Tracking Drugs and Lipids: Quantitative Mass Spectrometry Imaging of Liposomal Doxorubicin Delivery and Bilayer Fate in Three-Dimensional Tumor Models.

Targeted therapy to the tumor would greatly advance precision medicine. Many drug delivery vehicles have emerged, but liposomes are cited as the most successful to date. Recent efforts to develop liposomal drug delivery systems focus on drug distribution in tissues and ignore liposomal fate. In this study, we developed a novel method to elucidate both drug and liposomal bilayer distribution in a three-dimensional cell culture model using quantitative matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI qMSI) alongside fluorescence microscopy. Imaging liposomal distribution in a cell culture model is challenging, as lipids forming the bilayer are endogenous to the model system. To resolve this issue, we functionalized the bilayer by chemically cross-linking a fluorescent tag to the alkyne-containing lipid hexynoyl phosphoethanolamine (HPE). We synthesized liposomes incorporating the tagged HPE lipid and encapsulated within them doxorubicin, yielding a theranostic liposome capable of both drug delivery and monitoring liposomal uptake. We employed an "in-tissue" MALDI qMSI approach to generate a calibration curve with R2 = 0.9687, allowing for quantification of doxorubicin within spheroid sections at multiple time points. After 72 h of treatment with the theranostic liposomes, full doxorubicin penetration was observed. The metabolites doxorubicinone and 7-deoxydoxorubicinone were also detected after 48 h. Modification of the bilayer allowed for fluorescence microscopy tracking of liposomes, while MALDI MSI simultaneously permitted the imaging of drugs and metabolites. While we demonstrated the utility of our method with doxorubicin, this system could be applied to examine the uptake, release, and metabolism of many other liposome-encapsulated drugs.

Single Cell MALDI-MS Imaging of Lipids and Proteins in Senescent Fibroblasts.

In this study, we evaluate the lipidomic and proteomic profiles of human lung fibroblasts (hLFs) to interrogate changes occurring due to senescence. To study single cell populations, a comparison of cell adhered onto slides utilizing poly-D-lysine versus centrifugal force deposition was first analyzed to determine whether specific alterations were observed between preparations. The poly-D-lysine approach was than utilized to interrogate the lipidome of the cell populations and further evaluate potential applications of the MALDI-IHC platform for single-cell level analyses. Altogether, our results show the ability to detect lipids implicated in senescence and alterations to protein expression between normal and senescent fibroblast populations. This report is the first time that the MALDI-IHC system has been utilized at a single-cell level for analyzing the expression of proteins.

Spatial prey availability and pulsed reproductive tactics: Encounter risk in a canid-ungulate system.

Predation risk is a function of spatiotemporal overlap between predator and prey, as well as behavioural responses during encounters. Dynamic factors (e.g. group size, prey availability and animal movement or state) affect risk, but rarely are integrated in risk assessments. Our work targets a system where predation risk is fundamentally linked to temporal patterns in prey abundance and behaviour. For neonatal ungulate prey, risk is defined within a short temporal window during which the pulse in parturition, increasing movement capacity with age and antipredation tactics have the potential to mediate risk. In our coyote-mule deer (Canis latrans-Odocoileus hemionus) system, leveraging GPS data collected from both predator and prey, we tested expectations of shared enemy and reproductive risk hypotheses. We asked two questions regarding risk: (A) How does primary and alternative prey habitat, predator and prey activity, and reproductive tactics (e.g. birth synchrony and maternal defence) influence the vulnerability of a neonate encountering a predator? (B) How do the same factors affect behaviour by predators relative to the time before and after an encounter? Despite increased selection for mule deer and intensified search behaviour by coyotes during the peak in mule deer parturition, mule deer were afforded protection from predation via predator swamping, experiencing reduced per-capita encounter risk when most neonates were born. Mule deer occupying rabbit habitat (Sylvilagus spp.; coyote's primary prey) experienced the greatest risk of encounter but the availability of rabbit habitat did not affect predator behaviour during encounters. Encounter risk increased in areas with greater availability of mule deer habitat: coyotes shifted their behaviour relative to deer habitat, and the pulse in mule deer parturition and movement of neonatal deer during encounters elicited increased speed and tortuosity by coyotes. In addition to the spatial distribution of prey, temporal patterns in prey availability and animal behavioural state were fundamental in defining risk. Our work reveals the nuanced consequences of pulsed availability on predation risk for alternative prey, whereby responses by predators to sudden resource availability, the lasting effects of diversionary prey and inherent antipredation tactics ultimately dictate risk.

