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BACKGROUND: Excessive neutrophil inflammation is the hallmark of cystic fibrosis (CF) airway disease. Novel technologies for characterizing neutrophil dysfunction may provide insight into the nature of these abnormalities, revealing a greater mechanistic understanding and new avenues for CF therapies that target these mechanisms. METHODS: Blood was collected from individuals with CF in the outpatient clinic, CF individuals hospitalized for a pulmonary exacerbation, and non-CF controls. Using microfluidic assays and advanced imaging technologies, we characterized 1) spontaneous neutrophil migration using microfluidic motility mazes, 2) neutrophil migration to and phagocytosis of Staphylococcal aureus particles in a microfluidic arena, 3) neutrophil swarming on Candida albicans clusters, and 4) Pseudomonas aeruginosa-induced neutrophil transepithelial migration using micro-optical coherence technology (µOCT). RESULTS: Participants included 44 individuals: 16 Outpatient CF, 13 Hospitalized CF, and 15 Non-CF individuals. While no differences were seen with spontaneous migration, CF neutrophils migrated towards S. aureus particles more quickly than non-CF neutrophils (p

Imbalance between fat production and consumption causes various metabolic disorders. Nonalcoholic fatty liver disease (NAFLD), one such pathology, is characterized by abnormally increased fat synthesis and subsequent fat accumulation in hepatocytes1,2. While often comorbid with obesity and insulin resistance, this disease can also be found in lean individuals, suggesting specific metabolic dysfunction2. NAFLD has become one of the most prevalent liver diseases in adults worldwide, but its incidence in both children and adolescents has also markedly increased in developed nations3,4. Progression of this disease into nonalcoholic steatohepatitis (NASH), cirrhosis, liver failure, and hepatocellular carcinoma in combination with its widespread incidence thus makes NAFLD and its related pathologies a significant public health concern. Here, we review our understanding of the roles of dietary carbohydrates (glucose, fructose, and fibers) and the gut microbiota, which provides essential carbon sources for hepatic fat synthesis during the development of NAFLD., Fatty liver disease: A conspiracy of carbohydrates and gut microbes Evidence is emerging of a role for interactions between gut microbes and dietary carbohydrates in non-alcoholic fatty liver disease (NAFLD), one of the most prevalent liver disorders of adults worldwide, with children and adolescents also increasingly affected. NAFLD can progress into even more serious conditions such as steatohepatitis, cirrhosis, liver cancer and liver failure. Researchers led by Cholsoon Jang at the University of California Irvine review understanding of the role of dietary glucose, fructose, fiber and gut microbial metabolism in contributing to NAFLD. The involvement of gut microbes in hepatic assimilation of carbohydrates into fatty acids that accumulate in NAFLD indicates possible treatment strategies based on interfering with microbial metabolism. New understanding of the interactions between carbohydrate metabolism and gut microbes will also help reveal why some people develop NAFLD and suggest appropriate preventive interventions.

Pediatric mild traumatic brain injury (pmTBI) has received increased public scrutiny over the past decade, especially regarding children who experience persistent post-concussive symptoms (PPCS). However, several methods for defining PPCS exist in clinical and scientific literature, and even healthy children frequently exhibit non-specific, concussive-like symptoms. Inter-method agreement (six PPCS methods), observed misclassification rates, and other psychometric properties were examined in large cohorts of consecutively recruited adolescent patients with pmTBI (n = 162) 1 week and 4 months post-injury and in age/sex-matched healthy controls (HC; n = 117) at equivalent time intervals. Six published PPCS methods were stratified into Simple Change (e.g., International Statistical Classification of Diseases and Related Health Problems, 10th revision [ICD-10]) and Standardized Change (e.g., reliable change indices) algorithms.Among HC, test-retest reliability was fair to good across the 4-month assessment window, with evidence of bias (i.e., higher symptom ratings) during retrospective relative to other assessments. Misclassification rates among HC were higher (>30%) for Simple Change algorithms, with poor inter-rater reliability of symptom burden across HC and their parents. A 49% spread existed in terms of the proportion of pmTBI patients "diagnosed" with PPCS at 4 months, with superior inter-method agreement among standardized change algorithms. In conclusion, the self-reporting of symptom burden is only modestly reliable in typically developing adolescents over a 4-month period, with additional evidence for systematic bias in both adolescent and parental ratings. Significant variation existed for identifying pmTBI patients who had "recovered" (i.e., those who did not meet individual criteria for PPCS) from concussion across the six definitions, representing a considerable challenge for estimating the true incidence rate of PPCS in published literature. Although relatively straightforward to obtain, current findings question the utility of the most commonly used Simple Change scores for diagnosis of PPCS in clinical settings.

Introduction: Adolescent-onset cannabis use is rising in the era of marijuana legalization. Recent imaging studies have identified neuroanatomical differences between adult cannabis users and controls that are more prominent in early-onset users. Other studies point to sex-dependent effects of cannabis.Methods: A systematic review following PRISMA guidelines and subsequent effect-size seed-based d mapping (SDM) meta-analyses were conducted to investigate relationships between age (across the 12-to-21-year-old developmental window), sex, and gray matter volume (GMV) differences between cannabis using (CU) and typically developing (TD) youth.Results: Our search identified 1,326 citations, 24 of which were included in a qualitative analysis. A total of 6 whole-brain voxel-based morphometry (VBM) studies comparing regional GMV between 357 CU [mean (SD) age = 16.68 (1.28); 71% male] and 404 TD [mean (SD) age = 16.77 (1.36); 63% male] youth were included in the SDM-meta-analysis. Meta-analysis of whole-brain VBM studies identified no regions showing significant GMV difference between CU and TD youth. Meta-regressions showed divergent effects of age and sex on cortical GMV differences in CU vs. TD youth. Age effects were seen in the superior temporal gyrus (STG), with older-aged CU youth showing decreased and younger-aged CU youth showing increased STG GMV compared to age-matched TD youth. Parallel findings in the STG were also observed in relation to duration of CU (years) in supplemental meta-regressions. Regarding sex effects, a higher proportion of females in studies was associated with increased GMV in the middle occipital gyrus in CU vs. TD youth.Conclusions: These findings suggest that GMV differences between CU and TD youth, if present, are subtle, and may vary as a function of age, cumulative cannabis exposure, and sex in young people. Whether age- and sex-related GMV differences are attributable to common predispositional factors, cannabis-induced neuroadaptive changes, or both warrant further investigation.

