The Norms and Corporatization of Medicine Influence Physician Moral Distress in the United States.

PhenomenonMoral distress, which occurs when someone's moral integrity is seriously compromised because they feel unable to act in accordance with their core values and obligations, is an increasingly important concern for physicians. Due in part to limited understanding of the root causes of moral distress, little is known about which approaches are most beneficial for mitigating physicians' distress. Our objective was to describe system-level factors in United States (U.S.) healthcare that contribute to moral distress among pediatric hospitalist attendings and pediatric residents.ApproachIn this qualitative study, we conducted one-on-one semi-structured interviews with pediatric hospitalist attendings and pediatric residents from 4 university-affiliated, freestanding children's hospitals in the U.S. between August 2019 and February 2020. Data were coded with an iteratively developed codebook, categorized into themes, and then synthesized.FindingsWe interviewed 22 hospitalists and 18 residents. Participants described in detail how the culture of medicine created a context that cultivated moral distress. Norms of medical education and the practice of medicine created conflicts between residents' strong sense of professional responsibility to serve the best interests of their patients and the expectations of a hierarchical system of decision-making. The corporatization of the U.S. healthcare system created administrative and financial pressures that conflicted with the moral responsibility felt by both residents and hospitalists to provide the care that their patients and families needed.InsightsThese findings highlight the critical role of systemic sources of moral distress. These findings suggest that system-level interventions must supplement existing interventions that target individual health care providers. Preventing and managing moral distress will require a broad approach that addresses systemic drivers, such as the corporatization of medicine, which are entrenched in the culture of medicine.

Hypotensive Events in Pediatric Patients Receiving Dexmedetomidine for MRI.

PURPOSE: Dexmedetomidine, the preferred pediatric sedating agent for magnetic resonance imaging (MRI), has the side effect of hypotension. Newer recommendations for reporting adverse events in pediatric procedural sedation include using a two-pronged definition. Our aim was to describe the incidence of hypotension in patients undergoing sedated MRI and to identify demographic and clinical factors associated with hypotension, applying a two-pronged definition, where a numerical threshold/clinical criterion must be met as well as at least one clinical intervention performed. DESIGN: An observational cohort study. METHODS: Medical record data were extracted for outpatients less than 18 years of age sedated primarily with dexmedetomidine for MRI in a single center for over a seven-year period. Patients who received propofol as an adjunct were also included. Hypotension was defined using a two-pronged approach, as a 20% reduction in systolic blood pressure from baseline lasting ≥10 minutes, coupled with a fluid bolus. Analysis included descriptive statistics, t tests and logistic regression using discrete-time survival analysis. FINDINGS: Of the 1,590 patient encounters, 90 (5.7%) experienced hypotension. Males were significantly more likely to have hypotension. Patients with hypotension had overall longer appointment times, including longer sedation times and recovery time. Greater blood pressure (BP) variability in the preceding 20 minutes also increased the risk of hypotension. CONCLUSIONS: Our lower incidence of hypotension is likely related to the two-pronged intervention-based definition used, as it likely more accurately reflects clinically meaningful hypotension. To our knowledge, this is the first study using this approach with this population. Research further examining the relationship between prolonged sedation, blood pressure variability, gender, hypotension, and recovery time is needed. Understanding these relationships will help interdisciplinary teams, including nurses in pediatric procedural areas, to reduce the incidence of hypotension, potentially maximize patient safety, and optimize throughput.

Intersecting systemic and personal barriers to accessing social services: qualitative interviews in northern California.

BACKGROUND: Addressing social risks in the clinical setting can increase patient confidence in the availability of community resources and may contribute to the development of a therapeutic alliance which has been correlated with treatment adherence and improved quality of life in mental health contexts. It is not well understood what barriers patients face when trying to connect to community resources that help address social risks. This paper aims to describe patient-reported barriers to accessing and using social needs-related resources to which they are referred by a program embedded in a safety net primary care clinic. METHODS: This is a qualitative assessment of patient-reported barriers to accessing and using social needs assistance programs. We conducted over 100 in-depth interviews with individuals in Northern California who participated in a navigation and referral program to help address their social needs and describe a unique framework for understanding how policies and systems intersect with an individual's personal life circumstances. RESULTS: Individuals described two distinct domains of barriers: 1) systems-level barriers that were linked to the inequitable distribution of and access to resources, and 2) personal-level barriers that focused on unique limitations experienced by each patient and impacted the way that they accessed services in their communities. While these barriers often overlapped or manifested in similar outcomes, this distinction was key because the systems barriers were not things that individuals could control or overcome through their own initiative or by increasing individual capacity. CONCLUSIONS: Respondents describe intersecting systemic and personal barriers that compound patients' challenges to getting their social needs met; this includes both a picture of the inequitable distribution of and access to social services and a profile of the limitations created by individual life histories. These results speak to the need for structural changes to improve adequacy, availability, and accessibility of social needs resources. These findings highlight the need for advocacy to address systems barriers, especially the stigma that is faced by people who struggle with a variety of health and social issues, and investment in incentives to strengthen relationships between health care settings and social service agencies.

