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To evaluate the association between capillary refill time (CRT) measured by a medical device and sepsis among patients presenting to the Emergency Department (ED). This prospective observational study enrolled adult and pediatric patients during ED triage when sepsis was considered a potential diagnosis by the triage nurse. Patients were enrolled at an academic medical center between December 2020 and June 2022. CRT was measured by a research assistant using an investigational medical device. The outcomes included sepsis and septic shock defined using sep-3 criteria, septic shock defined as IV antibiotics and a vasopressor requirement, ICU admission, and hospital mortality. Other measures included patient demographics and vital signs at ED triage. We evaluated univariate associations between CRT and sepsis outcomes. We enrolled 563 patients in the study, 48 met Sep-3 criteria, 5 met Sep-3 shock criteria, and 11 met prior septic shock criteria (IV antibiotics and vasopressors to maintain mean arterial pressure of 65). Sixteen patients were admitted to the ICU. The mean age was 49.1 years, and 51% of the cohort was female. The device measured CRT was significantly associated with the diagnosis of sepsis by sep-3 criteria (OR 1.23, 95% CI 1.06–1-43), septic shock by sep-3 criteria (OR 1.57, 95% CI 1.02–2.40), and septic shock defined as receipt of IV antibiotics and a vasopressor requirement (OR 1.37, 95% CI 1.03–1.82). Patients with CRT >3.5 s measured by the DCR device had an odds ratio of 4.67 (95%CI 1.31–16.1) of septic shock (prior definition), and an odds ratio of 3.97 (95% CI 1.99–7.92) of ICU admission, supporting the potential for the 3.5-s cutoff of the DCR measurement. CRT measured by a medical device at ED triage was associated with the diagnosis of sepsis. Objective CRT measurement using a medical device may be a relatively simple way to improve sepsis diagnosis during ED triage. [ABSTRACT FROM AUTHOR]

Pediatric mental health presentations continue to increase across the US. These patients often board for significant periods of time and may require more resources than other acute non-mental health patients. This has important implications for the overall function of the emergency department (ED) as well as care of all ED patients. This study evaluated a policy developed to allow for inpatient hospital admission when 30% of the ED was occupied by boarding patients at a tertiary care children's hospital. We found an increase in the number of patients for whom this policy applied, and increased days/month this policy was executed over time. There was an increase in the average ED LOS and left without being seen rate during this time which we hypothesize would have been higher without this policy. A hospital policy allowing mental health patients to be admitted to the inpatient hospital once stabilized has the potential to improve ED flow and functionality. [ABSTRACT FROM AUTHOR]

Background & Aims We estimated the accuracy of FibroScan vibration-controlled transient elastography controlled attenuation parameter (CAP) and liver stiffness measurement (LSMs) in assessing steatosis and fibrosis in patients with suspected nonalcoholic liver disease (NAFLD). Methods We collected data from 450 consecutive adults who underwent liver biopsy analysis for suspected NAFLD at 7 centers in the United Kingdom from March 2014 through January 2017. FibroScan examinations with M or XL probe were completed within the 2 weeks of the biopsy analysis (404 had a valid examination). The biopsies were scored by 2 blinded expert pathologists according to nonalcoholic steatohepatitis clinical research network criteria. Diagnostic accuracy was estimated using the area under the receiver operating characteristic curves (AUROCs) for the categories of steatosis and fibrosis. We assessed effects of disease prevalence on positive and negative predictive values. For LSM, the effects of histological parameters and probe type were appraised using multivariable analysis. Results Using biopsy analysis as the reference standard, we found that CAP identified patients with steatosis with an AUROC of 0.87 (95% confidence interval [CI] 0.82–0.92) for S≥S1, 0.77 (95% CI 0.71–0.82) for S≥S2, and 0.70 (95% CI 0.64–0.75) for S=S3. Youden cutoff values for S≥S1, S≥S2, and S≥S3 were 302 dB/m, 331 dB/m, and 337 dB/m, respectively. LSM identified patients with fibrosis with AUROCs of 0.77 (95% CI 0.72–0.82) for F≥F2, 0.80 (95% CI 0.75–0.84) for F≥F3, and 0.89 (95% CI 0.84–0.93) for F=F4. Youden cutoff values for F≥F2, F≥F3, and F=F4 were 8.2 kPa, 9.7 kPa, and 13.6 kPa, respectively. Applying the optimal cutoff values, determined from this cohort, to populations of lower fibrosis prevalence increased negative predictive values and reduced positive predictive values. Multivariable analysis found that the only parameter that significantly affected LSMs was fibrosis stage (P <10–16); we found no association with steatosis or probe type. Conclusions In a prospective analysis of patients with NAFLD, we found CAP and LSM by FibroScan to assess liver steatosis and fibrosis, respectively, with AUROC values ranging from 0.70 to 0.89. Probe type and steatosis did not affect LSM. Study registration: ClinicalTrials.gov Identifier: NCT01985009. Graphical abstract [ABSTRACT FROM AUTHOR]

