Translation of non-canonical open reading frames as a cancer cell survival mechanism in childhood medulloblastoma.

A hallmark of high-risk childhood medulloblastoma is the dysregulation of RNA translation. Currently, it is unknown whether medulloblastoma dysregulates the translation of putatively oncogenic non-canonical open reading frames (ORFs). To address this question, we performed ribosome profiling of 32 medulloblastoma tissues and cell lines and observed widespread non-canonical ORF translation. We then developed a stepwise approach using multiple CRISPR-Cas9 screens to elucidate non-canonical ORFs and putative microproteins implicated in medulloblastoma cell survival. We determined that multiple lncRNA-ORFs and upstream ORFs (uORFs) exhibited selective functionality independent of main coding sequences. A microprotein encoded by one of these ORFs, ASNSD1-uORF or ASDURF, was upregulated, associated with MYC-family oncogenes, and promoted medulloblastoma cell survival through engagement with the prefoldin-like chaperone complex. Our findings underscore the fundamental importance of non-canonical ORF translation in medulloblastoma and provide a rationale to include these ORFs in future studies seeking to define new cancer targets.

Odour motion sensing enhances navigation of complex plumes.

Odour plumes in the wild are spatially complex and rapidly fluctuating structures carried by turbulent airflows1-4. To successfully navigate plumes in search of food and mates, insects must extract and integrate multiple features of the odour signal, including odour identity5, intensity6 and timing6-12. Effective navigation requires balancing these multiple streams of olfactory information and integrating them with other sensory inputs, including mechanosensory and visual cues9,12,13. Studies dating back a century have indicated that, of these many sensory inputs, the wind provides the main directional cue in turbulent plumes, leading to the longstanding model of insect odour navigation as odour-elicited upwind motion6,8-12,14,15. Here we show that Drosophila melanogaster shape their navigational decisions using an additional directional cue-the direction of motion of odours-which they detect using temporal correlations in the odour signal between their two antennae. Using a high-resolution virtual-reality paradigm to deliver spatiotemporally complex fictive odours to freely walking flies, we demonstrate that such odour-direction sensing involves algorithms analogous to those in visual-direction sensing16. Combining simulations, theory and experiments, we show that odour motion contains valuable directional information that is absent from the airflow alone, and that both Drosophila and virtual agents are aided by that information in navigating naturalistic plumes. The generality of our findings suggests that odour-direction sensing may exist throughout the animal kingdom and could improve olfactory robot navigation in uncertain environments.

The effect of an acute bout of exercise on circulating vitamin D metabolite concentrations: a randomised crossover study in healthy adults.

The effect of acute exercise on circulating concentrations of vitamin D metabolites is unclear. To address this knowledge gap, we examined the effect of a bout of treadmill-based exercise versus rest on circulating concentrations of 25(OH)D3, 25(OH)D2, 3-epi-25(OH)D3, 24,25(OH)2D3, 1,25(OH)2D3, and vitamin D2 and D3 in healthy men and women. Thirty-three healthy adults (14 females, 41 (15) years, body mass index 26.2 (3.7) kg/m2, V ̇ O 2 max ${{\dot{V}}_{{{{\mathrm{O}}}_{\mathrm{2}}}{\mathrm{max}}}}$ 36.2 (9.2) ml/kg/min; mean (SD)) completed two laboratory visits involving 60 min of moderate-intensity treadmill exercise (60% V ̇ O 2 max ${{\dot{V}}_{{{{\mathrm{O}}}_{\mathrm{2}}}{\mathrm{max}}}}$ ) versus 60 min of seated rest, both in an overnight fasted-state, as part of a randomised crossover design. Venous blood samples were drawn at baseline, immediately (0 h), 1 h and 24 h after the exercise or rest-period. There was a significant time × trial interaction effect for total circulating 25(OH)D (P = 0.0148), 25(OH)D3 (P = 0.0127) and 1,25(OH)2D3 (P = 0.0226). Immediately post-exercise, 25(OH)D, 25(OH)D3 and 1,25(OH)2D3 concentrations were significantly elevated compared to the control resting condition, and 1,25(OH) 2D3 remained significantly elevated 1 h later. Circulating albumin, vitamin D binding protein, calcium and parathyroid hormone were elevated immediately post-exercise. Thus, an acute bout of moderate intensity exercise transiently increases concentrations of circulating 25(OH)D and 1,25(OH)2D3 compared to resting conditions. KEY POINTS: Observational studies suggest that acute exercise might change circulating concentrations of vitamin D metabolites, but this has not been investigated using randomised crossover studies and using robust analytical procedures. In this study, we used a randomised crossover design to examine the effect of a bout of treadmill-based exercise (vs. rest) on circulating concentrations of a wide range of vitamin D metabolites in healthy humans. We show that an acute bout of moderate intensity exercise transiently increases concentrations of circulating 25(OH)D and 1,25(OH)2D3 compared to resting conditions. These findings indicate that regular exercise could lead to transient but regular windows of enhanced vitamin D biological action.

