosing metric and algorithm for difference classes of drugs may be widely different. Thus, studies are needed to evaluate current and novel metrics and methods for measuring body habitus as related to optimizing the dose and reducing pharmacokinetic and pharmacodynamic variability of anticancer agents in patients who are obese and morbidly obese.

Inclusion of Subjects who are Obese in Drug Development: Current Status and Opportunities.

The prevalence of obesity has grown tremendously in recent years and this population has an increased risk of disease comorbidities. The presence of disease comorbidities requires treatment interventions and proper dosing guidelines. However, drug development programs often do not have adequate representation of individuals who are obese in clinical trials, leaving gaps in the understanding of treatment response leading to a lack of adequate individualization options. Based on a recent survey of approved drug product package inserts, very few approved products included specific dosing based on obesity, in both adults and pediatrics. Reasons for the limited information on patients who are obese may include the under-reporting of information regarding such patients and a lack of clinical trial diversity in enrolling patient groups in whom obesity or obesity-related comorbidities are more prevalent. An inadvertent impact of the practice of exclusion of subsets of patients with some comorbidities in clinical trials may play a role in the reduced enrollment of individuals who are obese. Recently, regulatory authorities have taken specific initiatives to promote clinical trial diversity, including engaging with stakeholders and publishing regulatory guidance. These guidance documents highlight the need to enroll diverse clinical trial populations and provide recommendations on concepts related to drug development for obese populations. Such efforts will help to address the gap in information regarding drug response and dosing in patients who are obese.

Obesity Considerations in Pediatric Drug Development, 2016-2021.

Pediatric obesity is a global public health concern. Obesity-related physiological changes may affect the pharmacokinetics of drugs and lead to therapeutic failure or toxicities. An earlier review of pediatric drug development programs from 2007 to 2016 found that, of 89 programs listing obesity-related terms, only 4 (4%) products described pharmacokinetic changes associated with obesity. This review examined obesity considerations for 185 drug products for which pediatric drug development programs were submitted to the US Food and Drug Administration (FDA) between 2016 and 2021. The FDA-authored review documents and drug product labeling were queried for obesity-related terms and the review found 97/185 (52%) drug products had obesity-related terms in these sources. Of the 97 drug products, 55/97 (57%) had obesity-related terms in the FDA-authored reviews only, 13/97 (13%) had obesity-related terms in the drug product labeling only, and 29/97 (30%) had obesity-related terms in both FDA-authored reviews and drug product labeling. Most of the obesity-related information in the drug product labeling originated from data collected from adults. Only 13/185 (7%) drug product labeling contained obesity-related terms in reference to drug pharmacokinetics. Specific dosage recommendations for the use of the drug products in pediatric patients who are obese remain lacking. The dearth of available information to guide drug dosages in the obese pediatric population suggests that further research, innovative approaches, and evidence-based guidelines are needed to inform the optimal therapeutic use of drugs in this population.

Need for Representation of Pediatric Patients with Obesity in Clinical Trials.

Clinical trials are an integral aspect of drug development. Tremendous progress has been made in ensuring drug products are effective and safe for use in the intended pediatric population, but there remains a paucity of information to guide drug dosages in pediatric patients with obesity. This is concerning because obesity may influence the disposition of drug products. When pediatric patients with obesity are not enrolled in clinical trials, dosing options for use in this subpopulation may be suboptimal. Reliance on physiological-based dosing strategies that are not informed by evaluation of the pharmacokinetics of the drug product could lead to under- or over-dosing with ensuing therapeutic failure or toxicity consequences. Thus, representation of pediatric patients with obesity in clinical trials is crucial to understand the benefit-risk profile of drug products in this subpopulation. It is important to acknowledge that this is a challenging endeavor, but not one that is insurmountable. Collective efforts from multiple stakeholders including drug developers and regulators to enhance diversity in clinical trials can help fill critical gaps in knowledge related to the influence of obesity on drug disposition.

Metabolic Insights into Iron Deposition in Relapsing-Remitting Multiple Sclerosis via 7 T Magnetic Resonance Spectroscopic Imaging.