Background: Migraine headaches are a common reason for pediatric emergency department (ED) visits. Small studies suggest the potential efficacy of sub-anesthetic doses of propofol for migraine with a favorable side effect profile and potentially decreased length of stay (LOS).Objective: The objective of this study was to compare the efficacy of low-dose propofol (LDP) to standard therapy (ST) in pediatric migraine treatment.Methods: We conducted a prospective, pragmatic randomized controlled trial from April 2014 through June 2016 in the ED at two pediatric hospitals. Patients aged 7-19 years were eligible if they were diagnosed with migraine by the emergency physician and had a presenting visual analog pain score (VAS) of 6-10. Primary outcome was the percent of pain reduction. Secondary outcomes were ED LOS, 24-h rebound headache, return visits to the ED, and adverse reactions.Results: Seventy-four patients were enrolled, but 8 were excluded, leaving 66 patients in the final analysis (36 ST, 30 LDP). Pain reduction was 59% for ST and 51% for LDP (p = 0.34) with 72.2% vs. 73.3% achieving a VAS ≤ 4 with initial therapy (p = 0.92). There was a nonsignificant trend toward shorter median LOS from drug administration to final disposition favoring propofol (79 min vs. 111 min; p = 0.09). Rebound headache was significantly more common in the ST vs. LDP group (66.7% vs. 25.0%; p = 0.01).Conclusions: LDP did not achieve better pain reduction than ST, however, LDP was associated with significantly fewer rebound headaches and a nonsignificant trend toward shorter median LOS from drug administration to disposition. [ABSTRACT FROM AUTHOR]

Adolescent ingestions are common reasons for calls to poison centers in United States. As opposed to younger children who mostly have unintentional exposures, adolescent ingestions often result from intentional use. This manuscript reviews recent reports on adolescent ingestions related to intentional abuse, self-harm, and use of opioid medications. [ABSTRACT FROM AUTHOR]

Blood and blood-component therapy triggers immunological reactions in recipients. Transfusion-related immunomodulation [TRIM] is an important complex biological immune reaction to transfusion culminating in immunosuppression. The mechanisms underlying TRIM include the presence of residual leukocytes and apoptotic cells, the transfusion of immunosuppressive cytokines either present in donor components or generated during blood processing, the transfer of metabolically active growth factor-loaded microparticles and extracellular vesicles and the presence of free hemoglobin or extracellular vesicle-bound hemoglobin. TRIM variables include donor-specific factors as well as processing variables. TRIM may explain, at least in part, the controversial negative clinical outcomes observed in cancer patients receiving transfusion in the context of curative-intent surgeries. The use of novel technologies including metabolomics and proteomics on stored blood may pave the way for a deeper understanding of TRIM in general and its impact on cancer progression. [ABSTRACT FROM AUTHOR]

Purpose Suicide attempts by adolescents most commonly involve the overdose of medications. To date, there has been little information on the over-the-counter or prescription medicines that adolescents ingest for self-harm. Identification of medications chosen in suicide attempts may help guide anticipatory guidance to parents by primary care providers and Poison Centers in prevention programs. Methods This was a retrospective observational study using the American Association of Poison Control Center's National Poison Data System. Data were collected on patients aged 13–19 years old at the time of their substance ingestion, between the years 2004 and 2013 and that were coded as reason for ingestion of “intentional-suspected suicide.” Results During the 10-year study period, there were 390,560 poison center calls for intentional-suspected suicide in the United States between 2004 and 2013, accounting for 80.3% of all “intentional” ingestion calls in the adolescent population. Over the entire age range, the most common substance ingested included acetaminophen (10.9%), ibuprofen (9%), selective serotonin reuptake inhibitors (7.7%), atypical antipsychotic (6%), and antihistamines (5%). The most common medications coded as resulting in major clinical effects or death were antidepressants and atypical antipsychotics. Conclusions Adolescent ingestion choices for suicide attempts have remained relatively consistent over the past 10 years. However, there was a recent decrease in selective serotonin reuptake inhibitor ingestions. The most common medications used in an overdose attempt were ibuprofen and acetaminophen. Further preventative efforts are needed in this at-risk population from multiple providers at various levels. [ABSTRACT FROM AUTHOR]

Objective: To describe the inpatient management of pediatric migraine and the association between specific medications and hospital length of stay (LOS).Study Design: Historical cohort study review of patients age <19 years of age admitted to a single tertiary care children's hospital between 2010 and 2015 for treatment of migraine headache.Results: The cohort consisted of 58 encounters with an average patient age of 14.3 years (SD 3.2 years) with a female predominance (62%). The mean number of inpatient medications received by patients was 3 (range 1-7), with dopamine antagonists and dihydroergotamine used most commonly (67% and 59% of encounters, respectively). The average LOS was 56 hours (95% CI 48.2-63.2) and did not vary by medication received, although patients who received an opioid had a significantly longer LOS (79.2 vs 47.9 hours respectively; P < .001).Conclusions: Children admitted to the hospital for treatment of migraine headache frequently require a large number of medications over an average hospital LOS of more than 2 days without apparent differences based on medication received other than prolonged stays for subjects who received opioids. [ABSTRACT FROM AUTHOR]