Parenteral lipids shape gut bile acid pools and microbiota profiles in the prevention of cholestasis in preterm pigs.

Multi-component lipid emulsions, rather than soy-oil emulsions, prevent cholestasis by an unknown mechanism. Here, we quantified liver function, bile acid pools, and gut microbial and metabolite profiles in premature parenterally fed pigs given a soy-oil lipid emulsion, Intralipid (IL), a multi component lipid emulsion, SMOFlipid (SMOF), a novel emulsion with a modified fatty-acid composition [experimental emulsion (EXP)], or a control enteral diet (ENT) for 22 days. We assayed serum cholestasis markers, measured total bile acid levels in plasma, liver, and gut contents, and analyzed colonic bacterial 16S rRNA gene sequences and metabolomic profiles. Serum cholestasis markers (i.e., bilirubin, bile acids, and γ-glutamyl transferase) were highest in IL-fed pigs and normalized in those given SMOF, EXP, or ENT. Gut bile acid pools were lowest in the IL treatment and were increased in the SMOF and EXP treatments and comparable to ENT. Multiple bile acids, especially their conjugated forms, were higher in the colon contents of SMOF and EXP than in IL pigs. The colonic microbial communities of SMOF and EXP pigs had lower relative abundance of several gram-positive anaerobes, including Clostridrium XIVa, and higher abundance of Enterobacteriaceae than those of IL and ENT pigs. Differences in lipid and microbial-derived compounds were also observed in colon metabolite profiles. These results indicate that multi-component lipid emulsions prevent cholestasis and restore enterohepatic bile flow in association with gut microbial and metabolomic changes. We conclude that sustained bile flow induced by multi-component lipid emulsions likely exerts a dominant effect in reducing bile acid-sensitive gram-positive bacteria.

Patient Perspectives on Addressing Social Needs in Primary Care Using a Screening and Resource Referral Intervention.

BACKGROUND: Interest is growing in interventions to address social needs in clinical settings. However, little is known about patients' perceptions and experiences with these interventions. OBJECTIVE: To evaluate patients' experiences and patient-reported outcomes of a primary care-based intervention to help patients connect with community resources using trained volunteer advocates. DESIGN: Qualitative telephone interviews with patients who had worked with the volunteer advocates. Sample and recruitment targets were equally distributed between patients who had at least one reported success in meeting an identified need and those who had no reported needs met, based on the database used to document patient encounters. PARTICIPANTS: One hundred two patients. INTERVENTIONS: Patients at the study clinic were periodically screened for social needs. If needs were identified, they were referred to a trained volunteer advocate who further assessed their needs, provided them with resource referrals, and followed up with them on whether their need was met. APPROACH: Thematic analysis was used to code the data. KEY RESULTS: Interviewed patients appreciated the services offered, especially the follow-up. Patients' ability to access the resource to which they were referred was enhanced by assistance with filling out forms, calling community resources, and other types of navigation. Patients also reported that interacting with the advocates made them feel listened to and cared for, which they perceived as noteworthy in their lives. CONCLUSIONS: This patient-reported information provides key insights into a human-centered intervention in a clinical environment. Our findings highlight what works in clinical interventions addressing social needs and provide outcomes that are difficult to measure using existing quantitative metrics. Patients experienced the intervention as a therapeutic relationship/working alliance, a type of care that correlates with positive outcomes such as treatment adherence and quality of life. These insights will help design more patient-centered approaches to providing holistic patient care.

New generation lipid emulsions increase brain DHA and improve body composition, but not short-term neurodevelopment in parenterally-fed preterm piglets.

