A systematic review of the methodological quality of economic evaluations in genetic screening and testing for monogenic disorders

PurposeUnderstanding the value of genetic screening and testing for monogenic disorders requires high-quality, methodologically robust economic evaluations. This systematic review sought to assess the methodological quality among such studies and examined opportunities for improvement.MethodsWe searched PubMed, Cochrane, Embase, and Web of Science for economic evaluations of genetic screening/testing (2013-2019). Methodological rigor and adherence to best practices were systematically assessed using the British Medical Journal checklist.ResultsAcross the 47 identified studies, there were substantial variations in modeling approaches, reporting detail, and sophistication. Models ranged from simple decision trees to individual-level microsimulations that compared between 2 and >20 alternative interventions. Many studies failed to report sufficient detail to enable replication or did not justify modeling assumptions, especially for costing methods and utility values. Meta-analyses, systematic reviews, or calibration were rarely used to derive parameter estimates. Nearly all studies conducted some sensitivity analysis, and more sophisticated studies implemented probabilistic sensitivity/uncertainty analysis, threshold analysis, and value of information analysis.ConclusionWe describe a heterogeneous body of work and present recommendations and exemplar studies across the methodological domains of (1) perspective, scope, and parameter selection; (2) use of uncertainty/sensitivity analyses; and (3) reporting transparency for improvement in the economic evaluation of genetic screening/testing.     

Deciphering the molecular landscape of microcephaly in 87 Indian families by exome sequencing

Microcephaly is a frequent feature of neurodevelopmental disorders (NDDs). Our study presents the heterogeneous spectrum of genetic disorders in patients with microcephaly either in isolated form or in association with other neurological and extra-neural abnormalities. We present data of 91 patients from 87 unrelated families referred to our clinic during 2016–2020 and provide a comprehensive clinical and genetic landscape in the studied cohort. Molecular diagnosis using exome sequencing was made in 45 families giving a yield of 51.7%. In 9 additional families probable causative variants were detected. We identified disease causing variations in 49 genes that are involved in different functional pathways Among these, 36 had an autosomal recessive pattern, 8 had an autosomal dominant pattern (all inherited de novo), and 5 had an X-linked pattern. In 41 probands where sequence variations in autosomal recessive genes were identified 31 were homozygotes (including 16 from non-consanguineous families). The study added 28 novel pathogenic/likely pathogenic variations. The study also calls attention to phenotypic variability and expansion in spectrum as well as uncovers genes where microcephaly is not reported previously or is a rare finding. We here report phenotypes associated with the genes for ultra-rare NDDs with microcephaly namely ATRIP, MINPP1, PNPLA8, AIMP2, ANKLE2, NCAPD2 and TRIT1.     

CD44基因多态性与宫颈癌及非小细胞肺癌的相关性

背景与目的：CD44分子是众多肿瘤细胞的标志分子，其表达水平与肿瘤细胞的恶性程度有关。该研究探讨CD44基因中的单核苷酸多态性（single nucleotide polymorphism，SNP）位点与云南汉族人群宫颈癌和非小细胞肺癌（nonsmall cell lung cancer，NSCLC）易感性的相关性。方法：选取了CD44基因中的两个SNP位点rs13347和rs8193，采用TagMan基因分型的方法，分析这两个多态性位点在497例宫颈癌患者和500例健康对照个体以及483例NSCLC患者和471例健康对照个体中的分布特征，并分析CD44基因中的多态性位点与云南汉族人群宫颈癌和NSCLC的相关性。结果：rs13347和rs8193位点等位基因和基因型在宫颈癌组和对照组中的分布频率的差异无统计学意义（P>0.05）。而在NSCLC组和对照组的比较中：rs13347和rs8193位点等位基因在NSCLC组和对照组中的分布频率的差异有统计学意义（P=0.020和P=0.004）；这两个位点基因型在NSCLC组和对照组中分布频率的差异有统计学意义（P=0.027和P=0.020）；其中rs13347位点等位基因C在NSCLC组中的分布频率显著高于对照组，可能是NSCLC发生的风险因素（OR=1.250，95% CI：1.035～1.509），rs8193位点等位基因C在对照组中的分布频率显著高于NSCLC组，可能是NSCLC发生的保护性因素（OR=0.768，95%CI：0.641～0.921）。单倍型分析结果显示，rs13347C-rs8193T和rs13347T-rs8193C在NSCLC组和对照组中的分布频率差异有统计学意义（P=0.003和0.022）；该结果说明单倍型rs13347C-rs8193T可能是云南汉族人群NSCLC发生的风险性因素（OR=1.316，95%CI：1.096～1.579）。结论：CD44基因中的两个SNP位点rs13347和rs8193可能与云南汉族人群宫颈癌发病风险无关，而可能与云南汉族人群NSCLC具有相关性。     

