Screening for patients with Gaucher's disease using routine pathology results: PATHFINDER (ferritin, alkaline phosphatase, platelets) study.

AIMS: Lysosomal ß-glucocerebrosidase A (GBA) deficiency causes Gaucher disease (GD), a recessive disorder caused by bi-allelic mutations in GBA. The prevalence of GD is associated with ethnicity but largely unknown and potentially underestimated in many countries. GD may manifest with organomegaly, bone involvement, and neurological symptoms as well as abnormal laboratory biomarkers. This study attempted to screen for GD in patients using abnormal platelet, alkaline phosphatase (ALP), and ferritin results from laboratory databases. METHODS: Electronic laboratory databases were interrogated using a 2- to 4-year time interval to identify from clinical biochemistry records patients with a phenotype of reduced platelets (<150 × 109 /L) and either elevated ALP (>130 iu/L) or ferritin [>150 (female) or >250 µg/L (male)]. The mean value over the screening window was used to reduce variability in results. A dried blood spot sample was collected for the determination of GBA activity in patients meeting these criteria. If low GBA activity was found, then the concentration of the GD-specific biomarker glucosyl-sphingosine (lyso-GB1) was assayed, and the GBA gene sequenced. RESULTS: Samples were obtained from 1058 patients; 232 patients had low GBA activity triggering further analysis. No new cases of GD with homozygosity for pathogenic variants were identified, but 12 patients (1%) were identified to be carriers of a pathogenic variant in GBA. CONCLUSIONS: Pathology databases hold routine information that can be used to screen for patients with inherited errors of metabolism. However, biochemical screening using mean platelets, ALP, and ferritin has a low yield for unidentified cases of GD.

Survival prediction algorithms for COVID-19 patients admitted to a UK district general hospital.

OBJECTIVE: To collect and review data from consecutive patients admitted to Queen's Hospital, Burton on Trent for treatment of Covid-19 infection, with the aim of developing a predictive algorithm that can help identify those patients likely to survive. DESIGN: Consecutive patient data were collected from all admissions to hospital for treatment of Covid-19. Data were manually extracted from the electronic patient record for statistical analysis. RESULTS: Data, including outcome data (discharged alive/died), were extracted for 487 consecutive patients, admitted for treatment. Overall, patients who died were older, had very significantly lower Oxygen saturation (SpO2) on admission, required a higher inspired Oxygen concentration (IpO2) and higher CRP as evidenced by a Bonferroni-corrected (P < 0.0056). Evaluated individually, platelets and lymphocyte count were not statistically significant but when used in a logistic regression to develop a predictive score, platelet count did add predictive value. The 5-parameter prediction algorithm we developed was: [Formula: see text] CONCLUSION: Age, IpO2 on admission, CRP, platelets and number of lungs consolidated were effective marker combinations that helped identify patients who would be likely to survive. The AUC under the ROC Plot was 0.8129 (95% confidence interval 0.0.773 - 0.853; P < .001).

The implications of variations in nasal irrigation recipes in the United Kingdom.

OBJECTIVE: This study aims to investigate the variations in publicly available nasal irrigation recipes published in the United Kingdom (UK). DESIGN: Internet searches used to identify eligible nasal irrigation recipes. These were then examined for their physical and biochemical properties, through theoretical calculations and experimental measurement. SETTING: Recipes produced by healthcare providers or official national bodies in the UK. PARTICIPANTS: No human participants. MAIN OUTCOME MEASURES: Solution osmolality (classified into hypo-, iso- and hypertonic), acidity (pH) and specific gravity. RESULTS: Thirteen unique recipes were identified from 17 sources. Osmolality ranged from 166.2 to 1492.2 mosmol/kg in volumes ranging from 142 to 1136 mLs (isotonic range 275-295 mosmol/kg). Specific gravity ranged from 1.006 to 1.034. pH ranged from 7.74 to 8.11. No recipe produced a solution with isotonic properties. The majority produced hypertonic irrigations. CONCLUSIONS: Most publicly available nasal irrigation recipes produce hypertonic solutions but there is great variability in the osmolality and volume. UK organisations should take action to review published recipes to bring these into alignment with latest guidelines (recommending against hypertonic saline use) and reduce variability in patient interpretations.

Genetic risk scores in lipid disorders.

