Plozasiran, an RNA Interference Agent Targeting APOC3, for Mixed Hyperlipidemia.

BACKGROUND: Persons with mixed hyperlipidemia are at risk for atherosclerotic cardiovascular disease due to an elevated non-high-density lipoprotein (HDL) cholesterol level, which is driven by remnant cholesterol in triglyceride-rich lipoproteins. The metabolism and clearance of triglyceride-rich lipoproteins are down-regulated through apolipoprotein C3 (APOC3)-mediated inhibition of lipoprotein lipase. METHODS: We carried out a 48-week, phase 2b, double-blind, randomized, placebo-controlled trial evaluating the safety and efficacy of plozasiran, a hepatocyte-targeted APOC3 small interfering RNA, in patients with mixed hyperlipidemia (i.e., a triglyceride level of 150 to 499 mg per deciliter and either a low-density lipoprotein [LDL] cholesterol level of ≥70 mg per deciliter or a non-HDL cholesterol level of ≥100 mg per deciliter). The participants were assigned in a 3:1 ratio to receive plozasiran or placebo within each of four cohorts. In the first three cohorts, the participants received a subcutaneous injection of plozasiran (10 mg, 25 mg, or 50 mg) or placebo on day 1 and at week 12 (quarterly doses). In the fourth cohort, participants received 50 mg of plozasiran or placebo on day 1 and at week 24 (half-yearly dose). The data from the participants who received placebo were pooled. The primary end point was the percent change in fasting triglyceride level at week 24. RESULTS: A total of 353 participants underwent randomization. At week 24, significant reductions in the fasting triglyceride level were observed with plozasiran, with differences, as compared with placebo, in the least-squares mean percent change from baseline of -49.8 percentage points (95% confidence interval [CI], -59.0 to -40.6) with the 10-mg-quarterly dose, -56.0 percentage points (95% CI, -65.1 to -46.8) with the 25-mg-quarterly dose, -62.4 percentage points (95% CI, -71.5 to -53.2) with the 50-mg-quarterly dose, and -44.2 percentage points (95% CI, -53.4 to -35.0) with the 50-mg-half-yearly dose (P<0.001 for all comparisons). Worsening glycemic control was observed in 10% of the participants receiving placebo, 12% of those receiving the 10-mg-quarterly dose, 7% of those receiving the 25-mg-quarterly dose, 20% of those receiving the 50-mg-quarterly dose, and 21% of those receiving the 50-mg-half-yearly dose. CONCLUSIONS: In this randomized, controlled trial involving participants with mixed hyperlipidemia, plozasiran, as compared with placebo, significantly reduced triglyceride levels at 24 weeks. A clinical outcomes trial is warranted. (Funded by Arrowhead Pharmaceuticals; MUIR ClinicalTrials.gov number NCT04998201.).

Comprehensive characterization of the structure of Zr-based metallic glasses.

Structure of metallic glasses fascinates as the generic amorphous structural template for ubiquitous systems. Its specification necessitates determination of the complete hierarchical structure, starting from short-range-order (SRO) → medium-range-order (MRO) → bulk structure and free volume (FV) distribution. This link has largely remained elusive since previous investigations adopted one-technique-at-a-time approach, focusing on limited aspects of any one domain. Reconstruction of structure from experimental data inversion is non-unique for many of these techniques. As a result, complete and precise structural understanding of glass has not emerged yet. In this work, we demonstrate the first experimental pathway for reconstruction of the integrated structure, for Zr 67 Ni 33 and Zr 52 Ti 6 Al 10 Cu 18 Ni 14 glasses. Our strategy engages diverse (× 7) multi-scale techniques [XAFS, 3D-APT, ABED/NBED, FEM, XRD, PAS, FHREM] on the same glass. This strategy complemented mutual limitations of techniques and corroborated common parameters to generate complete, self-consistent and precise parameters. Further, MRO domain size and inter-void separation were correlated to identify the presence of FV at MRO boundaries. This enabled the first experimental reconstruction of hierarchical subset: SRO → MRO → FV → bulk structure. The first ever image of intermediate region between MRO domains emerged from this link. We clarify that determination of all subsets is not our objective; the essence and novelty of this work lies in directing the pathway towards finite solution, in the most logical and unambiguous way.

