Perinatal iron deficiency as an early risk factor for schizophrenia.

Growing evidence indicates that a suboptimal intrauterine environment confers risk for schizophrenia. The developmental model of schizophrenia posits that aberrant brain growth during early brain development and adolescence may interact to contribute to this psychiatric disease in adulthood. Although a variety of factors may perturb the environment of the developing fetus and predispose for schizophrenia later, a common mechanism has yet to be elucidated. Micronutrient deficiencies during the perinatal period are known to induce potent effects on brain development by altering neurodevelopmental processes. Iron is an important candidate nutrient to consider because of its role in energy metabolism, monoamine synthesis, synaptogenesis, myelination, and the high prevalence of iron deficiency (ID) in the mother-infant dyad. Understanding the current state of science regarding perinatal ID as an early risk factor for schizophrenia is imperative to inform empirical work investigating the etiology of schizophrenia and develop prevention and intervention programs. In this narrative review, we focus on perinatal ID as a common mechanism underlying the fetal programming of schizophrenia. First, we review the neural aberrations associated with perinatal ID that indicate risk for schizophrenia in adulthood, including disruptions in dopaminergic neurotransmission, hippocampal-dependent learning and memory, and sensorimotor gating. Second, we review the pathophysiology of perinatal ID as a function of maternal ID during pregnancy and use epidemiological and cohort studies to link perinatal ID with risk of schizophrenia. Finally, we review potential confounding phenotypes, including nonanemic causes of perinatal brain ID and future risk of schizophrenia.

Beyond family-level adversities: Exploring the developmental timing of neighborhood disadvantage effects on the brain.

A growing literature suggests that adversity is associated with later altered brain function, particularly within the corticolimbic system that supports emotion processing and salience detection (e.g., amygdala, prefrontal cortex [PFC]). Although neighborhood socioeconomic disadvantage has been shown to predict maladaptive behavioral outcomes, particularly for boys, most of the research linking adversity to corticolimbic function has focused on family-level adversities. Moreover, although animal models and studies of normative brain development suggest that there may be sensitive periods during which adversity exerts stronger effects on corticolimbic development, little prospective evidence exists in humans. Using two low-income samples of boys (n = 167; n = 77), Census-derived neighborhood disadvantage during early childhood, but not adolescence, was uniquely associated with greater amygdala, but not PFC, reactivity to ambiguous neutral faces in adolescence and young adulthood. These associations remained after accounting for several family-level adversities (e.g., low family income, harsh parenting), highlighting the independent and developmentally specific neural effects of the neighborhood context. Furthermore, in both samples, indicators measuring income and poverty status of neighbors were predictive of amygdala function, suggesting that neighborhood economic resources may be critical to brain development.

Repetitive Transcranial Magnetic Stimulation Delivered With an H-Coil to the Right Insula Reduces Functional Connectivity Between Insula and Medial Prefrontal Cortex.

OBJECTIVE: Insula neurocircuitry alterations are reported in a range of neuropsychiatric disorders holding promise for clinical interventions. We measured, in a pilot study, acute neuroplastic modulations resulting from high- and low-frequency stimulation with repetitive transcranial magnetic stimulation (rTMS) delivered via an H-coil that targeted the right insula and overlying prefrontal cortex. METHODS: Healthy, nonsmoking, adult participants (N = 28), in a within-participant, sham-controlled experiment, received a single rTMS session on four separate days. Participants received one session each of low- (1 Hz) and high (10 Hz)-frequency stimulation and two sessions of sham stimulation matched to each rTMS frequency. After each rTMS session, participants completed a functional magnetic resonance imaging (fMRI) scan while performing two cognitive tasks and a resting-state scan. The effect of rTMS was examined on task behavior as well as blood oxygenated level-dependent (BOLD) response during task performance and resting state. We expected low- and high-frequency stimulation to decrease and increase, respectively, insula and overlying cortical BOLD signal and network connectivity. RESULTS/CONCLUSIONS: There was no effect of rTMS, regardless of frequency, on task behavior or task-based BOLD response. There was an effect of rTMS compared to sham on rsFC between insula and medial prefrontal cortex, with connectivity reduced after rTMS compared to sham, regardless of frequency. Implications for using rTMS to the insula as a treatment for neuropsychiatric disorders are discussed in light of insula-medial prefrontal cortex connectivity.