Although much attention has been generated in popular media regarding the deleterious effects of pediatric mild traumatic brain injury (pmTBI), a paucity of empirical evidence exists regarding the natural course of biological recovery. Fifty pmTBI patients (12–18 years old) were consecutively recruited from Emergency Departments and seen approximately 1 week and 4 months post‐injury in this prospective cohort study. Data from 53 sex‐ and age‐matched healthy controls (HC) were also collected. Functional magnetic resonance imaging was obtained during proactive response inhibition and at rest, in conjunction with independent measures of resting cerebral blood flow. High temporal resolution imaging enabled separate modeling of neural responses for preparation and execution of proactive response inhibition. A priori predictions of failed inhibitory responses (i.e., hyperactivation) were observed in motor circuitry (pmTBI>HC) and sensory areas sub‐acutely and at 4 months post‐injury. Paradoxically, pmTBI demonstrated hypoactivation (HC>pmTBI) during target processing, along with decreased activation within prefrontal cognitive control areas. Functional connectivity within motor circuitry at rest suggested that deficits were limited to engagement during the inhibitory task, whereas normal resting cerebral perfusion ruled out deficits in basal perfusion. In conclusion, current results suggest blood oxygen‐level dependent deficits during inhibitory control may exceed commonly held beliefs about physiological recovery following pmTBI, potentially lasting up to 4 months post‐injury.

Cancer patient navigation in Canada began in 2002 in Nova Scotia with oncology nurses providing support to patients from diagnosis up to and including end of life. This novel study was carried out to determine navigation frequency and palliative care contact rates, and variations in these rates among adults who were diagnosed with cancer, navigated, and then died between 2011 and 2014. Among the 2,532 study subjects, 56.7% were navigated for more than one month and 30.6% had palliative care contact reported. Variations were observed by geographic area, cancer stage, time from diagnosis to death, and whether the person died of cancer. Further study of the role of navigation is advised for persons at end of life.

Background: Urinary tract infections (UTIs) are the most common serious bacterial infection in young febrile infants, and the urinalysis (UA) is an accurate screening test for emergency department (ED) evaluation. Precise estimates of risk of concomitant bacteremia and/or bacterial meningitis (invasive bacterial infections; IBI) in febrile infants ≤ 60 days have been based on presence of UTIs rather than positive UAs, and lack large prospective study. Objective: We sought to determine the prevalence of IBIs in febrile infants 0-28 …

Background Adopting a better understanding of how both older adults and health care providers view the community management of frailty is necessary for improving home health, especially facing the coronavirus disease 2019 (COVID‐19) pandemic. We conducted a qualitative focus group study to assess how both older adults and health care providers view frailty and virtual health care in home health. Methods Two focus groups enrolled home‐living older adults and health care professionals, respectively (n = 15). Questions targeting the use of virtual / telehealth technologies in‐home care for frail older adults were administered at audio‐recorded group interviews. Transcribed discussions were coded and analyzed using NVivo software. Results The older adult group emphasized the autonomy related to increasing frailty and social isolation and the need for transparent dissemination of health care planning. They were optimistic about remote technology‐based supports and suggested that telehealth / health‐monitoring/tracking were in high demand. Health care professionals emphasized the importance of a holistic biopsychosocial approach to frailty management. They highlighted the need for standardized early assessment and management of frailty. Conclusions The integrated perspectives provided an updated understanding of what older adults and practitioners value in home‐living supports. This knowledge is helpful to advancing virtual home care, providing better care for frail individuals with complex health care needs., The study represents an updated understanding of supporting home care of older adults in the new era, by integrating perspectives of both care providers and receivers. It highlights improving virtual technology adaptation for care services and early management of frailty.

Background & AimsContinued limitations in hepatocellular carcinoma (HCC) screening have led to late diagnosis with poor survival, despite well-defined high-risk patient populations. Our aim is to develop a non-invasive urine circulating tumor DNA (ctDNA) biomarker panel for HCC screening to aid in early detection.MethodsCandidate ctDNA biomarkers was prescreened in urine samples obtained from HCC, cirrhosis, and hepatitis patients. Then, 609 patient urine samples with HCC, cirrhosis, or chronic hepatitis B were collected from five academic medical centers and evaluated by serum alpha feto-protein (AFP) and urine ctDNA panel using logistic regression, a Two-Step machine learning algorithm, and iterated 10-fold cross-validation.ResultsMutated TP53, and methylated RASSF1a and GSTP1, were selected for the urine ctDNA panel. The sensitivity of AFP-alone (9.8 ng/mL cut-off) to detect HCC was 71% by Two-Step. The combination of ctDNA and AFP increased the sensitivity to 81% at a specificity of 90%. The AUROC for the combination of ctDNA and AFP vs. AFP-alone were 0.925 (95% CI, 0.924-0.925) and 0.877 (95% CI, 0.876-0.877), respectively. Notably, among the patients with AFP ConclusionsThe combination of urine ctDNA and serum AFP can increase HCC detection rates including in those patients with low-AFP. Given the ease of collection, a urine ctDNA panel could be a potential non-invasive HCC screening test.

Background Recent studies indicate that sex-based differences exist in co-occurring psychiatric symptoms and disorders among individuals with opioid use disorders (OUD). Whether these associations are present in adolescent samples and change during OUD treatment is poorly understood. Objectives In the current study, we examined sex-based differences in psychiatric symptoms and relationships among sex, psychiatric symptoms, and opioid use outcomes in youth with OUD receiving buprenorphine/naloxone (Bup/Nal) and psychosocial treatment. Methods The study randomly assigned one hundred and fifty-two youth (15–21 years old) diagnosed with OUD to either 12 weeks of treatment with Bup/Nal or up to 2 weeks of Bup/Nal detoxification with both treatment arms receiving weekly drug counseling as part of a multisite clinical trial (NIDA-CTN-0010). We compared psychiatric symptoms, assessed via the Youth Self Report (YSR) at baseline and week 12, across male and female OUD participants. The study used logistic regression models to identify sex and psychiatric symptom variables that were predictors of opioid positive urine (OPU) at week 12. Results Compared to males, females with OUD had higher mean psychiatric symptom scores at baseline across broad-band and narrow-band symptom domains. The study observed significant reductions in psychiatric symptom scores in both males and females during treatment, and by week 12, females only differed from males on anxious-depressive symptom scores. Females, in general, and youth of both sexes presenting to treatment with higher anxious depression scores were less likely to have a week-12 OPU. Conclusions Clinically significant sex-based differences in psychiatric symptoms are present at baseline among youth with OUD receiving Bup/Nal-assisted treatment and mostly resolve during treatment.

Background COVID-19, the disease caused by the highly infectious and transmissible coronavirus SARS-CoV-2, has quickly become a morbid global pandemic. Although the impact of SARS-CoV-2 infection in children is less clinically apparent, collecting high-quality biospecimens from infants, children, and adolescents in a standardized manner during the COVID-19 pandemic is essential to establish a biologic understanding of the disease in the pediatric population. This biorepository enables pediatric centers world-wide to collect samples uniformly to drive forward our understanding of COVID-19 by addressing specific pediatric and neonatal COVID-19-related questions. Methods A COVID-19 biospecimen collection study was implemented with strategic enrollment guidelines to include patients seen in urgent care clinics and hospital settings, neonates born to SARS-CoV-2 infected mothers, and asymptomatic children. The methodology described here, details the importance of establishing collaborations between the clinical and research teams to harmonize protocols for patient recruitment and sample collection, processing and storage. It also details modifications required for biobanking during a surge of the COVID-19 pandemic. Results Considerations and challenges facing enrollment of neonatal and pediatric cohorts are described. A roadmap is laid out for successful collection, processing, storage and database management of multiple pediatric samples such as blood, nasopharyngeal and oropharyngeal swabs, sputum, saliva, tracheal aspirates, stool, and urine. Using this methodology, we enrolled 327 participants, who provided a total of 972 biospecimens. Conclusions Pediatric biospecimens will be key in answering questions relating to viral transmission by children, differences between pediatric and adult viral susceptibility and immune responses, the impact of maternal SARS-CoV-2 infection on fetal development, and factors driving the Multisystem Inflammatory Syndrome in Children. The specimens in this biorepository will allow necessary comparative studies between children and adults, help determine the accuracy of current pediatric viral testing techniques, in addition to, understanding neonatal exposure to SARS-CoV-2 infection and disease abnormalities. The successful establishment of a pediatric biorepository is critical to provide insight into disease pathogenesis, and subsequently, develop future treatment and vaccination strategies.