输尿管支架管结壳患者尿液菌群的分布特点

目的探讨输尿管支架管结壳患者尿液菌群的分布特点。方法选取2018年10月至2019年3月在山东省立第三医院、山东大学齐鲁医院、济南市中心医院和济南市济钢医院就诊的35例输尿管支架管置入术后患者。纳入标准:年龄18~65岁;输尿管镜碎石术后留置内支架管4周。排除标准:尿液细菌培养阳性;严重肉眼血尿;近期口服抗生素;存在明显残石患者。本研究采用横断面研究方法(临床研究注册号为ChiCTR1800020025),根据有无支架管结壳将患者分为结壳组23例和无结壳组12例。收集拔管当日患者尿液行细菌16s DNA检测。使用UPARSE、UCHIME和RDP calssifier等软件分析两组患者尿液菌群分布特点,明确两组患者尿液中细菌种类总数、细菌丰度,以及丰度占比较大的细菌类别,比较两组患者尿液细菌种类、数量及细菌丰度的差异,明确结壳组患者尿液中丰度占比较大的细菌菌属。结果两组患者的年龄、性别、体质指数、置管侧别、内支架管型号及结石成分差异均无统计学意义(P>0.05)。16s DNA检测结果显示,结壳组丰度占比>1%的菌属数量为11个,丰度占比>0.01%的菌属数量为74个;无结壳组丰度占比>1%的菌属数量为7个,丰度占比>0.01%的菌属数量为11个,两组丰度占比>1%的菌属数量比较差异有统计学意义(t=5.12,P=0.000)。结壳组中菌属丰度占比前3位分别为乳杆菌属(23.1%)、拟杆菌属(18.8%)和未分级拟杆菌属(17.1%),非结壳组中菌属丰度占比前3位分别是为埃希菌-志贺菌属(32.2%)、肠球菌属(24.9%)和假单胞菌属(18.2%)。两组间差异最大的3种细菌是乳杆菌属(P=0.010),拟杆菌属(P=0.004)和未分级拟杆菌属(P=0.004)。结论支架管结壳患者尿液中细菌种类和数量都明显多于非支架管结壳患者。拟杆菌属细菌在支架管结壳患者尿液中的细菌种类丰度较大。     

Evaluating the inhibitory potential of Withania somnifera on platelet aggregation and inflammation enzymes: An in vitro and in silico study

Context Withania somnifera (L.) Dunal is traditionally used for treating various ailments, but lacks scientific evaluation.

Objective This study evaluates Withania somnifera (WS) for its effect on platelet activity and inflammatory enzymes.

Materials and methods Aqueous and ethanolic (1:1) leaf extracts were subjected to in vitro indirect haemolytic activity using Naja naja venom, human platelet aggregation was quantified for lipid peroxidation using arachidonic acid (AA) as agonist and 5-lipoxygenase (5-LOX) levels were determined using standard spectrometric assays. Further, molecular docking was performed by the ligand fit method using molegro software package (Molegro ApS, Aarhus, Denmark).

Results The study found that aqueous and ethanol extracts have very negligible effect (15%) with an IC₅₀ value of 13.8?mg/mL on PLA₂ from Naja naja venom. Further, extracts of WS also had very little effect (18%) with an IC₅₀ value of 16.6?mg/mL on malondialdehyde (MDA) formation. However, a 65% inhibition of 5-LOX with an IC₅₀ value of 0.92?mg/mL was observed in 1:1 ethanol extracts. The same was evident from SAR model with the active ingredient withaferin A binding predominantly on Phe 77, Tyr 98, Arg 99, Asp 164, Leu 168, Ser 382, Arg 395, Tyr 396 and Tyr 614 with an atomic contact energy value of??128.96 compared to standard phenidone (?103.61). Thus, the current study validates the application of WS for inflammatory diseases.

Conclusion This study reveals the inhibitory potential of W. somnifera on inflammatory enzymes and platelet aggregation. Thus, WS can serve as a newer, safer and affordable medicine for inflammatory diseases.     