PURPOSE OF REVIEW: Extensive work has gone into understanding the genetics of cardiovascular disease (CVD) and implicating genes involved in hyperlipidaemia. Translation into routine practise involves using genetic risk scores (GRS) to identify high-risk individuals in the general population. Some of these risk scores are beginning to disentangle the complex nature of CVD and inherited dyslipidaemias. RECENT FINDINGS: GRS of varying complexity have been used to identify high-risk groups of patients with polygenic CVD including some individuals with risk equivalent to monogenic disease. In phenotypic familial hypercholesterolaemia a six or 12 gene lipid GRS may identify polygenic cases that comprise up to 50% of cases. In high triglyceride syndromes including even cases of familial chylomicronaemia syndrome more than 80% of cases are polygenic and not even associated with rare variants. In both familial hypercholesterolaemia and familial chylomicronaemia syndrome individuals with polygenic disease have a lower risk than those with monogenic disease. SUMMARY: GRS show promise in identifying individuals with high risks of CVD. They have a close relationship with imaging markers. It is unclear whether GRS, imaging or both will be used to identify individuals at high risk of future events.

Cisplatin-resistant triple-negative breast cancer subtypes: multiple mechanisms of resistance.

BACKGROUND: Understanding mechanisms underlying specific chemotherapeutic responses in subtypes of cancer may improve identification of treatment strategies most likely to benefit particular patients. For example, triple-negative breast cancer (TNBC) patients have variable response to the chemotherapeutic agent cisplatin. Understanding the basis of treatment response in cancer subtypes will lead to more informed decisions about selection of treatment strategies. METHODS: In this study we used an integrative functional genomics approach to investigate the molecular mechanisms underlying known cisplatin-response differences among subtypes of TNBC. To identify changes in gene expression that could explain mechanisms of resistance, we examined 102 evolutionarily conserved cisplatin-associated genes, evaluating their differential expression in the cisplatin-sensitive, basal-like 1 (BL1) and basal-like 2 (BL2) subtypes, and the two cisplatin-resistant, luminal androgen receptor (LAR) and mesenchymal (M) subtypes of TNBC. RESULTS: We found 20 genes that were differentially expressed in at least one subtype. Fifteen of the 20 genes are associated with cell death and are distributed among all TNBC subtypes. The less cisplatin-responsive LAR and M TNBC subtypes show different regulation of 13 genes compared to the more sensitive BL1 and BL2 subtypes. These 13 genes identify a variety of cisplatin-resistance mechanisms including increased transport and detoxification of cisplatin, and mis-regulation of the epithelial to mesenchymal transition. CONCLUSIONS: We identified gene signatures in resistant TNBC subtypes indicative of mechanisms of cisplatin. Our results indicate that response to cisplatin in TNBC has a complex foundation based on impact of treatment on distinct cellular pathways. We find that examination of expression data in the context of heterogeneous data such as drug-gene interactions leads to a better understanding of mechanisms at work in cancer therapy response.

An update on trials of novel lipid-lowering drugs.

PURPOSE OF REVIEW: A number of novel trials have assessed the efficacy of new lipid-lowering therapies in cardiovascular disease (CVD). RECENT FINDINGS: Proprotein convertase subtilisin kexin-9 inhibitors reduce low-density lipoprotein cholesterol (LDL-C) by 50-55%. A CVD outcome trial in patients with acute coronary syndromes with evolocumab achieved a LDL-C of 0.8 mmol/l (31 mg/dl) and a 20% relative risk reduction in CVD events in 2.2 years. Cholesterol ester transfer protein inhibitors raise high-density lipoprotein cholesterol and can lower LDL-C. Anacetrapib reduced coronary artery disease events by 7%, but not wider composite CVD outcomes, in a population with chronic CVD with pretreatment LDL-C of 1.6 mmol/l (62 mg/dl). The conflicting outcomes of cholesterol ester transfer protein inhibitor trials means these compounds are not being developed further. Trials using lipid drugs targeting inflammation have previously been generally unsuccessful, but recent data on the interleukin-1B receptor antagonist canakinumab has proven the concept of intervention on inflammation in atherosclerosis by showing a reduction in acute coronary interventions, but at the predictable cost of increased infections. SUMMARY: Despite the success of proprotein convertase subtilisin kexin-9 inhibition, the ability to achieve low LDL-C with off-patent medications and the costs of novel therapies will limit their use even in high-risk patients and confine them to the highest-risk sub-groups of patients.