Highlights • Changes in WHO alcohol risk level are highly variable in youth treated for ADHD/SUD. • Achieving > 2-level reduction in WHO risk is linked to improvements in functioning. • Achieving > 2-level reduction in WHO risk is linked to decreased ADHD symptoms. • > 2-level reduction in WHO risk may be a valid non-abstinent AUD outcome in youth with ADHD/SUD., Introduction Abstinence from drinking represents the primary treatment target for alcohol use disorders (AUD) in youth, but few adolescents who engage in problematic drinking seek treatment. A reduction in World Health Organization (WHO) drinking risk level has been established as valid and reliable non-abstinent treatment target for AUD in adults but remains unstudied in youth. Methods The present study used data from the NIDA-CTN-0028 trial to examine associations between reductions in WHO drinking risk level and changes in global functioning and attention-deficit hyperactivity disorder (ADHD) symptoms during treatment in a sample of adolescents (ages 13–18 years) with ADHD and comorbid substance use disorder (SUD) (n = 297, 61% with AUD) receiving a 16-week intervention that combined ADHD pharmacotherapy (OROS-methylphenidate vs. placebo) and drug-focused cognitive-behavioral therapy. Results Shifts in drinking risk level during treatment were highly variable in adolescents treated for ADHD/SUD, and influenced by AUD diagnostic status. In the total sample, 15% of participants had a 2-level or greater reduction in WHO drinking risk level, with 59% and 24% showing no change or an increase in risk-level during treatment respectively. Achieving at least a 2-level change in WHO drinking risk level during treatment was associated with greater reduction in ADHD symptoms and better functional outcomes. Conclusions These findings parallel the adult AUD literature and provide preliminary support for the use 2-level reductions in WHO risk levels for alcohol use as a clinically valid non-abstinent treatment outcome for youth with ADHD and comorbid AUD.

Objective To evaluate diagnostic/prognostic implications of neurosensory testing during the subacute stage in patients with pediatric mild traumatic brain injury (pmTBI). Setting Recruitment from pediatric emergency department and urgent care clinics, assessment in a controlled environment. Participants In total, 146 pmTBI patients evaluated 7.4 ± 2.3 days and approximately 4 months postinjury; 104 age/sex-matched healthy controls (HCs) at equivalent time points. Design Prospective cohort study. Main measures Neurosensory examination based on sequence of 10 established tests of vestibular-ocular, oculomotor, vestibulospinal, and visual functioning. Results The amount of symptom provocation (positive change from pretest symptomatology) was significantly increased in pmTBI relative to HCs on every subtest 1 week postinjury, as were deficits in monocular accommodative amplitude and King-Devick Test errors. However, symptom provocation did not meaningfully alter diagnostic sensitivity/specificity relative to more easily obtained pretest symptom ratings. Evidence of clinically significant symptom provocation 1 week postinjury improved sensitivity (Δ = +12.9%) of identifying patients with persistent postconcussive symptoms 4 months postinjury on an independent symptom measure. Conclusions The diagnostic sensitivity/specificity of neurosensory testing in acutely concussed youth may be limited at 1 week postinjury as a function of natural recovery occurring in most emergency department cohorts. Neurosensory screening may have greater utility for identifying patients who experience delayed recovery.

Integrated hepatitis B virus (HBV) DNA detected in more than 85% of HBV-infected hepatocellular carcinoma (HBV-HCC) can cause insertional mutagenesis, chromosomal instability, sustained viral protein expression, and/or immune-mediated inflammation leading to HCC carcinogenesis. An opportunistic outcome of HBV DNA integration events, which occur randomly into the host genome, is the creation of a unique HBV-host junction sequence (HBV-JS) in individually infected hepatocytes representing a specific molecular signature of that cell. A noninvasive approach to detect HBV-JS's will enable frequent monitoring and aid in assessing HBV treatment efficacy and HCC disease progression. Here, we assessed the feasibility of detecting HBV-JS's in urine of HBV-infected patients as a proof-of-concept for utilizing urine as a noninvasive HBV-JS liquid biopsy for HBV-related disease monitoring. Utilizing an in-house developed HBV primer extension capture (PEC) NGS assay, we assessed early-stage HBV-patient tumor tissue and matched urine (n=8). Five of 8 urine samples contained detectable HCC tissue-derived HBV-JS's, including a TERT junction sequence. Next, we assessed 32 urine specimens collected from 28 HBV-infected patients including hepatitis (n=5), cirrhosis (n=11), HCC (n=4), and post-HCC (n=8). Interestingly, all urine samples contained HBV-JS sequences with 30 of 32 urines containing integrations in gene-coding regions. Of 351 unique HBV-JS in gene-coding regions identified in urine, 11 HBV-JS's have also been previously reported in tissue of HCC patients, including TERT. All eleven HBV-JS's were identified in cirrhosis or HCC patient cohorts. Furthermore, the distribution of urinary integrated HBV DNA in the HBV genome in all disease categories was found predominantly clustered in HBV DR1-2 (>70%), an integration hotspot, consistent with findings in tissue. Altogether this support the potential of urine as a noninvasive HBV-JS liquid biopsy to monitor HBV-infected patients for disease progression and treatment efficacy. Citation Format: Selena Lin, Yu-lan Kao, Robin Su, Ting-Tsung Chang, Yih-Jyh Lin, Yixiao Cui, Hie-Won Hann, Grace Park, Wei Song, Ying-Hsiu Su. Detection of liver-derived hepatitis B virus-host junction sequences in urine of hepatitis B infected patients for noninvasive disease monitoring [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 545.

Background The purpose of this manuscript was to evaluate the effectiveness of the Community Actions and Resources Empowering Seniors (CARES) model in measuring and mitigating frailty among community-dwelling older adults. Methods The CARES model is based on a goal-oriented multidisciplinary primary care plan which combines a comprehensive geriatric assessment (CGA) with health coaching. A total of 51 older adults (82 ± 7 years; 33 females) participated in the pilot phase of this initiative. Frailty was measured using the Clinical Frailty Scale (CFS) and the Frailty Index (FI-CGA) at baseline and at six-month follow-up. Results The FI-CGA at follow-up (0.21 ± 0.08) was significantly lower than the FI-CGA at baseline (0.24 ± 0.08), suggesting an average reduction of 1.8 deficits. Sixty-one per cent of participants improved their FI-CGA and 38% improved CFS categories. Participants classified as vulnerable/frail at baseline were more responsive to the intervention compared to non-frail participants. Conclusion Pilot data showed that it is feasible to assess frailty in primary care and that the CARES intervention might have a positive effect on frailty, a promising finding that requires further investigations. General practitioners who participate in the CARES model can now access their patients’ FI-CGA scores at point of service through their electronic medical records.

