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Item Deconstructing Disease-Related Malnutrition: A New Assessment Framework for Clinical Practice(Elsevier, 2023-04-27) St-Jules, David E.; Lloyd, Lyn; Meade, Anthony; Biruete, Annabel; Kistler, Brandon; Carrero, Juan-Jesus; Medicine, School of MedicineProtein-energy wasting (PEW) is a key cause of functional impairment and poor health outcomes in people with chronic kidney disease. While PEW can be mitigated with nutrition therapy, it is a complex myriad of disorders with numerous interacting etiologies and corresponding presentations, which make it difficult to diagnose and manage in practice. A variety of scoring rubrics have been developed to facilitate malnutrition assessment. Although these tools have greatly benefited the recognition and treatment of PEW, the typical format of grading specified PEW indicators has the potential to overlook or overstate highly relevant individual-specific factors. This review presents a simple framework for malnutrition assessment that can be used to complement and evaluate conventional assessment tools. Unlike standard tools, which are designed to identify and rate malnutrition risk and severity, the malnutrition framework is conceptual model that organizes PEW assessment into three distinct, but interacting facets of PEW risk: nutrient balance, nutrition status, and malnutrition risk. The new framework encourages critical thinking about PEW risk that may help clinicians plan and interpret assessments to efficiently and effectively manage this condition.Item Growth Anthropometrics as a Metric of Malnutrition Disparities Among Young Children Affected by HIV who are Orphaned Maternally, Paternally, or Totally in Western Kenya: A Retrospective Chart Review(Sage, 2023-02-17) Jansen, Shae; Apondi, Edith; Ayaya, Samuel O.; Kim, Jiae; McHenry, Megan S.; Graduate Medical Education, School of MedicineThis retrospective study investigated growth outcomes of Kenyan children born to women living with HIV, comparing children who were orphaned maternally, paternally, and totally (both parents deceased) to those who were non-orphaned. We reviewed HIV clinic visits performed in Kenya from January 2011 to August 2016 in children 0 to 4 years of age. Malnutrition was assessed using stunting, underweight status, and wasting (z-scores of ≤-2). Descriptive statistics, Chi-square, t-tests, multivariable logistic regression, and ANCOVA models were performed. Of 15 027 total children in the study population, 3.5% (n = 520) were orphaned maternally, 8.1% (n = 1222) were orphaned paternally, and 2.2% (n = 336) were orphaned totally. Children who were orphans had higher rates of malnutrition compared to non-orphans (P < .001). Children who were orphaned maternally and totally had lower anthropometric mean scores, presented to clinic later, and were more likely to be living with HIV. Children who are orphaned maternally or totally should be targeted in interventional strategies.Item Growth differentiation factor 15 (GDF15) elevation in children with newly diagnosed cancer(Frontiers Media, 2023-12-11) Runco, Daniel V.; DiMeglio, Linda A.; Vanderpool, Charles P.; Han, Yan; Daggy, Joanne; Kelley, Mary M.; Mikesell, Raya; Zimmers, Teresa A.; Pediatrics, School of MedicineBackground: Growth differentiation factor 15 (GDF15), an inflammatory marker and mediator of adult cancer cachexia, remains largely unexplored in children. GDF15 increases nausea, vomiting, and anorexia in cancer and contributes to malnutrition, with the potential to be a cachexia therapeutic target. No studies have examined GDF15 in children with newly diagnosed cancer. Our pilot study compares GDF15 in children with newly diagnosed cancer to age- and sex-matched controls and correlates levels with anthropometric measurements and quality of life (QOL). Methods: Children with newly diagnosed cancer aged 2-21 years were enrolled with serum GDF15 ELISA, anthropometric measures [height, weight, and mid-upper arm circumference (MUAC)], and QOL assessments (using PedsQL™ Core and Gastrointestinal Modules), which were collected at baseline and repeated 3 months later. Serum GDF15 levels were obtained from age- and sex-matched controls for comparison. Results: A total of 57 participants enrolled (N=30, cancer group; N=27, control group) with a median age of 8.8 years (IQR 5.6-15.9 years). The participants were primarily male (54.4%), white (82.5%), and non-Hispanic (82.5%). Cancer diagnoses included acute lymphoblastic leukemia (N=8), lymphoma (N=8), neuroblastoma (N=5), soft tissue tumors (N=4), acute myeloid leukemia (N=2), and single participants with brain, kidney, and bone tumors. Baseline GDF15 was higher in the cancer cohort compared to the control cohort (median=614.6pg/mL and 320.5pg/mL, respectively; p<0.001). When examining participants with evaluable baseline and 3-month follow-up GDF15 levels (N=18), GDF15 was not statistically different (median=657.1pg/mL and 675.3pg/mL, respectively; p=0.702). A total of 13 of the 30 participants and 21 caregivers completed the PedsQL™ Core and Gastrointestinal