Barriers to and Facilitators of Implementing Guidelines for Detecting Familial Hypercholesterolaemia in Australia.

BACKGROUND: Familial hypercholesterolaemia (FH) is a genetic condition that is a preventable cause of premature cardiovascular morbidity and mortality. High-level evidence and clinical practice guidelines support preventative care for people with FH. However, it is estimated that less than 10% of people at risk of FH have been detected using any approach across Australian health settings. The aim of this study was to identify the implementation barriers to and facilitators of the detection of FH in Australia. METHODS: Four, 2-hour virtual focus groups were facilitated by implementation scientists and a clinicians as part of the 2021 Australasian FH Summit. Template analysis was used to identify themes. RESULTS: There were 28 workshop attendees across four groups (n=6-8 each), yielding 13 barriers and 10 facilitators across three themes: (1) patient related, (2) provider related, and (3) system related. A "lack of care pathways" and "upskilling clinicians in identifying and diagnosing FH" were the most interconnected barriers and facilitators for the detection of FH. CONCLUSIONS: The relationships between barriers and facilitators across the patient, provider, and system themes indicates that a comprehensive implementation strategy is needed to address these different levels. Future research is underway to develop a model for implementing the Australian FH guidelines into practice.

RNA interference targeting ANGPTL3 for triglyceride and cholesterol lowering: phase 1 basket trial cohorts.

Elevated triglycerides and non-high-density lipoprotein cholesterol (HDL-C) are risk factors for atherosclerotic cardiovascular disease (ASCVD). ARO-ANG3 is an RNA interference therapy that targets angiopoietin-like protein 3 (ANGPTL3), a regulator of lipoprotein metabolism. This first-in-human, phase 1, randomized, placebo-controlled, open-label trial investigated single and repeat ARO-ANG3 doses in four cohorts of fifty-two healthy participants and one cohort of nine participants with hepatic steatosis, part of a basket trial. Safety (primary objective) and pharmacokinetics (in healthy participants) and pharmacodynamics (secondary objectives) of ARO-ANG3 were evaluated. ARO-ANG3 was generally well tolerated, with similar frequencies of treatment-emergent adverse events in active and placebo groups. Systemic absorption of ARO-ANG3 in healthy participants was rapid and sustained, with a mean Tmax of 6.0-10.5 h and clearance from plasma within 24-48 h after dosing with a mean t½ of 3.9-6.6 h. In healthy participants, ARO-ANG3 treatment reduced ANGPTL3 (mean -45% to -78%) 85 days after dose. Reductions in triglyceride (median -34% to -54%) and non-HDL-C (mean -18% to -29%) (exploratory endpoints) concentrations occurred with the three highest doses. These early-phase data support ANGPTL3 as a potential therapeutic target for ASCVD treatment. ClinicalTrials.gov identifier: NCT03747224.

RNA Interference Therapy Targeting Apolipoprotein C-III in Hypertriglyceridemia.

BACKGROUND: Apolipoprotein C-III (APOC3) inhibits triglyceride clearance by reducing lipoprotein lipase­mediated hydrolysis and hepatocyte uptake of triglyceride-rich lipoproteins. ARO-APOC3, a hepatocyte-targeting RNA interference therapeutic, inhibits APOC3 messenger ribonucleic acid expression, lowering triglyceride levels. The objective of this trial was to assess the safety, pharmacodynamic variables, and pharmacokinetic variables of ARO-APOC3 treatment. METHODS: Healthy participants and adults with hypertriglyceridemia were randomly assigned to receive escalating single (day 1) or repeat (days 1 and 29) doses, respectively, of subcutaneous injections of ARO-APOC3 10, 25, 50, or 100 mg or placebo; they were followed up until day 113. Additional cohorts of healthy participants and adults with chylomicronemia received repeat doses of open-label ARO-APOC3. The primary objective was to evaluate the safety and side effect profile of ARO-APOC3. Key secondary and exploratory objectives included pharmacokinetic variables and changes in serum APOC3, triglyceride, and cholesterol levels. RESULTS: Eighty-eight participants received ARO-APOC3 and 24 participants received placebo across double-blind and open-label cohorts. Treatment-emergent adverse events (AEs) of transient, mild to moderate liver transaminase changes occurred in 10 participants: 1 patient receiving ARO-APOC3 25 mg, 5 patients receiving ARO-APOC3 50 mg, and 4 participants receiving ARO-APOC3 100 mg (1 healthy participant and 3 patients with hypertriglyceridemia). These events were asymptomatic, and transaminase levels returned to near baseline by the end of the trial. No AEs related to thrombocytopenia or platelet declines were reported. In the hypertriglyceridemia cohorts, the day 113 mean changes from baseline in APOC3 at the 10-, 25-, 50-, and 100-mg doses were −62.0%, −81.7%, −90.1%, and −94.4%, respectively, compared with −1.6% with placebo. This corresponded to median changes in triglyceride levels of −65.6%, −69.9%, −81.2%, and −81.0% compared with −2.8% with placebo. CONCLUSIONS: In this small trial of short duration, ARO-APOC3 was associated with few AEs and reduced serum levels of APOC3 and triglycerides in healthy participants and patients with hypertriglyceridemia. (Funded by Arrowhead Pharmaceuticals, Inc.; ClinicalTrials.gov number, NCT03783377.)