直丝弓矫治器和Begg矫治器治疗安氏Ⅱ类1分类错[牙合]畸形疗效比较

目的:对比不同矫治器对错[牙合]畸形患者面高度及前后牙咬合关系的影响。方法:选取于笔者医院接受矫治的83例错[牙合]畸形患者,根据患者矫治器类型分为直丝弓组和Begg组,分别为42例和41例。比较并分析两组患者治疗前后牙咬合关系、硬组织、磨牙及面高度的变化情况。结果:矫治后,两组患者OJ-PPV、OB-PP、LMA-MPV、LMA-MPV均降低,Begg矫治组OJ-PPV水平显著高于直丝弓矫治组,OB-PP、LMA-MPV、LMA-MPV水平显著低于直丝弓矫治组,差异均具有统计学意义(P<0.05);两组患者LAFH、LAFH/TAFH、PFH/TAFH水平均升高,其中Begg矫治组患者LAFH水平显著低于直丝弓矫治组,差异均具有统计学意义(P<0.05);两组患者LMA-MP、LMC-MP水平均升高,差异具有统计学意义(P<0.05);矫治前后,两组患者SNA、SNA、ANB水平均无统计学差异(P>0.05)。结论:两种矫治器对错[牙合]畸形患者硬组织变化均无明显影响,其中Begg矫治对患者前后牙咬合关系改善作用更强,直丝弓对患者面高度的改善能力更强。     

NUDT15 is a key genetic factor for prediction of hematotoxicity in pediatric patients who received a standard low dosage regimen of 6-mercaptopurine

6-Mercaptopurine (6-MP) is commonly used for treatment of acute lymphoblastic leukemia (ALL). The incidence of hematotoxicity caused by this drug is quite high in Asians even using a standard low dosage regimen. The present study was aimed to elucidate the impact of thiopurine S-methyltransferase (TPMT), a nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15), inosine triphosphatase (ITPA) and ATP Binding Cassette Subfamily C Member 4 (ABCC4) polymorphisms on hematotoxicity in pediatric patients who received a standard low starting dose of 6-MP. One hundred and sixty-nine pediatric patients were enrolled and their genotypes were determined. Patients who carried NUDT15¹3 and NUDT15¹2 genotypes were at a 10–15 fold higher risk of severe neutropenia than those of the wild-type during the early months of the maintenance phase. Risk of neutropenia was not significantly increased in patients with other NUDT15 variants as well as in patients with TPMT, ITPA or ABCC4 variants. These results suggest that NUDT15 polymorphisms particularly, NUDT15¹3 and NUDT15¹2, play major roles in 6-MP-induced severe hematotoxicity even when using a standard low dosage of 6-MP and genotyping of these variants is necessary in order to obtain precise tolerance doses and avoid severe hematotoxicity in pediatric patients.     

Niven and Scott (2003): Sixteen years of hindsight

This paper revisits a 2003 publication in Nursing Philosophy: The need for accurate perception and informed judgement in determining the appropriate use of the nursing resource: hearing the patient's voice. The author suggests that the basic ideas and focus of this 16‐year‐old paper are still topical and relevant in considerations of nursing care. However, it is also suggested that greater attention to the importance of the nurse–patient relationship in considerations of resource allocation, and potential rationing of nursing care, would have strengthened the original paper.     

Lung Cancer Risk in Never-Smokers of European Descent is Associated With Genetic Variation in the 5p15.33 TERT-CLPTM1Ll Region

IntroductionInherited susceptibility to lung cancer risk in never-smokers is poorly understood. The major reason for this gap in knowledge is that this disease is relatively uncommon (except in Asians), making it difficult to assemble an adequate study sample. In this study we conducted a genome-wide association study on the largest, to date, set of European-descent never-smokers with lung cancer.MethodsWe conducted a two-phase (discovery and replication) genome-wide association study in never-smokers of European descent. We further augmented the sample by performing a meta-analysis with never-smokers from the recent OncoArray study, which resulted in a total of 3636 cases and 6295 controls. We also compare our findings with those in smokers with lung cancer.ResultsWe detected three genome-wide statistically significant single nucleotide polymorphisms rs31490 (odds ratio [OR]: 0.769, 95% confidence interval [CI]: 0.722–0.820; p value 5.31 × 10^-16), rs380286 (OR: 0.770, 95% CI: 0.723–0.820; p value 4.32 × 10^-16), and rs4975616 (OR: 0.778, 95% CI: 0.730–0.829; p value 1.04 × 10^-14). All three mapped to Chromosome 5 CLPTM1L-TERT region, previously shown to be associated with lung cancer risk in smokers and in never-smoker Asian women, and risk of other cancers including breast, ovarian, colorectal, and prostate.ConclusionsWe found that genetic susceptibility to lung cancer in never-smokers is associated to genetic variants with pan-cancer risk effects. The comparison with smokers shows that top variants previously shown to be associated with lung cancer risk only confer risk in the presence of tobacco exposure, underscoring the importance of gene-environment interactions in the etiology of this disease.