GeneWeaver: data driven alignment of cross-species genomics in biology and disease.

The GeneWeaver data and analytics website (www.geneweaver.org) is a publically available resource for storing, curating and analyzing sets of genes from heterogeneous data sources. The system enables discovery of relationships among genes, variants, traits, drugs, environments, anatomical structures and diseases implicitly found through gene set intersections. Since the previous review in the 2012 Nucleic Acids Research Database issue, GeneWeaver's underlying analytics platform has been enhanced, its number and variety of publically available gene set data sources has been increased, and its advanced search mechanisms have been expanded. In addition, its interface has been redesigned to take advantage of flexible web services, programmatic data access, and a refined data model for handling gene network data in addition to its original emphasis on gene set data. By enumerating the common and distinct biological molecules associated with all subsets of curated or user submitted groups of gene sets and gene networks, GeneWeaver empowers users with the ability to construct data driven descriptions of shared and unique biological processes, diseases and traits within and across species.

Review of referral criteria to lipid clinics and outcomes of treatment in four UK centres.

BACKGROUND: Little data exist on the referral patterns and effectiveness of lipid clinics. METHODS: An audit was conducted in four clinics of 100 consecutive referrals each. Data were recorded on referral criteria, cardiovascular disease (CVD) risk factors, drug history, investigations, diagnoses, therapies, results and referrals. RESULTS: Patients were aged 56 ± 14 years, 47% were male and 87% were primary prevention. Risk factors included smoking (16%), type 2 diabetes (13%) and hypertension (13%). Referrals were made for hypercholesterolaemia (68%), diagnosis of FH (31%), statin intolerance (23%) and hypertriglyceridaemia (23%). Initial total cholesterol (TC) was 7.65 ± 2.64 mmol/L, triglycerides (TG) 2.17 (0.41-76.9 mmol/L) mmol/L, HDL-C 1.53 ± 0.71 mmol/L, LDL-C 4.57 ± 1.66 mmol/L with non-HDL-C 5.90 ± 2.09 mmol/L. Criteria for FH were met in 21% with genetic testing in 13% and lipid cascade testing in 30% of index cases. Triglycerides >20 mmol/L were present in 4%. The diagnosis was changed in 21%: hypercholesterolaemia (7%), mixed hyperlipidaemia (7%) and hypertriglyceridaemia (7%). Hepatic steatosis was identified in 14.5%. Lipoprotein(a) levels >125 nmol/L occurred in 41% in one clinic. Therapy changes included altered statins (40%), addition of a fibrate (11%) or ezetimibe (8%). These reduced TC by 1.92 mmol/L (19%; P = 0.0001), LDL-C 1.07 mmol/L (15%; P = 0.02), non-HDL-C 1.50 mmol/L (16%; P < 0.001), and TG 2.3 (-4 to 38) mmol/L (16%; P < 0.001) with 11% extra achieving TG <5 mmol/L while HDL-C increased by 7% (P = 0.37). CONCLUSIONS: Lipid clinics have diverse functions including diagnosis of FH, managing severe hypercholesterolaemia, mixed hyperlipidaemia and statin intolerance. Effectiveness criteria of average reductions of 1.5 mmol/L in TC or non-HDL-C, 1 mmol/L in LDL-C and 2 mmol/L in TG would be reasonable for newly referred patients.

Severe Obesity and Sleep-Disordered Breathing as Risk Factors for Emergence Agitation in Pediatric Ambulatory Surgery.

PURPOSE: Sleep-disordered breathing (SDB) may be a critical risk factor for emergence agitation (EA). We hypothesized that SDB diagnosis is a predictor of EA in children after general anesthesia for ambulatory surgery. DESIGN: Prospective, observational, cohort study. METHODS: Children aged 4 to 17 years were assessed for the occurrence of EA. Differences in probability of EA were assessed using multivariable logistic regression analyses. FINDINGS: Of 1,076 children, 66 (6.1%) had EA. Compared with those without EA, children with EA were younger (P < .001), more likely to have had mask induction (P < .001) and a preoperative diagnosis of SDB (P = .008). On multivariable analysis, SDB, severe obesity, decreasing age in years, increasing first arousal pain score, and intraoperative use of sevoflurane were independently associated with EA. CONCLUSIONS: SDB and severe obesity may be critical independent predictors of EA in children. Mechanisms underlying these observations deserve further elucidation.