OBJECTIVE: To investigate the metabolic pattern of different types of iron accumulation in multiple sclerosis (MS) lesions, and compare metabolic alterations within and at the periphery of lesions and newly emerging lesions in vivo according to iron deposition. METHODS: 7 T MR spectroscopic imaging and susceptibility-weighted imaging was performed in 31 patients with relapsing-remitting MS (16 female/15 male; mean age, 36.9 ± 10.3 years). Mean metabolic ratios of four neuro-metabolites were calculated for regions of interest (ROI) of normal appearing white matter (NAWM), "non-iron" (lesion without iron accumulation on SWI), and three distinct types of iron-laden lesions ("rim": distinct rim-shaped iron accumulation; "area": iron deposition across the entire lesions; "transition": transition between "area" and "rim" accumulation shape), and for lesion layers of "non-iron" and "rim" lesions. Furthermore, newly emerging "non-iron" and "iron" lesions were compared longitudinally, as measured before their appearance and one year later. RESULTS: Thirty-nine of 75 iron-containing lesions showed no distinct paramagnetic rim. Of these, "area" lesions exhibited a 65% higher mIns/tNAA (p = 0.035) than "rim" lesions. Comparing lesion layers of both "non-iron" and "rim" lesions, a steeper metabolic gradient of mIns/tNAA ("non-iron" +15%, "rim" +40%) and tNAA/tCr ("non-iron" -15%, "rim" -35%) was found in "iron" lesions, with the lesion core showing +22% higher mIns/tNAA (p = 0.005) and -23% lower tNAA/tCr (p = 0.048) in "iron" compared to "non-iron" lesions. In newly emerging lesions, 18 of 39 showed iron accumulation, with the drop in tNAA/tCr after lesion formation remaining significantly lower compared to pre-lesional tissue over time in "iron" lesions (year 0: p = 0.013, year 1: p = 0.041) as opposed to "non-iron" lesions (year 0: p = 0.022, year 1: p = 0.231). CONCLUSION: 7 T MRSI allows in vivo characterization of different iron accumulation types each presenting with a distinct metabolic profile. Furthermore, the larger extent of neuronal damage in lesions with a distinct iron rim was reconfirmed via reduced tNAA/tCr concentrations, but with metabolic differences in lesion development between (non)-iron-containing lesions. This highlights the ability of MRSI to further investigate different types of iron accumulation and suggests possible implications for disease monitoring.

Onset of the Non-Medical Use of Prescription and Over-the-Counter Medications during Early Adolescence: Comparison with Alcohol, Tobacco, and Marijuana.

This study examined the prevalence and psychosocial predictors of the non-medical use of prescription and over-the-counter (OTC) medications and compared these to cigarette, marijuana, and alcohol use in a cohort of early adolescents (N = 1887) aged 11 to 13, a critical risk period for the initiation of substance use. Participants were students attending 22 middle schools in the northeastern United States. Participants completed surveys in the classroom, the first in the sixth grade and a second in the seventh grade, and the rate of overall substance use more than doubled from 5.5% to 11.9% over this period. Predictors of the onset of non-medical prescription and over-the-counter drug misuse overlapped substantially with those for marijuana and other substances. The perception of friends' substance use and the belief that substance use can help you deal with problems predicted the onset of marijuana use, OTC medication misuse, and prescription drug misuse. Decision-making skills were protective for the onset of all substance use outcomes. The findings of this study have important implications for prevention and suggest that a single comprehensive approach may be sufficient for preventing multiple forms of substance use onset during early adolescence.

Pediatric dosing for locally acting drugs in submissions to the U.S. Food and Drug Administration between 2002 and 2020.

Deriving pediatric doses for locally acting drugs (LADs) presents a unique challenge because limited systemic exposure hinders commonly used approaches such as pharmacokinetic matching to adults. This study systematically evaluated drug development practices used for pediatric dose selection of LADs approved by the U.S. Food and Drug Administration from 2002 to 2020. The three study objectives were: (1) to determine the dose selection approach for the labeled pediatric dose, (2) to examine the studied pediatric dose(s), and (3) to evaluate the characteristics of the pediatric clinical programs used to support the labeled pediatric dose. A total of 187 pediatric submissions were characterized for the labeled and studied pediatric doses of LADs. The pediatric dose was predominantly labeled as a flat dose (91%) and at a single-dose level (67%) similar to adults. The majority (68.4%) of the submissions had the same labeled dose for pediatrics and adults. Independent pharmacodynamic/efficacy studies in pediatric patients commonly (64.2%) provided supportive evidence for the labeled pediatric dose. Inhalation, nasal, and injectable submissions had the highest number of clinical trials, lowest usage of an extrapolation of efficacy approach, and utilized diverse approaches in selecting the studied pediatric doses. This article highlights approaches for LAD dosing in pediatric patients and can be used to inform drug development of these products in the pediatric population.