Pyruvate kinase M2 is a PHD3-stimulated coactivator for hypoxia-inducible factor 1.

The pyruvate kinase isoforms PKM1 and PKM2 are alternatively spliced products of the PKM2 gene. PKM2, but not PKM1, alters glucose metabolism in cancer cells and contributes to tumorigenesis by mechanisms that are not explained by its known biochemical activity. We show that PKM2 gene transcription is activated by hypoxia-inducible factor 1 (HIF-1). PKM2 interacts directly with the HIF-1α subunit and promotes transactivation of HIF-1 target genes by enhancing HIF-1 binding and p300 recruitment to hypoxia response elements, whereas PKM1 fails to regulate HIF-1 activity. Interaction of PKM2 with prolyl hydroxylase 3 (PHD3) enhances PKM2 binding to HIF-1α and PKM2 coactivator function. Mass spectrometry and anti-hydroxyproline antibody assays demonstrate PKM2 hydroxylation on proline-403/408. PHD3 knockdown inhibits PKM2 coactivator function, reduces glucose uptake and lactate production, and increases O(2) consumption in cancer cells. Thus, PKM2 participates in a positive feedback loop that promotes HIF-1 transactivation and reprograms glucose metabolism in cancer cells.

Unfavorable social determinants of health and mortality risk by cardiovascular disease status: Findings from a National Study of United States Adults.

BACKGROUND: The association between cumulative burden of unfavorable social determinants of health (SDoH) and all-cause mortality has not been assessed by atherosclerotic cardiovascular disease (ASCVD) status on a population level in the United States. METHODS: We assessed the association between cumulative social disadvantage and all-cause mortality by ASCVD status in the National Health Interview Survey, linked to the National Death Index. RESULTS: In models adjusted for established clinical risk factors, individuals experiencing the highest level of social disadvantage (SDoH-Q4) had over 1.5 (aHR = 1.55; 95%CI = 1.22, 1.96) and 2-fold (aHR = 2.21; 95% CI = 1.91, 2.56) fold increased risk of mortality relative to those with the most favorable social profile (SDoH-Q1), respectively for adults with and without ASCVD; those experiencing co-occurring ASCVD and high social disadvantage had up to four-fold higher risk of mortality (aHR = 3.81; 95%CI = 3.36, 4.32). CONCLUSIONS: These findings emphasize the importance of a healthcare model that prioritizes efforts to identify and address key social and environmental barriers to health and wellbeing, particularly in individuals experiencing the double jeopardy of clinical and social risk.

Comparison of guidelines for biological ancillary materials used for the manufacture of gene and cellular therapy products in Asia.

BACKGROUND AIMS: Although biologiocal ancillay materials (AMs) have specific risk associated with their derivations, it plays key role to manufature cell and gene therapy (CGT) products. It is important to understand the regulation relevant to AMs for developers. METHODS: The authors investigated the guidelines and pharmacopeia (hereinafter referred to as "guidelines") for biological AMs used for the manufacture of CGT products in Asia (China, India, Japan, Korea and Taiwan). In addition, the authors benchmarked the relevant guidelines in the United States (US) and European Union (EU). RESULTS AND DISCUSSIONS: The guidelines could be classified into two types based on whether specific AMs are scoped: (i) general guidelines for risk assessment of AMs and (ii) guidelines for specific AMs. The authors compared the risk categories for each type of AM provided in the general guidelines between the US and China and the specific requirements for bovine serum and trypsin in the guidelines of China, Japan, Taiwan, US and EU. The authors further compiled in-depth descriptions of the respective regulations in China, India, Japan, Korea and Taiwan. There is limited availability of some guidelines for specific AMs. Moreover, there are no common requirements established across the surveyed countries and regions. Therefore, the authors suggest a risk assessment approach for AMs with consideration of their biological origin and traceability, production steps applied and ability to control or remove AMs from the final medicinal product over the CGT manufacturing process.

Non-clinical, quality and environmental impact assessments of cell and gene therapy products: Report on the 5th Asia Partnership Conference of Regenerative Medicine - April 7, 2022.