Pro-protein subtilisin kexin-9 (PCSK9) inhibition in practice: lipid clinic experience in 2 contrasting UK centres.

BACKGROUND: Prescribing criteria have been suggested for proprotein convertase subtilisin kexin-9 (PCSK-9) inhibitors but few studies exist of their real-world effectiveness. METHODS: This study audited PCSK-9 inhibitor therapy in 105 consecutive patients from two hospital centres-a university hospital (UH; n = 70) and a district general hospital (DGH; n = 35). Baseline characteristics including cardiovascular disease risk factors, NICE qualification criteria, efficacy and side effects were assessed. RESULTS: Baseline LDL-C levels were similar in both centres. NICE criteria were met for 2.05 items in the whole study (UH patients 1.7 and DGH patients 2.7). District general hospital patients were more likely to have familial hypercholesterolaemia (89 vs 69%; P = .02); intolerance to statins (94 vs 52%; P < .001) and polyvascular disease (42% vs 17%; P = .005). Prescriptions (evolocumab 73%; alirocumab 23%) were collected by 76% of patients (UH 64% vs DGH 100%). Therapy was discontinued by time of review in 15% of patients (UH 7% vs DGH 25%; P = .02). In adherent patients PCSK-9 inhibitor treatment reduced TC by 28% (2.24 ± 2.39 mmol/L; P < .001) and LDL-C by 49% (2.10 ± 1.33 mmol/L; P < .001). A LDL-C < 2.5 mmol/L was achieved in 30% of patients and <2.0 mmol/L in 20%. PCSK-9 therapy was effective and safe in patients with increased lipoprotein (a), diagnosed muscle diseases (including myopathies and muscular dystrophy) or poststatin rhabdomyolysis, nephrotic syndrome or HIV disease. Mixed results were obtained in patients with significant mixed hyperlipidaemia. CONCLUSIONS: This study suggests that PCSK-9 inhibitors are effective but that prescriptions should not be changed to long-term delivery until patients have been reviewed and shown to be adherent.

Lipid clinic experience with bempedoic acid in three UK centres.

OBJECTIVE: Novel lipid-lowering therapies are being introduced. Few studies exist of the real-world effectiveness of adenosine-tri-phosphate citrate lyase inhibition with bempedoic acid. METHODS: This study audited bempedoic acid therapy in 216 consecutive patients from three hospital centres - a university hospital (n = 77) and two district general hospitals (n = 106 and 33). Cardiovascular disease (CVD) risk factors, prescription qualification criteria, efficacy and adverse effects were assessed. RESULTS: The population was aged 65.9 ± 11.0 years, 42% were male, 25% had type 2 diabetes, and 31% had familial hypercholesterolaemia. CVD was present in 19% and multibed vascular disease in 8%. Statin intolerance was reported in 92%. Bempedoic acid reduced total cholesterol by 1.58 ± 1.44 mmol/L (20%), LDL-C by 1.37 ± 1.31 mmol/L (27%), triglycerides by 0.22 mmol/L (2%) with an 0.06 mmol/L (1%) increase in HDL-C after 22 ± 9 months follow-up. An LDL-C <2.5 mmol/L was achieved in 40% and <2 mmol/L in 20%. Efficacy (r2 = .33) was predicted by baseline LDL-C (ß = .54; p <.001). No significant changes were seen in transaminases, creatinine, creatine kinase, urate or HbA1c. Treatment was discontinued by 33% of patients and occurred due to myalgia (43%), lack of efficacy (16%) and gastrointestinal adverse effects (15%). No cases of gout were observed. In a logistic regression only the number of previous drug classes not tolerated (ß = 1.60; p = .009) was a contributing factor to discontinuation. CONCLUSION: This audit suggests that bempedoic acid therapy is effective but that adverse effects and discontinuation are common. This suggests nocebo effects might be generalizable to all lipid-lowering drug therapies in susceptible individuals.

Views of general practitioners on the role of CA125 in primary care to diagnose ovarian cancer.