The Impact of Delayed Processing of Chilled Whole Blood Specimens on the Measurement of Nutritional Biomarkers in the United Kingdom National Diet and Nutrition Survey Rolling Programme.

BACKGROUND: The logistics of timely processing of blood specimens remains a barrier in population health studies to the generation of micronutrient status data. OBJECTIVES: To test a blood specimen processing protocol that includes overnight postage with cooling and its effect on nutritional biomarker concentrations. METHODS: This study was embedded within the United Kingdom National Diet and Nutrition Survey. Paired specimens were collected from 64 participants (16 y+). One set of specimens were processed within 2 h of collection ["field"] and paired samples were mailed in an insulated box with cold packs using an overnight postal service to a central laboratory ["postal"]. Specimen processing protocols were aligned across field sites and the central laboratory. Specimens were frozen and later analyzed using established methods for vitamins, minerals, lipids, ferritin, and C-reactive protein (CRP). Percent difference was calculated between protocols and compared with quality specifications determined from intra- and interindividual variation. RESULTS: In the postal protocol, ferritin [geometric mean percent difference (95% confidence interval)] [6% (3, 8)] (P = 0.002) and zinc [4% (1, 6)] (P = 0.004) were higher compared with the field protocol. Retinol [-3% (-4, -1)] (P < 0.0001) and selenium [-3% (-5, -1)] (P = 0.003) concentrations were lower in the postal protocol, whereas total [2% (1, 3)] and HDL [4% (2, 5)] cholesterol were higher (P < 0.0001) than in the field protocol. Percent differences were within the optimum quality specification for the majority of biomarkers, but ferritin, zinc, and selenium fell outside of the optimum limits. Higher ferritin concentration in the postal protocol led to a decrease in the proportion of specimens with ferritin concentration <15 µg/L from 13% to 9%. CONCLUSIONS: The majority of micronutrient biomarkers, serum lipids, and CRP were minimally affected by delayed processing when cooled. The study suggests acceptable stability of nutritional biomarkers within the described protocol, which can provide accurate data for nutritional biomarkers commonly measured in studies and surveys.

Multiple acyl-Coa dehydrogenase deficiency: an underdiagnosed disorder in adults.

Inherited metabolic diseases, as a first presentation in adults, are an under-recognised condition associated with significant morbidity and mortality. Diagnosis is challenging because of non-specific clinical and biochemical findings, resemblance to common conditions such as neuropsychiatric disorders and the misconception that these disorders predominantly affect paediatric populations. We describe a series of patients with multiple acyl-CoA dehydrogenase deficiency (MADD)/MADD-like disorders to highlight these diagnostic challenges.

Investigation into a Conformationally Locked (Z)-Azidoxime.

