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.

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.

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.

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.

Risk Factors and Prevention Strategies for Anxiety Disorders in Childhood and Adolescence.

Anxiety is prevalent in childhood and adolescence. Youth with maladaptive responses to common situations and stressors are at risk of having anxiety disorders. Persistent anxiety symptoms and anxiety disorders can be debilitating with long-term adverse outcomes in adulthood. Hence, decreasing the burden of anxiety disorders is an important public health priority. Development of anxiety disorders has a multifactorial etiology. There is a considerable complex interaction of genetics, temperament, parenting behavior, environmental triggers, and physiologic factors. Identification of these risk factors is key to early detection, prevention, and development of applicable management approaches. Despite several evidence-based treatments published, there are limited prevention strategies available. Effective implementation of prevention strategies is essential and can be achieved by either elimination or reduction of the negative risk factors or strengthening the protective factors on anxiety symptoms and anxiety disorders. This chapter reviews the common risk and protective factors and provides current literature on prevention strategies for pediatric and adolescent anxiety disorders.

Serelaxin as a potential treatment for renal dysfunction in cirrhosis: Preclinical evaluation and results of a randomized phase 2 trial.

BACKGROUND: Chronic liver scarring from any cause leads to cirrhosis, portal hypertension, and a progressive decline in renal blood flow and renal function. Extreme renal vasoconstriction characterizes hepatorenal syndrome, a functional and potentially reversible form of acute kidney injury in patients with advanced cirrhosis, but current therapy with systemic vasoconstrictors is ineffective in a substantial proportion of patients and is limited by ischemic adverse events. Serelaxin (recombinant human relaxin-2) is a peptide molecule with anti-fibrotic and vasoprotective properties that binds to relaxin family peptide receptor-1 (RXFP1) and has been shown to increase renal perfusion in healthy human volunteers. We hypothesized that serelaxin could ameliorate renal vasoconstriction and renal dysfunction in patients with cirrhosis and portal hypertension. METHODS AND FINDINGS: To establish preclinical proof of concept, we developed two independent rat models of cirrhosis that were characterized by progressive reduction in renal blood flow and glomerular filtration rate and showed evidence of renal endothelial dysfunction. We then set out to further explore and validate our hypothesis in a phase 2 randomized open-label parallel-group study in male and female patients with alcohol-related cirrhosis and portal hypertension. Forty patients were randomized 1:1 to treatment with serelaxin intravenous (i.v.) infusion (for 60 min at 80 µg/kg/d and then 60 min at 30 µg/kg/d) or terlipressin (single 2-mg i.v. bolus), and the regional hemodynamic effects were quantified by phase contrast magnetic resonance angiography at baseline and after 120 min. The primary endpoint was the change from baseline in total renal artery blood flow. Therapeutic targeting of renal vasoconstriction with serelaxin in the rat models increased kidney perfusion, oxygenation, and function through reduction in renal vascular resistance, reversal of endothelial dysfunction, and increased activation of the AKT/eNOS/NO signaling pathway in the kidney. In the randomized clinical study, infusion of serelaxin for 120 min increased total renal arterial blood flow by 65% (95% CI 40%, 95%; p < 0.001) from baseline. Administration of serelaxin was safe and well tolerated, with no detrimental effect on systemic blood pressure or hepatic perfusion. The clinical study's main limitations were the relatively small sample size and stable, well-compensated population. CONCLUSIONS: Our mechanistic findings in rat models and exploratory study in human cirrhosis suggest the therapeutic potential of selective renal vasodilation using serelaxin as a new treatment for renal dysfunction in cirrhosis, although further validation in patients with more advanced cirrhosis and renal dysfunction is required. TRIAL REGISTRATION: ClinicalTrials.gov NCT01640964.

Computed tomography myocardial perfusion vs 15O-water positron emission tomography and fractional flow reserve.

