UCP1 expression in human brown adipose tissue is inversely associated with cardiometabolic risk factors.

OBJECTIVE: Brown adipose tissue (BAT) is a therapeutic target for obesity. 18F-Fluorodeoxyglucose positron emission tomography (18F-FDG-PET) is commonly used to quantify human BAT mass and activity. Detectable 18F-FDG uptake by BAT is associated with reduced prevalence of cardiometabolic disease. However, 18F-FDG uptake may not always be a reliable marker of BAT thermogenesis, for example insulin resistance may reduce glucose uptake. Uncoupling protein 1 (UCP1) is the key thermogenic protein in BAT. Therefore, we hypothesized that UCP1 expression may be altered in individuals with cardiometabolic risk factors. METHODS: We quantified UCP1 expression as an alternative marker of thermogenic capacity in BAT and white adipose tissue (WAT) samples (n = 53) and in differentiated brown and white pre-adipocytes (n = 85). RESULTS: UCP1 expression in BAT, but not in WAT or brown/white differentiated pre-adipocytes, was reduced with increasing age, obesity and adverse cardiometabolic risk factors such as fasting glucose, insulin and blood pressure. However, UCP1 expression in BAT was preserved in obese subjects of <40 years of age. To determine if BAT activity was also preserved in vivo, we undertook a case-control study, performing 18F-FDG scanning during mild cold exposure in young (mean age ∼22y) normal weight and obese volunteers. 18F-FDG uptake by BAT and BAT volume were similar between groups, despite increased insulin resistance. CONCLUSION: 18F-FDG uptake by BAT and UCP1 expression are preserved in young obese adults. Older subjects retain precursor cells with the capacity to form new thermogenic adipocytes. These data highlight the therapeutic potential of BAT mass expansion and activation in obesity.

Epigenetic Impact of Curcumin and Thymoquinone on Cancer Therapeutics.

Today, one of the most prevalent reasons for death among people is carcinoma. Because it is still on the increase throughout the world, there is a critical need for in- -depth research on the pathogenic mechanisms behind the disease as well as for efficient treatment. In the field of epigenetics, gene expression alterations that are inherited but not DNA sequence changes are investigated. Three key epigenetic changes, histone modifications, DNA methylation and non-coding RNA (ncRNA) expression, are principally responsible for the initiation and progression of different tumors. These changes are interconnected and constitute many epigenetic changes. A form of polyphenolic chemical obtained from plants called curcumin has great bioactivity against several diseases, specifically cancer. A naturally occurring substance called thymoquinone is well-known for its anticancer properties. Thymoquinone affects cancer cells through a variety of methods, according to preclinical studies. We retrieved information from popular databases, including PubMed, Google Scholar, and CNKI, to summarize current advancements in the efficiency of curcumin against cancer and its epigenetic regulation in terms of DNA methylation, histone modifications, and miRNA expression. The present investigation offers thorough insights into the molecular processes, based on epigenetic control, that underlie the clinical use of curcumin and thymoquinone in cancerous cells.

Pediatric suicide: Review of a preventable tragedy.

Concepts of suicide are explored in this issue with a focus on suicide in children and adolescents. The epidemiology of pediatric suicide in the United States is reviewed; also, risk and protective factors, as well as prevention strategies, are discussed. Suicide in the pediatric athlete and the potential protective effect of exercise are examined. In addition, this analysis addresses the beneficial role of psychological management as well as current research on pharmacologic treatment and brain stimulation procedures as part of comprehensive pediatric suicide prevention. Though death by suicide in pediatric persons has been and remains a tragic phenomenon, there is much that clinicians, other healthcare professionals, and society itself can accomplish in the prevention of pediatric suicide as well as the management of suicidality in our children and adolescents.

Functional filter for whole-genome sequencing data identifies HHT and stress-associated non-coding SMAD4 polyadenylation site variants >5 kb from coding DNA.

Despite whole-genome sequencing (WGS), many cases of single-gene disorders remain unsolved, impeding diagnosis and preventative care for people whose disease-causing variants escape detection. Since early WGS data analytic steps prioritize protein-coding sequences, to simultaneously prioritize variants in non-coding regions rich in transcribed and critical regulatory sequences, we developed GROFFFY, an analytic tool that integrates coordinates for regions with experimental evidence of functionality. Applied to WGS data from solved and unsolved hereditary hemorrhagic telangiectasia (HHT) recruits to the 100,000 Genomes Project, GROFFFY-based filtration reduced the mean number of variants/DNA from 4,867,167 to 21,486, without deleting disease-causal variants. In three unsolved cases (two related), GROFFFY identified ultra-rare deletions within the 3' untranslated region (UTR) of the tumor suppressor SMAD4, where germline loss-of-function alleles cause combined HHT and colonic polyposis (MIM: 175050). Sited >5.4 kb distal to coding DNA, the deletions did not modify or generate microRNA binding sites, but instead disrupted the sequence context of the final cleavage and polyadenylation site necessary for protein production: By iFoldRNA, an AAUAAA-adjacent 16-nucleotide deletion brought the cleavage site into inaccessible neighboring secondary structures, while a 4-nucleotide deletion unfolded the downstream RNA polymerase II roadblock. SMAD4 RNA expression differed to control-derived RNA from resting and cycloheximide-stressed peripheral blood mononuclear cells. Patterns predicted the mutational site for an unrelated HHT/polyposis-affected individual, where a complex insertion was subsequently identified. In conclusion, we describe a functional rare variant type that impacts regulatory systems based on RNA polyadenylation. Extension of coding sequence-focused gene panels is required to capture these variants.

The serotonin transporter sustains human brown adipose tissue thermogenesis.

Activation of brown adipose tissue (BAT) in humans is a strategy to treat obesity and metabolic disease. Here we show that the serotonin transporter (SERT), encoded by SLC6A4, prevents serotonin-mediated suppression of human BAT function. RNA sequencing of human primary brown and white adipocytes shows that SLC6A4 is highly expressed in human, but not murine, brown adipocytes and BAT. Serotonin decreases uncoupled respiration and reduces uncoupling protein 1 via the 5-HT2B receptor. SERT inhibition by the selective serotonin reuptake inhibitor (SSRI) sertraline prevents uptake of extracellular serotonin, thereby potentiating serotonin's suppressive effect on brown adipocytes. Furthermore, we see that sertraline reduces BAT activation in healthy volunteers, and SSRI-treated patients demonstrate no 18F-fluorodeoxyglucose uptake by BAT at room temperature, unlike matched controls. Inhibition of BAT thermogenesis may contribute to SSRI-induced weight gain and metabolic dysfunction, and reducing peripheral serotonin action may be an approach to treat obesity and metabolic disease.

Ergogenic Aids and Testing in Pediatric Athletes.

In the quest for winning the game, some athletes take various chemicals (ie, drugs, herbs, or supplements) in attempts to develop greater strength, endurance, or other elements that bring a competitive advantage. There are more than 30,000 chemicals sold throughout the world with unrestrained and unproven claims; however, some athletes consume them with hopes of increasing their athletic abilities, often without knowledge of the potential adverse effects and with limited evidence of efficacy. Complicating this picture is that research on ergogenic chemicals is typically conducted with elite adult male athletes and not with athletes who are in high school. A few of these ergogenic aids include creatine, anabolic androgenic steroids, selective androgen receptor modulators, clenbuterol, androstenedione, dehydroepiandrosterone, human growth hormone, ephedrine, gamma hydroxybutyrate, caffeine, stimulants (amphetamines or methylphenidate), and blood doping. In this article, we describe the purpose of ergogenic aids as well as the potential side effects. [Pediatr Ann. 2023;52(6):e207-e212.].

Scope of Wnt signaling in the precise diagnosis and treatment of breast cancer.

Malignant breast cancers are responsible for a growing number of deaths among women globally. The latest research has demonstrated that Wnt signaling is pivotal in this disease, regulating a safe microenvironment for the growth and proliferation of cancer cells, sustained stemness, resistance to therapy, and aggregate formation. The three highly conserved Wnt signaling pathways, Wnt-planar cell polarity (PCP), Wnt/ß-catenin signaling and Wnt-Ca2+ signaling, assume various roles in the maintenance and amelioration of breast cancer. In this review, we examine ongoing studies on the Wnt signaling pathways and discuss how dysregulation of these pathways promotes breast cancers. We also look at how Wnt dysregulation could be exploited to foster new treatments for malignant breast cancers.