High nitrogen compounds find wide use in the development of new propellants and explosives as well as pharmaceutical chemistry as bioisosteres, bacterial stains, and antifungal agents. A class of underexplored high-nitrogen materials includes azidoximes and their 1-hydroxytetrazole isomers. Azidoximes possess an energetic azide group and are quite sensitive to impact, spark, and friction. Therefore, these materials are generated in situ and cyclized under mild acidic conditions to their 1-hydroxytetrazole isomers. Recently, we synthesized a novel 1,2,4-triazine-derived azidoxime; however, upon subjecting this material to established cyclization conditions, no reaction was observed, even after prolonged reaction times with heating. Additional 1,2,4-triazine-derived azidoximes also displayed a similar lack of reactivities. This observation led us to probe the reactivity of these materials with both a DFT investigation and crystallographically based electrostatic potential mapping. In all, the lack of reactivity toward cyclization was found to be due to an inability of 1,2,4-triazine-based azidoximes to isomerize into the reactive (E)-conformation, requiring an activation energy of 26.4 kcal mol-1.

Mechanism for analogous illusory motion perception in flies and humans.

Visual motion detection is one of the most important computations performed by visual circuits. Yet, we perceive vivid illusory motion in stationary, periodic luminance gradients that contain no true motion. This illusion is shared by diverse vertebrate species, but theories proposed to explain this illusion have remained difficult to test. Here, we demonstrate that in the fruit fly Drosophila, the illusory motion percept is generated by unbalanced contributions of direction-selective neurons' responses to stationary edges. First, we found that flies, like humans, perceive sustained motion in the stationary gradients. The percept was abolished when the elementary motion detector neurons T4 and T5 were silenced. In vivo calcium imaging revealed that T4 and T5 neurons encode the location and polarity of stationary edges. Furthermore, our proposed mechanistic model allowed us to predictably manipulate both the magnitude and direction of the fly's illusory percept by selectively silencing either T4 or T5 neurons. Interestingly, human brains possess the same mechanistic ingredients that drive our model in flies. When we adapted human observers to moving light edges or dark edges, we could manipulate the magnitude and direction of their percepts as well, suggesting that mechanisms similar to the fly's may also underlie this illusion in humans. By taking a comparative approach that exploits Drosophila neurogenetics, our results provide a causal, mechanistic account for a long-known visual illusion. These results argue that this illusion arises from architectures for motion detection that are shared across phyla.

Towards harmonization of directly measured free 25-hydroxyvitamin D using an enzyme-linked immunosorbent assay.

The majority of circulating 25-hydroxyvitamin D (25(OH)D) is protein bound and perhaps less available than the free fraction of 25(OH)D; therefore, researchers have proposed that the measurement of free 25(OH)D in human serum may be a better indicator of vitamin D health status than total 25(OH)D. The availability of a new enzyme-linked immunosorbent assay (ELISA) for the determination of free 25(OH)D provides a method for direct measurement of the low levels of non-protein bound 25(OH)D. As an initial step towards harmonization of measurements of free 25(OH)D, the ELISA was used to measure free 25(OH)D in three existing Standard Reference Materials (SRMs): SRM 972a Vitamin D Metabolites in Frozen Human Serum, SRM 2973 Vitamin D Metabolites in Frozen Human Serum (High Level), and SRM 1949 Frozen Prenatal Human Serum. Target values for free 25(OH)D in the nine SRM serum pools, obtained by combining the results from two laboratories, ranged from 3.76 ± 0.36 to 10.0 ± 0.58 pg/mL. Of particular significance is the assignment of free 25(OH)D target values to SRM 1949, which consists of four serum pools from non-pregnant female donors of reproductive age and pregnant women in each of the three trimesters and which also has values assigned for vitamin D binding protein, which increases during pregnancy. The availability of target values for free 25(OH)D in these SRMs will allow researchers to validate new analytical methods and to compare their results with other researchers as an initial step towards harmonization of measurements among different studies and laboratories.

Pilot study of universal screening of children and child-parent cascade testing for familial hypercholesterolaemia in Australia.