The 5th Asia Partnership Conference of Regenerative Medicine (APACRM) was held online on April 7, 2022 to promote regulatory harmonization of regenerative medicine products throughout Asia. The recognition of domestic regulatory guidelines within each country and region and the underpinning rationales are important initial steps toward the harmonization of regulations. The 5th APACRM featured open dialog regarding non-clinical, quality and environmental impact assessment settings for cell and gene therapy products through presentations from the industry and panel discussions with regulatory agencies. The latest updates on regenerative medicine fields in each country and region were also introduced. This paper summarizes the proceedings of the 5th APACRM for public dissemination to foster future discussion.

Polysocial Risk Scores: Implications for Cardiovascular Disease Risk Assessment and Management.

PURPOSE OF REVIEW: To review current evidence, discuss key knowledge gaps and identify opportunities for development, validation and application of polysocial risk scores (pSRS) for cardiovascular disease (CVD) risk prediction and population cardiovascular health management. RECENT FINDINGS: Limited existing evidence suggests that pSRS are promising tools to capture cumulative social determinants of health (SDOH) burden and improve CVD risk prediction beyond traditional risk factors. However, available tools lack generalizability, are cross-sectional in nature or do not assess social risk holistically across SDOH domains. Available SDOH and clinical risk factor data in large population-based databases are under-utilized for pSRS development. Recent advances in machine learning and artificial intelligence present unprecedented opportunities for SDOH integration and assessment in real-world data, with implications for pSRS development and validation for both clinical and healthcare utilization outcomes. pSRS presents unique opportunities to potentially improve traditional "clinical" models of CVD risk prediction. Future efforts should focus on fully utilizing available SDOH data in large epidemiological databases, testing pSRS efficacy in diverse population subgroups, and integrating pSRS into real-world clinical decision support systems to inform clinical care and advance cardiovascular health equity.

Changes in cortisol and corticosteroid receptors during dynamic salinity challenges in Mozambique tilapia.

In estuarine environments, euryhaline fish maintain a narrow range of internal osmolality despite daily changes in environmental salinity that can range from fresh water (FW) to seawater (SW). The capacity of euryhaline fish to maintain homeostasis in a range of environmental salinities is primarily facilitated by the neuroendocrine system. One such system, the hypothalamic-pituitary-interrenal (HPI) axis, culminates in the release of corticosteroids such as cortisol into circulation. Cortisol functions as both a mineralocorticoid and glucocorticoid in fish because of its roles in osmoregulation and metabolism, respectively. The gill, a key site for osmoregulation, and the liver, the primary storage site for glucose, are known targets of cortisol's actions during salinity stress. While cortisol facilitates acclimation to SW environments, less is known on its role during FW adaptation. In this study, we characterized the responses of plasma cortisol, mRNA expression of pituitary pro-opiomelanocortin (pomc), and mRNA expression of liver and gill corticosteroid receptors (gr1, gr2, and mr) in the euryhaline Mozambique tilapia (Oreochromis mossambicus) under salinity challenges. Specifically, tilapia were subjected to salinity transfer regimes from steady-state FW to SW, SW to FW (experiment 1) or steady state FW or SW to tidal regimen (TR, experiment 2). In experiment 1, fish were sampled at 0 h, 6 h, 1, 2, and 7 d post transfer; while in experiment 2, fish were sampled at day 0 and day 15. We found a rise in pituitary pomc expression and plasma cortisol following transfer to SW while branchial corticosteroid receptors were immediately downregulated after transfer to FW. Moreover, branchial expression of corticosteroid receptors changed with each salinity phase of the TR, suggesting rapid environmental modulation of corticosteorid action. Together, these results support the role of the HPI-axis in promoting salinity acclimation, including in dynamically-changing environments.

Low educational attainment is associated with higher all-cause and cardiovascular mortality in the United States adult population.