Quantitative mass spectrometry imaging: therapeutics & biomolecules.

Mass spectrometry imaging (MSI) has become increasingly utilized in the analysis of biological molecules. MSI grants the ability to spatially map thousands of molecules within one experimental run in a label-free manner. While MSI is considered by most to be a qualitative method, recent advancements in instrumentation, sample preparation, and development of standards has made quantitative MSI (qMSI) more common. In this feature article, we present a tailored review of recent advancements in qMSI of therapeutics and biomolecules such as lipids and peptides/proteins. We also provide detailed experimental considerations for conducting qMSI studies on biological samples, aiming to advance the methodology.

A Systematic Review and Meta-analysis of Chemical Exposures and Attention-Deficit/Hyperactivity Disorder in Children.

Exposure to certain chemicals prenatally and in childhood can impact development and may increase risk for attention-deficit/hyperactivity disorder (ADHD). Leveraging a larger set of literature searches conducted to synthesize results from longitudinal studies of potentially modifiable risk factors for childhood ADHD, we present meta-analytic results from 66 studies that examined the associations between early chemical exposures and later ADHD diagnosis or symptoms. Studies were eligible for inclusion if the chemical exposure occurred at least 6 months prior to measurement of ADHD diagnosis or symptomatology. Included papers were published between 1975 and 2019 on exposure to anesthetics (n = 5), cadmium (n = 3), hexachlorobenzene (n = 4), lead (n = 22), mercury (n = 12), organophosphates (n = 7), and polychlorinated biphenyls (n = 13). Analyses are presented for each chemical exposure by type of ADHD outcome reported (categorical vs. continuous), type of ADHD measurement (overall measures of ADHD, ADHD symptoms only, ADHD diagnosis only, inattention only, hyperactivity/impulsivity only), and timing of exposure (prenatal vs. childhood vs. cumulative), whenever at least 3 relevant effect sizes were available. Childhood lead exposure was positively associated with ADHD diagnosis and symptoms in all analyses except for the prenatal analyses (odds ratios (ORs) ranging from 1.60 to 2.62, correlation coefficients (CCs) ranging from 0.14 to 0.16). Other statistically significant associations were limited to organophosphates (CC = 0.11, 95% confidence interval (CI): 0.03-0.19 for continuous measures of ADHD outcomes overall), polychlorinated biphenyls (CC = 0.08, 95% CI: 0.02-0.14 for continuous measures of inattention as the outcome), and both prenatal and childhood mercury exposure (CC = 0.02, 95% CI: 0.00-0.04 for continuous measures of ADHD outcomes overall for either exposure window). Our findings provide further support for negative impacts of prenatal and/or childhood exposure to certain chemicals and raise the possibility that primary prevention and targeted screening could prevent or mitigate ADHD symptomatology. Furthermore, these findings support the need for regular review of regulations as our scientific understanding of the risks posed by these chemicals evolves.

Lipidomics Profiling Reveals Differential Alterations after FAS Inhibition in 3D Colon Cancer Cell Culture Models.