State of the Unit: Physician Gender Diversity in Pediatric Critical Care Medicine Leadership.

Gender disparities in leadership are receiving increased attention throughout medicine and medical subspecialties. Little is known about the disparities in Pediatric Critical Care Medicine. In this piece, we explore gender disparities in Pediatric Critical Care Medicine physician leadership. We examine physician leadership in the Accreditation Council for Graduate Medical Education fellowship programs, as well as a limited sample of major Pediatric Critical Care Medicine textbooks and societies. Overall, the gender composition of division directors is not significantly different from that of workforce composition, although regional differences exist. More women than men lead fellowship programs, at a higher ratio compared with workforce composition. However, greater gender disparities are present in editorial leadership in this limited analysis. We conclude by recommending potential paths forward for further study and intervention, such as tracking gender diversity and being cognizant of the unique challenges that women currently experience in professional advancement.

Discovery of candidate disease genes in ENU-induced mouse mutants by large-scale sequencing, including a splice-site mutation in nucleoredoxin.

An accurate and precisely annotated genome assembly is a fundamental requirement for functional genomic analysis. Here, the complete DNA sequence and gene annotation of mouse Chromosome 11 was used to test the efficacy of large-scale sequencing for mutation identification. We re-sequenced the 14,000 annotated exons and boundaries from over 900 genes in 41 recessive mutant mouse lines that were isolated in an N-ethyl-N-nitrosourea (ENU) mutation screen targeted to mouse Chromosome 11. Fifty-nine sequence variants were identified in 55 genes from 31 mutant lines. 39% of the lesions lie in coding sequences and create primarily missense mutations. The other 61% lie in noncoding regions, many of them in highly conserved sequences. A lesion in the perinatal lethal line l11Jus13 alters a consensus splice site of nucleoredoxin (Nxn), inserting 10 amino acids into the resulting protein. We conclude that point mutations can be accurately and sensitively recovered by large-scale sequencing, and that conserved noncoding regions should be included for disease mutation identification. Only seven of the candidate genes we report have been previously targeted by mutation in mice or rats, showing that despite ongoing efforts to functionally annotate genes in the mammalian genome, an enormous gap remains between phenotype and function. Our data show that the classical positional mapping approach of disease mutation identification can be extended to large target regions using high-throughput sequencing.

Gender Differences in the Psychosocial Determinants Underlying the Onset and Maintenance of Alcohol Use Disorder.

A large number of different mechanisms have been linked to Alcohol Use Disorder (AUD), including psychosocial, neurocognitive, affective, and neurobiological factors. Gender has been shown to impact the presentation and progression of AUD; yet, little work has been done to parse the different mechanisms underlying AUD within the lens of gender differences. A review of the literature on adolescence revealed that psychosocial factors, in particular lack of family social support and interactions with peers, drive the onset of alcohol use more strongly in girls relative to boys. However, research done on gender differences in disease progression in adults remains limited. Our gender-specific analysis of the mechanisms underlying AUD in adults revealed that lack of social support was causally linked to negative affect, mental health symptoms, and AUD symptom severity in women, but not men. These novel results suggest that psychosocial factors may play a gender-specific role not only in the onset of use in adolescence, but also in the maintenance of addiction in adults. If confirmed, this suggests the need for investigating gender-specific recovery trajectories. In this perspective piece, we review the literature regarding gender differences in the onset and maintenance of AUD and present original data that support unique risk factors in women.

Explainable machine learning analysis reveals sex and gender differences in the phenotypic and neurobiological markers of Cannabis Use Disorder.