INTRODUCTION: Educational attainment is an important social determinant of health (SDOH) for cardiovascular disease (CVD). However, the association between educational attainment and all-cause and CVD mortality has not been longitudinally evaluated on a population-level in the US, especially in individuals with atherosclerotic cardiovascular disease (ASCVD). In this nationally representative study, we assessed the association between educational attainment and the risk of all-cause and cardiovascular (CVD) mortality in the general adult population and in adults with ASCVD in the US. METHODS: We used data from the 2006-2014 National Death Index-linked National Health Interview Survey for adults ≥ 18 years. We generated age-adjusted mortality rates (AAMR) by levels of educational attainment (< high school (HS), HS/General Education Development (GED), some college, and ≥ College) in the overall population and in adults with ASCVD. Cox proportional hazards models were used to examine the multivariable-adjusted associations between educational attainment and all-cause and CVD mortality. RESULTS: The sample comprised 210,853 participants (mean age 46.3), representing ~ 189 million adults annually, of which 8% had ASCVD. Overall, 14.7%, 27%, 20.3%, and 38% of the population had educational attainment < HS, HS/GED, Some College, and ≥ College, respectively. During a median follow-up of 4.5 years, all-cause age-adjusted mortality rates were 400.6 vs. 208.6 and 1446.7 vs. 984.0 for the total and ASCVD populations for < HS vs ≥ College education, respectively. CVD age adjusted mortality rates were 82.1 vs. 38.7 and 456.4 vs 279.5 for the total and ASCVD populations for < HS vs ≥ College education, respectively. In models adjusting for demographics and SDOH, < HS (reference = ≥ College) was associated with 40-50% increased risk of mortality in the total population and 20-40% increased risk of mortality in the ASCVD population, for both all-cause and CVD mortality. Further adjustment for traditional risk factors attenuated the associations but remained statistically significant for < HS in the overall population. Similar trends were seen across sociodemographic subgroups including age, sex, race/ethnicity, income, and insurance status. CONCLUSIONS: Lower educational attainment is independently associated with increased risk of all-cause and CVD mortality in both the total and ASCVD populations, with the highest risk observed for individuals with < HS education. Future efforts to understand persistent disparities in CVD and all-cause mortality should pay close attention to the role of education, and include educational attainment as an independent predictor in mortality risk prediction algorithms.

Nonclinical and quality assessment of cell therapy products: Report on the 4th Asia Partnership Conference of Regenerative Medicine, April 15, 2021.

The 4th Asia Partnership Conference of Regenerative Medicine (APACRM) was held online on April 15, 2021, to promote regulatory harmonization of regenerative medicine products throughout Asia. Recognizing domestic regulatory guidelines within each country and region, and their underpinning rationales, is an important initial step toward a convergence of regulations. The 4th APACRM consisted of an open dialog with regulatory agencies regarding nonclinical and quality settings for cell therapy products (CTPs) through industry presentations and panel discussions with regulatory agencies. The latest updates on regenerative medicine fields in each country and region, and specific regulatory schematics in Japan, were also introduced. The objective of this paper is to summarize the proceedings of the 4th APACRM for public dissemination and to foster further discussion in the future.

Multi-Immune Agonist Nanoparticle Therapy Stimulates Type I Interferons to Activate Antigen-Presenting Cells and Induce Antigen-Specific Antitumor Immunity.

Cancer immunity is mediated by a delicate orchestration between the innate and adaptive immune system both systemically and within the tumor microenvironment. Although several adaptive immunity molecular targets have been proven clinically efficacious, stand-alone innate immunity targeting agents have not been successful in the clinic. Here, we report a nanoparticle optimized for systemic administration that combines immune agonists for TLR9, STING, and RIG-I with a melanoma-specific peptide to induce antitumor immunity. These immune agonistic nanoparticles (iaNPs) significantly enhance the activation of antigen-presenting cells to orchestrate the development and response of melanoma-sensitized T-cells. iaNP treatment not only suppressed tumor growth in an orthotopic solid tumor model, but also significantly reduced tumor burden in a metastatic animal model. This combination biomaterial-based approach to coordinate innate and adaptive anticancer immunity provides further insights into the benefits of stimulating multiple activation pathways to promote tumor regression, while also offering an important platform to effectively and safely deliver combination immunotherapies for cancer.

Histone demethylase JMJD2C is a coactivator for hypoxia-inducible factor 1 that is required for breast cancer progression.

Hypoxia-inducible factor 1 (HIF-1) activates transcription of genes encoding proteins that play key roles in breast cancer biology. We hypothesized that interaction of HIF-1 with epigenetic regulators may increase HIF-1 transcriptional activity, and thereby promote breast cancer progression. We report that the histone demethylase jumonji domain containing protein 2C (JMJD2C) selectively interacts with HIF-1α, but not HIF-2α, and that HIF-1α mediates recruitment of JMJD2C to the hypoxia response elements of HIF-1 target genes. JMJD2C decreases trimethylation of histone H3 at lysine 9, and enhances HIF-1 binding to hypoxia response elements, thereby activating transcription of BNIP3, LDHA, PDK1, and SLC2A1, which encode proteins that are required for metabolic reprogramming, as well as LOXL2 and L1CAM, which encode proteins that are required for lung metastasis. JMJD2C expression is significantly associated with expression of GLUT1, LDHA, PDK1, LOX, LOXL2, and L1CAM mRNA in human breast cancer biopsies. JMJD2C knockdown inhibits breast tumor growth and spontaneous metastasis to the lungs of mice following mammary fat pad injection. Taken together, these findings establish an important epigenetic mechanism that stimulates HIF-1-mediated transactivation of genes encoding proteins involved in metabolic reprogramming and lung metastasis in breast cancer.