Background: Opioid abuse is a public health epidemic in the United States. Much literature has focused on the prescribing practices of physicians and opioid misuse by adults. However, there are limited data on the effect of opioid prescriptions on adolescent recreational ingestion of these medications.Objectives: The objective of this study was to assess for a relationship between opioid prescribing practices across the United States and adolescent opioid ingestion calls to poison centers.Methods: This was an observational study using the National Poison Data System. The study population consisted of poison center calls regarding adolescents between 2005 and 2010 in the database with a coding of "intentional abuse" and an opioid ingestion. National opioid prescription estimates were generated using nationally representative outpatient and inpatient databases.Results: There were 4186 adolescent opioid ingestion calls during the study period. There was a general increase between 2005 and 2010 in both teen opioid abuse calls (617 in 2005 to 782 in 2010) and national opioid prescriptions (approximately 78 million in 2005 to 108 million in 2010). For each opioid prescription increase per 100 persons per year, the annual teen opioid abuse calls increased by 1.8% (95% confidence interval 0.9-2.8%), equivalent to an absolute increase of about 0.04 to 0.05 calls per 100,000 teens annually.Conclusions: There appears to be an association between opioid prescriptions nationally and poison center calls for adolescent opioid ingestions. This is particularly important in this patient population because of impulsivity and early exposure to substance abuse. Providers should be aware of the nonmedical use of opioids by adolescents and educate patients accordingly. [ABSTRACT FROM AUTHOR]

This article examines two multimodal compositions produced with the support of a multiliteracy center. Each case involves multiple people, technologies, and resources. Distribution and emergence —two concepts borrowed from complex systems theory—help us understand the distinctive nature of the composing practices exemplified by these two cases. More specifically, the composing practices described here can be understood as examples of Pea's (1993) “distributed intelligence” and Lindquist, Hart-Davidson, and Grabill's (2010) “distributed invention.” These two examples prompt me to hypothesize about the way multiliteracy centers can maximize their potential to facilitate distributed and emergent composing practices. I suggest that multiliteracy centers should consider adopting policies, structures, and designs that facilitate connections, support long visits, attend to affective dimensions of relationships, and encourage play. [ABSTRACT FROM AUTHOR]

Background: Headaches are common in the pediatric population, and increase in prevalence with age. The abortive medications currently used have a number of potential side effects. Sodium valproate (VPA) has been shown to be effective for acute treatment in the adult population, but no data exist in the pediatric population.Objective: The objective of this study was to evaluate the effectiveness of VPA for acute pediatric headache in the emergency department.Methods: This was a retrospective case series of all patients <19 years of age treated in the pediatric emergency department (PED) at two tertiary care pediatric hospitals and with a final diagnosis of migraine or headache who received parenteral VPA. Data collected included patient demographics, pain reduction, length of stay, and final disposition.Results: From July 2010 to February 2014, there were 16 patients who received VPA for acute headache in the PED; 4 were excluded. Eighty-three percent were discharged home. Mean length of stay in the PED before VPA was 395 min, and 120 min after VPA administration. Patients achieved a 17% mean pain score reduction before VPA and approximately an additional 40% mean pain reduction after VPA infusion.Conclusions: VPA appears to be an effective agent for acute pediatric headache in this small series. Patients responded well to VPA in a relatively short amount of time. Further studies are needed to evaluate its effectiveness in combination with other first-line medications or as a single agent. [ABSTRACT FROM AUTHOR]

Background & Aims Hepatitis C virus (HCV) associates with lipoproteins to form “lipoviral particles” (LVPs) that can facilitate viral entry into hepatocytes. Initial attachment occurs via heparan sulphate proteoglycans and low-density lipoprotein receptor (LDLR); CD81 then mediates a post-attachment event. Proprotein convertase subtilisin kexin type 9 (PCSK9) enhances the degradation of the LDLR and modulates liver CD81 levels. We measured LVP and PCSK9 in patients chronically infected with HCV genotype (G)3. PCSK9 concentrations were also measured in HCV-G1 to indirectly examine the role of LDLR in LVP clearance. Methods HCV RNA, LVP ( d <1.07 g/ml) and non-LVP ( d >1.07 g/ml) fractions, were quantified in patients with HCV-G3 (n = 39) by real time RT-PCR and LVP ratios (LVPr; LVP/(LVP + non-LVP)) were calculated. Insulin resistance (IR) was assessed using the homeostasis model assessment of IR (HOMA-IR). Plasma PCSK9 concentrations were measured by ELISA in HCV-G3 and HCV-G1 (n = 51). Results In HCV-G3 LVP load correlated inversely with HDL-C (r = −0.421; p = 0.008), and apoE (r = −0.428; p = 0.013). The LVPr varied more than 35-fold (median 0.286; range 0.027 to 0.969); PCSK9 was the strongest negative predictor of LVPr (R 2 = 16.2%; p = 0.012). HOMA-IR was not associated with LVP load or LVPr. PCSK9 concentrations were significantly lower in HCV-G3 compared to HCV-G1 ( p <0.001). PCSK9 did not correlate with LDL-C in HCV-G3 or G1. Conclusions The inverse correlation of LVP with apoE in HCV-G3, compared to the reverse in HCV-G1 suggests HCV genotype-specific differences in apoE mediated viral entry. Lower PCSK9 and LDL concentrations imply upregulated LDLR activity in HCV-G3. [ABSTRACT FROM AUTHOR]