Cost-effectiveness of cenobamate for focal seizures in people with drug-resistant epilepsy.

OBJECTIVE: This study was undertaken to estimate the cost-effectiveness of add-on cenobamate in the UK when used to treat drug-resistant focal seizures in adults who are not adequately controlled with at least two prior antiseizure medications, including at least one used adjunctively. METHODS: We estimated the cost per quality-adjusted life-year (QALY) for cenobamate compared to brivaracetam, eslicarbazepine, lacosamide, and perampanel in the UK National Health Service over a lifetime time horizon. We used a Markov cohort structure to determine response to treatment, using pooled data from three long-term studies of cenobamate. A network meta-analysis informed the likelihood of response to therapy with brivaracetam, eslicarbazepine, lacosamide, and perampanel relative to cenobamate. Once individuals discontinued treatment, they transitioned to subsequent treatment health states, including other antiseizure medicines, surgery, and vagus nerve stimulation. Costs included treatment, administration, routine monitoring, event management, and adverse events. Published evidence and expert opinion informed the likelihood of response to subsequent treatments, associated adverse events, and costs. Utility data were based on Short-Form six-dimension form utility. Discounting was applied at 3.5% per annum as per National Institute for Health and Care Excellence guidance. Uncertainty was explored through deterministic and probabilistic sensitivity analyses. RESULTS: In the base case, cenobamate led to cost savings of £51 967 (compared to brivaracetam), £21 080 (compared to eslicarbazepine), £33 619 (compared to lacosamide), and £28 296 (compared to perampanel) and increased QALYs of 1.047 (compared to brivaracetam), 0.598 (compared to eslicarbazepine), 0.776 (compared to lacosamide), and 0.703 (compared to perampanel) per individual over a lifetime time horizon. Cenobamate also dominated the four drugs across most sensitivity analyses. Differences were due to reduced seizure frequency with cenobamate relative to comparators. SIGNIFICANCE: Cenobamate improved QALYs and was less costly than brivaracetam, eslicarbazepine, lacosamide, and perampanel. Therefore, cenobamate may be considered as a cost-effective adjunctive antiseizure medication for people with drug-resistant focal seizures.

Psychosocial aspects of sports medicine in pediatric athletes: Current concepts in the 21st century.

Behavioral aspects of organized sports activity for pediatric athletes are considered in a world consumed with winning at all costs. In the first part of this treatise, we deal with a number of themes faced by our children in their sports play. These concepts include the lure of sports, sports attrition, the mental health of pediatric athletes (i.e., effects of stress, anxiety, depression, suicide in athletes, ADHD and stimulants, coping with injuries, drug use, and eating disorders), violence in sports (i.e., concepts of the abused athlete including sexual abuse), dealing with supervisors (i.e., coaches, parents), peers, the talented athlete, early sports specialization and sports clubs. In the second part of this discussion, we cover ergolytic agents consumed by young athletes in attempts to win at all costs. Sports doping agents covered include anabolic steroids (anabolic-androgenic steroids or AAS), androstenedione, dehydroepiandrostenedione (DHEA), human growth hormone (hGH; also its human recombinant homologue: rhGH), clenbuterol, creatine, gamma hydroxybutyrate (GHB), amphetamines, caffeine and ephedrine. Also considered are blood doping that includes erythropoietin (EPO) and concepts of gene doping. In the last section of this discussion, we look at disabled pediatric athletes that include such concepts as athletes with spinal cord injuries (SCIs), myelomeningocele, cerebral palsy, wheelchair athletes, and amputee athletes; also covered are pediatric athletes with visual impairment, deafness, and those with intellectual disability including Down syndrome. In addition, concepts of autonomic dysreflexia, boosting and atlantoaxial instability are emphasized. We conclude that clinicians and society should protect our precious pediatric athletes who face many challenges in their involvement with organized sports in a world obsessed with winning. There is much we can do to help our young athletes find benefit from sports play while avoiding or blunting negative consequences of organized sport activities.