AIM: Familial hypercholesterolaemia (FH) is a common and treatable cause of premature coronary artery disease. However, the majority of individuals with FH remain undiagnosed. This study investigated the feasibility, acceptability and cost-effectiveness of screening children aged 1-2 years for FH at the time of an immunisation. METHODS: Children 1-2 years of age were offered screening for FH with a point-of-care total cholesterol (TC) test by capillary-collected blood sample at the time of an immunisation. An additional blood sample was taken to allow genetic testing if the TC level was above the 95th percentile (>5.3 mmol/L). Parents of children diagnosed with FH were offered testing. Following detection of the affected parent, cascade testing of their first-degree blood relatives was performed. RESULTS: We screened 448 children with 32 (7.1%) having a TC ≥ 5.3 mmol/L. The FH diagnosis was confirmed in three children (1:150 screened). Reverse cascade testing of other family members identified a further five individuals with FH; hence, eight new cases of FH were diagnosed from screening 448 children (1:56 screened). Ninety-six percent of parents would screen future children for FH. The approach was cost-effective, at $3979 per quality-adjusted life year gained. CONCLUSION: In Western Australia, universal screening of children aged 1-2 years for FH, undertaken at the time of an immunisation, was a feasible and effective approach to detect children, parents and other blood relatives with FH. The approach was acceptable to parents and is potentially a highly cost-effective detection strategy for families at risk of FH.

Drosophila Sidekick is required in developing photoreceptors to enable visual motion detection.

The assembly of functional neuronal circuits requires growth cones to extend in defined directions and recognize the correct synaptic partners. Homophilic adhesion between vertebrate Sidekick proteins promotes synapse formation between retinal neurons involved in visual motion detection. We show here that Drosophila Sidekick accumulates in specific synaptic layers of the developing motion detection circuit and is necessary for normal optomotor behavior. Sidekick is required in photoreceptors, but not in their target lamina neurons, to promote the alignment of lamina neurons into columns and subsequent sorting of photoreceptor axons into synaptic modules based on their precise spatial orientation. Sidekick is also localized to the dendrites of the direction-selective T4 and T5 cells, and is expressed in some of their presynaptic partners. In contrast to its vertebrate homologs, Sidekick is not essential for T4 and T5 to direct their dendrites to the appropriate layers or to receive synaptic contacts. These results illustrate a conserved requirement for Sidekick proteins in establishing visual motion detection circuits that is achieved through distinct cellular mechanisms in Drosophila and vertebrates.

Delayed Processing of Chilled Whole Blood for 24 Hours Does Not Affect the Concentration of the Majority of Micronutrient Status Biomarkers.

BACKGROUND: The measurement of micronutrient status is essential to understand the health of individuals and populations, but there are limited data on the stability of micronutrients in whole blood. OBJECTIVES: The objective was to investigate the effects of delayed processing of whole blood on the stability of 25 micronutrient and selected clinical biomarkers. METHODS: Blood from 16 healthy adults was collected into EDTA, lithium heparin (LH), or serum tubes. Samples were processed within 2 hours of collection ("2-hour processed") or mailed overnight (boxed with frozen cold packs) before processing ("24-hour processed"). Micronutrient and clinical biomarker concentrations were quantified with validated methods. The concentration percentage difference between the 2- and 24-hour processed samples was calculated and was compared against quality specifications determined from intra- and interindividual variations. RESULTS: All analytes had a sample type where the percentage difference concentration between 2-hour and 24-hour processed samples was ≤4% and was acceptable based on calculated limits, including for biomarkers of vitamin A, vitamin D, thiamin, folate, vitamin B-12, iron (ferritin), and zinc status and for selected clinical markers, C-reactive protein, HDL and total cholesterol, and triglycerides. EDTA plasma vitamin C was lower compared to the 2-hour processed sample (geometric mean, 43%; 95% CI: 36%-49%). Pyridoxal-5-phosphate (vitamin B-6 biomarker) decreased, with differences from the 2-hour processed samples of -8% (95% CI: -13% to -2%) and -14% (95% CI: -18% to -9%) in LH plasma and serum, respectively. CONCLUSIONS: In blood collected from adult participants, delayed processing of chilled whole blood for 24 hours did not materially affect the measured concentrations of the majority of micronutrients and selected clinical biomarkers. This suggests that for these analytes, adherence to a 2-hour processing protocol may be unnecessary. This knowledge is valuable and may help to simplify logistics for sample transport and processing of blood samples for micronutrient status assessment.