Cancerous cells synthesize most of their lipids de novo to keep up with their rapid growth and proliferation. Fatty acid synthase (FAS) is a key enzyme in the lipogenesis pathway that is upregulated in many cancers and has gained popularity as a druggable target of interest for cancer treatment. The first FAS inhibitor discovered, cerulenin, initially showed promise for chemotherapeutic purposes until it was observed that it had adverse side effects in mice. TVB-2640 (Denifanstat) is part of the newer generation of inhibitors. With multiple generations of FAS inhibitors being developed, it is vital to understand their distinct molecular downstream effects to elucidate potential interactions in the clinic. Here, we profile the lipidome of two different colorectal cancer (CRC) spheroids treated with a generation 1 inhibitor (cerulenin) or a generation 2 inhibitor (TVB-2640). We observe that the cerulenin causes drastic changes to the spheroid morphology as well as alterations to the lipid droplets found within CRC spheroids. TVB-2640 causes higher abundances of polyunsaturated fatty acids (PUFAs) whereas cerulenin causes a decreased abundance of PUFAs. The increase in PUFAs in TVB-2640 exposed spheroids indicates it is causing cells to die via a ferroptotic mechanism rather than a conventional apoptotic or necrotic mechanism.

Systematic Review and Meta-analysis of the Relationship Between Exposure to Parental Substance Use and Attention-Deficit/Hyperactivity Disorder in Children.

Attention-deficit/hyperactivity disorder (ADHD) is characterized by persistent patterns of inattention, hyperactivity, and impulsiveness. Among US children and adolescents aged 3-17 years, 9.4% have a diagnosis of ADHD. Previous research suggests possible links between parental substance use and ADHD among children. We conducted a systematic review and meta-analysis of 86 longitudinal or retrospective studies of prenatal or postnatal alcohol, tobacco, or other parental substance use and substance use disorders and childhood ADHD and its related behavioral dimensions of inattention and hyperactivity-impulsivity. Meta-analyses were grouped by drug class and pre- and postnatal periods with combined sample sizes ranging from 789 to 135,732. Prenatal exposure to alcohol or tobacco and parent substance use disorders were consistently and significantly associated with ADHD among children. Other parental drug use exposures resulted in inconsistent or non-significant findings. Prevention and treatment of parental substance use may have potential for impacts on childhood ADHD.

Enhancement of Lipid Signals in Matrix-Assisted Laser Desorption/Ionization Mass Spectrometry with Ammonium Fluoride as a Matrix Additive.

Lipids are essential macromolecules that play a crucial role in numerous biological events. Lipids are structurally diverse which allows them to fulfill multiple functional roles. Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) is a powerful tool to understand the spatial localization of lipids within biological systems. Herein, we report the use of ammonium fluoride (NH4F) as a comatrix additive to enhance lipid detection in biological samples, with a signal increase of up to 200%. Emphasis was placed on anionic lipid enhancement with negative polarity measurements, with some preliminary work on cationic lipids detailed. We observed lipid signal enhancement of [M-H]- ions with the addition of NH4F additive attributed to a proton transfer reaction in several different lipid classes. Overall, our study demonstrates that the use of the NH4F comatrix additive substantially improves sensitivity for lipid detection in a MALDI system and is capable of being applied to a variety of different applications.

Crystalline Nanoparticles of Water-Soluble Covalent Basket Cages (CBCs) for Encapsulation of Anticancer Drugs.

We herein describe the preparation, assembly, recognition characteristics, and biocompatibility of novel covalent basket cage CBC-11, composed of four molecular baskets linked to four trivalent aromatic amines through amide groups. The cage is tetrahedral in shape and similar in size to small proteins (Mw =8637 g/mol) with a spacious nonpolar interior for accommodating multiple guests. While 24 carboxylates at the outer surface of CBC-11 render it soluble in aqueous phosphate buffer (PBS) at pH=7.0, the amphiphilic nature prompts its assembly into nanoparticles (d=250 nm, DLS). Cryo-TEM examination of nanoparticles revealed their crystalline nature with wafer-like shapes and hexagonally arranged cages. Nanoparticulate CBC-11 traps anticancer drugs irinotecan and doxorubicin, with each cage binding up to four drug molecules in a non-cooperative manner. The inclusion complexation resulted in nanoparticles growing in size and precipitating. In media containing mammalian cells (HCT 116, human colon carcinoma), the IC50 value of CBC-11 was above 100 µM. While this work presents the first example of a large covalent organic cage operating in water at the physiological pH and forming crystalline nanoparticles, it also demonstrates its biocompatibility and potential to act as a polyvalent binder of drugs for their sequestration or delivery.

