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Introduction: Advance care planning and symptom screening among patients with cancer require team-based approaches to ensure that these services are equitably and appropriately delivered. In several organizations across the United States, we trained and employed lay health workers (LHWs) to assist with delivering these services for patients with cancer. The aim of this study was to understand LHWs’ views on delivering these services. Methods: We conducted semi-structured interviews with 22 LHWs in 6 US-based clinical cancer care settings in 4 large cities. We recorded, transcribed, and analyzed interviews using the constant comparative method of qualitative analysis. Results: Participants noted the importance of their role in assisting with the delivery of advance care planning (ACP) and symptom screening services. Participants noted the importance of developing relationships with patients to engage openly in ACP and symptom screening discussions. Participants reported that ongoing training provided skills and empowered them to discuss sensitive issues with patients and their caregivers. Participants described challenges in their roles including communication with oncology providers and their own emotional well-being. Participants identified solutions to these challenges including formal opportunities for introduction with oncology clinicians and staff and grievance sessions with LHWs and other team members. Discussion: LHWs from several organizations endorsed the importance of their roles in ensuring the delivery of ACP and proactive symptom screening. LHWs noted challenges and specific solutions to improve their effectiveness in delivering these important services to patients after their diagnosis of cancer.

Alcoholism and high fat diet (HFD)-induced obesity individually promote insulin resistance and glucose intolerance in clinical populations, increasing risk for metabolic diseases. HFD can also stimulate alcohol intake in short-term clinical studies. Unfortunately, there is currently a disconnect between animal models and the clinical findings, as animal studies typically show that HFD decreases ethanol intake while ethanol intake mitigates HFD-induced effects on insulin and glucose dysfunction. However, most previous animal studies utilized forced or continuous HFD and/or ethanol. In three experiments we sought to determine whether HFD (HFD = 60% calories from fat) vs. control diet (chow = 16% fat) alters voluntary two-bottle choice ethanol intake in male C57Bl/6J mice given differing access schedules for 6–7 weeks, and we assessed the resultant impact on metabolic function via insulin and glucose tolerance tests. Experiment 1: Unlimited Access Ethanol + HFD (UAE + HFD; n = 15; 10% ethanol v/v, ad libitum diet and ethanol) or UAE + Chow (n = 15). Experiment 2: Limited Access Ethanol + HFD (LAE + HFD; n = 15; ethanol = 4 h/day; 3 days/week, ad libitum diet) or LAE + Chow (n = 15) with increasing ethanol concentrations (10%, 15%, 20%). Experiment 3: Intermittent HFD with limited access to ethanol (iHFD-E; HFD = single 24-h session/week; ethanol = 4 h/day; 4 days/week) (n = 10). UAE + HFD mice consumed significantly less ethanol and were insulin-resistant and hyperglycemic compared with UAE + Chow mice. LAE + HFD mice consumed ethanol similarly to LAE + Chow mice, but exhibited hyperglycemia, insulin resistance, and glucose intolerance. iHFD-E mice displayed binge eating-like behaviors and consumed significantly more ethanol than mice given ad libitum chow or HFD. iHFD-E mice did not have significantly altered body composition, but developed insulin insensitivity and glucose intolerance. These findings suggest that access schedules influence HFD effects on ethanol consumption and resultant metabolic dysfunction, ethanol intake does not improve HFD-induced metabolic dysfunction, and binge eating-like behaviors can transfer to binge drinking behaviors.

American Indian and Alaska Native (AI/AN) youth disproportionately face barriers accessing healthcare, including lack of access to culturally-specific resources. This paper details the creation of a culturally-specific Toolkit for AI/AN transgender and Two-Spirit youth, their relatives, and their healthcare providers across the United States (U.S.). The Toolkit aims to (1) deliver culturally-grounded resources to youth with diverse gender identities, (2) provide resources for families, and (3) increase healthcare provider awareness. A culturally-appropriate Toolkit, “Celebrating Our Magic”, was created from continual engagement with community partners over a six-month period to address identified needs. The Toolkit has been shared regionally with partners who helped with its creation and nationally with Indian Health Service (IHS), Tribal, and Urban clinics serving AI/AN youth. This Toolkit creation process could be applied to manuals or guides for work in other underserved communities.

Background and Objective Racial disparities in diagnosis and receipt of services for early childhood developmental delay (DD) are well known but studies have had difficulties distinguishing contributing patient, healthcare system, and physician factors from underlying prevalence. We examine rates of physician diagnoses of DD by preschool and kindergarten entry controlling for a child's objective development via scoring on validated developmental assessment along with other child characteristics. Methods We used data from the preschool and kindergarten entry waves of the Early Childhood Longitudinal Study, Birth Cohort. Dependent variables included being diagnosed with DD by a medical provider and receipt of developmental services. Logistic regression models tested whether a child's race was associated with both outcomes during preschool and kindergarten while controlling for the developmental assessments, as well as other contextual factors. Results Among 7950 children, 6.6% of preschoolers and 7.5% of kindergarteners were diagnosed with DD. Of preschool children with DD, 66.5% were receiving developmental services, while 69.1% of kindergarten children with DD were receiving services. Children who were Black, Asian, spoke a primary language other than English and had no health insurance were less likely to be diagnosed with DD despite accounting for cognitive ability. Black and Latinx children were less likely to receive services. Conclusions Racial minority children are less likely to be diagnosed by their pediatric provider with DD and less likely to receive services despite accounting for a child's objective developmental assessment. The pediatric primary care system is an important target for interventions to reduce these disparities.

Post-traumatic stress disorder (PTSD) presents a major public health problem for which currently available treatments are modestly effective. We report the findings of a randomized, double-blind, placebo-controlled, multi-site phase 3 clinical trial (NCT03537014) to test the efficacy and safety of 3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy for the treatment of patients with severe PTSD, including those with common comorbidities such as dissociation, depression, a history of alcohol and substance use disorders, and childhood trauma. After psychiatric medication washout, participants (n = 90) were randomized 1:1 to receive manualized therapy with MDMA or with placebo, combined with three preparatory and nine integrative therapy sessions. PTSD symptoms, measured with the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5, the primary endpoint), and functional impairment, measured with the Sheehan Disability Scale (SDS, the secondary endpoint) were assessed at baseline and at 2 months after the last experimental session. Adverse events and suicidality were tracked throughout the study. MDMA was found to induce significant and robust attenuation in CAPS-5 score compared with placebo (P

INTRODUCTION: Community-engaged adaptations of evidence-based interventions are needed to improve cancer care delivery for low-income and minority populations with cancer. The objective of this study was to adapt an intervention to improve end-of-life cancer care delivery using a community- partnered approach. METHODS: We used a two-step formative research process to adapt the evidence-based Lay health workers Educate Engage Encourage Patients to Share (LEAPS) cancer care intervention. The first step involved obtaining a series of adaptations through focus groups with 15 patients, 12 caregivers, and 6 leaders and staff of the Unite Here Health (UHH) payer organization, and 12 primary care and oncology care providers. Focus group discussions were recorded, transcribed, and analyzed using the constant comparative method of qualitative analysis. The second step involved finalization of adaptations from a community advisory board comprised of 4 patients, 2 caregivers, 4 oncology providers, 2 lay health workers and 4 UHH healthcare payer staff and executive leaders. RESULTS: Using this community-engaged approach, stakeholders identified critical barriers and solutions to intervention delivery which included: 1) expanding the intervention to ensure patient recruitment; 2) including caregivers; 3) regular communication between UHH staff, primary care and oncology providers; and 4) selecting outcomes that reflect patient-reported quality of life. CONCLUSIONS: This systematic and community-partnered approach to adapt an end-of-life cancer care intervention strengthened this existing intervention to promote the needs and preferences of patients, caregivers, providers, and healthcare payer leaders. This approach can be used to address cancer care delivery for low-income and minority patients with cancer.

INTRODUCTION: Despite advancements in cancer care, persistent gaps remain in the delivery of high-value end-of-life cancer care. The aim of this study was to examine views of health care payer organization stakeholders on approaches to the redesign of end-of-life cancer care delivery strategies to improve care. METHODS: We conducted semistructured interviews with 34 key stakeholders (eg, chief medical officers, medical directors) in 12 health plans and 22 medical group organizations across the United States. We recorded, transcribed, and analyzed interviews using the constant comparative method of qualitative analysis. RESULTS: Participants endorsed strategies to redesign end-of-life cancer care delivery to improve end-of-life care. Participants supported the use of nonprofessionals to deliver some cancer services through alternative formats (eg, telephone, Internet) and delivery of services in nonclinical settings. Participants reported that using nonprofessional providers to offer some services, such as goals of care discussions and symptom assessments, via telephone in community-based settings or in patients’ homes, may be more effective and efficient ways to deliver high-value cancer care services. Participants described challenges to redesign, including coordination with and acceptance by oncology providers and payment models required to financially support clinical changes. Some participants suggested solutions, including providing funding and logistic support to encourage implementation of care delivery innovations and to financially reward practices for delivery of high-value end-of-life cancer care services. CONCLUSION: Stakeholders from payer organizations endorsed opportunities to redesign cancer care delivery, and some are willing to provide logistic, design, and financial support to practices interested in improving end-of-life cancer care.

