Phase 2 of collaborative action around the implementation of virtual hearing aid care: Evaluation of a clinical practice guideline

Rationale

Following the onset of the COVID-19 pandemic, a clinical practice guideline (CPG) around virtual hearing aid practices was developed to fill a knowledge gap within the field of audiology. Details outlining the development and mobilization of this draft guideline were outlined as Phase 1 (described in a paired paper).

Aims and Objectives

This study describes Phase 2 of this project as part of the Knowledge-to-Action Framework, including an evaluation of the methodological quality of the guideline and the resulting tailored version of the document (v2.0).

Method

The Appraisal of Guidelines for Research and Evaluation II instrument was used to assess methodological quality and to guide revisions. Twenty-two clinicians, from a variety of clinical backgrounds, participated in the evaluation.

Results and Conclusion

Findings reported across six domains suggest high mean scores, ranging from 78% to 81%, in order of scope and purpose (highest rated), stakeholder involvement, rigour of development, applicability, clarity of presentation, and editorial independence. Specific recommendations made by in international co-creation team during the evaluation informed the final version of the CPG. Future development and evaluation efforts should aim to include greater representation from nontraditional practice contexts to strengthen global applicability.     

Sequencing of LRP2 Reveals Multiple Rare Variants Associated with Urinary Trefoil Factor-3

Novel biomarkers are being investigated to identify patients with kidney disease. We measured a panel of 13 urinary biomarkers in participants from the Offspring Cohort of the Framingham Heart Study. Using an Affymetrix chip with imputation to 2.5 M single-nucleotide polymorphisms (SNPs), we conducted a GWAS of these biomarkers (n=2640) followed by exonic sequencing and genotyping. Functional studies in zebrafish were used to investigate histologic correlation with renal function. Across all 13 biomarkers, there were 97 significant SNPs at three loci. Lead SNPs at each locus were rs6555820 (P=6.7×10⁻⁴⁹; minor allele frequency [MAF]=0.49) in HAVCR1 (associated with kidney injury molecule-1), rs7565788 (P=2.15×10⁻¹⁶; MAF=0.22) in LRP2 (associated with trefoil factor 3 [TFF3]), and rs11048230 (P=4.77×10⁻⁸; MAF=0.10) in an intergenic region near RASSF8 (associated with vascular endothelial growth factor). Validation in the CKDGen Consortium (n=67,093) showed that only rs7565788 at LRP2, which encodes megalin, was associated with eGFR (P=0.003). Sequencing of exons 16–72 of LRP2 in 200 unrelated individuals at extremes of urinary TFF3 levels identified 197 variants (152 rare; MAF<0.05), 31 of which (27 rare) were nonsynonymous. In aggregate testing, rare variants were associated with urinary TFF3 levels (P=0.003), and the lead GWAS signal was not explained by these variants. Knockdown of LRP2 in zebrafish did not alter the renal phenotype in static or kidney injury models. In conclusion, this study revealed common variants associated with urinary levels of TFF3, kidney injury molecule-1, and vascular endothelial growth factor and identified a cluster of rare variants independently associated with TFF3.Serum creatinine, as used in most GFR estimating equations, is the primary biomarker of CKD.¹ Creatinine has significant limitations as a biomarker. It is insensitive to early declines in kidney function, and there are important extrarenal factors that influence its concentration, thus increasing the potential for misclassification when it is used to diagnose renal disease.² As a result, novel biomarkers are being investigated that could allow earlier and more accurate diagnosis of CKD.³ It is likely, however, that these biomarkers also have non-GFR determinants, including genetic factors. For example, levels of cystatin C, a novel GFR biomarker, are known to be influenced by both nongenetic factors, such as adiposity and the metabolic syndrome,⁴ and the presence of specific genetic variants in the cystatin C-gene cluster.⁵Genome-wide association studies (GWAS) allow for the evaluation of genetic associations of biomarkers in an unbiased manner. These studies could illuminate previously unrecognized pathways for CKD pathogenesis, thus identifying new potential molecular targets for therapeutic intervention. Multiple variants have been identified in association with kidney function through GWAS,⁶ whereas a variant in CUBN encoding cubilin, a proximal tubular transport protein, has been associated with albuminuria.⁷ Recently, a GWAS identified a locus at PTGDS in association with another kidney biomarker, β-trace protein.⁸To gain additional insight into biologic pathways of renal function and kidney injury, we measured a panel of 13 urinary biomarkers in participants from the Framingham Heart Study (FHS) and performed a GWAS of their levels. Here, we report the primary results from these studies as well as follow-up work to identify whether rare variants in LRP2 are associated with levels of trefoil factor 3 (TFF3).     