BACKGROUND: NICE guidance on the investigation and treatment of ovarian cancer advocates that the tumour marker CA125 should be the first line investigation for women suspected of having ovarian cancer. METHODS: An internet-based survey, of primary care doctors in the West Midlands, was conducted in order to ascertain the views of general practitioners (GPs) of NICE guidance on the use of CA125 to triage suspected ovarian cancer cancers and the impact that this may have on referral pathways. RESULTS: In total 258 GPs responded to the questionnaire. Although 219 (84.9%) responders reported awareness of the NICE guidance only 146 (56.6%) had personally read the document. The majority 187 (72.5%) of respondents anticipated that their use of CA125 would increase as a result of the new guidance. Abdominal bloating (>50 years), persistent abdominal distension and the presence of an abdominal or pelvic mass/swelling were the symptoms felt to be most associated with ovarian cancer. When questioned on the management of a woman with a raised CA125 the majority of respondents reported that a normal ultrasound scan would not stop an urgent secondary care referral if the CA125 was raised. There was no significant difference in the opinions of GPs with <5 years primary care experience compared to GPs with 6+ years. CONCLUSION: The symptoms associated with ovarian cancer are well understood by the GPs that responded however, a coordinated programme of education and training is needed for GPs on the role of CA125 in ovarian cancer, in addition to clearly defined referral pathways, in order to address a likely significant increase in suspected ovarian cancer referrals to secondary care, most of whom will not have ovarian cancer.

Rising resistance of urinary tract pathogens in children: a cause for concern.

BACKGROUND: Urinary tract infection (UTI) is one of the common infections in childhood. Prompt diagnosis and treatment reduces the risk of complications. The choice of antibiotic to treat UTI varies from region to region. Rational use and appropriately chosen antibiotic reduces the emergence of resistant uropathogens. OBJECTIVE: We investigated the resistance pattern of uropathogens for commonly used antibiotics to treat UTI locally. METHODS: Data was collected between 2009 and 2019 on all infants and children under 16 years of age with culture proven UTI. Results were compared with previously published figures between 2002 and 2008. RESULTS: A total of 1002 samples were analysed (91/year). Male to female ratio was 1:4.6. About 94% of the samples grew E. coli. As before, high resistance rates were recorded to Amoxicillin and Trimethoprim (Z = -0.325: P = 0.7452; not significant). Overall, average resistance has decreased for Nitrofurantoin from 10% between 2002 and 2008 to 5.84% between 2009 and 2019 (Z = 3.002: P = 0.0027). On the other hand, Cefalexin resistance has increased from 7.4 to 14.56% between the two study periods (Z = -4.2: P = < 0.0002). CONCLUSION: Despite rising resistance rates, we recommend that Cefalexin should cautiously remain the antibiotic of choice for empirically treating uncomplicated urinary tract infections in secondary care pending urine culture. Nitrofurantoin should be reserved for treating non-coliform/atypical UTIs or multi-drug resistant UTIs. There is an ongoing need for clinicians in all geographic regions to continue to monitor antibiotic resistance rates every few years.

Current Perspectives on the Attainment of Lipid Modification Goals Relating to the Use of Statins and Ezetimibe for the Prevention of Cardiovascular Disease in the United Kingdom.

Despite widespread evidence of the effectiveness of lipid modification for the reduction of cardiovascular disease (CVD) risk, lipid modification goals are commonly underachieved in the United Kingdom (UK). In order to understand current UK lipid management guidance and the corresponding attainment of recommended lipid lowering goals relating to treatment with statins and ezetimibe, a literature review was conducted using PubMed focusing on publications between January 2017 and February 2020 in order to capture the most up-to-date literature. Identified publications were reviewed against key clinical guidelines for lipid management in relation to CVD risk from the National Institute for Health and Care Excellence (NICE, CG181), the Scottish Intercollegiate Guidelines Network (SIGN, 149) and European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS). Cholesterol lowering goals are central to current lipid lowering therapy guidance, although specific goals vary depending on the guideline and patients' individual risk profile. Current guidance by NICE and SIGN specifies that treatment should achieve a greater than 40% reduction in non-high-density lipoprotein cholesterol (non-HDL-C) at 3 months of treatment, while the ESC/EAS place emphasis on the lowering of low-density lipoprotein (LDL-C) and total cholesterol. Yet, despite widespread availability of guidance and consistent messaging that lipid lowering goals should be ambitious, current evidence suggests a significant proportion of UK patients have sub-optimal reductions in cholesterol/non-HDL-C/LDL-C. The reasons for this are reported to be multifactorial, including a lack of compliance with guidelines, particularly regarding high-intensity statin prescribing, patient adherence, statin intolerance and statin reluctance as well as wider genetic factors. A number of possible strategies to improve current lipid management and attainment of lipid-lowering goals were identified, including improving the patient-healthcare professional partnership, conducting audits of local prescribing versus guidance, implementing plans for the refinement of current services and considering alternative options such as cost-effective single pill combinations for improving adherence.