PURPOSE: New approaches are needed to overcome low supportive care and clinical trial participation among low-income and minority adults with cancer. The objective of this project was to determine whether a lay health worker intervention was associated with improvements in supportive care and trial participation. METHODS: We conducted a quality improvement initiative in collaboration with a union organization. We enrolled union members newly diagnosed with cancer into a 6-month lay health worker–led intervention from October 15, 2016, to February 28, 2017. The primary outcome was goals of care. Secondary outcomes were health-related quality of life (HRQOL), health care use, and trial participation. All outcomes except HRQOL were compared with a cohort of union members diagnosed within the 6-month preintervention period. RESULTS: Sixty-six adults participated in the intervention group, and we identified 72 adults in the control group. Demographic characteristics were similar between groups. The mean age was 56.0 years; 47 (34%) were male, and 22 were White (16%). Within 6 months enrollment, more intervention group participants, as compared with the control, had clinician-documented goals of care (94% v 26%; P < .001) and participated in cancer clinical trials (72% v 22%; P < .001). At 4 months postenrollment, as compared with baseline, intervention participants experienced HRQOL improvements (mean difference, 3.98 points; standard deviation, 2.83; P < .001). Before death, more intervention group participants used palliative care and hospice than the control group. CONCLUSION: Lay health worker–led interventions may improve supportive care and clinical trial participation among low-income and minority populations with cancer.

The prevalence of psychiatry disorders such as anxiety and depression has steadily increased in recent years in the United States. This increased risk for anxiety and depression is associated with excess weight gain, which is often due to over-consumption of western diets that are typically high in fat, as well as with binge eating disorders, which often overlap with overweight and obesity outcomes. This finding suggests that diet, particularly diets high in fat, may have important consequences on the neurocircuitry regulating emotional processing as well as metabolic functions. Depression and anxiety disorders are also often comorbid with alcohol and substance use disorders. It is well-characterized that many of the neurocircuits that become dysregulated by overconsumption of high fat foods are also involved in drug and alcohol use disorders, suggesting overlapping central dysfunction may be involved. Emerging preclinical data suggest that high fat diets may be an important contributor to increased susceptibility of binge drug and ethanol intake in animal models, suggesting diet could be an important aspect in the etiology of substance use disorders. Neuroinflammation in pivotal brain regions modulating metabolic function, food intake, and binge-like behaviors, such as the hypothalamus, mesolimbic dopamine circuits, and amygdala, may be a critical link between diet, ethanol, metabolic dysfunction, and neuropsychiatric conditions. This brief review will provide an overview of behavioral and physiological changes elicited by both diets high in fat and ethanol consumption, as well as some of their potential effects on neurocircuitry regulating emotional processing and metabolic function.

Damage is an inevitable consequence of life. For unicellular organisms, this leads to a trade-off between allocating resources into damage repair or into growth coupled with segregation of damage upon cell division, i.e., aging and senescence. Few studies considered repair as an alternative to senescence. None considered biofilms, where the majority of unicellular organisms live, although fitness advantages in well-mixed systems often turn into disadvantages in spatially structured systems such as biofilms. We compared the fitness consequences of aging versus an adaptive repair mechanism based on sensing damage, using an individual-based model of a generic unicellular organism growing in biofilms. We found that senescence is not beneficial provided that growth is limited by substrate availability. Instead, it is useful as a stress response to deal with damage that failed to be repaired when (i) extrinsic mortality was high; (ii) a degree of multicellularity was present; and (iii) damage segregation was effective., The extent of senescence due to damage accumulation—or aging—is evidently evolvable as it differs hugely between species and is not universal, suggesting that its fitness advantages depend on life history and environment. In contrast, repair of damage is present in all organisms studied. Despite the fundamental trade-off between investing resources into repair or into growth, repair and segregation of damage have not always been considered alternatives. For unicellular organisms, unrepaired damage could be divided asymmetrically between daughter cells, leading to senescence of one and rejuvenation of the other. Repair of “unicells” has been predicted to be advantageous in well-mixed environments such as chemostats. Most microorganisms, however, live in spatially structured systems, such as biofilms, with gradients of environmental conditions and cellular physiology as well as a clonal population structure. To investigate whether this clonal structure might favor senescence by damage segregation (a division-of-labor strategy akin to the germline-soma division in multicellular organisms), we used an individual-based computational model and developed an adaptive repair strategy where cells respond to their current intracellular damage levels by investing into repair machinery accordingly. Our simulations showed that the new adaptive repair strategy was advantageous provided that growth was limited by substrate availability, which is typical for biofilms. Thus, biofilms do not favor a germline-soma-like division of labor between daughter cells in terms of damage segregation. We suggest that damage segregation is beneficial only when extrinsic mortality is high, a degree of multicellularity is present, and an active mechanism makes segregation effective. IMPORTANCE Damage is an inevitable consequence of life. For unicellular organisms, this leads to a trade-off between allocating resources into damage repair or into growth coupled with segregation of damage upon cell division, i.e., aging and senescence. Few studies considered repair as an alternative to senescence. None considered biofilms, where the majority of unicellular organisms live, although fitness advantages in well-mixed systems often turn into disadvantages in spatially structured systems such as biofilms. We compared the fitness consequences of aging versus an adaptive repair mechanism based on sensing damage, using an individual-based model of a generic unicellular organism growing in biofilms. We found that senescence is not beneficial provided that growth is limited by substrate availability. Instead, it is useful as a stress response to deal with damage that failed to be repaired when (i) extrinsic mortality was high; (ii) a degree of multicellularity was present; and (iii) damage segregation was effective.

* Abbreviations: COVID-19 — : coronavirus disease 2019 PART — : Pediatricians Against Racism and Trauma We have seen the horrifying cell phone and surveillance video footage of the murder of George Floyd replay again and again in the last few weeks. The aftermath begs the question why this particular murder of a Black man by a police officer has sparked the international response so few have received.1 Scores of other Black men, women, and children have been killed by police since the 2014 murder of Eric Garner in New York City, in which he suffered an illegal chokehold and uttered the devastating refrain “I can’t breathe,” and countless others have been murdered over generations. These cases represent just the tip of the iceberg because these murders happened to be recorded on bystander cell phone video or police webcam capture. Moreover, it is the tip of another iceberg because these cases represent modern-day lynchings. The lynching of Black people in the United States was routine before the “civil rights era,” when there were major legal advances to change the treatment of Black Americans in this country. However, it was not until February 2020 that federal legislation, the Emmett Till Antilynching Act, was passed by the House of Representatives but is still … Address correspondence to Benard P. Dreyer, MD, FAAP, Division of Developmental and Behavioral Pediatrics, Department of Pediatrics, New York University Grossman School of Medicine and Department of Pediatrics, Bellevue Hospital Center, 550 First Ave, New York, NY 10016. E-mail: benard.dreyer{at}nyulangone.org

Institutional racism exists within Academic Pediatrics within the United States, and it affects our work as researchers, clinicians, and educators. Confronting institutional racism is a challenging life-long struggle for people of all races, but it should be part of the professional mission of all who work in Pediatrics. Creating a path to health equity for children in the United States will involve failure. We should not be daunted by that prospect.

RationaleIndividuals suffering from alcohol use disorder (AUD) demonstrate difficulty with decision-making and impulsivity that may be associated with impaired frontal cortical function. Therapeutics that enhance frontal dopamine tone could decrease impulsivity and in turn reduce alcohol consumption in individuals with AUD.ObjectivesTo determine if the catechol-O-methyltransferase (COMT) inhibitor tolcapone can attenuate alcohol consumption in individuals with AUD and whether this attenuation correlates with tolcapone-induced changes in laboratory-based decision-making tasks.MethodsWe used daily self-report and a novel group laboratory bar task to assess the effects of randomized double-blind crossover administration of tolcapone (100mg TID for 5days) on alcohol consumption and laboratory tasks assessing impulsivity in 55 non-treatment-seeking subjects with AUD.ResultsTolcapone significantly reduced self-reported alcohol consumption (t (54) = 2.05, p = 0.045). The effects of tolcapone on drinking significantly correlated with changes in impulsive decision-making, such that subjects with the greatest decrease in impulsive choice on tolcapone also reported the greatest decrease in alcohol consumption (r (45) = 0.40, p = 0.0053). We did not see effects of tolcapone on laboratory bar consumption. Adverse event (AE) reporting was low, with no significant difference in frequency or severity of AEs on tolcapone versus placebo.ConclusionsThese data demonstrate that COMT inhibitors such as tolcapone may be useful therapeutics for AUD.Trial registrationClinicalTrials.gov Identifier: NCT02740582.