Post-COVID conditions and healthcare utilization among adults with and without disabilities-2021 Porter Novelli FallStyles survey.

BACKGROUND: Adults with disabilities are at increased risk for SARS-CoV-2 infection and severe disease; whether adults with disabilities are at an increased risk for ongoing symptoms after acute SARS-CoV-2 infection is unknown. OBJECTIVES: To estimate the frequency and duration of long-term symptoms (>4 weeks) and health care utilization among adults with and without disabilities who self-report positive or negative SARS-CoV-2 test results. METHODS: Data from a nationwide survey of 4510 U.S. adults administered from September 24, 2021-October 7, 2021, were analyzed for 3251 (79%) participants who self-reported disability status, symptom(s), and SARS-CoV-2 test results (a positive test or only negative tests). Multivariable models were used to estimate the odds of having ≥1 COVID-19-like symptom(s) lasting >4 weeks by test result and disability status, weighted and adjusted for socio-demographics. RESULTS: Respondents who tested positive for SARS-CoV-2 had higher odds of reporting ≥1 long-term symptom (with disability: aOR = 4.50 [95% CI: 2.37, 8.54] and without disability: aOR = 9.88 [95% CI: 7.13, 13.71]) compared to respondents testing negative. Among respondents who tested positive, those with disabilities were not significantly more likely to experience long-term symptoms compared to respondents without disabilities (aOR = 1.65 [95% CI: 0.78, 3.50]). Health care utilization for reported symptoms was higher among respondents with disabilities who tested positive (40%) than among respondents without disabilities who tested positive (18%). CONCLUSIONS: Ongoing symptoms among adults with and without disabilities who also test positive for SARS-CoV-2 are common; however, the frequency of health care utilization for ongoing symptoms is two-fold among adults with disabilities.

Clinical Characteristics of Children With Tourette Syndrome With and Without Sleep Disorder.

BACKGROUND: Sleep problems are common in children with Tourette Syndrome (TS). However, research regarding their demographic and clinical profile is limited. METHODS: We examined characteristics of 114 children aged five to 17 years with a lifetime diagnosis of TS and compared children with sleep disorder (n = 32) and without sleep disorder (n = 82). Parent report from the 2014 National Survey of the Diagnosis and Treatment of ADHD and Tourette Syndrome provided demographics and clinical information, other diagnosed disorders, medication use, TS severity, and impairment. RESULTS: More children with TS with sleep disorder were from households with lower parental education (P < 0.01) and poverty (P = 0.04); had other diagnoses (P = 0.03), including obsessive-compulsive disorder (P < 0.01), oppositional defiant disorder or conduct disorder (P < 0.01), attention-deficit/hyperactivity disorder (ADHD) (P = 0.02), and autism (P = 0.03); and had ever used TS medication (P = 0.01) than children with TS without sleep disorder. More children with TS with sleep disorder had severe TS symptoms (P <0.01), tic-related impairment (P<0.01), and severe ADHD symptoms (P < 0.01) compared with children with TS without sleep disorder. CONCLUSIONS: Findings suggest greater parent-reported impact and tic-related interference in children with TS with sleep disorder compared with TS without sleep disorder. Results underscore the importance of monitoring and intervention for TS exacerbations, other diagnosed disorders, and medication use, and consideration of socioeconomic context in sleep disorder management and prevention in children with TS.

Surveillance of ADHD Among Children in the United States: Validity and Reliability of Parent Report of Provider Diagnosis.

OBJECTIVE: To evaluate the appropriateness of parent-reported diagnosis of ADHD as a surveillance tool. METHOD: We assessed agreement over time and concordance of parent-reported diagnosis against Diagnostic and Statistical Manual (DSM)-based criteria. We compared concordance of diagnosis and DSM-based criteria by child characteristics, including treatment. RESULTS: Among parents who reported their child had ADHD, 95.7% reported it again 2 years later. Comparing diagnosis with DSM-based criteria, specificity and negative predictive value were high, sensitivity was moderate, and positive predictive value was low. Most children with an ADHD diagnosis who did not meet DSM-based criteria met sub-threshold criteria or took medication for ADHD. Concordance differed by child characteristics and treatment. CONCLUSION: Parent-reported diagnosed ADHD is reliable over time. Although differences in parent-reported diagnosis and DSM-based criteria were noted, these may reflect children with milder symptoms or treated ADHD. Parent-report of child ADHD ever diagnosis may be a good single-item indicator for prevalence.