Essentials of a new clinical practice guidance on familial hypercholesterolaemia for physicians.

Familial hypercholesterolaemia (FH) is a common, heritable and preventable cause of premature coronary artery disease. New clinical practice recommendations are presented to assist practitioners in enhancing the care of all patients with FH. Core recommendations are made on the detection, diagnosis, assessment and management of adults, children and adolescents with FH. Management is under-pinned by the precepts of risk stratification, adherence to healthy lifestyles, treatment of non-cholesterol risk factors and appropriate use of low-density lipoprotein (LDL)-cholesterol-lowering therapies including statins, ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. The recommendations need to be utilised using judicious clinical judgement and shared decision-making with patients and families. New government-funded schemes for genetic testing and use of PCSK9 inhibitors, as well as the National Health Genomics Policy Framework, will enable adoption of the recommendations. However, a comprehensive implementation science and practice strategy is required to ensure that the guidance translates into benefit for all families with FH.

Lipoprotein(a) in Patients With Type 2 Diabetes and Premature Coronary Artery Disease in the Coronary Care Unit.

INTRODUCTION: Lipoprotein(a) [Lp(a)] and diabetes are independently associated with premature coronary artery disease (pCAD). However, there is an inverse relationship between Lp(a) concentration and type 2 diabetes (T2D) risk. We examine whether Lp(a) distribution in patients with pCAD differs between those with or without T2D, and whether elevated Lp(a) is associated with pCAD in patients with T2D. METHODS: Lp(a) concentration was measured in consecutive acute coronary syndrome (ACS) patients in two coronary care units (study one: ACS with or without diabetes, study two: ACS and diabetes). Elevated Lp(a) mass concentration was defined as ≥0.5 g/L and pCAD where CAD was diagnosed age <60 years. The association between elevated Lp(a) and pCAD was assessed using logistic regression. RESULTS: Of 449 patients, 233 (51.9%) had pCAD and 278 (61.9%) had T2D. In patients with pCAD, those with T2D had a significantly lower median Lp(a) concentration (0.13 g/L versus 0.27 g/L, p=0.004). In patients with T2D, elevated Lp(a) was significantly associated with pCAD (OR 2.419, 95% CI 1.513-3.867, p<0.001). After adjusting for gender, smoking, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides, elevated Lp(a) remained significantly associated with pCAD (OR 2.895, 95% CI 1.427-5.876, p=0.003) in patients with T2D. CONCLUSIONS: In coronary care patients with pCAD, patients with T2D had lower Lp(a) concentrations than those without T2D. Despite this, elevated Lp(a) remained predictive of pCAD in patients with T2D. Measurement of Lp(a) should be considered in younger adults with T2D to identify who may benefit from earlier preventative therapies to reduce pCAD burden.

Integrated Guidance for Enhancing the Care of Familial Hypercholesterolaemia in Australia.

Familial hypercholesterolaemia (FH) is a dominant and highly penetrant monogenic disorder present from birth that markedly elevates plasma low-density lipoprotein (LDL)-cholesterol concentration and, if untreated, leads to premature atherosclerosis and coronary artery disease (CAD). There are approximately 100,000 people with FH in Australia. However, an overwhelming majority of those affected remain undetected and inadequately treated, consistent with FH being a leading challenge for public health genomics. To further address the unmet need, we provide an updated guidance, presented as a series of systematically collated recommendations, on the care of patients and families with FH. These recommendations have been informed by an exponential growth in published works and new evidence over the last 5 years and are compatible with a contemporary global call to action on FH. Recommendations are given on the detection, diagnosis, assessment and management of FH in adults and children. Recommendations are also made on genetic testing and risk notification of biological relatives who should undergo cascade testing for FH. Guidance on management is based on the concepts of risk re-stratification, adherence to heart healthy lifestyles, treatment of non-cholesterol risk factors, and safe and appropriate use of LDL-cholesterol lowering therapies, including statins, ezetimibe, proprotein convertase subtilisin/kexin type 9 inhibitors and lipoprotein apheresis. Broad recommendations are also provided for the organisation and development of health care services. Recommendations on best practice need to be underpinned by good clinical judgment and shared decision making with patients and families. Models of care for FH need to be adapted to local and regional health care needs and available resources. A comprehensive and realistic implementation strategy, informed by further research, including assessments of cost-benefit, will be required to ensure that this new guidance benefits all Australian families with or at risk of FH.

