Sympathetic overdrive and unrestrained adipose lipolysis drive alcohol-induced hepatic steatosis in rodents.

OBJECTIVE: Hepatic steatosis is a key initiating event in the pathogenesis of alcohol-associated liver disease (ALD), the most detrimental organ damage resulting from alcohol use disorder. However, the mechanisms by which alcohol induces steatosis remain incompletely understood. We have previously found that alcohol binging impairs brain insulin action, resulting in increased adipose tissue lipolysis by unrestraining sympathetic nervous system (SNS) outflow. Here, we examined whether an impaired brain-SNS-adipose tissue axis drives hepatic steatosis through unrestrained adipose tissue lipolysis and increased lipid flux to the liver. METHODS: We examined the role of lipolysis, and the brain-SNS-adipose tissue axis and stress in alcohol induced hepatic triglyceride accumulation in a series of rodent models: pharmacological inhibition of the negative regulator of insulin signaling protein-tyrosine phosphatase 1ß (PTP1b) in the rat brain, tyrosine hydroxylase (TH) knockout mice as a pharmacogenetic model of sympathectomy, adipocyte specific adipose triglyceride lipase (ATGL) knockout mice, wildtype (WT) mice treated with ß3 adrenergic agonist or undergoing restraint stress. RESULTS: Intracerebral administration of a PTP1b inhibitor, inhibition of adipose tissue lipolysis and reduction of sympathetic outflow ameliorated alcohol induced steatosis. Conversely, induction of adipose tissue lipolysis through ß3 adrenergic agonism or by restraint stress worsened alcohol induced steatosis. CONCLUSIONS: Brain insulin resistance through upregulation of PTP1b, increased sympathetic activity, and unrestrained adipose tissue lipolysis are key drivers of alcoholic steatosis. Targeting these drivers of steatosis may provide effective therapeutic strategies to ameliorate ALD.

Pseudoclitoromegaly from acute T-cell lymphoblastic leukemia.

A 7-year-old girl presented with painful genital enlargement, which was first believed to be clitoromegaly of hormonal origin. However, on the physical exam the clitoris was not visible and the prepuce and labia minora were enlarged and tender. Magnetic resonance imaging demonstrated an infiltrative abnormal signal with restricted diffusion involving the enlarged clitoris and adjacent soft tissues of the prepuce and labia minora, confirming a nonhormonal infiltrative malignancy. The same abnormal signal was present in enlarged inguinal lymph nodes, the kidneys, and an anterior mediastinal mass. The pathologic diagnosis was T-cell acute lymphoblastic leukemia.

Factors affecting opioid management for injured children after hospital discharge.

INTRODUCTION: Prescription opioid misuse is a national crisis. Injured children often receive opioid medication at hospital discharge, but the role these prescriptions play in the opioid crisis has not been fully elucidated. Whether these opioids are administered, the duration of severe pain requiring opioids, and what the final disposition of unused opioids is in this population remain unknown. METHODS: A survey of parent/guardian perceptions of their child's pain after injury, duration of opioid administration, opioid storage and disposal, and perceptions of opioid education was designed. During a 12-month period, parents of injured children admitted to an ACS Level 1 Pediatric Trauma Center were prospectively enrolled by convenience sample. Surveys were in two steps with an enrollment survey prior to discharge and a follow-up survey 7-10 days after discharge. RESULTS: Seventy of 114 (61.4%) enrolled parents/guardians completed follow-up survey. Of the 79.1% that reported an opioid prescription for their child, 92.5% filled it. Of those reporting on opioid usage, 10.4% never used the opioid, 75% used opioids <3 days, 12.5% 4-7 days, 2% >7 days. Of those who filled the opioid prescription, 83.7% reported having leftover doses. Reasons for discontinuing opioids included the child no longer had pain (87.2%), the child ran out of medication (5.1%), other (7.7%). Regarding storage, 53.3% reported utilizing an unlocked bathroom cabinet, and 81.3% unlocked kitchen space. Of those reporting unused opioids, 83.3% reported not disposing them, and 38.2% reported no plan for disposal. CONCLUSION: The majority of parents/guardians of injured children report resolution of severe pain requiring opioids within 72 h of hospital discharge, and virtually all by 7 days. The majority of injured children were prescribed a greater number of doses than they needed to treat their pain. Many parents/guardians store opioids in unsecure locations and a significant proportion report no plan to dispose of unused opioid doses. Further investigation is warranted to quantify and address the gap between pain control needs and opioid prescribing practices. The rate of unsecure storage and plan to retain unused opioids are potential targets for discharge opioid education. TYPE OF STUDY: Cross-sectional survey. LEVEL OF EVIDENCE: Level IV.