Given the lack of evidence regarding effective pharmacological and non-pharmacological interventions for pediatric mild traumatic brain injury (mTBI) and the resultant lack of treatment recommendations reflected in consensus guidelines, variation in the management of pediatric mTBI is to be expected. We therefore surveyed practitioners across 15 centers in the United States and Canada who care for children with pediatric mTBI to evaluate common-practice variation in the management of pediatric mTBI. The survey, developed by a panel of pediatric mTBI experts, consisted of a 10-item survey instrument regarding providers' perception of common pediatric mTBI symptoms and mTBI interventions. Surveys were distributed electronically to a convenience sample of local experts at each center. Frequencies and percentages (with confidence intervals [CI]) were determined for survey responses. One hundred and seven respondents (71% response rate) included specialists in pediatric Emergency Medicine, Sports Medicine, Neurology, Neurosurgery, Neuropsychology, Neuropsychiatry, Physical and Occupational Therapy, Physiatry/Rehabilitation, and General Pediatrics. Respondents rated headache as the most prevalently reported symptom after pediatric mTBI, followed by cognitive problems, dizziness, and irritability. Of the 65 (61%; [95% CI: 51,70]) respondents able to prescribe medications, non-steroidal anti-inflammatory medications (55%; [95% CI: 42,68]) and acetaminophen (59%; [95% CI: 46,71]) were most commonly recommended. One in five respondents reported prescribing amitriptyline for headache management after pediatric mTBI, whereas topiramate (8%; [95% CI: 3,17]) was less commonly reported. For cognitive problems, methylphenidate (11%; [95% CI: 4,21]) was used more commonly than amantadine (2%; [95% CI: 0,8]). The most common non-pharmacological interventions were rest ("always" or "often" recommended by 83% [95% CI: 63,92] of the 107 respondents), exercise (59%; [95%CI: 49,69]), vestibular therapy (42% [95%CI: 33,53]) and cervical spine exercises (29% [95%CI: 21,39]). Self-reported utilization for common pediatric mTBI interventions varied widely across our Canadian and United States consortium. Future effectiveness studies for pediatric mTBI are urgently needed to advance the evidence-based care.

ObjectiveThe nosology for classifying structural MRI findings following pediatric mild traumatic brain injury (pmTBI) remains actively debated. Radiologic common data elements (rCDE) were developed to standardize reporting in research settings. However, some rCDE are more specific to trauma (probable rCDE). Other more recently proposed rCDE have multiple etiologies (possible rCDE), and may therefore be more common in all children. Independent cohorts of patients with pmTBI and controls were therefore recruited from multiple sites (New Mexico and Ohio) to test the dual hypothesis of a higher incidence of probable rCDE (pmTBI > controls) vs similar rates of possible rCDE on structural MRI.MethodsPatients with subacute pmTBI (n = 287), matched healthy controls (HC; n = 106), and orthopedically injured (OI; n = 71) patients underwent imaging approximately 1 week postinjury and were followed for 3–4 months.ResultsProbable rCDE were specific to pmTBI, occurring in 4%–5% of each sample, rates consistent with previous large-scale CT studies. In contrast, prevalence rates for incidental findings and possible rCDE were similar across groups (pmTBI vs OI vs HC). The prevalence of possible rCDE was also the only finding that varied as a function of site. Possible rCDE and incidental findings were not associated with postconcussive symptomatology or quality of life 3–4 months postinjury.ConclusionCollectively, current findings question the trauma-related specificity of certain rCDE, as well how these rCDE are radiologically interpreted. Refinement of rCDE in the context of pmTBI may be warranted, especially as diagnostic schema are evolving to stratify patients with structural MRI abnormalities as having a moderate injury.

Objectives As schools plan for re-opening, understanding the potential role children play in the coronavirus infectious disease 2019 (COVID-19) pandemic and the factors that drive severe illness in children is critical. Study design Children ages 0-22 years with suspected severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection presenting to urgent care clinics or being hospitalized for confirmed/suspected SARS-CoV-2 infection or multisystem inflammatory syndrome in children (MIS-C) at Massachusetts General Hospital were offered enrollment in the Massachusetts General Hospital Pediatric COVID-19 Biorepository. Enrolled children provided nasopharyngeal, oropharyngeal, and/or blood specimens. SARS-CoV-2 viral load, ACE2 RNA levels, and serology for SARS-CoV-2 were quantified. Results A total of 192 children (mean age, 10.2 ± 7.0 years) were enrolled. Forty-nine children (26%) were diagnosed with acute SARS-CoV-2 infection; an additional 18 children (9%) met the criteria for MIS-C. Only 25 children (51%) with acute SARS-CoV-2 infection presented with fever; symptoms of SARS-CoV-2 infection, if present, were nonspecific. Nasopharyngeal viral load was highest in children in the first 2 days of symptoms, significantly higher than hospitalized adults with severe disease (P = .002). Age did not impact viral load, but younger children had lower angiotensin-converting enzyme 2 expression (P = .004). Immunoglobulin M (IgM) and Immunoglobulin G (IgG) to the receptor binding domain of the SARS-CoV-2 spike protein were increased in severe MIS-C (P Conclusions This study reveals that children may be a potential source of contagion in the SARS-CoV-2 pandemic despite having milder disease or a lack of symptoms; immune dysregulation is implicated in severe postinfectious MIS-C.

Simple Summary The consumption of dietary fructose as sugar and high fructose corn syrup (HFCS), which is abundant in soft drinks, has markedly increased. This trend has been accompanied by an alarmingly increased incidence of non-alcoholic fatty liver disease (NAFLD). Recent studies using disease animal models such as mice and rats have revealed several important aspects of how our body handles fructose, especially when it is consumed in a large amount. Moreover, not only our bodily organs, but also microorganisms residing in the gut, have been shown to actively digest fructose and contribute to NAFLD. In this article, we summarize recent progress in our understanding of fructose metabolism at the organismal level. This review assembles scientific evidence that encourages the public to avoid an excess intake of fructose to prevent NAFLD and suggests potential drug targets to treat the disease. Abstract NAFLD has alarmingly increased, yet FDA-approved drugs are still lacking. An excessive intake of fructose, especially in liquid form, is a dietary risk factor of NAFLD. While fructose metabolism has been studied for decades, it is still controversial how fructose intake can cause NAFLD. It has long been believed that fructose metabolism solely happens in the liver and accordingly, numerous studies have investigated liver fructose metabolism using primary hepatocytes or liver cell lines in culture. While cultured cells are useful for studying detailed signaling pathways and metabolism in a cell-autonomous manner, it is equally important to understand fructose metabolism at the whole-body level in live organisms. In this regard, recent in vivo studies using genetically modified mice and stable isotope tracing have tremendously expanded our understanding of the complex interaction between fructose-catabolizing organs and gut microbiota. Here, we discuss how the aberrant distribution of fructose metabolism between organs and gut microbiota can contribute to NAFLD. We also address potential therapeutic interventions of fructose-elicited NAFLD.