The formaldehyde treated guar meal and prill fat, agro industrial by-products as dietary rumen protected protein and energy source: improves growth performance, feed conversion, nutrient utilization, microbial protein synthesis, blood metabolites and economic efficiency in growing dairy buffalo (Bubalus bubalis) calves.

The study investigated the effects of protein replacement with formaldehyde-treated guar meal (FTGM) and prill fat (PF) in the diet on performance of growing dairy buffalo calves. Thirty-two feedlots Surti breed dairy buffalo calves (age, 7.31 ± 0.34 months and body weight, 90.69 ± 6.19 kg) were assigned into four dietary treatments (n-8 calves/each): (1) control group, supplied basal diet as per ICAR (2013) nutrient requirements; (2) FTGM group, 30% crude protein (CP) requirement of concentrate mixture (dry matter basis (DMB)) replaced with FTGM in basal diet; (3) PF group, supplied basal diet + 100 g PF; and (4) FTGM + PF group, 30% CP requirement of concentrate mixture (DMB) replaced with FTGM in the basal diet + 100 g PF for 280 days. All the treatment diets were isonitrogenous. Growth performance was improved in FTGM + PF and FTGM groups. Apparent digestibility (%) of CP was increased in FTGM and FTGM + PF diet, while digestibility (%) of ether extract (EE) was increased in PF group. Serum total protein, albumen, urea nitrogen, and creatinine concentrations were higher in FTGM + PF and FTGM groups, whereas total cholesterol and triglycerides levels were greater in FTGM + PF and PF groups. Calculated methane emission had a discernible influence of treatment in FTGM and FTGM + PF. The overall cost of feeding per kilogram gain was lowest in FTGM and FTGM + PF groups. In conclusion, 30% CP replacement with FTGM with or without PF improved the growth performance, feed conversion ratio, and nutrient utilization; supported efficient utilization of resources; and economized the rearing of growing dairy buffalo calves.

The Role of Psychologists in Sport Medicine Practice.

Young athletes face a unique set of stressors from nonathletes that require careful screening and management. Internalizing disorders, substance use, overtraining, eating disorders, the female athlete triad, and sport-related injury are some psychological issues related to sports participation. Young athletes experiencing these conditions may experience functional impairment and distress on and off the field and management of these concerns includes routine screening and intervention. Embedding a psychologist within a pediatric sports medicine clinic improves patients' access to psychological screenings, early identification, and early intervention for these concerns athletes face.

Eighteen-year-old man with syncope with Helicobacter pylori as the culprit: a case report.

Helicobacter pylori (H. pylori) is amongst the most common chronic bacterial infection in humans. Pediatric patients appear to differ from their adult counterparts in terms of the prevalence, the complication rate, and the rate of antibiotic resistance. In this report, we present an 18-year-old man without any past medical history who was evaluated after an episode of syncope. Evaluation revealed a case of chronic H. pylori gastritis leading to gastrointestinal (GI) bleeding and weight loss, and his syncope was the byproduct of symptomatic anemia and physical exertion. Pediatricians should think of peptic ulcer disease (PUD) in evaluating poor weight gain/feeding in younger patients, and abdominal pain in older patients. Early diagnosis can prevent complications such as perforation, bleeding and obstruction. Endoscopy is the gold standard of diagnosis for H. pylori infection. Noninvasive testing with urease breath test and stool antigen test is reserved for post-treatment testing only. Treatment consists of a 14-day course of a proton-pump inhibitor (PPI) and amoxicillin. A third agent, either clarithromycin or metronidazole, is added depending on regional resistance patterns. Testing for eradication at least 4 weeks later is recommended. This case serves as a reminder to primary care providers to be aware of H. pylori infection, diagnosis, treatment and complications.

Medical perspectives on pediatric sports medicine-Selective topics.