symptom modules. QOL scores did not differ significantly at 3-month follow-up compared to baseline, but diarrhea worsened (p=0.017). Median participant response for diarrhea at baseline was 92.9 (IQR=92.9-96.4; N=13), which was significantly better than the follow-up (median=78.6; IQR= 71.4-92.9; p=0.017). There were no correlations between change in height, weight, or MUAC and change in GDF15 levels (p=0.351, 0.920, and 0.269 respectively). Conclusion: GDF15 was elevated in children with cancer at diagnosis compared to controls but did not correlate with anthropometric measurements or QOL. This pilot study will inform future prospective studies to better describe the natural history of GDF15 and its role in cachexia and as a potential therapeutic target.Item Growth of young HIV-infected and HIV-exposed children in western Kenya: A retrospective chart review(Public Library of Science, 2019-12-04) McHenry, Megan S.; Apondi, Edith; Ayaya, Samuel O.; Yang, Ziyi; Li, Wenfang; Tu, Wanzhu; Bi, Guanying; Sang, Edwin; Vreeman, Rachel C.; Pediatrics, School of MedicineIntroduction The objective of this study was to determine the growth patterns, rates of malnutrition, and factors associated with malnutrition in children born to HIV-infected mothers in western Kenya using data from an electronic medical record system. Methods This study was a retrospective chart review of HIV-infected (HIV+) and–exposed (HEU) children (<5 years) using data collected prospectively in the course of routine clinical care and stored in the electronic medical record system in western Kenya between January 2011 and August 2016. Demographics and anthropometrics were described, with Chi-square testing to compare proportions. Multiple variable logistic regression analysis was used to identify correlates of children being stunted, underweight, and wasted. We also examined growth curves, using a resampling method to compare the areas under the fitted growth curves to compare males/females and HIV+/HEU. Results Data from 15,428 children were analyzed. The children were 51.6% (n = 7,955) female, 5.2% (n = 809) orphans, 83.3% (n = 12,851) were HEU, and 16.7% (n = 2,577) were HIV+. For HIV+ children assessed at 24 months, 50.9% (n = 217) were stunted, 26.5% (n = 145) were underweight, and 13.6% (n = 58) were wasted, while 45.0% (n = 577) of HEU children were stunted, 14.8% (n = 255) were underweight, and 5.1% (n = 65) were wasted. When comparing mean z-scores, HIV+ children tended to have larger and earlier dips in z-scores compared to HIV-exposed children, with significant differences found between the two groups (p<0.001). Factors associated with an increased risk of malnutrition included being male, HIV+, and attending an urban clinic. Maternal antiretroviral treatment during pregnancy and mixed feeding at 3 months of age decreased the risk of malnutrition. Conclusions HIV+ and HEU children differ in their anthropometrics, with HIV+ children having overall lower z-scores. Continued efforts to develop and implement sustainable and effective interventions for malnutrition are needed for children born to HIV+ mothers.Item Investigating Differences in Nutritional Parameters in Ugandan Children with Plasmodium falciparum Severe Malaria(2020-07) Brown, Lucy; Co, Katrina; Bond, Caitlin; Opoka, Robert; Datta, Dibya; John, ChandyBackground: The past two decades have witnessed a 60% decline in global malaria mortality. However, two thirds of all malaria deaths continue to occur among children <5 years, with a majority in the WHO African Region. Malnutrition is an important risk factor for malaria. Wasting, Stunting and Underweight are crucial indicators of malnutrition, and are associated with increased mortality in children <5. Annually, 14 million children <5 are classified as wasted and 59 million children are classified as stunted. Objective: The objective of this study is to look at nutritional parameters, weight-for-age (WAZ), height-for-age (HAZ), and weight-for-height (WHZ), and how they differ over time in children <5 with severe malaria (SM) from the Ugandan cities Mulago and Jinja and the outcomes of mortality and nutritional parameters, underweight, stunting, and wasting. Methods: We defined underweight, stunting, and wasting as 2SD below the WAZ, HAZ, and WHZ means. We evaluated Z-scores and mortality status from children <5 years enrolled in a prospective cohort study (NDI, Neurodevelopmental Impairment in Children with Severe Malaria) at enrollment and 12-month follow-up between two sites. Results: WAZ, HAZ and WHZ at baseline were significantly lower among SM groups than in CC (p<0.01), and the SM group maintained significantly lower WHZ (p<0.01) and HAZ (p<0.001) at 12-month follow-up. Among the children who died, there were no significant differences of nutritional markers in Mulago, but in Jinja there was found to be a significant association between mortality and low WAZ (p<0.05) and underweight (p<0.05). Of children classified as underweight in Jinja, 37.5% of them died compared to 15.9% who survived; additionally, the odds ratio for decreased WAZ and mortality was 0.58 (p<0.05). Conclusion: Underweight, stunting, and wasting may be risk factors for SM, and underweight may exacerbate poor mortality outcomes in rural areas like Jinja. While underweight is worsened among children with SM at 1 month and normalizes by 12 months, stunting remains persistently low at 12 months. Nutritional interventions must be aimed at maintaining linear growth throughout the first year of SM in children <5 to reduce the risk factor of underweight on poor mortality outcomes.Item Malnutrition identification and management variability: An administrative database study of children with solid tumors(Wiley, 2022) Runco, Daniel V.; Stanek, Joseph R.; Yeager, Nicholas D.; Belsky, Jennifer A.; Pediatrics, School of MedicineBackground: Malnutrition during cancer treatment increases treatment-related morbidity and mortality. Our study better characterizes variability in malnutrition identification and treatment by examining nutrition-related diagnoses and support for children with central nervous system (CNS) and non-CNS solid tumors during therapy. We examined diagnosis of malnutrition, use of tube feeding or parenteral nutrition (PN), and appetite stimulants. Methods: We retrospectively reviewed 0 to 21-year-old patients in the Pediatric Health Information System from 2015 to 2019. Patients were classified as having (1) billed malnutrition diagnosis, (2) malnutrition diagnosis or using PN and enteral nutrition ("functional malnutrition"), and (3) any previous criteria or prescribed appetite stimulants ("possible malnutrition"), as well as associated risk factors. Results: Among 13,375 unique patients, CNS tumors were most common (24.4%). Overall, 26.5% of patients had malnutrition diagnoses, 45.4% met functional malnutrition criteria, and 56.0% had possible malnutrition. Patients with adrenal tumors had highest billed, functional, and possible malnutrition (36.6%, 64.1%, and 69.4%, respectively) followed by CNS tumors (29.1%, 52.4%, and 64.1%). Patients with adrenal tumors had highest rates of PN use (47.4%) and those with CNS tumors had the highest tube feeding use (26.8%). Hospital admissions with malnutrition had a longer hospital length of stay (LOS) (6 vs 3 days, P < 0.0001), more emergency department admissions (24.4% vs 21.8%, P < 0.0001), and more opioid use (58.6% vs 41.4%, P < 0.0001). Conclusions: Variability in malnutrition diagnoses hinders clinical care and nutrition research in pediatric oncology. Improving disease-specific recognition and treatment of malnutrition can target nutrition support, ensure appropriate reimbursement, and potentially improve outcomes for children with solid tumors.Item Malnutrition screening and treatment in pediatric oncology: a scoping review(BMC, 2022-12-22) Franke, Jessica; Bishop, Chris; Runco, Daniel V.; Pediatrics, School of MedicineBackground: Malnutrition and cachexia during pediatric cancer treatment worsen toxicity and quality-of-life. Clinical practice varies with lack of standard malnutrition definition and nutrition interventions. This scoping review highlights available malnutrition screening and intervention data in childhood cancer and the need for standardizing assessment and treatment. Methods: Ovid Medline, CINAHL, and Cochrane Library were searched for studies containing malnutrition as the primary outcome with anthropometric, radiographic, or biochemical measurements. Secondary outcomes included validated nutritional assessment or screening tools. Two authors reviewed full manuscripts for inclusion. Narrative analysis was chosen over statistical analysis due to study heterogeneity. Results: The search yielded 234 articles and 17 articles identified from reference searching. Nine met inclusion criteria with six nutritional intervention studies (examining appetite stimulants, nutrition supplementation, and proactive feeding tubes) and three nutritional screening studies (algorithms or nutrition support teams) each with variable measures and outcomes. Both laboratory evaluations (albumin, prealbumin, total protein) and body measurement (weight loss, mid-upper arm circumference) were used. Studies demonstrated improved weight, without difference between formula or appetite stimulant used. Screening studies yielded mixed results on preventing weight loss, weight gain, and survival. Conclusion: Our review demonstrated a paucity of evidence for malnutrition screening and intervention in pediatric cancer treatment. While a variety of malnutrition outcomes, interventions, and screening tools exist, nutritional interventions increased weight and decreased complications. Screening tools decreased malnutrition risk and may improve weight gain. Potential age- and disease-specific nutritional benefits and toxicities also exist, further highlighting the benefit of standardizing malnutrition definitions, screening, and interventions.Item Potential for elimination of folate and vitamin B12 deficiency in India using vitamin-fortified tea: a preliminary study(BMJ, 2021-06-23) Vora, Ravindra M.; Alappattu, Meryl J.; Zarkar, Apoorva D.; Soni, Mayur