Background: Psychosocial stress is a common comorbidity in chronic hepatitis B (CHB) patients. A diagnosis of CHB, the primary risk factor for liver cancer among Asian Americans, can be a significant source of psychological and emotional stress. Although the disease can be life-changing, there is a paucity of research on psychosocial stress in CHB patients. The purpose of this study is to examine the prevalence of serious psychological distress (SPD) and factors associated with SPD in Asian CHB patients. Method: It is a prospective study design with subjects identified from an existing patient cohort that were enrolled and then subsequently followed up. Information was gathered from the CHB patients using face-to-face interviews in Korean or English. Serious psychological distress was measured by the Kessler Scale (K6). Measures of stressful life events and Hepatitis B Quality of Life (HBQOL) (e.g., psychological well-being, anticipation anxiety, stigma) were used. A multivariate logistic regression model (including gender, age, level of education) was conducted for analysis. Results. Of 50 CHB patients 18 years and older, the 12-month prevalence of SPD was estimated at 20% using the optimal cut-off (>=13). In adjusted regression analysis, stressful life events and HBQOL-stigma were related to serous psychological distress: Those who had stressful life events (aOR=3.10, 95% CI 1.26-7.64) and those who had high scores of stigma (aOR=1.19, 95% CI 0.97-1.44, p=.08) had higher psychological distress. Those with more than a college education had decreased psychological distress (aOR=0.09, 95% CI 0.01-0.82). Conclusion: The finding indicates CHB patients had a higher prevalence of serious psychological distress than the general Asian population (2.6% from California Health Interview Survey). Stigma connected to hepatitis B diagnosis and stressful life events were important factors associated with mental health. This suggests that disease burden caused by hepatitis B infection may lead to poor mental health. Future studies will identify those who are at a high likelihood of developing a mental disorder and develop effective interventions for early detection of mental illness. Citation Format: Hee-Soon Juon, Grace Park, Klassen Ann, Hie-Won Hann. Factors associated with psychological distress among chronic hepatitis B patients [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr A102.

Neurosensory abnormalities are frequently observed following pediatric mild traumatic brain injury (pmTBI) and may underlie the expression of several common concussion symptoms and delay recovery. Importantly, active evaluation of neurosensory functioning more closely approximates real-world (e.g., physical and academic) environments that provoke symptom worsening. The current study determined whether symptom provocation (i.e., during neurosensory examination) improved classification accuracy relative to pre-examination symptom levels and whether symptoms varied as a function of point of care. Eighty-one pmTBI were recruited from the pediatric emergency department (PED; n = 40) or outpatient concussion clinic (n = 41), along with matched (age, sex, and education) healthy controls (HC; n = 40). All participants completed a brief (∼ 12 min) standardized neurosensory examination and clinical questionnaires. The magnitude of symptom provocation upon neurosensory examination was significantly higher for concussion clinic than for PED patients. Symptom provocation significantly improved diagnostic classification accuracy relative to pre-examination symptom levels, although the magnitude of improvement was modest, and was greater in the concussion clinic. In contrast, PED patients exhibited worse performance on measures of balance, vision, and oculomotor functioning than the concussion clinic patients, with no differences observed between both samples and HC. Despite modest sample sizes, current findings suggest that point of care represents a critical but highly under-studied variable that may influence outcomes following pmTBI. Studies that rely on recruitment from a single point of care may not generalize to the entire pmTBI population in terms of how neurosensory deficits affect recovery.

HIV infection has been associated with increased diabetes risk, but prior work has mostly focused on insulin resistance, as opposed to beta cell effects, or included patients on antiretroviral therapies (ART) directly linked to metabolic toxicity. In this analysis, we measured markers of glucose homeostasis and beta cell function, stress, and death in fasting sera from a cross section of HIV+ individuals off ART (n = 43), HIV+ individuals on ART (n = 23), and HIV- controls (n = 39). Markers included glucose, HOMA%S, HOMA%B, proinsulin:C-peptide ratio (PI:C ratio), and circulating preproinsulin (INS) DNA. We performed multiple linear regressions with adjustments for age, sex, race, BMI, and smoking status. Compared to HIV- controls, HIV+ participants off ART exhibited similar beta cell function and insulin sensitivity, without increases in markers of beta cell stress or death. Specifically, in HIV+ participants with CD4 counts

Frailty threatens the quality of life of seniors. As the leading cause for the disproportionate use of health care resources, frailty is a serious threat to the sustainability of the health care system. Mounting evidence suggests frailty can be prevented with early assessment and management. Primary care providers are well positioned to identify “at risk” seniors and enact care plans to prevent frailty from progressing. The Comprehensive Geriatric Assessment (CGA) has repeatedly demonstrated value in the clinical setting for enhanced outcomes for seniors. The Frailty Index (FI) is a reliable and sensitive measure of frailty that can be generated from the CGA (FI-CGA). Implementing the FI-CGA into the electronic medical records of primary care can enable the use of a reliable and valid measurement of frailty at point of service. Using the electronic FI-CGA in the clinic setting guides healthcare providers to make more meaningful and comprehensive healthcare decisions. Based on the degree of frailty, health coaching aims to both support the seniors competence in their self-management as well the adoption of health promoting behaviors like exercise and improved nutritional choices. The Community Actions and Resources Empowering Seniors (CARES) collaborative model in primary care aims to provide substantial healthcare cost savings over time by addressing frailty at early stages and decreasing costly hospital admissions. CARES further aims to improve the quality of life of seniors by generating a sense of empowerment and control over their risk for frailty through health coaching to adopt healthy aging strategies.

Frailty is characterized by loss of biological reserves across multiple systems and associated with increased risks of adverse outcomes. A Frailty Index (FI) constructed using items from the Comprehensive Geriatric Assessment (CGA) has been validated in geriatric medicine settings to estimate the level of frailty. Traditionally, the CGA used a paper form and the CGA-based FI calculation was a manual process. Here, we reported building of an electronic version of the assessment on personal computers (PC), i.e., standalone eFI-CGA, to benefit frailty assessment at points of care. The eFI-CGA was implemented as a software tool on the WinForms platform. It automated the FI calculation by counting deficits accumulation across multiple domains assessing medical conditions, cognition, balance, and dependency of activities of daily living. Debugging, testing, and optimization were performed to enhance the software performance with respect to automation accuracy (processing algorithm), friendly user interface (user manual and feedback), and data quality control (missing data and value constraints). Systematically-designed simulation dataset and anonymous real-world cases were both applied. The optimized assessment tool resulted in fast and convenient conductance of the CGA, and a 100% accuracy rate of the eFI-CGA automation for up to four decimals. The stand-alone eFI-CGA implementation has provided a PC-based software tool for use by geriatricians and primary and acute care providers, benefiting early detection and management of frailty at points of care for older adults.