The Effect of a Peanut-Enriched Weight Loss Diet Compared to a Low-Fat Weight Loss Diet on Body Weight, Blood Pressure, and Glycemic Control: A Randomized Controlled Trial.

The objective of this study was to examine the effect of consuming 35 g of peanuts prior to two main meals per day as part of a weight loss diet, compared to a traditional low-fat weight loss diet, on body weight, markers of glycemic control, and blood pressure in adults at risk of type 2 diabetes over 6 months. A two-arm randomized controlled trial was conducted. Adults (age > 18 years) with a BMI of >26 kg/m2 at risk of type 2 diabetes were randomized to the peanut group or the traditional low-fat-diet group (control). The peanut group was advised to consume 35 g of lightly salted dry-roasted peanuts prior to two main meals per day. Participants in the control group were given education to follow a low-fat diet. Both groups had dietetic counseling to restrict energy intake (women: <5500 kJ/1300 kcal/d; men: <7000 kJ/1700 kcal/d). Outcome assessment occurred at baseline, 3 months, and 6 months. In total, 107 participants were randomized (65% female; mean age 58 ± 14 years, BMI 33 ± 5.4 kg/m2, waist circumference 109 ± 13 cm, AUSDRISK score 15 ± 5 points), and 76 participants completed the study. No between-group difference in body weight (primary outcome) was observed at 6 months (mean difference, −0.12 kg; 95% CI, −2.42, 2.18; p = 0.92). The mean weight loss at 6 months was 6.7 ± 5.1 kg in the cohort (visit p < 0.001). HbA1c, fasting glucose, fasting insulin, 2-h glucose, and HOMA-IR were not different between the groups. Systolic blood pressure was reduced to a greater extent in the peanut group vs. the control group at 6 months (−5.33 mmHg; 95% CI, −9.23, −1.43; p = 0.008). Intake of 35 g of peanuts prior to two main meals per day, in the context of an energy-restricted diet, resulted in weight loss comparable to a traditional low-fat weight loss diet without preloads. Greater systolic blood pressure reductions were observed with peanut intake, which may lower cardiovascular disease risk.

The effect of cognitive behavioral stress management on perceived stress, biological stress markers and weight loss/regain, from a diet-induced weight loss program: A randomized controlled trial.