New generation, multicomponent parenteral lipid emulsions provide key fatty acids for brain growth and development, such as docosahexaenoic acid (DHA) and arachidonic acid (AA), yet the content may be suboptimal for preterm infants. Our aim was to test whether DHA and AA-enriched lipid emulsions would increase activity, growth, and neurodevelopment in preterm piglets and limit brain inflammation. Cesarean-delivered preterm pigs were given three weeks of either enteral preterm infant formula (ENT) or TPN with one of three parenteral lipid emulsions: Intralipid (IL), SMOFlipid (SMOF) or an experimental emulsion (EXP). Activity was continuously monitored and weekly blood sampling and behavioral field testing performed. At termination of the study, whole body and tissue metrics were collected. Neuronal density was assessed in sections of hippocampus (HC), thalamus, and cortex. Frontal cortex (FC) and HC tissue were assayed for fatty acid profiles and expression of genes of neuronal growth and inflammation. After 3 weeks of treatment, brain DHA content in SMOF, EXP and ENT pigs was higher (P < 0.01) in FC but not HC vs. IL pigs. There were no differences in brain weight or neuron density among treatment groups. Inflammatory cytokine TNFα and IL-1ß expression in brain regions were increased in IL pigs (P < 0.05) compared to other groups. Overall growth velocity was similar among groups, but IL pigs had higher percent body fat and increased insulin resistance compared to other treatments (P < 0.05). ENT pigs spent more time in higher physical activity levels compared to all TPN groups, but there were no differences in exploratory behavior among groups. We conclude that a soybean oil emulsion increased select brain inflammatory cytokines and multicomponent lipid emulsions enriched with DHA and AA in parenteral lipids results in increased cortical DHA and improved body composition without affecting short term neurodevelopmental outcomes.

Timing of Prenatal Magnetic Resonance Imaging in the Assessment of Congenital Diaphragmatic Hernia.

INTRODUCTION: Fetal magnetic resonance imaging (MRI) has been used to stratify severity of congenital diaphragmatic hernia (CDH) after ultrasound diagnosis. The purpose of this study was to determine if timing of MRI influenced prediction of severity of outcome in CDH. METHODS: A single institution retrospective review of all CDH referred to our institution from February 2004 to May 2017 was performed. Patients were included if they underwent at least 2 fetal MRIs prior to delivery. Prenatal MRI indices including observed-to-expected total fetal lung volume (o/e TFLV) were evaluated. Indices were categorized by trimester, either 2nd (20-27 weeks gestation) or 3rd trimester (>28 weeks gestation) and further analyzed for outcome predictability. Primary outcomes were survival, extracorporeal membrane oxygenation (ECMO), and pulmonary hypertension (PAH). Student t test and logistic and linear regression were used for data analyses. RESULTS: Of 256 fetuses evaluated for CDH, 197 were further characterized by MRI with 57 having both an MRI in the 2nd and 3rd trimesters. There was an average of 9.95 weeks (±4.3) between the 1st and 2nd MRI. Second trimester o/e TFLV was the only independent predictor of survival by logistic regression (OR 0.890, p < 0.01). Third trimester MRI derived lung volumes were associated with, and independent predictors of, severity of PAH and need for ECMO. Interval TFLV growth was a strong predictor of PAH postnatally (OR 0.361, p < 0.01). Overall cohort survival was 79%. CONCLUSION: Accuracy of MRI lung volumes to predict outcomes is dependent on the -gestational age at the time of exam. While MRI lung volumes at either the 2nd or 3rd trimester are predictive of morbidity, 2nd trimester lung volumes strongly correlated with mortality.

Prematurity blunts the feeding-induced stimulation of translation initiation signaling and protein synthesis in muscle of neonatal piglets.

Postnatal growth of lean mass is commonly blunted in preterm infants and may contribute to short- and long-term morbidities. To determine whether preterm birth alters the protein anabolic response to feeding, piglets were delivered at term or preterm, and fractional protein synthesis rates (Ks) were measured at 3 days of age while fasted or after an enteral meal. Activation of signaling pathways that regulate protein synthesis and degradation were determined. Relative body weight gain was lower in preterm than in term. Gestational age at birth (GAB) did not alter fasting plasma glucose or insulin, but when fed, plasma insulin and glucose rose more slowly, and reached peak value later, in preterm than in term. Feeding increased Ks in longissimus dorsi (LD) and gastrocnemius muscles, heart, pancreas, and kidney in both GAB groups, but the response was blunted in preterm. In diaphragm, lung, jejunum, and brain, feeding increased Ks regardless of GAB. Liver Ks was greater in preterm than term and increased with feeding regardless of GAB. In all tissues, changes in 4EBP1, S6K1, and PKB phosphorylation paralleled changes in Ks. In LD, eIF4E·eIF4G complex formation, phosphorylation of TSC2, mTOR, and rpS6, and association of mammalian target of rapamycin (mTOR1) complex with RagA, RagC, and Rheb were increased by feeding and blunted by prematurity. There were no differences among groups in LD protein degradation markers. Our results demonstrate that preterm birth reduces weight gain and the protein synthetic response to feeding in muscle, pancreas, and kidney, and this is associated with blunted insulin- and/or amino acid-induced translation initiation signaling.