Objective The objective of this clinical trial was to determine if an intervention of listening to nursery songs with integrated heartbeat sounds resulted in changes in anxiety levels in infants and children younger than 4 years in an emergent setting. Methods This is a randomized single-blinded controlled trial. The study included 62 children younger than 4 years who were deemed by the emergency physician to need a computed tomographic (CT) scan. The experimental group (Exp) (n = 30) listened to recorded children's songs with integrated heartbeat sounds ( Baby Go To Sleep compact disc) before and during the head CT. The controls (Con) (n = 32) had no music. Two scales to measure agitation were completed by a trained research associate: (1) a 10-cm visual analog scale (VAS) and (2) the Modified Ramsay Sedation Scale (MRSS). The research associate wore headphones blocking out all music. The research associate recorded agitation levels preintervention and postintervention on the 2 scales, whether there was successful completion of the head CT without pharmacologic intervention, and the frequency of medication use. Mann-Whitney U , t test, and logistic regression were used for analysis, and P Results There were no differences between groups in the age, sex, initial vital signs, diagnostic category, ethnicity, insurance status, rate of completion of head CT, rate of medication use, hospital admissions, or initial VAS or MRSS score. There was improvement on the VAS score in 53% of the Exp group subjects and 25% of the Con group subjects. The VAS score in the Exp group improved by 1.6 cm, whereas the Con group worsened by 0.8 cm after the intervention (difference = 2.4 cm, P = .03). There were no significant changes in MRSS scores. Accounting for age, sex, and admission status, the adjusted odds of having an improved sedation score were 3.2 (1.0-9.7) in the Exp group. Conclusion Measured on a VAS, there was a significant decrease in agitation in children undergoing a head CT when children's songs with integrated heartbeat sounds were played before and during the procedure.

Aim This study aimed to explore the potential of detecting hepatocellular carcinoma (HCC)-associated DNA markers, TP53 249T mutations and aberrant methylation of RASSF1A and GSTP1 genes, for monitoring HCC recurrence. HCC remains a leading cause of death worldwide, with one of the fastest growing incidence rates in the US. While treatment options are available and new ones emerging, there remains a poor prognosis of this disease mostly due to its late diagnosis and high recurrence rate. Although there are no specific guidelines addressing how HCC recurrence should be monitored, recurrence is usually monitored by serum-alpha fetal protein and imaging methods such as magnetic resonance imaging (MRI). However, early detection of recurrent HCC remains limited, particularly at the site of treated lesion. Methods Here, the authors followed 10 patients that were treated for a primary HCC, and monitored for months or years later. At these follow-up visits, urine was collected and tested retrospectively for 3 DNA biomarkers that associate with HCC development. Results This 10-patient study compared detection of urine DNA markers with MRI for monitoring HCC recurrence. Five patients were confirmed by MRI for recurrence, and all 5 had detectable DNA biomarkers up to 9 months before recurrence confirmation by MRI. Conclusion Overall, this suggests that detection of HCC-associated DNA markers in urine could provide a promising tool to complement detection of recurrent HCC by imaging.

Using exome sequence data from 159 families participating in the National Institutes of Health Undiagnosed Diseases Program, we evaluated the number and inheritance mode of reportable incidental sequence variants.Following the American College of Medical Genetics and Genomics recommendations for reporting of incidental findings from next-generation sequencing, we extracted variants in 56 genes from the exome sequence data of 543 subjects and determined the reportable incidental findings for each participant. We also defined variant status as inherited or de novo for those with available parental sequence data.We identified 14 independent reportable variants in 159 (8.8%) families. For nine families with parental sequence data in our cohort, a parent transmitted the variant to one or more children (nine minor children and four adult children). The remaining five variants occurred in adults for whom parental sequences were unavailable.Our results are consistent with the expectation that a small percentage of exomes will result in identification of an incidental finding under the American College of Medical Genetics and Genomics recommendations. Additionally, our analysis of family sequence data highlights that genome and exome sequencing of families has unavoidable implications for immediate family members and therefore requires appropriate counseling for the family.

The primary purpose of the study was to determine the factors that are associated with repeat emergency department (ED) visits in children with diabetes.Emergency department charts and billing data for children up to 18 years of age presenting to the ED with diabetic diagnoses over a 4-year period were reviewed.The overall rate of repeat visits to the ED was 0.24 visits per person-year of follow-up time. In univariate analyses, there were statistically significant effects of age, insurance category, sex, type of practice, and income. In a multivariate analysis, there was a significant interaction of insurance category and age. Revisit rate ratios for children older than 6 years were higher for those with Medicaid compared with those with commercial insurance. Diabetic boys were less likely to revisit the ED than were girls.Type of insurance was associated with repeated visits to the ED in children with diabetes. Other contributing factors included age group and sex.