Validation of the Diagnostic Interview Schedule for Children (DISC-5) Tic Disorder and Attention-Deficit/Hyperactivity Disorder Modules.

Effective methods to assess mental disorders in children are necessary for accurate prevalence estimates and to monitor prevalence over time. This study assessed updates of the tic disorder and attention-deficit/hyperactivity disorder (ADHD) modules of the Diagnostic Interview Schedule for Children, Version 5 (DISC-5) that reflect changes in diagnostic criteria in the Diagnostic and Statistical Manual of Mental Disorders (Fifth edition, DSM-5). The DISC-5 tic disorder and ADHD parent- and child-report modules were compared to expert clinical assessment for 100 children aged 6-17 years (40 with tic disorder alone, 17 with tic disorder and ADHD, 9 with ADHD alone, and 34 with neither) for validation. For the tic disorder module, parent-report had high (>90%) sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy, while the youth-report had high specificity and PPV, moderate accuracy (81.4%), and lower sensitivity (69.8%) and NPV (67.3%). The ADHD module performed less well: parent-report had high NPV (91.4%), moderate sensitivity (80.8%), and lower specificity (71.6%), PPV (50.0%), and accuracy (74.0%); youth-report had moderate specificity (82.8%) and NPV (88.3%), and lower sensitivity (65.0%), PPV (54.2%), and accuracy (78.6%). Adding teacher-report of ADHD symptoms to DISC-5 parent-report of ADHD increased sensitivity (94.7%) and NPV (97.1%), but decreased specificity (64.2%), PPV (48.7%), and accuracy (72.2%). These findings support using the parent-report tic disorder module alone or in combination with the child report module in future research and epidemiologic studies; additional validation studies are warranted for the ADHD module.

A Population-Based Study of the Utility of Screening for Tics and the Relative Contribution of Tics and Psychiatric Comorbidity to Academic and Social Impairment in Adolescents.

This study examined the performance of a brief screening tool for tics in adolescents. Academic and social impairment in students by tic screen status and emotional/behavioral problem status were examined. Data were collected as part of an epidemiologic study, the Project to Learn about Youth - Mental Health. Participants were 2,312 secondary school students at the Ohio site (47.4% female; 94.4% non-Hispanic white) and their teachers. Students completed 6 items from the Motor tic, Obsessions and compulsions, Vocal tic Evaluation Survey (MOVES-6) and the Strengths and Difficulties Questionnaire (SDQ). Teachers completed the Proxy Report Questionnaire for tics and SDQ. Based on responses to the MOVES-6, 11.1% of students screened positive for tics. Internal consistency was adequate (α = 0.76); inter-rater consistency between teachers and students was low (0.03). Based on student self-report, those who screened positive for tics self-reported more academic and social impairment than students who screened negative for tics; teacher-report of impairment was similar between those with a positive or negative tic screen. Students who screened positive for tics and reported internalizing difficulties reported more academic and social impairment than students with only a positive tic screen. Teachers perceived those screening positive for tics and externalizing difficulties as the most socially impaired. In conclusion, a positive self-reported tic screen was associated with self-reported academic and social impairment. Findings reveal the independent contribution of tics to impairment, even when internalizing and externalizing problems are present, and the potential utility of a school-based screening for tics in adolescents.

Health Care Access and Use Among Adults With and Without Vision Impairment: Behavioral Risk Factor Surveillance System, 2018.

