Pathogenic variants in HPRT1 lead to deficiency in hypoxanthine‐guanine phosphoribosyltransferase and are responsible for a spectrum of disorders. The severe phenotype is termed Lesch–Nyhan syndrome ...(LNS) and is inherited in an X‐linked recessive manner. Most individuals with LNS have profound intellectual and physical disabilities throughout life including self‐mutilating behaviors. Here, we present the case of a male infant who was diagnosed with LNS at 3 weeks of age via rapid exome sequencing (ES), which revealed a hemizygous maternally inherited deletion of at least 1.3 Mb of Xq26.3, including exons 2 to 9 of HPRT1. We discuss the critical time points leading to this diagnosis while highlighting his parents' values that guided the decision‐making. Genetic testing provided an early diagnosis for this infant that led to important considerations regarding goals of care in addition to raising new ethical concerns. This highlights the important role that early and rapid diagnostic genetic testing can play in helping families make difficult decisions. Additionally, this case highlights the complexity of discussing rare genetic diagnoses with families and facilitating critical discussions to empower the family toward making an informed decision.
Patients with Kawasaki disease can develop life-altering coronary arterial abnormalities, particularly in those resistant to intravenous immunoglobulin (IVIg) therapy. We tested the tumor necrosis ...factor α receptor antagonist etanercept for reducing both IVIg resistance and coronary artery (CA) disease progression.
In a double-blind multicenter trial, patients with Kawasaki disease received either etanercept (0.8 mg/kg;
= 100) or placebo (
= 101) subcutaneously starting immediately after IVIg infusion. IVIg resistance was the primary outcome with prespecified subgroup analyses according to age, sex, and race. Secondary outcomes included echocardiographic CA measures within subgroups defined by coronary dilation (
score >2.5) at baseline. We used generalized estimating equations to analyze
score change and a prespecified algorithm for change in absolute diameters.
IVIg resistance occurred in 22% (placebo) and 13% (etanercept) of patients (
= .10). Etanercept reduced IVIg resistance in patients >1 year of age (
= .03). In the entire population, 46 (23%) had a coronary
score >2.5 at baseline. Etanercept reduced coronary
score change in those with and without baseline dilation (
= .04 and
= .001); no improvement occurred in the analogous placebo groups. Etanercept (
= 22) reduced dilation progression compared with placebo (
= 24) by algorithm in those with baseline dilation (
= .03). No difference in the safety profile occurred between etanercept and placebo.
Etanercept showed no significant benefit in IVIg resistance in the entire population. However, preplanned analyses showed benefit in patients >1 year. Importantly, etanercept appeared to ameliorate CA dilation, particularly in patients with baseline abnormalities.
Variation exists in neonatal platelet transfusion practices. Recent studies found potential harm in liberal platelet transfusion practices, supporting the use of lower transfusion thresholds. Our aim ...was to reduce non-indicated platelet transfusions through implementation of a restrictive platelet transfusion guideline.
Platelet transfusions from January 2017 to December 2019 were classified as indicated or non-indicated using the new guideline. Interventions included guideline implementation and staff education. Outcomes were evaluated using statistical process control charts. Major bleeding was the balancing measure.
During study, 438 platelet transfusions were administered to 105 neonates. The mean number of non-indicated platelet transfusions/month decreased from 7.3 to 1.6. The rate of non-indicated platelet transfusions per 100 patient admissions decreased from 12.5 to 2.9. Rates of major bleeding remained stable.
Implementation of a restrictive neonatal platelet transfusion guideline significantly reduced potentially harmful platelet transfusions in our NICU without a change in major bleeding.
Short-acting b2-adrenergic receptor agonists are commonly used bronchodilators for symptom relief in asthmatics. The aim of this study was to test whether genetic variants in PDE4D gene, a key ...regulator of b2-adrenoceptor-induced cAMP turnover in airway smooth muscle cells, affect the response to short-acting b2-agonists. Bronchodilator responsiveness was assessed in 133 asthmatic children by % change in baseline forced expiratory volume in one second (FEV1) after administration of albuterol. The analyses were performed in patients with airway obstruction (FEV1/FVC ratio below 90%, n=93). FEV1 % change adjusted for baseline FEV1 values was significantly different between genotypes of rs1544791 G/A polymorphism (P=0.006) and −1345 C/T (rs1504982) promoter variation (P=0.03). The association remained significant with inclusion of age, sex, atopy, and controller medication into multivariate model (P=0.004 and P=0.02, resp.). Our work identifies new genetic variants implicated in modulation of asthma treatment, one of them (rs1544791) previously associated with asthma phenotype.
Neonatal nurses face an ever-changing practice landscape that requires swift decisions and actions. This is an up-to-date, comprehensive, quick referenceresource written specifically for neonatal ...nurses throughout the globe. Designed for speedy information retrieval, it encompasses vital information aboutcommonly encountered conditions and procedures on the neonatal unit. The handbook is written by outstanding neonatal practitioners in accessible languageand consistently formatted for ease of use.
Illustrations, diagrams and flow charts enhance information, which is divided into sections covering Systems Assessment and Management of Disorders,Special Care Considerations, and Procedures and Diagnostic Tests. Appendices deliver such valuable tools for clinical practice as a list of commonabbreviations and pertinent web resources. Also included are downloadable, digital, patient management tools, reusable templates, and quick-referencecalculation tools.