Objective To inform resource allocation toward a continuum of care for youth at risk of suicide, we examined unplanned 30-day readmissions after pediatric hospitalization for either suicide ideation (SI) or suicide attempt (SA). Methods We conducted a retrospective cohort study of a nationally representative sample of 133,516 hospitalizations for SI or SA among 6- to 17-year-olds to determine prevalence, risk factors, and characteristics of 30-day readmissions using the 2013 and 2014 Nationwide Readmissions Dataset (NRD). Risk factors for readmission were modeled using logistic regression. Results We identified 95,354 hospitalizations for SI and 38,162 hospitalizations for SA. Readmission rates within 30 days were 8.5% for SI and SA hospitalizations. Among 30-day readmissions, more than one-third (34.1%) occurred within 7 days. Among patients with any 30-day readmission, 11% had more than one readmission within 30 days. The strongest risk factors for readmission were SI or SA hospitalization in the 30 days preceding the index SI/SA hospitalization (adjusted odds ratio [AOR]: 3.14, 95% CI: 2.73-3.61) and hospitalization for other indications in the previous 30 days (AOR: 3.18, 95% CI: 2.67-3.78). Among readmissions, 94.5% were for a psychiatric condition and 63.4% had a diagnosis of SI or SA. Conclusions Quality improvement interventions to reduce unplanned 30-day readmissions among children hospitalized for SI or SA should focus on children with a recent prior hospitalization and should be targeted to the first week following hospital discharge. Funding Dr. Zima received funding from the Behavioral Health Centers of Excellence for California (SB852).

In a community-academic partnership, we implemented a group-based model for well-child care (WCC) (CenteringParenting) and conducted a pilot test for feasibility and acceptability among families at a federally qualified health center (FQHC).The FQHC implemented CenteringParenting for all WCC visits in the first year of life, starting at the 2-week visit. Over a 14-month time period, parents from each new CenteringParenting group were enrolled into the study. Baseline data were collected at enrollment (infant age31 days) and again at a 6-month follow-up survey. Main outcomes were feasibility and acceptability of CenteringParenting; we also collected exploratory measures (parent experiences of care, utilization, self-efficacy, and social support).Of the 40 parent-infant dyads enrolled in the pilot, 28 CenteringParenting participants completed the 6-month follow-up assessment. The majority of infants were Latino, black, or "other" race/ethnicity; over 90% were Medicaid insured. Of the 28 CenteringParenting participants who completed the 6-month follow-up, 25 completed all visits between ages 2 weeks and 6 months in the CenteringParenting group. Of the CenteringParenting participants, 97% to 100% reported having adequate time with their provider and sufficient patient education and having their needs met at visits; most reported feeling comfortable at the group visit, and all reported wanting to continue CenteringParenting for their WCC. CenteringParenting participants' mean scores on exploratory measures demonstrated positive experiences of care, overall satisfaction of care, confidence in parenting, and parental social support.A community-academic partnership implemented CenteringParenting; the intervention was acceptable and feasible for a minority, low-income population. We highlight key challenges of implementation.

Pullulan-hydrolysing enzymes, more commonly known as debranching enzymes for starch and other polysaccharides, are of great interest and have been widely used in the starch-saccharification industry. Type III pullulan hydrolase fromThermococcus kodakarensis(TK-PUL) possesses both pullulanase and α-amylase activities. Until now, only two enzymes in this class, which are capable of hydrolysing both α-1,4- and α-1,6-glycosidic bonds in pullulan to produce a mixture of maltose, panose and maltotriose, have been described. TK-PUL shows highest activity in the temperature range 95–100°C and has a pH optimum in the range 3.5–4.2. Its unique ability to hydrolyse maltotriose into maltose and glucose has not been reported for other homologous enzymes. The crystal structure of TK-PUL has been determined at a resolution of 2.8 Å and represents the first analysis of a type III pullulan hydrolyse. The structure reveals that the last part of the N-terminal domain and the C-terminal domain are significantly different from homologous structures. In addition, the loop regions at the active-site end of the central catalytic domain are quite different. The enzyme has a well defined calcium-binding site and possesses a rare vicinal disulfide bridge. The thermostability of TK-PUL and its homologues may be attributable to several factors, including the increased content of salt bridges, helical segments, Pro, Arg and Tyr residues and the decreased content of serine.

Publicly insured children needing referral to mental health (MH) services often do not access or receive services. The objective of this study was to identify gaps in communication and coordination between primary care providers (PCPs) and MH providers during the MH referral and care process for publicly insured children. Thirteen semi-structured interviews were conducted with 10 PCPs and staff from a federally qualified health center (FQHC) and 6 MH providers and staff from two local MH clinics. Interview participants identified multiple gaps in communication throughout the care process and different phases as priorities for improvement. PCPs described primary care-MH communication challenges during early phases, while MH providers described coordination challenges in transferring patients back to primary care for ongoing mental health management. Strategies are needed to improve primary care-specialty MH communication and coordination throughout all phases of the referral and care process, particularly at initial referral and transfer back to primary care.

The enzyme porphobilinogen deaminase (PBGD) is one of the key enzymes in tetrapyrrole biosynthesis. It catalyses the formation of a linear tetrapyrrole from four molecules of the substrate porphobilinogen (PBG). It has a dipyrromethane cofactor (DPM) in the active site which is covalently linked to a conserved cysteine residue through a thioether bridge. The substrate molecules are linked to the cofactor in a stepwise head-to-tail manner during the reaction, which is catalysed by a conserved aspartate residue: Asp82 in theB. megateriumenzyme. Three mutations have been made affecting Asp82 (D82A, D82E and D82N) and their crystal structures have been determined at resolutions of 2.7, 1.8 and 1.9 Å, respectively. These structures reveal that whilst the D82E mutant possesses the DPM cofactor, in the D82N and D82A mutants the cofactor is likely to be missing, incompletely assembled or disordered. Comparison of the mutant PBGD structures with that of the wild-type enzyme shows that there are significant domain movements and suggests that the enzyme adopts `open' and `closed' conformations, potentially in response to substrate binding.

Objectives: Persistent gaps in end-of-life cancer care delivery and growing associated expenditures remain imminent US public health issues. The objective of this study was to understand clinical providers’ experiences delivering cancer care for patients at the end of life and their perspectives on potential solutions to improve quality of care. Methods: Semistructured interviews were conducted with 75 cancer care providers across the United States. The interviews were recorded, transcribed, and analyzed using constant comparative method of qualitative analysis. Results: Providers identified 3 major cancer care delivery challenges including lack of time to educate patients and caregivers due to clinical volume and administrative burdens, ambiguity in determining both prognosis and timing of palliative care at the end-of-life, and lack of adequate systems to support non-face-to-face communication with patients. To address these challenges, providers endorsed several options for clinical practice redesign in their settings. These include use of a lay health worker to assist in addressing early advance care planning, proactive non-face-to-face communication with patients specifically regarding symptom management, and community and in-home delivery of cancer care services. Discussion: Specific strategies for cancer care redesign endorsed by health-care providers may be used to create interventions that can more efficiently and effectively address gaps in end-of-life cancer care.

The family B DNA polymerase fromPyrobaculum calidifontis(Pc-polymerase) consists of 783 amino acids and is magnesium-ion dependent. It has an optimal pH of 8.5, an optimal temperature of 75°C and a half-life of 4.5 h at 95°C, giving it greater thermostability than the widely usedTaqDNA polymerase. The enzyme is also capable of PCR-amplifying larger DNA fragments of up to 7.5 kb in length. It was shown to have functional, error-correcting 3′–5′ exonuclease activity, as do the related high-fidelity DNA polymerases fromPyrococcus furiosus,Thermococcus kodakarensisKOD1 andThermococcus gorgonarius, which have extensive commercial applications.Pc-polymerase has a quite low sequence identity of approximately 37% to these enzymes, which, in contrast, have very high sequence identity to each other, suggesting that theP. calidifontisenzyme is distinct. Here, the structure determination ofPc-polymerase is reported, which has been refined to anRfactor of 24.47% and anRfreeof 28.81% at 2.80 Å resolution. The domains of the enzyme are arranged in a circular fashion to form a disc with a narrow central channel. One face of the disc has a number of connected crevices in it, which allow the protein to bind duplex and single-stranded DNA. The central channel is thought to allow incoming nucleoside triphosphates to access the active site. The enzyme has a number of unique structural features which distinguish it from other archaeal DNA polymerases and may account for its high processivity. A model of the complex with the primer-template duplex of DNA indicates that the largest conformational change that occurs upon DNA binding is the movement of the thumb domain, which rotates by 7.6° and moves by 10.0 Å. The surface potential of the enzyme is dominated by acidic groups in the central region of the molecule, where catalytic magnesium ions bind at the polymerase and exonuclease active sites. The outer regions are richer in basic amino acids that presumably interact with the sugar-phosphate backbone of DNA. The large number of salt bridges may contribute to the high thermal stability of this enzyme.