Neuronal processes and glial precursors form a scaffold for wiring the developing mouse cochlea.

In the developing nervous system, axons navigate through complex terrains that change depending on when and where outgrowth begins. For instance, in the developing cochlea, spiral ganglion neurons extend their peripheral processes through a growing and heterogeneous environment en route to their final targets, the hair cells. Although the basic principles of axon guidance are well established, it remains unclear how axons adjust strategies over time and space. Here, we show that neurons with different positions in the spiral ganglion employ different guidance mechanisms, with evidence for both glia-guided growth and fasciculation along a neuronal scaffold. Processes from neurons in the rear of the ganglion are more directed and grow faster than those from neurons at the border of the ganglion. Further, processes at the wavefront grow more efficiently when in contact with glial precursors growing ahead of them. These findings suggest a tiered mechanism for reliable axon guidance.

Bridging the Gap: Utilizing a Pediatric Trauma Care Coordinator to Reduce Disparities for Pediatric Trauma Follow-Up Care.

An American College of Surgeons-verified Level I pediatric trauma center found that some children with severe and complex injuries experienced disruptions in trauma follow-up care because of the lack of centralized care coordination after hospital discharge. A review of the literature identified little guidance to address this issue. A quality improvement project assessed the gaps in care, identified high-risk patients, and developed a novel pediatric trauma care coordinator (PTCC) nursing position to bridge the gap. Enhancements to the trauma registry software helped create a log of family and provider communication events with and interventions by the PTCC. High-risk patients were defined as those with either a traumatic brain injury plus 1 other organ system injury requiring surgical specialist follow-up, or those with 3 or more different organ system injuries requiring follow-up with a surgical specialist. Costly return to health care (CRH), which we defined as emergency department visits for 72 hr or less or unplanned readmissions of 30 day or less after hospital discharge was selected as the primary outcome measure and assessed during the pre- and postimplementation periods. In the 12-month preimplementation period, 14 patients had a CRH rate of 14%, compared with the 12-month postimplementation period in which 18 patients had a CRH rate of 0%. Patients received a mean of 21.2 communication events and 14.1 intervention events from the PTCC in the postimplementation period. This report details the process of developing and implementing a PTCC nursing position, the tasks involved, and the initial results of this novel program.

Proximity to the Diaphragm Predicts the Presence of Rhabdomyomatous Dysplasia in Congenital Pulmonary Airway Malformations.

INTRODUCTION: Rhabdomyomatous dysplasia (RD) is a pathologic finding in CPAMs that was incorrectly attributed to their malignant potential. The increasing recognition of extrathoracic (intradiaphragmatic and intraabdominal) congenital pulmonary airway malformations (CPAMs) offers a clue to the origin of RD. We hypothesize that the presence of RD is related to the CPAM's anatomic location. MATERIALS AND METHODS: Retrospective review was performed of all children who underwent resection of a CPAM during a 10-year period. The age at the time of operation, location of the CPAM, and pathologic findings were collected. Peridiaphragmatic location was defined as within the inferior pulmonary ligament, deep to the diaphragmatic portion of the parietal pleura ("intradiaphragmatic") or adjacent to the abdominal side of the diaphragm. Statistical analysis was performed using Fisher's exact test for 2 × 2 tables. RESULTS: Twenty-six patients with CPAM were identified. Preoperative imaging was performed by computed tomography (CT) scan (16/26), ultrasound (5/26), magnetic resonance imaging (MRI) (1/26), and chest radiograph (4/26). The median age at resection was 15 months. Of these, 16 were pure cystic adenomatoid malformations, 4 were extralobar sequestrations, 4 were intralobar sequestrations, and 2 were bronchogenic cysts. Nine lesions were peridiaphragmatic with four being intradiaphragmatic (44%). Eight of the nine resected peridiaphragmatic lesions contained histologic evidence of rhabdomyomatous changes (89%, confidence interval [CI] 52-99%). None of the other lesions contained RD (CI 0-19%, p < 0.001). CONCLUSION: RD was seen exclusively, and in virtually all peridiaphragmatic CPAMs. While the exact significance of RD remains unclear, it may represent incorporation of striated muscle tissue associated with the developing diaphragm.