Selective medical perspectives of pediatric sports medicine are explored in this issue and behavioral perspectives of pediatric sports medicine are discussed in a subsequent journal issue. Concepts are considered now dealing with sports readiness involving the child and adolescent that involve understanding the limits imposed by growth and development at different ages as well as pubertal stages. Specializing in one sport too soon is not recommended. Sports readiness also involves understanding and counseling about proper diet and nutrition for maximum sports activity as well as overall health benefits. As clinicians understand sports readiness they can provide a beneficial pre-participation sports examination and deal with qualifications for sports play. Various medical conditions arise in dealing with pediatric persons involved in sports and these are considered in this discussion. They include the female athlete triad, iron deficiency anemia, sports anemia, musculoskeletal overuse injuries, obesity, sudden cardiac death, return to learning after sports-related concussion, epilepsy, asthma, diabetes mellitus, gastrointestinal disorders, genitourinary disorders and dermatology disorders in sports. Clinicians can be very helpful to these young athletes and work with them to ensure the full benefits of sport activities.

Pelvic inflammatory disease in the adolescent and young adult: An update.

Pelvic inflammatory disease (PID) is an infection of the female upper genital tract that is typically polymicrobial with classic core involvement of Neisseria gonorrhoeae and/or Chlamydia trachomatis, though other endogenous flora from the vagino-cervical areas can be involved as well. It is often a sexually transmitted disease but other etiologic routes are also noted. A variety of risk factors have been identified including adolescence, young adulthood, adolescent cervical ectropion, multiple sexual partners, immature immune system, history of previous PID, risky contraceptive practices and others. An early diagnosis and prompt treatment are necessary to reduce risks of PID complications such as chronic pelvic pain, ectopic pregnancy and infertility. Current management principles of PID are also reviewed. It is important for clinicians to screen sexually active females for common sexually transmitted infections such as Chlamydia trachomatis and provide safer sex education to their adolescent and young adult patients. Clinicians should provide comprehensive management to persons with PID and utilize established guidelines such as those from the US Centers for Disease Control and Prevention (CDC).

Integrated Behavioral Health: Definitions and Contexts.

Most children and adolescents with behavioral and mental health concerns first present to their pediatricians. Although pediatricians are fully cognizant of the importance of addressing behavioral and mental health concerns, they often find it difficult to deliver such care effectively and efficiently within a typical practice setting. Integration of medical and behavioral health care has emerged as a model to deliver such care. In the pediatric primary care practice, integrated behavioral health has been shown to be a cost-effective way to deliver high-quality care. This article describes basic definitions and contexts of integrated pediatric behavioral health.

Quantification of the effect of body mass index on cricothyroid membrane depth: a cross-sectional analysis of clinical CT images.

OBJECTIVES: The recommended front of neck access procedure in can't intubate, can't oxygenate scenarios relies on palpation of the cricothyroid membrane (CTM), or dissection of the neck down to the larynx if CTM is impalpable. CTM palpation is particularly challenging in obese patients, most likely due to an increased distance between the skin and the CTM (CTM depth). The aims of this study were to measure the CTM depth in a representative clinical sample, and to quantify the relationship between body mass index (BMI) and CTM depth. METHODS: This is a retrospective analysis of 355 clinical CT scans performed at a teaching hospital over an 8-month period. CTM depth was measured by two radiologists, and mean CTM depth calculated. Age, gender, height and weight were recorded, and BMI calculated. Linear relationships between patient characteristics and CTM depth were assessed in order to derive a predictive equation for calculating CTM depth. The variables included for this model were those with a strong association with CTM depth, that is, a p value of 0.10 or less. RESULTS: Mean CTM depth was 8.12 mm (IQR 6.36-11.70). There was no association between CTM depth and sex (ß -0.33, 95% CI -1.33 to 0.68, p=0.53), height (cm) (ß 0.01, 95% CI -0.05 to 0.06, p=0.79) or age (years) (ß -0.01, 95% CI 0.10 to 0.15, p=0.62). Increasing weight (kg) (ß 0.12, 95% CI 0.10 to 0.15, p<0.001) and BMI (kg/m3) (ß 0.52, 95% CI 0.44 to 0.60, p<0.001) were strongly associated with CTM depth. Predicted CTM depth increased from 6.4 mm (95% CI 4.9 to 8.1) at a BMI of 20 kg/m2 to 16.8 (95% CI 13.7 to 20.1) at BMI 40 kg/m2. CONCLUSION: CTM depth was strongly associated with BMI in a retrospective analysis of patients having clinical CT scans.