Objective: To describe the variability in diagnostic testing and treatment of headaches in children presenting to the emergency department (ED) with use of a nationally representative sample. Study design: This was a retrospective cohort study using the National Hospital Ambulatory Medical Care Survey during 2005-2009. To assess the use of evidence-based treatment, we analyzed all patients <18 years old in 2 groups: (1) primary discharge diagnosis of headache and (2) discharge diagnosis of migraine. Results: Four hundred forty-eight sampled ED visits from 2005-2009 represented a national estimate of 1.7 million visits with a discharge diagnosis of headache. A total of 95 visits represented a national estimate of 340 000 visits with a discharge diagnosis of migraine. Median age was 13.1 years and 60% were female with a primary diagnosis of headache. In this group, neuroimaging was performed in 37% of patients and 39% underwent blood tests. Nonsteroidal anti-inflammatory drugs and opioids were most commonly used for treatment. For children with a discharge diagnosis of migraine, approximately 40% of patients received non–evidence-based treatment, most commonly with opioid medications, and >20% of patients underwent computed tomography scanning. Conclusions: There is significant variability in the evaluation and treatment of pediatric headache in the ED. Despite evidence-based clinical guidelines for migraine headache, a large number of children continue to receive opioids and ionizing radiation in the ED. [Copyright &y& Elsevier]

Abstract: Context: Persistent pain after treatment for breast cancer (PPBCT) is a common side effect of breast cancer treatment, with prevalence as high as 50%. It is predominantly a neuropathic condition. Objectives: The aim of this cross-sectional, questionnaire-based study was to examine the emotional characteristics of patients with PPBCT in long-term breast cancer patients. A secondary objective was to characterize the risk factors and severity of that pain. Methods: From March 1, 2010 to April 9, 2010, long-term follow-up patients were invited to complete a questionnaire. This recorded their surgical and demographic data and ascertained whether they had PPBCT. If the patient had pain, she completed a range of validated self-report questionnaires and questions about the nature of the pain, including a visual analogue scale. Results: One hundred eleven patients completed the questionnaire; 33 (29.7%) patients reported chronic pain at a median time of 64 months postoperatively (interquartile range 54.25). Patients with persistent pain were not significantly more anxious (t105 =−0.369, P =0.713) or depressed (t105 =0.713, P =0.507) than patients without pain. Patients with constant pain compared with intermittent pain were significantly more anxious (t25 =−3.460, P =0.002). Preoperative pain conferred a fivefold increased risk of PPBCT (odds ratio [OR]=5.17, 95% confidence interval [CI]=1.79–14.97, P =0.002); chemotherapy conferred a threefold increased risk (OR=3.004, 95% CI=1.22–7.40, P =0.017). Conclusion: We have shown significant numbers of patients suffer from PPBCT. At a median time of 64.5 months, women with pain are not significantly more anxious or depressed than women without pain. Preoperative pain and chemotherapy have been highlighted as risk factors. [Copyright &y& Elsevier]

Background & Aims: Hepatitis C virus (HCV) interacts with apolipoproteins B (apoB) and E (apoE) to form infectious lipoviral particles (LVP). Response to peginterferon is influenced by interferon-stimulated genes (ISGs) and IL28B genotype. LDL cholesterol (LDL-C) also predicts interferon response, therefore we hypothesised that LVP may also be associated with interferon sensitivity. Methods: LVP (HCV RNA density ⩽1.07g/ml) and ‘non-LVP’ (d >1.07g/ml) were measured in 72 fasted HCV-G1 patients by iodixanol density gradient ultracentrifugation and the LVP ratio (LVP/LVP+non-LVP) was calculated. Fasting lipid profiles and apolipoproteins B and E were measured. Interferon-gamma-inducible protein 10kDa (IP10), a marker of ISGs, was measured by ELISA. Results: Complete early virological response (EVR) was associated with lower apoE (23.9±7.7 vs. 36.1±15.3mg/L, p =0.013), higher LDL-C (p =0.039) and lower LVP ratios (p =0.022) compared to null responders. In multivariate linear regression analysis, apoE was independently associated with LVP (R2 19.5%, p =0.003) and LVP ratio (p =0.042), and negatively with LDL-C (p <0.001). IP10 was significantly associated with ApoB (p =0.001) and liver stiffness (p =0.032). IL28B rs12979860 CC was associated with complete EVR (p =0.044), low apoE (CC 28±11 vs. CT/TT 35±13mg/L, p =0.048) and higher non-LVP (p =0.008). Logistic regression analysis indicated that patients with high LVP ratios were less likely to have EVR (odds ratio 0.01, p =0.018). Conclusions: In HCV-G1, interferon sensitivity is characterised by low LVP ratios and low apoE levels in addition to higher LDL-C and IL28B rs12979860 CC. Null-response is associated with increased LVP ratio. The association of apoE and LVP with peginterferon treatment response suggests that lipid modulation is a potential target to modify interferon sensitivity. [Copyright &y& Elsevier]

Atherosclerosis has been described as a liver disease of the heart . The liver is the central regulatory organ of lipid pathways but since dyslipidaemias are major contributors to cardiovascular disease and type 2 diabetes rather than liver disease, research in this area has not been a major focus for hepatologists. Virus–host interaction is a continuous co-evolutionary process involving the host immune system and viral escape mechanisms . One of the strategies HCV has adopted to escape immune clearance and establish persistent infection is to make use of hepatic lipid pathways. This review aims to: [•] update the hepatologist on lipid metabolism [•] review the evidence that HCV exploits hepatic lipid pathways to its advantage [•] discuss approaches to targeting host lipid pathways as adjunctive therapy. [ABSTRACT FROM AUTHOR]