Gaps in the Care of Familial Hypercholesterolaemia in Australia: First Report From the National Registry.

BACKGROUND: Familial hypercholesterolaemia (FH) is under-diagnosed and under-treated worldwide, including Australia. National registries play a key role in identifying patients with FH, understanding gaps in care and advancing the science of FH to improve care for these patients. METHODS: The FH Australasia Network has established a national web-based registry to raise awareness of the condition, facilitate service planning and inform best practice and care services in Australia. We conducted a cross-sectional analysis of 1,528 FH adults enrolled in the registry from 28 lipid clinics. RESULTS: The mean age at enrolment was 53.4±15.1 years, 50.5% were male and 54.3% had undergone FH genetic testing, of which 61.8% had a pathogenic FH-causing gene variant. Only 14.0% of the cohort were family members identified through cascade testing. Coronary artery disease (CAD) was reported in 28.0% of patients (age of onset 49.0±10.5 years) and 64.9% had at least one modifiable cardiovascular risk factor. The mean untreated LDL-cholesterol was 7.4±2.5 mmol/L. 80.8% of patients were on lipid-lowering therapy with a mean treated LDL-cholesterol of 3.3±1.7 mmol/L. Among patients receiving lipid-lowering therapies, 25.6% achieved an LDL-cholesterol target of <2.5 mmol/L without CAD or <1.8 mmol/L with CAD. CONCLUSION: Patients in the national FH registry are detected later in life, have a high burden of CAD and risk factors, and do not achieve guideline-recommended LDL-cholesterol targets. Genetic and cascade testing are under-utilised. These deficiencies in care need to be addressed as a public health priority.

Nitrogen-Rich Tetrazolo[1,5-b]pyridazine: Promising Building Block for Advanced Energetic Materials.

Two metal-free explosives, tetrazolo[1,5-b]pyridazine-containing molecules [6-azido-8-nitrotetrazolo[1,5-b]pyridazine-7-amine (3at) and 8-nitrotetrazolo[1,5-b]pyridazine-6,7-diamine (6)], were obtained via straightforward two-step synthetic routes from commercially available reagents. Compound 3at displays an excellent detonation performance (Dv = 8746 m s-1 and P = 31.5 GPa) that is superior to commercial primary explosives such as lead azide and diazodinitrophenol (DDNP). Compound 6 has superior thermal stability, remarkable insensitivity, and good detonation performance, strongly suggesting it as an acceptable secondary explosive. The initiating ability of compound 3at has been tested by detonating 500 mg of RDX with a surprisingly low minimum primary charge of 40 mg. The extraordinary initiating power surpasses conventional primary explosives, such as commercial DDNP (70 mg) and reported 6-nitro-7-azido-pyrazol[3,4-d][1,2,3]triazine-2-oxide (ICM-103) (60 mg). The outstanding detonation power of 3at contributes to its future prospects as a promising green primary explosive. In addition, the environmentally benign methodology for the synthesis of 3at effectively shortens the time from laboratory-scale research to practical applications.

Enforced Planar FOX-7-like Molecules: A Strategy for Thermally Stable and Insensitive π-Conjugated Energetic Materials.

Exploring new energetic derivatives of 1,1-diamino-2,2-dinitroethylene (FOX-7) is still a key aspect in the field of energetic materials. However, so far most of the attention has been focused on modification of FOX-7 via different reaction strategies. Now we report the design of three new FOX-7-like compounds (3-5) where one nitro group in FOX-7 is replaced by a nitrogen-rich heterocyclic ring. Each of them is characterized by single-crystal X-ray crystallography. Electronic structures are studied through computational methods in comparison with FOX-7. In addition, the chemical reactivity of 3 was also investigated. Its hydroxylammonium (7), hydrazinium (8), and ammonium (9) salts were prepared, and the nitrate product (10) was also isolated. Compound 10 has a C-N bond length of 1.577 Å that is one of the longest values found for the C-NO2 bond. It was found that the incorporation of a tetrazole or triazole ring into the backbone of a conjugated nitroenamine does lead to a planar structure, which not only enhances the thermal stability but also improves the sensitivity of the product.

