The longitudinal follow up of a universal neonatal hearing screen: The implications for confirming deafness in childhood

Abstract

Objective: To examine the implications of universal neonatal screening for confirming deafness in early childhood. Design: A cohort that had received a universal neonatal hearing screen was followed-up until school entry, and confirmation of deafness compared with that from parallel cohorts that had not received the screen. Study: Three 10-year cohorts were compared: a cohort of 35 668 enrolled for universal neonatal hearing screening, a historical cohort of 31 538 when neonatal screening was unavailable, and a cohort of 32 890 when targeted screening was in place. Results: Prevalence of deafness by school age was 3.65/1000 with a neonatal yield of 1.79/1000. The screen had been 89% sensitive to moderate and worse deafness, 79% to unilateral deafness, and 49% to mild impairments. The median age of confirmation had been reduced from 218 to 16 weeks, but for those not identified neonatally there had been no significant improvement in the age of confirmation over the previous 25 years. The yield from post-neonatal screens had been reduced from 1.8/1000 to 0.2/1000, and with a yield of 0.8/1000, reactive referral remained a more effective route to identification. Conclusions: Even with UNHS in place post-neonatal routes to identification need to be maintained and improvements investigated.     

Conversion factors for determining organ doses received by paediatric patients in high-resolution single slice computed tomography with narrow collimation

Estimations of organ doses D_T received during computed tomographic examinations are usually performed by applying conversion factors to basic dose indicators like the computed tomography dose index (CTDI) or the dose-length-product (DLP). In addition to the existing conversion factors for beam apertures of 5 mm or 10 mm, we present new DLP-D_T conversion factors adapted to high-resolution CT (HRCT) examinations of infants and young children with beam apertures of the order of 1 mm and under consideration of bow tie filtration. Calculations are performed on mathematical MIRD phantoms for an age range from 0, 1, 5, 10, 15 up to (for comparison) 30 years by adapting PCXMC, a Monte Carlo algorithm originally developed by STUK (Helsinki, Finland) for dose reconstructions in projection radiography. For this purpose, each single slice CT examination is approximated by a series of corresponding virtual planar radiographies comprising all focus positions. The transformation of CT exposure parameters into exposure parameters of the series of corresponding planar radiographies is performed by a specially developed algorithm called XCT. The DLP values are evaluated using the EGSRay code. The new method is verified at a beam aperture of 10 mm by comparison with formerly published conversion factors. We show that the higher spatial resolution leads to an enhanced DLP-D_T conversion factor if a small organ (e. g. thyroid gland, mammae, uterus, ovaries, testes) is exactly met by the chosen CT slice, while the conversion factor is drastically reduced if the chosen CT slice is positioned above or below the organ. This effect is utilized for dose-saving examinations with only a few single slices instead a full scan, which technique is applied in about 10% of all paediatric chest CT examinations.     

脂质蓄积指数和内脏脂肪指数对成年人代谢综合征的预测价值研究

背景　脂质蓄积指数（LAP）和内脏脂肪指数（VAI）是反映个体脂肪分布及内脏脂肪蓄积程度的重要指标，与肥胖相关的慢性代谢性疾病关系密切。目的　探讨LAP和VAI与成年人代谢综合征（MS）的相关性，并评估LAP、VAI对MS的预测价值。方法　纳入2018年9月至2019年5月在中日友好医院体检中心进行体检的708例受试者，其中MS患者249例（MS组），非MS患者459例（非MS组），比较两组患者LAP、VAI及相关生化指标。根据LAP、VAI四分位数将受试者进行分组（L1组、L2组、L3组、L4组各177例；V1组、V2组、V3组、V4组各177例），比较各组MS及其组分发生率。采用多因素Logistic回归分析计算不同LAP、VAI受试者MS的发生风险，并分别绘制不同性别LAP、VAI、腰围（WC）、体质指数（BMI）预测MS发生风险的受试者工作特征（ROC）曲线。结果　LAP和VAI与成年人MS发生率呈高强度正相关（Cramer's V=0.585、0.577）。多因素Logistic回归分析结果显示，在调整各危险因素后，L3组、L4组MS发生风险仍高于L1组，V3组、V4组MS发生风险仍高于V1组（P<0.001）。ROC曲线分析结果显示，男性LAP、VAI预测MS发生风险的ROC曲线下面积（AUC）分别为0.831〔95%CI（0.795，0.867）〕、0.825〔95%CI（0.788，0.863）〕，临界值分别为52.03、1.99；女性LAP、VAI预测MS发生风险的AUC分别为0.887〔95%CI（0.834，0.940）〕、0.886〔95%CI（0.827，0.945）〕，临界值分别为54.84、2.54。结论　LAP、VAI与成年人MS发生率呈高强度正相关，随着LAP、VAI增高，MS发生风险亦增高；LAP、VAI对MS有良好的预测价值，联合WC和BMI能有效预测MS。     

Solving the Faddeev-Merkuriev Equations in Total Orbital Momentum Representation via Spline Collocation and Tensor Product Preconditioning

The computational approach for solving the Faddeev-Merkuriev equations in total orbital momentum representation is presented. These equations describe a system of three quantum charged particles and are widely used in bound state and scattering calculations. The approach is based on the spline collocation method and exploits intensively the tensor product form of discretized operators and preconditioner, which leads to a drastic economy in both computer resources and time.     