Can time to healing in pediatric blunt splenic injury be predicted?

BACKGROUND: Current consensus guidelines do not recommend routine follow-up imaging for blunt splenic injury (BSI) in children. However, repeat imaging is recommended based on persistent symptoms. Wide variation of practice continues to exist among surgeons. By defining the natural evolution of BSI, we sought to identify patients at higher risk for delayed healing who could benefit from outpatient imaging. METHODS: A retrospective review of all children with BSI at a Level 1 Pediatric Trauma Center was completed. Grade of injury, hospital course, laboratory values and follow-up imaging results were obtained. Injured spleens were classified as 'healed', 'healing' (with echogenic scar), or 'non-healing' with persistence of parenchymal abnormalities. RESULTS: Between 2000 and 2014, 222 patients with BSI were identified. Seven patients (3%) underwent immediate splenectomy. Packed red blood cell transfusion was required in 13 (6%) of the 222 patients, and 3 (2%) of 145 with isolated splenic injuries. Seventy-one percent of patients underwent additional imaging 2-74 weeks post-injury. A receiver operating characteristics (ROC) curve was used to establish the relationship between sensitivity and specificity of capturing non-healing spleens over time. Optimal timing for post-injury imaging for grades I-II was 7-8 weeks; healing of higher-grade injuries could not accurately be predicted. CONCLUSIONS: If return to full physical activity, in particular contact sports, is contingent upon documented healing of the splenic parenchyma after blunt trauma in the pediatric population, follow-up imaging for low-grade injuries is best obtained around 7-8 weeks. No such recommendations can be made for high-grade splenic injuries, as the exact time to healing cannot be predicted based on initial data. LEVEL OF EVIDENCE: IV. Diagnostic test.

MiR-9 Controls Chemotactic Activity of Cord Blood CD34⁺ Cells by Repressing CXCR4 Expression

Improved approaches for promoting umbilical cord blood (CB) hematopoietic stem cell (HSC) homing are clinically important to enhance engraftment of CB-HSCs. Clinical transplantation of CB-HSCs is used to treat a wide range of disorders. However, an improved understanding of HSC chemotaxis is needed for facilitation of the engraftment process. We found that ectopic overexpression of miR-9 and antisense-miR-9 respectively down- and up-regulated C-X-C chemokine receptor type 4 (CXCR4) expression in CB-CD34⁺ cells as well as in 293T and TF-1 cell lines. Since CXCR4 is a specific receptor for the stromal cell derived factor-1 (SDF-1) chemotactic factor, we investigated whether sense miR-9 and antisense miR-9 influenced CXCR4-mediated chemotactic mobility of primary CB CD34⁺ cells and TF-1 cells. Ectopic overexpression of sense miR-9 and antisense miR-9 respectively down- and up-regulated SDF-1-mediated chemotactic cell mobility. To our knowledge, this study is the first to report that miR-9 may play a role in regulating CXCR4 expression and SDF-1-mediated chemotactic activity of CB CD34⁺ cells.

Nonoperative treatment of acute appendicitis in children: A feasibility study.

PURPOSE: Nonoperative treatment of acute appendicitis appears to be feasible in adults. It is unclear whether the same is true for children. METHODS: Children 5-18 years with <48 h symptoms of acute appendicitis were offered nonoperative treatment: 2 doses of piperacillin IV, then ampicillin/clavulanate ×1 week. Treatment failure (worsening on therapy) and recurrence (after completion of therapy) were noted. Patients who declined enrollment were asked to participate as controls. Cost-utility analysis was performed using Pediatric Quality of Life Scale (PedsQL®) to calculate quality-adjusted life month (QALM) for study and control patients. RESULTS: Twenty-four patients agreed to undergo nonoperative management, and 50 acted as controls. At a mean follow-up of 14 months, three of the 24 failed on therapy, and 2/21 returned with recurrent appendicitis at 43 and 52 days, respectively. Two patients elected to undergo an interval appendectomy despite absence of symptoms. Appendectomy-free rate at one year was therefore 71% (C.I. 50-87%). No patient developed perforation or other complications. Cost-utility analysis shows a 0.007-0.03 QALM increase and a $1359 savings from $4130 to $2771 per nonoperatively treated patient. CONCLUSION: Despite occasional late recurrences, antibiotic-only treatment of early appendicitis in children is feasible, safe, cost-effective and is experienced more favorably by patients and parents.