OBJECTIVES: Computed tomography (CT) can perform comprehensive cardiac imaging. We compared CT coronary angiography (CTCA) and CT myocardial perfusion (CTP) with 15O-water positron emission tomography (PET) and invasive coronary angiography (ICA) with fractional flow reserve (FFR). METHODS: 51 patients (63 (61-65) years, 80 % male) with known/suspected coronary artery disease (CAD) underwent 320-multidetector CTCA followed by "snapshot" adenosine stress CTP. Of these 22 underwent PET and 47 ICA/FFR. Obstructive CAD was defined as CTCA stenosis >50 % and CTP hypoperfusion, ICA stenosis >70 % or FFR <0.80. RESULTS: PET hyperaemic myocardial blood flow (MBF) was lower in obstructive than non-obstructive territories defined by ICA/FFR (1.76 (1.32-2.20) vs 3.11 (2.44-3.79) mL/(g/min), P < 0.001) and CTCA/CTP (1.76 (1.32-2.20) vs 3.12 (2.44-3.79) mL/(g/min), P < 0.001). Baseline and hyperaemic CT attenuation density was lower in obstructive than non-obstructive territories (73 (71-76) vs 86 (84-88) HU, P < 0.001 and 101 (96-106) vs 111 (107-114) HU, P 0.001). PET hyperaemic MBF corrected for rate pressure product correlated with CT attenuation density (r = 0.579, P < 0.001). There was excellent per-patient sensitivity (96 %), specificity (85 %), negative predictive value (90 %) and positive predictive value (94 %) for CTCA/CTP vs ICA/FFR. CONCLUSION: CT myocardial attenuation density correlates with 15O-water PET MBF. CTCA and CTP can accurately identify obstructive CAD. KEY POINTS: •CT myocardial perfusion can aid the assessment of suspected coronary artery disease. • CT attenuation density from "snapshot" imaging is a marker of myocardial perfusion. • CT myocardial attenuation density correlates with 15 O-water PET myocardial blood flow. • CT attenuation density is lower in obstructive territories defined by invasive angiography. • Diagnostic accuracy of CTCA+CTP is comparable to invasive angiography + fractional flow reserve.

Low and fixed dose of hydroxyurea is effective and safe in patients with HbSß(+) thalassemia with IVS1-5(G→C) mutation.

BACKGROUND: Despite compelling evidence that hydroxyurea is safe and effective in sickle cell disease, it is prescribed sparingly due to several barriers like knowledge gaps in certain genotypes, apprehension about its safety and toxicity, and limited resources. We undertook this study to find out the efficacy and safety of HU in patients with HbSß(+) -thalassemia with IVS1-5(G→C) mutation. PROCEDURE: We registered 318 patients with HbSß(+) -thalassemia with IVS1-5(G→C) mutation. Of these, 203 were enrolled for hydroxyurea treatment at a low and fixed dose of 10 mg/kg/day. One hundred four patients (Group-I: 37 children and Group-II: 67 adults) with ≥2 years of hydroxyurea treatment were studied. RESULTS: The rate of vaso-occlusive crises, requirement of blood transfusion and rate of hospitalization reduced from 3 to 0.5, 1 to 0 and 1 to 0 in Group-I and 3 to 0, 1 to 0 and 0.5 to 0 in Group-II respectively after HU therapy (P < 0.0001). %HbF level, hemoglobin, MCV and MCH increased significantly, whereas HbS, WBC, platelet count, serum-bilirubin and LDH levels decreased significantly after HU therapy. It has been observed that along with fairly subtle hematological changes following HU therapy, there was a substantial clinical improvement occurred in these patients. Transient myelotoxicity was observed in 4.8%. There was minimal gonadal toxicity without affecting reproductive function. CONCLUSION: In view of easy affordability, better acceptability, minimal toxicity, the need of infrequent monitoring and its potential effectiveness, low and fixed dose of hydroxyurea is suitable for treatment of patients with HbSß(+) -thalassemia in resource poor setting.

The effect of hydroxyurea on compound heterozygotes for sickle cell-hemoglobin D-Punjab--a single centre experience in eastern India.

BACKGROUND: Although hydroxyurea is the only effective agent for the treatment of sickle cell disease, published experience with this drug is limited to treatment of homozygous sickle cell anemia and HbS/ß thalassemia. The role of hydroxyurea in the treatment of patients with HbSD-Punjab, a rare hemoglobinopathy with phenotypic expression similar to that of sickle cell anemia is unknown. PROCEDURE: Over a period of 10 years, we followed 42 patients with HbSD-Punjab, of which 20 presented with severe clinical manifestations (≥3 episodes of VOC and/or ≥2 units of blood transfusion in the previous 12 months). These 20 patients were enrolled for treatment with hydroxyurea at a dose of 10 mg/kg/day and followed prospectively for a period of 24 months. RESULTS: The frequency of VOC decreased significantly and none of them required blood transfusion while receiving hydroxyurea. The HbF, total hemoglobin, MCV, MCH, and MCHC levels increased significantly, whereas HbS, WBC, platelet count, total serum bilirubin, and LDH levels decreased significantly in all the patients. No short-term drug toxicity was observed. CONCLUSION: This study describes the use of hydroxyurea therapy in patients with HbSD-Punjab. Low dose hydroxyurea (10 mg/kg/day) was found to be effective in reducing the clinical severity in patients with HbSD-Punjab without any short-term toxicity. In view of easy affordability amongst poor patients, widespread acceptability by patients and doctors, the need of infrequent monitoring and its potential effectiveness, low dose hydroxyurea is suitable for treatment of patients with HbSD-Punjab.

