UC Irvine Department of Medicine

Introduction: Children and adolescents are not impervious to the unprecedented epidemic of opioid misuse in the United States. In 2016 more than 88,000 adolescents between the ages of 12–17 reported misusing opioid medication, and evidence suggests that there has been a rise in opioid-related mortality for pediatric patients. A major source of prescribed opioids for the treatment of pain is the emergency department (ED). The current study sought to assess the complex relationship between opioid administration, pain severity, and parent satisfaction with children’s care in a pediatric ED.

Methods: We examined data from a tertiary pediatric care facility. A health survey questionnaire was administered after ED discharge to capture the outcome of parental likelihood of providing a positive facility rating. We abstracted patient demographic, clinical, and top diagnostic information using electronic health records. Data were merged and multivariable models were constructed. 

Results: We collected data from 15,895 pediatric patients between the ages of 0–17 years (mean = 6.69; standard deviation = 5.19) and their parents. Approximately 786 (4.94%) patients were administered an opioid; 8212 (51.70%) were administered a non-opioid analgesic; and 3966 (24.95%) expressed clinically significant pain (pain score >/= 4). Results of a multivariable regression analysis from these pediatric patients revealed a three-way interaction of age, pain severity, and opioid administration (odds ratio 1.022, 95% confidence interval, 1.006, 1.038, P = 0.007). Our findings suggest that opioid administration negatively impacted parent satisfaction of older adolescent patients in milder pain who were administered an opioid analgesic, but positively influenced the satisfaction scores of parents of younger children who were administered opioids. When pain levels were severe, the relationship between age and patient experience was not statistically significant.

Conclusion: This investigation highlights the complexity of the relationship between opioid administration, pain severity, and satisfaction, and suggests that the impact of opioid administration on parent satisfaction is a function of the age of the child.

Aberration of the "gut-liver axis" contributes to the development and progression of metabolic dysfunction-associated steatotic liver disease (MASLD). Here, we use multi-omics to analyze the gut microbiota composition and metabolic profile of patients with type-2 diabetes mellitus (T2DM). T2DM patients were screened for liver disease by blood tests, ultrasound, and liver stiffness measurements. Stool microbiota was analyzed by 16S rRNA gene sequencing; metabolomic profiling by Nuclear Magnetic Resonance spectroscopy and Ultra-High Performance-Mass Spectrometry. Microbiome and metabolic signatures were analyzed in the whole cohort and in matched subsets to identify signatures specific for steatosis (MASLD±) or fibrosis (Fibrosis±). Gut permeability was assessed in-vitro using monolayers of MDCK cells and trans-epithelial electric resistance (TEER). Cytokine profile was assessed in serum and stools.Overall, 285 patients were enrolled: 255 serum, 252 urine and 97 stool samples were analyzed. Anaeroplasma and Escherichia/Shigella ASVs were higher, while Butyricicoccus ASVs were lower in those with normal liver. In MASLD±, Butyricicoccus ASV was significantly higher in those with steatosis. In the Fibrosis±, Butyricicoccus ASV was significantly lower in those with fibrosis. Glycochenodeoxycholic acid-3-sulfate (G-UDCA-3S) appeared to be higher in MASLD with fibrosis. Fecal water from patients with MASLD and fibrosis caused the greatest drop in the TEER vs those with normal liver; this was reversed with protease inhibitors. Finally, fecal IL-13 was lower in MASLD with fibrosis. We identified microbiome signatures which were specific for steatosis and fibrosis and independent of other metabolic risk factors. Moreover, we conclude that protease-related gut permeability plays a role in those MASLD patients with fibrosis, and that disease progression is linked to a gut-liver axis which is at least partially independent of T2DM.

Excessive fructose intake is a risk factor for the development of obesity and its complications. Targeting ketohexokinase (KHK), the first enzyme of fructose metabolism, has been investigated for the management of metabolic dysfunction-associated steatotic liver disease (MASLD). We compared the effects of systemic, small molecule inhibitor of KHK enzymatic activity with hepatocyte-specific, N-acetylgalactosamine siRNA-mediated knockdown of KHK in mice on an HFD. We measured KHK enzymatic activity, extensively quantified glycogen accumulation, performed RNA-Seq analysis, and enumerated hepatic metabolites using mass spectrometry. Both KHK siRNA and KHK inhibitor led to an improvement in liver steatosis; however, via substantially different mechanisms, KHK knockdown decreased the de novo lipogenesis pathway, whereas the inhibitor increased the fatty acid oxidation pathway. Moreover, KHK knockdown completely prevented hepatic fructolysis and improved glucose tolerance. Conversely, the KHK inhibitor only partially reduced fructolysis, but it also targeted triokinase, mediating the third step of fructolysis. This led to the accumulation of fructose-1 phosphate, resulting in glycogen accumulation, hepatomegaly, and impaired glucose tolerance. Overexpression of wild-type, but not kinase-dead, KHK in cultured hepatocytes increased hepatocyte injury and glycogen accumulation after treatment with fructose. The differences between KHK inhibition and knockdown are, in part, explained by the kinase-dependent and -independent effects of KHK on hepatic metabolism.