Role of Radiosurgery in the Treatment of Brain Metastasis.

Craniotomy and stereotactic radiosurgery seem to be similarly effective and appropriate choices for the treatment of patients with favorable prognostic factors and limited brain metastases.

Serial aEEG recordings in a cohort of extremely preterm infants: feasibility and safety.

OBJECTIVE: Amplitude-integrated electroencephalography (aEEG) monitoring is increasing in the neonatal population, but the safety and feasibility of performing aEEG in extremely preterm infants have not been systematically evaluated. STUDY DESIGN: Inborn infants 23(0/7) to 28(6/7) weeks gestation or birth weight 401 to 1000 g were eligible. Serial, 6-h aEEG recordings were obtained from first week of life until 36 weeks postmenstrual age. Adverse events were documented, and surveys evaluated the impact of the aEEGs on routine care. Success of performing aEEGs according to protocol and aEEG quality were assessed. RESULT: A total of 102 infants were enrolled, with 755 recordings performed. 83% of recordings were performed according to schedule, and 96% were without adverse event. Bedside nurses reported no interference with routine care for 89% of recordings. 92% of recordings had acceptable signal quality. CONCLUSION: Serial aEEG monitoring is safe in preterm infants, with few adverse events and general acceptance by nursing staff.

Outcomes of extremely preterm infants following severe intracranial hemorrhage.

OBJECTIVE: Severe intracranial hemorrhage (ICH) is an important prognostic variable in extremely preterm (EPT) infants. We examined imaging and clinical variables that predict outcomes in EPT infants with severe ICH. STUDY DESIGN: Retrospective analysis of 353 EPT infants with severe ICH. Outcomes were compared by examining: (i) unilateral vs bilateral ICH; and (ii) presence vs absence of hemorrhagic parenchymal infarction (HPI). Regression analyses identified variables associated with death or neurodevelopmental impairment (NDI). RESULT: Bilateral ICH and HPI had higher rates of adverse outcomes and were independently associated with death/NDI. HPI was the most important variable for infants of lower birth weight, and bilateral ICH for larger infants. For infants surviving to 36 weeks, shunt placement was most associated with death/NDI. CONCLUSION: Bilateral ICH and the presence of HPI in EPT infants with severe ICH are associated with death/NDI, though the importance depends on birth weight and survival to 36 weeks.

Counteracting the enzymatic activity of dipeptidylpeptidase 4 for potential therapeutic advantage, with an emphasis on cord blood transplantation

Dipeptidylpeptidase (DPP) 4, also known as CD26, is an enzyme present on the surface of a number of different cell types. It is also found within cells and as a soluble protein in body fluids. It can specifically truncate proteins at the penultimate N-terminus residue for some amino acids, such as alanine, proline, serine, and perhaps others. DPP4 has been implicated in regulating the in vitro and in vivo functional activities of a number of hematopoietically active molecules, and this information, along with that on inhibition of DPP4, has been studied in efforts to enhance hematopoietic cell transplantation (HCT), hematopoiesis after stress in mouse models, and in the clinical setting of single-unit cord blood (CB) HCT. This article reviews the current status of this compound's effects on regulatory proteins, the field of CB HCT, a potential role for modulating DPP4 activity in enhancing single-unit CB HCT in adults, and future aspects in context of other cellular therapies and the area of regenerative medicine.

Efficacy of anatomic and physiologic indicators versus mechanism of injury criteria for trauma activation in pediatric emergencies.