Evaluating the coupling between foot pronation and tibial internal rotation continuously using vector coding.

Excessive pronation, because of its coupling with tibial internal rotation (TIR), has been implicated as a risk factor in the development of anterior knee pain (AKP). Traditionally, this coupling has been expressed as a ratio between the eversion range of motion and the TIR range of motion (Ev/TIR) that occurs during stance. Currently, this technique has not been used to evaluate specific injuries or the effects of sex. In addition, Ev/TIR is incapable of detecting coupling changes that occur throughout stance. Therefore, the purpose of this study was to compare the coupling between eversion and TIR in runners with (n = 19) and without AKP (n = 17) and across sex using the Ev/TIR ratio, and more continuously using vector coding. When using vector coding, significant coupling differences were noted in runners with AKP (34% to 38% stance), with runners with AKP showing relatively more TIR than eversion. Similarly significant differences were noted across sex (14%-25% and 36%-47% stance), with males transitioning from a loading to propulsive coordination pattern using a proximal to distal strategy, and female runners using a distal to proximal strategy. These differences were only detected when evaluating this coupling relationship using a continuous technique such as vector coding.

Vestibular afferent neurons develop normally in the absence of quantal/glutamatergic input.

The vestibular nerve is comprised of neuron sub-groups with diverse functions related to their intrinsic biophysical properties. This diversity is partly due to differences in the types and numbers of low-voltage-gated potassium channels found in the neurons' membranes. Expression for some low-voltage gated ion channels like KCNQ4 is upregulated during early post-natal development; suggesting that ion channel composition and neuronal diversity may be shaped by hair cell activity. This idea is consistent with recent work showing that glutamatergic input from hair cells is necessary for the normal diversification auditory neurons. To test if biophysical diversity is similarly dependent on glutamatergic input in vestibular neurons, we examined the maturation of the vestibular epithelium and ganglion neurons in Vglut3-ko mice whose hair cell synapses lack glutamate. Despite lacking glutamatergic input, the knockout mice showed no notable balance deficits and crossed challenging balance beams with little difficulty. Immunolabeling of the Vglut3-ko vestibular epithelia showed normal development as indicated by an identifiable striolar zone with calyceal terminals labeled by molecular marker calretinin, and normal expression of KCNQ4 by the end of the second post-natal week. We found similar numbers of Type I and Type II hair cells in the knockout and wildtype animals, regardless of epithelial zone. Thus, the presumably quiescent Type II hair cells are not cleared from the epithelium. Patch-clamp recordings showed that biophysical diversity of vestibular ganglion neurons in the Vglut3-ko mice is comparable to that found in wildtype controls, with a similar range firing patterns at both immature and juvenile ages. However, our results suggest a subtle biophysical alteration to the largest ganglion cells (putative somata of central zone afferents); those in the knockout had smaller net conductance and were more excitable than those in the wild type. Thus, unlike in the auditory nerve, glutamatergic signaling is unnecessary for producing biophysical diversity in vestibular ganglion neurons. And yet, because the input signals from vestibular hair cells are complex and not solely reliant on quantal release of glutamate, whether diversity of vestibular ganglion neurons is simply hardwired or regulated by a more complex set of input signals remains to be determined.

γδ T cells as critical anti-tumor immune effectors.

While the effector cells that mediate anti-tumor immunity have historically been attributed to αß T cells and natural killer cells, γδ T cells are now being recognized as a complementary mechanism mediating tumor rejection. γδ T cells possess a host of functions ranging from antigen presentation to regulatory function and, importantly, have critical roles in eliciting anti-tumor responses where other immune effectors may be rendered ineffective. Recent discoveries have elucidated how these differing functions are mediated by γδ T cells with specific T cell receptors and spatial distribution. Their relative resistance to mechanisms of dysfunction like T cell exhaustion has spurred the development of therapeutic approaches exploiting γδ T cells, and an improved understanding of these cells should enable more effective immunotherapies.