Differential action of TGR5 agonists on GLP-2 secretion and promotion of intestinal adaptation in a piglet short bowel model.

Enteroendocrine L cells and glucagon-like peptide 2 (GLP-2) secretion are activated in the intestinal adaptation process following bowel resection in patients with short bowel syndrome. We hypothesized that enteral activation of Takeda G protein-coupled receptor 5 (TGR5), expressed in enteroendocrine L cells, could augment endogenous GLP-2 secretion and the intestinal adaptation response. Our aim was to assess the efficacy of different TGR5 agonists to stimulate GLP-2 secretion and intestinal adaptation in a piglet short-bowel model. In study 1, parenterally fed neonatal pigs (n = 6/group) were gavaged with vehicle, olive extract (OE; 10 or 50 mg/kg), or ursolic acid (UA; 10 mg/kg), and plasma GLP-2 was measured for 6 h. In study 2, neonatal pigs (n = 6-8/group) were subjected to transection or 80% mid-small intestine resection and, after 2 days, assigned to treatments for 10 days as follows: 1) transection + vehicle (sham), 2) resection + vehicle (SBS), 3) resection + 30 mg UA (SBS + UA), and 4) resection + 180 mg/kg OE (SBS + OE). We measured plasma GLP-2, intestinal histology, cell proliferation, and gene expression, as well as whole body citrulline-arginine kinetics and bile acid profiles. In study 1, GLP-2 secretion was increased by UA and tended to be increased by OE. In study 2, SBS alone, but not additional treatment with either TGR5 agonist, resulted in increased mucosal thickness and crypt cell proliferation in remnant jejunum and ileum sections. SBS increased biliary and ileal concentration of bile acids and expression of inflammatory and farnesoid X receptor target genes, but these measures were suppressed by UA treatment. In conclusion, UA is an effective oral GLP-2 secretagogue in parenterally fed pigs but is not capable of augmenting GLP-2 secretion or the intestinal adaptation response after massive small bowel resection. NEW & NOTEWORTHY Therapeutic activation of endogenous glucagon-like peptide 2 (GLP-2) secretion is a promising strategy to improve intestinal adaptation in patients with short bowel syndrome. This study in neonatal pigs showed that oral supplementation with a selective Takeda G protein-coupled receptor 5 (TGR5) agonist is an effective approach to increase GLP-2 secretion. The results warrant further study to establish a more potent oral TGR5 agonist that can effectively improve intestinal adaptation in pediatric patients with SBS.

Fetal Surgery Decreases Anesthesia-Induced Neuroapoptosis in the Mid-Gestational Fetal Ovine Brain.

BACKGROUND: Studies demonstrating an association between anesthesia and brain cell death (neuroapoptosis) in young animals were performed without accompanying surgery. This study tests the hypothesis that fetal surgery decreases anesthesia-induced neuroapoptosis. MATERIALS AND METHODS: Seventy-day-pregnant ewes received 2% isoflurane for 1 h (low dose [LD]) or 4% for 3 h (high dose [HD]) with or without fetal surgery (S). Unexposed fetuses served as controls (C). Fetal brains were processed for neuroapoptosis using anti-caspase-3 antibodies. Data were analyzed using ANOVA. RESULTS: Twenty-eight fetal sheep were evaluated. Dentate gyrus neuroapoptosis was lower in the HD+S group (13.1 ± 3.76 × 105/mm3) than in the HD (19.1 ± 1.40 × 105/mm3, p = 0.012) and C groups (18.3 ± 3.55 × 105/mm3, p = 0.035). In the pyramidal layer of the hippocampus, neuroapoptosis was lower in the HD+S group (8.11 ± 4.88 × 105/mm3) than in the HD (14.8 ± 2.82 × 105/mm3, p = 0.006) and C groups (14.1 ± 4.54 × 105/mm3, p = 0.019). The LD+S group showed a trend towards a significant decrease in neuroapoptosis in the pyramidal layer (LD+S 7.51 ± 1.48 vs. LD 13.5 ± 1.87 vs. C 14.1 ± 4.54 × 105/mm3, p = 0.07) but not in the dentate gyrus. Fetal surgery did not affect neuroapoptosis in the frontal cortex or endplate. CONCLUSIONS: Fetal surgery decreases isoflurane-induced neuroapoptosis in the dentate gyrus and the pyramidal layer of mid-gestational fetal sheep. Long-term effects of these observations on memory and learning deserve further exploration.