Cannabis Use Disorder (CUD) has been linked to a complex set of neuro-behavioral risk factors. While many studies have revealed sex and gender differences, the relative importance of these risk factors by sex and gender has not been described. We used an "explainable" machine learning approach that combined decision trees [gradient tree boosting, XGBoost] with factor ranking tools [SHapley's Additive exPlanations (SHAP)] to investigate sex and gender differences in CUD. We confirmed that previously identified environmental, personality, mental health, neurocognitive, and brain factors highly contributed to the classification of cannabis use levels and diagnostic status. Risk factors with larger effect sizes in men included personality (high openness), mental health (high externalizing, high childhood conduct disorder, high fear somaticism), neurocognitive (impulsive delay discounting, slow working memory performance) and brain (low hippocampal volume) factors. Conversely, risk factors with larger effect sizes in women included environmental (low education level, low instrumental support) factors. In summary, environmental factors contributed more strongly to CUD in women, whereas individual factors had a larger importance in men.

Treating cocaine and opioid use disorder with transcranial magnetic stimulation: A path forward.

Developing new, effective treatments for substance use disorders (SUDs), especially cocaine and opioid use disorders (CUD and OUD), are of immense importance. These are chronic, relapsing brain diseases characterized by dysregulated circuits manifesting from neuroplastic change brought on by repeated exposure to substances of abuse. A potential treatment is therapeutically inducing neuroplastic change in targeted dysregulated circuits. One such intervention, repetitive transcranial magnetic stimulation (rTMS) has gained traction over the past two decades as a method of noninvasively stimulating cortical structures in order to induce subcortical neuroplastic change. By doing so, rTMS ameliorates symptoms that are consequent of dysregulations in disease-related circuits, such as craving, and reduces drug use. Although rTMS has been successfully applied as a treatment for other clinical disorders, progress toward treatment applications for SUDs has been stymied by what we dub "known unknowns". These are fundamental lines of research within the rTMS-SUD field that have yet to be systematically understood which could help to optimize TMS as an intervention for SUDs. Because progress in treatment for CUD and OUD is imperative given the widespread severity of OUD and the lack of treatment for CUD, it is necessary to critically reflect on the ways in which rTMS research for these disorders can most effectively move forward to help patients. We articulate six "known unknowns" and outline a direction of research to address each. Briefly, the "known unknowns" in the field are: 1) Cortical target selection, 2) subcortical circuit engagement, 3) optimizing rTMS sequences, 4) rTMS as an adjuvant to existing interventions, 5) manipulating brain state, and 6) selecting outcome measures. We also outline research design approaches to address these "known unknowns" in the rTMS-SUDs field. Unification of efforts across research laboratories is necessary to develop empirically validated treatments that will benefit patients in a timely fashion.

Physicians' perspectives on continuity of care for patients involved in the criminal justice system: A qualitative study.

BACKGROUND: In 2016, over 11 million individuals were admitted to prisons and jails in the United States. Because the majority of these individuals will return to the community, addressing their health needs requires coordination between community and correctional health care providers. However, few systems exist to facilitate this process and little is known about how physicians perceive and manage these transitions. OBJECTIVE: The goal of this study was to characterize physicians' views on transitions both into and out of incarceration and describe how knowledge of a patient's criminal justice involvement impacts patient care plans. METHODS: Semi-structured interviews were conducted between October 2018 and May 2019 with physicians from three community clinics in Hennepin County, Minnesota. Team members used a hybrid approach of deductive and inductive coding, in which a priori codes were defined based on the interview guide while also allowing for data-driven codes to emerge. RESULTS: Four themes emerged related to physicians' perceptions on continuity of care for patients with criminal justice involvement. Physicians identified disruptions in patient-physician relationships, barriers to accessing prescription medications, disruptions in insurance coverage, and problems with sharing medical records, as factors contributing to discontinuity of care for patients entering and exiting incarceration. These factors impacted patients differently depending on the direction of the transition. CONCLUSIONS: Our findings identified four disruptions to continuity of care that physicians viewed as key barriers to successful transitions into and out of incarceration. These disruptions are unlikely to be effectively addressed at the provider level and will require system-level changes, which Medicaid and managed care organizations could play a leading role in developing.