BACKGROUND: Heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF) are challenging conditions to treat due to complex pathophysiology and associated comorbidities. However, recent trials have demonstrated improved outcomes with guideline-directed medical therapy (GDMT) for each subtype of heart failure. OBJECTIVE: We investigated the relationship of determinants of health and risk factors with GDMT use for HFrEF and HFpEF in a large, diverse US cohort. METHODS: Using the NIH-sponsored All of Us Program, we compared demographics, risk factors (e.g., hypertension, diabetes, smoking), and SDOH measures between HFrEF and HFpEF in US adults aged 18 years and older. We examined the proportions of HFrEF patients receiving fewer than four or all four GDMTs. HFpEF patients receiving two medications were compared with those receiving less than two recommended medications. Multiple logistic regression was used for data analysis. RESULT: Of 6049 HFrEF patients, 5838 (97 %) received fewer than four GDMTs, and 210 (3 %) received quadruple therapy. Of 3774 HFpEF patients, 162 (4 %) were on 2/3 GDMT, and only 38 (1 %) were on all three recommended medications. Patients with ASCVD and diabetes had higher odds of being on more than half of the recommended GDMT for both HFrEF and HFpEF. Additionally, females had higher odds of being on 2/3 GDMT for HFpEF (1.46 [1.08, 2.00]). Race, income, education, and health insurance types did not predict GDMT optimization. CONCLUSION: HFrEF and HFpEF GDMT remain underutilized. Future efforts to address comorbidities and system-wide healthcare interventions may improve heart failure GDMT.

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BACKGROUND: Chronic kidney disease is common, affecting up to 13 % of the global population, and is predicted to become the fifth leading cause of life years lost by 2040. Individuals with end-stage kidney disease commonly develop complications such as protein-energy wasting and cachexia which further worsens their prognosis. The syndrome of renal cachexia is poorly understood, under-diagnosed and even if recognised has limited treatment options. OBJECTIVE: To explore the lived experience of renal cachexia for individuals with end-stage kidney disease and the interrelated experiences of their carers. DESIGN: This interpretive phenomenological study was designed to facilitate an in-depth exploration of how patients and carers experience of renal cachexia. To improve and document the quality, transparency, and consistency of patient and public involvement in this study the Guidance for Reporting Involvement of Patients and the Public-Short Format was followed. SETTING: The study was conducted across two nephrology directorates, within two healthcare trusts in the United Kingdom. PARTICIPANTS: Seven participants who met the inclusion criteria were recruited for this study, four patients (three female, one male) and three carers (two male, one female). METHODS: We employed a purposive sampling strategy. Data collection was conducted between July 2022 and December 2023. Interviews were semi-structured, audio-recorded, transcribed verbatim and analysed in six steps by two researchers using interpretive phenomenological analysis. Ethical approval was approved by the Office for Research Ethics Committees Northern Ireland (Reference: 22/NI/0107). RESULTS: Analysis generated six group experiential themes: the lived experience of appetite loss, functional decline and temporal coping, weight loss a visual metaphor of concern, social withdrawal and vulnerability, the emotional toll of eating challenges and psychological strain amidst a lack of information about cachexia. CONCLUSION: This is the first qualitative study exploring the lived experience of renal cachexia for patients and carers. Our study highlights that psycho-social and educational support is urgently needed. Additionally, healthcare professionals need better information provision to help them to recognise and respond to the needs of this population. Further research is required to develop models of holistic support which could help patients and carers cope with the impact of renal cachexia and optimally manage this syndrome within the family unit. REGISTRATION: N/A.

Psychological stress among frontline healthcare workers (HCWs) increased during the COVID-19 pandemic, elevating mental health risks. Heart rate variability biofeedback (HRV-BF) is an evidence-based intervention with potential to reduce psychological burden on frontline HCWs; however, no studies have examined its use among this population since the pandemic began. We designed a trial to assess the effects of a brief HRV-BF intervention delivered via telemedicine on measures of anxiety, depression and stress, and heart rate variability, compared to an in-person intervention. We hypothesised that the telemedicine intervention would be non-inferior to the in-person intervention. Using a randomized comparison trial design, we tested a 10-day brief heart rate variability biofeedback intervention among frontline HCWs during the COVID-19 pandemic. They received remote, 30-min guided sessions every other day and were taught methods of heart rate variability biofeedback. Depression, anxiety and stress were assessed at baseline, 10 days, and 40 days with additional measures of anxiety measured before and after each session. HRV scores were collected at baseline, as well as during the course of the 10 days. Multilevel modelling was used to examine the change in depression, anxiety, stress and HRV scores across multiple time points and session types (telemedicine vs. in-person). There was no significant differences between telemedicine (n = 32) and in-person (n = 15) interventions on the main outcomes. Both session types showed a significant decrease in depression, anxiety and stress scores across the entire intervention, and HRV scores significantly increased across both groups. Anxiety levels also significantly decreased after each session. The non-inferiority of the telemedicine intervention to a comparable in-person intervention affirms its promise for decreasing anxiety, depression and stress among frontline HCWs and may offer a cost-effective and feasible tool to use in crises situations.