Unfavorable social determinants of health and risk of mortality in adults with diabetes: findings from the National Health Interview Survey.

INTRODUCTION: Understanding the role of social determinants of health as predictors of mortality in adults with diabetes may help improve health outcomes in this high-risk population. Using population-based, nationally representative data, this study investigated the cumulative effect of unfavorable social determinants on all-cause mortality in adults with diabetes. RESEARCH DESIGN AND METHODS: We used data from the 2013-2018 National Health Interview Survey, linked to the National Death Index through 2019, for mortality ascertainment. A total of 47 individual social determinants of health were used to categorize participants in quartiles denoting increasing levels of social disadvantage. Poisson regression was used to report age-adjusted mortality rates across increasing social burden. Multivariable Cox proportional hazards models were used to assess the association between cumulative social disadvantage and all-cause mortality in adults with diabetes, adjusting for traditional risk factors. RESULTS: The final sample comprised 182 445 adults, of whom 20 079 had diabetes. In the diabetes population, mortality rate increased from 1052.7 per 100 000 person-years in the first quartile (Q1) to 2073.1 in the fourth quartile (Q4). In multivariable models, individuals in Q4 experienced up to twofold higher mortality risk relative to those in Q1. This effect was observed similarly across gender and racial/ethnic subgroups, although with a relatively stronger association for non-Hispanic white participants compared with non-Hispanic black and Hispanic subpopulations. CONCLUSIONS: Cumulative social disadvantage in individuals with diabetes is associated with over twofold higher risk of mortality, independent of established risk factors. Our findings call for action to screen for unfavorable social determinants and design novel interventions to mitigate the risk of mortality in this high-risk population.

A review and perspective on the neural basis of radiological expertise.

Radiological expertise requires tremendous time, effort, and training. While there has been a myriad of studies focusing on radiological expertise and error, the precise underlying neural mechanism still remains largely unexplored. In this article, we review potential neural mechanisms, namely, the fusiform face area, working memory, and predictive coding and propose experiments to test the predictive coding framework.

Vaccinating against cancer: getting to prime time.

Immunotherapies, such as immune checkpoint inhibitors, cellular therapies, and T-cell engagers, have fundamentally changed our approach to treating cancer. However, successes with cancer vaccines have been more difficult to realize. While vaccines against specific viruses have been widely adopted to prevent the development of cancer, only two vaccines can improve survival in advanced disease: sipuleucel-T and talimogene laherparepvec. These represent the two approaches that have the most traction: vaccinating against cognate antigen and priming responses using tumors in situ. Here, we review the challenges and opportunities researchers face in developing therapeutic vaccines for cancer.

Acute effects of an isometric neck warm-up programme on neck performance characteristics and ultrasound-based morphology.

OBJECTIVE: Athletic performance can be enhanced immediately after an isometric warm-up, a phenomenon termed post-activation performance enhancement (PAPE). While isometric warm-ups can improve lower extremity sprint and jump performance, neck-specific isometric warm-ups need development and validation for mild traumatic brain disorders and neck pain. This study examined acute effects of isometric warm-ups on neck performance and morphology. METHODS: Arm 1: Twenty-six adults (13 M:13F) completed neck performance testing before and after a 10-minute neck isometric warm-up or stationary bike (sham) between two visits. Testing included visual-motor reaction time, peak force, rate of force development, force steadiness, and force replication/proprioception measured by a 6-axis load cell. An inclinometer assessed range-of-motion. Paired t-tests and two-way ANOVA examined effects of neck/bike warm-up and interaction effects, respectively. Arm 2: 24 adults (11 M:13F) completed ultrasound scans of cervical muscles: before 20-minute rest (sham), and before/after a 5-min neck isometric warm-up. Longus colli cross-sectional area and sternocleidomastoid/upper trapezius thickness and stiffness, and cervical extensors thickness was assessed. One-way ANOVA compared morphological values at sham, before, and after warm-up. Significance was set at p < 0.05. RESULTS: Isometric neck warm-up increased rate of force development in flexion (p = 0.022), extension (p = 0.001-0.003), right lateral flexion (p = 0.004-0.032), left lateral flexion (p = 0.005-0.014), while peak force improved only in left lateral flexion (p = 0.032). Lateral flexion range-of-motion increased after neck warm-up (p = 0.003-0.026). Similarly, longus colli cross-sectional area (p = 0.016) and sternocleidomastoid thickness (p = 0.004) increased. CONCLUSIONS: Increased neck performance characteristics and morphology are likely due to PAPE effects of isometric neck warm-up. For coaches and athletes, simple isometric contractions could be added to existing warm-ups to reduce prevalence, incidence, and severity of mild traumatic brain injuries and neck pain.