Socioeconomic and Racial Disparities in Diabetic Ketoacidosis Admissions in Youth With Type 1 Diabetes.

OBJECTIVE: We sought to determine whether census tract poverty, race, and insurance status were associated with the likelihood and severity of diabetic ketoacidosis (DKA) hospitalization among youth with type 1 diabetes (T1D). METHODS: We conducted a retrospective population-based cohort study using Cincinnati Children's Hospital electronic medical record (EMR) data from January 1, 2011, to December 31, 2017, for T1D patients ≤18 years old. The primary outcome was admission for DKA. Secondary outcomes included DKA severity, defined by initial pH and bicarbonate, and length of stay. Exposures were the poverty rate for the youth's home census tract, parent-reported race, and insurance status. We used multivariable logistic regression to analyze effects on odds of admission. RESULTS: We identified 439 patients with T1D; 152 were hospitalized. The cohort was 48% female, 25% Black, and 36% publicly insured; the median age was 14 years. For every 10% increase in a youth's census tract poverty rate, the adjusted odds of admission increased by 22% (95% CI, 1.03-1.47). Public insurance status was associated with DKA admission (adjusted odds ratio [AOR], 2.71, 95% CI, 1.62-4.55) while race was not. There were no clinically meaningful differences in pH or bicarbonate by census tract poverty, race, or insurance status; however, Black patients experienced differences in care (eg, longer length of stay). CONCLUSION: Youth with T1D living in high poverty areas and on public insurance were significantly more likely to be admitted for DKA. Severity upon presentation was similar across exposures. Understanding contextual mechanisms by which disparities emerge will inform changes aimed at equitably improving care.

Peri-Intubation Cardiac Arrest in the Pediatric Emergency Department: A Novel System of Care.

Patients with physiologic disorders, such as hypoxemia or hypotension, are at high risk of peri-intubation cardiac arrest. Standardization improves emergency tracheal intubation safety, but no published reports describe initiatives to reduce the risk of cardiac arrest. This initiative aims to improve the care of children at risk of peri-intubation cardiac arrest in a pediatric emergency department (PED). We specifically aimed to increase the number of patients between those with peri-intubation cardiac arrest by 50%, from a baseline of 11-16, over 12-months. METHODS: Our multidisciplinary team outlined a theory of improvement and designed interventions aimed at key drivers. The primary intervention was creating a PICU-ED Team (PET) and a checklist to guide the assessment and mitigation of risk for peri-intubation arrest and rapid consultation of the pediatric intensivists. The PET was iteratively refined, and we collected data by a video review of tracheal intubations. RESULTS: Fifty-one patients with risk factors for peri-intubation arrest underwent tracheal -intubation in the PED from January 2016 to March 2020: 14 with PET activation since PET go-live in April 2019. None of the 14 PET patients had a peri-intubation cardiac arrest. Ninety-three percent (13/14) of PET patients were intubated in the PED, and 78% (10/13) of these patients had the first intubation attempt completed by PED physicians (balancing measures). CONCLUSION: We successfully developed the PET to mitigate the risk of peri-intubation cardiac arrest without significantly reducing key procedural opportunities for the PED. Initial data are promising, but further refinement is needed.

Identification of the Physiologically Difficult Airway in the Pediatric Emergency Department.