BACKGROUND: Improving quality of life (QOL) in advanced and metastatic cancer is a priority with increasing survivorship. This systematic review synthesizes psychosocial and behavioral interventions incorporating culture with the goal of examining their benefit for understudied and medically underserved populations with advanced and metastatic cancer. METHOD: Reports were systematically screened for (1) a focus on advanced and metastatic cancer survivors, (2) psychosocial or behavioral intervention intended to improve QOL, (3) evidence of incorporating the culture(s) of understudied/underserved populations, and (4) availability in English. Bias was evaluated using the JBI Critical Appraisal Checklist and the Methodological index for non-randomized studies. Qualitative synthesis and quantitative meta-analyses were completed. RESULTS: Eighty-six reports containing 5981 participants data were examined. Qualitative synthesis of 23 studies identified four overarching themes relevant for incorporating culture in interventions. Meta-analysis of 19 RCTs and 4 quasi-experimental studies containing considerable heterogeneity indicated greater improvements in QOL (g = 0.84), eudaimonic well-being (g = 0.53), distress (g = -0.49), and anxiety (g = -0.37) for main intervention conditions compared to controls. Meta-analysis of 10 single-arm trials containing minimal to moderate heterogeneity found benefit for anxiety (g = -0.54), physical symptoms (g = -0.39), and depression (g = -0.38). CONCLUSION: Psychosocial and behavioral interventions with cultural incorporation appear beneficial for improving QOL-related outcomes in advanced and metastatic cancer. Studies incorporating culture in psychosocial or behavioral interventions offer noteworthy insight and suggestions for future efforts such as attending to deep cultural structure.

BACKGROUND: Pain plays a significant role in emergency department (ED) visits, however safe and effective nonpharmacologic options are needed. Prior studies of acupuncture in the ED reported pain reduction with minimal side effects, but most were small and single site. METHODS: We conducted ACUITY, a prospectively designed multi-center feasibility RCT. Our goal was to recruit 165 adults with acute non-emergent pain ≥4 on a 0-10-point scale at three EDs affiliated with BraveNet Practice Based Research Network. At baseline and 45-60 min later (post), participants self-assessed their pain and anxiety using a 0-10 rating scale. The primary feasibility outcome was recruitment of participants, whereas secondary outcomes were retention, and participant/provider acceptability. RESULTS: From May 3, 2021, to September 24, 2022, 632 eligible individuals were approached and 165 enrolled (165/632: 26.1 %), meeting our recruitment goal. Notably, 42.4 % of enrollees were Black/African American, 42.4 % were White/Caucasian, and 13.9 % were Hispanic/Latino. Participants were randomized to Acupuncture (n = 83) or Usual care (n = 82), of which 151 (91.5 %) and 128 (77.6 %) provided pain and anxiety scores at post-treatment and 1-week respectively. Acupuncture was rated acceptable to participants and providers. Mean pain ratings (pre-to-post) were 7.4 (2.2) to 4.8 (2.8) for acupuncture and 7.1 (2.3) to 6.4 (2.5) for usual care. Mean anxiety ratings (pre-to-post) were 4.5 (3.4) to 2.5 (2.6) for acupuncture and 4.1 (3.4) to 3.5 (3.2) for usual care. CONCLUSION: Successful completion of ACUITY indicates we have the expertise and preliminary data to conduct a future definitive, multi-center RCT. TRIAL REGISTRATION CLINICAL TRIALSGOV: NCT04880733.

INTRODUCTION: The objective of this study was to examine the interplay of polygenic risk and individual lifestyle factors (and a composite score of lifestyle) as antecedents of CHD in a large multiethnic cohort. METHODS: We used Genetic Epidemiology Resource in Adult Health and Aging (GERA) cohort participants free of CHD at baseline (n = 60,568; 67 % female; 18 % non-European). The individual and joint associations of smoking, Mediterranean diet pattern, level of physical activity and polygenic risk with incident CHD were assessed using Cox regression adjusting for genetic ancestry and non-mediating risk factors. Hazard ratios (HRs) and number needed to treat (NNT) were estimated according to these lifestyle factors and polygenic risk categories. Strengths included large sample size, long-follow-up, ethnic diversity, a clinically-validated polygenic risk score (PRS), and rich phenotype information. RESULTS: After 14 years of follow-up, there were 3159 incident CHD events. We observed no statistically significant interactions between individual lifestyle factors and polygenic risk (all p > 0.23). For individuals with a high genetic risk, moving from the worse lifestyle combination (no favorable lifestyle factors) to the best lifestyle combination (all three) is associated with 52 % lower rate of CHD. The NNT was highest in the low polygenic risk group (34), lowest in the high polygenic risk group [19] and in-between (Jin et al., 2011) [24] in the intermediate polygenic risk group. CONCLUSIONS: Lifestyle and polygenic risk together influence the risk of incident CHD. Our results support consideration of polygenic risk in lifestyle interventions because those with high polygenic risk are likely to derive the most benefit.