To describe changes in the racial and ethnic diversity of the membership of a national academic health professional organization, the Academic Pediatric Association (APA) from 2009 to 2018.Administrative data from the APA was used for the study. Our sample was limited to dues-paying members of the APA with complete profile information. Data on race/ethnicity was collected by self-report and categorized as White, Hispanic, Black, Asian, or other. Gender was obtained by self-report (male/female). Membership type included physician, non-physician, or trainee and was provided by self-report. Age was calculated by subtracting the dues year from the year of birth. Descriptive statistics were used. Log-linear models were used to describe changes in membership race/ethnicity and expressed as relative risk.Three thousand one hundred and ninety-six unique individuals were included. Enrollment in the APA increased from 1429 in 2009 to 1803 in 2018. Females represented 68% of the sample. Six percent of the sample identified as Black, 5% as Hispanic, 12% as Asian, and 74% as White. Using log-linear models, the proportion of members identifying as Black increased from 4% to 6% (P.001), Asian 8% to 13% (P.001) and Hispanic increased 4% to 5% (P = .17).The APA has increased the representation of underrepresented racial and ethnic minorities in medicine within its membership. The APA and other academic pediatric professional organizations, can build on these current trends by continuing to invest in programming focused on increasing racial/ethnic minority groups underrepresented in medicine.

Introduction Equitable delivery of advance care planning and symptom management among patients is crucial to improving cancer care. Existing interventions to improve the uptake of these services have predominantly occurred in clinic settings and are limited in their effectiveness, particularly among low-income and minority populations. Methods The “Lay health worker Educates Engages and Activates Patients to Share (LEAPS)” intervention was developed to improve advance care planning and symptom management among low-income and minority hourly-wage workers with cancer, in two community settings. The intervention provides a lay health worker to all patients newly diagnosed with cancer and aims to educate and activate patients to engage in advance care planning and symptom management with their oncology providers. In this randomized clinical trial, we will evaluate the effect on quality of life (primary outcome) using the validated Functional Assessment of Cancer Therapy – General Survey, at enrollment, 4- and 12- months post-enrollment. We will examine between-group differences on our secondary outcomes of patient activation, patient satisfaction with healthcare decision-making, and symptom burden (at enrollment, 4- and 12-months post-enrollment), and total healthcare use and healthcare costs (at 12-months post-enrollment). Discussion Multilevel approaches are urgently needed to improve cancer care delivery among low-income and minority patients diagnosed with cancer in community settings. The current study describes the LEAPS intervention, the study design, and baseline characteristics of the community centers participating in the study. ClinicalTrials.gov Registration # NCT03699748 .

Purpose Stressful life events (SLEs) increase allostatic load and require adaptation. Experiencing SLEs has been associated with decreased health-related quality of life (HRQOL) among adolescents. This study examined racial/ethnic and developmental differences in the relationship between SLEs and HRQOL from preadolescence to midadolescence. Methods Data were from 4,824 participants in the Healthy Passages project, a population-based prospective longitudinal survey of fifth, seventh, and 10th grade adolescents in the U.S. HRQOL was measured with Pediatric Quality of Life Inventory and SLEs with items addressing family-related SLEs (e.g., the parent's death, separation, and divorce; family member's injury/illness; residential change; new child in the household). Results Adolescents, regardless of race/ethnicity, reported the highest SLEs and the lowest HRQOL in early adolescence. Analysis of an autoregressive model with cross-lagged effects showed that the concurrent relationships between SLEs and HRQOL were significantly negative across preadolescence, early adolescence, and midadolescence in African-American, Latinx, and white groups. Furthermore, adolescents had a negative cross-lagged association from SLEs in early adolescence to HRQOL in pre adolescence, but this was not the case among the other racial/ethnic groups. Conclusions Because the negative relationship between family-related SLEs and HRQOL persisted throughout stages of adolescent development, health services targeting adolescents should provide comprehensive family-centered care to alleviate the impact of family-related life stress. Relationships between family life stress and HRQOL varied by racial/ethnic groups, which should be considered by health professionals, teachers, and parents, and in prevention efforts. Latinx adolescents may be particularly vulnerable to time-lagged effects of such family-related stress.

BACKGROUND AND OBJECTIVES: Asthma is responsible for ∼1.7 million emergency department (ED) visits annually in the United States. Studies in adults have shown that anxiety and depression are associated with increased asthma-related ED use. Our objective was to assess this association in pediatric patients with asthma. METHODS: We identified patients aged 6 to 21 years with asthma in the Massachusetts All-Payer Claims Database for 2014 to 2015 using International Classification of Diseases, Ninth and 10th Revision codes. We examined the association between the presence of anxiety, depression, or comorbid anxiety and depression and the rate of asthma-related ED visits per 100 child-years using bivariate and multivariable analyses with negative binomial regression. RESULTS: Of 65 342 patients with asthma, 24.7% had a diagnosis of anxiety, depression, or both (11.2% anxiety only, 5.8% depression only, and 7.7% both). The overall rate of asthma-related ED use was 17.1 ED visits per 100 child-years (95% confidence interval [CI]: 16.7–17.5). Controlling for age, sex, insurance type, and other chronic illness, patients with anxiety had a rate of 18.9 (95% CI: 17.0–20.8) ED visits per 100 child-years, patients with depression had a rate of 21.7 (95% CI: 18.3–25.0), and patients with both depression and anxiety had a rate of 27.6 (95% CI: 24.8–30.3). These rates were higher than those of patients who had no diagnosis of anxiety or depression (15.5 visits per 100 child-years; 95% CI: 14.5–16.4; P < .001). CONCLUSIONS: Children with asthma and anxiety or depression alone, or comorbid anxiety and depression, have higher rates of asthma-related ED use compared with those without either diagnosis.

Human zinc-α2-glycoprotein (ZAG) is a 42 kDa adipokine which regulates body fat mass and is associated with cachexia and obesity. ZAG belongs to the major histocompatibility complex class I protein family and binds long-chain polyunsaturated fatty acids in its groove formed from the α1 and α2 domains. To identify the molecular basis of its lipid-binding function, we determined the first crystal structure at 2.49 Å resolution for fatty acid-bound ZAG, where the ligand was the fluorescent 11-(dansylamino)undecanoic acid (DAUDA). The 192 kDa crystallographic asymmetric unit contained six ZAG and eight fatty acid molecules in unique conformations. Six fatty acid molecules were localised to the ZAG grooves, where their tails were bound in two distinct conformations. The carboxylate groups of three fatty acids projected out of the groove, while the fourth was hydrogen bonded with R73 inside the groove. Other ligand-residue contacts were primarily hydrophobic. A new fatty acid site was revealed for two further DAUDA molecules at the ZAG α3 domains. Following conformational changes from unbound ZAG, the α3 domains formed tetrameric β-barrel structures lined by fatty acid molecules that doubled the binding capacity of ZAG. Analytical ultracentrifugation revealed that ZAG in solution was a monomer in the absence of DAUDA, but formed small amounts of tetramers with DAUDA. By showing that ZAG binds fatty acids in different locations, we demonstrate an augmented mechanism for fatty acid binding in ZAG that is distinct from other known fatty acid binding proteins, and may be relevant to cachexia.

Importance: The Engagement of Patients with Advanced Cancer (EPAC), comprised of a lay health worker (LHW) who assists patients with advance care planning, is an effective intervention for improving patient experiences and reducing acute care use and total health-care costs. The objective of this study was to assess patients’ and caregivers’ experiences with the intervention. Methods: We invited all patients enrolled in EPAC and their caregivers to complete an 8-item survey at the end of the intervention and a random 35% sample to participate in a qualitative interview to assess their experiences. At 15-month follow-up, we invited all caregivers of patients who died during the study to participate in a qualitative interview. We analyzed survey responses using bivariate methods and recorded, transcribed, and analyzed interviews using qualitative content analysis. Results: Sixty-nine patients were alive at completion of the intervention and all 30 identified caregivers completed the survey. All viewed the intervention as a critical part of cancer care and recommended the intervention for other patients. In qualitative interviews, among 30 patients, all reported improved comfort in discussing their end-of-life care preferences. In qualitative interviews with 24 bereaved caregivers, all viewed the intervention as critical in ensuring that their loved ones’ wishes were adhered to at the end of life. Conclusions and Relevance: Incorporating an LHW into end-of-life cancer care is an approach supported and viewed as highly effective in improving care by patients and caregivers. The LHW-led EPAC intervention is one solution that can significantly impact patient and caregiver experiences.