Pathogenic variants in HPRT1 lead to deficiency in hypoxanthine-guanine phosphoribosyltransferase and are responsible for a spectrum of disorders. The severe phenotype is termed Lesch-Nyhan syndrome ...(LNS) and is inherited in an X-linked recessive manner. Most individuals with LNS have profound intellectual and physical disabilities throughout life including self-mutilating behaviors. Here, we present the case of a male infant who was diagnosed with LNS at 3 weeks of age via rapid exome sequencing (ES), which revealed a hemizygous maternally inherited deletion of at least 1.3 Mb of Xq26.3, including exons 2 to 9 of HPRT1. We discuss the critical time points leading to this diagnosis while highlighting his parents' values that guided the decision-making. Genetic testing provided an early diagnosis for this infant that led to important considerations regarding goals of care in addition to raising new ethical concerns. This highlights the important role that early and rapid diagnostic genetic testing can play in helping families make difficult decisions. Additionally, this case highlights the complexity of discussing rare genetic diagnoses with families and facilitating critical discussions to empower the family toward making an informed decision.
A novel dual GIP and GLP-1 receptor agonist, LY3298176, was developed to determine whether the metabolic action of GIP adds to the established clinical benefits of selective GLP-1 receptor agonists ...in type 2 diabetes mellitus (T2DM).
LY3298176 is a fatty acid modified peptide with dual GIP and GLP-1 receptor agonist activity designed for once-weekly subcutaneous administration. LY3298176 was characterised in vitro, using signaling and functional assays in cell lines expressing recombinant or endogenous incretin receptors, and in vivo using body weight, food intake, insulin secretion and glycemic profiles in mice.
A Phase 1, randomised, placebo-controlled, double-blind study was comprised of three parts: a single-ascending dose (SAD; doses 0.25–8 mg) and 4-week multiple-ascending dose (MAD; doses 0.5–10 mg) studies in healthy subjects (HS), followed by a 4-week multiple-dose Phase 1 b proof-of-concept (POC; doses 0.5–15 mg) in patients with T2DM (ClinicalTrials.gov no. NCT02759107). Doses higher than 5 mg were attained by titration, dulaglutide (DU) was used as a positive control. The primary objective was to investigate safety and tolerability of LY3298176.
LY3298176 activated both GIP and GLP-1 receptor signaling in vitro and showed glucose-dependent insulin secretion and improved glucose tolerance by acting on both GIP and GLP-1 receptors in mice. With chronic administration to mice, LY3298176 potently decreased body weight and food intake; these effects were significantly greater than the effects of a GLP-1 receptor agonist.
A total of 142 human subjects received at least 1 dose of LY3298176, dulaglutide, or placebo. The PK profile of LY3298176 was investigated over a wide dose range (0.25–15 mg) and supports once-weekly administration. In the Phase 1 b trial of diabetic subjects, LY3298176 doses of 10 mg and 15 mg significantly reduced fasting serum glucose compared to placebo (least square mean LSM difference 95% CI: −49.12 mg/dL −78.14, −20.12 and −43.15 mg/dL −73.06, −13.21, respectively). Reductions in body weight were significantly greater with the LY3298176 1.5 mg, 4.5 mg and 10 mg doses versus placebo in MAD HS (LSM difference 95% CI: −1.75 kg −3.38, −0.12, −5.09 kg −6.72, −3.46 and −4.61 kg −6.21, −3.01, respectively) and doses of 10 mg and 15 mg had a relevant effect in T2DM patients (LSM difference 95% CI: −2.62 kg −3.79, −1.45 and −2.07 kg −3.25, −0.88, respectively.
The most frequent side effects reported with LY3298176 were gastrointestinal (vomiting, nausea, decreased appetite, diarrhoea, and abdominal distension) in both HS and patients with T2DM; all were dose-dependent and considered mild to moderate in severity.
Based on these results, the pharmacology of LY3298176 translates from preclinical to clinical studies. LY3298176 has the potential to deliver clinically meaningful improvement in glycaemic control and body weight. The data warrant further clinical evaluation of LY3298176 for the treatment of T2DM and potentially obesity.
•LY3298176 activates both GIP and GLP-1 receptor signaling in vitro.•LY3298176 lowers blood glucose in mice through actions on both incretin receptors.•LY3298176 reduced fasting glucose in humans with type 2 diabetes.•Weight loss was greater with LY3298176 than the selective GLP-1 receptor agonist, dulaglutide in healthy humans.•Tolerability of LY3298176 was comparable to GLP-1 receptor agonists.
With an increasing prevalence of obesity, there is a need for new therapies to improve body weight management and metabolic health. Multireceptor agonists in development may provide approaches to ...fulfill this unmet medical need. LY3437943 is a novel triple agonist peptide at the glucagon receptor (GCGR), glucose-dependent insulinotropic polypeptide receptor (GIPR), and glucagon-like peptide-1 receptor (GLP-1R). In vitro, LY3437943 shows balanced GCGR and GLP-1R activity but more GIPR activity. In obese mice, administration of LY3437943 decreased body weight and improved glycemic control. Body weight loss was augmented by the addition of GCGR-mediated increases in energy expenditure to GIPR- and GLP-1R-driven calorie intake reduction. In a phase 1 single ascending dose study, LY3437943 showed a safety and tolerability profile similar to other incretins. Its pharmacokinetic profile supported once-weekly dosing, and a reduction in body weight persisted up to day 43 after a single dose. These findings warrant further clinical assessment of LY3437943.
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•LY3437943 has triple agonist activity at the glucagon, GIP, and GLP-1 receptors•LY3437943 caused greater body weight loss in obese mice than tirzepatide•LY3437943 increased energy expenditure through glucagon receptor activation•Safety and tolerability of LY3437943 were similar to other incretin-based drugs
Coskun et al. demonstrate that LY3437943, a triple glucagon, GIP, and GLP-1 receptor agonist for the treatment of obesity and type 2 diabetes, can reduce body weight through increased energy expenditure and reduced calorie intake in obese mice. Its safety and tolerability in healthy participants were similar to other incretin-based therapies.
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