Obesity and psychosocial stress are inter-related chronic conditions which lead to increased cardiovascular morbidity and mortality. The aim of this parallel randomized controlled trial was to determine whether the addition of a structured cognitive behavioral stress management (CBSM) on to a commercial online weight loss program, resulted in greater weight loss than the standard weight loss program in isolation. Eligible participants were adults between the ages 18-65, BMI 30-45 kg/m2, with no major systemic or psychiatric conditions. Seventy-four participants were assigned according to simple randomization using computer generated random numbers to either a 3-month online Weight Watchers® program (n = 36), or Weight Watchers® plus 10 weekly sessions of CBSM (n = 38). The primary outcome was weight at 3 months compared to baseline. Secondary outcomes were weight at 12 months and subjective/objective stress system measures and metabolic markers at 3 and 12 months. The study was powered at 90% to detect a 5 kg difference in weight between the two groups at 3 months. Independent sample t-tests were used to analyze the difference in weight (in kg) between the groups and paired sample t-tests were used to analyze the difference within group at different time intervals. At follow-up, there was no significant difference in weight loss between the groups (1.8 kg, 2.1 kg). However, CBSM was effective in reducing psychological measures of stress (p < 0.05) and salivary cortisol (waking, 20-min post-waking) at 3-months; with the effect on stress persisting at 12-months within the CBSM group. The reduction in PSS at 3 months was significantly greater in the CBSM group (3.84, p = 0.028) compared to WW only group at 3 months. Addition of CBSM to a standard weight loss intervention did not improve the weight loss over the standard approach on its own, but the CBSM intervention improved psychological stress parameters and cortisol secretion in participants living with obesity.

Acute C-Terminal Crosslinking Telopeptide of Type I Collagen (CTX-1) Suppression with Milk Calcium or Calcium Carbonate Is Independent of Visceral Fat in a Randomized Crossover Study in Lean and Overweight Postmenopausal Women.

BACKGROUND: Postmenopausal women with higher visceral adipose tissue (VAT) present with suppressed bone resorption (lower C-terminal crosslinking telopeptide of type I collagen; CTX-1) and turnover (lower osteocalcin) but whether this blunts the effect of calcium is unknown. OBJECTIVES: The primary outcome of this study was the effect of VAT on changes in CTX-1 after intake of 2 forms of calcium. Secondary outcomes included changes in parathyroid hormone (PTH), serum calcium, phosphorus, and alkaline phosphatase (ALP). METHODS: Randomized open three period crossover trial conducted between 2017 and 2019 at the University of South Australia among 77 lean and overweight postmenopausal women (53-79 y) with BMI <25 kg/m2 and >27 kg/m2, respectively. Participants received a single dose of milk (1000 mg calcium), calcium carbonate tablet (1000 mg calcium), and fruit juice (no calcium) in random order with a 7-d washout period. Blood samples were collected at baseline and hourly for 5 h. Data was analyzed by repeated measures ANOVA of log-transformed data. RESULTS: At baseline, women with higher VAT had significantly lower CTX-1 and higher PTH (44% lower and 30% higher, respectively, between Q4 and Q1, P < 0.0001). VAT had no influence on the acute changes in CTX-1 or PTH with calcium or juice. A suppression of 44% in CTX-1 was seen with calcium carbonate and milk and a suppression of 18% with juice. PTH was suppressed more with calcium carbonate (47%) compared to milk (22%). Milk calcium reduced PTH and CTX-1 at 2 h, whereas calcium carbonate reduced PTH in 1 h. The suppression in CTX-1 was slower with lowest concentrations at 4-5 h. CONCLUSIONS: Intake of 1000 mg calcium from milk or from calcium carbonate is effective in acutely suppressing bone resorption in postmenopausal women irrespective of visceral fat. This trial is registered at http://www.ANZCTR.org.au/ACTRN12617000779370.aspx as ACTRN 12617000779370).

Acute C-Terminal Crosslinking Telopeptide of Type I Collagen (CTX-1) Suppression with Milk Calcium or Calcium Carbonate Is Independent of Visceral Fat in a Randomized Crossover Study in Lean and Overweight Postmenopausal Women.