OBJECTIVES: To improve the mental health (MH) referral process for children referred from primary care to community mental health clinics (CMHCs) by using a community-partnered approach. METHODS: Our partners were a multisite federally qualified health center and 2 CMHCs in Los Angeles County. We randomly assigned 6 federally qualified health center clinics to the intervention or as a control and implemented a newly developed telehealth-enhanced referral process (video orientation to the CMHC and a live videoconference CMHC screening visit) for all MH referrals from the intervention clinics. Our primary outcome was CMHC access defined by completion of the initial access point for referral (CMHC screening visit). We used multivariate logistic and linear regression to examine intervention impact on our primary outcome. To accommodate the cluster design, we used mixed-effect regression models. RESULTS: A total of 342 children ages 5 to 12 were enrolled; 86.5% were Latino, 61.7% were boys, and the mean age at enrollment was 8.6 years. Children using the telehealth-enabled referral process had 3 times the odds of completing the initial CMHC screening visit compared with children who were referred by using usual care procedures (80.49% vs 64.04%; adjusted odds ratio 3.02 [95% confidence interval 1.47 to 6.22]). Among children who completed the CMHC screening visit, intervention participants took 6.6 days longer to achieve it but also reported greater satisfaction with the referral system compared with controls. Once this initial access point in referral was completed, >80% of eligible intervention and control participants (174 of 213) went on to an MH visit. CONCLUSIONS: A novel telehealth-enhanced referral process developed by using a community-partnered approach improved initial access to CMHCs for children referred from primary care.

Context In our increasingly multicultural society, providing sensitive and respectful pediatric palliative care is vital. Objectives We held a one-day workshop conference with stakeholders and pediatric clinicians to identify suggestions for navigating conflict when cultural differences are present and for informing standard care delivery. Methods Participants explored cases in one of four workshops focused on differences based on race/ethnicity, economic disparity, religion/spirituality, or family values. Each workshop was facilitated by two authors; separate transcriptionists recorded workshop discussions in real time. We used content analyses to qualitatively evaluate the texts and generate recommendations. Results Participants included 142 individuals representing over six unique disciplines, 25 of the U.S., and three nations. Although the conference focused on pediatric palliative care, findings were broadly generalizable to most medical settings. Participants identified key reasons cultural differences may create tension and then provided frameworks for communication, training, and clinical care. Specifically, recommendations included phrases to navigate emotional conflict, broken trust, unfamiliar family values, and conflict. Suggested approaches to training and clinical care included the development of core competencies in communication, history taking, needs assessment, and emotional intelligence. Important opportunities for scholarship included qualitative studies exploring diverse patient and family experiences, quantitative studies examining health disparities, and randomized clinical trials testing interventions designed to improve community partnerships, communication, or child health outcomes. Conclusion Taken together, findings provide a foundation for collaboration between patients, families, and clinicians of all cultures.

Objectives School racial/ethnic segregation in U.S. schoolsDifferences in school racial/ethnic composition may increase health disparities by concentrating educational opportunities that confer long-term health benefits in schools serving predominantly wwhite students. For racial minority students, high concentrations of white students may increase exposure to racismis also associated with psychologicstress, which may ultimately reduceing the long-term health benefits from educational opportunities. Meanwhile associations of racial/ethnic academic tacking within schools and health have been mixed. We sought to test whether: 1) differences in racial/ethnic composition between schools and, 2) racial/ethnic distribution of students in academic tracks within schools are associated with long-term health benefits or risks for white, Black and Latinx students. Methods We analyzed the National Longitudinal Study of Adolescent to Adult Health (12,438 participants, collected 1994–2008), to test whether the school-level segregation (percent of non-Latinx white students at participants’ school during adolescence) was associated with adult health outcomes at ages 18–26 & 24–32, controlling for contextual factorscomparing Black, Latinx, and white students, and controlling for contextualf factors. A secondary analysis explored whether racial/ethnic cohorting across levels of English courses was associated with each health outcome. Results Attending a school with a higher percent of white students was associated with higher adult depression scores, substance abuse, and worse self-rated health for black Black students; lower depression scores, better self-rated health, and alcohol abuse for white students; and no health differences for Latinx students. Greater within school racial/ethnic cohorting across English courses was associated with increased odds of alcohol abuse for white students; decreased odds of alcohol abuse for Black and Latinx students; and decreased odds of drug abuse for Black students. Conclusion Among Bblack youth, attending a school with a higher percentage of white students is associated with worse behavioral health in adulthood. Understanding the potential impacts of school racial/ethnic composition on health is critical to designing policies that maximize access to opportunity and health.Education policies should comprehensively address school quality and racism to maximize adult health.

During efforts to crystallize the enzyme 2,4-dihydroxyacetophenone dioxygenase (DAD) fromAlcaligenessp. 4HAP, a small number of strongly diffracting protein crystals were obtained after two years of crystal growth in one condition. The crystals diffracted synchrotron radiation to almost 1.0 Å resolution and were, until recently, assumed to be formed by the DAD protein. However, when another crystal form of this enzyme was eventually solved at lower resolution, molecular replacement using this new structure as the search model did not give a convincing solution with the original atomic resolution data set. Hence, it was considered that these crystals might have arisen from a protein impurity, although molecular replacement using the structures of common crystallization contaminants as search models again failed. A script to perform molecular replacement usingMOLREPin which the first chain of every structure in the PDB was used as a search model was run on a multi-core cluster. This identified a number of prokaryotic phosphate-binding proteins as scoring highly in theMOLREPpeak lists. Calculation of an electron-density map at 1.1 Å resolution based on the solution obtained with PDB entry 2q9t allowed most of the amino acids to be identified visually and built into the model. ABLASTsearch then indicated that the molecule was most probably a phosphate-binding protein fromStenotrophomonas maltophilia(UniProt ID B4SL31; gene ID Smal_2208), and fitting of the corresponding sequence to the atomic resolution map fully corroborated this. Proteins in this family have been linked to the virulence of antibiotic-resistant strains of pathogenic bacteria and with biofilm formation. The structure of theS. maltophiliaprotein has been refined to anRfactor of 10.15% and anRfreeof 12.46% at 1.1 Å resolution. The molecule adopts the type II periplasmic binding protein (PBP) fold with a number of extensively elaborated loop regions. A fully dehydrated phosphate anion is bound tightly between the two domains of the protein and interacts with conserved residues and a number of helix dipoles.

Key Points Question Is a lay health worker–led screening and referral intervention associated with patient symptom burden, acute care use, and total costs of care? Findings In this multisite quality improvement study of 425 Medicare Advantage enrollees with a diagnosis of cancer who were provided usual cancer care augmented by a lay health worker trained to proactively screen patient symptoms, discuss symptoms with a physician assistant, and refer patients with uncontrolled symptoms to palliative care and behavioral medicine compared with 407 control patients diagnosed and treated in the year prior, patients in the intervention group were associated with significant reductions in symptom burden over time, and patients in the control group were associated with worsening symptoms over time. Patients who received the intervention were associated with fewer inpatient and emergency department visits and lower median total costs, and there were no differences in survival. Meaning The findings suggest that a lay health worker–led symptom screening and proactive referral intervention may improve value-based cancer care., Importance Undertreated patient symptoms require approaches that improve symptom burden. Objective To determine the association of a lay health worker–led symptom screening and referral intervention with symptom burden, survival, health care use, and total costs among Medicare Advantage enrollees with a new diagnosis of solid or hematologic malignant neoplasms. Design, Setting, and Participants This quality improvement study conducted at 9 community oncology practices from November 1, 2016, to October 31, 2018, compared newly diagnosed Medicare Advantage enrollees with solid or hematologic malignant neoplasms with patients diagnosed and treated 1 year prior. Analysis was conducted from August 1, 2019, to January 11, 2020. Interventions Usual care augmented by a lay health worker trained to screen symptoms and refer patients to palliative care and behavioral medicine. Main Outcomes and Measures The primary outcome was change in symptoms using the Edmonton Symptom Assessment Scale and the 9-item Patient Health Questionnaire at baseline and 6 and 12 months after enrollment. Secondary outcomes were between-group comparison of survival, 12-month health care use, and costs. Results Among 425 patients in the intervention group and 407 patients in the control group, the mean (SD) age was 78.8 (8.3) years, 345 (41.5%) were female, and 407 (48.9%) were non-Hispanic white. Patients in the intervention group experienced a lower symptom burden as measured by the Edmonton Symptom Assessment Scale score over time compared with patients in the control group (mean [SD] difference, −1.9 [14.2]; 95% CI, −3.77 to −0.19; P = .01 for the intervention group and 2.32 [17.7]; 95% CI, 0.47 to 4.19; P = .02 for the control group). Similar findings were noted in 9-item Patient Health Questionnaire depression scores (mean [SD] difference, −0.63 [3.99]; 95% CI, −1.23 to −0.028; P = .04 for the intervention group and 1.67 [5.49]; 95% CI, 0.95 to 2.37; P = .01 for the control group). Patients in the intervention group compared with patients in the control group had fewer mean (SD) inpatient visits (0.54 [0.77]; 95% CI, 0.47-0.61 vs 0.72 [1.12]; 95% CI, 0.61-0.83; P = .04) and emergency department visits (0.43 [0.76]; 95% CI, 0.36-0.50 vs 0.57 [1.00]; 95% CI, 0.48-0.67; P = .002) per 1000 patients per year and lower total costs (median, $17 869 [interquartile range, $6865-$32 540] vs median, $18 473 [interquartile range, $6415-$37 910]; P = .02). A total of 180 patients in the intervention group and 189 patients in the control group died within 12 months. Among those who died, patients in the intervention group had greater hospice use (125 of 180 [69.4%] vs 79 of 189 [41.8%]; odds ratio, 3.16; 95% CI, 2.13-4.69; P, This quality improvement study examines the association of a lay health worker–led symptom screening and referral intervention with symptom burden, survival, health care use, and total costs among Medicare Advantage enrollees with a new diagnosis of solid or hematologic malignant neoplasms.