Introduction: Frailty is a common geriatric syndrome associated with poor quality of life putting seniors at risk for adverse outcomes including falls, disability, institutionalization and death. Research has shown there are natural protective factors to frailty, and it is possible to slow the progression of frailty in such a way that at the time of death seniors are less frail However, proactive identification and measurement of frailty is not part of standard practice in primary health care and community settings, compounded by a lack of frailty awareness and readily accessible assessment tools. Therefore, seniors are at risk for becoming unnecessarily frail. Description of CARES: The Community Actions and Resources Empowering Seniors (CARES) project partnered primary care providers (PCP), their pre frail patients and community senior support organization volunteer coaches to enact a Wellness Plan that addresses health protective goals. The Wellness Plan was created by the senior and their PCP after a Comprehensive Geriatric Assessment (CGA) and created health protective goals in: intellectual, physical, emotional, social, spiritual and vocational fields. The volunteer coaches were trained by the preexisting Active Choices, a Self-Management BC program funded by the Ministry of Health. Following a 6 month period where Active Choices volunteers supported and mentored the seniors by telephone, the participants were re-examined to assess impact if any on their Frailty Index scores. Key Findings: Early results indicate great uptake of the ‘coaching’ concept and the benefit of increased socialization as a result of regular participant-coach interactions. The PCP noted early in the project their less than optimal understanding of geriatric assessments and their lack of facility with assessment tools. Brief education offered by geriatrician was well received indicating future opportunity to increase knowledge transfer. The Community organizations saw the benefit of increasing health protective goals in pre frail seniors and the reciprocal benefit to their volunteer coaches. Further, there was great enthusiasm in the community organizations to partner with health care providers to help citizens of their community. 3 World Congress on Integrated Care, Mexico City, Mexico, 19-21 November, 2015 International Journal of Integrated Care – Volume 15, 17 Nov – URN:NBN:NL:UI:10-1-117260 – http://www.ijic.org Highlights: The CARES project was a joint initiative between two healthcare jurisdictions in Canada ( FHA in BC and NSHA in Halifax). Supported by the Canadian Foundation of Healthcare Improvement, the two Health Authority teams shared knowledge about geriatric assessments and community volunteer organizations across the country. Future collaboration will result in a web based ‘Frailty Portal’ that will be made available to both provinces through a research grant and enable PCPs to proactively diagnose, treat and refer frail seniors. Conclusion: Aging population and frail seniors are placing increasing pressure on the healthcare system,additionally there is fragmentation between the primary care, health authorities and community resources. Primary care providers regularly encounter frail persons and are ideally situated to incorporate proactive and best practices in their daily clinical work The CARES project, through a multijurisdictional sharing of knowledge and expertise has successfully integrated PCP, health authority and community volunteers to enact health protective wellness plans to delay frailty showing improved frailty scores over a 6 month period in pre frail seniors. Conference abstract Spanish Introduccion: La fragilidad es un sindrome geriatrico comun asociado con la mala calidad de vida de la tercera edad que pone en riesgo de resultados adversos, incluyendo caidas, discapacidad, institucionalizacion y muerte. La investigacion ha demostrado que hay factores protectores naturales a la fragilidad, y es posible retardar la progresion de la fragilidad de una manera tal que en el momento de la tercera edad de muerte son menos fragiles Sin embargo, la identificacion proactiva y la medicion de la fragilidad no es parte de la practica estandar en los entornos de atencion de la salud y de la comunidad primaria, agravada por la falta de conciencia de la fragilidad y las herramientas de evaluacion de facil acceso. Por lo tanto, las personas mayores estan en riesgo de convertirse innecesariamente en personas fragiles. Descripcion de CARES: Las acciones de la comunidad y los recursos Empoderamiento de la tercera (CARES) se asocio con proveedores de atencion primaria (PCP), sus pacientes pre fragiles y apoyo de entrenadores de alto nivel de la comunidad, organizacion de voluntarios para promulgar un plan de bienestar que se ocupa de los objetivos de proteccion de salud. El Plan de Salud fue creado con el ejecutivo y su PCP despues de una valoracion geriatrica integral (CGA) y creo los objetivos de proteccion de la salud: intelectual, fisico, emocional, social, espiritual y campos vocacionales. Los entrenadores voluntarios fueron entrenados con las opciones activas pre existentes, un programa de Autogestion BC financiado por el Ministerio de Salud. Despues de un periodo de 6 meses donde las opciones activas voluntarios apoyados y asesorados las personas mayores por telefono, los participantes fueron reexaminada para evaluar el impacto en su caso en sus puntuaciones fragilidad Indice. Principales conclusiones: Los primeros resultados indican una gran absorcion del concepto 'Entrenamiento' y el beneficio de una mayor socializacion, como resultado de las interacciones regulares participante-entrenador. El PCP senalo al principio del proyecto menos de su comprension optima de las evaluaciones geriatricas y su falta de facilidad con herramientas de evaluacion. Educacion Breve ofrecida por geriatras fue bien recibida indicando futuras oportunidades de aumentar la transferencia de conocimientos. Las organizaciones comunitarias vieron la ventaja de aumentar los objetivos de proteccion de la salud en ancianos pre fragiles y el beneficio reciproco a sus entrenadores voluntarios. Ademas, hubo un gran entusiasmo en las organizaciones de la comunidad para asociarse con proveedores de atencion medica para ayudar a los ciudadanos de su comunidad. Aspectos destacados: El proyecto CARES fue una iniciativa conjunta entre dos jurisdicciones de salud en Canada (FHA en BC y NSHA en Halifax). Con el apoyo de la Fundacion Canadiense de Mejoramiento de la salud, los dos equipos de la Autoridad de Salud compartieron conocimientos sobre evaluaciones geriatricas y organizaciones de voluntarios de la comunidad en todo el pais. Colaboracion que en el futuro se traducira en una web basada en un 'Portal de fragilidad "que se pondra a disposicion de ambas provincias a traves de una beca de investigacion y permitira que los medicos de cabecera puedan diagnosticar de forma proactiva, tratar y referir personas mayores fragiles. 3 World Congress on Integrated Care, Mexico City, Mexico, 19-21 November, 2015 International Journal of Integrated Care – Volume 15, 17 Nov – URN:NBN:NL:UI:10-1-117260 – http://www.ijic.org Conclusion: El envejecimiento de la poblacion y los ancianos fragiles estan poniendo una presion creciente sobre el sistema de salud, ademas, existe la fragmentacion entre la atencion primaria, las autoridades sanitarias y los recursos de la comunidad. Los proveedores de atencion primaria se encuentran con regularidad personas fragiles y estan perfectamente situados para incorporar practicas proactivas y mejores en su trabajo clinico diario. El proyecto CARES, a traves de un intercambio multijurisdiccional de conocimientos y experiencia ha integrado con exito PCP, autoridades de salud y voluntarios de la comunidad para promulgar la salud planes de bienestar de proteccion para retrasar la fragilidad que muestra las puntuaciones de fragilidad mejoradas durante un periodo de 6 meses en ancianos pre fragiles.

Background: A major effort is underway to integrate primary and community care in Canada's western province of British Columbia and in Fraser Health, its largest health authority. Integrated care is a critical component of Fraser Health's planning, to meet the challenges of caring for a growing, elderly population that is presenting more complex and chronic medical conditions.Description of integrated practice: An integrated care model partners family physicians with community-based home health case managers to support frail elderly patients who live at home. It is resulting in faster response times to patient needs, more informed assessments of a patient's state of health and pro-active identification of emerging patient issues.Early results: The model is intended to improve the quality of patient care and maintain the patients’ health status, to help them live at home confidently and safely, as long as possible. Preliminary pilot data measuring changes in home care services is showing positive trends when it comes to extending the length of a person's survival/tenure in the community (living in their home vs. admitted to residential care or deceased).Conclusion: Fraser Health's case manager–general practitioner partnership model is showing promising results including higher quality, appropriate, coordinated and efficient care; improved patient, caregiver and physician interactions with the system; improved health and prevention of acute care visits by senior adult patients.

Familial Mediterranean fever (FMF) is a recessively inherited autoinflammatory disorder with high carrier frequencies in the Middle East. Pyrin, the protein mutated in FMF, regulates caspase-1 activation and consequently IL-1beta production through cognate interaction of its N-terminal PYRIN motif with the ASC adaptor protein. However, the preponderance of mutations reside in pyrin's C-terminal B30.2 domain. Here we demonstrate direct interaction of this domain with caspase-1. In lysates from cells not expressing ASC, reciprocal GST pull-downs demonstrated the interaction of pyrin with the p20 and p10 catalytic subunits of caspase-1. Coimmunoprecipitations of pyrin and caspase-1 from THP-1 human monocytic cells were consistent with the interaction of endogenous proteins. The C-terminal B30.2 domain of pyrin is necessary and sufficient for the interaction, and binding was reduced by FMF-associated B30.2 mutations. Full-length pyrin attenuated IL-1beta production in cells transfected with a caspase-1/IL-1beta construct, an effect diminished by FMF-associated B30.2 mutations and in B30.2 deletion mutants. Modeling of the crystal structure of caspase-1 with the deduced structure of the pyrin B30.2 domain corroborated both the interaction and the importance of M694V and M680I pyrin mutations. Consistent with a net inhibitory effect of pyrin on IL-1beta activation, small interfering RNA (siRNA)-mediated pyrin knockdown in THP-1 cells augmented IL-1beta production in response to bacterial LPS. Moreover, the IL-1 receptor antagonist anakinra suppressed acute-phase proteins in a patient with FMF and amyloidosis. Our data support a direct, ASC-independent effect of pyrin on IL-1beta activation and suggest heightened IL-1 responsiveness as one factor selecting for pyrin mutations.