BACKGROUND: Postmenopausal women with higher visceral adipose tissue (VAT) present with suppressed bone resorption (lower C-terminal crosslinking telopeptide of type I collagen; CTX-1) and turnover (lower osteocalcin) but whether this blunts the effect of calcium is unknown. OBJECTIVES: The primary outcome of this study was the effect of VAT on changes in CTX-1 after intake of 2 forms of calcium. Secondary outcomes included changes in parathyroid hormone (PTH), serum calcium, phosphorus, and alkaline phosphatase (ALP). METHODS: Randomized open three period crossover trial conducted between 2017 and 2019 at the University of South Australia among 77 lean and overweight postmenopausal women (53-79 y) with BMI <25 kg/m2 and >27 kg/m2, respectively. Participants received a single dose of milk (1000 mg calcium), calcium carbonate tablet (1000 mg calcium), and fruit juice (no calcium) in random order with a 7-d washout period. Blood samples were collected at baseline and hourly for 5 h. Data was analyzed by repeated measures ANOVA of log-transformed data. RESULTS: At baseline, women with higher VAT had significantly lower CTX-1 and higher PTH (44% lower and 30% higher, respectively, between Q4 and Q1, P < 0.0001). VAT had no influence on the acute changes in CTX-1 or PTH with calcium or juice. A suppression of 44% in CTX-1 was seen with calcium carbonate and milk and a suppression of 18% with juice. PTH was suppressed more with calcium carbonate (47%) compared to milk (22%). Milk calcium reduced PTH and CTX-1 at 2 h, whereas calcium carbonate reduced PTH in 1 h. The suppression in CTX-1 was slower with lowest concentrations at 4-5 h. CONCLUSIONS: Intake of 1000 mg calcium from milk or from calcium carbonate is effective in acutely suppressing bone resorption in postmenopausal women irrespective of visceral fat. This trial is registered at http://www.ANZCTR.org.au/ACTRN12617000779370.aspx as ACTRN 12617000779370).

Weight Loss Barriers and Dietary Quality of Intermittent and Continuous Dieters in Women with a History of Gestational Diabetes.

Weight-loss after gestational diabetes (GDM) lowers the risk of type-2 diabetes (T2DM). Intermittent energy restriction (IER) produces comparable weight-loss to continuous energy restriction (CER), but long-term adherence remains difficult in this population. This exploratory secondary analysis of a 12-month trial comparing IER to CER following GDM examined weight-loss and dietary quality associated with barriers to weight-loss or T2DM risk perception as assessed in a Likert scale questionnaire at baseline. The participants had a median (IQR) BMI of 32.6 (9.4) kg/m2 and 3 (4) years postpartum (n = 121). Forty-five percent (n = 54) of the participants thought they were at a high risk of developing T2DM. Greater affordability of healthy food was related with greater weight-loss at 3 months (p = 0.044, n = 85). At 12 months, there was no significant relationship between weight-loss and the barriers to weight-loss (p > 0.05). CER had superior improvement in dietary quality at 12 months (CER 11 ± 10, IER 6 ± 5.6, n = 42, p = 0.05). Under the Theoretical Domains Framework, the barriers were predominantly related to behavioral regulation (n = 83, 69%; n = 76, 63%) and environmental context and resources (n = 67, 56%). Interventions for diabetes prevention in this population should include behavioral regulation strategies, consider the family home environment, and ensure that the risk of T2DM is conveyed. Women choosing IER may benefit from education to improve their dietary quality.

The Effect of Magnesium Supplementation on Endothelial Function: A Randomised Cross-Over Pilot Study.

Evidence supports an association between low magnesium (Mg) intake and coronary heart disease and between Mg intake and endothelial function. The aim of this study was to assess the effect of one week of Mg supplementation on endothelial function, assessed by flow mediated dilatation (FMD). Nineteen healthy men and women completed this cross-over pilot study in which participants were randomised to take an over-the-counter magnesium supplement for one week or to follow their usual diet. Weight, FMD and blood pressure (BP) were taken on completion of each intervention and 24 h urine collections and blood samples were taken to assess compliance. Baseline serum Mg was within normal range for all participants. Urinary Mg and urinary magnesium-creatinine ratio (Mg/Cr) significantly increased between interventions, (p = 0.03, p = 0.005, respectively). No significant differences in FMD or BP were found between the interventions. A significant negative correlation was seen between age and FMD (r = -0.496, p = 0.031). When adjusted for age, saturated fat was negatively associated with FMD (p = 0.045). One week of Mg supplementation did not improve FMD in a healthy population.

The Acute Effect of Magnesium Supplementation on Endothelial Function: A Randomized Cross-Over Pilot Study.