Covalent probes can display unmatched potency, selectivity and duration of action, however, their discovery is challenging. In principle, fragments that can irreversibly bind their target can overcome the low affinity that limits reversible fragment screening. Such electrophilic fragments were considered non-selective and were rarely screened. We hypothesized that mild electrophiles might overcome the selectivity challenge, and constructed a library of 993 mildly electrophilic fragments. We characterized this library by a new high-throughput thiol-reactivity assay and screened them against ten cysteine-containing proteins. Highly reactive and promiscuous fragments were rare and could be easily eliminated. By contrast, we found selective hits for most targets. Combination with high-throughput crystallography allowed rapid progression to potent and selective probes for two enzymes, the deubiquitinase OTUB2, and the pyrophosphatase NUDT7. No inhibitors were previously known for either. This study highlights the potential of electrophile fragment screening as a practical and efficient tool for covalent ligand discovery.

* Abbreviations: CSHCN — : children with special health care needs SHCN — : special health care needs A comprehensive medical home is considered the foundation of quality primary care services for all children, particularly for those with special health care needs (SHCN).1,2 In the article “Access to the Medical Home Among Children With and Without Special Health Care Needs,”3 the authors describe results from the 2016 National Survey of Children’s Health, which revealed that children with special health care needs (CSHCN) were less likely than non-CSHCN to receive primary care that meets the medical home criteria3 of having a usual source of care, having a personal doctor or nurse, receiving necessary referrals, receiving needed care coordination, and receiving family-centered care.4 In addition, CSHCN with more qualifiers for SHCN status (a marker of higher medical complexity) are less likely to have access to a medical home than children with fewer SHCN qualifiers. However, CSHCN were more likely than non-CSHCN to have a usual source of care or personal doctor or nurse.3 Because less than half of the children surveyed had access to care in a medical home, it is clear that there are barriers within the current … Address correspondence to Molly Fuentes, MD, MS, Seattle Children’s Research Institute, 2001 Eighth Ave, Suite 624, Seattle, WA 98121. E-mail: molly.fuentes{at}seattlechildrens.org

Objective: To develop an intervention to improve the mental health referral and care process for children referred by primary care providers (PCPs) to community mental health clinics (MHCs) using a community partnered approach. Design: A Project Working Group (PWG) with representatives from each partner orga­nization met monthly for 6 months. Setting: Multi-site federally qualified health center (FQHC) and two community MHCs in Los Angeles county. Participants: 26 stakeholders (14 FQHC clinic providers/staff, 8 MHC providers/staff, 4 parents) comprised the PWG. Data Sources: Qualitative interviews, PWG meeting notes, intervention processes and workflow reports. Intervention: The PWG reviewed qualita­tive data from stakeholders (interviews of 7 parents and 13 providers/staff). The PWG met monthly to identify key transition points where access to and coordination of care were likely compromised and to develop solutions. Results: Three critical transition points and system solutions were identified: 1) Parents refuse initial referral to the MHC due to stigma regarding mental health services. Solution: During initial referral, parents watch a video introducing them to the MHC. 2) Parents don’t complete the MHC’s screening after referral. Solution: A live videoconference session connecting parents at the FQHC with MHC staff ensures completion of the screening and eligibility process. 3) PCPs reject transfer of patients back to primary care for ongoing psycho­tropic medication management. Solution: Regularly scheduled live videoconferences connect PCPs and MHC providers. Conclusions: A community partnered ap­proach to care design utilizing telehealth for care coordination between clinics can potentially be used to address key chal­lenges in MHC access for children. Ethn Dis. 2018;28(Suppl 2):457-466; doi:10.18865/ed.28.S2.457.

OBJECTIVE Mental health conditions (MHCs) are prevalent among hospitalized children and could influence the success of hospital discharge. We assessed the relationship between MHCs and 30-day readmissions. METHODS This retrospective, cross-sectional study of the 2013 Nationwide Readmissions Database included 512,997 hospitalizations of patients ages 3 to 21 years for the 10 medical and 10 procedure conditions with the highest number of 30-day readmissions. MHCs were identified by using the International Classification of Diseases, 9th Revision-Clinical Modification codes. We derived logistic regression models to measure the associations between MHC and 30-day, all-cause, unplanned readmissions, adjusting for demographic, clinical, and hospital characteristics. RESULTS An MHC was present in 17.5% of medical and 13.1% of procedure index hospitalizations. Readmission rates were 17.0% and 6.2% for medical and procedure hospitalizations, respectively. In the multivariable analysis, compared with hospitalizations with no MHC, hospitalizations with MHCs had higher odds of readmission for medical admissions (adjusted odds ratio [AOR], 1.23; 95% confidence interval [CI], 1.19-1.26] and procedure admissions (AOR, 1.24; 95% CI, 1.15-1.33). Three types of MHCs were associated with higher odds of readmission for both medical and procedure hospitalizations: depression (medical AOR, 1.57; 95% CI, 1.49-1.66; procedure AOR, 1.39; 95% CI, 1.17-1.65), substance abuse (medical AOR, 1.24; 95% CI, 1.18-1.30; procedure AOR, 1.26; 95% CI, 1.11-1.43), and multiple MHCs (medical AOR, 1.43; 95% CI, 1.37-1.50; procedure AOR, 1.26; 95% CI, 1.11-1.44). CONCLUSIONS MHCs are associated with a higher likelihood of hospital readmission in children admitted for medical conditions and procedures. Understanding the influence of MHCs on readmissions could guide strategic planning to reduce unplanned readmissions for children with cooccurring physical and mental health conditions.

This study sought to determine if disparities in insulin pump therapy among youth with type 1 diabetes (T1DM) persist despite recent increases in overall pump use rates.All patients aged 6 months-17 years, diagnosed with T1DM, and completed 4+ outpatient diabetes visits at an academically-affiliated pediatric health care center from 2011 to 2016 were identified (n = 2131). Data were collected from existing electronic medical records and a multivariable logistic regression model was used to identify factors associated with insulin pump therapy.Findings revealed one novel factor (patients/families whose primary language is Spanish [OR 0.47, p = 0.038] or other non-English languages [OR 0.47, p = 0.028]) and confirmed several previously known factors associated with lower insulin pump use: patients who were older (10-14 years OR 0.38, p 0.0001; 15+ years OR 0.15, p 0.0001), male (OR 0.80, p = 0.021), non-Hispanic black (OR 0.59, p = 0.009), American Indian/Alaska Native (OR 0.19, p = 0.023), had either government (OR 0.42, p 0.0001) or no insurance (OR 0.52, p = 0.004) and poor glycemic control (at least one HbASignificant disparities in insulin pump use in youth with T1DM persist despite known benefits associated with pump therapy and underlying causes remain unclear.Health care providers should explore barriers to insulin pump therapy, including limited English language proficiency.

PurposeAlthough incarceration may have life-long negative health effects, little is known about associations between child incarceration and subsequent adult health outcomes. The paper aims to discuss this issue.Design/methodology/approachThe authors analyzed data from 14,689 adult participants in the National Longitudinal Study of Adolescent to Adult Health (Add Health) to compare adult health outcomes among those first incarcerated between 7 and 13 years of age (child incarceration); first incarcerated at>or=14 years of age; and never incarcerated.FindingsCompared to the other two groups, those with a history of child incarceration were disproportionately black or Hispanic, male, and from lower socio-economic strata. Additionally, individuals incarcerated as children had worse adult health outcomes, including general health, functional limitations (climbing stairs), depressive symptoms, and suicidality, than those first incarcerated at older ages or never incarcerated.Research limitations/implicationsDespite the limitations of the secondary database analysis, these findings suggest that incarcerated children are an especially medically vulnerable population.Practical implicationsPrograms and policies that address these medically vulnerable children’s health needs through comprehensive health and social services in place of, during, and/or after incarceration are needed.Social implicationsMeeting these unmet health and social service needs offers an important opportunity to achieve necessary health care and justice reform for children.Originality/valueNo prior studies have examined the longitudinal relationship between child incarceration and adult health outcomes.