Acne in the first three decades of life: An update of a disorder with profound implications for all decades of life.

Acne vulgaris is a chronic, inflammatory, skin condition that involves the pilosebaceous follicles and is influenced by a variety of factors including genetics, androgen-stimulation of sebaceous glands with abnormal keratinization, colonization with Cutibacterium acnes (previously called Propionibacterium acnes), and pathological immune response to inflammation. Acne can occur at all ages and this discussion focuses on the first three decades of life. Conditions that are part of the differential diagnosis and/or are co-morbid with acne vulgaris are also considered. Acne in the first year of life includes neonatal acne (acne neonatorum) that presents in the first four weeks of life and infantile acne that usually presents between 3 and 6 months of the first year of life with a range of 3 to 16 months after birth. Acne rosacea is a chronic, inflammatory, skin condition that is distinct from acne vulgaris, typically presents in adults, and has four main types: erythemato-telangiectatic, papulopustular, phymatous and ocular. Treatment options for acne vulgaris include topical retinoids, topical benzoyl peroxide, antibiotics (topical, oral), oral contraceptive pills, isotretinoin, and others. Management must consider the increasing impact of antibiotic resistance in the 21st century. Psychological impact of acne can be quite severe and treatment of acne includes awareness of the potential emotional toll this disease may bring to the person with acne as well as assiduous attention to known side effects of various anti-acne medications (topical and systemic). Efforts should be directed at preventing acne-caused scars and depigmentation on the skin as well as emotional scars within the person suffering from acne.

Quantitative magnetic resonance imaging predicts individual future liver performance after liver resection for cancer.

The risk of poor post-operative outcome and the benefits of surgical resection as a curative therapy require careful assessment by the clinical care team for patients with primary and secondary liver cancer. Advances in surgical techniques have improved patient outcomes but identifying which individual patients are at greatest risk of poor post-operative liver performance remains a challenge. Here we report results from a multicentre observational clinical trial (ClinicalTrials.gov NCT03213314) which aimed to inform personalised pre-operative risk assessment in liver cancer surgery by evaluating liver health using quantitative multiparametric magnetic resonance imaging (MRI). We combined estimation of future liver remnant (FLR) volume with corrected T1 (cT1) of the liver parenchyma as a representation of liver health in 143 patients prior to treatment. Patients with an elevated preoperative liver cT1, indicative of fibroinflammation, had a longer post-operative hospital stay compared to those with a cT1 within the normal range (6.5 vs 5 days; p = 0.0053). A composite score combining FLR and cT1 predicted poor liver performance in the 5 days immediately following surgery (AUROC = 0.78). Furthermore, this composite score correlated with the regenerative performance of the liver in the 3 months following resection. This study highlights the utility of quantitative MRI for identifying patients at increased risk of poor post-operative liver performance and a longer stay in hospital. This approach has the potential to inform the assessment of individualised patient risk as part of the clinical decision-making process for liver cancer surgery.

Academic Performance Following Sport-Related Concussions in Children and Adolescents: A Scoping Review.

Sport-related concussions (SRC) are an increasingly common concern in young athletes, with long-term cognitive, physiological, behavioral, and psychological adverse outcomes. An estimated 1.1 million to 1.9 million SRCs occur per year in children <18 years old in the United States. The post-concussive state has demonstrated consequences in several domains, including athletics and academics, although much more research has been conducted on the former. The objective of this scoping review was to ascertain findings from published studies on the effects of SRCs on academic performance and quality of life of young student athletes. A total of 175 articles were screened within the PubMed and CINAHL databases, along with a Google search. Fourteen papers fulfilled the inclusion criteria and were analyzed in the review. Quantitative and qualitative data were collated and demonstrated the heterogeneity with which, post-concussion academic performance outcomes were measured; only 4 of the 14 studies utilized formal academic metrics such as changes in grade point average (GPA) or examination scores. While the results overall did show statistically significant implications on academic performance decline after SRC, it is clear that there remains a paucity of research determining the consequences of SRCs on academic performance in the school environment. Further research is needed to better understand how to implement accommodations in the student's learning environment and guide return-to-learn protocols for student athletes following SRC.