BACKGROUND: The risk factors for peri-intubation cardiac arrest in critically ill children are incompletely understood. The study objective was to derive physiologic risk factors for deterioration during tracheal intubation in a pediatric emergency department (PED). METHODS: This was a retrospective cohort study of patients undergoing emergency tracheal intubation in a PED. Using the published literature and expert opinion, a multidisciplinary team developed high-risk criteria for peri-intubation arrest: 1) hypotension, 2) concern for cardiac dysfunction, 3) persistent hypoxemia, 4) severe metabolic acidosis (pH < 7.1), 5) post-return of spontaneous circulation (ROSC), and 6) status asthmaticus. We completed a structured review of the electronic health record for a historical cohort of patients intubated in the PED. The primary outcome was peri-intubation arrest. Secondary outcomes included tracheal intubation success rate, extracorporeal membrane oxygenation (ECMO) activation, and in-hospital mortality. We compared outcomes between patients meeting one or more versus no high-risk criteria. RESULTS: Peri-intubation cardiac arrest occurred in 5.6% of patients who met at least one high-risk criterion compared to 0% in patients meeting none (5.6% difference, 95% confidence interval [CI] = 1.0 to 18.1, p = 0.028). Patients meeting at least one criterion had higher rates of any postintubation cardiac arrest in the PED (11.1% vs. 0%, 11.1% difference, 95% CI = 4.1 to 25.3, p = 0.0007), in-hospital mortality (25% vs. 2.3%, 22.7% difference, 95% CI = 11.0 to 38.9, p < 0.0001), ECMO activation (8.3% vs. 0%, 8.3% difference, 95% CI = 2.5 to 21.8, p = 0.004), and lower likelihood of first-pass intubation success (47.2% vs. 66.1%, -18.9% difference, 95% CI = -35.5 to -1.5, p = 0.038), respectively. CONCLUSIONS: We have developed criteria that successfully identify physiologically difficult airways in the PED. Children with hypotension, persistent hypoxemia, concern for cardiac dysfunction, severe metabolic acidosis, status asthmaticus or who are post-ROSC are at higher risk for peri-intubation cardiac arrest and in-hospital mortality. Further multicenter investigation is needed to validate our findings.

A mouse chromosome 4 balancer ENU-mutagenesis screen isolates eleven lethal lines.

BACKGROUND: ENU-mutagenesis is a powerful technique to identify genes regulating mammalian development. To functionally annotate the distal region of mouse chromosome 4, we performed an ENU-mutagenesis screen using a balancer chromosome targeted to this region of the genome. RESULTS: We isolated 11 lethal lines that map to the region of chromosome 4 between D4Mit117 and D4Mit281. These lines form 10 complementation groups. The majority of lines die during embryonic development between E5.5 and E12.5 and display defects in gastrulation, cardiac development, and craniofacial development. One line displayed postnatal lethality and neurological defects, including ataxia and seizures. CONCLUSION: These eleven mutants allow us to query gene function within the distal region of mouse chromosome 4 and demonstrate that new mouse models of mammalian developmental defects can easily and quickly be generated and mapped with the use of ENU-mutagenesis in combination with balancer chromosomes. The low number of mutations isolated in this screen compared with other balancer chromosome screens indicates that the functions of genes in different regions of the genome vary widely.

Accelerated Intermittent Theta-Burst Stimulation as a Treatment for Cocaine Use Disorder: A Proof-of-Concept Study.

There are no effective treatments for cocaine use disorder (CUD), a chronic, relapsing brain disease characterized by dysregulated circuits related to cue reactivity, reward processing, response inhibition, and executive control. Transcranial magnetic stimulation (TMS) has the potential to modulate circuits and networks implicated in neuropsychiatric disorders, including addiction. Although acute applications of TMS have reduced craving in urine-negative cocaine users, the tolerability and safety of administering accelerated TMS to cocaine-positive individuals is unknown. As such, we performed a proof-of-concept study employing an intermittent theta-burst stimulation (iTBS) protocol in an actively cocaine-using sample. Although our main goal was to assess the tolerability and safety of administering three iTBS sessions daily, we also hypothesized that iTBS would reduce cocaine use in this non-treatment seeking cohort. We recruited 19 individuals with CUD to receive three open-label iTBS sessions per day, with approximately a 60-min interval between sessions, for 10 days over a 2-week period (30 total iTBS sessions). iTBS was delivered to left dorsolateral prefrontal cortex (dlPFC) with neuronavigation guidance. Compliance and safety were assessed throughout the trial. Cocaine use behavior was assessed before, during, and after the intervention and at 1- and 4-week follow-up visits. Of the 335 iTBS sessions applied, 73% were performed on participants with cocaine-positive urine tests. Nine of the 14 participants who initiated treatment received at least 26 of 30 iTBS sessions and returned for the 4-week follow-up visit. These individuals reduced their weekly cocaine consumption by 78% in amount of dollars spent and 70% in days of use relative to pre-iTBS cocaine use patterns. Similarly, individuals reduced their weekly consumption of nicotine, alcohol, and THC, suggesting iTBS modulated a common circuit across drugs of abuse. iTBS was well-tolerated, despite the expected occasional headaches. A single participant developed a transient neurological event of uncertain etiology on iTBS day 9 and cocaine-induced psychosis 2 weeks after discontinuation. It thus appears that accelerated iTBS to left dlPFC administered in active, chronic cocaine users is both feasible and tolerable in actively using cocaine participants with preliminary indications of efficacy in reducing both the amount and frequency of cocaine (and other off target drug) use. The neural underpinnings of these behavioral changes could help in the future development of effective treatment of CUD.