Background Parent-focused Redesign for Encounters, Newborns to Toddlers (PARENT), is a well-child care (WCC) model that has demonstrated effectiveness in improving the receipt of comprehensive WCC services and reducing emergency department utilization for children aged 0 to 3 in low-income communities. PARENT relies on a health educator ("parent coach") to provide WCC services; it utilizes a Web-based previsit prioritization/screening tool (Well-Visit Planner) and an automated text message reminder/education service. We sought to assess intervention feasibility and acceptability among PARENT trial intervention participants. Methods Intervention parents completed a survey after a 12-month study period; a 26% random sample of them were invited to participate in a qualitative interview. Interviews were recorded, transcribed, and analyzed using the constant comparative method of qualitative analysis; survey responses were analyzed using bivariate methods. Results A total of 115 intervention participants completed the 12-month survey; 30 completed a qualitative interview. Nearly all intervention participants reported meeting with the coach, found her helpful, and would recommend continuing coach-led well visits (97–99%). Parents built trusting relationships with the coach and viewed her as a distinct and important part of their WCC team. They reported that PARENT well visits more efficiently used in-clinic time and were comprehensive and family centered. Most used the Well-Visit Planner (87%), and found it easy to use (94%); a minority completed it at home before the visit (18%). Sixty-two percent reported using the text message service; most reported it as a helpful source of new information and a reinforcement of information discussed during visits. Conclusions A parent coach–led intervention for WCC for young children is a model of WCC delivery that is both acceptable and feasible to parents in a low-income urban population.

L-Asparaginases catalyse the hydrolysis of asparagine to aspartic acid and ammonia. In addition, L-asparaginase is involved in the biosynthesis of amino acids such as lysine, methionine and threonine. These enzymes have been used as chemotherapeutic agents for the treatment of acute lymphoblastic leukaemia and other haematopoietic malignancies since the tumour cells cannot synthesize sufficient L-asparagine and are thus killed by deprivation of this amino acid. L-Asparaginases are also used in the food industry and have potential in the development of biosensors, for example for asparagine levels in leukaemia. The thermostable type I L-asparaginase fromThermococcus kodakarensis(TkA) is composed of 328 amino acids and forms homodimers in solution, with the highest catalytic activity being observed at pH 9.5 and 85°C. It has aKmvalue of 5.5 mMfor L-asparagine, with no glutaminase activity being observed. The crystal structure of TkA has been determined at 2.18 Å resolution, confirming the presence of two α/β domains connected by a short linker region. The N-terminal domain contains a highly flexible β-hairpin which adopts `open' and `closed' conformations in different subunits of the solved TkA structure. In previously solved L-asparaginase structures this β-hairpin was only visible when in the `closed' conformation, whilst it is characterized with good electron density in all of the subunits of the TkA structure. A phosphate anion resides at the active site, which is formed by residues from both of the neighbouring monomers in the dimer. The high thermostability of TkA is attributed to the high arginine and salt-bridge content when compared with related mesophilic enzymes.

Artocarpus incisa (breadfruit) seeds contain three different lectins (Frutalin, Frutapin (FTP) and Frutackin) with distinct carbohydrate specificities. The most abundant lectin is Frutalin, an α-D-galactose-specific carbohydrate-binding glycoprotein with antitumour properties and potential for tumour biomarker discovery as already reported. FTP is the second most abundant, but proved difficult to purify with very low yields and contamination with Frutalin frustrating its characterization. Here, we report for the first time high-level production and isolation of biologically active recombinant FTP in Escherichia coli BL21, optimizing conditions with the best set yielding >40 mg/l culture of soluble active FTP. The minimal concentration for agglutination of red blood cells was 62.5 µg/ml of FTP, a process effectively inhibited by mannose. Apo-FTP, FTP–mannose and FTP–glucose crystals were obtained, and they diffracted X-rays to a resolution of 1.58 (P212121), 1.70 (P3121) and 1.60 (P3121) Å respectively. The best solution showed four monomers per asymmetric unit. Molecular dynamics (MD) simulation suggested that FTP displays higher affinity for mannose than glucose. Cell studies revealed that FTP was non-cytotoxic to cultured mouse fibroblast 3T3 cells below 0.5 mg/ml and was also capable of stimulating cell migration at 50 µg/ml. In conclusion, our optimized expression system allowed high amounts of correctly folded soluble FTP to be isolated. This recombinant bioactive lectin will now be tested in future studies for therapeutic potential; for example in wound healing and tissue regeneration.

Objectives To determine the proportion of US children hospitalized for a primary mental health condition who are discharged to postacute care (PAC); whether PAC discharge is associated with demographic, clinical, and hospital characteristics; and whether PAC use varies by state. Study design Retrospective cohort study of a nationally representative sample of US acute care hospitalizations for children ages 2-20 years with a primary mental health diagnosis, using the 2009 and 2012 Kids' Inpatient Databases. Discharge to PAC was used as a proxy for transfer to an inpatient mental health facility. We derived adjusted logistic regression models to assess the association of patient and hospital characteristics with discharge to PAC. Results In 2012, 14.7% of hospitalized children (n = 248 359) had a primary mental health diagnosis. Among these, 72% (n = 178 214) had bipolar disorder, depression, or psychosis, of whom 4.9% (n = 8696) were discharged to PAC. The strongest predictors of PAC discharge were homicidal ideation (aOR, 24.9; 96% CI, 4.1-150.4), suicide and self-injury (aOR, 15.1; 95% CI, 11.7-19.4), and substance abuse–related medical illness (aOR, 5.0; 95% CI, 4.5-5.6). PAC use varied widely by state, ranging from 2.2% to 36.3%. Conclusions The majority of children hospitalized primarily for a mood disorder or psychosis were not discharged to PAC, and safety-related conditions were the primary drivers of the relatively few PAC discharges. There was substantial state-to-state variation. Target areas for quality improvement include improving access to PAC for children hospitalized for mood disorders or psychosis and equitable allocation of appropriate PAC resources across states.

Introduction: Cancer is a leading cause of death in the United States. Although treatments have improved, patients and caregivers continue to report significant gaps in their care. The objective of this study was to examine the views of patients and caregivers on their experiences with current cancer care delivery and identify key strategies to improve the delivery of care. Methods and Materials: Semistructured interviews were conducted with 75 patients and 45 caregivers across the United States. The interviews were recorded, transcribed, and analyzed using constant comparative method of qualitative analysis. Results: Participants reported multiple gaps in care delivery, including barriers in health communication with health care providers, lack of elucidation of care goals, lack of care coordination, and challenges in accessing care. Participants identified that greater use of nonphysician providers and alternative formats, such as telephone-based care and home and community-based care, would narrow these gaps. Conclusion: Understanding patients’ and caregivers’ experiences with gaps in cancer care delivery can inform cancer care delivery redesign efforts and lead to targeted interventions that result in patient-centered and family-oriented care.

BACKGROUND AND OBJECTIVES: Despite the widespread epidemic of mass incarceration in the US, relatively little literature exists examining the longitudinal relationship between youth incarceration and adult health outcomes. We sought to quantify the association of youth incarceration with subsequent adult health outcomes. METHODS: We analyzed data from 14 344 adult participants in the National Longitudinal Study of Adolescent to Adult Health. We used weighted multivariate logistic regressions to investigate the relationship between cumulative incarceration duration (none, 1 year) before Wave IV (ages 24–34 years) and subsequent adult health outcomes (general health, functional limitations, depressive symptoms, and suicidal thoughts). Models controlled for Wave I (grades 7–12) baseline health, sociodemographics, and covariates associated with incarceration and health. RESULTS: A total of 14.0% of adults reported being incarcerated between Waves I and IV. Of these, 50.3% reported a cumulative incarceration duration of 1 year. Compared with no incarceration, incarceration duration of < 1 month predicted subsequent adult depressive symptoms (odds ratio [OR] = 1.41; 95% confidence interval [CI], 1.11–1.80; P = .005). A duration of 1 to 12 months predicted worse subsequent adult general health (OR = 1.48; 95% CI, 1.12–1.96; P = .007). A duration of >1 year predicted subsequent adult functional limitations (OR = 2.92; 95% CI, 1.51–5.64; P = .002), adult depressive symptoms (OR = 4.18; 95% CI, 2.48–7.06; P < .001), and adult suicidal thoughts (OR = 2.34; 95% CI, 1.09–5.01; P = .029). CONCLUSIONS: Cumulative incarceration duration during adolescence and early adulthood is independently associated with worse physical and mental health later in adulthood. Potential mechanisms merit exploration.