INTRODUCTION: Adults with vision impairment may have unique needs when accessing health care to maintain good health. Our study examined the relationship between vision status and access to and use of health care. METHODS: We analyzed data on adults aged 18 years or older who participated in the 2018 Behavioral Risk Factor Surveillance System. Vision impairment was identified by a yes response to the question "Are you blind or do you have serious difficulty seeing, even when wearing glasses?" Survey questions assessed health care access over the past year (having health insurance coverage, a usual health care provider, or unmet health care needs because of cost) and use of health care during that period (routine checkup and dental visit). We estimated age-adjusted prevalence of our outcomes of interest and used bivariate analyses to compare estimates of the outcomes by vision impairment status. RESULTS: The prevalence of self-reported vision impairment was 5.3%. Compared with adults without impaired vision, adults with vision impairment had a lower prevalence of having health insurance coverage (80.6% vs 87.6%), a usual health care provider (71.9% vs 75.7%), or a dental visit in the past year (52.9% vs 67.2%) and a higher prevalence of having an unmet health care need in the past year because of cost (29.2% vs 12.6%). CONCLUSION: Adults with vision impairment reported lower access to and use of health care than those without. Further research can better identify and understand barriers to care to improve access to and use of health care among this population.

Childhood Physical Health and Attention Deficit/Hyperactivity Disorder: A Systematic Review and Meta-Analysis of Modifiable Factors.

Although neurobiologic and genetic factors figure prominently in the development of attention deficit/hyperactivity disorder (ADHD), adverse physical health experiences and conditions encountered during childhood may also play a role. Poor health is known to impact the developing brain with potential lifelong implications for behavioral issues. In attempt to better understand the relationship between childhood physical health and the onset and presence of ADHD symptoms, we summarized international peer-reviewed articles documenting relationships between a select group of childhood diseases or health events (e.g., illnesses, injuries, syndromes) and subsequent ADHD outcomes among children ages 0-17 years. Drawing on a larger two-phase systematic review, 57 longitudinal or retrospective observational studies (1978-2021) of childhood allergies, asthma, eczema, head injury, infection, or sleep problems and later ADHD diagnosis or symptomatology were identified and subjected to meta-analysis. Significant associations were documented between childhood head injuries, infections, and sleep problems with both dichotomous and continuous measures of ADHD, and between allergies with dichotomous measures of ADHD. We did not observe significant associations between asthma or eczema with ADHD outcomes. Heterogeneity detected for multiple associations, primarily among continuously measured outcomes, underscores the potential value of future subgroup analyses and individual studies. Collectively, these findings shed light on the importance of physical health in understanding childhood ADHD. Possible etiologic links between physical health factors and ADHD are discussed, as are implications for prevention efforts by providers, systems, and communities.

Stability of mental disorder prevalence estimates among school-aged children and adolescents: findings from the community-based project to learn about youth-mental health (PLAY-MH) and replication-PLAY-MH (Re-PLAY-MH), 2014-2017.

PURPOSE: This study evaluated the stability over time of prevalence estimates of mental disorders among school-aged children from the same community. METHODS: We compared screening status and weighted prevalence of selected mental disorders from the two-stage school-based South Carolina Project to Learn About Youth-Mental Health (Time 1) and its replication study (Time 2) conducted between 2014 and 2017. During stage 1, two teacher screeners were used to group students into high or low risk for a mental disorder. During stage 2, parents of selected students completed a structured diagnostic interview to assess whether their child met criteria for specific disorders. RESULTS: For stage 1, 19.9% of students screened as high risk for a mental disorder at Time 2 compared to 17.8% at Time 1. Among students included at both timepoints, 9.1% screened as high risk at both timepoints while screening status changed for 20.7%. The overall prevalence of included mental disorders was approximately 18% at both time points There were no differences (P-values >.05) in prevalence of individual mental disorders between Time 1 (range:0.3%-6.7%) and Time 2 (range:1.2%-7.7%). CONCLUSIONS: Study findings demonstrate that similar methodology yielded similar prevalence estimates of mental disorders and can inform community-level planning for improving mental health in children.

Risky business: How an herbivore navigates spatiotemporal aspects of risk from competitors and predators.