Magnesium (Mg) deficiency might be a catalyst in the process of endothelial dysfunction, an early event in the pathogenesis of atherosclerosis. The aim of this study was to determine the acute effect of an oral Mg supplement as compared to control on endothelial function assessed by flow-mediated dilatation (FMD). Nineteen participants (39 years, body mass index (BMI) 22.9 kg/m2) completed this randomized cross-over study. Blood pressure (BP) and FMD were measured and blood samples were taken before participants drank 200 mL water, with or without an over the counter Mg supplement (450 mg and 300 mg for men and women). Measurements were repeated at 60 and 120 min. There was a statistically significant two-way interaction between treatment and time on serum Mg (p = 0.037). A difference of -0.085 mm in FMD was observed 60-min post drink in the control group, as compared to baseline FMD, and no difference was observed in the supplement group as compared to baseline. Despite the non-significant interaction between treatment and time on FMD, once adjusted for baseline, the difference seen in the control group and the lack of change in the supplement group at 60 min post-drink suggests that Mg might attenuate the reduction in FMD post-prandially.

Iodine Excretion and Intake in Women of Reproductive Age in South Australia Eating Plant-Based and Omnivore Diets: A Pilot Study.

Women consuming a strictly vegan/plant-based diet may be at increased risk of low iodine intake due to avoidance of animal products containing iodine. The aim of this pilot study was to determine the iodine excretion and intake in women consuming vegan/plant based diets compared with women consuming omnivore diets. Fifty-seven women (n = 31 plant-based, n = 26 omnivores), provided two spot urine samples to assess urinary iodine concentration (UIC). Two days of dietary intake were also recorded by participants. As the data were not normally distributed results are reported as median (IQR). UIC was significantly different between groups, 44 (26-66) µg/L in the vegan/plant-based group versus 64 (40-88) µg/L in omnivores (p < 0.05). UIC did not meet the >100 µg/L level recommended by the World Health Organization. Iodine intake was also significantly different, 78 (62-91) µg/day in the vegan/plant-based group and 125 (86-175) µg/day in the omnivores (p = 0.000). Iodine intake and bread intake were correlated with iodine excretion (CC 0.410-4.11, p = 0.003). These data indicate iodine insufficiency in both groups of women as the median values were below the minimum WHO recommendation. A larger study assessing iodine excretion in the Australian women of reproductive age who are not pregnant or breastfeeding is needed to confirm these findings.

The effect of intermittent energy restriction on weight loss and diabetes risk markers in women with a history of gestational diabetes: a 12-month randomized control trial.

BACKGROUND: Weight loss after gestational diabetes (GDM) can prevent or delay the onset of type 2 diabetes. Intermittent energy restriction (IER) may offer an alternative to continuous energy restriction (CER) for weight loss. OBJECTIVES: We compared the effects of IER (2 days per week) to daily CER over 12 mo on weight loss and diabetes risk markers in overweight women with previous GDM. METHODS: Overweight females (n = 121) ≥18 y were randomized 1:1 to either IER [2-d 500 kcal (2100 kJ); n = 61] or CER [1500 kcal (6000 kJ); n = 60] in this 12-mo noninferiority trial. RESULTS: The trial was completed by 62 participants with a median age of 39.6 y [Quartile (Q) 1 to Quartile 3, 34.9 to 43.9 y] with a median BMI of 32.6 kg/m2 (Q1 to Q3, 28.5 to 37.9 kg/m2) at a median of 2.9 y after GDM (Q1 to Q3, 2.1 to 6.4 y; 49% attrition; IER n = 29; CER n = 30; P = 0.8). The mean ± SD weight loss was significant over time (P < 0.001) but not by diet group (IER -4.8 ± 5.0 kg; CER -3.2 ± 5.0; P = 0.2). The mean between-group difference was -1.6 kg (95% CI: -4.2 to 1.0 kg; P = 0.2). There were no significant between-group differences in change in HbA1c, fasting plasma glucose, fasting serum insulin, HOMA-IR or 2-h oral glucose tolerance at 12 mo (p>0.05). The trial was registered at https://www.anzctr.org.au/ (ACTRN12617001476325). CONCLUSIONS: IER produces comparable weight loss to CER over 12 mo in overweight women with previous GDM. The high dropout rate in this study is a limitation in the interpretation of these results. Larger studies are needed to confirm noninferiority of IER compared to CER.

Development and Validation of an Online Survey to Assess Perception of Diabetes Risk and Barriers and Facilitators to Weight Loss Following Gestational Diabetes.