Prematurity reduces citrulline-arginine-nitric oxide production and precedes the onset of necrotizing enterocolitis in piglets.

Necrotizing enterocolitis (NEC) is associated with low plasma arginine and vascular dysfunction. It is not clear whether low intestinal citrulline production, the precursor for arginine synthesis, occurs before and thus predisposes to NEC or if it results from tissue damage. This study was designed to test the hypothesis that whole body rates of citrulline, arginine, and nitric oxide synthesis are low in premature pigs and that they precede NEC. Piglets delivered by cesarean section at 103 days [preterm (PT)], 110 days [near-term (NT)], or 114 days [full-term (FT)] of gestation were given total parenteral nutrition and after 2 days orogastrically fed infant formula for 42 h to induce NEC. Citrulline and arginine fluxes were determined before and during the feeding protocol. Gross macroscopic and histological NEC scores and plasma fatty acid binding protein (iFABP) concentration were determined as indicators of NEC. Intestinal gene expression for enzymes of the arginine pathway were quantitated. A lower ( P < 0.05) survival rate was observed for PT (8/27) than for NT (9/9) and FT pigs (11/11). PT pigs had higher macroscopic gross ( P < 0.05) and histological NEC ( P < 0.05) scores and iFABP concentration ( P < 0.05) than pigs of more advanced gestational age. PT pigs had lower citrulline production and arginine fluxes ( P < 0.05) throughout and a reduced gene expression in genes of the citrulline-arginine pathway. In summary, intestinal enzyme expression and whole body citrulline and arginine fluxes were reduced in PT pigs compared with animals of more advance gestational age and preceded the development of NEC. NEW & NOTEWORTHY Arginine supplementation prevents necrotizing enterocolitis (NEC), the most common gastrointestinal emergency of prematurity. Citrulline (precursor for arginine) production is reduced during NEC, and this is believed to be a consequence of intestinal damage. In a swine model of NEC, we show that intestinal gene expression of the enzymes for citrulline production and whole body citrulline and arginine fluxes are reduced and precede the onset of NEC in premature pigs. Reduced citrulline production during prematurity may be a predisposition to NEC.

Postchallenge administration of brincidofovir protects healthy and immune-deficient mice reconstituted with limited numbers of T cells from lethal challenge with IHD-J-Luc vaccinia virus.

UNLABELLED: Protection from lethality by postchallenge administration of brincidofovir (BCV, CMX001) was studied in normal and immune-deficient (nude, nu/nu) BALB/c mice infected with vaccinia virus (VACV). Whole-body bioluminescence imaging was used to record total fluxes in the nasal cavity, lungs, spleen, and liver and to enumerate pox lesions on tails of mice infected via the intranasal route with 10(5) PFU of recombinant IHD-J-Luc VACV expressing luciferase. Areas under the flux curve (AUCs) were calculated for individual mice to assess viral loads. A three-dose regimen of 20 mg/kg BCV administered every 48 h starting either on day 1 or day 2 postchallenge protected 100% of mice. Initiating BCV treatment earlier was more efficient in reducing viral loads and in providing protection from pox lesion development. All BCV-treated mice that survived challenge were also protected from rechallenge with IHD-J-Luc or WRvFire VACV without additional treatment. In immune-deficient mice, BCV protected animals from lethality and reduced viral loads while animals were on the drug. Viral recrudescence occurred within 4 to 9 days, and mice succumbed ∼10 to 20 days after treatment termination. Nude mice reconstituted with 10(5) T cells prior to challenge with 10(4) PFU of IHD-J-Luc and treated with BCV postchallenge survived the infection, cleared the virus from all organs, and survived rechallenge with 10(5) PFU of IHD-J-Luc VACV without additional BCV treatment. Together, these data suggest that BCV protects immunocompetent and partially T cell-reconstituted immune-deficient mice from lethality, reduces viral dissemination in organs, prevents pox lesion development, and permits generation of VACV-specific memory. IMPORTANCE: Mass vaccination is the primary element of the public health response to a smallpox outbreak. In addition to vaccination, however, antiviral drugs are required for individuals with uncertain exposure status to smallpox or for whom vaccination is contraindicated. Whole-body bioluminescence imaging was used to study the effect of brincidofovir (BCV) in normal and immune-deficient (nu/nu) mice infected with vaccinia virus, a model of smallpox. Postchallenge administration of 20 mg/kg BCV rescued normal and immune-deficient mice partially reconstituted with T cells from lethality and significantly reduced viral loads in organs. All BCV-treated mice that survived infection were protected from rechallenge without additional treatment. In immune-deficient mice, BCV extended survival. The data show that BCV controls viral replication at the site of challenge and reduces viral dissemination to internal organs, thus providing a shield for the developing adaptive immunity that clears the host of virus and builds virus-specific immunological memory.