Impact of switching to tenofovir alafenamide on weight gain as compared to maintaining a non-tenofovir alafenamide containing regimen.

ABSTRACT: Evaluate the impact of switching to an anti-retroviral regimen containing tenofovir alafenamide (TAF) on weight and the development of metabolic complications compared to remaining on a non-TAF containing regimen.Single-center retrospective case-control study.We evaluated people living with human immunodeficiency virus (PLWH) who were on an anti-retroviral regimen not containing TAF and were switched to a regimen containing TAF between January 1, 2016 and September 30, 2018. The control group included PLWH on a TAF free regimen throughout the study period. The primary outcome was change in weight from baseline to 12 months postswitch. Secondary outcomes included percent change in weight, change in body mass index (BMI), change in BMI class, and new diagnoses of diabetes, hypertension, and hyperlipidemia (HLD) during the study period.PLWH switched to TAF (n = 446) demonstrated significantly greater mean increase in weight compared to the control group (n = 162) (1.97 vs 0.88 kg, P = .01), however the effect was only seen in those switched from tenofovir disoproxil fumarate. Those that switched to TAF also had a significantly higher percent increase in weight, increase in BMI, and BMI class. We observed a higher rate of new diagnosis of HLD in the control group compared to the TAF switch group during the study period.PLWH switched to TAF had greater increases in weight after 1 year as compared to those continuing on a TAF free regimen. However, this did not translate to higher rates of obesity related illnesses such as diabetes, hypertension, and HLD during the follow up period.

Interpretation of psychiatric genome-wide association studies with multispecies heterogeneous functional genomic data integration.

Genome-wide association studies and other discovery genetics methods provide a means to identify previously unknown biological mechanisms underlying behavioral disorders that may point to new therapeutic avenues, augment diagnostic tools, and yield a deeper understanding of the biology of psychiatric conditions. Recent advances in psychiatric genetics have been made possible through large-scale collaborative efforts. These studies have begun to unearth many novel genetic variants associated with psychiatric disorders and behavioral traits in human populations. Significant challenges remain in characterizing the resulting disease-associated genetic variants and prioritizing functional follow-up to make them useful for mechanistic understanding and development of therapeutics. Model organism research has generated extensive genomic data that can provide insight into the neurobiological mechanisms of variant action, but a cohesive effort must be made to establish which aspects of the biological modulation of behavioral traits are evolutionarily conserved across species. Scalable computing, new data integration strategies, and advanced analysis methods outlined in this review provide a framework to efficiently harness model organism data in support of clinically relevant psychiatric phenotypes.

Integration of evidence across human and model organism studies: A meeting report.

The National Institute on Drug Abuse and Joint Institute for Biological Sciences at the Oak Ridge National Laboratory hosted a meeting attended by a diverse group of scientists with expertise in substance use disorders (SUDs), computational biology, and FAIR (Findability, Accessibility, Interoperability, and Reusability) data sharing. The meeting's objective was to discuss and evaluate better strategies to integrate genetic, epigenetic, and 'omics data across human and model organisms to achieve deeper mechanistic insight into SUDs. Specific topics were to (a) evaluate the current state of substance use genetics and genomics research and fundamental gaps, (b) identify opportunities and challenges of integration and sharing across species and data types, (c) identify current tools and resources for integration of genetic, epigenetic, and phenotypic data, (d) discuss steps and impediment related to data integration, and (e) outline future steps to support more effective collaboration-particularly between animal model research communities and human genetics and clinical research teams. This review summarizes key facets of this catalytic discussion with a focus on new opportunities and gaps in resources and knowledge on SUDs.