Our objective was to describe the development and validation of a survey investigating barriers to weight loss, perception of diabetes risk, and views of diet strategies following gestational diabetes (GDM). The survey underwent three stages of development: generation of items, expert evaluation, and pilot testing. A content validation index (CVI) was calculated from expert responses regarding item relevance, coherence, clarity, and response options. Experts also responded to the domain fit of questions linked to the Theoretical Domains Framework (TDF). Pilot responders answered the survey and responded to review questions. Six experts in the field of nutrition, midwifery, psychology, or other health or medical research completed the expert review stage of the survey. In the pilot test, there were 20 responders who were women with previous GDM and who were living in Australia. The overall CVI from the expert review was 0.91. All questions except one received an I-CVI of >0.78 for relevance (n = 35). Fourteen of the 27 items linked to the TDF received an agreement ratio of <1.0. Twenty-seven of the 31 pilot questions were completed by ≥90% of responders. Pilot review questions revealed an agreement percentage of ≥86% (n = 12) regarding the survey's ease to complete, understand, importance, length, and interest level. The final survey tool consists of 30 items and achieved content validation through expert evaluation and pilot testing.

A safety, tolerability, and pharmacokinetic study of a novel simvastatin silica-lipid hybrid formulation in healthy male participants.

Simvastatin (SIM) is a commonly used cholesterol-lowering drug that can reduce the risk of major cardiovascular events. However, due to its poor intrinsic water solubility, the drug is poorly absorbed from the gastrointestinal tract and exhibits a low oral bioavailability of approximately 5%. The aim of this study was to fabricate and optimize SIM encapsulated silica-lipid hybrids (SLH) as a solid-state lipid-based formulation to enhance absorption and bioavailability during a human in vivo pharmacokinetic study. SLH formulations were formulated by spray drying a submicron emulsion with either Aerosil® 300 fumed silica nanoparticles (SLH-A) or Syloid® 244 amorphous micronized silica (SLH-B). A cross-over, double-blinded study design was implemented to evaluate the performance of SLH formulations compared with a commercially available formulation in 12 healthy male participants after oral administration under fasting conditions. SLH formulations enhanced the bioavailability of SIM up to 1.6-fold and more importantly the active simvastatin acid (SIMA), 3.5-fold when compared with an equivalent dose of commercial formulation. The results demonstrate that the porous nanostructure of SLH impact systemic SIM and SIMA concentrations and may serve as a novel approach to enhance the bioavailability of specifically the parent or metabolite. No significant difference was observed in exposure when SLH formulations were administered at 10 mg in comparison with 20 mg of the commercial formulation, suggesting the potential for dose reduction. The study indicated that SLH formulations were safe and well-tolerated when administered to healthy males, confirming the commercial potential of SLH to enhance the bioavailability of poorly water-soluble drugs. Graphical abstract.

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.

Effect of a moderate dose of fructose in solid foods on TAG, glucose and uric acid before and after a 1-month moderate sugar-feeding period.

There are few data on the effects on TAG, glucose and uric acid of chronic consumption of a moderate dose of fructose in solid foods. Twenty-eight participants with prediabetes and/or obesity and overweight commenced the study (BMI 32·3 kg/m2, age 44·7 years, fasting glucose 5·3 (sd 0·89) mmol/l and 2-h glucose 6·6 (sd 1·8) mmol/l). Twenty-four men and women who completed the study consumed, in random order, two acute test meals of muffins sweetened with either fructose or sucrose. This was followed by 4-week chronic consumption of 42 g/d of either fructose or sucrose in low-fat muffins after which the two meal tests were repeated. The sugar type in the chronic feeding period was also randomised. Fasting TAG increased after chronic consumption of fructose by 0·31 (sd 0·37) mmol/l compared with sucrose in those participants with impaired fasting glucose (IFG)/impaired glucose tolerance (IGT) (P = 0·004). Total cholesterol (0·33 mmol/l), LDL-cholesterol (0·24 mmol/l) and HDL-cholesterol (0·08 mmol/l) increased significantly over the 1- month feeding period with no differences between muffin types. Fasting glucose was not different after 1 month of muffin consumption. Uric acid response was not different between the two sugar types either baseline or 1 month, and there were no differences between baseline and 1 month. The increase in fasting TAG in participants with IFG/IGT suggests the need for caution in people at increased risk of type 2 diabetes.