Widening the spectrum of genetic testing in familial hypercholesterolaemia: Will it translate into better patient and population outcomes?

Familial hypercholesterolaemia (FH) is caused by pathogenic variants in LDLR, APOB or PCSK9. Impaired low-density lipoprotein (LDL) receptor function leads to decreased LDL catabolism and premature atherosclerotic cardiovascular disease (ASCVD). Thousands of LDLR variants are known, but assignation of pathogenicity requires accurate phenotyping, family studies and assessment of LDL receptor function. Precise, genetic diagnosis of FH using targeted next generation sequencing allows for optimal treatment, distinguishing FH from pathogenically distinct disorders requiring different treatment. Polygenic hypercholesterolaemia resulting from an accumulation of LDL cholesterol-raising single nucleotide polymorphisms (SNPs) could also be suspected by this approach. Similarly, ASCVD risk could be estimated by broader sequencing of cholesterol and non-cholesterol-related genes. Both of these areas require further research. The clinical management of FH, focusing on the primary or secondary prevention of ASCVD, has been boosted by PCSK9 inhibitor therapy. The efficacy of PCSK9 inhibitors in homozygous FH may be partly predicted by the LDLR variants. While expanded genetic testing in FH is clinically useful in providing an accurate diagnosis and enabling cost-effective testing of relatives, further research is needed to establish its value in improving clinical outcomes.

A genetic risk score predicts coronary artery disease in familial hypercholesterolaemia: enhancing the precision of risk assessment.

Familial hypercholesterolaemia (FH) is associated with increased risk of coronary artery disease (CAD); however, risk prediction and stratification remain a challenge. Genetic risk scores (GRS) may have utility in identifying FH patients at high CAD risk. The study included 811 patients attending the lipid disorders clinic at Royal Perth Hospital with mutation-positive (n = 251) and mutation-negative (n = 560) FH. Patients were genotyped for a GRS previously associated with CAD. Associations between the GRS, clinical characteristics, and CAD were assessed using regression analyses. The average age of patients was 49.6 years, and 44.1% were male. The GRS was associated with increased odds of a CAD event in mutation-positive [odds ratio (OR) = 3.3; 95% confidence interval (CI) = 1.3-8.2; P = .009] and mutation-negative FH patients (OR = 1.8; 95% CI = 1.0-3.3; P = .039) after adjusting for established predictors of CAD risk. The GRS was associated with greater subclinical atherosclerosis as assessed by coronary artery calcium score (P = .039). A high GRS was associated with CAD defined clinically and angiographically in FH patients. High GRS patients may benefit from more intensive management including lifestyle modification and aggressive lipid-lowering therapy. Further assessment of the utility of the GRS requires investigation in prospective cohorts, including its role in influencing the management of FH patients in the clinic.

Synthesis of Erythritol Tetranitrate Derivatives: Functional Group Tuning of Explosive Sensitivity.

Understanding the factors that affect explosive sensitivity is paramount to the safe handling and development of new explosives molecules. Erythritol tetranitrate (ETN) is an explosive that recently has attracted significant attention in the explosives community because of its ease of synthesis and physical properties. Herein, we report the synthesis of ETN derivatives using azide, nitramine, and nitrate ester functional groups. Impact, spark, and friction sensitivity measurements, computationally calculated explosive properties, and the crystal structure analysis of the ETN derivatives are reported. Mixing explosive functional groups led to changes in the explosive sensitivity, explosive performance as well as physical properties including melting point and physical state at room temperature. Overall, we have demonstrated that combining functional groups can enable the tuning of explosive and physical properties of a molecule. This tunability can potentially aid in the development of new explosives in which characteristics are varied to meet certain specifications.