Background: Anomalous aortic origin of a coronary artery from the opposite sinus with an intramural course between the great arteries (AAOCA) is associated with ischemia and sudden cardiac death in children, and surgical unroofing has been used to alleviate that risk. Methods: The cardiology database was reviewed to identify all patients with AAOCA who underwent surgical unroofing 10 years. Results: From March 1999 to September 2009, 27 patients with a mean age of 12.6 ± 3.5 years (range, 4–20 years) had surgical unroofing of AAOCA of the left coronary from the right sinus (left AAOCA, 7/27, 26%) or of the right coronary from the left sinus (right AAOCA, 20/27, 74%). Of these, 26 had diagnoses made by transthoracic echocardiography. Symptoms included resuscitated sudden cardiac death in 3, syncope in 8, and chest pain in 4. No symptoms were present in 12 cases of serendipitous diagnosis. Unroofing of the intramural portion was successfully performed in all cases. A slitlike coronary orifice was described at surgical inspection in 12 patients, 7 of whom had right AAOCA and no symptoms. All patients after unroofing have patent coronary flow by Doppler and normal echocardiography and exercise treadmill testing at mean follow-up of 1.8 years. None have activity restrictions. Conclusions: AAOCA is frequently characterized by an intramural course, which can be reliably identified by echocardiography. This form can be safely repaired by unroofing the intramural segment without early morbidity. Symptoms of possible ischemia are common but not always correlated with coronary ostial findings at surgery. [ABSTRACT FROM AUTHOR]

Abstract: An array of new technologies has made it much easier for non-specialists to fabricate three-dimensional products ranging from clothes to plastic prototypes. This article explores the implications of these new developments for composition and rhetoric using a heuristic derived from earlier discussions of visual and multimodal rhetoric. Analysis of these discussions suggests that at least four kinds of arguments are made for new rhetorical modes: arguments from infrastructural accessibility, from rhetorical effectiveness, from cultural status, and from (de)specialization. Applying this schema to three-dimensional fabricated rhetoric reveals that three-dimensional rhetoric is increasingly available as an option to ordinary citizens, offers distinctive rhetorical opportunities, is valued by the broader culture outside the academy, and can be usefully understood through analytical frameworks regularly used by the field of composition and rhetoric. This article concludes that when placed in the hands of ordinary rhetors, three-dimensional rhetoric is potentially transformative and offers important cultural and political opportunities. By appropriating the rhetoric of fabricated objects, we can more effectively achieve the goals of equality and social justice. [ABSTRACT FROM AUTHOR]

Abstract: This article focuses on Ink, a Multiplayer Online Game (MOG) being developed at Michigan State University. The design of Ink reflects the developers’ understanding of writing pedagogy and rhetorical theory. Ink allows players to enter into complex rhetorical situations that include exigencies, audiences, and rhetorical purposes. The developers of Ink hope that placing players in these rhetorical situations will facilitate literacy learning while simultaneously providing a satisfying game experience. Players will hopefully learn while having fun. In order to test the effectiveness of Ink as a game and learning environment, the authors designed a small-scale preliminary study with a focus group of student playtesters. The study was designed to answer three fundamental questions: Will players write? Will players have fun? Will players learn? The study generated some evidence that the answer to all three questions is “yes.” [Copyright &y& Elsevier]

Objectives: To characterize the frequency of opioid prescribing for pediatric headache in both ambulatory and emergency department (ED) settings, including prescribing rates by provider type.Study Design: A retrospective cohort study of Washington State Medicaid beneficiaries, aged 7-17 years, with an ambulatory care or ED visit for headache between January 1, 2012, and September 30, 2015. The primary outcome was any opioid prescribed within 1 day of the visit.Results: A total of 51 720 visits were included, 83% outpatient and 17% ED. There was a predominance of female (63.2%) and adolescent (59.4%) patients, and 30.5% of encounters involved a pediatrician. An opioid was prescribed in 3.9% of ED and 1.0% of ambulatory care visits (P < .001). Pediatricians were less likely to prescribe opioids in both ED (-2.70 percentage point; 95% CI, -3.53 to -1.88) and ambulatory settings (-0.31 percentage point; 95% CI, -0.54 to -0.08; P < .001).Conclusions: Opioid prescribing rates for pediatric headache were low, but significant variation was observed by setting and provider specialty. We identified opioid prescribing by nonpediatricians as a potential target for quality improvement efforts. [ABSTRACT FROM AUTHOR]