BACKGROUND: In pediatric trauma patients, adult triage criteria that use mechanism of injury (MOI) have been shown to result in overactivation of trauma teams. Anatomy- and physiology-based (APB) triage criteria have been recommended to improve the accuracy of trauma activations. At our Level 1 academic tertiary pediatric trauma referral center, we recently changed our triage criteria by emphasizing APB criteria and de-emphasizing MOI. This study was conducted to analyze the resulting change in accuracy of activations. METHODS: This was a criterion standard, cohort-controlled retrospective study comparing patients triaged by MOI criteria (January 2006 to March 2009) to those triaged by APB criteria (April 2009 to June 2010). Patients were subdivided according to trauma activation level as major (TMaj), minor (TMin), or consult (TC). Demographic, vital sign, injury pattern, trauma activation level, and emergency department disposition data were collected. Triage criteria were retrospectively applied to the patients according to the criteria that were in effect when they arrived. Patients were assigned to either high-risk (HR) or low-risk (LR) groups based on the need for urgent intervention (emergency department procedure, emergent operation, or blood transfusion), admission to intensive care unit, Injury Severity Score [ISS] of greater than 12, or death. Sensitivity and specificity of major activations were calculated using the following groups: true positive, trauma activation and HR; false positive, trauma activation and LR, false negative, no trauma activation and HR; true negative, no trauma activation and LR. Comparisons were then made between the MOI to the APB patients. RESULTS: The MOI and APB patients were similar in race (p = 0.201), sex (p = 0.639), and age (p = 0.643). The APB criteria resulted in 14% TMaj, 35% TMin, and 51% TC, compared with 41%, 23%, and 36%, respectively, for MOI. Median ISS in the APB group was 16 for TMaj, 5 for TMin, and 4 for TC compared with 8, 4, and 4, respectively, for MOI. Sensitivity for trauma activation of HR patients was 89.2% versus 89.1% (equivalent), while specificity increased from 45.8% to 65.8% for MOI versus APB, respectively. CONCLUSION: For pediatric trauma patients, the emphasis on APB triage criteria and de-emphasis on MOI results in selection of higher-acuity patients for major activation while maintaining acceptable undertriage and overtriage rates overall. This improved accuracy of major activation results in a more cost-efficient resource use and fewer unnecessary disruptions for the surgeon, operating room, and other staff while maintaining appropriate capture and evaluation of trauma patients. The low sensitivity noted in both the MOI and APB groups is largely caused by the broad definition of HR patients used in this study. We recommend the use of APB criteria for pediatric trauma triage. LEVEL OF EVIDENCE: Therapeutic study, level IV.

Patient preferences and physician practice patterns regarding breast radiotherapy.

PURPOSE: There are multiple current strategies for breast radiotherapy (RT). The alignment of physician practice patterns with best evidence and patient preferences will enhance patient autonomy and improve cancer care. However, there is little information describing patient preferences for breast RT and physician practice patterns. METHODS AND MATERIALS: Using a reliable and valid instrument, we assessed the preferences of 5,000 randomly selected women (with or without cancer) undergoing mammography. To assess practice patterns, 2,150 randomly selected physician-members of American Society for Radiation Oncology were surveyed. RESULTS: A total of 1,807 women (36%) and 363 physicians (17%) provided usable responses. The 95% confidence interval is < ± 2.3% for patients and < ± 5.3% for physicians. Patient preferences were hypofractionated whole breast irradiation (HF-WBI) 62%, partial breast irradiation (PBI) 28%, and conventionally fractionated whole breast irradiation (CF-WBI) 10%. By comparison, 82% of physicians use CF-WBI for more than 2/3 of women and 56% never use HF-WBI. With respect to PBI, 62% of women preferred three-dimensional (3D)-PBI and 38% favor brachytherapy-PBI, whereas 36% of physicians offer 3D-PBI and 66% offer brachytherapy-PBI. 70% of women prefer once-daily RT over 10 days vs. twice-daily RT over 5 days. 55% of physicians who use PBI do not offer PBI on clinical trial. CONCLUSIONS: HF-WBI, while preferred by patients and supported by evidence, falls behind the unproven and less preferred strategy of PBI in clinical practice. There is a discrepancy between women's preferences for PBI modality and type of PBI offered by physicians. Further alignment is needed between practice patterns, patient preferences, and clinical evidence.

Predictors of fatigue over 1 year among people with rheumatoid arthritis.