Revisiting outcomes of right congenital diaphragmatic hernia.

BACKGROUND: Studies comparing outcomes of right- and left-sided congenital diaphragmatic hernia (R-CDH and L-CDH) have yielded conflicting results. We hypothesized that R-CDH is associated with higher short-term pulmonary morbidity than L-CDH. METHODS: We reviewed all CDH patients at a tertiary children's hospital over 10 y. In prenatally diagnosed CDH, the observed-to-expected total fetal lung volume and percentage liver herniation (%LH) were calculated using fetal magnetic resonance imaging-based measurements. Outcomes were compared in patients with isolated CDH. Patients were subsequently matched by %LH to compare outcomes. RESULTS: Of 189 CDH patients, 37 (20.1 %) were R-CDH and 147 (79.9%) were L-CDH. Those with R-CDH were prenatally diagnosed at a significantly lower rate (40.5% versus 73.5%; P < 0.001) and later gestational age (26.5 ± 7.7 versus 22.6 ± 5.65 wk; P = 0.062). There was no difference in observed-to-expected total fetal lung volume between those with R-CDH and L-CDH (30.2 ± 11.1% versus 33.1 ± 14.2%; P = 0.471). Fetuses with R-CDH had a higher %LH than those with L-CDH (37.5 ± 14.1% versus 18.6 ± 12.2%; P < 0.001). Patients with isolated R-CDH had a higher need for extracorporeal membrane oxygenation than L-CDH (48% versus 27%; P = 0.055). There was no difference in duration of tracheal intubation, hospital stay, need for supplemental oxygen at 30-d of life or 6-mo mortality between groups. There was no difference in mortality and pulmonary morbidity when patients were matched by %LH. CONCLUSIONS: Compared to those with L-CDH, fetuses with R-CDH are less likely to be diagnosed prenatally and have a higher need for extracorporeal membrane oxygenation. The sidedness of the hernia defect was not associated with differences in short-term pulmonary morbidity in this large, contemporary single-institution experience of neonates with CDH.

Effects of postchallenge administration of ST-246 on dissemination of IHD-J-Luc vaccinia virus in normal mice and in immune-deficient mice reconstituted with T cells.

Whole-body bioimaging was used to study dissemination of vaccinia virus (VACV) in normal and in immune deficient (nu(-)/nu(-)) mice protected from lethality by postchallenge administration of ST-246. Total fluxes were recorded in the liver, spleen, lungs, and nasal cavities of live mice after intranasal infection with a recombinant IHD-J-Luc VACV expressing luciferase. Areas under the flux curve were calculated for individual mice to assess viral loads. Treatment for 2 to 5 days of normal BALB/c mice with ST-246 at 100 mg/kg starting 24 h postchallenge conferred 100% protection and reduced viral loads in four organs compared to control mice. Mice also survived after 5 days of treatment with ST-246 at 30 mg/kg, and yet the viral loads and poxes were higher in these mice compared to 100-mg/kg treatment group. Nude mice were not protected by ST-246 alone or by 10 million adoptively transferred T cells. In contrast, nude mice that received T cells and 7-day treatment with ST-246 survived infection and exhibited reduced viral loads compared to nonreconstituted and ST-246-treated mice after ST-246 was stopped. Similar protection of nude mice was achieved using adoptively transferred 1.0 and 0.1 million, but not 0.01 million, purified T cells or CD4(+) or CD8(+) T cells in conjunction with ST-246 treatment. These data suggest that ST-246 protects immunocompetent mice from lethality and reduces viral dissemination in internal organs and poxvirus lesions. Furthermore, immune-deficient animals with partial T cell reconstitution can control virus replication after a course of ST-246 and survive lethal vaccinia virus challenge.