Background: The assessment of capillary refill time (CRT) is a common physical examination technique. However, despite its importance and its widespread use, there is little standardization, which can lead to inaccurate assessments.Objective: In this article, we assessed how different physicians estimate CRT. We hypothesized that when different physicians are presented with the same recordings of CRT, clinicians will, on average, provide different CRT estimates.Methods: Using recordings of different fingertip compressions, physicians assessed and documented when capillary refill had returned to normal. Videos were recorded of the fingertips only, with no other identifying markers or subject characteristics provided. Videos were shown at one-quarter speed to allow time for recognition and response to the capillary refill. The primary outcome was physician estimates of CRT for each video recording.Results: An analysis of variance regression revealed significant differences in physician estimates of CRT when examining the same CRT videos from 34 subjects. Further regression analyses reveal the importance of controlling for the physician that is examining the patient when predicting a patient's CRT.Conclusions: Results indicate that some physicians gave, on average, slower CRT estimates, whereas others gave, on average, faster CRT estimates. Objective approaches and innovations in assessment of capillary refill have the potential to increase the diagnostic accuracy of this important clinical examination finding. [ABSTRACT FROM AUTHOR]

Background: Pediatric emergency department (PED) visits among children and adolescents with acute mental health needs have increased over the past decade with long wait times in the PED awaiting disposition.Objective: The objective of this study was to evaluate the effect of a new pediatric mental health liaison program with the hypothesis that this model reduces length of stay (LOS) and hospitalization rates among pediatric mental health patients.Methods: This was a pre- and postintervention retrospective study of the year prior to (June 2012-June 2013) and the year after (October 2013-October 2014) implementation of a new PED psychiatric team. All patients aged 1-18 years with a mental health International Classification of Diseases-9(th) Revision code were included. Patients who did not receive a Psychiatry consult in the PED were excluded.Results: There were 83 encounters in the year prior to and 129 encounters in the year after the implementation of the liaison program. There was an increase in the suicidality of mental health patients during this time. There was a significant decrease in mean PED LOS of 27% (95% confidence interval [CI] 0-46%; p = 0.05) from pre- to postintervention period. The decrease in the proportion of patients admitted/transferred to an inpatient psychiatric facility in the postintervention year was statistically significant (odds ratio 0.35; 95% CI 0.17-0.71; p < 0.01).Conclusions: The use of a dedicated child psychiatrist and mental health social worker to the PED results in significantly decreased LOS and need for admission without any change in return visit rate. Larger, multicenter studies are needed to confirm these findings. [ABSTRACT FROM AUTHOR]

Background & Aims: The physical association of hepatitis C virus (HCV) particles with lipoproteins in plasma results in distribution of HCV in a broad range of buoyant densities. This association is thought to increase virion infectivity by mediating cell entry via lipoprotein receptors. We sought to determine if factors that affect triglyceride-rich lipoprotein (TRL) metabolism alter the density and dynamics of HCV particles in the plasma of patients with chronic HCV infection. Methods: Fasting patients (n = 10) consumed a high-fat milkshake; plasma was collected and fractionated by density gradients. HCV- RNA was measured in the very-low-density fraction (VLDF, d < 1.025 g/mL) before and at 7 serial time points postprandially. Results: The amount of HCV RNA in the VLDF (HCVVLDF) increased a mean of 26-fold, peaking 180 minutes after the meal (P < .01). Quantification of HCV RNA throughout the density gradient fractions revealed that HCVVLDF rapidly disappeared, rather than migrating into the adjacent density fraction. Immuno-affinity separation of the VLDF, using antibodies that recognize apolipoprotein B–100 and not apolipoprotein B–48, showed that HCVVLDF is composed of chylomicron- and VLDL-associated HCV particles; peaking 120 and 180 minutes after the meal, respectively. Plasma from fasting HCV-infected patients mixed with uninfected plasma increased the quantity of HCVVLDF, compared with that mixed with phosphate-buffered saline, showing extracellular assembly of HCVVLDF. Conclusions: Dietary triglyceride alters the density and dynamics of HCV in plasma. The rapid clearance rate of HCVVLDF indicates that association with TRL is important for HCV infectivity. HCV particles, such as exchangeable apolipoproteins, appear to reassociate with TRLs in the vascular compartment. [ABSTRACT FROM AUTHOR]