Sampling and design challenges in studying the mental health consequences of disasters.

Disasters are unpredictable and frequently lead to chaotic post-disaster situations, creating numerous methodologic challenges for the study of the mental health consequences of disasters. In this commentary, we expand on some of the issues addressed by Kessler and colleagues, largely focusing on the particular challenges of (a) defining, finding, and sampling populations of interest after disasters and (b) designing studies in ways that maximize the potential for valid inference. We discuss these challenges - drawing on specific examples - and suggest potential approaches to each that may be helpful as a guide for future work. We further suggest research directions that may be most helpful in moving the field forward.

Disease prevention & health promotion: what's critical care got to do with it?

Health systems are increasingly investing in efforts to prevent disease and promote health for populations. By and large, these prevention-related interventions have not been inclusive of critical care and the intensive care unit (ICU). However, we suggest that there is value-to patients, families, health systems, and society at large-in extending this continuum into the ICU setting and including the ICU in disease prevention and health promotion efforts. Including the ICU in this continuum allows the critical care perspective to inform (I) advocacy for prevention; (II) efforts to improve disparities in health and health care; (III) mitigation of the negative effects of critical illness and injury as well as ICU exposure; and (IV) promotion of health and well-being in the community. As disease prevention and health promotion rise as priorities within health systems, critical care can and should join, even help lead, the effort.

Staffing and workforce issues in the pediatric intensive care unit.

The health care industry is in the midst of incredible change, and unfortunately, change is not easy. The intensive care unit (ICU) plays a critical role in the overall delivery of care to patients in the hospital. Care in the ICU is expensive. One of the best ways of improving the value of care delivered in the ICU is to focus greater attention on the needs of the critical care workforce. Herein, we highlight three major areas of concern-the changing model of care delivery outside of the traditional four walls of the ICU, the need for greater diversity in the pediatric critical care workforce, and the widespread problem of professional burnout and its impact on patient care.

White-matter tract abnormalities and antisocial behavior: A systematic review of diffusion tensor imaging studies across development.

Antisocial behavior (AB), including aggression, violence, and theft, is thought be underpinned by abnormal functioning in networks of the brain critical to emotion processing, behavioral control, and reward-related learning. To better understand the abnormal functioning of these networks, research has begun to investigate the structural connections between brain regions implicated in AB using diffusion tensor imaging (DTI), which assesses white-matter tract microstructure. This systematic review integrates findings from 22 studies that examined the relationship between white-matter microstructure and AB across development. In contrast to a prior hypothesis that AB is associated with greater diffusivity specifically in the uncinate fasciculus, findings suggest that adult AB is associated with greater diffusivity across a range of white-matter tracts, including the uncinate fasciculus, inferior fronto-occipital fasciculus, cingulum, corticospinal tract, thalamic radiations, and corpus callosum. The pattern of findings among youth studies was inconclusive with both higher and lower diffusivity found across association, commissural, and projection and thalamic tracts.