Fatigue is a systemic feeling of exhaustion that is a common symptom of many chronic illnesses, including the autoimmune inflammatory disease rheumatoid arthritis (RA). We examined predictors of levels of fatigue among people with RA using Leventhal's Common-Sense Model (CSM), which states that cognitive representations of an illness spur (or halt) people's efforts to cope and thereby influence outcomes of the illness. Our use of the CSM was designed in the light of evidence in the literature specific to fatigue in RA. Current fatigue was reported on a 100 mm visual analogue scale (with anchors "No fatigue" and "Unbearable fatigue") by 114 people (73.7% women) with RA at baseline and 1 year later. Baseline employment status, pain, impact of disability, sleep disruption frequency, depressed mood, perceptions of consequences, arthritis self-efficacy and attempts to cope by praying/hoping were also self-reported. Duration of RA and a haematological measure of systemic inflammation (erythrocyte sedimentation rate; ESR) were obtained from hospital records. Unexpectedly, RA duration did not predict fatigue after 1 year, although lower baseline inflammation did (controlling for baseline fatigue and other disease impact variables). This may be due to sampling flares of RA at baseline. Baseline perceptions that RA has severe consequences and is uncontrollable also predicted greater fatigue after 1 year but this relationship was not mediated by praying/hoping. Targeted psychological care to modify perceptions of severe consequences may therefore improve later fatigue for people with RA even when the condition is longstanding, but the mechanisms of any benefit require further investigation.

Polypharmacy among people with rheumatoid arthritis: the role of age, disease duration and comorbidity.

BACKGROUND: People with rheumatoid arthritis (RA) often have comorbidities with associated disability and complex medication regimens. Little published evidence exists about why people with RA require so many medications, although it is logical to hypothesize that this may relate to older age, longer duration of RA, more active RA, worse functional disability and a greater number of comorbidities. OBJECTIVES: We set out to quantify polypharmacy in RA and identify its predictors in an observational cohort. METHODS: The case notes of 348 people receiving secondary care for RA were reviewed to record polypharmacy. The 28-joint Disease Activity Score (DAS28) was calculated and the Health Assessment Questionnaire (HAQ) and the Self-administered Comorbidity Questionnaire (SCQ) were completed. RESULTS: The mean total number of medications was 5.39, with a maximum of 16; of these, a mean of 2.41 medications were directly for RA. A mediational relationship was identified: older age and longer RA duration were significant predictors of a greater total number of medications, but these relationships were explained by the greater number of comorbidities in older participants and those with longer RA duration. Polypharmacy was not related to RA activity or functional disability. CONCLUSIONS: Polypharmacy is common among people with RA and associates with older age and longer RA duration through a greater number of comorbidities. Regular review of the full treatment plan of individuals with RA by pharmacists and other health professionals specializing in rheumatology, to weigh the benefits and risks of each medication and their interactions in light of RA activity and comorbidities, is advocated.

Sleep disruption frequency in rheumatoid arthritis: perceived stress predicts poor outcome over one year.

BACKGROUND: Sleep is an important daily process that can be disrupted by chronic illnesses including rheumatoid arthritis (RA). AIMS: We tested whether demographic, medical and psychological factors act as predictors of change in frequency of sleep disruption associated with RA. METHODS: A cohort of 129 White British people with RA (mean duration of RA 7.19 years; mean age 55.40 years; 75% women) was followed for one year. Self-report questionnaires were employed to record demographic information and assess participants' sleep disruption (on a 4-point frequency scale), morning stiffness (duration), pain and fatigue (visual analogue scales), impact of disability, anxiety, depression, stress, coping, illness perceptions and self-efficacy. Hospital notes were reviewed for duration of RA, antidepressant use and comorbidity. RESULTS: Participants were split into those with sleep disruption that was consistently infrequent or decreasing in frequency (n = 56; 43%) and those with sleep disruption that was consistently frequent or increasing in frequency (n = 73; 57%). Results of a logistic regression demonstrated that greater perceived stress at baseline predicted sleep disruption that was consistently frequent or increasing in frequency over the year. Change in sleep disruption frequency was not predicted by any other assessed variable. Perceived stress at the end of the year was not predicted by change in frequency of sleep disruption. CONCLUSIONS: Self-reported frequency of sleep disruption among people with RA relates to perceived stress. Psychoeducational programmes that help people with RA manage their stress may be a non-pharmacological method of improving sleep quality and therefore merits testing in specific interventional studies.