S.; Karmarkar, Santosh J.; Antony, Aśok C.; Medicine, School of MedicineIntroduction: The majority of Indian women have a poor dietary folate and vitamin B12 intake resulting in their chronically low vitamin status, which contributes to anaemia and the high incidence of folate-responsive neural-tube defects (NTDs) in India. Although many countries have successfully deployed centrally-processed folate-fortified flour for prevention of NTDs, inherent logistical problems preclude widespread implementation of this strategy in India. Because tea-the second most common beverage worldwide (after water)-is consumed by most Indians every day, and appeared an ideal vehicle for fortification with folate and vitamin B12, we determined if daily consumption of vitamin-fortified tea for 2 months could benefit young women of childbearing-age in Sangli, India. Methods: Women (average age=20±2 SD) used teabags spiked with therapeutic doses of 1 mg folate plus either 0.1 mg vitamin B12 (Group-1, n=19) or 0.5 mg vitamin B12 (Group-2, n=19), or mock-fortified teabags (Group-0, n=5) to prepare a cup of tea every day for 2 months, following which their pre-intervention and post-intervention serum vitamin and haemoglobin concentrations were compared. Results: Most women had baseline anaemia with low-normal serum folate and below-normal serum vitamin B12 levels. After 2 months, women in both Group-1 and Group-2 exhibited significant increases in mean differences in pre-intervention versus post-intervention serum folate levels of 8.37 ng/mL (95% CIs 5.69 to 11.04, p<0.05) and 6.69 ng/mL (95% CI 3.93 to 9.44, p<0.05), respectively; however, Group-0 experienced an insignificant rise of 1.26 ng/mL (95% CI -4.08 to 0.16). In addition, over one-half and two-thirds of women in Group-1 and Group-2, respectively, exhibited increases in serum vitamin B12 levels over 300 pg/mL. There was also a significant post-interventional increase in the mean haemoglobin concentration in Group-1 of 1.45 g/dL (95% CI 0.64 to 2.26, p=0.002) and Group-2 of 0.79 g/dL (95% CI 0.11 to 1.42, p=0.027), which reflected a bona fide clinical response. Conclusion: Tea is an outstanding scalable vehicle for fortification with folate and vitamin B12 in India, and has potential to help eliminate haematological and neurological complications arising from inadequate dietary consumption or absorption of folate and vitamin B12.Item A role for HSC70 in regulating antigen trafficking and presentation during macronutrient deprivation(2015-02) Deffit, Sarah N.; Blum, Janice Sherry, 1957-; Kaplan, Mark H.; Bauer, Margaret E.; Yin, Xiao-MingGlobally, protein malnutrition remains problematic, adversely affecting several systems including the immune system. Although poorly understood, protein restriction severely disrupts host immunity and responses to infection. Induction of high-affinity, long-lasting immunity depends upon interactions between B and T lymphocytes. B lymphocytes exploit several pathways including endocytosis, macroautophagy, and chaperone-mediated autophagy to capture and deliver antigens to the endosomal network. Within the endosomal network antigens are processed and loaded onto major histocompatibility complex (MHC) class II molecules for display and recognition by T lymphocytes. To examine the effect of macronutrient malnutrition on MHC class II antigen presentation, we grew B lymphocytes in media containing amino acids, sugars and vitamins but lacking serum, which contains several types of macronutrients. Our studies show macronutrient stress amplified macroautophagy, favoring MHC class II presentation of cytoplasmic antigens targeted to autophagosomes. By contrast, macronutrient stress diminished MHC class II presentation of membrane antigens including the B cell receptor (BCR) and cytoplasmic proteins that utilize the chaperone-mediated autophagy pathway. The BCR plays a critical role in MHC class II antigen presentation, as it captures exogenous antigens leading to internalization and degradation within the endosomal network. While intracellular protease activity increased with macronutrient stress, endocytic trafficking and proteolytic turnover of the BCR was impaired. Addition of high molecular mass macronutrients restored endocytosis and antigen presentation, evidence of tightly regulated membrane trafficking dependent on macronutrient status. Cytosolic chaperone HSC70 has been shown to play a role in endocytosis, macroautophagy, chaperone-mediated autophagy and proteolysis by the proteasome, potentially connecting distinct routes of antigen presentation. Here, altering the abundance of HSC70 was sufficient to overcome the inhibitory effects of nutritional stress on BCR trafficking and antigen presentation suggesting macronutrient deprivation alters the availability of HSC70. Together, these results reveal a key role for macronutrient sensing in regulating immune recognition and the importance of HSC70 in modulating distinct membrane trafficking pathways during cellular stress. These results offer a new explanation for impaired immune responses in protein malnourished individuals.