Understanding factors that influence animal behavior is central to ecology. Basic principles of animal ecology imply that individuals should seek to maximize survival and reproduction, which means carefully weighing risk against reward. Decisions become increasingly complex and constrained, however, when risk is spatiotemporally variable. We advance a growing body of work in predator-prey behavior by evaluating novel questions where a prey species is confronted with multiple predators and a potential competitor. We tested how fine-scale behavior of female mule deer (Odocoileus hemionus) during the reproductive season shifted depending upon spatial and temporal variation in risk from predators and a potential competitor. We expected female deer to avoid areas of high risk when movement activity of predators and a competitor were high. We used GPS data collected from 76 adult female mule deer, 35 adult female elk, 33 adult coyotes, and six adult mountain lions. Counter to our expectations, female deer exhibited selection for multiple risk factors, however, selection for risk was dampened by the exposure to risk within home ranges of female deer, producing a functional response in habitat selection. Furthermore, temporal variation in movement activity of predators and elk across the diel cycle did not result in a shift in movement activity by female deer. Instead, the average level of risk within their home range was the predominant factor modulating the response to risk by female deer. Our results counter prevailing hypotheses of how large herbivores navigate risky landscapes and emphasize the importance of accounting for the local environment when identifying effects of risk on animal behavior. Moreover, our findings highlight additional behavioral mechanisms used by large herbivores to mitigate multiple sources of predation and potential competitive interactions.

A Systematic Review and Meta-analysis of Parental Depression, Antidepressant Usage, Antisocial Personality Disorder, and Stress and Anxiety as Risk Factors for Attention-Deficit/Hyperactivity Disorder (ADHD) in Children.

Poor parental mental health and stress have been associated with children's mental disorders, including attention-deficit/hyperactivity disorder (ADHD), through social, genetic, and neurobiological pathways. To determine the strength of the associations between parental mental health and child ADHD, we conducted a set of meta-analyses to examine the association of parent mental health indicators (e.g., parental depression, antidepressant usage, antisocial personality disorder, and stress and anxiety) with subsequent ADHD outcomes in children. Eligible ADHD outcomes included diagnosis or symptoms. Fifty-eight articles published from 1980 to 2019 were included. We calculated pooled effect sizes, accounting for each study's conditional variance, separately for test statistics based on ADHD as a dichotomous (e.g., diagnosis or clinical cutoffs) or continuous measurement (e.g., symptoms of ADHD subtypes of inattentiveness and hyperactivity/impulsivity). Parental stress and parental depression were significantly associated with increased risk for ADHD overall and both symptoms and diagnosis. Specifically, maternal stress and anxiety, maternal prenatal stress, maternal depression, maternal post-partum depression, and paternal depression were positively associated with ADHD. In addition, parental depression was associated with symptoms of ADHD inattentive and hyperactive/impulsive subtypes. Parental antisocial personality disorder was also positively associated with ADHD overall and specifically ADHD diagnosis. Prenatal antidepressant usage was associated with ADHD when measured dichotomously only. These findings raise the possibility that prevention strategies promoting parental mental health and addressing parental stress could have the potential for positive long-term impacts on child health, well-being, and behavioral outcomes.

State-Level Estimates of the Prevalence of Parent-Reported ADHD Diagnosis and Treatment Among U.S. Children and Adolescents, 2016 to 2019.

OBJECTIVE: To provide state-level estimates of diagnosed ADHD and associated treatment among children in the United States in 2016 to 2019. METHOD: This study used the National Survey of Children's Health to produce national and state-level estimates of lifetime diagnosis and current ADHD among all children aged 3 to 17 years (n=114,476), and national and state-level estimates of medication and behavioral treatment use among children with current ADHD. RESULTS: The state-level estimates of diagnosed ADHD ranged from 6.1% to 16.3%. Among children with current ADHD, state-level estimates of ADHD medication usage ranged from 37.8% to 81.4%, and state-level estimates of behavioral treatment ranged from 38.8% to 61.8%. CONCLUSION: There was substantial state-level variation for indicators of ADHD diagnosis and associated treatment. These state-level results can be used by policymakers, public health practitioners, health care providers, and other stakeholders to help address the service needs of children with ADHD in their states.