Validating a Conceptual Model on Topical Fluoride Hesitancy With Latino Parents.

Fluoride hesitancy is a growing public health challenge and interventions to address it may need to be tailored for minoritized subgroups to address oral health inequities. The goals of this qualitative study were to investigate the extent to which an existing conceptual model on topical fluoride hesitancy is applicable to Latino parents and whether applicability differed between Spanish-speaking Latino (SL) and English-speaking Latino (EL) parents. We conducted semi-structured one-on-one interviews with non-Latino English-speaking parents (N = 50), SL parents (n = 8), and EL parents (n = 8). We coded the transcripts deductively and compared our findings both qualitatively and quantitatively to an existing model on topical fluoride hesitancy comprising 21 categories classified into six domains. We compared frequencies across model domains and categories for Latino versus non-Latino parents as well as for SL versus EL parents. Latino parents were represented across all six domains and 21 categories of the conceptual model. Comparing Latino and non-Latino parents, representation was similar across Domains 1 to 3 (necessity, chemicals, and harm); Latino parents were more highly represented in Domains 4 to 6 (uncertainty, pressure, and choice) compared with non-Latino parents. A larger proportion of EL parents thought a healthy diet was more important than fluoride (Category 1d) and a larger proportion of SL parents felt they did not know enough about fluoride (Category 4a). An existing conceptual model on topical fluoride hesitancy was generally a good fit for SL and EL parents. However, differential representation across model categories suggests that fluoride-related communication and intervention approaches may need to be tailored to Latino parents based on language preference.

Initial development of the Sugar-Sweetened Fruit Drink Questionnaire for examining beliefs, knowledge, and behaviors in an intervention to reduce sugar-sweetened fruit drink intake in Alaska Native children.

OBJECTIVE: Alaska Native children may be at increased risk for dental caries because of added sugar intake from sugar-sweetened fruit drinks. This study describes development of a questionnaire to (a) assess Alaska Native caregivers' beliefs, knowledge, and behaviors regarding sugar-sweetened fruit drinks, and (b) describe behavior changes within a community-based intervention. METHODS: Questionnaire development was conducted in three phases with Yup'ik Alaska Native caregivers in Southwest Alaska: (1) initial selection and adaptation of questionnaire items; (2) cognitive testing; and (3) data collection. The Sugar-Sweetened Fruit Drink Questionnaire (SFDQ) contains 31 culturally-tailored items across six areas: beliefs/values, environment/skills, knowledge, motivation, self-efficacy, and behaviors. RESULTS: Eighty-one percent of caregivers gave their children sugar-sweetened fruit drinks. Motivations included: what they grew up with (52%), few other options (46%), makes child happy (46%), healthier than soda (45%), and others in community drink them (42%). On average, 93% of caregivers believed drinking a lot of sugar-sweetened fruit drinks leads to cavities in children and caregivers agreed (mean 4.1 on 5-point scale, 5 = strongly agree) it is important to limit sugar-sweetened fruit drinks. Among a sub-sample of respondents (n = 20), we found low to moderate temporal stability in some SFDQ items over a 10-14 day period, indicating respondent ambivalence and/or uncertainty. CONCLUSIONS: Using community-based participatory research methods, we developed a culturally tailored exploratory questionnaire that will be used to describe changes in caregiver knowledge, beliefs, attitudes, self-efficacy, and behavior within a planned intervention to reduce sugar-sweetened fruit drink intake in Alaska Native children.

A Qualitative Assessment of Factors Influencing Fluoride-Hesitant Parents' Trust of Dentists.

PURPOSE: The purpose of this study was to use fluoride-hesitant parents as a model to identify the factors that erode versus build trust in their child's dentists. METHODS: A qualitative study was conducted using a semi-structured interview guide with fluoride-hesitant parents recruited from two dental clinics and through snowball sampling. A content analysis was performed to identify factors that erode versus build parents' trust in their child's dentist. RESULTS: Of the 56 parents interviewed, most were female (91.1 percent) and white (57.1 percent) and had a mean age of 41±9.7 (standard deviation) years. Factors identified included five that erode trust (having trust violated previously, sensing discrepancies, getting pushed to accept fluoride, feeling dismissed, and sensing bias) and four that build trust (being treated as an individual, having a dentist who communicates, feeling supported and respected, and having a choice). CONCLUSIONS: Dentists' understanding of the factors that erode and build trust with parents could help providers develop patient-centered communication strategies.