Biomechanical and clinical outcomes with shock-absorbing insoles in patients with knee osteoarthritis: immediate effects and changes after 1 month of wear.

OBJECTIVES: To examine the effectiveness of shock-absorbing insoles in the immediate reduction of knee joint load, as well as reductions in knee joint load, pain, and dysfunction after 1 month of wear, in individuals with knee osteoarthritis (OA). DESIGN: Pre-post design with participants exposed to 2 conditions (normal footwear, shock-absorbing insoles) with a 1-month follow-up. SETTING: University laboratory for testing and general community for intervention. PARTICIPANTS: Community-dwelling individuals (N=16; 6 men, 10 women) with medial compartment knee OA. INTERVENTION: Participants were provided with sulcus length shock-absorbing insoles to be inserted into their everyday shoes. MAIN OUTCOME MEASURES: Primary outcome measures included the peak, early stance peak, and late stance peak external knee adduction moment (KAM); the KAM impulse (positive area under the KAM curve); and peak tibial vertical acceleration. Secondary outcomes included walking pain, the Western Ontario and McMaster Universities Osteoarthritis Index pain subscale and total score, and a timed stair climb task. RESULTS: There was a significant reduction in the late stance peak KAM with shock-absorbing insoles (P=.03) during follow-up compared with the baseline test session. No other immediate or longitudinal significant changes (P>.05) in the other KAM parameters or peak tibial acceleration after use of a shock-absorbing insole were observed. However, significant improvements in all measures of pain and function (P<.05) were observed. CONCLUSIONS: Shock-absorbing insoles produced significant reductions in self-reported knee joint pain and physical dysfunction with 1 month of wear in patients with knee OA despite no consistent changes in knee joint load. Further research using randomized controlled trials, with larger sample sizes and explorations into long-term use of shock-absorbing insoles and their effect on disease progression, is warranted.

Historical Portrayal of Hoarding Disorder in European Literature and Its Relationship to the Economic and Personal Circumstances of the Authors.

In 2013, hoarding disorder was officially recognized as a separate Diagnostic and Statistical Manual psychiatric diagnosis after years of debate. Prior to 2013, hoarding disorder was generally considered a subset of obsessive-compulsive disorder. Though modern medicine has only recently deepened the analysis of hoarding disorder, hoarding was regularly featured as a character trait in numerous European literary works dating back over 700 years. Several prominent European writers incorporated hoarding behavior in the fictional characters they created. Each author's individual social and economic experiences may have been motivators for perpetuating hoarding-like behavior. It can be postulated that specific historical events and economic circumstances in the country at the time of each author's life likely impacted their interpretation of hoarding behaviors, and the authors carried these influences into their portrayal of their fictional characters. This analysis discusses the various portrayals of hoarding in key pieces of literature and seeks to explain the rationale for these authors' inclusion of hoarding traits in their characters.

A Review of the Multi-Systemic Complications of a Ketogenic Diet in Children and Infants with Epilepsy.

Ketogenic diets (KDs) are highly effective in the treatment of epilepsy. However, numerous complications have been reported. During the initiation phase of the diet, common side effects include vomiting, hypoglycemia, metabolic acidosis and refusal of the diet. While on the diet, the side effects involve the following systems: gastrointestinal, hepatic, cardiovascular, renal, dermatological, hematologic and bone. Many of the common side effects can be tackled easily with careful monitoring including blood counts, liver enzymes, renal function tests, urinalysis, vitamin levels, mineral levels, lipid profiles, and serum carnitine levels. Some rare and serious side effects reported in the literature include pancreatitis, protein-losing enteropathy, prolonged QT interval, cardiomyopathy and changes in the basal ganglia. These serious complications may need more advanced work-up and immediate cessation of the diet. With appropriate monitoring and close follow-up to minimize adverse effects, KDs can be effective for patients with intractable epilepsy.