We examined the efficacy and safety of seladelpar, a selective peroxisome proliferator-activated receptor-delta agonist, in adults with primary biliary cholangitis (PBC) at risk of disease progression (alkaline phosphatase [ALP] ≥1.67xupper limit of normal [ULN]) who were receiving or intolerant to ursodeoxycholic acid. In this 52-week, phase II, dose-ranging, open-label study, patients were randomized (1:1) to seladelpar 5 mg/day (n = 53) or 10 mg/day (n = 55) or assigned to 2 mg/day (n = 11; United Kingdom sites after interim analysis) for 12 weeks. Doses could then be uptitrated to 10 mg/day. The primary efficacy endpoint was ALP change from baseline to Week 8. Mean baseline ALP was 300, 345, and 295 U/L in the 2 mg, 5 mg, and 10 mg cohorts, respectively. Twenty-one percent of patients had cirrhosis, 71% had pruritus. At Week 8, mean ± standard error ALP reductions from baseline were 26 ± 2.8%, 33 ± 2.6%, and 41 ± 1.8% in the 2 mg (n = 11), 5 mg (n = 49), and 10 mg (n = 52) cohorts (all p ≤0.005), respectively. Responses were maintained or improved at Week 52, after dose escalation in 91% and 80% of the 2 mg and 5 mg cohorts, respectively. At Week 52, composite response (ALP <1.67xULN, ≥15% ALP decrease, and normal total bilirubin) rates were 64%, 53%, and 67%, and ALP normalization rates were 9%, 13%, and 33% in the 2 mg, 5 mg, and 10 mg cohorts, respectively. Pruritus visual analog scale score was decreased in the 5 mg and 10 mg cohorts. There were no treatment-related serious adverse events, and 4 patients discontinued due to adverse events. Seladelpar demonstrated robust, dose-dependent, clinically significant, and durable improvements in biochemical markers of cholestasis and inflammation in patients with PBC at risk of disease progression. Seladelpar appeared safe and well tolerated and was not associated with any increase in pruritus. NCT02955602 2016-002996-91 Current treatment options for patients living with primary biliary cholangitis (PBC) are not optimal due to inadequate effectiveness or undesirable side effects. Patients with PBC who took seladelpar, a new treatment being developed for PBC, at increasing doses (2, 5, or 10 mg/day) for 1 year had clinically significant, dose-dependent improvements in key liver tests. Treatment appeared safe and was not associated with any worsening in patient self-reported itch scores. [Display omitted] • Seladelpar (2, 5, 10 mg) was assessed in patients with primary biliary cholangitis. • ALP was dose-dependently reduced by 23% to 43% at Week 12. • ALP was normalized in 33% of patients in the 10 mg cohort at Week 52. • Up to 67% of patients met the composite ALP and bilirubin endpoint at Week 52. • Seladelpar was safe, with no treatment-related serious adverse events or deaths. [ABSTRACT FROM AUTHOR]

Objective: The p15INK4B tumor suppressor is frequently silenced by promoter hypermethylation in myelodysplastic syndrome and acute myeloid leukemia (AML). Clinically approved DNA methylation inhibitors, such as 5-aza-2''-deoxycytidine, can reverse p15INK4B promoter methylation, but widespread clinical use of these inhibitors is limited by their toxicity and instability in aqueous solution. The cytidine analog zebularine is a stable DNA methylation inhibitor that has minimal toxicity in vitro and in vivo. We evaluated zebularine effects on p15INK4B reactivation and cell growth in vitro to investigate a potential role for zebularine in treating myeloid malignancies. Methods: We examined the specific effects of zebularine on reexpression of transcriptionally silenced p15INK4B and its global effects on cell cycle and apoptosis in AML cell lines and primary patient samples. Results: Zebularine treatment of AML193, which has a densely methylated p15INK4B promoter, results in a dose-dependent increase in p15INK4B expression that correlates with CpG island promoter demethylation and enrichment of local histone acetylation. We observed enhanced p15INK4B induction following co-treatment with zebularine and the histone deacetylase inhibitor Trichostatin A. Zebularine inhibits cell proliferation, arrests cells at G2/M, and induces apoptosis at dosages that effectively demethylate the p15INK4B promoter. Zebularine treatment of KG-1 cells and AML patient blasts with hypermethylated p15INK4B promoters also reactivates p15INK4B reexpression and induces apoptosis. Conclusion: Zebularine is an effective inhibitor of p15INK4B methylation and cell growth in human AML in vitro. Our results extend the spectrum of zebularine effects to nonepithelial malignancies and provide a strong rationale for evaluating its clinical utility in the treatment of myeloid malignancies. [Copyright &y& Elsevier]

• About two thirds of caregivers intend to vaccinate their children against COVID-19. • Most common reason for acceptance was to protect the child. • Most common reason for refusal was the vaccine's novelty. • Child age, chronic illness, vaccination history affects willingness. • Caregiver gender, vaccination history, concern about infection affect willingness. More than 100 COVID-19 vaccine candidates are in development since the SARS-CoV-2 genetic sequence was published in January 2020. The uptake of a COVID-19 vaccine among children will be instrumental in limiting the spread of the disease as herd immunity may require vaccine coverage of up to 80% of the population. Prior history of pandemic vaccine coverage was as low as 40% among children in the United States during the 2009 H1N1 influenza pandemic. To investigate predictors associated with global caregivers' intent to vaccinate their children against COVID-19, when the vaccine becomes available. An international cross sectional survey of 1541 caregivers arriving with their children to 16 pediatric Emergency Departments (ED) across six countries from March 26 to May 31, 2020. 65% (n = 1005) of caregivers reported that they intend to vaccinate their child against COVID-19, once a vaccine is available. A univariate and subsequent multivariate analysis found that increased intended uptake was associated with children that were older, children with no chronic illness, when fathers completed the survey, children up-to-date on their vaccination schedule, recent history of vaccination against influenza, and caregivers concerned their child had COVID-19 at the time of survey completion in the ED. The most common reason reported by caregivers intending to vaccinate was to protect their child (62%), and the most common reason reported by caregivers refusing vaccination was the vaccine's novelty (52%). The majority of caregivers intend to vaccinate their children against COVID-19, though uptake will likely be associated with specific factors such as child and caregiver demographics and vaccination history. Public health strategies need to address barriers to uptake by providing evidence about an upcoming COVID-19 vaccine's safety and efficacy, highlighting the risks and consequences of infection in children, and educating caregivers on the role of vaccination. [ABSTRACT FROM AUTHOR]