Pharmacological treatments prescribed to people with autism spectrum disorder (ASD) in primary health care

Rationale

Autism spectrum disorders (ASDs) affect 1 % of children, having significant impact on health and social outcomes. Psychotropic medication use by individuals with ASD in the USA increased over time, and polypharmacy occurred in >50 % of those prescribed. In the UK, no psychotropic drugs are approved in ASDs, and little is known about patterns of pharmacological treatment in the ASD population and associated co-morbidities.

Methods

We used The Health Improvement Network, a nationally representative primary care database, to assess the prevalence of ASD diagnoses, psychotropic drug prescribing and neuropsychiatric co-morbidities of 0–24 year olds between 1992 and 2008.

Results

ASD prevalence increased 65-fold from 0.01 % (1992) to 0.50 % (2008). Psychotropic drugs were prescribed to 29 % (1,619/5,651) of the ASD cohort; the most prescribed drugs were sleep medication (9.7 % of prescribed patients), psychostimulants (7.9 %) and antipsychotics (7.3 %). More patients were given psychostimulants and sleep medications over time from 1.5–6.3 % and 2.2–5.9 % respectively. Thirty-seven per cent of the cohort had ≥1 record of a neuropsychiatric co-morbidity, the most common being developmental difficulties and learning disabilities (12.6 %), behavioural, conduct and personality disorders (11.1 %) and attention deficit hyperactivity disorder (7.5 %).

Conclusions

British physicians are more conservative in prescribing practice than American colleagues. However, use of psychostimulants and antipsychotics is much higher in those with ASD than in the general population. Polypharmacy was seen in 34 % of prescribed patients in 2008. Additional studies examining use, efficacy, and long-term safety of antipsychotics and psychostimulants in autistic individuals are warranted.     

A novel fluorometric assay for aldo-keto reductase 1C3 predicts metabolic activation of the nitrogen mustard prodrug PR-104A in human leukaemia cells

Aldo-keto reductase 1C3 (AKR1C3, EC 1.1.1.188) metabolises steroid hormones, prostaglandins and xenobiotics, and activates the dinitrobenzamide mustard prodrug PR-104A by reducing it to hydroxylamine PR-104H. Here, we describe a functional assay for AKR1C3 in cells using the fluorogenic probe coumberone (a substrate for all AKR1C isoforms) in conjunction with a specific inhibitor of AKR1C3, the morpholylurea SN34037. We use this assay to evaluate AKR1C3 activity and PR-104A sensitivity in human leukaemia cells. SN34037-sensitive reduction of coumberone to fluorescent coumberol correlated with AKR1C3 protein expression by immunoblotting in a panel of seven diverse human leukaemia cell lines, and with SN34037-sensitive reduction of PR-104A to PR-104H. SN34037 inhibited aerobic cytotoxicity of PR-104A in high-AKR1C3 TF1 erythroleukaemia cells, but not in low-AKR1C3 Nalm6 pre-B cell acute lymphocytic leukaemia (B-ALL) cells, although variation in PR-104H sensitivity confounded the relationship between AKR1C3 activity and PR-104A sensitivity across the cell line panel. AKR1C3 mRNA expression showed wide variation between leukaemia patients, with consistently higher levels in T-ALL than B-ALL. In short term cultures from patient-derived paediatric ALL xenografts, PR-104A was more potent in T-ALL than B-ALL lines, and PR-104A cytotoxicity was significantly inhibited by SN34037 in T-ALL but not B-ALL. Overall, the results demonstrate that SN34037-sensitive coumberone reduction provides a rapid and specific assay for AKR1C3 activity in cells, with potential utility for identifying PR-104A-responsive leukaemias. However, variations in PR-104H sensitivity indicate the need for additional biomarkers for patient stratification.     

Left atrial appendage occlusion with the Amulet device: to tug or not to tug?

Journal of Interventional Cardiac Electrophysiology - Left atrial appendage occlusion (LAAO) involves a “tug test,” in which implanters pull on the device delivery cable to ensure...