Bioequivalence and Food Effect of Dapagliflozin/Saxagliptin/Metformin Extended-release Fixed-combination Drug Products Compared With Coadministration of the Individual Components in Healthy Subjects

PurposeFixed-combination drug products (FCDPs) for patients with type 2 diabetes mellitus (T2DM) may show efficacy comparable to their individual components (ICs) while improving adherence to treatment. This study evaluated the bioequivalence and safety of 2 dapagliflozin/saxagliptin/metformin extended-release (XR) FCDPs relative to their ICs: saxagliptin and dapagliflozin/metformin XR.MethodsThis randomized, open-label, single-dose, single-center crossover study was conducted in 84 healthy subjects aged 18–55 years. The primary objective was to evaluate the fed-state bioequivalence of a dapagliflozin 5-mg/saxagliptin 2.5-mg/metformin 1000-mg XR FCDP and a dapagliflozin 10-mg/saxagliptin 5-mg/metformin 1000-mg XR FCDP relative to the ICs. Secondary objectives included the evaluation of the effect of food on the pharmacokinetic (PK) parameters of saxagliptin, dapagliflozin, and metformin in both FCDPs and characterization of the PK parameters of the active metabolite of saxagliptin, 5-hydroxy saxagliptin, in healthy subjects. PK parameters (AUC_0–∞, AUC_0–t, and C_max) were used to assess the bioequivalence of the 2 FCDPs with their ICs. The C_max and AUC_0–t of the study drugs were compared between female and male subjects to assess sex differences in exposure. Safety and tolerability of both FCDPs and ICs were also assessed with adverse events, vital signs (systolic and diastolic blood pressures and pulse rate), 12-lead ECG, physical examinations, and laboratory assessments.FindingsBoth dapagliflozin/saxagliptin/metformin XR FCDPs were bioequivalent to their ICs. For the dapagliflozin 5-mg/saxagliptin 2.5-mg/metformin 1000-mg XR FCDP, the 90% CI for the geometric mean ratio of dapagliflozin C_max was slightly above the 80%–125% bioequivalence limit, which is unlikely to be clinically relevant. Food delayed the absorption of the study drugs in both FCDPs, which is unlikely to have a clinically relevant impact on efficacy. In both cohorts, exposure was higher in female subjects compared with male subjects, potentially due to the lower body weight of the female subjects. The safety profile and tolerability of the FCDPs were similar to those of their ICs, and no deaths or serious adverse events were reported.ImplicationsThese data support the use of the dapagliflozin/saxagliptin/metformin XR FCDP in patients with T2DM. ClinicalTrials.gov identifier: NCT03169959.     

Insights into the Progression of Labile Hb A1c to Stable Hb A1c via a Mechanistic Assessment of 2,3-Bisphosphoglycerate Facilitation of the Slow Nonenzymatic Glycation Process

Nonenzymatic glycation (NEG) of human hemoglobin (Hb A) consists of initial non covalent, reversible steps involving glucose and amino acid residues, which may also involve effector reagent(s) in the formation of labile Hb A_1c (the conjugate acid of the Schiff base). Labile Hb A_1c can then undergo slow, largely irreversible, formation of stable Hb A_1c (the Amadori product). Stable Hb A_1c is measured to assess diabetic progression after labile Hb A_1c removal. This study aimed to increase the understanding of the distinctions between labile and stable Hb A_1c from a mechanistic perspective in the presence of 2,3-bisphosphoglycerate (2,3-BPG). 2,3-Bisphosphoglycerate is an effector reagent that reversibly binds in the Hb A_1c pocket and modestly enhances overall NEG rate. The deprotonation of C2 on labile Hb A_1c in the formation of the Amadori product was previously proposed to be rate-limiting. Computational chemistry was used here to identify the mechanism(s) by which 2,3-BPG facilitates the deprotonation of C2 on labile Hb A_1c. 2,3-Bisphosphoglycerate is capable of abstracting protons on C2 and the α-nitrogen of labile Hb A_1c and can also deprotonate water and/or amino acid residues, therefore preparing these secondary reagents to deprotonate labile Hb A_1c. Parallel reactions not leading to an Amadori product were found that include formation of the neutral Schiff base, dissociation of glucose from the protein, and cyclic glycosylamine formation. These heretofore under appreciated parallel reactions may help explain both the selective removal of labile from stable Hb A_1c and the slow rate of NEG.     

A proposal for a drug product Manufacturing Classification System (MCS) for oral solid dosage forms

Abstract

This paper proposes the development of a drug product Manufacturing Classification System (MCS) based on processing route. It summarizes conclusions from a dedicated APS conference and subsequent discussion within APS focus groups and the MCS working party. The MCS is intended as a tool for pharmaceutical scientists to rank the feasibility of different processing routes for the manufacture of oral solid dosage forms, based on selected properties of the API and the needs of the formulation. It has many applications in pharmaceutical development, in particular, it will provide a common understanding of risk by defining what the “right particles” are, enable the selection of the best process, and aid subsequent transfer to manufacturing. The ultimate aim is one of prediction of product developability and processability based upon previous experience.

This paper is intended to stimulate contribution from a broad range of stakeholders to develop the MCS concept further and apply it to practice. In particular, opinions are sought on what API properties are important when selecting or modifying materials to enable an efficient and robust pharmaceutical manufacturing process. Feedback can be given by replying to our dedicated e-mail address (mcs@apsgb.org); completing the survey on our LinkedIn site; or by attending one of our planned conference roundtable sessions.