Qualitative evaluation of the pre-implementation phase of a rural dental clinic co-located within a health center in the Pacific Northwest of the United States.

OBJECTIVE: The development of a dental clinic within an existing Rural Health Clinic (RHC) was proposed to improve access to dental care for Medicaid enrollees in Washington. This qualitative study assessed the implementation of a co-located dental clinic in a rural community during the pre-implementation phase. Additionally, we sought to determine the needs and expectations of community members living in this rural Washington county. METHODS: This study took place in Jefferson County, Washington, a Dental Health Professional Shortage Area. Semi-structured interviews were conducted with 42 participants, consisting of administrators (n = 9), health providers (n = 9) and community members (n = 24). Administrators and health providers were interviewed by phone. Community members were interviewed in-person at Jefferson Healthcare primary care clinics or by phone. Interview data were deductively coded, and thematic analysis with a hybrid inductive-deductive approach was used to analyse coded data. RESULTS: Five themes were identified regarding local needs and expectations: dental care as a major need in the community, persisting barriers to dental care access, expecting more than a 'Medicaid experience', visions for a clinic that serves the community, and solutions outside the clinic to improve community oral health. CONCLUSIONS: By improving access to dental care, a co-located dental clinic is helping to address general dental care needs in rural communities. Policy-level solutions that address housing and food insecurity, improve public transportation, and retain and expand low-income adult Medicaid dental benefits may be needed to overcome persisting barriers to oral health.

A conceptual model on caregivers' hesitancy of topical fluoride for their children.

BACKGROUND: Topical fluoride hesitancy is a well-documented and growing public health problem. Despite extensive evidence that topical fluoride is safe and prevents tooth decay, an increasing number of caregivers are hesitant about their children receiving topical fluoride, leading to challenges in clinical settings where caregivers refuse preventive care. PURPOSE: To explore the determinants of topical fluoride hesitancy for caregivers with dependent children. METHODS: In this qualitative study, we interviewed 56 fluoride-hesitant caregivers to develop an inductive conceptual model of reasons why caregivers are hesitant. RESULTS: The core construct of the conceptual model of topical fluoride hesitancy centered on caregivers "wanting to protect and not mess up their child". Six domains comprised this core construct: thinking topical fluoride is unnecessary, wanting to keep chemicals out of my child's body, thinking fluoride is harmful, thinking there is too much uncertainty about fluoride, feeling pressured to get topical fluoride, and feeling fluoride should be a choice. CONCLUSIONS: Topical fluoride hesitancy is complex and multifactorial. Study findings provide insight for future efforts to understand and optimize caregivers' preventive care decision making.

GDE6 promotes progenitor identity in the vertebrate neural tube.

The generation of neurons in the central nervous system is a complex, stepwise process necessitating the coordinated activity of mitotic progenitors known as radial glia. Following neural tube closure, radial glia undergo a period of active proliferation to rapidly expand their population, creating a densely packed neurepithelium. Simultaneously, radial glia positioned across the neural tube are uniquely specified to produce diverse neuronal sub-types. Although these cellular dynamics are well studied, the molecular mechanisms governing them are poorly understood. The six-transmembrane Glycerophosphodiester Phosphodiesterase proteins (GDE2, GDE3, and GDE6) comprise a family of cell-surface enzymes expressed in the embryonic nervous system. GDE proteins can release Glycosylphosphatidylinositol-anchored proteins from the cell surface via cleavage of their lipid anchor. GDE2 has established roles in motor neuron differentiation and oligodendrocyte maturation, and GDE3 regulates oligodendrocyte precursor cell proliferation. Here, we describe a role for GDE6 in early neural tube development. Using RNAscope, we show that Gde6 mRNA is expressed by ventricular zone progenitors in the caudal neural tube. Utilizing in-ovo electroporation, we show that GDE6 overexpression promotes neural tube hyperplasia and ectopic growths of the neurepithelium. At later stages, electroporated embryos exhibit an expansion of the ventral patterning domains accompanied by reduced cross-repression. Ultimately, electroporated embryos fail to produce the full complement of post-mitotic motor neurons. Our findings indicate that GDE6 overexpression significantly affects radial glia function and positions GDE6 as a complementary factor to GDE2 during neurogenesis.