We examined the risk of preterm birth (PTB, 34 years for both, were also at higher odds of delivering their second baby prematurely (adjusted odds ratios 1.9 and 1.3, respectively). Women who deliver their first infant at

A number of X-ray analyses of an enzyme involved in a key early stage of tetrapyrrole biosynthesis are reported. Two structures of human 5-aminolaevulinate dehydratase (ALAD), native and recombinant, have been determined at 2.8 resolution, showing that the enzyme adopts an octameric quaternary structure in accord with previously published analyses of the enzyme from a range of other species. However, this is in contrast to the finding that a disease-related F12L mutant of the human enzyme uniquely forms hexamers [Breinig et al. (2003), Nature Struct. Biol.10, 757-763]. Monomers of all ALADs adopt the TIM-barrel fold; the subunit conformation that assembles into the octamer includes the N-terminal tail of one monomer curled around the (α/β)8 barrel of a neighbouring monomer. Both crystal forms of the human enzyme possess two monomers per asymmetric unit, termed A and B. In the native enzyme there are a number of distinct structural differences between the A and B monomers, with the latter exhibiting greater disorder in a number of loop regions and in the active site. In contrast, the second monomer of the recombinant enzyme appears to be better defined and the active site of both monomers clearly possesses a zinc ion which is bound by three conserved cysteine residues. In native human ALAD, the A monomer also has a ligand resembling the substrate ALA which is covalently bound by a Schiff base to one of the active-site lysines (Lys252) and is held in place by an ordered active-site loop. In contrast, these features of the active-site structure are disordered or absent in the B subunit of the native human enzyme. The octameric structure of the zinc-dependent ALAD from the hyperthermophile Pyrobaculum calidifontis is also reported at a somewhat lower resolution of 3.5 Å. Finally, the details are presented of a high-resolution structure of the Escherichia coli ALAD enzyme co-crystallized with a noncovalently bound moiety of the product, porphobilinogen (PBG). This structure reveals that the pyrrole side-chain amino group is datively bound to the active-site zinc ion and that the PBG carboxylates interact with the enzyme via hydrogen bonds and salt bridges with invariant residues. A number of hydrogen-bond interactions that were previously observed in the structure of yeast ALAD with a cyclic intermediate resembling the product PBG appear to be weaker in the new structure, suggesting that these interactions are only optimal in the transition state.X-ray structures of the enzyme 5-aminolaevulinate dehydratase (ALAD) purified from human blood, as well as the recombinant human form and the ALAD from the hyperthermophilic archaeon P. calidifontis, are reported, together with the structure of E. coli ALAD co-crystallized with a noncovalently bound moiety of the product, porphobilinogen. The structures give insight into the zinc-dependence of these enzymes, the possible role of electrostatics in substrate funnelling and details of the interactions made by the bound pyrrole end product.

OBJECTIVE: Mental health conditions are prevalent among children hospitalized for medical conditions and surgical procedures, but little is known about their influence on hospital resource use. The objectives of this study were to examine how hospitalization characteristics vary by presence of a comorbid mental health condition and estimate the association of a comorbid mental health condition with hospital length of stay (LOS) and costs. METHODS: Using the 2012 Kids’ Inpatient Database, we conducted a retrospective, nationally representative, cross-sectional study of 670 161 hospitalizations for 10 common medical and 10 common surgical conditions among 3- to 20-year-old patients. Associations between mental health conditions and hospital LOS were examined using adjusted generalized linear models. Costs of additional hospital days associated with mental health conditions were estimated using hospital cost-to-charge ratios. RESULTS: A comorbid mental health condition was present in 13.2% of hospitalizations. A comorbid mental health condition was associated with a LOS increase of 8.8% (from 2.5 to 2.7 days, P < .001) for medical hospitalizations and a 16.9% increase (from 3.6 to 4.2 days, P < .001) for surgical hospitalizations. For hospitalizations in this sample, comorbid mental health conditions were associated with an additional 31 729 (95% confidence interval: 29 085 to 33 492) hospital days and $90 million (95% confidence interval: $81 to $101 million) in hospital costs. CONCLUSIONS: Medical and surgical hospitalizations with comorbid mental health conditions were associated with longer hospital stay and higher hospital costs. Knowledge about the influence of mental health conditions on pediatric hospital utilization can inform clinical innovation and case-mix adjustment.

OBJECTIVE: To describe recent, 10-year trends in pediatric hospital resource use with and without a psychiatric diagnosis and examine how these trends vary by type of psychiatric and medical diagnosis cooccurrence. METHODS: A retrospective, longitudinal cohort analysis using hospital discharge data from 33 tertiary care US children’s hospitals of patients ages 3 to 17 years from January 1, 2005 through December 31, 2014. The trends in hospital discharges, hospital days, and total aggregate costs for each psychiatric comorbid group were assessed by using multivariate generalized estimating equations. RESULTS: From 2005 to 2014, the cumulative percent growth in resource use was significantly (all P < .001) greater for children hospitalized with versus without a psychiatric diagnosis (hospitalizations: +137.7% vs +26.0%; hospital days: +92.9% vs 5.9%; and costs: +142.7% vs + 18.9%). During this time period, the most substantial growth was observed in children admitted with a medical condition who also had a cooccurring psychiatric diagnosis (hospitalizations: +160.5%; hospital days: +112.4%; costs: +156.2%). In 2014, these children accounted for 77.8% of all hospitalizations for children with a psychiatric diagnosis; their most common psychiatric diagnoses were developmental disorders (22.3%), attention-deficit/hyperactivity disorder (18.1%), and anxiety disorders (14.2%). CONCLUSIONS: The 10-year rise in pediatric hospitalizations in US children’s hospitals is 5 times greater for children with versus without a psychiatric diagnosis. Strategic planning to meet the rising demand for psychiatric care in tertiary care children’s hospitals should place high priority on the needs of children with a primary medical condition and cooccurring psychiatric disorders.

ObjectiveTo examine recurrent preterm birth and early term birth in women's initial and immediately subsequent pregnancies.MethodsThis retrospective cohort study included 163,889 women who delivered their first and second liveborn singleton neonates between 20 and 44 weeks of gestation in California from 2005 through 2011. Data from hospital discharge records and birth certificates were used for analyses. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using logistic regression models adjusted for risk factors.ResultsShorter gestational duration in the first pregnancy increased the risk of subsequent preterm birth (both early, before 32 weeks of gestation, and later, from 32 to 36 weeks of gestation) as well as early term birth (37-38 weeks of gestation). Compared with women with a prior term birth, women with a prior early preterm birth (before 32 weeks of gestation) were at the highest risk for a subsequent early preterm birth (58/935 [6.2%] compared with 367/118,505 [0.3%], adjusted OR 23.3, 95% CI 17.2-31.7). Women with a prior early term birth had more than a twofold increased risk for subsequent preterm birth (before 32 weeks of gestation: 171/36,017 [0.5%], adjusted OR 2.0, 95% CI 1.6-2.3; from 32 to 36 weeks of gestation: 2,086/36,017 [6.8%], adjusted OR 3.0, 95% CI 2.9-3.2) or early term birth (13,582/36,017 [37.7%], adjusted OR 2.2, 95% CI 2.2-2.3).ConclusionBoth preterm birth and early term birth are associated with these outcomes in a subsequent pregnancy. Increased clinical attention and research efforts may benefit from a focus on women with a prior early term birth as well as those with prior preterm birth.

OBJECTIVES: We examined racial/ethnic disparities in attention-deficit/hyperactivity disorder (ADHD) diagnosis and medication use and determined whether medication disparities were more likely due to underdiagnosis or undertreatment of African-American and Latino children, or overdiagnosis or overtreatment of white children. METHODS: We used a population-based, multisite sample of 4297 children and parents surveyed over 3 waves (fifth, seventh, and 10th grades). Multivariate logistic regression examined disparities in parent-reported ADHD diagnosis and medication use in the following analyses: (1) using the total sample; (2) limited to children with an ADHD diagnosis or symptoms; and (3) limited to children without a diagnosis or symptoms. RESULTS: Across all waves, African-American and Latino children, compared with white children, had lower odds of having an ADHD diagnosis and of taking ADHD medication, controlling for sociodemographics, ADHD symptoms, and other potential comorbid mental health symptoms. Among children with an ADHD diagnosis or symptoms, African-American children had lower odds of medication use at fifth, seventh, and 10th grades, and Latino children had lower odds at fifth and 10th grades. Among children who had neither ADHD symptoms nor ADHD diagnosis by fifth grade (and thus would not likely meet ADHD diagnostic criteria at any age), medication use did not vary by race/ethnicity in adjusted analysis. CONCLUSIONS: Racial/ethnic disparities in parent-reported medication use for ADHD are robust, persisting from fifth grade to 10th grade. These findings suggest that disparities may be more likely related to underdiagnosis and undertreatment of African-American and Latino children as opposed to overdiagnosis or overtreatment of white children.