Background & Aims Single nucleotide polymorphisms (SNPs) near the interferon lambda 3 (IFNL3, previously known as IL28B) region are the strongest baseline predictors of sustained virologic response (SVR) to pegylated interferon and ribavirin therapy in hepatitis C virus (HCV) genotype 1 infection. Whether IFNL3 SNPs influence treatment response in genotype 2 and 3 (HCV-2/3) infection remains controversial. This study sought to clarify in a large cohort, whether SNPs in the IFNL3 region are associated with treatment response in HCV-2/3 patients. Methods The cohort comprised 1002 HCV-2/3 Caucasians patients treated with pegylated interferon-alpha and ribavirin who underwent genotyping for the SNPs rs12979860 and rs8099917 Results Overall, 736 (73.5%) patients achieved SVR (81.9%, 67.9%, and 57.8% for rs12979860 CC, CT, and TT [p=0.0001]; 78%, 68.7%, and 46.3% for rs8099917 TT, TG, and GG [p=0.0001]). By logistic regression, both rs12979860 CC and rs8099917 TT were independent predictors of SVR with an odds ratio (OR) of 2.39 (1.19-3.81) p=0.0001 and OR 1.85 (1.15-2.23) p=0.0001, respectively. IFNL3 responder genotypes were more frequent in relapsers than null-responders (p=0.0001 for both SNPs). On-treatment rapid virological response (RVR) was predictive of SVR only in those individuals with IFNL3 non-responder genotypes (rs12979860 CT/TT and rs8099917 TG/GG). Conclusions This adequately powered study in patients with HCV genotypes 2 or 3 infection clearly demonstrates that IFNL3 genotypes are the strongest baseline predictor of SVR, in keeping with the known association for genotype 1 infection. IFNL3 genotyping can aid in therapeutic decision making for these patients. [ABSTRACT FROM AUTHOR]

Abstract: Decitabine is a potent demethylating agent that exhibits clinical activity against myeloid malignancies. Numerous genes silenced by hypermethylation are reactivated by decitabine through a mechanism involving promoter demethylation with subsequent release of histone deacetylases (HDACs) and accumulation of acetylated histones. Recent studies indicating that decitabine also induces regional chromatin remodeling of some unmethylated genes suggest additional mechanisms of action. Decitabine reactivates unmethylated p21WAF1 in some AML cell lines but the possible occurrence of p21WAF1 methylation in AML in vivo has not been studied in detail and decitabine effects on p21WAF1 chromatin remodeling have not been reported. We found that p21WAF1 mRNA was undetectable in 6 of 24 AML patient samples and 4 of 5 AML cell lines but there was no evidence of p21WAF1 promoter methylation. However, decitabine induced p21WAF1 in AML cell lines KG-1 and KG-1a in association with release of HDAC1 and increased acetylated histone H3 at the unmethylated p21WAF1 promoter. Decitabine effects on p21WAF1 histone acetylation and induction were enhanced by the HDAC inhibitor trichostatin A and were independent of wild type p53. Our findings indicate that decitabine can relieve p21WAF1 repression in AML by a mechanism that involves release of HDAC1 without requiring promoter demethylation. Furthermore, our study provides evidence that combined decitabine and HDAC inhibitor treatment can enhance chromatin remodeling and reactivation of an unmethylated tumor suppressor gene. This latter finding is of relevance to the clinical use of these agents in AML as we found the p21WAF1 promoter to be unmethylated in vivo. [Copyright &y& Elsevier]

Epigenetic silencing of downstream components of the transforming growth factor beta pathway including the cyclin-dependent kinase inhibitors (CDKIs) p15INK4B, p27KIP1 and p21CIP1 is implicated in the pathogenesis of some hematological malignancies. Loss of p15INK4B expression due to promoter methylation occurs frequently in human T-cell acute lymphoblastic leukemia (T-ALL) but the expression and methylation status of p27KIP1 remains to be characterized in T-ALL or T-cell lymphoblastic lymphoma (T-LBL). As well, while some have reported a high frequency of p21CIP1 methylation in ALL patient samples others have found the gene to be unmethylated in this disease and the relationship between p21CIP1 expression and promoter methylation has not been examined in T-LBL. Using RNase protection assays (RPA) and methylation specific PCR (MSP), we found p27KIP1 to be expressed and its promoter unmethylated in 20 of 20 (100%) and 28 of 28 (100%) T-LBL/ALL samples, respectively. In contrast, p21CIP1 mRNA was absent in 7 of 14 (50%) T-LBL biopsies and 5 of 6 (83%) T-ALL cell lines. However, like p27KIP1 there was no evidence of p21CIP1 promoter methylation by MSP or temporal temperature gradient electrophoresis (TTGE) analysis of 35 CpG sites in any of the 28 T-LBL/ALLs analyzed. Similar to T-ALL, we found p15INK4B mRNA was absent in 13 of 14 (93%) T-LBL biopsies and its promoter methylated in 6 of 10 (64%) cases. Our results indicate that p21CIP1 mRNA is absent in human T-LBL biopsies and T-ALL cell lines at a high frequency. However, unlike p15INK4B, reduced p21CIP1 expression in T-LBL/ALL is independent of dense promoter-associated CpG methylation. In contrast to some hematological malignancies p27KIP1 methylation does not appear to contribute significantly to T-LBL/ALL pathogenesis. [Copyright &y& Elsevier]