A randomized controlled trial of peripheral blood mononuclear cell depletion in experimental human lung inflammation.

RATIONALE: Depletion of monocytes reduces LPS-induced lung inflammation in mice, suggesting monocytes as potential therapeutic targets in acute lung injury. OBJECTIVES: To investigate whether depletion of circulating blood monocytes has beneficial effects on markers of systemic and pulmonary inflammation in a human model of acute lung inflammation. METHODS: A total of 30 healthy volunteers were enrolled in a randomized controlled trial. Volunteers inhaled LPS at baseline, and were randomized to receive active mononuclear cell depletion by leukapheresis, or sham leukapheresis, in a double-blind fashion (15 volunteers per group). Serial blood counts were measured, bronchoalveolar lavage (BAL) was performed at 9 hours, and [(18)F]fluorodeoxyglucose positron emission tomography at 24 hours. The primary endpoint was the increment in circulating neutrophils at 8 hours. MEASUREMENTS AND MAIN RESULTS: As expected, inhalation of LPS induced neutrophilia and an up-regulation of inflammatory mediators in the blood and lungs of all volunteers. There was no significant difference between the depletion and sham groups in the mean increment in blood neutrophil count at 8 hours (6.16 × 10(9)/L and 6.15 × 10(9)/L, respectively; P = 1.00). Furthermore, there were no significant differences in BAL neutrophils or protein, positron emission tomography-derived measures of global lung inflammation, or cytokine levels in plasma or BAL supernatant between the study groups. No serious adverse events occurred, and no symptoms were significantly different between the groups. CONCLUSIONS: These findings do not support a role for circulating human monocytes in the early recruitment of neutrophils during LPS-mediated acute lung inflammation in humans.

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.

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.

Computed tomography angiography in the diagnosis of ANCA-associated small- and medium-vessel vasculitis.

Polyarteritis nodosa (PAN) is a systemic necrotizing vasculitis that typically occurs without detectable antineutrophil cytoplasmic antibody. It leads to aneurysm formation by affecting muscular arteries, usually those of medium size but also occasionally those of small size. Kidney involvement is common, leading to reduced glomerular filtration rate, hypertension, rupture of renal arterial aneurysms causing perinephric hematomas, and renal infarctions in those with severe vasculitis. Similar to PAN, microscopic polyangiitis (MPA) leads to aneurysm formation; however, MPA usually is associated with antineutrophil cytoplasmic antibody, and glomerulonephritis is a more common feature of MPA. Although kidney biopsy may show classic vascular changes in both PAN and MPA, this procedure is not without risk of significant bleeding due to aneurysm rupture. We present 2 cases of renal aneurysms that were diagnosed as MPA using computed tomography angiography (CTA), allowing implementation of appropriate immunosuppressive therapy. Follow-up CTA after treatment showed resolution of all previously observed abnormalities. CTA is a useful alternative to kidney biopsy in establishing both the extent of disease in renal aneurysms and allowing for tracking of disease progression and response to therapy.

Dietary supplementation with Bifidobacterium lactis NCC2818 from weaning reduces local immunoglobulin production in lymphoid-associated tissues but increases systemic antibodies in healthy neonates.

Weaning is associated with a major shift in the microbial community of the intestine, and this instability may make it more acquiescent than the adult microbiota to long-term changes. Modulation achieved through dietary interventions may have potentially beneficial effects on the developing immune system, which is driven primarily by the microbiota. The specific aim of the present study was to determine whether immune development could be modified by dietary supplementation with the human probiotic Bifidobacterium lactis NCC2818 in a tractable model of weaning in infants. Piglets were reared by their mothers before being weaned onto a solid diet supplemented with B. lactis NCC2818, while sibling controls did not receive supplementation. Probiotic supplementation resulted in a reduction in IgA (P<0·0005) and IgM (P<0·009) production by mucosal tissues but had no effect on IgG production (P>0·05). Probiotic-supplemented pigs had more mast cells than unsupplemented littermates (P<0·0001), although numbers in both groups were low. In addition, the supplemented piglets made stronger serum IgG responses to fed and injected antigens (P<0·05). The present findings are consistent with B. lactis NCC2818 reducing intestinal permeability induced by weaning, and suggest that the piglet is a valuable intermediate between rodent models and human infants. The results also strongly suggest that measures of the effect of probiotic supplementation on the immune system need to be interpreted carefully as proxy measures of health benefit. However, they are useful in developing an understanding of the mechanism of action of probiotic strains, an important factor in predicting favourable health outcomes of nutritional intervention.

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.].

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.

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.

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.