The introduction of highly portable computers extends the range of tools potentially useful to persons with functional impairments of prospective memory resulting from brain injury. This study reviews the experience of 12 patients with brain injury undergoing outpatient treatment using palmtop computers to assist with memory dependent activities in their everyday lives. During the initial supervised trial period, each was provided a palmtop computer based memory aid capable of generating audible and visible reminder cues. Subsequently, patients were contacted for follow-up between 2 months and 4 years after initial trial usage, and surveyed as to the utility of the computer. Nine patients found palmtop computers were useful during supervised trials. Seven of nine patients actually continued to use such devices after the usage trials had ended. Experience with this technology has shown it to be useful in a high proportion of patients for assisting with memory dependent functions.

Diffuse gastric adenocarcinoma or and ldquo;linitis plastica and rdquo; is characterized by a thickened and rigid stomach wall due to the diffuse infiltration of signet ring cells into the lower parts of the mucosa and submucosa of the stomach. This type of cancer is known to commonly metastasize to the liver, lungs, and ovaries, and metastasis to the gallbladder is extremely rare. We now report a case of a 79-year-old Caucasian female with diffuse gastric adenocarcinoma that metastasized to the gallbladder. The patient presented with symptoms mimicking acute cholecystitis. Histological analysis of the cholecystectomy specimen showed signet ring cells in the submucosa of the gallbladder wall. Further workup, which included esophagogastroduodenoscopy, revealed linitis plastic. This is the first case of gallbladder metastasis from diffuse gastric carcinoma reported in the United States. [Arch Clin Exp Surg 2012; 1(1.000): 54-57]

Retinal neovascularization (NV) is a serious complication of many ocular disease states, including diabetic retinopathy and retinopathy of prematurity (ROP). In these conditions, uncontrolled blood vessel growth results in severe vision loss; therefore, dietary interventions that could inhibit the progress of these diseases are clearly advantageous. Indeed, such a role for ω-3 polyunsaturated fatty acids (PUFAs), in particular eicosapentaenoic acid (EPA; C20:5 ω-3) and docosahexaenoic acid (DHA; C22:6 ω-3), in modulating angiogenesis is beginning to emerge.1–3 Dietary supplementation with ω-3 PUFAs has been shown to decrease pathologic retinal neovascularization in an animal model of oxygen-induced retinopathy (OIR).4 Although the health benefits of these fatty acids are now recognized for the prevention of cardiovascular disease, their mechanism of action and role in the modulation of vasoproliferative disorders are still poorly defined. Proliferative retinopathies proceed in two steps: the primary initiating insult is endothelial cell (EC) death, which results in capillary closure, ischemic hypoxia of the inner retina, and angiogenic growth factor production, leading to the second proliferative stage, which is characterized by sight-threatening NV. There is now a considerable amount of evidence to suggest that in the initial phase, vascular closure is caused by an oxidative-nitrosative insult.5–7 In the healthy vasculature, nitric oxide (NO) produced from eNOS has important antiapoptotic and survival functions, resulting in vasoprotection.5 In disease, however, there is a decrease in NO bioavailability and an increase in the generation of oxygen free radicals or O2−,6 the combined product of which is the highly reactive free radical peroxynitrite (ONOO−). Overall, this causes a shift in the nitroso-redox balance toward one which is pro-apoptotic resulting in adverse consequences on vessel integrity and culminating in vascular occlusion.5,8 The second proliferative NV phase is driven by vascular endothelial growth factor (VEGF) produced in response to tissue ischemia. The activity of VEGF is also dependent on free radical production, namely the production of eNOS and NADPH oxidase–derived NO and O2−, which act as second messengers to stimulate migration, proliferation, and angiogenesis.9–13 The role of ω-3 PUFAs in modifying these VEGF-mediated signaling cascades has not previously been described. NO and O2− are highly reactive short-lived free radicals that often must be produced in close proximity to their site of action to activate downstream signaling events. eNOS, the predominant NO-producing enzyme in the vasculature, facilitates localized signaling events by means an N-terminal acylation moiety that allows its subcellular localization to the plasma membrane and, in particular, to caveolae or lipid raft subdomains.14 These cholesterol-rich microdomains act as signal transduction scaffolds that facilitate the clustering of cell-surface receptors with downstream effector or adaptor molecules also localized to these domains, such as VEGFR-2 and the NADPH oxidase complex.15,16 In addition, they are enriched in the caveolae coat protein caveolin-1 (Cav-1), which is a potent negative regulator of eNOS.17 Indeed, the importance of this subcellular targeting for eNOS function is evident in studies showing that removal of the acyl group from eNOS misroutes the enzyme and reduces its activation by VEGF.18 Thus, it is clear that any disruption of the localization of eNOS to caveolae or lipid rafts will have significant effects both on NO production and on the efficiency of downstream signal transduction. PUFAs are incorporated into cellular membranes, where they can mediate their effects in 1 of 3 possible ways. First, they increase membrane fluidity and alter the subcellular localization of proteins.19,20 Second, through the competitive inhibition of the eicosanoid-synthesizing enzymes such as cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P-450 epoxygenases, these enzymes are necessary for arachidonic acid (AA; C20:4 ω-6)–derived eicosanoid production that is known to be proinflammatory and proangiogenic; ω-3 PUFAs compete with AA for access to these enzymes, reducing the production of AA-derived metabolites.21–23 Third, ω-3 PUFAs can be metabolized by COX and LOX to generate a different series of eicosanoids that are less inflammatory and have decreased growth-promoting properties.24,25 Here, because of the importance of subcellular localization for eNOS function, we were particularly interested in the effect that PUFA supplementation would have on microdomain composition. Indeed, some studies have shown that in macrovascular human umbilical vein endothelial cells (HUVECs), ω-3 PUFAs can disrupt eNOS caveolar localization.26,27 However, this finding was not correlated with angiogenic signaling pathways. In addition, there are significant differences between macrovascular and microvascular endothelial cells; importantly, cells of microvascular origin have significantly more Cav-1 resulting in the decreased sensitivity of microvascular ECs to atorvastatin compared with microvasculature ECs.28 Thus, such differences could potentially alter the responsiveness of microvascular ECs to ω-3 PUFA treatment and growth factor stimulation. Therefore, our aim was to investigate the effects of ω-3 PUFAs on NO and ROS production and to correlate these with angiogenic signaling and changes in subcellular localization of eNOS to caveolae in retinal microvascular endothelial cells (RMECs). In addition, because previous studies indicate that EPA and DHA may have different potencies, suggesting that one may have a therapeutic advantage, a major aim of this study was to perform a direct comparison between EPA and DHA.29